bluuebunny/crossref_metadata_2025 huggingface dataset:
An integrative resource for investigating genetic model of drug response in cancer
Authors: Guo Yi , Chen Xiang
Published: November 2019

Background

The most important goal of pharmacogenetics research is to obtain genetic models closely related to drug efficacyin vivoandin vitro, which can be used to measure individual responses and then to assess the sensitivity and toxicity of anticancer drugs. However, these models are scattered in different pharmacogenetic studies and are difficult to be effectively used and analyzed.

Results

To this end, we have developed an integrated resource named iGMDR that provides the genetic models of both clinical and preclinical anticancer drugs. iGMDR provides a unique resource for mining the links between anticancer drugs and individual genomes, which will attempt to discover cancer knowledge and unlock the potential value of this data.

Conclusions

We developed iGMDR as a web service whose code was released at GitHub repository of ModelLAB (https://github.com/ModelLAB-ZJU/iGMDR), it also provided online access and application interface (https://igmdr.modellab.cn). MySQL dump for the integrated resources was stored at zenodo.org (DOI: 10.5281/ zencomod.1432561).
The insulin receptor adaptor IRS2 is an APC/C substrate that promotes cell cycle protein expression and a robust spindle assembly checkpoint
Authors: Manohar Sandhya , Yu Qing , Gygi Steven P. , King Randall W.
Published: November 2019

Insulin receptor substrate 2 (IRS2) is an essential adaptor that mediates signaling downstream of the insulin receptor and other receptor tyrosine kinases. Transduction through IRS2-dependent pathways is important for coordinating metabolic homeostasis, and dysregulation of IRS2 causes systemic insulin signaling defects. Despite the importance of maintaining proper IRS2 abundance, little is known about what factors mediate its protein stability. We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1. Consistent with the APC/C’s role in degrading cell cycle regulators, quantitative proteomic analysis of IRS2-null cells revealed a deficiency in proteins involved in cell cycle progression. We further show that cells lacking IRS2 display a weakened spindle assembly checkpoint in cells treated with microtubule inhibitors. Together, these findings reveal a new pathway for IRS2 turnover and indicate that IRS2 is a component of the cell cycle control system in addition to acting as an essential metabolic regulator.
DNA-BOT: A low-cost, automated DNA assembly platform for synthetic biology
Authors: Storch Marko , Haines Matthew C. , Baldwin Geoff S.
Published: November 2019

Multi-part DNA assembly is the physical starting point for many projects in Synthetic and Molecular Biology. The ability to explore a genetic design space by building extensive libraries of DNA constructs is essential for creating programmed biological systems that perform the desired functions. With multiple DNA assembly methods and standards adopted in the Synthetic Biology community, automation of the DNA assembly process has received serious attention in recent years. Importantly, automating DNA assembly enables larger builds using less researcher time, increasing the accessible design space. However, these benefits currently incur high costs for both equipment and consumables. Here, we address this limitation by introducing low-cost DNA assembly with BASIC on OpenTrons (DNA-BOT). For this purpose, we developed an open-source software package dnabot (https://github.com/BASIC-DNA-ASSEMBLY/dnabot). We demonstrate the performance of DNA-BOT by simultaneously assembling 88 constructs composed of 10 genetic parts, exploring the promoter, ribosome binding site (RBS) and gene order design space for a 3-gene operon. All 88 constructs were assembled with high accuracy, at a cost of $1.50 - $5.50 per construct. This illustrates the efficiency, accuracy and affordability of DNA-BOT making it accessible for most labs and democratising automated DNA assembly.
Variation at the Klotho gene locus does not affect cognitive function in up to 335,074 British Caucasians in the UK Biobank
Authors: Amin Hasnat A , Drenos Fotios , Blakemore Alexandra I
Published: November 2019

The proportion of older adults in Western populations is increasing and there is, therefore, a need to define factors affecting maintenance of physical and cognitive health in old age. Variations in the Klotho (KL) gene, and specifically the KL-VS haplotype, have been identified by several authors as potentially influencing cognitive function and decline. We have attempted to verify the reported associations between KL variants, including the KL-VS haplotype, and cognitive function in up to 335,074 British Caucasian participants aged 40-79 years from the UK Biobank. We do not find evidence that KL-VS affects cognitive function or its decline with increasing age. We examined a further 244 KL variants and found that rs117650866 was associated with Prospective Memory, but could not replicate this in follow-up samples. In conclusion, there is insufficient evidence in the UK Biobank to support the concept that KL variants affect cognitive function or its rate of decline.
HIV-1 Envelope and MPER antibody structures in lipid assemblies
Authors: Rantalainen Kimmo , Berndsen Zachary T. , Antanasijevic Aleksandar , Schiffner Torben , Zhang Xi , Lee Wen-Hsin , Torres Jonathan L. , Zhang Lei , Irimia Adriana , Copps Jeffrey , Zhou Kenneth , Kwon Young Do , Law William H. , Schramm Chaim A. , Verardi Raffaello , Krebs Shelly , Kwong Peter D. , Doria-Rose Nicole A. , Wilson Ian A. , Zwick Michael B. , Yates John R. , Schief William R. , Ward Andrew B.
Published: November 2019

