bluuebunny/crossref_metadata_2025_split huggingface dataset:
Wastewater surveillance in smaller college communities may aid future public health initiatives
Authors: Lee Laura , Valmond Lescia , Thomas John , Kim Audrey , Austin Paul , Foster Michael , Matthews John , Kim Paul , Newman Jamie 
Published: June 2022

AbstractSince its declaration, the COVID-19 pandemic has resulted in over 530 million cases and over 6 million deaths worldwide. Predominant clinical testing methods, though invaluable, may create an inaccurate depiction of COVID-19 prevalence due to inadequate access, testing, or most recently under-reporting because of at-home testing. These concerns have created a need for unbiased, community-level surveillance. Wastewater-based epidemiology has been used for previous public health threats, and more recently has been established as a complementary method of SARS-CoV-2 surveillance. Here we describe the application of wastewater surveillance for SARS-CoV-2 in two university campus communities located in rural Lincoln Parish, Louisiana. This cost-effective approach is especially well suited to rural areas where limited access to testing may worsen the spread of COVID-19 and quickly exhaust the capacity of local healthcare systems. Our work demonstrates that local universities can leverage scientific resources to advance public health equity in rural areas and enhance their community involvement.
HCP5 prevents ubiquitination-mediated UTP3 degradation to inhibit apoptosis by activating c-Myc transcriptional activity
Authors: Nan Yabing , Luo Qingyu , Wu Xiaowei , Chang Wan , Zhao Pengfei , Liu Shi , Liu Zhihua 
Published: June 2022

AbstractInducing cancer cell apoptosis through cytotoxic reagents is the main therapeutic strategy for diverse cancer types. However, several antiapoptotic factors impede curative cancer therapy by driving cancer cells to resist cytotoxic agent-induced apoptosis, thus leading to refractoriness and relapse. To define critical antiapoptotic factors that contribute to chemoresistance in esophageal squamous cell carcinoma (ESCC), we generated two pairs of parental and apoptosis-resistant cell models through cisplatin (DDP) induction and then performed whole-transcriptome sequencing. We identified the long noncoding RNA (lncRNA) histocompatibility leukocyte antigen complex P5 (HCP5) as the chief culprit for chemoresistance. Mechanistically, HCP5 interacts with UTP3 small subunit processome component (UTP3) and prevents UTP3 degradation from E3 ligase tripartite motif containing 29 (TRIM29)-mediated ubiquitination. UTP3 then recruits c-Myc to activate vesicle-associated membrane protein 3 (VAMP3) expression. Activated VAMP3 suppresses caspase-dependent apoptosis and eventually leads to chemoresistance. Accordingly, the expression level of the HCP5/UTP3/c-Myc/VAMP3 axis in chemoresistant patients is significantly higher than that in chemosensitive patients. Thus, our study demonstrated that the HCP5/UTP3/c-Myc/VAMP3 axis plays an important role in the inhibition of cancer cell apoptosis and that HCP5 can be a promising chemosensitive target for cancer treatment.
Continuous tracking of task parameters tunes reaching control online
Authors: De Comite Antoine , Crevecoeur Frédéric , Lefèvre Philippe 
Published: June 2022

AbstractA hallmark of human reaching movements is that they are appropriately tuned to the task goal and to the environmental context. This was demonstrated by the way humans flexibly respond to mechanical and visual perturbations that happen during movement. Furthermore, it was previously showed that the properties of goal-directed control can change within a movement, following abrupt changes in the goal structure. Such online adjustment was characterized by a modulation of feedback gains following switches in target shape. However, it remains unknown whether the underlying mechanism merely switches between prespecified policies, or whether it results from continuous and potentially dynamic adjustments. Here, we address this question by investigating participants’ feedback control strategies in presence of various changes in target width during reaching. More specifically, we studied whether the feedback responses to mechanical perturbations were sensitive to the rate of change in target width, which would be inconsistent with the hypothesis of a single, discrete switch. Based on movement kinematics and surface EMG data, we observed a modulation of feedback response clearly dependent on dynamical changes in target width. Together, our results demonstrate a continuous and online transformation of task-related parameters into suitable control policies.Significance statementHumans can adjust their control policy online in response to changes in the goal structure. However, it was unknown whether this adjustment resulted from a switch between two policies, or from dynamic and continuous adjustments. To address this question, we investigated whether online adjustments were tuned to dynamic changes in goal target which varied at different rates. Our results demonstrated that online adjustments were tuned to the rate of change in target width, suggesting that human reaching control policies are derived based on continuous monitoring of task-related parameters supporting online and dynamic adjustments.
Enhancers that regulateTNFgene transcription in human macrophages in response to TLR3 stimulation
Authors: Gao Junfeng , Li Yapeng , Zhao Dianzheng , Guan Xiaoyu , Motsinger Kirby , Scott-Browne James , Chu Hong Wei , Huang Hua 
Published: June 2022

