bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide
Authors: Li Fei , Han Ming , Dai Pengfei , Xu Wei , He Juan , Tao Xiaoting , Wu Yang , Tong Xinyuan , Xia Xinyi , Guo Wangxin , Zhou Yunjiao , Li Yunguang , Zhu Yiqin , Zhang Xiaoyu , Liu Zhuang , Aji Rebiguli , Cai Xia , Li Yutang , Qu Di , Chen Yu , Jiang Shibo , Wang Qiao , Ji Hongbin , Xie Youhua , Sun Yihua , Lu Lu , Gao Dong 
Published: February 2021

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.
General synthetic strategy for regioselective ultrafast formation of disulfide bonds in peptides and proteins
Authors: Laps Shay , Atamleh Fatima , Kamnesky Guy , Sun Hao , Brik Ashraf 
Published: February 2021

AbstractDespite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery.
Long-term warming in a Mediterranean-type grassland affects soil bacterial functional potential but not bacterial taxonomic composition
Authors: Gao Ying , Ding Junjun , Yuan Mengting , Chiariello Nona , Docherty Kathryn , Field Chris , Gao Qun , Gu Baohua , Gutknecht Jessica , Hungate Bruce A. , Le Roux Xavier , Niboyet Audrey , Qi Qi , Shi Zhou , Zhou Jizhong , Yang Yunfeng 
Published: February 2021

AbstractClimate warming is known to impact ecosystem composition and functioning. However, it remains largely unclear how soil microbial communities respond to long-term, moderate warming. In this study, we used Illumina sequencing and microarrays (GeoChip 5.0) to analyze taxonomic and functional gene compositions of the soil microbial community after 14 years of warming (at 0.8–1.0 °C for 10 years and then 1.5–2.0 °C for 4 years) in a Californian grassland. Long-term warming had no detectable effect on the taxonomic composition of soil bacterial community, nor on any plant or abiotic soil variables. In contrast, functional gene compositions differed between warming and control for bacterial, archaeal, and fungal communities. Functional genes associated with labile carbon (C) degradation increased in relative abundance in the warming treatment, whereas those associated with recalcitrant C degradation decreased. A number of functional genes associated with nitrogen (N) cycling (e.g., denitrifying genes encoding nitrate-, nitrite-, and nitrous oxidereductases) decreased, whereasnifHgene encoding nitrogenase increased in the warming treatment. These results suggest that microbial functional potentials are more sensitive to long-term moderate warming than the taxonomic composition of microbial community.
Biofilm-isolated Listeria monocytogenes exhibits reduced systemic dissemination at the early (12–24 h) stage of infection in a mouse model
Authors: Bai Xingjian , Liu Dongqi , Xu Luping , Tenguria Shivendra , Drolia Rishi , Gallina Nicholas L. F. , Cox Abigail D. , Koo Ok-Kyung , Bhunia Arun K. 
Published: February 2021

AbstractEnvironmental cues promote microbial biofilm formation and physiological and genetic heterogeneity. In food production facilities, biofilms produced by pathogens are a major source for food contamination; however, the pathogenesis of biofilm-isolated sessile cells is not well understood. We investigated the pathogenesis of sessile Listeria monocytogenes (Lm) using cell culture and mouse models. Lm sessile cells express reduced levels of the lap, inlA, hly, prfA, and sigB and show reduced adhesion, invasion, translocation, and cytotoxicity in the cell culture model than the planktonic cells. Oral challenge of C57BL/6 mice with food, clinical, or murinized-InlA (InlAm) strains reveals that at 12 and 24 h post-infection (hpi), Lm burdens are lower in tissues of mice infected with sessile cells than those infected with planktonic cells. However, these differences are negligible at 48 hpi. Besides, the expressions of inlA and lap mRNA in sessile Lm from intestinal content are about 6.0- and 280-fold higher than the sessle inoculum, respectively, suggesting sessile Lm can still upregulate virulence genes shortly after ingestion (12 h). Similarly, exposure to simulated gastric fluid (SGF, pH 3) and intestinal fluid (SIF, pH 7) for 13 h shows equal reduction in sessile and planktonic cell counts, but induces LAP and InlA expression and pathogenic phenotypes. Our data show that the virulence of biofilm-isolated Lm is temporarily attenuated and can be upregulated in mice during the early stage (12–24 hpi) but fully restored at a later stage (48 hpi) of infection. Our study further demonstrates that in vitro cell culture assay is unreliable; therefore, an animal model is essential for studying the pathogenesis of biofilm-isolated bacteria.
Ab initio molecular dynamics and materials design for embedded phase-change memory
Authors: Sun Liang , Zhou Yu-Xing , Wang Xu-Dong , Chen Yu-Han , Deringer Volker L. , Mazzarello Riccardo , Zhang Wei 
Published: February 2021

