bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct observation of adaptive tracking on ecological timescales inDrosophila
Authors: Rudman Seth M. , Greenblum Sharon I. , Rajpurohit Subhash , Betancourt Nicolas J. , Hanna Jinjoo , Tilk Susanne , Yokoyama Tuya , Petrov Dmitri A. , Schmidt Paul
Published: April 2021

Direct observation of evolution in response to natural environmental change can resolve fundamental questions about adaptation including its pace, temporal dynamics, and underlying phenotypic and genomic architecture. We tracked evolution of fitness-associated phenotypes and allele frequencies genome-wide in ten replicate field populations ofDrosophila melanogasterover ten generations from summer to late fall. Adaptation was evident over each sampling interval (1-4 generations) with exceptionally rapid phenotypic adaptation and large allele frequency shifts at many independent loci. The direction and basis of the adaptive response shifted repeatedly over time, consistent with the action of strong and rapidly fluctuating selection. Overall, we find clear phenotypic and genomic evidence of adaptive tracking occurring contemporaneously with environmental change, demonstrating the temporally dynamic nature of adaptation.

One sentence summary

Rapid environmental change drives continuous phenotypic and polygenic adaptation, demonstrating the temporal dynamism of adaptation.
Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization
Authors: Balbach Melanie , Ghanem Lubna , Rossetti Thomas , Kaur Navpreet , Ritagliati Carla , Ferreira Jacob , Krapf Dario , Molina Lis C Puga , Santi Celia Maria , Hansen Jan Niklas , Wachten Dagmar , Fushimi Makoto , Meinke Peter T. , Buck Jochen , Levin Lonny R.
Published: April 2021

Soluble adenylyl cyclase (sAC: ADCY10) is essential for activating dormant sperm. Studies of freshly dissected mouse sperm identified sAC as needed for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in human sperm. Unlike dissected mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. Even in ejaculated human sperm, TDI-10229 interrupts stimulated motility and capacitation, and it prevents acrosome reaction in capacitated sperm. At present, there are no non-hormonal, pharmacological methods for contraception. Because sAC activity is required post-ejaculation at multiple points during the sperm’s journey to fertilize the oocyte, sAC inhibitors define candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in females.
TReNCo: Topologically associating domain (TAD) aware regulatory network construction
Authors: Bennett Christopher , Amin Viren , Kim Daehwan , Cobanoglu Murat , Malladi Venkat
Published: April 2021

There has long been a desire to understand, describe, and model gene regulatory networks controlling numerous biologically meaningful processes like differentiation. Despite many notable improvements to models over the years, many models do not accurately capture subtle biological and chemical characteristics of the cell such as high-order chromatin domains of the chromosomes. Topologically Associated Domains (TAD) are one of these genomic regions that are enriched for contacts within themselves. Here we present TAD-aware Regulatory Network Construction or TReNCo, a memory-lean method utilizing epigenetic marks of enhancer and promoter activity, and gene expression to create context-specific transcription factor-gene regulatory networks. TReNCo utilizes common assay’s, ChIP-seq, RNA-seq, and TAD boundaries as a hard cutoff, instead of distance based, to efficiently create context-specific TF-gene regulatory networks. We used TReNCo to define the enhancer landscape and identify transcription factors (TFs) that drive the cardiac development of the mouse. Our results show that we are able to build specialized adjacency regulatory network graphs containing biologically relevant connections and time dependent dynamics.
RFRSN: Improving protein fold recognition by siamese network
Authors: Han Ke , Liu Yan , Yu Dong-Jun
Published: April 2021

Protein fold recognition is the key to study protein structure and function. As a representative pattern recognition task, there are two main categories of approaches to improve the protein fold recognition performance: 1) extracting more discriminative descriptors, and 2) designing more effective distance metrics. The existing protein fold recognition approaches focus on the first category to finding a robust and discriminative descriptor to represent each protein sequence as a compact feature vector, where different protein sequence is expected to be separated as much as possible in the fold space. These methods have brought huge improvements to the task of protein fold recognition. However, so far, little attention has been paid to the second category. In this paper, we focus not only on the first category, but also on the second point that how to measure the similarity between two proteins more effectively. First, we employ deep convolutional neural network techniques to extract the discriminative fold-specific features from the potential protein residue-residue relationship, we name it SSAfold. On the other hand, due to different feature representation usually subject to varying distributions, the measurement of similarity needs to vary according to different feature distributions. Before, almost all protein fold recognition methods perform the same metrics strategy on all the protein feature ignoring the differences in feature distribution. This paper presents a new protein fold recognition by employing siamese network, we named it PFRSN. The objective of PFRSN is to learns a set of hierarchical nonlinear transformations to project protein pairs into the same fold feature subspace to ensure the distance between positive protein pairs is reduced and that of negative protein pairs is enlarged as much as possible. The experimental results show that the results of SSAfold and PFRSN are highly competitive.
Exogenous attention generalizes location transfer of perceptual learning in adults with amblyopia
Authors: Roberts Mariel , Carrasco Marisa
Published: April 2021