Structural and functional studies of HIV Env as a transmembrane protein have long been complicated by challenges associated with inherent flexibility of the molecule and the membrane-embedded hydrophobic regions. Thus, most structural studies have utilized soluble forms where the regions C-terminal to the ectodomain are deleted. Here, we present approaches for incorporating full-length, wild-type HIV-1 Env, as well as C-terminally truncated and stabilized versions, into lipid assemblies, providing a modular platform for Env structural studies by single particle electron microscopy. We reconstituted a full-length Env clone into a nanodisc with MSP1D1 scaffold, complexed it with an MPER targeting antibody 10E8, and structurally defined the full quaternary epitope of 10E8 consisting of lipid, MPER and ectodomain contacts. By aligning this and other Env-MPER antibody complex reconstructions with the lipid bilayer, we observe evidence of Env tilting as part of the neutralization mechanism for MPER-targeting antibodies. We also adapted the platform toward vaccine design purposes by introducing stabilizing mutations that allow purification of unliganded Env with peptidisc scaffold.
Can Living with an Alien Invasive Fish, Tilapia, Influence the Shoaling Decision-Making and Exploratory Behaviour of an Air-Breathing Freshwater Fish, the Climbing Perch?
Authors: Binoy V V , Ingle Bhagyasree J , Bhattacharya Aniket , Sinha Anindya
Published: November 2019

The biodiversity of freshwater aquatic ecosystems is threatened by invasive alien species across the world. We studied the impact of the presence of an invasive piscine species, the tilapia Oreochromis mossambicus and acquisition of familiarity with it on the social decision-making and exploratory behaviour of a native, air-breathing, freshwater fish, the climbing perch Anabas testudineus. Our results reveal that the climbing perch did not show any significant preference or aversion to any of the stimulus shoals when unfamiliar monospecific shoals of tilapia, mixed-species shoals of tilapia and climbing perch that were divergent in the composition, or groups comprising only tilapia familiar to the subject fish for a duration of 30, 60, 90 or 120 days, were presented in opposition to a shoal with an equal number of unfamiliar conspecific individuals. No preference for isolated familiar individual tilapia was also observed against its unfamiliar counterpart or a conspecific individual. It is also noteworthy that the propensity of subject climbing perch to initiate exploration of a novel area (a measure of boldness) or exploratory activity and its sociability remained unchanged under different social conditions, including presence of unfamiliar conspecific, familiar conspecific, unfamiliar heterospecific or familiar heterospecific individuals. These results are discussed in the light of ever-increasing levels of invasion by alien fish species and the struggle for survival that currently confront native piscine species in most tropical freshwater ecosystems globally.
Sensorimotor expectations bias motor resonance during observation of object lifting: The causal role of pSTS
Authors: Rens Guy , van Polanen Vonne , Botta Alessandro , Gann Mareike A. , Orban de Xivry Jean-Jacques , Davare Marco
Published: November 2019

Transcranial magnetic stimulation (TMS) studies have highlighted that corticospinal excitability (CSE) is increased during observation of object lifting, an effect termed ‘motor resonance’. This facilitation is driven by movement features indicative of object weight, such as object size or observed movement kinematics. Here, we investigated in 35 humans (23 females) how motor resonance is altered when the observer’s weight expectations, based on visual information, do not match the actual object weight as revealed by the observed movement kinematics. Our results highlight that motor resonance is not robustly driven by object weight but easily masked by a suppressive mechanism reflecting the correctness of the weight expectations. Subsequently, we investigated in 24 humans (14 females) whether this suppressive mechanism was driven by higher-order cortical areas. For this, we induced ‘virtual lesions’ to either the posterior superior temporal sulcus (pSTS) or dorsolateral prefrontal cortex (DLPFC) prior to having participants perform the task. Importantly, virtual lesion of pSTS eradicated this suppressive mechanism and restored object weight-driven motor resonance. In addition, DLPFC virtual lesion eradicated any modulation of motor resonance. This indicates that motor resonance is heavily mediated by top-down inputs from both pSTS and DLPFC. Altogether, these findings shed new light on the theorized cortical network driving motor resonance. That is, our findings highlight that motor resonance is not only driven by the putative human mirror neuron network consisting of the primary motor and premotor cortices as well as the anterior intraparietal sulcus, but also by top-down input from pSTS and DLPFC.

