Biology subjects

Haas, J.

Publications and source records attributed to Haas, J..

18 recordsLinked to original sources

bioRxiv2026

mRNA editing of the Alzheimer's risk gene APOE

Variants in the human APOE gene govern the risk of Alzheimer's disease and other disorders. Three major APOE variants in humans reflect C to T replacements at two positions in a single exon: an upstream variant (AE4 site) that differs between the ancestral APOE epsilon 4 allele (APOE4) (C) and human-specific APOE2/E3 (T), and a downstream variant (AE2 site) that differentiates APOE3/E4 (C) from APOE2 (T). It has long been assumed that APOE allelotypes are genomically encoded, but here we report that multiple individuals express brain APOE C or U/T variant transcripts that differ from genomically templated versions. We demonstrate up to 10% C to U, or U to C nucleotide replacement at AE4 and AE2, but not at other sites, and with no corresponding changes in genomic DNA. Single-cell transcriptomic datasets from brain microglia revealed sporadic (up to ~8%) C to U replacement at AE2. We found 0.4 to 1.6% of brain transcripts in human APOE knock-in mice harbor selective C to U changes at either AE4 or AE2 sites. Transfection of HepG2 or Huh7 cells with either mouse or human APOBEC1 led to efficient (>90%) C to U editing of APOE4 mRNA at the AE4 but not AE2 site, with lower (<10%) C to T editing of genomic DNA at the AE4 site by mouse, but not human, APOBEC1. Furthermore, interrogation of proteomic datasets revealed up to 4% of non-genomically encoded APOE peptides in human plasma, indicating that the edited APOE transcripts are functional in vivo. These data suggest that APOE mRNA is subject to RNA editing that interconverts the different allelic forms of APOE.

genetics↗

bioRxiv2026

Evolution of neurometabolic frugality in harvester ants

Despite the importance of neurometabolic costs in brain size evolution, quantitative data on brain metabolic rates are lacking. We measured ex vivo brain metabolic rates among species of the ant genus Pogonomyrmex to differentiate the roles of sociality and body size in brain evolution in a phylogenetic context. Worker body size and colony size (a proxy for social complexity) vary significantly among Pogonomyrmex species and were positively correlated. However, sociality was not a determinant of brain energetics. Worker body size strongly affected brain metabolism: 38% of resting metabolic rate was attributable to brain metabolism in species with the smallest workers, compared to 6% in species with the largest workers. More derived species had strikingly lower mass-specific brain metabolic costs, suggesting that increases in worker body size have selected for neurometabolic frugality through reductions in brain mass-specific metabolic rate. Additionally, smaller worker body sizes may require higher brain mass-specific energetic costs to achieve comparable performance by absolutely smaller brains. Our study shows that the social brain hypothesis does not explain patterns of brain size in Pogonomyrmex, but body size and evolutionary history strongly influence brain evolution in regard to both size and metabolic cost.

zoology↗

bioRxiv2025

Intra-subtype heterogeneity shapes treatment response in KMT2A-rearranged ALL across all age groups

BackgroundKMT2A-rearranged B-cell acute lymphoblastic leukemia (KMT2Ar B-ALL) exhibits significant heterogeneity in age of onset, developmental origins, and clinical outcomes. The interplay of individual factors influencing early treatment response within this high-risk molecular subtype remains poorly elucidated. We aimed to comprehensively assess how leukemic developmental state, fusion partner, and patient age jointly influence early treatment response and drug sensitivity. MethodsTo identify determinants of early treatment response to induction chemotherapy, we analysed 465 KMT2Ar B-ALL cases spanning a wide age range (1 month to 89 years) by integrating transcriptomic and genomic profiling with functional drug response and measurable residual disease (MRD) kinetics. Transcriptomic profiling was used to derive a developmental maturity score based on proximity to physiological B-cell differentiation from a normal B-lymphopoiesis reference. Using an ordinal regression model we identify gene expression programs associated with early MRD response. ResultsWe observed a strong inverse correlation between MRD clearance with advancing age (p=2.1E-04), proximity to early B-cell-precursor developmental state (low maturity score, p=1.3E-03) and AFF1 as fusion partner (p=7.0E-04). A combined model confirmed the predominate impact of both maturity and KMT2A fusion partner on MRD response, supporting the concept that the cells developmental state defines therapy response. Gene expression analysis identified cellular traits that relate to MRD response (e.g. chromatin organization, immune modulation and proliferation). This gene expression classifier grouped cases by MRD response but also by ex-vivo induction drug sensitivity. Notably, good responders to ex-vivo induction drugs were characterized by a higher maturity score (p=1.8E-03), whereas for less mature KMT2Ar B-ALL cases response profiles suggested higher Venetoclax sensitivity. ConclusionsOur study provides an integrative framework linking developmental phenotype, fusion partner, and MRD kinetics across the full age spectrum of KMT2Ar B-ALL. The maturity score, derived from bulk transcriptome data, offers a biologically relevant predictor of early treatment response and drug sensitivity. These insights may support future risk-adapted strategies and therapeutic targeting, particularly in immature KMT2Ar B-ALL.

