bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple receptor tyrosine kinases regulate dengue infection of hepatocytes
Authors: Bourgeois Natasha M. , Wei Ling , Ho Nhi N. T. , Neal Maxwell L. , Seferos Denali , Tongogara Tinotenda , Mast Fred D. , Aitchison John D. , Kaushansky Alexis 
Published: March 2024

IntroductionDengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be disrupted by existing therapeutics to prevent infection and/or disease progression.MethodsTo evaluate kinase regulation of DENV infection, we performed kinase regression (KiR), a machine learning approach that predicts kinase regulators of infection using existing drug-target information and a small drug screen. We infected hepatocytes with DENV in vitro in the presence of a panel of 38 kinase inhibitors then quantified the effect of each inhibitor on infection rate. We employed elastic net regularization on these data to obtain predictions of which of 291 kinases are regulating DENV infection.ResultsThirty-six kinases were predicted to have a functional role. Intriguingly, seven of the predicted kinases – EPH receptor A4 (EPHA4), EPH receptor B3 (EPHB3), EPH receptor B4 (EPHB4), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 2 (FGFR2), Insulin like growth factor 1 receptor (IGF1R), and ret proto-oncogene (RET) – belong to the receptor tyrosine kinase (RTK) family, which are already therapeutic targets in the clinic. We demonstrate that predicted RTKs are expressed at higher levels in DENV infected cells. Knockdown of EPHB4, ERBB2, FGFR2, or IGF1R reduces DENV infection in hepatocytes. Finally, we observe differential temporal induction of ERBB2 and IGF1R following DENV infection, highlighting their unique roles in regulating DENV.DiscussionCollectively, our findings underscore the significance of multiple RTKs in DENV infection and advocate further exploration of RTK-oriented interventions against dengue.
Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial
Authors: Ju Sang-Hyeon , Lim Joung Youl , Song Minchul , Kim Ji Min , Kang Yea Eun , Yi Hyon-Seung , Joung Kyong Hye , Lee Ju Hee , Kim Hyun Jin , Ku Bon Jeong 
Published: March 2024

ObjectivesChronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to β-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers.MethodsIn this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication.ResultsThe fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Treg) significantly decreased after intervention in the rosuvastatin/ezetimibe group (−4.5 ± 14.1% and −1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p=0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p=0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (p=0.314) or LDL-C (p=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (p=0.011), but not in the rosuvastatin group (p=0.339).ConclusionsWe observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels.
Comparison of saline infusion test and captopril challenge test in the diagnosis of Chinese with primary aldosteronism in different age groups
Authors: Sun Kaiwen , Gong Minghui , Yu Yang , Yang Minghui , Zhang Ying , Jiang Yinong , Song Wei 
Published: March 2024

BackgroundTo explore the diagnostic accuracy and the optimal cutoff value between the saline infusion test (SIT) and captopril challenge test (CCT) [including the value and suppression of plasma aldosterone concentration (PAC)] for primary aldosteronism (PA) diagnosing.MethodsA total of 318 patients with hypertension were consecutively enrolled, including 126 patients with PA and 192 patients with essential hypertension (EH), in this observational study. The characteristics of patients and laboratory examinations were collected and compared. The comparison between SIT and CCT was carried by drawing the receiver operator characteristic curve (ROC) and calculating the area under the curve (AUC) to explore the diagnostic accuracy and the optimal cutoff value.ResultsThe average age was 51.59 ± 10.43 in the PA group and 45.72 ± 12.44 in the EH group (p&lt;0.05). The optimal cutoff value was 10.7 ng/dL for post-CCT PAC, 6.8 ng/dL for post-SIT PAC, and 26.9% for suppression of post-CCT PAC. The diagnostic value of post-CCT PAC was the highest with 0.831 for the AUC and 0.552 for the Youden index. The optimal cutoff value for patients who were &lt;50 years old was 11.5 ng/dL for post-CCT PAC and 8.4 ng/dL for post-SIT PAC. The suppression of post-CCT PAC turned to 18.2% for those of age 50 or older.ConclusionCompared with SIT, CCT had a higher diagnostic value when post-CCT PAC was used as the diagnostic criterion in Chinese people, while the selection of diagnostic thresholds depended on patient age.
Deciphering thyroid function and CIMT: a Mendelian randomization study of the U-shaped influence mediated by apolipoproteins
Authors: Zhang Ming-zhu , Zhao Cong , Xing Xiao-ming , Lv Jie 
Published: March 2024

