bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep duration and brain structure – phenotypic associations and genotypic covariance
Authors: Fjell Anders M. , Sørensen Øystein , Wang Yunpeng , Amlien Inge K. , Baaré William F.C. , Bartrés-Faz David , Bertram Lars , Boraxbekk Carl-Johan , Brandmaier Andreas M. , Demuth Ilja , Drevon Christian A , Ebmeier Klaus P. , Ghisletta Paolo , Kievit Rogier , Kühn Simone , Madsen Kathrine Skak , Mowinckel Athanasia M , Nyberg Lars , Sexton Claire E. , Solé-Padullés Cristina , Vidal-Piñeiro Didac , Wagner Gerd , Watne Leiv Otto , Walhovd Kristine B. 
Published: February 2022

AbstractThe question of how much sleep is best for the brain attracts scientific and public interest, and there is concern that insuficient sleep leads to poorer brain health. However, it is unknown how much sleep is sufficient and how much is too much. We analyzed 51,295 brain magnetic resonnance images from 47,039 participants, and calculated the self-reported sleep duration associated with the largest regional volumes and smallest ventricles relative to intracranial volume (ICV) and thickest cortex. 6.8 hours of sleep was associated with the most favorable brain outcome overall. Critical values, defined by 95% confidence intervals, were 5.7 and 7.9 hours. There was regional variation, with for instance the hippocampus showing largest volume at 6.3 hours. Moderately long sleep (> 8 hours) was more strongly associated with smaller relative volumes, thinner cortex and larger ventricles than even very short sleep (< 5 hours), but effect sizes were modest. People with larger ICV reported longer sleep (7.5 hours), so not correcting for ICV yielded longer durations associated with maximal volume. Controlling for socioeconomic status, body mass index and depression symptoms did not alter the associations. Genetic analyses showed that genes related to longer sleep in short sleepers were related to shorter sleep in long sleepers. This may indicate a genetically controlled homeostatic regulation of sleep duration. Mendelian randomization analyses did not suggest sleep duration to have a causal impact on brain structure in the analyzed datasets. The findings challenge the notion that habitual short sleep is negatively related to brain structure.Significance statementAccording to consensus recommendations, adults should sleep between 7 and 9 hours to optimize their health. We found that sleeping less than the recommended amount was associated with greater regional brain volumes relative to intracranial volume, and very short sleep was only weakly related to smaller volumes. Genetic analyses did not show causal effects of sleep duration on brain structure. Taken together, the results suggest that habitual short sleep is not an important contributor to lower brain volumes in adults on a group level, and that large individual dfferences in sleep need likely exist.
A five-fold expansion of the global RNA virome reveals multiple new clades of RNA bacteriophages
Authors: Neri Uri , Wolf Yuri I. , Roux Simon , Camargo Antonio Pedro , Lee Benjamin , Kazlauskas Darius , Chen I. Min , Ivanova Natalia , Allen Lisa Zeigler , Paez-Espino David , Bryant Donald A. , Bhaya Devaki ,   RNA Virus Discovery Consortium, Krupovic Mart , Dolja Valerian V. , Kyrpides Nikos C. , Koonin Eugene V. , Gophna Uri 
Published: February 2022

SummaryHigh-throughput RNA sequencing offers unprecedented opportunities to explore the Earth RNA virome. Mining 5,150 diverse metatranscriptomes uncovered >2.5 million RNA viral contigs. Via analysis of the 330k novel RNA-dependent RNA polymerases (RdRP), this expansion corresponds to a five-fold increase of RNA virus diversity. Extended RdRP phylogeny supports monophyly of the five established phyla, reveals two putative new bacteriophage phyla and numerous putative novel classes and orders. The dramatically expandedLenarviricotaphylum, consisting of bacterial and related eukaryotic viruses, now accounts for a third of the RNA virome diversity. Identification of CRISPR spacer matches and bacteriolytic proteins suggests that subsets of picobirnaviruses and partitiviruses, previously associated with eukaryotes, infect prokaryotic hosts. Gene content analysis revealed multiple domains previously not found in RNA viruses and implicated in virus-host interactions. This vast collection of new RNA virus genomes provides insights into RNA virus evolution and should become a major resource for RNA virology.
Mathematical model of a cytokine storm
Authors: Kareva Irina , Berezovskaya Faina , Karev Georgy 
Published: February 2022

