bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mathematical modeling of vaccination rollout and NPIs lifting on COVID-19 transmission with VOC: a case study in Toronto, Canada
Authors: Aruffo Elena , Yuan Pei , Tan Yi , Gatov Evgenia , Moyles Iain , Bélair Jacques , Watmough James , Collier Sarah , Arino Julien , Zhu Huaiping 
Published: August 2021

ABSTRACTBackgroundSince December 2020, public health agencies have implemented a variety of vaccination strategies to curb the spread of SARS-CoV-2, along with pre-existing Nonpharmaceutical Interventions (NPIs). Initial strategy focused on vaccinating the elderly to prevent hospitalizations and deaths. With vaccines becoming available to the broader population, we aimed to determine the optimal strategy to enable the safe lifting of NPIs while avoiding virus resurgence.MethodsWe developed a compartmental deterministic SEIR model to simulate the lifting of NPIs under different vaccination rollout scenarios. Using case and vaccination data from Toronto, Canada between December 28, 2020 and May 19, 2021, we estimated transmission throughout past stages of NPI escalation/relaxation to compare the impact of lifting NPIs on different dates on cases, hospitalizations, and deaths, given varying degrees of vaccine coverages by 20-year age groups, accounting for waning immunity.ResultsWe found that, once coverage among the elderly is high enough (80% with at least one dose), the main age groups to target are 20-39 and 40-59 years, whereby first-dose coverage of at least 70% by mid-June 2021 is needed to minimize the possibility of resurgence if NPIs are to be lifted in the summer. While a resurgence was observed for every scenario of NPI lifting, we also found that under an optimistic vaccination coverage (70% by mid-June, postponing reopening from August 2021 to September 2021can reduce case counts and severe outcomes by roughly 80% by December 31, 2021.ConclusionsOur results suggest that focusing the vaccination strategy on the working-age population can curb the spread of SARS-CoV-2. However, even with high vaccination coverage in adults, lifting NPIs to pre-pandemic levels is not advisable since a resurgence is expected to occur, especially with earlier reopening.
Cognition-oriented treatments and physical exercise on cognitive function in Huntington’s disease: Protocol for systematic review
Authors: Huynh Katharine , Nategh Leila , Jamadar Sharna , Georgiou-Karistianis Nellie , Lampit Amit 
Published: August 2021

AbstractIntroductionCognitive impairments are prevalent in Huntington’s disease (HD), occurring many years prior to clinical diagnosis and are the most impactful on quality of life of patients. Cognitive interventions and exercise have been found to be efficacious in improving cognitive function in several clinical populations (e.g., older adults with mild cognitive impairment and dementia). However, the utility of cognitive interventions has not been systematically reviewed in HD. This systematic review aims to examine the efficacy of cognitive and physical interventions on cognitive function in HD.MethodsElectronic databases (MEDLINE, EMBASE, PsycINFO, CENTRAL) were searched through till 10 May 2021 for interventional studies investigating the effect of cognition-oriented treatments and physical exercise on cognitive function in individuals with HD, compared to any control or no control. The primary outcome is change on objective measures of cognition. Additional outcomes include change in psychosocial, functional and neuroimaging measures. Variations of effects based on population and study factors will be considered. Risk of bias will be assessed using the Cochrane RoB 2 tool and ROBINS-I tool. Where appropriate, outcomes will be pooled using random-effects meta-analyses, heterogeneity will be examined using tau2and I2statistics, and moderators will be examined using meta-regression models.DiscussionThis review will systematically evaluate the efficacy of cognitive and physical interventions on improving cognitive function in HD. The eligibility criteria and planned analyses will allow for a comprehensive assessment of certainty in the evidence that will inform future trials and clinical practice.RegistrationThis protocol was registered on PROSPERO (CRD42021259152).
Genetic compensation of triacylglycerol biosynthesis in the green microalga Chlamydomonas reinhardtii
Authors: Lee Yi-Ying , Park Rudolph , Miller Stephen M. , Li Yantao 
Published: August 2021

