bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized clinical trial quality has improved over time but is still not good enough: an analysis of 176,620 randomized controlled trials published between 1966 and 2018
Authors: Vinkers Christiaan H. , Lamberink Herm J. , Tijdink Joeri K. , Heus Pauline , Bouter Lex , Glasziou Paul , Moher David , Damen Johanna A. , Hooft Lotty , Otte Willem M.
Published: April 2020

Background

Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. There is increasing attention for responsible research practices including reporting guidelines, but it is unknown whether these efforts have improved RCT quality (i.e. reduced risk of bias). We therefore mapped trends over time in trial publication, trial registration, reporting according to CONSORT, and characteristics of publication and authors.

Methods

Meta-information of 176,620 RCTs published between 1966 and 2018 was extracted. Risk of bias probability (four domains: random sequence generation, allocation concealment, blinding of patients/personnel, and blinding of outcome assessment) was assessed using validated risk-of-bias machine learning tools. In addition, trial registration and reporting according to CONSORT were assessed with automated searches. Characteristics were extracted related to publication (number of authors, journal impact factor, medical discipline) and authors (gender and Hirsch-index).

Findings

The annual number of published RCTs substantially increased over four decades, accompanied by increases in the number of authors (5.2 to 7.8), institutions (2.9 to 4.8), female authors (20 to 42%, first authorship; 17 to 29%, last authorship), and Hirsch-indices (10 to 14, first authorship; 16 to 28, last authorship). Risk of bias remained present in most RCTs but decreased over time for the domains allocation concealment (63 to 51%), random sequence generation (57 to 36%), and blinding of outcome assessment (58 to 52%). Trial registration (37 to 47%) and CONSORT (1 to 20%) rapidly increased in the latest period. In journals with higher impact factor (>10), risk of bias was consistently lower, higher levels of trial registration more frequent, and mentioning CONSORT.

Interpretation

The likelihood of bias in RCTs has generally decreased over the last decades. This may be driven by increased knowledge and improved education, augmented by mandatory trial registration, and more stringent reporting guidelines and journal requirements. Nevertheless, relatively high probabilities of bias remain, particularly in journals with lower impact factors. This emphasizes that further improvement of RCT registration, conduct, and reporting is still urgently needed.

Funding

This study was funded by The Netherlands Organisation for Health Research and Development (445001002).
SARS-CoV-2 On-the-Spot Virus Detection Directly from Patients
Authors: Ben-Assa Nadav , Naddaf Rawi , Gefen Tal , Capucha Tal , Hajjo Haitham , Mandelbaum Noa , Elbaum Lilach , Rogov Peter , Daniel King A. , Kaplan Shai , Rotem Assaf , Chowers Michal , Szwarcwort-Cohen Moran , Paul Mical , Geva-Zatorsky Naama
Published: April 2020

Many countries are currently in a lockdown state due to the SARS-CoV-2 pandemic. One key aspect to transition safely out of lockdown is to continuously test the population for infected subjects. Currently, detection is performed at points of care using quantitative reverse-transcription PCR (RT-qPCR), and requires dedicated professionals and equipment. Here, we developed a protocol based on Reverse Transcribed Loop-Mediated Isothermal Amplification (RT-LAMP) for detection of SARS-CoV-2. This protocol is applied directly on SARS-CoV-2 nose and throat swabs, with no RNA purification step required. We tested this protocol on over 180 suspected patients, and compared its results to the standard method. We further succeeded to apply the protocol on self-sampled saliva from confirmed cases. Since the proposed protocol provides results on-the-spot, and can detect SARS-CoV-2 from saliva, it can allow simple and continuous surveillance of the community.
Inf-Net: Automatic COVID-19 Lung Infection Segmentation from CT Images
Authors: Fan Deng-Ping , Zhou Tao , Ji Ge-Peng , Zhou Yi , Chen Geng , Fu Huazhu , Shen Jianbing , Shao Ling
Published: April 2020

Coronavirus Disease 2019 (COVID-19) spread globally in early 2020, causing the world to face an existential health crisis. Automated detection of lung infections from computed tomography (CT) images offers a great potential to augment the traditional healthcare strategy for tackling COVID-19. However, segmenting infected regions from CT slices faces several challenges, including high variation in infection characteristics, and low intensity contrast between infections and normal tissues. Further, collecting a large amount of data is impractical within a short time period, inhibiting the training of a deep model. To address these challenges, a novel COVID-19 Lung Infection Segmentation Deep Network (Inf-Net) is proposed to automatically identify infected regions from chest CT slices. In ourInf-Net, a parallel partial decoder is used to aggregate the high-level features and generate a global map. Then, the implicit reverse attention and explicit edge-attention are utilized to model the boundaries and enhance the representations. Moreover, to alleviate the shortage of labeled data, we present a semi-supervised segmentation framework based on a randomly selected propagation strategy, which only requires a few labeled images and leverages primarily unlabeled data. Our semi-supervised framework can improve the learning ability and achieve a higher performance. Extensive experiments on ourCOVID-SemiSegand real CT volumes demonstrate that the proposedInf-Netoutperforms most cutting-edge segmentation models and advances the state-of-the-art performance.
COVID-19: One-month impact of the French lockdown on the epidemic burden
Authors: Roux Jonathan , Massonnaud Clément , Crépey Pascal
Published: April 2020

1

On March 16 2020, French authorities ordered a large scale lockdown to counter the COVID-19 epidemic wave rising in the country, stopping non-essential economic, educational, and entertainment activities, maintaining mainly food retailers and healthcare institutions. One month later, the number of new hospitalizations and ICU admissions had reached a plateau and were beginning a slow descent.

