bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two conserved oligomer interfaces of NSP7 and NSP8 underpin the dynamic assembly of SARS-CoV-2 RdRP
Authors: Biswal Mahamaya , Diggs Stephen , Xu Duo , Khudaverdyan Nelli , Lu Jiuwei , Fang Jian , Blaha Gregor , Hai Rong , Song Jikui 
Published: April 2021

Abstract
Replication of the ∼30 kb-long coronavirus genome is mediated by a complex of non-structural proteins (NSP), in which NSP7 and NSP8 play a critical role in regulating the RNA-dependent RNA polymerase (RdRP) activity of NSP12. The assembly of NSP7, NSP8 and NSP12 proteins is highly dynamic in solution, yet the underlying mechanism remains elusive. We report the crystal structure of the complex between NSP7 and NSP8 of SARS-CoV-2, revealing a 2:2 heterotetrameric form. Formation of the NSP7-NSP8 complex is mediated by two distinct oligomer interfaces, with interface I responsible for heterodimeric NSP7-NSP8 assembly, and interface II mediating the heterotetrameric interaction between the two NSP7-NSP8 dimers. Structure-guided mutagenesis, combined with biochemical and enzymatic assays, further reveals a structural coupling between the two oligomer interfaces, as well as the importance of these interfaces for the RdRP activity of the NSP7-NSP8-NSP12 complex. Finally, we identify an NSP7 mutation that differentially affects the stability of the NSP7-NSP8 and NSP7-NSP8-NSP12 complexes leading to a selective impairment of the RdRP activity. Together, this study provides deep insights into the structure and mechanism for the dynamic assembly of NSP7 and NSP8 in regulating the replication of the SARS-CoV-2 genome, with important implications for antiviral drug development.
Integrating multiple references for single-cell assignment
Authors: Duan Bin , Chen Shaoqi , Chen Xiaohan , Zhu Chenyu , Tang Chen , Wang Shuguang , Gao Yicheng , Fu Shaliu , Liu Qi 
Published: April 2021

AbstractEfficient single-cell assignment is essential for single-cell sequencing data analysis. With the explosive growth of single-cell sequencing data, multiple single-cell sequencing data sources are available for the same kind of tissue, which can be integrated to further improve single-cell assignment; however, an efficient integration strategy is still lacking due to the great challenges of data heterogeneity existing in multiple references. To this end, we present mtSC, a flexible single-cell assignment framework that integrates multiple references based on multitask deep metric learning designed specifically for cell type identification within tissues with multiple single-cell sequencing data as references. We evaluated mtSC on a comprehensive set of publicly available benchmark datasets and demonstrated its state-of-the-art effectiveness for integrative single-cell assignment with multiple references.
LigAdvisor: a versatile and user-friendly web-platform for drug design
Authors: Pinzi Luca , Tinivella Annachiara , Gagliardelli Luca , Beneventano Domenico , Rastelli Giulio 
Published: April 2021

Abstract
Although several tools facilitating in silico drug design are available, their results are usually difficult to integrate with publicly available information or require further processing to be fully exploited. The rational design of multi-target ligands (polypharmacology) and the repositioning of known drugs towards unmet therapeutic needs (drug repurposing) have raised increasing attention in drug discovery, although they usually require careful planning of tailored drug design strategies. Computational tools and data-driven approaches can help to reveal novel valuable opportunities in these contexts, as they enable to efficiently mine publicly available chemical, biological, clinical, and disease-related data. Based on these premises, we developed LigAdvisor, a data-driven webserver which integrates information reported in DrugBank, Protein Data Bank, UniProt, Clinical Trials and Therapeutic Target Database into an intuitive platform, to facilitate drug discovery tasks as drug repurposing, polypharmacology, target fishing and profiling. As designed, LigAdvisor enables easy integration of similarity estimation results with clinical data, thereby allowing a more efficient exploitation of information in different drug discovery contexts. Users can also develop customizable drug design tasks on their own molecules, by means of ligand- and target-based search modes, and download their results. LigAdvisor is publicly available at https://ligadvisor.unimore.it/.
Environmental and sex-specific molecular signatures of glioma causation
Authors: Claus Elizabeth B , Cannataro Vincent L , Gaffney Stephen G , Townsend Jeffrey P 
Published: April 2021

Abstract

Background
The relative importance of genetic and environmental risk factors in gliomagenesis remains uncertain.

