bluuebunny/crossref_metadata_2025_split huggingface dataset:
Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model
Authors: Zhao Xue-Jun , Mohsen Al-Walid , Mihalik Stephanie , Solo Keaton , Basu Shakuntala , Aliu Ermal , Shi Huifang , Kochersberger Catherine , Karunanidhi Anuradha , Van’t Land Clinton , Coughlan Kimberly A , Siddiqui Summar , Rice Lisa M , Hillier Shawn , Guadagnin Eleonora , DeAntonis Christine , Giangrande Paloma H , Martini Paolo G V , Vockley Jerry 
Published: May 2023

Abstract
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD- deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm−/− mice. Administration of multiple intravenous doses of the hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm−/− mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart and skeletal muscle homogenates. Treated Acadm−/− mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in the liver from treated Acadm−/− mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency.
Gallbladder cancer-associated genetic variants rs1003349 and rs1004030 regulate MMP14 expression by altering SOX10- and MYB-binding sites
Authors: J Vinay , Palo Ananya , Besra Kusumbati , Dixit Manjusha 
Published: May 2023

AbstractThe pathogenesis of gallbladder cancer is complex, involving environmental and genetic risk factors. The matrix metallopeptidase 14 (MMP14) alters the tumor microenvironment and promotes tumorigenesis. In this study, we have characterized the role of the MMP14 promoter variants rs1004030 and rs1003049 in gallbladder cancer pathogenesis. Previously, we have shown the association of rs1004030 and rs1003049 with GBC and allele-specific differential expression of MMP14 in GBC patients. These variants reside within the cis-regulatory element (CRE) with high DNase and H3K4me3 signals, suggesting an active regulatory role in MMP14 expression. The luciferase-based reporter assay showed the role of promoter variants on expression levels in two GBC cell lines. Deleting the 119 bp promoter region surrounding the variants rs1004030 and rs1003049 by CRISPR-Cas9 genome editing resulted in reduced MMP14 expression in G415 cells. Electrophoretic mobility shift assay shows the presence of risk allele ‘C’/‘G’ at rs1004030 and rs1003049 and create binding sites for transcription factors SOX10 and MYB, respectively. Further, stable knockdown of these transcription factors in G415 and TGBC1TKB cells showed reduced expression of MMP14. However, in both GBC cells, ectopic expression of these transcription factors increased the expression of MMP14. Rescue of MYB and SOX10 expression levels showed a significant increase in luciferase activity only in risk allele-carrying constructs. In conclusion, our study unveils a mechanistic role of the MMP14 promoter variants rs1004030 and rs1003049 in gallbladder cancer.
An in vivo functional assay to characterize human STAT5B genetic variants during zebrafish development
Authors: Landi Estefanía , Karabatas Liliana , Rodríguez Gomez Tomás , Salatino Lucía , Scaglia Paula , Ramírez Laura , Keselman Ana , Braslavsky Débora , Sanguineti Nora , Pennisi Patricia , Rey Rodolfo A , Bergadá Ignacio , Jasper Héctor G , Domené Horacio M , Plazas Paola V , Domené Sabina 
Published: May 2023