Visual perceptual learning (VPL) is a behavioral manifestation of brain neuroplasticity. However, its practical effectiveness is limited because improvements are often specific to the trained conditions and require significant time and effort. It is critical to understand the conditions that promote learning and transfer. Covert endogenous (voluntary) and exogenous (involuntary) spatial attention help overcome VPL location specificity in neurotypical adults, but whether they also do so for people with atypical visual development is unknown. This is the first study to investigate the role of exogenous attention during VPL in adults with amblyopia, an ideal population given their asymmetrically developed, but highly plastic, visual cortex. Here we show that training on a discrimination task leads to improvements in foveal contrast sensitivity, acuity, and stereoacuity. Remarkably, exogenous attention helps generalize learning beyond trained spatial locations. Our findings reveal that attention can enhance the effectiveness of perceptual learning during rehabilitation of visual disorders.
Post-outbreak surveillance strategies to support proof of freedom from foot-and-mouth disease
Authors: Bradhurst Richard , Garner Graeme , East Iain , Death Clare , Dodd Aaron , Kompas Tom
Published: April 2021

Whilst emergency vaccination may help contain foot-and-mouth disease in a previously FMD-free country, its use complicates post-outbreak surveillance and the recovery of FMD-free status. A structured surveillance program is required that can distinguish between vaccinated and residually infected animals, and provide statistical confidence that the virus is no longer circulating in previously infected areas.

Epidemiological models have been well-used to investigate the potential benefits of emergency vaccination during a control progam and when/where/whom to vaccinate in the face of finite supplies of vaccine and personnel. Less well studied are post-outbreak issues such as the management of vaccinated animals and the implications of having used vaccination during surveillance regimes to support proof-of-freedom. This paper presents enhancements to the Australian Animal Disease Model (AADIS) that allow comparisons of different post-outbreak surveillance sampling regimes for establishing proof-of-freedom from FMD.

A case study is provided that compares a baseline surveillance sampling regime (derived from current OIE guidelines), with an alternative less intensive sampling regime. It was found that when vaccination was not part of the control program, a reduced sampling intensity significantly reduced the number of samples collected and the cost of the post-outbreak surveillance program, without increasing the risk of missing residual infected herds.
Th17 T cells and immature dendritic cells are the preferential initial targets after rectal challenge with an SIV-based replication-defective dual-reporter vector
Authors: Maric Danijela , Grimm Wesley A. , Greco Natalie , McRaven Michael D. , Fought Angela J. , Veazey Ronald S. , Hope Thomas J.
Published: April 2021

Understanding the earliest events of HIV sexual transmission is critical to develop and optimize HIV prevention strategies. To gain insights into the earliest steps of HIV rectal transmission, including cellular targets, rhesus macaques were intra-rectally challenged with a single-round SIV-based dual reporter that expresses luciferase and iRFP670 upon productive transduction. The vector was pseudotyped with the HIV-1 envelope JRFL. Regions of tissue containingfociof luminescent, transduced cells were identified macroscopically using anin vivoimaging system, and individual transduced cells expressing fluorescent protein were identified and phenotyped microscopically. This system revealed that anal and rectal tissues are both susceptible to transduction 48 hours after the rectal challenge. Detailed phenotypic analysis revealed that on average, 62% of transduced cells are CCR6+T cells—the vast majority of which express RORγT, a Th17 lineage-specific transcription factor. The second most common target cells were immature dendritic cells at 20%. These two cell types were transduced at the rates that are four to five times higher than their relative abundances indicate. Our work demonstrates that Th17 T and immature dendritic cells are preferential initial targets of HIV/SIV rectal transmission.

IMPORTANCE

Men and women who participate in unprotected receptive anal intercourse are at high risk for acquiring HIV. Whilein vitrodata have developed a framework for understanding HIV cell tropism, the initial target cells in the rectal mucosa have not been identified. In this study, we identify these early host cells by using an innovative rhesus macaque rectal challenge model and methodology, which we previously developed. Thus, by shedding light on these early HIV/SIV transmission events, this study provides a specific cellular target for future prevention strategies.
Sewage PromotesVibrio vulnificusGrowth and Alters Gene Expression
Authors: Conrad James W. , Harwood Valerie J.
Published: April 2021

