bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thiourea derivatives inhibit key diabetes‐associated enzymes and advanced glycation end‐product formation as a treatment for diabetes mellitus
Authors: Ullah Imran , Hassan Mukhtiar , Khan Khalid M. , Sajid Muhammad , Umar Muhammad , Hassan Said , Ullah Amin , El‐Serehy Hamed A. , Charifi Wafa , Yasmin Humaira 
Published: December 2022

AbstractThis study was designed to screen novel thiourea derivatives against different enzymes, such as α‐amylase, α‐glucosidase, protein tyrosine phosphatase 1 B, and advanced glycated end product (AGEs). A cytotoxicity analysis was performed using rat L6 myotubes and molecular docking analysis was performed to map the binding interactions between the active compounds and α‐amylase and α‐glucosidase. The data revealed the potency of five compounds, including E (1‐(2,4‐difluorophenyl)‐3‐(3,4‐dimethyl phenyl) thiourea), AG (1‐(2‐methoxy‐5‐(trifluoromethyl) phenyl)‐3‐(3‐methoxy phenyl) thiourea), AF (1‐(2,4‐dichlorophenyl)‐3‐(4‐ethylphenyl) thiourea), AD (1‐(2,4‐dichlorophenyl)‐3‐(4‐ethylphenyl) thiourea), and AH (1‐(2,4‐difluorophenyl)‐3‐(2‐iodophenyl) thiourea), showed activity against α‐amylase. The corresponding percentage inhibitions were found to be 85 ± 1.9, 82 ± 0.7, 75 ± 1.2, 72 ± 0.4, and 65 ± 1.1%, respectively. These compounds were then screened using in vitro assays. Among them, AH showed the highest activity against α‐glucosidase, AGEs, and PTP1B, with percentage inhibitions of 86 ± 0.4% (IC50 = 47.9 μM), 85 ± 0.7% (IC50 = 49.51 μM), and 85 ± 0.5% (IC50 = 79.74 μM), respectively. Compound AH showed an increased glucose uptake at a concentration of 100 μM. Finally, an in vivo study was conducted using a streptozotocin‐induced diabetic mouse model and PTP1B expression was assessed using real‐time PCR. Additionally, we examined the hypoglycemic effect of compound AH in diabetic rats compared to the standard drug glibenclamide.
Circular RNA expression profile identifies circMGEA5 as a novel metastasis‐promoting factor and potential biomarker in osteosarcoma
Authors: Liu Wei , Long Qiuping , Zhang Wei , Zeng Dehui , Hu Bingbing , Liu Shengyao , Li Chen 
Published: December 2022

AbstractOsteosarcoma (OS) is associated with a high incidence of lung metastasis, which leads to a high risk of cancer death. Circular RNA (circRNA), a novel class of noncoding RNA, is emerging as a key player in human cancer. Herein, we explored the role of circMGEA5 in OS metastasis by conducting circRNA expression microarray. CircMGEA5 was significantly upregulated in metastatic OS tissues compared to primary tissues. High circMGEA5 was positively related with shorter overall and disease‐free survival time. Knockdown of circMGEA5 suppressed OS cell migration, invasion, and epithelial–mesenchymal transition (EMT). Mechanistically, circMGEA5 acted as a competing endogenous RNA (ceRNA) to directly sponge miR‐153‐3p and miR‐8084, resulting in increasing ZEB1 and Snail expression, respectively, thereby inducing EMT and metastasis. In turn, ZEB1 and Snail were capable to bind to circMGEA5 promoter, activating circMGEA5 transcription, thus forming a positive feedback loop. Furthermore, we established the tail vein injection model and found that circMGEA5 depletion remarkably reduced lung metastasis nodules generated by OS cells. In sum, our findings, for the first time, reveal the metastasis‐promoting role of circMGEA5 in OS. Targeting of this newly identified ceRNA axis may be crucial in the development of novel therapies for metastatic OS patients.
Effects of the pathological E200K mutation on human prion protein: A computational screening and molecular dynamics approach
Authors: Gharemirshamloo Fatemeh Rahimi , Majumder Ranabir , Kumar S. Udhaya , Doss C. George Priya , Bamdad Kourosh , Frootan Fateme , Un Cemal 
Published: December 2022

