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Aim: The primary aim of this study was to analyze frequency and characteristics of combined facial and peripheral trauma with consecutive hospitalization and treatment.
Materials and methods: The study included all patients with concomitant orthopedic-traumatolgical (OT) and craniomaxillofacial (CMF) injuries admitted to our level I trauma center in 2018. The data were collected by analysis of the institution’s database and radiological reviews and included age, sex, injury type, weekday and time of presentation. All patients were examined and treated by a team of surgeons specialized in OT and CMF directly after presentation.
Results: A total number of 1040 combined OT and CMF patients were identified. Mean age was 33.0 ± 26.2 years. 67.3% (n = 700) were male patients. Primary presentation happened most frequently on Sundays (n = 199) and between 7 and 8 pm (n = 74). 193 OT fractures were documented, where cervical spine injuries were most frequent (n = 30). 365 facial and skull fractures were recorded. 10.8% of the 204 patients with fractures of the viscerocranium presented with at least one fracture of the extremity, 7.8% (16/204) with cervical spine fractures, 33.3% (68/204) with signs of closed brain trauma and 9.8% (20/204) with intracranial hemorrhage.
Discussion: The study shows a high frequency of combined facial with OT-injuries and brain damage in a predominantly young and male cohort. Attendance by interdisciplinary teams of both CMF and OT surgeons specialized in cervical spine trauma surgery is highly advisable for adequate treatment.
Conclusion: Diagnostics and treatment should be performed by a highly specialized OT and CMF team, with a consulting neurosurgeon in a level-1 trauma center to avoid missed diagnoses and keep mortality low.
Successful consolidation of associative memories relies on the coordinated interplay of slow oscillations and sleep spindles during non-rapid eye movement (NREM) sleep. This enables the transfer of labile information from the hippocampus to permanent memory stores in the neocortex. During senescence, the decline of the structural and functional integrity of the hippocampus and neocortical regions is paralleled by changes of the physiological events that stabilize and enhance associative memories during NREM sleep. However, the currently available evidence is inconclusive as to whether and under which circumstances memory consolidation is impacted during aging. To approach this question, 30 younger adults (19–28 years) and 36 older adults (63–74 years) completed a memory task based on scene–word associations. By tracing the encoding quality of participants’ individual memory associations, we demonstrate that previous learning determines the extent of age-related impairments in memory consolidation. Specifically, the detrimental effects of aging on memory maintenance were greatest for mnemonic contents of intermediate encoding quality, whereas memory gain of poorly encoded memories did not differ by age. Ambulatory polysomnography (PSG) and structural magnetic resonance imaging (MRI) data were acquired to extract potential predictors of memory consolidation from each participant’s NREM sleep physiology and brain structure. Partial Least Squares Correlation was used to identify profiles of interdependent alterations in sleep physiology and brain structure that are characteristic for increasing age. Across age groups, both the ‘aged’ sleep profile, defined by decreased slow-wave activity (0.5–4.5 Hz), and a reduced presence of slow oscillations (0.5–1 Hz), slow, and fast spindles (9–12.5 Hz; 12.5–16 Hz), as well as the ‘aged’ brain structure profile, characterized by gray matter reductions in the medial prefrontal cortex, thalamus, entorhinal cortex, and hippocampus, were associated with reduced memory maintenance. However, inter-individual differences in neither sleep nor structural brain integrity alone qualified as the driving force behind age differences in sleep-dependent consolidation in the present study. Our results underscore the need for novel and age-fair analytic tools to provide a mechanistic understanding of age differences in memory consolidation.
Flat Panel CT Pooled Blood Volume-Mappen vor mechanischer Rekanalisation beim akuten Schlaganfall
(2020)
In der Akutdiagnostik des Schlaganfalles sind die Multislice Computertomographie (MSCT) sowie gegebenenfalls die Kernspintomographie die radiologischen Methoden der Wahl zunächst zur Differenzierung eines ischämischen oder hämorrhagischen Geschehens sowie im Falle einer Ischämie zur Darstellung des Gefäßverschlusses und der Perfusionssituation. Mit Hilfe von Flat Panel Detektoren (flat panel detector computed tomography (FDCT)) in Angiographie-Einheiten konnten zunächst Schnittbilder des Kopfes ähnlich denen einer konventionellen MSCT angefertigt werden, womit ein Blutungsausschluss möglich ist. Des Weiteren wurden sogenannte „Pooled Blood Volume“ (PBV)-Karten entwickelt, welche konzipiert wurden, um das Areal mit vermindertem zerebralem Blutvolumen (cerebral blood volume = CBV) und somit annäherungsweise den Infarktkern darzustellen.
Innerhalb der letzten 10 Jahre hat sich die mechanische Rekanalisation als Therapie des akuten Verschlusses proximaler zerebraler Arterien durchgesetzt. Häufig müssen Patienten für die Intervention aus peripheren Krankenhäusern in Schlaganfall-Zentren verlegt werden, sodass eine Aktualisierung der zerebralen Perfusionsparameter zur Darstellung der Progression der Ischämie und zur Prognose-Abschätzung erstrebenswert ist. Gäbe es die Möglichkeit einer solchen Bildgebung innerhalb der Angiographie- und Interventions-Einheit, so könnte wertvolle Zeit, welche sonst für den innerklinischen Transport, Umlagerung des Patienten etc. benötigt wird, eingespart werden. Auch bei schwer betroffenen Patienten, welche direkt in das jeweilige Schlaganfall-Zentrum eingeliefert werden, könnte somit die Zeit zwischen Ankunft in der Klinik bis zur Gefäß-Rekanalisation bedeutsam verkürzt werden.
In der vorliegenden Studie wurde die Zuverlässigkeit der PBV-Karten hinsichtlich der Abschätzung des späteren Infarktareales untersucht. Hierfür wurden bei 29 aufeinanderfolgenden Patienten mit akuten intrakraniellen Verschlüssen der Arteria carotis interna oder Arteria cerebri media das präinterventionelle Volumen der in den Quellbildern der PBV-Karten dargestellten Minderperfusion mit dem finalen Infarktvolumen, wie es sich in den postinterventionellen konventionellen MSCT-Kontrollen darstellte, verglichen. Außerdem wurde durch Bestimmung der Hounsfield-Einheiten die Stärke der Minderperfusion in dem Areal der PBV-Veränderung gemessen und mit der gesunden Gegenseite verglichen. Die mechanische Rekanalisation war bei 26 der Patienten erfolgreich.
Insgesamt war das mediane präinterventionelle PBV-Defizit 9-mal größer als das mediane finale Infarktvolumen (86,4 ml (10,3; 111,6) versus 9,6 ml (3,6; 36,8)). Dieses Ergebnis basierte insbesondere auf der Subgruppe der erfolgreich rekanalisierten Patienten (PBV Defizit: 87,5 ml (10,6; 115,1), finales Infarktvolumen: 8,7 ml (3,6; 29)). Im Falle einer frustranen Intervention wurde das finale Infarktvolumen eher unterschätzt (PBV Defizit: 86,4 ml (5,9; -), finales Infarktvolumen: 116,4 ml (3,5; -)). Es gab keinen signifikanten Unterschied zwischen der HU Ratio im Bereich des später infarzierten Gewebes (0,45 (0,29; 0,51)) und der umgebenden minderperfundierten „Penumbra“ (0,4 (0,33; 0,5)) (p=0,679). Die HU Ratio zeigte eine signifikante negative Korrelation mit dem Volumen der PBV-Läsion (r= -0,448, p= 0,008).
Zusammenfassend wurde aus den Ergebnissen dieser Studie geschlossen, dass die FDCT PBV-Karten nicht zuverlässig das finale Infarktvolumen prognostizieren und daher keinen Einfluss auf die akute Therapieentscheidung haben sollten. Ursächlich sind technische und methodische Limitationen sowie die Art des untersuchten Perfusionsparameters.
Background: Experienced and anticipated regret influence physicians’ decision-making. In medicine, diagnostic decisions and diagnostic errors can have a severe impact on both patients and physicians. Little empirical research exists on regret experienced by physicians when they make diagnostic decisions in primary care that later prove inappropriate or incorrect. The aim of this study was to explore the experience of regret following diagnostic decisions in primary care.
Methods: In this qualitative study, we used an online questionnaire on a sample of German primary care physicians. We asked participants to report on cases in which the final diagnosis differed from their original opinion, and in which treatment was at the very least delayed, possibly resulting in harm to the patient. We asked about original and final diagnoses, illness trajectories, and the reactions of other physicians, patients and relatives. We used thematic analysis to assess the data, supported by MAXQDA 11 and Microsoft Excel 2016.
