bluuebunny/crossref_metadata_2025_split huggingface dataset:
γ-Protocadherins control synapse formation and peripheral branching of touch sensory neurons
Authors: Meltzer Shan , Comeau Katelyn , Chirila Anda , Osei-Asante Emmanuella , DeLisle Michelle , Zhang Qiyu , Kalish Brian T. , Tasnim Aniqa , Huey Erica , Fuller Leah C. , Flaherty Erin K. , Lefebvre Julie L. , Maniatis Tom , Garrett Andrew M. , Weiner Joshua A. , Ginty David D. 
Published: May 2022

SummaryLight touch sensation begins with activation of low-threshold mechanoreceptor (LTMR) endings in the skin and propagation of their signals to the spinal cord and brainstem. We found that the clustered protocadherin gamma (Pcdhg) gene locus, which encodes 22 cell-surface homophilic binding proteins, is required in somatosensory neurons for normal behavioral reactivity to a range of tactile stimuli. Developmentally, distinct Pcdhg isoforms mediate LTMR synapse formation through neuron-neuron interactions and peripheral axonal branching through neuron-glia interactions. The Pcdhgc3 isoform mediates homophilic interactions between sensory axons and spinal cord neurons to promote synapse formationin vivo, and is sufficient to induce postsynaptic specializationsin vitro. Moreover, loss of Pcdhgs and somatosensory synaptic inputs to the dorsal horn lead to fewer corticospinal synapses onto dorsal horn neurons. These findings reveal essential roles for Pcdhg isoform diversity in somatosensory neuron synapse formation, peripheral axonal branching, and step-wise assembly of central mechanosensory circuitry.
Variation in glutamate and GABA genes and their association with brain structure and chemistry in autism
Authors: Naaijen Jilly , Arenella Martina , Zöllner Helge J , Puts Nicolaas A , Lythgoe David J , Brandeis Daniel , Durston Sarah , Poelmans Geert , Ruisch I Hyun , Buitelaar Jan K 
Published: May 2022

AbstractThe excitatory/inhibitory (E/I) imbalance hypothesis posits that an imbalance between glutamatergic and GABAergic neurotransmission contributes to autism symptomatology. Whether this is due to altered GABAergic or glutamatergic functioning, or both, remains largely unknown. We integrated genetic, brain structure and brain chemistry data to investigate the relationship between E/I genetic variation and expression, glutamate concentrations and cortical thickness (CT). Participants (60 autism and 104 neurotypical controls, aged 8-13 years) underwent magnetic resonance imaging and spectroscopy for glutamate quantification in the anterior cingulate cortex (ACC) and left dorsal striatum. Genetic involvement in these regional glutamate concentration levels was investigated using competitive gene-set association and polygenic scores (PGS). Further, glutamate as well as GABA gene-set expression profiles were investigated in relation to CT. Aggregated genetic variation in the glutamate gene-set was associated with ACC but not striatal glutamate concentrations. PGS analysis, however, showed a genome-wide PGS for autism to be predictive of striatal but not ACC glutamate levels. Expression profiles of GABAergic-but not glutamatergic genes were associated with differences in cortical thickness between groups. This study showed differential involvement of aggregated glutamatergic and GABAergic genetic variation in brain structure and chemistry in autism, which suggests regional variability in E/I imbalance.
Genetic characterisation of the Theileria annulata cytochrome b locus and its impact on buparvaquone resistance in ruminants
Authors: Ali Qasim , Zahid Osama , Mhadhbi Moez , Jones Ben , Darghouth Mohamed Aziz , Raynes George , Afshan Kiran , Birtles Richard , Sargison Neil D. , Betson Martha , Chaudhry Umer 
Published: May 2022