BackgroundCarotid Intima-Media Thickness (CIMT) is a key marker for atherosclerosis, with its modulation being crucial for cardiovascular disease (CVD) risk assessment. While thyroid function’s impact on cardiovascular health is recognized, the causal relationship and underlying mechanisms influencing CIMT remain to be elucidated.MethodsIn this study, Mendelian Randomization (MR) was employed to assess the causal relationship between thyroid function and CIMT. Thyroid hormone data were sourced from the Thyroidomics Consortium, while lipid traits and CIMT measurements were obtained from the UK Biobank. The primary analysis method was a two-sample MR using multiplicative random effects inverse variance weighting (IVW-MRE). Additionally, the study explored the influence of thyroid hormones on lipid profiles and assessed their potential mediating role in the thyroid function-CIMT relationship through multivariate MR analysis.ResultsThe study revealed that lower levels of Free Thyroxine (FT4) within the normal range are significantly associated with increased CIMT. This association was not observed with free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), or TPOAb. Additionally, mediation analysis suggested that apolipoprotein A-I and B are involved in the relationship between thyroid function and CIMT. The findings indicate a potential U-shaped curve relationship between FT4 levels and CIMT, with thyroid hormone supplementation in hypothyroid patients showing benefits in reducing CIMT.ConclusionThis research establishes a causal link between thyroid function and CIMT using MR methods, underscoring the importance of monitoring thyroid function for early cardiovascular risk assessment. The results advocate for the consideration of thyroid hormone supplementation in hypothyroid patients as a strategy to mitigate the risk of carotid atherosclerosis. These insights pave the way for more targeted approaches in managing patients with thyroid dysfunction to prevent cardiovascular complications.
Proinflammatory cytokines suppress nonsense-mediated RNA decay to impair regulated transcript isoform processing in pancreatic β cells
Authors: Ghiasi Seyed M. , Marchetti Piero , Piemonti Lorenzo , Nielsen Jens H. , Porse Bo T. , Mandrup-Poulsen Thomas , Rutter Guy A. 
Published: March 2024

IntroductionProinflammatory cytokines are implicated in pancreatic ß cell failure in type 1 and type 2 diabetes and are known to stimulate alternative RNA splicing and the expression of nonsense-mediated RNA decay (NMD) components. Here, we investigate whether cytokines regulate NMD activity and identify transcript isoforms targeted in ß cells.MethodsA luciferase-based NMD reporter transiently expressed in rat INS1(832/13), human-derived EndoC-ßH3, or dispersed human islet cells is used to examine the effect of proinflammatory cytokines (Cyt) on NMD activity. The gain- or loss-of-function of two key NMD components, UPF3B and UPF2, is used to reveal the effect of cytokines on cell viability and function. RNA-sequencing and siRNA-mediated silencing are deployed using standard techniques.ResultsCyt attenuate NMD activity in insulin-producing cell lines and primary human ß cells. These effects are found to involve ER stress and are associated with the downregulation of UPF3B. Increases or decreases in NMD activity achieved by UPF3B overexpression (OE) or UPF2 silencing raise or lower Cyt-induced cell death, respectively, in EndoC-ßH3 cells and are associated with decreased or increased insulin content, respectively. No effects of these manipulations are observed on glucose-stimulated insulin secretion. Transcriptomic analysis reveals that Cyt increases alternative splicing (AS)-induced exon skipping in the transcript isoforms, and this is potentiated by UPF2 silencing. Gene enrichment analysis identifies transcripts regulated by UPF2 silencing whose proteins are localized and/or functional in the extracellular matrix (ECM), including the serine protease inhibitor SERPINA1/α-1-antitrypsin, whose silencing sensitizes ß-cells to Cyt cytotoxicity. Cytokines suppress NMD activity via UPR signaling, potentially serving as a protective response against Cyt-induced NMD component expression.ConclusionOur findings highlight the central importance of RNA turnover in ß cell responses to inflammatory stress.
Thyroid function and polycystic ovary syndrome: a Mendelian randomization study
Authors: Zhao Zhendan , Gao Yuehua , Pei Xiaoqing , Wang Wenhao , Wang Ruixian , Zhang Huawei 
Published: March 2024

