bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell transcriptomic atlas of the human substantia nigra in Parkinson’s disease
Authors: Wang Qian , Wang Minghui , Choi Insup , Ho Lap , Farrell Kurt , Beaumont Kristin G. , Sebra Robert , Crary John F , Davis David A. , Sun Xiaoyan , Zhang Bin , Yue Zhenyu 
Published: March 2022

AbstractParkinson’s disease (PD) is a common and complex neurodegenerative disorder. Loss of neuromelanin-containing dopaminergic (DA) neurons in the substantia nigra (SN) is a hallmark of PD neuropathology; the etiology of PD remains unclear. Single-cell (-nucleus) RNA sequencing (sc or snRNAseq) has significantly advanced our understanding of neurodegenerative diseases including Alzheimer’s, but limited progress has been made in PD. Here we generated by far the largest snRNAseq data of high-quality 315,867 nuclei from the human SN including 9 healthy controls and 23 idiopathic PD cases across different Braak stages. Clustering analysis identified major brain cell types including DA neurons, excitatory neurons, inhibitory neurons, glial cells, endothelial, pericytes, fibroblast and T-cells in the human SN. By combining immunostaining and validating against the datasets from independent cohorts, we identified three molecularly distinct subtypes of DA-related neurons, including a RIT2-enriched population, in human aged SN. All DA neuron subtypes degenerated in PD, whereas the composition of non-neuronal cell clusters including major glial types showed little change. Our study delineated cell-type-specific PD-linked gene expression in the SN and their alterations in PD. Examination of cell-type-based transcriptomic changes suggests the complexity and diversity of molecular mechanisms of PD. Analysis of the remaining DA neurons of the three subtypes from PD demonstrated alterations of common gene sets associated with neuroprotection. Our findings highlight the heterogeneity of DA neurons in the human SN and suggest molecular basis for vulnerability and resilience of human DA neurons in PD. Our cohort thus provides a valuable resource for dissecting detailed mechanisms of DA neuron degeneration and identifying new neuroprotective strategies for PD.
Chemical inhibition of prolyl hydroxylases impairs angiogenic competence of human vascular endothelium through metabolic reprogramming
Authors: Tiwari Ratnakar , Bommi Prashant V. , Gao Peng , Schipma Matthew J. , Zhou Yalu , Quaggin Susan E. , Chandel Navdeep S. , Kapitsinou Pinelopi P. 
Published: March 2022

ABSTRACTEndothelial cell (EC) metabolism has emerged as a driver of angiogenesis. While hypoxia inactivates prolyl-4 hydroxylase domain containing proteins 1-3 (PHD1-3) and stabilizes hypoxia inducible factors (HIFs) stimulating angiogenesis, the effects of PHDs on EC functions remain unclear. Here, we investigated the impact of PHD inhibition by dimethyloxalylglycine (DMOG) on angiogenic competence and metabolism of human vascular ECs. PHD inhibition reduced EC proliferation, migration, and tube formation capacities. Furthermore, transcriptomic and metabolomic analyses revealed an unfavorable metabolic reprogramming for angiogenesis following treatment with DMOG. Despite the induction of glycolytic genes and high levels of lactate, multiple genes encoding sub-units of mitochondrial complex I were suppressed with concurrent decline in nicotinamide adenine dinucleotide (NAD+) levels. Importantly, defective EC migration due to DMOG could be partially restored by augmenting NAD+ levels. Combined, our data provide metabolic insights into the mechanism by which chemical PHD inhibition impairs angiogenic competence of human vascular ECs.
Pharmacological manipulations of physiological arousal and sleep-like slow waves modulate sustained attention
Authors: Pinggal Elaine , Dockree Paul M. , O’Connell Redmond G. , Bellgrove Mark A. , Andrillon Thomas 
Published: March 2022