We developed a spatialized, deterministic, age-structured, and compartmental SARS-CoV-2 transmission model able to reproduce the pre-lockdown dynamic of the epidemic in each of the 13 French metropolitan regions. Thanks to this model, we estimate, at regional and national levels, the total number of hospitalizations, ICU admissions, hospital beds requirements (hospitalization and ICU), and hospital deaths which may have been prevented by this massive and unprecedented intervention in France.

If no control measures had been set up, between March 19 and April 19 2020, our analysis shows that almost 23% of the French population would have been affected by COVID-19 (14.8 million individuals). Hence, the French lockdown prevented 587,730 hospitalizations and 140,320 ICU admissions at the national level. The total number of ICU beds required to treat patients in critical conditions would have been 104,550, far higher than the maximum French ICU capacity. This first month of lockdown also permitted to avoid 61,739 hospital deaths, corresponding to a 83.5% reduction of the total number of predicted deaths.

Our analysis shows that in absence of any control measures, the COVID-19 epidemic would have had a critical morbidity and mortality burden in France, overwhelming in a matter of weeks French hospital capacities.
Influenza-Negative Influenza-Like Illness (fnILI) Z-Score as a Proxy for Incidence and Mortality of COVID-19
Authors: Mirza Fatima N. , Malik Amyn A. , Omer Saad B.
Published: April 2020

Though ideal for determining the burden of disease, SARS-CoV2 test shortages preclude its implementation as a robust surveillance system in the US. We correlated the use of the derivative influenza-negative influenza-like illness (fnILI) z-score from the CDC as a proxy for incident cases and disease-specific deaths. For every unit increase of fnILI z-score, the number of cases increased by 70.2 (95%CI[5.1,135.3]) and number of deaths increased by 2.1 (95%CI[1.0,3.2]). FnILI data may serve as an accurate outcome measurement to track the spread of the and allow for informed and timely decision-making on public health interventions.
Dynamical SPQEIR model assesses the effectiveness of non-pharmaceutical interventions against COVID-19 epidemic outbreaks
Authors: Proverbio Daniele , Kemp Françoise , Magni Stefano , Husch Andreas , Aalto Atte , Mombaerts Laurent , Skupin Alexander , Gonçalves Jorge , Ameijeiras-Alonso Jose , Ley Christophe
Published: April 2020

Against the current COVID-19 pandemic, governments worldwide have devised a variety of non-pharmaceutical interventions to suppress it, but the efficacy of distinct measures is not yet well quantified. In this paper, we propose a novel tool to achieve this quantification. In fact, this paper develops a new extended epidemic SEIR model, informed by a socio-political classification of different interventions, to assess the value of several suppression approaches. First, we inquire the conceptual effect of suppression parameters on the infection curve. Then, we illustrate the potential of our model on data from a number of countries, to perform cross-country comparisons. This gives information on the best synergies of interventions to control epidemic outbreaks while minimising impact on socio-economic needs. For instance, our results suggest that, while rapid and strong lock-down is an effective pandemic suppression measure, a combination of social distancing and contact tracing can achieve similar suppression synergistically. This quantitative understanding will support the establishment of mid- and long-term interventions, to prepare containment strategies against further outbreaks. This paper also provides an online tool that allows researchers and decision makers to interactively simulate diverse scenarios with our model.
Characterizing clinical progression of COVID-19 among patients in Shenzhen, China: an observational cohort study
Authors: Bi Qifang , Hong Chengcheng , Meng Juan , Wu Zhenke , Zhou Pengzheng , Ye Chenfei , Sun Binbin , Kucirka Lauren M. , Azman Andrew S. , Wang Tong , Chen Jiancong , Wang Zhaoqin , Liu Lei , Lessler Justin , Edwards Jessie K. , Ma Ting , Zhang Guoliang
Published: April 2020

Background

Understanding clinical progression of COVID-19 is a key public health priority that informs resource allocation during an emergency. We characterized clinical progression of COVID-19 and determined important predictors for faster clinical progression to key clinical events and longer use of medical resources.

Methods and Findings

The study is a single-center, observational study with prospectively collected data from all 420 patients diagnosed with COVID-19 and hospitalized in Shenzhen between January 11th and March 10th, 2020 regardless of clinical severity. Using competing risk regressions according to the methods of Fine and Gray, we found that males had faster clinical progression than females in the older age group and the difference could not be explained by difference in baseline conditions or smoking history. We estimated the proportion of cases in each severity stage over 80 days following symptom onset using a nonparametric method built upon estimated cumulative incidence of key clinical events. Based on random survival forest models, we stratified cases into risk sets with very different clinical trajectories. Those who progressed to the severe stage (22%,93/420), developed acute respiratory distress syndrome (9%,39/420), and were admitted to the intensive care unit (5%,19/420) progressed on average 9.5 days (95%CI 8.7,10.3), 11.0 days (95%CI 9.7,12.3), and 10.5 days (95%CI 8.2,13.3), respectively, after symptom onset. We estimated that patients who were admitted to ICUs remained there for an average of 34.4 days (95%CI 24.1,43.2). The median length of hospital stay was 21.3 days (95%CI, 20.5,22.2) for cases who did not progress to the severe stage, but increased to 52.1 days (95%CI, 43.3,59.5) for those who required critical care.