BackgroundMultiple evidence suggests that thyroid function is associated with polycystic ovary syndrome (PCOS), but whether thyroid function is causally related to PCOS is unclear. To investigate whether the association reflect causality, a Mendelian randomization (MR) analysis was conducted.MethodsSingle nucleotide polymorphisms (SNPs) involved in this study were acquired from The ThyroidOmics Consortium and the IEU Open Genome-wide association study (GWAS) database, respectively. In forward MR analysis, we included normal free thyroxine (FT4, n=49,269), normal thyroid-stimulating hormone (TSH, n=54,288), hypothyroidism (n=53,423) and hyperthyroidism (n=51,823) as exposure. The outcome was defined as PCOS in a sample size of 16,380,318 individuals. The exposure in the reverse MR analyses was chosen as PCOS, while the outcome consisted of the four phenotypes of thyroid function. The inverse-variance weighted (IVW) method was performed as the major analysis, supplemented by sensitivity analyses.ResultsThe occurrence of PCOS was associated with increased risk of hyperthyroidism (IVW, OR=1.08, 95%CI=1.02-1.13, P=0.004). No evidence suggested that other phenotypes of thyroid function were related to PCOS.ConclusionsOur findings demonstrate a cause-and-effect connection between PCOS and hyperthyroidism. The study established foundation for further investigation for interaction between thyroid function and PCOS.
Forest types outpaced tree species in centroid-based range shifts under global change
Authors: Abbasi Akane O. , Woodall Christopher W. , Gamarra Javier G. P. , Hui Cang , Picard Nicolas , Ochuodho Thomas , de-Miguel Sergio , Sahay Rajeev , Fei Songlin , Paquette Alain , Chen Han Y. H. , Catlin Ann Christine , Liang Jingjing 
Published: March 2024

IntroductionMounting evidence suggests that geographic ranges of tree species worldwide are shifting under global environmental changes. Little is known, however, about if and how these species’ range shifts may trigger the range shifts of various types of forests. Markowitz’s portfolio theory of investment and its broad application in ecology suggest that the range shift of a forest type could differ substantially from the range shifts of its constituent tree species.MethodsHere, we tested this hypothesis by comparing the range shifts of forest types and the mean of their constituent species between 1970–1999 and 2000–2019 across Alaska, Canada, and the contiguous United States using continent-wide forest inventory data. We first identified forest types in each period using autoencoder neural networks and K-means cluster analysis. For each of the 43 forest types that were identified in both periods, we systematically compared historical range shifts of the forest type and the mean of its constituent tree species based on the geographic centroids of interpolated distribution maps.ResultsWe found that forest types shifted at 86.5 km·decade-1 on average, more than three times as fast as the average of constituent tree species (28.8 km·decade-1). We showed that a predominantly positive covariance of the species range and the change of species relative abundance triggers this marked difference.DiscussionOur findings provide an important scientific basis for adaptive forest management and conservation, which primarily depend on individual species assessment, in mitigating the impacts of rapid forest transformation under climate change.
Association of autoimmune and allergic diseases with senile cataract: a bidirectional two-sample Mendelian randomization study
Authors: Yuan Weichen , Li Xiangrui , Wang Guan , Qu Bo , Zhao Fangkun 
Published: March 2024