cancer biology↗

bioRxiv2025

Heterocellular and homocellular electrically coupled networks of the thalamus and cortex revealed by focal photomapping

Electrical synapses are expressed ubiquitously across the brain and are crucial components of active neural circuitry and connectomes. Identification of coupled networks in living tissue is limited by technical demands of multiplexed recordings, and no dyes, fluorescent reporters, or genetic labels can currently fill the gap. We introduce a novel method of identifying and quantifying electrical synapses, opto-{delta}L, that combines focal photostimulation of soma-targeted opsins with a spike timing-based computation for the strength of electrical synapses to rapidly measure and map electrically coupled networks in vitro. We leverage opto-{delta}L to show that coupled networks of the mature thalamic reticular nucleus extend as far as 100 m, synapse promiscuously across genetic subtypes of neurons, and couple 1-4 neighboring neurons to each recorded hub cell. We also demonstrate application of opto-{delta}L to cortical networks. These results highlight the broad potential of opto-{delta}L to interrogate the identity and roles of electrical synapses in circuitry, behavior, and cognition. TeaserElectrically coupled neural networks are newly unmasked by functional photomapping.

neuroscience↗

bioRxiv2025

Sarcomeric Remodelling in Human Heart Failure unraveled by single molecule long read sequencing

Dysregulation of alternative splicing - mediated by factors such as RBM20 or SLM2 - can affect proper gene isoform control disrupts gene isoform homeostasis and underpins severe cardiomyopathy in both animal models and patients. Although innovative therapies target various sarcomeric components, the impact of isoform switching in cardiac disease remains poorly understood. Here, we applied nanopore long-read sequencing to map the full-length transcriptome of left ventricular tissue from thirteen nonfailing controls, ten patients with dilated cardiomyopathy (DCM), and ten with ischemic cardiomyopathy (ICM). Our analysis identified 78,520 transcripts, 31% of which represent novel isoforms of known genes. Notably, the transcriptomes of DCM and ICM were largely indistinguishable, indicating that end-stage heart failure is characterized by a convergent isoform landscape, irrespective of disease etiology. Among 11 prototypical sarcomere genes, 10 displayed highly significant isoform shifts (p= 5.23x10-45 - 2.89x10-200). Focusing on tropomyosin, we observed that while the predominant cardiac gene TPM1 showed moderate up-regulation of its transcript isoforms, transcripts derived from TPM3--typically expressed at lower levels in the healthy heart--were markedly increased in heart failure.

genetics↗

bioRxiv2023

Systemic Lupus Erythematosus Serum Stimulation of Human Intestinal Organoids Induces Changes in Goblet Cell Differentiation and Mitochondrial Fitness

Human intestinal epithelial cells are the interface between potentially harmful luminal content and basally residing immune cells. Their role is not only nutrient absorption but also the formation of a tight monolayer that constantly secrets mucus creating a multi-layered protective barrier. Alterations in this barrier can lead to increased gut permeability which is frequently seen in individuals with chronic extraintestinal autoimmune diseases, such as Systemic Lupus Erythematosus (SLE). Despite recent advances in identifying alterations in gut microbiota composition in SLE patients, not much attention has been given to the epithelial barrier itself. To date, it remains largely unexplored which role and function intestinal epithelial cells have in SLE pathology. Here, we present a unique near-physiologic in vitro model specifically designed to examine the effects of SLE on the epithelial cells. We utilize human colon organoids that are stimulated with serum obtained from SLE patients. Combining bulk and scRNA transcriptomic analysis with functional assays revealed that SLE serum stimulation induced a unique expression profile marked by a type I interferon gene signature. Additionally, organoids exhibited decreased mitochondrial fitness, alterations in mucus composition and imbalanced cellular composition. Similarly, transcriptomic analysis of SLE human colon biopsies revealed a downregulation of epithelial secretory markers. Our work uncovers a crucial connection between SLE and intestinal homeostasis that might be promoted in vivo through the blood, offering insights into the causal connection of barrier dysfunction and autoimmune diseases.

