bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epstein-Barr virus LMP1 enhances levels of large extracellular vesicle-associated PD-L1
Authors: Abou Harb Monica , Meckes David G. , Sun Li 
Published: September 2023

ABSTRACT
The circulating nature of extracellular vesicles (EVs) allows for the transfer of cargo to proximal or distant cells, making them vital mediators of cellular communication. Epstein-Barr virus (EBV)–infected cells have been found to release EVs containing viral proteins, such as the major viral oncogene latent membrane protein 1 (LMP1). LMP1 has been observed to regulate the cellular gene expression of the programmed cell death protein 1 ligand (PD-L1), a protein known to suppress the immune system through binding to a receptor found on cytotoxic T cells. Recent studies have established that PD-L1 is packaged into small EVs (sEVs), potentially contributing to the evasion of lung cancer cells from the immune system. Furthermore, it has been observed that large EVs (lEVs) are shed in significant quantities by tumor cells, with elevated levels of lEVs being associated with disease metastasis and cancer aggressiveness. The present study demonstrated that lEVs from nasopharyngeal carcinoma cells exhibit a significant enrichment of PD-L1. Furthermore, the EBV protein LMP1 was found to play a key role in regulating PD-L1 levels within these lEVs. These PD-L1+ lEVs containing LMP1 are likely to contribute to the immunosuppressive microenvironment found in EBV-associated cancers.

IMPORTANCE
A growing body of evidence has supported the notion that viruses utilize EVs and associated pathways to incorporate viral products. This allows for the evasion of an immune response while enabling viral spread within the host. Given that viral proteins often elicit strong antigenic peptides that are recognized by T cells, the regulation of the PD-L1 pathway through the overexpression of lEV-associated PD-L1 may serve as a strategy for immune evasion by viruses. The discovery that EBV LMP1 increases the secretion of PD-L1 in larger EVs identifies a new potential target for immune blockade therapy in EBV-associated cancers. Our findings may help to clarify the mechanism of LMP1-mediated enhancement of PD-L1 packaging into lEVs and may lead to the identification of more specific targets for treatment. Additionally, the identification of lEV biomarkers that predict a viral origin of disease could allow for more targeted therapies to be developed.
Dengue virus NS1 secretion is regulated via importin-subunit β1 controlling expression of the chaperone GRp78 and targeted by the clinical drug ivermectin
Authors: Denolly Solène , Guo Hongbo , Martens Miriam , Płaszczyca Anna , Scaturro Pietro , Prasad Vibhu , Kongmanas Kessiri , Punyadee Nuntaya , Songjaeng Adisak , Mairiang Dumrong , Pichlmair Andreas , Avirutnan Panisadee , Bartenschlager Ralf 
Published: September 2023

ABSTRACT
Dengue virus (DENV) is a major human pathogen. An important pathogenicity factor is non-structural protein 1 (NS1) required for viral replication and secreted from infected cells. A clinical study indicated that the anti-parasitic drug ivermectin lowers NS1 blood levels without affecting viremia. Ivermectin targets nuclear transport by binding to importin-α, but how NS1 secretion in patients is suppressed by this drug is unknown. We show that ivermectin impairs folding and secretion of endoplasmic reticulum-luminal glycoproteins, including NS1. Proteomic analysis identified chaperones interacting with NS1, including GRp78 (78-kDa glucose-regulated protein, also known as HSPA5 or BIP). This chaperone increased in abundance on DENV infection via activation of the unfolded protein response (UPR). Ivermectin blocked the nuclear transport of transcription factors required for UPR, thus impairing GRp78 upregulation and NS1 secretion. Reduction of GRp78 and NS1 secretion was also observed in patients treated with ivermectin. These results link nuclear transport and its inhibition by ivermectin to folding and secretion of luminal glycoproteins, including DENV NS1.

