bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell type-specific role of CBX2-cPRC1 at the onset of spermatogonial differentiation
Authors: Kim Jongmin J. , Steinson Emma R. , Lau Mei Sheng , Page David C. , Kingston Robert E. 
Published: August 2022

SummaryPolycomb group (PcG) proteins maintain the repressed state of lineage-inappropriate genes and are therefore essential for embryonic development and adult tissue homeostasis. One critical function of PcG complexes is modulating chromatin structure. Canonical Polycomb repressive complex 1 (cPRC1), particularly its component CBX2, can compact chromatin and phase separate in vitro. These activities are hypothesized to be critical for forming a repressed physical environment in cells. While much has been learned by studying these PcG activities in cell culture models, it is largely unexplored how cPRC1 regulates adult stem cells and their subsequent differentiation during tissue homeostasis in living animals. Here, we show that CBX2 is upregulated as spermatogonial stem cells differentiate and is required in the differentiating spermatogonia of the male germ line. CBX2 forms condensates, similar to previously described Polycomb bodies, that co-localize with repressed target genes in differentiating spermatogonia. Single cell analyses of mosaic Cbx2 mutant testes show CBX2 is specifically required to produce differentiating, A1 spermatogonia. Furthermore, the domain of CBX2 responsible for compaction and phase separation is needed for the long-term maintenance of male germ cells in the animal. These results emphasize that the regulation of chromatin structure by CBX2 at a specific stage of spermatogenesis is critical for the continued production of sperm and, ultimately, the transmission of genetic material to the next generation.
Neither sharpened nor lost: the unique role of attention in children’s neural representations
Authors: Jung Yaelan , Forest Tess Allegra , Bernhardt-Walther Dirk , Finn Amy S. 
Published: August 2022

AbstractOne critical feature of children’s cognition is their relatively immature attention. Decades of research have shown that children’s attentional abilities mature slowly over the course of development, including the ability to filter out distracting information. Despite such rich behavioral literature, little is known about how developing attentional abilities modulate neural representations in children. This information is critical to understanding exactly how attentional development shapes the way children process information. One intriguing possibility is that attention might be less likely to impact neural representations in children as compared with adults. In particular, representations of attended items may be less likely to be sharpened relative to unattended items in children as compared to adults. To investigate this possibility, we measured brain activity using fMRI while adults (21-31 years) and children (7-9 years) performed a one-back working memory task in which they were directed to attend to either motion direction or an object in a complex display where both were present. We used multivoxel pattern analysis and compared decoding accuracy of attended and unattended information. Consistent with attentional sharpening, we found higher decoding accuracy for task-relevant information (i.e., objects in the object-attended condition) than for task-irrelevant information (i.e., motion in the object-attended condition) in adults’ visual cortices. However, in children’s visual cortices, both task-relevant and task-irrelevant information were decoded equally well. What’s more, exploratory whole-brain analysis showed that the children represent task-irrelevant information more than adults in multiple regions across the brain, including the prefrontal cortex. These findings show that 1) attention does not sharpen neural representations in the child visual cortex, and further 2) that the developing brain can represent more information than the adult brain.
Serinc5 restricts HIV membrane fusion by altering lipid order and heterogeneity in the viral membrane
Authors: Ward Amanda E. , Sokovikova Daria , Waxham M. Neal , Heberle Frederick A. , Levental Ilya , Levental Kandice R. , Kiessling Volker , White Judith M. , Tamm Lukas K. 
Published: August 2022

AbstractThe host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A compelling body of work also suggests Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5’s effects on HIV pseudoviral membranes. Using fluorescence lifetime imaging with an order sensitive dye, FLIPPER-TR, and by measuring pseudoviral membrane thickness via cryo electron microscopy (cryoEM), Serinc5 was found to increase membrane heterogeneity, skewing the distribution towards a larger fraction of the viral membrane in an ordered phase. We also directly observed for the first time the coexistence of membrane domains within individual viral membrane envelopes. Using a TIRF-based single particle fusion assay, we found that incorporation of exogenous phosphatidylethanolamine (PE) into the viral membrane rescued HIV pseudovirus fusion from restriction by Serinc5, which was accompanied by decreased membrane heterogeneity and order. This effect was specific for PE and did not depend on acyl chain length or saturation. Together, these data suggest that Serinc5 alters multiple interrelated properties of the viral membrane—lipid chain order, rigidity, line tension, and lateral pressure—which decrease accessibility of fusion intermediates and disfavor completion of fusion. These biophysical insights into Serinc5 restriction of HIV infectivity could contribute to the development of novel antivirals that exploit the same weaknesses of HIV and potentially other enveloped viruses.
Structural insights into viral genome replication by the severe fever with thrombocytopenia syndrome virus L protein
Authors: Williams Harry M. , Thorkelsson Sigurdur R. , Vogel Dominik , Milewski Morlin , Busch Carola , Cusack Stephen , Grünewald Kay , Quemin Emmanuelle R.J. , Rosenthal Maria 
Published: August 2022

