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We present the first 3-D model of seismic P and S velocities in the crust and uppermost mantle beneath the Gulf of Aqaba and surrounding areas based on the results of passive travel time tomography. The tomographic inversion was performed based on travel time data from ∼ 9000 regional earthquakes provided by the Egyptian National Seismological Network (ENSN), and this was complemented with data from the International Seismological Centre (ISC). The resulting P and S velocity patterns were generally consistent with each other at all depths. Beneath the northern part of the Red Sea, we observed a strong high-velocity anomaly with abrupt limits that coincide with the coastal lines. This finding may indicate the oceanic nature of the crust in the Red Sea, and it does not support the concept of gradual stretching of the continental crust. According to our results, in the middle and lower crust, the seismic anomalies beneath the Gulf of Aqaba seem to delineate a sinistral shift (∼ 100 km) in the opposite flanks of the fault zone, which is consistent with other estimates of the left-lateral displacement in the southern part of the Dead Sea Transform fault. However, no displacement structures were visible in the uppermost lithospheric mantle.
Background: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Growing evidence indicates that tumor-initiating cells (TICs) are responsible for tumor growth and progression. Conventional chemotherapeutics do not sufficiently eliminate TICs, leading to tumor relapse. We aimed to gain insight into TIC biology by comparing the transcriptome of primary TIC cultures and their normal stem cell counterparts to uncover expression differences.
Methods: We established colonosphere cultures derived from the resection of paired specimens of primary tumor and normal mucosa in patients with CRC. These colonospheres, enriched for TICs, were used for differential transcriptome analyses to detect new targets for a TIC-directed therapy. Effects of target inhibition on CRC cells were studied in vitro and in vivo.
Results: Pathway analysis of the regulated genes showed enrichment of genes central to PI3K/AKT and Wnt-signaling. We identified CD133 as a marker for a more aggressive CRC subpopulation enriched with TICs in SW480 CRC cells in an in vivo cancer model. Treatment of CRC cells with the selective AKT inhibitor MK-2206 caused a decrease in cell proliferation, particularly in the TIC fraction, resulting in a significant reduction of the stemness capacity to form colonospheres in vitro and to initiate tumor formation in vivo. Consequently, MK-2206 treatment of mice with established xenograft tumors exhibited a significant deceleration of tumor progression. Primary patient-derived tumorsphere growth was significantly inhibited by MK-2206.
Conclusion: This study reveals that AKT signaling is critical for TIC proliferation and can be efficiently targeted by MK-2206 representing a preclinical therapeutic strategy to repress colorectal TICs.
Background: This study evaluated the effects of a combined innovative training regime consisting of stochastic resonance whole-body vibration (SR-WBV) and a dance video game (DVG) on physical performance and muscle strength in long-term-care dwelling elderly.
Methods: Thirthy long-term-care elderly were randomly allocated to an intervention group (IG; n = 16) receiving combined SR-WBV training and DVG, or a sham group (SG; n = 14). IG performed five sets one minute of SR-WBV, with one minute rest between sets (base frequency 3 Hz up to 6 Hz, Noise 4) during the first five weeks on three days per week. From week five to eight a DVG was added to SR-WBV for IG on three days per week. SG performed a five-set SR-WBV program (1 Hz, Noise 1) lasting five times one minute, with one minute rest in between, three days a week. From week five to eight stepping exercises on a trampoline were added on three days per week. Primary outcome: Short physical performance battery (SPPB). Secondary outcome: isometric maximal voluntary contraction (IMVC), and sub phases of IMVC (Fsub), isometric rate of force development (IRFD) and sub time phases of IRFD (IRFDsub) were measured at baseline, after four and eight weeks. ANOVA with repeated measures was used for analyses of time and interaction effects and MANOVA determined between group intervention effects.
Results: Between group effects revealed significant effects on the SPPB primary outcome after four weeks F(1, 27) = 6.17; p = 0.02) and after eight weeks F(1,27) = 11.8; p = 0.002). Secondary muscle function related outcome showed significant between group effects in IG on IRFD, Fsub 30 ms, 100 ms, 200 ms and IRFDsub 0-30 ms, 0-50 ms, 0-100 ms and 100-200 ms compared to SG (all p < 0.05).
Conclusions: Eight weeks SR-WBV and DVG intervention improved lower extremity physical function and muscle strength compared to a sham intervention in long-term-care elderly. SR-WBV and DVG seems to be effective as a training regime for skilling up in long-term-care elderly.
The endoplasmic reticulum–mitochondria encounter structure (ERMES) connects the mitochondrial outer membrane with the ER. Multiple functions have been linked to ERMES, including maintenance of mitochondrial morphology, protein assembly and phospholipid homeostasis. Since the mitochondrial distribution and morphology protein Mdm10 is present in both ERMES and the mitochondrial sorting and assembly machinery (SAM), it is unknown how the ERMES functions are connected on a molecular level. Here we report that conserved surface areas on opposite sides of the Mdm10 β-barrel interact with SAM and ERMES, respectively. We generated point mutants to separate protein assembly (SAM) from morphology and phospholipid homeostasis (ERMES). Our study reveals that the β-barrel channel of Mdm10 serves different functions. Mdm10 promotes the biogenesis of α-helical and β-barrel proteins at SAM and functions as integral membrane anchor of ERMES, demonstrating that SAM-mediated protein assembly is distinct from ER-mitochondria contact sites.
Background: Expected growth in the demand for health services has generated interest in the more effective deployment of health care assistants. Programs encouraging German general practitioners (GPs) to share responsibility for care with specially qualified health care assistants in the family practice (VERAHs) have existed for several years. But no studies have been conducted on the tasks German GPs are willing to rely on specially qualified personnel to perform, what they are prepared to delegate to all non-physician practice staff and what they prefer to do themselves.
Methods: As part of an evaluation study on the deployment of VERAHs in GP-centered health care, we used a questionnaire to ask about task delegation within the practice team. From a list of tasks that VERAHs are specifically trained to carry out, GPs were asked to indicate which they actually delegate. We also asked GPs why they had employed a VERAH in their practice and for their opinions on the benefits and limitations of assigning tasks to VERAHs. The aim of the study was to find out which tasks GPs delegate to their specially qualified personnel, which they permit all HCAs to carry out, and which tasks they do not delegate at all.
Results: The survey was filled in and returned by 245 GPs (83%). Some tasks were exclusively delegated to VERAHs (e.g. home visits), while others were delegated to all HCAs (e.g. vaccinations). About half the GPs rated the assessment of mental health, as part of the comprehensive assessment of a patient’s condition, as the sole responsibility of a GP.
The possibility to delegate more complex tasks was the main reason given for employing a VERAH. Doctors said the delegation of home visits provided them with the greatest relief.
Conclusions: In Germany, where GPs are solely accountable for the health care provided in their practices, experience with the transfer of responsibility to other non-physician health care personnel is still very limited. When HCAs have undergone special training, GPs seem to be prepared to delegate tasks that demand a substantial degree of know-how, such as home visits and case management. This “new” role allocation within the practice may signal a shift in the provision of health care by family practice teams in Germany.
In the cochlea of the mustached bat, cochlear resonance produces extremely sharp frequency tuning to the dominant frequency of the echolocation calls, around 61 kHz. Such high frequency resolution in the cochlea is accomplished at the expense of losing temporal resolution because of cochlear ringing, an effect that is observable not only in the cochlea but also in the cochlear nucleus. In the midbrain, the duration of sounds is thought to be analyzed by duration-tuned neurons, which are selective to both stimulus duration and frequency. We recorded from 57 DTNs in the auditory midbrain of the mustached bat to assess if a spectral-temporal trade-off is present. Such spectral-temporal trade-off is known to occur as sharp tuning in the frequency domain which results in poorer resolution in the time domain, and vice versa. We found that a specialized sub-population of midbrain DTNs tuned to the bat’s mechanical cochlear resonance frequency escape the cochlear spectral-temporal trade-off. We also show evidence that points towards an underlying neuronal inhibition that appears to be specific only at the resonance frequency.
Contemporary liberalism and republicanism present clearly distinct programs for domestic politics, but the same cannot be said when it comes to global politics: the burgeoning literature on global republicanism has reproduced the divide between cosmopolitan and associational views familiar from long-standing debates among liberal egalitarians. Should republicans be cosmopolitans? Despite presence of a range of views in the literature, there is an emerging consensus that the best answer is no. This paper aims to resist the emerging consensus, arguing that republicans should be cosmopolitans. The considerations offered against cosmopolitanism generally rest on an incomplete understanding of the relationship between economic inequality or poverty on the one hand, and domination on the other. Insofar as republicans agree that promoting freedom from domination should be our central political aim, they should regard the reduction of economic inequality and poverty at home and abroad as equally pressing.
Retrograde transport of NF-κB from the synapse to the nucleus in neurons is mediated by the dynein/dynactin motor complex and can be triggered by synaptic activation. The caliber of axons is highly variable ranging down to 100 nm, aggravating the investigation of transport processes in neurites of living neurons using conventional light microscopy. We quantified for the first time the transport of the NF-κB subunit p65 using high-density single-particle tracking in combination with photoactivatable fluorescent proteins in living mouse hippocampal neurons. We detected an increase of the mean diffusion coefficient (Dmean) in neurites from 0.12±0.05 to 0.61±0.03 μm2/s after stimulation with glutamate. We further observed that the relative amount of retrogradely transported p65 molecules is increased after stimulation. Glutamate treatment resulted in an increase of the mean retrograde velocity from 10.9±1.9 to 15±4.9 μm/s, whereas a velocity increase from 9±1.3 to 14±3 μm/s was observed for anterogradely transported p65. This study demonstrates for the first time that glutamate stimulation leads to an increased mobility of single NF-κB p65 molecules in neurites of living hippocampal neurons.
BACKGROUND: Evaluation of latest generation automated attenuation-based tube potential selection (ATPS) impact on image quality and radiation dose in contrast-enhanced chest-abdomen-pelvis computed tomography examinations for gynaecologic cancer staging.
METHODS: This IRB approved single-centre, observer-blinded retrospective study with a waiver for informed consent included a total of 100 patients with contrast-enhanced chest-abdomen-pelvis CT for gynaecologic cancer staging. All patients were examined with activated ATPS for adaption of tube voltage to body habitus. 50 patients were scanned on a third-generation dual-source CT (DSCT), and another 50 patients on a second-generation DSCT. Predefined image quality setting remained stable between both groups at 120 kV and a current of 210 Reference mAs. Subjective image quality assessment was performed by two blinded readers independently. Attenuation and image noise were measured in several anatomic structures. Signal-to-noise ratio (SNR) was calculated. For the evaluation of radiation exposure, CT dose index (CTDIvol) values were compared.
RESULTS: Diagnostic image quality was obtained in all patients. The median CTDIvol (6.1 mGy, range 3.9-22 mGy) was 40 % lower when using the algorithm compared with the previous ATCM protocol (median 10.2 mGy · cm, range 5.8-22.8 mGy). A reduction in potential to 90 kV occurred in 19 cases, a reduction to 100 kV in 23 patients and a reduction to 110 kV in 3 patients of our experimental cohort. These patients received significantly lower radiation exposure compared to the former used protocol.
CONCLUSION: Latest generation automated ATPS on third-generation DSCT provides good diagnostic image quality in chest-abdomen-pelvis CT while average radiation dose is reduced by 40 % compared to former ATPS protocol on second-generation DSCT.
Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.
Trichopsis vittata (Cuvier, 1831) is a small, freshwater gourami (Fam: Osphronemidae) native to southeast Asia. It was first detected in Florida in the 1970s and seems to have persisted for decades in a small area. In this study, we documented T. vittata’s ecophysiological tolerances (salinity and low-temperature) and qualitatively compared them to published values for other sympatric non-native species that have successfully invaded much of the Florida peninsula. Trichopsis vittata survived acute salinity shifts to 16 psu and was able to survive up to 20 psu when salinity was raised more slowly (5 psu per week). In a cold-tolerance experiment, temperature was lowered from 24 °C at 1 °C hr-1 until fish died. Mean temperature at death (i.e., lower lethal limit) was 7.2 °C. Trichopsis vittata seems as tolerant or more tolerant than many other sympatric non-native fishes for the variables we examined. However, T. vittata is the only species that has not dispersed since its introduction. Species other than T. vittata have broadly invaded ranges, many of which include the entire lower third of the Florida peninsula. It is possible that tolerance to environmental parameters serves as a filter for establishment, wherein candidate species must possess the ability to survive abiotic extremes as a first step. However, a species’ ability to expand its geographic range may ultimately rely on a secondary set of criteria including biotic interactions and life-history variables.
