bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic assembly of the calcium hemostasis modulator 1 channel gates ATP permeation
Authors: Ren Yue , Li Yang , Wang Yaojie , Wen Tianlei , Lu Xuhang , Chang Shenghai , Zhang Xing , Shen Yuequan , Yang Xue 
Published: September 2021

SummaryCalcium hemostasis modulator 1 (CALHM1) is a voltage- and Ca2+-gated ATP channel that plays an important role in neuronal signaling. The currently reported CALHM structures are all in an ATP-conducting state, and the gating mechanism of ATP permeation remains elusive. Here, we report three cryo-EM reconstructions ofDanio rerioheptameric CALHM1s with ordered or flexible long C-terminal helices as well asDanio reriooctameric CALHM1 with flexible long C-terminal helices at resolutions of 3.2 Å, 2.9 Å, and 3.5 Å. Structural analysis revealed that the heptameric CALHM1s are in an ATP nonconducting state in which the pore diameter in the middle is approximately 6.6 Å. Compared with those inside the octameric CALHM1s, the N- helices inside heptameric CALHM1s are in the “down” position to avoid steric clash with neighboring TM1 helices. Molecular dynamic simulation shows that the pore size is significantly increased for ATP molecule permeation during the movement of the N- helix from the “down” position to the “up” position. Therefore, we proposed a mechanism in which the “piston-like” motion of the N-helix drives the dynamic assembly of the CALHM1 channel for ATP molecule permeation. Our results provide insights into the ATP permeation mechanism of the CALHM1 channel.
Modelling the potential role of super spreaders on COVID-19 transmission dynamics
Authors: Mushanyu Josiah , Chukwu Williams , Nyabadza Farai , Muchatibaya Gift 
Published: September 2021

AbstractSuperspreading phenomenon has been observed in many infectious diseases and contributes significantly to public health burden in many countries. Superspreading events have recently been reported in the transmission of the COVID-19 pandemic. The present study uses a set of nine ordinary differential equations to investigate the impact of superspreading on COVID-19 dynamics. The model developed in this study addresses the heterogeineity in infectiousness by taking into account two forms of transmission rate functions for superspreaders based on clinical (infectivity level) and social or environmental (contact level). The basic reproduction number has been derived and the contribution of each infectious compartment towards the generation of new COVID-19 cases is ascertained. Data fitting was performed and parameter values were estimated within plausible ranges. Numerical simulations performed suggest that control measures that decrease the effective contact radius and increase the transmission rate exponent will be greatly beneficial in the control of COVID-19 in the presence of superspreading phenomena.
Deficient auditory gamma-BOLD coupling in schizophrenia is related to sensory gating deficits
Authors: Jacob Michael S. , Sargent Kaia , Roach Brian J. , Shamshiri Elhum A. , Mathalon Daniel H. , Ford Judith M. 
Published: September 2021

BackgroundSchizophrenia is associated with aberrant gamma band power, hypothesized to reflect imbalance in the excitation-inhibition (E/I) ratio and undermine neural signal efficiency. Relationships between resting-state gamma, E/I balance, and regional hemodynamics from the fMRI BOLD signal are unknown.MethodsWe recorded simultaneous EEG-fMRI at rest, with eyes open, in people with schizophrenia (n= 57) and people without a psychiatric diagnosis (n= 46) and identified gamma and aperiodic EEG parameters associated with E/I balance. Measures from all EEG channels were entered into a whole-brain, parametric modulation analysis followed by statistical correction for multiple comparisons. Sensory gating was assessed using the Sensory Gating Inventory, and psychotic symptoms were assessed using the Positive and Negative Syndrome Scale.ResultsAcross groups, gamma power modestly predicts a steeper aperiodic slope (greater inhibition), without group differences in either gamma power or aperiodic slope. In schizophrenia, gamma-BOLD coupling was reduced in bilateral auditory regions of the superior temporal gyri and inversely correlated with sensory gating deficits and symptom severity. Analysis of the spectral features of scanner sounds revealed distinct peaks in the gamma range, reflecting a rapidly repeating scanner pulse sound present throughout the resting state recording.ConclusionRegional hemodynamic support for putative inhibitory and excitatory contributions to resting EEG are aberrant in SZ. Deficient gamma coupling to auditory BOLD may reflect impaired gating of fMRI-scanner sound.
Aberrant transcript usage induces homologous recombination deficiency and predicts therapeutic responses
Authors: Kang Hyeon Gu , Hwangbo Haeun , Kim Myung Ji , Kim Sinae , Lee Eun Ji , Park Min Ji , Kim Jae-Weon , Kim Byoung-Gie , Cho Eun-Hae , Chang Suhwan , Lee Jung-Yun , Choi Jung Kyoon 
Published: September 2021

ABSTRACTBRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors causing low precision in predicting samples that will respond to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA damaging agents. Here, we present molecular evidence and clinical utility of transcriptional HRD (tHRD) that is based on aberrant transcript usage (TU) of minor isoforms. Specifically, increased TU of non-functional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Our functional assays validated its association with impaired HR activity. Remarkably, tHRD detection based on the TU pattern of key genes was superior to gHRD or BRCA1/2 screening in accuracy for predicting the responses of cell lines and cancer patients to PARP inhibitors and genotoxic drugs. In particular, this approach demonstrated the capability to reflect functional HR status, particularly when applied to our cohort of olaparib users with acquired platinum resistance in ovarian cancer. Hence, the tHRD-based diagnostic tests are expected to broaden the clinical utility of PARP inhibitors.
Overcoming Tumor Heterogeneity by Ex Vivo Arming of T Cells Using Multiple Bispecific Antibodies
Authors: Park Jeong A , Cheung Nai-Kong V. 
Published: September 2021

ABSTRACTPurposeTumoral heterogeneity is a hallmark of tumor evolution and cancer progression, being a longstanding challenge to targeted immunotherapy. Ex vivo armed T cells (EATs) using IgG-[L]- scFv bispecific antibodies (BsAbs) are potent tumor-specific cytotoxic effectors. To improve the anti-tumor efficacy of EATs against heterogeneous solid tumors, we explored multi-antigen targeting approaches.MethodsEx vivo expanded T cells were armed with BsAbs built on the IgG-[L]-scFv platform, where an anti-CD3 (huOKT3) scFv was attached to the carboxyl end of both light chains of a tumor specific IgG. Multispecificity was created by combining monospecific EATs, combining BsAbs on the same T cell, or combining specificities on the same antibody. Three multi-antigens targeting EAT strategies were tested: (1) pooled EATs (simultaneous combination of monospecific EATs or alternate EATs (alternating combination of monospecific EATs), (2) dual-EATs or multi- EATs (T cells simultaneously armed with ≥ 2 BsAbs), and (3) TriAb-EATs [T cells armed with BsAb specific for two tumor targets besides CD3 (TriAb)]. The properties and efficiencies of these 3 strategies were evaluated by flow cytometry, in vitro cytotoxicity, cytokine release assays, and in vivo studies performed in BALB-Rag2-/-IL-2R-γc-KO (BRG) mice xenografted with cancer cell line (CDX) or patient-derived tumor (PDX).ResultsMulti-EATs retained target antigen specificity and anti-tumor potency. Cytokine release with multi-EATs in the presence of tumor cells was substantially less than when multiple BsAbs were mixed with unarmed T cells. When tested against CDXs or PDXs, dual- or multi-EATs effectively suppressed tumor growth without clinical toxicities. Most importantly, dual- or multi- EATs were highly efficient in preventing clonal escape while mono- or TriAb- EATs were not as efficient.ConclusionArming T cells with multiple BsAbs enabled multi-specific T cell immunotherapy which overcomes tumor heterogeneity without excessive cytokine release.
Drosophila centrocortin is dispensable for centriole duplication but contributes to centrosome separation
Authors: Mehta Dipen S. , Ryder Pearl V. , Lee Jina , Zein-Sabatto Hala , Lerit Dorothy A. 
Published: September 2021

