bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards a phenome-wide view of Parkinson’s disease
Authors: Olsen Abby L. , Locascio Joseph J. , Tuncali Idil , Laroussi Nada , Abatzis Elena , Kamenskaya Polina , Kuras Yuliya , Yi Tom , Videnovic Aleksandar , Hayes Michael T. , Ho Gary P. H. , Paulson Jordan , Khurana Vikram , Herrington Todd M. , Hyman Bradley T. , Selkoe Dennis J. , Growdon John H. , Gomperts Stephen N. , Riise Trond , Schwarzschild Michael A. , Hung Albert Y. , Wills Anne-Marie , Scherzer Clemens R. 
Published: February 2022

Background and ObjectivesMany studies have examined the relation between PD and environmental variables serially --- one candidate association at a time. In the real world however, both environmental exposures and patients are much more complex, including correlated environmental exposures, polypharmacy, and complex comorbidities. Here we begin to characterize a holistic view of environmental, health, and pharmacological traits linked to patients with PD.MethodsThe Harvard Biomarkers Study (HBS) is a large case-control study of PD patients and healthy controls that includes an extensive questionnaire covering past medical and social history data and is thus well-suited for such an exploratory study. Sixty-four environmental, pharmacological, and clinical features were evaluated for associations with PD using logistic regression analysis with backward elimination.ResultsMale gender, coronary artery disease, depression, anxiety, restless leg syndrome, head trauma, ibuprofen use, co-enzyme Q10 use, and vitamin D supplementation were significantly positively associated with PD. By contrast, asthma/chronic obstructive pulmonary disease (COPD), naproxen, ezetimibe, and smoking were significantly negatively associated with PD.DiscussionThis study shows that unbiased, data-rich exploration of the Parkinson phenome has the promise to uncover, prioritize, and clarify associations between environment, multi-system health phenotypes, and PD in a patient-centric manner. Associations with coronary artery disease, mood disorders, and the cholesterol-absorption inhibitor ezetimibe were revealed that have been largely neglected in traditional hypothesis-driven investigations. Interestingly, asthma/COPD was inversely associated with PD, and this was independent of smoking history. Furthermore, well-established associations were confirmed for male gender, smoking, head trauma, and restless legs syndrome.
A cross-sectional analysis of self-reported needs and health service utilization among transgender women in Lima, Peru
Authors: Carosella Elizabeth A. , Huerta Leyla , Galea Jerome T. , Lecca Leonid , Ramos Karen , Hernandez Giulianna , Franke Molly F. , Peinado Jesús 
Published: February 2022

AbstractPurposeGlobally, transgender women (TGW) experience wide-ranging barriers to health and care, with disproportionately high risks of infectious and chronic diseases. Despite these vulnerabilities, research on access to care for transgender populations in low- and middle-income countries is extremely limited. Furthermore, existing studies have primarily focused on human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS), with less emphasis on TGW’s broader health needs. This study analyzed patterns of morbidity and health service uptake among TGW in Lima, Peru. The purpose was to better understand health outreach and service needs to inform targeting and design of future community-level interventions.MethodsThis cross-sectional study surveyed a convenience sample of 301 TGW in metropolitan Lima, Peru. Data was collected between September – October 2020. This paper provides descriptive statistics and results of bivariate and multivariable regression models.ResultsHealth coverage and access to care were suboptimal. Less education and older age were positively associated with illness and HIV and tuberculosis (TB) testing. Gender identity sub-group (i.e., woman, trans or transgender, transsexual, “transformista,” “travesti,” and other) was associated with HIV testing and pre-exposure prophylaxis (PrEP) usage. Both awareness of and interest in PrEP were low, as was usage among those who were interested in taking PrEP.ConclusionFuture public health efforts should be tailored to meet the diverse needs of TGW, expand TB testing, bridge the gap between PrEP interest and use, and increase insurance coverage and access to trans-friendly services to promote improved health outcomes.
Association study of HLA with the kinetics of SARS-CoV-2 spike specific IgG antibody responses to BNT162b2 mRNA vaccine
Authors: Khor Seik-Soon , Omae Yosuke , Takeuchi Junko S. , Fukunaga Ami , Yamamoto Shohei , Tanaka Akihito , Matsuda Kouki , Kimura Moto , Maeda Kenji , Ueda Gohzoh , Mizoue Tetsuya , Ujiie Mugen , Mitsuya Hiroaki , Ohmagari Norio , Sugiura Wataru , Tokunaga Katsushi 
Published: February 2022

