bluuebunny/crossref_metadata_2025 huggingface dataset:
Vaccine Hyporesponse Induced By Individual Antibiotic Treatment In Mice And Non-Human Primates Is Diminished Upon Recovery Of The Gut Microbiome
Authors: Swaminathan Gokul , Citron Michael , Xiao Jianying , Norton James E , Reens Abigail L , Topçuoğlu Begüm D. , Maritz Julia M , Lee Keun-Joong , Freed Daniel C , Weber Teresa M , White Cory H , Kadam Mahika , Spofford Erin , Bryant-Hall Erin , Salituro Gino , Kommineni Sushma , Liang Xue , Danilchanka Olga , Fontenot Jane A , Woelk Christopher H , Gutierrez Dario A , Hazuda Daria J , Hannigan Geoffrey D
Published: April 2021

Emerging evidence demonstrates a connection between microbiome composition and suboptimal response to vaccines (vaccine hyporesponse). Harnessing the interaction between microbes and the immune system could provide novel therapeutic strategies for improving vaccine response. Currently we do not fully understand the mechanisms and dynamics by which the microbiome influences vaccine response. Using both mouse and non-human primate models, we report that short-term oral treatment with a single antibiotic (vancomycin) results in disruption of the gut microbiome and this correlates with a decrease in systemic levels of antigen-specific IgG upon subsequent parenteral vaccination. We further show that recovery of microbial diversity before vaccination prevents antibiotic-induced vaccine hyporesponse, and that the antigen specific IgG response correlates with the recovery of microbiome diversity. RNA-sequencing analysis of small intestine, spleen, whole blood, and secondary lymphoid organs from antibiotic treated mice revealed a dramatic impact on the immune system, and a muted inflammatory signature is correlated with loss of bacteria fromLachnospiraceae, Ruminococcaceae, andClostridiaceae. These results suggest that microbially modulated immune pathways may be leveraged to promote vaccine response and will inform future vaccine design and development strategies.

Importance

Antibiotic-induced gut microbiome disruption has been linked to reduced vaccine efficacy. Despite these observations, there remains a knowledge gap in the specific mechanisms by which antibiotics and the gut microbiome influence vaccine efficacy. We aim to contribute to the field’s growing mechanistic understanding by presenting a detailed analysis of antibiotic treatment and recovery as it relates to vaccine response and the microbiome. Using animal models, we show that short-term antibiotic treatment prior to vaccination results in diminished vaccine-specific immune responses, and that these are correlated with specific microbiome signatures. We also demonstrate the converse, in which gut microbiome recovery can result in improved vaccine response. We further reveal that antibiotics can significantly alter multiple relevant immune pathways and this alteration in immune tone may contribute to the vaccine hyporesponse. We expect our findings will enable the continued prosecution of the role of the microbiome in modulating the host immune system.
Taking aim at the perceptual side of motor learning: Exploring how explicit and implicit learning encode perceptual error information through depth vision
Authors: Campagnoli Carlo , Domini Fulvio , Taylor Jordan A.
Published: April 2021

Motor learning in visuomotor adaptation tasks results from both explicit and implicit processes, each responding differently to an error signal. While the motor output side of these processes is extensively studied, their visual input side is relatively unknown. We investigated if and how depth perception affects the computation of error information by explicit and implicit motor learning. Two groups of participants threw virtual darts at a virtual dartboard while receiving perturbed endpoint feedback. The Delayed group was allowed to re-aim and their feedback was delayed to emphasize explicit learning, while the Clamped group received clamped cursor feedback which they were told to ignore, and continued to aim straight at the target to emphasize implicit adaptation. Both groups played this game in a highly detailed virtual environment (Depth condition) and in an empty environment (No-Depth condition). The Delayed group showed an increase in error sensitivity under Depth relative to No-Depth conditions. In contrast, the Clamped group adapted to the same degree under both conditions. The movement kinematics of the Delayed participants also changed under the Depth condition, consistent with the target appearing more distant, unlike the Clamped group. A comparison of the Delayed behavioral data with a perceptual task from the same individuals showed that the effect of the Depth condition on the re-aiming direction was consistent with an increase in the scaling of the error distance and size. These findings suggest that explicit and implicit learning processes may rely on different sources of perceptual information.

New & Noteworthy

We leveraged a classic sensorimotor adaptation task to perform a first systematic assessment of the role of perceptual cues in the estimation of an error signal in the 3D space during motor learning. We crossed two conditions presenting different amounts of depth information, with two manipulations emphasizing explicit and implicit learning processes. Explicit learning responded to the visual conditions, consistent with perceptual reports, while implicit learning appeared to be independent of them.
Statistical properties of the MetaCore network of protein-protein interactions
Authors: Kotelnikova Ekaterina , Frahm Klaus M. , Lages José , Shepelyansky Dima L
Published: April 2021

