bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of SARS-CoV-2 entry inhibitors based on ACE2 receptor or engineered Spike-binding peptides
Authors: Llewellyn George N. , Chen Hsu-Yu , Rogers Geoffrey L. , Huang Xiaoli , Sell Philip J. , Henley Jill E. , Cannon Paula M. 
Published: August 2023

ABSTRACT
With increasing resistance of SARS-CoV-2 variants to antibodies, there is interest in developing entry inhibitors that target essential receptor-binding regions of the viral Spike protein and thereby present a high bar for viral resistance. Such inhibitors could be derivatives of the viral receptor, ACE2, or peptides engineered to interact specifically with the Spike receptor-binding pocket. We compared the efficacy of a series of both types of entry inhibitors, constructed as fusions to an antibody Fc domain. Such a design can increase protein stability and act to both neutralize free virus and recruit effector functions to clear infected cells. We tested the reagents against prototype variants of SARS-CoV-2, using both Spike pseudotyped vesicular stomatitis virus vectors and replication-competent viruses. These analyses revealed that an optimized ACE2 derivative could neutralize all variants we tested with high efficacy. In contrast, the Spike-binding peptides had varying activities against different variants, with resistance observed in the Spike proteins from Beta, Gamma, and Omicron (BA.1 and BA.5). The resistance mapped to mutations at Spike residues K417 and N501 and could be overcome for one of the peptides by linking two copies in tandem, effectively creating a tetrameric reagent in the Fc fusion. Finally, both the optimized ACE2 and tetrameric peptide inhibitors provided some protection to human ACE2 transgenic mice challenged with the SARS-CoV-2 Delta variant, which typically causes death in this model within 7–9 days.

IMPORTANCE

The increasing resistance of SARS-CoV-2 variants to therapeutic antibodies has highlighted the need for new treatment options, especially in individuals who do not respond to vaccination. Receptor decoys that block viral entry are an attractive approach because of the presumed high bar to developing viral resistance. Here, we compare two entry inhibitors based on derivatives of the ACE2 receptor, or engineered peptides that bind to the receptor-binding pocket of the SARS-CoV-2 Spike protein. In each case, the inhibitors were fused to immunoglobulin Fc domains, which can further enhance therapeutic properties, and compared for activity against different SARS-CoV-2 variants. Potent inhibition against multiple SARS-CoV-2 variants was demonstrated
in vitro
, and even relatively low single doses of optimized reagents provided some protection in a mouse model, confirming their potential as an alternative to antibody therapies.
SARS-CoV-2 Omicron entry is type II transmembrane serine protease-mediated in human airway and intestinal organoid models
Authors: Mykytyn Anna Z. , Breugem Tim I. , Geurts Maarten H. , Beumer Joep , Schipper Debby , van Acker Romy , van den Doel Petra B. , van Royen Martin E. , Zhang Jingshu , Clevers Hans , Haagmans Bart L. , Lamers Mart M. 
Published: August 2023

ABSTRACT
SARS-CoV-2 can enter cells after its spike protein is cleaved by either type II transmembrane serine proteases (TTSPs), like TMPRSS2, or cathepsins. It is now widely accepted that the Omicron variant uses TMPRSS2 less efficiently and instead enters cells via cathepsins, but these findings have yet to be verified in more relevant cell models. Although we could confirm efficient cathepsin-mediated entry for Omicron in a monkey kidney cell line, experiments with protease inhibitors showed that Omicron (BA.1 and XBB1.5) did not use cathepsins for entry into human airway organoids and instead utilized TTSPs. Likewise, CRISPR-edited intestinal organoids showed that entry of Omicron BA.1 relied on the expression of the serine protease TMPRSS2 but not cathepsin L or B. Together, these data force us to rethink the concept that Omicron has adapted to cathepsin-mediated entry and indicate that TTSP inhibitors should not be dismissed as prophylactic or therapeutic antiviral strategy against SARS-CoV-2.