Results: 29 GPs described one case each (14 female/15 male patients, aged 1.5–80 years, response rate < 1%). In 26 of 29 cases, the final diagnosis was more serious than the original diagnosis. In two cases, the diagnoses were equally serious, and in one case less serious. Clinical trajectories and the reactions of patients and relatives differed widely. Although only one third of cases involved preventable harm to patients, the vast majority (27 of 29) of physicians expressed deep feelings of regret.
Conclusion: Even if harm to patients is unavoidable, regret following diagnostic decisions can be devastating for clinicians, making them ‘second victims’. Procedures and tools are needed to analyse cases involving undesirable diagnostic events, so that ‘true’ diagnostic errors, in which harm could have been prevented, can be distinguished from others. Further studies should also explore how physicians can be supported in dealing with such events in order to prevent them from practicing defensive medicine.
Background Polypharmacy interventions are resource-intensive and should be targeted to those at risk of negative health outcomes. Our aim was to develop and internally validate prognostic models to predict health-related quality of life (HRQoL) and the combined outcome of falls, hospitalisation, institutionalisation and nursing care needs, in older patients with multimorbidity and polypharmacy in general practices.
Methods Design: two independent data sets, one comprising health insurance claims data (n=592 456), the other data from the PRIoritising MUltimedication in Multimorbidity (PRIMUM) cluster randomised controlled trial (n=502). Population: ≥60 years, ≥5 drugs, ≥3 chronic diseases, excluding dementia. Outcomes: combined outcome of falls, hospitalisation, institutionalisation and nursing care needs (after 6, 9 and 24 months) (claims data); and HRQoL (after 6 and 9 months) (trial data). Predictor variables in both data sets: age, sex, morbidity-related variables (disease count), medication-related variables (European Union-Potentially Inappropriate Medication list (EU-PIM list)) and health service utilisation. Predictor variables exclusively in trial data: additional socio-demographics, morbidity-related variables (Cumulative Illness Rating Scale, depression), Medication Appropriateness Index (MAI), lifestyle, functional status and HRQoL (EuroQol EQ-5D-3L). Analysis: mixed regression models, combined with stepwise variable selection, 10-fold cross validation and sensitivity analyses.
Results Most important predictors of EQ-5D-3L at 6 months in best model (Nagelkerke’s R² 0.507) were depressive symptoms (−2.73 (95% CI: −3.56 to −1.91)), MAI (−0.39 (95% CI: −0.7 to −0.08)), baseline EQ-5D-3L (0.55 (95% CI: 0.47 to 0.64)). Models based on claims data and those predicting long-term outcomes based on both data sets produced low R² values. In claims data-based model with highest explanatory power (R²=0.16), previous falls/fall-related injuries, previous hospitalisations, age, number of involved physicians and disease count were most important predictor variables.
Conclusions Best trial data-based model predicted HRQoL after 6 months well and included parameters of well-being not found in claims. Performance of claims data-based models and models predicting long-term outcomes was relatively weak. For generalisability, future studies should refit models by considering parameters representing well-being and functional status.
Genetic code expansion facilitates position-selective modification of nucleic acids and proteins
(2020)
Transcription and translation obey to the genetic code of four nucleobases and 21 amino acids evolved over billions of years. Both these processes have been engineered to facilitate the use of non-natural building blocks in both nucleic acids and proteins, enabling researchers with a decent toolbox for structural and functional analyses. Here, we review the most common approaches for how labeling of both nucleic acids as well as proteins in a site-selective fashion with either modifiable building blocks or spectroscopic probes can be facilitated by genetic code expansion. We emphasize methodological approaches and how these can be adapted for specific modifications, both during as well as after biomolecule synthesis. These modifications can facilitate, for example, a number of different spectroscopic analysis techniques and can under specific circumstances even be used in combination.
Es ist schon merkwürdig: Für keines der großen Konzilien des Spätmittelalters schien in den letzten Jahren eine Gesamtdarstellung so nah wie im Fall des Pisanum. Dieter Girgensohn und Hélenè Millet legten eine Fülle von Einzelstudien vor, doch keiner der beiden goss sie in die Form eines opus magnum, sieht man von einem Aufsatzband der französischen Kollegin ab. Durch Mona Kirsch erfuhr die Synode 2016 eine zwar viele Facetten erfassende Würdigung im Rahmen einer ritualgeschichtlich grundierten Geschichte des allgemeinen Konzils im Spätmittelalter, zu der für sie aber die auf Pisa folgenden und damit eng verbundenen Versammlungen von Konstanz und Basel nicht gehörten. Und nun erklärt Florian Eßer gleich mehrfach, bei seinem hier anzuzeigenden, immerhin 874-seitigen Werk handele es sich keinesfalls um eine Gesamtdarstellung. Was die Frage aufwirft, wer angesichts einer solch zerklüfteten Landschaft partieller Monumente das finale Wagnis überhaupt noch angehen mag.
Am ehesten wohl Florian Eßer selbst, der eine auf umfassender Kenntnis der ungedruckten wie gedruckten Quellen beruhende und die gesamte Forschung zum Thema rezipierende Studie vorgelegt hat, die weniger als Dissertation – die sie ist – denn fast schon als Habilitationsschrift gelten darf. Nur wünscht man sich und ihm, dass er sich künftig in der Kunst des Kürzens und Streichens übt. Denn hier wird viel in der Sache wohlgemerkt Treffendes derart breit bis in die feinsten Einzelheiten und Verästelungen ausgeführt, ja ausgewalzt, dass dem Autor am Ende dabei offensichtlich selbst nicht mehr so recht wohl war, widmet er sein Opus doch Freundin, Eltern und Freunden, "auch wenn (beziehungsweise weil) sie es vermutlich nie lesen werden" (S. 14). ...
Stabilization exercise (SE) is evident for the management of chronic non-specific low back pain (LBP). The optimal dose-response-relationship for the utmost treatment success is, thus, still unknown. The purpose is to systematically review the dose-response-relationship of stabilisation exercises on pain and disability in patients with chronic non-specific LBP. A systematic review with meta-regression was conducted (Pubmed, Web of Knowledge, Cochrane). Eligibility criteria were RCTs on patients with chronic non-specific LBP, written in English/German and adopting a longitudinal core-specific/stabilising/motor control exercise intervention with at least one outcome for pain intensity and/or disability. Meta-regressions (dependent variable = effect sizes (Cohens d) of the interventions (for pain and for disability), independent variable = training characteristics (duration, frequency, time per session)), and controlled for (low) study quality (PEDro) and (low) sample sizes (n) were conducted to reveal the optimal dose required for therapy success. From the 3,415 studies initially selected, 50 studies (n = 2,786 LBP patients) were included. N = 1,239 patients received SE. Training duration was 7.0 ± 3.3 weeks, training frequency was 3.1 ± 1.8 sessions per week with a mean training time of 44.6 ± 18.0 min per session. The meta-regressions’ mean effect size was d = 1.80 (pain) and d = 1.70 (disability). Total R2 was 0.445 and 0.17. Moderate quality evidence (R2 = 0.231) revealed that a training duration of 20 to 30 min elicited the largest effect (both in pain and disability, logarithmic association). Low quality evidence (R2 = 0.125) revealed that training 3 to 5 times per week led to the largest effect of SE in patients with chronic non-specific LBP (inverted U-shaped association). In patients with non-specific chronic LBP, stabilization exercise with a training frequency of 3 to 5 times per week (Grade C) and a training time of 20 to 30 min per session (Grade A) elicited the largest effect on pain and disability.
Primary determinants of communities in deadwood vary among taxa but are regionally consistent
(2020)
The evolutionary split between gymnosperms and angiosperms has far‐reaching implications for the current communities colonizing trees. The inherent characteristics of dead wood include its role as a spatially scattered habitat of plant tissue, transient in time. Thus, local assemblages in deadwood forming a food web in a necrobiome should be affected not only by dispersal ability but also by host tree identity, the decay stage and local abiotic conditions. However, experiments simultaneously manipulating these potential community drivers in deadwood are lacking. To disentangle the importance of spatial distance and microclimate, as well as host identity and decay stage as drivers of local assemblages, we conducted two consecutive experiments, a 2‐tree species and 6‐tree species experiment with 80 and 72 tree logs, respectively, located in canopy openings and under closed canopies of a montane and a lowland forest. We sampled saproxylic beetles, spiders, fungi and bacterial assemblages from logs. Variation partitioning for community metrics based on a unified framework of Hill numbers showed consistent results for both studies: host identity was most important for sporocarp‐detected fungal assemblages, decay stage and host tree for DNA‐detected fungal assemblages, microclimate and decay stage for beetles and spiders and decay stage for bacteria. Spatial distance was of minor importance for most taxa but showed the strongest effects for arthropods. The contrasting patterns among the taxa highlight the need for multi‐taxon analyses in identifying the importance of abiotic and biotic drivers of community composition. Moreover, the consistent finding of microclimate as the primary driver for saproxylic beetles compared to host identity shows, for the first time that existing evolutionary host adaptions can be outcompeted by local climate conditions in deadwood.