IMPORTANCE
Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1 (NS1), a glycoprotein that is secreted from infected cells. Here we study the mode of action of the widely used drug ivermectin, used to treat parasitic infections and recently shown to lower NS1 blood levels in DENV-infected patients. We found that ivermectin blocks the nuclear transport of transcription factors required for the expression of chaperones that support the folding and secretion of glycoproteins, including NS1. Impairing nuclear transport of these transcription factors by ivermectin or depleting them from infected cells dampens NS1 folding and thus its secretion. These results reveal a novel mode of action of ivermectin that might apply to other flaviviruses as well.
Two-sided effects of the organic phosphorus phytate on a globally important marine coccolithophorid phytoplankton
Authors: Li Jiashun , Zhang Kaidian , Li Ling , Wang Yujie , Wang Cong , Lin Senjie 
Published: September 2023

ABSTRACT

Dissolved organic phosphorus (DOP) is a potential source of aquatic eutrophication and pollution because it can potentially stimulate growth in some species and inhibit growth in other species of algae, the foundation of the marine ecosystem. Inositol hexaphosphate (also named phytic acid or PA), an abundant organophosphate, is presumably ubiquitous in the marine environment, but how it affects marine primary producers is poorly understood. Here, we investigated the bioavailability of this DOP to the cosmopolitan coccolithophore
Emiliania huxleyi
. Our results showed that
E
.
huxleyi
cells can take up PA and dissolved inorganic phosphorus (DIP) simultaneously. Absorbed PA can efficiently support algal growth, producing cell yield between DIP and phosphorus (P)-depleted conditions. Accordingly, PA supply as the sole P source highly influences cellular metabolism and nutrient stoichiometry. Particularly, PA-grown cultures exhibited enhanced carbon fixation, increased lipid content, activated energy metabolism, and induced nitrogen assimilation. However, our data suggest that PA may also exert some levels of toxic effects on
E. huxleyi
. This study provides novel insights into the variable effects of a DOP on marine phytoplankton, which will inform new inquiries about how the complex DOP constituencies in the ocean will shape phytoplankton community structure and function.

IMPORTANCE
The dissolved organic phosphorus (DOP) utilization in phytoplankton plays vital roles in cellular P homeostasis, P-nutrient niche, and the dynamics of community structure in marine ecosystems, but its mechanisms, potentially varying with species, are far from clear. In this study, we investigated the utilization of a widespread DOP species, which is commonly produced by plants (land plants and marine macrophytes) and released into coastal areas, in a globally distributed bloom-forming coccolithophore species in various phosphorus environments. Using a combination of physiological and transcriptomic measurements and analyses, our experimental results revealed the complex mechanism and two-sided effects of DOP (major algal growth-supporting and minor toxic effects) in this species, providing a novel perspective on phytoplankton nutrient regulation.
Detailed descriptions of physical activity patterns among individuals with diabetes and prediabetes: the Lolland-Falster Health Study
Authors: Mortensen Sofie Rath , Skou Søren T , Brønd Jan Christian , Ried-Larsen Mathias , Petersen Therese Lockenwitz , Jørgensen Lars Bo , Jepsen Randi , Tang Lars Hermann , Bruun-Rasmussen Neda Esmailzadeh , Grøntved Anders 
Published: September 2023

IntroductionThis study aimed to describe objectively measured physical activity patterns, including daily activity according to day type (weekdays and weekend days) and the four seasons, frequency, distribution, and timing of engagement in activity during the day in individuals with diabetes and prediabetes and compared with individuals with no diabetes.Research design and methodsThis cross-sectional study included data from the Danish household-based, mixed rural-provincial population study, The Lolland-Falster Health Study from 2016 to 2020. Participants were categorized into diabetes, prediabetes, and no diabetes based on their glycated hemoglobin level and self-reported use of diabetes medication. Outcome was physical activity in terms of intensity (time spent in sedentary, light, moderate, vigorous, and moderate to vigorous physical activity (MVPA) intensities), adherence to recommendations, frequency and distribution of highly inactive days (<5 min MVPA/day), and timing of engagement in activity assessed with a lower-back worn accelerometer.ResultsAmong 3157 participants, 181 (5.7 %) had diabetes and 568 (18.0 %) had prediabetes. Of participants with diabetes, 63.2% did not adhere to the WHO recommendations of weekly MVPA, while numbers of participants with prediabetes and participants with no diabetes were 59.5% and 49.6%, respectively. Around a third of participants with diabetes were highly inactive daily (<5 min MVPA/day) and had >2 consecutive days of inactivity during a 7-days period. Mean time spent physically active at any intensity (light, moderate, and vigorous) during a day was lower among participants with diabetes compared with participants with no diabetes and particularly from 12:00 to 15:00 (mean difference of −6.3 min MVPA (95% CI −10.2 to −2.4)). Following adjustments, significant differences in physical activity persisted between diabetes versus no diabetes, but between participants with prediabetes versus no diabetes, results were non-significant after adjusting for body mass index.ConclusionsInactivity was highly prevalent among individuals with diabetes and prediabetes, and distinct daily activity patterns surfaced when comparing these groups with those having no diabetes. This highlights a need to optimize current diabetes treatment and prevention to accommodate the large differences in activity engagement.
Parental diabetes distress is a stronger predictor of child HbA1c than diabetes device use in school-age children with type 1 diabetes
Authors: Patton Susana R , Kahhan Nicole , Pierce Jessica S , Benson Matthew , Fox Larry A , Clements Mark A 
Published: September 2023