Conclusions

Our analyses provide insights into clinical progression of cases starting early in the course of infection. Patient characteristics near symptom onset both with and without lab parameters have tremendous potential for predicting clinical progression and informing strategic response.
Conformational Tuning of Amylin by Charged Styrene-maleic-acid Copolymers
Authors: Sahoo Bikash R. , Souders Christopher L. , Nakayama Takahiro W. , Deng Zhou , Linton Hunter , Suladze Saba , Ivanova Magdalena I. , Reif Bernd , Ando Toshio , Martyniuk Christopher J. , Ramamoorthy Ayyalusamy
Published: April 2020

Human amylin forms structurally heterogeneous amyloids that have been linked to type-2 diabetes. Thus, understanding the molecular interactions governing amylin aggregation can provide mechanistic insights in its pathogenic formation. Here, we demonstrate that fibril formation of amylin is altered by synthetic amphipathic copolymer derivatives of the styrene- maleic-acid (SMAQA and SMAEA). High-speed AFM is used to follow the real-time aggregation of amylin by observing the rapid formation ofde novoglobular oligomers and arrestment of fibrillation by the positively-charged SMAQA. We also observed an accelerated fibril formation in the presence of the negatively-charged SMAEA. These findings were further validated by fluorescence, SOFAST-HMQC, DOSY and STD NMR experiments. Conformational analysis by CD and FT-IR revealed that the SMA copolymers modulate the conformation of amylin aggregates. While the species formed with SMAQA are α-helical, the ones formed with SMAEA are rich in β-sheet structure. The interacting interfaces between SMAEA or SMAQA and amylin are mapped by NMR and microseconds all-atom MD simulation. SMAEA displayed π-π interaction with Phe23, electrostatic π-cation interaction with His18 and hydrophobic packing with Ala13 and Val17; whereas SMAQA showed a selective interaction with amylin’s C-terminus (residues 31-37) that belongs to one of the two β-sheet regions (residues 14-19 and 31-36) involved in amylin fibrillation. Toxicity analysis showed both SMA copolymers to be non-toxicin vitroand the amylin species formed with the copolymers showed minimal deformity to zebrafish embryos. Together, this study demonstrates that chemical tools, such as copolymers, can be used to modulate amylin aggregation, alter the conformation of species.
COVID-19 serial interval estimates based on confirmed cases in public reports from 86 Chinese cities
Authors: Du Zhanwei , Xu Xiaoke , Wu Ye , Wang Lin , Cowling Benjamin J. , Meyers Lauren Ancel
Published: April 2020

As a novel coronavirus (COVID-19) continues to spread widely and claim lives worldwide, its transmission characteristics remain uncertain. Here, we present and analyze the serial intervals–the time period between the onset of symptoms in an index (infector) case and the onset of symptoms in a secondary (infectee) case–of 339 confirmed cases of COVID-19 identified from 264 cities in mainland China prior to February 19, 2020. Here, we provide the complete dataset in both English and Chinese to support further COVID-19 research and modeling efforts.
Value of SiPM PET in myocardial perfusion imaging using Rubidium-82
Authors: Koenders S.S. , van Dalen J.A. , Jager P.L. , Knollema S. , Timmer JR , Mouden M. , Slump C.H. , van Dijk J.D.
Published: April 2020

Background

PET scanners using silicon photomultipliers with digital readout (SiPM PET) have an improved temporal and spatial resolution compared to PET scanners using conventional photomultiplier tubes (PMT PET). However, the effect on image quality and visibility of perfusion defects in myocardial perfusion imaging (MPI) is unknown. Our aim was to determine the value of a SiPM PET scanner in MPI.

Methods

We prospectively included 30 patients who underwent rest and regadenoson-induced stress Rubidium-82 (Rb-82) MPI on the D690 PMT PET (GE Healthcare) and within three weeks on the Vereos SiPM PET (Philips Healthcare). Two expert readers scored the image quality and assessed the existence of possible defects. In addition, interpreter’s confidence, myocardial blood flow (MBF) and myocardial flow reserve (MFR) values were compared.

Results

Image quality improved (p=0.03) using the Vereos as compared to the D690. Image quality of the Vereos and the D690 was graded fair in 20% and 10%, good in 60% and 50%, and excellent in 20% and 40%, respectively. Defect interpretation and interpreter’s confidence did not differ between the D690 and the Vereos (p>0.50). There were no significant differences in rest MBF (p≥0.29), stress MBF (p≥0.11) and MFR (p≥0.51).