IMPORTANCE

Coronavirus entry relies on host proteases that activate the viral fusion protein, spike. These proteases determine the viral entry route, tropism, host range, and can be attractive drug targets. Whereas earlier studies using cell lines suggested that the Omicron variant of SARS-CoV-2 has changed its protease usage, from cell surface type II transmembrane serine proteases (TTSPs) to endosomal cathepsins, we report that this is not the case in human airway and intestinal organoid models, suggesting that host TTSP inhibition is still a viable prophylactic or therapeutic antiviral strategy against current SARS-CoV-2 variants and highlighting the importance of relevant human
in vitro
cell models.
APOBEC3 degradation is the primary function of HIV-1 Vif determining virion infectivity in the myeloid cell line THP-1
Authors: Ikeda Terumasa , Shimizu Ryo , Nasser Hesham , Carpenter Michael A. , Cheng Adam Z. , Brown William L. , Sauter Daniel , Harris Reuben S. 
Published: August 2023

ABSTRACT

HIV-1 must overcome multiple innate antiviral mechanisms to replicate in CD4
+
T lymphocytes and macrophages. Previous studies have demonstrated that the apolipoprotein B mRNA editing enzyme polypeptide-like 3 (APOBEC3, A3) family of proteins (at least A3D, A3F, A3G, and stable A3H haplotypes) contribute to HIV-1 restriction in CD4
+
T lymphocytes. Virus-encoded virion infectivity factor (Vif) counteracts this antiviral activity by degrading A3 enzymes allowing HIV-1 replication in infected cells. In addition to A3 proteins, Vif also targets other cellular proteins in CD4
+
T lymphocytes, including PPP2R5 proteins. However, whether Vif primarily degrades only A3 proteins during viral replication is currently unknown. Herein, we describe the development and characterization of
A3F
-,
A3F/A3G
-, and
A3A
-to-
A3G
-null THP-1 cells. In comparison to Vif-proficient HIV-1, Vif-deficient viruses have substantially reduced infectivity in parental and
A3F
-null THP-1 cells, and a more modest decrease in infectivity in
A3F/A3G
-null cells. Remarkably, disruption of A3A–A3G protein expression completely restores the infectivity of Vif-deficient viruses in THP-1 cells. These results indicate that the primary function of Vif during infectious HIV-1 production from THP-1 cells is the targeting and degradation of A3 enzymes.

IMPORTANCE

HIV-1 Vif neutralizes the HIV-1 restriction activity of A3 proteins. However, it is currently unclear whether Vif has additional essential cellular targets. To address this question, we disrupted
A
3
A
to
A
3
G
genes in the THP-1 myeloid cell line using CRISPR and compared the infectivity of wild-type HIV-1 and Vif mutants with the selective A3 neutralization activities. Our results demonstrate that the infectivity of Vif-deficient HIV-1 and the other Vif mutants is fully restored by ablating the expression of cellular A3A to A3G proteins. These results indicate that A3 proteins are the only essential target of Vif that is required for fully infectious HIV-1 production from THP-1 cells.
Exhaled CO2monitoring to guide non-invasive ventilation at birth: a systematic review
Authors: Monnelly Vix , Josephsen Justin B , Isayama Tetsuya , de Almeida Maria Fernanda B , Guinsburg Ruth , Schmölzer Georg M , Rabi Yacov , Wyckoff Myra H , Weiner Gary , Liley Helen G , Solevåg Anne Lee 
Published: August 2023