Significance Statement

Observation of object lifting activates the observer’s motor system in a weight-specific fashion: Corticospinal excitability is larger when observing lifts of heavy objects compared to light ones. Interestingly, here we demonstrate that this weight-driven modulation of corticospinal excitability is easily suppressed by the observer’s expectations about object weight and that this suppression is mediated by the posterior superior temporal sulcus. Thus, our findings show that modulation of corticospinal excitability during observed object lifting is not robust but easily altered by top-down cognitive processes. Finally, our results also indicate how cortical inputs, originating remotely from motor pathways and processing action observation, overlap with bottom-up motor resonance effects.
Exploring valence bias as a metric for frontoamygdalar connectivity and depressive symptoms in childhood
Authors: Petro Nathan M. , Tottenham Nim , Neta Maital
Published: November 2019

Negativity bias is a core feature of depression that is associated with dysfunctional frontoamygdalar connectivity; this pathway is associated with emotion regulation and sensitive to neurobiological change during puberty. We used a valence bias task (ratings of emotional ambiguity) as a potential early indicator of depression risk and differences in frontoamygdalar connectivity. Previous work using this task demonstrated that children normatively have a negative bias that attenuates with maturation. Here, we test the hypothesis that persistence of this negativity bias as manturation ensues may reveal differences in emotion regulation development, and may be associated with increased risk for depression. Within a restricted age range (6-13 years), we tested the moderating role of puberty on relationships between valence bias, depressive symptoms, and frontoamygdalar connectivity. A negative bias was associated with increased depressive symptoms for those at more advanced pubertal stages (within this sample) and less regulatory frontoamygdalar connectivity, whereas a more positive bias was associated with more regulatory connectivity patterns. These data suggest that with maturation, individual differences in positivity biases and associated emotion regulation circuitry confer a differential risk for depression. Longitudinal work is necessary to determine the directionality of these effects and explore the influence of early life events.
SLAST: Simple Local Alignment Search Tool
Authors: Bermúdez Juanjo
Published: November 2019

We present a local alignment search tool not based on the usual strategy of seed and grow often employed for these tools. Instead, we just find regions in the database sequences having a high density of seed matches and then we perform a Smith-Waterman local alignment of the query sequence into these regions. This approach has some advantages for some use cases.
Affinity-engineered human antibodies detect celiac disease gluten pMHC complexes and inhibit T-cell activation
Authors: Frick Rahel , Høydahl Lene S. , Hodnebrug Ina , Kumari Shraddha , Berntsen Grete , Jeliazkov Jeliazko R. , Gunnarsen Kristin S. , Frigstad Terje , Vik Erik S. , Lundin Knut E.A. , Yaqub Sheraz , Jahnsen Jørgen , Gray Jeffrey J. , Sollid Ludvig M. , Sandlie Inger , Løset Geir Åge
Published: November 2019

Antibodies specific for antigenic peptides bound to major histocompatibility complex (MHC) molecules are valuable tools for studies of antigen presentation. Such T-cell receptor (TCR)-like antibodies may also have therapeutic potential in human disease due to their ability to target disease-associated antigens with high specificity. We previously generated celiac disease (CeD) relevant TCR-like antibodies that recognize the prevalent gluten epitope DQ2.5-glia-α1a in complex with HLA-DQ2.5. Here, we report on second-generation high-affinity antibodies towards this epitope as well as a panel of novel TCR-like antibodies to another immunodominant gliadin epitope, DQ2.5-glia-α2. The strategy for affinity engineering was based on Rosetta modeling combined with pIX phage display and is applicable to similar protein engineering efforts. We isolated picomolar affinity binders and validated them in Fab and IgG format. Flow cytometry experiments with CeD biopsy material confirm the unique disease specificity of these TCR-like antibodies and reinforce the notion that B cells and plasma cells have a dominant role in gluten antigen presentation in the inflamed CeD gut. Further, the lead candidate 3.C11 potently inhibited CD4+ T-cell activation and proliferation in vitro in an HLA and epitope specific manner, pointing to a potential for targeted disease interception without compromising systemic immunity.

Significance Statement

Consumption of gluten-containing food drives celiac disease in genetically predisposed individuals. The underlying disease mechanism is not fully understood, but it is strictly dependent on activation of pathogenic T cells. We have engineered high-affinity human antibodies recognizing the T-cell target HLA-DQ2.5 in complex with gluten epitopes and studied cell-specific antigen presentation in patients, which shows that plasma cells and not dendritic cells dominate the inflamed tissue. The only available treatment is lifelong adherence to a gluten-free diet, which is difficult and not effective in all cases. We show that at least one of our antibodies can specifically inhibit activation of pathogenic T-cells in vitro and therefore shows promise for therapy.
Mapping cellular-scale internal stiffness in 3D tissues with smart material hydrogel probes
Authors: Mok Stephanie , Al Habyan Sara , Ledoux Charles , Lee Wontae , MacDonald Katherine , McCaffrey Luke , Moraes Christopher
Published: November 2019