AbstractCytokine storm is a life-threatening inflammatory response that is characterized by hyperactivation of the immune system, and which can be caused by various therapies, auto-immune conditions, or pathogens, such as respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease COVID-19. While initial causes of cytokine storms can vary, late-stage clinical manifestations of cytokine storm converge and often overlap, and therefore a better understanding of how normal immune response turns pathological is warranted. Here we propose a theoretical framework, where cytokine storm phenomenology is captured using a conceptual mathematical model, where cytokines can both activate and regulate the immune system. We simulate normal immune response to infection, and through variation of system parameters identify conditions where, within the frameworks of this model, cytokine storm can arise. We demonstrate that cytokine storm is a transitional regime, and identify three main factors that must converge to result in storm-like dynamics, two of which represent individual-specific characteristics, thereby providing a possible explanation for why some people develop CRS, while others may not. We also discuss possible ecological insights into cytokine-immune interactions and provide mathematical analysis for the underlying regimes. We conclude with a discussion of how results of this analysis can be used in future research.
A network of cytosolic (co)chaperones promotes the biogenesis of mitochondrial signal-anchored outer membrane proteins
Authors: Drwesh Layla , Heim Benjamin , Graf Max , Kehr Linda , Hansen-Palmus Lea , Franz-Wachtel Mirita , Macek Boris , Kalbacher Hubert , Buchner Johannes , Rapaport Doron 
Published: February 2022

AbstractSignal-anchored (SA) proteins are anchored into the mitochondrial outer membrane (OM) via a single transmembrane segment at their N-terminus while the bulk of the proteins is facing the cytosol. These proteins are encoded by nuclear DNA, translated on cytosolic ribosomes, and are then targeted to the organelle and inserted into its OM by import factors. Recently, research on the insertion mechanisms of these proteins into the mitochondrial OM have gained a lot of attention. In contrast, the early cytosolic steps of their biogenesis are unresolved. Using various proteins from this category and a broad set of in vivo, in organello, and in vitro assays, we reconstituted the early steps of their biogenesis. We identified a subset of molecular (co)chaperones that interact with newly synthesized SA proteins, namely, Hsp70 and Hsp90 chaperones and co-chaperones from the Hsp40 family like Ydj1 and Sis1. These interactions were mediated by the hydrophobic transmembrane segments of the SA proteins. We further demonstrate that interfering with these interactions inhibits the biogenesis of SA proteins to varying extents. Finally, we could demonstrate direct interaction of peptides corresponding to the transmembrane segments of SA proteins with the (co)chaperones and reconstitute in vitro the transfer of such peptides from the Hsp70 chaperone to the mitochondrial Tom70 receptor. Collectively, this study unravels an array of cytosolic chaperones and mitochondrial import factors that facilitates the targeting and membrane integration of mitochondrial SA proteins.
Single-nucleus transcriptomic analysis reveals divergence of glial cells in peripheral somatosensory system between human and mouse
Authors: Zhang Donghang , Wei Yiyong , Liu Jin , Yang Yaoxin , Ou Mengchan , Chen Yali , Shen Jiefei , Zhu Tao , Zhou Cheng 
Published: February 2022