Vibrio vulnificusis a naturally-occurring, potentially lethal pathogen found in coastal waters, fish, and shellfish. Sewage spills in coastal waters occur when infrastructure fails due to severe storms or age, and may affect bacterial populations by altering nutrient levels. This study investigated effects of sewage on clonal and naturalV. vulnificuspopulations in microcosms. Addition of 1% sewage to estuarine water caused the density of a pure culture ofV. vulnificusCMCP6 and a naturalV. vulnificuspopulation to increase significantly, whether measured by qPCR or culture. Changes in the transcription of six virulence- and survival-associated genes in response to sewage were assessed using continuous culture. Exposure to sewage affected transcription of genes that may be associated with virulence. Specifically, sewage modulated the oxidative stress response by altering superoxide dismutase transcription, significantly increasingsodBtranscription while repressingsodA. Sewage also repressed transcription ofnptA, which encodes a sodium-phosphate cotransporter. Sewage had no effect onsodCtranscription or the putative virulence-associated geneshupAorwza. The effects of environmentally relevant levels of sewage onV. vulnificuspopulations and gene transcription suggest that sewage spills that impact warm coastal waters could lead to an increased risk ofV. vulnificusinfections.

Importance

Vibrio vulnificusinfections have profound impacts such as limb amputation and death for individuals with predisposing conditions. The warming climate is contributing to risingV. vulnificusprevalence in waters that were previously too cold to support high levels of the pathogen. Climate change is also expected to increase precipitation in many regions, which puts more pressure on wastewater infrastructure and will result in more frequent sewage spills. The finding that 1% wastewater in estuarine water leads to tenfold to 1000-fold greaterV. vulnificusconcentrations suggests that human exposure to oysters and estuarine water could have greater health impacts in the future. Further, wastewater had a significant effect on gene transcription and has the potential to affect virulence during the initial environment-to-host transition.
Quantitative systems pharmacology modeling of avadomide-induced neutropenia enables virtual clinical dose and schedule finding studies
Authors: Abbiati Roberto A. , Pourdehnad Michael , Carrancio Soraya , Pierce Daniel W. , Kasibhatla Shailaja , McConnell Mark , Trotter Matthew W. B. , Loos Remco , Santini Cristina C. , Ratushny Alexander V.
Published: April 2021

Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia, however the identification of optimal dosing schedules remains a clinical challenge.

Quantitative Systems Pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development.

We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage.

The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort.

Model utility was demonstrated by simulating avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low grade-neutropenia.
Time-averaging and emerging nonergodicity upon resetting of fractional Brownian motion and heterogeneous diffusion processes
Authors: Wang Wei , Cherstvy Andrey G. , Kantz Holger , Metzler Ralf , Sokolov Igor M.
Published: April 2021

How different are the results of constant-rate resetting of anomalous-diffusion processes in terms of their ensemble-averaged versus time-averaged mean-squared displacements (MSDs versus TAMSDs) and how does the process of stochastic resetting impact nonergodicity? These are the main questions addressed in this study. Specifically, we examine, both analytically and by stochastic simulations, the implications of resetting on the MSD-and TAMSD-based spreading dynamics of fractional Brownian motion (FBM) with a long-time memory, of heterogeneous diffusion processes (HDPs) with a power-law-like space-dependent diffusivityD(x) =D0|x|γ, and of their “combined” process of HDP-FBM. We find, i.a., that the resetting dynamics of originally ergodic FBM for superdiffusive choices of the Hurst exponent develops distinct disparities in the scaling behavior and magnitudes of the MSDs and mean TAMSDs, indicating so-called weak ergodicity breaking (WEB). For subdiffusive HDPs we also quantify the nonequivalence of the MSD and TAMSD, and additionally observe a new trimodal form of the probability density function (PDF) of particle’ displacements. For all three reset processes (FBM, HDPs, and HDP-FBM) we compute analytically and verify by stochastic computer simulations the short-time (normal and anomalous) MSD and TAMSD asymptotes (making conclusions about WEB) as well as the long-time MSD and TAMSD plateaus, reminiscent of those for “confined” processes. We show that certain characteristics of the reset processes studied are functionally similar, despite the very different stochastic nature of their nonreset variants. Importantly, we discover nonmonotonicity of the ergodicity breaking parameter EB as a function of the resetting rater. For all the reset processes studied, we unveil a pronounced resetting-induced nonergodicity with a maximum of EB at intermediaterand EB ∼ (1/r)-decay at largervalues. Together with the emerging MSD-versus-TAMSD disparity, this pronouncedr-dependence of the EB parameter can be an experimentally testable prediction. We conclude via discussing some implications of our results to experimental systems featuring resetting dynamics.
Lizard feeding enhancesIxodes pacificusvector competency
Authors: Ring Kacie , Couper Lisa , Sapiro Anne L. , Yarza Fauna , Yang X. Frank , Clay Keith , Mateusiak Chase , Chou Seemay , Swei Andrea
Published: April 2021