IntroductionDiabetes distress (DD) describes the unrelenting emotional and behavioral challenges of living with, and caring for someone living with, type 1 diabetes (T1D). We investigated associations between parent-reported and child-reported DD, T1D device use, and child glycated hemoglobin (HbA1c) in 157 families of school-age children.Research design and methodsParents completed the Parent Problem Areas in Diabetes-Child (PPAID-C) and children completed the Problem Areas in Diabetes-Child (PAID-C) to assess for DD levels. Parents also completed a demographic form where they reported current insulin pump or continuous glucose monitor (CGM) use (ie, user/non-user). We measured child HbA1c using a valid home kit and central laboratory. We used correlations and linear regression for our analyses.ResultsChildren were 49% boys and 77.1% non-Hispanic white (child age (mean±SD)=10.2±1.5 years, T1D duration=3.8±2.4 years, HbA1c=7.96±1.62%). Most parents self-identified as mothers (89%) and as married (78%). Parents’ mean PPAID-C score was 51.83±16.79 (range: 16–96) and children’s mean PAID-C score was 31.59±12.39 (range: 11–66). Higher child HbA1c correlated with non-pump users (r=−0.16, p<0.05), higher PPAID-C scores (r=0.36, p<0.001) and higher PAID-C scores (r=0.24, p<0.001), but there was no association between child HbA1c and CGM use. A regression model predicting child HbA1c based on demographic variables, pump use, and parent-reported and child-reported DD suggested parents’ PPAID-C score was the strongest predictor of child HbA1c.ConclusionsOur analyses suggest parent DD is a strong predictor of child HbA1c and is another modifiable treatment target for lowering child HbA1c.
Prevention and promotion effects of Self Help Plus: secondary analysis of cluster randomised controlled trial data among South Sudanese refugee women in Uganda
Authors: Augustinavicius Jura , Purgato Marianna , Tedeschi Federico , Musci Rashelle , Leku Marx Ronald , Carswell Kenneth , Lakin Daniel , van Ommeren Mark , Cuijpers Pim , Sijbrandij Marit , Karyotaki Eirini , Tol Wietse A , Barbui Corrado 
Published: September 2023

IntroductionEvidence-based and scalable prevention and promotion focused mental health and psychosocial support interventions are needed for conflict-affected populations in humanitarian settings. This study retrospectively assessed whether participation in Self Help Plus (SH+) versus enhanced usual care (EUC) resulted in reduced incidence of probable mental disorder and increased positive mental health and well-being post-intervention among South Sudanese refugee women in Uganda.MethodsThis study used secondary data from treatment-oriented pilot (n=50) and fully-powered cluster randomised controlled trials (cRCT)s (n=694) of SH+ versus EUC. Data from baseline and post-intervention assessments were combined. A composite latent indicator for mental health problems was generated using mental health and well-being measures included in both cRCTs. In order to assess incidence, a binary variable approximating probable mental disorder was created to exclude those with probable mental disorder from the analysis sample and as the primary prevention outcome. The promotive effects of SH+ relative to EUC were examined in the same sample by assessing subjective well-being and psychological flexibility scale scores.ResultsA single factor for mental health problems was identified with all factor loadings >0.30 and acceptable internal consistency (α=0.70). We excluded 161 women who met criteria for probable mental disorder at baseline. Among those with at least moderate psychological distress but without probable mental disorder at baseline and with follow-up data (n=538), the incidence of probable mental disorder at post-intervention was lower among those who participated in SH+ relative to EUC (Risk ratio =0.16, 95% CI: 0.05 to 0.53). Participation in SH+ versus EUC was also associated with increased subjective well-being (β=2.62, 95% CI: 1.63 to 3.60) and psychological flexibility (β=4.55, 95% CI: 2.92 to 6.18) at post-intervention assessment.ConclusionsThese results support the use and further testing of SH+ as a selective and indicated prevention and promotion focused psychosocial intervention in humanitarian settings.Trial registration numberISRCTN50148022.
Screening for renal cell carcinoma in renal transplant recipients: a single-centre retrospective study
Authors: Yohannan Binoy , Sridhar Arthi , Kaur Harmanpreet , DeGolovine Aleksandra , Maithel Neha 
Published: September 2023