AbstractMacrophages play a critical role in inflammatory responses during infections. These cells are activated by infections through stimulation of TLRs expressed on their cell surface and produce pro-inflammatory cytokines, including TNF. However, distal enhancers that regulateTNFgene transcription in human macrophages have not been investigated. This study used an unbiased genomic approach to identify six candidate enhancers in human primary alveolar macrophages within a 131 kb region from the transcription start site (TSS) of theTNFgene, covering 13 genes. Of these candidate enhancers, five showed enhancer activity, with three targeting theTNFgene and two targeting neighboring genes. Deletion of the distalTNFE-16 enhancer led to a 73% reduction inTNFgene transcription in response to poly (I:C) stimulation in the THP-1 human leukemia monocytic cell line. Additionally, deletion of the E-7.1/hHS-8 enhancer resulted in a 41% reduction inTNFmRNA, while deletion of the PE enhancer had a lesser effect, resulting in a 52% reduction inTNFgene transcription. Massively parallel reporter assays (MPRA) indicated that the transcription factor AP-1 and EGR1-binding sites at the distalTNFE-16 enhancer were crucial in mediating enhancer activity. This study shows that both distal and proximal enhancers work together to fully transcribe theTNFgene in human macrophages in response to TLR ligand poly (I:C) stimulation.
The Neural Architecture of Theory-based Reinforcement Learning
Authors: Tomov Momchil S. , Tsividis Pedro A. , Pouncy Thomas , Tenenbaum Joshua B. , Gershman Samuel J. 
Published: June 2022

AbstractHumans learn internal models of the environment that support efficient planning and flexible generalization in complex, real-world domains. Yet it remains unclear how such internal models are represented and learned in the brain. We approach this question within the framework of theory-based reinforcement learning, a strong form of model-based reinforcement learning in which the model is an intuitive theory – a rich, abstract, causal model of the environment built on a natural ontology of physical objects, intentional agents, relations, and goals. We used a theory-based reinforcement learning model to analyze brain data from human participants learning to play different Atari-style video games while undergoing functional MRI. Theories inferred by the theory-based model explained the signal in inferior frontal gyrus and other prefrontal areas better than several alternative models. Brain activity increased in response to theory update events in inferior frontal gyrus, occipital cortex, and fusiform gyrus, with separate learning signals for different theory components. This corresponded with a transient strengthening of theory representations in those regions. Finally, the effective connectivity pattern during theory updating suggests that information flows top-down from theory-coding regions in the prefrontal cortex to theory updating regions in occipital and temporal cortex. These results are consistent with a neural architecture in which top-down theory representations originating in prefrontal regions shape sensory predictions in visual areas, where factorized theory prediction errors are computed and in turn trigger bottom-up updates of the theory. This initial sketch provides a foundation for understanding of the neural representations and computations that support efficient theory-based reinforcement learning in complex, naturalistic environments.
Structures of perforin-2 in solution and on a membrane reveal mechanisms for pore formation
Authors: Yu Xiulian , Ni Tao , Munson George , Zhang Peijun , Gilbert Robert J. C. 
Published: June 2022

