bluuebunny/crossref_metadata_2025_split huggingface dataset:
Location specific small RNA annealing to the HCV 5’ UTR promotes Hepatitis C Virus replication by favoring IRES formation and stimulating virus translation
Authors: Kunden Rasika D. , Ghezelbash Sarah , Khan Juveriya Q. , Wilson Joyce A. 
Published: March 2020

ABSTRACTHepatitis C virus (HCV) genome replication requires annealing of a liver specific small-RNA, miR-122 to 2 sites on 5’ untranslated region (UTR). Annealing has been reported to a) stabilize the genome, b) promote translation, and c) induce the canonical HCV 5’ UTR Internal Ribosome Entry Site (IRES) structure. In this report we identify the relative impact of small RNA annealing on the three functions ascribed to miR-122 and generate a mechanistic model for miR-122 promotion of HCV. First, we identified that perfectly complementary small RNAs that anneal to different locations on the HCV 5’ UTR stimulate replication with varying efficiencies and mapped the region on the HCV genome to which small RNA annealing promotes virus replication. Second, by using a panel of small RNAs that promote with varying efficiencies we link HCV replication induction with translation stimulation and 5’ UTR RNA structure modifications. However, replication promotion was not linked to genome stabilization since all small RNAs tested could stabilize the viral genome regardless of their ability to promote replication. Thus, we propose that miR-122 annealing promotes HCV replication primarily by activating the HCV IRES and stimulating translation, and that miR-122-induced HCV genome stabilization is insufficient alone but enhances virus replication.Graphical Abstract
Resolving fate and transcriptome of hematopoietic stem cell clones
Authors: Pei Weike , Shang Fuwei , Wang Xi , Fanti Ann-Kathrin , Greco Alessandro , Busch Katrin , Klapproth Kay , Zhang Qin , Quedenau Claudia , Sauer Sascha , Feyerabend Thorsten B. , Höfer Thomas , Rodewald Hans-Reimer 
Published: March 2020

AbstractAdult bone marrow harbors a mosaic of hematopoietic stem cell (HSC) clones of embryonic origin, and recent work suggests that such clones may have coherent lineage fates. To probe under physiological conditions whether HSC clones with different fates are transcriptionally distinct, we developedPolyloxExpress– a Cre recombinase-dependent DNA substrate for in situ barcoding that allows parallel readout of barcodes and transcriptomes in single cells. We describe differentiation-inactive, multilineage and lineage-restricted HSC clones, find that they reside in distinct regions of the transcriptional landscape of hematopoiesis, and identify corresponding gene signatures. All clone types contain proliferating HSCs, indicating that differentiation-inactive HSCs can undergo symmetric self-renewal. Our work establishes an approach for studying determinants of stem cell fate in vivo and provides molecular evidence for fate coherence of HSC clones.
Explicit feedback and instruction do not change shoulder muscle activity reduction after shoulder fixation
Authors: Maeda Rodrigo S. , Zdybal Julia M. , Gribble Paul L. , Pruszynski J. Andrew 
Published: March 2020

AbstractGenerating pure elbow rotation requires contracting muscles at both the shoulder and elbow joints to counter torques that arise at the shoulder when the forearm rotates (i.e., intersegmental dynamics). Previous work has shown that human participants learn to reduce their shoulder muscle activity if the same elbow movement is performed after the shoulder joint is mechanically locked, which is appropriate because locking the shoulder joint eliminates the torques that arise at the shoulder when the forearm rotates. However, this learning is slow (i.e., it unfolds over hundreds of trials) and incomplete (i.e., shoulder activity is not fully eliminated). Here we investigated whether and how the addition of explicit strategies and biofeedback modulate this type of learning. Three groups of human participants (N = 55) performed voluntary pure elbow rotations using a robotic exoskeleton that permits shoulder and elbow rotation in a horizontal plane. Participants did the task with the shoulder free to move (baseline), then with the shoulder joint locked by the robotic manipulandum (adaptation), and then with the shoulder free to move again (post-adaptation). The first group of participants performed this protocol and received no instructions about what to do after their shoulder was locked. The second group of participants received visual feedback about their shoulder muscle activity after each movement and was instructed to reduce their shoulder activity to zero. The third group of participants also received visual biofeedback, but it was removed part way through the experiment. We found that, although all groups learned, the rate and magnitude of learning was not reliably different across the groups. Taken together, our results suggest that learning new arm dynamics, unlike other motor learning paradigms, unfolds independent of explicit instructions, biofeedback and task instructions.
Opposing influence of top-down and bottom-up input on different types of excitatory layer 2/3 neurons in mouse visual cortex
Authors: Jordan Rebecca , Keller Georg B. 
Published: March 2020

