bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fitness landscape of a dynamic RNA structure
Authors: Soo Valerie WC , Swadling Jacob B , Faure Andre J , Warnecke Tobias 
Published: June 2020

ABSTRACTRNA structures are dynamic. As a consequence, mutational effects can be hard to rationalize with reference to a single static native structure. We reasoned that deep mutational scanning experiments, which couple molecular function to fitness, should capture mutational effects across multiple conformational states simultaneously. Here, we provide a proof-of-principle that this is indeed the case, using the self-splicing group I intron from Tetrahymena thermophila as a model system. We comprehensively mutagenized two 4-bp segments of the intron that come together to form the P1 extension (P1ex) helix at the 5’ splice site and, following cleavage at the 5’ splice site, dissociate to allow formation of an alternative helix (P10) at the 3’ splice site. Using an in vivo reporter system that couples splicing activity to fitness in E. coli, we demonstrate that fitness is driven jointly by constraints on P1ex and P10 formation and that patterns of epistasis can be used to infer the presence of intramolecular pleiotropy. Importantly, using a machine learning approach that allows quantification of mutational effects in a genotype-specific manner, we show that the fitness landscape can be deconvoluted to implicate P1ex or P10 as the effective genetic background in which molecular fitness is compromised or enhanced. Our results highlight deep mutational scanning as a tool to study transient but important conformational states, with the capacity to provide critical insights into the evolution and evolvability of RNAs as dynamic ensembles. Our findings also suggest that, in the future, deep mutational scanning approaches might help us to reverse-engineer dynamic interactions and critical non-native states from a single fitness landscape.
Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue
Authors: Cui Xin , Jing Jia , Wu Rui , Cao Qiang , Li Fenfen , Li Ke , Wang Shirong , Yu Liqing , Schwartz Gary , Shi Huidong , Shi Hang , Xue Bingzhong 
Published: June 2020

AbstractActivation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a novel fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NTF3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NTF3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NTF3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NTF3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC+/-). Increasing NTF3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC+/- mice or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NTF3 is an important fat-derived neurotrophic factor regulating SNS innervation, energy metabolism and obesity.
Unlocking Elementary Conversion Modes: ecmtool unveils all capabilities of metabolic networks
Authors: Clement Tom J. , Baalhuis Erik B. , Teusink Bas , Bruggeman Frank J. , Planqué Robert , de Groot Daan H. 
Published: June 2020

AbstractThe metabolic capabilities of cells determine their biotechnological potential, fitness in ecosystems, pathogenic threat levels, and function in multicellular organisms. Their comprehensive experimental characterisation is generally not feasible, particularly for unculturable organisms. In principle, the full range of metabolic capabilities can be computed from an organism’s annotated genome using metabolic network reconstruction. However, current computational methods cannot deal with genome-scale metabolic networks. Part of the problem is that these methods aim to enumerate all metabolic pathways, while computation of all (elementally balanced) conversions between nutrients and products would suffice. Indeed, the elementary conversion modes (ECMs, defined by Urbanczik and Wagner) capture the full metabolic capabilities of a network, but the use of ECMs has not been accessible, until now. We extend and explain the theory of ECMs, implement their enumeration inecmtool, and illustrate their applicability. This work contributes to the elucidation of the full metabolic footprint of any cell.
RNA interference dynamics in juvenileFasciola hepaticaare altered duringin vitrogrowth and development
Authors: McCusker Paul , Hussain Wasim , McVeigh Paul , McCammick Erin , Clarke Nathan G. , Robb Emily , McKay Fiona M. , Brophy Peter M. , Timson David J. , Mousley Angela , Marks Nikki J. , Maule Aaron G. 
Published: June 2020