AbstractThe human prion protein gene (PRNP) is mapped to the short arm of chromosome 20 (20pter‐12). Prion disease is associated with mutations in the prion protein‐encoding gene sequence. Earlier studies found that the mutation G127V in the PRNP increases protein stability. In contrast, the mutation E200K, which has the highest mutation rate in the prion protein, causes Creutzfeldt–Jakob disease (CJD) in humans and induces protein aggregation. We aimed to identify the structural mechanisms of E200k and G127V mutations causing CJD. We used a variety of bioinformatic algorithms, including SIFT, PolyPhen, I‐Mutant, PhD‐SNP, and SNP& GO, to predict the association of the E200K mutation with prion disease. MD simulation is performed, and graphs for root mean square deviation, root mean square fluctuation, radius of gyration, DSSP, principal component analysis, porcupine, and free energy landscape are generated to confirm and prove the stability of the wild‐type and mutant protein structures. The protein is analyzed for aggregation, and the results indicate more fluctuations in the protein structure during the simulation owing to the E200K mutation; however, the G127V mutation makes the protein structure stable against aggregation during the simulation.
Cross‐sectional and longitudinal associations between body flexibility and sarcopenia
Authors: Gao Peng , Gan Da , Li Shanshan , Kang Qingcong , Wang Xiaoyan , Zheng Weifang , Xu Xiaochen , Zhao Xueyin , He Wei , Wu Joyce , Lu Ying , Hsing Ann W. , Zhu Shankuan 
Published: December 2022

AbstractBackgroundThe associations between body flexibility and sarcopenia were not well understood. This study aimed to explore the cross‐sectional and longitudinal associations of flexibility with sarcopenia.MethodsOur study selected participants aged 50–80 from the WELL‐China cohort and the Lanxi cohort. Participants from the urban area of the Lanxi cohort were followed up 4 years later. Body flexibility was measured by the sit‐and‐reach test. Muscle mass was evaluated by dual‐energy X‐ray absorptiometry. Muscle strength was evaluated using handgrip strength. Sarcopenia was defined as having both low muscle mass and low muscle strength. We used multivariable logistic regressions to assess the cross‐sectional associations of body flexibility with low muscle mass, low muscle strength and sarcopenia. We also used multivariable logistic regressions to explore the associations of baseline flexibility and 4‐year changes in flexibility with incident low muscle mass, low muscle strength and sarcopenia.ResultsA total of 9453 participants were enrolled in the cross‐sectional study, and 1233 participants were included in the longitudinal analyses. In the cross‐sectional analyses, compared with low body flexibility, high body flexibility was inversely associated with low muscle mass (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.50–0.68; P < 0.001), low muscle strength (OR, 0.62; 95% CI, 0.55–0.69; P < 0.001) and sarcopenia (OR, 0.52; 95% CI, 0.41–0.65; P < 0.001), and these associations did not differ in different age groups, sex or physical activity levels. In the longitudinal analyses, compared with participants with low body flexibility, participants with high body flexibility had lower risk of the incident low muscle strength (OR, 0.53; 95% CI, 0.38–0.74; P < 0.001) and sarcopenia (OR, 0.36; 95% CI, 0.21–0.61; P < 0.001), but not incident low muscle mass (OR, 0.59; 95% CI, 0.33–1.06; P = 0.076). Every 1‐cm increase in flexibility during 4 years was associated with reduced risk of incident low muscle mass (OR, 0.96; 95% CI, 0.93–1.00; P = 0.025), low muscle strength (OR, 0.96; 95% CI, 0.94–0.98; P = 0.002) and sarcopenia (OR, 0.96; 95% CI, 0.93–0.99; P = 0.007).ConclusionsHigh flexibility was associated with reduced risk of incident low muscle strength and sarcopenia. Increases in flexibility were associated with reduced risk of incident low muscle mass, low muscle strength and sarcopenia. Flexibility exercises and monitoring the dynamic change of flexibility might be helpful in preventing sarcopenia among adults aged 50 years or over.
Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1–Arih2 axis
Authors: Jiang Xuan , Ji Siyu , Yuan Fenglai , Li Tushuai , Cui Siyuan , Wang Wei , Ye Xianlong , Wang Rong , Chen Yongquan , Zhu Shenglong 
Published: December 2022

