bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions
Authors: Gwon Mi‐Gyeong , An Hyun‐Jin , Kim Jung‐Yeon , Kim Woon‐Hae , Gu Hyemin , Kim Hyun‐Ju , Leem Jaechan , Jung Hyun Jin , Park Kwan‐Kyu 
Published: November 2019

AbstractKidney fibrosis is a common process of various kidney diseases leading to end‐stage renal failure irrespective of etiology. Myofibroblasts are crucial mediators in kidney fibrosis through production of extracellular matrix (ECM), but their origin has not been clearly identified. Many study proposed that epithelial and endothelial cells become myofibroblasts by epithelial dedifferentiation and endothelial‐mesenchymal transition (EndoMT). TGF‐β1/Smad signaling plays a crucial role in partly epithelial‐mensencymal transition (EMT) and EndoMT. Thus, we designed the TGF‐β1/Smad oligodeoxynucleotide (ODN), a synthetic short DNA containing complementary sequence for Smad transcription factor and TGF‐β1 mRNA. Therefore, this study investigated the anti‐fibrotic effect of synthetic TGF‐β1/Smad ODN on UUO‐induced kidney fibrosis in vivo model and TGF‐β1‐induced in vitro model. To examine the effect of TGF‐β1/Smad ODN, we performed various experiments to evaluate kidney fibrosis. The results showed that UUO induced inflammation, ECM accumulation, epithelial dedifferentiation and EndoMT processes, and tubular atrophy. However, synthetic TGF‐β1/Smad ODN significantly suppressed UUO‐induced fibrosis. Furthermore, synthetic ODN attenuated TGF‐β1‐induced epithelial dedifferentiation and EndoMT program via blocking TGF‐β1/Smad signaling. In conclusion, this study demonstrated that administration of synthetic TGF‐β1/Smad ODN attenuates kidney fibrosis, epithelial dedifferentiation, and EndoMT processes. The findings propose the possibility of synthetic ODN as a new effective therapeutic tool for kidney fibrosis.
Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling
Authors: Hollenhorst Monika I. , Jurastow Innokentij , Nandigama Rajender , Appenzeller Silke , Li Lei , Vogel Jörg , Wiederhold Stephanie , Althaus Mike , Empting Martin , Altmüller Janine , Hirsch Anna K. H. , Flockerzi Veit , Canning Brendan J. , Saliba Antoine‐Emmanuel , Krasteva‐Christ Gabriela 
Published: November 2019

AbstractFor protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter “taste” substances are most probably initiated by tracheal brush cells (BC). Our single‐cell RNA‐seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5). We directly demonstrate the secretion of acetylcholine (ACh) from BC upon stimulation with the Tas2R agonist denatonium. Inhibition of the taste transduction cascade abolished the increase in [Ca2+]i in BC and subsequent ACh‐release. ACh‐release is regulated in an autocrine manner. While the muscarinic ACh‐receptors M3R and M1R are activating, M2R is inhibitory. Paracrine effects of ACh released in response to denatonium included increased [Ca2+]i in ciliated cells. Stimulation by denatonium or with Pseudomonas quinolone signaling molecules led to an increase in mucociliary clearance in explanted tracheae that was Trpm5‐ and M3R‐mediated. We show that ACh‐release from BC via the bitter taste cascade leads to immediate paracrine protective responses that can be boosted in an autocrine manner. This mechanism represents the initial step for the activation of innate immune responses against pathogens in the airways.
Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer
Authors: Matos Carolina O. , Passos Yulli M. , do Amaral Mariana J. , Macedo Bruno , Tempone Matheus H. , Bezerra Ohanna C. L. , Moraes Milton O. , Almeida Marcius S. , Weber Gerald , Missailidis Sotiris , Silva Jerson L. , Uversky Vladimir N. , Pinheiro Anderson S. , Cordeiro Yraima 
Published: November 2019

