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Turoňová, Beata ; Sikora, Mateusz ; Schürmann, Christoph ; Hagen, Wim ; Welsch, Sonja ; Blanc, Florian E. C. ; Bülow, Sören von ; Gecht, Michael ; Bagola, Katrin ; Hörner, Cindy ; Zandbergen, Ger van ; Mosalaganti, Shyamal Narayan ; Schwarz, Andre ; Covino, Roberto ; Mühlebach, Michael D. ; Hummer, Gerhard ; Krijnse-Locker, Jacomine ; Beck, Martin
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the major focus for vaccine development. We combine cryo electron tomography, subtomogram averaging and molecular dynamics simulations to structurally analyze S in situ. Compared to recombinant S, the viral S is more heavily glycosylated and occurs predominantly in a closed pre-fusion conformation. We show that the stalk domain of S contains three hinges that give the globular domain unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. The structure of native S contributes to our understanding of SARS-CoV-2 infection and the development of safe vaccines. The large scale tomography data set of SARS-CoV-2 used for this study is therefore sufficient to resolve structural features to below 5 Ångstrom, and is publicly available at EMPIAR-10453.
Klevanski, Maja ; Herrmannsdörfer, Frank ; Venkataramani, Varun ; Saß, Steffen ; Heilemann, Mike ; Kuner, Thomas
Understanding the nano-architecture of protein machines in diverse subcellular compartments remains a challenge despite rapid progress in super-resolution microscopy. While single-molecule localization microscopy techniques allow the visualization and identification of cellular structures with near-molecular resolution, multiplex-labeling of tens of target proteins within the same sample has not yet been achieved routinely. However, single sample multiplexing is essential to detect patterns that threaten to get lost in multi-sample averaging. Here, we report maS3TORM (multiplexed automated serial staining stochastic optical reconstruction microscopy), a microscopy approach capable of fully automated 3D direct STORM (dSTORM) imaging and solution exchange employing a re-staining protocol to achieve highly multiplexed protein localization within individual biological samples. We demonstrate 3D super-resolution images of 15 targets in single cultured cells and 16 targets in individual neuronal tissue samples with <10 nm localization precision, allowing us to define distinct nano-architectural features of protein distribution within the presynaptic nerve terminal.
González Palomares, Eugenia ; López Jury, Luciana ; García Rosales, Francisco ; Hechavarria-Cueria, Julio C.
The auditory midbrain (inferior colliculus, IC) plays an important role in sound processing, acting as hub for acoustic information extraction and for the implementation of fast audio-motor behaviors. IC neurons are topographically organized according to their sound frequency preference: dorsal IC regions encode low frequencies while ventral areas respond best to high frequencies, a type of sensory map defined as tonotopy. Tonotopic maps have been studied extensively using artificial stimuli (pure tones) but our knowledge of how these maps represent information about sequences of natural, spectro-temporally rich sounds is sparse. We studied this question by conducting simultaneous extracellular recordings across IC depths in awake bats (Carollia perspicillata) that listened to sequences of natural communication and echolocation sounds. The hypothesis was that information about these two types of sound streams is represented at different IC depths since they exhibit large differences in spectral composition, i.e., echolocation covers the high-frequency portion of the bat soundscape (> 45 kHz), while communication sounds are broadband and carry most power at low frequencies (20–25 kHz). Our results showed that mutual information between neuronal responses and acoustic stimuli, as well as response redundancy in pairs of neurons recorded simultaneously, increase exponentially with IC depth. The latter occurs regardless of the sound type presented to the bats (echolocation or communication). Taken together, our results indicate the existence of mutual information and redundancy maps at the midbrain level whose response cannot be predicted based on the frequency composition of natural sounds and classic neuronal tuning curves.
García Rosales, Francisco ; López Jury, Luciana ; González Palomares, Eugenia ; Cabral-Calderı́n, Yuranny ; Kössl, Manfred ; Hechavarria-Cueria, Julio C.
Neural oscillations are at the core of important computations in the mammalian brain. Interactions between oscillatory activities in different frequency bands, such as delta (1-4 Hz), theta (4-8 Hz), or gamma (>30 Hz), are a powerful mechanism for binding fundamentally distinct spatiotemporal scales of neural processing. Phase-amplitude coupling (PAC) is one such plausible and well-described interaction, but much is yet to be uncovered regarding how PAC dynamics contribute to sensory representations. In particular, although PAC appears to have a major role in audition, the characteristics of coupling profiles in sensory and integration (i.e. frontal) cortical areas remain obscure. Here, we address this question by studying PAC dynamics in the frontal-auditory field (FAF; an auditory area in the bat frontal cortex) and the auditory cortex (AC) of the bat Carollia perspicillata. By means of simultaneous electrophysiological recordings in frontal and auditory cortices examining local-field potentials (LFPs), we show that the amplitude of gamma-band activity couples with the phase of low-frequency LFPs in both structures. Our results demonstrate that the coupling in FAF occurs most prominently in delta/high-gamma frequencies (1-4/75-100 Hz), whereas in the AC the coupling is strongest in the theta/low-gamma (2-8/25-55 Hz) range. We argue that distinct PAC profiles may represent different mechanisms for neuronal processing in frontal and auditory cortices, and might complement oscillatory interactions for sensory processing in the frontal-auditory cortex network.
Animals extract behaviorally relevant signals from “noisy” environments. To investigate signal extraction, echolocating provides a rich system testbed. For orientation, bats broadcast calls and assign each echo to the corresponding call. When orienting in acoustically enriched environments or when approaching targets, bats change their spectro-temporal call design. Thus, to assess call adjustments that are exclusively meant to facilitate signal extraction in “noisy” environments, it is necessary to control for distance-dependent call changes. By swinging bats in a pendulum, we tested the influence of acoustic playback on the echolocation behavior of Carollia perspicillata. This paradigm evokes reproducible orientation behavior and allows a precise definition of the influence of the acoustic context. Our results show that bats dynamically switch between different adaptations to cope with sound-based navigation in acoustically contaminated environments. These dynamics of echolocation behavior may explain the large variety of adaptations that have been reported in the bat literature.
Bojkova, Denisa ; Costa, Rui ; Bechtel, Marco ; Ciesek, Sandra ; Michaelis, Martin ; Cinatl, Jindrich
It becomes more and more obvious that deregulation of host metabolism play an important role in SARS-CoV-2 pathogenesis with implication for increased risk of severe course of COVID-19. Furthermore, it is expected that COVID-19 patients recovered from severe disease may experience long-term metabolic disorders. Thereby understanding the consequences of SARS-CoV-2 infection on host metabolism can facilitate efforts for effective treatment option. We have previously shown that SARS-CoV-2-infected cells undergo a shift towards glycolysis and that 2-deoxy-D-glucose (2DG) inhibits SARS-CoV-2 replication. Here, we show that also pentose phosphate pathway (PPP) is remarkably deregulated. Since PPP supplies ribonucleotides for SARS-CoV-2 replication, this could represent an attractive target for an intervention. On that account, we employed the transketolase inhibitor benfooxythiamine and showed dose-dependent inhibition of SARS-CoV-2 in non-toxic concentrations. Importantly, the antiviral efficacy of benfooxythiamine was further increased in combination with 2DG.
Endogenous clocks enable organisms to adapt their physiology and behavior to daily variation in environmental conditions. Metabolic processes in cyanobacteria to humans are effected by the circadian clock, and its dysregulation causes metabolic disorders. In mouse and Drosophila were shown that the circadian clock directs translation of factors involved in ribosome biogenesis and synchronizes protein synthesis. However, the role of clocks in Drosophila neurogenesis and the potential impact of clock impairment on neural circuit formation and function is less understood. Here we demonstrate that light stimuli or circadian clock causes a defect in neural stem cell growth and proliferation accompanied by reduced nucleolar size. Further, we define that light and clock independently affect the InR/TOR growth regulatory pathway due to the effect on regulators of protein biosynthesis. Altogether, these data suggest that alterations in growth regulatory pathways induced by light and clock are associated with impaired neural development.
Otomo, Kanako ; Perkins, Jessica ; Kulkarni, Anand ; Stojanovic, Strahinja ; Roeper, Jochen ; Paladini, Carlos A.
The firing pattern of ventral midbrain dopamine neurons is controlled by afferent and intrinsic activity to generate prediction error signals that are essential for reward-based learning. Given the absence of intracellular in vivo recordings in the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. By establishing stable in vivo whole-cell recordings of >100 spontaneously active midbrain dopamine neurons in anaesthetized mice, we identified the repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. We demonstrate that dopamine neuron in vivo activity deviates from a single spike pacemaker pattern by eliciting transient increases in firing rate generated by at least two diametrically opposing biophysical mechanisms: a transient depolarization resulting in high frequency plateau bursts associated with a reactive, depolarizing shift in action potential threshold; and a prolonged hyperpolarization preceding slower rebound bursts characterized by a predictive, hyperpolarizing shift in action potential threshold. Our findings therefore illustrate a framework for the biophysical implementation of prediction error and sensory cue coding in dopamine neurons by tuning action potential threshold dynamics.
Baumgarten, Nina ; Schmidt, Florian ; Wegner, Martin ; Hebel, Marie ; Kaulich, Manuel ; Schulz, Marcel Holger
Genome-wide CRISPR screens are becoming more widespread and allow the simultaneous interrogation of thousands of genomic regions. Although recent progress has been made in the analysis of CRISPR screens, it is still an open problem how to interpret CRISPR mutations in non-coding regions of the genome. Most of the tools concentrate on the interpretation of mutations introduced in gene coding regions. We introduce a computational pipeline that uses epigenomic information about regulatory elements for the interpretation of CRISPR mutations in non-coding regions. We illustrate our approach on the analysis of a genome-wide CRISPR screen in hTERT-RPE-1 cells and reveal novel regulatory elements that mediate chemoresistance against doxorubicin in these cells. We infer links to established and to novel chemoresistance genes. Our approach is general and can be applied on any cell type and with different CRISPR enzymes.
Prost, Stefan ; Petersen, Malte ; Grethlein, Martin ; Hahn, Sarah Joy ; Kuschik-Maczollek, Nina ; Olesiuk, Martyna Ewa ; Reschke, Jan-Olaf ; Schmey, Tamara Elke ; Zimmer, Caroline ; Gupta, Deepak Kumar ; Schell, Tilman ; Coimbra, Raphael T. F. ; Raad, Jordi de ; Lammers, Fritjof ; Winter, Sven ; Janke, Axel
Background: Ever decreasing costs along with advances in sequencing and library preparation technologies enable even small research groups to generate chromosome-level assemblies today. Here we report the generation of an improved chromosome-level assembly for the Siamese fighting fish (Betta splendens) that was carried out during a practical university Master’s course. The Siamese fighting fish is a popular aquarium fish and an emerging model species for research on aggressive behaviour. We updated the current genome assembly by generating a new long-read nanopore-based assembly with subsequent scaffolding to chromosome-level using previously published HiC data.
Findings: The use of nanopore-based long-read data sequenced on a MinION platform (Oxford Nanopore Technologies) allowed us to generate a baseline assembly of only 1,276 contigs with a contig N50 of 2.1 Mbp, and a total length of 441 Mbp. Scaffolding using previously published HiC data resulted in 109 scaffolds with a scaffold N50 of 20.7 Mbp. More than 99% of the assembly is comprised in 21 scaffolds. The assembly showed the presence of 95.8% complete BUSCO genes from the Actinopterygii dataset indicating a high quality of the assembly.
Conclusion: We present an improved full chromosome-level assembly of the Siamese fighting fish generated during a university Master’s course. The use of ~35× long-read nanopore data drastically improved the baseline assembly in terms of continuity. We show that relatively in-expensive high-throughput sequencing technologies such as the long-read MinION sequencing platform can be used in educational settings allowing the students to gain practical skills in modern genomics and generate high quality results that benefit downstream research projects.
Entorhinal-retrosplenial circuits for allocentric-egocentric transformation of boundary coding
(2020)
Spatial navigation requires landmark coding from two perspectives, relying on viewpoint-invariant and self-referenced representations. The brain encodes information within each reference frame but their interactions and functional dependency remains unclear. Here we investigate the relationship between neurons in the rat's retrosplenial cortex (RSC) and entorhinal cortex (MEC) that increase firing near boundaries of space. Border cells in RSC specifically encode walls, but not objects, and are sensitive to the animal’s direction to nearby borders. These egocentric representations are generated independent of visual or whisker sensation but are affected by inputs from MEC that contains allocentric spatial cells. Pharmaco- and optogenetic inhibition of MEC led to a disruption of border coding in RSC, but not vice versa, indicating allocentric-to-egocentric transformation. Finally, RSC border cells fire prospective to the animal’s next motion, unlike those in MEC, revealing the MEC-RSC pathway as an extended border coding circuit that implements coordinate transformation to guide navigation behavior.
Sanz Perl, Yonatan ; Pallavicini, Carla ; Pérez Ipiña, Ignacio ; Demertzi, Athena ; Bonhomme, Vincent ; Martial, Charlotte ; Panda, Rajanikant ; Annen, Jitka ; Ibañez, Agustín ; Kringelbach, Morten L. ; Deco, Gustavo ; Laufs, Helmut ; Sitt, Jacobo D. ; Laureys, Steven ; Tagliazucchi, Enzo
Central Europe was affected by a compressional tectonic event in the Late Cretaceous, caused by the convergence of Iberia and Europe. Basement uplifts, inverted graben structures and newly formed marginal troughs are the main expressions of crustal shortening. Although the maximum activity occurred in a short period between 90 and 75 Ma, the exact timing of this event is still unclear. Dating of start and end of basin inversion is very different depending on the applied method. On the basis of borehole data, facies and thickness maps, the timing of basin re-organisation was reconstructed for several basins in Central Europe. The obtained data point to a synchronous start of basin inversion already at 95 Ma (Cenomanian), 5 Million years earlier than commonly assumed. The end of the Late Cretaceous compressional event is more difficult to pinpoint, because regional uplift and salt migration disturb the signal of shifting marginal troughs. Unconformities of Late Campanian to Paleogene age on inverted structures indicate slowly declining uplift rates.
Several studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that are affected by DNA methylation. Overall, we find that CpG methylation decreases the likelihood of binding for the majority of TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding.
Griesinger, Frank ; Eberhardt, Wilfried E. E. ; Nusch, Arnd ; Reiser, Marcel ; Zahn, Mark-Oliver ; Maintz, Christoph ; Bernhardt, Christiane ; Losem, Christoph ; Stenzinger, Albrecht ; Heukamp, Lukas ; Büttner, Reinhard ; Marschner, Sebastian ; Jänicke, Martina ; Fleitz, Annette ; Spring, Lisa ; Sahlmann, Jörg ; Karatas, Aysun ; Hipper, Annette ; Weichert, Wilko ; Heilmann, Monika ; Sadjadian, Parvis ; Gleiber, Wolfgang ; Grah, Christian ; Waller, Cornelius ; Reck, Martin ; Rittmeyer, Achim ; Christopoulos, Petros ; Sebastian, Martin ; Thomas, Michael
Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the “real-world” setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany.
