bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of severe chronic fatigue
Authors: Oakley Julia , Hill Martin , Giess Adam , Tanguy Mélanie , Elgar Greg 
Published: November 2023

Abstract
Background
Causative genetic variants cannot yet be found for many disorders with a clear heritable component, including chronic fatigue disorders like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These conditions may involve genes in difficult-to-align genomic regions that are refractory to short read approaches. Structural variants in these regions can be particularly hard to detect or define with short reads, yet may account for a significant number of cases. Long read sequencing can overcome these difficulties but so far little data is available regarding the specific analytical challenges inherent in such regions, which need to be taken into account to ensure that variants are correctly identified. Research into chronic fatigue disorders faces the additional challenge that the heterogeneous patient populations likely encompass multiple aetiologies with overlapping symptoms, rather than a single disease entity, such that each individual abnormality may lack statistical significance within a larger sample. Better delineation of patient subgroups is needed to target research and treatment.

Methods
We use nanopore sequencing in a case of unexplained severe fatigue to identify and fully characterise a large inversion in a highly homologous region spanning the AKR1C gene locus, which was indicated but could not be resolved by short-read sequencing. We then use GC–MS/MS serum steroid analysis to investigate the functional consequences.

Results
Several commonly used bioinformatics tools are confounded by the homology but a combined approach including visual inspection allows the variant to be accurately resolved. The DNA inversion appears to increase the expression of AKR1C2 while limiting AKR1C1 activity, resulting in a relative increase of inhibitory GABAergic neurosteroids and impaired progesterone metabolism which could suppress neuronal activity and interfere with cellular function in a wide range of tissues.

Conclusions
This study provides an example of how long read sequencing can improve diagnostic yield in research and clinical care, and highlights some of the analytical challenges presented by regions containing tandem arrays of genes. It also proposes a novel gene associated with a novel disease aetiology that may be an underlying cause of complex chronic fatigue. It reveals biomarkers that could now be assessed in a larger cohort, potentially identifying a subset of patients who might respond to treatments suggested by the aetiology.
Cyanidin-3-O-glucoside protects the brain and improves cognitive function in APPswe/PS1ΔE9 transgenic mice model
Authors: Baek Hana , Sanjay  , Park Miey , Lee Hae-Jeung 
Published: November 2023

AbstractCyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic pathway, autophagy, tau phosphorylation, neuronal cell death, and synaptic plasticity in Alzheimer’s disease models have not been reported, we attempted to investigate the same in the brains of APPswe/PS1ΔE9 mice were analyzed. After oral administration of C3G (30 mg/kg/day) for 16 weeks, the cortical and hippocampal regions in the brains of APPswe/PS1ΔE9 mice were analyzed. C3G treatment reduced the levels of soluble and insoluble Aβ (Aβ40 and Aβ42) peptides and reduced the protein expression of the amyloid precursor protein, presenilin-1, and β-secretase in the cortical and hippocampal regions. And C3G treatment upregulated the expression of autophagy-related markers, LC3B-II, LAMP-1, TFEB, and PPAR-α and downregulated that of SQSTM1/p62, improving the autophagy of Aβ plaques and neurofibrillary tangles. In addition, C3G increased the protein expression of phosphorylated-AMPK/AMPK and Sirtuin 1 and decreased that of mitogen-activated protein kinases, such as phosphorylated-Akt/Akt and phosphorylated-ERK/ERK, thus demonstrating its neuroprotective effects. Furthermore, C3G regulated the PI3K/Akt/GSK3β signaling by upregulating phosphorylated-Akt/Akt and phosphorylated-GSK3β/GSK3β expression. C3G administration mitigated tau phosphorylation and improved synaptic function and plasticity by upregulating the expression of synapse-associated proteins synaptophysin and postsynaptic density protein-95. Although the potential of C3G in the APPswe/PS1ΔE9 mouse models has not yet been reported, oral administration of the C3G is shown to protect the brain and improve cognitive behavior.
Graphical Abstract
In-house ELISA protocols for capsid p24 detection of diverse HIV isolates
Authors: Molina Mariano A. , Vink Monique , Berkhout Ben , Herrera-Carrillo Elena 
Published: November 2023

Abstract
Background
The capsid p24 (CA-p24) antigen is a component of the viral capsid of human immunodeficiency virus (HIV) that has been commonly used for clinical diagnosis and monitoring of HIV infections in Enzyme-linked Immunosorbent Assays (ELISAs). Commercial CA-p24 ELISAs are widely used in research settings, but these kits are costly and have limited breadth for detecting diverse HIV isolates.