BackgroundMany observational studies have been reported that patients with autoimmune or allergic diseases seem to have a higher risk of developing senile cataract, but the views are not consistent. In order to minimize the influence of reverse causality and potential confounding factors, we performed Mendelian Randomization (MR) analysis to investigate the genetic causal associations between autoimmune, allergic diseases and senile cataract.MethodsSingle nucleotide polymorphisms associated with ten common autoimmune and allergic diseases were obtained from the IEU Open genome-wide association studies (GWAS) database. Summary-level GWAS statistics for clinically diagnosed senile cataract were obtained from the FinnGen research project GWAS, which consisted of 59,522 individuals with senile cataracts and 312,864 control individuals. MR analysis was conducted using mainly inverse variance weighted (IVW) method and further sensitivity analysis was performed to test robustness.ResultsAs for ten diseases, IVW results confirmed that type 1 diabetes (OR = 1.06; 95% CI = 1.05-1.08; p = 2.24×10-12), rheumatoid arthritis (OR = 1.05; 95% CI = 1.02-1.08; p = 1.83×10-4), hypothyroidism (OR = 2.4; 95% CI = 1.42-4.06; p = 1.12×10-3), systemic lupus erythematosus (OR = 1.02; 95% CI = 1.01-1.03; p = 2.27×10-3), asthma (OR = 1.02; 95% CI = 1.01-1.03; p = 1.2×10-3) and allergic rhinitis (OR = 1.07; 95% CI = 1.02-1.11; p = 2.15×10-3) were correlated with the risk of senile cataract. Celiac disease (OR = 1.04; 95% CI = 1.01-1.08; P = 0.0437) and atopic dermatitis (OR = 1.05; 95% CI = 1.01-1.10; P = 0.0426) exhibited a suggestive connection with senile cataract after Bonferroni correction. These associations are consistent across weighted median and MR Egger methods, with similar causal estimates in direction and magnitude. Sensitivity analysis further proved that these associations were reliable.ConclusionsThe results of the MR analysis showed that there were causal relationships between type 1 diabetes, rheumatoid arthritis, hypothyroidism, systemic lupus erythematosus, asthma, allergic rhinitis and senile cataract. To clarify the possible role of autoimmune and allergy in the pathophysiology of senile cataract, further studies are needed.
The molecular detection of carbapenem markers with a two-levels amplification screening protocol: epidemiological and resistome insights
Authors: Calvo Maddalena , Migliorisi Giuseppe , Maugeri Gaetano , Bongiorno Dafne , Bonomo Carmelo , Nicitra Emanuele , Scalia Guido , Stefani Stefania 
Published: March 2024

ObjectivesCarbapenem-resistance is a challenging healthcare concern and require specific stewardship programs. Monitoring workflows include the identification from surveillance samples, such as rectal swabs. Although culture assays represent the gold standard, data report a significant effectiveness in detecting carbapenemases genes directly from rectal swabs. The aim of this study was to evaluate the REALQUALITY Carba-Screen kit (AB ANALITICA, Padova, Italy) in detecting carbapenemases genes directly from rectal swabs, also comparing its effectiveness to culture assays results. A next-generation sequencing (NGS) was performed to investigate the positive samples about resistance markers and sequence type (ST).MethodsA number of 136 rectal swabs were collected from the University Hospital Policlinico of Catania critical wards. The samples simultaneously underwent culture and molecular assays (REALQUALITY Carba-Screen kit). The molecular method included two-steps. The first step (1 h and 6 min) rapidly excluded negative samples, while the second one (1 h and 6 min) included only positive samples for a resistance confirmation. All the positive culture samples underwent NGS analysis.ResultsStatistical evaluations demonstrated high sensitivity (100%) and detection rates (92.6%) for the REALQUALITY Carba-Screen kit, which mostly correlated to the standard workflow. All the culture positive results matched the positive molecular results, which were mainly confirmed by the NGS resistome analysis. The identified ST appeared to be diversified and different from the clinically significative strains of the same setting, furnishing interesting epidemiological evidence.ConclusionThe molecular detection allowed a coordinate approach in a high-prevalence multi-drug-resistance area. The rapid identification with a multi-step procedure accelerated the infection control procedures, while the preliminary negative results reduced the overtreatment episodes. The molecular method efficacy was confirmed through the NGS. In conclusion, the molecular screening could initially lead to a more conservative approach, which may be reevaluated after a culture result about the microorganisms’ identification and susceptibility profile.
Comparative efficacy of acupuncture point stimulation treatments for dialysis patients with uremic pruritus: a systematic review and network meta-analysis
Authors: Lu Po-Hsuan , Chuo Hui-En , Chiu Ling-Ya , Lai Chien-Cheng , Wang Jen-Yu , Lu Ping-Hsun 
Published: March 2024