AbstractBNT162b2, an mRNA-based SARS-CoV-2 vaccine (Pfizer-BioNTech), is one of the most effective COVID-19 vaccines and has been approved by more than 130 countries worldwide. However, several studies have reported that the COVID-19 vaccine shows high interpersonal variability in terms of humoral and cellular responses, such as those with respect to SARS-CoV-2 spike protein immunoglobulin (Ig)G, IgA, IgM, neutralizing antibodies, and CD4+ & CD8+ T cells. The objective of this study is to investigate the kinetic changes in anti-SARS-CoV-2 spike IgG (IgG-S) profiles and adverse reactions and their associations with HLA profiles among 100 hospital workers from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. DQA1*03:03:01 (P = 0.017; Odd ratio (OR) 2.80, 95%Confidence interval (CI) 1.05–7.25) was significantly associated with higher IgG-S production after two doses of BNT162b2 while DQB1*06:01:01:01 (P = 0.028, OR 0.27, 95%CI 0.05–0.94) was significantly associated with IgG-S declines after two doses of BNT162b2. No HLA alleles were significantly associated with either local symptoms or fever. However, C*12:02:02 (P = 0.058; OR 0.42, 95%CI 0.15–1.16), B*52:01:01 (P = 0.031; OR 0.38, 95%CI 0.14–1.03), DQA1*03:02:01 (P = 0.028; OR 0.39, 95%CI 0.15–1.00) and DPB1*02:01:02 (P = 0.024; OR 0.45, 95%CI 0.21–0.97) appeared significantly associated with protection against systemic symptoms after two doses of BNT162b2 vaccination. Further studies with larger sample sizes are clearly warranted to determine HLA allele associations with the production and long-term sustainability of IgG-S after COVID-19 vaccination.
Oscillations without cortex: Working memory modulates brainwaves in the endbrain of crows
Authors: Hahn Lukas Alexander , Balakhonov Dmitry , Lundqvist Mikael , Nieder Andreas , Rose Jonas 
Published: February 2022

SummaryComplex cognition requires coordinated neuronal activity at the network level. In mammals, this coordination results in distinct dynamics of local field potentials (LFP) that have been central in many models of higher cognition. Because these models are based on mammalian data, they often implicitly assume a cortical organization. Higher associative regions of the brains of birds do not have cortical layering, yet these regions have neuronal single-cell correlates of higher cognition that are very similar to those found in mammals. Here we recorded LFP in the avian equivalent of prefrontal cortex while crows performed a highly controlled and cognitively demanding working memory task, adapted from monkeys. To further ensure that recordings reflected only cognitive processes detached from motor-related activities we trained and monitored the animals to keep their head still. We found signatures in local field potentials, modulated by working memory. Frequencies of a narrow gamma (30-59 Hz) and the beta band (13-19 Hz) contained information about the location of the target items on the screen and were modulated by working memory load. This indicates a critical involvement of these bands in ongoing cognitive processing. We also observed bursts in the beta and gamma frequencies, similar to those observed in monkeys. Such bursts are a vital part of ‘activity silent’ models of working memory. Thus, despite the lack of a cortical organization the avian associative pallium can create LFP signatures reminiscent of those observed in primates. This points towards a critical cognitive function of oscillatory dynamics evolved through convergence in species capable of complex cognition.Relevance statementContemporary models of higher cognition, like those of working memory, often include temporal dynamics of neural activity such as gamma oscillations. Birds and mammals convergently evolved these cognitive functions and here we show that, despite the large evolutionary distance and largely different brain organization, crows share many of the oscillatory fingerprints reported in primates. This indicates that neural networks required for such LFP phenomena have evolved in parallel and may be critical to higher cognition.
Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth
Authors: Ku Zhiqiang , Xie Xuping , Lin Jianqing , Gao Peng , El Sahili Abbas , Su Hang , Liu Yang , Ye Xiaohua , Li Xin , Fan Xuejun , Goh Boon Chong , Xiong Wei , Boyd Hannah , Muruato Antonio E. , Deng Hui , Xia Hongjie , Jing Zou , Kalveram Birte K. , Menachery Vineet D. , Zhang Ningyan , Lescar Julien , Shi Pei-Yong , An Zhiqiang 
Published: February 2022