ABSTRACTProcessing in cortical circuits is driven by combinations of cortical and subcortical inputs. These signals are often conceptually categorized as bottom-up input, conveying sensory information, and top-down input, conveying contextual information. Using intracellular recordings in mouse visual cortex, we measured neuronal responses to visual input, locomotion, and visuomotor mismatches. We show that layer 2/3 (L2/3) neurons compute a difference between top-down motor-related input and bottom-up visual flow input. Most L2/3 neurons responded to visuomotor mismatch with either hyperpolarization or depolarization, and these two response types were associated with distinct physiological properties. Consistent with a subtraction of bottom-up and top-down input, visual and motor-related inputs had opposing influence in L2/3 neurons. In infragranular neurons, we found no evidence of a difference-computation and responses were consistent with a positive integration of visuomotor inputs. Our results provide evidence that L2/3 functions as a bidirectional comparator of top-down and bottom-up input.
Disease stage-specific pathogenicity of CD138 (syndecan 1)-expressing T cells in systemic lupus erythematosus
Authors: Liu Lunhua , Takeda Kazuyo , Akkoyunlu Mustafa 
Published: March 2020

ABSTRACTObjectiveTo identify and characterize CD138 (syndecan 1)-expressing T cells in SLE-prone mice.MethodsWe characterized CD138-expressing T cells in MRL/Lpr mice by flow cytometry assay and by gene analysis. Functional properties of TCRβ+CD138+ cells were assessed either by activating through TCR or by co-incubating with purified B cells in the presence of auto-antigens. Purified TCRβ+CD138+ cells were adoptively transferred into MRL/Lpr mice and lupus disease was assessed by measuring serum auto-antibodies, proteinuria and by histopathological evaluation of kidney.ResultsWe found that the frequency of TCRβ+CD138+ cells was significantly higher in MRL/Lpr mice than in wild-type MRL mice (p < 0.01), and the increase in their numbers correlated with disease severity. Majority of the TCRβ+CD138+ cells were CD4 and CD8 double-negative and 20% were CD4. Compared to TCRβ+CD138− cells, TCRβ+CD138+ cells exhibited central memory phenotype with reduced ability to proliferate, and produce the cytokines IFNγ and IL-17. When co-cultured with B cells, the ability of TCRβ+CD138+ cells to promote plasma cell formation and autoreactive antibody production was dependent on the presence of auto-antigens and CD4 co-receptor expression. Surprisingly, adoptively transferred TCRβ+CD138+ cells slowed down the disease progression in young MRL/Lpr mice but had the opposite effect when DNA was co-administered or when TCRβ+CD138+ cells were transferred into older MRL/Lpr mice with established disease.ConclusionHere, we provided evidence for the pathogenic role of CD138-expressing T cells when auto-antigens are exposed to immune system. Thus, monitoring the changes in TCRβ+CD138+ cell-frequency may serve as a tool to assess SLE severity. Moreover, CD138-expressing T cells may be targeted to alleviate lupus progression.
Glucose Production and Glucose Disposal Integrated by an Intrinsic Inverse Coupling in Vivo: hypothesis of inter-organ reflex on glucose regulation
Authors: Liu Nan , Zou Wei , Xing Ying , Zhang Xi , Song Bin , Wang Chen 
Published: March 2020