The MetaCore commercial database describes interactions of proteins and other chemical molecules and clusters in the form of directed network between these elements, viewed as nodes. The number of nodes goes beyond 40 thousands with almost 300 thousands links between them. The links have essentially bi-functional nature describing either activation or inhibition actions between proteins. We present here the analysis of statistical properties of this complex network applying the methods of the Google matrix, PageRank and CheiRank algorithms broadly used in the frame of the World Wide Web, Wikipedia, the world trade and other directed networks. We specifically describe the Ising PageRank approach which allows to treat the bi-functional type of protein-protein interactions. We also show that the developed reduced Google matrix algorithm allows to obtain an effective network of interactions inside a specific group of selected proteins. This method takes into account not only direct protein-protein interactions but also recover their indirect nontrivial couplings appearing due to summation over all the pathways passing via the global bi-functional network. The developed analysis allows to espablish an average action of each protein being more oriented to activation or inhibition. We argue that the described Google matrix analysis represents an efficient tool for investigation of influence of specific groups of proteins related to specific diseases.
Beyond linear regression: mapping models in cognitive neuroscience should align with research goals
Authors: Ivanova Anna A. , Schrimpf Martin , Anzellotti Stefano , Zaslavsky Noga , Fedorenko Evelina , Isik Leyla
Published: April 2021

Many cognitive neuroscience studies use large feature sets to predict and interpret brain activity patterns. Feature sets take many forms, from human stimulus annotations to representations in deep neural networks. Of crucial importance in all these studies is the mapping model, which defines the space of possible relationships between features and neural data. Until recently, most encoding and decoding studies have used linear mapping models. Increasing availability of large datasets and computing resources has recently allowed some researchers to employ more flexible nonlinear mapping models instead; however, the question of whether nonlinear mapping models can yield meaningful scientific insights remains debated. Here, we discuss the choice of a mapping model in the context of three overarching desiderata: predictive accuracy, interpretability, and biological plausibility. We show that, contrary to popular intuition, these desiderata do not map cleanly onto the linear/nonlinear divide; instead, each desideratum can refer to multiple research goals, each of which imposes its own constraints on the mapping model. Moreover, we argue that, instead of categorically treating the mapping models as linear or nonlinear, we should instead aim to estimate the complexity of these models. We show that, in many cases, complexity provides a more accurate reflection of restrictions imposed by various research goals. Finally, we outline several complexity metrics that can be used to effectively evaluate mapping models.
Intermittent fasting and caloric restriction interact with genetics to shape physiological health in mice
Authors: Zhang Guozhu , Deighan Andrew , Raj Anil , Robinson Laura , Donato Hannah J. , Garland Gaven , Leland Mackenzie , Martin-McNulty Baby , Kolumam Ganesh A. , Riegler Johannes , Freund Adam , Wright Kevin M. , Churchill Gary
Published: April 2021

Dietary interventions can dramatically affect physiological health and organismal lifespan. The degree to which organismal health is improved depends upon genotype and the severity of dietary intervention, but neither the effects of these factors, nor their interaction, have been quantified in an outbred population. Moreover, it is not well understood what physiological changes occur shortly after dietary change and how these may affect the health of early adulthood population. In this article, we investigated the effect of six month exposure of either caloric restriction or intermittent fasting on a broad range of physiological traits in 960 one year old Diversity Outbred mice. We found caloric restriction and intermittent fasting affected distinct aspects of physiology and neither the magnitude nor the direction (beneficial or detrimental) of effects were concordant with the severity of the intervention. In addition to the effects of diet, genetic variation significantly affected 31 of 36 traits (heritabilties ranged from 0.04-0.65). We observed significant covariation between many traits that was due to both diet and genetics and quantified these effects with phenotypic and genetic correlations. We genetically mapped 16 diet-independent and 2 diet-dependent significant quantitative trait loci, both of which were associated with cardiac physiology. Collectively, these results demonstrate the degree to which diet and genetics interact to shape the physiological health of early adult-hood mice following six months of dietary intervention.
Focal fMRI signal enhancement with implantable inductively coupled detectors
Authors: Chen Yi , Wang Qi , Choi Sangcheon , Zeng Hang , Takahashi Kengo , Qian Chunqi , Yu Xin
Published: April 2021

Despite extensive efforts to increase the signal-to-noise ratio (SNR) of fMRI images for brain-wide mapping, technical advances of focal brain signal enhancement are lacking, in particular, for animal brain imaging. Emerging studies have combined fMRI with fiber optic-based optogenetics to decipher circuit-specific neuromodulation from meso to macroscales. Acquiring fMRI signal with high spatiotemporal resolution is needed to bridge cross-scale functional dynamics, but SNR of targeted cortical regions is a limiting factor. We have developed a multi-modal fMRI imaging platform with an implanted inductive coil detector. This detector boosts the tSNR of MRI images, showing a 2-3 fold sensitivity gain over conventional coil configuration. In contrast to the cryoprobe or array coils with limited spaces for implanted brain interface, this setup offers a unique advantage to study brain circuit connectivity with optogenetic stimulation and can be further extended to other multi-modal fMRI mapping schemes.
Autophagy Induced by Palmitic Acid: a Brake in NAFLD Neutrophils
Authors: Peng Zhicheng , Wang Heyuan , Hsu Alan Y. , Du Xiliang , Yang Yuchen , Fang Baochen , Li Yunfei , Zhu Yiwei , Song Yuxiang , Li Xiaobing , Wang Zhe , Li Xinwei , Liu Guowen
Published: April 2021