Patients and methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1.
Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4–10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9–9.2) with druggable ALK alterations.
Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.
Wurzel, Patrick ; Ackermann, Jörg ; Schäfer, Hendrik ; Scharf, Sonja ; Hansmann, Martin-Leo ; Koch, Ina
Human lymph nodes play a central part of immune defense against infection agents and tumor cells. Lymphoid follicles are compartments of the lymph node which are spherical, mainly filled with B cells. B cells are cellular components of the adaptive immune systems. In the course of a specific immune response, lymphoid follicles pass different morphological differentiation stages. The morphology and the spatial distribution of lymphoid follicles can be sometimes associated to a particular causative agent and development stage of a disease. We report our new approach for the automatic detection of follicular regions in histological whole slide images of tissue sections immuno-stained with actin. The method is divided in two phases: (1) shock filter-based detection of transition points and (2) segmentation of follicular regions. Follicular regions in 10 whole slide images were manually annotated by visual inspection, and sample surveys were conducted by an expert pathologist. The results of our method were validated by comparing with the manual annotation. On average, we could achieve a Zijbendos similarity index of 0.71, with a standard deviation of 0.07.
García Rosales, Francisco ; López Jury, Luciana ; González Palomares, Eugenia ; Cabral-Calderı́n, Yuranny ; Hechavarria-Cueria, Julio C.
Most mammals rely on the extraction of acoustic information from the environment in order to survive. However, the mechanisms that support sound representation in auditory neural networks involving sensory and association brain areas remain underexplored. In this study, we address the functional connectivity between an auditory region in frontal cortex (the frontal auditory field, FAF) and the auditory cortex (AC) in the bat Carollia perspicillata. The AC is a classic sensory area central for the processing of acoustic information. On the other hand, the FAF belongs to the frontal lobe, a brain region involved in the integration of sensory inputs, modulation of cognitive states, and in the coordination of behavioural outputs. The FAF-AC network was examined in terms of oscillatory coherence (local-field potentials, LFPs), and within an information theoretical framework linking FAF and AC spiking activity. We show that in the absence of acoustic stimulation, simultaneously recorded LFPs from FAF and AC are coherent in low frequencies (1-12 Hz). This “default” coupling was strongest in deep AC layers and was unaltered by acoustic stimulation. However, presenting auditory stimuli did trigger the emergence of coherent auditory-evoked gamma-band activity (>25 Hz) between the FAF and AC. In terms of spiking, our results suggest that FAF and AC engage in distinct coding strategies for representing artificial and natural sounds. Taken together, our findings shed light onto the neuronal coding strategies and functional coupling mechanisms that enable sound representation at the network level in the mammalian brain.
Lewis, Christopher Murphy ; Jianguang, Ni ; Wunderle, Thomas ; Jendritza, Patrick ; Lazar, Andreea ; Diester, Ilka ; Fries, Pascal
Synchronization has been implicated in neuronal communication, but causal evidence remains indirect. We used optogenetics to generate depolarizing currents in pyramidal neurons of cat visual cortex, emulating excitatory synaptic inputs under precise temporal control, while measuring spike output. Cortex transformed constant excitation into strong gamma-band synchronization, revealing the well-known cortical resonance. Increasing excitation with ramps increased the strength and frequency of synchronization. Slow, symmetric excitation profiles revealed hysteresis of power and frequency. Crucially, white-noise input sequences enabled causal analysis of network transmission, establishing that cortical resonance selectively transmits coherent input components. Models composed of recurrently coupled excitatory and inhibitory units uncovered a crucial role of feedback inhibition and suggest that hysteresis can arise through spike-frequency adaptation. The presented approach provides a powerful means to investigate the resonance properties of local circuits and probe how these properties transform input and shape transmission.
Lewis, Christopher Murphy ; Jianguang, Ni ; Wunderle, Thomas ; Jendritza, Patrick ; Diester, Ilka ; Fries, Pascal
The gamma rhythm has been implicated in neuronal communication, but causal evidence remains indirect. We measured spike output of local neuronal networks and emulated their synaptic input through optogenetics. Opsins provide currents through somato-dendritic membranes, similar to synapses, yet under experimental control with high temporal precision. We expressed Channelrhodopsin-2 in excitatory neurons of cat visual cortex and recorded neuronal responses to light with different temporal characteristics. Sine waves of different frequencies entrained neuronal responses with a reliability that peaked for input frequencies in the gamma band. Crucially, we also presented white-noise sequences, because their temporal unpredictability enables analysis of causality. Neuronal spike output was caused specifically by the input’s gamma component. This gamma-specific transfer function is likely an emergent property of in-vivo networks with feedback inhibition. The method described here could reveal the transfer function between the input to any one and the output of any other neuronal group.
The plant family Brassicaceae includes some of the most studied hosts of plant microbiomes, targeting microbial diversity, community assembly rules, and effects on host performance. Compared to bacteria, eukaryotes in the brassicaceous microbiome remain understudied, especially under natural settings. Here, we assessed the impact of host identity and age on the assembly of fungal and oomycete root communities, using DNA metabarcoding of roots and associated soil of three annual co-habiting Brassicaceae collected at two time points. Our results showed that fungal communities are more diverse and structured than those of oomycetes. In both cases, plant identity and sampling time had little influence on community variation, whereas root/soil compartment had a strong effect by exerting control on the entry of soil microorganisms into the roots. The enrichment in roots of specific fungi suggests a specialization towards the asymptomatic colonization of plant tissues, which could be relevant to host’s fitness and health.
Heim, Ramona Julia ; Bucharova, Anna ; Brodt, Leya ; Kamp, Johannes ; Rieker, Daniel ; Soromotin, Andrey V. ; Yurtaev, Andrey ; Hölzel, Norbert
Wildfires are relatively rare in subarctic tundra ecosystems, but they can strongly change ecosystem properties. Short-term fire effects on subarctic tundra vegetation are well documented, but long-term vegetation recovery has been studied less. The frequency of tundra fires will increase with climate warming. Understanding the long-term effects of fire is necessary to predict future ecosystem changes.
We used a space-for-time approach to assess vegetation recovery after fire over more than four decades. We studied soil and vegetation patterns on three large fire scars (>44, 28 and 12 years old) in dry, lichen-dominated forest tundra in Western Siberia. On 60 plots, we determined soil temperature and permafrost thaw depth, sampled vegetation and measured plant functional traits. We assessed trends in NDVI to support the field-based results on vegetation recovery.
Soil temperature, permafrost thaw depth and total vegetation cover had recovered to pre-fire levels after >44 years, as well as total vegetation cover. In contrast, after >44 years, functional groups had not recovered to the pre-fire state. Burnt areas had lower lichen and higher bryophyte and shrub cover. The dominating shrub species, Betula nana, exhibited a higher vitality (higher specific leaf area and plant height) on burnt compared with control plots, suggesting a fire legacy effect in shrub growth. Our results confirm patterns of shrub encroachment after fire that were detected before in other parts of the Arctic and Subarctic. In the so far poorly studied Western Siberian forest tundra we demonstrate for the first time, long-term fire-legacies on the functional composition of relatively dry shrub- and lichen-dominated vegetation.
Signal transfer of visual stimuli to V4 occurs in gamma-rhythmic, pulsed information packages
(2020)
Summary Selective visual attention allows the brain to focus on behaviorally relevant information while ignoring irrelevant signals. As a possible mechanism, routing by synchronization was proposed: neural populations sending attended signals align their gamma-rhythmic activities with receiving populations, such that spikes from the senders arrive at excitability peaks of the receivers, enhancing signal transfer. Conversely, the non-attended signals arrive unaligned to the receiver’s oscillation, reducing signal transfer. Therefore, visual signals should be transferred through periodically pulsed information packages, resulting in a modulation of the stimulus content within the receiver’s activity by its gamma phase and amplitude. To test this prediction, we quantified gamma phase-specific stimulus content within neural activity from area V4 of macaques performing a visual attention task. For the attended stimulus we find enhanced stimulus content reaching its maximum near excitability peaks, with effect magnitude increasing with oscillation amplitude, establishing a functional link between selective processing and gamma activity.
Chiu, Wei-Hua ; Kovacheva, Lora ; Musgrove, Ruth E. ; Arien-Zakay, Hadar ; Koprich, James B. ; Brotchie, Jonathan M. ; Yaka, Rami ; Ben-Zvi, Danny ; Hanani, Menachem ; Roeper, Jochen ; Goldberg, Joshua A.
No disease modifying therapy is currently available for Parkinson’s disease (PD), the second most common neurodegenerative disease. The long non-motor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By developing a mutant α-synuclein selective-overexpression mouse model of prodromal PD, we identified a cell-autonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which in turn reduces gastrointestinal motility which is a common, very early symptom of prodromal PD. We show for the first time a causal chain of events from α-synuclein via a biophysical dysfunction of specific neuronal populations to a clinically relevant prodromal symptom. These findings can facilitate the rational design of clinical biomarkers to identify people at risk for PD.
Learning in the eyes: specific changes in gaze patterns track explicit and implicit visual learning
(2020)
What is the link between eye movements and sensory learning? Although some theories have argued for a permanent and automatic interaction between what we know and where we look, which continuously modulates human information- gathering behavior during both implicit and explicit learning, there exist surprisingly little evidence supporting such an ongoing interaction. We used a pure form of implicit learning called visual statistical learning and manipulated the explicitness of the task to explore how learning and eye movements interact. During both implicit exploration and explicit visual learning of unknown composite visual scenes, eye movement patterns systematically changed in accordance with the underlying statistical structure of the scenes. Moreover, the degree of change was directly correlated with the amount of knowledge the observers acquired. Our results provide the first evidence for an ongoing and specific interaction between hitherto accumulated knowledge and eye movements during both implicit and explicit learning.
Gagl, Benjamin ; Richlan, Fabio ; Ludersdorfer, Philipp ; Sassenhagen, Jona ; Eisenhauer, Susanne ; Gregorova, Klara ; Fiebach, Christian
To characterize the left-ventral occipito-temporal cortex (lvOT) role during reading in a quantitatively explicit and testable manner, we propose the lexical categorization model (LCM). The LCM assumes that lvOT optimizes linguistic processing by allowing fast meaning access when words are familiar and filter out orthographic strings without meaning. The LCM successfully simulates benchmark results from functional brain imaging. Empirically, using functional magnetic resonance imaging, we demonstrate that quantitative LCM simulations predict lvOT activation across three studies better than alternative models. Besides, we found that word-likeness, which is assumed as input to LCM, is represented posterior to lvOT. In contrast, a dichotomous word/non-word contrast, which is assumed as the LCM’s output, could be localized to upstream frontal brain regions. Finally, we found that training lexical categorization results in more efficient reading. Thus, we propose a ventral-visual-stream processing framework for reading involving word-likeness extraction followed by lexical categorization, before meaning extraction.
Gagl, Benjamin ; Sassenhagen, Jona ; Haan, Sophia ; Gregorova, Klara ; Richlan, Fabio ; Fiebach, Christian
Most current models assume that the perceptual and cognitive processes of visual word recognition and reading operate upon neuronally coded domain-general low-level visual representations – typically oriented line representations. We here demonstrate, consistent with neurophysiological theories of Bayesian-like predictive neural computations, that prior visual knowledge of words may be utilized to ‘explain away’ redundant and highly expected parts of the visual percept. Subsequent processing stages, accordingly, operate upon an optimized representation of the visual input, the orthographic prediction error, highlighting only the visual information relevant for word identification. We show that this optimized representation is related to orthographic word characteristics, accounts for word recognition behavior, and is processed early in the visual processing stream, i.e., in V4 and before 200 ms after word-onset. Based on these findings, we propose that prior visual-orthographic knowledge is used to optimize the representation of visually presented words, which in turn allows for highly efficient reading processes.
Gagl, Benjamin ; Sassenhagen, Jona ; Haan, Sophia ; Gregorova, Klara ; Richlan, Fabio ; Fiebach, Christian
Most current models assume that the perceptual and cognitive processes of visual word recognition and reading operate upon neuronally coded domain-general low-level visual representations – typically oriented line representations. We here demonstrate, consistent with neurophysiological theories of Bayesian-like predictive neural computations, that prior visual knowledge of words may be utilized to ‘explain away’ redundant and highly expected parts of the visual percept. Subsequent processing stages, accordingly, operate upon an optimized representation of the visual input, the orthographic prediction error, highlighting only the visual information relevant for word identification. We show that this optimized representation is related to orthographic word characteristics, accounts for word recognition behavior, and is processed early in the visual processing stream, i.e., in V4 and before 200 ms after word-onset. Based on these findings, we propose that prior visual-orthographic knowledge is used to optimize the representation of visually presented words, which in turn allows for highly efficient reading processes.
Mental imagery provides an essential simulation tool for remembering the past and planning the future, with its strength affecting both cognition and mental health. Research suggests that neural activity spanning prefrontal, parietal, temporal, and visual areas supports the generation of mental images. Exactly how this network controls the strength of visual imagery remains unknown. Here, brain imaging and transcranial magnetic phosphene data show that lower resting activity and excitability levels in early visual cortex (V1-V3) predict stronger sensory imagery. Further, electrically decreasing visual cortex excitability using tDCS increases imagery strength, demonstrating a causative role of visual cortex excitability in controlling visual imagery. Together, these data suggest a neurophysiological mechanism of cortical excitability involved in controlling the strength of mental images.
Background: Nations are imposing unprecedented measures at large-scale to contain the spread of COVID-19 pandemic. Recent studies indicate that measures such as lockdowns may have slowed down the growth of COVID-19. However, in addition to substantial economic and social costs, these measures also limit the exposure to Ultraviolet-B radiation (UVB). Emerging observational evidence indicate the protective role of UVB and vitamin D in reducing the severity and mortality of COVID-19 deaths. In this observational study, we empirically outline the independent protective roles of lockdown and UVB exposure as measured by ultraviolet index (UVI), whilst also examining whether the severity of lockdown is associated with a reduction in the protective role.
Methods: We apply a log-linear fixed-effects model to a panel dataset of 162 countries over a period of 108 days (n=6049). We use the cumulative number of COVID-19 deaths as the dependent variable and isolate the mitigating influence of lockdown severity on the association between UVI and growth-rates of COVID-19 deaths from time-constant country-specific and time-varying country-specific potentially confounding factors.
Findings: After controlling for time-constant and time-varying factors, we find that a unit increase in UVI and lockdown severity are independently associated with 17% [-1.8 percentage points] and 77% [-7.9 percentage points] decline in COVID-19 deaths growth rate, indicating their respective protective roles. However, the widely utilized and least severe lockdown (recommendation to not leave the house) already fully mitigates the protective role of UVI by 95% [1.8 percentage points] indicating its downside.