AbstractStructural conversion of cellular prion protein (PrPC) into scrapie PrP (PrPSc) and subsequent aggregation are key events associated with the onset of transmissible spongiform encephalopathies (TSEs). Experimental evidence supports the role of nucleic acids (NAs) in assisting this conversion. Here, we asked whether PrP undergoes liquid‐liquid phase separation (LLPS) and if this process is modulated by NAs. To this end, two 25‐mer DNA aptamers, A1 and A2, were selected against the globular domain of recombinant murine PrP (rPrP90‐231) using SELEX methodology. Multiparametric structural analysis of these aptamers revealed that A1 adopts a hairpin conformation. Aptamer binding caused partial unfolding of rPrP90‐231 and modulated its ability to undergo LLPS and fibrillate. In fact, although free rPrP90‐231 phase separated into large droplets, aptamer binding increased the number of droplets but noticeably reduced their size. Strikingly, a modified A1 aptamer that does not adopt a hairpin structure induced formation of amyloid fibrils on the surface of the droplets. We show here that PrP undergoes LLPS, and that the PrP interaction with NAs modulates phase separation and promotes PrP fibrillation in a NA structure and concentration‐dependent manner. These results shed new light on the roles of NAs in PrP misfolding and TSEs.
Labelling chest x-ray reports using an open-source NLP and ML tool for text data binary classification
Authors: Towfighi Sohrab , Agarwal Arnav , Mak Denise Y. F. , Verma Amol 
Published: November 2019

AbstractThe chest x-ray is a commonly requested diagnostic test on internal medicine wards which can diagnose many acute pathologies needing intervention. We developed a natural language processing (NLP) and machine learning (ML) model to identify the presence of opacities or endotracheal intubation on chest x-rays using only the radiology report. This a preliminary report of our work and findings. Using the General Medicine Inpatient Initiative (GEMINI) dataset, housing inpatient clinical and administrative data from 7 major hospitals, we retrieved 1000 plain film radiology reports which were classified according to 4 labels by an internal medicine resident. NLP/ML models were developed to identify the following on the radiograph reports: the report is that of a chest x-ray, there is definite absence of an opacity, there is definite presence of an opacity, the report is a follow-up report with minimal details in its text, and there is an endotracheal tube in place. Our NLP/ML model development methodology included a random search of either TF-IDF or bag-of-words for vectorization along with random search of various ML models. Our Python programming scripts were made publicly available on GitHub to allow other parties to train models using their own text data. 100 randomly generated ML pipelines were compared using 10-fold cross validation on 75% of the data, while 25% of the data was left out for generalizability testing. With respect to the question of whether a chest x-ray definitely lacks an opacity, the model’s performance metrics were accuracy of 0.84, precision of 0.94, recall of 0.81, and receiver operating characteristic area under curve of 0.86. Model performance was worse when trained against a highly imbalanced dataset despite the use of an advanced oversampling technique.
Far from MCAR: obtaining population-level estimates of HIV viral suppression
Authors: Balzer Laura B. , Ayieko James , Kwarisiima Dalsone , Chamie Gabriel , Charlebois Edwin D. , Schwab Joshua , van der Laan Mark J. , Kamya Moses R. , Havlir Diane V. , Petersen Maya L. 
Published: November 2019

ABSTRACTBackgroundPopulation-level estimates of disease prevalence and control are needed to assess the effectiveness of prevention and treatment strategies. However, available data are often subject to differential missingness. Consider population-level HIV viral suppression: proportion of all HIV-positive persons who are suppressing viral replication. Individuals with measured HIV status, and, among HIV-positive individuals, those with measured viral suppression are likely to differ from those without such measurements.MethodsWe discuss three sets of assumptions sufficient to identify population-level suppression over time in the intervention arm of the SEARCH Study (NCT01864603), a community randomized trial in rural Kenya and Uganda (2013-2017). Using data on nearly 100,000 participants, we compare estimates from an unadjusted approach assuming data are missing-completely-at-random (MCAR); stratification on age group, sex, and community; and, targeted maximum likelihood estimation (TMLE) with Super Learner to adjust for baseline and time-updated predictors of measurement.ResultsDespite high annual coverage of testing, estimates of population-level viral suppression varied by identification assumption. Unadjusted estimates were most optimistic: 50% of HIV-positive persons suppressed at baseline, 80% at Year 1, 85% at Year 2, and 85% at Year 3. Stratification on baseline predictors yielded slightly lower estimates, and full adjustment reduced estimates further: 42% of HIV-positive persons suppressed at baseline, 71% at Year 1, 76% at Year 2, and 79% at Year 3.ConclusionsEstimation of population-level disease burden and treatment coverage require appropriate adjustment for missingness. Even in “Big Data” settings, estimates relying on the MCAR assumption or baseline stratification should be interpreted with caution.
Cancer Predisposition Sequencing Reporter (CPSR): a flexible variant report engine for high-throughput germline screening in cancer
Authors: Nakken Sigve , Saveliev Vladislav , Hofmann Oliver , Møller Pål , Myklebost Ola , Hovig Eivind 
Published: November 2019

