bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic epidemiology of a densely sampled COVID-19 outbreak in China
Authors: Geidelberg Lily , Boyd Olivia , Jorgensen David , Siveroni Igor , Nascimento Fabricia F. , Johnson Robert , Ragonnet-Cronin Manon , Fu Han , Wang Haowei , Xi Xiaoyue , Chen Wei , Liu Dehui , Chen Yingying , Tian Mengmeng , Tan Wei , Zai Junjie , Sun Wanying , Li Jiandong , Li Junhua , Volz Erik M , Li Xingguang , Nie Qing
Published: March 2020

Analysis of genetic sequence data from the SARS-CoV-2 pandemic can provide insights into epidemic origins, worldwide dispersal, and epidemiological history. With few exceptions, genomic epidemiological analysis has focused on geographically distributed data sets with few isolates in any given location. Here we report an analysis of 20 whole SARS-CoV 2 genomes from a single relatively small and geographically constrained outbreak in Weifang, People’s Republic of China. Using Bayesian model-based phylodynamic methods, we estimate a mean basic reproduction number (R0) of 3.47 (95% highest posterior density interval: 1.78-5.47) in Weifang, and a mean effective reproduction number (Rt) that falls below 1 on February 2nd. We further estimate the number of infections through time and compare these estimates to confirmed diagnoses by the Weifang Centers for Disease Control. We find that these estimates are consistent with reported cases and there is unlikely to be a large undiagnosed burden of infection over the period we studied.
Utilization of Electronic Health Records for the Assessment of Adiponectin Receptor Autoantibodies during the Progression of Cardio-metabolic Comorbidities
Authors: Pugia Michael J. , Pradhan Meeta , Qi Rong , Eastes Doreen L. , Geisinger Anna , Mills Bradley J. , Baird Zane , Wijeratne Aruna , McAhren Scott M. , Mosley Amber L. , Shekhar Anantha , Robertson Daniel H.
Published: March 2020

BACKGROUND

Diabetes is a complex, multi-symptomatic disease that drives healthcare costs through its complications as the prevalence of this disease grows rapidly world-wide. Real-world electronic health records (EHRs) coupled with patient biospecimens, biological understanding, and technologies can lead to identification of new diagnostic markers.

METHODS

We analyzed the 20-year EHRs of 1862 participants with midpoint samples (10-year) in an observational study of type 2 diabetes and cardiovascular arterial disease (CVAD) conducted by the Fairbanks Institute to test the diagnostic biomarkers. Participants were assigned to four cohorts (healthy, diabetes, CVAD, CVAD+diabetes) based on EHR data analysis. The immunoassay reference range for circulating autoantibodies against the C-terminal fragment of adiponectin receptor 1 (IgG-CTF) was determined and used to predict outcomes post-sample.

RESULTS

The IgG-CTF reference range was determined [75–821 ng/mL] and out-of-range values of IgG-CTF values predicted increased likelihood of additional comorbidities and mortality determined from the EHRs 10 years after sample collection. The probability of mortality was lower in patients with elevated IgG-CTF >821 ng/mL [OR 0.49–0.0] and higher in patients with lowered IgG-CTF <75 ng/mL [OR 3.74–9.64]. Although many patients at the time of sample collection had other conditions (hypertension, hyperlipidemia, or elevated uristatin values), only hypertension correlated with increased likelihood of mortality (OR 4.36–5.34).

CONCLUSIONS

This study confirms that retrospective analysis of biorepositories coupled with EHRs can provide insight into novel diagnostic markers and the IgG-CTF marker can predict the likelihood of progressing to additional comorbidities or mortality.
Protocol of a randomized controlled trial testing inhaled Nitric Oxide in mechanically ventilated patients with severe acute respiratory syndrome in COVID-19 (SARS-CoV-2)
Authors: Lei Chong , Su Binxiao , Dong Hailong , Bellavia Andrea , Di Fenza Raffaele , Fakhr Bijan Safaee , Gianni Stefano , Grassi Luigi Giuseppe , Pinciroli Riccardo , Vassena Emanuele , Berra Lorenzo
Published: March 2020

Introduction

Severe acute respiratory syndrome (SARS-CoV-2) due to novel Coronavirus (2019-nCoV) related infection (COVID-19) is characterized by severe ventilation perfusion mismatch leading to refractory hypoxemia. To date, there is no specific treatment available for 2019-nCoV. Nitric oxide is a selective pulmonary vasodilator gas used as a rescue therapy in refractory hypoxemia due to acute respiratory distress syndrome (ARDS). In has also shown in-vitro and clinical evidence that inhaled nitric oxide gas (iNO) has antiviral activity against other strains of coronavirus. The primary aim of this study is to determine whether inhaled NO improves oxygenation in patients with hypoxic SARS-CoV2. This is a multicenter randomized controlled trial with 1:1 individual allocation. Patients will be blinded to the treatment.