Local stiffness plays a critical role in cell function, but measuring rigidity at cellular length scales in living 3D tissues presents considerable challenges. Here we present thermoresponsive, smart material microgels that can be dispersed or injected into tissues and optically assayed to measure internal tissue stiffness over several weeks. We first develop the material design principles to measure tissue stiffness across physiological ranges, with spatial resolutions approaching that of individual cells. Using the microfabricated sensors, we demonstrate that mapping internal stiffness profiles of live multicellular spheroids at high resolutions reveal distinct architectural patterns, that vary with subtle differences in spheroid aggregation method. Finally, we determine that small sites of unexpectedly high stiffness (> 250 kPa) develop in invasive breast cancer spheroids, and inin vivomouse model tumors as the cancer progresses towards metastatic disease. These highly focal sites of increased intratumoral stiffness likely form via active cell mechanical behavior, and suggest new possibilities for how early mechanical cues that drive cancer cells towards invasion might arise within the evolving tumor microenvironment.
Oxygen-responsive p53 tetramer-octamer switch controls cell fate
Authors: Taxak Shashank , Pati Uttam
Published: November 2019

Solid tumors require an efficient decision-making mechanism to progress through a gradient of hypoxia. Here, we show that an oxygen-sensory p53 tetramer-octamer switch makes cell decision for survival or death in variable hypoxia. Trapping homo-oligomers from biosynthesis cycle, we found a metastable p53 tetramer in cells. Under the operation of switch, tetramer segregates the p53 character of a tumor suppressor and promoter. The p53 switch generates a pattern of its on-off state in time that is specific to the strength of hypoxia. A bidirectional tetramer-octamer conversion in on state decides the restoration of basal state by forward and programs apoptosis upon the reverse shift via p53-MDM2 loop. However, reversible dimertetramer transitions in off state trigger chaperoning of HIF-1 complex by tetramer in forward and oncogenic gain-of-function by prion-like dimers in reverse direction. Temporal on-off patterns calibrate stabilized p53 pool by defining the abundance of dimer, tetramer and octamer that ultimately decides diverse cellular outcomes in hypoxia. Through multi-chromophore FRET, we further show that chaperoning of HIF-1 may modulate angiogenesis through a possible flip-flop of the p53T-HIF-1 complex upon DNA. Our results demonstrate how p53 can sense oxygen and act upon its homo-oligomerization states to control cell fate in hypoxic tumors.
The role of integrin αvand CD44 in GBM migration in human brain
Authors: Binder Zev A. , Ji Kim Sarah Hyun , Wu Pei-Hsun , Giri Anjil , Gallia Gary L. , Pardo Carlos A. , Wirtz Denis
Published: November 2019

Glioblastoma (GBM) is the most common primary adult malignant brain tumor. Recurrence is driven invading tumor cells that escape surgical resection and demonstrate resistance to standard-of-care chemotherapy and radiotherapy. A large body of research has been conducted on tumor cell motility. However, typicalin vitromodels make use of polystyrene culture dishes, which exhibit significantly different physical parameters than brain tissue. Here we report on the use of human organotypic brain slices as anex vivoapproach for the dynamic study of GBM cell motility.

Temporal lobectomy tissue from epilepsy patients was obtained and cut into 350µm thick slices. After the tissue slices had a week’s incubation for recovery, fluorescently labeled tumor cells were seeded. We then tracked individual tumor cells using time-lapse fluorescent confocal microscopy. Quantification of motility characteristics, including mean squared displacement, total path length, and consistency, allowed for comparison of different conditions, including knockdown of cell surface proteins integrin αv(ITGAV) and CD44.

Human organotypics demonstrated minimal variability across specimen in terms of motility parameters, including total path length, averaged instantaneous velocity, and consistency. Knockdown of the traditional motility protein ITGAV showed little effect on overall motility while knockdown of CD44 resulted in a significant reduction in both averaged instantaneous velocity and total path length. When the same parameters were examined using Matrigel, ITGAV and CD44 both showed decreased motility, highlighting the impact of the physical environment on cell behavior. Finally, cell motility in mouse organotypic slices was decreased when compared to human organotypic slices.

Here we demonstrate the use of human organotypic brain slices in the study of GBM cell invasion. This model system offers a physiologically-relevant environment in which to examine the dynamic process of cell motility.
Testing Models of the Visual Word Form Area Using Combined ERP and fMRI Using the Special Properties of Chinese Characters
Authors: Xiang Dan , Dien Joseph , Bolger Donald J.
Published: November 2019

The visual word form area or VWFA has been of special interest for studies of reading and dyslexia and yet there are conflicting models regarding its function. Here we put the Local Combination Detector, Lexicon, and Interactive accounts to the test, using a combination of event-related potentials and functional magnetic resonance imaging. We do so using both pseudoword and reversed radical false word manipulations with Chinese characters, making use of its special properties. We recorded event-related potentials with 68 channels while twenty native Chinese speakers were making rhyme and meaning judgments on single Chinese characters and BOLD signals were collected in a 3T magnet using multi-plane EPI with a further fifteen native Chinese speakers. The word N170 showed a prolongation for reversed radical false characters while the VWFA also showed an effect of reversal, albeit only for pseudocharacters. Furthermore, an N450 rhyming effect was observed in the phonological task compared to the semantic task, but only via an interaction with reversal. The source analysis of the N450 co-registered with a Supplementary Motor Area activation. The combination of these observations suggests that the ventral orthographic pathway is partially order insensitive and that full phonological encoding occurs relatively late, supporting and expanding a model of dyslexia. Overall, they best support a version of the Lexicon account of the VWFA.
Two Ways to Change Your Mind: Effects of Intentional Strength and Motor Costs on Changes of Intention
Authors: Löffler Anne , Sylaidi Anastasia , Fountas Zafeirios , Haggard Patrick
Published: November 2019