Abstract
Growth hormone (GH) binding to GH receptor activates janus kinase 2 (JAK2)-signal transducer and activator of transcription 5b (STAT5b) pathway, which stimulates transcription of insulin-like growth factor-1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3) and insulin-like growth factor acid-labile subunit (IGFALS). Although STAT5B deficiency was established as an autosomal recessive disorder, heterozygous dominant-negative STAT5B variants have been reported in patients with less severe growth deficit and milder immune dysfunction. We developed an in vivo functional assay in zebrafish to characterize the pathogenicity of three human STAT5B variants (p.Ala630Pro, p.Gln474Arg and p.Lys632Asn). Overexpression of human wild-type (WT) STAT5B mRNA and its variants led to a significant reduction of body length together with developmental malformations in zebrafish embryos. Overexpression of p.Ala630Pro, p.Gln474Arg or p.Lys632Asn led to an increased number of embryos with pericardial edema, cyclopia and bent spine compared with WT STAT5B. Although co-injection of WT and p.Gln474Arg and WT and p.Lys632Asn STAT5B mRNA in zebrafish embryos partially or fully rescues the length and the developmental malformations in zebrafish embryos, co-injection of WT and p.Ala630Pro STAT5B mRNA leads to a greater number of embryos with developmental malformations and a reduction in body length of these embryos. These results suggest that these variants could interfere with endogenous stat5.1 signaling through different mechanisms. In situ hybridization of zebrafish embryos overexpressing p.Gln474Arg and p.Lys632Asn STAT5B mRNA shows a reduction in igf1 expression. In conclusion, our study reveals the pathogenicity of the STAT5B variants studied.
Epigenotype–genotype–phenotype correlations in SETD1A and SETD2 chromatin disorders
Authors: Lee Sunwoo , Menzies Lara , Hay Eleanor , Ochoa Eguzkine , Docquier France , Rodger Fay , Deshpande Charu , Foulds Nicola C , Jacquemont Sébastien , Jizi Khadije , Kiep Henriette , Kraus Alison , Löhner Katharina , Morrison Patrick J , Popp Bernt , Richardson Ruth , van Haeringen Arie , Martin Ezequiel , Toribio Ana , Li Fudong , Jones Wendy D , Sansbury Francis H , Maher Eamonn R 
Published: May 2023

Abstract
Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of &gt; 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype–genotype–phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.
Genome of tetraploid sour cherry (Prunus cerasus L.) ‘Montmorency’ identifies three distinct ancestral Prunus genomes
Authors: Goeckeritz Charity Z , Rhoades Kathleen E , Childs Kevin L , Iezzoni Amy F , VanBuren Robert , Hollender Courtney A 
Published: May 2023

AbstractSour cherry (Prunus cerasus L.) is a valuable fruit crop in the Rosaceae family and a hybrid between progenitors closely related to extant Prunus fruticosa (ground cherry) and Prunus avium (sweet cherry). Here we report a chromosome-scale genome assembly for sour cherry cultivar Montmorency, the predominant cultivar grown in the USA. We also generated a draft assembly of P. fruticosa to use alongside a published P. avium sequence for syntelog-based subgenome assignments for ‘Montmorency’ and provide compelling evidence P. fruticosa is also an allotetraploid. Using hierarchal k-mer clustering and phylogenomics, we show ‘Montmorency’ is trigenomic, containing two distinct subgenomes inherited from a P. fruticosa-like ancestor (A and A') and two copies of the same subgenome inherited from a P. avium-like ancestor (BB). The genome composition of ‘Montmorency’ is AA'BB and little-to-no recombination has occurred between progenitor subgenomes (A/A' and B). In Prunus, two known classes of genes are important to breeding strategies: the self-incompatibility loci (S-alleles), which determine compatible crosses, successful fertilization, and fruit set, and the Dormancy Associated MADS-box genes (DAMs), which strongly affect dormancy transitions and flowering time. The S-alleles and DAMs in ‘Montmorency’ and P. fruticosa were manually annotated and support subgenome assignments. Lastly, the hybridization event ‘Montmorency’ is descended from was estimated to have occurred less than 1.61 million years ago, making sour cherry a relatively recent allotetraploid. The ‘Montmorency’ genome highlights the evolutionary complexity of the genus Prunus and will inform future breeding strategies for sour cherry, comparative genomics in the Rosaceae, and questions regarding neopolyploidy.
Metabarcoding Used for the First Time to Identify Prey of Wild Totoaba macdonaldi
Authors: Mroue-Ruiz F H , Pacheco-Sandoval A , Lago-Lestón A , Giffard-Mena I , Abadía-Cardoso A , Chong-Robles J , Schramm Y 
Published: May 2023

