bluuebunny/crossref_metadata_2025 huggingface dataset:
Scalable metabolic pathway analysis
Authors: Øyås Ove , Stelling Jörg
Published: August 2020

The scope of application of genome-scale constraint-based models (CBMs) of metabolic networks rapidly expands toward multicellular systems. However, comprehensive analysis of CBMs through metabolic pathway analysis remains a major computational challenge because pathway numbers grow combinatorially with model sizes. Here, we define the minimal pathways (MPs) of a metabolic (sub)network as a subset of its elementary flux vectors. We enumerate or sample them efficiently using iterative minimization and a simple graph representation of MPs. These methods outperform the state of the art and they allow scalable pathway analysis for microbial and mammalian CBMs. Sampling random MPs fromEscherichia coli’s central carbon metabolism in the context of a genome-scale CBM improves predictions of gene importance, and enumerating all minimal exchanges in a host-microbe model of the human gut predicts exchanges of metabolites associated with host-microbiota homeostasis and human health. MPs thereby open up new possibilities for the detailed analysis of large-scale metabolic networks.
A collaborative resource platform for non-human primate neuroimaging
Authors: Messinger Adam , Sirmpilatze Nikoloz , Heuer Katja , Loh Kep Kee , Mars Rogier B. , Sein Julien , Xu Ting , Glen Daniel , Jung Benjamin , Seidlitz Jakob , Taylor Paul , Toro Roberto , Garza-Villarreal Eduardo A. , Sponheim Caleb , Wang Xindi , Benn R. Austin , Cagna Bastien , Dadarwal Rakshit , Evrard Henry C. , Garcia-Saldivar Pamela , Giavasis Steven , Hartig Renée , Lepage Claude , Liu Cirong , Majka Piotr , Merchant Hugo , Milham Michael P. , Rosa Marcello G.P. , Tasserie Jordy , Uhrig Lynn , Margulies Daniel S. , Klink P. Christiaan
Published: August 2020

Neuroimaging non-human primates (NHPs) is a growing, yet highly specialized field of neuroscience. Resources that were primarily developed for human neuroimaging often need to be significantly adapted for use with NHPs or other animals, which has led to an abundance of custom, in-house solutions. In recent years, the global NHP neuroimaging community has made significant efforts to transform the field towards more open and collaborative practices. Here we present the PRIMatE Resource Exchange (PRIME-RE), a new collaborative online platform for NHP neuroimaging. PRIME-RE is a dynamic community-driven hub for the exchange of practical knowledge, specialized analytical tools, and open data repositories, specifically related to NHP neuroimaging. PRIME-RE caters to both researchers and developers who are either new to the field, looking to stay abreast of the latest developments, or seeking to collaboratively advance the field.
Multiplex-GAM: genome-wide identification of chromatin contacts yields insights not captured by Hi-C
Authors: Beagrie Robert A. , Thieme Christoph J. , Annunziatella Carlo , Baugher Catherine , Zhang Yingnan , Schueler Markus , Kukalev Alexander , Kempfer Rieke , Chiariello Andrea M. , Bianco Simona , Li Yichao , Scialdone Antonio , Welch Lonnie R. , Nicodemi Mario , Pombo Ana
Published: August 2020

Technologies for measuring 3D genome topology are increasingly important for studying mechanisms of gene regulation, for genome assembly and for mapping of genome rearrangements. Hi-C and other ligation-based methods have become routine but have specific biases. Here, we develop multiplex-GAM, a faster and more affordable version of Genome Architecture Mapping (GAM), a ligation-free technique to map chromatin contacts genome-wide. We perform a detailed comparison of contacts obtained by multiplex-GAM and Hi-C using mouse embryonic stem (mES) cells. We find that both methods detect similar topologically associating domains (TADs). However, when examining the strongest contacts detected by either method, we find that only one third of these are shared. The strongest contacts specifically found in GAM often involve “active” regions, including many transcribed genes and super-enhancers, whereas in Hi-C they more often contain “inactive” regions. Our work shows that active genomic regions are involved in extensive complex contacts that currently go under-estimated in genome-wide ligation-based approaches, and highlights the need for orthogonal advances in genome-wide contact mapping technologies.
Hypoxia regulates endogenous double-stranded RNA production via reduced mitochondrial DNA transcription
Authors: Arnaiz Esther , Miar Ana , Dias Antonio Gregorio , Prasad Naveen , Schulze Ulrike , Waithe Dominic , Rehwinkel Jan , Harris Adrian L.
Published: August 2020

Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reaveal a mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.
Combination of ipratropium bromide and salbutamol in children and adolescents with asthma: a meta-analysis
Authors: Xu Hongzhen , Tong Lin , Gao Peng , Hu Yan , Wang Huijuan , Chen Zhimin , Fang Luo
Published: August 2020

Background

A combination of ipratropium bromide (IB) and salbutamol is commonly used to treat asthma in children and adolescents; however, there has been a lack of consistency in its usage in clinical practice.

Objective

To evaluate the efficacy and safety of IB + salbutamol in the treatment of asthma in children and adolescents.