AbstractBackgroundSarcopenia, the age‐related decline in skeletal muscle mass and function, diminishes life quality in elderly people. Improving the capacity of skeletal muscle differentiation is expected to counteract sarcopenia. However, the mechanisms underlying skeletal muscle differentiation are complex, and effective therapeutic targets are largely unknown.MethodsThe human Gene Expression Omnibus database, aged mice and primary skeletal muscle cells were used to assess the expression level of pyruvate dehydrogenase B (PDHB) in human and mouse aged state. d‐Galactose (d‐gal)‐induced sarcopenia mouse model and two classic cell models (C2C12 and HSkMC) were used to assess the myogenic effect of PDHB and the underlying mechanisms via immunocytochemistry, western blotting, quantitative real‐time polymerase chain reaction, RNA interference or overexpression, dual‐luciferase reporter assay, RNA sequencing and untargeted metabolomics.ResultsWe identified that a novel target PDHB promoted myogenic differentiation. PDHB expression decreased in aged mouse muscle relative to the young state (−50% of mRNA level, P < 0.01) and increased during mouse and primary human muscle cell differentiation (+3.97‐fold, P < 0.001 and +3.79‐fold, P < 0.001). Knockdown or overexpression of PDHB modulated the expression of genes related to muscle differentiation, namely, myogenic factor 5 (Myf5) (−46%, P < 0.01 and −27%, P < 0.05; +1.8‐fold, P < 0.01), myogenic differentiation (MyoD) (−55%, P < 0.001 and −34%, P < 0.01; +2.27‐fold, P < 0.001), myogenin (MyoG) (−60%, P < 0.001 and −70%, P < 0.001; +5.46‐fold, P < 0.001) and myosin heavy chain (MyHC) (−70%, P < 0.001 and −69%, P < 0.001; +3.44‐fold, P < 0.001) in both C2C12 cells and HSkMC. Metabolomic and transcriptomic analyses revealed that PDHB knockdown suppressed pyruvate metabolism (P < 0.001) and up‐regulated ariadne RBR E3 ubiquitin protein ligase 2 (Arih2) (+7.23‐fold, P < 0.001) in cellular catabolic pathways. The role of forkhead box P1 (FoxP1) (+4.18‐fold, P < 0.001)‐mediated Arih2 transcription was the key downstream regulator of PDHB in muscle differentiation. PDHB overexpression improved d‐gal‐induced muscle atrophy in mice, which was characterized by significant increases in grip strength, muscle mass and mean muscle cross‐sectional area (1.19‐fold to 1.5‐fold, P < 0.01, P < 0.05 and P < 0.001).ConclusionsThe comprehensive results show that PDHB plays a sarcoprotective role by suppressing the FoxP1–Arih2 axis and may serve as a therapeutic target in sarcopenia.
Association of weight change and in‐hospital mortality in patients with repeated hospitalization for heart failure
Authors: Konishi Masaaki , Kaneko Hidehiro , Itoh Hidetaka , Matsuoka Satoshi , Okada Akira , Kamiya Kentaro , Sugimoto Tadafumi , Fujiu Katsuhito , Michihata Nobuaki , Jo Taisuke , Takeda Norifumi , Morita Hiroyuki , Tamura Kouichi , Yasunaga Hideo , Komuro Issei 
Published: December 2022

AbstractBackgroundAlthough weight loss in heart failure (HF) is a detrimental condition known as cachexia, weight gain caused by fluid retention should also be considered harmful. However, studies with sufficient number of patients examining the impact of weight change and its interval on in‐hospital mortality in HF have not been conducted thus far. We sought to elucidate the association of weight change with in‐hospital mortality in patients with HF.MethodsThis retrospective observational study used data from the Diagnosis Procedure Combination database, a nationwide inpatient health claims database in Japan. In total, 48 234 patients repeatedly hospitalized for HF (median 82 [74–87] years; 46.4% men) between 2010 and 2018 were included. Weight change was derived from body weight at the first and second admissions.ResultsThe median weight change and interval between two hospitalizations were −3.1 [−8.3 to −1.8] % and 172 [67–420] days, with 66.9% of overall cohort experiencing any weight loss. As a result of multivariable‐adjusted logistic regression analysis, weight loss <−5.0% and weight gain >+5.0% were associated with increased in‐hospital mortality (adjusted odds ratio [OR] [95% confidence interval]: 1.46 [1.31–1.62], P < 0.001 and 1.23 [1.08–1.40], P = 0.002, respectively) whereas mild weight loss and gain of 2.0–5.0% were not (OR [95% confidence interval]: 0.96 [0.84–1.10], P = 0.57 and 1.07 [0.92–1.25], P = 0.37, respectively), in comparison with patients with a stable weight (fluctuating no more than −2.0% to +2.0%) used as a reference. Restrictive cubic spline models adjusted for multiple background factors illustrated that higher mortality in patients with weight loss was observed across all subgroups of the baseline body mass index (<18.5, 18.5–24.9 and ≥25.0 kg/m2). In patients with short (<90 days) and middle (<180 days) intervals between the two hospitalizations, both weight loss and weight gain were associated with high mortality, whereas the association between weight gain and high mortality was attenuated in those with longer intervals.ConclusionsBoth weight loss and weight gain in patients with repeated hospitalization for HF were associated with high in‐hospital mortality, especially weight loss and short/middle‐term weight gain. Such patients should be treated with caution in a setting of repeated hospitalization for HF.
Ars2‐containing bispecific, Fab‐ and IgG1‐format BAR‐bodies to target DLBCL cells
Authors: Kiefer Maximilian , Thurner Lorenz , Bock Theresa , Cetin Onur , Kos Igor , Lesan Vadim , Kaddu‐Mulindwa Dominic , Bittenbring Joerg Thomas , Fadle Natalie , Regitz Evi , Hoth Markus , Neumann Frank , Preuss Klaus‐Dieter , Pfreundschuh Michael , Christofyllakis Konstantinos , Bewarder Moritz 
Published: December 2022