AbstractThe value of high-throughput germline genetic testing is increasingly recognized in clinical cancer care. Disease-associated germline variants in cancer patients are important for risk management and surveillance, surgical decisions, and can also have major implications for treatment strategies since many are in DNA repair genes. With the increasing availability of high-throughput DNA sequencing in cancer clinics and research, there is thus a need to provide clinically oriented sequencing reports for germline variants and their potential therapeutic relevance on a per-patient basis. To meet this need we have developed the Cancer Predisposition Sequencing Reporter (CPSR), an open-source computational workflow that generates a structured report of germline variants identified in known cancer predisposition genes, highlighting markers of therapeutic, prognostic, and diagnostic relevance. A fully automated variant classification procedure based on more than 30 refined ACMG criteria represents an integral part of the workflow. Importantly, the set of cancer predisposition genes profiled in the report can be flexibly chosen from more than 40 virtual gene panels established by scientific experts, enabling customization of the report for different screening purposes and clinical contexts. The report can be configured to also list actionable secondary variant findings as recommended by ACMG, as well as the status of low-risk variants from genome-wide association studies in cancer. CPSR demonstrates superior sensitivity and comparable specificity for the detection of pathogenic variants when compared to existing algorithms. Technically, the tool is implemented in Python/R, and is freely available through Docker technology. Source code, documentation, example reports, and installation instructions are accessible via the project GitHub page: https://github.com/sigven/cpsr.
Transcranial Magnetic Stimulation-induced motor cortex activity influences visual awareness judgments
Authors: Hobot Justyna , Koculak Marcin , Paulewicz Borysław , Sandberg Kristian , Wierzchoń Michał 
Published: November 2019

AbstractThe influence of non-visual information on visual awareness judgments has recently gained substantial interest. Using single-pulse Transcranial Magnetic Stimulation (TMS), we investigate the potential contribution of evidence from the motor system to judgment of visual awareness. We hypothesized that TMS-induced activity in the primary motor cortex (M1) would increase reported visual awareness as compared to the control condition. Additionally, we investigated whether TMS-induced motor-evoked potential could measure accumulated evidence for stimulus perception. Following stimulus presentation and TMS, participants first rated their visual awareness verbally using the Perceptual Awareness Scale, after which they responded manually to a Gabor orientation identification task. Delivering TMS to M1 resulted in higher average awareness ratings as compared to the control condition, in both correct and incorrect identification task response trials, when the hand with which participants responded was contralateral to the stimulated hemisphere (TMS-response-congruent trials). This effect was accompanied by longer Perceptual Awareness Scale response times, irrespective of the congruence between TMS and identification response. Moreover, longer identification response times were observed in TMS-response-congruent trials in the M1 condition as compared to the control condition. Additionally, the amplitudes of motor-evoked potentials were related to the awareness ratings when response congruence was taken into account. We argue that motor-evoked potential can serve as an indirect measure of evidence accumulated for stimulus perception and that longer Perceptual Awareness Scale response times and higher amplitudes of motor-evoked potentials in the M1 condition reflect integration of additional evidence with visual awareness judgment. In conclusion, we advocate that motor activity influences perceptual awareness judgments.
Testosterone improves muscle function of the extensor digitorum longus in rats with sepsis
Authors: Wang Jinlong , Wu Tong 
Published: November 2019