Methods

The MEDLINE, Embase, and Cochrane Library as well as other Chinese biomedical databases (including China Biological Medicine Database, Chinese National Knowledge Infrastructure, Chongqing VIP, and Wanfang Chinese language bibliographic database) were systematically searched from the date of database inception to 02/09/2019 for randomized controlled trials in children and adolescents (≤18 years) with asthma who received IB + salbutamol or salbutamol alone. The primary outcomes included hospital admission and adverse events. A random effects model with a 95% confidence interval (CI) was used. Subgroup analysis was performed according to age, severity of asthma, and co-interventions with other asthma controllers. This study was registered with PROSPERO.

Results

Of the 637 studies that were identified, 55 met the inclusion criteria and involved 6396 participants. IB + salbutamol significantly reduced the risk of hospital admission compared with salbutamol alone (risk ratio [RR] 0.79; 95% CI 0.66–0.95; p = 0.01; I2= 40%). Subgroup analysis only showed significant difference in the risk of hospital admission in participants with severe asthma exacerbation (RR 0.71; 95% CI 0.60–0.85; p = 0.0001; I2= 0%) and moderate-to-severe exacerbation (RR 0.69; 95% CI 0.50–0.96; p = 0.03; I2= 3%). There were no significant differences in the risk of adverse events between IB + salbutamol group and salbutamol alone group (RR 1.77; 95% CI 0.63–4.98).

Conclusion

IB + salbutamol may be more effective than salbutamol alone for the treatment of asthma in children and adolescents, especially in those with severe and moderate to severe asthma exacerbation. Future prospective research on these subgroup population are needed.
MASSpy: Building, simulating, and visualizing dynamic biological models in Python using mass action kinetics
Authors: Haiman Zachary B. , Zielinski Daniel C. , Koike Yuko , Yurkovich James T. , Palsson Bernhard O.
Published: August 2020

Mathematical models of metabolic networks utilize simulation to study system-level mechanisms and functions. Various approaches have been used to model the steady state behavior of metabolic networks using genome-scale reconstructions, but formulating dynamic models from such reconstructions continues to be a key challenge. Here, we present the Mass Action Stoichiometric Simulation Python (MASSpy) package, an open-source computational framework for dynamic modeling of metabolism. MASSpy utilizes mass action kinetics and detailed chemical mechanisms to build dynamic models of complex biological processes. MASSpy adds dynamic modeling tools to the COnstraint-Based Reconstruction and Analysis Python (COBRApy) package to provide an unified framework for constraint-based and kinetic modeling of metabolic networks. MASSpy supports high-performance dynamic simulation through its implementation of libRoadRunner; the Systems Biology Markup Language (SBML) simulation engine. Three case studies demonstrate how to use MASSpy: 1) to simulate dynamics of detailed mechanisms of enzyme regulation; 2) to generate an ensemble of kinetic models using Monte Carlo sampling to approximate missing numerical values of parameters and to quantify uncertainty, and 3) to overcome issues that arise when integrating experimental data with the computation of functional states of detailed biological mechanisms. MASSpy represents a powerful tool to address challenge that arise in dynamic modeling of metabolic networks, both at a small and large scale.

Author Summary

Genome-scale reconstructions of metabolism appeared shortly after the first genome sequences became available. Constraint-based models are widely used to compute steady state properties of such reconstructions, but the attainment of dynamic models has remained elusive. We thus developed the MASSpy software package, a framework that enables the construction, simulation, and visualization of dynamic metabolic models. MASSpy is based on the mass action kinetics for each elementary step in an enzymatic reaction mechanism. MASSpy seamlessly unites existing software packages within its framework to provide the user with various modeling tools in one package. MASSpy integrates community standards to facilitate the exchange of models, giving modelers the freedom to use the software for different aspects of their own modeling workflows. Furthermore, MASSpy contains methods for generating and simulating ensembles of models, and for explicitly accounting for biological uncertainty. MASSpy has already demonstrated success in a classroom setting. We anticipate that the suite of modeling tools incorporated into MASSpy will enhance the ability of the modeling community to construct and interrogate complex dynamic models of metabolism.
Home-EEG assessment of possible compensatory mechanisms for sleep disruption in highly irregular shift workers – The ANCHOR study
Authors: Mentink Lara J. , Thomas Jana , Melis René J.F. , Olde Rikkert Marcel G.M. , Overeem Sebastiaan , Claassen Jurgen A.H.R.
Published: August 2020

Study objectives

While poor sleep quality has been related to increased risk of Alzheimer’s disease, long-time shift workers (maritime pilots) did not manifest evidence of early Alzheimer’s disease in a recent study. We explored two hypotheses of possible compensatory mechanisms for sleep disruption: Increased efficiency in generating deep sleep during workweeks (model 1) and rebound sleep during rest weeks (model 2).

Methods

We used data from ten male maritime pilots (mean age: 51.6±2.4 years) with a history of approximately 18 years of irregular shift work. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). A single lead EEG-device was used to investigate sleep in the home/work environment, quantifying total sleep time (TST), deep sleep time (DST), and deep sleep time percentage (DST%). Using multilevel models, we studied the sleep architecture of maritime pilots over time, at the transition of a workweek to a rest week.

Results

Maritime pilots reported worse sleep quality in workweeks compared to rest weeks (PSQI=8.2±2.2 vs. 3.9±2.0; p<0.001). Model 1 showed a trend towards an increase in DST% of 0.6% per day during the workweek (p=0.08). Model 2 did not display an increase in DST% in the rest week (p=0.87).