AbstractThe Ge2Sb2Te5 alloy has served as the core material in phase-change memories with high switching speed and persistent storage capability at room temperature. However widely used, this composition is not suitable for embedded memories—for example, for automotive applications, which require very high working temperatures above 300 °C. Ge–Sb–Te alloys with higher Ge content, most prominently Ge2Sb1Te2 (‘212’), have been studied as suitable alternatives, but their atomic structures and structure–property relationships have remained widely unexplored. Here, we report comprehensive first-principles simulations that give insight into those emerging materials, located on the compositional tie-line between Ge2Sb1Te2 and elemental Ge, allowing for a direct comparison with the established Ge2Sb2Te5 material. Electronic-structure computations and smooth overlap of atomic positions (SOAP) similarity analyses explain the role of excess Ge content in the amorphous phases. Together with energetic analyses, a compositional threshold is identified for the viability of a homogeneous amorphous phase (‘zero bit’), which is required for memory applications. Based on the acquired knowledge at the atomic scale, we provide a materials design strategy for high-performance embedded phase-change memories with balanced speed and stability, as well as potentially good cycling capability.
Inference of phenotype-relevant transcriptional regulatory networks elucidates cancer type-specific regulatory mechanisms in a pan-cancer study
Authors: Emad Amin , Sinha Saurabh 
Published: February 2021

AbstractReconstruction of transcriptional regulatory networks (TRNs) is a powerful approach to unravel the gene expression programs involved in healthy and disease states of a cell. However, these networks are usually reconstructed independent of the phenotypic (or clinical) properties of the samples. Therefore, they may confound regulatory mechanisms that are specifically related to a phenotypic property with more general mechanisms underlying the full complement of the analyzed samples. In this study, we develop a method called InPheRNo to identify “phenotype-relevant” TRNs. This method is based on a probabilistic graphical model that models the simultaneous effects of multiple transcription factors (TFs) on their target genes and the statistical relationship between the target genes’ expression and the phenotype. Extensive comparison of InPheRNo with related approaches using primary tumor samples of 18 cancer types from The Cancer Genome Atlas reveals that InPheRNo can accurately reconstruct cancer type-relevant TRNs and identify cancer driver TFs. In addition, survival analysis reveals that the activity level of TFs with many target genes could distinguish patients with poor prognosis from those with better prognosis.
A single dose investigational subunit vaccine for human use against Nipah virus and Hendra virus
Authors: Geisbert Thomas W. , Bobb Kathryn , Borisevich Viktoriya , Geisbert Joan B. , Agans Krystle N. , Cross Robert W. , Prasad Abhishek N. , Fenton Karla A. , Yu Hao , Fouts Timothy R. , Broder Christopher C. , Dimitrov Antony S. 
Published: February 2021