Methods
Using whole-exome sequencing data from 1105 adult gliomas, we evaluate the relative contribution to cancer cell lineage proliferation and survival of single-nucleotide mutations in tumors by IDH mutation subtype and sex. We also quantify the contributions of COSMIC cancer mutational signatures to these tumors, identifying possible risk exposures.

Results
IDH-mutant tumors exhibited few unique recurrent substitutions—all in coding regions, while IDH wild-type tumors exhibited many substitutions in non-coding regions. The importance of previously reported mutations in IDH1/2, TP53, EGFR, PTEN, PIK3CA, and PIK3R1 was confirmed; however, the largest cancer effect in IDH wild-type tumors was associated with mutations in the low-prevalence BRAF V600E. Males and females exhibited mutations in a similar set of significantly overburdened genes, with some differences in variant sites—notably in the phosphoinositide 3-kinase (PI3K) pathway. In IDH-mutant tumors, PIK3CA mutations were located in the helical domain for females and the kinase domain for males; variants of import also differed by sex for PIK3R1. Endogenous age-related mutagenesis was the primary molecular signature identified; a signature associated with exogenous exposure to haloalkanes was identified and noted more frequently in males.

Conclusions
Cancer-causing mutations in glioma primarily originated as a consequence of endogenous rather than exogenous factors. Mutations in helical vs kinase domains of genes in the phosphoinositide 3-kinase (PI3K) pathway are differentially selected in males and females. Additionally, a rare environmental risk factor is suggested for some cases of glioma—particularly in males.
Proper protein folding in the endoplasmic reticulum is required for attachment of a glycosylphosphatidylinositol anchor in plants
Authors: Shin Yun-Ji , Vavra Ulrike , Strasser Richard 
Published: April 2021

Abstract
Endoplasmic reticulum (ER) quality control processes recognize and eliminate misfolded proteins to maintain cellular protein homeostasis and prevent the accumulation of defective proteins in the secretory pathway. Glycosylphosphatidylinositol (GPI)-anchored proteins carry a glycolipid modification, which provides an efficient ER export signal and potentially prevents the entry into ER-associated degradation (ERAD), which is one of the major pathways for clearance of terminally misfolded proteins from the ER. Here, we analyzed the degradation routes of different misfolded glycoproteins carrying a C-terminal GPI-attachment signal peptide in Arabidopsis thaliana. We found that a fusion protein consisting of the misfolded extracellular domain from Arabidopsis STRUBBELIG and the GPI-anchor attachment sequence of COBRA1 was efficiently targeted to hydroxymethylglutaryl reductase degradation protein 1 complex-mediated ERAD without the detectable attachment of a GPI anchor. Non-native variants of the GPI-anchored lipid transfer protein 1 (LTPG1) that lack a severely misfolded domain, on the other hand, are modified with a GPI anchor and targeted to the vacuole for degradation. Impaired processing of the GPI-anchoring signal peptide by mutation of the cleavage site or in a GPI-transamidase-compromised mutant caused ER retention and routed the non-native LTPG1 to ERAD. Collectively, these results indicate that for severely misfolded proteins, ER quality control processes are dominant over ER export. For less severely misfolded proteins, the GPI anchor provides an efficient ER export signal resulting in transport to the vacuole.
Identifying parameters associated with delayed diagnosis in axial spondyloarthritis: data from the European map of axial spondyloarthritis
Authors: Garrido-Cumbrera Marco , Navarro-Compán Victoria , Bundy Christine , Mahapatra Raj , Makri Souzi , Correa-Fernández José , Christen Laura , Delgado-Domínguez Carlos Jesús , Poddubnyy Denis ,   the EMAS Working Group
Published: April 2021

Abstract

Objective
To identify the parameters associated with self-reported diagnostic delay (DD) in axial spondyloarthritis (axSpA) patients across Europe.