Changes of Mind are a striking example of the human ability to flexibly reverse decisions after commitment to an initial choice, and to change actions according to circumstances. Previous studies of Changes of Mind largely focused on perceptual choices. Here we investigate reversals ofvoluntary, endogenousaction decisions. In a novel version of the random-dot motion task, participants moved to a target that matched both the perceived dot-motion direction and an internally-generated intention (which colour target to move to). Movement trajectories revealed whether and when participants 1) perceived a change in dot-motion direction, or additionally 2) changed the colour that they chose to move to (‘Change of Intention’). Changes of Intention were less frequent in participants with strong colour intentions, as indicated by high performance costs in trials where perceptual information conflicted with the endogenous intention (Exp. 1). Additionally, Changes of Intention were more frequent when motor costs of intention pursuit were high (Exp. 2). These findings were simulated using an attractor network model that continuously integrates voluntary intentions, sensory evidence, and motor costs. This argues in favour of a unifying framework for dynamic decision-making processes, in which voluntary actions emerge from a dynamic combination of internal action tendencies and external environmental factors.
Sex differences in cognitive performance, style and domain relationships in mosquitofish (Gambusia affinis)
Authors: Wallace Kelly J. , Rausch Richie T. , Ramsey Mary E. , Cummings Molly E.
Published: November 2019

Given that the sexes often differ in their ecological and sexual selection pressures, sex differences in cognitive properties are likely. While research on sexually dimorphic cognitionoften focuses on performance, it commonly overlooks how sexes diverge across multiple cognitive tasks (cognitive domains) and in behaviors associated with cognitive performance (cognitive style). We tested male and female western mosquitofish (Gambusia affinis) in three cognitive tasks: associative learning (numerical discrimination), cognitive flexibility (detour task), and spatio-temporal learning (shuttlebox). We characterized statistical relationships between cognitive performances and cognitive style during the associative learning task with measures of anxiety, boldness, exploration, reaction time, and activity. We found sex differences in performance, cognitive style, and the relationships between cognitive domains. Females outperformed males in spatio-temporal learning task, while the sexes performed equally in associate learning and cognitive flexibility assays. Females (but not males) exhibited a ‘fast-exploratory’ cognitive style during associative learning trials. Meanwhile, only males showed a significant positive relationship between domains (associative learning and cognitive flexibility). We propose that these sexually dimorphic cognitive traits result from strong sexual conflict in this taxon; and emphasize the need to explore suites of sex-specific cognitive traits and broader comparative work examining sexual selection and cognition.

Highlights

Males and females perform at similar levels in associative learning and cognitive flexibility assays, but females tend to outperform males on a spatio-temporal learning task.

Female performance in associative learning trials (numerical discrimination task) can be predicted by cognitive style behaviors (exploration, reaction time, and activity); whereas male performance cannot.

Males, but not females, show a predictive relationship between associative learning and cognitive flexibility performance.

Our results demonstrate that sex differences in cognition extend beyond performance into cognitive style and domain relationships, suggesting that investigations into animal personality and cognition require more comprehensive characterization.
Repurposing disulfiram (Tetraethylthiuram Disulfide) as a potential drug candidate againstBorrelia burgdorferi in vitro and in vivo
Authors: Potula Hari-Hara SK , Shahryari Jahanbanoo , Inayathullah Mohammed , Malkovskiy Andrey Victorovich , Kim Kwang-Min , Rajadas Jayakumar
Published: November 2019

Lyme disease caused by theBorrelia burgdorferi(Bb or B. burgdorferi) is a most common vector-borne, multi-systemic disease in USA. Although, most Lyme disease patients can be cured with a course of antibiotic treatment, a significant percent of patient population fail to be disease-free post-treatment, necessitating the development of more effective therapeutics. We previously found several drugs including disulfiram having with good activity againstB. burgdorferi. In current study, we evaluated the potential of repurposing the FDA approved disulfiram drug for itsborreliacidal activity. Ourin vitroresults indicate disulfiram shows excellentborreliacidal activity against both the log and stationary phaseB. burgdorferi. Subsequent mice studies have determined that the disulfiram eliminatedB. burgdorfericompletely from hearts and urinary bladder by day 28 post infection, demonstrating the practical application and efficacy of disulfiram againstB. burgdorferi in vivo. Moreover, disulfiram treated mice showed reduced expression of inflammatory markers and protected against histopathology and organ damage. Furthermore, disulfiram treated mice showed significantly lower amounts of total antibody titers (IgM and IgG) at day 21 and total IgG2b at day 28 post infection. Mechanistically, cellular analysis of lymph nodes revealed a decrease in percentage of CD19+ B cells and increase in total percentage of CD3+ T cells, CD3+ CD4+ T helpers, and naïve and effector memory cells in disulfiram-treated mice. Together, we demonstrate that disulfiram has the potential and could be repurposed as an effective antibiotic for treating Lyme disease in near future.
AutoGenome: An AutoML Tool for Genomic Research
Authors: Liu Denghui , Xu Chi , He Wenjun , Xu Zhimeng , Fu Wenqi , Zhang Lei , Yang Jie , Peng Guangdun , Han Dali , Bai Xiaolong , Qiao Nan
Published: November 2019