AbstractOne major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)2 design (14-H-06) but not the CrossMAb design (14-crs-06) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.
HIV-2 Immature Particle Morphology Provides Insights into Gag Lattice Stability and Virus Maturation
Authors: Talledge Nathaniel , Yang Huixin , Shi Ke , Coray Raffaele , Yu Guichuan , Arndt William G. , Meng Shuyu , Baxter Gloria C. , Mendonça Luiza M. , Castaño-Díez Daniel , Aihara Hideki , Mansky Louis M. , Zhang Wei 
Published: February 2022

AbstractRetrovirus immature particle morphology consists of a membrane enclosed, pleomorphic, spherical and incomplete lattice of Gag hexamers. Previously, we demonstrated that human immunodeficiency virus type 2 (HIV-2) immature particles possess a distinct and extensive Gag lattice morphology. To better understand the nature of the continuously curved hexagonal Gag lattice, we have used single particle cryo-electron microscopy with a retrovirus to determine the HIV-2 Gag lattice structure for immature virions. The reconstruction map at 5.5 Å resolution revealed a stable, wineglass-shaped Gag hexamer structure with structural features consistent with other lentiviral immature Gag structures. Cryo-electron tomography provided evidence for nearly complete ordered Gag lattice structures in HIV-2 immature particles. We also solved a 1.98 Å resolution crystal structure of the carboxyl-terminal domain (CTD) of the HIV-2 capsid (CA) protein that identified a structured helix 12 supported via an interaction of helix 10 in the absence of the SP1 region of Gag. Residues at the helix 10-12 interface proved critical in maintaining HIV-2 particle release and infectivity. Taken together, our findings provide the first 3D organization of HIV-2 immature Gag lattice and important insights into both HIV Gag lattice stabilization and virus maturation.
Dissociable neural correlates of multisensory coherence and selective attention
Authors: Peng Fei , Bizley Jennifer K. , Schnupp Jan W. , Auksztulewicz Ryszard 
Published: February 2022

AbstractPrevious work has demonstrated that performance in an auditory selective attention task can be enhanced or impaired, depending on whether a task-irrelevant visual stimulus is temporally coherent with a target auditory stream or with a competing distractor. However, it remains unclear how audiovisual (AV) temporal coherence and auditory selective attention interact at the neurophysiological level. Here, we measured neural activity using electroencephalography (EEG) while participants performed an auditory selective attention task, detecting deviants in a target audio stream. The amplitude envelope of the two competing auditory streams changed independently, while the radius of a visual disc was manipulated to control the audiovisual coherence. Analysis of the neural responses to the sound envelope demonstrated that auditory responses were enhanced independently of the attentional condition: both target and masker stream responses were enhanced when temporally coherent with the visual stimulus. In contrast, attention enhanced the event-related response (ERP) evoked by the transient deviants, independently of AV coherence. Finally, we identified a spatiotemporal component of the ERP, likely originating from the superior temporal gyrus and the frontoparietal network, in which both attention and coherence synergistically modulated ERP amplitude. These results provide evidence for dissociable neural signatures of bottom-up (coherence) and top-down (attention) effects in the AV object formation.
TYPE I INTERFERON-DEPENDENT CELLULAR REMODELING DURING ACUTE PULMONARY MHV INFECTION
Authors: Grabherr S. , Waltenspühl A. , Lütge M. , Büchler L. , Cheng H.W. , Zielińska K. , Caviezel-Firner S. , Krebs P. , Ludewig B. , Pikor N.B. 
Published: February 2022