AbstractFor over a decade RNA interference (RNAi) has been an important molecular tool for functional genomics studies in parasitic flatworms. Despite this, our understanding of RNAi dynamics in many flatworm parasites, such as the temperate liver fluke (Fasciola hepatica), remains rudimentary. The ability to maintain developing juvenile flukein vitroprovides the opportunity to perform functional studies during development of the key pathogenic life stage. Here, we investigate the RNAi competence of developing juvenile liver fluke. Firstly, all life stages examined possess, and express, core candidate RNAi effectors encouraging the hypothesis that all life stages ofF. hepaticaare RNAi competent. RNAi effector analyses supported growing evidence that parasitic flatworms have evolved a separate clade of RNAi effectors with unknown function. Secondly, we assessed the impact of growth / development duringin vitroculture on RNAi inF. hepaticajuveniles and found that during the first week post-excystment liver fluke juveniles exhibit quantitatively lower RNAi mediated transcript knockdown when maintained in growth inducing media. This did not appear to occur in olderin vitrojuveniles, suggesting that rapidly shifting transcript dynamics over the first week following excystment alters RNAi efficacy after a single 24 hour exposure to double stranded (ds)RNA. Finally, RNAi efficiency was found to be improved through use of a repeated dsRNA exposure methodology that has facilitated silencing of genes in a range of tissues, thereby increasing the utility of RNAi as a functional genomics tool inF. hepatica.
MlaFEDB displays flippase activity to promote phospholipid transport towards the outer membrane of Gram-negative bacteria
Authors: Hughes Gareth W. , Sridhar Pooja , Nestorow Stephanie A. , Wotherspoon Peter J. , Cooper Benjamin F. , Knowles Timothy J. 
Published: June 2020

AbstractMlaFEDB is a Gram-negative inner membrane protein complex involved in the inter membrane trafficking of phospholipids. Originally proposed to transport phospholipids in a retrograde direction, recent evidence suggests MlaFEDB may actually export phospholipids from the inner membrane to the periplasmic carrier protein, MlaC, potentially suggesting a role in either anterograde trafficking of phospholipids to the outer membrane or bidirectional phospholipid movement. MlaFEDB is part of the ABC transporter superfamily of proteins and has been shown to hydrolyse ATP through the cytoplasmic facing MlaF component. However, the movement of PLs from FEDB to MlaC has been shown to occur in an ATP independent fashion hence the role of ATP hydrolysis within this complex remains unclear. In this study we sought to elucidate the role of ATP and provide evidence to suggest MlaFEDB has flippase activity, utilising ATP hydrolysis to translocate phospholipids from the outer to the inner leaflet of the IM. We also show that in the absence of ATP MlaFEDB mediates the loading of MlaC with phospholipids directly from the inner leaflet only. Our data provides a novel role for MlaFEDB and presents a link between Mla driven phospholipid transport and ATP hydrolysis.
CD47 prevents the elimination of diseased fibroblasts in scleroderma
Authors: Lerbs Tristan , Cui Lu , King Megan E. , Chai Tim , Muscat Claire , Shibata Tyler , Wernig Gerlinde 
Published: June 2020

AbstractScleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression, but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the “don’t-eat-me-signal” CD47 and whether blocking CD47 enables the body’s immune system to get rid of diseased fibroblasts. To test this approach, we used aJun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated JUN and increased promotor accessibilities of both JUN and the CD47. Next, we established our scleroderma model demonstrating thatJunmediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1-fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study is the first to demonstrate the efficiency of combining different immunotherapies in treating scleroderma and provide a rationale for combining CD47 and IL6 inhibition in clinical trials.
Characterization of alkaline stress tolerance mechanisms inLotusforage species modulated byPantoea eucalypti
Authors: Campestre Maria Paula , Castagno Nazareno Luis , Antonelli Cristian Javier , Maguire Vanina Giselle , Escaray Francisco Jose , Ruiz Oscar Adolfo 
Published: June 2020