Deep learning have made great successes in traditional fields like computer vision (CV), natural language processing (NLP) and speech processing. Those achievements greatly inspire researchers in genomic study and make deep learning in genomics a very hot topic. Convolutional neural network (CNN) and recurrent neural network (RNN) are frequently used for genomic sequence prediction problems; multiple layer perception (MLP) and auto-encoders (AE) are frequently used for genomic profiling data like RNA expression data and gene mutation data. Here, we introduce a new neural network architecture, named residual fully-connected neural network (RFCN) and demonstrate its advantage for modeling genomic profiling data. We further incorporate AutoML algorithms and implement AutoGenome, an end-to-end automated genomic deep learning framework. By utilizing the proposed RFCN architectures, automatic hyper-parameter search and neural architecture search algorithms, AutoGenome can train high-performance deep learning models for various kinds of genomic profiling data automatically. To make researchers better understand the trained models, AutoGenome can assess the feature importance and export the most important features for supervised learning tasks, and the representative latent vectors for unsupervised learning tasks. We envision AutoGenome to become a popular tool in genomic studies.
Interactions between cytoplasmic and nuclear genomes confer sex-specific effects on lifespan inDrosophila melanogaster
Authors: Vaught Rebecca C. , Voigt Susanne , Dobler Ralph , Clancy David J. , Reinhardt Klaus , Dowling Damian K.
Published: November 2019

A large body of studies has demonstrated that genetic variation that resides outside of the cell nucleus can affect the organismal phenotype. The cytoplasm is home to the mitochondrial genome and, at least in arthropods, often hosts intracellular endosymbiotic bacteria such asWolbachia. While numerous studies have implicated epistatic interactions between cytoplasmic and nuclear genetic variation as key to mediating patterns of phenotypic expression, two outstanding questions remain. Firstly, the relative contribution of mitochondrial genetic variation to other cytoplasmic sources of variation in shaping the phenotypic outcomes of cyto-nuclear interactions remains unknown. Secondly, it remains unclear whether the outcomes of cyto-nuclear interactions will manifest differently across the two sexes, as might be predicted given that cytoplasmic genomes are screened by natural selection only through females as a consequence of their maternal inheritance. Here, we address these questions, creating a fully-crossed set of replicated cyto-nuclear populations derived from three geographically distinct populations ofDrosophila melanogaster, and measuring the lifespan of males and females from each population. We report cyto-nuclear interactions for lifespan, with the outcomes of these interactions differing across the sexes, and reconcile these findings with information on the full mitochondrial sequences andWolbachiainfection status of each of the populations.
An open database of resting-state fMRI in awake rats
Authors: Liu Yikang , Perez Pablo D. , Ma Zilu , Ma Zhiwei , Dopfel David , Cramer Samuel , Tu Wenyu , Zhang Nanyin
Published: November 2019

Rodent models are essential to translational research in health and disease. Investigation in rodent brain function and organization at the systems level using resting-state functional magnetic resonance imaging (rsfMRI) has become increasingly popular, owing to its high spatial resolution and whole-brain coverage. Due to this rapid progress, shared rodent rsfMRI databases can be of particular interest and importance to the scientific community, as inspired by human neuroscience and psychiatric research that are substantially facilitated by open human neuroimaging datasets. However, such databases in rats are still lacking. In this paper, we share an open rsfMRI database acquired in 90 rats with a well-established awake imaging paradigm that avoids anesthesia interference. Both raw and preprocessed data are made publically available. Procedures in data preprocessing to remove artefacts induced by the scanner, head motion, non-neural physiological noise are described in details. We also showcase inter-regional functional connectivity and functional networks calculated from the database.
Conductance-based Adaptive Exponential integrate-and-fire model
Authors: Górski Tomasz , Depannemaecker Damien , Destexhe Alain
Published: November 2019