A vector’s susceptibility and ability to transmit a pathogen— termed vector competency—determines disease outcomes, yet the ecological factors influencing tick vector competency remain largely unknown.Ixodes pacificus, the vector ofBorrelia burgdorferi(Bb) in the western U.S., feeds on rodents, birds, and lizards. While rodents and birds are reservoirs forBband infect juvenile ticks, lizards areBb-refractory. DespiteI. pacificusfeeding on a range of hosts, it is undetermined how larval host bloodmeal identity affects future nymphal vector competency. We experimentally evaluate the influence of larval host bloodmeal onBbacquisition by nymphalI. pacificus. LarvalI. pacificuswere fed on either lizards or mice and after molting, nymphs were fed onBb-infected mice. We found that lizard-fed larvae were significantly more likely to become infected withBbduring their next bloodmeal than mouse-fed larvae. We also conducted the first RNA-seq analysis on whole-bodiedI. pacificusand found significant upregulation of antioxidants and antimicrobial peptides in the lizard-fed group. Our results indicate that the lizard bloodmeal significantly alters vector competency and gene regulation in ticks, highlighting the importance of host bloodmeal identity in disease transmission and upends prior notions about the role of lizards in Lyme disease transmission.
Social steerability modulates perceptual biases
Authors: Anlló Hernán , Watanabe Katsumi , Sackur Jérôme , de Gardelle Vincent
Published: April 2021

Verbal hints can bias perceptual decision-making, even when the information they provide is false. Whether individuals may be more or less susceptible to such perceptual influences, however, remains unclear. We asked naive participants to indicate the dominant color in a series of stimuli, after giving them a false statement about which color would likely dominate. As anticipated, this statement biased participants’ perception of the dominant color, as shown by a correlated shift of their perceptual decisions, confidence judgments and response times. Crucially, this perceptual bias was more pronounced in participants with higher levels of susceptibility to social influence, as measured by a standard suggestibility scale. Together, these results indicate that even without much apparatus, simple verbal hints can affect our perceptual reality, and that social steerability can determine how much they do so. Susceptibility to suggestion might thus be considered an integral part of perceptual processing.

Statement of relevance

At a time when fake news soar, understanding the role that simple verbal descriptions play in how we perceive the world around us is paramount. Extensive research has shown that perception is permeable to well-orchestrated manipulation. Comparatively less attention has been paid to the perceptual impact of false information when the latter is imparted simply and straightforwardly, through short verbal hints and instructions. Here we show that even a single sentence suffices to bias perceptual decision-making, and that critically, this bias varies across individuals as a function of susceptibility to social influence. Considering how here perception was biased by a single, plain sentence, we argue that researchers, communicators and policy-makers should pay careful attention to the role that social suggestibility plays in how we build our perceptual reality.
Clonal inactivation of telomerase promotes accelerated stem cell differentiation
Authors: Hasegawa Kazuteru , Zhao Yang , Garbuzov Alina , Corces M. Ryan , Chen Lu , Cheung Peggie , Wei Yuning , Chang Howard Y. , Artandi Steven E.
Published: April 2021

Telomerase is intimately associated with stem cells and upregulated in cancer, where it serves essential roles through its catalytic action in elongating telomeres, nucleoprotein caps that protect chromosome ends1. Overexpression of the telomerase reverse transcriptase (TERT) enhances cell proliferation through telomere-independent means, yet definitive evidence for such a direct role in stem cell function has yet to be revealed through loss-of-function studies. Here, we show that conditional deletion of TERT in spermatogonial stem cells (SSCs) markedly impairs competitive clone formation. Using lineage-tracing from theTertlocus, we find that TERT-expressing SSCs yield long-lived clones, but that selective TERT-inactivation in SSCs causes accelerated stem cell differentiation thereby disrupting clone formation. This requirement for TERT in clone formation is bypassed by expression of a catalytically inactive TERT transgene and occurs independently of the canonical telomerase complex. TERT inactivation induces a genome-wide reduction in open chromatin evident in purified SSCs, but not in committed progenitor cells. Loss of TERT causes reduced activity of the MYC oncogene and transgenic expression of MYC in TERT-deleted SSCs efficiently rescues clone formation. These data reveal a required catalytic activity-independent role for TERT in preventing stem cell differentiation, forge a genetic link between TERT and MYC and suggest new means by which TERT may promote tumorigenesis.
Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy
Authors: Rusilowicz-Jones Emma V. , Barone Francesco G. , Lopes Fernanda Martins , Stephen Elizabeth , Mortiboys Heather , Urbé Sylvie , Clague Michael J.
Published: April 2021