ABSTRACTSevere fever with thrombocytopenia syndrome virus (SFTSV) is a phenuivirus that has rapidly become endemic in several East Asian countries. The large (L) protein of SFTSV, which includes the RNA-dependent RNA polymerase (RdRp), is responsible for catalysing viral genome replication and transcription. Here, we present 5 cryo-electron microscopy (cryo-EM) structures of the L protein in several states of the genome replication process, from pre-initiation to late-stage elongation, at a resolution of up to 2.6 Å. We identify how the L protein binds the 5′ viral RNA in a hook-like conformation and show how the distal 5′ and 3′ RNA ends form a duplex positioning the 3′ RNA terminus in the RdRp active site ready for initiation. We also observe the L protein stalled in the early- and late-stages of elongation with the RdRp core accommodating a 9-bp product-template duplex. This duplex ultimately splits with the template binding to a designated 3′ secondary binding site. The structural data and observations are complemented byin vitrobiochemical and cell-based mini-replicon assays. Altogether, our data provide novel key insights into the mechanism of viral genome replication by the SFTSV L protein and will aid drug development against segmented negative-strand RNA viruses.
Extracellular heparan 6-O-endosulfatases SULF1 and SULF2 in HNSC and other malignancies
Authors: Yang Yang , Ahn Jaeil , Edwards Nathan , Benicky Julius , Rozeboom Aaron M. , Davidson Bruce , Karamboulas Christina , Nixon Kevin C.J. , Ailles Laurie , Goldman Radoslav 
Published: August 2022

ABSTRACTSULF1 and SULF2 are oncogenic in a number of human malignancies, including head and neck squamous cell carcinoma (HNSC). The function of these two heparan sulfate editing enzymes was previously considered largely redundant but the biology of cancer suggests differences that we explore in our RNAseq and RNAScope studies of HNSC and in a pan cancer analysis using the TCGA and CPTAC (proteomics) data. Our studies document a consistent upregulation of SULF1 and SULF2 in HNSC which is associated with poor survival outcomes. SULF2 expression increases in multiple malignancies but less consistently than SULF1, which uniformly increases in the tumor tissues and negatively impacts survival in several types of cancer. Meanwhile, SULF1 showed low expression in cancer cell lines and a scRNAseq study of HNSC shows that SULF1 is not supplied by epithelial tumor cells, like SULF2, but is secreted by cancer associated fibroblasts. Our RNAScope and PDX analysis of the HNSC tissues fully confirm the stromal source of SULF1 and explain the uniform impact of this enzyme on the biology of multiple malignancies. In summary, the SULF1 enzyme, supplied by a subset of cancer associated fibroblasts, is upregulated and negatively impacts HNSC survival at an early stage of the disease progression while the SULF2 enzyme, supplied by tumor cells, impacts survival at later stages of HNSC. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparan sulfatases in cancer diseases.
Stimulation of the muscarinic receptor M4 activates quiescent neural precursor cells and ameliorates medial septum cholinergic lesion-induced impairments in adult hippocampal neurogenesis
Authors: Madrid Lidia I. , Bandhavkar Saurabh , Hafey Katelyn , Jimenez-Martin Javier , Milne Michael , Coulson Elizabeth J. , Jhaveri Dhanisha J. 
Published: August 2022

AbstractCholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis and hippocampus-dependent cognitive and mood-related functions. However, the contribution of basal forebrain medial septum (MS) and diagonal band of Broca (DBB) cholinergic neurons that innervate the hippocampus and the identity of the cholinergic receptor(s) that regulate the production and maturation of new neurons are not completely understood. Using a targeted, selective ablation approach, we show that MS/DBB cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus. We demonstrate that the muscarinic acetycholine receptor subtype M4 (M4 mAChR) is expressed on a population of quiescent neural precursor cells (NPCs) and that its pharmacological stimulation via intra-hippocampal or systemic administration of M4-selective modulators leads to their activation, thereby enhancing neurogenesis in vivo. Furthermore, we show that the activation of M4 mAChR-expressing quiescent NPCs ameliorates the MS/DBB cholinergic lesion-induced decrease in hippocampal neurogenesis. In contrast, the impairment in the morphological maturation of adult-born neurons due to MS/DBB cholinergic neuron loss is further exacerbated by the systemic administration of an M4-selective allosteric potentiator. These findings reveal novel and stage-specific roles of cholinergic signaling in regulating adult hippocampal neurogenesis. They also uncouple the positive role of selective M4 potentiators in enhancing the production of new neurons from the M4-induced inhibition of their morphological maturation, at least in the context of cholinergic dysfunction.Significance statementCholinergic signaling plays an important role in the regulation of adult hippocampal neurogenesis and cognitive function, with impairments in these processes reported as early pathogenic events in age-related dementia. Here, we uncover the presence of cholinergic-responsive hippocampal precursor cells that are are directly activated by selective stimulation of the muscarinic receptor subtype M4. Furthermore, M4-mediated stimulation rescues the decrease in the level of hippocampal neurogenesis following the sepal-hippocampal cholinergic neuron loss. We also reveal that septal-hippocampal cholinergic dysfunction impairs the structural maturation of hippocampal adult-born neurons, an effect which is further exacerbated by M4 receptor modulators. These findings reveal stage-specific roles of cholinergic signaling in regulating functionally relevant adult hippocampal neurogenesis.
Cognitive effects of thalamostriatal degeneration are ameliorated by normalizing striatal cholinergic activity
Authors: Becchi Serena , Chieng Billy , Bradfield Laura A. , Capellán Roberto , Leung Beatrice K. , Balleine Bernard W. 
Published: August 2022