Interpretation: We find that lockdown severity and UVI are independently associated with a slowdown in the daily growth rates of cumulative COVID-19 deaths. However, we find consistent evidence that increase in lockdown severity is associated with a significant reduction in the protective role of UVI in reducing COVID-19 deaths. Our results suggest that lockdowns in conjunction with adequate exposure to UVB radiation might have provided even more substantial health benefits, than lockdowns alone. For example, we estimate that there would be 21% fewer deaths on average with sufficient UVB exposure while people were recommended not to leave their house. Therefore, our study outlines the importance of considering UVB exposure, especially while implementing lockdowns and may support policy decision making in countries imposing such measures.
Competing Interest Statement: RKM is a PhD researcher at Goethe University, Frankfurt. He also is an employee of a multinational chemical company involved in vitamin D business and holds the shares of the company. This study is intended to contribute to the ongoing COVID-19 crisis and is not sponsored by his company. All other authors declare no competing interests. The views expressed in the paper are those of the authors and do not represent that of any organization. No other relationships or activities that could appear to have influenced the submitted work.
The clinical and economic value of a successful shutdown during the SARS-CoV-2 pandemic in Germany
(2020)
Background and aim A shutdown of businesses enacted during the SARS-CoV-2 pandemic can serve different goals, e.g., preventing the intensive care unit (ICU) capacity from being overwhelmed (‘flattening the curve’) or keeping the reproduction number substantially below one (‘squashing the curve’). The aim of this study was to determine the clinical and economic value of a shutdown that is successful in ‘flattening’ or ‘squashing the curve’ in Germany.
Methods In the base case, the study compared a successful shutdown to a worst-case scenario with no ICU capacity left to treat COVID-19 patients. To this end, a decision model was developed using, e.g., information on age-specific fatality rates, ICU outcomes, and the herd protection threshold. The value of an additional life year was borrowed from new, innovative oncological drugs, as cancer reflects a condition with a similar morbidity and mortality burden in the general population in the short term as COVID-19.
Results A shutdown that is successful in ‘flattening the curve’ is projected to yield an average health gain between 0.02 and 0.08 life years (0.2 to 0.9 months) per capita in the German population. The corresponding economic value ranges between €1543 and €8027 per capita or, extrapolated to the total population, 4% to 19% of the gross domestic product (GDP) in 2019. A shutdown that is successful in ‘squashing the curve’ is expected to yield a minimum health gain of 0.10 life years (1.2 months) per capita, corresponding to 24% of the GDP in 2019. Results are particularly sensitive to mortality data and the prevalence of undetected cases.
Conclusion A successful shutdown is forecasted to yield a considerable gain in life years in the German population. Nevertheless, questions around the affordability and underfunding of other parts of the healthcare system emerge.
Antimicrobial resistance is a major threat to global health and food security today. Scheduling cycling therapies by targeting phenotypic states associated to specific mutations can help us to eradicate pathogenic variants in chronic infections. In this paper, we introduce a logistic switching model in order to abstract mutation networks of collateral resistance. We found particular conditions for which unstable zero-equilibrium of the logistic maps can be stabilized through a switching signal. That is, persistent populations can be eradicated through tailored switching regimens.
Starting from an optimal-control formulation, the switching policies show their potential in the stabilization of the zero-equilibrium for dynamics governed by logistic maps. However, employing such switching strategies, deserve a specific characterization in terms of limit behaviour. Ultimately, we use evolutionary and control algorithms to find either optimal and sub-optimal switching policies. Simulations results show the applicability of Parrondo’s Paradox to design cycling therapies against drug resistance.
COVID-19 pandemic has underlined the impact of emergent pathogens as a major threat for human health. The development of quantitative approaches to advance comprehension of the current outbreak is urgently needed to tackle this severe disease. In this work, several mathematical models are proposed to represent SARS-CoV-2 dynamics in infected patients. Considering different starting times of infection, parameters sets that represent infectivity of SARS-CoV-2 are computed and compared with other viral infections that can also cause pandemics.
Based on the target cell model, SARS-CoV-2 infecting time between susceptible cells (mean of 30 days approximately) is much slower than those reported for Ebola (about 3 times slower) and influenza (60 times slower). The within-host reproductive number for SARS-CoV-2 is consistent to the values of influenza infection (1.7-5.35). The best model to fit the data was including immune responses, which suggest a slow cell response peaking between 5 to 10 days post onset of symptoms. The model with eclipse phase, time in a latent phase before becoming productively infected cells, was not supported. Interestingly, both, the target cell model and the model with immune responses, predict that virus may replicate very slowly in the first days after infection, and it could be below detection levels during the first 4 days post infection. A quantitative comprehension of SARS-CoV-2 dynamics and the estimation of standard parameters of viral infections is the key contribution of this pioneering work.
Tanneberger, Anna Maria ; Maawi, Sarah al- ; Herrera-Vizcaíno, Carlos ; Orlowska, Anna ; Kubesch, Alica ; Sader, Robert Alexander ; Kirkpatrick, Charles James ; Ghanaati, Shahram Michael
Objectives: The aim of the present study was to characterize the cellular reaction to a xenogeneic resorbable collagen membrane of porcine origin using a subcutaneous implantation model in Wistar rats over 30 days.
Materials and methods: Ex vivo, liquid platelet-rich fibrin (PRF), a leukocyte and platelet-rich cell suspension, was used to evaluate the blood cell membrane interaction. The material was implanted subcutaneously in rats. Sham-operated rats without biomaterial displayed physiological wound healing (control group). Histological, immunohistological, and histomorphometric analyses were focused on the inflammatory pattern, vascularization rate, and degradation pattern.
Results: The membrane induced a large number of mononuclear cells over the observation period, including lymphocytes, macrophages, and fibroblasts. After 15 days, multinucleated giant cells (MNGCs) were observed on the biomaterial surface. Their number increased significantly, and they proceeded to the center of the biomaterial on day 30. These cells highly expressed CD-68, calcitonin receptor, and MMP-9, but not TRAP or integrin-ß3. Thus, the membrane lost its integrity and underwent disintegration as a consequence of the induction of MNGCs. The significant increase in MNGC number correlated with a high rate of vascularization, which was significantly higher than the control group. Physiological wound healing in the control group did not induce any MNGCs at any time point. Ex vivo blood cells from liquid-PRF did not penetrate the membrane.
Conclusion: The present study suggests a potential role for MNGCs in biomaterial degradation and questions whether it is beneficial to accept them in clinically approved biomaterials or focus on biomaterials that induce only mononuclear cells. Thus, further studies are necessary to identify the function of biomaterial-induced MNGCs.
Clinical relevance: Understanding the cellular reaction to biomaterials is essential to assess their suitability for specific clinical indications and outline the potential benefit of specific group of biomaterials in the respective clinical indications.
Combining market data with a publicly available monthly snapshot of Deutsche Börse’s index ranking list, I create a model that predicts index changes in the DAX, MDAX, SDAX, and TecDAX from 2010 to 2019 before they are officially announced. Even though I empirically show that index changes are predictable, they still earn sizeable post-announcement 1-day abnormal returns up to 1.42% and − 1.54% for promotions and demotions, respectively. While abnormal returns are larger in smaller stocks, I find no evidence that they are related to funding constraints or additional risk for trading on wrong predictions. A trading strategy that trades according to my model yields an annualized Sharpe ratio of 0.83 while being invested for just 4 days a year.
Sikora, Mateusz ; Bülow, Sören von ; Blanc, Florian E. C. ; Gecht, Michael ; Covino, Roberto ; Hummer, Gerhard
The severity of the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, calls for the urgent development of a vaccine. The primary immunological target is the SARS-CoV-2 spike (S) protein. S is exposed on the viral surface to mediate viral entry into the host cell. To identify possible antibody binding sites not shielded by glycans, we performed multi-microsecond molecular dynamics simulations of a 4.1 million atom system containing a patch of viral membrane with four full-length, fully glycosylated and palmitoylated S proteins. By mapping steric accessibility, structural rigidity, sequence conservation and generic antibody binding signatures, we recover known epitopes on S and reveal promising epitope candidates for vaccine development. We find that the extensive and inherently flexible glycan coat shields a surface area larger than expected from static structures, highlighting the importance of structural dynamics in epitope mapping.
Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physicochemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein–protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low-complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS-LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model. For a scaling factor α = 0.65, we recover experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS-LCD condenses. In the region of phase separation, we simulate FUS-LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS-LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01–0.4 mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02 Pa s for the FUS-LCD droplets with scaling factors α in the range of 0.625–0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
Hintergrund: Die Erstversorgung von Wunden und kleinere chirurgische Eingriffe gehören neben der hochspezialisierten Medizin zu den allgemein notwendigen Grundleistungen der Notfallversorgung in den Kliniken. Die Vergütung der ambulanten Notfallleistungen für gesetzlich Versicherte erfolgt derzeit nach dem Einheitlichen Bewertungsmaßstab (EBM), welchem die betriebswirtschaftliche Aufwandserfassung des niedergelassenen Sektors als Kalkulationsgrundlage dient. Krankenhäuser haben im Vergleich zu Arztpraxen wesentlich höhere Vorhaltungskosten.
Ziel der Arbeit: In dieser Arbeit wird das entstehende Kosten-Erlös-Verhältnis der ambulanten Wundversorgung in einer Notaufnahme durch die Vergütung nach EBM analysiert.
Material und Methoden: Die Daten wurden in der Notaufnahme des Universitätsklinikums Frankfurt am Main über 12 Monate erhoben. Eingeschlossen wurden alle Patienten, die in diesem Zeitraum eine Wundversorgung mittels Naht erhielten. Die Kosten wurden der Abrechnung nach EBM 01210 (bzw. 01212) mit der Zusatzpauschale für kleinchirurgische Eingriffe EBM 02301 gegenübergestellt.
Ergebnisse: Im Beobachtungszeitraum wurden 1548 Patienten versorgt; das entspricht 19,52 % aller unfallchirurgischen Fälle. Den Kosten einer Standardwundversorgung in Höhe von 45,40 € steht eine Vergütung von 31,83 € gegenüber. Die Berechnung des Gesamterlöses weist einen Defizitbetrag von 13,57 € pro ambulantem Fall auf; dies entspricht einem Jahresdefizit von 21.006,36 €.
Diskussion: Es konnte gezeigt werden, dass ohne Betrachtung der relevanten Vorhaltekosten in keinem Fall eine Kostendeckung erreicht werden kann.
Die bisherige Vergütung der ambulanten Wundversorgung nach EBM erscheint unzureichend. Eine Anpassung bzw. Zusatzvergütung scheint notwendig, um eine ausreichende Versorgungsqualität in Zukunft sicherstellen zu können.
This paper defends The Transformation of Values into Prices on the Basis of Random Systems, published in EIER, by answering to the Comments made in the same journal by Professors Mori, Morioka and Yamazaki. The clarifications mainly concern the justification of the randomness assumptions, the conditions needed to obtain the equality of total profit with total surplus value in the simplified one-industry system and the invariance of the results to changes in the units of measurement.
Summary We introduce fsbrain, an R package for the visualization of neuroimaging data. The package can be used to visualize vertex-wise and region-wise morphometry data, parcellations, labels and statistical results on brain surfaces in three dimensions (3D). Voxel data can be displayed in lightbox mode. The fsbrain package offers various customization options and produces publication quality plots which can be displayed interactively, saved as bitmap images, or integrated into R notebooks.
Availability and Implementation The software, source code and documentation are available under the MIT license at https://github.com/dfsp-spirit/fsbrain. Releases can be installed directly from the Comprehensive R Archive Network (CRAN).
Visual scene perception is mediated by a set of cortical regions that respond preferentially to images of scenes, including the occipital place area (OPA) and parahippocampal place area (PPA). However, the differential contribution of OPA and PPA to scene perception remains an open research question. In this study, we take a deep neural network (DNN)-based computational approach to investigate the differences in OPA and PPA function. In a first step we search for a computational model that predicts fMRI responses to scenes in OPA and PPA well. We find that DNNs trained to predict scene components (e.g., wall, ceiling, floor) explain higher variance uniquely in OPA and PPA than a DNN trained to predict scene category (e.g., bathroom, kitchen, office). This result is robust across several DNN architectures. On this basis, we then determine whether particular scene components predicted by DNNs differentially account for unique variance in OPA and PPA. We find that variance in OPA responses uniquely explained by the navigation-related floor component is higher compared to the variance explained by the wall and ceiling components. In contrast, PPA responses are better explained by the combination of wall and floor, that is scene components that together contain the structure and texture of the scene. This differential sensitivity to scene components suggests differential functions of OPA and PPA in scene processing. Moreover, our results further highlight the potential of the proposed computational approach as a general tool in the investigation of the neural basis of human scene perception.
Joppe, Mirko ; D'Imprima, Edoardo ; Salustros, Nina ; Paithankar, Karthik Shivaji ; Vonck, Janet ; Grininger, Martin ; Kühlbrandt, Werner
Single-particle electron cryo-microscopy (cryoEM) has undergone a `resolution revolution' that makes it possible to characterize megadalton (MDa) complexes at atomic resolution without crystals. To fully exploit the new opportunities in molecular microscopy, new procedures for the cloning, expression and purification of macromolecular complexes need to be explored. Macromolecular assemblies are often unstable, and invasive construct design or inadequate purification conditions and sample-preparation methods can result in disassembly or denaturation. The structure of the 2.6 MDa yeast fatty acid synthase (FAS) has been studied by electron microscopy since the 1960s. Here, a new, streamlined protocol for the rapid production of purified yeast FAS for structure determination by high-resolution cryoEM is reported. Together with a companion protocol for preparing cryoEM specimens on a hydrophilized graphene layer, the new protocol yielded a 3.1 Å resolution map of yeast FAS from 15 000 automatically picked particles within a day. The high map quality enabled a complete atomic model of an intact fungal FAS to be built.
Modular polyketide synthases (PKSs) produce complex, bioactive secondary metabolites in assembly line-like multistep reactions. Longstanding efforts to produce novel, biologically active compounds by recombining intact modules to new modular PKSs have mostly resulted in poorly active chimeras and decreased product yields. Recent findings demonstrate that the low efficiencies of modular chimeric PKSs also result from rate limitations in the transfer of the growing polyketide chain across the non-cognate module:module interface and further processing of the non-native polyketide substrate by the ketosynthase (KS) domain. In this study, we aim at disclosing and understanding the low efficiency of chimeric modular PKSs and at establishing guidelines for modular PKSs engineering. To do so, we work with a bimodular PKS testbed and systematically vary substrate specificity, substrate identity, and domain:domain interfaces of the KS involved reactions. We observe that KS domains employed in our chimeric bimodular PKSs are bottlenecks with regards to both substrate specificity as well as interaction with the ACP. Overall, our systematic study can explain in quantitative terms why early oversimplified engineering strategies based on the plain shuffling of modules mostly failed and why more recent approaches show improved success rates. We moreover identify two mutations of the KS domain that significantly increased turnover rates in chimeric systems and interpret this finding in mechanistic detail.