Small-scale thermal upwellings under the northern East African Rift from S travel time tomography
(2016)
There is a long-standing debate over how many and what types of plumes underlie the East African Rift and whether they do or do not drive its extension and consequent magmatism and seismicity. Here we present a new tomographic study of relative teleseismic S and SKS residuals that expands the resolution from previous regional studies below the northern East African Rift to image structure from the surface to the base of the transition zone. The images reveal two low-velocity clusters, below Afar and west of the Main Ethiopian Rift, that extend throughout the upper mantle and comprise several smaller-scale (about 100 km diameter), low-velocity features. These structures support those of our recent P tomographic study below the region. The relative magnitude of S to P residuals is around 3.5, which is consistent with a predominantly thermal nature of the anomalies. The S and P velocity anomalies in the low-velocity clusters can be explained by similar excess temperatures in the range of 100–200°C, consistent with temperatures inferred from other seismic, geochemical, and petrological studies. Somewhat stronger VS anomalies below Afar than west of the Main Ethiopian Rift may include an expression of volatiles and/or melt in this region. These results, together with a comparison with previous larger-scale tomographic models, indicate that these structures are likely small-scale upwellings with mild excess temperatures, rising from a regional thermal boundary layer at the base of the upper mantle.
Estimates suggest that more than 25,000 to 125,000 people die annually from snakebite envenomation worldwide. In contrast to this major disease burden, thorough bibliometric studies do not exist so far that illustrate the overall research activity over a long time span. Therefore, the NewQIS-platform conducted an analysis on snakebite envenoming using the Thomson Reuters database Web of Science. To determine and assess changes regarding the scientific activities and to specifically address the more recent situation we analyzed two time intervals (t). During the first time interval from 1900 to 2007 (t1) 13,015 publications (p) were identified. In the following period (2008–2016 = t2) 4,982 publications were identified by the same search strategy. They originate from 114 (t1) respectively 121 countries (t2), with the USA (p = 3518), Brazil (p = 1100) and Japan (p = 961) being most productive in the first period, and the USA (p = 1087), Brazil (p = 991) and China (p = 378) in the second period, respectively. Setting the publication numbers in relation to GDP/capita, Brazil leads with 92 publications per 10,000 Int$GDP/capita, followed by India with 79 publications per 10000 Int$GDP/capita (t1). Comparing the country’s publication activity with the Human Development Index level indicates that the majority of the publications is published by highly developed countries. When calculating the average citation rates (citations per published item = CR) mainly European countries show the highest ranks: From 1900–2007 Sweden ranks first with a CR = 27, followed by the Netherlands (CR = 24.8), Switzerland (CR = 23), Spain, Austria and the USA (CR = 22). From 2008 to 2016 the highest rate achieves Switzerland with a value of 24.6, followed by Belgium (CR = 18.1), Spain (CR = 16.7), Costa Rica (CR = 14.9) and Netherlands (CR = 14). Compared with this, the USA was placed at rank 13 (CR = 9,5).
In summary, the present study represents the first density-equalizing map projection and in-depth scientometric analysis of the global research output on snakebites and its venoms. So it draws a sketch of the worldwide publication architecture and indicates that countries with a high incidence of snakebites and a low economical level still need to be empowered in carrying out research in this area.
In modern welfare states, family policies may resolve the tension between employment and care-focused demands. However these policies sometimes have adverse consequences for distinct social groups. This study examined gender and educational differences in working parents’ perceived work–family conflict and used a comparative approach to test whether family policies, in particular support for child care and leave from paid work, are capable of reducing work–family conflict as well as the gender and educational gaps in work–family conflict. We use data from the European Social Survey 2010 for 20 countries and 5296 respondents (parents), extended with information on national policies for maternity and parental leave and child care support from the OECD Family Database. Employing multilevel analysis, we find that mothers and the higher educated report most work–family conflict. Policies supporting child care reduce the level of experienced work–family conflict; family leave policy appears to have no alleviating impact on working parents’ work–family conflict. Our findings indicate that family policies appear to be unable to reduce the gender gap in conflict perception and even widen the educational gap in work–family conflict.
The aim of this preliminary prospective RCT was to histologically evaluate peri-implant soft tissues around titanium abutments treated using different cleaning methods. Sixteen patients were randomized into three groups: laboratory customized abutments underwent Plasma of Argon treatment (Plasma Group), laboratory customized abutments underwent cleaning by steam (Steam Group), and abutments were used as they came from industry (Control Group). Seven days after the second surgery, soft tissues around abutments were harvested. Samples were histologically analyzed. Soft tissues surrounding Plasma Group abutments predominantly showed diffuse chronic infiltrate, almost no acute infiltrate, with presence of few polymorphonuclear neutrophil granulocytes, and a diffuse presence of collagenization bands. Similarly, in Steam Group, the histological analysis showed a high variability of inflammatory expression factors. Tissues harvested from Control Group showed presence of few neutrophil granulocytes, moderate presence of lymphocytes, and diffuse collagenization bands in some sections, while they showed absence of acute infiltrate in 40% of sections. However, no statistical difference was found among the tested groups for each parameter (p > 0.05). Within the limit of the present study, results showed no statistically significant difference concerning inflammation and healing tendency between test and control groups.
The spliceosomal protein SF3b49, a component of the splicing factor 3b (SF3b) protein complex in the U2 small nuclear ribonucleoprotein, contains two RNA recognition motif (RRM) domains. In yeast, the first RRM domain (RRM1) of Hsh49 protein (yeast orthologue of human SF3b49) reportedly interacts with another component, Cus1 protein (orthologue of human SF3b145). Here, we solved the solution structure of the RRM1 of human SF3b49 and examined its mode of interaction with a fragment of human SF3b145 using NMR methods. Chemical shift mapping showed that the SF3b145 fragment spanning residues 598-631 interacts with SF3b49 RRM1, which adopts a canonical RRM fold with a topology of β1-α1-β2-β3-α2-β4. Furthermore, a docking model based on NOESY measurements suggests that residues 607-616 of the SF3b145 fragment adopt a helical structure that binds to RRM1 predominantly via α1, consequently exhibiting a helix-helix interaction in almost antiparallel. This mode of interaction was confirmed by a mutational analysis using GST pull-down assays. Comparison with structures of all RRM domains when complexed with a peptide found that this helix-helix interaction is unique to SF3b49 RRM1. Additionally, all amino acid residues involved in the interaction are well conserved among eukaryotes, suggesting evolutionary conservation of this interaction mode between SF3b49 RRM1 and SF3b145.
A hallmark of several major neurological diseases is neuronal cell death. In addition to this primary pathology, secondary injury is seen in connected brain regions in which neurons not directly affected by the disease are denervated. These transneuronal effects on the network contribute considerably to the clinical symptoms. Since denervated neurons are viable, they are attractive targets for intervention. Therefore, we studied the role of Sphingosine-1-phosphate (S1P)-receptor signaling, the target of Fingolimod (FTY720), in denervation-induced dendritic atrophy. The entorhinal denervation in vitro model was used to assess dendritic changes of denervated mouse dentate granule cells. Live-cell microscopy of GFP-expressing granule cells in organotypic entorhino-hippocampal slice cultures was employed to follow individual dendritic segments for up to 6 weeks after deafferentation. A set of slice cultures was treated with FTY720 or the S1P-receptor (S1PR) antagonist VPC23019. Lesion-induced changes in S1P (mass spectrometry) and S1PR-mRNA levels (laser microdissection and qPCR) were determined. Denervation caused profound changes in dendritic stability. Dendritic elongation and retraction events were markedly increased, resulting in a net reduction of total dendritic length (TDL) during the first 2 weeks after denervation, followed by a gradual recovery in TDL. These changes were accompanied by an increase in S1P and S1PR1- and S1PR3-mRNA levels, and were not observed in slice cultures treated with FTY720 or VPC23019. We conclude that inhibition of S1PR signaling prevents dendritic destabilization and denervation-induced dendrite loss. These results suggest a novel neuroprotective effect for pharmaceuticals targeting neural S1PR pathways.
Cl(-) plays a crucial role in neuronal function and synaptic inhibition. However, the impact of neuronal morphology on the diffusion and redistribution of intracellular Cl(-) is not well understood. The role of spines in Cl(-) diffusion along dendritic trees has not been addressed so far. Because measuring fast and spatially restricted Cl(-) changes within dendrites is not yet technically possible, we used computational approaches to predict the effects of spines on Cl(-) dynamics in morphologically complex dendrites. In all morphologies tested, including dendrites imaged by super-resolution STED microscopy in live brain tissue, spines slowed down longitudinal Cl(-) diffusion along dendrites. This effect was robust and could be observed in both deterministic as well as stochastic simulations. Cl(-) extrusion altered Cl(-) diffusion to a much lesser extent than the presence of spines. The spine-dependent slowing of Cl(-) diffusion affected the amount and spatial spread of changes in the GABA reversal potential thereby altering homosynaptic as well as heterosynaptic short-term ionic plasticity at GABAergic synapses in dendrites. Altogether, our results suggest a fundamental role of dendritic spines in shaping Cl(-) diffusion, which could be of relevance in the context of pathological conditions where spine densities and neural excitability are perturbed.
Alu elements are retrotransposons that frequently form new exons during primate evolution. Here, we assess the interplay of splicing repression by hnRNPC and nonsense-mediated mRNA decay (NMD) in the quality control and evolution of new Alu-exons. We identify 3100 new Alu-exons and show that NMD more efficiently recognises transcripts with Alu-exons compared to other exons with premature termination codons. However, some Alu-exons escape NMD, especially when an adjacent intron is retained, highlighting the importance of concerted repression by splicing and NMD. We show that evolutionary progression of 3' splice sites is coupled with longer repressive uridine tracts. Once the 3' splice site at ancient Alu-exons reaches a stable phase, splicing repression by hnRNPC decreases, but the exons generally remain sensitive to NMD. We conclude that repressive motifs are strongest next to cryptic exons and that gradual weakening of these motifs contributes to the evolutionary emergence of new alternative exons.
Ruijs-Aalfs syndrome is a segmental progeroid syndrome resulting from mutations in the SPRTN gene. Cells derived from patients with SPRTN mutations elicit genomic instability and people afflicted with this syndrome developed hepatocellular carcinoma. Here we describe the molecular mechanism by which SPRTN contributes to genome stability and normal cellular homeostasis. We show that SPRTN is a DNA-dependent mammalian protease required for resolving cytotoxic DNA-protein crosslinks (DPCs)— a function that had only been attributed to the metalloprotease Wss1 in budding yeast. We provide genetic evidence that SPRTN and Wss1 function distinctly in vivo to resolve DPCs. Upon DNA and ubiquitin binding, SPRTN can elicit proteolytic activity; cleaving DPC substrates and itself. SPRTN null cells or cells derived from patients with Ruijs-Aalfs syndrome are impaired in the resolution of covalent DPCs in vivo. Collectively, SPRTN is a mammalian protease required for resolving DNA-protein crosslinks in vivo whose function is compromised in Ruijs-Aalfs syndrome patients.
Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3' untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3' ends.
Background: Archaeal membranes have phytanyl ether lipids instead of common fatty acid-glycerol esters in bacterial and eukaryotic cells. Sulfolobus and Thermoplasma species have unique membrane-spanning tetraether lipids (TEL), which form stable liposomes. Recently, we cultured Thermoplasma species from the Indonesian volcano Tangkuban Perahu and isolated TEL. The purpose of this in vitro study is to investigate the transfer of fluorescent dye from stable TEL liposomes to cultured colon carcinoma cells.