Conclusions

Our findings indicated that increased efficiency in generating deep sleep during workweeks is a more likely compensatory mechanism for sleep disruption in the maritime pilot cohort than rebound sleep during rest weeks. Compensatory mechanisms for poor sleep quality might mitigate sleep disruption-related risk of developing Alzheimer’s disease. These results should be used as a starting point for future studies including larger, more diverse populations of shift workers.
How the Motor Aspect of Speaking Influences the Blink Rate
Authors: Brych Mareike , Murali Supriya , Händel Barbara
Published: August 2020

The blink rate increases if a person indulges in a conversation compared to quiet rest. Since various factors were suggested to explain this increase, the present study tested the influence of motor activity, cognitive processes and auditory input on the blink rate but at the same time excluding any social interaction. While the cognitive and auditory factors only showed a minor influence, mere mouth movements during speaking highly increased the blink rate. Even more specific, lip movements, but less jaw movements, are likely responsible for the increase during a conversation. Such purely motor related influences on the blink rate advise caution when using blinks as neurological indicators during patient interviews.
Genome-wide RNAi screen for regulators of UPRmtinCaenorhabditis elegansmutants with defects in mitochondrial fusion
Authors: Haeussler Simon , Yeroslaviz Assa , Rolland Stéphane G. , Luehr Sebastian , Conradt Barbara
Published: August 2020

The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmtin response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen inCaenorhabditis elegansmutants lacking the genefzo-1, which encodes the ortholog of mammalian Mitofusin. We find that approximately 90% of the 299 suppressors and 86 enhancers identified are conserved in humans and that one third of the conserved genes have been implicated in human disease. Furthermore, many of the 385 genes have roles in developmental processes, which suggests that mitochondrial function and the response to stress are defined during development and maintained throughout life. In addition, we find that enhancers are predominantly ‘mitochondrial’ genes and suppressors ‘non-mitochondrial’ genes, which indicates that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function that when disrupted can be compensated for by a variety of cellular processes. Our analysis of ‘non-mitochondrial’ enhancers and ‘mitochondrial’ suppressors suggests that organellar contact sites, especially between ER and mitochondria, are of importance for mitochondrial homeostasis. Finally, we uncovered several genes involved in IP3signaling that modulate UPRmtinfzo-1mutants, found a potential link between pre-mRNA splicing and UPRmtactivation and identified theMiga-1/2orthologK01D12.6as required for mitochondrial dynamics inC. elegans.
Switching environments, synchronous sex, and the evolution of mating types
Authors: Berríos-Caro Ernesto , Galla Tobias , Constable George W. A.
Published: August 2020

While facultative sex is common in sexually reproducing species, for reasons of tractability most mathematical models assume that such sex is asynchronous in the population. In this paper, we develop a model of switching environments to instead capture the effect of an entire population transitioning synchronously between sexual and asexual modes of reproduction. We use this model to investigate the evolution of the number of self-incompatible mating types in finite populations, which empirically can range from two to thousands. When environmental switching is fast, we recover the results of earlier studies that implicitly assumed populations were engaged in asynchronous sexual reproduction. However when the environment switches slowly, we see deviations from previous asynchronous theory, including a lower number of mating types at equilibrium and bimodality in the stationary distribution of mating types. We provide analytic approximations for both the fast and slow switching regimes, as well as a numerical scheme based on the Kolmogorov equations for the system to quickly evaluate the model dynamics at intermediate parameters. Our approach exploits properties of integer partitions in number theory. We also demonstrate how additional biological processes such as selective sweeps can be accounted for in this switching environment framework, showing that beneficial mutations can further erode mating type diversity in synchronous facultatively sexual populations.
Inoculation with highly-related mycorrhizal fungal siblings, and their interaction with plant genoptypes, strongly shapes tropical mycorrhizal fungal community structure
Authors: Ordoñez Yuli Marcela , Villard Lucas , Ceballos Isabel , Masclaux Frédéric G. , Rodriguez Alia , Sanders Ian R.
Published: August 2020

Arbuscular mycorrhizal fungi (AMF) have the potential to increase crop yields and all globally important crops form the mycorrhizal symbiosis. Only a few studies have investigated the impact of introduced AMF on local AMF communities and most studies have only investigated effects of one isolate. We studied the impact on AMF community structure of inoculating roots of the globally important crop cassava with highly genetically-related clonal siblings of two genetically differentRhizophagus irregularisisolates. We hypothesized that inoculation withR. irregularissiblings differentially influences the structure and the diversity of the pre-existing AMF community colonizing cassava. Alpha and beta taxonomic and phylogenetic AMF diversity were strongly and significantly altered differentially following inoculation with sibling AMF progeny. In most cases, the effects were also cassava-genotype specific. Although biomass production and AMF colonization were also both differentially affected by inoculation with siblingR. irregularisprogeny these variables were not correlated with changes in the AMF community structure. The results highlight that investigations on the impact of an introduced AMF species, that use only one isolate, are unlikely to be representative of the overall effects of that AMF species and that the genetic identity of the host must be considered. The amount of inoculum added was very small and effects were observed 12 months following inoculation. That such a small amount of almost genetically identical fungal inoculum can strongly differentially influence AMF community structure 12 months following inoculation, indicates that AMF communities in tropical soils are not very resistant to perturbation.
Neural repetition suppression modulates time perception: Evidence from electrophysiology and pupillometry
Authors: Kruijne Wouter , Olivers Christian N. L. , van Rijn Hedderik
Published: August 2020