Methods
Data from 2652 patients from 13 countries who participated in the European Map of Axial Spondyloarthritis (EMAS) were collected through an online survey (2017–2018). DD was calculated as the difference between age at diagnosis and age at symptom onset reported by participants. Associations between DD and sociodemographic characteristics, as well as disease-related factors were explored through univariable and multivariable linear regression analysis.

Results
Average DD was 7.4  (8.4) years with a variation between countries. The variables associated with longer DD in the final multivariable regression model were: younger age at symptom onset (b = −0.26; 95% CI: −0.28, −0.23), female gender (b = 1.34; 95% CI: 0.73, 1.96) and higher number of health-care professionals (HCPs) seen before diagnosis (b = 1.19; 95% CI: 0.95, 1.43). There was a significant interaction between the female gender and the number of HCPs seen before diagnosis. A substantial variation of the DD across European countries was observed.

Conclusion
In this sample of axSpA patients, average DD was greater than 7 years. Younger age at symptom onset, female gender, higher number of HCPs seen before diagnosis, and being diagnosed by rheumatologist were the parameters associated with a longer DD in axSpA. These findings indicate a need for continuing efforts dedicated to recognition of patients with a high probability of axSpA on the level of non-rheumatology specialists and facilitating referral to a rheumatologist for timely diagnosis.
Transforming Lives of Former Foster Youths: A Campus-Based Support Program Grounded in Social Work Values
Authors: Lee Madeline Y , Mickelson James , Quijada Leigh , Orr Laurie 
Published: April 2021

Abstract
Support programs to improve higher education outcomes for former foster youths have emerged in the past 20 years, but literature to guide their development and implementation is limited. This conceptual article presents the program logic model for ACE [Achieving College Excellence] Scholars Services, the comprehensive, campus-based program supporting former foster youths grounded in social work values at California State University San Marcos (CSUSM). ACE has a noncompetitive application process that accepts an unrestricted number of students, known as ACE Scholars. To focus on the unique needs of former foster youths, students who are on probation, experiencing homeless, and unaccompanied minors are included if they have also experienced foster care. Funded by private donors, the Center for ACE Scholars on CSUSM’s campus provides an inviting, welcoming space that reflects the inclusive support ACE Scholars receive. By increasing educational attainment and opportunities for this vulnerable population, ACE aims to improve outcomes for former foster youths and their next generation. Articulating this program logic model provides implications for developing and implementing support programs for former foster youths on college campuses and sets the foundation for evaluating the impact of ACE Scholars Services.
Converging Roles of the Aryl Hydrocarbon Receptor in Early Embryonic Development, Maintenance of Stemness, and Tissue Repair
Authors: Zablon Hesbon A , Ko Chia-I , Puga Alvaro 
Published: April 2021

Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor well-known for its adaptive role as a sensor of environmental toxicants and mediator of the metabolic detoxification of xenobiotic ligands. In addition, a growing body of experimental data has provided indisputable evidence that the AHR regulates critical functions of cell physiology and embryonic development. Recent studies have shown that the naïve AHR—that is, unliganded to xenobiotics but activated endogenously—has a crucial role in maintenance of embryonic stem cell pluripotency, tissue repair, and regulation of cancer stem cell stemness. Depending on the cellular context, AHR silences the expression of pluripotency genes Oct4 and Nanog and potentiates differentiation, whereas curtailing cellular plasticity and stemness. In these processes, AHR-mediated contextual responses and outcomes are dictated by changes of interacting partners in signaling pathways, gene networks, and cell-type-specific genomic structures. In this review, we focus on AHR-mediated changes of genomic architecture as an emerging mechanism for the AHR to regulate gene expression at the transcriptional level. Collective evidence places this receptor as a physiological hub connecting multiple biological processes whose disruption impacts on embryonic development, tissue repair, and maintenance or loss of stemness.
Safety of Nitrous Oxide Anesthesia in a Selected Group of Patients Undergoing Neurosurgery: An Exploratory Subgroup Analysis of the ENIGMA Trials
Authors: Patel Kishan K. , Sun Xin , Cheng Joseph , Schaller Karl , Tessitore Enrico , Gondar Renato , Gaudet John , Myles Paul S. , Leslie Kate , Nouri Aria 
Published: April 2021

Background:
The Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia (ENIGMA)-I and ENIGMA-II were randomized clinical trials that assessed the safety of nitrous oxide anesthesia in patients undergoing noncardiac surgery. In this study, we performed an exploratory pooled analysis of both ENIGMA trials to assess the safety of nitrous oxide in a selected group of patients undergoing neurosurgery.