Methods: TEL was extracted from cultured cells with chloroform-methanol (1:1), then it was fractionated and purified via diethylaminoethyl-cellulose-acetate columns and activated charcoal for the formation of stable liposomes. For the fluorescence exchange assay, TEL liposomes were loaded with water-soluble carboxyfluorescein (CF). Staining experiments were conducted with various cell cultures, and T84 colon carcinoma cells were chosen for the main experiments. Liposome stability was tested by light scattering and electron microscopic size determinations as well as by unspecific CF release at low pH (6.0–7.4) and increased temperature (4–50°C/70°C).
Results: TEL liposomes exhibit high stability and extremely low proton permeability at low pH. CF staining of cultured T84 colon carcinoma cells appeares more intensive from TEL liposomes than from dipalmitoylphosphatidylcholine liposomes.
Conclusion: The results of this in vitro study demonstrate CF staining of colon carcinoma cells and high stability of TEL liposomes at low pH, matching the condition in the gastro-intestinal (GI) route and in the urogentital (UG) tract. For this reason, in vivo studies on liposomal fluorescent photosensitizers for topical application of photodynamic cancer therapy in the GI and UG tracts should be carried out.
Background: In Europe, the number of females exhibiting oppositional defiant disorder (ODD) and conduct disorder (CD) is growing. Many of these females live in youth welfare institutions. Consequently, there is a great need for evidence-based interventions within youth welfare settings. A recently developed approach targeting the specific needs of girls with ODD and CD in residential care is START NOW. The aim of this group-based behavioural skills training programme is to specifically enhance emotional regulation capacities to enable females with CD or ODD to appropriately deal with daily-life demands. It is intended to enhance psychosocial adjustment and well-being as well as reduce oppositional and aggressive behaviour. We present the study protocol (version 4.1; 10 February 2016) of the FemNAT-CD intervention trial titled "Group-Based Treatment of Adolescent Female Conduct Disorders: The Central Role of Emotion Regulation".
Methods/design: The study is a prospective, confirmatory, cluster-randomised, parallel-group, multi-centre, randomised controlled trial with 128 institutionalised female adolescents who fulfil the diagnostic criteria of ODD and/or CD. Institutions/wards will be randomised either to provide the 12-week skills training as an add-on intervention or to provide treatment as usual. Once the first cycle is completed, each institution will run a second cycle with the opposite condition. Primary endpoints are the pre-post change in number of CD/ODD symptoms as assessed by a standardised, semi-structured psychiatric interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime, CD/ODD section) between baseline and the end of intervention, as well as between baseline and a 3-month follow-up point. Secondary objectives include pre-post change in CD/ODD-related outcome measures, most notably emotional regulation on a behavioural and neurobiological level after completion of START NOW compared with treatment as usual.
Discussion: To our knowledge, this study is the first to date to systematically investigate the effectiveness of an adapted integrative psychosocial intervention designed for female adolescents with ODD and CD in youth welfare settings.
Trial registration: German Clinical Trials Register (DRKS) identifier: DRKS00007524. Registered on 18 December 2015 and with the World Health Organisation International Clinical Trials Registry Platform.
Acetaminophen (APAP, N-acetyl-p-aminophenol, or paracetamol) overdosing is a prevalent cause of acute liver injury. While clinical disease is initiated by overt parenchymal hepatocyte necrosis in response to the analgetic, course of intoxication is substantially influenced by associated activation of innate immunity. This process is supposed to be set in motion by release of danger-associated molecular patterns (DAMPs) from dying hepatocytes and is accompanied by an inflammatory cytokine response. Murine models of APAP-induced liver injury emphasize the complex role that DAMPs and cytokines play in promoting either hepatic pathogenesis or resolution and recovery from intoxication. Whereas the function of key inflammatory cytokines is controversially discussed, a subclass of specific cytokines capable of efficiently activating the hepatocyte signal transducer and activator of transcription (STAT)-3 pathway stands out as being consistently protective in murine models of APAP intoxication. Those include foremost interleukin (IL)-6, IL-11, IL-13, and IL-22. Above all, activation of STAT3 under the influence of these cytokines has the capability to drive hepatocyte compensatory proliferation, a key principle of the regenerating liver. Herein, the role of these specific cytokines during experimental APAP-induced liver injury is highlighted and discussed in a broader perspective. In hard-to-treat or at-risk patients, standard therapy may fail and APAP intoxication can proceed toward a fatal condition. Focused administration of recombinant STAT3-activating cytokines may evolve as novel therapeutic approach under those ill-fated conditions.
If a report on state and perspectives of the history of social law is to be written, two problems involving demarcation have to be dealt with in advance. 1. What is social law? 2. What kind of literature has to be considered as a part of the history of social law? In both cases the boundaries can definitely be drawn in a subjective manner and can be oriented towards the interests and competences of the author insofar as the criteria are plausible. ...
Social law is an important cornerstone of the normative constitution of the modern state, if not one the most important. The stability of market-based societies in the current era primarily resulted from both the existence of legally guaranteed provisions against the risks of life and the legal mechanisms that make the social inequalities bearable – or, at the very least, that ensure a minimum standard of living and prevent those affected from being completely excluded from social participation. Social law is, however, not just a stabilizing element for democratically constituted market societies in a normal situation. Over the course of the 20th century, it was also used to great effect by dictatorial and authoritarian regimes as a means of securing power, and it was employed more often in times of war and crisis in order to keep peace within the state, to attenuate or pacify fragile social situations, not to mention to generate social consensus. Throughout all the ups and downs of recent history, social law has remained a key element involved in the shaping of society. ...
It is widely thought that the international community, taken as a whole, is required to take action to prevent terrorism. Yet, what each state is required to do in this project is unclear and contested. This article examines a number of bases on which we might assign responsibilities to conduct counterterrorist operations to states. I argue that the ways in which other sorts of responsibilities have been assigned to states by political philosophers will face significant limitations when used to assign the necessary costs of preventing terrorism. I go on to suggest that appealing to the principle of fairness—which assigns obligations on the basis of benefits received from cooperative endeavours—may be used to make up the shortfall, despite this principle having received relatively little attention in existing normative accounts of states’ responsibilities.
Introduction: In the time of increasing resistance and paucity of new drug development there is a growing need for strategies to enhance rational use of antibiotics in German and Austrian hospitals. An evidence-based guideline on recommendations for implementation of antibiotic stewardship (ABS) programmes was developed by the German Society for Infectious Diseases in association with the following societies, associations and institutions: German Society of Hospital Pharmacists, German Society for Hygiene and Microbiology, Paul Ehrlich Society for Chemotherapy, The Austrian Association of Hospital Pharmacists, Austrian Society for Infectious Diseases and Tropical Medicine, Austrian Society for Antimicrobial Chemotherapy, Robert Koch Institute.
Materials and methods: A structured literature research was performed in the databases EMBASE, BIOSIS, MEDLINE and The Cochrane Library from January 2006 to November 2010 with an update to April 2012 (MEDLINE and The Cochrane Library). The grading of recommendations in relation to their evidence is according to the AWMF Guidance Manual and Rules for Guideline Development.
Conclusion: The guideline provides the grounds for rational use of antibiotics in hospital to counteract antimicrobial resistance and to improve the quality of care of patients with infections by maximising clinical outcomes while minimising toxicity. Requirements for a successful implementation of ABS programmes as well as core and supplemental ABS strategies are outlined. The German version of the guideline was published by the German Association of the Scientific Medical Societies (AWMF) in December 2013.
The process of electron-loss to the continuum (ELC) has been studied for the collision systems U28++H2 at a collision energy of 50 MeV/u, U28++N2 at 30 MeV/u, and U28++Xe at 50 MeV/u. The energy distributions of cusp electrons emitted at an angle of 0∘ with respect to the projectile beam were measured using a magnetic forward-angle electron spectrometer. For these collision systems far from equilibrium charge state, a significantly asymmetric cusp shape is observed. The experimental results are compared to calculations based on first-order perturbation theory, which predict an almost symmetric cusp shape. Some possible reasons for this discrepancy are discussed.
The covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to proteins generates a signal that regulates transcription, response to cell stress, and differentiation. Ufmylation is initiated by ubiquitin-like modifier activating enzyme 5 (UBA5), which activates and transfers UFM1 to ubiquitin-fold modifier-conjugating enzyme 1 (UFC1). The details of the interaction between UFM1 and UBA5 required for UFM1 activation and its downstream transfer are however unclear. In this study, we described and characterized a combined linear LC3-interacting region/UFM1-interacting motif (LIR/UFIM) within the C terminus of UBA5. This single motif ensures that UBA5 binds both UFM1 and light chain 3/γ-aminobutyric acid receptor-associated proteins (LC3/GABARAP), two ubiquitin (Ub)-like proteins. We demonstrated that LIR/UFIM is required for the full biological activity of UBA5 and for the effective transfer of UFM1 onto UFC1 and a downstream protein substrate both in vitro and in cells. Taken together, our study provides important structural and functional insights into the interaction between UBA5 and Ub-like modifiers, improving the understanding of the biology of the ufmylation pathway.
Highlights
• Cryo-EM structure of a yeast F1Fo-ATP synthase dimer
• Inhibitor-free X-ray structure of the F1 head and rotor complex
• Mechanism of ATP generation by rotary catalysis
• Structural basis of cristae formation in the inner mitochondrial membrane
Summary
We determined the structure of a complete, dimeric F1Fo-ATP synthase from yeast Yarrowia lipolytica mitochondria by a combination of cryo-EM and X-ray crystallography. The final structure resolves 58 of the 60 dimer subunits. Horizontal helices of subunit a in Fo wrap around the c-ring rotor, and a total of six vertical helices assigned to subunits a, b, f, i, and 8 span the membrane. Subunit 8 (A6L in human) is an evolutionary derivative of the bacterial b subunit. On the lumenal membrane surface, subunit f establishes direct contact between the two monomers. Comparison with a cryo-EM map of the F1Fo monomer identifies subunits e and g at the lateral dimer interface. They do not form dimer contacts but enable dimer formation by inducing.
The first step in methanol metabolism in methylotrophic yeasts, the oxidation of methanol and higher alcohols with molecular oxygen to formaldehyde and hydrogen peroxide, is catalysed by alcohol oxidase (AOX), a 600-kDa homo-octamer containing eight FAD cofactors. When these yeasts are grown with methanol as the carbon source, AOX forms large crystalline arrays in peroxisomes. We determined the structure of AOX by cryo-electron microscopy at a resolution of 3.4 Å. All residues of the 662-amino acid polypeptide as well as the FAD are well resolved. AOX shows high structural homology to other members of the GMC family of oxidoreductases, which share a conserved FAD binding domain, but have different substrate specificities. The preference of AOX for small alcohols is explained by the presence of conserved bulky aromatic residues near the active site. Compared to the other GMC enzymes, AOX contains a large number of amino acid inserts, the longest being 75 residues. These segments are found at the periphery of the monomer and make extensive inter-subunit contacts which are responsible for the very stable octamer. A short surface helix forms contacts between two octamers, explaining the tendency of AOX to form crystals in the peroxisomes.
Ribosome recycling orchestrated by the ATP binding cassette (ABC) protein ABCE1 can be considered as the final—or the first—step within the cyclic process of protein synthesis, connecting translation termination and mRNA surveillance with re-initiation. An ATP-dependent tweezer-like motion of the nucleotide-binding domains in ABCE1 transfers mechanical energy to the ribosome and tears the ribosome subunits apart. The post-recycling complex (PRC) then re-initiates mRNA translation. Here, we probed the so far unknown architecture of the 1-MDa PRC (40S/30S·ABCE1) by chemical cross-linking and mass spectrometry (XL-MS). Our study reveals ABCE1 bound to the translational factor-binding (GTPase) site with multiple cross-link contacts of the helix–loop–helix motif to the S24e ribosomal protein. Cross-linking of the FeS cluster domain to the ribosomal protein S12 substantiates an extreme lever-arm movement of the FeS cluster domain during ribosome recycling. We were thus able to reconstitute and structurally analyse a key complex in the translational cycle, resembling the link between translation initiation and ribosome recycling.
The P300/CBP-associated factor plays a central role in retroviral infection and cancer development, and the C-terminal bromodomain provides an opportunity for selective targeting. Here, we report several new classes of acetyl-lysine mimetic ligands ranging from mM to low micromolar affinity that were identified using fragment screening approaches. The binding modes of the most attractive fragments were determined using high resolution crystal structures providing chemical starting points and structural models for the development of potent and selective PCAF inhibitors.