Synopsis
Totoaba macdonaldi is an endangered endemic fish of the Gulf of California. Overexploitation resulted in the Mexican government banning the fishing of this species in 1975, and it being listed as endangered. However, the species is still subject to illegal fishing. Despite its conservation status, little is known about totoaba biology. The present study aimed to implement, for the first time, a metabarcoding protocol to describe the totoaba diet. Four wild totoaba individuals, seized by Mexican law enforcement agents, were dissected, and their stomach contents were collected. Three representative amplicon libraries were generated for cephalopods, chordates, and eukaryotes. After sequencing, 18 different taxa were identified, of which 11 species were recognized as prey. The totoaba were found to have consumed Pacific anchovy (Cetengraulis mysticetus), flathead grey mullet (Mugil cephalus), bigeye croaker (Micropogonias megalops), northern anchovy (Engraulis mordax), ocean whitefish (Caulolatilus princeps), milkfish (Chanos chanos), and Pacific sardine (Sardinops sagax). Members of the Euphausiidae family (krill) were also identified. This study identified up to four times more species in much fewer samples than previous studies based on morphological recognition, thus confirming metabarcoding as an effective method for studying the feeding habits of this species and one providing the tools required for further analysis of the totoaba diet.
The impact of mitral valve surgery on ventricular arrhythmias in patients with Barlow’s disease: preliminary results of a prospective study
Authors: Ascione Guido , Azzola Guicciardi Nicolò , Lorusso Roberto , Boccellino Antonio , Lapenna Elisabetta , Del Forno Benedetto , Carino Davide , Bisogno Arturo , Palmisano Anna , D’Angelo Giuseppe , Della Bella Paolo , Esposito Antonio , Agricola Eustachio , Alfieri Ottavio , Castiglioni Alessandro , Maisano Francesco , Vergara Pasquale , De Bonis Michele 
Published: May 2023

Abstract

OBJECTIVES
Aim of this study was to evaluate arrhythmic burden of patients with Barlow’s disease and significant mitral regurgitation (MR) and assess the impact of mitral repair on ventricular arrhythmias (VA) in this group of subjects.

METHODS
We prospectively included 88 consecutive patients with Barlow’s disease referred to our Institution from February 2021 to May 2022. All enrolled patients underwent 24-h Holter monitoring before surgery. Sixty-three of them completed 3 months echocardiographic and Holter follow-up. Significant arrhythmic burden was defined as ≥1% premature ventricular beats/24 h or at least one episode of non-sustained ventricular tachycardia (VT), VT or ventricular fibrillation.

RESULTS
At baseline, 29 patients (33%) were arrhythmogenic (AR), while 59 (67%) were not [non-arrhythmogenic (NAR)]. AR subjects tended to be more often females with history of palpitations. Sixty-three patients completed 3-months follow-up. Twenty of them (31.7%) were AR at baseline and 43 (68.3%) were not. Among AR patients, 9 (45%) remained AR after mitral surgery, while 11 (55%) became NAR. Considering NAR subjects at baseline, after mitral valve repair 8 (18.6%) evolved into AR, while 35 (81.4%) remained NAR. A higher prevalence of pre-operative MAD was found among patients experiencing VA reduction if compared with patients who remained arrhythmogenic (63.6% vs 11.1%, P = 0.028).

CONCLUSIONS
In our experience, one-third of Barlow’s patients referred for mitral surgery showed a significant arrhythmic burden. Almost half of the subjects arrhythmogenic at baseline were free from significant VA after mitral repair. However, a minority (18.6%) of subjects without arrhythmic burden at baseline experienced significant VA at follow-up.
Mortality and cancer incidence in UK military veterans involved in human experiments at Porton Down: 48-year follow-up
Authors: Archer Gemma , Keegan Thomas J , Carpenter Lucy M , Venables Katherine M , Fear Nicola T 
Published: May 2023

Abstract

Background
We investigated whether military personnel involved in chemical warfare agent research at Porton Down had increased rates of mortality or cancer incidence.