There is limited knowledge on the prevalence and risk factors of diabetic retinopathy (DR) in dialysis patients. We have investigated the association between diabetes mellitus and lipid-related biomarkers and retinopathy in hemodialysis patients. We reviewed 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) who participated in the German Diabetes and Dialysis Study (4D Study). Associations between categorical clinical, biochemical variables and diabetic retinopathy were examined by logistic regression. On average, patients were 66 ± 8 years of age, 54% were male and the HbA1c was 6.7% ± 1.3%. DR, found in 71% of the patients, was significantly and positively associated with fasting glucose, HbA1c, time on dialysis, age, systolic blood pressure, body mass index and the prevalence of other microvascular diseases (e.g. neuropathy). Unexpectedly, DR was associated with high HDL cholesterol and high apolipoproteins AI and AII. Patients with coronary artery disease were less likely to have DR. DR was not associated with gender, smoking, diastolic blood pressure, VLDL cholesterol, triglycerides, and LDL cholesterol. In summary, the prevalence of DR in patients with type 2 diabetes mellitus requiring hemodialysis is higher than in patients suffering from T2DM, who do not receive hemodialysis. DR was positively related to systolic blood pressure (BP), glucometabolic control, and, paradoxically, HDL cholesterol. This data suggests that glucose and blood pressure control may delay the development of DR in patients with diabetes mellitus on dialysis.
Autologous chimeric antigen receptor-modified (CAR) T cells with specificity for CD19 showed potent antitumor efficacy in clinical trials against relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). Contrary to T cells, natural killer (NK) cells kill their targets in a non-antigen-specific manner and do not carry the risk of inducing graft vs. host disease (GvHD), allowing application of donor-derived cells in an allogenic setting. Hence, unlike autologous CAR-T cells, therapeutic CD19-CAR-NK cells can be generated as an off-the-shelf product from healthy donors. Nevertheless, genetic engineering of peripheral blood (PB) derived NK cells remains challenging and optimized protocols are needed. In our study, we aimed to optimize the generation of CD19-CAR-NK cells by retroviral transduction to improve the high antileukemic capacity of NK cells. We compared two different retroviral vector platforms, the lentiviral and alpharetroviral, both in combination with two different transduction enhancers (Retronectin and Vectofusin-1). We further explored different NK cell isolation techniques (NK cell enrichment and CD3/CD19 depletion) to identify the most efficacious methods for genetic engineering of NK cells. Our results demonstrated that transduction of NK cells with RD114-TR pseudotyped retroviral vectors, in combination with Vectofusin-1 was the most efficient method to generate CD19-CAR-NK cells. Retronectin was potent in enhancing lentiviral/VSV-G gene delivery to NK cells but not alpharetroviral/RD114-TR. Furthermore, the Vectofusin-based transduction of NK cells with CD19-CARs delivered by alpharetroviral/RD114-TR and lentiviral/RD114-TR vectors outperformed lentiviral/VSV-G vectors. The final generated CD19-CAR-NK cells displayed superior cytotoxic activity against CD19-expressing target cells when compared to non-transduced NK cells achieving up to 90% specific killing activity. In summary, our findings present the use of RD114-TR pseudotyped retroviral particles in combination with Vectofusin-1 as a successful strategy to genetically modify PB-derived NK cells to achieve highly cytotoxic CD19-CAR-NK cells at high yield.
Im Verlauf einer Erkundungsexpedition des britischen Militärs in Ägypten wurde 1917 in der Westwüste zwischen der Oase Dachla und dem Gilf Kebir an der Grenze zu Libyen und dem Sudan von dem mitreisenden britischen Geologen und Geographen Jon Ball am Fuße einer von zwei weithin sichtbaren Geländeerhebungen aus Sandstein eine größere Anzahl von Gefäßen bzw. Gefäßresten aus Ton entdeckt. Ball bezeichnete die nördliche der beiden Erhebungen mit einer Höhe von ca. 39 m der vielen Gefäßfunde wegen als Pottery Hill. Die heutige Bezeichnung ist der arabische Name Abu Ballas. Die Entfernung zur Oase Dachla beträgt etwa 200 km. Die Geländeerhebungen waren zunächst nur als geographische Fixpunkte in der sonst ebenen Wüste von Interesse. ...
Multicentre comparison of quantitative PCR-based assays to detect SARS-CoV-2, Germany, March 2020
(2020)
Containment strategies and clinical management of coronavirus disease (COVID-19) patients during the current pandemic depend on reliable diagnostic PCR assays for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we compare 11 different RT-PCR test systems used in seven diagnostic laboratories in Germany in March 2020. While most assays performed well, we identified detection problems in a commonly used assay that may have resulted in false-negative test results during the first weeks of the pandemic.
Congenital diaphragmatic hernia (CDH) is a relatively common and life-threatening birth defect, characterized by incomplete formation of the diaphragm. Because CDH herniation occurs at the same time as preacinar airway branching, normal lung development becomes severely disrupted, resulting almost invariably in pulmonary hypoplasia. Despite various research efforts over the past decades, the pathogenesis of CDH and associated lung hypoplasia remains poorly understood. With the advent of molecular techniques, transgenic animal models of CDH have generated a large number of candidate genes, thus providing a novel basis for future research and treatment. This review article offers a comprehensive overview of genes and signaling pathways implicated in CDH etiology, whilst also discussing strengths and limitations of transgenic animal models in relation to the human condition.
In the last two decades, new unpredicted charmonium-like states with extraordinary characteristics have been observed experimentally. These states also known as the XYZ states, e.g., the Y(4260) or the X(3872), are mostly interpreted as QCD allowed exotic hadrons. One of the leading hadron physics experiments in the world, the Beijing Electron Spectrometer III (BESIII) at the Beijing Electron-Positron Collider II (BEPCII) is aiming towards revealing the internal structure of these states. It has brought numerous breakthrough discoveries including the discovery of the charged Zc(3900). In order to understand the nature of the Y(4260) state and its decay patterns, an inclusive analysis is performed for different recoil systems (π+π−,K+K− and K±π∓) using the BESIII data samples for center of mass energies above 4 GeV collected between 2013 and 2019. The aim of this analysis is twofold: on one hand, we search for new unobserved charmonium-like decay channels using the missing mass technique and on the other hand, it provides an accurate inclusive cross section measurement for e+e−→X π+π−, with the X being the J/ψ, hc and ψ(2S), respectively. Two resonant structures, the Y(4220) and the Y(4390), are observed in the inclusive energy dependent Born cross section of e+e−→hc π+π−, which is consistent with the BESIII exclusive measurements. Moreover, the energy dependent cross section of e+e−→J/ψ π+π− is investigated, in which two resonances have consistently been observed with the previous BESIII exclusive studies, namely, the Y(4220) and the Y(4320). In the (K±π±) recoil system, possible Y(4260) open charm decay channels are investigated. Two enhancements are observed in the inclusive energy dependent cross section of e+e−→DD above 4.13GeV, which could possibly be the ψ(4160)and the ψ(4415).
A large number of chemicals are constantly introduced to surface water from anthropogenic and natural sources. Although substantial efforts have been made to identify these chemicals (e.g potentially anthropogenic contaminants) in surface waters using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS), a large number of LC-HRMS chemical signals often with high peak intensity are left unidentified. In addition to synthetic chemicals and transformation products, these signals may also represent plant secondary metabolites (PSMs) released from vegetation through various pathways such as leaching, surface run-off and rain sewers or input of litter from vegetation. While this may be considered as a confounding factor in screening of water contaminants, it could also contribute to the cumulative toxic risk of water contamination. However, it is hardly known to what extent these metabolites contribute to the chemical mixture of surface waters. Thus, reducing the number of unknowns in water samples by identifying also PSMs in significant concentrations in surface waters will help to improve monitoring and assessment of water quality potentially impacted by complex mixtures of natural and synthetic compounds. Therefore, the main focus of the present study was to identify the occurrence of PSMs in river waters and explore the link between the presence of vegetation along rivers and detection of their corresponding PSMs in river
water.