Inspired by the physiology of neuronal systems in the brain, artificial neural networks have become an invaluable tool for machine learning applications. However, their biological realism and theoretical tractability are limited, resulting in poorly understood parameters. We have recently shown that biological neuronal firing rates in response to distributed inputs are largely independent of size, meaning that neurons are typically responsive to the proportion, not the absolute number, of their inputs that are active. Here we introduce such a normalisation, where the strength of a neuron’s afferents is divided by their number, to various sparsely-connected artificial networks. The learning performance is dramatically increased, providing an improvement over other widely-used normalisations in sparse networks. The resulting machine learning tools are universally applicable and biologically inspired, rendering them better understood and more stable in our tests.
Achieving functional neuronal dendrite structure through sequential stochastic growth and retraction
(2020)
Castro, André Ferreira ; Baltruschat, Lothar Gunnar ; Stürner, Tomke ; Bahrami, Amirhoushang ; Jedlička, Peter ; Tavosanis, Gaia ; Cuntz, Hermann
Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of stochastic growth and retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.
Achieving functional neuronal dendrite structure through sequential stochastic growth and retraction
(2020)
Castro, André Ferreira ; Baltruschat, Lothar Gunnar ; Stürner, Tomke ; Bahrami, Amirhoushang ; Jedlička, Peter ; Tavosanis, Gaia ; Cuntz, Hermann
Class I ventral posterior dendritic arborisation (c1vpda) proprioceptive sensory neurons respond to contractions in the Drosophila larval body wall during crawling. Their dendritic branches run along the direction of contraction, possibly a functional requirement to maximise membrane curvature during crawling contractions. Although the molecular machinery of dendritic patterning in c1vpda has been extensively studied, the process leading to the precise elaboration of their comb-like shapes remains elusive. Here, to link dendrite shape with its proprioceptive role, we performed long-term, non-invasive, in vivo time-lapse imaging of c1vpda embryonic and larval morphogenesis to reveal a sequence of differentiation stages. We combined computer models and dendritic branch dynamics tracking to propose that distinct sequential phases of targeted growth and stochastic retraction achieve efficient dendritic trees both in terms of wire and function. Our study shows how dendrite growth balances structure–function requirements, shedding new light on general principles of self-organisation in functionally specialised dendrites.
Dendrites display a striking variety of neuronal type-specific morphologies, but the mechanisms and principles underlying such diversity remain elusive. A major player in defining the morphology of dendrites is the neuronal cytoskeleton, including evolutionarily conserved actin-modulatory proteins (AMPs). Still, we lack a clear understanding of how AMPs might support developmental phenomena such as neuron-type specific dendrite dynamics. To address precisely this level of in vivo specificity, we concentrated on a defined neuronal type, the class III dendritic arborisation (c3da) neuron of Drosophila larvae, displaying actin-enriched short terminal branchlets (STBs). Computational modelling reveals that the main branches of c3da neurons follow a general growth model based on optimal wiring, but the STBs do not. Instead, model STBs are defined by a short reach and a high affinity to grow towards the main branches. We thus concentrated on c3da STBs and developed new methods to quantitatively describe dendrite morphology and dynamics based on in vivo time-lapse imaging of mutants lacking individual AMPs. In this way, we extrapolated the role of these AMPs in defining STB properties. We propose that dendrite diversity is supported by the combination of a common step, refined by a neuron type-specific second level. For c3da neurons, we present a molecular model of how the combined action of multiple AMPs in vivo define the properties of these second level specialisations, the STBs.
The way in which dendrites spread within neural tissue determines the resulting circuit connectivity and computation. However, a general theory describing the dynamics of this growth process does not exist. Here we obtain the first time-lapse reconstructions of neurons in living fly larvae over the entirety of their developmental stages. We show that these neurons expand in a remarkably regular stretching process that conserves their shape. Newly available space is filled optimally, a direct consequence of constraining the total amount of dendritic cable. We derive a mathematical model that predicts one time point from the previous and use this model to predict dendrite morphology of other cell types and species. In summary, we formulate a novel theory of dendrite growth based on detailed developmental experimental data that optimises wiring and space filling and serves as a basis to better understand aspects of coverage and connectivity for neural circuit formation.
Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physico-chemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model, respectively. For a scaling factor α = 0.65, we recover the experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS LCD condenses. In the region of phase separation, we simulate FUS LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01 to 0.4mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02Pas for the FUS LCD droplets with scaling factors α in the range of 0.625 to 0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.
The protein Atg2 has been proposed to form a membrane tether that mediates lipid transfer from the ER to the phagophore in autophagy. However, recent kinetic measurements on the human homolog ATG2A indicated a transport rate of only about one lipid per minute, which would be far too slow to deliver the millions of lipids required to form a phagophore on a physiological time scale. Here, we revisit the analysis of the fluorescence quenching experiments. We develop a detailed kinetic model of the lipid transfer between two membranes bridged by a tether that forms a conduit for lipids. The model provides an excellent fit to the fluorescence experiments, with a lipid transfer rate of about 100 per second and protein. At this rate, Atg2-mediated transfer can supply a significant fraction of the lipids required in autophagosome biogenesis. Our kinetic model is generally applicable to lipid-transfer experiments, in particular to proteins forming organelle contact sites in cells.
Binding of the spike protein of SARS-CoV-2 to the human angiotensin converting enzyme 2 (ACE2) receptor triggers translocation of the virus into cells. Both the ACE2 receptor and the spike protein are heavily glycosylated, including at sites near their binding interface. We built fully glycosylated models of the ACE2 receptor bound to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Using atomistic molecular dynamics (MD) simulations, we found that the glycosylation of the human ACE2 receptor contributes substantially to the binding of the virus. Interestingly, the glycans at two glycosylation sites, N90 and N322, have opposite effects on spike protein binding. The glycan at the N90 site partly covers the binding interface of the spike RBD. Therefore, this glycan can interfere with the binding of the spike protein and protect against docking of the virus to the cell. By contrast, the glycan at the N322 site interacts tightly with the RBD of the ACE2-bound spike protein and strengthens the complex. Remarkably, the N322 glycan binds into a conserved region of the spike protein identified previously as a cryptic epitope for a neutralizing antibody. By mapping the glycan binding sites, our MD simulations aid in the targeted development of neutralizing antibodies and SARS-CoV-2 fusion inhibitors.
Active efficient coding explains the development of binocular vision and its failure in amblyopia
(2020)
The development of vision during the first months of life is an active process that comprises the learning of appropriate neural representations and the learning of accurate eye movements. While it has long been suspected that the two learning processes are coupled, there is still no widely accepted theoretical framework describing this joint development. Here we propose a computational model of the development of active binocular vision to fill this gap. The model is based on a new formulation of the Active Efficient Coding theory, which proposes that eye movements, as well as stimulus encoding, are jointly adapted to maximize the overall coding efficiency. Under healthy conditions, the model self-calibrates to perform accurate vergence and accommodation eye movements. It exploits disparity cues to deduce the direction of defocus, which leads to co-ordinated vergence and accommodation responses. In a simulated anisometropic case, where the refraction power of the two eyes differs, an amblyopia-like state develops, in which the foveal region of one eye is suppressed due to inputs from the other eye. After correcting for refractive errors, the model can only reach healthy performance levels if receptive fields are still plastic, in line with findings on a critical period for binocular vision development. Overall, our model offers a unifying conceptual framework for understanding the development of binocular vision.
Klann, Kevin ; Bojkova, Denisa ; Tascher, Georg ; Ciesek, Sandra ; Münch, Christian ; Cinatl, Jindrich
SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinder therapy development. We employed a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phospho-proteomics. We identified viral protein phosphorylation and defined phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways were activated. Drug-protein network analyses revealed GFR signaling as key pathway targetable by approved drugs. Inhibition of GFR downstream signaling by five compounds prevented SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as central pathway essential for SARS-CoV-2 replication. It provides with novel strategies for COVID-19 treatment.
Michaelis, Martin ; Voges, Yvonne ; Rothweiler, Florian ; Weipert, Fabian ; Zia-Ahmad, Amara ; Cinatl, Jaroslav ; Deimling, Andreas von ; Westermann, Frank ; Rödel, Franz ; Wass, Mark N. ; Cinatl, Jindrich
The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). 77 cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
Bojkova, Denisa ; McGreig, Jake E. ; McLaughlin, Katie-May ; Masterson, Stuart G. ; Widera, Marek ; Krähling, Verena ; Ciesek, Sandra ; Wass, Mark N. ; Michaelis, Martin ; Cinatl, Jindrich
SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.
McLaughlin, Katie-May ; Bechtel, Marco ; Bojkova, Denisa ; Wass, Mark N. ; Michaelis, Martin ; Cinatl, Jindrich
SARS-CoV-2 is the causative agent of COVID-19. Severe COVID-19 disease has been associated with disseminated intravascular coagulation and thrombosis, but the mechanisms underlying COVID-19-related coagulopathy remain unknown. Since the risk of severe COVID-19 disease is higher in males than in females and increases with age, we combined proteomics data from SARS-CoV-2-infected cells with human gene expression data from the Genotype-Tissue Expression (GTEx) database to identify gene products involved in coagulation that change with age, differ in their levels between females and males, and are regulated in response to SARS-CoV-2 infection. This resulted in the identification of transferrin as a candidate coagulation promoter, whose levels increases with age and are higher in males than in females and that is increased upon SARS-CoV-2 infection. A systematic investigation of gene products associated with the GO term “blood coagulation” did not reveal further high confidence candidates, which are likely to contribute to COVID-19-related coagulopathy. In conclusion, the role of transferrin should be considered in the course of COVID-19 disease and further examined in ongoing clinic-pathological investigations.
Einleitung: Begehen zwei Menschen infolge einer gemeinsamen Entscheidung Suizid, wird dies als Doppelsuizid oder gemeinschaftlicher Suizid definiert. Die rechtsmedizinische Begutachtung hängt von den Umständen des konkreten Einzelfalls ab und kann für die rechtliche Würdigung insbesondere bei Konstellationen, bei denen ein Beteiligter überlebt hat, wichtige Hinweise liefern.
Material und Methoden: Für einen 25-Jahres-Zeitraum von 1995 bis 2019 wurden retrospektiv alle Sektionsfälle mit vollendeten und versuchten Doppelsuiziden analysiert und, soweit erhältlich, mit den Ermittlungsakten abgeglichen.
Ergebnisse: Unter den erhobenen 23 Doppelsuizidfällen fanden sich 16 vollendete sowie 7 Fälle mit jeweils einem Überlebenden. In 83 % der Fälle handelte es sich um Ehepaare bzw. eingetragene Lebensgemeinschaften, in 13 % um Personen, die sich zuvor in einer psychiatrischen Einrichtung, und in 4 % um Personen, die sich in einem „Suizidforum“ im Internet kennengelernt hatten. Der Mittelwert des Sterbealters betrug bei den Männern 57,8 und bei den Frauen 63,4 Jahre. In etwa zwei Drittel der Fälle wurden Erkrankungen als vorherrschendes Suizidmotiv angegeben. Als häufigste Methode wurde eine Intoxikation gewählt. Am zweithäufigsten fanden Schusswaffen Anwendung, wobei ausnahmslos der Mann zuerst einen oder mehrere Kopfschüsse auf seine Frau abgab, bevor er sich suizidierte. Der häufigste Sterbe- und Auffindeort war das gemeinsame Bett der Suizidenten.
Diskussion: Im Gegensatz zu Suiziden i. Allg. wurden die Doppelsuizide am häufigsten mittels einer Intoxikation als sogenannte weiche Methode verübt. In Anlehnung an die rechtsmedizinische Literatur werden für einen Doppelsuizid typische Merkmale herausgearbeitet.
Schlussfolgerung: Doppelsuizide stellen seltene Fälle in der rechtsmedizinischen Praxis dar, wobei die Abgrenzung zu einem erweiterten Suizid (Homizid-Suizid) schwierig werden kann und zugleich unabdingbar ist. Hierfür ist eine ganzheitliche Berücksichtigung der Vorgeschichte, der rechtsmedizinisch erhobenen Befunde und der kriminalistischen Umstände erforderlich.
Bei Suizidformen mit mehreren Suizidenten und Opfern werden teilweise in Literatur und Rechtsprechung eine unterschiedliche Nomenklatur und Interpretation der Begrifflichkeiten vorgenommen. Der Beitrag analysiert die Begrifflichkeiten und befasst sich im Speziellen mit dem Phänomen des Doppelsuizids. Historische Fälle von Doppelsuiziden werden angeführt. Anhand von Fallkonstellationen werden rechtliche Bewertungen vorgenommen, die beim einseitig fehlgeschlagenen Doppelsuizid praxisrelevant werden können. Dabei werden die mitunter konträren Auffassungen in der einschlägigen Literatur und der Rechtsprechung dargestellt und Lösungsansätze aufgezeigt. Zudem verdeutlichen die Fallkonstellationen die Relevanz einer umfassenden Tatortarbeit und einer tatnahen Klärung der Motivationslage bei dem Überlebenden bzw. den Verstorbenen.
The 𝒮-cone provides a common framework for cones of polynomials or exponen- tial sums which establish non-negativity upon the arithmetic-geometric inequality, in particular for sums of non-negative circuit polynomials (SONC) or sums of arithmetic- geometric exponentials (SAGE). In this paper, we study the S-cone and its dual from the viewpoint of second-order representability. Extending results of Averkov and of Wang and Magron on the primal SONC cone, we provide explicit generalized second- order descriptions for rational S-cones and their duals.
Mia, Ibnul ; Le, Melanie Thanh Phuong ; Arendt, Christophe ; Brand, Diana ; Bremekamp, Sina ; D’Angelo, Tommaso ; Puntmann, Valentina O. ; Nagel, Eike
The aim of this study is to provide a systematic assessment of the influence of the position on the arterial input function (AIF) for perfusion quantification. In 39 patients with a wide range of left ventricular function the AIF was determined using a diluted contrast bolus of a cardiac magnetic resonance imaging in three left ventricular levels (basal, mid, apex) as well as aortic sinus (AoS). Time to peak signal intensities, baseline corrected peak signal intensity and upslopes were determined and compared to those obtained in the AoS. The error induced by sampling the AIF in a position different to the AoS was determined by Fermi deconvolution. The time to peak signal intensity was strongly correlated (r2 > 0.9) for all positions with a systematic earlier arrival in the basal (− 2153 ± 818 ms), the mid (− 1429 ± 928 ms) and the apical slice (− 450 ± 739 ms) relative to the AoS (all p < 0.001). Peak signal intensity as well as upslopes were strongly correlated (r2 > 0.9 for both) for all positions with a systematic overestimation in all positions relative to the AoS (all p < 0.001 and all p < 0.05). Differences between the positions were more pronounced for patients with reduced ejection fraction. The error of averaged MBF quantification was 8%, 13% and 27% for the base, mid and apex. The location of the AIF significantly influences core parameters for perfusion quantification with a systematic and ejection fraction dependent error. Full quantification should be based on obtaining the AIF as close as possible to the myocardium to minimize these errors.