cell biology↗

bioRxiv2023

Clade-Specific MPXV PCR Assays

In an evolving infectious disease outbreak, there are two priorities: rapid and accurate detection of the causative agent and characterization of its spread. The polymerase chain reaction (PCR) assay is an effective and portable diagnostic method that can quickly provide information associated with virulence, transmissibility, and pathogenicity. Compared to genomic sequencing, PCR requires less infrastructure, funding, and training. However, the development of sensitive and specific primer sequences is costly, particularly those with subspecies resolution. The recent mpox (monkeypox) virus outbreak underscores the need for the rapid development of clade-specific primers, particularly when there are differences in morbidity and mortality rates. Current mpox assays use primer sequences that also bind to the broader Orthopoxvirus genus, resulting in suspect diagnoses, delays in treatment, and poor allocation of scarce healthcare resources. Additionally, these orthopox-based primer sets cannot distinguish between different mpox clades and cannot illuminate intra-clade evolution over the course of the outbreak. Here, we present the in silico design and in vitro testing of novel clade-specific mpox assays. ImportanceThere is an ongoing global outbreak of Mpox disease, an illness with a characteristic blistering rash progression. The Mpox virus clusters into two clades with differing levels of virulence and mortality rates. Thus, proper sample identification is critical for surveillance and the public health response programs that rely on such data. Accordingly, the US government specifically lists Clade I under the Federal Select Agent Program. Current diagnostics may fail to identify the virus or its clade membership as the genome mutates. In this work, we demonstrate an end-to-end workflow to quickly evaluate existing PCR assays and design new ones for clade-based identification with respect to large sequence databases in service of preventing a catastrophic fog-of-war from forming during an outbreak.

bioinformatics↗

bioRxiv2022

ModelCIF: An extension of PDBx/mmCIF data representation for computed structure models

ModelCIF (github.com/ihmwg/ModelCIF) is a data information framework developed for and by computational structural biologists to enable delivery of Findable, Accessible, Interoperable, and Reusable (FAIR) data to users worldwide. It is an extension of the Protein Data Bank Exchange / macromolecular Crystallographic Information Framework (PDBx/mmCIF), which is the global data standard for representing experimentally-determined, three-dimensional (3D) structures of macromolecules and associated metadata. ModelCIF provides an extensible data representation for deposition, archiving, and public dissemination of predicted 3D models of proteins. The PDBx/mmCIF framework and its extensions (e.g., ModelCIF) are managed by the Worldwide Protein Data Bank partnership (wwPDB, wwpdb.org) in collaboration with relevant community stakeholders such as the wwPDB ModelCIF Working Group (wwpdb.org/task/modelcif). This semantically rich and extensible data framework for representing computed structure models (CSMs) accelerates the pace of scientific discovery. Herein, we describe the architecture, contents, and governance of ModelCIF, and tools and processes for maintaining and extending the data standard. Community tools and software libraries that support ModelCIF are also described.

bioinformatics↗

bioRxiv2021

A novel non-genetic murine model of hyperglycemia and hyperlipidemia-associated accelerated atherosclerosis

ObjectiveAtherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s). Methods and ResultsWild-type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less -SMA-positive area) and had more inflammation (increased plasma IL-1{beta} level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks. ConclusionWe established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice.

pharmacology and toxicology↗

bioRxiv2021

Electrical synapse asymmetry results from, and masks, neuronal heterogeneity

Electrical synapses couple inhibitory neurons across the brain, underlying a variety of functions that are modifiable by activity. Despite recent advances, many basic functions and contributions of electrical synapses within neural circuitry remain underappreciated. Among these is the source and impact of electrical synapse asymmetry. Using multi-compartmental models of neurons coupled through dendritic electrical synapses, we investigated intrinsic factors that contribute to synaptic asymmetry and that result in modulation of spike time between coupled cells. We show that electrical synapse location along a dendrite, input resistance, internal dendritic resistance, or directional conduction of the electrical synapse itself each alter asymmetry as measured by coupling between cell somas. Conversely, true synapse asymmetry can be masked by each of these properties. Furthermore, we show that asymmetry alters the spiking timing and latency of coupled cells by up to tens of milliseconds, depending on direction of conduction or dendritic location of the electrical synapse. These simulations illustrate that causes of asymmetry are multifactorial, may not be apparent in somatic measurements of electrical coupling, influence dendritic processing, and produce a variety of outcomes on spike timing of coupled cells. Our findings highlight aspects of electrical synapses that should be considered in experimental demonstrations of coupling, and when assembling networks containing electrical synapses.