AbstractDespite recent advances in the therapy of diffuse large B‐cell lymphoma, not otherwise specified (DLBCL), around 30% of patients develop refractory disease or relapse after first‐line treatment. Recently, Ars2 was reported as the auto‐antigenic target of the B‐cell receptor (BCR) in approximately 25% of activated B‐cell DLBCL cases. Ars2 could be used to specifically target B cells expressing Ars2‐reactive BCRs. However, the optimal therapeutic format to integrate Ars2 into has yet to be determined. To mimic therapeutic antibody formats, Ars2‐containing bispecific and IgG1‐like constructs (BCR antigens for reverse [BAR]‐bodies) were developed. Two bispecific BAR‐bodies connecting single‐chain antibodies against CD16 or CD3 to the BCR‐binding epitope of Ars2 were constructed. Both constructs showed strong binding to U2932 cells and induced effector cell‐dependent and selective cytotoxicity against U2932 cells of up to 44% at concentrations of 20 μg/ml. Additionally, IgG1‐format Ars2 BAR‐bodies were constructed by replacing the variable heavy‐ and light‐chain regions of a full‐length antibody with the Ars2 epitope. IgG1‐format Ars2 BAR‐bodies also bound selectively to U2932 and OCI‐Ly3 cells and induced selective cytotoxicity of up to 60% at 10 μg/ml. In conclusion, Ars2‐containing bispecific and IgG1‐format BAR‐bodies both are new therapeutic formats to target DLBCL cells.
Pathogenic variants of the coenzyme A biosynthesis‐associated enzyme phosphopantothenoylcysteine decarboxylase cause autosomal‐recessive dilated cardiomyopathy
Authors: Bravo‐Alonso Irene , Morin Matías , Arribas‐Carreira Laura , Álvarez Mar , Pedrón‐Giner Consuelo , Soletto Lucia , Santolaria Carlos , Ramón‐Maiques Santiago , Ugarte Magdalena , Rodríguez‐Pombo Pilar , Ariño Joaquín , Moreno‐Pelayo Miguel Ángel , Pérez Belén 
Published: December 2022

AbstractCoenzyme A (CoA) is an essential cofactor involved in a range of metabolic pathways including the activation of long‐chain fatty acids for catabolism. Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway strongly conserved across prokaryotes and eukaryotes. In humans, it involves five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK [isoforms 1–4]), 4′‐phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To date, inborn errors of metabolism associated with all of these genes, except PPCDC, have been described, two related to neurodegeneration with brain iron accumulation (NBIA), and one associated with a cardiac phenotype. This paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro and p.Ala95Val) of PPCDC. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 4′‐phosphopantothenoylcysteine to 4′‐phosphopantetheine in CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues highly conserved across different species; p.Thr53Pro is involved in the binding of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation. Patient‐derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant. In summary, this work describes a new, ultra‐rare, severe inborn error of metabolism due to pathogenic variants of PPCDC.
Understanding reasons for image rejection by radiologists and radiographers
Authors: Decoster Robin , Toomey Rachel , Smits Dirk , Haygood Tamara Miner , Ryan Marie‐Louise 
Published: December 2022