Methods and analysis

Intubated patients admitted to the intensive care unit with confirmed SARS-CoV-2 infection and severe hypoxemia will be randomized to receive inhalation of NO (treatment group) or not (control group). Treatment will be stopped when patients are free from hypoxemia for more than 24 hours. The primary outcome evaluates levels of oxygenation between the two groups at 48 hours. Secondary outcomes include rate of survival rate at 28 and 90 days in the two groups, time to resolution of severe hypoxemia, time to achieve negativity of SARS-CoV-2 RT-PCR tests.

Ethics and dissemination

The study protocol has been approved by the Investigational Review Board of Xijing Hospital (Xi’an, China) and pending the Partners Human Research Committee (Boston, USA). Recruitment will start after approval of both IRBs and local IRBs at other enrolling centers. Results of this study will be published in scientific journals, presented at scientific meetings, reported through flyers and posters, and published on related website or media in combating against this widespread contagious diseases.

Trial registration

Clinicaltrials.gov. NCT submitted

Strengths and limitations of this study

— Supplementation with nitric oxide (NO) might improve oxygenation and survival of SARS-CoV-2 patients.

— The antiviral activity of NO inhalation will be explored by measuring the time difference between the two groups to reach SARS-CoV-2 RT- PCR negativity.

— The spread of the disease worldwide determines the geographic areas of study and the recruitment rate of patients.
Prospective Evaluation of Transpancreatic Sphincterotomy Comparing to Needle-knife Precut in Difficult Biliary Cannulation: Short-and Long-term Outcomes
Authors: Tabak Fatema , Ji Guo-Zhong , Miao Lin
Published: March 2020

Background/Aims

Transpancreatic sphincterotomy (TPS) can be an alternative approach of biliary access in difficult cannulation cases. We aimed to prospectively evaluate the efficacy and safety of TPS compared to needle-knife precut (NKP), considering the late consequences of both techniques.

Methods

A total of 122 enrolled patients have been divided into three groups based on the applied secondary cannulation techniques. Selective cannulation success, ERCP procedure findings, and immediate adverse events were compared between groups. We investigated the long-term outcomes during six-month after the procedure.

Results

Successful selective cannulation was achieved in 92.9% with TPS similarly to other groups. The mean procedure time was shorter in the TPS group without significant difference. Using TPS did not affect the rate of post-ERCP pancreatitis (PEP) with less frequent post-ERCP bleeding and perforation after TPS compared to NKP, without significant difference. Patients who received TPS, NKP, or both had no symptoms related to papillary stenosis or chronic pancreatitis during the follow-up period.

Conclusions

Using TPS was useful to achieve success cannulation in difficult cases with an acceptable PEP rate. Furthermore, it was associated with reducing bleeding and perforation rates comparing with NKP and no differences related to the long term consequences within the follow-up period.
Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study
Authors: Li Na , Han Lefei , Peng Min , Lv Yuxia , Ouyang Yin , Liu Kui , Yue Linli , Li Qiannan , Sun Guoqiang , Chen Lin , Yang Lin
Published: March 2020

Background

The ongoing epidemics of coronavirus disease 2019 (COVID-19) have caused serious concerns about its potential adverse effects on pregnancy. There are limited data on maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia.

Methods

We conducted a case-control study to compare clinical characteristics, maternal and neonatal outcomes of pregnant women with and without COVID-19 pneumonia.

Results

During January 24 to February 29, 2020, there were sixteen pregnant women with confirmed COVID-19 pneumonia and eighteen suspected cases who were admitted to labor in the third trimester. Two had vaginal delivery and the rest took cesarean section. Few patients presented respiratory symptoms (fever and cough) on admission, but most had typical chest CT images of COVID-19 pneumonia. Compared to the controls, COVID-19 pneumonia patients had lower counts of white blood cells (WBC), neutrophils, C-reactive protein (CRP), and alanine aminotransferase (ALT) on admission. Increased levels of WBC, neutrophils, eosinophils, and CRP were found in postpartum blood tests of pneumonia patients. There were three (18.8%) and two (10.5%) of the mothers with confirmed or suspected COVID-19 pneumonia had preterm delivery due to maternal complications, which were significantly higher than the control group. None experienced respiratory failure during hospital stay. COVID-19 infection was not found in the newborns and none developed severe neonatal complications.

Conclusion

Severe maternal and neonatal complications were not observed in pregnant women with COVID-19 pneumonia who had vaginal delivery or caesarean section. Mild respiratory symptoms of pregnant women with COVID-19 pneumonia highlight the need of effective screening on admission.
Dose-dependent oral glucocorticoid cardiovascular risk in people with immune-mediated inflammatory diseases
Authors: Pujades-Rodriguez Mar , Morgan Ann W , Cubbon Richard M , Wu Jianhua
Published: March 2020

Background

Evidence for the association between glucocorticoid dose and cardiovascular risk is weak for moderate and low doses. To quantify glucocorticoid dose-dependent cardiovascular risk in people with six immune-mediated inflammatory diseases.

