bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterozygous variant in FGFR3 underlying severe phenotypes in the second trimester: a case report
Authors: Chen Shujun , Dong Hongmei , Luo Yong , Zhang Yingpin , Li Pan 
Published: April 2023

Abstract
Background
Achondroplasia is a congenital skeletal system malformation caused by missense variant of FGFR3 gene with an incidence of 1 per 20,000–30,000 newborns, which is an autosomal dominant inheritance disease. Despite similar imaging features, the homozygous achondroplasia is absolutely lethal due to thoracic stenosis, whereas heterozygous achondroplasia does not lead to fetal death.

Case presentation
A fetus with progressive rhizomelic short limbs and overt narrow chest was detected by prenatal ultrasound in the second trimester. Gene sequencing results of amniotic fluid sample indicated a rare missense variant NM_000142.4: c.1123G > T(p.Gly375Cys), leading to a glycine to cysteine substitution. Re-sequencing confirmed that it was a heterozygous variant, and thoracic stenosis was then confirmed in the corpse by radiological examination.

Conclusions
We identified a heterozygous variant of the FGFR3 gene as the rare pathogenic variant of severe achondroplasia in a fetus. Heterozygous variants of p.Gly375Cys may have a severe phenotype similar to homozygote. It’s crucial to combine prenatal ultrasound with genetic examination to differentiate heterozygous from homozygous achondroplasia. The p.Gly375Cys variant of FGFR3 gene may serve as a vital target for the diagnosis of severe achondroplasia.
MiRNA-93: a novel signature in human disorders and drug resistance
Authors: Hussen Bashdar Mahmud , Abdullah Snur Rasool , Rasul Mohammed Fatih , Jawhar Zanko Hassan , Faraj Goran Sedeeq Hama , Kiani Arda , Taheri Mohammad 
Published: April 2023

AbstractmiRNA-93 is a member of the miR-106b-25 family and is encoded by a gene on chromosome 7q22.1. They play a role in the etiology of various diseases, including cancer, Parkinson’s disease, hepatic injury, osteoarthritis, acute myocardial infarction, atherosclerosis, rheumatoid arthritis, and chronic kidney disease. Different studies have found that this miRNA has opposing roles in the context of cancer. Recently, miRNA-93 has been downregulated in breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, and renal cancer. However, miRNA-93 is up-regulated in a wide variety of malignancies, such as lung, colorectal, glioma, prostate, osteosarcoma, and hepatocellular carcinoma. The aim of the current review is to provide an overview of miRNA-93's function in cancer disorder progression and non-cancer disorders, with a focus on dysregulated signaling pathways. We also give an overview of this miRNA's function as a biomarker of prognosis in cancer and emphasize how it contributes to drug resistance based on in vivo, in vitro, and human studies.
Molecular characterization of coxsackievirus B5 from the sputum of pneumonia children patients of Kunming, Southwest China
Authors: Tan Miao , Suo Jiale , Zhang Zhilei , He Wenji , Tan Li , Jiang Haiyan , Li Ming , He Juan , Pan Yue , Xu Bin , Yan Lingmei , Bin Songtao , Gan Zhengyan , Sun Yuxing , Jiang Hongchao , Sun Qiangming , Zhang Zhen 
Published: April 2023

Abstract
Background
CVB5 can cause respiratory infections. However, the molecular epidemiological information about CVB5 in respiratory tract samples is still limited. Here, we report five cases in which CVB5 was detected in sputum sample of pneumonia children patients from Kunming, Southwest China.

Methods
CVB5 isolates were obtained from sputum samples of patients with pneumonia. Whole-genome sequencing of CVB5 isolates was performed using segmented PCR, and phylogenetic, mutation and recombination analysis. The effect of mutations in the VP1 protein on hydration were analyzed by Protscale. The tertiary models of VP1 proteins were established by Colabfold, and the effect of mutations in VP1 protein on volume modifications and binding affinity were analyzed by Pymol software and PROVEAN.