BackgroundUremic pruritus (UP) is a common complication of chronic kidney disease that causes sleep disturbances and increases all-cause mortality. Currently, the first-line medications for UP exhibit inadequate pruritus control with adverse effects. Various acupuncture point stimulation treatments (APSTs) have been shown to be effective as adjuvant therapies in UP, and a network meta-analysis can offer relative efficacy estimates for treatments for which head-to-head studies have not been performed.MethodsWe conducted a random-effects network meta-analysis on a consistency model to compare the different APSTs for UP. The primary outcomes were the mean visual analog scale (VAS) score and effectiveness rate (ER).ResultsThe network meta-analysis retrieved 27 randomized controlled trials involving 1969 patients. Compared with conventional treatment alone, combination treatment with acupuncture (mean difference, −2.63; 95% confidence interval, −3.71 to −1.55) was the most effective intervention in decreasing VAS scores, followed by acupoint injection and massage (mean difference, −2.04; 95% confidence interval, −3.96 to −0.12). In terms of the ER, conventional treatment with acupuncture and hemoperfusion (risk ratio, 14.87; 95% confidence interval, 2.18 to 101.53) was superior to other therapeutic combinations. Considering the VAS score and ER, combination treatment with acupoint injection and massage showed benefits in treating UP.ConclusionOur network meta-analysis provided relative efficacy data for choosing the optimal adjuvant treatment for UP. Combined treatment with acupuncture was more effective than conventional treatment only and was the most promising intervention for treating UP.Systematic review registration: PROSPERO (CRD42023425739: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023425739).
Predictors of overload in parents of children with neuromuscular diseases
Authors: Rodríguez A. A. , García M. , Martínez Oscar , López-Paz J. F. , García I. , Pérez-Nuñez P. , Amayra I. 
Published: March 2024

IntroductionParents of children with neuromuscular diseases experience multiple difficulties in their daily lives that affect their physical and psychological health. The risk factors for these health issues have not been sufficiently investigated. Therefore, the aim of this study was to analyze the potential predictors of overload in these parents, including QoL, somatic symptomatology, life satisfaction, psychological adjustment and certain sociodemographic variables.MethodsA cross-sectional research study was conducted among parents who are caregivers for children with NMD in Spain. A convenience sample of 110 parents who were contacted by associations and hospitals was used. Variables were evaluated using the sociodemographic questionnaire, CarerQol-7D, PHQ-15, Barthel Index, Psychological Adaptation Scale, Zarit Overload Scale and Satisfaction with Life Scale.ResultsOne of the most relevant findings of the present study is the identification of 3 overload groups (mild to moderate, moderate to severe, and severe overload) based on life satisfaction and somatic symptom scores within the predictive model of the discriminate analysis. Wilk’s lambda of the discriminant function was 0.568, χ2 (2, n = 55) = 8.815, p &lt; 0.001.DiscussionThis study presents a model that reveals the influence of unemployment, having a child with a severe level of dependency, the presence of somatic symptomatology and life satisfaction on caregiver overload. Likewise, the caregiver’s self-esteem could be a protective factor against overload.