Methods and Findings

Population-based cohort analysis of medical records from 389 primary care practices contributing data to the UK Clinical Practice Research Datalink, linked to hospital admissions and deaths in 1998-2017. There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n=25,581), inflammatory bowel disease (n=27,739), rheumatoid arthritis (n=25,324), systemic lupus erythematosus (n=3951), and/or vasculitis (n=5199); and no prior cardiovascular disease (CVD). Mean age was 56 years and 34.1% were men. Median follow-up time was 5.0 years. Time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios of first all-cause and type-specific CVD.

We found 13,426 (15.3%) people with incident CVD, including 6,013 atrial fibrillation, 7,727 heart failure and 2,809 acute myocardial infarction events. At 1 and 5 years, the cumulative risks of all-cause CVD increased from 1.5% in periods of non-use to 9.1% for a daily prednisolone-equivalent dose of ≥25.0mg, and from 7.6% to 29.9%, respectively. We found strong dose-dependent estimates for all immune-mediated diseases (hazard ratio [HR] for <5.0mg daily dose vs. non-use=1.74, 95%CI 1.64-1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus), all cardiovascular outcomes, regardless of disease activity level. The highest estimates were for heart failure and acute myocardial infarction.

Conclusions

We estimated glucocorticoid dose-dependent cardiovascular risk in six immune-mediated diseases. Results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.
Predicting the cumulative number of cases for the COVID-19 epidemic in China from early data
Authors: Liu Z. , Magal P. , Seydi O. , Webb G.
Published: March 2020

We model the COVID-19 coronavirus epidemic in China. We use early reported case data to predict the cumulative number of reported cases to a final size. The key features of our model are the timing of implementation of major public policies restricting social movement, the identification and isolation of unreported cases, and the impact of asymptomatic infectious cases.
The role of the C2A domain of synaptotagmin 1 in asynchronous neurotransmitter release
Authors: Shields Mallory C. , Bowers Matthew R. , Kramer Hannah L. , Fulcer McKenzie M. , Perinet Lara C. , Metz Marissa J. , Reist Noreen E.
Published: March 2020

Following nerve stimulation, there are two distinct phases of Ca2+-dependent neurotransmitter release: a fast, synchronous release phase, and a prolonged, asynchronous release phase. Each of these phases is tightly regulated and mediated by distinct mechanisms. Synaptotagmin 1 is the major Ca2+sensor that triggers fast, synchronous neurotransmitter release upon Ca2+binding by its C2A and C2B domains. It has also been implicated in the inhibition of asynchronous neurotransmitter release, as blocking Ca2+binding by the C2A domain of synaptotagmin 1 results in increased asynchronous release. However, the mutation used to block Ca2+binding in the previous experiments (aspartate to asparagine mutations,sytD-N) had the unintended side effect of mimicking Ca2+binding, raising the possibility that the increase in asynchronous release was an artifact of ostensibly constitutive Ca2+binding. To directly test this C2A inhibition hypothesis, we utilized an alternate C2A mutation that we designed to block Ca2+binding without mimicking it (an aspartate to glutamate mutation,sytD-E). Analysis of both the originalsytD-Nmutation and our alternatesytD-Emutation at theDrosophilaneuromuscular junction showed differential effects on asynchronous release, as well as on synchronous release and the frequency of spontaneous release. Importantly, we found that asynchronous release is not increased in thesytD-Emutant. Thus, our work provides new mechanistic insight into synaptotagmin 1 function during Ca2+-evoked synaptic transmission and demonstrates that Ca2+binding by the C2A domain of synaptotagmin 1 does not inhibit asynchronous neurotransmitter releasein vivo.

Significance statement

This study provides mechanistic insights into synaptotagmin function during asynchronous neurotransmitter release and supports a dramatically different hypothesis regarding the mechanisms triggering asynchronous vesicle fusion. Using two distinct C2A mutations that block Ca2+binding, we report opposing effects on synchronous, spontaneous, and asynchronous neurotransmitter release. Importantly, our data demonstrate that Ca2+binding by the C2A domain of synaptotagmin does not regulate asynchronous release and thus disprove the current inhibition hypothesis. We propose a spatial competition hypothesis to explain these seemingly discordant results of the differing C2A Ca2+binding mutations.
A single cell atlas reveals distinct immune landscapes in transplant and primary tumors that determine response or resistance to immunotherapy
Authors: Wisdom Amy J. , Mowery Yvonne M. , Hong Cierra S. , Qin Xiaodi , Zhang Dadong , Himes Jonathon E. , Chen Lan , Fradin Hélène , Muise Eric S. , Xu Eric S. , Carpenter David J. , Kent Collin L. , Smythe Kimberly S. , Williams Nerissa , Luo Lixia , Ma Yan , Owzar Kouros , Bradley Todd , Kirsch David G.
Published: March 2020