Innate immune suppression and high blood fatty acid levels are the pathological basis of multiple metabolic diseases. Neutrophil vacuolation is an indicator of the immune status of patients, which is associated with autophagy-dependent granule degradation. Vacuolated neutrophils are observed in ethanol toxicity and septicemia patients due to the changes in their blood constituents, but how about the neutrophils in nonalcoholic fatty liver disease (NAFLD) patient is unknown. Here, we confirmed that an adhesion deficiency and an increased autophagy level existed in NAFLD neutrophils, and the three neutrophil granule subunits, namely, the azurophil granules, specific granules and gelatinase granules, could be engulfed by autophagosomes for degradation, and these autophagy-triggered granule degradation events were associated with vacuolation in palmitic acid (PA)-treated and NAFLD neutrophils. Concordantly, the adhesion-associated molecules CD11a, CD11b, CD18 and Rap1 on the three granule subunits were degraded during PA induced autophagy. Moreover, the cytosolic CD11a, CD11b, CD18 and Rap1 were targeted by Hsc70 and then delivered to lysosomal-like granules for degradation. Notably,in vitro and ex vivo, PA induced autophagy by inhibiting the p-PKCα/PKD2 pathway. Overall, we showed that high blood PA level inhibited the p-PKCα/PKD2 pathway to induce NAFLD neutrophil autophagy, which promoted the degradation of CD11a, CD11b, CD18 and Rap1 and further decreased the adhesion of neutrophils, thereby impairing the neutrophil function of NAFLD patients. This theory provides a new therapeutic strategy to improve the immune deficiency in NAFLD patients.

Visual Abstract

Key Points

Vacuolation and adhesion deficiency of NAFLD neutrophils are associated with autophagy-dependent granule degradation

PA inhibits p-PKCα/PKD2 to induce autophagy, which induces the degradation of CD11a, CD11b, CD18 and Rap1 and decreases neutrophil adhesion
Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques
Authors: Hasenkrug Kim J. , Feldmann Friederike , Myers Lara , Santiago Mario L. , Guo Kejun , Barrett Bradley S. , Mickens Kaylee L. , Carmody Aaron , Okumura Atsushi , Rao Deepashri , Collins Madison M. , Messer Ronald J. , Lovaglio Jamie , Shaia Carl , Rosenke Rebecca , van Doremalen Neeltje , Clancy Chad , Saturday Greg , Hanley Patrick , Smith Brian , Meade-White Kimberly , Shupert W. Lesley , Hawman David W. , Feldmann Heinz
Published: April 2021

Severe COVID-19 has been associated with T cell lymphopenia1,2, but no causal effect of T cell deficiency on disease severity has been established. To investigate the specific role of T cells in recovery from SARS-CoV-2 infections we studied rhesus macaques that were depleted of either CD4+, CD8+or both T cell subsets prior to infection. Peak virus loads were similar in all groups, but the resolution of virus in the T cell-depleted animals was slightly delayed compared to controls. The T cell-depleted groups developed virus-neutralizing antibody responses and also class-switched to IgG. When re-infected six weeks later, the T cell-depleted animals showed anamnestic immune responses characterized by rapid induction of high-titer virus-neutralizing antibodies, faster control of virus loads and reduced clinical signs. These results indicate that while T cells play a role in the recovery of rhesus macaques from acute SARS-CoV-2 infections, their depletion does not induce severe disease, and T cells do not account for the natural resistance of rhesus macaques to severe COVID-19. Neither primed CD4+or CD8+T cells appeared critical for immunoglobulin class switching, the development of immunological memory or protection from a second infection.
Ventral tegmental area glutamate neurons mediate the nonassociative consequences of traumatic stress
Authors: McGovern Dillon J. , Ecton Koy L. , Huynh David T. , Rau Andrew R. , Hentges Shane T. , Ly Annie , Baratta Michael V. , Root David H.
Published: April 2021

Exposure to trauma is a risk factor for the development of a number of mood disorders, and may enhance vulnerability to future adverse life events. Recent data implicate ventral tegmental area (VTA) glutamate neuronal activity as functionally important for signaling aversive or threating stimuli. However, it is unknown whether VTA glutamate neurons regulate transsituational outcomes that result from stress and whether these neurons are sensitive to stressor controllability. This work established an operant mouse paradigm to examine the impact of stressor controllability on VTA glutamate neuron function and stressor outcome. Uncontrollable (inescapable) stress, but not physically identical controllable (escapable) stress, produced social avoidance in male mice. Cell-type-specific calcium recordings showed that both controllable and uncontrollable stressors increased VTA glutamate neuronal activity. Chemogenetic reduction of VTA glutamate neuron activity prevented the behavioral sequelae of uncontrollable stress. Our results provide causal evidence that mice can be used to model stressor controllability and that VTA glutamate neurons may contribute to transsituational stressor outcomes, such as social avoidance and exaggerated fear that are observed within trauma-related disorders.
Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice
Authors: Borrelli Kristyn N. , Yao Emily J. , Yen Will W. , Ruan Qiu T. , Chen Melanie M. , Kelliher Julia C. , Langan Carly R. , Scotellaro Julia L. , Babbs Richard K. , Beierle Jacob C. , Logan Ryan W. , Johnson William Evan , Wachman Elisha M. , Cruz-Martín Alberto , Bryant Camron D.
Published: April 2021