Methods:
Data from each ENIGMA trial were collated into a single database. Information regarding patient demographics, comorbidities, medication use, anesthesia, surgical procedure, and postoperative complications was extracted. Multivariate logistic regression was conducted for postoperative complications to assess the risk associated with nitrous oxide.

Results:
A total of 830 patients were included in our analysis: 417 received nitrous oxide anesthesia, and 413 received nitrous oxide-free anesthesia. Baseline patient and perioperative characteristics were comparable. Procedural data were available for 535 patients (64%); of these, 507 (95%) underwent spinal neurosurgery and 28 (5%) underwent cranial neurosurgery. Patients in the nitrous oxide group had lower inspired oxygen concentration (30% vs. 38%; P<0.001) and end-tidal volatile agent concentration (0.56 vs. 0.89 minimal alveolar concentration equivalents; P<0.001) compared with the nitrous oxide-free group. Use of nitrous oxide was not associated with increased risk of postoperative complications (myocardial infarction, cardiac arrest, stroke, infection, severe vomiting, fever, pneumonia, pneumothorax, blood transfusion, venous thromboembolism, or death) (odds ratio: 1.22; 95% confidence interval: 0.89-1.65; P=0.22) or prolonged length of hospital stay (median 5.0 vs. 4.2 d for nitrous oxide and nitrous oxide-free groups; P=0.28).

Conclusion:
Nitrous oxide did not increase the risk of postoperative complications or prolonged length of hospital stay in the neurosurgical cohort enrolled in the ENIGMA-I and ENIGMA-II trials.
System of Psychological Support Based on Positive Suggestions to the Critically Ill Using ICU Doulas
Authors: Karnatovskaia Lioudmila V. , Schultz Jason M. , Niven Alexander S. , Steele Amanda J. , Baker Brittany A. , Philbrick Kemuel L. , del Valle Kathryn T. , Johnson Kimberly R. , Gajic Ognjen , Varga Katalin 
Published: April 2021

Background:
Surviving critical illness often creates a lasting psychological impact, including depression, anxiety, and post-traumatic stress. Memories of frightening and delusional experiences are the largest potentially modifiable risk factor, but currently, there is no proven intervention to improve these inciting factors. Psychological support based on positive suggestion is a psychotherapeutic approach that can be provided even to patients in altered cognitive states and is therefore a viable psychotherapy intervention throughout the ICU stay. Traditional ICU care team members have limited time and training to provide such psychological support to patients. Doulas are trained supportive companions who have been effectively used to provide patient advocacy and emotional support in other clinical settings and may address this need. Our aim was to train and implement a psychological support based on positive suggestion program for the critically ill using doulas, and measure acceptance of this intervention through stakeholder feedback.

Methods:
Doula training included three objectives: an introduction to ICU practice structure and policies; education about fundamental aspects of critical care conditions and procedures; and didactic and hands-on learning experiences in effective use of psychological support based on positive suggestion in the critically ill. Doulas were evaluated at the end of their training and during subsequent clinical activities using competency-based assessments as well as through survey-based questions and interviews with key stakeholders.

Results:
The ICU doulas performed psychological support based on positive suggestion on 43 critically ill patients in the ICU setting. Stakeholder feedback from nurses, patients, and patient families was positive. The majority (28/32) of surveyed bedside ICU nurses reported that the doulas’ involvement was helpful for both patients and nurses alike. All interviewed family members offered positive comments about the ICU doula presence and of the 40 patients who recalled the intervention 37 found it comforting.