Methods
Commercial CA-p24 antibodies were used as capture and detection antibodies. Specific CA-p24 ELISAs were established with these antibodies and tested for the detection of HIV-1 isolates with the aim of developing in-house protocols to recognize HIV-1 infections in vitro for research purposes.

Results
Here we present four protocols for in-house ELISAs to detect HIV CA-p24 using commercial antibodies. The assays were able to detect the CA-p24 antigen of different HIV-1 isolates tested. Comparison between the protocols showed that these in-house ELISAs exhibit high specificity, sensitivity, and reproducibility for CA-p24 quantitation but their reactivity varied per HIV-1 isolate and subtype.

Conclusions
These optimized ELISA protocols represent valuable tools to investigate HIV-1 infections in research facilities at a lower price than commercial CA-p24 kits.
Anodal transcranial direct current stimulation associated with aerobic exercise on the functional and physical capacity of patients with heart failure with reduced ejection fraction: ELETRIC study protocol
Authors: da Silva Vanessa Christina Costa , da Silva Arêas Fernando Zanela , Lopes Antônio Luiz Ribeiro Boechat , de Almeida e Val Fernando Fonseca , da Costa Allyson Guimarães , dos Santos Joana Colares Correa , Ferreira João Marcos Bemfica Barbosa , Peixoto Tinoco Arêas Guilherme 
Published: November 2023

Abstract
Background
The hallmark symptom of heart failure (HF) is severe exercise intolerance. Fortunately, accumulated evidence suggests that exercise programs improve physical performance, enhance autonomy in daily activities and quality of life, and reduce cardiovascular and other hospitalizations. Recently, experimental studies have explored the application of non-invasive brain stimulation techniques, especially transcranial direct current stimulation (tDCS), aiming to improve physical performance due to its ability to modulate brain functioning. The primary objective of the present study is to evaluate the effects of anodal tDCS associated with aerobic exercise on the functional capacity of patients with HF with reduced ejection fraction (HFrEF). Secondary objectives are to compare the effects of tDCS associated with aerobic exercise vs. sham-tDCS associated with aerobic exercise on cardiopulmonary exercise capacity; inflammatory cytokines; and quality of life.

Methods
This is a two-arm, prospectively registered, randomized trial with concealed allocation, double-blind, and intention-to-treat analysis. Forty-four patients with HFrEF will be recruited. The experimental group will undertake 25–30 min aerobic exercise training associated with tDCS, for 4 weeks. The control group will undergo the same aerobic exercise training, but with sham-tDCS. The primary outcome will be functional performance by the 6-min walk test. Secondary outcomes will include cardiopulmonary exercise capacity, inflammatory cytokines, and quality of life. Outcomes will be collected by a researcher blinded to group allocation at baseline (T0) and after 4 weeks of intervention (T1).

Discussion
Although previous studies have investigated the combined effect of tDCS on T3 area and physical performance and have suggested that tDCS could have reduced ratings of perceived exertion by affecting the activity of the insular cortex, and therefore increase exercise tolerance, this study is the first to evaluate the effects of the addition of anodal tDCS to aerobic exercise training for improving physical and functional performance, decreasing the perceived exertion, altering the quantification of inflammatory cytokines, and improving the subclinical values of the cardiopulmonary test in patients with HFrEF, which could result in an important advance in cardiac rehabilitation for patients with chronic HF.