ABSTRACTThe loss of neurons in parafascicular thalamus (Pf) and of their inputs to dorsomedial striatum (DMS) are associated with Lewy body disease (LBD) and Parkinson’s disease dementia (PDD) and have been linked to the effects of neuroinflammation. In rats, these inputs regulate the function of striatal cholinergic interneurons (CINs) that are necessary for the flexible encoding of the action-outcome (AO) associations for goal-directed action. We found that these inputs modify the encoding, not retrieval, of new AO associations and cause burst-pause firing of CINs in the DMS during AO remapping. These adaptive effects were abolished by neuroinflammation in the Pf, resulting in the loss of goal-directed control when the rats were required to update AO associations after a change in contingency. We found that the neuronal and behavioral deficits induced by inflammation in the Pf were rescued by administration of selegiline, a MAO-B inhibitor that we found also enhances ATPase activity in CINs, suggesting a potential treatment for cognitive deficits associated with inflammation affecting the function of midline thalamic nuclei and related structures.
A megaprotein-based molecular bridge critical for lipid trafficking and cold resilience
Authors: Wang Changnan , Wang Bingying , Pandey Taruna , Long Yong , Zhang Jianxiu , Oh Fiona , Sima Jessica , Guo Ruyin , Liu Yun , Zhang Chao , Mukherjee Shaeri , Bassik Michael , Lin Weichun , Deng Huichao , Vale Goncalo , McDonald Jeffrey , Shen Kang , Ma Dengke K. 
Published: August 2022

AbstractCells adapt to cold by increasing levels of unsaturated phospholipids and membrane fluidity through homeostatic mechanisms conserved in nearly all forms of life. As most eukaryotic enzymes for lipid synthesis and desaturation localize on endoplasmic reticulum (ER) membranes, it remains unknown how ER-resident lipids rapidly distribute to plasma membranes (PM). Here we report an exceptionally large and evolutionarily conserved protein LPD-3 in C. elegans that plays critical roles in lipid trafficking and cold resilience. We identified lpd-3 mutants in a mutagenesis screen for genetic suppressors of the lipid desaturase FAT-7, and found that the 452 kDa megaprotein LPD-3 bridges ER and PM, consisting of a structurally predicted hydrophobic tunnel for lipid trafficking. Loss of LPD-3 caused abnormal cellular distribution of phospholipids, diminished FAT-7 abundance, and organismic vulnerability to cold. These phenotypic defects of lpd-3 mutants were rescued by Lecithin comprising unsaturated phospholipids. Importantly, we found that deficient lpd-3 homologues in Zebrafish and mammalian cells led to defects similar to those observed in C. elegans. As mutations in KIAA1109/BLTP1, the human orthologue of lpd-3, cause Alkuraya-Kucinskas syndrome, we propose that the LPD-3 family proteins may serve as evolutionarily conserved “highway bridges” critical for ER-associated non-vesicular trafficking of lipids and resilience to cold stress in eukaryotic cells.
Genetic Association of CSN2 Variant 6:85451298C>A with A1/A2 Milk Phenotype in Pakistani Cows
Authors: Ullah Sibghat , Ahmed Zubair , Karim Asma , Saif Rashid 
Published: August 2022

