bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Random Matrix Approach to Single Cell RNA-seq Analysis
Authors: Leviyang Sivan 
Published: July 2023

AbstractSingle cell RNA-seq (scRNAseq) workflows typically start with a raw expression matrix and end with the clustering of sampled cells. Viewed broadly, scRNAseq is a signal processing workflow that takes a transcriptional signal as input and outputs a cell clustering. Currently, we lack a quantitative framework through which to describe the input signal and assess the dependence of correct clustering on the signal properties. As a result, fundamental questions regarding the resolution of scRNAseq remain unanswered and experimentalists have little guidance in determining whether a hypothesized cell type will be clustered by a particular scRNAseq experiment.In this work, we define the notion of a transcriptional signal associated with a gene module, show that the tools of random matrix theory can be used to characterize the signal as it moves through a common (PCA-based) scRNAseq workflow, and develop estimates for cell clustering based on the signal properties and, in particular, the signal strength. We give a formula - that can be computed from expression data - for the signal strength, providing a framework through which scRNAseq resolution can be investigated.
TheDrosophilacardiogenic transcription factors Myocyte enhancer factor-2 and Tinman contribute to heart lumen enlargement through direct activation of the collagen geneMultiplexin
Authors: Lovato TyAnna L. , Ryan Danielle , Bileckyj Cayleen , Johnston Christopher A. , Cripps Richard M. 
Published: July 2023

AbstractDuring embryogenesis, the Drosophila heart forms a lumen, the posterior region of which is increased in diameter and corresponds to the heart proper. To identify the transcriptional control of this morphogenetic process, we analyzed the formation and enlargement of the heart lumen in mutants for the myogenic transcription factor geneMyocyte enhancer factor-2(Mef2). We found thatMef2contributes to both lumen formation and lumen expansion, the latter through a requirement for bothMef2and the cardiogenic genetinman(tin) to activate the collagen geneMultiplexin(Mp). To determine if Tin and MEF2 act directly upon theMpgene, we identified an enhancer whose activity recapitulates the cardiac expression ofMp. This enhancer contains binding sites for both Tin and MEF2 and is activated in tissue culture by MEF2 but not Tin. We did not observe synergistic activation of the enhancer when the factors were in combination, despite documenting a direct physical interaction between Tin and MEF2 in vitro. In vivo, the Tin sites are required for normal enhancer activity, whereas mutation of the MEF2 sites results in expanded expression of an enhancer-lacZreporter, suggesting that transcriptional repression may also contribute to regulation ofMp. Our studies underline how transcription factors must utilize combinatorial interactions to achieve organ-specific and region-specific patterns of gene expression and cell morphogenesis.
Sex peptide receptor is not required for refractoriness to remating or induction of egg laying inAedes aegypti
Authors: Amaro I. Alexandra , Wohl Margot P. , Pitcher Sylvie , Alfonso-Parra Catalina , Avila Frank W. , Paige Andrew S. , Helinski Michelle , Duvall Laura B. , Harrington Laura C. , Wolfner Mariana F. , McMeniman Conor J. 
Published: July 2023

AbstractAcross diverse insect taxa, the behavior and physiology of females dramatically changes after mating – processes largely triggered by the transfer of seminal proteins from their mates. In the vinegar flyDrosophila melanogaster, the seminal protein sex peptide (SP) decreases the likelihood of female flies remating and causes additional behavioral and physiological changes that promote fertility including increasing egg production. Although SP is only found in theDrosophilagenus, its receptor, sex peptide receptor (SPR), is the widely-conserved myoinhibitory peptide (MIP) receptor. To test the functional role of SPR in mediating post-mating responses in a non-Drosophiladipteran, we generated two independentSpr-knockout alleles in the yellow fever mosquitoAedes aegypti. Although SPR is needed for post-mating responses inDrosophilaand the cotton bollwormHelicoverpa armigera,SprmutantAe. aegyptishow completely normal post-mating decreases in remating propensity and increases in egg laying. In addition, injection of synthetic SP or accessory gland homogenate fromD. melanogasterinto virgin female mosquitoes did not elicit these post-mating responses. Our results indicate thatSpris not required for these canonical post-mating responses inAe. aegypti, indicating that unknown signaling pathways are likely responsible for these behavioral switches in this disease vector.
Age-Related Balance Problems in Mice Are Sharpened by the Loss of Calcitonin Gene-Related Peptide (CGRP) and a Vestibular Challenge
Authors: Rahman Shafaqat M. , Hauser Catherine , Luebke Anne E. 
Published: July 2023