Conclusion

SiPM PET provides an improved image quality in comparison to PMT PET. Defect interpretation, interpreter’s confidence and absolute blood flow measurements were comparable between both systems. SiPM PET is therefore a reliable technique for MPI using Rb-82.
In-silico studies of Riparin B in the design of drugs: Physicochemical, pharmacokinetic and pharmacodynamic parameters
Authors: Rodrigues Aldenora Maria Ximenes , Costa Rayla Kelly Magalhães , Machado Ranyelison Silva , Gutierrez Stanley Juan Chavez , das Chagas Alves Lima Francisco , de Oliveira Aldeídia Pereira
Published: April 2020

The process involved in the research, discovery and development of drugs is characterized by high extensive and complex cost linked to scientific and technological innovations, and it is necessary to study and verify the progress of research carried out in the field that results in patent applications.Aniba riparia (Nees) Mezis a plant species often used for therapeutic purposes, where its pharmacological properties are associated to the presence of alkaloids called riparins. 5 synthetic analog compounds (riparins A, B, C, D, E and F) were developed from natural riparins. These molecules, natural and synthetic, showed several pharmacological activities in tests performedin vitro and in vivo, highlighting the Central Nervous System (CNS). The objective of this work was to evaluate the physical-chemical, pharmacokinetic parameters (absorption, distribution, metabolism, excretion and toxicity) and pharmacodynamic parameters (bioactivity and adverse reactions) of Riparin B by means ofin silicocomputational prediction.Online softwaresuch asPre-ADMET, SwissADME, Molinspirationand PASSon linewere used for the analysis. Riparin B fits the characteristics ofdruglikeness, pharmacokinetic properties appropriate to the predicted patterns and activities within the scope for the treatment of AD, demonstrating a possible potential in the inhibition of AChE. Therefore, in silico results allow us to conclude that riparin B is predicted to be a potential future drug candidate, especially via oral administration, due to its relevant Drug-likeness profile, bioavailability, excellent liposolubility and adequate pharmacokinetics, including at the level of CNS, penetrating the blood-brain barrier.
Synaptic processes and immune-related pathways implicated in Tourette Syndrome
Authors: Tsetsos Fotis , Yu Dongmei , Sul Jae Hoon , Huang Alden Y. , Illmann Cornelia , Osiecki Lisa , Darrow Sabrina M. , Hirschtritt Matthew E. , Greenberg Erica , Muller-Vahl Kirsten R. , Stuhrmann Manfred , Dion Yves , Rouleau Guy A. , Aschauer Harald , Stamenkovic Mara , Schlögelhofer Monika , Sandor Paul , Barr Cathy L. , Grados Marco A. , Singer Harvey S. , Nöthen Markus M. , Hebebrand Johannes , Hinney Anke , King Robert A. , Fernandez Thomas V. , Barta Csaba , Tarnok Zsanett , Nagy Peter , Depienne Christel , Worbe Yulia , Hartmann Andreas , Budman Cathy L. , Rizzo Renata , Lyon Gholson J. , McMahon William M. , Batterson James R. , Cath Danielle C. , Malaty Irene A. , Okun Michael S. , Berlin Cheston , Woods Douglas W. , Lee Paul C. , Jankovic Joseph , Robertson Mary M. , Gilbert Donald L. , Brown Lawrence W. , Coffey Barbara J. , Dietrich Andrea , Hoekstra Pieter J. , Kuperman Samuel , Zinner Samuel H. , Wagner Michael , Knowles James A , Willsey A. Jeremy , Tischfield Jay A. , Heiman Gary A. , Cox Nancy J. , Freimer Nelson B. , Neale Benjamin M. , Davis Lea K. , Coppola Giovanni , Mathews Carol A. , Scharf Jeremiah M. , Paschou Peristera
Published: April 2020

Tourette Syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with Tourette Syndrome (TS) and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating Ligand-gated Ion Channel Signaling, Lymphocytic, and Cell Adhesion and Trans-synaptic Signaling processes. MAGMA analysis further supported the involvement of the Cell Adhesion and Trans-synaptic Signaling gene set. The Lympho-cytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of Ligand-gated Ion Channel Signaling reinforce the role of GABA in TS, while the association of Cell Adhesion and Trans-synaptic Signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders.
COVID-19 in Iran: A Deeper Look Into The Future
Authors: Kafieh Rahele , Arian Roya , Saeedizadeh Narges , Minaee Shervin , Amini Zahra , Yadav Sunil Kumar , Vaezi Atefeh , Rezaei Nima , Javanmard Shaghayegh Haghjooy
Published: April 2020

The novel corona-virus (COVID-19) has led to a pandemic, affecting almost all countries and regions in a few weeks, and therefore a global plan is needed to overcome this battle. Iran has been among the first few countries that has been affected severely, after China, which forced the government to put some restriction and enforce social distancing in majority of the country. In less than 2 months, Iran has more than 80,000 confirmed cases, and more than 5,000 death. Based on the official statistics from Iran’s government, the number of daily cases has started to go down recently, but many people believe if the lockdown is lifted without proper social distancing enforcement, there is a possibility for a second wave of COVID-19 cases. In this work, we analyze at the data for the number cases in Iran in the past few weeks, and train a predictive model to estimate the possible future trends for the number of cases in Iran, depending on the government policy in the coming weeks and months. Our analysis may help political leaders and health officials to take proper action toward handling COVID-19 in the coming months.
Interacting evolutionary pressures drive mutation dynamics and health outcomes in aging blood
Authors: Skead Kimberly , Houle Armande Ang , Abelson Sagi , Agbessi Mawusse , Bruat Vanessa , Lin Boxi , Soave David , Shlush Liran , Wright Stephen , Dick John , Morris Quaid , Awadalla Philip
Published: April 2020