AbstractNipah and Hendra viruses are highly pathogenic bat-borne paramyxoviruses recently included in the WHO Blueprint priority diseases list. A fully registered horse anti-Hendra virus subunit vaccine has been in use in Australia since 2012. Based on the same immunogen, the Hendra virus attachment glycoprotein ectodomain, a subunit vaccine formulation for use in people is now in a Phase I clinical trial. We report that a single dose vaccination regimen of this human vaccine formulation protects against otherwise lethal challenges of either Hendra or Nipah virus in a nonhuman primate model. The protection against the Nipah Bangladesh strain begins as soon as 7 days post immunization with low dose of 0.1 mg protein subunit. Our data suggest this human vaccine could be utilized as efficient emergency vaccine to disrupt potential spreading of Nipah disease in an outbreak setting.
Poromechanical controls on spontaneous imbibition in earth materials
Authors: Haghi Amir H. , Chalaturnyk Richard , Blunt Martin J. , Hodder Kevin , Geiger Sebastian 
Published: February 2021

AbstractOver the last century, the state of stress in the earth’s upper crust has undergone rapid changes because of human activities associated with fluid withdrawal and injection in subsurface formations. The stress dependency of multiphase flow mechanisms in earth materials is a substantial challenge to understand, quantify, and model for many applications in groundwater hydrology, applied geophysics, CO2 subsurface storage, and the wider geoenergy field (e.g., geothermal energy, hydrogen storage, hydrocarbon recovery). Here, we conduct core-scale experiments using N2/water phases to study primary drainage followed by spontaneous imbibition in a carbonate specimen under increasing isotropic effective stress and isothermal conditions. Using X-ray computed micro-tomography images of the unconfined specimen, we introduce a novel coupling approach to reconstruct pore-deformation and simulate multiphase flow inside the deformed pore-space followed by a semi-analytical calculation of spontaneous imbibition. We show that the irreducible water saturation increases while the normalized volume of spontaneously imbibed water into the specimen decreases (46–25%) in response to an increase in effective stress (0–30 MPa), leading to higher residual gas saturations. Furthermore, the imbibition rate decreases with effective stress, which is also predicted by a numerical model, due to a decrease in water relative permeability as the pore-space becomes more confined and tortuous. This fundamental study provides new insights into the physics of multiphase fluid transport, CO2 storage capacity, and recovery of subsurface resources incorporating the impact of poromechanics.
Correlation of cochlear aperture stenosis with cochlear nerve deficiency in congenital unilateral hearing loss and prognostic relevance for cochlear implantation
Authors: Orzan Eva , Pizzamiglio Giulia , Gregori Massimo , Marchi Raffaella , Torelli Lucio , Muzzi Enrico 
Published: February 2021

AbstractThe use of neonatal hearing screening has enabled the identification of congenital unilateral sensorineural hearing loss (USNHL) immediately after birth, and today there are several intervention options available to minimize potential adverse effects of this disease, including cochlear implantation. This study aims to analyze the characteristics of the inner ear of a homogeneous group of congenital non-syndromic USNHL to highlight the features of the inner ear, which can help in clinical, surgical, and rehabilitative decision-making. A retrospective chart review was carried out at a tertiary referral center. Systematic diagnostic work-up and rigorous inclusion–exclusion criteria were applied to 126 children with unilateral hearing impairment, leading to a selection of 39 strictly congenital and non-syndromic USNHL cases, undergoing computed tomography (CT) and magnetic resonance (MR) imaging studies. The frequency and type of malformations of the inner ear in USNHL and unaffected contralateral ears were assessed, with an in-depth analysis of the deficiency of the cochlear nerve (CND), the internal auditory canal (IAC) and the cochlear aperture (CA). Inner ear anomalies were found in 18 out of 39 (46%) of the USNHL patients. In 1 subject, the anomalies were bilateral, and the CND resulted in the predominant identified defect (78% of our abnormal case series), frequently associated with CA stenosis. Only 3 out of 14 children with CND presented stenosis of the IAC. CND and CA stenosis (and to a much lesser extent IAC stenosis) are a frequent association within congenital and non-syndromic USNHL that could represent a distinct pathological entity affecting otherwise healthy infants. In the context of a diagnostic work-up, the evaluation with CT and MRI measurements should take place in a shared decision-making setting with thorough counseling. Both imaging techniques have proven useful in differentiating the cases that will most likely benefit from the cochlear implant, from those with potentially poor implant performance.
A case–control study of clinical characteristics and risk factors of symptomatic postpartum pubic symphysis diastasis
Authors: Sung Ji-Hee , Kang Mina , Lim Seung-Jae , Choi Suk-Joo , Oh Soo-young , Roh Cheong-Rae 
Published: February 2021