AbstractPerforin-2 (PFN2, MPEG1) is a key pore-forming protein in mammalian innate immunity restricting intracellular bacteria proliferation. It forms a membrane-bound pre-pore complex that converts to a pore-forming structure upon acidification; but its mechanism of conformational transition has been debated. Here we used cryo-electron microscopy, tomography and subtomogram averaging to determine structures of PFN2 in pre-pore and pore conformations in isolation and bound to liposomes. In isolation and upon acidification, the pre-assembled complete pre-pore rings convert to pores in both flat ring and twisted conformations. The twisted pore structure suggests an intermediate or alternative state to the flat conformation, and a capacity to distort the underlying membrane during membrane insertion. On membranes, in situ assembled PFN2 pre-pores display various degrees of completeness; whereas PFN2 pores are mainly incomplete arc structures that follow the same subunit packing arrangements as found in isolation. Both assemblies on membranes use their P2 β-hairpin for binding to the lipid membrane surface. These structural snapshots in different states reveal a molecular mechanism for PFN2 pre-pore to pore transition on a targeted membrane.
Cloacal virome of an ancient host lineage – the tuatara (Sphenodon punctatus) – reveals abundant and diverse diet-related viruses
Authors: Waller Stephanie J. , Lamar Sarah , Perry Benjamin J. , Grimwood Rebecca M. , Holmes Edward C. , Geoghegan Jemma L. 
Published: June 2022

1.AbstractTuatara (Sphenodon punctatus) are one of the most phylogenetically isolated species and provide a unique host system to study virus evolution. While the tuatara genome, sequenced in 2020, revealed many endogenous viral elements, we know little of the exogenous viruses that infect tuatara. We performed a metatranscriptomics study of tuatara cloaca samples from a wild population on Takapourewa (Stephens Island), Aotearoa New Zealand. From these data we identified 49 potentially novel viral species that spanned 20 RNA viral families and/or orders, the vast majority (48) of which were likely dietary related. Notably, using a protein structure homology search, we identified a highly divergent novel virus within the Picornaviridae which may directly infect tuatara. Additionally, two endogenous tuatara adintoviruses were characterised that exhibited long-term viral-host co-divergence. Overall, our results indicate that the tuatara cloacal virome is highly diverse likely due a large number of dietary related viruses.
The faecal metabolome and its determinants in inflammatory bowel disease
Authors: Vila Arnau Vich , Hu Shixian , Andreu-Sánchez Sergio , Collij Valerie , Jansen B. H. , Augustijn Hannah E. , Bolte Laura , Ruigrok Renate A.A.A. , Abu-Ali Galeb , Giallourakis Cosmas , Schneider Jessica , Parkinson John , Garawi Amal Al , Zhernakova Alexandra , Gacesa Ranko , Fu Jingyuan , Weersma Rinse K. 
Published: June 2022

ABSTRACTObjectiveInflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn’s disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD.DesignWe measured 1,684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 IBD patients and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant’s lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels.ResultsWe identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC = 0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of Ruminococcus gnavus was positively associated with tryptamine levels. In addition, we found 158 associations between metabolites and dietary patterns, and polymorphisms near NAT2 strongly associated with coffee metabolism.ConclusionIn this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.
Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation
Authors: Hilander Taru , Monteuuis Geoffray , Awadhpersad Ryan , Broda Krystyna L. , Pohjanpelto Max , Pyman Elizabeth , Singh Sachin Kumar , Nyman Tuula A. , Crevel Isabelle , Taylor Robert W. , Saada Ann , Balboa Diego , Battersby Brendan J. , Jackson Christopher B. , Carroll Christopher J. 
Published: June 2022

SummaryMitochondrial ribosomes (mitoribosomes) have undergone substantial structural remodelling throughout evolution. Compared to their prokaryotic counterparts, mitoribosomes show a substantial loss of ribosomal RNA, whilst acquiring unique protein subunits located on the periphery of the ribosomal subunit structures. We set out to investigate the functional properties of all 14 unique (mitochondrial-specific or supernumerary) human mitoribosomal proteins in the small subunit. Using genome editing with CRISPR-Cas9, we made knockouts for each subunit in HEK293 cells to study the effect on mitoribosome assembly and function in protein synthesis. Unexpectedly, we show that each supernumerary knockout leads to a unique mitoribosome assembly defect with variable impact on mitochondrial protein synthesis. Our data demonstrates that all supernumerary subunits are essential structural components except mS37. Surprisingly, we found the stability of mS37 was reduced in all our supernumerary knockouts of the small and large ribosomal subunits as well as patient-derived lines with mitoribosome assembly defects. We identified that a redox regulated CX9C motif in mS37 was essential for protein stability, suggesting a potential mechanism to regulate mitochondrial protein synthesis. Together, our findings support a modular assembly of the human mitochondrial small ribosomal subunit mediated by essential supernumerary subunits and identify a redox regulatory role involving mS37 in mitochondrial protein synthesis in health and disease.
The columnar structure of human telomeric chromatin suggests mechanisms for telomere maintenance
Authors: Soman Aghil , Wong Sook Yi , Korolev Nikolay , Surya Wahyu , Lattman Simon , Vogirala Vinod K. , Chen Qinming , Berezhnoy Nikolay V. , van Noort John , Rhodes Daniela , Nordenskiöld Lars 
Published: June 2022