AbstractGlial cells play a crucial role in regulating physiological and pathological functions, such as sensation, infections, acute injuries, and chronic neurodegenerative disorders. Glial cells include astrocytes, microglia, and oligodendrocytes in the central nervous system (CNS) and satellite glial cells (SGCs) in the peripheral nervous system (PNS). Despite the understanding of glial subtypes and functional heterogeneity in animal models achieved by single-cell or single-nucleus RNA sequencing, no research has investigated the transcriptomic profiles of glial cells in the human PNS and spinal cord. Here, we used high-throughput single-nucleus RNA sequencing to map the cellular and molecular heterogeneity of SGCs in the human dorsal root ganglion (DRG) and astrocytes, microglia, and oligodendrocytes in the human spinal cord. To explore the conservation and divergence across species, we compared these human findings with those from mice. Additionally, the expression profiles of risk genes of common DRG and spinal cord diseases in glial cells were compared between humans and mice. As a result, little SGCs heterogeneity was found in both human and mouse DRG. In the human spinal cord, astrocytes, microglia, and oligodendrocytes were respectively divided into six distinct transcriptomic subclusters. In the mouse spinal cord, astrocytes, microglia, and oligodendrocytes were divided into six, five, and six distinct transcriptomic subclusters, respectively. The comparative results revealed substantial heterogeneity in all glial cells between humans and mice. Notably, we also identified transcriptomic heterogeneity in several classical genes and risk genes for neurological disorders across humans and mice. Together, the present data comprehensively profiled glial cell heterogeneity and provides a powerful resource for investigating the cellular basis of glial-related physiological and pathological conditions in peripheral somatosensory system.
Creating De Novo Overlapped Genes
Authors: Logel Dominic Y. , Jaschke Paul R. 
Published: February 2022

AbstractFuture applications of synthetic biology will rely on deploying engineered cells outside of lab environments for long periods of time. Currently, a significant roadblock to this application is the potential for deactivating mutations in engineered genes. A recently developed method to protect engineered coding sequences from mutation is called Constraining Adaptive Mutations using Engineered Overlapping Sequences (CAMEOS). In this chapter we provide a workflow for utilising CAMEOS to create synthetic overlaps between two genes, one essential (infA) and one non-essential (aroB), to protect the non-essential gene from mutation and loss of protein function. In this workflow we detail the methods to collect large numbers of related protein sequences, produce multiple sequence alignments (MSAs), use the MSAs to generate Hidden Markov Models and Markov Random Field models, and finally generate a library of overlapping coding sequences through CAMEOS scripts. To assist practitioners with basic coding skills to try out the CAMEOS method, we have created a virtual machine containing all the required packages already installed, that can be downloaded and run locally.
Systematic analysis and prediction of genes associated with disorders on chromosome X
Authors: Leitão Elsa , Schröder Christopher , Parenti Ilaria , Dalle Carine , Rastetter Agnès , Kühnel Theresa , Kuechler Alma , Kaya Sabine , Gérard Bénédicte , Schaefer Elise , Nava Caroline , Drouot Nathalie , Engel Camille , Piard Juliette , Duban-Bedu Bénédicte , Villard Laurent , Stegmann Alexander P.A. , Vanhoutte Els K. , Verdonshot Job A.J , Kaiser Frank J. , Mau-Them Frédéric Tran , Scala Marcello , Striano Pasquale , Frints Suzanna G.M. , Argilli Emanuela , Sherr Elliott H. , Elder Fikret , Buratti Julien , Keren Boris , Mignot Cyril , Héron Delphine , Mandel Jean-Louis , Gecz Jozef , Kalscheuer Vera M. , Horsthemke Bernhard , Piton Amélie , Depienne Christel 
Published: February 2022

AbstractDisease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using a neural network trained to distinguish disease-associated from dispensable genes, we classify 235 genes, including 121 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.
Glycemic variability and all-cause mortality in a large prospective southern European cohort of patients with differences in glycemic status
Authors: Salinero-Fort Miguel A. , San Andrés-Rebollo F. Javier , Cárdenas-Valladolid Juan , Mostaza José M. , Lahoz Carlos , Rodriguez-Artalejo Fernando , Gómez-Campelo Paloma , Vich-Pérez Pilar , Jiménez-García Rodrigo , López de Andrés Ana , de Miguel-Yanes José M. 
Published: February 2022