The opioid epidemic led to an increase in the number of Neonatal Opioid Withdrawal Syndrome (NOWS) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15mg/kg, s.c.) twice daily for postnatal days (P) 1-14, an approximate of the third trimester of human gestation. Male and female mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA-sequencing. Morphine induced weight loss from P2-14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increased at P7 in females, emerging earlier than males. On P7 and P14, both morphine exposed female and male mice displayed hyperalgesia on the hot plate and tail flick assays, with females having greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like behavior in the open-field arena at P21. Transcriptome analysis of the brainstem (medulla plus pons), an area implicated in opioid withdrawal and NOWS, identified pathways enriched for noradrenergic signaling in females and males. We also found sex-specific pathways related to mitochondrial function and neurodevelopment in females and circadian entrainment in males. Sex-specific transcriptomic neuroadaptations implicate unique neurobiological mechanisms underlying NOWS-like behaviors.

SIGNIFICANCE STATEMENT

Neonatal opioid withdrawal syndrome (NOWS) is a poorly understood condition that has both a genetic and environmental component and is thought to be mechanistically distinct from opioid withdrawal in adults. The development of murine models for measuring neurobehavioral responses is critical for informing the neurobiological adaptations underlying NOWS. Using outbred mice that more closely model human genetic variation, we discovered a surprising degree of sexual dimorphism in behavioral timing and severity of NOWS-model behaviors as well as transcriptomic adaptations in brain tissue that together suggest distinct mechanisms and sex-specific therapeutics for reversing withdrawal symptoms and restoring brain function.
Detection of Junctional Ectopic Tachycardia by Central Venous Pressure
Authors: Tan Xin , Dai Yanwan , Humayun Ahmed Imtiaz , Chen Haoze , Allen Genevera I. , Jain Parag N.
Published: April 2021

Central venous pressure (CVP) is the blood pressure in the venae cavae, near the right atrium of the heart. This signal waveform is commonly collected in clinical settings, and yet there has been limited discussion of using this data for detecting arrhythmia and other cardiac events. In this paper, we develop a signal processing and feature engineering pipeline for CVP waveform analysis. Through a case study on pediatric junctional ectopic tachycardia (JET), we show that our extracted CVP features reliably detect JET with comparable results to the more commonly used electrocardiogram (ECG) features. This machine learning pipeline can thus improve the clinical diagnosis and ICU monitoring of arrhythmia. It also corroborates and complements the ECG-based diagnosis, especially when the ECG measurements are unavailable or corrupted.
Genomic and epigenomic adaptation in SP-R210 (Myo18A) isoform-deficient macrophages
Authors: Yau Eric , Chen Yan , Song Chunhua , Webb Jason , Carillo Marykate , Ikawasawa Yuka Imamura , Tang Zhenyuan , Takahashi Yoshinori , Umstead Todd M , Dovat Sinisa , Chroneos Zissis C.
Published: April 2021

1

Macrophages play fundamental roles in regulation of inflammatory responses to pathogens, resolution of inflammation and tissue repair, and maintenance of tissue homeostasis. The long (L) and short (S) isoforms of SP-R210/MYO18A, a macrophage receptor for surfactant protein A (SP-A) and C1q, regulate basal and inflammatory macrophage phenotype at multiple gene expression, translational, and subcellular levels in addition to their SP-A and C1q-mediated functions; disruption of L renders macrophages hyper-inflammatory, although the underlying mechanism had previously been unexplored. We asked whether disruption of the L isoform led to the hyper-inflammatory state via alteration of global genomic responses. RNA sequencing analysis of SP-R210L(DN) macrophages revealed basal and influenza induced upregulation of genes associated with inflammatory pathways, including TLR, RIG-I, NOD, and cytoplasmic DNA signaling, whereas knockdown of both SP-R210 isoforms (L and S) only resulted in increased RIG-I and NOD signaling. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis showed increased genome-wide deposition of the pioneer transcription factor PU.1 in SP-R210L(DN) compared to WT cells. ChIP-seq analysis of histone H3 methylation showed alterations in both repressive (H3K9me3 and H3K27me3) and transcriptionally active (H3K9me3) histone marks. Influenza A virus (IAV) infection, which stimulates an array of cytosolic and TLR-mediated antiviral mechanisms, resulted in differential redistribution between proximal promoter and distal sites and decoupling of PU.1 binding from Toll-like receptor regulated gene promoters in SP-R210L(DN) cells. Our findings suggest that SP-R210L-deficient macrophages are poised with an open PU.1-primed chromatin conformation to rapidly respond to inflammatory and metabolic stimuli.
Plasticity of cold hardiness in the eastern spruce budworm,Choristoneura fumiferana
Authors: Butterson Skye , Roe Amanda D. , Marshall Katie E.
Published: April 2021