ABSTRACTImpaired type I interferon (IFN) responses are predictive of severe disease during pulmonary coronavirus infection. In the periphery, dampened IFN-responsiveness is associated with viremia and hypercytokinemia, however the resolution of IFN-dependent innate immune responses in the lungs remains limited. Here, we aimed to elucidate the early dynamics of antiviral immunity and define the IFN-dependent mechanisms limiting viral spread during pulmonary infection with the murine hepatitis virus (MHV), a beta-coronavirus. While several innate immune cell types infiltrated the lungs concomitant with viral replication, the influx of type I IFN-responsive myeloid cells was essential for viral containment and prevention of fatal disease. Combining high-resolution transcriptomic analysis and genetic attenuation of interferon signaling, we delineated IFN-dependent cell-intrinsic and population-based transcriptional changes that determined viral replication and inflammatory maturation, respectively. While monocyte-derived macrophages exhibited the strongest pro-inflammatory transcriptional reprogramming during pulmonary infection, these maturation programs were impaired in the absence of IFN-signalling. Instead, IFN-deficient monocyte-derived macrophages expressed genes encoding for neutrophil attractants and IL1β, resulting in enhanced lung injury. Our results reveal the requirement for type I IFN-induced antiviral states and inflammation-induced maturation programs to secure pulmonary viral containment.
Single-cell RNA profiling of Plasmodium vivax-infected hepatocytes reveals parasite- and host- specific transcriptomic signatures and therapeutic targets
Authors: Ruberto Anthony A , Maher Steven P , Vantaux Amélie , Joyner Chester J , Bourke Caitlin , Balan Balu , Jex Aaron , Mueller Ivo , Witkowski Benoit , Kyle Dennis E 
Published: February 2022

ABSTRACTThe resilience of Plasmodium vivax, the most widely distributed malaria-causing parasite in humans, is attributed to its ability to produce dormant liver forms known as hypnozoites, which can activate weeks, months, or even years after an initial mosquito bite. The factors underlying hypnozoite formation and activation are poorly understood, as is the parasite’s influence on the host hepatocyte. Here, we shed light on transcriptome-wide signatures of both the parasite and the infected host cell by sequencing over 1,000 P. vivax-infected hepatocytes at single-cell resolution. We distinguish between replicating schizonts and hypnozoites at the transcriptional level, identifying key differences in transcripts encoding for RNA-binding proteins associated with cell fate. In infected hepatocytes, we show that genes associated with energy metabolism and antioxidant stress response were upregulated, and those involved in the host immune response downregulated, suggesting both schizonts and hypnozoites alter the host intracellular environment. The transcriptional markers in schizonts, hypnozoites, and infected hepatocytes revealed here pinpoint potential factors underlying dormancy and can inform therapeutic targets against P. vivax liver-stage infection.
Inadvertent Transfer of Murine VL30 Retrotransposons to CAR-T Cells
Authors: Lee Sung Hyun , Hao Yajing , Gui Tong , Dotti Gianpietro , Savoldo Barbara , Zou Fei , Kafri Tal 
Published: February 2022