neuroscience↗

bioRxiv2020

Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients

Cancer therapies have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of cancer. ACT-iPSC-CM generated from individuals with CD20+ B-cell lymphoma cancer who had received high doses of DOX and suffered cardiac dysfunction were observed to be persistently more susceptible to DOX toxicity compared to control-iPSC-CM. ACT-iPSC-CM exhibited increased DOX-dependent disorganized myofilament structure and cell death, as well as higher reactive oxygen species (ROS) compared to controls. Importantly, analysis of engineered heart muscle (EHM) from ACT-iPSC-CM showed an impaired DOX-dependent mechanical functionality. Transcriptome profiles of EHM are in line with a disturbed adjustment to DOX-dependent alteration of Ca2+ homeostasis in ACT-iPSC-CM. Furthermore, genetic variants in different cardiac key regulators were uncovered. In conclusion, we developed the first human iPSC-CM and EHM model of DOX-induced cardiac dysfunction in patients with B-cell lymphoma. Our results suggest that DOX-related stress resulted in decreased contractile activity and finally in heart failure in ACT patients. Brief summaryDevelopment of the first human iPSC-CM model of DOX-induced cardiac dysfunction in patients with aggressive B cell lymphoma and high-dose DOX treatment.

cell biology↗

bioRxiv2019

Asparagine deprivation causes a reversible inhibition of Human Cytomegalovirus acute virus replication

As obligate intracellular pathogens, viruses rely on the host cell machinery to replicate efficiently, with the host metabolism extensively manipulated for this purpose. High throughput siRNA screens provide a systematic approach for the identification of novel host-virus interactions. Here, we report a large-scale screen for host factors important for human cytomegalovirus (HCMV), consisting of 6,881 siRNAs. We identified 47 proviral factors and 68 antiviral factors involved in a wide range of cellular processes including the mediator complex, proteasome function and mRNA splicing. Focused characterisation of one of the hits, asparagine synthetase (ASNS), demonstrated a strict requirement for asparagine for HCMV replication which leads to an early block in virus replication before the onset of DNA amplification. This effect is specific to HCMV, as knockdown of ASNS had little effect on herpes simplex virus-1 or influenza A virus replication, suggesting the restriction is not simply due to a failure in protein production. Remarkably, virus replication could be completely rescued seven days post-infection with addition of exogenous asparagine, indicating that while virus replication is restricted at an early stage, it maintains the capacity for full replication days after initial infection. This study represents the most comprehensive siRNA screen for the identification of host factors involved in HCMV replication and identifies the non-essential amino acid, asparagine as a critical factor in regulating HCMV virus replication. These results have implications for control of viral latency and the clinical treatment of HCMV in patients.\n\nImportanceHCMV accounts for more than 60% of complications associated with solid organ transplant patients. Prophylactic or preventative treatment with antivirals, such as ganciclovir, reduces the occurrence of early onset HCMV disease. However, late onset disease remains a significant problem and prolonged treatment, especially in patients with suppressed immune systems, greatly increases the risk of antiviral resistance. Very few antivirals have been developed for use against HCMV since the licensing of ganciclovir, and of these, the same viral genes are often targeted, reducing the usefulness of these drugs against resistant strains. An alternative approach is to target host genes essential for virus replication. Here we demonstrate that HCMV replication is highly dependent on levels of the amino acid asparagine and knockdown of a critical enzyme involved in asparagine synthesis results in severe attenuation of virus replication. These results suggest that reducing asparagine levels through dietary restriction or chemotherapeutic treatment could limit HCMV replication in patients.

microbiology↗

bioRxiv2019

A novel mechanism for amplification of sensory responses by the amygdala-TRN projections.