In order to achieve the goals of the present thesis, two chemical screening approaches, namely, non-target and target screening using LC-HRMS were implemented. (1) Non-target analysis involving a novel approach has been applied to associate unknown peaks of high intensity in LC-HRMS to PSMs from surrounding vegetation by focusing on peaks overlapping between river water and aqueous plant extracts (Annex A1). (2) LC–HRMS target screening in river waters were performed for about 160 PSMs, which were selected from a large phytotoxin database (Annex A2 and A3) considering their expected abundance in the vegetation, their potential mobility, persistence and toxicity in the water cycle and commercial availability of standards.
In non-target screening (Annex A1), a high number of overlapping peaks has been found in between aqueous plant extracts and water from adjacent location, suggesting a significant impact of vegetation on chemical mixtures detectable in river waters. The chemical structures were assigned for 12 pairs of peaks while several pairs of peaks
whose MS/MS spectra matched but no structure suggestion were made by the implemented software tools for retrieving possible chemical structure. Nevertheless, the pairs of peaks with matching spectra represented the same chemical structure. The identified compound belonged to different compound classes such as coumarins, flavonoids besides others. For the identified PSMs individual concentration up to 5 µg/L were measured. The concentration and the number of detected PSMs per sample were correlated with the rain event and vegetation coverage.
Target screening unraveled the occurrence of 33 out of 160 target compounds in river waters (Annex A2 and A3). The identified compounds belonged to different classes such as alkaloids, coumarins, flavonoids, and other compounds. Individual compound concentrations were up to several thousand ng/L with the toxic alkaloids narciclasine and
lycorine recording highest maximum concentrations. The neurotoxic alkaloid coniine from poison hemlock was detected at concentrations up to 0.4 µg/L while simple coumarins
esculetin and fraxidin occurred at concentrations above 1 µg/L. The occurrence of some PSMs in river water were correlated to the specific vegetation growing along the rivers while the others were linked to a wide range of vegetation. As an example, narciclasine and lycorine was emitted by the dominant plant species from Amaryllidaceae family (e.g. Galanthus nivalis (snow drop), Leucojum vernum and Anemone nemorosa) while intermedine and echimidine were from Symphytum officinale. The ubiquitous occurrence of simple coumarins fraxidin, scopoletin and aesculetin could be linked to their presence in a wide range of vegetation.
Due to lack of aquatic toxicity data for the identified PSMs (in both target and non-target) and extremely scarce exposure data, no reliable risk assessment was possible.
Alternatively, risk estimation was performed using the threshold for toxicological concern (TTC) concept developed for drinking water contaminants. Many of the identified PSMs
exceeded the TTC value (0.1 µg/L) thus caution should be taken when using such surface waters for drinking water abstraction or recreational use.
This thesis provides an overview of the occurrence of PSMs in river water impacted by the massive presence of vegetation. Concentration for many of the identified PSMs are well within the range of those of synthetic environmental contaminants. Thus, this study adds to a series of recent results suggesting that possibly toxic PSMs occur in relevant concentrations in European surface waters and should be considered in monitoring and risk assessment of water resources. Aquatic toxicity data for PSMs are extensively lacking but are required to include these compounds in the assessment of risks to aquatic organisms and for eliminating risks to human health during drinking water production.
O presente texto apresenta uma reflexão sobre a educação dos sentidos a partir do estudo das obras “A indústria cultural” de Theodor W. Adorno e “A obra de arte na era de sua reprodutibilidade técnica” de Walter Benjamin. Primeiramente apresentamos uma breve contextualização histórica sobre o período no qual se desenvolveram os referentes textos. Em seguida buscamos demonstrar através do pensamento de Walter Benjamin como a arte passou a educar os sentidos das classes trabalhadoras a partir da sua reprodutibilidade técnica. Nas considerações finais, apontamos a importância da leitura de ambas as obras para possíveis reflexões acerca da formação do discurso nas tomadas de decisão social e cultural na atualidade. Como também buscamos compreender a função política da arte na formação crítica do sujeito.
Particulate autogenous tooth roots are used for alveolar bone augmentation surgery; however, dental plaque may provoke an inflammatory response that may counteract the desired graft consolidation process. Traditional mechanical cleaning of extracted teeth may be of support to lower a possible inflammatory response of the autograft. To test this assumption, extracted porcine teeth were left either uncleaned or underwent mechanical cleaning with a toothbrush and toothpaste before being fragmented and subjected to acid lysis, termed as unclean acid dentine lysate (ucADL) and clean acid dentine lysate (cADL), respectively. The inflammatory responses of murine macrophage RAW 264.7 cells being exposed to the respective acid dentine lysates were evaluated at the level of inflammatory gene expression and IL6 immunoassays. We report here that acid lysates obtained from uncleaned teeth provoked a robust increase in IL1β, IL6, and COX2 in RAW 264.7 cells. The mechanical removal of dental plaque significantly reduced the inflammatory response. Consistently, Limulus tests revealed that tooth cleaning lowers the presence of endotoxins in dentine lysates. To further prove the involvement of endotoxins, a toll-like receptor 4 (TLR4) inhibitor TAK242 was introduced. TAK242 abolished the inflammatory response provoked by acid lysates obtained from uncleaned teeth in RAW 264.7 cells. Moreover, nuclear translocation and phosphorylation of the TLR4 downstream NFκB-p65 were attenuated at the presence of cleaned versus uncleaned dentine lysates. Taken together, our data support the importance of dental plaque removal of teeth being extracted for alveolar bone augmentation surgery.
An overexpression of the E3 ubiquitin ligase TRIM25 is implicated in several human cancers and frequently correlates with a poor prognosis and occurrence of therapy resistance in patients. Previous studies of our group have identified the mRNA encoding the pro-apoptotic caspase-2 as a direct target of the ubiquitous RNA binding protein human antigen R (HuR). The constitutive HuR binding observed in colon carcinoma cells negatively interferes with the translation of caspase-2 mainly through binding to the 5' untranslated region (UTR) of caspase-2 and thereby confers an increased survival of tumor cells. The main objective of this thesis was to unravel novel regulatory proteins critically involved in the control of caspase-2 translation and their impact on therapeutic drug resistance of human colon carcinoma cells. By employing RNA affinity chromatography in combination with mass-spectrometry, among several putative caspase-2 mRNA binding proteins, we have identified the tripartite motif-containing protein 25 (TRIM25) as novel caspase-2 translation regulatory protein in colon carcinoma cells. The constitutive TRIM25 binding to caspase-2 mRNA in two different human colorectal carcinoma cell lines was validated by ribonucleoprotein (RNP)-immunoprecipitation (RIP)-RT-PCR assay and by means of biotin-labeled RNA-pull-down assay. Since caspase-2 is a caspase which is particularly involved in the DNA-damage-induced apoptosis, I tested the functional relevance of negative caspase-2 regulation by TRIM25 for chemotherapeutic drug-induced cell death of different adenocarcinoma cells by RNA interference (RNAi)- mediated loss-of-function and gain-of-function approaches. In the first part of the thesis, I could demonstrate that transient silencing of TRIM25 caused a significant increase in caspase-2 protein levels without affecting the amount of corresponding mRNAs. Mechanistically, the TRIM25 silencing-triggered increase in caspase-2 was totally impaired by cycloheximide, indicating that the stimulatory effects on caspase-2 levels depend on protein synthesis. This finding was corroborated by RNP/polysomal fractionation, which revealed that the transient knockdown of TRIM25 caused a significant redistribution of caspase-2 transcripts from the fraction of RNP particles to that from translationally active polyribosomes.
The second part of my thesis aimed at the elucidation of the functional consequences of the negative caspase-2 regulation by TRIM25 for enhanced tumor cell survival. Thereby, I found that the siRNA-mediated knockdown of TRIM25 caused a significant increase in the chemotherapeutic drug-induced cleavage of caspase-3 and to elevations in cytoplasmic cytochrome c levels implicating that TRIM25 depletion did mainly affect the intrinsic apoptotic pathway. Concordantly, the ectopic expression of TRIM25 caused a reduction in caspase-2 protein levels, concomitant with an attenuated sensitivity of tumor cells to doxorubicin.