AbstractThis study was designed to elucidate the physiological responses of threeLotusforage accessions to alkaline stress and the influence of the inoculation of aPantoea eucalyptiendophyte strain on its mitigation. One-month-old diploid accessions ofLotus corniculatus(Lc) andLotus tenuis(Lt), and the interspecific hybrid LtxLc obtained from these parental accessions, were exposed to alkaline stress (pH 8.2) by the addition of NaHCO310 mM to the nutrient solution for 2 weeks. The results indicated that Lt and the LtxLc hybrid are alkaline-tolerant compared to Lc, based on the observation that their dry mass is not reduced under stress, and symptoms of chlorosis do not appear on leaf blades, in contrast to observations of the Lc accession subjected to identical growth and stress conditions. In Lc and LtxLc accessions, the Fe2+concentration decreased in the aerial part under stress and increased in the roots. Interveinal chlorosis observed in the youngest leaves of Lc during alkaline treatment was accompanied with a higher reduction of Fe2+levels in shoots and a higher increment of Fe2+in roots, compared to the other accession. Plant inoculation also tended to acidify the medium under alkalinity, contributing to Fe accumulation in the roots. Moreover, the inoculation caused a considerable increase in Fe2+content in shoots in all threeLotusforage species under alkaline treatment.Fv/Fmand PIABSwere only reduced in Lc under alkaline treatment. Inoculation reverted this effect and improved the ABS/RC and DIo/RC ratios in all three accessions. In addition, under alkaline conditions, Lc dissipated more energy than control plants. Expression of the metal-transporting gene NRAMP1 increased in the inoculated Lc accession under stress, while remaining unmodified in Lt and LtxLc hybrid.Altogether, the results obtained make clear the importance of inoculation withP. eucalypti, which contributed significantly to the mitigation of alkaline stress. Thus, all the results provide useful information for improving alkaline tolerance traits inLotusforage species and their interspecific hybrids.
When to be a male? Role of resource-limitation and pollinators in determining floral sex in an andromonoecious spiderwort
Authors: Albal Asawari , Azad G , Shrotri Saket , Gowda Vinita 
Published: June 2020

AbstractThe evolution and maintenance of sexual systems in plants is often driven by resource allocation and pollinator preferences, and very little is known about their role in determining floral sex expression in plants. In annual, entomophilous plants three major constraints can be identified towards optimal reproduction: 1) nutrient resources available from the environment, 2) nutrient resources allocated towards reproduction, i.e., fruits vs. flowers, and 3) pollinator visitations.Andromonoecy is a sexual system where plants bear both staminate and hermaphrodite flowers on the same inflorescence. The optimal resource allocation hypothesis suggests that under nutrient constraints, plants will produce more male flowers since they are energetically cheaper to produce over the more expensive hermaphrodite flowers. We test this hypothesis in the andromonoeciousMurdannia simplex(Commelinaceae) by quantifying male and hermaphrodite flowers in a natural population and contrasting the distribution of the two sexes in plants from two resource conditions (stream population vs. plateau population). We next carried out choice experiments to test pollinator preference towards a specific sex.We found that inM. simplex, production of hermaphrodite flowers is resource-dependent and under resource constraints fewer numbers of flowers were produced and most of them were males. We failed to observe pollinator preference towards either sex butAmegilla spp. andApis ceranashowed higher visitation towards the most abundant sex within a trial, suggesting frequency-dependent visitation. Thus, we conclude that environmentally driven resource constraints play a bigger role in driving floral sex expression inMurdanniaover direct pollinator-driven constraints.
Public health interventions in India slowed the spread of COVID-19 epidemic dynamics
Authors: Singh Balbir B , Lowerison Mark , Lewinson Ryan T. , Vallerand Isabelle A. , Deardon Rob , Gill Játinder PS , Gill Baljit Singh , Barkema Herman W 
Published: June 2020