Results
A total of five CVB5 complete genome sequences were obtained. No obvious homologous recombination signals comparing with other coxsackie B viruses were observed in the five isolates. Phylogenetic analysis showed that the five CVB5 sputum isolates were from an independent branch in genogroup E. Due to the mutation, the structure and spatial of the VP1 protein N-terminus have changed significantly. Comparing to the Faulkner (CVB5 prototype strain), PROVEAN revealed three deleterious substitutions: Y75F, N166T (KM35), T140I (KM41). The last two of the three deleterious substitutions significantly increased the hydrophobicity of the residues.

Conclusions
We unexpectedly found five cases of CVB5 infection instead of rhinoviruses infection during our routine surveillance of rhinoviruses in respiratory tract samples. All five patients were hospitalized with pneumonia symptoms and were not tested for enterovirus during their hospitalization. This report suggests that enterovirus surveillance in patients with respiratory symptoms should be strengthened.
Central nervous system insulin signaling can influence the rate of insulin influx into brain
Authors: Nguyen Van , Thomas Peter , Pemberton Sarah , Babin Alice , Noonan Cassidy , Weaver Riley , Banks William A. , Rhea Elizabeth M. 
Published: April 2023

Abstract
Background
Insulin transport across the blood-brain barrier (BBB) is a highly regulated, saturable process, known to be affected by many peripheral substrates including insulin itself and triglycerides. This is in contrast to insulin leakage into peripheral tissues. Whether the central nervous system (CNS) can control the rate of insulin uptake by brain remains to be determined. Insulin BBB interactions are impaired in Alzheimer’s disease (AD) and CNS insulin resistance is widely prevalent in AD. Therefore, if CNS insulin controls the rate of insulin transport across the BBB, then the defective transport of insulin seen in AD could be one manifestation of the resistance to CNS insulin observed in AD.

Methods
We investigated whether enhancing CNS insulin levels or induction of CNS insulin resistance using an inhibitor of the insulin receptor altered the blood-to-brain transport of radioactively labeled insulin in young, healthy mice.

Results
We found that insulin injected directly into the brain decreased insulin transport across the BBB for whole brain and the olfactory bulb in male mice, whereas insulin receptor blockade decreased transport in female mice for whole brain and hypothalamus. Intranasal insulin, currently being investigated as a treatment in AD patients, decreased transport across the BBB of the hypothalamus.

Conclusions
These results suggest CNS insulin can control the rate of insulin brain uptake, connecting CNS insulin resistance to the rate of insulin transport across the BBB.
Urate-lowering therapy following a treat-to-target continuation strategy compared to a treat-to-avoid-symptoms discontinuation strategy in gout patients in remission (GO TEST Finale): study protocol of a multicentre pragmatic randomized superiority trial
Authors: Peeters Iris Rose , den Broeder Alfons A. , Taylor William J , den Broeder Nathan , Flendrie Marcel , van Herwaarden Noortje 
Published: April 2023

Abstract

Background

Long-term gout treatment is based on reducing serum urate levels using urate-lowering therapy (ULT). Most guidelines recommend using a lifelong continuation treat-to-target (T2T) strategy, in which ULT is dosed or combined until a serum urate target has been reached and maintained. However, a frequently used alternative strategy in clinical practice is a treat-to-avoid-symptoms (T2S) ULT discontinuation strategy, with the possibility of restarting the medication. This latter strategy aims at an acceptable symptom state, regardless of serum urate levels. High-quality evidence to support either strategy for patients in prolonged remission while using ULT is lacking.

Methods
We developed an investigator-driven pragmatic, open-label, multicentre, randomized, superiority treatment strategy trial (GO TEST Finale). At least 278 gout patients using ULT who are in remission (>12 months, preliminary gout remission criteria) will be randomized 1:1 to a continued T2T strategy (treatment target serum urate < 0.36 mmol/l) or switched to a T2S discontinuation strategy in which ULT is tapered to stop and restarted in case of (persistent or recurrent) flaring. The primary outcome is the between-group difference in the proportion of patients not in remission during the last 6 months of 24 months follow-up and will be analyzed using a two proportion z test. Secondary outcomes are group differences in gout flare incidence, reintroduction or adaptation of ULT, use of anti-inflammatory drugs, serum urate changes, occurrence of adverse events (with a special interest in cardiovascular and renal events), and cost-effectiveness.