We introduce a novel approach based on elas- tic and inelastic scattering rates to extract the hyper-surface of the chemical freeze-out from a hadronic transport model in the energy range from Elab = 1.23 AGeV to √sNN = 62.4 GeV. For this study, the Ultra-relativistic Quantum Molecular Dynamics (UrQMD) model combined with a coarse-graining method is employed. The chemical freeze- out distribution is reconstructed from the pions through sev- eral decay and re-formation chains involving resonances and taking into account inelastic, pseudo-elastic and string excita- tion reactions. The extracted average temperature and baryon chemical potential are then compared to statistical model analysis. Finally we investigate various freeze-out criteria suggested in the literature. We confirm within this micro- scopic dynamical simulation, that the chemical freeze-out at all energies coincides with ⟨E⟩/⟨N⟩ ≈ 1 GeV, while other criteria, like s/T 3 = 7 and nB +nB ̄ ≈ 0.12 fm−3 are limited to higher collision energies.
Der Tumormarker Sialinsäure
(2020)
Die vorliegende Übersicht zum Tumormarker Sialinsäure wird im Rahmen der Serie „Tumormarker“ des Zentralblatts für Arbeitsmedizin, Arbeitsschutz und Ergonomie publiziert, die sich mit dem immer häufigeren Gebrauch der Bestimmung von spezifischen Markern bei sog. Manager-Vorsorgen und Check-up-Untersuchungen beschäftigt. Sialinsäure eignet sich grundsätzlich nicht für solche Vorsorgen, sondern ist ein Marker zur Therapie‑, Verlaufs- und Rezidivkontrolle von Mundhöhlenkarzinomen. Hier zeigt dieser eine hohe Sensitivität und Spezifität, wobei der Marker aber auf keinen Fall als Screeningparameter zur Frühdiagnostik eingesetzt werden soll.
The production of light (anti-)nuclei and (anti-)hypernuclei in ultra-relativistic heavy-ion collisions, but also in more elementary collisions as proton–proton and proton–nucleus collisions, became recently a focus of interest. In particular, the fact that these objects are all loosely bound compared to the temperature and energies, e.g. the kinetic energies involved, is often stressed out to be special for their production. The binding energies of these (anti-)nuclei is between 130 keV (Λ separation energy in the hypertriton) and about 8 MeV per nucleon. Whereas the connected temperatures are of the order of 100 to 160 MeV. This lead to some difficulties in the interpretation of the usually discussed production models, i.e. coalescence and statistical-thermal models, as will be discussed here. In this brief review we discuss selected highlights of the production of light (anti-)nuclei, such as (anti-)deuteron, (anti-)helium and (anti-)alpha nuclei. In addition, we will discuss the current status of the highly debated lifetime of the (anti-)hypertriton and connected measurements and model results.
Köffer, Jasmin ; Scheiper-Welling, Stefanie ; Verhoff, Marcel A. ; Bajanowski, Thomas ; Kauferstein, Silke
The sudden infant death syndrome (SIDS) is one of the leading causes of postneonatal infant death. It has been shown that there exists a complex relationship between SIDS and inherited cardiac disease. Next-generation sequencing and surveillance of cardiac channelopathy and cardiomyopathy genes represent an important tool for investigating the cause of death in SIDS cases. In the present study, targeted sequencing of 80 genes associated with genetic heart diseases in a cohort of 31 SIDS cases was performed. To determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for SIDS, a stringent variant classification was applied and the percentage of rare (minor allele frequency ≤ 0.2%) and ultra-rare variants (minor allele frequency ≤ 0.005%) in these genes was assessed. With a minor allele frequency of ≤ 0.005%, about 20% of the SIDS cases exhibited a variant of uncertain significance (VUS), but in only 6% of these cases, gene variants proved to be “potentially informative.” The present study shows the importance of careful variant interpretation. Applying stringent criteria misinterpretations are avoided, as the results of genetic analyses may have an important impact of the family members involved.
We investigate hadronic particle spectra and flow characteristics of heavy-ion reactions in the FAIR/NICA energy range of 1 AGeV ≤ Elab ≤ 10 AGeV within a relativistic ideal hydrodynamic one-fluid approach. The particlization is realized by sampling the Cooper-Frye distribution for a grand canonical hadron gas on a hypersurface of constant energy density. Results of the hydrodynamic calculations for different underlying equations of state are presented and compared with experimental data and microscopic transport simulations. The sensitivity of the approach to physical model inputs concerning the initial state and the particlization is studied.
Verboket, René ; Mühlenfeld, Nils ; Sterz, Jasmina ; Störmann, Philipp ; Marzi, Ingo ; Balcik, Yunus ; Rosenow, Felix ; Strzelczyk, Adam ; Willems, Laurent Maximilian
Hintergrund: Die Analyse krankheitsspezifischer Kosten gewinnt in einem zunehmend ökonomisch ausgerichteten Gesundheitssystem an Relevanz, wobei vor allem chronische Erkrankungen aufgrund der langen Krankheitsdauer sowie häufiger Hospitalisierung und Arztbesuche von besonderem Interesse sind. Epilepsien stellen eine häufige neurologische Erkrankung dar, welche mit paroxysmal auftretenden epileptischen Anfällen und häufig hiermit assoziierten Verletzungen einhergeht und alle Altersgruppen betrifft.
Ziel: Ziel der Arbeit ist die Aufarbeitung der stationären Behandlungskosten anfallsbedingter Verletzungen sowie die Analyse hinsichtlich relevanter kostenverursachender Faktoren. Mittels alternativer Kalkulation der Versorgungskosten soll zusätzlich der Frage nach potenziellen Vergütungsproblemen im aktuellen DRG-System („diagnosis related groups“) nachgegangen werden.
Methoden: Grundlage dieser monozentrischen, retrospektiven Analyse ist der tatsächliche Erlös der stationären Behandlung von 62 Patienten, die zwischen 01/2010 und 01/2018 im Universitätsklinikum Frankfurt aufgrund von Verletzungen im Rahmen epileptischer Anfälle erfolgte. Die Analyse potenzieller kostenverursachender Faktoren bezog sich auf relevante soziodemographische und klinische Aspekte, die alternative Kalkulation der Versorgungskosten wurde mit gängigen gesundheitsökonomischen Methoden durchgeführt.
Ergebnisse: Der mittlere DRG-Erlös betrug 7408 € (±8993 €, Median 5086 €, Spanne 563–44.519 €), die mittleren kalkulierten Kosten 9423 € (±11.113 €, 5626 €, Spanne 587–49.830 €). Als signifikant kostenverursachender Faktor konnte eine Liegedauer ≥7 Tage (p = 0,014) identifiziert werden. Aufgrund des signifikanten Unterschieds (p < 0,001) zwischen Erlös und kalkulierten Kosten erfolgte eine Analyse nach Faktoren für potenzielle Vergütungsprobleme, welche für eine Aufenthaltsdauer von ≥7 Tagen (p = 0,014) sowie für eine Behandlung auf Intensivstation (p = 0,019) signifikant verblieb.
Schlussfolgerung: Die stationären Versorgungskosten von Patienten mit Frakturen aufgrund epileptischer Anfälle sind hoch und daher gesundheitsökonomisch relevant. Generell scheint die auf Fallpauschalen basierende Vergütung nach G‑DRG die tatsächlichen Kosten zu decken, bei Patienten mit einer langen Liegedauer oder einen Aufenthalt auf Intensivstation können jedoch Vergütungsprobleme bestehen.
Purpose: The primary treatment goals for advanced-stage thumb carpometacarpal (CMC) joint osteoarthritis are complete pain relief and restoration of thumb strength. The purpose of the present study was to introduce a variation of the abductor pollicis longus (APL) suspension arthroplasty using a single looping of a radial slip from the APL tendon around the flexor carpi radialis (FCR) tendon combined with RegJoint™ interposition and to determine its efficacy in the treatment of thumb CMC joint osteoarthritis.
Methods: Between 2015 and 2017, 21 patients were included. The average age was 60.8 years (range 48–79). The mean follow-up was 27.7 months (range 8–50). Evaluation included pain, radial and palmar abduction, tip pinch and grip strength, and Disabilities of the Arm, Shoulder, and Hand (DASH) score.
Results: Pain averaged 0.3 (range 0–4) at rest and 1.4 (range 0–4) on exertion. The radial and palmar abduction were 97% and 99% compared to the contralateral side. The tip pinch and grip strength were 4.1 kg (range 3–6.5) and 22 kg (range 13.3–40), respectively. The DASH score accounted for 18.5 (range 0.8–41.7).
Conclusion: The modified APL suspension interposition arthroplasty was an efficient and simplified option for the treatment of thumb CMC joint osteoarthritis, with results comparable or better than other published procedures. The APL suspension technique was easy to perform avoiding difficult bone tunneling and incision of the FCR tendon. The RegJoint™ interposition as spacer prevented impingement of the first metacarpal base on the second metacarpal base or the trapezoid bone.
Developmental loss of ErbB4 in PV interneurons disrupts state-dependent cortical circuit dynamics
(2020)
GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal, development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.
Von A bis Å. (Fast) alles über die Frankfurter Skandinavistik. Ausgabe 1 ; Wintersemester 2020/21
(2020)
Waard, Antonius A. de ; Verkerk, Tamara ; Jongsma, Marlieke L. M. ; Hoefakker, Kelly ; Sethumadhavan, Sunesh ; Gerke, Carolin ; Bliss, Sophie ; Janssen, George M. C. ; Ru, Arnoud H. de ; Claas, Frans H. J. ; Mulder, Arend ; Tampé, Robert ; Veelen, Peter A. van ; Halenius, Anne ; Spaapen, Robbert M.
With the emergence of immunotherapies, the understanding of functional HLA class I antigen presentation to T cells is more relevant than ever. Current knowledge on antigen presentation is based on decades of research in a wide variety of cell types with varying antigen presentation machinery (APM) expression patterns, proteomes and HLA haplotypes. This diversity complicates the establishment of individual APM contributions to antigen generation, selection and presentation. Therefore, we generated a novel Panel of APM Knockout Cell lines (PAKC) from the same genetic origin. After CRISPR/Cas9 genome-editing of ten individual APM components in a human cell line, we derived clonal cell lines and confirmed their knockout status and phenotype. We then show how PAKC will accelerate research on the functional interplay between APM components and their role in antigen generation and presentation. This will lead to improved understanding of peptide-specific T cell responses in infection, cancer and autoimmunity.
Active efficient coding explains the development of binocular vision and its failure in amblyopia
(2020)
The development of vision during the first months of life is an active process that comprises the learning of appropriate neural representations and the learning of accurate eye movements. While it has long been suspected that the two learning processes are coupled, there is still no widely accepted theoretical framework describing this joint development. Here, we propose a computational model of the development of active binocular vision to fill this gap. The model is based on a formulation of the active efficient coding theory, which proposes that eye movements as well as stimulus encoding are jointly adapted to maximize the overall coding efficiency. Under healthy conditions, the model self-calibrates to perform accurate vergence and accommodation eye movements. It exploits disparity cues to deduce the direction of defocus, which leads to coordinated vergence and accommodation responses. In a simulated anisometropic case, where the refraction power of the two eyes differs, an amblyopia-like state develops in which the foveal region of one eye is suppressed due to inputs from the other eye. After correcting for refractive errors, the model can only reach healthy performance levels if receptive fields are still plastic, in line with findings on a critical period for binocular vision development. Overall, our model offers a unifying conceptual framework for understanding the development of binocular vision.
Salabura, Piotr ; Adamczewski-Musch, Jörn ; Arnoldi-Meadows, Benedict ; Belounnas, Amel ; Belyaev, Alexei V. ; Blanco, Alberto ; Blume, Christoph ; Böhmer, Michael ; Borisenko, S. ; Chlad, Lukáš ; Chudoba, Petr ; Ciepał, Izabela ; Dittert, Dominique ; Dreyer, Jörn ; Esmail, Waleed Ahmed Mohammed ; Dürr, Michael ; Fabbietti, Laura ; Fateev, Oleg ; Fonte, Paulo ; Friese, Jürgen ; Fröhlich, Ingo ; Förtsch, Jörg ; Galatyuk, Tetyana ; Gernhäuser, Roman ; Golosov, Oleg ; Golubeva, Marina ; Greifenhagen, Robert ; Guber, Fedor ; Gumberidze, Malgorzata ; Harabasz, Szymon ; Hensch, Roman ; Höhne, Claudia ; Holzmann, Romain ; Huck, Holger ; Ierusalimov, Alexander P. ; Ivashkin, Alexander ; Kämpfer, Burkhard ; Kampert, Karl-Heinz ; Kardan, Behruz ; Koenig, Ilse ; Koenig, Wolfgang ; Kornakov, Georgy ; Kornas, Frédéric Julian ; Kotte, Roland ; Kozela, Adam ; Kres, Ievgenii ; Kuboś, Joanna ; Kugler, Andrej ; Kulessa, Pawel ; Ladygin, Vladimir P. ; Lalik, Rafał Tomasz ; Lebedev, Alexei ; Lebedev, Semen ; Linev, Serguei ; Lopes, Luis Alberto Vieira ; Lorenz, Manuel ; Lykasov, Gennady ; Mahmoud, Tariq ; Malige, Akshay ; Markert, Jochen ; Matulewicz, Tomasz ; Maurus, Steffen ; Metag, Volker ; Michel, Jan ; Morozov, Sergey ; Müntz, Christian ; Naumann, Lothar ; Nowakowski, Krzysztof ; Otto, Jan-Hendrik ; Patel, Vivek ; Pauly, Christian ; Pechenov, Vladimir ; Pechenova, Olga ; Petukhov, Oleg ; Pfeifer, Dennis ; Piasecki, Krzysztof ; Pietraszko, Jerzy ; Prozorov, Alexandr ; Przygoda, Witold ; Pysz, Krzysztof ; Ramstein, Béatrice ; Rathod, Narendra ; Reshetin, Andrey ; Ritman, James Lambrecht ; Rodríguez Ramos, Pablo ; Rost, Adrian ; Salabura, Piotr ; Scozzi, Federico ; Seck, Florian ; Selyuzhenkov, Ilya ; Shabanov, I. ; Singh, Udai ; Smyrski, Jerzy ; Spies, Simon ; Ströbele, Herbert ; Stroth, Joachim ; Stumm, Julia ; Svoboda, Ondřej ; Szala, Melanie ; Tlustý, Pavel ; Traxler, Michael ; Ungethüm, Carina ; Vázquez Doce, Oton ; Wagner, Vladimir ; Weber, Adrian Amatus ; Wendisch, Christian ; Wiebusch, Michael ; Wintz, Peter ; Wirth, Joana ; Zhilin, Alexander ; Zumbruch, Peter W.
Radiative transition of an excited baryon to a nucleon with emission of a virtual massive photon converting to dielectron pair (Dalitz decays) provides important information about baryon-photon coupling at low q2 in timelike region. A prominent enhancement in the respective electromagnetic transition Form Factors (etFF) at q2 near vector mesons ρ/ω poles has been predicted by various calculations reflecting strong baryon-vector meson couplings. The understanding of these couplings is also of primary importance for the interpretation of the emissivity of QCD matter studied in heavy ion collisions via dilepton emission. Dedicated measurements of baryon Dalitz decays in proton-proton and pion-proton scattering with HADES detector at GSI/FAIR are presented and discussed. The relevance of these studies for the interpretation of results obtained from heavy ion reactions is elucidated on the example of the HADES results.