Many forms of behavior require selective amplification of neuronal representations of relevant environmental signals. Following emotional learning, sensory stimuli drive enhanced responses in the sensory cortex. However, the brain circuits that underlie emotionally driven control of the sensory representations remain poorly understood. Here we identify a novel pathway between the basolateral amygdala (BLA), an emotional learning center in the mouse brain, and the inhibitory nucleus of the thalamus (TRN). We demonstrate that activation of this pathway amplifies sound-evoked activity in the central auditory pathway. Optogenetic activation of BLA suppressed spontaneous, but not tone-evoked activity in the auditory cortex (AC), effectively amplifying tone-evoked responses in AC. Anterograde and retrograde viral tracing identified robust BLA projections terminating at TRN. Optogenetic activation of amygdala-TRN pathway mimicked the effect of direct BLA activation, amplifying tone-evoked responses in the auditory thalamus and cortex. The results are explained by a computational model of the thalamocortical circuitry. In our model, activation of TRN by BLA suppresses spontaneous activity in thalamocortical cells, and as a result, thalamocortical neurons are primed to relay relevant sensory input. These results demonstrate a novel circuit mechanism for shining a neural spotlight on behaviorally relevant signals and provide a potential target for treatment of neuropsychological disorders, in which emotional control of sensory processing is disrupted.

neuroscience↗

bioRxiv2019

The ELIXIR Core Data Resources: fundamental infrastructure for the life sciences

MotivationLife science research in academia, industry, agriculture, and the health sector depends critically on free and open data resources. ELIXIR (www.elixir-europe.org), the European Research Infrastructure for life sciences data, has identified a set of Core Data Resources within Europe that are of most fundamental importance for the long-term preservation of biological data. We explore characteristics of their usage, impact and assured funding horizon to assess their value and importance as an infrastructure, to understand sustainability of the infrastructure, and to demonstrate a model for assessing Core Data Resources worldwide. ResultsThe nineteen resources currently designated ELIXIR Core Data Resources form a data infrastructure in Europe which is a subset of the worldwide open life science data infrastructure. We show that, from 2014 to 2018, data managed by the Core Data Resources more than tripled while staff numbers increased by less than a tenth. Additionally, support for the Core Data Resources is precarious: together they have assured funding for less than a third of current staff after four years. Our findings demonstrate the importance of the ELIXIR Core Data Resources as repositories for research data and knowledge, while also demonstrating the uncertain nature of the funding environment for this infrastructure. ELIXIR is working towards longer-term support for the Core Data Resources and, through the Global Biodata Coalition, aims to ensure support for the worldwide life science data resource infrastructure of which the ELIXIR Core Data Resources are a subset. Contactrachel.drysdale@elixir-europe.org Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2019

Activity-dependent long-term potentiation of electrical synapses in the mammalian thalamus

Activity-dependent changes of synapse strength have been extensively characterized at chemical synapses, but the relationship between physiological forms of activity and strength at electrical synapses remains poorly understood. For mammalian electrical synapses composed of hexomers of connexin36, physiological forms of neuronal activity in coupled pairs has thus far have only been linked to long-term depression; activity that results in strengthening of electrical synapses has not yet been identified. The thalamic reticular nucleus (TRN), a central brain area primarily connected by gap junctional (electrical) synapses, regulates cortical attention to the sensory surround. Bidirectional plasticity of electrical synapses may be a key mechanism underlying these processes in both healthy and diseased states. Here we show in electrically coupled TRN pairs that tonic spiking in one neuron results in long-term potentiation of electrical synapses between coupled pairs of TRN neurons. Potentiation is expressed asymmetrically, indicating that regulation of connectivity depends on the direction of use. Further, potentiation depends on calcium flux, and we thus propose a calcium-based activity rule for bidirectional plasticity of electrical synapse strength. Because electrical synapses dominate intra-TRN connectivity, these synapses and their modifications are key regulators of thalamic attention circuitry. More broadly, bidirectional modifications of electrical synapses are likely to be a widespread and powerful principle for ongoing, dynamic reorganization of neuronal circuitry across the brain.\n\nSummaryLong-term potentiation results from spiking in one cell of an electrically coupled pair. Asymmetry of synapses increases following unidirectional activity. We suggest a calcium-based rule for electrical synapse plasticity.

neuroscience↗

bioRxiv2017

Electrical synapses between inhibitory neurons shape the responses of principal neurons to transient inputs in the thalamus

