bluuebunny/crossref_metadata_2025 huggingface dataset:
Diverse viruses in deep-sea hydrothermal vent fluids have restricted dispersal across ocean basins
Authors: Thomas Elaina , Anderson Rika , Li Viola , Rogan Jenni , Huber Julie A.
Published: June 2020

In the ocean, viruses impact microbial mortality, regulate biogeochemical cycling, and alter the metabolic potential of microbial lineages. At deep-sea hydrothermal vents, abundant viruses infect a wide range of hosts among the archaea and bacteria that inhabit these dynamic habitats. However, little is known about viral diversity, host range, and biogeography across different vent ecosystems, which has important implications for how viruses manipulate microbial function and evolution. Here, we examined viral diversity, viral and host distribution, and viral-host interactions in microbial metagenomes generated from venting fluids from several vent sites within three different geochemically and geographically distinct hydrothermal systems: Piccard and Von Damm vent fields at the Mid-Cayman Rise in the Caribbean Sea, and at several vent sites within Axial Seamount in the Pacific Ocean. Analysis of viral sequences and Clustered Regularly InterSpaced Palindromic Repeats (CRISPR) spacers revealed highly diverse viral assemblages and evidence of active infection. Network analysis revealed that viral host range was relatively narrow, with very few viruses infecting multiple microbial lineages. Viruses were largely endemic to individual vent sites, indicating restricted dispersal, and in some cases viral assemblages persisted over time. Thus, we show that hydrothermal vent fluids are home to novel, diverse viral assemblages that are highly localized to specific regions and taxa.

Importance

Viruses play important roles in manipulating microbial communities and their evolution in the ocean, yet not much is known about viruses in deep-sea hydrothermal vents. However, viral ecology and evolution are of particular interest in hydrothermal vent habitats because of their unique nature: previous studies have indicated that most viruses in hydrothermal vents are temperate rather than lytic, and it has been established that rates of horizontal gene transfer (HGT) are particularly high among thermophilic vent microbes, and viruses are common vectors for HGT. If viruses have broad host range or are widespread across vent sites, they have increased potential to act as gene-sharing “highways” between vent sites. By examining viral diversity, distribution, and infection networks across disparate vent sites, this study provides the opportunity to better characterize and constrain the viral impact on hydrothermal vent microbial communities. We show that viruses in hydrothermal vents are diverse and apparently active, but most have restricted host range and are not widely distributed among vent sites. Thus, the impacts of viral infection are likely to be highly localized and constrained to specific taxa in these habitats.
MYBL2 regulates ATM to control replication initiation and prevent replication stress in pluripotent stem cells
Authors: Blakemore Daniel , Vilaplana Nuria , Almaghrabi Ruba , Gonzalez Elena , Moya Miriam , Ward Carl , Murphy George , Gambus Agnieszka , Petermann Eva , Stewart Grant S. , García Paloma
Published: June 2020

Replication stress, a major cause of genome instability in cycling cells, is mainly prevented by the ATR-dependent replication stress response pathway in somatic cells. However, the replication stress response pathway in embryonic stem cells (ESCs) may be substantially different due to alterations in cell cycle phase length. The transcription factor MYBL2, which is implicated in cell cycle regulation, is expressed between hundred to thousand-fold more highly in ESCs compared to somatic cells. Here we show that MYBL2 functions to activate ATM and suppress replication stress in ESCs. Consequently, loss of MYBL2 or inhibition of ATM or Mre11 in ESCs, results in replication fork slowing, increased fork stalling and elevated origin firing. Additionally, we demonstrate that inhibition of CDC7 activity rescues replication stress induced by MYBL2 loss and ATM inhibition, suggesting that uncontrolled new origin firing may underlie the replication stress phenotype resulting from loss/inhibition of MYBL2 and ATM. Overall, this study proposes that in addition to ATR, a MYBL2-MRN-ATM replication stress response pathway functions in ESCs to control DNA replication initiation and prevent genome instability.
Patients’ Derived Short-Term Glioma Culture: Identification of Aggressive, Drug-Resistant Phenotype
Authors: Beevi Syed Sultan , Verma Vinod Kumar , Panigrahi Manas Kumar , Bhale Aishwarya , Madigubba Sailaja , Chowdary Radhika , Korabathina Radhika , Reddy Sukrutha Gopal
Published: June 2020

Background

Clinical management of glioma is crucial irrespective of tumor grade. Despite newer treatment modalities, the prognosis of glioma is abysmal and, survival statistics are not remarkable.In vitroglioma culture is emerging as a standard model to get insight into phenotypic transformation, drug response, and tumor relapse. In this viewpoint, this study established comprehensive patient-specific short-term cultures comprising low-grade, and high-grade glioma, and evaluated their pertinence in the potential disease management.

Methods

50 patients with MRI diagnosed glioma were recruited for this study. Primary glioma cultures established from fresh surgical tumor tissues, which were then evaluated for their intrinsic growth kinetics, response to temozolomide, and expression profile of Glial-Mesenchymal Transition (GMT) markers along with an oncogenic marker, cMyc.

Results

Short-term glioma culture was successfully established in 40 clinical samples. Glioma culture, irrespective of tumor grade, displayed two distinct patterns of growth kinetics – one with shorter doubling time (high-proliferating) and another group with longer doubling time (low-proliferating). Significant distinctive features were noticed between these two groups in terms of response to temozolomide, the expression pattern of GMT markers and their association with 1p/19q co-deletion and p53 expression.