AbstractGenetic compensation through transcriptional adaptation has been proposed to explain phenotypic differences between gene knockouts and knockdowns. With the rapid development of reverse genetic tools such as CRISPR/Cas9 and RNAi in microalgae, it is increasingly important to assess whether genetic compensation affects the phenotype of engineered algal mutants. While exploring triacylglycerol (TAG) biosynthesis pathways in Chlamydomonas reinhardtii, it was discovered that knockout of certain genes catalyzing rate-limiting steps of TAG biosynthesis, type-2 diacylglycerol acyltransferase genes (DGTTs), triggered genetic compensation under abiotic stress conditions. Genetic compensation of a DGTT1 null mutation by a related PDAT gene was observed regardless of the strain background or mutagenesis approach, e.g., CRISPR/Cas 9 or insertional mutagenesis. However, no compensation was found in the PDAT knockout mutant. The effect of PDAT knockout was evaluated in a Δvtc1 mutant, in which PDAT was up-regulated under stress. Knockout of PDAT in the Δvtc1 background induced a 12.8-fold upregulation of DGTT1 and a 272.3% increase in TAG content in Δvtc1/pdat1 cells, while remaining viable. These data suggest that genetic compensation contributes to the genetic robustness of microalgal TAG biosynthetic pathways, maintaining lipid and redox homeostasis in the knockout mutants under abiotic stress with a mechanism distinct from that found in plants. This work demonstrates examples of genetic compensation in microalgae, implies the physiological relevance of genetic compensation in TAG biosynthesis, and provides guidance for future genetic engineering and mutant characterization efforts.
Genome sequencing of the vermicompost strainStenotrophomonas maltophiliaUENF-4GII and population structure analysis of theS. maltophiliaSm3 genogroup
Authors: Pedrosa-Silva Francisnei , Matteoli Filipe P. , Passarelli-Araujo Hemanoel , Olivares Fabio L. , Venancio Thiago M. 
Published: August 2021

ABSTRACTTheStenotrophomonas maltophiliacomplex (Smc) is a cosmopolitan bacterial group that has been proposed an emergent multidrug-resistant pathogen. Taxonomic studies support the genomic heterogeneity of Smc, which comprises genogroups exhibiting a range of phenotypically distinct strains from different sources. Here, we report the genome sequencing and in-depth analysis ofS. maltophiliaUENF-4GII, isolated from vermicompost. This genome harbors a unique region encoding a penicillin-binding protein (pbpX) that was carried by a transposon, as well as horizontally-transferred genomic islands involved in anti-phage defense via DNA modification, and pili glycosylation. We also analyzed all available Smc genomes to investigate genes associated with resistance and virulence, niche occupation, and population structure.S. maltophiliaUENF-4GII belongs to genogroup 3 (Sm3), which comprises three phylogenetic clusters (PC). Pan-GWAS analysis uncovered 471 environment-associated and 791 PC-associated genes, including antimicrobial resistance (e.g.blaL1 andblaR1) and virulence determinants (e.g.treS andkatG) that provide insights on the resistance and virulence potential of Sm3 strains. Together, the results presented here provide the grounds for more detailed clinical and ecological investigations ofS. maltophilia.
Aged mouse ovarian immune milieu shows a shift towards adaptive immunity and attenuated cell function
Authors: Yaakov Tal Ben , Wasserman Tanya , Savir Yonatan 
Published: August 2021

AbstractThe immune system plays a major role in maintaining many physiological processes in the reproductive system. However, a complete characterization of the immune milieu in the ovary, and particularly how it is affected by maternal aging, is still lacking. In this work, we utilize single-cell RNA sequencing and flow cytometry to construct a complete description of the murine ovarian immune system and its changes along with pre-estropause aging. We show that the ovarian immune cells composition undergoes an extensive shift with age towards adaptive immunity. We analyze the effect of aging on gene expression and chemokine and cytokine networks and show an overall decreased expression of inflammatory mediators together with an increased senescent cells recognition. Our results reveal the changes in the aging ovarian immune system of the fertile female as it copes with the inflammatory stimulations during repeated cycles and the increasing need for clearance of accumulating atretic follicles.
Cooperation between CYB5R3 and NOX4 via coenzyme Q mitigates endothelial inflammation
Authors: Yuan Shuai , Hahn Scott A. , Miller Megan P. , Sanker Subramaniam , Calderon Michael J , Sullivan Mara , Dosunmu-Ogunbi Atinuke M. , Fazzari Marco , Li Yao , Reynolds Michael , Wood Katherine C , St. Croix Claudette M. , Stolz Donna , Cifuentes-Pagano Eugenia , Navas Placido , Shiva Sruti , Schopfer Francisco J. , Pagano Patrick J. , Straub Adam C. 
Published: August 2021

