bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating metabolites and molecular lipid species are associated with future cardiovascular morbidity and mortality in type 1 diabetes
Authors: Ferreira-Divino Luis F. , Suvitaival Tommi , Rotbain Curovic Viktor , Tofte Nete , Trošt Kajetan , Mattila Ismo M. , Theilade Simone , Winther Signe A. , Hansen Tine W. , Frimodt-Møller Marie , Legido-Quigley Cristina , Rossing Peter 
Published: July 2022

Abstract
Background
Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes.

Methods
The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use.

Results
Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01–1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67–0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70–0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59–0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58–0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04–1.68], p = 0.02), was associated with an increased risk.

Conclusions
Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes.
Slc2a6 regulates myoblast differentiation by targeting LDHB
Authors: Jiang Xuan , Feng Ninghan , Zhou Yizhou , Ye Xianlong , Wang Rong , Zhang Jingwei , Cui Siyuan , Ji Siyu , Chen Yongquan , Zhu Shenglong 
Published: July 2022

Abstract
Background
Type 2 diabetes mellitus is a global health problem. It often leads to a decline in the differentiation capacity of myoblasts and progressive loss of muscle mass, which in turn results in deterioration of skeletal muscle function. However, effective therapies against skeletal muscle diseases are unavailable.

Methods
Skeletal muscle mass and differentiation ability were determined in db/+ and db/db mice. Transcriptomics and metabolomics approaches were used to explore the genetic mechanism regulating myoblast differentiation in C2C12 myoblasts.

Results
In this study, the relatively uncharacterized solute carrier family gene Slc2a6 was found significantly up-regulated during myogenic differentiation and down-regulated during diabetes-induced muscle atrophy. Moreover, RNAi of Slc2a6 impaired the differentiation and myotube formation of C2C12 myoblasts. Both metabolomics and RNA-seq analyses showed that the significantly differentially expressed genes (e.g., LDHB) and metabolites (e.g., Lactate) during the myogenic differentiation of C2C12 myoblasts post-Slc2a6-RNAi were enriched in the glycolysis pathway. Furthermore, we show that Slc2a6 regulates the myogenic differentiation of C2C12 myoblasts partly through the glycolysis pathway by targeting LDHB, which affects lactic acid accumulation.

Conclusion
Our study broadens the understanding of myogenic differentiation and offers the Slc2a6-LDHB axis as a potential therapeutic target for the treatment of diabetes-associated muscle atrophy.
Combinatorial targeting of a chromatin complex comprising Dot1L, menin and the tyrosine kinase BAZ1B reveals a new therapeutic vulnerability of endocrine therapy-resistant breast cancer
Authors: Salvati Annamaria , Melone Viola , Sellitto Assunta , Rizzo Francesca , Tarallo Roberta , Nyman Tuula A. , Giurato Giorgio , Nassa Giovanni , Weisz Alessandro 
Published: July 2022

Abstract
Background
Targeting vulnerabilities of cancer cells by inhibiting key regulators of cell proliferation or survival represents a promising way to overcome resistance to current therapies. In breast cancer (BC), resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor alpha (ERα) signaling to the genome. Targeting components of the ERα pathway in these tumors represents, therefore, a rational way toward effective new treatments. Interaction proteomics identified several proteins associated with ERα in BC cells, including epigenetic complexes controlling gene transcription comprising the scaffold protein menin and the histone methyltransferase Dot1L.

Methods
We combined chromatin immunoprecipitation, transcriptome sequencing, siRNA-mediated gene knockdown (kd), pharmacological inhibition coupled to cellular and functional assays and interaction proteomics in antiestrogen (AE)-sensitive and AE-resistant human BC cell models to: map menin and Dot1L chromatin localization, search for their common and specific target genes, measure the effects of single or combinatorial knockdown or pharmacological inhibition of these proteins on cell proliferation and survival, and characterize their nuclear interactomes.

Results
Dot1L and menin associate in MCF-7 cells chromatin, where they co-localize in a significant fraction of sites, resulting in co-regulation of genes involved, among others, in estrogen, p53, HIF1α and death receptor signaling, regulation of cell cycle and epithelial-to-mesenchymal transition. Specific inhibitors of the two factors synergize with each other for inhibition of cell proliferation of AE (tamoxifen or fulvestrant)-sensitive and AE-resistant BC cells. Menin and Dot1L interactomes share a sizeable fraction of their nuclear partners, the majority being known BC fitness genes. Interestingly, these include B-WICH and WINAC complexes that share BAZ1B, a bromodomain protein comprising a tyrosine–protein kinase domain playing a central role in chromatin remodeling and transcriptional regulation. BAZ1B kd caused significant inhibition of ERα expression, proliferation and transcriptome changes resulting in inhibition of estrogen, myc, mTOR, PI3K and AKT signaling and metabolic pathways in AE-sensitive and AE-resistant BC cells.