Despite impressive responses in some patients, immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Nearly all preclinical immunotherapy studies utilize transplant tumor models, but cure rates of transplant tumor models treated with immunotherapy often overestimate patient responses. Here, we show that transplant tumors are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous tumors. We generated a single-cell atlas of tumor-infiltrating immune cells from transplant and primary tumors treated with radiation and immunotherapy, which reveals striking differences in their immune landscapes. Although radiotherapy remodels myeloid cell phenotypes in primary and transplant tumors, only transplant tumors are enriched for CD8+ T cells that mediate tumor clearance while mice with primary sarcomas demonstrate tumor-specific tolerance. These results identify distinct microenvironments in tumors that coevolve with the immune system, which promote tolerance that must be overcome for immune-mediated cancer cures.
Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme inde novopyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2
Authors: Xiong Rui , Zhang Leike , Li Shiliang , Sun Yuan , Ding Minyi , Wang Yong , Zhao Yongliang , Wu Yan , Shang Weijuan , Jiang Xiaming , Shan Jiwei , Shen Zihao , Tong Yi , Xu Liuxin , Yu Chen , Liu Yingle , Zou Gang , Lavillete Dimitri , Zhao Zhenjiang , Wang Rui , Zhu Lili , Xiao Gengfu , Lan Ke , Li Honglin , Xu Ke
Published: March 2020

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacyin vivoand low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.
Effective Assessments of a Short-duration Poor Posture on Upper Limb Muscle Fatigue before Physical Exercise
Authors: Lu Lei , Robinson Mark , Tan Ying , Goonewardena Kusal , Guo Xinliang , Mareels Iven , Oetomo Denny
Published: March 2020

A forward head and rounded shoulder posture is a poor posture that is widely seen in everyday life. It is known that sitting in such a poor posture with long hours will bring health issues such as muscle pain. However, it is not known whether sitting in this poor posture for a short period of time will affect human activities. This paper investigates the effects of a shortduration poor posture before some typical physical activities such as push-ups. The experiments are set up as follows. Fourteen male subjects are asked to do push-ups until fatigue with two surface electromyography (sEMG) at the upper limb. Two days later, they are asked to sit in this poor posture for 15 mins with 8 sEMG sensors located at given back muscles. Then they do the push-ups after the short-duration poor posture. The observations from the median frequency of sEMG signals at the upper limb indicate that the short-duration poor posture does affect the fatigue procedure of push-ups. A significant decreasing trend of the performance of push-ups is obtained after sitting in this poor posture. Such effects indicate that some parts of the back muscles indeed get fatigued with only 15 minutes sitting in this poor posture. By further investigating the time-frequency components of sEMG of back muscles, it is observed that the low and middle frequencies of sEMG signals from the infraspinatus muscle of the dominant side are demonstrated to be more prone to fatigue with the poor posture. Although this study focuses only on push-ups, similar experiments can be arranged for other physical exercises as well. This study provides new insights into the effect of a short-duration poor posture before physical activities. These insights can be used to guide athletes to pay attention to postures before physical activities to improve performance and reduce the risk of injury.
Consensus-seeking and conflict-resolving ---an fMRI study on college couples’ shopping interaction
Authors: Jo HanShin , Chen Chiu-Yueh , Chen Der-Yow , Weng Ming-Hung , Kung Chun-Chia
Published: March 2020

One of the typical campus scenes is the social interaction between college couples, and the lesson couples must keep learning is to adapt to each other. This fMRI study investigated the shopping interactions of 30 college couples, one lying inside and the other outside the scanner, beholding the same item from two connected PCs, making preference ratings and subsequent buy/not-buy decisions. The behavioral results showed the clear modulation of significant others’ preferences onto one’s own decisions, and the contrast of the “shop-together vs. shop-alone”, and the “congruent (both liked or disliked the item, 68%) vs. incongruent (one liked but the other disliked, and vice versa)” together trials, both revealed bilateral temporal parietal junction (TPJ) among other reward-related regions, likely reflecting mentalizing during preference harmony. Moreover, when contrasting “own-high/other-low vs. own-low/other-high” incongruent trials, left anterior inferior parietal lobule (l-aIPL) was parametrically mapped, and the “yield (e.g., own-high/not-buy) vs. insist (e.g., own-low/not-buy)” modulation further revealed left lateral-IPL (l-lIPL), together with left TPJ forming a local social decision network that was further constrained by the mediation analysis among left TPJ-lIPL-aIPL. In sum, these results exemplify, via the two-person fMRI, the neural substrate of shopping interactions between couples.
Enhancing biocompatibility of rhodamine fluorescent probes by a neighbouring group effect
Authors: Bucevičius Jonas , Kostiuk Georgij , Gerasimaitė Rūta , Gilat Tanja , Lukinavičius Gražvydas
Published: March 2020