AbstractAging impacts the vestibular system and contributes to imbalance. In fact, in the elderly balance deficits often precede changes in cognition. However, imbalance research is limited in assessing aging mouse models that are deficient in neuromodulators like Calcitonin Gene-Related Peptide (CGRP). We studied the loss of CGRP and its effects in the aging mouse, namely its effect on both static and dynamic imbalances. In addition, postural sway and rotarod testing were performed before and after a vestibular challenge (VC) in the 129S wildtype and the αCGRP (−/−) null mice. Four age groups were tested that correspond to young adulthood, late adulthood, middle age, and senescence in humans. Our results suggest wildtype mice experience a decline in rotarod ability with increased age, while the αCGRP (−/−) null mice perform poorly on rotarod early in life and do not improve. Our postural sway study suggests that a vestibular challenge can lead to significantly reduced CoP ellipse areas (freezing behaviors) in older mice, and this change occurs earlier in the αCGRP (−/−) null mouse. These results indicate that αCGRP is an important component of static and dynamic balance; and that the loss of αCGRP can contribute to balance complications that may compound with aging.
The gut microbiome across the cardiovascular risk spectrum
Authors: Prins Femke M. , Collij Valerie , Groot Hilde E. , Björk Johannes R. , Swarte J. Casper , Andreu-Sánchez Sergio , Jansen Bernadien H. , Fu Jingyuan , Harmsen Hermie J.M. , Zhernakova Alexandra , Lipsic Erik , van der Harst Pim , Weersma Rinse K. , Gacesa Ranko 
Published: July 2023

AbstractRationaleDespite significant progress in treatment strategies, cardiovascular disease remains a leading cause of death worldwide. Identifying new potential targets is crucial for enhancing preventive and therapeutic strategies. The gut microbiome has been associated with the development of coronary artery disease (CAD), however our understanding of the precise changes in the gut microbiome occurring during CAD development remains limited.ObjectiveTo investigate microbiome changes in participants without clinically manifest CAD with different cardiovascular risk levels and in patients with ST-elevation myocardial infarction (STEMI).Methods and ResultsIn this cross-sectional study we characterized the gut microbiome using metagenomics of 411 fecal samples from individuals with low (n=130), intermediate (n=130) and high (n=125) cardiovascular risk based on the Framingham score, and STEMI patients (n=26). We analyzed alpha and beta diversity of the gut microbiome and differential abundance of species and functional pathways among the different groups while accounting for confounders including medication and technical covariates.Abundances ofCollinsella stercoris, Flavonifractor plautiiandRuthenibacterium lactatiformansshowed a positive trend with cardiovascular risk, while Streptococcus thermophiluswas negatively associated. Furthermore, in the differential abundance analysis we identified eight species and 49 predicted metabolic pathways that were differently abundant among the groups. These species included species linked to inflammation. Starch biosynthesis and phenolic compound degradation pathways were enriched in the gut microbiome of STEMI patients, while pathways associated with vitamin, lipid and amino-acid biosynthesis were depleted.ConclusionsWe identified four microbial species that demonstrated a gradual trend in their abundance from low risk individuals to those with STEMI, and species and pathways that were differently abundant in STEMI patients compared to groups without clinically manifest CAD. Further investigation is warranted to gain deeper understanding of their precise role in CAD progression and potential implications, with the ultimate goal of identifying novel therapeutic targets.Graphical abstractCreated withBioRender.com
Oscillatory-Quality of sleep spindles: from properties to function
Authors: Blanco-Duque Cristina , Bond Suraya A. , Krone Lukas B. , Dufour Jean-Phillipe , Gillen Edward C.P. , Kahn Martin C. , Purple Ross J. , Bannerman David M. , Mann Edward O. , Achermann Peter , Olbrich Eckehard , Vyazovskiy Vladyslav V. 
Published: July 2023