ObjectivesThe primary objective of our study was to evaluate the effectiveness of renal cell carcinoma (RCC) screening in renal transplant (RT) recipients.DesignSingle-centre retrospective study.Setting and participants1998 RT recipients who underwent RT at Memorial Hermann Hospital (MHH) Texas Medical Center (TMC) between 1 January 1999 and 31 December 2019 were included and we identified 16 patients (0.8%) with RCC. An additional four patients with RCC who underwent RT elsewhere but received follow-up at MHH TMC were also included. Subject races included white (20%), black (50%), Hispanic (20%) and Asian (10%).Outcome measuresThe RCC stage at diagnosis and outcomes were compared between patients who were screening versus those who were not.ResultsWe identified a total of 20 patients with post-RT RCC, 75% of whom were men. The median age at diagnosis was 56 years. RCC histologies included clear cell (75%), papillary (20%) and chromophobe (5%). Patients with post-RT RCC who had screening (n=12) underwent ultrasound or CT annually or every 2 years, whereas eight patients had no screening. All 12 patients who had screening had early-stage disease at diagnosis (stage I (n=11) or stage II (n=1)) and were cured by nephrectomy (n=10) or cryotherapy (n=2). In patients who had no screening, three (37.5%) had stage IV RCC at diagnosis and all of whom died of metastatic disease. There was a statistically significant difference in RCC-specific survival in patients who were screened (p=0.01) compared with those who were not screened.ConclusionAll RT recipients who had RCC diagnosed based on screening had early-stage disease and there were no RCC-related deaths. Screening is an effective intervention in RT recipients to reduce RCC-related mortality.
Association of neck circumference-related indices with metabolic, atherogenic and liver function biomarkers in patients with non-alcoholic fatty liver disease: a cross-sectional study
Authors: Arefhosseini Sara , Tutunchi Helda , Tavakkoli Shahrzad , Arefhosseini Seyed Rafie , Ebrahimi-Mameghani Mehrangiz 
Published: September 2023

ObjectiveThe present study aimed to establish the association of neck circumference (NC)-related indices with metabolic, atherogenic and liver function biomarkers in patients with non-alcoholic fatty liver disease (NAFLD).DesignCross-sectional study.SettingOutpatient clinics of Tabriz University of Medical Sciences.ParticipantsA total of 175 adult patients with NAFLD diagnosed by abdominal ultrasonography were included in this study. Sociodemographic characteristics, anthropometric measures and metabolic, atherogenic and liver function biomarkers were assessed.ResultsResults on 107 women and 68 men with NAFLD showed that 52%, 45.1% and 2.9% of patients had mild, moderate and severe NAFLD, respectively. There were significant differences in most of the anthropometric indices, serum levels of ferritin, creatinine and uric acid as well as liver enzymes, and Aspartate Aminotransferase (AST) to Platelet Ratio Index (APRI) between the genders (p<0.01). However, no significant differences were found in the glycaemic, lipid profile and atherogenic biomarkers. Both NC and neck-to-height ratio (NHtR) were significantly associated with body mass index (BMI) (p=0.018, p<0.001, respectively), waist circumference (WC) (p<0.001, p=0.044, respectively) and waist-to-hip ratio (WHR) (p<0.001, p=0.026, respectively) while results showed only a significant relationship between neck-to-waist ratio (NWR) with BMI (p<0.001) and WC (p<0.001). Among metabolic factors, there were significant and positive correlations between NC and serum haemoglobin A1c (r=0.198, p<0.001), AST (r=0.300, p<0.001), alanine aminotransferase (ALT) (r=0.348, p<0.001), ferritin (r=0.403, p<0.001) and uric acid (r=0.347, p=0.003) while AST/ALT ratio was inversely related to NC (r=−0.226, p=0.003). APRI, Lipid Accumulation Product Index and also Hepatic Steatosis Index were significantly correlated with NC, NHtR and NWR (p<0.01).Conclusions and relevanceNC-related indices, particularly NC and NHtR, were correlated with some metabolic and liver function biomarkers (apart from lipid profile and atherogenic factors) in patients with NAFLD.
Facilitators of and barriers to patient and public involvement in building learning health systems in community health services settings: a scoping review protocol
Authors: Hung Lillian , Wong Karen Lok Yi , Chan Ian , Vasarhelyi Krisztina 
Published: September 2023