ABSTRACTNADPH oxidase 4 (NOX4) regulates endothelial inflammation by producing reactive oxygen species. Since coenzyme Q (CoQ) mimics affect NOX4 activity, we hypothesize that cytochrome b5 reductase 3 (CYB5R3), a CoQ reductase abundant in vascular endothelial cells, modulates inflammatory activation.Mice lacking endothelial CYB5R3 (R3 KO), under lipopolysaccharides (LPS) challenge, showed exacerbated hypotension, decreased acetylcholine-induced vasodilation, and elevated vascular adhesion molecule 1 (Vcam-1) mRNA in aorta. In vitro, silencingCyb5r3enhanced LPS-induced VCAM-1 protein in a NOX4 dependent manner. APEX2- based electron microscopy and proximity biotinylation demonstrated CYB5R3’s localization on the mitochondrial outer membrane and its interaction with NOX4, which was further confirmed by the proximity ligation assay. Notably,Cyb5r3silenced HAECs had less total H2O2but more mitochondrial O2•-. Using inactive or non-membrane bound active CYB5R3, we found CYB5R3 activity and membrane translocation were needed for optimal generation of H2O2by NOX4. Lastly, CoQ deficient cells showed decreased NOX4-derived H2O2, indicating a requirement for endogenous CoQ in NOX4 activity.In conclusion, CYB5R3 mitigates endothelial inflammatory activation by assisting in NOX4-dependent H2O2generation via CoQ.NOVELTY AND SIGNIFICANCEWhat Is Known?NADPH oxidase 4 (NOX4) reportedly produces primarily hydrogen peroxide (H2O2) and, to a lesser extent, superoxide (O2•-) and has been shown to have both beneficial and deleterious effects in the cardiovascular system.NOX4 activity can be affected by NAD(P)H quinone oxidoreductase 1 (NQO1), a CoQ reductase, and synthetic quinone compounds used to mimic CoQ.Cytochrome b5 reductase 3 (CYB5R3) is known to reduce CoQ and is highly expressed in endothelial cells.What New Information Does This Article Contribute?In vivo, the lack of endothelial CYB5R3 causes exacerbated lipopolysaccharides (LPS)-induced inflammatory signaling, endothelial dysfunction, and hypotension.Endothelial CYB5R3 mitigates inflammatory signaling by LPS and tumor necrosis factor α (TNF-α) in a NOX4 dependent manner.In endothelial cells, CYB5R3 and NOX4 reside in close proximity on the mitochondrial outer membrane.NOX4’s ability to generate H2O2depends on the membrane translocation and activity of CYB5R3 and the presence of endogenous CoQ.NONSTANDARD Abbreviations and AcronymsProtein names are abbreviated as capital letters (e.g., CYB5R3), while the corresponding gene names are annotated as in italic lower cases (e.g.,Cyb5r3).
Integrin signalingviaactin cytoskeleton activates MRTF/SRF to entrain circadian clock
Authors: Xiong Xuekai , Li Weini , Nam Jin , Ma Ke 
Published: August 2021