The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1/Parkin pathway leading to mitophagy. These include Parkinson’s disease and pulmonary fibrosis. We provide a detailed cell biological characterisation of a benzenesulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in anin vitroenzymatic assay. The current compound offers increased selectivity over previously described inhibitors. It enhances mitophagy and generates a signature response for USP30 inhibition following mitochondrial depolarisation. This includes enhancement of TOM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson’s disease patients carrying loss of function Parkin mutations, compound 39 could significantly restore mitophagy to a level approaching control values. USP30 is located on both mitochondria and peroxisomes and has also been linked to the PINK1 independent pexophagy pathway. Using a fluorescence reporter of pexophagy expressed in U20S cells, we observe increased pexophagy upon application of compound 39 that recapitulates the previously described effect for USP30 depletion. This provides the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover.
DTI-Voodoo: machine learning over interaction networks and ontology-based background knowledge predicts drug–target interactions
Authors: Hinnerichs Tilman , Hoehndorf Robert
Published: April 2021

Motivation

In silicodrug–target interaction (DTI) prediction is important for drug discovery and drug repurposing. Approaches to predict DTIs can proceed indirectly, top-down, using phenotypic effects of drugs to identify potential drug targets, or they can be direct, bottom-up and use molecular information to directly predict binding potentials. Both approaches can be combined with information about interaction networks.

Results

We developed DTI-Voodoo as a computational method that combines molecular features and ontology-encoded phenotypic effects of drugs with protein–protein interaction networks, and uses a graph convolutional neural network to predict DTIs. We demonstrate that drug effect features can exploit information in the interaction network whereas molecular features do not. DTI-Voodoo is designed to predict candidate drugs for a given protein; we use this formulation to show that common DTI datasets contain intrinsic biases with major affects on performance evaluation and comparison of DTI prediction methods. Using a modified evaluation scheme, we demonstrate that DTI-Voodoo improves significantly over state of the art DTI prediction methods.

Availability

DTI-Voodoo source code and data necessary to reproduce results are freely available athttps://github.com/THinnerichs/DTI-VOODOO.

Contact

tilman.hinnerichs@kaust.edu.sa

Supplementary information

Supplementary data are available athttps://github.com/THinnerichs/DTI-VOODOO.
Highly variable fidelity drives symbiont community composition in an obligate symbiosis
Authors: Mankowski Anna , Kleiner Manuel , Erséus Christer , Leisch Nikolaus , Sato Yui , Volland Jean-Marie , Hüttel Bruno , Wentrup Cecilia , Woyke Tanja , Wippler Juliane , Dubilier Nicole , Gruber-Vodicka Harald
Published: April 2021

Many animals are obligately associated with microbial symbionts that provide essential services such as nutrition or protection against predators. It is assumed that in such obligate associations fidelity between the host and its symbionts must be high to ensure the evolutionary success of the symbiosis. We show here that this is not the case in marine oligochaete worms, despite the fact that they are so dependent on their bacterial symbionts for their nutrition and waste recycling that they have lost their digestive and excretory systems. Our metagenomic analyses of 64 gutless oligochaete species from around the world revealed highly variable levels of fidelity not only across symbiont lineages, but also within symbiont clades. We hypothesize that in gutless oligochaetes, selection within host species for locally adapted and temporally stable symbiont communities leads to varying levels of symbiont fidelity and shuffles the composition of symbiont assemblages across geographic and evolutionary scales.
Adhesion-growth factor crosstalk regulates AURKB activation and ERK signaling in re-adherent fibroblasts
Authors: Inchanalkar Siddhi , Balasubramanian Nagaraj
Published: April 2021

Aurora kinases despite their similarity have distinct roles in the cell cycle, which is regulated by cell-matrix adhesion and growth factors. This study reveals loss of adhesion and re-adhesion to differentially regulate Aurora kinases. AURKB activation that drops on the loss of adhesion recovers on re-adhesion in serum-deprived conditions but not in the presence of serum growth factors. A rapid 30min serum treatment of serum-deprived cells blocks the adhesion-dependent recovery of AURKB, which negatively corelates with Erk activation. AZD mediated inhibition of AURKB in serum-deprived re-adherent cells promotes Erk activation and membrane ruffling, comparable to presence of serum. These studies thus define a novel adhesion-growth factor-dependent regulation of AURKB that controls adhesion-dependent Erk activation in re-adherent fibroblasts.
The evolution of regulatory elements in the emerging promoter variant strains of HIV-1
Authors: Bhange Disha , Prasad Nityanand , Singh Swati , Prajapati Harshit Kumar , Maurya Shesh Prakash , Gopalan Bindu Parachalil , Nadig Sowmya , Chaturbhuj Devidas , Boobalan Jayaseelan , Dinesha Thongadi Ramesh , Ahamed Syed Fazil , Singh Navneet , Brahmaiah Anangi , Mehta Kavita , Gohil Yuvrajsinh , Balakrishnan Pachamuthu , Das Bimal Kumar , Dias Mary , Gangakhedkar Raman , Mehendale Sanjay , Paranjape Ramesh , Saravanan Shanmugam , Shet Anita , Solomon Sunil Suhas , Thakar Madhuri , Ranga Udaykumar
Published: April 2021