IntroductionThe development of learning health systems (LHSs) has often focused on optimally leveraging data. More attention should be paid to patient and public involvement or community engagement in forming learning communities that work together to build LHS. This scoping review aims to identify facilitators of and barriers to involving patients and the public in building LHSs in community health services settings.Methods and analysisWe will use the Joanna Briggs Institute’s scoping review methodology. We will review literature in English published from 1 January 2007 to 31 December 2022. The databases that will be searched are MEDLINE, CINAHL, Embase, Web of Science, Scopus, AgeLine, PsycINFO and Web of Science. Key inclusion and exclusion criteria include the following: we will only consider a learning community in a community health services context (eg, home care, long-term care, primary care); we will exclude literature on acute care settings; and we will consider any research designs apart from big data analytics. We will review all sources, including university student theses and dissertations. The review will proceed in three steps: (1) we will identify keywords and index terms from the MEDLINE and CINAHL databases; (2) using the keywords and index terms identified in step (1), we will search other databases and (3) we will handsearch the reference lists of the selected literature and will search for grey literature using Google. Two research assistants will screen the titles and abstracts separately, with reference to the inclusion criteria. Two researchers will then assess the full text of selected studies, also in reference to the inclusion criteria. We will present the findings in a charting table and provide a narrative summary.Ethics and disseminationThis work does not require ethics approval because the data for this scoping review are publicly available. The findings will be presented in a journal article and at conferences.
Incidence of atrial fibrillation in cryptogenic stroke with patent foramen ovale closure: protocol for the prospective, observational PFO-AF study
Authors: Badoz Marc , Derimay François , Serzian Guillaume , Besutti Matthieu , Rioufol Gilles , Frey Pierre , Guenancia Charles , Ecarnot Fiona , Meneveau Nicolas , Chopard Romain 
Published: September 2023

IntroductionAfter closure of patent foramen ovale (PFO) due to stroke, atrial fibrillation (AF) occurs in up to one in five patients. However, data are sparse regarding the possible pre-existence of AF in these patients prior to PFO closure, and about recurrence of AF in the long term after the procedure. No prospective study to date has investigated these topics in patients with implanted cardiac monitor (ICM). The PFO-AF study (registered with ClinicalTrials.gov under the numberNCT04926142) will investigate the incidence of AF occurring within 2 months after percutaneous closure of PFO in patients with prior stroke. AF will be identified using systematic ICM. Secondary objectives are to assess incidence and burden of AF in the 2 months prior to, and up to 2 years after PFO closure.Methods and analysisProspective, multicentre, observational study including 250 patients with an indication for PFO closure after stroke, as decided by interdisciplinary meetings with cardiologists and neurologists. Patients will undergo implantation of a Reveal Linq device (Medtronic). Percutaneous PFO closure will be performed 2 months after device implantation. Follow-up will include consultation, ECG and reading of ICM data at 2, 12 and 24 months after PFO closure. The primary endpoint is occurrence of AF at 2 months, defined as an episode of AF or atrial tachycardia/flutter lasting at least 30 s, and recorded by the ICM and/or any AF or atrial tachycardia/flutter documented on ECG during the first 2 months of follow-up.Ethics and disseminationThe study was approved by the Ethics Committee ‘Comité de Protection des Personnes (CPP) Sud-Méditerranéen III’ on 2 June 2021 and registered with ClinicalTrials.gov (NCT04926142). Findings will be presented in national and international congresses and peer-reviewed journals.Trial registration numberNCT04926142.