Trial registration
Brazilian Registry of Clinical Trials (ReBEC) RBR-10w787j6. Registered on 25 April 2023. https://ensaiosclinicos.gov.br/pesquisador
Predicting attrition of men with a history of violence from randomised clinical trials
Authors: Doring Natalie , Hwang Ye In , Akpanekpo Emaediong , Gullotta Mathew , Ton Bianca , Knight Lee , Knight Crosbi , Schofield Peter , Butler Tony Gerard 
Published: November 2023

AbstractPreventing dropout (attrition) from clinical trials is vital for improving study validity. Dropout is particularly important in justice-involved populations as they can be very challenging to engage and recruit in the first instance. This study identifies factors associated with dropout in a double-blind, placebo-controlled randomised control trial of a selective serotonin reuptake inhibitor (SSRI) aimed at reducing reoffending in highly impulsive men with histories of violent offending. Age, education, social support, psychiatric history, and length of previous incarceration were identified as factors that predict attrition. These findings are consistent with previous research examining variables associated with attrition in clinical trials for community and offender populations. We also explored referral source and treatment allocation as attrition predictors. Although neither significantly predicted attrition, we identified that there are discernible differences in the median time to attrition among the referral source subgroups. Understanding factors that predict treatment completion and attrition will allow researchers to identify participants for whom additional provisions may optimise retention and inform development of targeted interventions.
TIGIT reverses IFN-α-promoted Th1-like Tregs via in-sequence effects dependent on STAT4
Authors: Yu Shihan , Gu Jia , Wang Rui , Lee Seunghyun , Shan Yu , Wang Jiakai , Sun Yini , Ma Xiaoxue 
Published: November 2023

Abstract
Objectives
The induction direction of interferon (IFN)-α in T-cell phenotype and function varies depending on the activation state of the cell and the time of stimulation. To assess the effects of elevated IFN-α on regulatory T cells (Tregs) in systemic lupus erythematosus (SLE) patients, we investigated the differentiation of Th1-like Tregs under in-sequence and out-of-sequence conditions and the reversal effect of activating TIGIT on immune suppression.

Methods
Phenotypes and activation levels of Tregs from SLE patients and healthy controls were analyzed using flow cytometry. In vitro culture conditions based on the sequence of TCR activation and IFN-α stimulation simulated in-sequence or out-of-sequence effects. CD4+T cells and Tregs were cultured under the above conditions with or without TIGIT agonist. Expression of related characteristic markers and phosphorylation levels of AKT, mTOR, and STATs were detected using flow cytometry and ELISA.

Results
The frequency of Th1-like Tregs and activation levels of Tregs increased, but TIGIT expression in Tregs decreased in SLE patients. IFN-α promoted the conversation of Tregs to Th1-like Tregs while reducing immunosuppressive function under in-sequence conditions. The STAT4 pathway, but not the STAT1 pathway, was crucial for the IFN-α-mediated in-sequence effects. Reactivation of TIGIT reversed Th1 polarization of Tregs by suppressing AKT/mTOR and STAT4 signaling.

Conclusions
Our findings suggest that IFN-α mediated in-sequence effects on Tregs may be responsible for the expansion of Th1-like Tregs in SLE. TIGIT can restore immune suppression damage in Tregs and represents a potential therapeutic target for SLE.
LEP (G2548A-G19A) and ADIPOQ (T45G-G276T) gene polymorphisms are associated with markers for metabolic syndrome
Authors: Ortega Fred Luque , Camberos Alejandra Martínez , Arredondo Martín Irigoyen , Magallanes Noemí García , Meraz Eliakym Arámbula 
Published: November 2023

Abstract
Background and aims
There is a link between genetics with metabolic balance and adiposity homeostasis on metabolic syndrome (MetS). Polymorphism in adipokine genes such as leptin and adiponectin may play an important role in its development. This study aimed to determine the association of the individual and general components of MetS with genetic alterations in LEP (rs7799039 and rs2167270) and ADIPOQ (rs1501299 and rs2241766) genes in the Mexican population.