In a multicentric, observational, investigator-blinded, and longitudinal clinical study of 764 ART-naïve subjects, we identified nine different promoter-variant strains of HIV-1 subtype C (HIV-1C) emerging in the Indian population, with some of these variants being reported for the first time. Unlike several previous studies, our work here focuses on the evolving viral regulatory elements, not coding sequences. The emerging viral strains contain additional copies of the existing transcription factor binding sites (TFBS), including TCF-1α/LEF-1, RBEIII, AP-1, and NF-κB, created by sequence duplication. The additional TFBS are genetically diverse and may blur the distinction between the modulatory region of the promoter and the viral enhancer. In a follow-up analysis, we found trends, but not significant associations between any specific variant promoter and prognostic markers, probably because the emerging viral strains might not have established mono infections yet. Illumina sequencing of four clinical samples containing a co-infection indicated the domination of one strain over the other and establishing a stable ratio with the second strain at the follow-up time-points. Since a single promoter regulates viral gene expression and constitutes the master regulatory circuit with Tat, the acquisition of additional and variant copies of the TFBS may significantly impact viral latency and latent reservoir characteristics. Further studies are urgently warranted to understand how the diverse TFBS profiles of the viral promoter may modulate the characteristics of the latent reservoir, especially following the initiation of antiretroviral therapy.

Significance Statement

A unique conglomeration of TFBS enables the HIV-1 promoter to accomplish two diametrically opposite functions – transcriptional activation and transcriptional silencing. The various phases of viral latency -establishment, maintenance, and reversal -collectively determine the replication fitness of individual viral strains. A profound variation in the TFBS composition of the viral promoter may significantly alter the viral latency properties and the latent reservoir characteristics. Although the duplication of certain TFBS remains a quality unique to HIV-1C, the high-level genetic recombination of HIV-1 may promote the transfer of such molecular properties to the other HIV-1 subtypes. The emergence of several promoter-variant viral strains may make the task of a ‘functional cure’ more challenging in HIV-1C.
Judgments of agency are affected by sensory noise without recruiting metacognitive processing
Authors: Constant Marika , Salomon Roy , Filevich Elisa
Published: April 2021

Judgments of agency, our sense of control over our actions and the environment, often occur in noisy conditions. We examined the computations underlying judgments of agency, in particular under the influence of sensory noise. Building on previous literature, we studied whether judgments of agency incorporate uncertainty in the same way that confidence judgments do, which would imply that the former share computational mechanisms with metacognitive judgments. In two tasks, participants rated agency, or confidence in a decision about their agency, over a virtual hand that tracked their movements, either synchronously or with a delay and either under high or low noise. We compared the predictions of two computational models to participants’ ratings and found that agency ratings, unlike confidence, were best explained by a model involving no estimates of sensory noise. We propose that agency judgments reflect first-order measures of the internal signal, without involving metacognitive computations, challenging the assumed link between the two cognitive processes.
Thermodynamic stability of G-quadruplex and overlapping m6A: Position-dependent collaborators in allele frequency and fitness?
Authors: Gulec Cagri
Published: April 2021

Background

Post-transcriptional modifications like m6A, and secondary structures like G-quadruplex (G4), play an important role in RNA processing. Despite an emerging number of studies focusing on m6A and G4 separately, there are less studies about their synergy.

Aim

Since m6A is known to be enzymatically created in DRACH-motif, and genetic variants may create a novel DRACH-motif or abolish a pre-existing DRACH-motif, we can suppose that the variants may affect gene product level through modulating m6A-G4 colocalization, which consequently may affect fitness and change allele frequency. To test this hypothesis, rare and common variants in selected human genes were investigated in terms of their effect on m6A-G4 colocalization.

Methods

Genomic sequences and variant features were fetched from GRCh37/hg19 and Biomart-Ensembl databases, respectively. Counting the number of putative m6A- and G4-motifs in sequences and statistical analysis were performed with appropriate libraries of Python3.7.

Results

Common variants creating novel m6A-motif were found more frequently inside than outside G4, and displayed unequal distribution throughout pre-mRNA. Unequal distribution of m6A-creating variants seemed to be related to their effect on thermodynamic stability of the overlapping-G4.