AbstractSustained attention describes our ability to keep a constant focus on a given task. This ability is modulated by our physiological state of arousal. Although lapses of sustained attention have been linked with dysregulations of arousal, the underlying physiological mechanisms remain unclear. An emerging body of work proposes that the intrusion during wakefulness of sleep-like slow waves, a marker of the transition toward sleep, could mechanistically account for attentional lapses. This study aimed to expose, via pharmacological manipulations of the monoamine system, the relationship between the occurrence of sleep-like slow waves and the behavioural consequences of sustained attention failures. In a double-blind, randomised-control trial, 32 healthy human male participants received methylphenidate, atomoxetine, citalopram or placebo during four separate experimental sessions. During each session, electroencephalography (EEG) was used to measure neural activity whilst participants completed a visual task requiring sustained attention. Methylphenidate, which increases wake-promoting dopamine and noradrenaline across cortical and subcortical areas, improved behavioural performance whereas atomoxetine, which increases dopamine and noradrenaline predominantly over frontal cortices, led to more impulsive responses. Additionally, citalopram, which increases sleep-promoting serotonin, led to more missed trials. Based on EEG recording, citalopram was also associated with an increase in sleep-like slow waves. Importantly, compared to a classical marker of arousal such as alpha power, only slow waves differentially predicted both misses and faster responses in a region-specific fashion. These results suggest that a decrease in arousal can lead to local sleep intrusions during wakefulness which could be mechanistically linked to impulsivity and sluggishness.Significance StatementWe investigated whether the modulation of attention and arousal could not only share the same neuromodulatory pathways but also rely on similar neuronal mechanisms; for example, the intrusion of sleep-like activity within wakefulness. To do so, we pharmacologically manipulated noradrenaline, dopamine, and serotonin in a four-arm, randomised, placebo-controlled trial and examined the consequences on behavioural and EEG indices of attention and arousal. We showed that sleep-like slow waves can predict opposite behavioural signatures: impulsivity and sluggishness. Slow waves may be a candidate mechanism for the occurrence of attentional lapses since the relationship between slow-wave occurrence and performance is region-specific and the consequences of these local sleep intrusions are in line with the cognitive functions carried by the underlying brain regions.
SpyChIP identifies cell type-specific transcription factor occupancy from complex tissues
Authors: Feng Siqian , Mann Richard S. 
Published: March 2022

AbstractChromatin immunoprecipitation (ChIP) is an important technique for characterizing protein-DNA binding in vivo. One drawback of ChIP based techniques is the lack of cell type-specificity when profiling complex tissues. To overcome this limitation, we developed SpyChIP to identify cell type-specific transcription factor (TF) binding sites in native physiological contexts without tissue dissociation or nuclei sorting. SpyChIP takes advantage of a specific covalent isopeptide bond that rapidly forms between the 15 amino acid SpyTag and the 17 kD protein SpyCatcher. In SpyChIP, the target TF is fused with SpyTag by genome engineering, and an epitope tagged SpyCatcher is expressed in cell populations of interest, where it covalently binds to SpyTag-TF. Cell type-specific ChIP is obtained by immunoprecipitating chromatin prepared from whole tissues using antibodies directed against the epitope-tagged SpyCatcher. Using SpyChIP, we identified the genome-wide binding profiles of the Hox protein Ubx in two distinct cell types of the Drosophila haltere disc. Our results revealed extensive region-specific Ubx-DNA binding events, highlighting the significance of cell type-specific ChIP and the limitations of whole tissue ChIP approaches. Analysis of Ubx::SpyChIP results provided novel insights into the relationship between chromatin accessibility and Ubx-DNA binding, as well as different mechanisms Ubx employs to regulate its downstream cis-regulatory modules (CRMs). In addition to SpyChIP, we suggest that SpyTag-SpyCatcher technology, as well as other covalent interaction peptide pairs, has many potential in vivo applications that were previously unachievable.
Charge transfer of unconfined regions in quasi-periodic quantum wells : DNA nanostructure study
Authors: Tai Alan 
Published: March 2022

AbstractThis study presents a quantum well model using transfer matrix to analyse the charge transfer characteristic in DNA nanostructure sequences. The unconfined state or unbound state above the quantum well are used to investigate the carrier behaviours in nanostructure of semiconductor. Similar analysis and simulations can be applied to the understanding of charge transfer in DNA nanostructure with sequence of periodic and quasi-periodic sequences. The model was validated with experiments using photoreflectance spectroscopy on nanostructure in semiconductor superlattice. In addition, the results published by the study of Thermoelectric effect and its dependence on molecular length and sequence in single DNA molecules[1] were used to compare with the simulations by the quantum well model. The results show agreement and can provide new insight into charge transfer and transport in DNA nanostructure with different types of sequences.
A gut commensal protozoa remotely shapes a lung niche for asthma-promoting eosinophils
Authors: Burrows Kyle , Ngai Louis , Chiaranunt Pailin , Cao Eric , Streutker Catherine J. , Forde Brian , O’Mahony Liam , Mortha Arthur 
Published: March 2022