AbstractThe circadian clock is entrained to daily environmental cues. Integrin-linked intracellular signalingviaactin cytoskeleton dynamics transduces cellular niche signals to induce Myocardin-related Transcription Factor (MRTF)/Serum Response Factor (SRF)-mediated transcription. So far, how the integrin-associated signaling cascade may transmit cellular physical cues to entrain circadian clock remains to be defined. Using combined pharmacological and genetic approaches, here we show that the transcription factors mediating integrin to actin cytoskeleton signaling, MRTF-A and SRF, exert direct transcriptional control of core clock components, and that this signaling cascade modulates key properties of clock circadian activity. Pharmacological inhibition of MRTF/SRF activity by disrupting actin polymerization significantly augmented clock amplitude with period shortening, whereas an actin polymerizing compound attenuated oscillation amplitude with period lengthening. Genetic loss-of-function ofSrforMrtfmimics that of actin-depolymerizing agents, validating the role of actin dynamics in driving clock function. Furthermore, integrin-mediated focal adhesion with extracellular matrix and its downstream signaling modulates the circadian clock, as blockade of integrin, focal adhesion kinase or Rho-associated kinase (ROCK) increased clock amplitude and shortened period length. Mechanistically, we identify specific core clock transcription regulators,Per1, Per2andNr1d1, as direct target genes of MRTF-A/SRF. Collectively, our findings uncovered an integrin-actin cytoskeleton-MRTF/SRF signaling cascade in linking clock entrainment to its extracellular microenvironment, which may mediate cellular adaptation to its physical niche.Author SummaryThe circadian clock anticipates and adapts to environmental changes. Interestingly, serum, as a universal clock synchronizing signal, drives intracellular actin cytoskeleton reorganization through modulation of MRTF/SRF activity. However, mechanisms that may transduce extracellular niche signals to circadian clock remains to be defined. We hypothesize that integrin-mediated intracellular signaling to actin cytoskeleton links extracellular microenvironment with MRTF/SRF transcriptional regulation to control clock function. Using small molecules and genetic approaches targeting distinct steps of integrin-actin cytoskeleton-MRTF/SRF signaling cascade, we uncover the effects of this pathway in controlling circadian clock oscillation. We also identify specific core clock regulators as direct gene target genes of MRTF and SRF-mediated transcriptional control. Our study revealed how integrin-mediated cellular interaction with its physical environment influences its intrinsic clock properties through signaling transductionviaactin cytoskeleton remodeling, and that this mechanism may facilitate circadian clock adaptation to cellular physical niche.
Paramecium Polycomb Repressive Complex 2 physically interacts with the small RNA binding PIWI protein to repress transposable elements
Authors: Pina Caridad Miró , Kawaguchi Takayuki , Charmant Olivia , Michaud Audrey , Cohen Isadora , Humbert Adeline , Jaszczyszyn Yan , Del Maestro Laurence , Holoch Daniel , Ait-Si-Ali Slimane , Arnaiz Olivier , Margueron Raphaël , Duharcourt Sandra 
Published: August 2021

SUMMARYPolycomb Repressive Complex 2 (PRC2) maintains transcriptionally silent genes in a repressed state via deposition of histone H3 K27 trimethyl (me3) marks. PRC2 has also been implicated in silencing transposable elements (TEs) yet how PRC2 is targeted to TEs remains unclear. To address this question, we performed tandem affinity purification combined with mass spectrometry and identified proteins that physically interact with the Paramecium Enhancer-of-zeste Ezl1 enzyme, which catalyzes H3K9me3 and H3K27me3 deposition at TEs. We show that the Paramecium PRC2 core complex comprises four subunits, each required in vivo for catalytic activity. We also identify PRC2 cofactors, including the RNA interference (RNAi) effector Ptiwi09, which are necessary to target H3K9me3 and H3K27me3 to TEs. We find that the physical interaction between PRC2 and the RNAi pathway is mediated by a RING finger protein and that small RNA recruitment of PRC2 to TEs is analogous to the small RNA recruitment of H3K9 methylation SU(VAR)3-9 enzymes.
Uncertainty avoidance versus conditioned reinforcement: exploring paradoxical choice in rats
Authors: Ajuwon Victor , Ojeda Andrés , Murphy Robin A. , Monteiro Tiago , Kacelnik Alex 
Published: August 2021

