bluuebunny/crossref_metadata_2025_split huggingface dataset:
USING PHYLOGENETICS TO INFER HIV-1 TRANSMISSION DIRECTION BETWEEN KNOWN TRANSMISSION PAIRS
Authors: Villabona-Arenas Christian Julian , Hué Stéphane , Baxter James A. C. , Hall Matthew , Lythgoe Katrina A. , Bradley John , Atkins Katherine E. 
Published: May 2021

AbstractInferring the transmission direction between linked individuals living with HIV provides unparalleled power to understand the epidemiology that determines transmission. Phylogenetic ancestral state reconstruction approaches infer the transmission direction by identifying the individual in whom the most recent common ancestor of the virus populations originated. However, these methods vary in their accuracy but it is unclear why. To evaluate the performance of phylogenetic ancestral state reconstruction, we inferred the transmission direction for 112 HIV transmission pairs where transmission direction was known and detailed additional information was available. We then fit a statistical model to evaluate the extent to which epidemiological, sampling, genetic and phylogenetic factors influenced the outcome of the inference. We repeated the analysis under real-life conditions with only routinely-collected data. We found that the inference of transmission direction depends principally on the topology class and branch length characteristics of the phylogeny. Under real-life conditions, the probability of identifying the correct transmission direction increases from 52%—when a monophyletic-monophyletic or paraphyletic-polyphyletic tree topology is observed, when the sample size in both partners is small and when the tip closest to the root does not agree with the state at the root—to 93% when a paraphyletic-monophyletic topology is observed, when the sample size is large and when the tip closest to the root agrees with root state. Our results suggest that discordance between previous studies in inferring the transmission direction can be explained by differences in key phylogenetic properties that arise due to different evolutionary, epidemiological and sampling processes.Significance StatementIdentifying the direction of infectious disease transmission between individuals provides unparalleled power to understand infectious disease epidemiology. With epidemiological and clinical information typically unable to distinguish the direction, phylogenetic analysis of pathogen sequence data is an alternative approach. However, when these phylogenetic methods have been implemented, their accuracy is highly variable, and the reasons for this discordance is unknown. Here we analyse sequence data from over 100 pairs of individuals for whom both the direction of transmission of HIV is known and detailed epidemiological and sampling information is available. We find that easily quantifiable phylogenetic characteristics discriminate whether a phylogenetically-inferred transmission direction is correct. Our analysis highlights that phylogenetic approaches are unsuitable for individual-level analysis such as forensic investigations.
Occupation and COVID-19 mortality in England: a national linked data study of 14.3 million adults
Authors: Nafilyan Vahé , Pawelek Piotr , Ayoubkhani Dan , Rhodes Sarah , Pembrey Lucy , Matz Melissa , Coleman Michel P , Allemani Claudia , Windsor-Shellard Ben , van Tongeren Martie , Pearce Neil 
Published: May 2021

AbstractObjectiveTo estimate occupational differences in COVID-19 mortality, and test whether these are confounded by factors, such as regional differences, ethnicity and education or due to non-workplace factors, such as deprivation or pre-pandemic health.DesignRetrospective cohort studySettingPeople living in private households EnglandParticipants14,295,900 people aged 40-64 years (mean age 52 years, 51% female) who were alive on 24 January 2020, living in private households in England in 2019, were employed in 2011, and completed the 2011 census.Main outcome measuresCOVID-19 related death, assessed between 24 January 2020 and 28 December 2020. We estimated age-standardised mortality rates per 100,000 person-years at risk (ASMR) stratified by sex and occupations. To estimate the effect of occupation due to work-related exposures, we used Cox proportional hazard models to adjust for confounding (region, ethnicity, education), as well as non-workplace factors that are related to occupation.ResultsThere is wide variation between occupations in COVID-19 mortality. Several occupations, particularly those involving contact with patients or the public, show three-fold or four-fold risks. These elevated risks were greatly attenuated after adjustment for confounding and mediating non-workplace factors. For example, the hazard ratio (HR) for men working as taxi and cab drivers or chauffeurs changed from 4.60 [95%CI 3.62-5.84] to 1.47 [1.14-1.89] after adjustment. More generally, the overall HR for men working in essential occupations compared with men in non-essential occupations changed from 1.45 [1.34 - 1.56] to 1.22 [1.13 - 1.32] after adjustment. For most occupations, confounding and other mediating factors explained about 70% to 80% of the age-adjusted hazard ratios.ConclusionsWorking conditions are likely to play a role in COVID-19 mortality, particularly in occupations involving contact with COVID-19 patients or the public. However, there is also a substantial contribution from non-workplace factors, including regional factors, socio-demographic factors, and pre-pandemic health.
Chromatin state barriers enforce an irreversible mammalian cell fate decision
Authors: Blanco M. Andrés , Sykes David B. , Gu Lei , Wu Mengjun , Petroni Ricardo , Karnik Rahul , Wawer Mathias , Rico Joshua , Li Haitao , Jacobus William D. , Jambhekar Ashwini , Cheloufi Sihem , Meissner Alexander , Hochedlinger Konrad , Scadden David T. , Shi Yang 
Published: May 2021