ObjectiveMeasuring exhaled carbon dioxide (ECO2) during non-invasive ventilation at birth may provide information about lung aeration. However, the International Liaison Committee on Resuscitation (ILCOR) only recommends ECO2detection for confirming endotracheal tube placement. ILCOR has therefore prioritised a research question that needs to be urgently evaluated: ‘In newborn infants receiving intermittent positive pressure ventilation by any non-invasive interface at birth, does the use of an ECO2monitor in addition to clinical assessment, pulse oximetry and/or ECG, compared with clinical assessment, pulse oximetry and/or ECG only, decrease endotracheal intubation in the delivery room, improve response to resuscitation, improve survival or reduce morbidity?’.DesignSystematic review of randomised and non-randomised studies identified by Ovid MEDLINE, Embase and Cochrane CENTRAL search until 1 August 2022.SettingDelivery room.PatientsNewborn infants receiving non-invasive ventilation at birth.InterventionECO2measurement plus routine assessment compared with routine assessment alone.Main outcome measuresEndotracheal intubation in the delivery room, response to resuscitation, survival and morbidity.ResultsAmong 2370 articles, 23 were included; however, none had a relevant control group. Although studies indicated that the absence of ECO2may signify airway obstruction and ECO2detection may precede a heart rate increase in adequately ventilated infants, they did not directly address the research question.ConclusionsEvidence to support the use of an ECO2monitor to guide non-invasive positive pressure ventilation at birth is lacking. More research on the effectiveness of ECO2measurement in addition to routine assessment during non-invasive ventilation of newborn infants at birth is needed.PROSPERO registration numberCRD42022344849.
Is neglect of self-clearance biasing TB vaccine impact estimates?
Authors: Scarponi Danny , Clark Rebecca A , Weerasuriya Chathika Krishan , Emery Jon , Houben Rein M G J , White Richard , McCreesh Nicky 
Published: August 2023

BackgroundMathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals withMycobacterium tuberculosis(Mtb) infection remain at lifelong risk of tuberculosis disease. Recent research provides evidence that self-clearance of Mtb infection may be common, which may affect the potential impact of new vaccines that only take in infected or uninfected individuals. We explored how the inclusion of self-clearance in models of tuberculosis affects the estimates of vaccine impact in China and India.MethodsFor both countries, we calibrated a tuberculosis model to a scenario without self-clearance and to various scenarios with self-clearance. To account for the current uncertainty in self-clearance properties, we varied the rate of self-clearance, and the level of protection against reinfection in self-cleared individuals. We introduced potential new vaccines in 2025, exploring vaccines that work in uninfected or infected individuals only, or that are effective regardless of infection status, and modelling scenarios with different levels of vaccine efficacy in self-cleared individuals. We then estimated the relative disease incidence reduction in 2050 for each vaccine compared with the no vaccination scenario.FindingsThe inclusion of self-clearance increased the estimated relative reductions in incidence in 2050 for vaccines effective only in uninfected individuals, by a maximum of 12% in China and 8% in India. The inclusion of self-clearance increased the estimated impact of vaccines only effective in infected individuals in some scenarios and decreased it in others, by a maximum of 14% in China and 15% in India. As would be expected, the inclusion of self-clearance had minimal impact on estimated reductions in incidence for vaccines that work regardless of infection status.InterpretationsOur work suggests that the neglect of self-clearance in mathematical models of tuberculosis vaccines does not result in substantially biased estimates of tuberculosis vaccine impact. It may, however, mean that we are slightly underestimating the relative advantages of vaccines that work in uninfected individuals only compared with those that work in infected individuals.
Global environmental risk factors of schizophrenia: a study protocol for systematic review and meta-analysis of cohort studies
Authors: Mahdavinoor Seyyed Muhammad Mahdi , Mollaei Aghil , Farhang Sara 
Published: August 2023