Discussion
This study will be the first clinical trial comparing two ULT treatment strategies in patients with gout in remission. It will contribute to more specific and unambiguous guideline recommendations and improved cost-effectiveness of long-term gout treatment. It also paves the way (exploratory) to individualized long-term ULT treatment. In this article, we elaborate on some of our trial design choices and their clinical and methodological consequences.

Trial registration
International Clinical Trial Registry Platform (ICTRP) NL9245. Registered on 2 February 2021 (METC Oost-Nederland NL74350.091.20); EudraCT EUCTR2020-005730-15-NL. Registered on 11 January 2021.
Safety and effectiveness of standardized exercise training in patients with pulmonary hypertension associated with heart failure with preserved ejection fraction (TRAIN-HFpEF-PH): study protocol for a randomized controlled multicenter trial
Authors: Palevičiūtė Eglė , Čelutkienė Jelena , Šimbelytė Toma , Gumbienė Lina , Jurevičienė Elena , Zakarkaitė Diana , Čėsna Sigitas , Eichstaedt Christina A. , Benjamin Nicola , Grünig Ekkehard 
Published: April 2023

Abstract
Background
Left heart failure (HF) is characterized by an elevation in left-sided filling pressures, causing symptoms of dyspnea, impairing exercise capacity, and leading to pulmonary venous congestion and secondary pulmonary hypertension (PH). There is an increased incidence of PH associated with left heart disease, particularly with heart failure with preserved ejection fraction (HFpEF-PH). Treatment possibilities in HFpEF-PH are non-specific and very limited, thus additional pharmacological and non-pharmacological therapeutic strategies are needed. Various types of exercise-based rehabilitation programs have been shown to improve exercise capacity and quality of life (QoL) of HF and PH patients. However, no study focused on exercise training in the population of HFpEF-PH. This study is designed to investigate whether a standardized low-intensity exercise and respiratory training program is safe and may improve exercise capacity, QoL, hemodynamics, diastolic function, and biomarkers in patients with HFpEF-PH.

Methods
A total of 90 stable patients with HFpEF-PH (World Health Organization functional class II–IV) will be randomized (1:1) to receive a 15-week specialized low-intensity rehabilitation program, including exercise and respiratory therapy and mental gait training, with an in-hospital start, or standard care alone. The primary endpoint of the study is a change in 6-min walk test distance; secondary endpoints are changes in peak exercise oxygen uptake, QoL, echocardiographic parameters, prognostic biomarkers, and safety parameters.

Discussion
To date, no study has investigated the safety and efficacy of exercising specifically in the HFpEF-PH population. We believe that a randomized controlled multicenter trial, which protocol we are sharing in this article, will add important knowledge about the potential utility of a specialized low-intensity exercise and respiratory training program for HFpEF-PH and will be valuable in finding optimal treatment strategies for these patients.

Trial registration
ClinicalTrials.gov NCT05464238. July 19, 2022.
Assessment of binding interaction to salmon sperm DNA of two antiviral agents and ecofriendly nanoparticles: comprehensive spectroscopic study
Authors: Abdel Hakiem Ahmed Faried , El-Sagheir Ahmed Mohsen Kamal , Draz Mohammed E. , Mohamed Niveen A. , Aboraia Ahmed Safwat 
Published: April 2023