AbstractThe gut microbiome influences chronic inflammation of the airways via the gut-lung axis. However, causal connections between microbes and their host, including the underlying mechanisms for this phenomenon remain largely unknown. Here, we show that colonization with the gut commensal protozoa,Tritrichomonas musculis(T.mu), remotely shapes the lung immune landscape and exacerbates allergic airway inflammation. We demonstrate that colonization withT.mu mediates the T and B cell-dependent accumulation and activation of inflammatory group 2 innate lymphoid cells in the lungs to constitute a tripartite immune network that serves as a niche for lung eosinophils. Animals colonized withT.mushow severely exacerbated allergic inflammation in the airways and reveal a new protozoan-driven gut-lung axis that remotely shapes the lung immune network to potentiate chronic pulmonary inflammation.One-Sentence SummaryA gut microbe exacerbates asthma severity by promoting lung eosinophilia through a tripartite lymphocyte immune network.
Candida albicans filamentation does not require the cAMP-PKA pathway in vivo
Authors: Wakade Rohan S. , Kamara Juraj , Wellington Melanie , Krysan Damian J. 
Published: March 2022

AbstractCandida albicans is one of the most prevalent human fungal pathogens. Its ability to transition between budding yeast and filamentous morphological forms (pseudohyphae and hyphae) is tightly associated with its pathogenesis. Based on in vitro studies, the cAMP-Protein Kinase A (PKA) pathway is a key regulator of C. albicans morphogenesis. Using an intravital imaging approach, we investigated the role of the cAMP-PKA pathway during infection. Consistent with their roles in vitro, the downstream effectors of the cAMP-PKA pathway Efg1 and Nrg1 function, respectively, as an activator and a repressor of in vivo filamentation. Surprisingly, strains lacking the adenylyl cyclase, CYR1, showed only slightly reduced filamentation in vivo despite being completely unable to filament in RPMI+10% serum at 37°C. Consistent with these findings, deletion of the catalytic subunits of PKA (Tpk1 and Tpk2), either singly or in combination, generated strains that also filamented in vivo but not in vitro. In vivo transcription profiling of C. albicans isolated from both ear and kidney tissue showed that the expression of a set of 184 environmentally responsive correlated well with in vitro filamentation (R2 0.62-0.68) genes. This concordance suggests that the in vivo and in vitro transcriptional responses are similar but that the upstream regulatory mechanisms are distinct. As such, these data emphatically emphasize that C. albicans filamentation is a complex phenotype that occurs in different environments through an intricate network of distinct regulatory mechanisms.ImportanceThe fungus Candida albicans causes a wide range of disease in humans from common diaper rash to life-threatening infections in patients with compromised immune systems. As such, the mechanisms for its ability to cause disease are of wide interest. An intensely studied virulence property of C. albicans is its ability to switch from a round yeast form to filament-like forms (hyphae and pseudohyphae). Surprisingly, we have found that a key signaling pathway that regulates this transition in vitro, the protein kinase A pathway, is not required for filamentation during infection of the host. Our work not only demonstrates that the regulation of filamentation depends upon the specific environment C. albicans inhabits but also underscores the importance of studying these mechanisms during infection.
Drug design and repurposing with a sequence-to-drug paradigm
Authors: Chen Lifan , Fan Zisheng , Chang Jie , Yang Ruirui , Guo Hao , Zhang Yinghui , Yang Tianbiao , Zhou Chenmao , Chen Zhengyang , Zheng Chen , Hao Xinyue , Zhang Keke , Cui Rongrong , Ding Yiluan , Zhang Naixia , Luo Xiaomin , Jiang Hualiang , Zhang Sulin , Zheng Mingyue 
Published: March 2022