SummaryBackgroundThe government of India implemented social distancing interventions to contain the COVID-19 epidemic. However, effects on epidemic dynamics are yet to be understood.MethodsRates of laboratory-confirmed COVID-19 infections per day and effective reproduction number (Rt) were estimated for 4 periods (Pre-lockdown and Lockdown Phases 1 to 3) according to nationally implemented phased interventions. Adoption of these interventions was estimated using Google mobility data. Estimates at the national level and for 12 Indian states most affected by COVID-19 are presented.FindingsDaily case rates ranged from 0·03 to 30·05/10 million people across 4 discrete periods in India. From May 4-17, 2020, the National Capital Territory (NCT) of Delhi had the highest case rate (222/10 million people/day), whereas Kerala had the lowest (2·18/10 million/day). AverageRtwas 1·99 (95% CI 1·93-2·06) for India; it ranged from 1·38 to 2·78, decreasing over time. Median mobility in India decreased in all contact domains, with the lowest being 21% in retail/recreation (95% CI 13-46%), except home which increased to 129% (95% CI 117-132%) compared to the 100% baseline value.InterpretationThe Indian government imposed strict contact mitigation, followed by a phased relaxation, which slowed the spread of COVID-19 epidemic progression in India. The identified daily COVID-19 case rates andRtwill aid national and state governments in formulating ongoing COVID-19 containment plans. Furthermore, these findings may inform COVID-19 public health policy in developing countries with similar settings to India.FundingNon-funded.
CLINICAL PROPERTIES AND DIAGNOSTIC METHODS OF COVID-19 INFECTION IN PREGNANCIES: META-ANALYSIS
Authors: Uygun-Can Banu , Acar-Bolat Bilge 
Published: June 2020

AbstractWe aimed to summarize reliable medical evidence by the meta-analysis of all published retrospective studies that examined data based on the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by clinical symptoms, molecular (RT-PCR) diagnosis and characteristic CT imaging features in pregnant women. MEDLINE PubMed, SCOPUS, ISI Web of Science, Clinical Key, and CINAHL databases were used to select the studies. Then, 384 articles were received, including the studies until 01/MAY/2020. As a result of the full-text evaluation, 12 retrospective articles covering all the data related were selected. A total of 181 pregnant cases with SARS-CoV-2 infections were included in the meta-analysis within the scope of these articles. According to the results, the incidence of fever was 38.1% (95% CI: 14.2–65%), and cough was 22% (95% CI: 10.8–35.2%) among all clinical features of pregnant cases with SARS-CoV-2 infection. So, fever and cough are the most common symptoms in pregnant cases with SARS-CoV- infection, and 91.8% (95% CI: 76.7–99.9%) of RT-PCR results are positive. Moreover, abnormal CT incidence is 97.9% (95% CI: 94.2–99.9%) positive. No case was death. However, as this virus spreads globally, it should not be overlooked that the incidence will increase in pregnant women and may be in the risky group. RT-PCR and CT can be used together in an accurate and safe diagnosis. In conclusion, these findings will provide important guidance for current studies regarding the clinical features and correct detection of SARS-CoV-2 infection in pregnant women, as well as whether it will create emergency tables that will require the use of a viral drug.
The effect of strict lock down measures on Covid-19 seroprevalence rate and herd immunity
Authors: Sughayer Maher A. , Mansour Asem , Nuirat Abeer Al , Souan Lina , Ghanem Mohammad , Siag Mahmoud 
Published: June 2020

AbstractBackgroundCovid-19 seroprevalence rates and serological tests are important tools in understanding the epidemiology of the disease and help in the fight against it. Seroprevalence rates vary according to the population studied and the test employed and they range from 0.133 to 25.7%. The purpose of this study is to assess the seroprevalence rate in a population of healthy blood donors living under strict lockdown measures in Jordan which has in total 144 confirmed cases per million population.MethodsLeft-over sera and plasma samples from 746 healthy blood donors were tested using a commercially available FDA approved kit having a sensitivity and specificity of 100% and 99.8% respectively. External positive controls were used for validation.ResultsMore than 80% of the donors were men 18-63 year old and residing in the capital city of Jordan, Amman. All tested specimens were negative yielding a zero seroprevalence rate in this healthy blood donor population.ConclusionStrict lockdown measures effectively limit intracommunity spread of the infection, however at the cost of lack of any acquired community immunity. Additionally the use of highly specific test is recommended in low prevalence setting.
Effect of metabolic syndrome components on the risk of malignancy in patients with gallbladder lesions
Authors: Deng Zheng , Xuan Yan , Li Xinxing , Crawford William J , Yuan Zhiqing , Chen Zhoukan , Brooks Anastasia , Liang Xiaowen , Wang Haolu , Chen Tao 
Published: June 2020