AbstractSleep spindles are traditionally defined as 10-15Hz thalamo-cortical oscillations typical of NREM sleep. While substantial heterogeneity in the appearance or spatio-temporal dynamics of spindle events is well recognised, the physiological relevance of the underlying fundamental property - the oscillatory strength - has not been studied. Here we introduce a novel metric calledoscillatory Quality(o-Quality), which is derived by fitting an auto-regressive model to short segments of electrophysiological signals, recorded from the cortex in mice, to identify and calculate the damping of spindle oscillations. We find that theo-Qualityof spindles varies markedly across cortical layers and regions and reflects the level of synchrony within and between cortical networks. Furthermore, theo-Qualityof spindles varies as a function of sleep-wake history, determines the strength of coupling between spindles and slow waves, and influences the responsiveness to sensory stimulation during sleep. Thus, theo-Qualityemerges as a metric that, for the first time, directly links the spatio-temporal dynamics of sleep spindles with their functional role.
Uncertainties regarding cerebral palsy diagnosis: opportunities to operationalize the consensus definition
Authors: Aravamuthan Bhooma R , Fehlings Darcy L , Novak Iona , Gross Paul , Alyasiri Noor , Tilton Ann , Shevell Michael , Fahey Michael , Kruer Michael 
Published: July 2023

AbstractBackground and ObjectivesCerebral palsy (CP), the most common motor disability of childhood, is variably diagnosed. We hypothesized that child neurologists and neurodevelopmentalists, often on the frontlines of CP diagnosis in North America, harbor uncertainties regarding the practical application of the most recent CP consensus definition from 2006.MethodsWe conducted a cross-sectional survey of child neurologists and neurodevelopmentalists at the 2022 Child Neurology Society Annual Meeting. Attendees were provided the 2006 CP consensus definition and asked whether they had any uncertainties about the practical application of the definition across four hypothetical clinical vignettes.ResultsOf 230 attendees, 164 responded to the closing survey questions (71%). 145/164 (88%) expressed at least one uncertainty regarding the clinical application of the 2006 definition. Overwhelmingly, these areas of uncertainty focused on: 1) Age, both with regards to the minimum age of diagnosis and the maximum age of brain disturbance or motor symptom onset, (67/164, 41%), and 2) Interpretation of the term “non-progressive” (48/164, 29%). The vast majority of respondents (157/164, 96%) answered ‘Yes’ to the question: Do you think we should revise the 2006 consensus definition of CP?DiscussionWe propose that the uncertainties we identified could be addressed by operationalizing the 2006 consensus definition to support a more uniform CP diagnosis. To address the most common CP diagnostic uncertainties we identified, we propose 3 points of clarification based on the available literature: 1) Motor symptoms/signs should be present by 2 years old; 2) CP can and should be diagnosed as early as possible, even if activity limitation is not yet present, if motor symptoms/signs can be reasonably predicted to yield activity limitation (e.g. by using standardized examination instruments, Brain MRI, and a suggestive clinical history); and 3) The clinical motor disability phenotype should be non-progressive through 5 years old. We anticipate that operationalizing the 2006 definition of CP in this manner could clarify the uncertainties we identified among child neurologists and neurodevelopmentalists and reduce the diagnostic variability that currently exists.
MicroRNA-122-mediated liver detargeting enhances the tissue specificity of cardiac genome editing
Authors: Yang Luzi , Guo Congting , Liu Zhanzhao , Chen Zhan , Sun Yueshen , Hu Xiaomin , Zheng Yanjiang , Li Yifei , Gao Fei , Zhou Pingzhu , Pu William T. , Guo Yuxuan 
Published: July 2023