Human time perception is malleable and subject to many biases. For example, it has repeatedly been shown that stimuli that are physically intense or that are unexpected seem to last longer. Two hypotheses have been proposed to account for such biases: one states that these temporal illusions are the result of heightened arousal which speeds up neural clock dynamics, whereas the alternative ‘magnitude coding’ account states that the magnitude of sensory responses causally modulates perceived durations. Common experimental paradigms used to study temporal biases can not dissociate between these accounts, as arousal and sensory magnitude covary and modulate each other. Here, we present two temporal discrimination experiments where flashing stimuli demarcated the start and end of a to-be-timed interval. These stimuli could either be in the same or in a different location, which led to different sensory responses due to neural repetition suppression. Crucially, changes and repetitions were fully predictable, allowing us to explore effects of sensory response magnitude without changes in arousal or surprise. Intervals with changing markers were perceived as lasting longer than those with repeating markers. We measured EEG (Experiment 1) and pupil size (Experiment 2), and found that temporal perception related to changes in event-related potentials (P2) and pupil constriction, both of which have been related to responses in the sensory cortex. Conversely, correlates of surprise and arousal (P3 amplitude and pupil dilation) were unaffected by stimulus repetitions and changes. These results demonstrate that sensory magnitude affects time perception even under constant levels of arousal.
Rbx1 Cullin-Ring ligase E3 and Ube2m neddylation E2 differentially governs the fitness of Treg cells
Authors: Wu Di , Li Haomin , Liu Mingwei , Qin Jun , Sun Yi
Published: August 2020

Cullin-RING Ligases (CRLs) are a family of multi-unit E3 ubiquitin ligases with two members of RING family proteins, acting as the catalytic subunit: RING-box 1 (Rbx1) couples with CRLs1-4, whereas RING-box 2 (Rbx2/Sag) couples mainly with CRL5.1–4Activity of CRLs requires neddylation on their Cullin subunit, catalyzed by neddylation enzyme cascades E1, E2 and E3. Ube2m and Ube2f are two neddylation E2s responsible for neddylation of Cullins in CRLs1-4 or CRL5, respectively.5–6Regulatory T cells (Treg cells) are specialized immunosuppressive CD4+T lymphocytes, that play pivotal roles in maintaining immune homeostasisin vivo.7–10Whether and how Rbx1-Rbx2/CRLs and Ube2m-Ube2f/neddylation regulate Treg cell homeostasis and function are currently unknown. Here we show that while mice with a Treg-specific deletion ofRbx2/Sagshowed no obvious phenotype, mice withRbx1deletion in Treg cells developed an early-onset fetal inflammatory disorders and death at day ~25 after birth (~p25), with disrupted homeostasis and functions of Treg cells, indicating Rbx1 as a prominent regulator of Treg cells. Single cell transcriptome assay showed that Rbx1 is essential for the maintenance of the effector subpopulations in Treg cells. The whole genome transcriptome and proteomics analysis revealed that Rbx1 regulates several inflammatory pathways, such as T-cell receptor, IL-17, TNFα, NFκB, chemokine, cytokine-cytokine receptor interaction, as well as energy and purine metabolisms. Accumulation of Acly, Fto and Nfkbib proteins, upon Rbx1 depletion suggests that these are likely the novel substrates of CRLs1-4 in Treg cells. Consistently, whileUbe2fdeletion showed no obvious phenotype, mice withUbe2mdeletion in Treg cells also suffers from inflammatory disorders, but to a much lesser severity with a 50% of death rate at ~150 days of age. Since Rbx1 is a dual E3 as a component of CRLs1-4 ligase and as a neddylation co-E3, downstream of Ube2m E2 for neddylation activation of CRLs1-45, much severe phenotypes inFoxp3cre;Rbx1fl/flmice suggestsRbx1may have additional function independent of neddylation activation in Treg cells. Indeed, unbiased transcriptome comparison betweenRbx1-deficient andUbe2m-deficient Treg cells, revealed that the former had greater as well as unique alteration in the signaling pathways controlling the inflammatory responses. Collectively, our study shows that the Ube2m-Rbx1 axis of the neddylation-CRL is required for the maintenance of homeostasis and functional fitness of Treg cells in the fine control of immune tolerance; with implication that targeting the neddylation/CRLs, such as a small molecule inhibitor pevonedistat11, currently in the Phase II clinic trial for anticancer therapy, may have novel application in the treatment of human diseases associated with overactivated Treg cells.
Biochemical and mathematical lessons from the evolution of the SARS-CoV-2 virus: paths for novel antiviral warfare
Authors: Cluzel Nicolas , Lambert Amaury , Maday Yvon , Turinici Gabriel , Danchin Antoine
Published: August 2020