SummaryStem and progenitor cells have the capacity to balance self-renewal and differentiation. Hematopoietic myeloid progenitors replenish more than 25 billion terminally differentiated neutrophils every day under homeostatic conditions and can increase this output in response to stress or infection. At what point along the spectrum of maturation do progenitors lose capacity for self-renewal and become irreversibly committed to differentiation? Using a system of conditional myeloid development that can be toggled between self-renewal and differentiation, we interrogated determinants of this ‘point of no return’ in differentiation commitment. Irreversible commitment is due primarily to loss of open regulatory site access and disruption of a positive feedback transcription factor activation loop. Restoration of the transcription factor feedback loop extends the window of cell plasticity and alters the point of no return. These findings demonstrate how the chromatin state enforces and perpetuates cell fate and identifies potential avenues for manipulating cell identity.HighlightsThere exists a point of irreversible commitment in granulocytic differentiationChromatin state dynamics establish the transition from self-renewal to differentiation commitmentReduced chromatin accessibility underlies an irreversible loss of regulatory site accessRestoration of a transcription factor feedback loop alters the differentiation commitment point
Sortilin exhibits tumor suppressor-like activity by limiting EGFR transducing function
Authors: Lapeyronnie E. , Granet C. , Tricard J. , Gallet F. , Yassine M. , Chermat A. , Jauberteau MO , Bertin F. , Melloni B. , Vincent F. , Naves T. , Lalloué F. 
Published: May 2021

SUMMARYLung cancer is the leading cause of cancer deaths worldwide and remains one of the most incurable. Tyrosine kinase receptors, such as the epidermal growth factor receptor (EGFR), are often aberrantly activated and drive tumor growth. Monotherapy with tyrosine kinase inhibitors to deactivate EGFR has shown initial efficacy, but their benefits tend to decline over time. EGFR acts as a transcriptional factor promoting the expression of co-oncogenic drivers, which, in turn, interact with canonical EGFR mutations to induce therapeutic relapse. This study reports that sortilin, a crucial regulator of cytoplasmic EGFR, attenuates its transducing function. Genome-wide chromatin binding revealed that sortilin interacts with gene regulatory elements occupied by EGFR. These results suggest a model, in which sortilin exhibits potential tumor suppressor-like activity by concurrently binding to regulatory elements of cMYC. Sortilin expression in lung adenocarcinoma may be predictive of the efficacy of anti-EGFR strategies.
Dynamic optimization reveals alveolar epithelial cells as key mediators of host defense in invasive aspergillosis
Authors: Ewald Jan , Rivieccio Flora , Radosa Lukáš , Schuster Stefan , Brakhage Axel A. , Kaleta Christoph 
Published: May 2021