AbstractThe direct binding of antiviral agents; Daclatasvir and valacyclovir and green synthesized nanoparticles to salmon sperm DNA have been assessed in a comparative study. The nanoparticles were synthesized by the hydrothermal autoclave method and have been fully characterized. The interactive behavior and competitive binding of the analytes to DNA in addition to the thermodynamic properties were deeply investigated by the UV–visible spectroscopy. The binding constants were monitored in the physiological pH conditions to be 1.65 × 106, 4.92 × 105 and 3.12 × 105 for daclatasvir,valacyclovir and quantum dots, respectively. The significant changes in the spectral features of all analytes have proven intercalative binding. The competitive study has confirmed that, daclatasvir, valacyclovir, and the quantum dots have exhibited groove binding. All analytes have shown good entropy and enthalpy values indicating stable interactions. The electrostatic and non-electrostatic kinetic parameters have been determined through studying the binding interactions at different concentrations of KCl solutions. A molecular modelling study has been applied to demonstrate the binding interactions and their mechanisms. The obtained results were complementary and afforded new eras for the therapeutic applications.
Ovulatory signal-triggered chromatin remodeling in ovarian granulosa cells by HDAC2 phosphorylation activation-mediated histone deacetylation
Authors: Jin Jiamin , Ren Peipei , Li Xiang , Zhang Yinyi , Yang Weijie , Ma Yerong , Lai Mengru , Yu Chao , Zhang Songying , Zhang Yin-Li 
Published: April 2023

Abstract
Background
Epigenetic reprogramming is involved in luteinizing hormone (LH)-induced ovulation; however, the underlying mechanisms are largely unknown.

Results
We here observed a rapid histone deacetylation process between two waves of active transcription mediated by the follicle-stimulating hormone (FSH) and the LH congener human chorionic gonadotropin (hCG), respectively. Analysis of the genome-wide H3K27Ac distribution in hCG-treated granulosa cells revealed that a rapid wave of genome-wide histone deacetylation remodels the chromatin, followed by the establishment of specific histone acetylation for ovulation. HDAC2 phosphorylation activation coincides with histone deacetylation in mouse preovulatory follicles. When HDAC2 was silenced or inhibited, histone acetylation was retained, leading to reduced gene transcription, retarded cumulus expansion, and ovulation defect. HDAC2 phosphorylation was associated with CK2α nuclear translocation, and inhibition of CK2α attenuated HDAC2 phosphorylation, retarded H3K27 deacetylation, and inactivated the ERK1/2 signaling cascade.

Conclusions
This study demonstrates that the ovulatory signal erases histone acetylation through activation of CK2α-mediated HDAC2 phosphorylation in granulosa cells, which is an essential prerequisite for subsequent successful ovulation.
Unravelling the skillset of point-of-care ultrasound: a systematic review
Authors: Mulder Tessa A. , van de Velde Tim , Dokter Eveline , Boekestijn Bas , Olgers Tycho J. , Bauer Martijn P. , Hierck Beerend P. 
Published: April 2023

Abstract
Background
The increasing number of physicians that are trained in point-of-care ultrasound (POCUS) warrants critical evaluation and improvement of current training methods. Performing POCUS is a complex task and it is unknown which (neuro)cognitive mechanisms are most important in competence development of this skill. This systematic review was conducted to identify determinants of POCUS competence development that can be used to optimize POCUS training.

Methods
PubMed, Web of Science, Cochrane Library, Emcare, PsycINFO and ERIC databases were searched for studies measuring ultrasound (US) skills and aptitude. The papers were divided into three categories: “Relevant knowledge”, “Psychomotor ability” and ‘Visuospatial ability’. The ‘Relevant knowledge’ category was further subdivided in ‘image interpretation’, ‘technical aspects’ and ‘general cognitive abilities’. Visuospatial ability was subdivided in visuospatial subcategories based on the Cattell-Horn-Carroll (CHC) Model of Intelligence v2.2, which includes visuospatial manipulation and visuospatial perception. Post-hoc, a meta-analysis was performed to calculate pooled correlations.

Results
26 papers were selected for inclusion in the review. 15 reported on relevant knowledge with a pooled coefficient of determination of 0.26. Four papers reported on psychomotor abilities, one reported a significant relationship with POCUS competence. 13 papers reported on visuospatial abilities, the pooled coefficient of determination was 0.16.