AbstractControl of tropical theileriosis depends on the use of a single drug, buparvaquone, the efficacy of which is compromised by the emergence of resistance. The present study was undertaken to improve understanding of the role of mutations conferring buparvaquone resistance in Theileria annulata, and the effects of selection pressures on their emergence and spread. First, we investigated genetic characteristics of the cytochrome b locus associated with buparvaquone resistance in 10 susceptible and 7 resistant T. annulata isolates. The 129G (GGC) mutation was found in the Q01 binding pocket and 253S (TCT) and 262S (TCA) mutations were identified within the Q02 binding pocket. Next, we examined field isolates and identified cytochrome b mutations 129G (GGC), 253S (TCT) and 262S (TCA) in 21/75 buffalo-derived and 19/119 cattle-derived T. annulata isolates, providing evidence of positive selection pressure. Both hard and soft selective sweeps were identified, with striking differences between isolates. For example, 19 buffalo-derived and 7 cattle-derived isolates contained 129G (GGC) and 253S (TCT) resistance haplotypes at a high frequency, implying the emergence of resistance by a single mutation. Two buffalo-derived and 11 cattle-derived isolates contained equally high frequencies of 129G (GGC), 253S (TCT), 129G (GGC)/253S (TCT) and 262S (TCA) resistance haplotypes, implying the emergence of resistance by pre-existing and or recurrent mutations. Phylogenetic analysis further revealed that 9 and 21 unique haplotypes in buffalo and cattle-derived isolates were present in a single lineage, suggesting a single origin. We propose that animal migration between farms is an important factor in the spread of buparvaquone resistance in endemic regions of Pakistan. The overall outcomes will be useful in understanding how drug resistance emerges and spreads, and this information will help design strategies to optimise the use and lifespan of the single most drug use to control tropical theileriosis.
De novo lipogenesis fuels adipocyte autophagosome membrane dynamics
Authors: Rowland Leslie A. , Guilherme Adilson , Henriques Felipe , DiMarzio Chloe , Wetoska Nicole , Kelly Mark , Reddig Keith , Hendricks Gregory , Pan Meixia , Han Xianlin , Ilkayeva Olga R. , Newgard Christopher B. , Czech Michael P. 
Published: May 2022

SummaryAutophagy is a homeostatic degradative process for cell components that enables stress resilience and can determine cellular fate and function. However, lipid sources for the rapid membrane expansions of autophagosomes, the workhorses of autophagy, are poorly understood. Here, we identify de novo lipogenesis (DNL) as a critical source of fatty acids (FA) to fuel autophagosome dynamics in adipocytes. Adipocyte fatty acid synthase (Fasn) deficiency markedly impairs autophagy, evident by autophagosome accumulation, and severely compromises degradation of the autophagic substrate p62. Autophagy dependence on FA produced by Fasn is not fully alleviated by exogenous FA in cultured adipocytes even though lipid droplet size is restored. Imaging studies reveal that Fasn colocalizes with nascent autophagosomes, while loss of Fasn decreases certain membrane phosphoinositides known to be required for autophagosome assembly. Together, our studies highlight a newly appreciated function for adipocyte DNL in autophagosome membrane formation and provide evidence that localized FA synthesis contributes to autophagosome dynamics.
Ferric reductase-related proteins mediate fungal heme acquisition
Authors: Roy Udita , Yaish Shir , Weissman Ziva , Pinsky Mariel , Dey Sunanda , Horev Guy , Kornitzer Daniel 
Published: May 2022

ABSTRACTHeme can serve as iron source in many environments, including the iron-poor animal host environment. The fungal pathobiont Candida albicans expresses a family of extracellular CFEM hemophores that capture heme from host proteins and transfer it across the cell wall to the cell membrane, to be endocytosed and utilized as heme or iron source. Here we identified Frp1 and Frp2, two ferric reductase (FRE)-related proteins that lack an extracellular N-terminal substrate-binding domain, as being required for hemoglobin heme utilization and for sensitivity to toxic heme analogs. Frp1/2 redistribute from the ER to the plasma membrane in the presence of hemoglobin, consistent with a direct role in heme trafficking. Expression of Frp1 with the CFEM hemophore Pga7 can promote heme utilization in Saccharomyces cerevisiae as well, confirming the functional interaction between these proteins. Sequence and structure comparison reveals that the CFEM hemophores are related to the FRE substrate-binding domain that is missing in Frp1/2. We conclude that Frp1/2 and the CFEM hemophores form a functional complex that evolved from ferric reductases to enable extracellular heme uptake.
Aurora A and cortical flows promote polarization and cytokinesis by inducing asymmetric ECT-2 accumulation
Authors: Longhini Katrina M , Glotzer Michael 
Published: May 2022