Discussion

Selective m6A-G4 colocalization suggests that m6A-motif is favorable when overlapping with G4. Besides, thermodynamic stability may lead to unequal distribution of m6A-G4 colocalization, because m6A-creating alleles seem to have lower frequency if stabilizes overlapping-G4 in 3-prime-side, but not in 5-prime-side. We can conclude that the fitness, and consequently frequency of an m6A-creating variant is prone to become higher or lower depending on its position and effect on the overlapping-G4 stability.
Striatal and prefrontal D2R and SERT distributions contrastingly correlate with default-mode connectivity
Authors: Ionescu Tudor M. , Amend Mario , Hafiz Rakibul , Biswal Bharat B. , Maurer Andreas , Pichler Bernd J. , Wehrl Hans F. , Herfert Kristina
Published: April 2021

The molecular substrate of resting-state functional connectivity (rs-FC) remains poorly understood. We aimed to elucidate interactions of dopamine D2 receptor (D2R) and serotonin transporter (SERT) availabilities in main dopaminergic and serotonergic projection areas with the default-mode network (DMN) and two other resting-state networks (RSNs), the salience (SN) and sensorimotor networks (SMN). We performed simultaneous PET/fMRI scans in rats using [11C]raclopride and [11C]DASB to image D2R and SERT distributions, showing for the first time direct relationships between rs-FC and molecular properties of the rodent brain. We found negative associations between CPu D2R availability and all RSNs investigated. Strikingly, medial prefrontal SERT correlated both positively with anterior DMN rs-FC and negatively with rs-FC between the other networks, underlining serotonin’s intricate role in this region. By further elucidating the link between molecular brain properties and its network-level function, our data support future diagnostic and therapeutic strategies.

Teaser

Simultaneous PET/fMRI indicates direct associations between monoaminergic neurotransmission and brain functional networks.
Cdc48 influence on separase levels is independent of mitosis and suggests translational sensitivity of separase
Authors: Vijayakumari Drisya , Müller Janina , Hauf Silke
Published: April 2021

Cdc48 (p97/VCP) is a AAA-ATPase that can extract ubiquitinated proteins from their binding partners and channel substrates to the proteasome. A fission yeastcdc48mutant (cdc48-353) shows low levels of the cohesin protease, separase, and pronounced chromosome segregation defects in mitosis. Separase initiates chromosome segregation when its binding partner securin is ubiquitinated and degraded. The low separase levels in thecdc48-353mutant have been attributed to a failure to extract ubiquitinated securin from separase resulting in co-degradation of separase along with securin. If true, this establishes Cdc48 as a key regulator of mitosis. In contrast, we show here that low separase levels in thecdc48-353mutant are independent of mitosis. Moreover, we find no evidence of enhanced separase degradation in the mutant. Instead, we suggest that thecdc48-353mutant uncovers specific requirements for separase translation. Our results highlight a need to better understand how this key mitotic enzyme is synthesized.
The right time and place: time- and age-dependent vaccine-enhanced mucosal immunity to parasite infection
Authors: Liu Wei , McNeilly Tom N. , Mitchell Mairi , Burgess Stewart T.G. , Nisbet Alasdair J. , Matthews Jacqueline B. , Babayan Simon A.
Published: April 2021

Individuals vary broadly in their response to vaccination and subsequent exposure to infection, causing persistence of both infection and transmission. The prevalence of poor vaccine responders hampers the development of vaccines, especially against parasitic helminths. Yet despite having substantial economic and societal impact, the immune mechanisms that underlie such variability, especially at the site of parasite infection, remain poorly understood. Previous trials using a prototype vaccine for the control of the gastric parasiticTeladorsagia circumcincta, one of the highest impact parasites affecting sheep, revealed substantial variation in protection between individuals, which we hypothesised may in part be driven by age at vaccination. Here, to characterise how immunity at the mucosal site of infection developed in vaccinated lambs, we inserted gastric cannulae into the abomasa (true stomachs) of three-month- and six-month-old lambs before vaccination, and performed a longitudinal analysis of their local immune response during subsequent challenge infection. We found that the vaccine caused systemic changes in the baseline immune profile within the abomasum before any parasite exposure had occurred and reduced parasite burden and egg output once lambs were infected, regardless of age. However, age affected how vaccinated lambs responded to subsequent infection across multiple immune pathways, with only a minority of protective immune pathways being independent of age. This resulted in younger lambs being more susceptible to infection regardless of vaccine status. The identification of age-dependent (mostly adaptive) and age-independent (mostly innate) protective immune pathways should help refine the formulation of vaccines against these and potentially other helminth parasites of ruminants, and could indicate specificities of anti-helminth immunity more generally.
Feature-based attention enables robust, long-lasting location transfer in human perceptual learning
Authors: Hung Shao-Chin , Carrasco Marisa
Published: April 2021