Study of hard core repulsive interactions in an hadronic gas from a comparison with lattice QCD
(2016)
We study the influence of hard-core repulsive interactions within the Hadron-Resonace Gas model in comparison to first principle calculation performed on a lattice. We check the effect of a bag-like parametrization for particle eigenvolume on flavor correlators, looking for an extension of the agreement with lattice simulations up to higher temperatures, as was yet pointed out in an analysis of hadron yields measured by the ALICE experiment. Hints for a flavor depending eigenvolume are present.
Non-Timber Forest Products (NTFPs) make a major contribution to the livelihoods and diets of rural households in the savanna ecosystems of West Africa. However, land use change and climatic variability might affect their availability in the future. Based on a survey among 227 households in Northern Benin, we investigated local substitution patterns for the seeds of the three socio-economically most important NTFP-species in the region, Vitellaria paradoxa, Adansonia digitata and Parkia biglobosa, being major sources for protein, fat, and micronutrients in local daily diets. Our study compared substitution patterns between, firstly, three income groups, to assess whether a households’ socio-economic status has an influence on the choice of surrogates (low cost vs. more costly options). Secondly, we compared substitution patterns between the five major ethnic groups in the study region (the Fulani, the Bariba, the Ditammarie, the Kabiyé and the Yom). The choice of substitutes differed significantly across income groups. However, the poorest households clearly show to be the most vulnerable: up to 30 % of the sampled households stated they would lack an adequate replacement for the NTFPs in question. Furthermore, ethnic affiliation showed to have a considerable impact on the preferred alternative products due to underlying cultural traditions of plant use. Subsequently, aiming at maintaining – and enhancing – the local supply of V. paradoxa, P. biglobosa and A. digitata in order to secure their contributions to local diets, local land use policy should have a particular focus on their ethnic-conditioned use and particularly the specific requirements of the poorest community members.
Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.
Although the mechanistic target of rapamycin (mTOR) inhibitor, everolimus, has improved the outcome of patients with renal cell carcinoma (RCC), improvement is temporary due to the development of drug resistance. Since many patients encountering resistance turn to alternative/complementary treatment options, an investigation was initiated to evaluate whether the natural compound, sulforaphane (SFN), influences growth and invasive activity of everolimus-resistant (RCCres) compared to everolimus-sensitive (RCCpar) RCC cell lines in vitro. RCC cells were exposed to different concentrations of SFN and cell growth, cell proliferation, apoptosis, cell cycle, cell cycle regulating proteins, the mTOR-akt signaling axis, adhesion to human vascular endothelium and immobilized collagen, chemotactic activity, and influence on surface integrin receptor expression were investigated. SFN caused a significant reduction in both RCCres and RCCpar cell growth and proliferation, which correlated with an elevation in G2/M- and S-phase cells. SFN induced a marked decrease in the cell cycle activating proteins cdk1 and cyclin B and siRNA knock-down of cdk1 and cyclin B resulted in significantly diminished RCC cell growth. SFN also modulated adhesion and chemotaxis, which was associated with reduced expression of the integrin subtypes α5, α6, and β4. Distinct differences were seen in RCCres adhesion and chemotaxis (diminished by SFN) and RCCpar adhesion (enhanced by SFN) and chemotaxis (not influenced by SFN). Functional blocking of integrin subtypes demonstrated divergent action on RCC binding and invasion, depending on RCC cell sensitivity to everolimus. Therefore, SFN administration could hold potential for treating RCC patients with established resistance towards everolimus.
Post-translational modification of proteins with ubiquitin-like SUMO modifiers is a tightly regulated and highly dynamic process. The SENP family of SUMO-specific isopeptidases comprises six cysteine proteases. They are instrumental in counterbalancing SUMO conjugation, but their regulation is not well understood. We demonstrate that in hypoxic cell extracts, the catalytic activity of SENP family members, in particular SENP1 and SENP3, is inhibited in a rapid and fully reversible process. Comparative mass spectrometry from normoxic and hypoxic cells defines a subset of hypoxia-induced SUMO1 targets, including SUMO ligases RanBP2 and PIAS2, glucose transporter 1, and transcriptional regulators. Among the most strongly induced targets, we identified the transcriptional co-repressor BHLHE40, which controls hypoxic gene expression programs. We provide evidence that SUMOylation of BHLHE40 is reversed by SENP1 and contributes to transcriptional repression of the metabolic master regulator gene PGC-1α. We propose a pathway that connects oxygen-controlled SENP activity to hypoxic reprogramming of metabolism.
Background: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response.
Methods: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively.
Results: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed.
Conclusions: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted.
Trial registration: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.
Dry open rocky grassland vegetation on shallow ultramafic soils in the Central Balkans represents typical secondary grasslands, which have developed mainly in the zone of thermophilous mixed deciduous broadleaved and pine forests. Although all relevant national and regional syntaxonomic reviews classify these rocky grasslands within the distinct order Halacsyetalia sendtneri, the syntaxonomic position of the order in different systems of classification has varied in the past. Considering this as well as the fact that there have been no synoptic works on this specific vegetation type, we gathered all available data on the order Halacsyetalia sendtnerii from the serpentinites of the Western and Central Balkan Peninsula for its critical evaluation. The results obtained in our analyses allowed us to propose a new syntaxonomic concept, which is partly in accordance with previously published syntaxonomic schemes. Two alliances can be distinguished: Centaureo kosaninii-Bromion fibrosi and Potentillion visianii, for which the diagnoses, diagnostic and constant taxa are given. Furthermore, we discussed the syntaxonomic position of the order Halacsyetalia sendtneri with respect to the classes Festuco-Brometea and Koelerio-Corynephoretea, as within the analysed associations, many taxa diagnostic for the class Koelerio-Corynephoretea were registered. The thermophytic pioneer grasslands and therophyte sward communities included in the alliance Thymion jankae nomen. inval., characterised by the absence of typical species of the order Halascyetalia sendtneri and presence of taxa diagnostic for the class Koelerio-Corynephoretea, are temporarily left within the order Halacsyetalia sendtneri. Finally, we provided nomenclatural adjustments for the analysed associations when necessary, although a conclusive judgement regarding all the associations currently included within the analysed order can only be made after more detailed field surveys including data on cryptogams as well as joint analyses including all floristically and ecologically similar syntaxa (e.g. Astragalo-Potentilletalia, Festucetalia valesiacae).
Chromosomal translocations of the human mixed-lineage leukemia (MLL) gene have been analyzed for more than 20 yr at the molecular level. So far, we have collected about 80 direct MLL fusions (MLL-X alleles) and about 120 reciprocal MLL fusions (X-MLL alleles). The reason for the higher amount of reciprocal MLL fusions is that the excess is caused by 3-way translocations with known direct fusion partners. This review is aiming to propose a solution for an obvious problem, namely why so many and completely different MLL fusion alleles are always leading to the same leukemia phenotypes (ALL, AML, or MLL). This review is aiming to explain the molecular consequences of MLL translocations, and secondly, the contribution of the different fusion partners. A new hypothesis will be posed that can be used for future research, aiming to find new avenues for the treatment of this particular leukemia entity.
Purpose: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).
Methods: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.
Results: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.
Conclusions: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI–TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
Purpose: Quantitative T2'-mapping detects regional changes of the relation of oxygenated and deoxygenated hemoglobin (Hb) by using their different magnetic properties in gradient echo imaging and might therefore be a surrogate marker of increased oxygen extraction fraction (OEF) in cerebral hypoperfusion. Since elevations of cerebral blood volume (CBV) with consecutive accumulation of Hb might also increase the fraction of deoxygenated Hb and, through this, decrease the T2’-values in these patients we evaluated the relationship between T2’-values and CBV in patients with unilateral high-grade large-artery stenosis.
Materials and Methods Data from 16 patients (13 male, 3 female; mean age 53 years) with unilateral symptomatic or asymptomatic high-grade internal carotid artery (ICA) or middle cerebral artery (MCA) stenosis/occlusion were analyzed. MRI included perfusion-weighted imaging and high-resolution T2’-mapping. Representative relative (r)CBV-values were analyzed in areas of decreased T2’ with different degrees of perfusion delay and compared to corresponding contralateral areas.
Results: No significant elevations in cerebral rCBV were detected within areas with significantly decreased T2’-values. In contrast, rCBV was significantly decreased (p<0.05) in regions with severe perfusion delay and decreased T2’. Furthermore, no significant correlation between T2’- and rCBV-values was found. Conclusions rCBV is not significantly increased in areas of decreased T2’ and in areas of restricted perfusion in patients with unilateral high-grade stenosis. Therefore, T2’ should only be influenced by changes of oxygen metabolism, regarding our patient collective especially by an increase of the OEF. T2’-mapping is suitable to detect altered oxygen consumption in chronic cerebrovascular disease.
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling
(2016)
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine–threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species‐generating NADPH oxidase‐4 (Nox4) is induced downstream of ATF4, binds to a PP1‐targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4‐regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia–reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4–GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress.
Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases
(2016)
Anti-angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor-A (VEGF-A) have revolutionized treatment of retinal vascular diseases including age-related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti-VEGF-A monotherapy efficacy by targeting both VEGF-A and angiopoietin-2 (ANG-2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF-A. Simultaneous VEGF-A and ANG-2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain-exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF-A and ANG-2. RG7716 showed greater efficacy than anti-VEGF-A alone in a non-human primate laser-induced CNV model after intravitreal delivery. Modification of RG7716’s FcRn and FccR binding sites disabled the antibodies’ Fc-mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential nextgeneration therapy for neovascular indications of the eye.
In this paper I intend to discuss the relation of Marcuse’s theory of technology to its grounding in the possibilities he believed lay inherent, but as yet untapped in nature. Marcuse was an early critic of what he considered to be the exploitative, predatory approach to nature brought about through the direction of technology, industry and science under consumer capitalism, however his alternative; a “new science” and “new technology” which would treat nature as an “ally” in the general struggle for liberation and emancipation, was not without its problems.
Telling and selling literary fiction in early Malay language newspapers in colonial Indonesia
(2016)
When newspapers in the colloquial Malay language appeared in the Dutch East Indies in the middle of the nineteenth century, they did more than just publish news reports and advertisements. They also created a new platform for the telling and distribution of literary fiction. In effect, literary texts soon played an important role in the vernacular print media. The first part of this article analyses the attraction of newspaper literature from the perspective of both the reader and the editor in general and gives a survey of the various forms of literary genres which can be found in newspapers in the late nineteenth and early twentieth century. In the second part, one particular serialized novel will be discussed in detail to demonstrate how the mode of publication also influenced the way stories were told.
To crack the neural code and read out the information neural spikes convey, it is essential to understand how the information is coded and how much of it is available for decoding. To this end, it is indispensable to derive from first principles a minimal set of spike features containing the complete information content of a neuron. Here we present such a complete set of coding features. We show that temporal pairwise spike correlations fully determine the information conveyed by a single spiking neuron with finite temporal memory and stationary spike statistics. We reveal that interspike interval temporal correlations, which are often neglected, can significantly change the total information. Our findings provide a conceptual link between numerous disparate observations and recommend shifting the focus of future studies from addressing firing rates to addressing pairwise spike correlation functions as the primary determinants of neural information.
Precise temporal coding is necessary for proper acoustic analysis. However, at cortical level, forward suppression appears to limit the ability of neurons to extract temporal information from natural sound sequences. Here we studied how temporal processing can be maintained in the bats’ cortex in the presence of suppression evoked by natural echolocation streams that are relevant to the bats’ behavior. We show that cortical neurons tuned to target-distance actually profit from forward suppression induced by natural echolocation sequences. These neurons can more precisely extract target distance information when they are stimulated with natural echolocation sequences than during stimulation with isolated call-echo pairs. We conclude that forward suppression does for time domain tuning what lateral inhibition does for selectivity forms such as auditory frequency tuning and visual orientation tuning. When talking about cortical processing, suppression should be seen as a mechanistic tool rather than a limiting element.