Korn, Sophie ; Dhamotharan, Karthikeyan ; Fürtig, Boris ; Hengesbach, Martin ; Löhr, Frank ; Qureshi, Nusrat ; Richter, Christian ; Saxena, Krishna ; Schwalbe, Harald ; Tants, Jan-Niklas ; Weigand, Julia ; Wöhnert, Jens ; Schlundt, Andreas
The ongoing pandemic caused by the Betacoronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) demonstrates the urgent need of coordinated and rapid research towards inhibitors of the COVID-19 lung disease. The covid19-nmr consortium seeks to support drug development by providing publicly accessible NMR data on the viral RNA elements and proteins. The SARS-CoV-2 genome encodes for approximately 30 proteins, among them are the 16 so-called non-structural proteins (Nsps) of the replication/transcription complex. The 217-kDa large Nsp3 spans one polypeptide chain, but comprises multiple independent, yet functionally related domains including the viral papain-like protease. The Nsp3e sub-moiety contains a putative nucleic acid-binding domain (NAB) with so far unknown function and consensus target sequences, which are conceived to be both viral and host RNAs and DNAs, as well as protein-protein interactions. Its NMR-suitable size renders it an attractive object to study, both for understanding the SARS-CoV-2 architecture and drugability besides the classical virus’ proteases. We here report the near-complete NMR backbone chemical shifts of the putative Nsp3e NAB that reveal the secondary structure and compactness of the domain, and provide a basis for NMR-based investigations towards understanding and interfering with RNA- and small-molecule-binding by Nsp3e.
Piekarski, Florian ; Kaufmann, Jost ; Engelhardt, Thomas ; Raimann, Florian ; Lustenberger, Thomas ; Marzi, Ingo ; Lefering, Rolf ; Zacharowski, Kai ; Meybohm, Patrick
Purpose: Trauma is the leading cause of death in children. In adults, blood transfusion and fluid resuscitation protocols changed resulting in a decrease of morbidity and mortality over the past 2 decades. Here, transfusion and fluid resuscitation practices were analysed in severe injured children in Germany.
Methods: Severely injured children (maximum Abbreviated Injury Scale (AIS) ≥ 3) admitted to a certified trauma-centre (TraumaZentrum DGU®) between 2002 and 2017 and registered at the TraumaRegister DGU® were included and assessed regarding blood transfusion rates and fluid therapy.
Results: 5,118 children (aged 1–15 years) with a mean ISS 22 were analysed. Blood transfusion rates administered until ICU admission decreased from 18% (2002–2005) to 7% (2014–2017). Children who are transfused are increasingly seriously injured. ISS has increased for transfused children aged 1–15 years (2002–2005: mean 27.7–34.4 in 2014–2017). ISS in non-transfused children has decreased in children aged 1–15 years (2002–2005: mean 19.6 to mean 17.6 in 2014–2017). Mean prehospital fluid administration decreased from 980 to 549 ml without affecting hemodynamic instability.
Conclusion: Blood transfusion rates and amount of fluid resuscitation decreased in severe injured children over a 16-year period in Germany. Restrictive blood transfusion and fluid management has become common practice in severe injured children. A prehospital restrictive fluid management strategy in severely injured children is not associated with a worsened hemodynamic state, abnormal coagulation or base excess but leads to higher hemoglobin levels.
Peronospora aquilegiicola is a destructive pathogen of columbines and has wiped out most Aquilegia cultivars in several private and public gardens throughout Britain. The pathogen, which is native to East Asia was noticed in England and Wales in 2013 and quickly spread through the country, probably by infested plants or seeds. To our knowledge, the pathogen has so far not been reported from other parts of Europe. Here, we report the emergence of the pathogen in the northwest of Germany, based on morphological and phylogenetic evidence. As the pathogen was found in a garden in which no new columbines had been planted recently, we assume that the pathogen has already spread from its original point of introduction in Germany. This calls for an increased attention to the further spread of the pathogen and the eradication of infection spots to avoid the spread to naturally occurring columbines in Germany and to prevent another downy mildew from becoming a global threat, like Peronospora belbahrii and Plasmopara destructor, the downy mildews of basil and balsamines, respectively.
Oomycetes infecting diatoms are biotrophic parasitoids and live in both marine and freshwater environments. They are ubiquitous, but the taxonomic affinity of many species remains unclear and the majority of them have not been studied for their molecular phylogeny. Only recently, the phylogenetic and taxonomic placement of some diatom-infecting, early-diverging oomycetes was resolved, including the genera Ectrogella, Miracula, Olpidiopsis, and Pontisma. A group of holocarpic diatom parasitoids with zoospores swarming within the sporangium before release were found to be unrelated to the known genera with diatom-infecting species, and were re-classified to a new genus, Diatomophthora. However, about a dozen species of holocarpic diatom parasitoids with unclear affinity remained unsequenced, which includes a commonly occurring species so far identified as Ectrogella perforans. However, this assignment to Ectrogella is doubtful, as the species was not reported to feature a clear-cut diplanetism, a hallmark of Ectrogella s. str. and the whole class Saprolegniomycetes. It was the aim of the current study to clarify the phylogenetic affinities of the species and if the rather broad host range reported is correct or a reflection of cryptic species. By targeted screening, the parasitoid was rediscovered from Helgoland Roads, North Sea and Oslo Fjord, Southern Norway and investigated for its phylogenetic placement using small ribosomal subunit (18S) sequences. Stages of its life cycle on different marine diatoms were described and its phylogenetic placement in the genus Diatomophthora revealed. A stable host-parasite axenic culture from single spore strains of the parasitoid were established on several strains of Pleurosigma intermedium and Coscinodiscus concinnus. These have been continuously cultivated along with their hosts for more than 2 years, and cultural characteristics are reported. Cross-infection trials revealed the transferability of the strains between hosts under laboratory conditions, despite some genetic distance between the pathogen strains. Thus, we hypothesise that D. perforans might be in the process of active radiation to new host species.
Geoffrey Burnstock will be remembered as the scientist who set up an entirely new field of intercellular communication, signaling via nucleotides. The signaling cascades involved in purinergic signaling include intracellular storage of nucleotides, nucleotide release, extracellular hydrolysis, and the effect of the released compounds or their hydrolysis products on target tissues via specific receptor systems. In this context ectonucleotidases play several roles. They inactivate released and physiologically active nucleotides, produce physiologically active hydrolysis products, and facilitate nucleoside recycling. This review briefly highlights the development of our knowledge of two types of enzymes involved in extracellular nucleotide hydrolysis and thus purinergic signaling, the ectonucleoside triphosphate diphosphohydrolases, and ecto-5′-nucleotidase.
Wenzel, Mike ; Humke, Clara Julia ; Wicker, Sabine ; Mani, Jens ; Engl, Tobias A. ; Hintereder, Gudrun ; Vogl, Thomas J. ; Wild, Peter Johannes ; Köllermann, Jens ; Rödel, Claus ; Asgharie, S. ; Theißen, Lena Hermine ; Welte, Maria-Noemi ; Kluth, Luis ; Mandel, Philipp ; Chun, Felix ; Preißer, Felix Martin ; Becker, Andreas
hintergrund: Männer in Deutschland sterben früher als Frauen und nehmen weniger häufig Krebsvorsorgeuntersuchungen wahr.
Fragestellung: Ziel war die prospektive Evaluation einer „Movember-Gesundheitsinitiative“ am Universitätsklinikum Frankfurt (UKF) im November 2019.
Methoden: Im Rahmen der „Movember-Gesundheitsinitiative“ wurde allen männlichen Mitarbeitern des UKF ab dem 45. Lebensjahr und bei erstgradiger familiärer Vorbelastung eines Prostatakarzinoms ab dem 40. Lebensjahr im November 2019 gemäß S3-Leitlinien der Deutschen Gesellschaft für Urologie (DGU) eine Prostatakarzinom-Vorsorgeuntersuchung angeboten.
Ergebnisse: Insgesamt nahmen 14,4 % der Mitarbeiter teil. Eine familiäre Vorbelastung gaben insgesamt 14,0 % Teilnehmer an. Das mediane Alter betrug 54 Jahre. Der mediane PSA(prostataspezifisches Antigen)-Wert lag bei 0,9 ng/ml, der mediane PSA-Quotient bei 30 %. Bei 5 % (n = 6) zeigte sich ein suspekter Tastbefund in der DRU (digital-rektale Untersuchung). Nach Altersstratifizierung (≤ 50 vs. > 50 Lebensjahre) zeigten sich signifikante Unterschiede im medianen PSA-Wert (0,7 ng/ml vs. 1,0 ng/ml, p < 0,01) und der bereits zuvor durchgeführten urologischen Vorsorge (12,1 vs. 42,0 %, p < 0,01). Vier Teilnehmer (3,3 %) zeigten erhöhte Gesamt-PSA-Werte. Bei 32,2 % der Teilnehmer zeigte sich mindestens ein kontrollbedürftiger Befund. Insgesamt wurden 6 Prostatabiopsien durchgeführt. Hierbei zeigte sich in einem Fall ein intermediate-risk Prostatakarzinom (Gleason 3 + 4, pT3a, pPn1, pNx, R0).
Schlussfolgerungung: Im Rahmen der UKF-Movember-Gesundheitsinitiative 2019 konnten durch ein Vorsorgeangebot 121 Männer für eine Prostatakrebs-Vorsorge inklusive PSA-Testung gewonnen werden. Auffällige/kontrollbedürftige Befunde zeigten sich bei 32,2 %. Bei einem Mitarbeiter wurde ein therapiebedürftiges Prostatakarzinom entdeckt und therapiert.
La creación de audio-podcasts ofrece una excelente oportunidad para representar de forma oral los contenidos de matemáticas usando medios digitales tanto en la formación docente, como en la educación primaria. Sin embargo, en el proceso de creación de los audio- -podcasts hay fases gráficas-escritas y otras orales que están estrechamente vinculadas entre sí. Este artículo trata sobre la creación y utilización de podcast en la educación primaria (PriMaPodcast) y en la formación docente (MathePodcast) tanto para la enseñanza como para la investigación.Mathematics audio-podcasts: communication and representation with ICTLa creación de audio-podcasts ofrece una excelente oportunidad para representar de forma oral los contenidos de matemáticas usando medios digitales tanto en la formación docente, como en la educación primaria. Sin embargo, en el proceso de creación de los audio- -podcasts hay fases gráficas-escritas y otras orales que están estrechamente vinculadas entre sí. Este artículo trata sobre la creación y utilización de podcast en la educación primaria (PriMaPodcast) y en la formación docente (MathePodcast) tanto para la enseñanza como para la investigación.
Frankfurt, Leonid ; Strikman, Mark ; Larionov, Alexei ; Lehrach, Andreas ; Maier, Rudolf ; Hees, Hendrik van ; Spieles, Christian ; Vovchenko, Volodymyr ; Stöcker, Horst
Exciting new scientific opportunities are presented for the PANDA detector at the High Energy Storage Ring in the redefined p¯¯¯p(A) collider mode, HESR-C, at the Facility for Antiproton and Ion Research (FAIR) in Europe. The high luminosity, L∼1031 cm−2 s−1, and a wide range of intermediate and high energies, sNN−−−√ up to 30 GeV for p¯¯¯p(A) collisions will allow to explore a wide range of exciting topics in QCD, including the study of the production of excited open charm and bottom states, nuclear bound states containing heavy (anti)quarks, the interplay of hard and soft physics in the dilepton production, probing short-range correlations in nuclei, and the exploration of the early, complete p¯¯¯-p- annihilation phase, where an initially pure Yang–Mills gluon plasma is formed.
Harth, Simon ; Wagner, Jacqueline ; Sens, Tamina ; Choe, Jun-yong ; Benz, Philipp ; Weuster-Botz, Dirk ; Oreb, Igor-Mislav
D-Galacturonic acid (GalA) is the major constituent of pectin-rich biomass, an abundant and underutilized agricultural byproduct. By one reductive step catalyzed by GalA reductases, GalA is converted to the polyhydroxy acid l-galactonate (GalOA), the first intermediate of the fungal GalA catabolic pathway, which also has interesting properties for potential applications as an additive to nutrients and cosmetics. Previous attempts to establish the production of GalOA or the full GalA catabolic pathway in Saccharomyces cerevisiae proved challenging, presumably due to the inefficient supply of NADPH, the preferred cofactor of GalA reductases. Here, we tested this hypothesis by coupling the reduction of GalA to the oxidation of the sugar alcohol sorbitol that has a higher reduction state compared to glucose and thereby yields the necessary redox cofactors. By choosing a suitable sorbitol dehydrogenase, we designed yeast strains in which the sorbitol metabolism yields a “surplus” of either NADPH or NADH. By biotransformation experiments in controlled bioreactors, we demonstrate a nearly complete conversion of consumed GalA into GalOA and a highly efficient utilization of the co-substrate sorbitol in providing NADPH. Furthermore, we performed structure-guided mutagenesis of GalA reductases to change their cofactor preference from NADPH towards NADH and demonstrated their functionality by the production of GalOA in combination with the NADH-yielding sorbitol metabolism. Moreover, the engineered enzymes enabled a doubling of GalOA yields when glucose was used as a co-substrate. This significantly expands the possibilities for metabolic engineering of GalOA production and valorization of pectin-rich biomass in general.
Mühlenfeld, Nils ; Schindler, Cora ; Sterz, Jasmina ; Thönissen, Philipp Nikolaus ; Störmann, Philipp ; Marzi, Ingo ; Verboket, René
Zuraw, Bruce L. ; Lumry, William R. ; Johnston, Douglas T. ; Aygören-Pürsün, Emel ; Banerji, Aleena ; Bernstein, Jonathan A. ; Christiansen, Sandra C. ; Jacobs, Joshua S. ; Sitz, Karl V. ; Gower, Richard G. ; Gagnon, Remi ; Wedner, H. James ; Kinaciyan, Tamar ; Hakl, Roman ; Hanzlíková, Jana ; Anderson, John T. ; McNeil, Donald L. ; Fritz, Stephen B. ; Yang, William H. ; Tachdjian, Raffi ; Busse, Paula J. ; Craig, Timothy J. ; Li, H. Henry ; Farkas, Henriette ; Best, Jessica M. ; Clemons, Desiree ; Cornpropst, Melanie ; Dobo, Sylvia M. ; Iocca, Heather A. ; Kargl, Deborah ; Nagy, Eniko ; Murray, Sharon C. ; Collis, Phil ; Sheridan, William P. ; Maurer, Marcus ; Riedl, Marc A.
Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.
Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).
Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.
Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.
Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
In welchen Situationen steht ein Tier unter Stress und wie beeinflusst Stress dessen Wohlbefinden? Dies sind die Kernfragen, mit denen Zoos konfrontiert sind, wenn es darum geht, den Bedürfnissen ihrer Tiere gerecht zu werden. Die Beantwortung dieser Fragen ist jedoch angesichts der großen individuellen Variabilität des Inputs, der Stress hervorrufen kann,und des Outputs, der das Wohlbefinden bestimmt, eine Herausforderung. Um diese Herausforderung zu meistern, brauchen Zoos Kenntnisse darüber, welche Haltungsbedingungen und Managementsituationen Verhaltens-, physiologische oder emotionale Veränderungen hervorrufen, sowohl positive als auch negative. Dies trifft insbesondere auf Arten zu, die aufgrund ihrer Biologie und des großen öffentlichen Interesses große Anforderungen an das Management in Menschenobhut stellen, wie den Afrikanischen Elefanten. Die vorliegende Arbeit hatte daher das Ziel, unter Berücksichtigung der individuellen Variation die Auswirkungen bestimmter Managementsituationen auf physiologischen Stress und das Wohlbefinden der Tiere zu evaluieren.
Für diese Arbeit wurden zehn Afrikanische Elefanten aus drei Zoos im Rahmen eines Experiments in 2016 und 2017 mehrmals untersucht. Dieses Experiment umfasste zum einen die Messung von physiologischem Stress auf der Basis der Konzentration des „Stresshormons“ Cortisol im Speichel der Elefanten. Zu diesem Zweck wurden an bestimmten Tagen und zu folgenden Zeitpunkten Speichelproben entnommen: morgens, nachmittags vor und mehrmals nach einer von zwei Managementsituationen (positives Verstärkungstraining [PRT] und neuartiges Enrichmentobjekt [NOV]). Zum anderen diente die Exposition gegenüber dem neuartigen Enrichmentobjekt als sogenannter Novel Object Test. Dieser Standardtest der Persönlichkeitsforschung bei Tieren deckte bei anderen Arten konsistente Verhaltensunterschiede zwischen Individuen auf. Um zu untersuchen, ob dies auch auf Afrikanische Elefanten zutrifft, wurden die individuellen Verhaltensreaktionen auf das neuartige Objekt aufgezeichnet. Darüber hinaus wurden unabhängig von dem Experiment vor und nach einem Transport jeweils morgens und nachmittags Speichelproben von dem transferierten Tier und von zwei Tieren im Bestimmungszoo gesammelt, um den Effekt dieses potenziellen Stressors auf die individuellen Cortisolspiegel zu untersuchen.
Publikation A zeigt, dass die Elefanten unter den Bedingungen des Routinemanagements (das heißt dem routinemäßigen Tagesablauf der Tierpflege) am Morgen signifikant höhere Cortisolwerte im Speichel aufwiesen als am Nachmittag. Diese diurnale Variation der Cortisolsekretion ist typisch für tagaktive Arten und wurde daher auch für die untersuchten Elefanten erwartet. Unter Stressbedingungen wurde weder ein signifikanter Unterschied zwischen den Cortisolspiegeln vor und nach dem Transport noch zwischen den Cortisolwerten am Morgen und am Nachmittag festgestellt. Der prozentuale Unterschied zwischen dem morgendlichen und nachmittäglichen Cortisolspiegel war jedoch beim transferierten Tier nach dem Transport wesentlich geringer als vor dem Transport, was möglicherweise auf eine Stressreaktion auf den Transport und die Eingewöhnung im neuen Zoo hindeutet. Darüber hinaus zeigten sich deutliche Cortisolanstiege unmittelbar nach der ersten Zusammenführung des transferierten Tiers mit dem Bullen im neuen Zoo. Dieses Ergebnis demonstriert zum einen, dass Cortisol physiologischen Stress widerspiegelt. Zum anderen zeigt es die Notwendigkeit, zeitnah nach einem Stressor Speichelproben zu entnehmen, was nach dem Transport nicht möglich war.
Die Studie in Manuskript B zeigt unterschiedliche durchschnittliche Zeitverläufe der Cortisolantworten im Speichel auf die Managementsituationen PRT und NOV. PRT könnte aufgrund des beobachteten cortisolsenkenden und damit potenziell stresspuffernden Effekts förderlich für das Wohlbefinden sein. NOV induzierte im Mittel eine moderate, kurzfristige Cortisolantwort. Dies deutet darauf hin, dass die Tiere geringem physiologischem Stress ausgesetzt waren, mit dem sie jedoch erfolgreich umgehen konnten. Außerdem bestand eine bemerkenswerte individuelle Variation in den Cortisolverläufen in derselben Situation. Die Unterschiede im Cortisolspiegel zwischen den Tieren hingen mit dem Alter (bei NOV) und dem Zoo (bei PRT) zusammen. Der Effekt des Geschlechts und des Haltungssystems auf den Cortisolspiegel war hingegen variabel. Die Ergebnisse der Studie zeigen, dass die individuelle Variation der Cortisolsekretion unbedingt berücksichtigt werden muss, um physiologischen Stress zuverlässig zu erkennen.
Die Studie in Manuskript C ergab, dass sich die untersuchten Tiere im Novel Object Test konsistent in ihrem Verhalten gegenüber einem neuartigen Objekt unterschieden. Dieses Ergebnis zeigt, dass der Novel Object Test auch bei Elefanten genutzt werden kann, um die Persönlichkeit der Tiere zu untersuchen...
Barbagallo, Massimo ; Aberle, Oliver ; Alcayne, Victor ; Amaducci, Simone ; Andrzejewski, Józef ; Audouin, Laurent ; Babiano Suarez, Victor ; Bacak, Michael ; Bennett, Samuel ; Berthoumieux, Eric ; Bosnar, Damir ; Brown, Adam S. ; Busso, Maurizio ; Caamaño, Manuel ; Caballero Ontanaya, Luis ; Calviani, Marco ; Calviño Tavares, Francisco ; Cano-Ott, Daniel ; Casanovas Hoste, Adrià ; Cerutti, Francesco ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Cristallo, Sergio ; Damone, Lucia Anna ; Davies, Paul John ; Diakaki, Maria ; Dietz, Mirco ; Domingo-Pardo, César ; Dressler, Rugard ; Ducasse, Quentin ; Dupont, Emmeric ; Durán, Ignacio ; Eleme, Zinovia ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Gonçalves, Isabel Maria Ferro ; Finocchiaro, Paolo ; Furman, Valter ; Garg, Ruchi ; Gawlik, Aleksandra ; Gilardoni, Simone ; Göbel, Kathrin ; González Romero, Enrique Miguel ; Guerrero Sánchez, Carlos ; Gunsing, Frank ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Jericha, Erwin ; Jiri, U. ; Junghans, Arnd Rudolf ; Kadi, Yacine ; Käppeler, Franz ; Kimura, Atsushi ; Knapová, Ingrid ; Kokkoris, Michael ; Kopatch, Yuri N. ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Ladarescu, Ion ; Lederer-Woods, Claudia ; Lerendegui-Marco, Jorge ; Lonsdale, Sarah-Jane ; Macina, Daniela ; Manna, Alice ; Martı́nez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Michalopoulou, Veatriki ; Milazzo, Paolo Maria ; Millán Callado, María de los Ángeles ; Mingrone, Federica ; Moreno-Soto, Javier ; Musumarra, Agatino ; Negret, Alexandru ; Ogállar Ruiz, Francisco ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Petrone, Cristina ; Piersanti, Luciano ; Pirovano, Elisa ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Ramos Doval, Diego ; Reifarth, René ; Rochman, Dimitri ; Rubbia, Carlo ; Sabaté- Gilarte, M. ; Saxena, Alok ; Schillebeeckx, Peter ; Schumann, Dorothea ; Sekhar, Adhitya ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Sprung, Peter ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tarifeño-Saldivia, Ariel ; Tassan-Got, Laurent ; Thomas, Benedikt ; Torres-Sánchez, Pablo ; Tsinganis, Andrea ; Urlaß, Sebastian ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vescovi, Diego ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Woods, Philip John ; Wright, Tobias J. ; Žugec, Petar
Although the 12C(n,p)12B and 12C(n,d)11B reactions are of interest in several fields of basic and applied Nuclear Physics the present knowledge of these two cross-sections is far from being accurate and reliable, with both evaluations and data showing sizable discrepancies. As part of the challenging n_TOF program on (n,cp) nuclear reactions study, the energy differential cross-sections of the 12C(n,p)12B and 12C(n,d)11 B reactions have been measured at CERN from the reaction thresholds up to 30 MeV neutron energy. Both measurements have been recently performed at the long flight-path (185 m) experimental area of the n_TOF facility at CERN using a pure (99.95%) rigid graphite target and two silicon telescopes. In this paper an overview of the experiment is presented together with a few preliminary results.
Babiano Suarez, Victor ; Lerendegui-Marco, Jorge ; Balibrea Correa, Javier ; Caballero Ontanaya, Luis ; Calvo, David ; Ladarescu, Ion ; Domingo-Pardo, César ; Calviño Tavares, Francisco ; Casanovas Hoste, Adrià ; Tarifeño-Saldivia, Ariel ; Alcayne, Victor ; Guerrero Sánchez, Carlos ; Millán Callado, María de los Ángeles ; Rodrı́guez-González, María Teresa ; Barbagallo, Massimo ; Aberle, Oliver ; Amaducci, Simone ; Andrzejewski, Józef ; Audouin, Laurent ; Bacak, Michael ; Bennett, Samuel ; Berthoumieux, Eric ; Billowes, Jonathan ; Bosnar, Damir ; Brown, Adam ; Busso, Maurizio ; Caamaño, Manuel ; Calviani, Marco ; Cano-Ott, Daniel ; Cerutti, Francesco ; Chiaveri, Enrico ; Colonna, Nicola ; Cortés Rossell, Guillem Pere ; Cortés-Giraldo, Miguel Antonio ; Cosentino, Luigi ; Cristallo, Sergio ; Damone, Lucia Anna ; Davies, Paul John ; Diakaki, Maria ; Dietz, Mirco ; Dressler, Rugard ; Ducasse, Quentin ; Dupont, Emmeric ; Durán, Ignacio ; Eleme, Zinovia ; Fernández Domínguez, Beatriz ; Ferrari, Alfredo ; Finocchiaro, Paolo ; Furman, Valter ; Göbel, Kathrin ; Garg, Ruchi ; Gawlik, Aleksandra ; Gilardoni, Simone ; Gonçalves, Isabel Maria Ferro ; González Romero, Enrique Miguel ; Gunsing, Frank ; Harada, Hideo ; Heinitz, Stephan ; Heyse, Jan ; Jenkins, David ; Junghans, Arnd Rudolf ; Käppeler, Franz ; Kadi, Yacine ; Kimura, Atsushi ; Knapova, Ingrid ; Kokkoris, Michael ; Kopatch, Yuri N. ; Krtička, Milan ; Kurtulgil, Cem Deniz ; Lederer-Woods, Claudia ; Leeb, Helmut ; Lonsdale, Sarah Jane ; Macina, Daniela ; Manna, Alice ; Martinez, Trinitario ; Masi, Alessandro ; Massimi, Cristian ; Mastinu, Pierfrancesco ; Mastromarco, Mario ; Maugeri, Emilio Andrea ; Mazzone, Annamaria ; Mendoza Cembranos, Emilio ; Mengoni, Alberto ; Michalopoulou, Veatriki ; Milazzo, Paolo Maria ; Mingrone, Federica ; Moreno-Soto, Javier ; Musumarra, Agatino ; Negret, Alexandru ; Ogállar Ruiz, Francisco ; Oprea, Andreea ; Patronis, Nikolas ; Pavlik, Andreas ; Perkowski, Jarosław ; Piersanti, Luciano ; Petrone, Cristina ; Pirovano, Elisa ; Porras Sánchez, José Ignacio ; Praena, Javier ; Quesada Molina, José Manuel ; Ramos Doval, Diego ; Rauscher, Thomas ; Reifarth, René ; Rochman, Dimitri ; Rubbia, Carlo ; Sabaté-Gilarte, Marta ; Saxena, Alok ; Schillebeeckx, Peter ; Schumann, Dorothea ; Sekhar, Adhitya ; Smith, Alastair Gavin ; Sosnin, Nikolay V. ; Sprung, Peter ; Stamatopoulos, Athanasios ; Tagliente, Giuseppe ; Taı́n Enríquez, José Luis ; Tassan-Got, Laurent ; Thomas, Th. ; Torres-Sánchez, Pablo ; Tsinganis, Andrea ; Ulrich, Jiri ; Urlaß, Sebastian ; Valenta, Stanislav ; Vannini, Gianni ; Variale, Vincenzo ; Vaz, Pedro ; Ventura, Alberto ; Vescovi, Diego ; Vlachoudis, Vasilis ; Vlastou, Rosa ; Wallner, Anton ; Woods, Philip John ; Wright, Tobias ; Žugec, Petar
i-TED is an innovative detection system which exploits Compton imaging techniques to achieve a superior signal-to-background ratio in (n,γ) cross-section measurements using time-of-flight technique. This work presents the first experimental validation of the i-TED apparatus for high-resolution time-of-flight experiments and demonstrates for the first time the concept proposed for background rejection. To this aim both 197Au(n,γ) and 56Fe(n,γ) reactions were measured at CERN n\_TOF using an i-TED demonstrator based on only three position-sensitive detectors. Two \cds detectors were also used to benchmark the performance of i-TED. The i-TED prototype built for this study shows a factor of ∼3 higher detection sensitivity than state-of-the-art \cds detectors in the ∼10~keV neutron energy range of astrophysical interest. This paper explores also the perspectives of further enhancement in performance attainable with the final i-TED array consisting of twenty position-sensitive detectors and new analysis methodologies based on Machine-Learning techniques.
Malkomes, Patrizia ; Edmaier, Franziska ; Liese, Juliane ; Reinisch-Liese, Alexander ; Youzouri, Hanan el ; Schreckenbach, Teresa ; Bucher, Andreas M. ; Bechstein, Wolf Otto ; Schnitzbauer, Andreas
Purpose: The management of patients with suspected appendicitis remains a challenge in daily clinical practice, and the optimal management algorithm is still being debated. Negative appendectomy rates (NAR) continue to range between 10 and 15%. This prospective study evaluated the accuracy of a diagnostic pathway in acute appendicitis using clinical risk stratification (Alvarado score), routine ultrasonography, gynecology consult for females, and selected CT after clinical reassessment.
Methods: Patients presenting with suspected appendicitis between November 2015 and September 2017 from age 18 years and above were included. Decision-making followed a clear management pathway. Patients were followed up for 6 months after discharge. The hypothesis was that the algorithm can reduce the NAR to a value of under 10%.
Results: A total of 183 patients were included. In 65 of 69 appendectomies, acute appendicitis was confirmed by histopathology, corresponding to a NAR of 5.8%. Notably, all 4 NAR appendectomies had other pathologies of the appendix. The perforation rate was 24.6%. Only 36 patients (19.7%) received a CT scan. The follow-up rate after 30 days achieved 69%, including no patients with missed appendicitis. The sensitivity and specificity of the diagnostic pathway was 100% and 96.6%, respectively. The potential saving in costs can be as much as 19.8 million €/100,000 cases presenting with the suspicion of appendicitis.