AbstractIn the early C. elegans embryo, cell polarization and cytokinesis are interrelated yet distinct processes. Here, we sought to understand a poorly understood aspect of cleavage furrow positioning. Early C. elegans embryos deficient in the cytokinetic regulator centralspindlin form furrows, due to an inhibitory activity that depends on aster positioning relative to the polar cortices. Here, we show polar relaxation is associated with depletion of cortical ECT-2, a RhoGEF, specifically at the posterior cortex. Asymmetric ECT-2 accumulation requires intact centrosomes, Aurora A (AIR-1), and myosin-dependent cortical flows. Within a localization competent ECT-2 fragment, we identified three putative phospho-acceptor sites in the PH domain of ECT-2 that render ECT-2 responsive to inhibition by AIR-1. During both polarization and cytokinesis, our results suggest that centrosomal AIR-1 breaks symmetry via ECT-2 phosphorylation; this local inhibition of ECT-2 is amplified by myosin-driven flows that generate regional ECT-2 asymmetry. Together, these mechanisms cooperate to induce polarized assembly of cortical myosin, contributing to both embryo polarization and cytokinesis.
Tissue libraries enable rapid determination of conditions that preserve antibody labeling in cleared mouse and human tissue
Authors: Zwang Theodore J. , Bennett Rachel E. , Lysandrou Maria , Woost Benjamin , Zhang Anqi , Lieber Charles M. , Richardson Douglas S. , Hyman Bradley T. 
Published: May 2022

AbstractDifficulty achieving complete, specific, and homogenous staining is a major bottleneck preventing the widespread use of tissue clearing techniques to image large volumes of human tissue. In this manuscript, we describe a procedure to rapidly design immunostaining protocols for antibody labeling of cleared brain tissue. We prepared libraries of .5-1.0 mm thick tissue sections that are fixed, pre-treated, and cleared via similar, but different procedures to optimize staining conditions for a panel of antibodies. Results from a library of mouse tissue correlate well with results from a similarly prepared library of human brain tissue, suggesting mouse tissue is an adequate substitute for protocol optimization. These data show that procedural differences do not influence every antibody-antigen pair in the same way, and minor changes can have deleterious effects, therefore, optimization should be conducted for each target. The approach outlined here will help guide researchers to successfully label a variety of targets, thus removing a major hurdle to accessing the rich 3D information available in large, cleared human tissue volumes.
Oral cholestyramine prevents enrichment of diverse daptomycin-resistance mutations in intestinal Enterococcus faecium
Authors: Morley Valerie J. , Sim Derek G. , Penkevich Aline , Woods Robert J. , Read Andrew F. 
Published: May 2022

AbstractBackground and ObjectivesPreviously, we showed proof-of-concept in a mouse model that oral administration of cholestyramine prevented enrichment of daptomycin-resistant Enterococcus faecium in the gastrointestinal (GI) tract during daptomycin therapy. Cholestyramine binds daptomycin in the gut, which removes daptomycin selection pressure and so prevents the enrichment of resistant clones. Here, we investigated two open questions related to this approach: 1) can cholestyramine prevent the enrichment of diverse daptomycin mutations emerging de novo in the gut? 2) how does the timing of cholestyramine administration impact its ability to suppress resistance?MethodologyMice with GI E. faecium were treated with daptomycin with or without cholestyramine, and E. faecium was cultured from feces to measure changes in daptomycin susceptibility. A subset of clones was sequenced to investigate the genomic basis of daptomycin resistance.ResultsCholestyramine prevented the enrichment of diverse resistance mutations that emerged de novo in daptomycin-treated mice. Whole-genome sequencing revealed that resistance emerged through multiple genetic pathways, with most candidate resistance mutations observed in the clsA gene. Additionally, we observed that cholestyramine was most effective when administration started prior to the first dose of daptomycin. However, beginning cholestyramine after the first daptomycin dose reduced the frequency of resistant E. faecium compared to not using cholestyramine at all.Conclusions and ImplicationsCholestyramine prevented the enrichment of diverse daptomycin-resistance mutations in intestinal E. faecium populations during daptomycin treatment, and it is a promising tool for managing transmission of daptomycin-resistant E. faecium.
Uncoupling from transcription protects polyadenylation site cleavage from inhibition by DNA damage
Authors: Sfaxi Rym , Biswas Biswendu , Boldina Galina , Cadix Mandy , Servant Nicolas , Chen Huimin , Larson Daniel R. , Dutertre Martin , Robert Caroline , Vagner Stéphan 
Published: May 2022