Methods and results
The polymorphisms of the LEP gene rs7799039 and rs2167270, together with rs1501299 and rs2241766 polymorphisms of the ADIPOQ gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 328 individuals (n = 131 MetS). The rs7799039 under the recessive inheritance model was found to be associated with increased risk of MetS (OR = 2.16, 95% CI = 1.06–4.37), dyslipidemia (OR = 7.97, 95% CI = 2.17–29.36), low HDL (OR = 7.01, 95% CI = 1.65–29.71) and hypertension (OR = 13.02, 95% CI = 1.76–96.44); the heterozygote demonstrate a protective effect on MetS (OR = 0.48, 95% CI = 0.28–0.88) and diabetes (OR = 0.09, 95% CI = 0.02–0.53) under the over the dominant model. Haplotype analysis showed linkage disequilibrium between the SNPs of ADIPOQ rs1501299/rs2241766, and their association as risk factors for low HDL and hypertension.

Conclusion
The association of rs7799039 with the presence of MetS, suggests a risk factor for the development of dyslipidemia, as well as its heterozygous as a protective factor for DM. There is a linkage disequilibrium between the SNPs of ADIPOQ.
Evaluation of the effectiveness regarding the participation of pharmacists in perioperative blood glucose management via the iGMS: a pilot RCT
Authors: Song Jinfang , Pan Xiaojun , Chen Ya , Ding Yongjuan , Li Xia 
Published: November 2023

Abstract
Background
Excellent blood glucose management is a key guarantee for successful progress of surgery. However, the impact of clinical pharmacists on blood glucose management of perioperative patients needs to be further investigated. To investigate the effectiveness regarding the participation of pharmacists in blood glucose management via the informatized glucose management system (iGMS) on perioperative patients with type 2 diabetes mellitus (T2DM).

Methods
The working mode of clinical pharmacists participating in blood glucose management of perioperative patients with diabetes was constructed. A total of 300 patients with T2DM who underwent elective surgery were recruited and divided into a clinical pharmacist management group (intervention group) of 150 patients (94 men and 56 women; mean age: 44.38 ± 14.03 years) and a control group of 150 patients (101 men and 49 women; mean age: 47.85 ± 12.26 years) between September 2019 to April 2020. The outcomes of perioperative blood glucose management, and healthcare indicators such as preoperative waiting time, total hospitalization time, postoperative infection rate and other indicators were analyzed statistically between the two groups.

Result
In the blood glucose management team of the whole hospital, the physicians, clinical pharmacists and nurses of blood glucose management in endocrinology department were the core members, and were responsible for perioperative blood glucose management of the participants in the intervention group. All subjects had lower blood glucose after 3 days of management compared to the time of admission, and blood glucose was significantly lower in the intervention group compared to the control group (P < 0.05). As compared with the control group, subjects in intervention group demonstrated significant differences in outcome measures. The relevant parameters included preoperative blood glucose compliance rate (60.67% vs. 35.33%, P<0.05), preoperative waiting time [(5.27 ± 3.34) vs. (7.45 ± 4.38), P<0.05], length of hospitalization [(11.11 ± 4.56) vs. (14.87 ± 5.39), P<0.05], incidence of hypoglycemia (8.67% vs. 18.00%, P<0.05), incidence of hyperglycemia (32.00% vs. 62.67%, P<0.05) and postoperative infection rate (18.00% vs. 24.67%, P > 0.05).

Conclusion
The involvement of clinical pharmacists in blood glucose management utilizing the iGMS can control the blood glucose level of patients with T2DM in the perioperative period more stably and effectively, thereby leading to an improvement in the quality of healthcare.
EFL learners’ boredom coping strategies: the role of teacher-student rapport and support
Authors: Zhang Yanbo 
Published: November 2023

Abstract
Background
A significant issue in the language education context is examining the coping strategies that learners apply to combat boredom in the class environment. As a significant contextual element affecting different dimensions of learners’ acquisition, teacher support in general education has been extensively studied but widely neglected in the English as a Foreign Language (EFL) setting. Also, having a relationship with a teacher can help a learner cope better with school challenges as the teacher can act as a reference for the learner.