AbstractAmong patients with Intensive care unit-acquired weakness (ICUAW), skeletal muscle strength often decreases significantly. This study aimed to explore the effects of testosterone propionate on skeletal muscle using rat model of sepsis. Male SD rats were randomly divided into experimental group, model control group, sham operation group and blank control group. Rats in experimental group were given testosterone propionate 2 times a week, 10 mg/kg for 3 weeks. Maximal contraction force, fatigue index and cross-sectional area of the extensor digitorum longus (EDL) were measured. Myosin, IGF-1, p-AKT and p-mTOR levels in EDL were detected by Western blot. Histological changes of the testis and prostate were detected by hematoxylin and eosin staining. We found that maximal contraction force and fatigue index of EDL in experimental group were significantly higher than in model control group. Cross sectional area of fast MHC muscle fiber of EDL in group was significantly higher than in model control group. The levels of myosin, IGF-1, p-AKT and p-mTOR of EDL in experimental group were significantly higher than in model control group. In addition, no testicle atrophy and prostate hyperplasia was detected in experimental group. In conclusion, these results suggest that testosterone propionate can significantly improve skeletal muscle strength, endurance and volume of septic rats, and the mechanism may be related to the activation of IGF-1/AKT pathway. Moreover, testosterone propionate with short duration does not cause testicular atrophy and prostate hyperplasia in septic rats. Therefore, testosterone propionate is a potential treatment for muscle malfunction in ICUAW patients.
The TARANI/ UBIQUITIN SPECIFIC PROTEASE 14 destabilizes the AUX/IAA transcriptional repressors and regulates auxin response inArabidopsis thaliana
Authors: Majumdar Parinita , Karidas Premananda , Siddiqi Imran , Nath Utpal 
Published: November 2019

ABSTRACTAuxin response is regulated by a group of AUX/IAA transcriptional inhibitors that suppress auxin signaling in the absence of the hormone. While the degradation of these proteins upon auxin signaling has been well studied, the molecular control of their rapid turn-over is not clearly understood. Here, we report that the TARANI/ UBIQUITIN PROTEASE 14 protein inArabidopsis thaliana(Arabidopsis) is required for AUX/IAA degradation. Thetnimutation was originally identified in a forward genetic screen to isolate mutants with altered leaf shape. Detailed phenotypic analysis revealed thattnidisplays pleiotropic phenotypic alterations that resemble auxin-related defects. The activity of auxin responsive reportersDR5::GUS,DR5::nYFPandIAA2::GUSwas reduced intniorgans, implying thatTNIis required for normal auxin response. Genetic interaction studies suggested thatTNIacts along withTIR1,ARF7,AUX1andPIN1– molecules involved in auxin signaling or transport. A map-based cloning approach combined with next-generation sequencing identifiedTNIasUBIQUITIN SPECIFIC PROTEASE14which is involved in ubiquitin recycling. Intni, the mutant primary transcript is spliced inefficiently, which is predicted to produce an aberrant protein product in addition to the normal protein, where a polypeptide corresponding to the 3rdintron in inserted in-frame within the Zn-finger domain of UBP14. Thetniplants accumulated poly-ubiquitin chains and excess poly-ubiquitinated proteins due to reduced TNI activity. Improper ubiquitin recycling affected the degradation of DII:VENUS, IAA18:GUS and HS::AXR3-NT:GUS, resulting in their stabilization in thetnimutant. Thus, our study identified a function for TNI/UBP14 in regulating auxin response through ubiquitin recycling.
Lgr5+ telocytes are a signaling hub at the intestinal villus tip
Authors: Halpern Keren Bahar , Massalha Hassan , Zwick Rachel K. , Moor Andreas E. , Castillo-Azofeifa David , Rozenberg Milena , Farack Lydia , Egozi Adi , Miller Dan R. , Averbukh Inna , Harnik Yotam , Weinberg-Corem Noa , de Sauvage Frederic J. , Amit Ido , Klein Ophir D. , Shoshkes-Carmel Michal , Itzkovitz Shalev 
Published: November 2019