To test the functional impact of caspase-2 in the TRIM25 depletion-dependent sensitization to drug-induced apoptosis, I employed a siRNA-mediated knockdown of caspase-2. Interestingly, the strong induction of caspase-3 and -7 cleavage after doxorubicin treatment was fully impaired after the additional knockdown of caspase-2, indicating the sensitizing effects by TRIM25 knockdown depend on caspase-2.
Data from this thesis identified the TRIM25 as a novel RNA-binding protein of caspase-2 mRNA, which negatively interferes with the translation of caspase-2 and which functionally contributes to chemotherapeutic drug resistance of colon carcinoma cells. Interfering with the negative TRIM25-caspase-2 axis may represent a promising therapeutic avenue for sensitizing colorectal cancers to conventional anti-tumor therapies.
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.
Characterization of neonates born to mothers with SARS-CoV-2 infection: review and meta-analysis
(2020)
Characterization of neonates born to mothers with SARS-CoV-2 infection has been partially carried out. There has been no systematic review providing a holistic neonatal presentation including possible vertical transmission. A systematic literature search was performed using PubMed, Google Scholar and Web of Science up to June, 6 2020. Studies on neonates born to mothers with SARS-CoV-2 infection were included. A binary random effect model was used for prevalence and 95% confidence interval. 32 studies involving 261 neonates were included in meta-analysis. Most neonates born to infected mothers did not show any clinical abnormalities (80.4%). Clinical features were dyspnea in 11 (42.3%) and fever in 9 newborns (19.1%). Of 261 neonates, 120 neonates were tested for infection, of whom 12 (10.0%) tested positive. Swabs from placenta, cord blood and vaginal secretion were negative. Neonates are mostly non affected by the mother's SARS-CoV-2 infection. The risk of vertical transmission is low.
Background: Approximately one in three patients suffers from preoperative anaemia. Even though haemoglobin is measured before surgery, anaemia management is not implemented in every hospital. Objective: Here, we demonstrate the implementation of an anaemia walk-in clinic at an Orthopedic University Hospital. To improve the diagnosis of iron deficiency (ID), we examined whether reticulocyte haemoglobin (Ret-He) could be a useful additional parameter. Material and Methods: In August 2019, an anaemia walk-in clinic was established. Between September and December 2019, major orthopaedic surgical patients were screened for preoperative anaemia. The primary endpoint was the incidence of preoperative anaemia. Secondary endpoints included Ret-He level, red blood cell (RBC) transfusion rate, in-hospital length of stay and anaemia at hospital discharge. Results: A total of 104 patients were screened for anaemia. Preoperative anaemia rate was 20.6%. Intravenous iron was supplemented in 23 patients. Transfusion of RBC units per patient (1.7 ± 1.2 vs. 0.2 ± 0.9; p = 0.004) and hospital length of stay (13.1 ± 4.8 days vs. 10.6 ± 5.1 days; p = 0.068) was increased in anaemic patients compared to non-anaemic patients. Ret-He values were significantly lower in patients with ID anaemia (33.3 pg [28.6–40.2 pg]) compared to patients with ID (35.3 pg [28.9–38.6 pg]; p = 0.015) or patients without anaemia (35.4 pg [30.2–39.4 pg]; p = 0.001). Conclusion: Preoperative anaemia is common in orthopaedic patients. Our results proved the feasibility of an anaemia walk-in clinic to manage preoperative anaemia. Furthermore, our analysis supports the use of Ret-He as an additional parameter for the diagnosis of ID in surgical patients.
Background: The gut microbiome can influence life history traits associated with host fitness such as fecundity and longevity. In most organisms, these two life history traits are traded-off, while they are positively linked in social insects. In ants, highly fecund queens can live for decades, while their non-reproducing workers exhibit much shorter lifespans. Yet, when fertility is induced in workers by death or removal of the queen, worker lifespan can increase. It is unclear how this positive link between fecundity and longevity is achieved and what role the gut microbiome and the immune system play in this. To gain insights into the molecular regulation of lifespan in social insects, we investigated fat body gene expression and gut microbiome composition in workers of the ant Temnothorax rugatulus in response to an experimental induction of fertility and an immune challenge.
Results: Fertile workers upregulated several molecular repair mechanisms, which could explain their extended lifespan. The immune challenge altered the expression of several thousand genes in the fat body, including many immune genes, and, interestingly, this transcriptomic response depended on worker fertility. For example, only fertile, immune-challenged workers upregulated genes involved in the synthesis of alpha-ketoglutarate, an immune system regulator, which extends the lifespan in Caenorhabditis elegans by down-regulating the TOR pathway and reducing oxidant production. Additionally, we observed a dramatic loss in bacterial diversity in the guts of the ants within a day of the immune challenge. Yet, bacterial density did not change, so that the gut microbiomes of many immune challenged workers consisted of only a single or a few bacterial strains. Moreover, the expression of immune genes was linked to the gut microbiome composition, suggesting that the ant host can regulate the microbiome in its gut.
Conclusions: Immune system flare-ups can have negative consequence on gut microbiome diversity, pointing to a previously underrated cost of immunity. Moreover, our results provide important insights into shifts in the molecular regulation of fertility and longevity associated with insect sociality.
Die Therapie langstreckiger Knochendefekte stellt auch weiterhin eine große Herausforderung dar. Dies beruht unter anderem darauf, dass der therapeutische Goldstandard - die Verwendung von autogener Knochensubstanz aus dem Beckenkamm - neben der begrenzten Verfügbarkeit vor allem Komplikationen im Bereich der Entnahmestelle mit sich bringen kann. Es wurde bisher aber noch kein durchschlagendes Ergebnis in der Entwicklung neuer Scaffolds zum Einsatz bei langstreckigen Knochendefekten erreicht. Dies kann eine Vielzahl an Ursachen haben, die sich von der verwendeten Ausgangssubstanz, bis hin zum verwendeten Design erstrecken können. Neben dem Ausgangsmaterial spielen vor
allem die Formgebung und physikalische Eigenschaften, wie Porosität und Mikroarchitektur, eine wichtige Rolle.
Ein aktueller Ansatz zur Nutzung als alternatives Knochenersatzmaterial ist das Knochen-Tissue-Engineering. Hierbei werden körpereigene, knochen-regenerative Zellen mit einem dreidimensionalen Gerüststoff (Knochenersatzmaterial oder -scaffold) kombiniert und in den Knochendefekt implantiert. In dieser Arbeit wurde der Fokus auf die Designentwicklung eines neuen Kochenersatz-Scaffolds gelegt. Nach Vorbild schon vorgestellter Knochenersatzdesigns und unter Berücksichtigung einer Grundstruktur, die auch Phasen der Knochenheilung wie die Frakturhämatomausbreitung und initiale Nährstoffversorgung einbeziehen sollte, wurden mehrere Designs (Raster, Tempel, Zwiebel) entwickelt. Mithilfe des additiv extrusionsbasierten Schmelzschichtverfahrens (Fused Filament Fabrication) wurden die in Computer-Aided Design entworfenen Scaffolds realisiert.
Dieser Ansatz beinhaltet, unter Verwendung des resorbierbaren und biokompatiblen Trägerpolymers Polylaktat, mehrstufige Designs, die kleine biologisch funktionelle Einheiten in eine tragende, kompressionsfeste Rahmenstruktur einbetten. Hierdurch entsteht einerseits die nötige mechanische Belastbarkeit und andererseits eine offene Architektur mit Poren, die Diffusion von Sauerstoff und
Nährstoffen in die inneren Bereiche des Implantats ermöglicht. Es wurden verschiedene Designs entwickelt, gedruckt und mechanisch sowie in vitro in den Kernbereichen Zelladhäsion, Zellaktivität und osteogene Differenzierung nach Besiedelung mit Saos-2-Zellen charakterisiert.
Ein weiterer Entwicklungsschritt stellte das Einführen eines neuartigen, innerhalb der Designs kompatiblen Baukastensystems dar. Hierdurch wird nicht nur die Anpassbarkeit an den Knochendefekt verbessert, es sind auch weitere Funktionen ergänzbar und die unterschiedlichen Designs untereinander kombinierbar.
Die Ergebnisse dieser Dissertationsarbeit dienen als Basis für einen völlig neuen Ansatz von Knochenersatzmaterialien mit positiven biologischen sowie biophysikalischen Eigenschaften.