High latitude insect populations must cope with extreme conditions, particularly cold temperatures. Insects use a variety of cold hardiness mechanisms to withstand this temperature stress, and these can drive geographic distributions through overwintering mortality. The degree of cold hardiness can be altered by two evolved responses: phenotypic plasticity and local adaptation. Phenotypic plasticity can occur within or between generations (transgenerational plasticity; TGP), and local adaptation can evolve through directional selection in response to regional climatic differences. We used the eastern spruce budworm,Choristoneura fumiferana(Lepidoptera: Tortricidae) as a model to explore the role that variable winter temperatures play in inducing two aspects of plasticity in cold hardiness: TGP and local adaptation in phenotypic plasticity. This species is one of the most destructive boreal forest pests in North America, therefore accurately predicting overwintering survival is essential for effective management. While we found no evidence of TGP in cold hardiness, there was a long-term fitness cost to larvae that experienced repeated cold exposures. We also found evidence of local adaptation in both seasonal and short-term plasticity of cold hardiness. These findings provide evidence for the importance of phenotypic plasticity and local adaptation when modelling species distributions.
Evidence or Confidence: What is really monitored during a decision?
Authors: Lee Douglas G. , Daunizeau Jean , Pezzulo Giovanni
Published: April 2021

Assessing our confidence in the choices we make is of paramount importance to making adaptive decisions, and it is thus no surprise that we excel in this ability. However, standard models of decision-making, such as the drift-diffusion model (DDM), treat confidence assessment as a post-hoc or parallel process that does not directly influence the choice, which depends only on accumulated evidence. Here, we pursue the alternative hypothesis that what is monitored during a decision is an evolving sense of confidence (that the to-be-selected option is the best) rather than raw evidence. Monitoring confidence has the appealing consequence that the decision threshold corresponds to a desired level of confidence for the choice, and that confidence improvements can be traded off against the resources required to secure them. We show that most previous findings on perceptual and value-based decisions traditionally interpreted from anevidence-accumulationperspective can be explained more parsimoniously from our novelconfidence-drivenperspective. Furthermore, we show that our novelconfidence-driven DDM(cDDM) naturally generalizes to decisions involving any number of alternative options – which is notoriously extemporaneous using traditional DDM or related models. Finally, we discuss future empirical evidence that could be useful in adjudicating between these alternatives.
Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast
Authors: Denney Ashley S. , Weems Andrew D. , McMurray Michael A.
Published: April 2021

Life requires the oligomerization of individual proteins into higher-order assemblies. In order to form functional oligomers, monomers must adopt appropriate three-dimensional structures. Molecular chaperones transiently bind nascent or misfolded proteins to promote proper folding. Single missense mutations frequently cause disease by perturbing folding despite chaperone engagement. A misfolded mutant capable of oligomerizing with wild-type proteins can dominantly poison oligomer function. We previously found evidence that human-disease-linked mutations inSaccharomyces cerevisiaeseptin proteins slow folding and attract chaperones, resulting in a kinetic delay in oligomerization that prevents the mutant from interfering with wild-type function. Here we build upon our septin studies to develop a new approach to identifying chaperone interactions in living cells, and use it to expand our understanding of chaperone involvement, kinetic folding delays, and oligomerization in the recessive behavior of tumor-derived mutants of the tumor suppressor p53. We find evidence of increased binding of several cytosolic chaperones to a recessive, misfolding-prone mutant, p53(V272M). Similar to our septin results, chaperone overexpression inhibits the function of p53(V272M) with minimal effect on the wild type. Unlike mutant septins, p53(V272M) is not kinetically delayed under conditions in which it is functional. Instead, it interacts with wild-type p53 but this interaction is temperature sensitive. At high temperatures or upon chaperone overexpression, p53(V272M) is excluded from the nucleus and cannot function or perturb wild-type function. Chaperone inhibition liberates the mutant to enter the nucleus where it has a slight dominant-negative effect. These findings provide new insights into the effects of missense mutations.
Reconstructing SNP Allele and Genotype Frequencies from GWAS Summary Statistics
Authors: Yang Zhiyu , Paschou Peristera , Drineas Petros
Published: April 2021