AbstractPre-mRNA 3’-end processing by cleavage and polyadenylation (CPA) is a nuclear process in which RNA polymerase II (Pol II) transcripts are cleaved at the polyadenylation site (PAS cleavage) before addition of a poly(A) tail. While PAS cleavage is usually coupled to transcription termination, for some pre-mRNAs it occurs post-transcriptionally, i.e. after pre-mRNA release from chromatin to nucleoplasm through a downstream co-transcriptional cleavage (CoTC) event. DNA-damaging agents such as ultraviolet-C (UV) irradiation trigger rapid shutdown of pre-mRNA 3’-end processing. However, specific compensatory mechanisms exist to ensure efficient 3’-end processing for some pre-mRNAs encoding proteins involved in the DNA damage response (DDR), such as the p53 tumor suppressor protein. Here, we show that PAS cleavage of the p53 pre-mRNA occurs in part post-transcriptionally, in a PCF11-independent manner, in the nucleoplasm, following a CoTC-type event. Upon UV-irradiation, cells with an engineered deletion of the p53 CoTC site exhibit impaired 3’-end processing of the p53 pre-mRNA, decreased mRNA and protein levels of p53 and its transcriptional target, p21, and altered cell cycle progression. Finally, using a transcriptome-wide analysis of PAS cleavage, we identified additional-including DDR related-pre-mRNAs whose PAS cleavage is maintained in response to UV and occurs post-transcriptionally. These findings indicate that CoTC-type cleavage of pre-mRNAs, followed by PAS cleavage in the nucleoplasm, allows specific pre-mRNAs to escape 3’-end processing inhibition in response to UV-induced DNA damage.
Representing linguistic communicative goals in the premotor cortex
Authors: Chang Wenshuo , Wang Lihui , Yang Ruolin , Wang Xingchao , Gao Zhixian , Zhou Xiaolin 
Published: May 2022

SummaryLinguistic communication is often regarded as an action conveying the speaker’s communicative goal to the addressee. With both correlational (an fMRI study) and causal (a lesion study) evidence, we demonstrated that communicative goals are represented in human premotor cortex. Participants read scripts each containing a sentence said by the speaker with a goal of either a promise, a request, or a reply. The fMRI results showed that the premotor cortex represented more information on communicative goals than the perisylvian language regions. The lesion study results showed that, relative to healthy controls, the understanding of communicative goals was impaired in patients with lesions in the premotor cortex, whereas no reliable difference between the healthy controls and lesion controls. These findings convergently suggest that the premotor cortex is crucial for representing the goals conveyed by language, supporting the theoretical view that linguistic communication can be seen as a goal-directed action.
Population History and Genome Wide Association Studies of Birth Weight in a Native High Altitude Ladakhi Population
Authors: Bhandari Sushil , Dolma Padma , Mukerji Mitali , Prasher Bhavana , Montgomery Hugh , Kular Dalvir , Jain Vandana , Dadhwal Vatsla , Williams David J , Bhattacharyaa Aniket , Gilbert Edmund , Cavalleri Gianpiero L , Hillman Sara L 
Published: May 2022

AbstractPathological low birth weight due to fetal growth restriction (FGR)is an important predictor of adverse obstetric and neonatal outcomes. It is more common amongst native lowlanders when gestating in the hypoxic environment of high altitude, whilst populations who have resided at high altitude for many generations are relatively protected. Genetic study of pregnant populations at high altitude permits exploration of the role of hypoxic in FGR pathogenesis, and perhaps of FGR pathogenesis more broadly.We studied the umbilical cord blood DNA of 316 neonates born to pregnant women managed at the Sonam Norboo Memorial Hospital, Ladakh (altitude 3540m) between February 2017-January 2019. Principal component, admixture and genome wide association studies (GWAS) were applied to dense single nucleotide polymorphism (SNP) genetic data, to explore ancestry and genetic predictors of low birth weight.Our findings support Tibetan ancestry in the Ladakhi population, with subsequent admixture with neighboring Indo-Aryan populations. Fetal growth protection was evident in Ladakhi neonates. Although no variants achieved genome wide significance, we observed nominal association of seven variants across genes (ZBTB38, ZFP36L2, HMGA2, CDKAL1, PLCG1) previously associated with birthweight.
Signaling dynamics distinguish high and low priority neutrophil attractant receptors
Authors: Lundgren Stefan M. , Rocha-Gregg Briana L. , Akdoǧan Emel , Mysore Maya N. , Hayes Samuel L. , Collins Sean R. 
Published: May 2022