Day-to-day art criticism and art theory are qualitatively distinct. Whereas the best art criticism entails a closeness to its objects which is attuned to particularity, art theory inherently makes generalized claims, whether these claims are extrapolated from the process of art criticism or not. However, this article argues that these dynamics are effectively reversed if we consider the disparity between the criticism of so-called political art and attempts over the last century to elaborate theory which accounts for the political in art qua art. Art theory has located the political force of art precisely in the way that its particularity opposes or resists the status quo. Art criticism, on the other hand, tends to treat artwork as a text to be interpreted whose particularity may as well dissolve when translated into discourse. Drawing from the work of Theodor W. Adorno, this article argues that political art theory calls for art criticism more attuned to experience if it is to elucidate art’s critical valence.
Photorhabdus and Xenorhabdus bacteria live in a highly specific symbiosis with nematodes that belong to the genus of Heterorhabditis and Steinernema, respectively. These cruiser type nematodes actively search for soil-dwelling insects and infect them via natural openings. Inside of the insect, the bacteria are released into the hemocoel where they start producing an array of secondary metabolites to bypass the insect immune system and kill the prey within 48 hours. Many of those natural products possess bioactivities against other bacteria, fungi, protozoa or insects, which makes them interesting candidates for pharmaceutical applications. Even though advanced molecular biological methods in combination with bioinformatics tools can now be used to predict biosynthetic gene clusters (BGCs) and their products, there are still many BGCs with unknown products. Even for the plethora of natural products that were successfully identified in the last couple of years, the exact ecological function often remains elusive, as laboratory conditions can vary considerably from the natural environment of the bacteria. Knowledge about the natural conditions that stimulate, or repress production of certain natural products and their underlying regulatory mechanisms yield new approaches for natural product research and enables possibilities for selective manipulations of the regulatory cascades.
The overarching goal of this work was to examine the regulatory networks in Photorhabdus and Xenorhabdus strains. The first part of this work focused on the Hfq-dependent regulation of specialized metabolite production. In those genera, the RNA chaperone, Hfq, represses expression of hexA, which encodes for a global transcriptional regulator that acts as the master repressor for SM production. Multiple global approaches were used to identify the sRNA ArcZ, which targets a specific region in the 5’-untranslated region of the hexA mRNA and ultimately guides Hfq in order to repress its expression. It was shown that a deletion of arcZ led to a drastic reduction of SM production in Photorhabdus and Xenorhabdus, consistent with the phenotype of their respective hfq deletion mutants. Transcriptomic profiling revealed far-reaching effects on the transcriptome, with up to 735 coding sequences significantly affected in the arcZ deletion strain. Finally, it was shown that the resulting chemical background, devoid of SMs, in combination with targeted promotor exchange can be used to exclusively overproduce a desired natural product, representing an alternative route of genetic manipulation.
The second part of this work focused on the influence and identification of insect related compounds that affect SM production in P. laumondii, X. szentirmaii and X. nematophila. Insect homogenate was generated from G. mellonella larvae, a model host for these bacteria. Supplementation of the cultivation medium with homogenate induced considerable shifts in the SM profiles of those bacteria. A global effect on the transcriptional output was determined by transcriptomic profiling. The core response to the simulation of an insect environment consisted of ten CDS, eight of which are involved in the degradation of fatty acids or the import of maltose and maltodextrin into the cells. Two abundant components in the insect homogenate, trehalose and putrescin, were added to the cultivation medium of those strains and subsequent HPLC-MS analysis revealed a direct correlation of their concentration in the medium and the production titres of certain SMs. These results indicated that the bacteria sense the insect environment via different insect specific components in order to initiate a metabolic adjustment, which is probably required for adaptation to the insect host.
The last part of this work examined the influence of other, so far not directly related genes on SM production, based on the isolation of P. laumondii transposon-insertion mutants with clear phenotypic alterations. Re-sequencing and SM profiling of the mutant strains revealed that a transposon-insertion in the gene encoding for a putative DNA-adenine methyltransferase affected SM production. The phenotype was confirmed by deleting this gene. Based on Single-Molecule Real-Time sequencing, the complete methylome of the WT, deletion- and complementation mutant were analysed (experimental work performed by Sacha J. Pidot, Melbourne, Australia). No obvious alterations were detected in the methylation patterns of the strains, indicating that the dam gene product does not methylate the adenine in GATC-motifs, as it was described in literature for E. coli. This data raises the question what the function of the putative DNA-adenine methyltransferase is in P. laumondii and how it can influence the secondary metabolism. Even though there is currently no clear evidence, the potential role of epigenetic gene regulation mechanisms should be considered in further work.
In a previous study, EphB4 was demonstrated to be a positive regulator of A375-melanoma growth but a negative regulator of tumor vascularization and perfusion. To distinguish between EphB4 forward and ephrinB2 reverse signaling, we used the commercially available EphB4 kinase inhibitor NVP-BHG712 (NVP), which was later identified as its regioisomer NVPiso. Since there have been reported significant differences between the inhibition profiles of NVP and NVPiso, we compared the influence of NVP and NVPiso on tumor characteristics under the same experimental conditions. Despite the different inhibitory profiles of NVP and NVPiso, the comparative study conducted here showed the same EphB4-induced effects in vivo as in the previous investigation. This confirmed the conclusion that EphB4-ephrinB2 reverse signaling is responsible for increased tumor growth as well as decreased tumor vascularization and perfusion. These results are further substantiated by microarrays showing differences between mock-transfected and EphB4-transfected (A375-EphB4) cells with respect to at least 9 angiogenesis-related proteins. Decreased expression of vascular endothelial growth factor (VEGF), angiotensin 1 (Ang-1), and protein kinase B (Akt/PKB), together with the increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor beta-2 (TGF-β2), is consistent with the impaired vascularization of A375-EphB4 xenografts. Functional overexpression of EphB4 in A375-EphB4 cells was confirmed by activation of a variety of signaling pathways, including the Janus kinase/signal transducers and activators of transcription (JAK/STAT), rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen activated protein kinase kinase (Ras/Raf/MEK), and nuclear factor kappa-B (NFkB) pathways.
We analyze the relations between ethnographic data and theory through an examination of materiality in research practices, arguing that data production is a form of material theorizing. This entails reviewing and (re-)applying practice-theoretical discussions on materiality to questions of ethnography, and moving from understanding theory primarily as ideas to observing theorizing in all steps of research practice. We introduce “pocketing” as a heuristic concept to analyze how and when ethnographic data materializes: the concept defines data’s materiality relationally, through the affective and temporal dimensions of practice. It is discussed using two examples: in a study on everyday architectural experience where ethnographic data materialized as bodies affected by architecture; and in a study on digital cooperation where research data’s materialization was distributed over time according to the use of a company database. By conceptualizing data’s materiality as practice-bound, “pocketing” facilitates understanding the links between data and theory in ethnographic data production.
Type IV pili are flexible filaments on the surface of bacteria, consisting of a helical assembly of pilin proteins. They are involved in bacterial motility (twitching), surface adhesion, biofilm formation and DNA uptake (natural transformation). Here, we use cryo-electron microscopy and mass spectrometry to show that the bacterium Thermus thermophilus produces two forms of type IV pilus ("wide" and "narrow"), differing in structure and protein composition. Wide pili are composed of the major pilin PilA4, while narrow pili are composed of a so-far uncharacterized pilin which we name PilA5. Functional experiments indicate that PilA4 is required for natural transformation, while PilA5 is important for twitching motility.
The overall survival for patients with acute lymphoblastic leukemia (ALL) often is the function of age, in particular in 2019 analysis revealed that 5-year overall survival for patients older than 20 years remains below 35% (American Cancer Society, Cancer Facts &Figures 2019). Importantly, one of the major issues in ALL therapy is the ability of tumor cells to escape the treatment via the establishment of an immunosuppressive environment. The tumor microenvironment has gained tremendous importance in the past decade. This is largely based on the reasoning that, in order to devise better therapeutic strategies for patients, we need to gain better understanding into how malignant cells transform their microenvironment to promote growth, escape immune control and gain therapeutic resistance.
TAM receptors (TAMRs) are engaged in innate immune cells as a feed-back mechanism to terminate the immune response and promote the return to homeostasis (Rothlin et al. 2007). In the context of cancers, aberrant TAMR signaling was mainly explored concerning its pro-oncogenic function (Paolino and Penninger 2016). There are only limited data available suggesting the modulation of cancer immune response via TAMR signaling in highly immunogenic solid tumor models (Paolino et al. 2014; Ubil et al. 2018). So far, however, little is known about their potential indirect immune-modulatory function in hematological malignancies. Taking into account the pronounced importance of TAMR signaling in immune cells combined with the leukemic immune tolerance, the current study focused on the function of TAMR and their ligands in anti-leukemic immunity.