AbstractIntroductionA core element of a radiographer's role is the decision on whether a radiograph is sufficient for diagnosis, or a repeat examination is needed. Studies illustrate the disagreement on the diagnostic value of radiographs between radiographers and radiologists, which may influence repeat examinations. This study investigates if parameters contributing to image quality are possible determinants to explain the difference between professions.MethodsA total of 74 radiographers and radiologists from three different countries assessed three data sets (chest PA, hip HBL, c‐spine lateral), each containing 25 radiographs. All observers scored image quality in terms of anatomical visualisation, positioning, collimation, detector exposure and judged the diagnostic value using the ACR RadLex classification. All assessments were performed on a clinically relevant display. Visual grading characteristics were used to compare image quality evaluations between groups.ResultsRadiographers scored the visualisation of anatomical structures lower than radiologists though the difference was not statistically significant. A difference in classification using the RadLex categories – with radiographers rejecting more radiographs – was demonstrated. Only the subjective evaluation of the detector exposure correlated statistically with RadLex ratings. There was no difference between radiographers and radiologists when reviewing patient positioning and collimation.ConclusionRadiographers and radiologists agree on the visualisation of anatomical structures, but radiographers are more critical towards the diagnostic value. Within the criteria studied, the evaluation of anatomical structures does not explain the difference. Radiographs have a higher change of being rejected if the observer (subjectively) assessed the detector exposure as inappropriate. This correlation is stronger for radiographers.
Seasonally freeze–thaw changes on the Qinghai–Tibet plateau and their possible causes
Authors: Yan Feng , Wang Yanjiao , Lu Qi , Qiao Li 
Published: December 2022

AbstractKnown as the “roof of the world”, 50%–56% area of the Qinghai–Tibet Plateau (QTP) is covered by seasonal frozen ground (SFG), which has an important impact on local and global climate change, terrestrial ecosystems, and regional energy and hydrological cycles. In this study, long‐term observational data of air and soil water (precipitation and soil moisture) and heat [surface air temperature (SAT) and soil temperature (ST)] at 30 meteorological stations were used to study the temporal and spatial changes of SFG and their possible causes for the central‐eastern QTP (CEQTP). The results showed that latitude and altitude are the key factors affecting the spatial distributions of seasonal freeze–thaw activities of CEQTP. The stations with deeper freeze depths and more freeze days are mainly located in high‐altitude and high‐latitude regions, and those with shallower freeze depths and fewer freeze days are mainly located in the low‐altitude and low‐latitude regions of the southern QTP. This may be the reason that latitude and altitude are the key factors determining the temperature distribution on the CEQTP. SAT, ST, precipitation, and soil moisture are all significant correlations with the freeze depth, freeze days, freeze start date (FSD) and thaw end date (TED), and the abrupt change years of them are also consistent; they are the important factors affecting the freeze–thaw changes (FTCs) of SFG. Among them, ST is the key factor influencing the FTCs of SFG, and the variations of monthly average soil temperature (MAST) at 0–320 cm depths are the inverse of those of the monthly average freeze depth and freeze days during the year. Using the MAST data at 0–320 cm depths and the 0°C ST threshold, the soil freeze–thaw processes at different depths on the CEQTP are revealed. Affected by global warming, SAT and ST at different depths on the CEQTP have shown the upward trends since the 1980s. Additionally, precipitation and soil moisture have also increased substantially, especially since the late 1990s. Enhancement of warming and wetting conditions from the land surface to the deep soil have accelerated the thawing of SFG, and led to the delay of FSD and the advance of TED, which further caused the reduction of freeze depth and freeze days of SFG on the QTP, especially since the late 1990s.
Critical analysis ofCMIPspast climate model projections in a regional context: The Iberian climate
Authors: Soares Pedro M. M. , Lemos Gil , Lima Daniela C. A. 
Published: December 2022

AbstractThe Iberian Peninsula is a known climate change hotspot. In the last decades, the Coupled Model Intercomparison Project (CMIP) has allowed for thousands of Global Climate Model (GCM) simulations to be conducted, an important tool to assess and understand future changes in Earth's climate. The comparison of past future projections with observations provides a robust evaluation of the models’ skill according to different emission scenarios. Here, a comprehensive performance assessment of GCM‐simulated mean, maximum, and minimum temperatures, and accumulated precipitation is conducted for Iberia, by retrospectively comparing historical simulations and past future projections from CMIPs 1 to 6 with reference datasets. From means to extremes, and multi‐year intra‐annual cycles to inter‐annual trends, GCM simulations are compared with Iberia0.1 and E‐OBS observational gridded datasets, and ERA5 reanalysis. The matching between the variables’ distributions is assessed through the distribution added values (DAVs), a measure of gain or loss in performance between CMIPs. Results show relevant improvements in the description of the Iberian climate throughout the CMIP effort, for historical and past future periods. While the representation of intra‐annual cycles (inter‐annual trends) is enhanced after CMIP3 (CMIP2), GCMs from all CMIPs are generally able to depict the observed warming trend. Nevertheless, until 2021, a slight detrimental effect in the performance of CMIP6 models is found, in comparison with CMIP5 ones, with positive DAVs obtained only for past future temperature projections (less than 2%). A continuous monitorization of modelling accuracy for Iberia is needed, considering the increasing relevance of climate change information for adaptation strategies.