Conclusion

Our findings effectively demonstrated the practicality of the development of short-term glioma culture toward a functional approach for personalized medicine. Our study revealed the presence of a highly proliferative, drug-resistant phenotype irrespective of tumor grade. Hence, short-term culture could be an important prognostic tool for predicting patient clinical responses and cue about imminent tumor relapse.
Bacteriocin production inStreptococcus gallolyticusis controlled by a complex 4-component regulatory system with activator and anti-activator activities
Authors: Proutière Alexis , Périchon Bruno , du Merle Laurence , Varet Hugo , Trieu-Cuot Patrick , Dramsi Shaynoor
Published: June 2020

Bacteriocins are natural antimicrobial peptides produced by bacteria to kill closely related competitors. The opportunistic pathogenStreptococcus gallolyticus(Sgg) was recently shown to outcompete commensal enterococci of the murine microbiota in tumoral conditions thanks to the production of a two-peptide bacteriocin named gallocin. We here identified 4 genes involved in the regulatory control of gallocin inSggUCN34, respectively encoding a histidine kinase/response regulator two-component system (BlpH/BlpR), a secreted peptide (GSP), and a putative regulator of unknown function (BlpS). While BlpR is a typical 243-aa response regulator possessing a phospho-receiver domain and a LytTR DNA-binding domain, BlpS is a 108-aa protein containing only a LytTR domain. Our results showed that the secreted peptide GSP activates the dedicated two-component system BlpH/BlpR to induce gallocin transcription. A genome-wide transcriptome analysis indicates that this regulatory system (GSP-BlpH/BlpR) is highly specific for bacteriocin production. Importantly, as opposed to BlpR, BlpS was shown to repress gallocin gene transcription. A conserved operator DNA sequence of 30-bp was found in all promoter regions regulated by BlpR and BlpS. EMSA assays showed direct and specific binding of the two gallocin regulators to various regulated promoter regions in a dose dependent manner. Gallocin expression appears tightly controlled inSggby quorum sensing and antagonistic activity of 2 LytTR-containing proteins.

Significance

Streptococcus gallolyticus(Sgg), formely known asS. bovisbiotype I, is an opportunistic pathogen causing septicemia and endocarditis in the elderly often associated with asymptomatic colonic neoplasia. We previously showed thatSggproduces a bacteriocin, termed gallocin, enabling colonization of the colon in tumoral conditions by outcompeting commensal members of the gut. Here we characterized a 4-component regulatory system that regulates gallocin transcription, which is activated by the response regulator BlpR. BlpR itself is activated by a quorum sensing peptide GSP and a dedicated histidine kinase BlpH. Interestingly, BlpS, a small DNA-binding protein co-transcribed with BlpR was found to repress gallocin genes transcription, likely by antagonizing BlpR. Understanding gallocin regulation is crucial to preventSggcolon colonization in tumoral conditions.
HDAC4 controls senescence and aging by safeguarding the epigenetic identity and ensuring the genomic integrity
Authors: Di Giorgio Eros , Paluvai Harikrishnareddy , Dalla Emiliano , Ranzino Liliana , Renzini Alessandra , Moresi Viviana , Cutano Valentina , Picco Raffaella , Brancolini Claudio
Published: June 2020

The epigenome of senescent cells is characterized by a deep redistribution of H3K27 acetylation. H3K27 is target of class IIa Histone Deacetylases (HDAC4, 5, 7, 9) as part of large repressive complexes. We report here that, among class IIa HDACs, HDAC4 is post-transcriptionally downregulated during senescence and aging. HDAC4 knock-out (KO) triggers premature senescence as a result of two waves of biological events: the accumulation of replication stress (RS) and the expression of inflammatory genes. The latter is achieved directly, through the activation of enhancers (TEs) and super-enhancers (SEs) that are normally monitored by HDAC4, and indirectly, through the de-repression of repetitive elements of retroviral origin (ERVs). The accumulation of DNA damage and the activation of the inflammatory signature influence each other and integrate into a synergistic response required for senescence onset. Our work discloses the key role played by HDAC4 in maintaining epigenome identity and genome integrity.
Central processing of leg proprioception inDrosophila
Authors: Agrawal Sweta , Dickinson Evyn S , Sustar Anne , Gurung Pralaksha , Shepherd David , Truman Jim , Tuthill John C
Published: June 2020

Proprioception, the sense of self-movement and position, is mediated by mechanosensory neurons that detect diverse features of body kinematics. Although proprioceptive feedback is crucial for accurate motor control, little is known about how downstream circuits transform limb sensory information to guide motor output. Here, we investigate neural circuits inDrosophilathat process proprioceptive information from the fly leg. We identify three cell-types from distinct developmental lineages that are positioned to receive input from proprioceptor subtypes encoding tibia position, movement, and vibration. 13Bα neurons encode femur-tibia joint angle and mediate postural changes in tibia position. 9Aα neurons also drive changes in leg posture, but encode a combination of directional movement, high frequency vibration, and joint angle. Activating 10Bα neurons, which encode tibia vibration at specific joint angles, elicits pausing in walking flies. Altogether, our results reveal that central circuits integrate information across proprioceptor subtypes to construct complex sensorimotor representations that mediate diverse behaviors, including reflexive control of limb posture and detection of leg vibration.
Fructose Metabolism Contributes to the Warburg effect
Authors: Han Bing , Wang Lu , Zhang Jingyu , Wei Meilin , Rajani Cynthia , Wei Runming , Wang Jingye , Yang Haining , Carbone Michele , Xie Guoxiang , Zhou Wen , Jia Wei
Published: June 2020

Fructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, it remains unclear why cancer cells favor fructose metabolism and how they acquire a sufficient amount of fructose. Here we report that cancer cells convert glucose into fructose through intra- and extracellular polyol pathways. The fructose metabolism bypasses normal aerobic respiration’s self-control to supply excessive metabolites to glycolysis and promotes the Warburg effect. Inhibition of fructose production drastically suppressed glycolysis and ATP production in cancer. Furthermore, we determined that a glucose transporter, SLC2A8/GLUT8, exports intracellular fructose to other cells in the tumor microenvironment. Taken together, our study suggests that the Warburg effect is achieved by means of fructose metabolism, instead of glucose metabolism alone.
Unveiling inter individual variability of human fibroblast innate immune response using robust cell-based protocols
Authors: Chansard A. , Dubrulle N. , Poujol de Mollens M. , Falanga P. B. , Stephen T. , Hasan M. , van Zandbergen G. , Aulner N. , Shorte S. L. , David-Watine B. ,   for the Milieu Intérieur Consortium
Published: June 2020

The LabEx Milieu Interieur (MI) project is a clinical study centered on the detailed characterization of the baseline and induced immune responses in blood samples from 1000 healthy donors. Analyses of these samples has lay ground for seminal studies on the genetic and environmental determinants of immunologic variance in a healthy cohort population. In the current study we developed in vitro methods enabling standardized quantification of MI-cohort-derived primary fibroblasts responses. Our results show that in vitro human donor cohort fibroblast responses to stimulation by different MAMPs analogs allows to characterize individual donor immune-phenotype variability. The results provide proof-of-concept foundation to a new experimental framework for such studies.

A bio-bank of primary fibroblast lines was generated from 323 out of 1,000 healthy individuals selected from the MI-study cohort. To study inter-donor variability of innate immune response in primary human dermal fibroblasts we chose to measure the TLR3 and TLR4 response pathways, both receptors being expressed and previously studied in fibroblasts. We established high-throughput automation compatible methods for standardized primary fibroblast cell activation, using purified MAMPS analogs, poly I:C and LPS that stimulate TLR3 and TLR4 pathways respectively. These results were in turn compared with a stimulation method using infection by HSV-1 virus. Our “Add-only” protocol minimizes high-throughput automation system variability facilitating whole process automation from cell plating through stimulation to recovery of cell supernatants, and fluorescent labeling. Images were acquired automatically by high-throughput acquisition on an automated high-content imaging microscope. Under these methodological conditions standardized image acquisition provided for quantification of cellular responses allowing biological variability to be measured with low system noise and high biological signal fidelity. Optimal for automated analysis of immuno-phenotype of primary human cell responses our method and experimental framework as reported here is highly compatible to high-throughput screening protocols like those necessary for chemo-genomic screening. In context of primary fibroblasts derived from donors enrolled to the MI-clinical-study our results open the way to assert the utility of studying immune-phenotype characteristics relevant to a human clinical cohort.
The evolution of Sox gene repertoires and regulation of segmentation in arachnids
Authors: Baudouin-Gonzalez Luis , Schoenauer Anna , Harper Amber , Blakeley Grace , Seiter Michael , Arif Saad , Sumner-Rooney Lauren , Russell Steven , Sharma Prashant P. , McGregor Alistair P.
Published: June 2020

The Sox family of transcription factors regulate many processes during metazoan development, including stem cell maintenance and nervous system specification. Characterising the repertoires and roles of these genes can therefore provide important insights into animal evolution and development. We further characterised the Sox repertoires of several arachnid species with and without an ancestral whole genome duplication (WGD), and compared their expression between the spiderParasteatoda tepidariorumand the harvestmanPhalangium opilio. We also found that most Sox families have been retained as ohnologs after WGD and evidence for potential subfunctionalisation and/or neofunctionalization events. Our results also suggest thatSox21b-1likely regulated segmentation ancestrally in arachnids, playing a similar role to the closely related SoxB gene,Dichaete, in insects. We previously showed thatSox21b-1is required for the simultaneous formation of prosomal segments and sequential addition of opisthosomal segments inP. tepidariorum. We studied the expression and function ofSox21b-1further in this spider and found that while this gene regulates the generation of both prosomal and opisthosomal segments, it plays different roles in the formation of these tagmata reflecting their contrasting modes of segmentation and deployment of gene regulatory networks with different architectures.
SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells
Authors: Martinat Charlotte , Cormier Arthur , Tobaly-Tapiero Joёlle , Palmic Noé , Casartelli Nicoletta , Coggins Si’Ana A. , Buchrieser Julian , Persaud Mirjana , Diaz-Griffero Felipe , Espert Lucile , Bossis Guillaume , Lesage Pascale , Schwartz Olivier , Kim Baek , Margottin-Goguet Florence , Saïb Ali , Zamborlini Alessia
Published: June 2020

SAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of the dNTP substrates. Yet, phosphorylation of T592 downregulates SAMHD1 antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute to viral restriction. Here, we show that SAMHD1 is SUMOylated on residue K595, a modification that relies on the presence of a proximal SUMO-interacting motif (SIM). Loss of K595 SUMOylation suppresses the restriction activity of SAMHD1, even in the context of the constitutively active phospho-ablative T592A mutant but has no impact on dNTP depletion. Conversely, the artificial fusion of SUMO to a non-SUMOylatable inactive SAMHD1 variant restores its antiviral function. These observations clearly establish that the absence of T592 phosphorylation cannot fully account for the restriction activity of SAMHD1. We find that concomitant SUMOylation of K595 is required to stimulate a dNTPase-independent antiviral activity.
A RIF1/KAP1-based toggle switch stabilises the identities of the inactive and active X chromosomes during X inactivation
Authors: Enervald Elin , Powell Lynn Marie , Boteva Lora , Foti Rossana , Ruiz Nerea Blanes , Kibar Gözde , Piszczek Agnieszka , Cavaleri Fatima , Vingron Martin , Cerase Andrea , Buonomo Sara B.C.
Published: June 2020

The onset of random X inactivation in mouse requires the switch from a symmetric to an asymmetric state, where the identities of the future inactive and active X chromosomes are assigned. Here we show that RIF1 and KAP1 are two fundamental factors for the definition of the asymmetry. Our data show that at the onset of mESC differentiation, upregulation of the long non-coding RNA Tsix weakens the symmetric RIF1 association with theXistpromoter, and opens a window of opportunity for a more stable association of KAP1. KAP1 is required to sustain high levels of Tsix, thus reinforcing and propagating the asymmetry, and, as a result, marking the future active X chromosome. Furthermore, we show that RIF1 association with the future inactive X chromosome is essential for Xist upregulation. This double-bookmarking system, based on the mutually exclusive relationships of Tsix and RIF1, and RIF1 and KAP1, thus coordinates the identification of the inactive and active X chromosomes and initiates a self-sustaining loop that transforms an initially stochastic event into a stably inherited asymmetric X chromosome state.
Sleeping While Awake: The Intrusion of Neural Activity Associated with Sleep Onset in the Awake Human Brain
Authors: Hawes Stephanie , Innes Carrie R. H. , Parsons Nicholas , Drummond Sean P.A. , Caeyensberghs Karen , Jones Richard D. , Poudel Govinda R.
Published: June 2020

Sleep can intrude into the awake human brain when sleep deprived or fatigued, even while performing cognitive tasks. However, how the brain activity associated with sleep onset can co-exist with the activity associated with cognition in the awake humans remains unexplored. Here, we used simultaneous fMRI and EEG to generate fMRI activity maps associated with EEG theta (4-7 Hz) activity associated with sleep onset. We implemented a method to track these fMRI activity maps in individuals performing a cognitive task after well-rested and sleep-deprived nights. We found frequent intrusions of the fMRI maps associated with sleep-onset in the task-related fMRI data. These sleep events elicited a pattern of transient fMRI activity, which was spatially distinct from the task-related activity in the frontal and parietal areas of the brain. They were concomitant with reduced arousal as indicated by decreased pupil size and increased response time. Graph theoretical modelling showed that the activity associated with sleep onset emerges from the basal forebrain and spreads anterior-posteriorly via the brain’s structural connectome. We replicated the key findings in an independent dataset, which suggests that the approach can be reliably used in understanding the neuro-behavioural consequences of sleep and circadian disturbances in humans.
RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site
Authors: Haza Katarzyna Z , Martin Heather L , Rao Ajinkya , Turner Amy L , Saunders Sophie E , Petersen Britta , Tiede Christian , Tipping Kevin , Tang Anna A , Ajayi Modupe , Taylor Thomas , Fishwick Keri M , Adams Thomas L , Gaule Thembaninkosi G. , Trinh Chi H , Johnson Matthew , Breeze Alexander L , Edwards Thomas A , McPherson Michael J , Tomlinson Darren C
Published: June 2020

RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. We have identified two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signalling pathways with distinct isoform and mutant profiles. Affimer K6 is the first biologic to bind in the SI/SII pocket, whilst Affimer K3 is the first non-covalent inhibitor of the SII region, revealing a novel RAS conformer with a large, druggable SII/α3 pocket. This work demonstrates the potential of using biologics with small interface surfaces to select novel druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins.
Grazing pressure-induced shift in planktonic bacterial communities with the dominance of acIII-A1 actinobacterial lineage in soda pans
Authors: Szabó Attila , Korponai Kristóf , Somogyi Boglárka , Vajna Balázs , Vörös Lajos , Horváth Zsófia , Boros Emil , Szabó-Tugyi Nóra , Márialigeti Károly , Felföldi Tamás
Published: June 2020