Conclusion: The risk-stratified diagnostic algorithm yields a high diagnostic accuracy for patients with suspicion of appendicitis. Its implementation can safely reduce the NAR, simultaneously minimizing the use of CT scans and optimizing healthcare-related costs in the treatment of acute appendicitis.
We have designed and implemented an experimental module in the 2014 Health and Retirement Study to measure older persons' willingness to defer claiming of Social Security benefits. Under the current system’ status quo where delaying claiming boosts eventual benefits, we show that 46% of the respondents would delay claiming and work longer. If respondents were instead offered an actuarially fair lump sum payment instead of higher lifelong benefits, about 56% indicate they would delay claiming. Without a work requirement, the average amount needed to induce delayed claiming is only $60,400, while when part-time work is stipulated, the amount is slightly higher, $66,700. This small difference implies a low utility value of leisure foregone, of under 20% of average household income.
The modern tontine : an innovative instrument for longevity risk management in an aging society
(2020)
We investigate whether a historical pension concept, the tontine, yields enough innovative potential to extend and improve the prevailing privately funded pension solutions in a modern way. The tontine basically generates an age-increasing cash flow, which can help to match the increasing financing needs at old ages. In contrast to traditional pension products, however, the tontine generates volatile cash flows, which means that the insurance character of the tontine cannot be guaranteed in every situation. By employing Multi Cumulative Prospect Theory (MCPT) we answer the question to what extent tontines can be a complement to or a substitute for traditional annuities. We find that it is only optimal to invest in tontines for a certain range of initial wealth. In addition, we investigate in how far the tontine size, the volatility of individual liquidity needs and expected mortality rates contribute to the demand for tontines.
Seiler, Alexander ; Brandhofe, Annemarie ; Gracien, René-Maxime ; Pfeilschifter, Waltraud ; Hattingen, Elke ; Deichmann, Ralf ; Nöth, Ulrike ; Wagner, Marlies
Purpose: To investigate cortical thickness and cortical quantitative T2 values as imaging markers of microstructural tissue damage in patients with unilateral high-grade internal carotid artery occlusive disease (ICAOD).
Methods: A total of 22 patients with ≥70% stenosis (mean age 64.8 years) and 20 older healthy control subjects (mean age 70.8 years) underwent structural magnetic resonance imaging (MRI) and high-resolution quantitative (q)T2 mapping. Generalized linear mixed models (GLMM) controlling for age and white matter lesion volume were employed to investigate the effect of ICAOD on imaging parameters of cortical microstructural integrity in multivariate analyses.
Results: There was a significant main effect (p < 0.05) of the group (patients/controls) on both cortical thickness and cortical qT2 values with cortical thinning and increased cortical qT2 in patients compared to controls, irrespective of the hemisphere. The presence of upstream carotid stenosis had a significant main effect on cortical qT2 values (p = 0.01) leading to increased qT2 in the poststenotic hemisphere, which was not found for cortical thickness. The GLMM showed that in general cortical thickness was decreased and cortical qT2 values were increased with increasing age (p < 0.05).
Conclusion: Unilateral high-grade carotid occlusive disease is associated with widespread cortical thinning and prolongation of cortical qT2, presumably reflecting hypoperfusion-related microstructural cortical damage similar to accelerated aging of the cerebral cortex. Cortical thinning and increase of cortical qT2 seem to reflect different aspects and different pathophysiological states of cortical degeneration. Quantitative T2 mapping might be a sensitive imaging biomarker for early cortical microstructural damage.
Determination of the effective dose of bone marrow mononuclear cell therapy for bone healing in vivo
(2020)
Janko, Maren Carina ; Pöllinger, Sabrina ; Schaible, Alexander ; Bellen, Marlene ; Schröder, Katrin ; Heilani, Myriam Widad ; Fremdling, Charlotte ; Marzi, Ingo ; Nau, Christoph Heinrich Eugen ; Henrich, Dirk ; Verboket, René
Introduction: Cell-based therapy by bone marrow mononuclear cells (BMC) in a large-sized bone defect has already shown improved vascularization and new bone formation. First clinical trials are already being conducted. BMC were isolated from bone marrow aspirate and given back to patients in combination with a scaffold within some hours. However, the optimal concentration of BMC has not yet been determined for bone healing. With this study, we want to determine the optimal dosage of the BMC in the bone defect to support bone healing.
Material and methods: Scaffolds with increasing BMC concentrations were inserted into a 5 mm femoral defect, cell concentrations of 2 × 106 BMC/mL, 1 × 107 BMC/mL and 2 × 107 BMC/mL were used. Based on the initial cell number used to colonize the scaffolds, the groups are designated 1 × 106, 5 × 106 and 1 × 107 group. Bone healing was assessed biomechanically, radiologically (µCT), and histologically after 8 weeks healing time.
Results: Improved bone healing parameters were noted in the 1 × 106 and 5 × 106 BMC groups. A significantly higher BMD was observed in the 1 × 106 BMC group compared to the other groups. Histologically, a significantly increased bone growth in the defect area was observed in group 5 × 106 BMC. This finding could be supported radiologically.
Conclusion: It was shown that the effective dose of BMC for bone defect healing ranges from 2 × 106 BMC/mL to 1 × 107 BMC/mL. This concentration range seems to be the therapeutic window for BMC-supported therapy of large bone defects. However, further studies are necessary to clarify the exact BMC-dose dependent mechanisms of bone defect healing and to determine the therapeutically effective range more precisely.
The Brachybasidiaceae are a family of 22 known species of plant-parasitic microfungi belonging to Exobasidiales, Basidiomycota. Within this family, species of the largest genus Kordyana develop balls of basidia on top of stomatal openings. Basidial cells originate from fungal stroma filling substomatal chambers. Species of Kordyana typically infect species of Commelinaceae. During fieldwork in the neotropics, fungi morphologically similar to Kordyana spp. were found on Goeppertia spp. (syn. Calathea spp., Marantaceae), namely on G. panamensis in Panama and on G. propinqua in Bolivia. These specimens are proposed as representatives of a genus new to science, Marantokordyana, based on the distinct host family and molecular sequence data of ITS and LSU rDNA regions. The specimens on the two host species represent two species new to science, M. oberwinkleriana on G. panamensis and M. boliviana on G. propinqua. They differ by the size and shape of their basidia, molecular sequence data of ITS and LSU rDNA regions, and host plant species. In the past, the understanding of Brachybasidiaceae at order and family level was significantly improved by investigation realized by Franz Oberwinkler and his collaborators at the University of Tübingen, Germany. On species level, however, our knowledge is still very poor due to incomplete species descriptions of several existing names in literature, scarceness of specimens, as well as sequence data lacking for many taxa and for further barcode regions. Especially species of Kordyana and species of Dicellomyces are in need of revision.
Sreeramulu, Sridhar ; Richter, Christian ; Kühn, Till ; Azzaoui, Kamal ; Blommers, Marcel Jules José ; Del Conte, Rebecca ; Fragai, Marco ; Trieloff, Nils ; Schmieder, Peter ; Nazaré, Marc ; Specker, Edgar ; Ivanov, Vladimir ; Oschkinat, Hartmut ; Banci, Lucia ; Schwalbe, Harald
Fragment-based screening has evolved as a remarkable approach within the drug discovery process both in the industry and academia. Fragment screening has become a more structure-based approach to inhibitor development, but also towards development of pathway-specific clinical probes. However, it is often witnessed that the availability, immediate and long-term, of a high quality fragment-screening library is still beyond the reach of most academic laboratories. Within iNEXT (Infrastructure for NMR, EM and X-rays for Translational research), a EU-funded Horizon 2020 program, a collection of 782 fragments were assembled utilizing the concept of “poised fragments” with the aim to facilitate downstream synthesis of ligands with high affinity by fragment ligation. Herein, we describe the analytical procedure to assess the quality of this purchased and assembled fragment library by NMR spectroscopy. This quality assessment requires buffer solubility screening, comparison with LC/MS quality control and is supported by state-of-the-art software for high throughput data acquisition and on-the-fly data analysis. Results from the analysis of the library are presented as a prototype of fragment progression through the quality control process.
Schiweck, Carmen ; Claes, Stephan ; Oudenhove, Lukas van ; Lafit, Ginette ; Vaessen, Thomas ; Beeck, Gommaar op de ; Berghmans, Raf ; Wijkhuijs, Annemarie ; Müller, Norbert ; Arolt, Volker ; Drexhage, Hemmo ; Vrieze, Elske
Circulating monocytes contribute to inflammatory processes. We here validate abnormal expression of inflammation-related genes in monocytes of a large and well-characterised group of MDD patients, and relate the outcomes to pertinent clinical characteristics. Thirty-two genes of a previously established inflammation-related gene signature were assessed in 197 patients with MDD, and 151 controls collected during the EU-MOODINFLAME project. Monocyte gene- expression data were related to age, sex, BMI, depression severity, childhood adversity (CA) and suicide risk (SR). Three distinct gene profiles were identified within the MDD group (downregulated, mixed upregulated and strongly upregulated genes). Patients in the merged upregulated groups had a significantly higher prevalence of CA and high SR. Using hierarchical clustering of the genes, we found a cluster of mainly cytokine (production)-related genes; patients with SR had a significantly higher expression of this cluster than patients without SR (particularly for IL-6, IL1A and IL1B). Such difference did not emerge for patients with and without CA. A downregulated gene profile was found for patients not exposed to CA and without SR (particularly for glucocorticoid-signalling genes NR3C1a and HSPA1/B). No inflammatory changes were observed for healthy controls exposed to CA. Our data show that inflammatory activation in MDD is not uniform, and that immunologically discernible phenotypes of depression can be linked to CA and high SR. The absence of monocyte inflammatory activation in healthy controls exposed to CA suggests an inflammatory involvement in MDD-prone individuals exposed to early stressors, but not healthy controls.
Wölke, Sandra ; Donath, Helena ; Theis, Marius ; Kieslich, Matthias ; Auburger, Georg ; Schubert, Ralf ; Schrewe, Roland ; Zielen, Stefan ; Dücker, Ruth Pia
Ataxia telangiectasia (A-T) is a devastating multi-system disorder characterized by progressive cerebellar ataxia and immunodeficiency. The neurological decline may be caused by multiple factors of which ongoing inflammation and oxidative stress may play a dominant role. The objective of the present investigation was to determine cerebrospinal fluid (CSF) proteins and possible low-grade inflammation and its relation to age and neurological deterioration. In the present study, we investigated 15 patients with A-T from 2 to 16 years. Our investigation included blood and CSF tests, clinical neurological examination, A-T score, and MRI findings. The albumin ratio (AR) was analyzed to determine the blood–brain-barrier function. In addition, inflammatory cytokines (IL-1α, IL-6, IL-8, IL-12 p40, IL-17A, IFN-γ, TNF-α) were measured by the multiplex cytometric bead array. We compared the results with those from an age-matched control group. Three of the A-T patients were analyzed separately (one after resection of a cerebral meningioma, one after radiation and chemotherapy due to leukemia, one after stem cell transplantation). Patient had significantly more moderate and severe side effects due to CSF puncture (vomiting, headache, need for anti-emetic drugs) compared with healthy controls. Total protein, albumin, and the AR increased with age indicating a disturbed blood barrier function in older children. There were no differences for cytokines in serum and CSF with the exception of IL-2, which was significantly higher in controls in serum. The AR is significantly altered in A-T patients, but low-grade inflammation is not detectable in serum and CSF.
Batarfi, AbdulAziz ; Alenezi, Haitham ; Alshehri, Abdulrahman ; Balelah, Saud ; Kazim, Hameedullah ; Algthami, Mohammed ; Hussain, Mariam M. ; Alshehri, Nada ; Alsharif, Rahaf ; Ashour, Hadeel ; Althobaiti, Mutaz ; Alotaibi, Shomokh ; Steinmetz, Helmuth ; Förch, Christian
Fasting Ramadan is known to influence patients’ medication adherence. Data on patients’ behavior to oral anticoagulant (OAC) drug intake during Ramadan is missing. We aimed to determine patient-guided modifications of OAC medication regimen during Ramadan and to evaluate its consequences. A multicenter cross-sectional study conducted in Saudi Arabia. Data were collected shortly after Ramadan 2019. Participants were patients who fasted Ramadan and who were on long-term anticoagulation. Patient-guided medication changes during Ramadan in comparison to the regular intake schedule before Ramadan were recorded. Modification behavior was compared between twice daily (BID) and once daily (QD) treatment regimens. Rates of hospital admission during Ramadan were determined. We included 808 patients. During Ramadan, 53.1% modified their intake schedule (31.1% adjusted intake time, 13.2% skipped intakes, 2.2% took double dosing). A higher frequency of patient-guided modification was observed in patients on BID regimen compared to QD regimen. During Ramadan, 11.3% of patients were admitted to hospital. Patient-guided modification was a strong predictor for hospital admission. Patient-guided modification of OAC intake during Ramadan is common, particularly in patients on BID regimen. It increases the risk of hospital admission during Ramadan. Planning of OAC intake during Ramadan and patient education on the risk of low adherence are advisable.
Frey, Katharina ; Zöllner, Johann Philipp ; Knake, Susanne ; Oganian, Yulia ; Kay, Lara ; Mahr, Katharina Brigitte ; Keil, Fee ; Willems, Laurent Maximilian ; Menzler, Katja ; Bauer, Sebastian ; Schubert-Bast, Susanne ; Rosenow, Felix ; Strzelczyk, Adam
Objective: To evaluate the incidence and risk factors of generalized convulsive seizure (GCS)-related fractures and injuries during video-EEG monitoring.
Methods: We analyzed all GCSs in patients undergoing video-EEG-monitoring between 2007 and 2019 at epilepsy centers in Frankfurt and Marburg in relation to injuries, falls and accidents associated with GCSs. Data were gathered using video material, EEG material, and a standardized reporting form.
Results: A total of 626 GCSs from 411 patients (mean age: 33.6 years; range 3–74 years; 45.0% female) were analyzed. Severe adverse events (SAEs) such as fractures, joint luxation, corneal erosion, and teeth loosening were observed in 13 patients resulting in a risk of 2.1% per GCS (95% CI 1.2–3.4%) and 3.2% per patient (95% CI 1.8–5.2%). Except for a nasal fracture due to a fall onto the face, no SAEs were caused by falls, and all occurred in patients lying in bed without evidence of external trauma. In seven patients, vertebral body compression fractures were confirmed by imaging. This resulted in a risk of 1.1% per GCS (95% CI 0.5–2.2%) and 1.7% per patient (95% CI 0.8–3.3%). These fractures occurred within the tonic phase of a GCS and were accompanied by a characteristic cracking noise. All affected patients reported back pain spontaneously, and an increase in pain on percussion of the affected spine section.
Conclusions: GCSs are associated with a substantial risk of fractures and shoulder dislocations that are not associated with falls. GCSs accompanied by audible cracking, and resulting in back pain, should prompt clinical and imaging evaluations.