A small population of self-renewing, hematopoietic stem cells continuously reconstitutes our immune system. As we age, these cells, or their pluripotent descendants, accumulate somatic mutations; some of these mutations provide selection advantages and increase in frequency in the peripheral blood cell population. This process of positive selection, deemed age-related clonal hematopoiesis (ARCH), is associated with increased risk for cardiac disease and blood malignancies, like acute myeloid leukemia (AML). However, it remains unclear why some people with ARCH do not progress to AML, even when their blood cells harbor well-known AML driver mutations. Here, we examine whether negative selection can play a role in determining AML progression by modelling the complex interplay of positive and negative selective processes. Using a novel approach combining deep learning and population genetic models, we detect pervasive negative selection in targeted sequence data from the blood of 92 pre-AML individuals and 385 healthy controls. We find that the relative proportion of passenger to driver mutations is critical in determining if the selective advantage conferred to a cell by a known driver mutation is able to overwhelm negative selection acting on passenger mutations and allow clones harbouring disease-predisposing mutations to rise to dominance. We find that a subset of non-driver genes is enriched for mildly damaging mutations in healthy individuals fitting purifying models of evolution suggesting that mutations in these genes might confer a protective role against disease-predisposing clonal expansions. Through exploring non drivercentric models of evolution, we show how different classes of evolution act to shape hematopoietic dynamics and subsequent health outcome which may better inform disease prediction and unveil novel therapeutic targets. We anticipate that our results and modelling techniques can be broadly applied to identify both driver mutations and those mildly damaging passenger mutations, as well as help understand the early evolution of cancer in other cells and tissues.
Detection of epistasis between ACTN3 and SNAP-25 with an insight towards gymnastic aptitude identification
Authors: Płóciennik Łukasz , Zaucha Jan , Zaucha Jan Maciej , Łukaszuk Krzysztof , Jóźwicki Marek , Płóciennik Magdalena , Cięszczyk Paweł
Published: April 2020

In this study, we performed an analysis of the impact of performance enhancing polymorphisms (PEPs) on gymnastic aptitude while considering epistatic effects. Seven PEPs (rs1815739, rs8192678, rs4253778, rs6265, rs5443, rs1076560, rs362584) were considered in a case (gymnasts) – control (sedentary individuals) setting. The study sample comprised of two athletes’ sets: 27 elite (aged 24.8 ± 2.1 years) and 46 sub-elite (aged 19.7 ± 2.4 years) sportsmen as well as a control group of 245 sedentary individuals (aged 22.5 ± 2.1 years). The DNA was derived from saliva and PEP alleles were determined by PCR, RT-PCR. Following Multifactor Dimensionality Reduction, logistic regression models were built. The synergistic effect for rs1815739 × rs362584 reached 5.43%. The rs1815739 × rs362584 epistatic regression model exhibited a good fit to the data (Chi-squared = 33.758, p ≈ 0) achieving a significant improvement in sportsmen identification over naïve guessing. The area under the receiver operating characteristic curve was 0.715 (Z-score = 38.917, p ≈ 0). In contrast, the additive ACTN3 – SNAP-25 logistic regression model has been verified as non-significant.

We demonstrate that a gene involved in the differentiation of muscle architecture – ACTN3 and a gene, which plays an important role in the nervous system – SNAP-25 interact. From the perspective originally established by the Berlin Academy of Science in 1751, the matter of communication between the brain and muscles via nerves adopts molecular manifestations. Further in-vitro investigations are required to explain the molecular details of the rs1815739 – rs362584 interaction.
Targeting Thymidine Phosphorylase with Tipiracil Hydrochloride is a Safe and Effective Antithrombotic Therapy
Authors: Zulfiker Abu Hasanat Md , Belcher Adam , Li Oliver Qiyue , Yue Hong , Gupta Anirban Sen , Wei Li
Published: April 2020

Rationale

Most of the current anti-platelet drugs inhibit platelet function permanently and have systemic side effects, including thrombocytopenia and hemorrhage. We previously found that thymidine phosphorylase (TYMP), a platelet cytoplasmic protein, facilitates multiple agonist induced platelet activation and enhances thrombosis. A specific TYMP inhibitor, namely, tipiracil hydrochloride (TPI), has been approved by the U.S. Food and Drug Administration for clinical use as an auxiliary drug making it possible to be repositioned as an anti-platelet medicine.

Objective

We aimed to test the hypothesis that TPI is a novel and safe anti-platelet drug by examining its role in platelet activation and thrombosis using both in vitro and in vivo studies.