The emergence of genomewide association studies (GWAS) has led to the creation of large repositories of human genetic variation, creating enormous opportunities for genetic research and worldwide collaboration. Methods that are based on GWAS summary statistics seek to leverage such records, overcoming barriers that often exist in individual-level data access while also offering significant computational savings. Here, we propose a novel framework that can reconstruct allelic and genotypic counts/frequencies for each SNP from case-control GWAS summary statistics. Our framework is simple and efficient without the need of any complicated underlying assumptions. Illustrating the great potential of this framework we also propose three summary-statistics-based applications implemented in a new software package (ReACt): GWAS meta-analysis (with and without sample overlap), case-case GWAS, and, for the first time, group polygenic risk score (PRS) estimation. We evaluate our methods against the current state-of-the-art on both synthetic data and real genotype data and show high performance in power and error control. Our novel group PRS method based on summary statistics could not be achieved prior to our proposed framework. We demonstrate here the potential applications and advantages of this approach. Our work further highlights the great potential of summary-statistics-based methodologies towards elucidating the genetic background of complex disease and opens up new avenues for research.
Herbaceous production lost to tree encroachment in United States rangelands
Authors: Morford Scott L. , Allred Brady W. , Twidwell Dirac , Jones Matthew O. , Maestas Jeremy D. , Roberts Caleb P. , Naugle David E.
Published: April 2021

Rangelands of the United States provide ecosystem services that benefit society and rural economies. Native tree encroachment is often overlooked as a primary threat to rangelands due to the slow pace of tree cover expansion and the positive public perception of trees. Still, tree encroachment fragments these landscapes and reduces herbaceous production, thereby threatening habitat quality for grassland wildlife and the economic sustainability of animal agriculture.

Recent innovations in satellite remote sensing permit the tracking of tree encroachment and the corresponding impact on herbaceous production. We analyzed tree cover change and herbaceous production across the western United States from 1990 to 2019.

We show that tree encroachment is widespread in U.S. rangelands; absolute tree cover has increased by 50% (77,323 km2) over 30 years, with more than 25% (684,852 km2) of U.S. rangeland area experiencing tree cover expansion. Since 1990, 302 ± 30 Tg of herbaceous biomass have been lost. Accounting for variability in livestock biomass utilization and forage value reveals that this lost production is valued at between $4.1 - $5.6 billion U.S. dollars.

Synthesis and applications: The magnitude of impact of tree encroachment on rangeland loss is similar to conversion to cropland, another well-known and primary mechanism of rangeland loss in the U.S. Prioritizing conservation efforts to prevent tree encroachment can bolster ecosystem and economic sustainability, particularly among privately-owned lands threatened by land-use conversion.
The chromatin remodeler Ino80 mediates alternative RNAPII pausing site determination
Authors: Cheon Youngseo , Han Sungwook , Kim Taemook , Lee Daeyoup
Published: April 2021

Promoter-proximal pausing of RNA polymerase II (RNAPII) is a critical step in early transcription elongation for the precise regulation of gene expression. Here, we provide evidence of promoter-proximal pausing-like distributions of RNAPII inS. cerevisiae. We found that genes bearing an alternative pausing site utilize Ino80p to properly localize RNAPII pausing at the first pausing site and to suppress the accumulation of RNAPII at the second pausing site, which is tightly associated with the +1 nucleosome. This alternative pausing site determination was dependent on the remodeling activity of Ino80p to modulate the +1 nucleosome position and might be controlled synergistically with Spt4p. Furthermore, we observed similar Ino80-dependent RNAPII pausing in mouse embryonic stem cells (mESCs). Based on our collective results, we hypothesize that the chromatin remodeler Ino80 plays a highly conserved role in regulating early RNAPII elongation to establish intact pausing.
First-principles model of optimal translation factors stoichiometry
Authors: Lalanne Jean-Benoît , Li Gene-Wei
Published: April 2021

Enzymatic pathways have evolved uniquely preferred protein expression stoichiometry in living cells, but our ability to predict the optimal abundances from basic properties remains underdeveloped. Here we report a biophysical, first-principles model of growth optimization for core mRNA translation, a multi-enzyme system that involves proteins with a broadly conserved stoichiometry spanning two orders of magnitude. We show that a parsimonious flux model constrained by proteome allocation is sufficient to predict the conserved ratios of translation factors through maximization of ribosome usage The analytical solutions, without free parameters, provide an interpretable framework for the observed hierarchy of expression levels based on simple biophysical properties, such as diffusion constants and protein sizes. Our results provide an intuitive and quantitative understanding for the construction of a central process of life, as well as a path toward rational design of pathway-specific enzyme expression stoichiometry.
Re-investigating the coughing rat model of pertussis to understandBordetella pertussispathogenesis
Authors: Hall Jesse M. , Kang Jason , Kenney Sophia M. , Wong Ting Y. , Bitzer Graham J. , Kelly Claire O. , Kisamore Caleb A. , Boehm Dylan T. , DeJong Megan A. , Wolf M. Allison , Sen-Kilic Emel , Horspool Alexander M. , Bevere Justin R , Barbier Mariette , Damron F. Heath
Published: April 2021