Conclusions
Identification of a functional interplay between ERα, Dot1L, menin and BAZ1B and the significant effects of their co-inhibition on cell proliferation and survival in cell models of endocrine therapy-resistant BC reveal a new therapeutic vulnerability of these aggressive diseases.
Effect of menopausal hormone therapy on methylation levels in early and late postmenopausal women
Authors: Hilser James R. , Hartiala Jaana A. , Sriprasert Intira , Kono Naoko , Cai Zhiheng , Karim Roksana , DeYoung Joseph , Mack Wendy J. , Hodis Howard N. , Allayee Hooman 
Published: July 2022

AbstractBackgroundCardiovascular disease (CVD) remains the leading cause of death among postmenopausal women but standard primary prevention strategies in women are not as effective as in men. By comparison, the Early versus Late Intervention Trial with Estradiol (ELITE) study demonstrated that hormone therapy (HT) was associated with significant reduction in atherosclerosis progression in women who were within six years of menopause compared to those who were 10 or more years from menopause. These findings are consistent with other studies showing significant reductions in all-cause mortality and CVD with HT, particularly when initiated in women younger than 60 years of age or within 10 years since menopause. To explore the biological mechanisms underlying the age-related atheroprotective effects of HT, we investigated changes in methylation of blood cells of postmenopausal women who participated in ELITE.ResultsWe first validated the epigenetic data generated from blood leukocytes of ELITE participants by replicating previously known associations between smoking and methylation levels at previously identified CpG sites, such as cg05575921 at theAHRRlocus. An epigenome-wide association study (EWAS) evaluating changes in methylation through interactions with time-since-menopause and HT revealed two significantly associated CpG sites on chromosomes 12 (cg19552895;p = 1.1 × 10–9) and 19 (cg18515510;p = 2.4 × 10–8). Specifically, HT resulted in modest, but significant, increases in methylation levels at both CpGs but only in women who were 10 or more years since menopause and randomized to HT. Changes in carotid artery intima-media thickness (CIMT) from baseline to 36 months after HT were not significantly correlated with changes in methylation levels at either cg19552895 or cg18515510. Evaluation of other previously identified CpG sites at which methylation levels in either blood or vascular tissue were associated with atherosclerosis also did not reveal any differences in methylation as a function of HT and time-since-menopause or with changes in CIMT.ConclusionsWe identified specific methylation differences in blood in response to HT among women who were 10 or more years since menopause. The functional consequence of these change with respect to atherosclerosis progression and protective effects of HT remains to be determined and will require additional studies.
Imbalance of flight–freeze responses and their cellular correlates in the Nlgn3−/y rat model of autism
Authors: Anstey Natasha J. , Kapgal Vijayakumar , Tiwari Shashank , Watson Thomas C. , Toft Anna K. H. , Dando Owen R. , Inkpen Felicity H. , Baxter Paul S. , Kozić Zrinko , Jackson Adam D. , He Xin , Nawaz Mohammad Sarfaraz , Kayenaat Aiman , Bhattacharya Aditi , Wyllie David J. A. , Chattarji Sumantra , Wood Emma R. , Hardt Oliver , Kind Peter C. 
Published: July 2022

AbstractBackgroundMutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lackingNlgn3.MethodsThis study uses a range of behavioural tests to understand differences in fear response behaviour inNlgn3−/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype andNlgn3−/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM).ResultsWe observed that, unlike the wildtype,Nlgn3−/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices fromNlgn3−/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour inNlgn3−/y than wildtype rats, indicating the functional impact of the increased cellular excitability.LimitationsOur findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated withNLGN3mutations appears during the first few years of life.ConclusionsWe describe altered fear responses inNlgn3−/yrats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD.
Coats disease in adolescence and adulthood with preserved vision after laser photocoagulation monotherapy: two case reports
Authors: Adriono Gitalisa Andayani , Nadhira Andi Marsa , Mahfudz Sausan Rasyid 
Published: July 2022

Abstract
Background
This case report describes two rare cases of Coats disease in nonjuvenile patients with preserved vision.