Astatic soda pans of the Pannonian Steppe are unique environments with respect to their multiple extreme physical and chemical characteristics (high daily water temperature fluctuation, high turbidity, alkaline pH, salinity, polyhumic organic carbon concentration, hypertrophic state and special ionic composition). However, little is known about the seasonal dynamics of the bacterial communities inhabiting these lakes and the role of environmental factors that have the main impact on their structure. Therefore, two soda pans were sampled monthly between April 2013 and July 2014 to reveal changes in the planktonic community. By late spring in both years, a sudden shift in the community structure was observed, the previous algae-associated bacterial communities had collapsed, resulting the highest ratio of actinobacteria within the bacterioplankton (89%, with the dominance of acIII-A1 lineage) ever reported in the literature. Before these peaks, an extremely high abundance (>10,000 individuum l−1) of microcrustaceans (MoinaandArctodiaptomus) was observed. OTU-based statistical approaches showed that in addition to algal blooms and water-level fluctuations, zooplankton densities had the strongest effect on the composition of bacterial communities. In these extreme environments, this implies a surprisingly strong, community-shaping top-down role of microcrustacean grazers.
Linear-Nonlinear Cascades Capture Synaptic Dynamics
Authors: Rossbroich Julian , Trotter Daniel , Beninger John , Tóth Katalin , Naud Richard
Published: June 2020

Short-term synaptic dynamics differ markedly across connections and strongly regulate how action potentials communicate information. To model the range of synaptic dynamics observed in experiments, we have developed a flexible mathematical framework based on a linear-nonlinear operation. This model can capture various experimentally observed features of synaptic dynamics and different types of heteroskedasticity. Despite its conceptual simplicity, we show that it is more adaptable than previous models. Combined with a standard maximum likelihood approach, synaptic dynamics can be accurately and efficiently characterized using naturalistic stimulation patterns. These results make explicit that synaptic processing bears algorithmic similarities with information processing in convolutional neural networks.

Author summary

Understanding how information is transmitted relies heavily on knowledge of the underlying regulatory synaptic dynamics. Existing computational models for capturing such dynamics are often either very complex or too restrictive. As a result, effectively capturing the different types of dynamics observed experimentally remains a challenging problem. Here, we propose a mathematically flexible linear-nonlinear model that is capable of efficiently characterizing synaptic dynamics. We demonstrate the ability of this model to capture different features of experimentally observed data.
PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning
Authors: Wei Hai , Lambie Eric J. , Osório Daniel S. , Carvalho Ana X. , Conradt Barbara
Published: June 2020

The mechanism(s) through which mammalian kinase MELK promotes tumorigenesis is not understood. We find that theC. elegansorthologue of MELK, PIG-1, promotes apoptosis by partitioning an anti-apoptotic factor. TheC. elegansNSM neuroblast divides to produce a larger cell that differentiates into a neuron and a smaller cell that dies. We find that in this context, PIG-1 is required for partitioning of CES-1 Snail, a transcriptional repressor of the pro-apoptotic geneegl-1BH3-only.pig-1MELK is controlled by both aces-1Snail- andpar-4LKB1-dependent pathway, and may act through phosphorylation and cortical enrichment of nonmuscle myosin II prior to neuroblast division. We propose thatpig-1MELK-induced local contractility of the actomyosin network plays a conserved role in the acquisition of the apoptotic fate. Our work also uncovers an auto-regulatory loop through whichces-1Snail controls its own activity through the formation of a gradient of CES-1 Snail protein.

Significance Statement

Apoptosis is critical for the elimination of ‘unwanted’ cells. What distinguishes wanted from unwanted cells in developing animals is poorly understood. We report that in theC. elegansNSM neuroblast lineage, the level of CES-1, a Snail-family member and transcriptional repressor of the pro-apoptotic geneegl-1, contributes to this process. In addition, we demonstrate thatC. elegansPIG-1, the orthologue of mammalian proto-oncoprotein MELK, plays a critical role in controlling CES-1Snaillevels. Specifically, during NSM neuroblast division, PIG-1MELKcontrols partitioning of CES-1Snailinto one but not the other daughter cell thereby promoting the making of one wanted and one unwanted cell. Furthermore, we present evidence that PIG-1MELKacts prior to NSM neuroblast division by locally activating the actomyosin network.
In silico analysis of imprinted gene expression in the mouse skin
Authors: Marr Alexandra K. , Boughorbel Sabri , Toufiq Mohammed , Anbari Mohammed El , Chouchane Aouatef I. , Kino Tomoshige
Published: June 2020

1.

Imprinted genes help mediate embryonic cell proliferation and differentiation, but their roles after birth are far less well understood. A subset of 16 imprinted gene network (IGN) genes is expressed at higher levels in stem cell progenitor cells of adult skeletal muscle and epidermis compared to their differentiated counterparts. While these genes function in muscle regeneration, their role in the skin is poorly understood. We assessed the expression profiles of these 16 IGN genes in publicly available datasets and revealed elevated expression of IGN genes in the telogen and early anagen phases in mouse skin. We also identified IGN genes among a list of previously identified hair cycle-associated genes. Furthermore, our results suggest that IGN genes form part of a larger network and function predominantly as upstream regulators of hair cycle-regulated genes. Based on thesein silicodata, we propose a potential novel role of these 16 IGN genes as upstream regulators of hair cycle-associated genes. We speculate that IGN gene dysregulation participates in syndromes characterized by an impaired hair cycle. Thus, IGN gene expression might serve as a point of therapeutic intervention for patients suffering from cutaneous pathologies such as common hair-loss disorders.
Goats Given Transdermal Flunixin Meglumine Displayed Less Pain Behavior After Castration
Authors: Lee Amanda , Graves Meggan , Lear Andrea , Cox Sherry , Caldwell Marc , Krawczel Peter
Published: June 2020