The intrinsic electrophysiological properties of single neurons can be described by a broad spectrum of models, from the most realistic Hodgkin-Huxley type models with numerous detailed mechanisms to the phenomeno-logical models. The Adaptive Exponential integrate-and-fire (AdEx) model has emerged as a convenient “middle-ground” model. With a low computational cost, but keeping biophysical interpretation of the parameters, it has been extensively used for simulations of large neural networks. However, because of its current-based adaptation, it can generate unrealistic behaviors. We show the limitations of the AdEx model and to avoid them, we introduce the Conductance-based Adaptive Exponential integrate-and-fire model (CAdEx). We give an analysis of the dynamics of the CAdEx model and show the variety of firing patterns it can produce. We propose the CAdEx model as a richer alternative to perform network simulations with simplified models reproducing neuronal intrinsic properties.
Topological constraints in early multicellularity favor reproductive division of labor
Authors: Yanni David , Jacobeen Shane , Márquez-Zacarías Pedro , Weitz Joshua S , Ratcliff William C. , Yunker Peter J.
Published: November 2019

Reproductive division of labor (e.g., germ-soma specialization) is a hallmark of the evolution of multicellularity, signifying the emergence of a new type of individual and facilitating the evolution of increased organismal complexity. A large body of work from evolutionary biology, economics, and ecology has shown that specialization is beneficial when further division of labor produces an accelerating increase in absolute productivity (i.e., productivity is a convex function of specialization). Here we show that reproductive specialization is qualitatively different from classical models of resource sharing, and can evolve even when the benefits of specialization are saturating (i.e., productivity is a concave function of specialization). Through analytical theory and evolutionary individual based simulations, our work demonstrates that reproductive specialization is strongly favored in sparse networks of cellular interactions, such as trees and filaments, that reflect the morphology of early, simple multicellular organisms, highlighting the importance of restricted social interactions in the evolution of reproductive specialization. More broadly, we find that specialization is strongly favored, despite saturating returns on investment, in a wide range of scenarios in which sharing is asymmetric.
Transcriptome-wide association analysis of 211 neuroimaging traits identifies new genes for brain structures and yields insights into the gene-level pleiotropy with other complex traits
Authors: Zhao Bingxin , Shan Yue , Yang Yue , Li Tengfei , Luo Tianyou , Zhu Ziliang , Li Yun , Zhu Hongtu
Published: November 2019

Structural and microstructural variations of human brain are heritable and highly polygenic traits, with hundreds of associated genes founded in recent genome-wide association studies (GWAS). Using gene expression data, transcriptome-wide association studies (TWAS) can prioritize these GWAS findings and also identify novel gene-trait associations. Here we performed TWAS analysis of 211 structural neuroimaging phenotypes in a discovery-validation analysis of six datasets. Using a cross-tissue approach, TWAS discovered 204 associated genes (86 new) exceeding Bonferroni significance threshold of 1.37*10−8(adjusted for testing multiple phenotypes) in the UK Biobank (UKB) cohort, and validated 18 TWAS or previous GWAS-detected genes. The TWAS-significant genes of brain structures had been linked to a wide range of complex traits in different domains. Additional TWAS analysis of 11 cognitive and mental health traits detected 69 overlapping significant genes with brain structures, further characterizing the genetic overlaps among these brain-related traits. Through TWAS gene-based polygenic risk scores (PRS) prediction, we found that TWAS PRS gained substantial power in association analysis compared to conventional variant-based PRS, and up to 6.97% of phenotypic variance (p-value=7.56*10−31) in testing datasets can be explained by UKB TWAS-derived PRS. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.
A novel vaccine targeting the viral protease cleavage sites protects Mauritian cynomolgus macaques against vaginal SIVmac251 infection
Authors: Li Hongzhao , Omange Robert W. , Liang Binhua , Toledo Nikki , Hai Yan , Liu Lewis R. , Schalk Dane , Crecente-Campo Jose , Dacoba Tamara G. , Lambe Andrew B. , Lim So-Yon , Li Lin , Kashem Mohammad Abul , Wan Yanmin , Correia-Pinto Jorge F. , Liu Xiao Qing , Balshaw Robert F. , Li Qingsheng , Schultz-Darken Nancy , Alonso Maria J. , Whitney James B. , Plummer Francis A. , Luo Ma
Published: November 2019

After over three decades of research, an effective anti-HIV vaccine remains elusive. Unconventional and novel vaccine strategies are needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provides greater than 80% protection of Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses are correlated with vaccine efficacy. The PCS vaccine does not induce immune activation and inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune environment generated by the PCS vaccine predicts vaccine efficacy. Our study demonstrates for the first time that a novel vaccine which targets viral maturation, but lacks full Env and Gag proteins as immunogens, can prevent intravaginal infection in a highly stringent NHP/SIV challenge model. Targeting HIV maturation thus offers a novel approach to developing an effective HIV vaccine.