Case presentation
Two otherwise healthy Asian males aged 15 and 29 years old presented with unilateral gradual blurred vision and scotoma, respectively. Visual acuity was 6/6 (0 logMAR) with no other abnormalities observed in the anterior segment of the eyes. Both posterior segment examinations and fluorescein angiography revealed retinal telangiectatic vessels, exudation, and hemorrhage. Additionally, optical coherence tomography of the first patient showed subfoveal fluid. Both patients were diagnosed with stage 2 Coats disease. Laser photocoagulation was performed on both patients. The first patient showed initial good response to therapy with resolution of the subfoveal fluid; however, he developed cataract and underwent cataract surgery after 3 years. In the second case, although the exudates and hemorrhage still persisted, the macula was spared and the patient did not have visual complaints. No adverse events were reported, and final visual acuity of both patients remained 6/6.

Conclusions
Coats disease in adolescence and adulthood may present with good vision. In mild and moderate cases of Coats disease, laser photocoagulation monotherapy may help preserve vision. Nevertheless, as recurrences and complications may still occur later in life, lifelong monitoring is recommended.
Smoking and drinking behavior, knowledge, and attitudes among urban and rural public-school students in Efate Island, Vanuatu: a comparative study
Authors: Nakaseko Emi , Kotera Sayaka , Nakazawa Minato 
Published: July 2022

Abstract
Background
Underage smoking and drinking are public health issues in Vanuatu. This study aims to describe the behavior, knowledge, attitudes, and perceptions of parents, siblings, and peers regarding smoking and drinking among urban and rural public-school students in Vanuatu.

Methods
This cross-sectional study included 358 students (urban, 217; rural, 141; aged 12–14 years) from the public schools in Efate Island, Vanuatu. Data were collected using self-administered questionnaires. Chi-square and Mann–Whitney U tests were used to determine the rural–urban differences.

Results
Urban students showed a higher prevalence of ever smoking (13.5%), ever drinking (16.9%), intention to smoke (11.1%), and intention to drink (14.0%) compared to rural students (10.3%, 8.3%, 5.8%, and 9.5%, respectively); although a significant difference was only observed in the prevalence of ever drinking. Urban students were more likely to be aware of the health hazards of substance use and showed higher self-efficacy to refuse tobacco and alcohol compared to rural students. Parents in rural areas were less likely to talk about the health hazards of substance use with their children and were more likely to offer tobacco or alcohol to them compared to parents in urban areas.

Conclusions
The results provide evidence of rural–urban differences in the behavior, attitude, knowledge, and perceptions of parental behavior regarding smoking and drinking. The findings suggest that issues related to underage smoking and drinking differ between urban and rural students. Future intervention programs for reducing underage smoking and drinking should be adapted in recognition of urban and rural differences.
Compressive Behavior of Concrete Containing Glass Fibers and Confined with Glass FRP Composites
Authors: Yahiaoui Djarir , Saadi Mohamed , Bouzid Tayeb 
Published: July 2022

AbstractIn this paper, numerous experimental tests were carried out to study the behavior of concrete containing glass fibers and confined with glass fiber-reinforced polymer (GFRP). Concrete specimens containing different fiber percentages ( 0.3 wt.%, 0.6 wt.%, 0.9 wt.% or 1.2 wt.%) and with different strengths of concrete (8.5 MPa, 16 MPa and 25 MPa) and different confinement levels (two, four and six layers of GFRP) were used as research parameters. The samples were tested to failure under pure axial compression. The results imply that the confinement effect with GFRP is relatively higher for concrete samples containing glass fiber (GFCC) with a percentage equal to 0.6 wt.%. The theoretical of stress ratios (fcc/fco) estimated by using existing ultimate strength models are found to be close to the experimental results for high strength of GFCC, but not close to the experimental results for low strength of GFCC.
Changes in obsessive–compulsive symptoms during inpatient treatment of anorexia nervosa
Authors: Meule Adrian , Voderholzer Ulrich 
Published: July 2022