Methods
This was a historical cohort study comprising male UK veterans who participated in the ‘Service Volunteer Programme’, 1941–89, identified from Porton Down experiment books, and a comparison group of similar ‘non-Porton Down’ veterans identified from military personnel files. Of 19 233 records retrieved for each group, 18 133 (94%) Porton Down and 17 591 (92%) non-Porton Down were included in our analytical sample. Mortality and cancer incidence data were obtained from national registries up to December 2019.

Results
Over a median follow-up of 48.1 years, 10 935 Porton Down veterans (60.3%) and 10 658 non-Porton Down veterans (60.6%) had died. After adjustment for age, year of birth and military service characteristics, overall, Porton Down veterans had a 6% higher rate of all-cause mortality compared with non-Porton Down veterans [hazard ratio (HR) = 1.06, 95% confidence interval (CI) 1.03–1.09]. For cause-specific mortality, Porton Down veterans had higher rates of death from genitourinary diseases (HR = 1.34, 95% CI 1.05–1.70) and deaths attributable to alcohol (HR = 1.44, 95% CI 1.07–1.94), with weaker associations observed for deaths from infectious and parasitic diseases (HR = 1.32, 95% CI 0.99–1.78), lung cancer (HR = 1.10, 95% CI 1.01–1.20) and external causes (HR = 1.15, 95% CI 1.00–1.32). Associations with all-cause mortality were stronger for veterans who attended Porton Down between 1960 and 1964 (HR = 1.34, 95% CI 1.19–1.50); likelihood-ratio test, P = 0.006. There was no association between attendance at Porton Down and overall cancer incidence (HR = 1.00, 95% CI 0.95–1.03).

Conclusions
Overall, mortality rates were slightly higher in Porton Down veterans, but there was no difference in cancer incidence. Associations for mortality were stronger in Porton Down veterans who attended in the early 1960s.
Mapping tuberculosis prevalence in Ethiopia using geospatial meta-analysis
Authors: Alene Kefyalew Addis , Python Andre , Weiss Daniel J , Elagali Ahmed , Wagaw Zeleke Alebachew , Kumsa Andargachew , Gething Peter W , Clements Archie C A 
Published: May 2023

Abstract

Background
Reliable and detailed data on the prevalence of tuberculosis (TB) with sub-national estimates are scarce in Ethiopia. We address this knowledge gap by spatially predicting the national, sub-national and local prevalence of TB, and identifying drivers of TB prevalence across the country.

Methods
TB prevalence data were obtained from the Ethiopia national TB prevalence survey and from a comprehensive review of published reports. Geospatial covariates were obtained from publicly available sources. A random effects meta-analysis was used to estimate a pooled prevalence of TB at the national level, and model-based geostatistics were used to estimate the spatial variation of TB prevalence at sub-national and local levels. Within the MBG Plugin Framework, a logistic regression model was fitted to TB prevalence data using both fixed covariate effects and spatial random effects to identify drivers of TB and to predict the prevalence of TB.

Results
The overall pooled prevalence of TB in Ethiopia was 0.19% [95% confidence intervals (CI): 0.12%–0.28%]. There was a high degree of heterogeneity in the prevalence of TB (I2 96.4%, P &lt;0.001), which varied by geographical locations, data collection periods and diagnostic methods. The highest prevalence of TB was observed in Dire Dawa (0.96%), Gambela (0.88%), Somali (0.42%), Addis Ababa (0.28%) and Afar (0.24%) regions. Nationally, there was a decline in TB prevalence from 0.18% in 2001 to 0.04% in 2009. However, prevalence increased back to 0.29% in 2014. Substantial spatial variation of TB prevalence was observed at a regional level, with a higher prevalence observed in the border regions, and at a local level within regions. The spatial distribution of TB prevalence was positively associated with population density.