AbstractCentrosomes are microtubule-organizing centers that duplicate exactly once to organize the bipolar mitotic spindle required for error-free mitosis. Prior work indicated that Drosophila centrocortin (cen) is required for normal centrosome separation, although a role in centriole duplication was not closely examined. Through time-lapse recordings of rapid syncytial divisions, we monitored centriole duplication and the kinetics of centrosome separation in control versus cen null embryos. Our data suggest that although cen is dispensable for centriole duplication, it contributes to centrosome separation.
Hopanoids confer robustness to physicochemical variability in the niche of the plant symbiont Bradyrhizobium diazoefficiens
Authors: Tookmanian Elise , Junghans Lisa , Kulkarni Gargi , Ledermann Raphael , Saenz James , Newman Dianne K. 
Published: September 2021

AbstractClimate change poses a threat to soil health and agriculture, but the potential effects of climate change on soil bacteria that can help maintain soil health are understudied. Rhizobia are a group of bacteria that increase soil nitrogen content through a symbiosis with legume plants. The soil and symbiosis are potentially stressful environments, and the soil will likely become even more stressful as the climate changes. Many rhizobia within the bradyrhizobia clade, like Bradyrhizobium diazoefficiens, possess the genetic capacity to synthesize hopanoids, steroid-like lipids similar in structure and function to cholesterol. Hopanoids are known to protect against stresses relevant to the niche of B. diazoefficiens. Paradoxically, mutants unable to synthesize the extended class of hopanoids participate in similarly successful symbioses compared to the wild type, despite being delayed in root nodule initiation. Here, we show that in B. diazoefficiens, the in vitro growth defects of extended hopanoid deficient mutants can be at least partially compensated for by the physicochemical environment, specifically by optimal osmotic and divalent cation concentrations. Through biophysical measurements, we show that extended hopanoids confer robustness to environmental variability. These results help explain the discrepancy between previous in vitro and in planta results and indicate that hopanoids may provide a greater fitness advantage to rhizobia in the variable soil environment than the more controlled environment within root nodules. To improve the legume-rhizobia symbiosis through either bioengineering or strain selection, it will be important to consider the full lifecycle of rhizobia, from the soil to the symbiosis.ImportanceRhizobia, such as B. diazoefficiens, play an important role in the nitrogen cycle by making nitrogen gas bioavailable through symbiosis with legume plants. As climate change threatens soil health, this symbiosis has reentered the spotlight as a more sustainable source of soil nitrogen than the energy-intensive Haber-Bosch process. Efforts to use rhizobia as biofertilizers have been effective; however, long term integration of rhizobia into the soil community has been less successful. This work represents a small step towards improving the legume-rhizobia symbiosis by identifying a cellular component—hopanoid lipids—that confers robustness to environmental stresses rhizobia are likely to encounter in soil microenvironments as sporadic desiccation and flooding events become more common.
Descriptive epidemiology of COVID-19 deaths during the first wave of pandemic in India - a single center experience
Authors: Tendulkar Prakash , Pragya  , Panda Prasan Kumar , Bhadoria Ajeet Singh , Kulshreshtha Poorvi 
Published: September 2021