Particularly in savannas, termites are ecosystem engineers and a keystone group in ecology. For the understanding of the savanna vegetation, mound building termites are of particular interest. Due to their special soil chemistry and physical structure, termite mounds often host other plants than the surrounding savanna. As our knowledge of the specific contribution of mound-building termites to overall savanna diversity and ecosystem dynamics doubtlessly is not complete, this paper summarises the state of the art in order to stimulate further research. According to the research interest of the authors, focus is laid on the West African savanna and on the genus Macrotermes.
A new global synthesis and biomization of long (> 40 kyr) pollen-data records is presented and used with simulations from the HadCM3 and FAMOUS climate models and the BIOME4 vegetation model to analyse the dynamics of the global terrestrial biosphere and carbon storage over the last glacial–interglacial cycle. Simulated biome distributions using BIOME4 driven by HadCM3 and FAMOUS at the global scale over time generally agree well with those inferred from pollen data. Global average areas of grassland and dry shrubland, desert, and tundra biomes show large-scale increases during the Last Glacial Maximum, between ca. 64 and 74 ka BP and cool substages of Marine Isotope Stage 5, at the expense of the tropical forest, warm-temperate forest, and temperate forest biomes. These changes are reflected in BIOME4 simulations of global net primary productivity, showing good agreement between the two models. Such changes are likely to affect terrestrial carbon storage, which in turn influences the stable carbon isotopic composition of seawater as terrestrial carbon is depleted in 13C.
In Italy most of the habitats hosting terricolous lichens are found in the Alps and along the coasts, but some lichen-rich plant communities are also present in the Po Plain. We report a study of terrico-lous lichen communities found in dry grasslands attributed to Spergulo vernalis-Corynephoretum canescentis in the western Po Plain (Northern Italy), in accordance with the Braun-Blanquet approach. Relevés (138) were carried out in several developmental stages of the Corynephorus grassland. They were sorted manually and analyzed using ANOSIM, non-parametric MANOVA and PCA. Indicator species of the groups were found by means of INDVAL and SIMPER analyses and literature. Seven lichen vegetation types were distinguished. These were attributable to 4 described associations: Stere-ocauletum condensati, Cladonietum foliaceae (in which we found 3 subassociations: typicum, cladonietosum furcatae and cladonietosum subrangiformis), Cladonietum mitis and Cladonietum rei, and to one impoverished community (Cetraria aculeata community). Ordination of floristic variables showed several overlaps between communities, underlining the depleted floristic conditions found in the study area, where several species occur in many communities and other species are very rare, and thus play a minor role in the differentiation of the lichen vegetation types. Overlaps are also referable to intermediate conditions between one community and another, reflecting dynamic relationships, with Stereocauletum condensati, Cetraria aculeata community and Cladonietum foliaceae typicum having the most distinct pioneer character and Cladonietum mitis being the most evolved. Ordination of eco-logical variables based on the indices of substrate pH, light and humidity requirements and tolerance to eutrophication showed several overlaps between the communities, found to be from acidophytic to subneutrophytic, from rather to very photophytic, from mesophytic to rather xerophytic and from anitrophytic to slightly nitrophytic. Rarity in Italy and conservation needs are discussed in detail, also in comparison with the situation of the same communities in central European Corynephorus grasslands. These grasslands and their typical lichen communities are rare in Italy and, though somewhat depleted, they are the habitat of several threatened lichen species at the southern margin of their distribution range. Therefore management plans should always consider both the cryptogamic and the vascular plant communities.
Natural sounds contain information on multiple timescales, so the auditory system must analyze and integrate acoustic information on those different scales to extract behaviorally relevant information. However, this multi-scale process in the auditory system is not widely investigated in the literature, and existing models of temporal integration are mainly built upon detection or recognition tasks on a single timescale. Here we use a paradigm requiring processing on relatively ‘local’ and ‘global’ scales and provide evidence suggesting that the auditory system extracts fine-detail acoustic information using short temporal windows and uses long temporal windows to abstract global acoustic patterns. Behavioral task performance that requires processing fine-detail information does not improve with longer stimulus length, contrary to predictions of previous temporal integration models such as the multiple-looks and the spectro-temporal excitation pattern model. Moreover, the perceptual construction of putatively ‘unitary’ auditory events requires more than hundreds of milliseconds. These findings support the hypothesis of a dual-scale processing likely implemented in the auditory cortex.
This report provides a brief review of the 20th annual meeting of the German Language Branch of the Society of Environmental Toxicology and Chemistry (SETAC GLB) held from September 7th to 10th 2015 at ETH (Swiss Technical University) in Zurich, Switzerland. The event was chaired by Inge Werner, Director of the Swiss Centre for Applied Ecotoxicology (Ecotox Centre) Eawag-EPFL, and organized by a team from Ecotox Centre, Eawag, Federal Office of the Environment, Federal Office of Agriculture, and Mesocosm GmbH (Germany). Over 200 delegates from academia, public agencies and private industry of Germany, Switzerland and Austria attended and discussed the current state of science and its application presented in 75 talks and 83 posters. In addition, three invited keynote speakers provided new insights into scientific knowledge ‘brokering’, and—as it was the International Year of Soil—the important role of healthy soil ecosystems. Awards were presented to young scientists for best oral and poster presentations, and for best 2014 master and doctoral theses. Program and abstracts of the meeting (mostly in German) are provided as Additional file 1.
The abiotic and biotic drivers of rapid diversification in Andean bellflowers (Campanulaceae)
(2016)
The tropical Andes of South America, the world's richest biodiversity hotspot, are home to many rapid radiations. While geological, climatic, and ecological processes collectively explain such radiations, their relative contributions are seldom examined within a single clade. We explore the contribution of these factors by applying a series of diversification models that incorporate mountain building, climate change, and trait evolution to the first dated phylogeny of Andean bellflowers (Campanulaceae: Lobelioideae). Our framework is novel for its direct incorporation of geological data on Andean uplift into a macroevolutionary model. We show that speciation and extinction are differentially influenced by abiotic factors: speciation rates rose concurrently with Andean elevation, while extinction rates decreased during global cooling. Pollination syndrome and fruit type, both biotic traits known to facilitate mutualisms, played an additional role in driving diversification. These abiotic and biotic factors resulted in one of the fastest radiations reported to date: the centropogonids, whose 550 species arose in the last 5 million yr. Our study represents a significant advance in our understanding of plant evolution in Andean cloud forests. It further highlights the power of combining phylogenetic and Earth science models to explore the interplay of geology, climate, and ecology in generating the world's biodiversity.
Plant-released flavonoids induce the transcription of symbiotic genes in rhizobia and one of the first bacterial responses is the synthesis of so called Nod factors. They are responsible for the initial root hair curling during onset of root nodule development. This signal exchange is believed to be essential for initiating the plant symbiosis with rhizobia affiliated with the Alphaproteobacteria. Here, we provide evidence that in the broad host range strain Sinorhizobium fredii NGR234 the complete lack of quorum sensing molecules results in an elevated copy number of its symbiotic plasmid (pNGR234a). This in turn triggers the expression of symbiotic genes and the production of Nod factors in the absence of plant signals. Therefore, increasing the copy number of specific plasmids could be a widespread mechanism of specialized bacterial populations to bridge gaps in signaling cascades.
The elliptic-flow ratio of neutrons with respect to protons or light complex particles in reactions of heavy ions at pre-relativistic energies has been proposed as an observable sensitive to the strength of the symmetry term of the nuclear equation of state at supra-saturation densities. In the ASY-EOS experiment at the GSI laboratory, flows of neutrons and light charged particles were measured for 197Au+197Au collisions at 400 MeV/nucleon. Flow results obtained for the Au+Au system, in comparison with predictions of the UrQMD transport model, confirm the moderately soft to linear density dependence of the symmetry energy deduced from the earlier FOPI-LAND data.
Calmodulins (CaMs) are important mediators of Ca2+ signals that are found ubiquitously in all eukaryotic organisms. Plants contain a unique family of calmodulin-like proteins (CMLs) that exhibit greater sequence variance compared to canonical CaMs. The Arabidopsis thaliana proteins AtCML4 and AtCML5 are members of CML subfamily VII and possess a CaM domain comprising the characteristic double pair of EF-hands, but they are distinguished from other members of this subfamily and from canonical CaMs by an N-terminal extension of their amino acid sequence. Transient expression of yellow fluorescent protein-tagged AtCML4 and AtCML5 under a 35S-promoter in Nicotiana benthamiana leaf cells revealed a spherical fluorescence pattern. This pattern was confirmed by transient expression in Arabidopsis protoplasts under the native promoter. Co-localization analyses with various endomembrane marker proteins suggest that AtCML4 and AtCML5 are localized to vesicular structures in the interphase between Golgi and the endosomal system. Further studies revealed AtCML5 to be a single-pass membrane protein that is targeted into the endomembrane system by an N-terminal signal anchor sequence. Self-assembly green fluorescent protein and protease protection assays support a topology with the CaM domain exposed to the cytosolic surface and not the lumen of the vesicles, indicating that AtCML5 could sense Ca 2+ signals in the cytosol. Phylogenetic analysis suggests that AtCML4 and AtCML5 are closely related paralogues originating from a duplication event within the Brassicaceae family. CML4/5-like proteins seem to be universally present in eudicots but are absent in some monocots. Together these results show that CML4/5-like proteins represent a flowering plant-specific subfamily of CMLs with a potential function in vesicle transport within the plant endomembrane system.
he study of the resonant structures in neutron-nucleus cross-sections, and therefore of the compound-nucleus reaction mechanism, requires spectroscopic measurements to determine with high accuracy the energy of the neutron interacting with the material under study.
To this purpose, the neutron time-of-flight facility n_TOF has been operating since 2001 at CERN. Its characteristics, such as the high intensity instantaneous neutron flux, the wide energy range from thermal to few GeV, and the very good energy resolution, are perfectly suited to perform high-quality measurements of neutron-induced reaction cross sections. The precise and accurate knowledge of these cross sections plays a fundamental role in nuclear technologies, nuclear astrophysics and nuclear physics.
Two different measuring stations are available at the n_TOF facility, called EAR1 and EAR2, with different characteristics of intensity of the neutron flux and energy resolution. These experimental areas, combined with advanced detection systems lead to a great flexibility in performing challenging measurement of high precision and accuracy, and allow the investigation isotopes with very low cross sections, or available only in small quantities, or with very high specific activity.
The characteristics and performances of the two experimental areas of the n_TOF facility will be presented, together with the most important measurements performed to date and their physics case. In addition, the significant upcoming measurements will be introduced.
Photosystem II (PSII) catalyzes the unique reaction of light-dependent water oxidation and subsequent reduction of plastoquinone at the beginning of the photosynthetic electron transport chain. The mature complex consists of at least 20 protein-subunits and over 80 cofactors. Further proteins are required for biogenesis and repair of PSII. Most of these proteins interact specifically with assembly intermediates during defined steps in PSII assembly. This review shall emphasize the function of the two factors Psb27 and Psb28 during the biogenesis and repair of PSII in cyanobacteria and give an impression of their potential biochemical, structural and physiological properties in plants considering the fact that they both have homologues in all oxygenic photosynthetic organisms. We hypothesize that Psb28 may have retained its function in higher plants while the two Psb27 forms bind differently to PSII intermediates depending on PSII core phosphorylation state.
The papers here collected are divided in an English and an Italian section, to facilitate the reader who is confident, or prefers, only one of these languages. In both sections, Critical Theory is addressed in a twofold way: as regards its origins in the so-called School of Frankfurt and as concerns its further and contemporary developments, from an interdisciplinary perspective.
The decay properties of the Pygmy Dipole Resonance (PDR) have been investigated in the semi-magic N=82 nucleus 140Ce using a novel combination of nuclear resonance fluorescence and γ–γ coincidence techniques. Branching ratios for transitions to low-lying excited states are determined in a direct and model-independent way both for individual excited states and for excitation energy intervals. Comparison of the experimental results to microscopic calculations in the quasi-particle phonon model exhibits an excellent agreement, supporting the observation that the Pygmy Dipole Resonance couples to the ground state as well as to low-lying excited states. A 10% mixing of the PDR and the [21+ x PDR] is extracted.