Bordetella pertussis(Bp) is a highly contagious bacterium that is the causative agent of whooping cough (pertussis). Currently, acellular pertussis vaccines (aP; DTaP; Tdap) are used to prevent pertussis disease. However, it is clear that the aP vaccine efficacy quickly wanes, resulting in the re-emergence of pertussis. Furthermore, recent work performed by the CDC suggest that current circulating strains are genetically distinct from strains of the past. Emergence of genetically diverging strains combined with waning aP vaccine efficacy call for re-evaluation of current animal models of pertussis. In this study, we used the rat model of pertussis to compare two genetically divergent strains Tohama 1 and D420. We intranasally challenged seven-week-old Sprague-Dawley rats with 108viable Tohama 1 and D420 and measured the hallmark signs/symptoms ofBpinfection such as neutrophilia, pulmonary inflammation, and paroxysmal cough using whole body plethysmography. Onset of cough occurred between 2-4 days afterBpchallenge averaging five coughs per fifteen minutes, with peak coughing occurring at day eight post infection averaging upward of thirteen coughs per fifteen minutes. However, we observed an increase of coughs in rats infected with clinical isolate D420 through 12 days post challenge. The rats exhibited increased bronchial restriction followingBpinfection. Histology of the lung and flow cytometry confirm both cellular infiltration and pulmonary inflammation. D420 infection induced higher production of anti-BpIgM antibodies compared to Tohama 1 infection. The coughing rat model provides a way of characterizing disease manifestation differences betweenBpstrains.
Litter commensal bacteria can limit the horizontal gene transfer of antimicrobial resistance toSalmonellain chickens
Authors: Oladeinde Adelumola , Abdo Zaid , Zwirzitz Benjamin , Woyda Reed , Lakin Steven M. , Press Maximilian O. , Cox Nelson A. , Thomas Jesse C. , Looft Torey , Rothrock Michael J. , Zock Gregory , Lawrence Jodie Plumblee , Cudnik Denice , Ritz Casey , Aggrey Samuel E. , Liachko Ivan , Grove Jonas R. , Wiersma Crystal
Published: April 2021

Fostering a ’balanced’ gut microbiome through the administration of beneficial microbes that can competitively exclude pathogens has gained a lot of attention and use in human and animal medicine. However, little is known about how microbes affect the horizontal gene transfer of antimicrobial resistance (AMR). To shed more light on this question, we challenged neonatal broiler chicks raised on reused broiler chicken litter – a complex environment made up of decomposing pine shavings, feces, uric acid, feathers, and feed, withSalmonellaHeidelberg (S. Heidelberg), a model pathogen. Neonatal chicks challenged withS. Heidelberg and raised on reused litter were more resistant toS. Heidelberg cecal colonization than chicks grown on fresh litter. Furthermore, chicks grown on reused litter were at a lower risk of colonization withS. Heidelberg strains that encoded AMR on IncI1 plasmids. We used 16S rRNA gene sequencing and shotgun metagenomics to show that the major difference between chicks grown on fresh litter and reused litter was the microbiome harbored in the litter and ceca. The microbiome of reused litter samples was more uniform and enriched in functional pathways related to the biosynthesis of organic and antimicrobial molecules than fresh litter samples. We found thatE. coliwas the main reservoir of plasmids encoding AMR and that the IncI1 plasmid was maintained at a significantly lower copy per cell in reused litter compared to fresh litter. These findings support the notion that commensal bacteria play an integral role in the horizontal transfer of plasmids encoding AMR to pathogens likeSalmonella.

Importance/Significance

Antimicrobial resistance spread is a worldwide health challenge, stemming in large part, from the ability of microorganisms to share their genetic material through horizontal gene transfer. To address this issue, many countries and international organization have adopted a One health approach to curtail the proliferation of antimicrobial resistant bacteria. This includes the removal and reduction of antibiotics used in food animal production and the development of alternatives to antibiotics. However, there is still a significant knowledge gap in our understanding of how resistance spreads in the absence of antibiotic selection and the role commensal bacteria play in reducing antibiotic resistance transfer. In this study, we show that commensal bacteria play a key role in reducing the horizontal gene transfer of antibiotic resistance toSalmonellaand provide the identity of the bacterial species that potentially perform this function in broiler chickens and also postulate the mechanism involved.
Early embryonic loss following intravaginal Zika virus challenge in rhesus macaques
Authors: Newman Christina M. , Tarantal Alice F. , Martinez Michele L. , Simmons Heather A. , Morgan Terry K. , Zeng Xiankun , Rosinski Jenna R. , Bliss Mason I. , Bohm Ellie K. , Dudley Dawn M. , Aliota Matthew T. , Friedrich Thomas C. , Miller Christopher J. , O’Connor David H.
Published: April 2021

