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PloS One 2024Preeclampsia (PE) is characterized by hypertension and proteinuria mostly after 20 weeks of gestation. It affects 2-8% of pregnancies worldwide, with detrimental...
BACKGROUND AND AIM
Preeclampsia (PE) is characterized by hypertension and proteinuria mostly after 20 weeks of gestation. It affects 2-8% of pregnancies worldwide, with detrimental consequences for both mother and foetus. Evidence, suggests that genetic factors, including vitamin D receptor (VDR) gene polymorphisms, could contribute to PE complexity. However, their role in the Ghanaian population remains underexplored. We assessed the interplay between Vitamin D, VDR gene variants and preeclampsia risk in Ghanaian women.
METHODS
This unmatched case-control study was conducted at Kumasi South Hospital, Ghana, from June to November 2022. A total of 162 participants consisting of 62 PE cases and 100 normotensive controls were enrolled. Clinical and obstetric data were collected. Blood samples were also collected for DNA extraction and vitamin D assay. Genotyping of VDR Fok1 and Bsm1 gene variants was performed using Polymerase Chain Reaction (PCR) and Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis whereas Vitamin D levels were estimated using sandwich ELISA. Statistical analyses were computed with SPSS version 25 and GraphPad prism version 8.0. A p-value of < 0.05 was considered statistically significant.
RESULTS
Vitamin D concentration were significantly lower in the PE group (p < 0.0001). Vitamin D deficiency (aOR = 3.311, 95% CI: 1.584-6.921, p = 0.0010) was significantly associated with a three-fold increase in preeclampsia risk, whilst VDR gene variants, particularly the "bb" genotype (cOR = 0.227, 95% CI: 0.055-0.944, p = 0.0410) was associated with reduced risk of PE. There was no association between the distribution of Fok1 genotypes and PE.
CONCLUSION
This study highlights a significant association between vitamin D deficiency and an increased risk of PE among Ghanaian women. However, the VDR gene variant, "bb", genotype, for Bsm1 reduces the risk of PE.
Topics: Humans; Female; Receptors, Calcitriol; Pre-Eclampsia; Pregnancy; Ghana; Adult; Case-Control Studies; Vitamin D; Genetic Predisposition to Disease; Genotype; Vitamin D Deficiency; Polymorphism, Single Nucleotide; Young Adult; Risk Factors
PubMed: 38814968
DOI: 10.1371/journal.pone.0303778 -
ELife May 2024Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important...
Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from -null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen-enriched cell population, and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency, and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.
Topics: Animals; Female; Pregnancy; Genomic Imprinting; Mice; Polycomb Repressive Complex 2; Fetal Development; Placenta; Oocytes; Amino Acid Transport System A
PubMed: 38813868
DOI: 10.7554/eLife.81875 -
Disease Models & Mechanisms May 2024Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor...
Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.
Topics: Microglia; Amyotrophic Lateral Sclerosis; MicroRNAs; Animals; Female; Mice, Transgenic; Male; Mutation; Sex Characteristics; DNA-Binding Proteins; Mice; Extracellular Space; Humans; Lipopolysaccharides; Gene Expression Regulation
PubMed: 38813848
DOI: 10.1242/dmm.050638 -
Frontiers in Public Health 2024Residents of long-term care facilities (LTCFs) are at high risk of morbidity and mortality due to COVID-19, especially when new variants of concern (VOC) emerge. To...
INTRODUCTION
Residents of long-term care facilities (LTCFs) are at high risk of morbidity and mortality due to COVID-19, especially when new variants of concern (VOC) emerge. To provide intradisciplinary data in order to tailor public health interventions during future epidemics, available epidemiologic and genomic data from Slovenian LTCFs during the initial phases of the COVID-19 pandemic was analyzed.