AbstractBackgroundFew studies have analyzed the relationship between glucose variability (GV) and adverse health outcomes in patients with differences in glycemic status. The present study tests the hypothesis that GV predicts all-cause mortality regardless of glycemic status after simple (age and sex) and full adjustment (age, sex, cardiovascular disease, hypertension, use of aspirin, statins, GLP-1 receptor agonists, SGLT-2 inhibitors and DPP-4 inhibitors, baseline FPG and average HbA1c).MethodsProspective cohort study with 795 normoglycemic patients, 233 patients with prediabetes, and 4,102 patients with type 2 diabetes. GV was measured using the coefficient of variation of fasting plasma glucose (CV-FPG) over 12 years of follow-up. The outcome measure was all-cause mortality.ResultsA total of 1,223 patients (657 men, 566 women) died after a median of 9.8 years of follow-up, with an all-cause mortality rate of 23.35/1,000 person-years. In prediabetes or T2DM patients, the fourth quartile of CV-FPG exerted a significant effect on all-cause mortality after simple and full adjustment. A sensitivity analysis excluding participants who died during the first year of follow-up revealed the following results for the highest quartile in the fully adjusted model: overall, HR (95%CI) =1.54 (1.26-1.89); dysglycemia (prediabetes and T2DM), HR=1.41 (1.15-1.73); T2DM, HR=1.36 (1.10-1.67).ConclusionWe found CV-FPG to be useful for measurement of GV. It could also be used for the prognostic stratification of patients with dysglycemia.
Ingestible capsule for detecting labile inflammatory biomarkers in situ
Authors: Inda ME , Jimenez M , Liu Q , Phan NV , Ahn J , Steiger C , Wentworth A , Riaz A , Zirtiloglu T , Wong K , Ishida K , Fabian N , Jenkins J , Kuosmanen J , Madani W , McNally R , Lai Y , Hayward A , Mimee M , Nadeau P , Chandrakasan AP , Traverso G , Yazicigil RT , Lu TK 
Published: February 2022

ABSTRACTTransient molecules in the gastrointestinal (GI) tract, such as nitric oxide and hydrogen sulfide, are key signals and mediators of inflammatory bowel disease (IBD). Because these molecules are extremely short-lived in the body, they are difficult to detect. To track these reactive molecules in the GI tract, we have developed a miniaturized device that integrates genetically-engineered probiotic biosensors with a custom-designed photodetector and readout chip. Leveraging the molecular specificity of living sensors, we genetically encoded bacteria to respond to IBD-associated molecules by luminescing. Low-power electronic readout circuits (nanowatt power) integrated into the device convert the light from just 1 μL of bacterial culture into a wireless signal. We demonstrate biosensor monitoring in the GI tract of small and large animal models and integration of all components into a sub-1.4 cm3ingestible form factor capable of supporting wireless communication. The wireless detection of short-lived, disease-associated molecules could support earlier diagnosis of disease than is currently possible, more accurate tracking of disease progression, and more timely communication between patient and their care team supporting remote personalized care.
Antigen-dependent inducible T cell reporter system for PET imaging of breast cancer and glioblastoma
Authors: Shin Jaehoon , Parker Matthew F. L. , Zhu Iowis , Alanizi Aryn , Rodriguez Carlos I. , Liu Raymond , Watchmaker Payal B. , Kalita Mausam , Blecha Joseph , Luu Justin , Wright Brian , Lapi Suzanne E. , Flavell Robert R. , Okada Hideho , Tlsty Thea D. , Roybal Kole T. , Wilson David M. 
Published: February 2022