Methods and Results

By co-expression of TYMP and Lyn or Lyn-SH3 domain tagged with glutathione S-transferase, we showed the direct evidence that TYMP binds to the SH3 domain in its partners. TYMP haplodeficiency is sufficient to inhibit thrombosis in vivo regardless of gender. TPI treatment rapidly inhibited collagen- and ADP-induced platelet aggregation, which copied the phenotype of TYMP deficient platelets. Under both normal and hyperlipidemic conditions, treating wild type (WT) mice with TPI via intraperitoneal injection, intravenous injection, or gavage feeding dramatically inhibited thrombosis without inducing significant bleeding. Even administered above the effective dose, TPI has a lower bleeding side effect compared to aspirin and clopidogrel. Most importantly, intravenously delivery of TPI alone or combined with tissue plasminogen activator dramatically inhibited the growth of developing thrombi. Dual administration of very low dose of aspirin and TPI also dramatically inhibited thrombosis without disturbing hemostasis.

Conclusion

This pharmacological study demonstrated that TYMP participates in multiple signaling pathways in platelet and plays a mechanistic role in regulating platelet activation and thrombosis. TPI, a specific TYMP inhibitor, would be a novel safe anti-platelet and anti-thrombosis medicine.
High thermal plasticity and vulnerability in extreme environments at the warm distributional edge: the case of a tidepool shrimp
Authors: Amsalem Eyal , Rilov Gil
Published: April 2020

1.

Climate change threatens the resilience of species, especially at their warm distributional edge in extreme environments. However, not much is known about the thermal vulnerability of marine intertidal species at this edge. We investigated the thermal vulnerability of the tidepool shrimp,Palaemon elegansin the fast-warming southeastern Mediterranean, its warm distributional edge. Tidepool organisms experience strong and fast thermal fluctuations. This might make them more resilient to change, but also bring them closer to their thermal limits during extreme conditions. To test the shrimp’s resilience, we tested three hypotheses: (1)P. elegancein the southeast Mediterranean has higher critical thermal maximum (CTMax) than in cooler regions, (2) the shrimp possess seasonal acclimatization, but (3) long exposure to extreme summer temperatures might erode its thermal performance making it vulnerable to future climate change. We characterized the shrimp’s thermal environment and population dynamics, determined CTMax and tested diverse physiological performance attributes (respiration, digestion, activity, growth) under a wide range of temperatures during winter and summer.P. eleganshas a wide optimum performance range between 20-30°C during summer and its CTMax is 38.1°C, higher than its Atlantic counterparts. However, its warming tolerance is only 0.3°C, indicating low capacity for dealing with further warming in pools compared to northeast Atlantic populations that have wider tolerance. Prolonged exposure to current mean summer values in open water (∼ 32°C) would also significantly reduce its performance and increase mortality. This suggests that its population viability may be reduced under continuous regional warming and intensification of extreme events.
An integrated mosquito small RNA genomics resource reveals dynamic evolution and host responses to viruses and transposons
Authors: Ma Qicheng , Srivastav Satyam P. , Gamez Stephanie , Feitosa-Suntheimer Fabiana , Patterson Edward I. , Johnson Rebecca M. , Matson Erik R. , Gold Alexander S. , Brackney Douglas E. , Connor John H. , Colpitts Tonya M. , Hughes Grant L. , Rasgon Jason L. , Nolan Tony , Akbari Omar S. , Lau Nelson C.
Published: April 2020

Although mosquitoes are major transmission vectors for pathogenic arboviruses, viral infection has little impact on mosquito health. This immunity is due in part to mosquito RNA interference (RNAi) pathways that generate antiviral small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). RNAi also maintains genome integrity by potently repressing mosquito transposon activity in the germline and soma. However, viral and transposon small RNA regulatory pathways have not been systematically examined together in mosquitoes. Therefore, we developed an integrated Mosquito Small RNA Genomics (MSRG) resource that analyzes the transposon and virus small RNA profiles in mosquito cell cultures and somatic and gonadal tissues across four medically important mosquito species. Our resource captures both somatic and gonadal small RNA expression profiles within mosquito cell cultures, and we report the evolutionary dynamics of a novel Mosquito-Conserved piRNA Cluster Locus (MCpiRCL) composed of satellite DNA repeats. In the larger culicine mosquito genomes we detected highly regular periodicity in piRNA biogenesis patterns coinciding with the expansion of Piwi pathway genes. Finally, our resource enables detection of crosstalk between piRNA and siRNA populations in mosquito cells during a response to virus infection. The MSRG resource will aid efforts to dissect and combat the capacity of mosquitoes to tolerate and spread arboviruses.
Reproductive phasiRNA loci and DICER-LIKE5, but not microRNA loci, diversified in monocotyledonous plants
Authors: Patel Parth , Mathioni Sandra M. , Hammond Reza , Harkess Alex E. , Kakrana Atul , Arikit Siwaret , Dusia Ayush , Meyers Blake C.
Published: April 2020