The article aims to sharpen the neo-republican contribution to international political thought by challenging Pettit’s view that only representative states may raise a valid claim to non-domination in their external relations. The argument proceeds in two steps: First I show that, conceptually speaking, the domination of states, whether representative or not, implies dominating the collective people at least in its fundamental, constitutive power. Secondly, the domination of states – and thus of their peoples – cannot be justified normatively in the name of promoting individual non-domination because such a compensatory rationale misconceives the notion of domination in terms of a discrete exercise of power instead of as an ongoing power relation. This speaks in favour of a more inclusive law of peoples than Pettit (just as his liberal counterpart Rawls) envisages: In order to accommodate the claim of collective peoples to non-domination it has to recognize every state as a member of the international order.
Like most jurisdictions, Australia is managing a broad range of invasive alien species. Here, we provide the first holistic quantification of how much invasive species impact Australia’s economy, and how much Australia spends on their management. In the 01–02 financial year (June to July), the combined estimated cost (economic losses and control) of invasive species was $9.8 billion, rising to $13.6 billion in the 11–12 financial year. Approximately $726 million of grants funded through the Commonwealth of Australia (i.e. federal funding) was spent on invasive species management and research between 1996 to 2013. In 01–02, total national expenditure on invasive species was $2.31 billion, rising to $3.77 billion in 11–12. Agriculture accounted for more than 90% of the total cost. For 01–02 and 11–12, these expenditure figures equate to $123 and $197 per person per year respectively, as well as 0.32 and 0.29% of GDP respectively. All values provided here are most likely to be underestimates of the real values due to the significant constraints of the data obtainable. Invasive species are clearly a significant economic burden in Australia. Given the extent of the issue of invasive species globally, there is a clear need for better quantifications of both economic loss and expenditure in more jurisdictions, as well as in Australia.
The growth of freshly formed aerosol particles can be the bottleneck in their survival to cloud condensation nuclei. It is therefore crucial to understand how particles grow in the atmosphere. Insufficient experimental data has impeded a profound understanding of nano-particle growth under atmospheric conditions. Here we study nano-particle growth in the CLOUD (Cosmics Leaving OUtdoors Droplets) chamber, starting from the formation of molecular clusters. We present measured growth rates at sub-3 nm sizes with different atmospherically relevant concentrations of sulphuric acid, water, ammonia and dimethylamine. We find that atmospheric ions and small acid-base clusters, which are not generally accounted for in the measurement of sulphuric acid vapour, can participate in the growth process, leading to enhanced growth rates. The availability of compounds capable of stabilizing sulphuric acid clusters governs the magnitude of these effects and thus the exact growth mechanism. We bring these observations into a coherent framework and discuss their significance in the atmosphere.
DESPITE A RECENT SLIGHT RECOVERY FROM CRISIS LOW LEVELS, STOCK MARKET PARTICIPATION IN GERMANY IS STILL AT ONLY 14% OF ADULT POPULATION. PREVIOUS RESEARCH SHOWED THAT TRADITIONAL PERSONAL ADVICE – DUE TO HIGH COSTS AND MISALIGNED INCENTIVES – CAN HARDLY ALLEVIATE PRIVATE INVESTORS' INVESTMENT MISTAKES, OF WHICH STOCK MARKET NON-PARTICIPATION IS ONE. ROBOADVICE IS A "HOT TOPIC" IN REGULATORY AND INDUSTRY DISCUSSIONS. THE RESULTS OF THIS STUDY SHOW EMPIRICAL EVIDENCE THAT INVITATIONS TO ROBO-ADVICE INCREASE STOCK MARKET PARTICIPATION.
Background: Lectures remain an important teaching method to present and structure knowledge to many students concurrently. Adequate measures are necessary to maintain the quality of the lectures. The aim of this study was to determine the impact on the lecture quality using written structured feedback and to compare the ratings of surgical lectures between students and surgical peers.
Methods: Prospective analysis of two consecutive surgical lecture series for undergraduate students at Goethe-University Medical School was performed before and after evaluation of the lecturers via independent written feedback from trained undergraduate students and surgeons. The 22-item feedback instrument covered three areas of performance: content, visualization, and delivery. Additional suggestions for improvement were provided from
both students and surgical peers who anonymously attended the lectures. The lecturers, experienced surgeons, as well as the student and peer raters were blinded in terms of the aim and content of the study. Their response to the feedback was collected using a web-based 13-item questionnaire. The Kendall’s-W coefficient was computed to calculate inter-rater reliability (IRR). Differences between ratings before and after feedback were analyzed using Student’s t-test for dependent samples. The Kolmogorov-Smirnov-test was used for independent samples.
Results: A total of 22 lectures from a possible 32 given by 13 lecturers were included and analyzed by at least three surgeons and two students. There were significant improvements in overall score as well as in the details of 9 of the 13 items were found. The average inter-rater reliability was 0.71. There were no differences in the ratings as a function of the rater’s level of expertise (peers vs. students). We found that 13/23 lecturers (56.5%) answered the questionnaire, and 92% strongly agreed that the written feedback was useful. 76.9% of the lecturers revised their lecture based on the written feedback requiring on average 112.5 min (range from 20 to 300 min).
Conclusions: Overall, this study indicates that structured written feedback provided by trained peers and students that is subsequently discussed by the lecturers concerned is a highly effective and efficient method to improve aspects of lecturing. We anticipate that structured written feedback by trained students that is discussed by the lecturers concerned will improve lecturing.
Keywords: Lecture, Feedback, Surgery, Peer-feedback, Evaluation, Undergraduate training
The effects of acute physical exercise on memory, peripheral BDNF, and cortisol in young adults
(2016)
In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans.
Within the family of NADPH oxidases, NOX4 is unique as it is predominantly localized in the endoplasmic reticulum, has constitutive activity, and generates hydrogen peroxide (H2O2). We hypothesize that these features are consequences of a so far unidentified NOX4-interacting protein. Two-dimensional blue native (BN) electrophorese combined with SDS-PAGE yielded NOX4 to reside in macromolecular complexes. Interacting proteins were screened by quantitative SILAC (stable isotope labeling of amino acids in cell culture) co-immunoprecipitation (Co-IP) in HEK293 cells stably overexpressing NOX4. By this technique, several interacting proteins were identified with calnexin showing the most robust interaction. Calnexin also resided in NOX4-containing complexes as demonstrated by complexome profiling from BN-PAGE. The calnexin NOX4 interaction could be confirmed by reverse Co-IP and proximity ligation assay, whereas NOX1, NOX2, or NOX5 did not interact with calnexin. Calnexin deficiency as studied in mouse embryonic fibroblasts from calnexin(-/-)mice or in response to calnexin shRNA reduced cellular NOX4 protein expression and reactive oxygen species formation. Our results suggest that endogenous NOX4 forms macromolecular complexes with calnexin, which are needed for the proper maturation, processing, and function of NOX4 in the endoplasmic reticulum.
The Fire Modeling Intercomparison Project (FireMIP), phase 1: experimental and analytical protocols
(2016)
The important role of fire in regulating vegetation community composition and contributions to emissions of greenhouse gases and aerosols make it a critical component of dynamic global vegetation models and Earth system models. Over two decades of development, a wide variety of model structures and mechanisms have been designed and incorporated into global fire models, which have been linked to different vegetation models. However, there has not yet been a systematic examination of how these different strategies contribute to model performance. Here we describe the structure of the first phase of the Fire Model Intercomparison Project (FireMIP), which for the first time seeks to systematically compare a number of models. By combining a standardized set of input data and model experiments with a rigorous comparison of model outputs to each other and to observations, we will improve the understanding of what drives vegetation fire, how it can best be simulated, and what new or improved observational data could allow better constraints on model behavior. Here we introduce the fire models used in the first phase of FireMIP, the simulation protocols applied, and the benchmarking system used to evaluate the models. The works published in this journal are distributed under the Creative Commons Attribution 3.0 License. This license does not affect the Crown copy-right work, which is re-usable under the Open Government Licence (OGL). The Creative Commons Attribution 3.0 License and the OGL are interoperable and do not conflict with, reduce, or limit each other.
Background: The systematic analysis of a large number of comparable plant trait data can support investigations into phylogenetics and ecological adaptation, with broad applications in evolutionary biology, agriculture, conservation, and the functioning of ecosystems. Floras, i.e., books collecting the information on all known plant species found within a region, are a potentially rich source of such plant trait data. Floras describe plant traits with a focus on morphology and other traits relevant for species identification in addition to other characteristics of plant species, such as ecological affinities, distribution, economic value, health applications, traditional uses, and so on. However, a key limitation in systematically analyzing information in Floras is the lack of a standardized vocabulary for the described traits as well as the difficulties in extracting structured information from free text.
Results: We have developed the Flora Phenotype Ontology (FLOPO), an ontology for describing traits of plant species found in Floras. We used the Plant Ontology (PO) and the Phenotype And Trait Ontology (PATO) to extract entity-quality relationships from digitized taxon descriptions in Floras, and used a formal ontological approach based on phenotype description patterns and automated reasoning to generate the FLOPO. The resulting ontology consists of 25,407 classes and is based on the PO and PATO. The classified ontology closely follows the structure of Plant Ontology in that the primary axis of classification is the observed plant anatomical structure, and more specific traits are then classified based on parthood and subclass relations between anatomical structures as well as subclass relations between phenotypic qualities.
Conclusions: The FLOPO is primarily intended as a framework based on which plant traits can be integrated computationally across all species and higher taxa of flowering plants. Importantly, it is not intended to replace established vocabularies or ontologies, but rather serve as an overarching framework based on which different application- and domain-specific ontologies, thesauri and vocabularies of phenotypes observed in flowering plants can be integrated.
The German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh) : a success story
(2016)
This article gives a comprehensive overview on the strategy, the development and the progress of the German postgraduate degree program in ecotoxicology (SETAC GLB and GDCh). The program soon prompted positive results: more than 10 years now the courses had an average enrolment rate of 90 %, and employment-seeking graduates from the first courses mostly succeeded in quickly finding employment relevant to their training. With over 450 students enrolled to date, the degree program contributes significantly to the field of Environmental Chemistry and Ecotoxicology.
The essay, originally written in German as an introduction to a volume of collected papers, shows the influence of the Historical School of Law on legal, historical and social sciences in Germany throughout the 19th and even 20th centuries – a time span running contrary to the dominate view that sees the end of the School in the middle of the 19th century. In my view the School constitutes not only a method for developing norms of private law out of the historical materials of Roman and German-Germanic laws, but is based on a wider conception of culture, law and history that is also connected to the political positions of that time. In Savigny’s founding pamphlet, "The vocation of our time ...", two major theoretical topics for this long-lasting influence can be found: The Romantic one, which views law as a part of culture and parallel to language and custom, based on the "spirit of the people", and, on the other side, the rationality of the European tradition of Roman law, which was developed and administered by jurists. These two basic points, in part standing in contradiction to one another, form a fertile tension that provides an impulse to the intellectual discussions and new movements in jurisprudence and history analysed in the text. Realism, founded in the connection of both sciences to political and social life, builds a kind of "basso continuo" and acts as a counterbalance to the former two. And it is in this context that the works of Jacob Grimm, Puchta and Beseler, Heinrich Brunner, Georg von Below and others are analysed, in particular the works of Otto von Gierke and Max Weber. Finally, evidence is furnished that a new image of the medieval period, and its impact on law, as a centre of Western identity was outlined in the 20th century by authors like Ernst Kantorowicz, Fritz Kern, Otto Brunner and, last but not least, by Harold J. Berman (walking in the footsteps of Eugen Rosenstock- Huessy), all of whom were situated in different ways within the tradition of the broader, cultural-based Romantic view.
The concept of freedom as non-domination that is associated with neo-republican theory provides a guiding ideal in the global, not just the domestic arena, and does so even on the assumption that there will continue to be many distinct states. It argues for a world in which states do not dominate members of their own people and, considered as a corporate body, no people is dominated by other agencies: not by other states and not, for example, by any international agency or multi-national corporation. This ideal is not only attractive in the abstract, it also supports a concrete range of sensible, if often radical international policies.