AbstractBackgroundObsessive–compulsive disorder (OCD) is one of the most prevalent comorbidities in anorexia nervosa (AN). As AN is a severe, life-threatening condition, reducing obsessive–compulsive symptomatology is not the primary objective during treatment of AN and, thus, these symptoms may remain unchanged or may even increase in terms of a “symptom shift”.MethodsIn this retrospective analysis, we examined clinical records of 149 adolescents (n = 96, 64%) and adults (n = 53, 36%) with AN (6 males, 4%) who received inpatient treatment and completed the Obsessive–Compulsive Inventory–Revised at admission and discharge.ResultsObsessive–compulsive symptoms decreased from admission to discharge, irrespective of whether patients had comorbid OCD or not. Within-person decreases in obsessive–compulsive symptoms weakly correlated with increases in body weight.ConclusionsThese results indicate that obsessive–compulsive symptoms decrease during inpatient treatment of AN although they are not primarily targeted during treatment. Furthermore, these improvements seem to be associated with general improvements in AN symptomatology, suggesting the absence of a “symptom shift”. Yet, effect sizes were small and obsessive–compulsive symptoms were still clinically elevated in patients with comorbid OCD at discharge, suggesting that these patients need OCD-specific, psychotherapeutic aftercare.
Construct validity and factor structure of the Kessler-10 in South Africa
Authors: Hoffman Jacob , Cossie Qhama , Ametaj Amantia A. , Kim Hannah H. , James Roxanne , Stroud Rocky E. , Stevenson Anne , Zingela Zukiswa , Stein Dan J. , Gelaye Bizu 
Published: July 2022

Abstract
Background
The Kessler Psychological Distress Scale (K-10) is a short screening tool developed to identify, with good sensitivity, non-specific psychological distress in the general population. Sensitivity and specificity of the K-10 have been examined in various clinical populations in South Africa; however, other psychometric properties, such as construct validity and factor structure, have not been evaluated. We present evidence of the prevalence and severity of psychological distress in an outpatient setting in South Africa and evaluate the internal reliability, construct validity, and factor structure of the K-10 in this population.

Methods
We explored prevalence estimates of psychological distress using previously established cutoffs and assessed the reliability (consistency) of the K-10 by calculating Cronbach’s alpha, item-total correlations and omega total and hierarchical coefficients. Construct validity and factor structure of the K-10 were examined through split-sample exploratory factor analysis (EFA) followed by confirmatory factor analysis (CFA), comparing several theoretical models and the EFA.

Results
Overall, there was low prevalence of psychological distress in our sample of 2591 adults, the majority of whom were between the ages of 18–44 (77.7%). The K-10 showed good construct validity and reliability, with a Cronbach’s alpha of 0.84 and omega total of 0.88. EFA yielded a four-factor solution with likely measurement artifacts. CFA showed that the four-factor model from EFA displayed the best comparative fit indices, but was likely overfitted. The unidimensional model with correlated errors was deemed the best fitting model based on fit indices, prior theory, and previous studies.

Conclusion
The K-10 displays adequate psychometric properties, good internal reliability, and good fit with a unidimensional-factor structure with correlated errors. Further work is required to determine appropriate cutoff values in different populations and clinical subgroups within South Africa to aid in determining the K-10’s clinical utility.
Macromolecules in polysorbate 80 for injection: an important cause of anaphylactoid reactions
Authors: Li Yue , Duan Jinlian , Xia Heng , Li Yongkun , Shu Bin , Duan Weigang 
Published: July 2022

AbstractPolysorbate 80 for injection (TW80) is a common excipient used for injection whose macromolecular impurities, including those that cause anaphylactoid reactions, are frequently ignored. The main aim of this study was to prove that the macromolecular impurities in the excipient are an important cause of anaphylactoid reactions. Component A (containing macromolecules > 100 kDa), Component B (containing macromolecules from 10 to 100 kDa), and Component C (containing substances < 10 kDa) were prepaired from the original TW80 using ultrafilters. The original TW80 contained numerous substances with molecular weights > 10kD. The original TW80 and Components A and B caused strong anaphylactoid reactions in both guinea pigs and rabbits by intravenous administration. Moreover, the original TW80 and Components A and B even caused strong passive cutaneous anaphylactoid (PCA) reactions and pulmonary capillary permeability. The PCA reaction and increased permeability were partly prevented by cromolyn sodium. Additionally, the original TW80 and Components A and B caused vasodilation and severe hemolysis in vitro. The anaphylactoid reactions were associated with histamine release but not with mast cell degranulation. Nevertheless, Component C almost caused no anaphylactoid reactions or hemolysis and was weaker in the few reactions that ocurred. Taken together, these results suggest that macromolecular substances are one of the main risk factors responsible for anaphylactoid reactions and hemolysis caused by TW80.