AbstractDrug development based on target proteins has been a successful approach in recent decades. A conventional structure-based drug design pipeline is a complex, human-engineered pipeline with multiple independently optimized steps. Advances in end-to-end differentiable learning suggest the potential benefits of similarly reformulating drug design. Here, we proposed a new sequence-to-drug paradigm that discovers drug-like small-molecule modulators directly from protein sequences and validated this concept for the first time in three stages. First, we designed TransformerCPI2.0 as a core tool for the sequence-to-drug paradigm, which exhibited competitive performance with conventional structure-based drug design approaches. Second, we validated the binding knowledge that TransformerCPI2.0 has learned. Third, we applied a sequence-to-drug paradigm to discover new hits for E3 ubiquitin-protein ligases: speckle-type POZ protein (SPOP), ring finger protein 130 (RNF130) which does not have a 3D structure, and repurposed proton pump inhibitors (PPIs) for ADP-ribosylation factor 1 (ARF1). This first proof of concept shows that the sequence-to-drug paradigm is a promising direction for drug development.
Pre-equilibrium biosensors: A new approach towards rapid and continuous molecular measurements
Authors: Maganzini Nicolò , Thompson Ian , Wilson Brandon , Soh Hyongsok Tom 
Published: March 2022

AbstractAlmost all biosensors that use ligand-receptor binding operate under equilibrium conditions. However, at low ligand concentrations, the equilibration with the receptor (e.g., antibodies and aptamers) become slow and thus equilibrium-based biosensors are inherently limited in making measurements that are both rapid and sensitive. In this work, we provide a theoretical foundation for a novel method through which biosensors can quantitatively measure ligand concentration before reaching equilibrium. Rather than only measuring receptor binding at a single time-point, the pre-equilibrium approach leverages the receptor’s kinetic response to instantaneously quantify the changing ligand concentration. Importantly, analyzing the biosensor output in frequency domain, rather than in the time domain, we show the degree to which noise in the biosensor affects the accuracy of the pre-equilibrium approach. Through this analysis, we provide the conditions under which the signal-to-noise ratio of the biosensor can be maximized for a given target concentration range and rate of change. As a model, we apply our theoretical analysis to continuous insulin measurement and show that with a properly selected antibody, the pre-equilibrium approach could make the continuous tracking of physiological insulin fluctuations possible.
Intact maternal buffering of stress response in infant rats despite altered responsivity towards maternal olfactory cues in the valproic acid model of autism-like behavior
Authors: White Amanda M. , An Xianli , Debiec Jacek 
Published: March 2022

AbstractDisrupted processing of social cues and altered social behaviors are among the core symptoms of autism spectrum disorders (ASDs), and they emerge as early as the first year of life. These differences in sensory abilities may affect the ability of children with ASDs to securely attach to a caregiver and experience caregiver buffering of stress. Prenatal exposure to valproic acid (VPA) has been used to model some aspects of ASDs in rodents. Here, we asked whether prenatal VPA exposure altered infant rats’ behavioral responsivity to maternal olfactory cues in an odor preference test and affected maternal buffering of infants’ stress responsivity to shock. In the odor preference test, one-week old rats treated with VPA during pregnancy appeared to have impaired social recognition and/or may be less motivated to approach social odors in early infancy. These effects were particularly prominent in female pups. In two-week old rats, VPA-exposed pups and saline-exposed pups showed similar preferences for home cage bedding. Although VPA-exposed pups may initially have a deficit in this attachment-related behavior they do recover typical responses to home cage bedding in later infancy. Both control and VPA-exposed pups showed robust stress hormone responses to repeated shocks, an effect which was blocked when a calm mother was present during shock exposure. No sex differences in the effect of maternal presence on the stress response to shock and no interactions between sex and prenatal drug exposure were observed. Although VPA-exposed pups may show impaired responsivity to maternal cues in early infancy, maternal presence is still capable of regulating the stress response in VPA-exposed pups. In this study we demonstrate the importance of utilizing multiple batteries of tests in assessing behavior, dissecting the behavior on one test into different components. Our results inform about the underlying behavioral characteristics of some of the ASD phenotypes, including sex differences reported by clinical studies, and could shed light on potential opportunities for intervention.
Building community resilience during COVID‐19: Learning from rural Bangladesh
Authors: Ahmad Farooq , Chowdhury Rashedur , Siedler Benjamin , Odek Wilson 
Published: March 2022