Fluorescence microscopy is an essential tool for understanding dynamic processes in living cells and organisms. However, many fluorescent probes for labelling cellular structures suffer from unspecific interactions and low cell permeability. Herein, we demonstrate that the neighbouring group effect which results from positioning an amide group next to a carboxyl group in the benzene ring of rhodamines dramatically increases cell permeability of the rhodamine-based probes through stabilizing a fluorophore in a hydrophobic spirolactone state. Based on this principle, we create probes targeting tubulin, actin and DNA. Their superb staining intensity, tuned toxicity and specificity allows long-term 3D confocal and STED nanoscopy with sub-30 nm resolution. As a result, the real microtubule diameter of 23 nm was resolved inside a living cell for the first time. Due to their unrestricted cell permeability and efficient accumulation on tubulin, the new probes produce high contrast images at sub-nanomolar concentrations.
Kernel integration by Graphical LASSO
Authors: Nørgaard Sarah Kristine , Linder-Steinlein Kristoffer , Eliasen Anders Ulrik , Stokholm Jakob , Chawez Bo L. , Bønnelykke Klaus , Bisgaard Hans , Smilde Age K. , Rasmussen Morten A.
Published: March 2020

Integration of unstructured and very diverse data is often required for a deeper understanding of complex biological systems. In order to uncover communalities between heterogeneous data, the data is often harmonized by constructing a kernel and numerical integration is performed. In this study we propose a method for data integration in the framework of an undirected graphical model, where the nodes represent individual data sources of varying nature in terms of complexity and underlying distribution, and where the edges represent the partial correlation between two blocks of data. We propose a modified GLASSO for estimation of the graph, with a combination of cross-validation and extended Bayes Information Criterion for sparsity tuning. Furthermore, hierarchical clustering on the weighted consensus kernels from a fixed network is used to partitioning the samples into different classes. Simulations show increasing ability to uncover true edges with increasing sample size andsignal to noise. Likewise, identification of non existing edges towards disconnected nodes is feasible. The framework is demonstrated for integration of longitudinal symptom burden data from the 2nd and 3rd year of life with 21 diseases precursors as well as the development of asthma and eczema at the age of 6 years from 403 children from the COPSAC2010 mother-child cohort, suggesting that maternal predisposition as well as being born preterm indirectly lead to higher risk of asthma via increased respiratory symptom burden.
The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
Authors: Matsuyama Shutoku , Kawase Miyuki , Nao Naganori , Shirato Kazuya , Ujike Makoto , Kamitani Wataru , Shimojima Masayuki , Fukushi Shuetsu
Published: March 2020

Steroid compounds, which are expected to have dual functions in blocking host inflammation and MERS-CoV replication, were screened from a chemical library. Within this library, ciclesonide, an inhaled corticosteroid, suppressed human coronavirus replication in cultured cells, but did not suppress replication of respiratory syncytial virus or influenza virus. The effective concentration of ciclesonide to block SARS-CoV-2 (the cause of COVID-19) replication (EC90) was 6.3 μM. After the eleventh consecutive MERS-CoV passage in the presence of ciclesonide, a resistant mutation was generated, which resulted in an amino acid substitution (A25V) in nonstructural protein (NSP) 15, as identified using reverse genetics. A recombinant virus with the mutation was also resistant to ciclesonide suppression of viral replication. These observations suggest that the effect of ciclesonide was specific to coronavirus, suggesting this is a candidate drug for treatment of patients suffering MERS or COVID-19.
Human-like telomeres in Zostera marina reveal a mode of transition from the plant to the human telomeric sequences
Authors: Peska Vratislav , Mátl Martin , Mandákova Terezie , Vitales Daniel , Fajkus Petr , Fajkus Jiří , Garcia Sònia
Published: March 2020

A previous study describing the genome of Zostera marina, the most widespread seagrass in the Northern hemisphere, revealed some genomic signatures of adaptation to the aquatic environment. Important features related to the ‘back-to-the-sea’ reverse evolutionary pathway were found, such as the loss of stomatal genes, while other functions like an algal-like cell wall composition were acquired. Beyond these, the genome structure and organization were comparable to the majority of plant genomes sequenced, except for one striking feature that went unnoticed at that time: the presence of human-like instead of the expected plant-type telomeric sequences. By using different experimental approaches including FISH, NGS and Ba131 analysis, we have confirmed its telomeric location in the chromosomes of Z. marina. We have also identified its telomerase RNA subunit (TR), confirming the presence of the human-type telomeric sequence in the template region. Remarkably, this region was found to be very variable even in clades with a highly conserved telomeric sequence across their species. Based on this observation, we propose that alternative annealing preferences in the template borders can explain the transition between the plant and human telomeric sequences. The further identification of paralogues of TR in several plant genomes brought us to the hypothesis that plants may keep an increased ability to change their telomeric sequence. We discuss the implications of this occurrence in the evolution of telomeres while introducing a mechanistic model for the transition from the plant to the human telomeric sequences.
Expression of Wilm’s Tumor Gene in Endometrium with Potential Link to Gestational Vascular Transformation
Authors: Zhang Peilin
Published: March 2020

Background

WT1 is a transcription factor with versatile cellular functions in embryonic development, maintenance of adult tissue functions and regenerations. WT1 is known to be regulated by progesterone and it is abundantly expressed in endometrium, but its function is unclear.

Design

WT1 expression was detected by immunohistochemical staining in endometrium of various physiological and pathological conditions.