As multimodal sensory information proceeds to the cortex, it is intercepted and processed by the nuclei of the thalamus. The main source of inhibition within thalamus is the reticular nucleus (TRN), which collects signals both from thalamocortical relay neurons and from thalamocortical feedback. Within the reticular nucleus, neurons are densely interconnected by connexin36-based gap junctions, known as electrical synapses. Electrical synapses have been shown to coordinate neuronal rhythms, including thalamocortical spindle rhythms, but their role in shaping or modulating transient activity is less understood. We constructed a four-cell model of thalamic relay and TRN neurons, and used it to investigate the impact of electrical synapses on closely timed inputs delivered to thalamic relay cells. We show that the electrical synapses of the TRN assist cortical discrimination of these inputs through effects of truncation, delay or inhibition of thalamic spike trains. We expect that these are principles whereby electrical synapses play similar roles in processing of transient activity in excitatory neurons across the brain.

neuroscience↗

bioRxiv2017

Lessons Learned: Recommendations for Establishing Critical Periodic Scientific Benchmarking

The dependence of life scientists on software has steadily grown in recent years. For many tasks, researchers have to decide which of the available bioinformatics software are more suitable for their specific needs. Additionally researchers should be able to objectively select the software that provides the highest accuracy, the best efficiency and the highest level of reproducibility when integrated in their research projects.\n\nCritical benchmarking of bioinformatics methods, tools and web services is therefore an essential community service, as well as a critical component of reproducibility efforts. Unbiased and objective evaluations are challenging to set up and can only be effective when built and implemented around community driven efforts, as demonstrated by the many ongoing community challenges in bioinformatics that followed the success of CASP. Community challenges bring the combined benefits of intense collaboration, transparency and standard harmonization. Only open systems for the continuous evaluation of methods offer a perfect complement to community challenges, offering to larger communities of users that could extend far beyond the community of developers, a window to the developments status that they can use for their specific projects. We understand by continuous evaluation systems as those services which are always available and periodically update their data and/or metrics according to a predefined schedule keeping in mind that the performance has to be always seen in terms of each research domain.\n\nWe argue here that technology is now mature to bring community driven benchmarking efforts to a higher level that should allow effective interoperability of benchmarks across related methods. New technological developments allow overcoming the limitations of the first experiences on online benchmarking e.g. EVA. We therefore describe OpenEBench, a novel infra-structure designed to establish a continuous automated benchmarking system for bioinformatics methods, tools and web services.\n\nOpenEBench is being developed so as to cater for the needs of the bioinformatics community, especially software developers who need an objective and quantitative way to inform their decisions as well as the larger community of end-users, in their search for unbiased and up-to-date evaluation of bioinformatics methods. As such OpenEBench should soon become a central place for bioinformatics software developers, community-driven benchmarking initiatives, researchers using bioinformatics methods, and funders interested in the result of methods evaluation.

bioinformatics↗

bioRxiv2017

Spatial and temporal control of norovirus protease activity is determined by polyprotein processing and intermolecular interactions within the viral replication complex.

Norovirus infections are a major cause of acute viral gastroenteritis and a significant burden to human health globally. A vital process for norovirus replication is the processing of the nonstructural polyprotein, by an internal protease, into the necessary viral components required to form the viral replication complex. This cleavage occurs at different rates resulting in the accumulation of stable precursor forms. In this report, we characterized how precursor forms of the norovirus protease accumulate during infection. Using stable forms of the protease precursors we demonstrated that these are all proteolytically active in vitro, but that when expressed in cells, activity is determined by both substrate and protease localization. Whilst all precursors could cleave a replication complex-associated substrate, only a subset of precursors lacking NS4 were capable of efficiently cleaving a cytoplasmic substrate. For the first time, the full range of protein-protein interactions between murine and human norovirus proteins were mapped by LUMIER assay, with conserved interactions between replication complex members, modifying the localization of a subset of precursors. Finally, we demonstrate that re-targeting of a poorly cleaved artificial cytoplasmic substrate to the replication complex is sufficient to permit efficient cleavage in the context of norovirus infection. This offers a model for how norovirus can regulate the timing of substrate cleavage throughout the replication cycle. The norovirus protease represents a key target in the search for effective antiviral treatments for norovirus infection. An improved understanding of protease function and regulation, as well as identification of interactions between the other non-structural proteins, offers new avenues for antiviral drug design.

microbiology↗