AbstractPaying a cost to reduce uncertainty can be adaptive, because better informed decision-makers can align their preferences to opportunities. However, birds and mammals display an appetite for information that they cannot use to functionally alter behaviour or its outcomes. We explore two putative motivational mechanisms for this paradoxical behaviour. The ‘information hypothesis’, proposes that reducing uncertainty is reinforcing per se, consistent with the concept of curiosity: a motivation to know, in the absence of instrumental benefits. In contrast, the ‘conditioned reinforcement hypothesis’ sees information-seeking as a consequence of asymmetries in secondarily acquired reinforcement: responding increments caused by post-choice stimuli announcing positive outcomes (S+) exceed decrements caused by stimuli signalling absence of reward (S−). We contrast these hypotheses experimentally. Rats chose between two equally profitable options delivering food probabilistically after a fixed delay. In the informative option (Info), the outcome (food/no food) was signalled immediately after choice, whereas in the non-informative option (NoInfo) outcomes were uncertain until the delay lapsed. Subjects preferred Info when (1) outcomes were signalled by salient auditory cues, (2) only the absence of reward was signalled, and (3) only reward was signalled, though acquisition was slower when rewards were not explicitly signalled. Our results show that a salient good news signal is not required as a conditioned reinforcer to generate paradoxical preferences. Terminal preferences support the information hypothesis but the slower acquisition of Info preference when S+ is not present is consistent with the conditioning account. We conclude that both uncertainty reduction and conditioned reinforcement influence choice.
Stoney vs. Histed: Quantifying the Spatial Effects of Intracortical Microstimulation
Authors: Kumaravelu Karthik , Sombeck Joseph , Miller Lee E. , Bensmaia Sliman J. , Grill Warren M. 
Published: August 2021

ABSTRACTBackgroundIntracortical microstimulation (ICMS) is used to map neural circuits and restore lost sensory modalities such as vision, hearing, and somatosensation. The spatial effects of ICMS remain controversial: Stoney and colleagues proposed that the volume of somatic activation increased with stimulation intensity, while Histed et al. suggested activation density, but not somatic activation volume, increases with stimulation intensity.ObjectiveWe used computational modeling to quantify the spatial effects of ICMS intensity and unify the apparently paradoxical findings of Histed and Stoney.MethodsWe implemented a biophysically-based computational model of a cortical column comprising neurons with realistic morphology and representative synapses. We quantified the spatial effects of single pulse ICMS, including the radial distance to activated neurons and the density of activated neurons as a function of stimulation intensity.ResultsAt all amplitudes, the dominant mode of somatic activation was by antidromic propagation to the soma following axonal activation, rather than via trans-synaptic activation. There were no occurrences of direct activation of somata or dendrites. The volume over which antidromic action potentials were initiated grew with stimulation amplitude, while the volume of somatic activations did not. However, the density of somatic activation within the activated volume increased with stimulation amplitude.ConclusionsThe results resolve the apparent paradox between Stoney and Histed’s results by demonstrating that the volume over which action potentials are initiated grows with ICMS amplitude, consistent with Stoney. However, the volume occupied by the activated somata remains approximately constant, while the density of activated neurons within that volume increase, consistent with Histed.HIGHLIGHTSImplemented a biophysically-based computational model of cortical column comprising cortical neurons with realistic morphology and representative synapses.Quantified the spatial patterns of neural activation by intracortical microstimulation to resolve the paradoxical findings of Stoney et al., 1968 and Histed et al., 2009.The dominant mode of neural activation near the electrode was direct (i.e., via antidromic propagation from direct activation of the axon) and not trans-synaptic.The dominant effect of increased ICMS intensity was to increase the density of activated neurons but not the volume of activation.
BubR1 recruitment to the kinetochore via Bub1 enhances Spindle Assembly Checkpoint signaling
Authors: Banerjee Anand , Chen Chu , Humphrey Lauren , Tyson John J. , Joglekar Ajit P. 
Published: August 2021

AbstractDuring mitosis, unattached kinetochores in a dividing cell activate the Spindle Assembly Checkpoint (SAC) and delay anaphase onset by generating the anaphase-inhibitory Mitotic Checkpoint Complex (MCC). These kinetochores generate the MCC by recruiting MCC constituent proteins, including BubR1. In principle, BubR1 recruitment to signaling kinetochores should increase its local concentration and promote MCC formation. However, in human cells BubR1 is mainly thought to sensitize the SAC to silencing; whether BubR1 localization to signaling kinetochores per se enhances SAC signaling activity remains unknown. Therefore, we used ectopic SAC activation systems (eSAC) to isolate two molecules that recruit BubR1 to the kinetochore: the checkpoint protein Bub1 and the KI and MELT motifs in the kinetochore protein KNL1, and observed their contribution to eSAC signaling. Our quantitative analyses and mathematical modeling show that the Bub1-mediated BubR1 recruitment to the human kinetochore promotes SAC signaling and highlight BubR1’s dual role of directly strengthening the SAC and indirectly silencing it.