AbstractBackgroundWith the looming threat of recurrent waves of COVID-19 in the presence of mutated strains, it’s of paramount importance to understand the demographic and clinical attributes of COVID-19 related mortalities in each pandemic waves. This could help policy makers, public health experts, and clinicians to better plan preventive and management strategies to curb COVID-19 related mortality.MethodThis was a hospital record based, retrospective cross-sectional descriptive study, at a tertiary care hospital in Rishikesh, India. The study included all deceased patients between March 2020 and January 2021 (first wave) who tested positive for SARS-CoV-2 by RT-PCR and were hospitalized. The study was done to describe demography, clinical presentation, laboratory parameters, treatment given and associated complications of all COVID-19 deaths.ResultOut of 424 mortalities, 298 (70.38%) were males and 126 (29.62%) were females. Mean age of patients was 55.85 ± 16.24 years, out of which 19.5 percent were less than 45 years old, 33.6 percent were 45 to 60 years old and 41.8% were more than 60 years old. Comorbidity in the form of type 2 diabetes mellitus was present in 41.4% [95% CI (41.4-51.1)], hypertension in 39.8% [95% CI (35.1-44.6)], and coronary artery disease in 15.2% [95% CI (11.8-18.8)]. At the time of presentation, shortness of breath was present in 73.6% [95% CI (69.1 -77.7)], fever in 64.92% [95% CI (60.1-69.4)], and cough in 46.1%, [95% CI (41.1-50.8)]. Deranged laboratory parameters were lymphopenia in 90.2% [95% CI (86.8-92.7)], transaminitis in 59.7% [95% CI (54.8-64.3)], and hypercreatinemia in 37.7% [95% CI (33.1-42.5)]. Complications manifested were acute respiratory distress syndrome in 78.3% [95% CI (74-82.1)] and shock in 54.7% [95% CI (49.8-59.5)]. Median time duration between onset of symptom and hospital admission was 5 days (IQR = 3 - 5 days) and median length of hospital stay was 9 days (IQR = 4 - 14 days).ConclusionDuring first pandemic wave, COVID-19 related mortality was 2.37 times higher among males, 2.14 times in age group >60 than <45 years. Most common associated comorbidities (>40%) were type 2 diabetes mellitus and hypertension. Most common associated symptoms (>60%) were shortness of breath and fever. Lymphopenia was seen in >90% cases while liver involvement in 60% and kidney in 38% cases. Median hospital stay was doubled the pre-hospital illness.
Gene signatures and host-parasite interactions revealed by dual single-cell profiling of Plasmodium vivax liver infection
Authors: Mancio-Silva Liliana , Gural Nil , Wadsworth Marc H. , Butty Vincent L. , Hughes Travis K. , March Sandra , Nerurkar Niketa , Roobsoong Wanlapa , Fleming Heather E. , Whittaker Charlie , Levine Stuart S. , Sattabongkot Jetsumon , Shalek Alex K. , Bhatia Sangeeta N. 
Published: September 2021

SUMMARYMalaria-causing P. vivax parasites can linger in the human liver for weeks to years, and then reactivate to cause recurrent blood-stage infection. While an important target for malaria eradication, little is known about the molecular features of the replicative and non-replicative states of intracellular P. vivax parasites, or the human host-cell responses to them. Here, we leverage a bioengineered human microliver platform to culture Thai clinical isolates of P. vivax in primary human hepatocytes and conduct transcriptional profiling of infected cultures. By coupling enrichment strategies with bulk and single-cell analyses, we captured both parasite and host transcripts in individual hepatocytes throughout the infection course. We defined host- and state-dependent transcriptional signatures and identified previously unappreciated populations of replicative and non-replicative parasites, sharing features with sexual transmissive forms. We found that infection suppresses transcription of key hepatocyte function genes, and that P. vivax elicits an innate immune response that can be manipulated to control infection. Our work provides an extendible framework and resource for understanding host-parasite interactions and reveals new insights into the biology of malaria dormancy and transmission.
The Shigella type III effector protein OspB is a cysteine protease
Authors: Wood Thomas E. , Westervelt Kathleen A. , Yoon Jessica M. , Eshleman Heather D. , Levy Roie , Burnes Henry , Slade Daniel J. , Lesser Cammie F. , Goldberg Marcia B. 
Published: September 2021