AbstractThe intestinal epithelium is a structured organ composed of crypts harboring Lgr5+ stem cells, and villi harboring differentiated cells. Spatial transcriptomics have demonstrated profound zonation of epithelial gene expression along the villus axis, but the mechanisms shaping this spatial variability are unknown. Here, we combined laser capture micro-dissection and single cell RNA sequencing to uncover spatially zonated populations of mesenchymal cells along the crypt-villus axis. These included villus tip telocytes (VTTs) that express Lgr5, a gene previously considered a specific crypt epithelial stem cell marker. VTTs are elongated cells that line the villus tip epithelium and signal through Bmp morphogens and the non-canonical Wnt5a ligand. Their ablation strongly perturbs the zonation of enterocyte genes induced at the villus tip. Our study provides a spatially-resolved cell atlas of the small intestinal stroma and exposes Lgr5+ villus tip telocytes as regulators of the epithelial spatial expression programs along the villus axis.
Welcoming back my arm: Affective touch increases body ownership following right hemisphere stroke
Authors: Jenkinson Paul M. , Papadaki Cristina , Besharati Sahba , Moro Valentina , Gobbetto Valeria , Crucianelli Laura , Kirsch Louise P. , Avesani Renato , Ward Nick S. , Fotopoulou Aikaterini 
Published: November 2019

AbstractRight hemisphere stroke can impair the ability to recognise one’s contralesional body parts as belonging to one’s self. The study of this so-called ‘disturbed sense of limb ownership’ (DSO) can provide unique insights into the neurocognitive mechanisms of body ownership. Here, we address a hypothesis built upon experimental studies on body ownership in healthy volunteers. These studies have shown that affective (pleasant) touch, an interoceptive modality associated with unmyelinated, slow-conducting C tactile afferents, has a unique role in the sense of body ownership. Here we systematically investigated whether affective touch stimulation could increase body ownership in patients with DSO following right hemisphere stroke. An initial feasibility study in 16 adult, acute stroke patients enabled us to optimise and calibrate an affective touch protocol to be administered by the bedside. The main experiment, conducted with a different sample of 26 right hemisphere patients, assessed changes in limb ownership elicited following self-(patient) versus other-(experimenter) generated tactile stimulation, using a velocity known to optimally activate C-tactile fibres (i.e. 3cm/s), and a second velocity that is suboptimal for C-tactile activation (i.e. 18cm/s). We further examined the specificity and mechanism of observed changes in limb ownership in secondary analyses looking at (1) the influence of perceived intensity and pleasantness of touch, (2) touch laterality, and (3) level of DSO on ownership change, as well as (4) changes in unilateral neglect arising from touch. Findings indicated a significant increase in limb ownership following experimenter-administered, CT-optimal touch. Voxel-based Lesion-Symptom Mapping (VLSM) identified damage to the right insula and, more substantially, the right corpus callosum, associated with a failure to increase body ownership following experimenter-administered, affective touch. Our findings suggest that affective touch can increase the sense of body-part ownership following right hemisphere stroke, potentially due to its unique role in the multisensory integration processes that underlie the sense of body ownership.
Statistical prediction of the future impairs episodic encoding of the present
Authors: Sherman Brynn E. , Turk-Browne Nicholas B. 
Published: November 2019

AbstractMemory is typically thought of as enabling reminiscence about past experiences. However, memory also informs and guides processing of future experiences. These two functions of memory are often at odds: remembering specific experiences from the past requires storing idiosyncratic properties that define particular moments in space and time, but by definition such properties will not be shared with similar situations in the future and thus may not be applicable to future situations. We discovered that, when faced with this conflict, the brain prioritizes prediction over encoding. Behavioral tests of recognition and source recall showed that items allowing for prediction of what will appear next based on learned regularities were less likely to be encoded into memory. Brain imaging revealed that the hippocampus was responsible for this interference between statistical learning and episodic memory. The more that the hippocampus predicted the category of an upcoming item, the worse the current item was encoded. This competition may serve an adaptive purpose, focusing encoding on experiences for which we do not yet have a predictive model.