AbstractPostpartum pubic symphysis diastasis (PPSD) refers to the separation of pubic symphysis after delivery. It is typically diagnosed based on clinical symptoms and radiologic findings. This study tried to assess clinical characteristics and risk factors of PPSD. This was a nested case–control study matched for year of delivery and gestational age at delivery using a retrospective cohort of women who delivered vaginally at a single institution. The incidence of PPSD was 0.156% (33/21,131). The incidence rate increased from 0.08% (7/9328) in 2000–2004 to 0.13% (9/7138) in 2005–2009 and to 0.36% (17/4665) in 2010–2016, simultaneously with an increase of maternal age (30.7 ± 3.5 years in 2000–2004 to 31.8 ± 3.8 years in 2005–2009 and 32.8 ± 3.8 years in 2010–2016). Nulliparity was associated with a higher incidence of PPSD (81.8% in cases vs. 57.6% in controls, p = 0.01). Other factors including pre-pregnancy body mass index, weight gain during pregnancy, gestational diabetes, induction of labor, duration of labor, epidural anesthesia, vacuum-assisted delivery, episiotomy, neonatal sex and birth weight failed to show difference between the two groups. In short, the incidence of PPSD increased with time along with an increase of maternal age. Nulliparity was the only significant risk factor for PPSD.
Automatic ganglion cell detection for improving the efficiency and accuracy of hirschprung disease diagnosis
Authors: Greenberg Ariel , Aizic Asaf , Zubkov Asia , Borsekofsky Sarah , Hagege Rami R. , Hershkovitz Dov 
Published: February 2021

AbstractHistopathologic diagnosis of Hirschsprung's disease (HSCR) is time consuming and requires expertise. The use of artificial intelligence (AI) in digital pathology is actively researched and may improve the diagnosis of HSCR. The purpose of this research was to develop an algorithm capable of identifying ganglion cells in digital pathology slides and implement it as an assisting tool for the pathologist in the diagnosis of HSCR. Ninety five digital pathology slides were used for the construction and training of the algorithm. Fifty cases suspected for HSCR (727 slides) were used as a validation cohort. Image sets suspected to contain ganglion cells were chosen by the algorithm and then reviewed and scored by five pathologists, one HSCR expert and 4 non-experts. The algorithm was able to identify ganglion cells with 96% sensitivity and 99% specificity (in normal colon) as well as to correctly identify a case previously misdiagnosed as non-HSCR. The expert was able to achieve perfectly accurate diagnoses based solely on the images suggested by the algorithm, with over 95% time saved. Non-experts would require expert consultation in 20–58% of the cases to achieve similar results. The use of AI in the diagnosis of HSCR can greatly reduce the time and effort required for diagnosis and improve accuracy.
Three-dimensional ultrastructure of giant mitochondria in human non-alcoholic fatty liver disease
Authors: Shami Gerald J. , Cheng Delfine , Verhaegh Pauline , Koek Ger , Wisse Eddie , Braet Filip 
Published: February 2021