Conclusions:
Our program successfully trained two doulas to work effectively in the ICU setting performing patient-centered psychological support based on positive suggestion interventions. Their training improved their skill sets and was reported as beneficial by patients, families, and critical care nursing. This training program offers a proof of concept that could be applied in other medical centers, bringing doulas more commonly into the ICU practice to help humanize the experience for patients, families, and medical teams.
Respiratory Support Adjustments and Monitoring of Mechanically Ventilated Patients Performing Early Mobilization: A Scoping Review
Authors: González-Seguel Felipe , Camus-Molina Agustín , Jasmén Anita , Molina Jorge , Pérez-Araos Rodrigo , Graf Jerónimo 
Published: April 2021

Objectives:
This scoping review is aimed to summarize current knowledge on respiratory support adjustments and monitoring of metabolic and respiratory variables in mechanically ventilated adult patients performing early mobilization.

Data Sources:
Eight electronic databases were searched from inception to February 2021, using a predefined search strategy.

Study Selection:
Two blinded reviewers performed document selection by title, abstract, and full text according to the following criteria: mechanically ventilated adult patients performing any mobilization intervention, respiratory support adjustments, and/or monitoring of metabolic/respiratory real-time variables.

Data Extraction:
Four physiotherapists extracted relevant information using a prespecified template.

Data Synthesis:
From 1,208 references screened, 35 documents were selected for analysis, where 20 (57%) were published between 2016 and 2020. Respiratory support settings (ventilatory modes or respiratory variables) were reported in 21 documents (60%). Reported modes were assisted (n = 11) and assist-control (n = 9). Adjustment of variables and modes were identified in only seven documents (20%). The most frequent respiratory variable was the Fio
2, and only four studies modified the level of ventilatory support. Mechanical ventilator brand/model used was not specified in 26 documents (74%). Monitoring of respiratory, metabolic, and both variables were reported in 22 documents (63%), four documents (11%) and 10 documents (29%), respectively. These variables were reported to assess the physiologic response (n = 21) or safety (n = 13). Monitored variables were mostly respiratory rate (n = 26), pulse oximetry (n = 22), and oxygen consumption (n = 9). Remarkably, no study assessed the work of breathing or effort during mobilization.

Conclusions:
Little information on respiratory support adjustments during mobilization of mechanically ventilated patients was identified. Monitoring of metabolic and respiratory variables is also scant. More studies on the effects of adjustments of the level/mode of ventilatory support on exercise performance and respiratory muscle activity monitoring for safe and efficient implementation of early mobilization in mechanically ventilated patients are needed.
Long-term Outcomes after Postnatal Cytomegalovirus Infection in Low Birthweight Preterm Infants
Authors: Stark Ashley , Cantrell Sarah , Greenberg Rachel G. , Permar Sallie R. , Weimer Kristin E. D. 
Published: April 2021

Background:
Cytomegalovirus (CMV) is the most common viral infection seen in newborns. Although postnatally acquired CMV (pCMV) infection rarely results in serious manifestations in term infants, preterm infants can develop severe clinical illness. However, the long-term implications of pCMV infection of preterm infants are unknown. Few robust studies on long-term outcomes of pCMV infection have been performed, and those reported often present conflicting results. Our objective was to assess the long-term outcomes for low birthweight (LBW) preterm infants after pCMV infection.

Methods:
A systematic review of English and non-English articles using MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science was conducted. Search strategies included a mix of keywords and database-specific subject headings for CMV and LBW infants. Editorials, comments, reviews and animal-only studies were excluded. Case reports, observational, experimental and randomized controlled trials that examined pCMV in preterm or VLBW infants and long-term (>1 month) impact of pCMV were included.

Results:
pCMV infection in preterm infants is associated with increased risk for pulmonary and neurologic complications and increases length of stay. There is less evidence to suggest that pCMV is associated with necrotizing enterocolitis, ophthalmologic, audiologic and anthropomorphic complications in preterm infants.

Conclusions:
Preterm infants with pCMV, especially those with symptomatic infection, may have long-term pulmonary and neurodevelopmental morbidity compared with their pCMV negative counterparts. Our results highlight the importance of pCMV detection and prevention in preterm infants in the neonatal intensive care unit. Large prospective studies are needed to fully define outcomes and determine if treatment improves outcomes.