Epigenetic marks critically control gene expression and thus the cellular activity state. The functions of many epigenetic modifiers in the vascular system have not yet been studied. We screened for histone modifiers in endothelial cells and observed a fairly high expression of the histone plant homeodomain finger protein 8 (PHF8). Given its high expression, we hypothesize that this histone demethylase is important for endothelial cell function. Overexpression of PHF8 catalyzed the removal of methyl-groups from histone 3 lysine 9 (H3K9) and H4K20, whereas knockdown of the enzyme increased H3K9 methylation. Knockdown of PHF8 by RNAi also attenuated endothelial proliferation and survival. As a functional readout endothelial migration and tube formation was studied. PHF8 siRNA attenuated the capacity for migration and developing of capillary-like structures. Given the impact of PHF8 on cell cycle genes, endothelial E2F transcription factors were screened, which led to the identification of the gene repressor E2F4 to be controlled by PHF8. Importantly, PHF8 maintains E2F4 but not E2F1 expression in endothelial cells. Consistently, chromatin immunoprecipitation revealed that PHF8 reduces the H3K9me2 level at the E2F4 transcriptional start site, demonstrating a direct function of PHF8 in endothelial E2F4 gene regulation. Conclusion: PHF8 by controlling E2F4 expression maintains endothelial function.
The Hydrogen Dependent Carbon dioxide Reductase (HDCR) from Acetobacterium woodii presents a promising solution to the issue of H2 storage by reversibly coupling H2 oxidation to CO2 reduction. We here report on the electrocatalytic properties of the hydrogenase (Hase) module in the intact complex, including (an)aerobic oxidation, CO inhibition and the first systematic analysis of the catalytic bias (CB) of a Hase. CB depends on pH, regardless of the H2 concentration, despite a higher affinity for H2 than other FeFe-Hases. Remarkably, CO inhibition is fully reversible under all oxidation states of the active site, making HDCR the first "syngas-friendly" FeFe-Hase.
Ambrosia artemisiifolia is an invasive annual herb infamous for the high allergenicity of its pollen, which is related to increasing medical costs. Additionally, it can cause serious yield losses as agricultural weed. Common ragweed seeds accumulate in the soil and can remain therein viable for decades, which poses a problem for the sustainable management of these populations. A long term management should thus target a reduction of the soil seed bank. We observed the influence of four different mowing regimes on the ragweed soil seed bank at six roadside populations in eastern Austria. The mowing regimes were based on methods from common roadside management practice and specifically adapted to reduce seed production. After three years of application, the soil seed bank was indeed reduced by 45 to 80 percent through three of the four mowing regimes tested. Therefore, we suggest that the best mowing regime for the most effective reduction of the size of the soil seed bank is the one consisting of one cut just after the beginning of female flowering (around the 3rd week of August in Eastern Central Europe), followed by a second cut 2–3 weeks later.
Bilberry (Vaccinium myrtillus L.) is a dwarf shrub with high ecological relevance as habitat and as a food source for many animals in mountain forests of central Europe. This species benefits from conifer forests and declines with an increase of broadleaved tree species in the canopy. The ongoing large-scale conversion from conifer to broadleaved forests may significantly alter the ground vegetation, especially the dominance of a key species such as bilberry. We used morphological indicators to investigate the vitality of bilberry. The first objective was to determine whether the vitality of bilberry is negatively impacted by increasing the proportion of beech (Fagus sylvatica L.) in Norway spruce (Picea abies Karst.) forests. The vitality of bilberry was measured by its cover, height, biomass, shoot length and basal diameter. The second objective was to determine whether these changes in bilberry vitality were related to light, canopy cover, soil pH, organic layer mass and tree species. The data was collected from three study areas in the southern and central Black Forest. The bedrock consisted of gneiss and granite whereas the stands were either: pure beech, a mixture of beech and spruce or pure spruce. The stands were located adjacent to each other. On all three areas a higher vitality of bilberry was observed under spruce compared to beech. Mixed effect models show that the occurrence of spruce is the most important variable explaining the increase in bilberry biomass. Light had a small positive effect, whereas soil properties had negligible effects and were site specific. These results are a strong indication of the negative influence that beech has on bilberry in conifer dominated forests. This has to be taken into consideration when developing silvicultural approaches and should be a consideration when making plans for the preservation of habitat for species like capercaillie (Tetrao urogallus L.). This is even more important today because the recent trend in central European forestry is to increase the proportion of beech.
One hallmark of MLL-r leukemia is the highly specific gene expression signature indicative for commonly deregulated target genes. An usual read-out for this transcriptional deregulation is the HOXA gene cluster, where upregulated HOXA genes are detected in MLL-r AML and ALL patients. In case of t(4;11) leukemia, this simple picture becomes challenged, because these patients separate into HOXAhi- and HOXAlo-patients. HOXAlo-patients showed a reduced HOXA gene transcription, but instead overexpressed the homeobox gene IRX1. This transcriptional pattern was associated with a higher relapse rate and worse outcome. Here, we demonstrate that IRX1 binds to the MLL-AF4 complex at target gene promotors and counteract its promotor activating function. In addition, IRX1 induces transcription of HOXB4 and EGR family members. HOXB4 is usually a downstream target of c-KIT, WNT and TPO signaling pathways and necessary for maintaining and expanding in hematopoietic stem cells. EGR proteins control a p21-dependent quiescence program for hematopoietic stem cells. Both IRX1-dependend actions may help t(4;11) leukemia cells to establish a stem cell compartment. We also demonstrate that HDACi administration is functionally interfering with IRX1 and MLL-AF4, a finding which could help to improve new treatment options for t(4;11) patients.
Background: In vertebrates, several anatomical regions located within the nasal cavity mediate olfaction. Among these, the main olfactory epithelium detects most conventional odorants. Olfactory sensory neurons, provided with cilia exposed to the air, detect volatile chemicals via an extremely large family of seven-transmembrane chemoreceptors named odorant receptors. Their genes are expressed in a monogenic and monoallelic fashion: a single allele of a single odorant receptor gene is transcribed in a given mature neuron, through a still uncharacterized molecular mechanism known as odorant receptor gene choice.
Aim: Odorant receptor genes are typically arranged in genomic clusters, but a few are isolated (we call them solitary) from the others within a region broader than 1 Mb upstream and downstream with respect to their transcript's coordinates. The study of clustered genes is problematic, because of redundancy and ambiguities in their regulatory elements: we propose to use the solitary genes as simplified models to understand odorant receptor gene choice.
Procedures: Here we define number and identity of the solitary genes in the mouse genome (C57BL/6J), and assess the conservation of the solitary status in some mammalian orthologs. Furthermore, we locate their putative promoters, predict their homeodomain binding sites (commonly present in the promoters of odorant receptor genes) and compare candidate promoter sequences with those of wild-caught mice. We also provide expression data from histological sections.
Results: In the mouse genome there are eight intact solitary genes: Olfr19 (M12), Olfr49, Olfr266, Olfr267, Olfr370, Olfr371, Olfr466, Olfr1402; five are conserved as solitary in rat. These genes are all expressed in the main olfactory epithelium of three-day-old mice. The C57BL/6J candidate promoter of Olfr370 has considerably varied compared to its wild-type counterpart. Within the putative promoter for Olfr266 a homeodomain binding site is predicted. As a whole, our findings favor Olfr266 as a model gene to investigate odorant receptor gene choice.
Background and aim. In the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis.
Material and methods. To further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions.
Results. We noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster.
Conclusions. Thus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP.
The recently described shrub Epacris browniae (family Ericaceae) an endemic Blue Mountains species, occurs on treeless, dry, rocky, Sydney Montane Heath, on Narrabeen and Hawkesbury Sandstone in the upper Blue Mountains, 100 km west of Sydney, New South Wales, (c. 33° 40' S; 150° 22' E) at altitudes above 800 m, and within the 1300 mm Average Annual Rainfall isohyet. Based on our surveys in the Blue Mountains (incorporating 46 locations), the Area of Occurrence of the species is estimated at 525 square km, within which the Area of Occupation is 25 hectares. The northern limit is Mt Wilson, southern limit, Mt Solitary, western limit appears to lie between Clarence and Narrow Neck (Katoomba) and eastern limit is Lawson Ridge.
The species grows either on flat terrain or on gentle southern or western slopes, sometimes blending into escarpment complex, on soils of moderate acidity (pH 6.5–6.8) and good drainage, associated most commonly with Banksia ericifolia and, in descending order of abundance, with Leptospermum trinervium, Allocasuarina distyla, Kunzea capitata, Allocasuarina nana and Hakea dactyloides.
Epacris browniae flowers in November and seeds ripen in March. Seeds are shiny, brown, minutely warty, about 0.6 mm long, and weigh 0.038 mg.
Epacris browniae does not resprout after fire. Average stem diameters at three sites with known single fire histories correlate strongly with likely maximum age and confirm that the species is a facultative reseeder with a potential lifespan of up to 50 years.
Despite its relatively narrow habitat and area of occupancy Epacris browniae is well conserved within National Parks in the Blue Mountains but its susceptibility to Phytophthora, an exotic pathogen in the Blue Mountains is unknown.
Background: Cancer screening participation rates in Germany differ depending on patients’ gender. International studies have found that patient–physician gender concordance fosters recommendation and conducting of cancer screening, and especially cancer screening for women.
Objectives: We aimed to ascertain whether gender concordance influences general practitioners' (GPs’) rating of the usefulness of cancer screening, as well as their recommendations and readiness to conduct cancer screening in general practice in Germany.
Methods: For an exploratory cross-sectional survey, 500 randomly selected GPs from all over Germany were asked to fill in a questionnaire on cancer screening in general practice between March and June 2015. We asked them to rate the usefulness of each cancer screening examination, how frequently they recommended and conducted them and whether they viewed GPs or specialists as responsible for carrying them out. We used multiple logistic regression to analyse gender effect size by calculating odds ratios.
Results: Our study sample consisted of 139 GPs of which 65% were male. Male and female GPs did not differ significantly in their rating of the general usefulness of any of the specified cancer screening examinations. Male GPs were 2.9 to 6.8 times as likely to consider GPs responsible for recommending and conducting PSA testing and digital rectal examinations and were 3.7 to 7.9 times as likely to recommend and conduct these examinations on a regular basis.
Conclusion: Patient–physician gender concordance made it more likely that male-specific cancer screenings would be recommended and conducted, but not female-specific screenings.
Purpose: In secondary progressive Multiple Sclerosis (SPMS), global neurodegeneration as a driver of disability gains importance in comparison to focal inflammatory processes. However, clinical MRI does not visualize changes of tissue composition outside MS lesions. This quantitative MRI (qMRI) study investigated cortical and deep gray matter (GM) proton density (PD) values and T1 relaxation times to explore their potential to assess neuronal damage and its relationship to clinical disability in SPMS.
Materials and Methods: 11 SPMS patients underwent quantitative T1 and PD mapping. Parameter values across the cerebral cortex and deep GM structures were compared with 11 healthy controls, and correlation with disability was investigated for regions exhibiting significant group differences.
Results: PD was increased in the whole GM, cerebral cortex, thalamus, putamen and pallidum. PD correlated with disability in the whole GM, cerebral cortex, putamen and pallidum. T1 relaxation time was prolonged and correlated with disability in the whole GM and cerebral cortex.
Conclusion: Our study suggests that the qMRI parameters GM PD (which likely indicates replacement of neural tissue with water) and cortical T1 (which reflects cortical damage including and beyond increased water content) are promising qMRI candidates for the assessment of disease status, and are related to disability in SPMS.