AbstractThe COVID‐19 pandemic has brought overwhelming challenges to developing countries which are already resource‐constrained and lack adequate social safety nets. Specifically, lockdown has adversely impacted marginalized communities (e.g., labourer, fish wholesaler and small business owner) and informal sector employees who rely on meager daily wages for their survival. Set in the contested climate of the emergency response to the COVID‐19 outbreak in Phulbari, Dinajpur, Bangladesh, we examine the early response of the community to the pandemic. Drawing on 24 in‐depth interviews with members of this community, we find that the existing central and regional government structure has failed to deal with the crisis. Yet, we show how collective effort at the local community level, led by volunteers and community leaders, is crucial in the fight against hardship during lockdown.
Using a structural vulnerability framework to understand the impact of COVID‐19 on the lives of Medicaid beneficiaries receiving substance use treatment in New York City
Authors: Zhen‐Duan Jenny , Gade Neerav , Falgas‐Bagué Irene , Sue Kimberly L. , DeJonckheere Melissa , Alegría Margarita 
Published: March 2022

AbstractObjectiveTo investigate how the COVID‐19 pandemic impacted low‐income individuals with substance use disorder (SUD) in New York City (NYC) during the beginning of the pandemic, using a structural competency and structural vulnerability theoretical framework and a qualitative research approach.Data SourcesPrimary qualitative data were collected from racial/ethnic minority adults enrolled in Medicaid receiving outpatient substance use treatment (e.g., medication, counseling) in NYC.Study DesignSemi‐structured in‐depth qualitative interviews (N = 20) were conducted during “stay‐at‐home” orders in NYC, the first epicenter of the COVID‐19 pandemic in the United States. Interviews were conducted over the phone during the earlier stages of the pandemic, between April 2020 and June 2020.Data Collection/Extraction MethodsSemi‐structured in‐depth interviews were conducted and audio recorded, transcribed, and analyzed using a thematic analysis approach.Principal FindingsThree themes were yielded from our thematic analysis: (1) COVID‐19 heightened food insecurity and housing conditions increased risks of infection; (2) stay‐at‐home orders limited access to resources but had positive impacts in strengthening social relationships and reducing substance use triggers; and (3) although COVID‐19 created challenges for treatment, most described that SUD care improved during the pandemic.ConclusionsWhile COVID‐19 exacerbated numerous structural vulnerabilities among low‐income individuals with SUD, programmatic adaptations to COVID‐19 SUD care, including telehealth and loosening restrictions around medications for opioid use disorders mitigated past difficulties that patients had faced. Reducing structural vulnerabilities for Medicaid patients will require continuation of telehealth treatment delivery, retaining flexible medication regulations, and mobilizing community resources to mitigate economic disparities.
Application of emerging technologies to obtain legume protein isolates with improved techno‐functional properties and health effects
Authors: Bou Ricard , Navarro‐Vozmediano Paola , Domínguez Rubén , López‐Gómez Miguel , Pinent Montserrat , Ribas‐Agustí Albert , Benedito José J. , Lorenzo José M. , Terra Ximena , García‐Pérez José V. , Pateiro Mirian , Herrera‐Cervera José A. , Jorba‐Martín Rosa 
Published: March 2022

AbstractCurrent demand of consumers for healthy and sustainable food products has led the industry to search for different sources of plant protein isolates and concentrates. Legumes represent an excellent nonanimal protein source with high‐protein content. Legume species are distributed in a wide range of ecological conditions, including regions with drought conditions, making them a sustainable crop in a context of global warming. However, their use as human food is limited by the presence of antinutritional factors, such as protease inhibitors, lectins, phytates, and alkaloids, which have adverse nutritional effects. Antitechnological factors, such as fiber, tannins, and lipids, can affect the purity and protein extraction yield. Although most are removed or reduced during alkaline solubilization and isoelectric precipitation processes, some remain in the resulting protein isolates. Selection of appropriate legume genotypes and different emerging and sustainable facilitating technologies, such as high‐power ultrasound, pulsed electric fields, high hydrostatic pressure, microwave, and supercritical fluids, can be applied to increase the removal of unwanted compounds. Some technologies can be used to increase protein yield. The technologies can also modify protein structure to improve digestibility, reduce allergenicity, and tune technological properties. This review summarizes recent findings regarding the use of emerging technologies to obtain high‐purity protein isolates and the effects on techno‐functional properties and health.