AbstractBackgroundThe cardiac troponin T (Tnnt2) promoter is broadly utilized for cardiac specific gene expression, particularly via adeno-associated virus (AAV)-based gene transfer. However, these vectors drive lower-level ectopic gene expression in other tissues, most notably in the liver. Whether the AAV-Tnnt2vectors remain tissue-specific in applications sensitive to low or transient gene expression, such as gene editing, remains unclear.MethodsThe tissue specificity of AAV9-Tnnt2vectors was evaluated in mice using Cre-LoxP-based fluorescence reporters and CRISPR/Cas9-mediated somatic mutagenesis. CRISPR/Cas9-triggered AAV integration into host genome was further assessed by quantitative PCR.ResultsIn mice treated with AAV-Tnnt2-GFP, GFP signal was specifically observed in the heart by confocal imaging. However, when AAV-Tnnt2-Cre was administered to mice carrying LoxP-STOP-LoxP fluorescence reporters, the reporter signals were observed in up to 50% hepatic cells. Similarly, the AAV-Tnnt2-SaCas9 vector extensively edited the hepatic genome as measured by targeted amplicon-sequencing. Cas9-triggered AAV integration into the host genome was also validated in the liver. Inclusion of target sequences for microRNA-122, a highly expressed, liver-specific microRNA, in the AAV transgene’s 3’ untranslated region (3’ UTR) markedly reduced ectopic transgene expression, genome editing and AAV integration in the liver.ConclusionsThe heavily used AAV-Tnnt2system exhibits liver leakiness that severely impairs the cardiac specificity of AAV-based genetic manipulation. This problem can be mitigated via miR122-mediated liver detargeting.
Interferons are the key cytokines acting on pancreatic islets in type 1 diabetes
Authors: Coomans de Brachène Alexandra , Alvelos Maria Ines , Szymczak Florian , Zimath Priscila Laiz , Castela Angela , Marmontel de Souza Bianca , Roca Rivada Arturo , Marín-Cañas Sandra , Yi Xiaoyan , Op de Beeck Anne , Morgan Noel G. , Sonntag Sebastian , Jawurek Sayro , Title Alexandra C. , Yesildag Burcak , Pattou François , Kerr-Conte Julie , Montanya Eduard , Nacher Montserrat , Marselli Lorella , Marchetti Piero , Richardson Sarah J. , Eizirik Decio L. 
Published: July 2023

AbstractThe pro-inflammatory cytokines IFNα, IFNγ, IL-1β and TNFα may contribute to innate and adaptive immune responses during islet inflammation (insulitis) in type 1 diabetes (T1D). We used deep RNA-sequencing analysis to characterize the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by T1D. IFNα and IFNγ had a much greater impact on the beta cell transcriptome when compared to IL-1β and TNFα. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from T1D patients, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to “danger signals” such as viral infections. These data suggest that IFNα and IFNγ are the central cytokines at the islet level in T1D, contributing to the triggering and amplification of autoimmunity.
Cranes soar on thermal updrafts behind cold fronts as they migrate across the sea
Authors: Pekarsky Sasha , Shohami David , Horvitz Nir , Bowie Rauri C. K. , Kamath Pauline L. , Markin Yuri , Getz Wayne M. , Nathan Ran 
Published: July 2023

AbstractThermal soaring conditions above the sea have long been assumed absent or too weak for terrestrial migrating birds, forcing large obligate soarers to take long detours and avoid sea crossing, and facultative soarers to cross exclusively by costly flapping flight. Thus, while atmospheric convection does develop at sea and is utilized by some seabirds, it has been largely ignored in avian migration research. Here we provide direct evidence for routine thermal soaring over open sea in the common crane, the heaviest facultative soarer known among terrestrial migrating birds. Using high-resolution biologging from 44 cranes tracked across their transcontinental migration over 4 years, we show that soaring characteristics and performance were no different over sea than over land in mid-latitudes. Sea-soaring occurred predominantly in autumn when large water-air temperature difference followed mid-latitude cyclones. Our findings challenge a fundamental paradigm in avian migration research and suggest that large soaring migrants avoid sea crossing not due to absence or weakness of thermals but due to their uncertainty and the costs of prolonged flapping. Marine cold air outbreaks, imperative to the global energy budget and climate system, may also be important for bird migration, calling for more multidisciplinary research across biological and atmospheric sciences.
Engagement of sialylated glycans with Siglec receptors on myeloid suppressor cells inhibit anti-cancer immunity via CCL2
Authors: Wieboldt Ronja , Carlini Emanuele , Lin Chia-wei , Börsch Anastasiya , Zingg Andreas , Lardinois Didier , Herzig Petra , Don Leyla , Zippelius Alfred , Läubli Heinz , Rodrigues Mantuano Natalia 
Published: July 2023