Result

WT1 was detected in endometrial stromal cells and vascular smooth muscle cells in both proliferative and secretory phases of menstrual cycles. WT1 appeared increased in vascular smooth muscle cells in spiral artery in early pregnancy and WT1 was also detected in regenerative endothelial cells and smooth muscle cells in decidual vasculopathy at term. WT1 expression was decreased in endometrial stromal cells in adenomyosis (endometriosis).

Conclusion

WT1 potentially links the hormonal (progesterone) effects on endometrial decidualization and may play a role in gestational vascular transformation during pregnancy and restoration after pregnancy.
Cell-based analysis ofCADvariants identifies individuals likely to benefit from uridine therapy
Authors: del Caño-Ochoa Francisco , Ng Bobby G. , Abedalthagafi Malak , Almannai Mohammed , Cohn Ronald D. , Costain Gregory , Elpeleg Orly , Houlden Henry , Karimiani Ehsan Ghayoor , Liu Pengfei , Manzini M. Chiara , Maroofian Reza , Muriello Michael , Al-Otaibi Ali , Patel Hema , Shimon Edvardson , Sutton V. Reid , Toosi Mehran Beiraghi , Wolfe Lynne A. , Rosenfeld Jill A. , Freeze Hudson H. , Ramón-Maiques Santiago
Published: March 2020

Purpose

Pathogenic autosomal recessive variants inCAD, encoding the multienzymatic protein initiating pyrimidinede novobiosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size ofCADwith over 1000 missense variants and the non-specific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity ofCADvariants and to select affected individuals that might benefit from uridine therapy.

Methods

Using CRISPR/Cas9, we generated a humanCAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinantCADrestores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype.

Results

We identified 25 individuals with biallelic variants inCADand a phenotype consistent with a CAD deficit. We used theCAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype.

Conclusions

We designed a cell-based assay to test the pathogenicity ofCADvariants, identifying 11 CAD deficient individuals, who could benefit from uridine therapy.
Confound modelling in UK Biobank brain imaging
Authors: Alfaro-Almagro Fidel , McCarthy Paul , Afyouni Soroosh , Andersson Jesper L. R. , Bastiani Matteo , Miller Karla L. , Nichols Thomas E. , Smith Stephen M.
Published: March 2020

Dealing with confounds is an essential step in large cohort studies to address problems such as unexplained variance and spurious correlations. UK Biobank is a powerful resource for studying associations between imaging and nonimaging measures such as lifestyle factors and health outcomes, in part because of the large subject numbers. However, the resulting high statistical power also raises the sensitivity to confound effects, which therefore have to be carefully considered. In this work we describe a set of possible confounds (including non-linear effects and interactions) that researchers may wish to consider for their studies using such data. We include descriptions of how we can estimate the confounds, and study the extent to which each of these confounds affects the data, and the spurious correlations that may arise if they are not controlled. Finally, we discuss several issues that future studies should consider when dealing with confounds.
Development of a clostridia-based cell-free system for prototyping genetic parts and metabolic pathways
Authors: Krüger Antje , Mueller Alexander P. , Rybnicky Grant A. , Engle Nancy L. , Yang Zamin K. , Tschaplinski Tim J. , Simpson Sean D. , Köpke Michael , Jewett Michael C.
Published: March 2020

Gas fermentation by autotrophic bacteria, such as clostridia, offers a sustainable path to numerous bioproducts from a range of local, highly abundant, waste and low-cost feedstocks, such as industrial flue gases or syngas generated from biomass or municipal waste. Unfortunately, designing and engineering clostridia remains laborious and slow. The ability to prototype individual genetic parts, gene expression, and biosynthetic pathway performancein vitrobefore implementing them in cells could help address these bottlenecks by speeding up design. Unfortunately, a high-yielding cell-free gene expression (CFE) system from clostridia has yet to be developed. Here, we report the development and optimization of a high-yielding (236 ± 24 µg/mL) batch CFE platform from the industrially relevant anaerobe,Clostridium autoethanogenum.A key feature of the platform is that both circular and linear DNA templates can be applied directly to the CFE reaction to program protein synthesis. We demonstrate the ability to prototype gene expression, and quantitatively map cell-free metabolism in lysates from this system. We anticipate that theC. autoethanogenumCFE platform will not only expand the protein synthesis toolkit for synthetic biology, but also serve as a platform in expediting the screening and prototyping of gene regulatory elements in non-model, industrially relevant microbes.
Innate sensitivity and plastic mechanisms in auditory cortex for reliable maternal behavior
Authors: Schiavo Jennifer K. , Valtcheva Silvana , Bair-Marshall Chloe , Song Soomin C. , Martin Kathleen A. , Froemke Robert C.
Published: March 2020