AbstractAspergillus fumigatusis an important human fungal pathogen and its conidia are constantly inhaled by humans. In immunocompromised individuals, conidia can grow out as hyphae that damage lung epithelium. The resulting invasive aspergillosis is associated with devastating mortality rates. Since infection is a race between the innate immune system and the outgrowth ofA. fumigatusconidia, we use dynamic optimization to obtain insight into the recruitment and depletion of alveolar macrophages and neutrophils. Using this model, we obtain key insights into major determinants of infection outcome on host and pathogen side. On the pathogen side, we predictin silicoand confirmin vitrothat germination speed is a key virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. On the host side, we find that epithelial cells play a so far underappreciated role in fungal clearance and are potent mediators of cytokine release which we confirmex vivo. Further, our model affirms the importance of neutrophils in invasive aspergillosis and underlines that the role of macrophages remains elusive. We expect that our model will contribute to improvement of treatment protocols by focusing on the critical components of immune response to fungi but also fungal virulence.
Reverting the mode of action of the mitochondrial FOF1-ATPase by Legionella pneumophila preserves its replication niche
Authors: Escoll Pedro , Platon Lucien , Dramé Mariatou , Sahr Tobias , Schmidt Silke , Rusniok Christophe , Buchrieser Carmen 
Published: May 2021

ABSTRACTLegionella pneumophila, the causative agent of Legionnaires’ disease, a severe pneumonia, injects via a type-IV-secretion-system (T4SS) more than 300 proteins into macrophages, its main host cell in humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing mitochondrial oxidative phosphorylation (OXPHOS) early after infection. Here we show that despite reduced OXPHOS, the mitochondrial membrane potential (Δψm) is maintained during infection of primary human monocyte-derived macrophages (hMDMs). We reveal that L. pneumophila reverses the ATP-synthase activity of the mitochondrial FOF1-ATPase to ATP-hydrolase activity in a T4SS-dependent manner, which leads to a conservation of the Δψm, preserves mitochondrial polarization and prevents macrophage cell death. Analyses of T4SS effectors known to target mitochondrial functions revealed that LpSpl is partially involved in conserving the Δψm, but not LncP and MitF. The inhibition of the L. pneumophila-induced “reverse mode” of the FOF1-ATPase collapsed the Δψm and caused cell death in infected cells. Single-cell analyses suggested that bacterial replication occurs preferentially in hMDMs that conserved the Δψm and showed delayed cell death. This direct manipulation of the mode of activity of the FOF1-ATPase is a newly identified feature of L. pneumophila allowing to delay host cell death and thereby to preserve the bacterial replication niche during infection.
Wnt signaling mediates acquisition of blood-brain barrier properties in naïve endothelium derived from human pluripotent stem cells
Authors: Gastfriend Benjamin D. , Nishihara Hideaki , Canfield Scott G. , Foreman Koji L. , Engelhardt Britta , Palecek Sean P. , Shusta Eric V. 
Published: May 2021

ABSTRACTEndothelial cells (ECs) in the central nervous system (CNS) acquire their specialized blood-brain barrier (BBB) properties in response to extrinsic signals, with Wnt/β-catenin signaling coordinating multiple aspects of this process. Our knowledge of CNS EC development has been advanced largely by animal models, and human pluripotent stem cells (hPSCs) offer the opportunity to examine BBB development in anin vitrohuman system. Here we show that activation of Wnt signaling in hPSC-derived naïve endothelial progenitors, but not in matured ECs, leads to robust acquisition of canonical BBB phenotypes including expression of GLUT-1, increased claudin-5, and decreased PLVAP. RNA-seq revealed a transcriptome profile resembling ECs with CNS-like characteristics, including Wnt-upregulated expression ofLEF1,APCDD1, andZIC3. Together, our work defines effects of Wnt activation in naïve ECs and establishes an improved hPSC-based model for interrogation of CNS barriergenesis.
Membrane phase separation drives organization at B cell receptor clusters
Authors: Shelby Sarah A. , Castello-Serrano Ivan , Wisser Kathleen C. , Levental Ilya , Veatch Sarah L. 
Published: May 2021

SUMMARYHeterogeneity in intact cell plasma membranes has been explained by analogy to coexisting liquid-ordered and liquid-disordered phases, although models based on this idea fall short of describing the rich structure within cell membranes. Here, a new framework of lipid-driven plasma membrane heterogeneity is presented, drawing on quantitative measurements of protein partitioning and dynamics within B cell receptor clusters in live B lymphocyte plasma membranes, compared to coexisting phases in isolated plasma membranes. We propose that membrane domains in cells integrate the thermodynamic state of the membrane and the magnitude of the applied stimulus to give rise to a tunable response. This framework is supported through functional observations of B cell receptor phosphorylation in perturbed systems.
Sperm cryopreservation impacts the early development of equine embryos by downregulating specific transcription factors
Authors: Ortiz-Rodríguez José M , Martín-Cano FE Francisco E. , Gaitskell-Phillips Gemma , Barrientos A Álvarez , Rodríguez-Martínez Heriberto , Gil Maria C. , Ortega-Ferrusola C , Peña Fernando J. 
Published: May 2021