SummaryOverexpression of sialic acids on glycans, called hypersialylation is a common alteration found in cancer. Hypersialylation can, for example, enhance immune evasion via interaction with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we tested the role of sialic acid on myeloid-derived suppressor cells (MDSCs) and their interaction with Siglec receptors. We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors. In murine cancer models of emergency myelopoiesis, Siglec-E knockout on myeloid cells resulted in prolonged survival and increased infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation led to strong reduction of their suppressive potential. We further identified CCL2 as mediator involved in T cell suppression upon interaction of sialoglycans and Siglec receptors on MDSCs. Our results provide mechanistic insights how sialylated glycans inhibit anti-cancer immunity by facilitating CCL2 expression.Abstract Figure
Mechanical coupling coordinates microtubule growth
Authors: Leeds Bonnibelle K. , Kostello Katelyn F. , Liu Yuna Y. , Nelson Christian R. , Biggins Sue , Asbury Charles L. 
Published: July 2023

AbstractDuring mitosis, kinetochore-attached microtubules form bundles (k-fibers) in which many filaments grow and shorten in near-perfect unison to align and segregate each chromosome. However, individual microtubules grow at intrinsically variable rates, which must be tightly regulated for a k-fiber to behave as a single unit. This exquisite coordination might be achieved biochemically, via selective binding of polymerases and depolymerases, or mechanically, because k-fiber microtubules are coupled through a shared load that influences their growth. Here, we use a novel dual laser trap assay to show that microtubule pairs growingin vitroare coordinated by mechanical coupling. Kinetic analyses show that microtubule growth is interrupted by stochastic, force-dependent pauses and indicate persistent heterogeneity in growth speed during non-pauses. A simple model incorporating both force-dependent pausing and persistent growth speed heterogeneity explains the measured coordination of microtubule pairs without any free fit parameters. Our findings illustrate how microtubule growth may be synchronized during mitosis and provide a basis for modeling k-fiber bundles with three or more microtubules, as found in many eukaryotes.
Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy
Authors: Kaya Hatem Elif Kamber , Ward Madison A. , Vangala Janakiram R. , Byers Holly A. , Diaz Antonio , Kaushik Susmita , Cuervo Ana Maria , Radhakrishnan Senthil K. 
Published: July 2023

ABSTRACTCells exposed to proteotoxic stress invoke adaptive responses aimed at restoring proteostasis. Our previous studies have established a firm role for the transcription factor Nuclear factor erythroid derived 2-related factor 1 (Nrf1, also called NFE2L1) in responding to proteotoxic stress elicited by inhibition of cellular proteasome. Following proteasome inhibition, Nrf1 mediates new proteasome synthesis, thus enabling the cells to mitigate the proteotoxic stress. Here we report that under similar circumstances, multiple components of the autophagy lysosomal pathway (ALP) are transcriptionally upregulated in an Nrf1-dependent fashion, thus providing the cells with an additional route to cope with proteasome insufficiency. In response to proteasome inhibitors, Nrf1-deficient cells displayed profound defects in invoking autophagy and clearance of aggresomes. This phenomenon was also recapitulated in NGLY1 knockout cells (a model for NGLY1 disease) where Nrf1 is known to be non-functional. Overall, our results significantly expand the role of Nrf1 in shaping the cellular response to proteotoxic stress.