About half of present-day cloud condensation nuclei originate from atmospheric nucleation, frequently appearing as a burst of new particles near midday1. Atmospheric observations show that the growth rate of new particles often accelerates when the diameter of the particles is between one and ten nanometres2,3. In this critical size range, new particles are most likely to be lost by coagulation with pre-existing particles4, thereby failing to form new cloud condensation nuclei that are typically 50 to 100 nanometres across. Sulfuric acid vapour is often involved in nucleation but is too scarce to explain most subsequent growth5,6, leaving organic vapours as the most plausible alternative, at least in the planetary boundary layer7,8,9,10. Although recent studies11,12,13 predict that low-volatility organic vapours contribute during initial growth, direct evidence has been lacking. The accelerating growth may result from increased photolytic production of condensable organic species in the afternoon2, and the presence of a possible Kelvin (curvature) effect, which inhibits organic vapour condensation on the smallest particles (the nano-Köhler theory)2,14, has so far remained ambiguous. Here we present experiments performed in a large chamber under atmospheric conditions that investigate the role of organic vapours in the initial growth of nucleated organic particles in the absence of inorganic acids and bases such as sulfuric acid or ammonia and amines, respectively. Using data from the same set of experiments, it has been shown15 that organic vapours alone can drive nucleation. We focus on the growth of nucleated particles and find that the organic vapours that drive initial growth have extremely low volatilities (saturation concentration less than 10−4.5 micrograms per cubic metre). As the particles increase in size and the Kelvin barrier falls, subsequent growth is primarily due to more abundant organic vapours of slightly higher volatility (saturation concentrations of 10−4.5 to 10−0.5 micrograms per cubic metre). We present a particle growth model that quantitatively reproduces our measurements. Furthermore, we implement a parameterization of the first steps of growth in a global aerosol model and find that concentrations of atmospheric cloud concentration nuclei can change substantially in response, that is, by up to 50 per cent in comparison with previously assumed growth rate parameterizations.
This study reports and discusses new radiometric ages, petrographical and volcanological observations and whole rock geochemical data of the rocks of the Rudnik Mts. volcano-intrusive complex. The complex hosts a Pb-Zn-Ag deposit and belongs to the Serbo-Macedonian metallogenetic belt. Two distinct igneous events are distignuished. The first occurred >30 Ma and was mainly characterized by extrusive and shallow intrusive dacites and andesites and was unrelated to mineralization. The second igneous event occurred <23 Ma and was highly heterogeneous in terms of volcanic products and petrographic varieties, but with predominance of quartzlatites. The dacite-andesites (first event) and the quartzlatites (second event) are geochemically similar and display a calc-alkaline affinity and highly incompatible element enriched patterns on spider diagrams, but the younger quartzlatites are richer in K2O, Rb and Ba and poorer in Sr. This is taken as evidence that mixing between an ultrapotassic lamprophyre/lamproite magma and an acid calc-alkaline (dacite-like) magma was essential petrogenetic processes during the second event. The proposed simplified volcanological model suggests that this mixing was responsible for triggering strongly explosive volcanic activity as well as for providing conditions for active hydrothermal and mineralization processes. The observed link between a specific magmatic phase and ore deposit formation can be a general phennomenon in the Balkans, and must be addressed by further and more advanced studies.
Biomass burning impacts vegetation dynamics, biogeochemical cycling, atmospheric chemistry, and climate, with sometimes deleterious socio-economic impacts. Under future climate projections it is often expected that the risk of wildfires will increase. Our ability to predict the magnitude and geographic pattern of future fire impacts rests on our ability to model fire regimes, using either well-founded empirical relationships or process-based models with good predictive skill. While a large variety of models exist today, it is still unclear which type of model or degree of complexity is required to model fire adequately at regional to global scales. This is the central question underpinning the creation of the Fire Model Intercomparison Project (FireMIP), an international initiative to compare and evaluate existing global fire models against benchmark data sets for present-day and historical conditions. In this paper we review how fires have been represented in fire-enabled dynamic global vegetation models (DGVMs) and give an overview of the current state of the art in fire-regime modelling. We indicate which challenges still remain in global fire modelling and stress the need for a comprehensive model evaluation and outline what lessons may be learned from FireMIP.
Biomass burning impacts vegetation dynamics, biogeochemical cycling, atmospheric chemistry, and climate, with sometimes deleterious socio-economic impacts. Under future climate projections it is often expected that the risk of wildfires will increase. Our ability to predict the magnitude and geographic pattern of future fire impacts rests on our ability to model fire regimes, either using well-founded empirical relationships or process-based models with good predictive skill. A large variety of models exist today and it is still unclear which type of model or degree of complexity is required to model fire adequately at regional to global scales. This is the central question underpinning the creation of the Fire Model Intercomparison Project - FireMIP, an international project to compare and evaluate existing global fire models against benchmark data sets for present-day and historical conditions. In this paper we summarise the current state-of-the-art in fire regime modelling and model evaluation, and outline what lessons may be learned from FireMIP.
Biological control of weeds in Vanuatu began in 1935, with the introduction of the tingid Teleonemia scrupulosa to control Lantana camara. To date, nine biological control agents have been intentionally introduced to control eight weed species. Seven of these agents have established on their respective hosts while an eighth, Zygogramma bicolorata, an agent for Parthenium hysterophorus has only recently been released and establishment is unlikely. The fate of a ninth agent, Heteropsylla spinulosa, released for the control of Mimosa diplotricha is unclear. Six other biological control agents, including Epiblema strenuana which was first detected in 2014 on P. hysterophorus on Efate have spread into the country unintentionally. Control of the target weeds range from inadequate to very good. By far the most successful agent has been Calligrapha pantherina which was introduced to control Sida acuta and Sida rhombifolia. The beetle was released on 14 islands and managed to spread to at least another 10 islands where it has effectively controlled both Sida spp. Control of the two water weeds, Eichhornia crassipes by Neochetina bruchi and N. eichhorniae and Pistia stratiotes by Neohydronomus affinis, has also been fairly good in most areas. Two agents, T. scrupulosa and Uroplata girardi, were released on L. camara, and four other agents have been found on the weed, but L. camara is still not under adequate control. The rust Puccinia spegazzinii was first released on Mikania micrantha in 2012 and successfully established. Anecdotal evidence suggests that it is having an impact on M. micrantha, but detailed monitoring is required to determine its overall impact. Future prospects for weed biological control in Vanuatu are positive, with the expected greater spread of recently released agents and the introduction of new agents for P. hysterophorus, L. camara, Dolichandra unguis-cati and Spathodea campanulata.
The swine plasma metabolome chronicles "many days" biological timing and functions linked to growth
(2016)
The paradigm of chronobiology is based almost wholly upon the daily biological clock, or circadian rhythm, which has been the focus of intense molecular, cellular, pharmacological, and behavioral, research. However, the circadian rhythm does not explain biological timings related to fundamental aspects of life history such as rates of tissue/organ/body size development and control of the timing of life stages such as gestation length, age at maturity, and lifespan. This suggests that another biological timing mechanism is at work. Here we focus on a "many days" (multidien) chronobiological period first observed as enigmatic recurring growth lines in developing mammalian tooth enamel that is strongly associate with all adult tissue, organ, and body masses as well as life history attributes such as gestation length, age at maturity, weaning, and lifespan, particularly among the well studied primates. Yet, knowledge of the biological factors regulating the patterning of mammalian life, such as the development of body size and life history structure, does not exist. To identify underlying molecular mechanisms we performed metabolome and genome analyses from blood plasma in domestic pigs. We show that blood plasma metabolites and small non-coding RNA (sncRNA) drawn from 33 domestic pigs over a two-week period strongly oscillate on a 5-day multidien rhythm, as does the pig enamel rhythm. Metabolomics and genomics pathway analyses actually reveal two 5-day rhythms, one related to growth in which biological functions include cell proliferation, apoptosis, and transcription regulation/protein synthesis, and another 5-day rhythm related to degradative pathways that follows three days later. Our results provide experimental confirmation of a 5-day multidien rhythm in the domestic pig linking the periodic growth of enamel with oscillations of the metabolome and genome. This association reveals a new class of chronobiological rhythm and a snapshot of the biological bases that regulate mammalian growth, body size, and life history.
This commentary on Edwin Carels’ essay “Revisiting Tom Tom: Performative anamnesis and autonomous vision in Ken Jacobs’ appropriations of Tom Tom the Piper’s Son” broadens up the media-archaeological framework in which Carels places his text. Notions such as Huhtamo’s topos and Zielinski’s “deep time” are brought into the discussion in order to point out the difficulty to see what there is to see and to question the position of the viewer in front of experimental films like Tom Tom the Piper’s Son and its remakes.
Background: It is occasionally difficult to distinguish the stellate reticulum-like region of ameloblastoma from the fibrous connective tissue stroma. This difficulty is further pronounced in the plexiform variant of ameloblastoma that has very sparse fibrous connective tissue.
Aim: To test the utility of Azan trichrome stain in marking tumour regions and the peri-tumour environment of ameloblastoma.
Materials and Methods: Sections were prepared for 18 formalin fixed paraffin-embedded blocks of ameloblastoma cases and stained with Azan trichrome stain according to the manufacturer's specification.
Results and Conclusions: The tumour areas were stained mostly brown, with the ameloblasts mainly marked as deep brown while the stellate reticulum-like region was light brown. The structures in the peri-tumour region were marked with different shades of blue. Azan trichrome staining was able to distinguish between the fibrous connective tissue and the stellate reticulum-like areas in 100% of the cases.
We study the effect of thermal charm production on charmonium regeneration in high energy nuclear collisions. By solving the kinetic equations for charm quark and charmonium distributions in Pb+Pb collisions, we calculate the global and differential nuclear modification factors RAA(Npart) and RAA(pt) for J/ψ s. Due to the thermal charm production in hot medium, the charmonium production source changes from the initially created charm quarks at SPS, RHIC and LHC to the thermally produced charm quarks at Future Circular Collider (FCC), and the J/ψ suppression (RAA<1) observed so far will be replaced by a strong enhancement (RAA>1) at FCC at low transverse momentum.
Thomas Reedy (1842-1929), gardener from 1854-1926 at Camden Park, the family estate of the Macarthurs in western Sydney was sent by Sir William Macarthur on the Chevert Expedition to New Guinea in 1875. He collected plants on islands off the Queensland coast; Cape Grenville; around the Somerset outpost on the tip of Cape York; on islands in the Torres Strait; and around two locations on the mainland of southern Papua New Guinea. Reedy sent or brought back 800-1000 living plants, in addition to an unknown number of seeds, and at least 157 dried specimens, the latter sent to Baron Ferdinand von Mueller in Melbourne. This study is focused on locating the dried plant specimens now held in herbaria and highlighting their significance.
Reedy is something of an enigma with little ever written about him. His initial has been presented erroneously since 1875 and has gone through various morphs including J, P, M and T; searches for Reedy best use all these initials or
just his family name.
Thyroid hormone is a crucial regulator of gene expression in the developing and adult retina. Here we sought to map sites of thyroid hormone signaling at the cellular level using the transgenic FINDT3 reporter mouse model in which neurons express β-galactosidase (β-gal) under the control of a hybrid Gal4-TRα receptor when triiodothyronine (T3) and cofactors of thyroid receptor signaling are present. In the adult retina, nearly all neurons of the ganglion cell layer (GCL, ganglion cells and displaced amacrine cells) showed strong β-gal labeling. In the inner nuclear layer (INL), a minority of glycineric and GABAergic amacrine cells showed β-gal labeling, whereas the majority of amacrine cells were unlabeled. At the level of amacrine types, β-gal labeling was found in a large proportion of the glycinergic AII amacrines, but only in a small proportion of the cholinergic/GABAergic ‘starburst’ amacrines. At postnatal day 10, there also was a high density of strongly β-gal-labeled neurons in the GCL, but only few amacrine cells were labeled in the INL. There was no labeling of bipolar cells, horizontal cells and Müller glia cells at both stages. Most surprisingly, the photoreceptor somata in the outer nuclear layer also showed no β-gal label, although thyroid hormone is known to control cone opsin expression. This is the first record of thyroid hormone signaling in the inner retina of an adult mammal. We hypothesize that T3 levels in photoreceptors are below the detection threshold of the reporter system. The topographical distribution of β-gal-positive cells in the GCL follows the overall neuron distribution in that layer, with more T3-signaling cells in the ventral than the dorsal half-retina.
Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.
This paper intends to present some considerations on a possible epistemology of noise as a response to theory of recognition and its bases on theory of communicative action. The principal movement will be to recover some aspects of Marcuse’s and Foucault’s perspective on the disturbances narratives in social sphere. The interest for them becomes stronger from Habermas’ perspective on their “performative contradicions”. Both of them would appeal to social aspects that escapes from critical normativities. Foucault’s structures of power as well as Marcuse’s psychoanalytical drives would represent aspects of the same Habermasian problem: the absence of auto-critical rationality. However, we can question: what would offer to the two authors the limits of communicative action?