AbstractThe type III secretion system is required for virulence of many pathogenic bacteria. Bacterial effector proteins delivered into target host cells by this system modulate host signaling pathways and processes in a manner that promotes infection. Here, we define the activity of the effector protein OspB of the human pathogen Shigella spp., the etiological agent of shigellosis and dysenteric disease. Using the yeast Saccharomyces cerevisiae as a model organism, we show that OspB sensitizes cells to inhibition of TORC1, the central regulator of growth and metabolism. In silico analyses reveal that OspB bears structural homology to bacterial cysteine proteases, and we define a conserved cysteine-histidine catalytic dyad required for OspB function. Using yeast genetic screens, we identify a crucial role for the arginine N-degron pathway in the growth inhibition phenotype and show that inositol hexakisphosphate is an OspB cofactor. We find that a yeast substrate for OspB is the TORC1 component Tco89p, proteolytic cleavage of which generates a C-terminal fragment that is targeted for degradation via the arginine N-degron pathway; processing and degradation of Tco89p is required for the OspB phenotype. In all, we demonstrate that the Shigella T3SS effector OspB is a cysteine protease and decipher its interplay with eukaryotic cell processes.ImportanceShigella spp. are important human pathogens and one of the leading causes of diarrheal mortality worldwide, especially in children. Virulence depends on the Shigella type III secretion system (T3SS), and definition of the roles of the bacterial effector proteins secreted by the T3SS is key to understanding Shigella pathogenesis. The effector protein OspB has been shown to contribute to a range of phenotypes during infection, yet the mechanism of action is unknown. Here, we show that OspB possesses cysteine protease activity in both yeast and mammalian cells, and that enzymatic activity of OspB depends on a conserved cysteine-histidine catalytic dyad. We determine how its protease activity sensitizes cells to TORC1 inhibition in yeast, finding that OspB cleaves a component of yeast TORC1, and that the degradation of the C-terminal cleavage product is responsible for OspB mediated hypersensitivity to TORC1 inhibitors. Thus, OspB is a cysteine protease that depends on a conserved cysteine-histidine catalytic dyad.
Retrovirus-induced leukemia – hijack of T-cell activation mechanisms revealed by single-cell analysis
Authors: Tan Benjy Jek Yang , Sugata Kenji , Reda Omnia , Matsuo Misaki , Uchiyama Kyosuke , Miyazato Paola , Hahaut Vincent , Yamagishi Makoto , Uchimaru Kaoru , Suzuki Yutaka , Ueno Takamasa , Suzushima Hitoshi , Katsuya Hiroo , Tokunaga Masahito , Uchiyama Yoshikazu , Nakamura Hideaki , Sueoka Eisaburo , Utsunomiya Atae , Ono Masahiro , Satou Yorifumi 
Published: September 2021

AbstractHuman T-cell leukemia virus type 1 (HTLV-1) mainly infects CD4+T-cells and induces chronic, persistent infection in infected individuals with some progressing to develop adult T-cell leukemia/lymphoma (ATL). Whilst HTLV-1 alters cellular differentiation, activation and survival, it is unknown whether and how these changes contribute to malignant transformation of infected T-cells. In this study, we used single-cell RNA-Seq and TCR-Seq to investigate T-cell differentiation and HTLV-1-mediated transformation processes. We analyzed 87,742 single cells from peripheral blood of 12 infected and 3 uninfected individuals. Using multiple independent bioinformatic methods, we demonstrated that naïve T-cells dynamically change into activated T-cells including infected cells, which seamlessly transitioned into ATL cells characterized by clonally expanded, highly-activated T-cells. Notably, the more activated ATL cells are, the more they acquire Treg signatures. Intriguingly, HLA class II genes were uniquely induced in infected cells, further upregulated in ATL cells and was induced by viral protein Tax. Functional assays revealed that by upregulating HLA class II, HTLV-1-infected cells can act as tolerogenic antigen presenting cells (APCs) to induce anergy of antigen specific T-cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1-mediated transformation and immune escape at single-cell level.Graphical Abstract
Attention-based deep multiple instances learning for classifying circular RNA and other long non-coding RNA
Authors: Liu Yunhe , Fu Qiqing , peng Xueqing , Zhu Chaoyu , Liu Gang , Liu Lei 
Published: September 2021

AbstractCircular RNA (circRNA) is a distinguishable circular formed long non-coding RNA (lncRNA), which has specific roles in transcriptional regulation, multiple biological processes. The identification of circRNA from other lncRNA is necessary for relevant research. In this study, we designed attention-based multi-instance learning (MIL) network architecture, which can be fed with raw sequence, to learn the sparse features in sequences and accomplish the identification task for circRNAs. The model outperformed previously reported models. Following the effectiveness validation of the attention score by the handwritten digit dataset, the key sequence loci underlying circRNAs recognition were obtained based on the corresponding attention score. Moreover, the motif enrichment analysis of the extracted key sequences identified some of the key motifs for circRNA formation. In conclusion, we designed a deep learning network architecture suitable for gene sequence learning with sparse features and implemented to the circRNA identification, and the network has a strong representation capability with its indication of some key loci.