IntroductionSchizophrenia is a chronic, complex and severe psychiatric disorder affecting millions of people every year and inflicting different costs to the individual, family and community. A growing body of evidence has introduced several genetic and environmental factors and their interactions as aetiological factors of schizophrenia. The goal of this systematic review and meta-analysis is to present an updated representation of the global environmental risk factors of schizophrenia.Method and analysisThis protocol is developed and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guideline. We will systematically search the databases such as PubMed, Scopus, Web of Science, PsycINFO and Embase until 30 September 2022. We include Cohort studies that have reported one or more risk factors of schizophrenia. We will also search Google Scholar search engine and references lists of included articles. Extracting the relevant data and assessing the quality of the included studies will be independently performed by different authors of our team. The risk of bias for the included studies will be evaluated using Newcastle-Ottawa Scale. Subgroup analysis, meta-regression or sensitivity analysis will be our solution to deal with heterogeneity between studies. We will use a funnel diagram as well as Begg and Egger tests to check for possible publication bias.Ethics and disseminationEthical approval is not required because there will be no primary data collection or human involvement. The results of this study will be published in an international peer-reviewed journal.PROSPERO registration numberCRD42022359327.
Derivation and external validation of a risk score for clinically important declines in health and function among two longitudinal cohorts of women in the mid-life
Authors: Solomon Daniel H , Santacroce Leah , Shadyab Aladdin , Haring Bernhard , Burnett-Bowie Sherri-Ann M , Karvonen-Gutierrez Carrie , Colvin Alicia , Jackson Rebecca , LeBoff Meryl S , Ruppert Kristine , Valencia Celina I , Avis Nancy E , Manson JoAnn E 
Published: August 2023

ObjectivesWomen in mid-life often develop chronic conditions and experience declines in physical health and function. Identifying factors associated with declines provides opportunity for targeted interventions. We derived and externally validated a risk score for clinically important declines over 10 years among women ages 55–65 using the Physical Component Summary Score (PCS) of the SF-36.DesignDerivation and validation of a risk score.SettingTwo longitudinal cohorts from sites in the USA were used.ParticipantsWomen from the Study of Women’s Health Across the Nation (SWAN) and women from the Women’s Health Initiative (WHI) Observational Study and/or clinical trials.Outcome measuresA clinically important decline over 10 years among women ages 55–65 using the PCS of the SF-36 predictors was measured at the beginning of the 10 years of follow-up.ResultsSeven factors—lower educational attainment, smoking, higher body mass index, history of cardiovascular disease, history of osteoarthritis, depressive symptoms and baseline PCS level—were found to be significant predictors of PCS decline among women in SWAN with an area under the curve (AUC)=0.71 and a Brier Score=0.14. The same factors were associated with a decline in PCS in WHI with an AUC=0.64 and a Brier Score=0.18. Regression coefficients from the SWAN analysis were used to estimate risk scores for PCS decline in both cohorts. Using a threshold of a 30% probability of a significant decline, the risk score created a binary test with a specificity between 89%–93% and an accuracy of 73%–79%.ConclusionsSeven clinical variables were used to create a valid risk score for PCS declines that was replicated in an external cohort. The risk score provides a method for identifying women at high risk for a significant mid-life PCS decline.
Impact of armed conflicts on HIV treatment outcomes in sub-Saharan Africa: protocol for a systematic review and meta-analysis
Authors: Kebede Hafte Kahsay , Gesesew Hailay , Ward Paul 
Published: August 2023

IntroductionArmed conflicts have significant negative impacts on the entire healthcare system in general and HIV care system in particular. Sub-Saharan Africa is suffering from a disproportionate double burden of armed conflict and HIV infection. Nevertheless, the impact of the armed conflict on the HIV treatment outcomes in conflict settings in sub-Saharan Africa has not been thoroughly and systematically synthesised. This protocol outlines a review that aims to summarise the available evidence on the impact of armed conflict on HIV treatment outcomes in sub-Saharan Africa.Methods and analysisA systematic review of all quantitative studies that assess the impact of armed conflicts on HIV treatment outcomes will be conducted. The systematic search will start with a preliminary search of Google Scholar, followed by implementation of the full search strategy across five databases (MEDLINE, PubMed, CINAHL, SCOPUS and Web of Science) and the screening of titles and abstracts then relevant full texts. Bibliographies will be reviewed to identify additional relevant studies. We will include studies conducted in sub-Saharan Africa that were published in English between 1 January 2002 and 31 December 2022. Methodological validity of the included studies will be assessed using standardised critical appraisal instruments from the Joanna Briggs Institute (JBI) Meta-Analysis of Statistics Assessment and Review Instrument. Data will be extracted using standardised JBI instruments and analysed through narrative synthesis, and meta-analyses and regression. Heterogeneity will be assessed using I2and Χ2tests.Ethics and disseminationSince this study will not involve gathering primary data, formal ethical approval is not required. Journal publications, conference presentations and a media release will be used to share the study findings.PROSPERO registration numberCRD42022361924.
COVID-19 era-related e-learning: a cross-sectional web-scale study of cyberchondria, internet addiction and anxiety-related symptomatology among university nursing students
Authors: Mrayyan Majd T , Alkhawaldeh Ja'far M , Alfayoumi Imad , Algunmeeyn Abdullah , Abunab Hamzeh Y , Suliman W A , Abu Hasheesh Mohammad , Shudifat Raed 
Published: August 2023