AbstractThe cow is a very important mammal from the bovine family renowned for providing milk, meat and hide around the globe. β-casein is one of the principal proteins found in cow’s milk encoded by the CSN2 gene with 12-13 reported genetic variants present on Chr.6 in the cow’s genome. The current study investigated A1/A2 associated variant g.6:85451298C>A (rs43703011) in exon 7th according to the GenBank ID: M55158.1 position 8101C>A (c.245C>A), which is responsible to change the 67th amino acid of the β-casein polypeptide from proline (CCT, A2) to histidine (CAT, A1). The milk containing A2 protein variant is good while A1 milk has some negative effects on human health due to the production of β-casmomorphin-7. Genetic screening of the subject variant was conducted using ARMS-PCR on 48 native and exotic cows from Pakistan. Our initial results showed that 37.5% of the population is homozygous wild-type (C/C), 56.25% is heterozygous (C/A) and the remaining 6.25% is homozygous mutant-type (A/A). Additionally, the Chi-square association test was applied using the PLINK data analysis toolset which presented a significant p-value of 2.811×10−3 and OR of 3.8 with an alternative allele frequency of 0.2 and 0.5 in native and exotic populations respectively. Hence, there is significant variability in A1/A2 genotype which may be addressed by adopting selective breeding programs in Pakistan.
Systematic analysis of IL-1 cytokine signaling by high-risk HPV oncoproteins
Authors: Castagnino Paola , Kim Hee Won , Lam Long Kwan Metthew , Basu Devraj , White Elizabeth A. 
Published: August 2022

ABSTRACTHuman papillomavirus (HPV) E6 and E7 oncoproteins are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how E6 and E7 alter the cellular response to the pro-inflammatory cytokine IL-1β. Models of early-stage HPV infection and of established HPV-positive head and neck cancers exhibited similar dysregulation of IL-1 pathway genes and suppressed transcriptional responses to IL-1β treatment. Such overlap in cell responses supports that changes induced by HPV E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1β-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells.IMPORTANCEHuman papillomavirus (HPV) infection is responsible for nearly 5% of the worldwide cancer burden. HPV-positive tumors develop over years to decades in tissues that are subject to frequent stimulation by pro-inflammatory cytokines. However, the effects of HPV oncoproteins on the cellular response to cytokine stimulation are not well defined. We analyzed IL-1 cytokine signaling in several models of HPV biology and disease. We found that HPV16 E6 and E7 oncoproteins mediate a broad and potent suppression of cellular responses to IL-1β in models of both early and late stages of carcinogenesis. Our data provide a resource for future investigation of IL-1 signaling in HPV-positive cells and cancers.
Mortality Improvements in Adult Patients Hospitalised with Community Acquired COVID-19 in Wales From March 2020 to December 2021
Authors: Barry Simon M , Davies Gareth R , Davies Chris R , Lewis Keir E 
Published: August 2022

ABSTRACTBackgroundA COVID-19 hospital guideline was implemented across all acute hospitals in Wales in March 2020, and data was collected across the first 3 Waves of the pandemic. We aimed to observe trends in mortality with a focus on ward-based outcomes.MethodsRetrospective case-note review of data for adults admitted to hospital with community acquired COVID-19 between March 2020 and December 2021Results5887 cases were analysed. Overall mortality from COVID-19 fell from 31.5% in Wave 1 to 22.6% in Wave 2 to 18.8% in Wave 3 (p<0.01). Ward mortality for patients on oxygen fell from 34.6% in Wave 1 to 19.5% in Wave 2 (p<0.01) to 14.3% in Wave 3 (p=0.03). For those managed with CPAP/HFNO on wards, the mortality reduced from 58.9% in Wave 1 to 45.6% in Wave 2 (p=0.05) and further to 42.6% in Wave 3 (p=0.03). The mortality for patients managed with CPAP/HFNO on ICU reduced from 43.8% in Wave 1 to 24.7% in Wave 2 (p=0.12) and further to 20.4% in Wave 3 (p=0.03). Patients receiving CPAP/HFNO on the wards were on average 11 years older and more co-morbid than those on ICU. In Wave 3, 77% of hospital admissions with COVID-19 were unvaccinated with mortality rates of 20.5% compared to 4.8% mortality in those who had received three vaccines (p<0.01).ConclusionsThere were successive reductions in mortality in inpatients over the 3 Waves reflecting new treatments and better management of complications. The impact of vaccines on outcomes of hospitalised patients was notable in Wave 3.Key MessagesWhat is the key question?What are the outcomes from COVID-19 pneumonitis managed on respiratory wards and how have they changed over successive waves of the pandemic?What is the bottom line?Significant improvements in mortality over time were noted in patients requiring oxygen, CPAP or HFNO. Patients managed with these modalities in ICU had lower mortality rates than those on wards, but they were younger and less co-morbid. In wave 3 patients were largely unvaccinated with higher mortality rates than those who were fully vaccinated.Why read on?This is a national study including all acute hospitals in Wales over three waves of the pandemic from March 2020 to December 2021. It is the first paper to demonstrate at a national level the outcomes of ward management of COVID pneumonitis over successive waves.