In the fight against the spread of COVID-19 the emphasis is on vaccination or on reactivating existing drugs used for other purposes. The tight links that necessarily exist between the virus as it multiplies and the metabolism of its host are systematically ignored. Here we show that the metabolism of all cells is coordinated by the availability of a core building block of the cell’s genome, cytidine triphosphate (CTP). This metabolite is also the key to the synthesis of the viral envelope and to the translation of its genome into proteins. This unique role explains why evolution has led to the early emergence in animals of an antiviral immunity enzyme, viperin, that synthesizes a toxic analogue of CTP. The constraints arising from this dependency guide the evolution of the virus. With this in mind, we explored the real-time experiment taking place before our eyes using probabilistic modelling approaches to the molecular evolution of the virus. We have thus followed, almost on a daily basis, the evolution of the composition of the viral genome to link it to the progeny produced over time, particularly in the form of blooms that sparked a firework of viral mutations. Some of those certainly increase the propagation of the virus. This led us to make out the critical role in this evolution of several proteins of the virus, such as its nucleocapsid N, and more generally to begin to understand how the virus ties up the host metabolism to its own benefit. A way for the virus to escape CTP-dependent control in cells would be to infect cells that are not expected to grow, such as neurons. This may account for unexpected body sites of viral development in the present epidemic.
Multiplexed fractionated proteomics reveals synaptic factors associated with cognitive resilience in Alzheimer's Disease
Authors: Carlyle Becky Catherine , Kandigian Savannah E , Kreuzer Johannes , Das Sudeshna , Trombetta Bianca A , Kuo Yikai , Bennett David A , Schneider Julie A , Petyuk Vladislav A , Kitchen Robert R , Morris Robert , Nairn Angus C , Hyman Bradley T , Haas Wilhelm , Arnold Steven E
Published: August 2020

Alzheimer's disease (AD) is a complex neurodegenerative disease defined by the presence of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, and driven by dysproteostatis, inflammation, metabolic dysfunction, and oxidative injury, eventually leading to synapse loss and cell death. Synapse loss correlates with cognitive impairment and may occur independently of the extent of AD pathology. To understand how synaptic composition is changed in relation to AD neuropathology and cognition, highly sensitive multiplexed liquid chromatography mass-spectrometry was used to quantify biochemically enriched synaptic proteins from the parietal association cortex of 100 subjects with contrasting AD pathology and cognitive performance. Functional analysis showed preservation of synaptic signaling, ion transport, and mitochondrial proteins in normal aged and "resilient" (cognitively unimpaired with AD pathology) individuals. Compared to these individuals, those with cognitive impairment showed significant metabolic differences and increased immune- and inflammatory-related proteins, establishing the synapse as a potential integration point for multiple AD pathophysiologies.
Distinguishing between recent balancing selection and incomplete sweep using deep neural networks
Authors: Isildak Ulas , Stella Alessandro , Fumagalli Matteo
Published: August 2020

1

Balancing selection is an important adaptive mechanism underpinning a wide range of phenotypes. Despite its relevance, the detection of recent balancing selection from genomic data is challenging as its signatures are qualitatively similar to those left by ongoing positive selection. In this study we developed and implemented two deep neural networks and tested their performance to predict loci under recent selection, either due to balancing selection or incomplete sweep, from population genomic data. Specifically, we generated forward-in-time simulations to train and test an artificial neural network (ANN) and a convolutional neural network (CNN). ANN received as input multiple summary statistics calculated on the locus of interest, while CNN was applied directly on the matrix of haplotypes. We found that both architectures have high accuracy to identify loci under recent selection. CNN generally outperformed ANN to distinguish between signals of balancing selection and incomplete sweep and was less affected by incorrect training data. We deployed both trained networks on neutral genomic regions in European populations and demonstrated a lower false positive rate for CNN than ANN. We finally deployed CNN within theMEFVgene region and identified several common variants predicted to be under incomplete sweep in a European population. Notably, two of these variants are functional changes and could modulate susceptibility to Familial Mediterranean Fever, possibly as a consequence of past adaptation to pathogens. In conclusion, deep neural networks were able to characterise signals of selection on intermediate-frequency variants, an analysis currently inaccessible by commonly used strategies.
Expression of Tim-3 drives naïve Treg to an effector-like state with enhanced suppressive activity
Authors: Banerjee Hridesh , Nieves-Rosado Hector , Kulkarni Aditi , Murter Benjamin , Chandran Uma R. , Chang Alexander , Szymczak-Workman Andrea L. , Vujanovic Lazar , Ferris Robert L. , Kane Lawrence P.
Published: August 2020

Regulatory T cells (Treg) are critical mediators of self-tolerance but can also limit effective anti-tumor immunity. We and others previously reported that 40-60% percent of Treg-infiltrating head and neck cancer (HNC) and other tumors highly express Tim-3, compared with about 5% in lymphoid organs. Tumor-infiltrating Tim-3+Treg also have enhanced suppressive function and display a more effector-like phenotype. Using a novel mouse model with cell type-specific Tim-3 expression, we show here that expression of Tim-3 by Treg is sufficient to drive Treg to a more effector-like phenotype, resulting in enhanced suppressive activity and increased tumor growth. These findings may help to reconcile previous reports that some Tim-3 antibodies enhance T cell responsesin vivo, while expression of Tim-3 has a cell-intrinsic ability to enhance TCR signaling and T cell activation. Thus, we propose that Tim-3 regulates anti-tumor immunity at least in part through enhancement of Treg function. To our knowledge, this is the first example in which expression of a single co-stimulatory molecule is sufficient to drive differentiation of Treg in this manner.
Biomechanical Characterization of SARS-CoV-2 Spike RBD and Human ACE2 Protein-Protein Interaction
Authors: Cao W. , Dong C. , Kim S. , Hou D. , Tai W. , Du L. , Im W. , Zhang X.F.
Published: August 2020