AbstractBackground and AimsThe malignant potential of gallbladder lesions is debated, and there is limited guidance on surveillance. Predicting their risk of malignancy could help clinicians manage and potentially improve prognosis. We evaluated the independent and joint effects of metabolic syndrome components on the risk of malignancy among patients with gallbladder lesions.MethodsUsing a multicenter database, consecutive patients with pathologically confirmed gallbladder lesions between 2012 and 2019 were identified. Univariate and multivariate logistic regression analyses were used to evaluate the effects of metabolic syndrome components (diabetes, hypertension, dyslipidemia, obesity) as additive or combined indicators for the risk of malignancy. Unadjusted and adjusted odds ratios were calculated.ResultsOf the 625 patients, 567 patients were identified with benign gallbladder lesions and 58 patients with gallbladder cancer (GBC). Among all metabolic syndrome components, the proportion of GBC patients with dyslipidemia (63.8%) was significantly greater than benign gallbladder polyps (42.2%, P = 0.002). In multivariate logistic regression analysis, dyslipidemia was associated with a 2.67-fold increase in the risk of GBC (95% confidence interval 1.17-6.09). Dyslipidemia is an independent risk factor for malignancy (adjusted odds ratio 2.164, 95% confidence interval 1.165-4.021), regardless of whether the other risk factors and metabolic syndrome components are combined. Dyslipidemia (adjusted odds ratio 2.164, 95% confidence interval 1.165-4.021) and decreased high-density lipoprotein (HDL, adjusted odds ratio 3.035, 95% confidence interval 1.645-5.600) were closely associated with increased risk of malignancy.ConclusionsDyslipidemia is associated with a 2.67-fold increase in the risk of malignancy, regardless of the presence of other metabolic syndrome components. Dyslipidemia is an independent risk factor for malignancy in patients with gallbladder lesions.
Kidney Biomarkers and Major Adverse Kidney Events in Critically Ill Patients
Authors: Flannery Alexander H. , Bosler Katherine , Ortiz-Soriano Victor , Gianella Fabiola , Prado Victor , Toto Robert D. , Moe Orson W. , Neyra Javier A. 
Published: June 2020

AbstractBackgroundSeveral biomarkers of acute kidney injury (AKI) have been examined for their ability to predict AKI earlier than serum creatinine. Few studies have focused on using kidney biomarkers to better predict major adverse kidney events (MAKE), an increasingly used composite outcome in critical care nephrology research.MethodsSingle-center prospective study collecting blood and urine samples from critically ill patients with AKI KDIGO stage 2 or above, and matched controls from a single, tertiary care intensive care unit. Samples were collected at 24-48 hours after AKI diagnosis (cases) or ICU admission (controls), 5-7 days later, and 4-6 weeks following discharge for AKI patients. The primary outcome of interest was MAKE at hospital discharge.ResultsSerum/urinary neutrophil gelatinase-associated lipocalin, serum/urinary cystatin C, and urinary kidney injury molecule-1 early in the AKI or ICU course were all significantly higher in patients with MAKE compared to those not experiencing MAKE at hospital discharge. Serum cystatin C, and to a lesser extent serum NGAL, significantly improved upon a clinical prediction model of MAKE as assessed by the area under the receiver operating characteristic curve.Patients without MAKE experienced a greater decline in serum NGAL from initial measurement to second measurement than those patients experiencing MAKE.ConclusionEarly measures of kidney biomarkers in critically ill patients are associated with MAKE. This relationship appears to be greatest with serum NGAL and cystatin C, which display additive utility to a clinical prediction model. Trending serum NGAL may also have utility in predicting MAKE.