AbstractFor more than a decade genetically engineered autologous T-cells have been successfully employed as immunotherapy drugs for patients with incurable blood cancers. The active component in some of these game-changing medicines are autologous T-cells that express viral vector-delivered chimeric antigen receptors (CARs), which specifically target proteins that are preferentially expressed on cancer cells. Some of these therapeutic CAR expressing T-cells (CAR-Ts) are engineered via transduction with γ-retroviral vectors (γ-RVVs) produced in a stable producer cell line that was derived from murine PG13 packaging cells (ATCC CRL-10686). Earlier studies reported on the co-packaging of murine virus-like 30S RNA (VL30) genomes with γ-retroviral vectors generated in murine stable packaging cells. In an earlier study VL30 mRNA was found to enhance the metastatic potential of human melanoma cells. These findings raise biosafety concerns regarding the possibility that therapeutic CAR-Ts have been inadvertently contaminated with potentially oncogenic VL30 retrotransposons. In this study, we demonstrated the presence of infectious VL30 particles in PG13 cells conditioned media and observed the ability of these particles to deliver transcriptionally active VL30 genomes to human cells. Notably, VL30 genomes packaged by HIV-1-based vector particles transduced naïve human cells in culture. Furthermore, we detected transfer and expression of VL30 genomes in clinical-grade CAR-Ts generated by transduction with PG13 cells-derived γ-retroviral vectors. Our findings raise biosafety concerns regarding the use of murine packaging cell lines in ongoing clinical applications.
New efficient intercellular spread mode of respiratory syncytial virus contributes to neutralization escape and persistence
Authors: Zhang Wei , Lin Xue , Zhang Lu-Jing , Chen Li , Sun Yong-Peng , Si Jun-Yu , Zhao Min , Wu Guang-Hua , Zhan Lu-Ting , Wang Ying-Bin , Xia Ning-Shao , Zheng Zi-Zheng 
Published: February 2022

SummaryThere is no licensed vaccine or therapeutic antibody for respiratory syncytial virus (RSV). The induction of high-titer, potent neutralizing antibodies cannot completely inhibit breakthrough infection and enhanced respiratory disease (ERD), encouraging a focus on the relationship between virus intercellular spread and neutralizing antibodies. By blocking the known intercellular spread modes and with the aid of ultrahigh-resolution imaging, we observed a new efficient mode of intercellular spread in which RSV-infected cells directly transfer viral materials (including viral replication factories) to neighboring cells through protruding open-ended microfilament-rich intercellular nanotubes. The new mode is virion-independent and antibody-insensitive, beginning as early as 3 h post infection. Furthermore, replication-defective viral genomes (DVGs) might also utilize the new mode, facilitating the establishment of latent viral infections. Therefore, our data provide a new perspective on RSV cell-to-cell spread and might help to explain the immune escape and latent persistence of paramyxoviruses.
Allele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage
Authors: Balasooriya Gayan I. , Spector David L. 
Published: February 2022

AbstractEach mammalian autosomal gene is represented by two alleles in diploid cells. Yet, no insights have been made in regard to allele-specific regulatory mechanisms of autosomes. Here we used allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. We found that monoallelically expressed autosomal genes in mESCs and mouse blastocyst cells are differentially regulated based on the genetic background of the parental alleles. However, the genetic background of the allele does not affect the establishment of monoallelic genes in differentiated cardiomyocytes. Additionally, we observed epigenetic differences between deterministic and random autosomal monoallelic genes. Moreover, we also found a greater contribution of the maternal versus paternal allele to the development and homeostasis of cardiac tissue and in cardiac health, highlighting the importance of maternal influence in male cardiac tissue homeostasis. Our findings emphasize the significance of allele- specific insights into gene regulation in development, homeostasis and disease.
Different dopaminergic neurons signal absolute and relative aversive value in the Drosophila mushroom body
Authors: Villar Maria E. , Pavão-Delgado Miguel , Amigo Marie , Jacob Pedro F. , Merabet Nesrine , Pinot Anthony , Perry Sophie A. , Waddell Scott , Perisse Emmanuel 
Published: February 2022

AbstractAnimals use prior experience to assign absolute (good or bad) and also relative (better or worse) value to new experience. These learned values guide appropriate later decision-making. While our understanding of how the dopaminergic system computes absolute value is relatively advanced, the mechanistic underpinnings of relative valuation are unclear. Here we reveal mechanisms of absolute and relative aversive valuation in Drosophila. Three types of punishment-sensitive dopaminergic neurons (DANs) drive intensity-scaled plasticity at their respective mushroom body output neuron (MBON) connections to code absolute aversive value. In contrast, by comparing current and previous aversive experiences the MBON-DAN network can code relative aversive value by recruiting a specific subtype of reward-coding dopaminergic neurons which assigns a ‘better than’ value to the lesser of two aversive experiences. This study therefore provides an important functional consequence of having opposing populations of DANs and illustrates how these can operate together as a system within the MB network to code and compare sequential aversive experience to learn relative aversive value.