AbstractTelomeres, the ends of eukaryotic chromosomes, play pivotal roles in ageing and cancer and are targets of DNA damage and response. However, little is known about the structure and organization of telomeric chromatin at the molecular level. We used electron microscopy and single-molecule magnetic tweezers to characterize well-defined telomeric chromatin fibers of kilobasepair length. The cryo-EM structure of the compact telomeric tetranucleosome revealed a novel columnar folding, unusually short nucleosome repeat length of ∼132bp and the role of the histone N-terminal tails in stabilizing this structure. This is the first near-high resolution structure of chromatin with a native DNA sequence. The columnar structure exposes the DNA, making them susceptible to DNA damage. The telomeric tetranucleosome also exists in an alternative well-defined state, with one nucleosome open, accessible to protein factors. This suggests that protein factors, which plays a role in maintaining telomeres, can bind to telomeric chromatin in its compact heterochromatic form. The features of the telomeric chromatin structure reveals important insights of significant relevance for telomere function in vivo that provides information on mechanisms of nucleosome recognition by chromatin factors
Modes of inhibition used by phage anti-CRISPRs to evade type I-C Cascade
Authors: O’Brien Roisin E. , Bravo Jack P.K. , Ramos Delisa , Hibshman Grace N. , Wright Jacquelyn T. , Taylor David W. 
Published: June 2022

AbstractCascades are RNA-guided multi-subunit CRISPR-Cas surveillances complexes that target foreign nucleic acids for destruction. Here, we present a 2.9-Å resolution cryo-electron (cryo-EM) structure of the D. vulgaris type I-C Cascade bound to a double-stranded (ds)DNA target. Our data shows how the 5’-TTC-3’ protospacer adjacent motif (PAM) sequence is recognized, and provides a unique mechanism through which the displaced, single-stranded non-target strand (NTS) is stabilized via stacking interactions with protein subunits in order to favor R-loop formation and prevent dsDNA re-annealing. Additionally, we provide structural insights into how diverse anti-CRISPR (Acr) proteins utilize distinct strategies to achieve a shared mechanism of type I-C Cascade inhibition by blocking initial DNA binding. These observations provide a structural basis for directional R-loop formation and reveal how divergent Acr proteins have converged upon common molecular mechanisms to efficiently shut down CRISPR immunity.
Functional evolutionary convergence of long noncoding RNAs involved in embryonic development
Authors: Olazagoitia-Garmendia Ane , Senovilla-Ganzo Rodrigo , Garcia-Moreno Fernando , Castellanos-Rubio Ainara 
Published: June 2022

AbstractLong noncoding RNAs (lncRNAs) have been identified in almost all vertebrates, but the functional characterization of these RNA molecules is being challenging, mainly due to the lack of linear sequence homology between species. In this work, we aimed to find functional evolutionary convergent lncRNAs involved in development by screening of k-mer content (non linear similarity) and secondary structure-based approaches combined within silico, in vitroandin vivovalidation analysis. From the currently identified Madagascar gecko genes, we found a lncRNA with a similar k-mer content and structurally concordant with the human lncRNAEVX1AS. Analysis of function related characteristics together with locus-specific targeting of human and geckoEVX1AS(i.e. CRISPR Display) in human neuroepithelial cells and chicken mesencephalon confirmed that geckoEvx1as-likelncRNA mimics humanEVX1ASfunction and inducesEVX1expression independently of the target species. Our data show functional conservation of non-homologous lncRNAs and presents a useful approach for the definition and manipulation of lncRNA function within different model organisms.
An anti-steatosis response regulated by oleic acid through lipid droplet-mediated ERAD enhancement
Authors: Castillo-Quan Jorge Iván , Steinbaugh Michael J. , Paulette Fernández-Cárdenas L. , Pohl Nancy K. , Wu Ziyun , Zhu Feimei , Moroz Natalie , Teixeira Veronica , Bland Monet S. , Lehrbach Nicolas J. , Mazzeo Lorenza E. Moronetti , Teufl Magdalena , Blackwell T. Keith 
Published: June 2022