Pain management should be utilized with castration to reduce physiological and behavioral changes. Transdermal application of drugs require less animal management and fewer labor risks, which can occur with oral administration or injections. The objective was to determine the effects of transdermal flunixin meglumine on meat goats’ behavior post-castration. Male goats (N = 18; mean body weight ± standard deviation: 26.4 ± 1.6 kg) were housed individually in pens and randomly assigned to 1 of 3 treatments: (1) castrated, dosed with transdermal flunixin meglumine; (2) castrated, dosed with transdermal placebo; and (3) sham castrated, dosed with transdermal flunixin meglumine. Body position, rumination, and head- pressing were observed for 1 h ± 10 minutes twice daily on days −1, 0, 1, 2, and 5 around castration. Each goat was observed once every 5-minutes (scan samples) and reported as percentage of observations. Accelerometers were used to measure standing, lying, and laterality (total time, bouts, and bout duration). A linear mixed model was conducted using GLIMMIX. Fixed effects of treatment, day relative to castration, and treatment*day relative to castration and random effect of date and goat nested within treatment were included. Treatment 1 goats (32.7 ± 2.8%) and treatment 2 goats (32.5 ± 2.8%) ruminated less than treatment 3 goats (47.4 ± 2.8%,P= 0.0012). Head pressing was greater on day of castration in treatment 2 goats (P< 0.001). Standing bout duration was greatest in treatment 2 goats on day 1 post-castration (P< 0.001). Lying bout duration was greatest in treatment 2 goats on day 1 post-castration compared to treatment 1 and treatment 3 goats(P< 0.001). Transdermal flunixin meglumine improved goats’ fluidity of movement post-castration and decreased head pressing, indicating a mitigation of pain behavior.
A Parasite Coat Protein Binds Suramin to Confer Drug Resistance
Authors: Zeelen Johan , van Straaten Monique , Verdi Joseph , Hempelmann Alexander , Hashemi Hamidreza , Perez Kathryn , Jeffrey Philip D. , Hälg Silvan , Wiedemar Natalie , Mäser Pascal , Papavasiliou F. Nina , Stebbins C. Erec
Published: June 2020

Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly one hundred years. Recent studies revealed that trypanosome strains that express the Variant Surface Glycoprotein VSGsur possess heightened resistance to suramin. We show here that VSGsur binds tightly to suramin, other VSGs do not, and that together with VSG13 it defines a structurally divergent subgroup of these coat proteins. The co-crystal structure of VSGsur with suramin reveals that the chemically symmetric drug binds within a large cavity in the VSG homodimer asymmetrically, primarily through contacts of its central benzene rings. Structure-based, loss-of-contact mutations in VSGsur significantly decrease the affinity to suramin and lead to a loss of the resistance phenotype. Altogether, these data show that the resistance phenotype is dependent on the binding of suramin to VSGsur, establishing that the VSG proteins can possess functionality beyond their role in antigenic variation.
Locus coeruleus spiking differently correlates with somatosensory cortex activity and pupil diameter
Authors: Yang Hongdian , Bari Bilal A. , Cohen Jeremiah Y. , O’Connor Daniel H.
Published: June 2020

We examined the relationships between activity in the locus coeruleus (LC), activity in the primary somatosensory cortex (S1), and pupil diameter in mice performing a tactile detection task. While LC spiking consistently preceded S1 membrane potential depolarization and pupil dilation, the correlation between S1 and pupil was more heterogeneous. Furthermore, the relationships between LC, S1 and pupil varied on timescales of sub-seconds to seconds within trials. Our data suggest that pupil diameter can be dissociated from LC spiking and cannot be used as a stationary index of LC activity.
Landscape and Selection of Vaccine Epitopes in SARS-CoV-2
Authors: Smith Christof C. , Entwistle Sarah , Willis Caryn , Vensko Steven , Beck Wolfgang , Garness Jason , Sambade Maria , Routh Eric , Olsen Kelly , Kodysh Julia , O’Donnell Timothy , Haber Carsten , Heiss Kirsten , Stadler Volker , Garrison Erik , Grant Oliver C. , Woods Robert J. , Heise Mark , Vincent Benjamin G. , Rubinsteyn Alex
Published: June 2020

There is an urgent need for a vaccine with efficacy against SARS-CoV-2. We hypothesize that peptide vaccines containing epitope regions optimized for concurrent B cell, CD4+T cell, and CD8+T cell stimulation would drive both humoral and cellular immunity with high specificity, potentially avoiding undesired effects such as antibody-dependent enhancement (ADE). Additionally, such vaccines can be rapidly manufactured in a distributed manner. In this study, we combine computational prediction of T cell epitopes, recently published B cell epitope mapping studies, and epitope accessibility to select candidate peptide vaccines for SARS-CoV-2. We begin with an exploration of the space of possible T cell epitopes in SARS-CoV-2 with interrogation of predicted HLA-I and HLA-II ligands, overlap between predicted ligands, protein source, as well as concurrent human/murine coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, viral source protein abundance, sequence conservation, coverage of high frequency HLA alleles and co-localization of CD4+and CD8+T cell epitopes. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering to select regions with surface accessibility, high sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. From 58 initial candidates, three B cell epitope regions were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we propose a set of SARS-CoV-2 vaccine peptides for use in subsequent murine studies and clinical trials.