AbstractFor the past several decades, chimeric antigen receptor T cell (CAR T) therapies have shown promise in the treatment of cancers. These treatments would greatly benefit from companion imaging biomarkers to follow the trafficking of T cells in vivo. Using synthetic biology, we engineered T cells with a chimeric receptor SyNthetic Intramembrane Proteolysis Receptor (SNIPR) that induces overexpression of an exogenous reporter gene cassette upon recognition of specific tumor markers. We then applied a SNIPR-based positron emission tomography (PET) reporter system to two cancer-relevant antigens, human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor variant III (EGFRvIII), commonly expressed in breast and glial tumors respectively. Antigen-specific reporter induction of the SNIPR-PET T cells was confirmed in vitro using GFP fluorescence, luciferase luminescence, and the HSV-TK PET reporter with [18F]FHBG. T cells associated with their target antigens were successfully imaged using PET in dual xenograft HER2+/HER2- and EGFRvIII+/EGFRvIII-animal models, with > 10-fold higher [18F]FHBG signals seen in antigen-expressing tumors versus the corresponding controls. The main innovation described is therefore PET detection of T cells via specific antigen-induced signals, in contrast to reporter systems relying on constitutive gene expression.
Hypothalamic astrocytes control systemic glucose metabolism and energy balance via regulation of extra-synaptic glutamate signaling
Authors: Chao Daniela Herrera Moro , Kirchner Matthew K , Pham Cuong , Foppen Ewout , Denis Raphael GP , Castel Julien , Morel Chloe , Montalban Enrica , Hassouna Rim , Bui Linh-Chi , Renault Justine , Mouffle Christine , García-Cáceres Cristina , Tschöp Matthias H. , Li Dongdong , Martin Claire , Stern Javier E , Luquet Serge H 
Published: February 2022

SummaryThe hypothalamus is key in the control of energy balance. However, to this day strategies targeting hypothalamic neurons failed to provide viable option to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here we show that obesity promotes anatomically restricted remodeling of hypothalamic astrocyte activity. In the paraventricular nucleus (PVN) of the hypothalamus, chemogenetic manipulation of astrocytes results in bidirectional control of neighboring neuron activity, autonomic outflow, glucose metabolism and energy balance. Such process recruits a mechanism involving the astrocytic control of ambient glutamate levels, which becomes defective in obesity. Positive or negative chemogenetic manipulation of PVN astrocyte Ca2+ signals respectively worsen or improves metabolic status of diet-induced obese mice. Collectively, these findings highlight a yet unappreciated role for astrocyte in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy.
Clustered transposon insertion via formation of chromatin loops
Authors: Prizak Roshan , Hilbert Lennart 
Published: February 2022

Transposons, which are DNA sequences that can move to new positions in the genome, make up a large fraction of eukaryotic genomes and occur in clusters. The insertion of transposons into the genome is hindered by compact folding of chromatin, supposedly preventing aberrant or even pathogenic insertion. Chromatin can, however, be decompacted as a consequence of transposon insertion, leading to increased accessibility and, in consequence, further insertions. While these observations suggest a positive feedback between chromatin unfolding and transposon insertion, how such a feedback might contribute to clustered transposon insertion remains poorly understood. In this study, we analyze polymer models of a self-interacting chromatin domain that unfolds as increasing numbers of transposons are inserted and block the self-interaction. On the one hand, we find that, if additional transposons are inserted adjacently to already inserted transposons, the unfolding of the chromatin domain changes from a sharp globule-coil transition to a more gradual extension of loops from a core that remains folded. On the other hand, we find that adjacent transposon insertion emerges either when transposases are excluded from densely packed chromatin, or when transposon insertion proceeds very quickly in relation to the thermal equilibration of polymer configurations. We thus derive from our model physical conditions for clustered transposon insertion and the resulting spatial compartmentalization of chromatin. An according role was recently suggested for LINE-1 and Alu repeats, which occur in clusters and drive the mesoscopic compartmentalization of the mammalian genome.Significance StatementA large part of the genome is composed of repetitive sequences, so-called transposons. Transposons are involved in important processes, such as early embryonic development or control over which genes are used by the cell. Transposons frequently occur in clusters, where many similar sequence motifs are grouped together. Recent studies suggest that the insertion of transposons can result in local unfolding of the genome, favoring insertion of yet more transposons. Our work simulates a simplified region of the genome and transposases, which are the molecules that insert transposons into the genome. Surprisingly, large and fast-acting transposases favor the formation of distinct loops that contain most of the inserted transposons, providing a potential explanation for the clustered insertion of transposons.