The current COVID-19 pandemic has led to a devastating impact across the world. SARS-CoV-2 (the virus causing COVID-19) is known to use receptor-binding domain (RBD) at viral surface spike (S) protein to interact with the angiotensin-converting enzyme 2 (ACE2) receptor expressed on many human cell types. The RBD–ACE2 interaction is a crucial step to mediate the host cell entry of SARS-CoV-2. Recent studies indicate that the ACE2 interaction with the SARS-CoV-2 S protein has higher affinity than its binding with the structurally identical S protein of SARS-CoV-1, the virus causing the 2002-2004 SARS outbreak. However, the biophysical mechanism behind such binding affinity difference is unclear. This study utilizes a combined single-molecule force spectroscopy and steered molecular dynamics (SMD) simulation approach to quantify the specific interactions between CoV-2 or CoV-1 RBD and ACE2. Depending on the loading rates, the unbinding forces between CoV-2 RBD and ACE2 range from 70 to 110 pN, and are 30-50% higher than those of CoV-1 RBD and ACE2 under similar loading rates. SMD results indicate that CoV-2 RBD interacts with the N-linked glycan on Asn90 of ACE2. This interaction is mostly absent in the CoV-1 RBD–ACE2 complex. During the SMD simulations, the extra RBD-N-glycan interaction contributes to a greater force and prolonged interaction lifetime. The observation is confirmed by our experimental force spectroscopy study. After the removal of N-linked glycans on ACE2, its mechanical binding strength with CoV-2 RBD decreases to a similar level of the CoV-1 RBD–ACE2 interaction. Together, the study uncovers the mechanism behind the difference in ACE2 binding between SARS-CoV-2 and SARS-CoV-1, and could aid in the development of new strategies to block SARS-CoV-2 entry.

STATEMENT OF SIGNIFICANCE

This study utilizes a combined single-molecule force spectroscopy and steered molecular dynamics simulation approach to quantify the specific interactions between SARS-CoV-2 or SARS-CoV-1 receptor-binding domain and human ACE2. The study reveals the mechanism behind the difference in ACE2 binding between SARS-CoV-2 and SARS-CoV-1, and could aid in the development of new strategies to block SARS-CoV-2 entry.
The avian W chromosome is a refugium for endogenous retroviruses with likely effects on female-biased mutational load and genetic incompatibilities
Authors: Peona Valentina , Palacios-Gimenez Octavio M. , Blommaert Julie , Liu Jing , Haryoko Tri , Jønsson Knud A. , Irestedt Martin , Zhou Qi , Jern Patric , Suh Alexander
Published: August 2020

It is a broadly observed pattern that the non-recombining regions of sex-limited chromosomes (Y and W) accumulate more repeats than the rest of the genome, even in species like birds with a low genome-wide repeat content. Here we show that in birds with highly heteromorphic sex chromosomes, the W chromosome has a transposable element (TE) density of >55% compared to the genome-wide density of <10%, and contains over half of all full-length (thus potentially active) endogenous retroviruses (ERVs) of the entire genome. Using RNA-seq and protein mass spectrometry data, we were able to detect signatures of female-specific ERV expression. We hypothesise that the avian W chromosome acts as a refugium for active ERVs, likely leading to female-biased mutational load that may influence female physiology similar to the “toxic-Y” effect inDrosophila. Furthermore, Haldane’s rule predicts that the heterogametic sex has reduced fertility in hybrids. We propose that the excess of W-linked active ERVs over the rest of the genome may be an additional explanatory variable for Haldane’s rule, with consequences for genetic incompatibilities between species through TE/repressor mismatches in hybrids. Together, our results suggest that the sequence content of female-specific W chromosomes can have effects far beyond sex determination and gene dosage.
Computer Simulations of the interaction between SARS-CoV-2 spike glycoprotein and different surfaces
Authors: Malaspina David C. , Faraudo Jordi
Published: August 2020

A prominent feature of coronaviruses is the presence of a large glycoprotein spike protruding from a lipidic membrane. This glycoprotein spike determines the interaction of coronaviruses with the environment and the host. In this paper, we perform all atomic Molecular Dynamics simulations of the interaction between the SARS-CoV-2 trimeric glycoprotein spike and surfaces of materials. We considered a material with high hydrogen bonding capacity (cellulose) and a material capable of strong hydrophobic interactions (graphite). Initially, the spike adsorbs to both surfaces through essentially the same residues belonging to the receptor binding subunit of its three monomers. Adsorption onto cellulose stabilizes in this configuration, with the help of a large number of hydrogen bonds developed between cellulose and the three receptor binding domains (RBD) of the glycoprotein spike. In the case of adsorption onto graphite, the initial adsorption configuration is not stable and the surface induces a substantial deformation of the glycoprotein spike with a large number of adsorbed residues not pertaining to the binding subunits of the spike monomers.
Understanding the evolution of multiple drug resistance in structured populations
Authors: McLeod David V. , Gandon Sylvain
Published: August 2020