Conclusion
The results of this study showed that TB prevalence varied substantially at sub-national and local levels in Ethiopia. Spatial patterns were associated with population density. These results suggest that targeted interventions in high-risk areas may reduce the burden of TB in Ethiopia and additional data collection would be required to make further inferences on TB prevalence in areas that lack data.
Fine and coarse particulate air pollution and hospital admissions for a wide range of respiratory diseases: a nationwide case-crossover study
Authors: Lei Jian , Chen Renjie , Liu Cong , Zhu Yixiang , Xue Xiaowei , Jiang Yixuan , Shi Su , Gao Ya , Kan Haidong , Xuan Jianwei 
Published: May 2023

Abstract

Background
The associations between fine and coarse particulate matter (PM2.5 and PM2.5–10) air pollution and hospital admissions for full-spectrum respiratory diseases were rarely investigated, especially for age-specific associations. We aim to estimate the age-specific associations of short-term exposures to PM2.5 and PM2.5–10 with hospital admissions for full-spectrum respiratory diseases in China.

Methods
We conducted an individual-level case-crossover study based on a nationwide hospital-based registry including 153 hospitals across 20 provincial regions in China in 2013–20. We applied conditional logistic regression models and distributed lag models to estimate the exposure- and lag-response associations.

Results
A total of 1 399 955 hospital admission records for various respiratory diseases were identified. The associations of PM2.5 and PM2.5–10 with total respiratory hospitalizations lasted for 4 days, and an interquartile range increase in PM2.5 (34.5 μg/m3) and PM2.5–10 (26.0 μg/m3) was associated with 1.73% [95% confidence interval (95% CI): 1.34%, 2.12%)] and 1.70% (95% CI: 1.31%, 2.10%) increases, respectively, in total respiratory hospitalizations over lag 0–4 days. Acute respiratory infections (i.e. pneumonia, bronchitis and bronchiolitis) were consistently associated with PM2.5 or PM2.5–10 exposure across different age groups. We found the disease spectrum varied by age, including rarely reported findings (i.e. acute laryngitis and tracheitis, and influenza) among children and well-established associations (i.e. chronic obstructive pulmonary disease, asthma, acute bronchitis and emphysema) among older populations. Besides, the associations were stronger in females, children and older populations.

Conclusions
This nationwide case-crossover study provides robust evidence that short-term exposure to both PM2.5 and PM2.5–10 was associated with increased hospital admissions for a wide range of respiratory diseases, and the spectra of respiratory diseases varied by age. Females, children and older populations were more susceptible.
Development of resource treatment technology for fracturing backflow fluids of tight sandstone
Authors: Gao Feng , Yang Chunpeng , Zhao Rui , Sang Junqiang , Meng Fanbin , Ren Liming , Ji Yaxiong , Yang Yuning 
Published: May 2023

Abstract
Fracturing is an important means to realize the development value of tight sandstone unconventional reservoirs, which consumes serious water resources and generates high viscosity of backflow fluid with petroleum and suspended matter pollutants. Therefore, it is of great significance to recycle fracturing fluid from tight sandstone with low-carbon and environmental protection. In this study, the fracturing fluid of tight sandstone in a block of a certain oilfield was collected as the research object, and a comprehensive water quality analysis was carried out. The combined process technology for resource treatment of fracturing flowback fluid in tight sandstone were formed by studying on the influence factors of oxidation gel breaking, flocculation sedimentation, ion removal, filtration and process optimization. After treatment, the mass concentration of iron ion in fracturing flowback fluid was less than 5 mg/L, the mass concentration of suspended matter was less than 10 mg/L, and the mass concentration of oil was less than 5 mg/L, which could meet the water quality requirements of fluid distribution and reuse, and avoid the environmental pollution risk of flowback fluid effectively, while the consumption level of water resources in fracturing construction also was greatly reduced. This paper will have positive significance for the resource treatment technology and development of tight sandstone fracturing fluid.