AbstractGiant mitochondria are peculiarly shaped, extremely large mitochondria in hepatic parenchymal cells, the internal structure of which is characterised by atypically arranged cristae, enlarged matrix granules and crystalline inclusions. The presence of giant mitochondria in human tissue biopsies is often linked with cellular adversity, caused by toxins such as alcohol, xenobiotics, anti-cancer drugs, free-radicals, nutritional deficiencies or as a consequence of high fat Western diets. To date, non-alcoholic fatty liver disease is the most prevalent liver disease in lipid dysmetabolism, in which mitochondrial dysfunction plays a crucial role. It is not well understood whether the morphologic characteristics of giant mitochondria are an adaption or caused by such dysfunction. In the present study, we employ a complementary multimodal imaging approach involving array tomography and transmission electron tomography in order to comparatively analyse the structure and morphometric parameters of thousands of normal- and giant mitochondria in four patients diagnosed with non-alcoholic fatty liver disease. In so doing, we reveal functional alterations associated with mitochondrial gigantism and propose a mechanism for their formation based on our ultrastructural findings.
Designing a bed-side system for predicting length of stay in a neonatal intensive care unit
Authors: Singh Harpreet , Cho Su Jin , Gupta Shubham , Kaur Ravneet , Sunidhi S. , Saluja Satish , Pandey Ashish Kumar , Bennett Mihoko V. , Lee Henry C. , Das Ritu , Palma Jonathan , McAdams Ryan M. , Kaur Avneet , Yadav Gautam , Sun Yao 
Published: February 2021

AbstractIncreased length of stay (LOS) in intensive care units is directly associated with the financial burden, anxiety, and increased mortality risks. In the current study, we have incorporated the association of day-to-day nutrition and medication data of the patient during its stay in hospital with its predicted LOS. To demonstrate the same, we developed a model to predict the LOS using risk factors (a) perinatal and antenatal details, (b) deviation of nutrition and medication dosage from guidelines, and (c) clinical diagnoses encountered during NICU stay. Data of 836 patient records (12 months) from two NICU sites were used and validated on 211 patient records (4 months). A bedside user interface integrated with EMR has been designed to display the model performance results on the validation dataset. The study shows that each gestation age group of patients has unique and independent risk factors associated with the LOS. The gestation is a significant risk factor for neonates < 34 weeks, nutrition deviation for < 32 weeks, and clinical diagnosis (sepsis) for ≥ 32 weeks. Patients on medications had considerable extra LOS for ≥ 32 weeks’ gestation. The presented LOS model is tailored for each patient, and deviations from the recommended nutrition and medication guidelines were significantly associated with the predicted LOS.
Tracking COVID-19 using online search
Authors: Lampos Vasileios , Majumder Maimuna S. , Yom-Tov Elad , Edelstein Michael , Moura Simon , Hamada Yohhei , Rangaka Molebogeng X. , McKendry Rachel A. , Cox Ingemar J. 
Published: February 2021

AbstractPrevious research has demonstrated that various properties of infectious diseases can be inferred from online search behaviour. In this work we use time series of online search query frequencies to gain insights about the prevalence of COVID-19 in multiple countries. We first develop unsupervised modelling techniques based on associated symptom categories identified by the United Kingdom’s National Health Service and Public Health England. We then attempt to minimise an expected bias in these signals caused by public interest—as opposed to infections—using the proportion of news media coverage devoted to COVID-19 as a proxy indicator. Our analysis indicates that models based on online searches precede the reported confirmed cases and deaths by 16.7 (10.2–23.2) and 22.1 (17.4–26.9) days, respectively. We also investigate transfer learning techniques for mapping supervised models from countries where the spread of the disease has progressed extensively to countries that are in earlier phases of their respective epidemic curves. Furthermore, we compare time series of online search activity against confirmed COVID-19 cases or deaths jointly across multiple countries, uncovering interesting querying patterns, including the finding that rarer symptoms are better predictors than common ones. Finally, we show that web searches improve the short-term forecasting accuracy of autoregressive models for COVID-19 deaths. Our work provides evidence that online search data can be used to develop complementary public health surveillance methods to help inform the COVID-19 response in conjunction with more established approaches.