Visual perceptual learning (VPL) is typically specific to the trained location and feature. However, the degree of specificity depends upon particular training protocols. Manipulating covert spatial attention during training facilitates learning transfer to other locations. Here we investigated whether feature-based attention (FBA), which enhances the representation of particular features throughout the visual field, facilitates VPL transfer, and how long such an effect would last. To do so, we implemented a novel task in which observers discriminated a stimulus orientation relative to two reference angles presented simultaneously before each block. We found that training with FBA enabled remarkable location transfer, reminiscent of its global effect across the visual field, but preserved orientation specificity in VPL. Critically, both the perceptual improvement and location transfer persisted after one year. Our results reveal robust, long-lasting benefits induced by FBA in VPL, and have translational implications for improving generalization of training protocols in visual rehabilitation.
Above- and below-ground biodiversity responses to the prolonged flood pulse in central-western Amazonia, Brazil
Authors: Bredin Yennie K. , Hess Laura L. , Scabin Andressa B. , Dunthorn Micah , Haugaasen Torbjørn , Peres Carlos A. , Nilsson Henrik R. , Antonelli Alexandre , Ritter Camila D.
Published: April 2021

Amazonia encompasses forests that grow in areas that are periodically inundated by overflowing rivers. The inundation depth and duration vary according to the slope of the terrain, creating a flooding gradient. This gradient directly affects the biota, but the effect on soil organisms remains elusive. Here, we use DNA metabarcoding to estimate prokaryote and eukaryote diversity from soil and litter samples in a seasonally flooded forest and its adjacent unflooded forest in central-western Amazonia using 16S and 18S gene sequences, respectively. We characterize the below-ground diversity and community composition based on Amplicon Sequence Variants (ASVs) along the flooding gradient. We test for the relationship of soil biota with the flooding gradient, soil properties and above-ground woody plant diversity. The flooding gradient did not explain below-ground biodiversity. Nor was the below-ground diversity explained by the above-ground woody plant diversity. However, we found taxonomic groups not previously reported in Amazonian seasonally flooded forests. Also, the flooding gradient and woody plant diversity did, in part, explain the community composition of soil bacteria. Although the effects of the flooding gradient, soil properties and above-ground woody plant diversity is hard to quantify, our results thus indicate that flood stress could influence below-ground bacterial community composition.
The brain integrates proprioceptive information to ensure robust locomotion
Authors: Santuz Alessandro , Laflamme Olivier D. , Akay Turgay
Published: April 2021

Robust locomotion relies on information from proprioceptors: sensory organs that communicate the position of body parts to the spinal cord and brain. Proprioceptive circuits in the spinal cord are known to regulate locomotion in challenging environments. Yet, the regulatory importance of the brain remains less clear. Here, through mouse genetic studies and in vivo electrophysiology, we examined the role of the brain in integrating proprioceptive information during locomotion. The systemic removal of proprioceptors left the animals in a constantly perturbed state, similar to that observed during mechanically perturbed locomotion in wild type and characterised by longer and less accurate activation patterns. In contrast, after surgically interrupting the ascending proprioceptive projection to the brain through the dorsal column pathway, wild-type mice showed normal walking behaviour, but lost the ability to respond to external perturbations. Our findings provide direct evidence of a pivotal role for ascending proprioceptive information in achieving safe locomotion.
Prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine
Authors: Rathnasinghe Raveen , Salvatore Mirella , Zheng Hongyong , Jangra Sonia , Kehrer Thomas , Mena Ignacio , Schotsaert Michael , Muster Thomas , Palese Peter , García-Sastre Adolfo
Published: April 2021

The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an immediate antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.
In-scanner head motion and structural covariance networks
Authors: Pardoe Heath R. , Martin Samantha P.
Published: April 2021

In-scanner head motion systematically reduces estimated regional gray matter volumes obtained from structural brain MRI. Here, we investigate how head motion affects structural covariance networks that are derived from regional gray matter volumetric estimates. We acquired motion-affected and motion-free whole brain T1-weighted MRI in 29 healthy adult subjects and estimated relative regional gray matter volumes using a voxel-based morphometry approach. Structural covariance network analyses were undertaken while systematically increasing the number of motion-affected scans included in the analysis. We demonstrate that the standard deviation in regional gray matter estimates increases as the number of motion-affected scans increases. This subsequently increases pair-wise correlations between regions, a key determinant for construction of structural covariance networks. We further demonstrate that head motion systematically alters graph theoretic metrics derived from these networks. Our findings suggest that in-scanner head motion is a source of error that violates the assumption that structural covariance networks reflect neuroanatomical connectivity between brain regions. Results of structural covariance studies should be interpreted with caution, particularly when subject groups are likely to move their heads in the scanner.