This work uncovers the mechanism of dampening anti-leukemic immune response via TAMR signaling on macrophages using the syngeneic BCR-ABL1 B-ALL mouse model. Using genetic depletion of GAS6 in the host environment or ablation of AXL and/or MERTK receptors in macrophages the bone marrow microenvironment could be rewired in order to achieve an efficient anti-leukemic immune response. In particular, the GAS6/AXL blockade triggers an effective NKand T- cell-dependent anti-leukemic response that results in prolonged survival. This finding specifically tackles the obstacle of inefficient bridging between innate and adaptive immune response typical for hematological malignancies in contrast to solid tumors (E. K. Curran, Godfrey, and Kline 2017).
Besides establishing the vital function of TAMR signaling in anti-leukemic immunity using murine models, the analysis of human blood plasma revealed that age-related immune dysregulation was manifested by significant GAS6 decrease and PROS1 upregulation among elderly donors (>60 y.o.) compared to controls (<25 y.o.). These data are indicative that TAMR signaling likely favors the age-dependent immune system decline, which in turn is associated with a poor survival rate of elderly patients diagnosed with leukemia.
In conclusion, using a preclinical ALL model here it was identified in vivo, that Axl significantly increases upon B-ALL challenge in Mph and NK cells. Therefore, AXL targeting, using the orally bioavailable selective inhibitor Bemcentinib, could serve as a powerful approach to revert early immunosuppression created by leukemia.
Taken together these data propose the AXL receptor as a novel immune checkpoint and attractive candidate for the development of a new therapeutic approach via unleashing the patient’s own immune system to combat leukemic cells.
Introduction: Gastroesophageal reflux disease (GERD) is associated with accelerated decline in lung health in children with cystic fibrosis (CF). Thus, antireflux surgery (ARS) is offered to a selected CF cohort with refractory GERD, but outcomes remain poorly investigated. This study aimed to determine the incidence of GERD in children with CF and to evaluate complications and outcomes of ARS. Materials and Methods: A systematic literature-based search was conducted using various online databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The number of GERD cases in pediatric CF cohorts who underwent diagnostic investigation(s) was recorded. Data on postoperative complications and outcomes (including symptoms, lung function, and nutritional status) following ARS were analyzed. Results: Ten articles (n = 289 patients) met the defined inclusion criteria (51% male; age range, 0.5 month–36 years). The overall incidence of GERD was 46% (range, 19–81%), derived from seven studies (n = 212 patients). Four publications (n = 82 patients) reported on ARS due to uncontrolled GERD. All ARSs were Nissen fundoplication (majority with gastrostomy placement). Major postoperative complications occurred in 15 (18%) patients, two required redo-ARS. Median follow-up time was 2 years (range, 3 months–6 years); 59% showed symptom improvement, and pulmonary exacerbations and decline in lung function were reduced. Nutritional status mainly improved in milder CF cases. There were no deaths related to ARS. Conclusion: Approximately half of pediatric CF patients have GERD. Published data for children with CF are limited and heterogeneous in terms of GERD diagnosis and outcomes following ARS. However, ARS has shown to slow the deterioration of lung function in CF.
The FUBP1-FUSE complex is an essential component of a transcription molecular machinery that is necessary for tight regulation of expression of many key genes including c-Myc and p21. FUBP1 utilizes its four articulated KH modules, which function cooperatively, for FUSE nucleotide binding. To understand molecular mechanisms fundamental to the intermolecular interaction, we present a set of crystal structures, as well ssDNA-binding characterization of FUBP1 KH domains. All KH1-4 motifs were highly topologically conserved, and were able to interact with FUSE individually and independently. Nevertheless, differences in nucleotide binding properties among the four KH domains were evident, including higher nucleotide-binding potency for KH3 as well as diverse nucleotide sequence preferences. Variations in amino acid compositions at one side of the binding cleft responsible for nucleobase resulted in diverse shapes and electrostatic charge interaction, which might feasibly be a contributing factor for different nucleotide-binding propensities among KH1-4. Nonetheless, conservation of structure and nucleotide-binding property in all four KH motifs is essential for the cooperativity of multi KH modules present in FUBP1 towards nanomolar affinity for FUSE interaction. Comprehensive structural comparison and ssDNA binding characteristics of all four KH domains presented here provide molecular insights at a fundamental level that might be beneficial for elucidating the mechanisms of the FUBP1-FUSE interaction.
Pain is the most frequent cause triggering patients to visit a physician. The worldwide incidence of chronic pain is in the range of 20% of adults, and chronic pain conditions are frequently associated with several comorbidities and a drastic decrease in patients’ quality of life. Although several approved analgesics are available, such therapy is often not satisfying due to insufficient efficacy and/or severe side effects. Therefore, novel strategies for the development of safe and highly efficacious pain killers are urgently needed. To reach this goal, it is necessary to clarify the causes and signal transduction cascades underlying the onset and progression of the different types of chronic pain. The papers in this Special Issue cover a wide variety of mechanisms involved in different pain types such as inflammatory, neuropathic or cancer pain. Therefore, the results summarized here might contribute to a better understanding of the mechanisms in chronic pain and thereby to the development of novel therapeutic strategies for pain patients.
Low-to-moderate quality meta-analytic evidence shows that motor control stabilisation exercise (MCE) is an effective treatment of non-specific low back pain. A possible approach to overcome the weaknesses of traditional meta-analyses would be that of a prospective meta-analyses. The aim of the present analysis was to generate high-quality evidence to support the view that motor control stabilisation exercises (MCE) lead to a reduction in pain intensity and disability in non-specific low back pain patients when compared to a control group. In this prospective meta-analysis and sensitivity multilevel meta-regression within the MiSpEx-Network, 18 randomized controlled study arms were included. Participants with non-specific low back pain were allocated to an intervention (individualized MCE, 12 weeks) or a control group (no additive exercise intervention). From each study site/arm, outcomes at baseline, 3 weeks, 12 weeks, and 6 months were pooled. The outcomes were current pain (NRS or VAS, 11 points scale), characteristic pain intensity, and subjective disability. A random effects meta-analysis model for continuous outcomes to display standardized mean differences between intervention and control was performed, followed by sensitivity multilevel meta-regressions. Overall, 2391 patients were randomized; 1976 (3 weeks, short-term), 1740 (12 weeks, intermediate), and 1560 (6 months, sustainability) participants were included in the meta-analyses. In the short-term, intermediate and sustainability, moderate-to-high quality evidence indicated that MCE has a larger effect on current pain (SMD = −0.15, −0.15, −0.19), pain intensity (SMD = −0.19, −0.26, −0.26) and disability (SMD = −0.15, −0.27, −0.25) compared with no exercise intervention. Low-quality evidence suggested that those patients with comparably intermediate current pain and older patients may profit the most from MCE. Motor control stabilisation exercise is an effective treatment for non-specific low back pain. Sub-clinical intermediate pain and middle-aged patients may profit the most from this intervention.
Study design: Systematic review with meta-analysis and meta-regression.
Background and objectives: We systematically reviewed and delineated the existing evidence on sustainability effects of motor control exercises on pain intensity and disability in chronic low back pain patients when compared with an inactive or passive control group or with other exercises. Secondary aims were to reveal whether moderating factors like the time after intervention completion, the study quality, and the training characteristics affect the potential sustainability effects.
Methods: Relevant scientific databases (Medline, Web of Knowledge, Cochrane) were screened. Eligibility criteria for selecting studies: All RCTs und CTs on chronic (≥ 12/13 weeks) nonspecific low back pain, written in English or German and adopting a longitudinal core-specific/stabilizing sensorimotor control exercise intervention with at least one pain intensity and disability outcome assessment at a follow-up (sustainability) timepoint of ≥ 4 weeks after exercise intervention completion.
Results and conclusions: From the 3,415 studies that were initially retrieved, 10 (2 CTs & 8 RCTs) on N = 1081 patients were included in the review and analyses. Low to moderate quality evidence shows a sustainable positive effect of motor control exercise on pain (SMD = -.46, Z = 2.9, p < .001) and disability (SMD = -.44, Z = 2.5, p < .001) in low back pain patients when compared to any control. The subgroups’ effects are less conclusive and no clear direction of the sustainability effect at short versus mid versus long-term, of the type of the comparator, or of the dose of the training is given. Low quality studies overestimated the effect of motor control exercises.
Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the existing literature on sCD163 and sCD206 function and shedding, and potential as biomarkers in acute and chronic liver diseases with a particular focus on Acute-on-Chronic Liver Failure (ACLF). In multiple studies sCD163 and sCD206 are elevated in relation to liver disease severity and established as reliable predictors of morbidity and mortality. However, differences in expression- and shedding-stimuli for CD163 and CD206 may explain dissimilarities in prognostic utility in patients with acute decompensation of cirrhosis and ACLF.
Background: Hyperhomocysteinemia is considered a possible contributor to the complex pathology of Alzheimer’s disease (AD). For years, researchers in this field have discussed the apparent detrimental effects of the endogenous amino acid homocysteine in the brain. In this study, the roles of hyperhomocysteinemia driven by vitamin B deficiency, as well as potentially beneficial dietary interventions, were investigated in the novel AppNL-G-F knock-in mouse model for AD, simulating an early stage of the disease. Methods: Urine and serum samples were analyzed using a validated LC-MS/MS method and the impact of different experimental diets on cognitive performance was studied in a comprehensive behavioral test battery. Finally, we analyzed brain samples immunohistochemically in order to assess amyloid-β (Aβ) plaque deposition. Results: Behavioral testing data indicated subtle cognitive deficits in AppNL-G-F compared to C57BL/6J wild type mice. Elevation of homocysteine and homocysteic acid, as well as counteracting dietary interventions, mostly did not result in significant effects on learning and memory performance, nor in a modified Aβ plaque deposition in 35-week-old AppNL-G-F mice. Conclusion: Despite prominent Aβ plaque deposition, the AppNL-G-F model merely displays a very mild AD-like phenotype at the investigated age. Older AppNL-G-F mice should be tested in order to further investigate potential effects of hyperhomocysteinemia and dietary interventions.
Iron is part of many redox and other enzymes and, thus, it is essential for all living beings. Many oxic environments have extremely low concentrations of free iron. Therefore, many prokaryotic species evolved siderophores, i.e., small organic molecules that complex Fe3+ with very high affinity. Siderophores of bacteria are intensely studied, in contrast to those of archaea. The haloarchaeon Haloferax volcanii contains a gene cluster that putatively encodes siderophore biosynthesis genes, including four iron uptake chelate (iuc) genes. Underscoring this hypothesis, Northern blot analyses revealed that a hexacistronic transcript is generated that is highly induced under iron starvation. A quadruple iuc deletion mutant was generated, which had a growth defect solely at very low concentrations of Fe3+, not Fe2+. Two experimental approaches showed that the wild type produced and exported an Fe3+-specific siderophore under low iron concentrations, in contrast to the iuc deletion mutant. Bioinformatic analyses revealed that haloarchaea obtained the gene cluster by lateral transfer from bacteria and enabled the prediction of enzymatic functions of all six gene products. Notably, a biosynthetic pathway is proposed that starts with aspartic acid, uses several group donors and citrate, and leads to the hydroxamate siderophore Schizokinen.
We study odd parity J=1/2 and J=3/2 Ξc resonances using a unitarized coupled-channel framework based on a SU(6)lsf×HQSS-extended Weinberg–Tomozawa baryon–meson interaction, while paying a special attention to the renormalization procedure. We predict a large molecular ΛcK¯ component for the Ξc(2790) with a dominant 0− light-degree-of-freedom spin configuration. We discuss the differences between the 3/2− Λc(2625) and Ξc(2815) states, and conclude that they cannot be SU(3) siblings, whereas we predict the existence of other Ξc-states, one of them related to the two-pole structure of the Λc(2595). It is of particular interest a pair of J=1/2 and J=3/2 poles, which form a HQSS doublet and that we tentatively assign to the Ξc(2930) and Ξc(2970), respectively. Within this picture, the Ξc(2930) would be part of a SU(3) sextet, containing either the Ωc(3090) or the Ωc(3119), and that would be completed by the Σc(2800). Moreover, we identify a J=1/2 sextet with the Ξb(6227) state and the recently discovered Σb(6097). Assuming the equal spacing rule and to complete this multiplet, we predict the existence of a J=1/2 Ωb odd parity state, with a mass of 6360 MeV and that should be seen in the ΞbK¯ channel.
Correction to: Scientific Reports https://doi.org/10.1038/srep21848, published online 22 February 2016
This Article contains an error. Among the studied species, the orangutan was erroneously specified as Bornean orangutan Pongo pygmaeus. In fact, the studied individual was a Sumatran orangutan Pongo abelii.
Venture capital-backed firms, unavoidable value-destroying trade sales, and fair value protections
(2020)
This paper investigates the implications of the fair value protections contemplated by the standard corporate contract (i.e., the standard contract form for which corporate law provides) for the entrepreneur–venture capitalist relationship, focusing, in particular, on unavoidable value-destroying trade sales. First, it demonstrates that the typical entrepreneur–venture capitalist contract does institutionalize the venture capitalist’s liquidity needs, allowing, under some circumstances, for counterintuitive instances of contractually-compliant value destruction. Unavoidable value-destroying
trade sales are the most tangible example. Next, it argues that fair value protections can prevent the entrepreneur and venture capitalist from allocating the value that these transactions generate as they would want. Then, it shows that the reality of venture capital-backed firms calls for a process of adaptation of the standard corporate contract that has one major step in the deactivation or re-shaping of fair value protections. Finally, it argues that a standard corporate contract aiming to promote social welfare through venture capital should feature flexible fair value protections
People with Parkinson’s disease (PD) experience a gradual loss of functional abilities that affects all facets of their daily life. There is a lack of longitudinal studies on coping styles in relation to the disease progression among people with PD. The aim of this study was to explore how coping styles in PD evolve over a 3-year period. Data from the longitudinal project “Home and Health in People Ageing with PD” was utilized (N = 158), including baseline and 3-year follow-up assessments. Coping was captured by ratings of 13 different coping styles. A factor analysis was conducted to analyse patterns of coping styles. Stability and change were analysed for each of the 13 styles with respect to the course of the disease. The factor analysis revealed four coping patterns: pessimistic, optimistic, persistent and support-seeking. The stability of each coping style over time ranged from 75.3% to 90.5%. Those who experienced a worsening of the disease were most inclined to change their coping style (p = 0.006). The results suggest that even when facing severe challenges due to PD in daily life, coping styles remain relatively stable over time. However, a worsening in PD severity appeared to trigger a certain re-evaluation of coping styles.
Machine Learning (ML) is so pervasive in our todays life that we don't even realise that, more often than expected, we are using systems based on it. It is also evolving faster than ever before. When deploying ML systems that make decisions on their own, we need to think about their ignorance of our uncertain world. The uncertainty might arise due to scarcity of the data, the bias of the data or even a mismatch between the real world and the ML-model. Given all these uncertainties, we need to think about how to build systems that are not totally ignorant thereof. Bayesian ML can to some extent deal with these problems. The specification of the model using probabilities provides a convenient way to quantify uncertainties, which can then be included in the decision making process.
In this thesis, we introduce the Bayesian ansatz to modeling and apply Bayesian ML models in finance and economics. Especially, we will dig deeper into Gaussian processes (GP) and Gaussian process latent variable model (GPLVM). Applied to the returns of several assets, GPLVM provides the covariance structure and also a latent space embedding thereof. Several financial applications can be build upon the output of the GPLVM. To demonstrate this, we build an automated asset allocation system, a predictor for missing asset prices and identify other structure in financial data.
It turns out that the GPLVM exhibits a rotational symmetry in the latent space, which makes it harder to fit. Our second publication reports, how to deal with that symmetry. We propose another parameterization of the model using Householder transformations, by which the symmetry is broken. Bayesian models are changed by reparameterization, if the prior is not changed accordingly. We provide the correct prior distribution of the new parameters, such that the model, i.e. the data density, is not changed under the reparameterization. After applying the reparametrization on Bayesian PCA, we show that the symmetry of nonlinear models can also be broken in the same way.
In our last project, we propose a new method for matching quantile observations, which uses order statistics. The use of order statistics as the likelihood, instead of a Gaussian likelihood, has several advantages. We compare these two models and highlight their advantages and disadvantages. To demonstrate our method, we fit quantiled salary data of several European countries. Given several candidate models for the fit, our method also provides a metric to choose the best option.
We hope that this thesis illustrates some benefits of Bayesian modeling (especially Gaussian processes) in finance and economics and its usage when uncertainties are to be quantified.