Abstract Figure
The effects of sustained fitness improvement on the gut microbiome: A longitudinal, repeated measures case-study approach
Authors: Barton Wiley , Cronin Owen , Garcia-Perez Isabel , Whiston Ronan , Holmes Elaine , Woods Trevor , Molloy Catherine B. , Molloy Michael G. , Shanahan Fergus , Cotter Paul D. , O’Sullivan Orla
Published: June 2020

Objective

The composition and metabolic function of the gut microbiome in the elite athlete differs from that of non-athletes. However, short-term fitness improvement in the sedentary adult does not replicate the microbiome characteristics seen in the athlete. Whether sustained fitness improvement over a prolonged period can lead to pronounced and beneficial alteration in the gut microbiome is unknown. The objective was to explore this possibility.

Methods

This study used a repeated-measures, case-study approach to explore changes in the gut microbiome of two unfit volunteers undertaking progressive exercise training over a 6-month period. Training was to culminate in the completion of a marathon or Olympic-distance triathlon. The volunteers were sampled every two weeks for six months and microbiome, metabolome, diet, body composition, and cardiorespiratory fitness data were recorded.

Results

Both participants completed their respective goals with improved body composition and fitness parameters over the training period. Increases in α-diversity of the gut microbiota occurred with sustained training and fluctuations occurred in response to training events (e.g., injury, illness and training peaks). Participants’ fat mass and BMI reduced during the study and was significantly associated with increased urinary measurements of N-methyl nicotinate (P value < 0.001) and hippurate (P value < 0.05), and decreased phenylacetylglutamine (P value < 0.05).

Conclusion

These results suggest that sustained fitness improvements result in alterations to gut microbiota and physiologically-relevant metabolites. This study provides longitudinal analysis of the response of the gut microbiome to real-world events during progressive fitness training, including intercurrent illness and injury.
Rapid non-invasive detection of Influenza-A-infection by multicapillary column coupled ion mobility spectrometry
Authors: Steppert Claus , Steppert Isabel , Bollinger Thomas , Sterlacci William
Published: June 2020

Infectious pathogens are a global issue. Global air travelling offers an easy and fast opportunity not only for people but also for infectious diseases to spread around the world within a few days. Also, large public events facilitate increasing infection numbers. Therefore, a rapid on-site screening for infected people is urgently needed.

Due to the small size and easy handling, the ion mobility spectrometry coupled with a multicapillary column (MCC-IMS) is a very promising, sensitive method for the on-site identification of infectious pathogens based on scents, representing volatile organic compounds (VOCs).

The purpose of this study was to prospectively assess whether identification of Influenza-A-infection based on VOCs by MCC-IMS is possible in breath. Nasal breath was investigated in 24 consecutive persons with and without Influenza-A-infection by MCC-IMS. In 14 Influenza-A-infected patients, infection was proven by PCR of nasopharyngeal swabs. Four healthy staff members and six patients with negative PCR result served as controls. For picking up relevant VOCs in MCC-IMS spectra, software based on cluster analysis followed by multivariate statistical analysis was applied. With only four VOCs canonical discriminant analysis was able to distinguish Influenza-A-infected patients from not infected with 100% sensitivity and 100% specificity.

This present proof-of-concept-study yields encouraging results showing a rapid diagnosis of viral infections in nasal breath within 5 minutes by MCC-IMS. The next step is to validate the results with a greater number of patients with Influenza-A-infection as well as other viral diseases, especially COVID-19.

Registration number at ClinicalTrials.gov NCT04282135.
Host response-based screening to identify undiagnosed cases of COVID-19 and expand testing capacity
Authors: Cheemarla Nagarjuna R. , Brito Anderson F. , Fauver Joseph R. , Alpert Tara , Vogels Chantal B.F. , Omer Saad B. , Ko Albert I. , Grubaugh Nathan D. , Landry Marie L. , Foxman Ellen F.
Published: June 2020

The COVID-19 pandemic has created unprecedented challenges in diagnostic testing. At the beginning of the epidemic, a confluence of factors resulted in delayed deployment of PCR-based diagnostic tests, resulting in lack of testing of individuals with symptoms of the disease. Although these tests are now more widely available, it is estimated that a three- to ten-fold increase in testing capacity will be required to ensure adequate surveillance as communities reopen1. In response to these challenges, we evaluated potential roles of host response-based screening in the diagnosis of COVID-19. Previous work from our group showed that the nasopharyngeal (NP) level of CXCL10, a protein produced as part of the host response to viral infection, is a sensitive predictor of respiratory virus infection across a wide spectrum of viruses2. Here, we show that NP CXCL10 is elevated during SARS-CoV-2 infection and use a CXCL10-based screening strategy to identify four undiagnosed cases of COVID-19 in Connecticut in early March. In a second set of samples tested at the Yale New Haven Hospital, we show that NP CXCL10 had excellent performance as a rule-out test (NPV 0.99, 95% C.I. 0.985-0.997). Our results demonstrate how biomarker-based screening could be used to leverage existing PCR testing capacity to rapidly enable widespread testing for COVID-19.