Conclusion
There was a lot of heterogeneity in methods to assess possible determinants of POCUS competence and POCUS competence acquisition. This makes it difficult to draw strong conclusions on which determinants should be part of a framework to improve POCUS education. However, we identified two determinants of POCUS competence development: relevant knowledge and visuospatial ability. The content of relevant knowledge could not be retrieved in more depth. For visuospatial ability we used the CHC model as theoretical framework to analyze this skill. We could not point out psychomotor ability as a determinant of POCUS competence.
Functional gradients of the medial parietal cortex in a healthy cohort with family history of sporadic Alzheimer’s disease
Authors: Veréb Dániel , Mijalkov Mite , Chang Yu-Wei , Canal-Garcia Anna , Gomez-Ruis Emiliano , Maass Anne , Villeneuve Sylvia , Volpe Giovanni , Pereira Joana B. 
Published: April 2023

Abstract

Background
The medial parietal cortex is an early site of pathological protein deposition in Alzheimer’s disease (AD). Previous studies have identified different subregions within this area; however, these subregions are often heterogeneous and disregard individual differences or subtle pathological alterations in the underlying functional architecture. To address this limitation, here we measured the continuous connectivity gradients of the medial parietal cortex and assessed their relationship with cerebrospinal fluid (CSF) biomarkers, ApoE ε4 carriership and memory in asymptomatic individuals at risk to develop AD.

Methods
Two hundred sixty-three cognitively normal participants with a family history of sporadic AD who underwent resting-state and task-based functional MRI using encoding and retrieval tasks were included from the PREVENT-AD cohort. A novel method for characterizing spatially continuous patterns of functional connectivity was applied to estimate functional gradients in the medial parietal cortex during the resting-state and task-based conditions. This resulted in a set of nine parameters that described the appearance of the gradient across different spatial directions. We performed correlation analyses to assess whether these parameters were associated with CSF biomarkers of phosphorylated tau181 (p-tau), total tau (t-tau), and amyloid-ß1-42 (Aß). Then, we compared the spatial parameters between ApoE ε4 carriers and noncarriers, and evaluated the relationship between these parameters and memory.

Results
Alterations involving the superior part of the medial parietal cortex, which was connected to regions of the default mode network, were associated with higher p-tau, t-tau levels as well as lower Aß/p-tau levels during the resting-state condition (p < 0.01). Similar alterations were found in ApoE ε4 carriers compared to non-carriers (p < 0.003). In contrast, lower immediate memory scores were associated with changes in the middle part of the medial parietal cortex, which was connected to inferior temporal and posterior parietal regions, during the encoding task (p = 0.001). No results were found when using conventional connectivity measures.

Conclusions
Functional alterations in the medial parietal gradients are associated with CSF AD biomarkers, ApoE ε4 carriership, and lower memory in an asymptomatic cohort with a family history of sporadic AD, suggesting that functional gradients are sensitive to subtle changes associated with early AD stages.
Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism and masculinization of intermediate metabolism in women with polycystic ovary syndrome (PCOS)
Authors: Escobar-Morreale Héctor F. , Martínez-García M. Ángeles , Insenser María , Cañellas Nicolau , Correig Xavier , Luque-Ramírez Manuel 
Published: April 2023

Abstract
Background
The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the art proton nuclear magnetic resonance spectroscopy metabolomics profiling, that androgen excess in women induces also a certain masculinization of intermediate metabolism that is modulated by obesity.

Methods
Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected in order to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity defined by a body mass index ≥ 30 kg/m2. Subjects maintained the same diet unrestricted in carbohydrates for 3 days before sampling and maintained their lifestyle and exercise patterns prior and during the study. Plasma samples were submitted to proton nuclear magnetic resonance spectroscopy metabolomics profiling.

Results
Obesity associated a metabolomics profile mainly characterized by increased branched chain and aromatic aminoacids. Regardless of obesity, this unfavorable profile also characterized men as compared with control women, and was shared by women with PCOS. Notably, the negative impact of obesity on metabolomics profile was restricted to women, with obese men showing no further deterioration when compared with their non-obese counterparts.

Conclusions
Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism, and masculinization of intermediate metabolism in women with PCOS, further suggesting a role for sex and sex hormones in the regulation of intermediate metabolism.