ABSTRACTGlucose production (GP) and glucose disposal (Rd) are two decisive and fundamental parameters in glucose turnover and in glucose homeostasis regulation. In conventional theory, GP and Rd were responsive to regulatory factors respectively and independently of each other. Even though GP and Rd responded in reverse to insulin, GP for suppression and Rd for elevation, these inverse alterations used to be attributed to insulin multiple functions both on hepatic GP, directly or indirectly, and on whole-body glucose Rd. However, in the present study, we found GP and Rd were inversely coupled intrinsically no matter which side was the target of insulin by comparison of Rd and GP data pairs between peripheral vein insulin infusion protocol and portal vein insulin infusion protocol in rats. Furthermore, neither circulating NEFA nor HFD induced resistance broke the GP-Rd inverse coupling, but both of them reduced the responses of both GP and Rd to insulin. In conclusion, we provide the evidence that GP and Rd are two coupled parameters in vivo and they alter in reverse simultaneously, the mechanism under which needs further investigation but we tend to believe an inter-organ neural reflex was involved.
Acute gastrointestinal injury in critically ill patients with coronavirus disease 2019 in Wuhan, China
Authors: Sun Jia-Kui , Zou Lei , Liu Ying , Zhang Wen-Hao , Li Jing-Jing , Kan Xiao-Hua , Chen Jiu-Dong , Shi Qian-Kun , Yuan Shou-Tao , Gu Wei , Qi Jian-Wei 
Published: March 2020

AbstractBackgroundTo investigate the prevalence and outcomes of acute gastrointestinal injury (AGI) in critically ill patients with coronavirus disease 2019 (COVID-19).MethodsIn this clinical retrospective study, demographic data, laboratory parameters, AGI grades, clinical severity and outcomes were collected. The primary endpoints were AGI incidence and 28-day mortality, the secondary endpoints were organ dysfunction and septic shock incidence.ResultsFrom February 10 to March 10 2020, 83 critically ill patients of 1314 patients with COVID-19 were enrolled. Seventy-two (86.7%) patients had AGI during hospital stay, of them, 30 had AGI grade I, 35 had AGI grade II, 5 had AGI grade III, and 2 had AGI grade IV. The incidence of AGI grade II and above was 50.6%. As of March 16, 40 (48.2%) patients died within 28 days of admission, the median hospital stay was 12.0 days, ranging from 3 days to 27 days. Multiple organ dysfunction syndrome developed in 58 (69.9%) patients, septic shock in 16 (19.3%) patients. Patients with worse AGI grades had worse clinical variables, higher septic shock incidence and 28-day mortality. Sequential organ failure assessment scores (SOFA) (95% CI, 1.374-2.860; P <0.001), white blood cell (WBC) counts (95% CI, 1.037-1.379; P =0.014), duration of mechanical ventilation (MV) (95% CI, 1.020-1.340; P =0.025) were risk factors for the development of AGI grade II and above. Non-survivors were accompanied by higher incidence of AGI grade III to IV than survivors (17.5% vs. 0.0%, P =0.004).ConclusionsThe AGI incidence was 86.7%, and hospital mortality was 48.2% in critically ill patients with COVID-19. SOFA scores, WBC counts, and duration of MV were risk factors for the development of AGI grade II and above. Patients with worse AGI grades had worse clinical severity variables, higher septic shock incidence and 28-day mortality.
Epidemiological Tools that Predict Partial Herd Immunity to SARS Coronavirus 2
Authors: Kamikubo Yasuhiko , Takahashi Atsushi 
Published: March 2020