One Sentence Summary

We describe a host-response based screening strategy to identify undiagnosed cases of COVID-19 and to expand capacity for PCR-based testing.
Reparations for Black American Descendants of Persons Enslaved in the U.S. and Their Estimated Impact on SARS-CoV-2 Transmission
Authors: Richardson Eugene T. , Malik Momin M. , Darity William A. , Mullen A. Kirsten , Malik Maya , Maybank Aletha , Bassett Mary T. , Farmer Paul E. , Worden Lee , Jones James Holland
Published: June 2020

Background

In the United States, Black Americans are suffering from significantly disproportionate incidence and mortality rates of COVID-19. The potential for racial-justice interventions, including reparations payments, to ameliorate these disparities has not been adequately explored.

Methods

We compared the COVID-19 time-varying Rt curves of relatively disparate polities in terms of social equity (South Korea vs. Louisiana). Next, we considered a range of reproductive ratios to back-calculate the transmission rates βi→j for 4 cells of the simplified next-generation matrix (from which R0 is calculated for structured models) for the outbreak in Louisiana. Lastly, we modeled the effect that monetary payments as reparations for Black American descendants of persons enslaved in the U.S. would have had on pre-intervention βi→j.

Results

Once their respective epidemics begin to propagate, Louisiana displays Rt values with an absolute difference of 1.3 to 2.5 compared to South Korea. It also takes Louisiana more than twice as long to bring Rt below 1. We estimate that increased equity in transmission consistent with the benefits of a successful reparations program (reflected in the ratio βb→b / βw→w) could reduce R0 by 31 to 68%.

Discussion

While there are compelling moral and historical arguments for racial injustice interventions such as reparations, our study describes potential health benefits in the form of reduced SARS-CoV-2 transmission risk. As we demonstrate, a restitutive program targeted towards Black individuals would not only decrease COVID-19 risk for recipients of the wealth redistribution; the mitigating effects would be distributed across racial groups, benefitting the population at large.

Funding

ETR and LW are supported by NIGMS MIDAS grant R01 GM130900. ETR is also supported by NIAID K08 AI139361. WAD is supported by NIMHD R01 MD011606, NSF SES 1851845, and IES R305A190484. MMM is supported by the Ethics and Governance of Artificial Intelligence Fund.
SWATH-MS based proteomic profiling of Pancreatic Ductal Adenocarcinoma tumours reveals the interplay between the extracellular matrix and related intracellular pathways
Authors: Nweke EE , Naicker P , Aron S , Stoychev S , Devar J , Tabb DL , Jones OJ , Smith MD , Candy GP
Published: June 2020

Pancreatic cancer accounts for 2.8% of new cancer cases worldwide and is projected to become the second leading cause of cancer-related deaths by 2030. Patients of African ancestry appear to be at an increased risk for pancreatic ductal adenocarcinoma (PDAC), with worse severity and outcomes. The purpose of this study was to map the proteomic and genomic landscape of a cohort of PDAC patients of African ancestry.

Thirty tissues (15 tumours and 15 normal adjacent tissues) were obtained from consenting South African PDAC patients. Optimisation of the sample preparation method allowed for the simultaneous extraction of high-purity protein and DNA for SWATH-MS and OncoArray SNV analyses.

We quantified 3402 proteins with 49 upregulated and 35 downregulated proteins at a minimum 2.1 fold change and FDR adjusted p-value (q-value) ≤ 0.01 when comparing tumour to normal adjacent tissue. Many of the upregulated proteins in the tumour samples are involved in extracellular matrix formation (ECM) and related intracellular pathways. Proteins such as EMIL1, KBTB2, and ZCCHV involved in the regulation of ECM proteins were observed to be dysregulated in pancreatic tumours. Approximately 11% of the dysregulated proteins, including ISLR, BP1, PTK7 and OLFL3, were predicted to be secretory proteins. Additionally, we identified missense mutations in some upregulated proteins, such as MYPN, ESTY2 and SERPINB8. These findings help in further elucidating the biology of PDAC and may aid in identifying future plausible markers for the disease.
Adjusting for Allometric Scaling in ABIDE I Challenges Subcortical Volume Differences in Autism Spectrum Disorder
Authors: Williams Camille Michèle , Peyre Hugo , Toro Roberto , Beggiato Anita , Ramus Franck
Published: June 2020

To properly adjust for total brain volume (TBV), brain allometry – the non-linear scaling relationship between regional volumes and TBV – was considered when examining subcortical volumetric differences between typically developing (TD) and Autistim Spectrum Disorder (ASD) individuals.

Autism Brain Imaging Data Exchange I (N = 654) data was analyzed with two methodological approaches: univariate Linear Mixed Effects Models and multivariate Multiple Group Confirmatory Factor Analyses. Analyses were conducted on the entire sample and in subsamples based on age, sex, and Full Scale Intelligence Quotient (FSIQ). A similar ABIDE I study was replicated and the impact of different TBV adjustments on neuroanatomical group differences was investigated.

No robust subcortical allometric or volumetric group differences were observed in the entire sample across methods. Exploratory analyses suggested that allometric scaling and volume group differences may exist in certain subgroups defined by age, sex, and/or FSIQ. The type of TBV adjustment influenced some reported volumetric and scaling group differences.

This study supports the absence of robust volumetric differences between ASD and TD individuals in the investigated volumes when adjusting for brain allometry, expands the literature by finding no group difference in allometric scaling, and further suggests that differing TBV adjustments contribute to the variability of reported neuroanatomical differences in ASD.