ABSTRACTEquine embryos were obtained by insemination with either fresh or frozen-thawed spermatozoa at 8, 10 and 12 h post spontaneous ovulation, maintaining the pairs mare-stallion for the type of semen used. Next generation sequencing (NGS) was performed in all embryos and bioinformatic and enrichment analysis performed on the 21,058 identified transcripts. A total of 165 transcripts were downregulated in embryos obtained with cryopreserved spermatozoa respect embryos resulting from an insemination with fresh spermatozoa (p=0.021, q=0.1). The enrichment analysis using human orthologs using g:profiler on the downregulated transcripts marked an enrichment in transcription factors (TFs) in mRNAs downregulated in embryos obtained after insemination with cryopreserved spermatozoa. The 12 mRNAs (discriminant variables) most significantly downregulated in these embryos included among others, the chromatin-remodeling ATPase INO80, Lipase maturation factor 1 LMF1, the mitochondrial mRNA pseudouridine synthase RPUSD3, LIM and cysteine-rich domains protein 1, LMCD1. Sperm cryopreservation also caused a significant impact on the embryos at 8 to 10 days of development, but especially in the transition from 10 to 12 days. Overall, our findings provide strong evidence that insemination with cryopreserved spermatozoa poses a major impact in embryo development that may compromise its growth and viability, probably due to modifications in sperm proteins induced by cryopreservation. Identification of specific factors in the spermatozoa causing these changes may improve cryopreservation.
Evaluation of BOLD effects in the rat cortex
Authors: Just Nathalie 
Published: May 2021

AbstractPurposeThis study aimed to characterize Blood oxygen level-dependent (BOLD) effects in1H-MR spectra obtained during optogenetic activation of the rat forelimb cortex for the correction and estimation of accurate metabolite concentration changes.MethodsT2*-induced effects were characterized by linewidth changes and amplitude changes of water, NAA and tCr spectral peaks during the stimulation paradigm. Spectral linewidth-matching procedures were used to correct for the line-narrowing effect induced by BOLD. For an increased understanding of spectroscopic BOLD effects and the optimized way to correct them, a 1 Hz line-narrowing effect was also simulated on mouseproton MR spectrum1H-fMRS data acquired using STEAM acquisitions at 9.4T in rats (n=8) upon optogenetic stimulation of the primary somatosensory cortex were used. Data were analyzed with MATLAB routines and LCModel. Uncorrected and corrected1H-MR spectra of simulated and in-vivo data were quantified and compared. BOLD-corrected difference spectra were also calculated and analyzed.ResultsSignificant mean increases in water and NAA peak heights (+ 1.1% and +4.5%, respectively) were found accompanied by decreased linewidths (−0.5 Hz and −2.8%) upon optogenetic stimulation. These estimates were used for further definition of an accurate line-broadening factor (lb). Usage of an erroneous lb introduced false-positive errors in metabolite concentration change estimates thereby altering the specificity of findings. Using different water scalings within LCModel, the water and metabolite BOLD contributions were separated.ConclusionThe linewidth-matching procedure using a precise lb factor remains the most performant approach for the accurate quantification of small (±0.3 μmol/g) metabolic changes in1H-fMRS studies. A simple and preliminary compartmentation of BOLD effects was proposed, which will require validation.
All-atom Simulations Uncover the Molecular Terms of NKCC1 Transport Mechanism
Authors: Janoš Pavel , Magistrato Alessandra 
Published: May 2021