In monocots other than maize and rice, the repertoire and diversity of microRNAs (miRNAs) and the populations of phased, secondary, small interfering RNAs (phasiRNAs) are poorly characterized. To remedy this, we sequenced small RNAs from vegetative and dissected inflorescence tissue in 28 phylogenetically diverse monocots and from several early-diverging angiosperm lineages, as well as publicly available data from 10 additional monocot species. We annotated miRNAs, siRNAs and phasiRNAs across the monocot phylogeny, identifying miRNAs apparently lost or gained in the grasses relative to other monocot families, as well as a number of tRNA fragments misannotated as miRNAs. Using our miRNA database cleaned of these misannotations, we identified conservation at the 8th, 9th, 19thand 3’ end positions that we hypothesize are signatures of selection for processing, targeting, or Argonaute sorting. We show that 21-nt reproductive phasiRNAs are far more numerous in grass genomes than other monocots. Based on sequenced monocot genomes and transcriptomes, DICER-LIKE5 (DCL5), important to 24-nt phasiRNA biogenesis, likely originated via gene duplication before the diversification of the grasses. This curated database of phylogenetically diverse monocot miRNAs, siRNAs, and phasiRNAs represents a large collection of data that should facilitate continued exploration of small RNA diversification in flowering plants.
Structural Basis of RNA Cap Modification by SARS-CoV-2 Coronavirus
Authors: Viswanathan Thiruselvam , Arya Shailee , Chan Siu-Hong , Qi Shan , Dai Nan , Hromas Robert A. , Park Jun-Gyu , Oladunni Fatai , Martinez-Sobrido Luis , Gupta Yogesh K.
Published: April 2020

The novel severe acute respiratory syndrome coronoavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused over 2 million infections worldwide in four months. In SARS coronaviruses, the non-structural protein 16 (nsp16) methylates the 5’-end of virally encoded mRNAs to mimic cellular mRNAs, thus protecting the virus from host innate immune restriction. We report here the high-resolution structure of a ternary complex of full-length nsp16 and nsp10 of SARS-CoV-2 in the presence of cognate RNA substrate and a methyl donor, S-adenosyl methionine. The nsp16/nsp10 heterodimer was captured in the act of 2’-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We reveal large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This structure provides new mechanistic insights into the 2’-O methylation of the viral mRNA cap. We also discovered a distantly located ligand-binding site unique to SARS-CoV-2 that may serve as an alternative target site for antiviral development.
Conservation and divergence of DNA replication control inChlamydomonas reinhardtii
Authors: Ikui Amy E. , Ueki Noriko , Pecani Kresti , Cross Frederick
Published: April 2020

We recently isolated temperature-sensitive cell cycle mutants inChlamydomonas reinhardtiifor which the causative mutations were located in genes annotated for potential involvement in DNA replication.Chlamydomonashas a very long G1 period during which cells grow up to ~10-fold without division, followed by rapid cycles of DNA replication and mitosis (‘multiple fission’). All of the candidate DNA replication mutants tested were defective in completion of the first round of DNA replication, and also failed to produce mitotic spindles. For a subset of the mutants, we rescued temperature-sensitive lethality with tagged transgenes and used the resulting strains to analyze abundance and localization control of the tagged protein. All of the DNA replication proteins tested were essentially undetectable until late G1, accumulated during the period of multiple fission and then were degraded as cells completed their terminal divisions. MCM4 and MCM6 were localized to the nucleus during the division cycle except for transient cytoplasmic localization during mitosis. CDC45 showed strict protein location to the nucleus and co-localized to spindles during mitosis. In contrast, CDC6 was detected in the nucleus only transiently during early divisions within the overall multiple fission cycle. Cdc6 protein levels were very low, but increased upon treatment with MG132, a proteasome inhibitor. We also tested if these DNA replication proteins are regulated by cyclin dependent kinase (CDK). There are two main CDKs inChlamydomonas, CDKA1 and CDKB1. We found that CDC6 protein level was severely reduced in acdka1mutant, but not in acdkb1mutant. MG132 did not detectably increase CDC6 levels in thecdka1mutant, suggesting that CDKA1 upregulates CDC6 at the transcription level. Since MCM4, MCM6 and CDC6 were all essentially undetectable during the long G1 before DNA replication cycles began, we speculate that loading of origins with the MCM helicase may not occur until the end of the long G1, unlike in the budding yeast system. These results provide a microbial framework for approaching replication control in the plant kingdom.
Regulatory control circuits for stabilizing long-term anabolic product formation in yeast
Authors: D’Ambrosio Vasil , Dore Eleonora , Di Blasi Roberto , van den Broek Marcel , Sudarsan Suresh , Horst Jolanda ter , Ambri Francesca , Sommer Morten O.A. , Rugbjerg Peter , Keasling Jay. D , Mans Robert , Jensen Michael K.
Published: April 2020

Engineering living cells for production of chemicals, enzymes and therapeutics can burden cells due to use of limited native co-factor availability and/or expression burdens, totalling a fitness deficit compared to parental cells encoded through long evolutionary trajectories to maximise fitness. Ultimately, this discrepancy puts a selective pressure against fitness-burdened engineered cells under prolonged bioprocesses, and potentially leads to complete eradication of high-performing engineered cells at the population level. Here we present the mutation landscapes of fitness-burdened yeast cells engineered for vanillin-β-glucoside production. Next, we design synthetic control circuits based on transcriptome analysis and biosensors responsive to vanillin-β-glucoside pathway intermediates in order to stabilize vanillin-β-glucoside production over ∼55 generations in sequential passage experiments. Furthermore, using biosensors with two different modes of action we identify control circuits linking vanillin-β-glucoside pathway flux to various essential cellular functions, and demonstrate control circuits robustness and 92% higher vanillin-β-glucoside production, including 5-fold increase in total vanillin-β-glucoside pathway metabolite accumulation, in a fed-batch fermentation compared to vanillin-β-glucoside producing cells without control circuits.
How did SARS-CoV-19 spread in India from Italy, Iran and China? Genetic surveillance of early cases and virus demography
Authors: Thakur Mukesh , Singh Abhishek , Joshi Bheem Dutt , Ghosh Avijit , Singh Sujeet Kumar , Singh Neha , Sharma Lalit Kumar , Chandra Kailash
Published: April 2020