Infant cries evoke powerful responses in parents1–4. To what extent are parental animals innately sensitive to neonatal vocalizations, or might instead learn about key vocal cues for appropriate parenting responses? In mice, naive virgins do not recognize the meaning of pup distress calls, but begin to retrieve pups to the nest following cohousing with a mother and litter5–8. These isolation calls can be variable, requiring co-caring virgins to generalize across features for reliable retrieval9, 10. Here, using behavioral studies combined with two-photon imaging and whole-cell recordings, we show that the onset of maternal behavior in mice results from the interaction between innate sensitivities and experience-dependent processes. We found that pup calls with inter-syllable intervals (ISIs) ranging from 75 to 375 ms elicited pup retrieval, and experienced auditory cortex generalized across these ISIs. In contrast, naive cortex was narrowly tuned to the most common or ‘prototypical’ ISIs due to enhanced short-term depression of inhibitory inputs. Behavioral testing revealed that naive virgins were also more sensitive to prototypical calls than calls at other rates. Inhibitory and excitatory spiking and synaptic responses were initially mismatched in naive cortex, with untuned inhibition and overly-narrow excitation. Monitoring neuronal populations over cohousing revealed that excitatory neuronal responses broadened to represent a wide range of ISIs, while inhibitory neurons sharpened to form a perceptual boundary. Finally, we presented synthetic calls during cohousing and observed that neural and behavioral responses adjusted to match these statistics. Using inhibitory optogenetics, we found that auditory cortical activity was required to learn about specific features, whereas the oxytocinergic system was generally recruited for retrieval learning and plasticity in temporal tuning. Neuroplastic mechanisms therefore build on an innate sensitivity in the auditory cortex, enabling rapid plasticity for reliable parenting behavior.
Treating the Network: Targeted inhibition of two specific microRNAs in the brainstem prevents the development of hypertension
Authors: Gorky Jonathan , DeCicco Danielle , Achanta Sirisha , Schwaber James , Vadigepalli Rajanikanth
Published: March 2020

We here test the concept that disease states may result not from a single cause but from small changes in a network that are collectively significant. We recently showed that development of hypertension (HTN) in the spontaneously hypertensive rat (SHR) model of human essential hypertension is accompanied by changes in microRNA expression levels in the brainstem tracking the development of HTN1,2. This led to the hypothesis that preventing the change in microRNA levels could prevent the development of HTN. We propose that hypertension emerges from a network that has been pushed out of a normotensive equilibrium into a compensatory, pathological state. We show that small perturbations in the gene regulatory networks in the brainstem by selectively blocking two microRNAs highlighted in our previous results, miR-135a and miR-376a, is sufficient to prevent development of hypertension in the SHR model. This effect appears driven by only modest changes in the expression of rate-limiting genes, many of which are targets of these miRNAs, suggesting that the combination of genes that are targeted in the network is responsible for the effect. The demonstration that hypertension is an emergent property of an underlying regulatory network suggests that a new treatment paradigm altogether is needed.

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Identification of viruses belonging to the familyPartitiviridaefrom plant transcriptomes
Authors: Jo Yeonhwa , Cho Won Kyong
Published: March 2020

Viruses in the familyPartitiviridaeconsist of non-enveloped viruses with bisegmented double-stranded RNA genomes. Viruses in this family have been identified from plants and fungi. In this study, we identified several viruses belonging to the familyPartitiviridaeusing plant transcriptomes. From 11 different plant species, we identified a total of 74 RNA segments representing 23 partitiviruses. Of 74 RNA segments, 28 RNA segments encode RNA-dependent RNA polymerases (RdRp) while 46 RNA segments encode coat proteins (CPs). According to ICTV demarcation for the familyPartitiviridae, 25 RNAs encoding RdRp and 41 RNAs encoding CP were novel RNA segments. In addition, we identified eight RNA segments (three for RdRp and five for CP) belonging to the known partitivruses. Taken together, this study provides the largest number of partitiviruses from plant transcriptomes in a single study.
Infrared assessment of human facial temperature in the presence and absence of common cosmetics
Authors: Zheng Kaikai , Dong Ruoyu , Wang Huan , Granick Steve
Published: March 2020

Using a sensitive research-grade infrared camera, we find that common facial cosmetics and lotions mask skin temperature in assays of the human forehead. We test a family of 10 commonly-used cosmetic products and find that volatile liquids and creams lower thermal skin temperature by at least 2 C for up to 5-10 min and at least 1 C for up to 20 min, respectively. Powder and cream that contains brightening agent lower indefinitely the skin temperature sensed by infrared camera. With the qualification that these experiments were performed in a controlled laboratory setting rather than the mass crowd screening environment where infrared temperature sensing of humans sees widespread use, our tests suggest that for human subjects whose face was treated with certain cosmetics and lotions, infrared-based screening for elevated facial temperature (fever) can be unreliable.
No one-size-fits-all solution to clean GBIF
Authors: Zizka Alexander , Carvalho Fernanda Antunes , Calvente Alice , Baez-Lizarazo Mabel Rocio , Cabral Andressa , Ramos Coelho Jéssica Fernanda , Colli-Silva Matheus , Fantinati Mariana Ramos , Fernandes Moabe Ferreira , Ferreira-Araújo Thais , Lambert Moreira Fernanda Gondim , da Cunha Santos Nathália Michelly , Borges Santos Tiago Andrade , dos Santos-Costa Renata Clicia , Serrano Filipe Cabreirinha , da Silva Ana Paula Alves , Soares Arthur de Souza , de Souza Paolla Gabryelle Cavalcante , Tomaz Eduardo Calisto , Fonseca Vale Valéria , Vieira Tiago Luiz , Antonelli Alexandre
Published: March 2020