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) and is primarily transmitted byAedesspecies mosquitoes; however, ZIKV can also be sexually transmitted. During the initial epidemic and in places where ZIKV is now considered endemic, it is difficult to disentangle the risks and contributions of sexual versus vector-borne transmission to adverse pregnancy outcomes. To examine the potential impact of sexual transmission of ZIKV on pregnancy outcome, we challenged three rhesus macaques (Macaca mulatta) three times intravaginally with 1 × 107PFU of a low passage, African lineage ZIKV isolate (ZIKV-DAK) in the first trimester (∼30 days gestational age). Samples were collected from all animals initially on days 3 through 10 post challenge, followed by twice, and then once weekly sample collection; ultrasound examinations were performed every 3-4 days then weekly as pregnancies progressed. All three dams had ZIKV RNA detectable in plasma on day 3 post-ZIKV challenge. At approximately 45 days gestation (17-18 days post-challenge), two of the three dams were found to have nonviable embryos by ultrasound. Viral RNA was detected in recovered tissues and at the maternal-fetal interface (MFI) in both cases. The remaining viable pregnancy proceeded to near term (∼155 days gestational age) and ZIKV RNA was detected at the MFI but not in fetal tissues. These results suggest that sexual transmission of ZIKV may represent an underappreciated risk of pregnancy loss during early gestation.
Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory
Authors: Tonnerre Pierre , Wolski David , Subudhi Sonu , Al-Jabban Jihad , Hoogeveen Ruben C. , Damasio Marcos , Drescher Hannah K. , Bartsch Lea M. , Tully Damien C. , Sen Debattama R. , Bean David J. , Brown Joelle , Torres-Cornejo Almudena , Robidoux Maxwell , Kvistad Daniel , Alatrakchi Nadia , Cui Ang , Lieb David , Cheney James A. , Gustafson Jenna , Lewis-Ximenez Lia L , Massenet-Regad Lucile , Eisenhaure Thomas , Aneja Jasneet , Haining W. Nicholas , Chung Raymond T. , Hacohen Nir , Allen Todd M. , Kim Arthur Y. , Lauer Georg M.
Published: April 2021

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.
Pupil diameter tracked during motor adaptation in humans
Authors: Yokoi Atsushi , Weiler Jeffrey
Published: April 2021

Pupil diameter, under constant illumination, is known to reflect individuals’ internal states, such as surprise about observation and environmental uncertainty. Despite the growing use of pupillometry in cognitive learning studies as an additional measure for examining internal states, few studies have used pupillometry in human motor learning studies. Here we provide the first detailed characterization of pupil diameter changes in a short-term reach adaptation paradigm. We measured pupil changes in 91 human participants while they adapted to abrupt, gradual, or switching force field conditions. Sudden increases in movement error caused by the introduction/reversal of the force field resulted in strong phasic pupil dilation during movement accompanied by a transient increase in tonic pre-movement baseline pupil diameter in subsequent trials. In contrast, clear changes in pupil responses were absent when the force field was gradually introduced, indicating that error drove the changes in pupil responses. Nevertheless, we found an association between baseline pupil diameter and awareness of the gradually-introduced perturbation assessed post-experimentally. In all experiments, we also found a strong co-occurrence of larger baseline pupil diameter and slower reaction and movement time after each set break. Interestingly, error-induced pupil responses gradually became insensitive after experiencing multiple reversals. Collectively, these results suggest that tonic baseline pupil diameter reflects one’s belief about environmental uncertainty, whereas phasic pupil dilation during movement reflects surprise about a sensory outcome (i.e., movement error), and both effects are modulated by novelty. Our results provide a new approach for non-verbally assessing participants’ internal states during motor learning.
Transport of Ketoprofen in Mammalian Blood Plasma
Authors: Czub Mateusz P. , Shabalin Ivan G. , Minor Wladek
Published: April 2021

Ketoprofen is a popular non-steroidal anti-inflammatory drug (NSAID) transported in the bloodstream mainly by serum albumin (SA). Ketoprofen is known to have multiple side effects and interactions with hundreds of other drugs, which might be related to its vascular transport by SA. Our work reveals that ketoprofen binds to a different subset of drug binding sites on human SA than has been observed for other species, despite the conservation of drug sites between species. We discuss potential reasons for the observed differences in the drug’s preferences for particular sites, including ketoprofen binding determinants in mammalian SAs and the effect of fatty acids on drug binding. The presented results show that the SA drug sites to which a particular drug binds cannot be easily predicted based only on a complex of SA from another species and the conservation of drug sites between species.
Membrane lectins enhance SARS-CoV-2 infection and influence the neutralizing activity of different classes of antibodies
Authors: Lempp Florian A. , Soriaga Leah , Montiel-Ruiz Martin , Benigni Fabio , Noack Julia , Park Young-Jun , Bianchi Siro , Walls Alexandra C. , Bowen John E. , Zhou Jiayi , Kaiser Hannah , Agostini Maria , Meury Marcel , Dellota Exequiel , Jaconi Stefano , Cameroni Elisabetta , Virgin Herbert W. , Lanzavecchia Antonio , Veesler David , Purcell Lisa , Telenti Amalio , Corti Davide
Published: April 2021

Investigating the mechanisms of SARS-CoV-2 cellular infection is key to better understand COVID-19 immunity and pathogenesis. Infection, which involves both cell attachment and membrane fusion, relies on the ACE2 receptor that is paradoxically found at low levels in the respiratory tract, suggesting that additional mechanisms facilitating infection may exist. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding Ig-like lectin 1 (SIGLEC1) function as auxiliary receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the N-terminal domain (NTD) or to the conserved proteoglycan site at the base of the Receptor Binding Domain (RBD), while poorly neutralizing infection of ACE2 over-expressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the Receptor Binding Motif (RBM), while potently neutralizing infection of ACE2 over-expressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.