One Sentence Summary

The anti-PCS T cell responses and the immune environment induced by the novel PCS vaccine are key correlates of vaccine efficacy
Hippocampal spatial memory representations in mice are heterogeneously stable
Authors: Levy Samuel J , Kinsky Nathaniel R , Mau William , Sullivan David W , Hasselmo Michael E
Published: November 2019

The population of hippocampal neurons actively coding space continually changes across days as mice repeatedly perform tasks. Many hippocampal place cells become inactive while other previously silent neurons become active, challenging the belief that stable behaviors and memory representations are supported by stable patterns of neural activity. Active cell replacement may disambiguate unique episodes that contain overlapping memory cues, and could contribute to reorganization of memory representations. How active cell replacement affects the evolution of representations of different behaviors within a single task is unknown. We trained mice to perform a Delayed Non-Match to Place (DNMP) task over multiple weeks, and performed calcium imaging in area CA1 of the dorsal hippocampus using head-mounted miniature microscopes. Cells active on the central stem of the maze “split” their calcium activity according to the animal’s upcoming turn direction (left or right), the current task phase (study or test), or both task dimensions, even while spatial cues remained unchanged. We found that different splitter neuron populations were replaced at unequal rates, resulting in an increasing number of cells modulated by turn direction and a decreasing number of cells with combined modulation by both turn direction and task phase. Despite continual reorganization, the ensemble code stably segregated these task dimensions. These results show that hippocampal memories can heterogeneously reorganize even while behavior is unchanging.

Significance statement

Single photon calcium imaging using head-mounted miniature microscopes in freely moving animals, has enabled researchers to measure the long term stability of hippocampal pyramidal cells during repeated behaviors. Previous studies have demonstrated instability of neural circuit components including dendritic spines and axonal boutons. It is now known that single units in the neuronal population exhibiting behaviorally relevant activity eventually become inactive and that previously silent neurons can quickly acquire task-relevant activity. The function of such population dynamics is unknown. We show here that population dynamics differ for cells coding distinct task dimensions, suggesting such dynamics are part of a mechanism for latent memory reorganization. These results add to a growing body of work showing that maintenance of episodic memory is an ongoing and dynamic process.
Effective Combination Immunotherapy using Oncolytic Viruses to Deliver CAR Targets to Solid Tumors
Authors: Park Anthony K. , Fong Yuman , Chen Nanhai G. , Jeang Brook , Tilakawardane Dileshni , Murad John P. , Kim Sang-In , Lu Jianming , Thomas Sandra H. , Forman Stephen J. , Priceman Saul J.
Published: November 2019

Chimeric antigen receptor (CAR)-engineered T cell therapy for solid tumors is limited by the lack of tumor-restricted and homogeneous expression of tumor antigens1,2. Therefore, we engineered an oncolytic virus to express a non-signaling, truncated CD19 (CD19t) protein for tumor-selective delivery, enabling targeting by CD19-specific CAR T cells. Infecting tumor cells with a chimeric oncolytic vaccinia virus coding for CD19t (OV19t) producedde novoCD19 surface-antigen expression prior to virus-mediated tumor lysis. Co-cultured CD19-CAR T cells secreted cytokines and elicited potent cytolytic activity against infected tumors. Using multiple mouse tumor models, intratumoral delivery of OV19t induced tumor expression of CD19t and improved tumor control following CD19-CAR T cell administration. CAR T cell–mediated tumor killing also promoted release of virus from dying tumor cells, which propogated tumor expression of CD19t. These data demonstrate a novel immunotherapy approach utilizing oncolytic viruses to promotede novoCAR T cell targeting of solid tumors.

One Sentence Summary

We describe a novel and effective combination immunotherapy utilizing oncolytic viruses to deliver de novo cell surface expression of CD19 antigen promoting CD19-CAR T cell anti-tumor responses against solid tumors.
Reduction of cybersickness during and immediately following noisy galvanic vestibular stimulation
Authors: Weech Séamas , Wall Travis , Barnett-Cowan Michael
Published: November 2019

The mechanism underlying cybersickness during virtual reality (VR) exposure is still poorly understood, although research has highlighted a causal role for visual-vestibular sensory conflict. Recently established methods for reducing cybersickness include galvanic vestibular stimulation (GVS) to mimic absent vestibular cues in VR, or vibration of the vestibular organs to add noise to the sensory modality. Here, we examined if applying noise to the vestibular system using noisy-current GVS also affects sickness severity in VR. Participants were exposed to one of two VR games that were classified as either moderate or intense with respect to their nauseogenic effects. The VR content lasted for 50 minutes and was broken down into 3 blocks: 30 minutes of gameplay during exposure to either noisy GVS (±1750 μA) or sham stimulation (0 μA), and 10 minutes of gameplay before and after this block. We characterized the effects of noisy GVS in terms of post-minus-pre-exposure cybersickness scores. For the intense VR content, we found a main effect of noisy vestibular stimulation. Participants reported lower cybersickness scores during and directly after exposure to GVS. However, this difference was quickly extinguished (∼3-6 min) after further exposure to VR, indicating that sensory adaptation did not persist after stimulation was terminated. In contrast, there were no differences between the sham and GVS group for the moderate VR content. The results show the potential for reducing cybersickness with simple non-invasive sensory stimulation. We discuss the prospect that noise-induced sensory re-weighting is responsible for the observed effects, and address other possible mechanisms.