Species occurrence records provide the basis for many biodiversity studies. They derive from georeferenced specimens deposited in natural history collections and visual observations, such as those obtained through various mobile applications. Given the rapid increase in availability of such data, the control of quality and accuracy constitutes a particular concern. Automatic filtering is a scalable and reproducible means to identify potentially problematic records and tailor datasets from public databases such as the Global Biodiversity Information Facility (GBIF;www.gbif.org), for biodiversity analyses. However, it is unclear how much data may be lost by filtering, whether the same filters should be applied across all taxonomic groups, and what the effect of filtering is on common downstream analyses. Here, we evaluate the effect of 13 recently proposed filters on the inference of species richness patterns and automated conservation assessments for 18 Neotropical taxa, including terrestrial and marine animals, fungi, and plants downloaded from GBIF. We find that a total of 44.3% of the records are potentially problematic, with large variation across taxonomic groups (25 - 90%). A small fraction of records was identified as erroneous in the strict sense (4.2%), and a much larger proportion as unfit for most downstream analyses (41.7%). Filters of duplicated information, collection year, and basis of record, as well as coordinates in urban areas, or for terrestrial taxa in the sea or marine taxa on land, have the greatest effect. Automated filtering can help in identifying problematic records, but requires customization of which tests and thresholds should be applied to the taxonomic group and geographic area under focus. Our results stress the importance of thorough recording and exploration of the meta-data associated with species records for biodiversity research.
Mitochondrial Complex II In Intestinal Epithelial Cells Regulates T-cell Mediated Immunopathology
Authors: Fujiwara Hideaki , Mathew Anna V , Kovalenko Ilya , Pal Anupama , Lee Ho-Joon , Peltier Daniel , Kim Stephanie , Liu Chen , Oravecz-Wilson Katherine , Li Lu , Sun Yaping , Byun Jaeman , Saunders Tom , Rehemtulla Alnawaz , Lyssiotis Costas A , Pennarthur Subramanian , Reddy Pavan
Published: March 2020

Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic diseases such as graft-versus-host disease (GVHD), inflammatory bowel disease (IBD) and immune checkpoint blockade (ICB) mediated colitis, respectively. Despite significant advances in understanding the aberrant biology of T cells in these diseases, little is known about how the fundamental biological processes of the target IECs influence the disease severity. Here, through analyses of metabolic pathways of IECs, we identified disruption of oxidative phosphorylation without a concomitant change in glycolysis and an increase in succinate levels in several distinct in vivo models of T cell mediated gastrointestinal damage such as GVHD, IBD and ICB mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses identified a critical role for IEC intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations that contributed to the severity of intestinal damage. The critical mechanistic role of IEC intrinsic SDHA was confirmed by complementary chemical and genetic reduction of SDHA and with IEC specific deletion of SDHA. Further in vitro and in vivo mechanistic studies demonstrated that loss of SDHA in IECs was mediated by the perforin-granzyme from the T cells. The loss of SDHA was also validated in human clinical samples. These data identify a critical role for the alteration of the IEC specific mitochondrial complex II component SDHA in the regulation of the severity of T cell mediated intestinal diseases.
Emergent properties in microbiome networks reveal the anthropogenic disturbance of farming practices in vineyard soil fungal communities
Authors: Ortiz-Álvarez Rüdiger , Ortega-Arranz Hector , Ontiveros Vicente J. , Ravarani Charles , Acedo Alberto , Belda Ignacio
Published: March 2020

Agro-ecosystems are human-managed natural systems, and therefore are subject to generalized ecological rules. A deeper understanding of the factors impacting on the biotic component of ecosystem stability is needed for promoting the sustainability and productivity of global agriculture. Here we propose a method to determine ecological emergent properties through the inference of network properties in local microbial communities, and to use them as biomarkers of the anthropogenic impact of different farming practices on vineyard soil ecosystem functioning. In a dataset of 350 vineyard soil samples from USA and Spain we observed that fungal communities ranged from random to small-world network arrangements with differential levels of niche specialization. Some of the network properties studied were strongly correlated, defining patterns of ecological emergent properties that are influenced by the intensification level of the crop management. Low-intervention practices (from organic to biodynamic approaches) promoted densely clustered networks, describing an equilibrium state based on mixed (generalist-collaborative) communities. Contrary, in conventionally managed vineyards, we observed highly modular (niche-specialized) low clustered communities, supported by a higher degree of selection (more co-exclusion proportion). We also found that, although geographic factors can explain the different fungal community arrangements in both countries, the relationship between network properties in local fungal communities better capture the impact of farming practices regardless of the location. Thus, we hypothesize that local network properties can be globally used to evaluate the effect of ecosystem disturbances in crops, but also in when evaluating the effect of clinical interventions or to compare microbiomes of healthy vs. disturbed conditions.