ObjectiveThe study assessed COVID-19 era-related e-learning cyberchondria, internet addiction and anxiety-related symptomatology among nursing students. The relationships, predictors and differences between the studied concepts were measured.DesignIn 2021, a quantitative cross‐sectional research design using a web survey with a sample size of 333 nursing students yielded a response rate of 70%.ResultsNursing students had a moderate level of cyberchondria, low to moderate internet addiction, a moderate to severe level of anxiety and depression, and a normal stress level. Demographic characteristics, cyberchondria, internet addiction and anxiety-related symptomatology were significantly correlated. Grade point average, age, type of organisation where the students were trained and level of education were significant predictors of the studied variables. Significant differences in the studied concepts were found based on the sample’s characteristics such as gender, type of organisations or universities where the students were trained or studied, and age.ConclusionCyberchondria, internet addiction, depression, anxiety and stress symptomatology are troublesome. Higher education organisations might benefit from examining the variables of interest and investigating the relations between internet addiction and depression and anxiety symptomatology among nursing students. Such research will aid in tailoring treatments to assist vulnerable students by targeting counselling and educational efforts toward building a future generation of nurses with reduced cyberchondria, internet addiction and anxiety-related symptomatology.
Efficacy and safety of Android artificial pancreas system use at home among adults with type 1 diabetes mellitus in China: protocol of a 26-week, free-living, randomised, open-label, two-arm, two-phase, crossover trial
Authors: Lei Mengyun , Lin Beisi , Ling Ping , Liu Zhigu , Yang Daizhi , Deng Hongrong , Yang Xubin , Lv Jing , Xu Wen , Yan Jinhua 
Published: August 2023

IntroductionDo-it-yourself artificial pancreas system (DIY APS) is built using commercially available insulin pump, continuous glucose monitoring (CGM) and an open-source algorithm. Compared with commercial products, DIY systems are affordable, allow personalised settings and provide updated algorithms, making them a more promising therapy for most patients with type 1 diabetes mellitus (T1DM). Many small and self-reported observational studies have found that their real-world use was associated with potential metabolic and psychological benefits. However, rigorous-designed studies are urgently needed to confirm its efficacy and safety.Methods and analysisIn this 26-week randomised, open-label, two-arm, two-phase, crossover trial, participants aged 18–75 years, with T1DM and glycated haemoglobin (HbA1c) 7–11%, will use AndroidAPS during one 12-week period and sensor-augmented pump during another 12-week period. This study will recruit at least 24 randomised participants. AndroidAPS consists of three components: (1) real-time CGM; (2) insulin pump; (3) AndroidAPS algorithm implemented in Android smartphone. The primary endpoint is time in range (3.9–10.0 mmol/L) derived from CGM. The main secondary endpoints include percentage of sensor glucose values below, within and above target range; mean sensor glucose value; measures of glycaemic variability and centralised HbA1c. Safety endpoints mainly include the frequency of hypoglycaemia events, diabetic ketoacidosis and other serious adverse events.Ethics and disseminationThis study has been approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University. There will be verbal and written information regarding the trial given to each participant. The study will be disseminated through peer-reviewed publications and conference presentations.Overall statusRecruiting.Study start11 February 2023.Primary completion31 July 2024.Trial registration numberClinicalTrials.gov Registry (NCT05726461).