AbstractThe secondary-active Na-K-Cl Cotransporter 1 (NKCC1), member of the Cation Chloride Cotransporters (CCC) family, ensures the electroneutral movement of Cl-, Na+, K+ ions across cellular membranes. NKCC1 regulates Cl- homeostasis and cell volume, handling a pivotal role in transepithelial water transport and neuronal excitability. Aberrant NKCC1 transport is hence implicated in a variety of human diseases (hypertension, renal disorders, neuropathies, cancer). Building on the newly-resolved NKCC1 cryo-EM structure, all-atom enhanced sampling simulations unprecedentedly unlock the mechanism of NKCC1-mediated ions transport, assessing the order and the molecular basis of its interdependent ions translocation. Our outcomes strikingly advance the understanding of the physiological mechanism of CCCs transporters and disclose a key role of CCC-conserved asparagine residues, whose side-chain promiscuity ensures the transport of both negatively and positively charged ions along the same translocation route. This study sets a conceptual basis to devise NKCC-selective inhibitors to treat diseases linked to Cl- dishomeostasis.Abstract Figure
Wiring logic of the early rodent olfactory system revealed by high-throughput sequencing of single neuron projections
Authors: Chen Yushu , Chen Xiaoyin , Baserdem Batuhan , Zhan Huiqing , Li Yan , Davis Martin B. , Kebschull Justus M. , Zador Anthony M. , Koulakov Alexei A. , Albeanu Dinu F. 
Published: May 2021

AbstractThe structure of neuronal connectivity often provides insights into the relevant stimulus features, such as spatial location, orientation, sound frequency, etc1–6. The olfactory system, however, appears to lack structured connectivity as suggested by reports of broad and distributed connections both from the olfactory bulb to the piriform cortex7–22 and within the cortex23–25. These studies have inspired computational models of circuit function that rely on random connectivity26–33. It remains, nonetheless, unclear whether the olfactory connectivity contains spatial structure. Here, we use high throughput anatomical methods (MAPseq and BARseq)34–38 to analyze the projections of 5,309 bulb and 30,433 piriform cortex output neurons in the mouse at single-cell resolution. We identify previously unrecognized spatial organization in connectivity along the anterior-posterior axis (A-P) of the piriform cortex. We find that both the bulb projections to the cortex and the cortical outputs are not random, but rather form gradients along the A-P axis. Strikingly, these gradients are matched: bulb neurons targeting a given location within the piriform cortex co-innervate extra-piriform regions that receive strong inputs from neurons within that piriform locus. We also identify signatures of local connectivity in the piriform cortex. Our findings suggest an organizing principle of matched direct and indirect olfactory pathways that innervate extra-piriform targets in a coordinated manner, thus supporting models of information processing that rely on structured connectivity within the olfactory system.
ADP-ribose triggers neuronal ferroptosis by rewiring purine and pyrimidine metabolism
Authors: Ni Haoqi , He Yingying , Cui Peng , Chen Hebing , Lv Guoqing , Lei Huiyan , Wang Feng , ZhuGe Qichuan , Chen Baodong , Liang Ling , Zhang Yong , You Fuping , Yuan Lin 
Published: May 2021

ABSTRACTHyperactivation of NAD+-consuming pathways frequently occurs in neurological diseases, however therapies replenishing NAD+levels show limited therapeutic efficacy, indicating more complex underlying pathophysiology. Here, we delineate a pathogenic link between ADP-ribose —a product of NAD+consumption—and a metabolic rewiring-dependent form of neuronal ferroptosis. We demonstrate that oxidative stress induces neurons to produce ADP-ribose through the PARP1-PARG axis. ADP-ribose directly binds and inhibits the equilibrative nucleoside transporter ENT2, remodelingde novopurine and pyrimidine synthesis by hyperactivating the inosine-hypoxanthine-xanthine oxidase and glutamine-dihydroorotate-dihydroorotate dehydrogenase axes. This overproduces superoxide radicals and drives lipid peroxidation and neuronal ferroptosis. Elevated ADP-ribose levels were observed in neurological disease models, and acute ADP-ribose exposure severely reduced mouse brain neuronsin vivo. Critically, interventions blocking ADP-ribose signaling alleviated cognitive decline in mouse intracerebral hemorrhage models. Our findings characterize ADP-ribose signaling as linking NAD+consumption to neuronal ferroptosis, and provide a theraputic strategy for neuropathologies involving NAD+consumption and oxidative stress.