The evolution of multidrug resistance (MDR) is a pressing public health concern. Yet many aspects, such as the role played by population structure, remain poorly understood. Here we argue that studying MDR evolution by focusing upon the dynamical equations for linkage disequilibrium (LD) can greatly simplify the calculations, generate more insight, and provide a unified framework for understanding the role of population structure. We demonstrate how a general epidemiological model of MDR evolution can be recast in terms of the LD equations. These equations reveal how the different forces generating and propagating LD operate in a dynamical setting at both the population and metapopulation levels. We then apply these insights to show how the LD perspective: (i) explains equilibrium patterns of MDR, (ii) provides a simple interpretative framework for transient evolutionary dynamics, and (iii) can be used to assess the consequences of different drug prescription strategies for MDR evolution.
VirPreNet: A weighted ensemble convolutional neural network for the virulence prediction of influenza A virus using all 8 segments
Authors: Yin Rui , Luo Zihan , Zhuang Pei , Lin Zhuoyi , Kwoh Chee Keong
Published: August 2020

Motivation

Influenza viruses are persistently threatening public health, causing annual epidemics and sporadic pandemics. The evolution of influenza viruses remains to be the main obstacle in the effectiveness of antiviral treatments due to rapid mutations. Previous work has been investigated to reveal the determinants of virulence of the influenza A virus. To further facilitate flu surveillance, explicit detection of influenza virulence is crucial to protect public health from potential future pandemics.

Results

In this paper, we propose a weighted ensemble convolutional neural network for the virulence prediction of influenza A viruses named VirPreNet that uses all 8 segments. Firstly, mouse lethal dose 50 is exerted to label the virulence of infections into two classes, namely avirulent and virulent. A numerical representation of amino acids named ProtVec is applied to the 8-segments in a distributed manner to encode the biological sequences. After splittings and embeddings of influenza strains, the ensemble convolutional neural network is constructed as the base model on the influenza dataset of each segment, which serves as the VirPreNet’s main part. Followed by a linear layer, the initial predictive outcomes are integrated and assigned with different weights for the final prediction. The experimental results on the collected influenza dataset indicate that VirPreNet achieves state-of-the-art performance combining ProtVec with our proposed architecture. It outperforms baseline methods on the independent testing data. Moreover, our proposed model reveals the importance of PB2 and HA segments on the virulence prediction. We believe that our model may provide new insights into the investigation of influenza virulence.

Contact

yinr0002@e.ntu.edu.sg

Availability and Implementation

Codes and data to generate the VirPreNet are publicly available athttps://github.com/Rayin-saber/VirPreNet
Independent Tryptophan pathway inTrichoderma asperellumandT koningiopsis: New insights with bioinformatic and molecular analysis
Authors: Mariana Uribe Bueno , Hernández-Mendoza JL , Armando García Carlos , Veronica Ancona , Larios-Serrato Violeta
Published: August 2020

The synthesis of Indole Acetic Acid from tryptophan has been described in plants, fungi and bacteria; it is thus known as tryptophan-dependent indole acetic acid. Four possible pathways of IAA formation have been described, including the indole acetonitrile acid (IAN), indole acetamide (IAM), indole-pyruvic (IAP) and tryptamine (TRM) pathways. Of these, the indole acetonitrile pathway is particularly important because when this compound is transformed into IAA, a nitrogenated molecule is released. The microorganisms that have this pathway are thus called nitrogen fixers. There is another little-studied pathway called TRP-Independent, so-called because the IAA that is formed in it can have an exogenous origin, chorismic acid (CHA), and it enters the pathway through anthranilic acid (ANA). The TRP-Independent pathway is made up of three stages. The first from CHA to ANA, the second from AA to IAA and the third from TRP to ANA through Kynurenine (KYN). This work describes the different stages of the pathway, as well as the enzymes and the genes that control the production of IAA, using a bioinformatic analysis of the genes involved, which were identified by PCR. An expression analysis showed that onlyT asperellumhas the necessary genes to incorporate ANA into the TRP-I pathway and synthesize IAA through it. The analysis also detected the gene that regulates anthranilate phosphoribosyl transferase (AFT), an enzyme necessary for the synthesis of AIA from ANA; the presence of this gene was confirmed in the two species analyzed.
Diversification, disparification, and hybridization in the desert shrubsEncelia
Authors: Singhal Sonal , Roddy Adam B. , DiVittorio Christopher , Sanchez-Amaya Ary , Henriquez Claudia L. , Brodersen Craig R. , Fehlberg Shannon , Zapata Felipe
Published: August 2020

There are multiple hypotheses for the spectacular plant diversity found in deserts. We explore how different factors, including the roles of ecological opportunity and selection, promote diversification and disparification inEncelia, a lineage of woody plants in the deserts of the Americas.

Using a nearly complete species-level phylogeny along with a broad set of phenotypic traits, we estimate divergence times and diversification rates, identify instances of hybridization, quantify trait disparity, and assess phenotypic divergence across environmental gradients.