SUMMARYThe outbreak of SARS coronavirus 2 (SARS-CoV-2), which occurred in Wuhan, China in December 2019, has caused a worldwide pandemic of coronavirus disease 2019 (COVID-19). However, there is a lack of epidemiological tools to guide effective public policy development. Here we present epidemiological evidence that SARS-CoV-2 S type exited Wuhan or other epicenters in China earlier than L type and conferred partial resistance to the virus on infected populations. Analysis of regional disparities in incidence has revealed that a sharp decline in influenza epidemics is a useful surrogate indicator for the undocumented spread of SARS-CoV-2. The biggest concern in the world is knowing when herd immunity has been achieved and scheduling a time to regain the living activities of each country. This study provides a useful tool to guide the development of local policies to contain the virus.
Myositis associated anti-NT5C1A autoantibody in clinical practice
Authors: Ikenaga Chiseko , Findlay Andrew R. , Goyal Namita A. , Robinson Sarah , Cauchi Jonathan , Hussain Yessar , Wang Leo H. , Kershen Joshua C. , Beson Brent A. , Wallendorf Michael , Bucelli Robert C. , Mozaffar Tahseen , Pestronk Alan , Weihl Conrad C. 
Published: March 2020

ABSTRACTObjectiveTo define the diagnostic utility and clinicopathologic features correlating with anti-cytosolic 5′-nucleotidase 1A (NT5C1A) antibody positivity in idiopathic inflammatory myopathies (IIMs).Methods4987 patients had anti-NT5C1A status clinically tested between 2014 and 2019 in the Washington University neuromuscular clinical laboratory. Using clinicopathologic information available for 630 of these patients, we classified them as inclusion body myositis (IBM), dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), non-specific myositis, or non-inflammatory muscle diseases.ResultsAnti-NT5C1A was found in 182/287 patients with IBM (63%), 11/53 patients with dermatomyositis (21%), 7/27 patients with antisynthetase syndrome (26%), 9/76 patients with IMNM (12%), 20/84 patients with non-specific myositis (24%), and 6/103 patients with non-inflammatory muscle diseases (6%). The sensitivity and specificity of anti-NT5C1A seropositivity for the diagnosis of IBM was 63% and 85%, respectively. Anti-NT5C1A positive IBM patients had a higher frequency of finger flexion weakness (p<0.01) and their biopsies harbored more COX negative fibers (p=0.04). 18% of anti-NT5C1A negative IBM patients seroconverted to anti-NT5C1A positive on repeat testing.ConclusionsThis is the largest description of patients tested by a clinical diagnostic lab for anti-NT5C1A. We confirm the sensitivity and specificity of anti-NT5C1A for IBM and identified clinicopathologic features in IBM which correlate with anti-NT5C1A status. Notably, anti-NT5C1A testing increased both the diagnostic sensitivity and specificity of IBM when combined with patient age, gender and creatine kinase (CK) level. We propose that future IBM diagnostic criteria include anti-NT5C1A testing.
The current state of COVID-19 in Australia: importation and spread
Authors: Liebig Jessica , Jurdak Raja , El Shoghri Ahmad , Paini Dean 
Published: March 2020

AbstractBackgroundThe rapid global spread of coronavirus disease (COVID-19) is unprecedented. The outbreak has quickly spread to more than 100 countries reporting over 100,000 confirmed cases. Australia reported its first case of COVID-19 on 25th January 2020 and has since implemented travel restrictions to stop further introduction of the virus.MethodsWe analysed daily global COVID-19 data published by the World Health Organisation to investigate the spread of the virus thus far. To assess the current risk of COVID-19 importation and local spread in Australia we predict international passenger flows into Australia during 2020.FindingsOur analysis of global data shows that Australia can expect a similar growth rate of reported cases as observed in France and the United States. We identify travel patterns of Australian citizens/residents and foreign travellers that can inform the implementation of new and the alteration of existing travel restrictions related to COVID-19.InterpretationOur findings identify the risk reduction potential of current travel bans, based on the proportion of returning travellers to Australia that are residents or visitors. The similarity of the exponential growth in the epidemic curve in Australia to other countries guides forecasts of COVID-19 growth in Australia, and opportunities for drawing lessons from other countries with more advanced outbreaks.
Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer
Authors: Nicolle Rémy , Blum Yuna , Duconseil Pauline , Vanbrugghe Charles , Brandone Nicolas , Poizat Flora , Roques Julie , Bigonnet Martin , Gayet Odile , Rubis Marion , Dou Samir , Elarouci Nabila , Armenoult Lucile , Ayadi Mira , de Reyniès Aurélien , Giovannini Marc , Grandval Philippe , Garcia Stephane , Canivet Cindy , Cros Jérôme , Bournet Barbara , Buscail Louis ,   BACAP Consortium, Moutardier Vincent , Gilabert Marine , Iovanna Juan , Dusetti Nelson 
Published: March 2020