ABSTRACTHuman neutrophils respond to multiple chemical attractants to guide their migration from the vasculature to sites of infection and injury, where they clear pathogens and amplify inflammation. To properly focus their responses during this complex navigation, neutrophils distinguish between attractants to modulate their responses. They prioritize pathogen and injury derived signals over long-range inflammatory signals secreted by host cells. Different attractants can also drive qualitatively different modes of migration. As receptors recognizing both classes of attractant couple to Gαi G-proteins, it remains unclear how downstream signaling pathways distinguish and prioritize between the inputs. Here, we use live-cell imaging to demonstrate that the responses differ in their signaling dynamics: low priority attractants cause transient responses, while responses to high priority attractants are sustained. We observe this difference in both primary neutrophils and differentiated HL-60 cells, for signaling outputs of calcium, a major regulator of secretion, and Cdc42, a primary regulator of polarity and cell steering. We find that the rapid attenuation of Cdc42 activation in response to LTB4 depends on the threonine 308 and serine 310 phosphorylation sites in the C-terminal tail of its receptor LTB4R, in a manner independent of endocytosis. Mutation of these residues to alanine impairs attractant prioritization, although it does not affect attractant-dependent differences in migration persistence. Our results indicate that distinct temporal regulation of shared signaling pathways distinguishes receptors and contributes to chemoattractant prioritization.
How did the COVID-19 lockdown impact patients with dual diagnoses?
Authors: Ghosh Abhishek , Bn Subodh , Sharma Kshitiz , Roub Fazl e , Mahintamani Tathagata , Basu Debasish , Mattoo Surendra Kumar 
Published: May 2022

Purpose
Individuals with dual diagnoses might experience significant clinical and social vulnerabilities during the pandemic and lockdown. This study aims to compare medication adherence, substance use, clinical stability and overall functioning before and during lockdown periods.

Design/methodology/approach
This was a cross-sectional survey among patients registered in dual diagnosis clinic of an addiction psychiatry center in Northern India between March 2019 and February 2020. This study approached 250 patients for telephonic interviews. This study assessed adherence to medications with the brief adherence rating scale (BARS). Global functioning was measured by global assessment of functioning. Clinical interviews assessed substance use and the clinical status of psychiatric disorders.

Findings
One hundred fifty patients were recruited. The mean age of the sample was 35.8 years. The sample had a slight preponderance of alcohol dependence. Depressive disorder was the largest category of psychiatric diagnosis. Compared to prelockdown period, during the lockdown, there were an increased number of days of nonadherence (X2 17.61, p <  0.05), proportion of patients underdosing (X2 8.96, p = 0.003) and lower BARS scores (t = 10.52, df = 144, p < 0.0001). More patients were abstinent from substances during the lockdown (X2 49.02, p < 0.0001). Clinical stability of psychiatric disorders did not differ during the two-time points, but overall functioning decreased during the lockdown (t = 2.118, p = 0.036). This study observed a small positive correlation (r = 0.2, p = 0.02) between functioning and adherence levels.

Originality/value
Lockdown was associated with poor medication adherence, change in substance use patterns and functional impairment. In the future, treatment programs and policies must take preemptive steps to minimize the effects of restrictions.
Idiosyncratic volatility, turnover and the cross-section of stock returns: evidence from the Korean stock market
Authors: Kim Jungmu , Lee Changjun , Lee Woo-Hyuk , Ok Youngkyung , Truong Thuy Thi Thu 
Published: May 2022

PurposeThe authors aim to understand the driving forces behind the idiosyncratic volatility puzzle in the Korean stock market. The authors study the Korean stock market because previous works report a strong idiosyncratic volatility puzzle in Korea, and the market for the exchange-traded funds (ETFs) including low volatility ETFs has experienced drastic growth in Korea.Design/methodology/approachUsing common stocks listed either on KOSPI or KOSDAQ over the period 1997–2016, the authors estimate idiosyncratic volatility using the Fama–French three-factor model. In addition, based on prior literature, the authors use turnover as a proxy for overvaluation. The authors then study the role of turnover in understanding the idiosyncratic volatility puzzle in Korea.FindingsThe authors find that turnover is highly associated with idiosyncratic volatility. Turnover is extremely large among firms with high idiosyncratic volatility and the puzzle disappears after we control for turnover, meaning that turnover subsumes the explanatory power of idiosyncratic volatility for equity returns. The authors also find underperformance of stocks with high turnover and high idiosyncratic volatility exclusively during earnings announcement periods. Overall, our finding implies that the puzzle arises since high idiosyncratic volatility stocks due to high turnover are overvalued and experience correction afterwards.Originality/valueLiterature has suggested explanations based on lottery preferences of investors and market frictions behind the idiosyncratic volatility puzzle. What makes our study distinct from previous work is that we find the role of turnover in understanding the idiosyncratic volatility puzzle using turnover measure as a proxy for overvaluation in the Korean stock market.