AbstractAlthough excessive lipid accumulation is a hallmark of obesity-related pathologies, some lipids are beneficial. Oleic acid (OA), the most abundant monounsaturated fatty acid (FA), promotes health and longevity. Here we show that OA benefits C. elegans by activating the endoplasmic reticulum (ER)-resident transcription factor SKN-1A (Nrf1/NFE2L1) in a lipid homeostasis response. SKN-1A/Nrf1 is cleared from the ER by the ER-associated degradation (ERAD) machinery and stabilized when proteasome activity is low, and canonically maintains proteasome homeostasis. Unexpectedly, OA increases nuclear SKN-1A levels independently of proteasome activity, through lipid droplet (LD)-mediated enhancement of ERAD. In turn, SKN-1A reduces steatosis by reshaping the lipid metabolism transcriptome, and mediates longevity from OA provided through endogenous accumulation, reduced H3K4 trimethylation, or dietary supplementation. Our findings reveal a surprising mechanism of FA signal transduction, and a lipid homeostasis pathway that provides strategies for opposing steatosis and aging, and may mediate benefits of the OA-rich Mediterranean diet.
Analytical approaches for antimalarial antibody responses to confirm historical and recent malaria transmission: an example from the Philippines
Authors: Macalinao Maria Lourdes M. , Fornace Kimberly M. , Reyes Ralph A. , Bareng Alison Paolo N. , Hall Tom , Adams John H. , Huon Christèle , Chitnis Chetan E. , Luchavez Jennifer S. , Tetteh Kevin K. A. , Yui Katsuyuki , Hafalla Julius Clemence R. , Espino Fe Esperanza J. , Drakeley Chris J. 
Published: June 2022

AbstractBackgroundAssessing the status of malaria transmission in endemic areas becomes increasingly challenging as countries approach elimination. Serology can provide robust estimates of malaria transmission intensities, and multiplex serological assays allow for simultaneous assessment of markers of recent and historical malaria exposure.MethodsHere, we evaluated different statistical and machine learning methods for analyzing multiplex malaria-specific antibody response data to classify recent and historical exposure toPlasmodium falciparumandP. vivax. To assess these methods, we utilized samples from a health-facility based survey (n=9132) in the Philippines, where we quantified antibody responses against 8P. falciparumand 6P. vivax-specific antigens from 3 sites with varying transmission intensity.FindingsMeasurements of antibody responses and seroprevalence were consistent with the 3 sites’ known endemicity status. For predictingP. falciparuminfection, a machine learning (ML) approach (Random Forest model) using 4 serological markers (PfGLURP R2, Etramp5.Ag1, GEXP18 and PfMSP119) gave better predictions for cases in Palawan (AUC: 0·9591, CI 0·9497-0·9684) than individual antigen seropositivity. Although the ML approach did not improveP. vivaxinfection predictions, ML classifications confirmed the absence of recent exposure toP. falciparumandP. vivaxin both Occidental Mindoro and Bataan. For predicting historicalP. falciparumandP. vivaxtransmission, seroprevalence and seroconversion rates based on cumulative exposure markers AMA1 and MSP119showed reliable trends in the 3 sites.InterpretationOur study emphasizes the utility of serological markers in predicting recent and historical exposure in a sub-national elimination setting, and also highlights the potential use of machine learning models using multiplex antibody responses to improve assessment of the malaria transmission status of countries aiming for elimination. This work also provides baseline antibody data for monitoring risk in malaria-endemic areas in the Philippines.FundingNewton Fund, Philippine Council for Health Research and Development, and UK Medical Research Council.