SARS-CoV-19 after emerging from Wuhan, drastically devastated all sectors of human life by crushing down the global economy and increased psychological burden on public, government, and healthcare professionals. We manifested by analyzing 35 early coronavirus cases of India, that virus introduction in India, occurred from Italy, Iran and China and population demography apparently revealed a rapid population expansion after the outbreak with a present steady growth. We depicted nucleotide substitutions in structural genes, drove for the adaptive selection and plead for sequencing more genomes to facilitate identification of new emerged mutants, genetic evolution and disease transmission caused by coronavirus.
A research agenda for problematising profit and profitability
Authors: Lowe Alan , Nama Yesh , Preda Alexandru
Published: April 2020

Purpose

The purpose of this paper is to advance a research agenda on the topic of problematising profit and profitability. This paper also acts as an introduction to this Accounting, Auditing & Accountability (AAAJ) special section which aims to foster the development of literature focussing on critically evaluating issues surrounding profit and profitability and their sometimes, deleterious effects on society. The authors encourage an interdisciplinary discussion on the concepts of profit and profitability and various ways in which the authors could potentially problematise these concepts.

Design/methodology/approach

The authors undertake a purposive interdisciplinary review to provide context on problematising profit and profitability by briefly discussing the evolution of the concept of profit and by reviewing some contemporary debates and discussions about the role and status of profit and profitability.

Findings

In order to further develop the literature on problematising profit and profitability, it is important to broaden the analytical framework in order to (1) uncover the assumptions that make profitable activities possible as well as justifications of such activities; (2) analyse the practices of profit not only in the sense of computational practices but also in the sense of strategic and rhetorical calculations; (3) evaluate the practices of profit and profitability where they are situated within social and power relationships and (4) connect practices of profit to specific social imaginaries of profit.

Originality/value

In setting out a future research agenda, this paper fosters theoretical and methodological pluralism and encourages box-breaking research in the research community focussing on problematising profit and profitability in various settings. The perspectives offered in this paper provides not only a basis for further research in this critical area of discourse and regulation on the role and status of profit and profitability but also provides emancipatory potential for practitioners (to be reflective of their practices and their undesired consequences of such practices) whose overarching focus is on these accounting numbers.
Why do consumers buy organic food? Results from an S–O–R model
Authors: Liang Austin Rong-Da , Lim Wai-Mun
Published: April 2020

Purpose

Organic food consumption is a complex process that makes it difficult for organic food businesses to develop appropriate marketing strategies. This study thus adopted the stimuli–organism–response (S–O–R) model to create a comprehensive framework to understand consumers' organic food purchase decisions.

Design/methodology/approach

This study collected 592 valid samples in organic food chain stores and markets by random sampling method. Meanwhile, structural equation modelling was adopted to test hypotheses.

Findings

The research findings indicate that consumer preference for natural food was the most important factor for enhancing purchase intention, followed by health consciousness, health risk, attitude towards organic food and trust in labelling. Perceptions of nutritional value positively influenced attitudes towards organic food and trust in labelling, followed by perceptions of environmental effects; conversely, attitudes towards organic food labelling had the least effect on increasing trust in labelling. Attitudes towards organic food labelling was the most important factor influencing positive attitudes towards organic food, followed by consumer perception of environmental protection effects.

Originality/value

This study demonstrates the relative influence of different variables on organic food purchase intention. Compared with consumer attitude towards organic food and trust in labelling, consumers' individual health was the most important factor influencing their purchase intention. As health and naturalness are attractive factors for consumers, the organic food industry can emphasize health protection in their marketing strategies.
A dynamic evolutionary game model of web celebrity brand eWOM marketing control strategy
Authors: Liao Mengjie , Zhang Jian , Wang Ruimei
Published: April 2020

Purpose

This paper aims to recognize whether government policy supervision or social network platform supervision can effectively promote the control of misconducts of web celebrity brand eWOM marketing and to identify the key factors influencing the unhealthy web celebrity marketing environment.

Design/methodology/approach

Theoretical research was employed to develop a practical approach for applying evolutionary game theory to eWOM marketing controlling strategies modeling via dynamic visualization, systematic simulation experiments.

Findings

Evolutionary game theory combined with dynamic simulation modeling can provide a formal approach to understanding web celebrity brand eWOM marketing decision-making in social media, which can thus support the control of unhealthy web celebrity marketing environment. The results demonstrate that the reasonable control of social platform control costs may be more effective than the government policy on web celebrity fake brand eWOM marketing behaviors.

Originality/value

The study enriches the research on the management and control of eWOM marketing as well as provides guidance for the sustainable development of the web celebrity economy in social media.