We show thatEnceliaoriginated and diversified recently (mid-Pleistocene) and rapidly, with rates comparable to notable adaptive radiations in plants.Enceliaprobably originated in the hot deserts of North America, with subsequent diversification across steep environmental gradients. We uncover multiple instances of gene flow between species. The radiation ofEnceliais characterized by fast rates of phenotypic evolution, trait lability, and extreme disparity across environments and between species-pairs with overlapping geographic ranges.

Enceliaexemplifies how interspecific gene flow in combination with high trait lability can enable exceptionally fast diversification and disparification across steep environmental gradients.
Global variation in the SARS-CoV-2 proteome reveals the mutational hotspots in the drug and vaccine candidates
Authors: Patro L Ponoop Prasad , Sathyaseelan Chakkarai , Uttamrao Patil Pranita , Rathinavelan Thenmalarchelvi
Published: August 2020

To accelerate the drug and vaccine development against the severe acute respiratory syndrome virus 2 (SARS-CoV-2), a comparative analysis of SARS-CoV-2 proteome has been performed in two phases by considering manually curated 31389 whole genome sequences from 84 countries. Among the 9 mutations that occur at a high significance (T85I-NPS2, L37F-NSP6, P323L-NSP12, D614G-spike, Q57H-ORF3a, G251V-ORF3a, L84S-ORF8, R203K-nucleocapsid and G204R-nucleocapsid), R203K-nucleocapsid and G204R-nucleocapsid are co-occurring (dependent) mutations and P323L-NSP12 and D614G-spike often appear simultaneously. Other notable variations that appear with a moderate to low significance are, M85-NSP1 deletion, D268-NSP2 deletion, 112 amino acids deletion in ORF8, a phenylalanine insertion amidst F34-F36 (NSP6) and several co-existing (dependent) substitution/deletion (I559V & P585S in NSP2, P504L & Y541C in NSP13, G82 & H83 deletions in NSP1 and K141, S142 & F143 deletions in NSP2) mutations. P323L-NSP12, D614G-spike, L37F-NSP6, L84S-ORF8 and the sequences deficient of the high significant mutations have led to 4 major SARS-CoV-2 clades. The top 5 countries bearing all the high significant and majority of the moderate significant mutations are: USA, England, Wales, Australia and Scotland. Further, the majority of the significant mutations have evolved in the first phase and have already transmitted around the globe indicating the positive selection pressure. Among the 26 SARS-CoV-2 proteins, nucleocapsid protein, ORF3a, ORF8, RNA dependent RNA polymerase and spike exhibit a higher heterogeneity compared with the rest of the proteins. However, NSP9, NSP10, NSP8, the envelope protein and NSP4 are highly resistant to mutations and can be exploited for drug/vaccine development.
Insecticide resistance status ofAedes aegyptiin Bangladesh
Authors: Al-Amin Hasan Mohammad , Johora Fatema Tuj , Irish Seth R. , Hossainey Muhammad Riadul Haque , Vizcaino Lucrecia , Paul Kishor Kumar , Khan Wasif A. , Haque Rashidul , Alam Mohammad Shafiul , Lenhart Audrey
Published: August 2020

Background

Arboviral diseases including dengue and chikungunya are major public health concern in Bangladesh, with unprecedented levels of transmission reported in recent years. The primary approach to control these diseases is control ofAedes aegyptiusing pyrethroid insecticides. Although chemical control is long-practiced, no comprehensive analysis ofAe. aegyptisusceptibility to insecticides has previously been conducted. This study aimed to determine the insecticide resistance status ofAe. aegyptiin Bangladesh and investigate the role of detoxification enzymes and altered target site sensitivity as resistance mechanisms.

Methods

Aedeseggs were collected using ovitraps from five districts across the country and in eight neighborhoods of the capital city Dhaka from August to November 2017. CDC bottle bioassays were conducted for permethrin, deltamethrin, malathion, and bendiocarb using 3-5-day old F0-F2non-blood fed female mosquitoes. Biochemical assays were conducted to detect metabolic resistance mechanisms and real-time PCR was performed to determine the frequencies of the knockdown resistance (kdr) mutations Gly1016, Cys1534, and Leu410.

Results

High levels of resistance to permethrin were detected in allAe. aegyptipopulations, with mortality ranging from 0 – 14.8% at the diagnostic dose. Substantial resistance continued to be detected against higher (2X) doses of permethrin (5.1 – 44.4% mortality). Susceptibility to deltamethrin and malathion varied between populations while complete susceptibility to bendiocarb was observed in all populations. Significantly higher levels of esterase and oxidase activity were detected in most of the test populations as compared to the susceptible reference Rockefeller strain. A significant association was detected between permethrin resistance and the presence of Gly1016 and Cys1534 homozygotes. The frequency ofkdralleles varied across the Dhaka populations, and Leu410 was not detected in any of the tested populations.

Conclusions

The detection of widespread pyrethroid resistance and multiple mechanisms highlights the urgency for implementing alternateAe. aegypticontrol strategies. In addition, implementing routine monitoring of insecticide resistance inAe. aegyptiin Bangladesh will lead to a greater understanding of susceptibility trends over space and time, thereby enabling the development of improved control strategies.