Methods
To this end, 268 EFL learners participated to fill out the three scales namely, Teacher Support, Teacher-Student Rapport (T-SR), and learners’ Boredom Coping Strategies (BCS).

Results
Using multiple regressions, the results revealed that there are constructive links between these concepts as they affect learners’ BCS, and both T-SR and teacher support were predictors of learners’ BCS while the better predictor was teacher support.

Conclusions
As a result, it can be assumed that these two elements can enhance the students’ BCS in language acquisition which ends in declining boredom. Additionally, this research may have further implications for the team members of language teaching in academic environments.
Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma
Authors: Mariotto Elena , Rampazzo Elena , Bortolozzi Roberta , Rruga Fatlum , Zeni Ilaria , Manfreda Lorenzo , Marchioro Chiara , Canton Martina , Cani Alice , Magni Ruben , Luchini Alessandra , Bresolin Silvia , Viola Giampietro , Persano Luca 
Published: November 2023

AbstractChemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening (HTS), highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting.
Prolonged use of neuromuscular blocking agents is associated with increased long-term mortality in mechanically ventilated medical ICU patients: a retrospective cohort study
Authors: Lin Chun , Chao Wen-Cheng , Pai Kai-Chih , Yang Tsung-Ying , Wu Chieh-Liang , Chan Ming-Cheng 
Published: November 2023

Abstract
Background
Neuromuscular blockade agents (NMBAs) can be used to facilitate mechanical ventilation in critically ill patients. Accumulating evidence has shown that NMBAs may be associated with intensive care unit (ICU)-acquired weakness and poor outcomes. However, the long-term impact of NMBAs on mortality is still unclear.

Methods
We conducted a retrospective analysis using the 2015–2019 critical care databases at Taichung Veterans General Hospital, a referral center in central Taiwan, as well as the Taiwan nationwide death registry profile.

Results
A total of 5709 ventilated patients were eligible for further analysis, with 63.8% of them were male. The mean age of enrolled subjects was 67.8 ± 15.8 years, and the one-year mortality was 48.3% (2755/5709). Compared with the survivors, the non-survivors had a higher age (70.4 ± 14.9 vs 65.4 ± 16.3, p < 0.001), Acute Physiology and Chronic Health Evaluation II score (28.0 ± 6.2 vs 24.7 ± 6.5, p < 0.001), a longer duration of ventilator use (12.6 ± 10.6 days vs 7.8 ± 8.5 days, p < 0.001), and were more likely to receive NMBAs for longer than 48 h (11.1% vs 7.8%, p < 0.001). After adjusting for age, sex, and relevant covariates, the use of NMBAs for longer than 48 h was found to be independently associated with an increased risk of mortality (adjusted HR: 1.261; 95% CI: 1.07–1.486). The analysis of effect modification revealed that this association was tended to be strong in patients with a Charlson Comorbidity Index of 3 or higher.

Conclusions
Our study demonstrated that prolonged use of NMBAs was associated with an increased risk of long-term mortality in critically ill patients requiring mechanical ventilation. Further studies are needed to validate our findings.
MicroServices-driven enterprise architecture model for infrastructure optimization
Authors: Abd-Elwahab A. M. , Mohamed A. G. , Shaaban E. M. 
Published: November 2023

AbstractEnterprise architecture (EA) is a discipline that is becoming increasingly important for businesses that are undergoing digital transformation. EA encompasses the practice of designing and managing the entire architecture of an organization, including its business processes, information systems, and technology infrastructure. In this paper, we will explore the main objectives of EA in digital transformation and the ways in which EA can help businesses achieve their digital transformation goals. Enterprise architects can use MicroServices technology to enable digital transformation by designing the MicroServices architecture, establishing best practices and standards, supporting tools such as DevOps, aligning with the enterprise's cloud strategy, and enabling data integration. Decision makers can use enterprise architecture with MicroServices to make digital transformation by leveraging the benefits of MicroServices architecture to achieve their digital transformation goals.