AbstractBACKGROUNDA significant gap in pancreatic ductal adenocarcinoma (PDAC) patient’s care is the lack of molecular parameters characterizing tumors and allowing a personalized treatment. The goal of this study was to examine whole PDAC transcriptomic profiles to define a signature that would predict aggressiveness and treatment responsiveness better than done until now.METHODS AND PATIENTSTumors were obtained from 76 consecutive resectable (n=40) or unresectable (n=36) tumors. PDAC were transplanted in mice to produce patient-drived xenografts (PDX). PDX were classified according to their histology into five groups, from highly undifferentiated to well differentiated. This classification resulted strongly associated with tumors aggressiveness. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n=598) of resected tumors; ii/ 60 advanced tumors obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumors.RESULTSA unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumors (e.g. 308 consecutive resected PDAC, HR=0.321 95% CI [0.207;0.5] and 60 locally-advanced or metastatic PDAC, HR=0.308 95% CI [0.113;0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumor response: -0.67, p-value < 0.001).CONCLUSIONWe identified a transcriptomic signature (PAMG) that, unlike all other stratification schemas already proposed, classifies PDAC along a continuous gradient. It can be performed on formalin-fixed paraffin-embedded samples and EUS-guided biopsies showing a strong prognostic value and predicting mFOLFIRINOX responsiveness. We think that PAMG could unify all PDAC preexisting classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.Trial RegistrationThe PaCaOmics study is registered atwww.clinicaltrials.govwith registration numberNCT01692873. The validation BACAP study is registered atwww.clinicaltrials.govwith registration numberNCT02818829.
Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala
Authors: Burtscher Johannes , Copin Jean-Christophe , Sandi Carmen , Lashuel Hilal A. 
Published: March 2020

AbstractIncreasing evidence suggests that crosstalk between α-synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinson’s disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinson’s disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology.Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala.We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinson’s disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as α-synuclein pathology in male mice.Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions.Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model.Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinson’s disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of α-synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.
Reconstruction of the Hypothalamo-Neurohypophysial System and Functional Dissection of Magnocellular Oxytocin Neurons in the Brain
Authors: Zhang Bin , Qiu Liyao , Xiao Wei , Ni Hong , Chen Lunhao , Wang Fan , Mai Weihao , Gong Hui , Duan Shumin , Li Anan , Gao Zhihua 
Published: March 2020

SUMMARYThe hypothalamo-neurohypophysial system (HNS), comprising hypothalamic magnocellular neuroendocrine cells (MNCs) and the neurohypophysis, plays a pivotal role in regulating reproduction and fluid homeostasis by releasing oxytocin and vasopressin into the bloodstream. However, it remains incompletely understood on its structure and whether it contributes to the central actions of oxytocin and vasopressin. Using viral tracing and whole brain imaging, we reconstructed the three-dimensional architecture of the HNS and uncovered that subsets of MNCs collaterally project to multiple extrahypothalamic regions. Moreover, selective activation of magnocellular oxytocin neurons promoted peripheral oxytocin release and facilitated central oxytocin-mediated social interactions. Further, MNCs-released oxytocin in the caudate putamen enhanced locomotion to orchestrate social investigation. Our work reveals the previously unrecognized complexity of the HNS and provides structural and functional evidence for MNCs in coordinating both peripheral and central oxytocin-mediated actions, which will shed light on the mechanistic understanding of oxytocin-related psychiatric diseases.