METHODS
The first part of the study included SARS-CoV-2 reverse-transcription Real-Time PCR (rtRT-PCR) positive LTCF residents, from 21 facilities with COVID-19 outbreaks occurring in October 2020. The second part of the study included SARS-CoV-2 rtRT-PCR positive LTCF residents and staff between January and April 2021, when VOC Alpha emerged in Slovenia. Next-generation sequencing (NGS) was used to acquire SARS-CoV-2 genomes, and lineage determination. In-depth phylogenetic and mutational profile analysis were performed and coupled with available field epidemiological data to assess the dynamics of SARS-CoV-2 introduction and transmission.
RESULTS
370/498 SARS-CoV-2 positive residents as well as 558/699 SARS-CoV-2 positive residents and 301/358 staff were successfully sequenced in the first and second part of the study, respectively. In October 2020, COVID-19 outbreaks in the 21 LTCFs were caused by intra-facility transmission as well as multiple independent SARS-CoV-2 introductions. The Alpha variant was confirmed in the first LTCF resident approximately 1.5 months after the first Alpha case was identified in Slovenia. The data also showed a slower replacement of existing variants by Alpha in residents compared to staff and the general population.
DISCUSSION
Multiple SARS CoV-2 introductions as well as intra-facility spreading impacted disease transmission in Slovenian LTCFs. Timely implementation of control measures aimed at limiting new introductions while controlling in-facility transmission are of paramount importance, especially as new VOCs emerge. Sequencing, in conjunction with epidemiological data, can facilitate the determination of the need for future improvements in control measures to protect LTCF residents from COVID-19 or other respiratory infections.
Topics: Humans; COVID-19; Slovenia; SARS-CoV-2; Long-Term Care; Aged; Female; Male; Disease Outbreaks; Aged, 80 and over; High-Throughput Nucleotide Sequencing; Phylogeny; Middle Aged
PubMed: 38813418
DOI: 10.3389/fpubh.2024.1406777 -
Heliyon May 2024This study explored the frequency of lipid-lowering drug use in the thalassemia population and investigated the association of thalassemia, hemoglobinopathies, and serum...
This study explored the frequency of lipid-lowering drug use in the thalassemia population and investigated the association of thalassemia, hemoglobinopathies, and serum 25(OH)D levels with lipid profile and red blood cell parameters. A combination of cross-sectional and community-based studies was conducted with 615 participants from the southern Thai population. Thalassemia and hemoglobinopathies were diagnosed using hemoglobin analysis and polymerase chain reaction-based methods to genotype globin genes. Biochemical parameters such as lipid profile, fasting blood sugar (FBS), and serum 25(OH)D levels were assessed using standard enzymatic methods and electrochemiluminescence immunoassays. Differences in the means of hematological and biochemical parameters between the thalassemia and non-thalassemia groups were compared and analyzed. A significantly lower frequency of lipid-lowering drug use was observed in the thalassemia group. Thalassemia, with clearly defined abnormalities in red blood cells, is associated with a 4.72-fold decreased risk of taking lipid-lowering drugs. Among thalassemia participants, the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly lower than those in non-thalassemia participants. The prevalence of hypovitaminosis D in carriers of thalassemia and/or hemoglobinopathies in the southern Thai population was 53 % in females and 21 % in males. The highest lipid profile was observed in samples without thalassemia and hypovitaminosis D. The genetics of thalassemia and hemoglobinopathies with obviously abnormal red blood cells could explain the variable lipid levels, in addition to lipid metabolism-related genes and environmental factors. However, the effect of thalassemia on lipid levels in each population may differ according to its prevalence. A larger sample size is required to confirm this association, especially in countries with a high prevalence of thalassemia.
PubMed: 38813217
DOI: 10.1016/j.heliyon.2024.e31374 -
Frontiers in Molecular Biosciences 2024Breast cancer represents the most prevalent malignancy among women. Recent advancements in translational research have focused on the identification of novel biomarkers...
Breast cancer represents the most prevalent malignancy among women. Recent advancements in translational research have focused on the identification of novel biomarkers capable of providing valuable insights into patient outcomes. Furthermore, comprehensive investigations aimed at discovering novel miRNAs, unraveling their biological functions, and deciphering their target genes have significantly contributed to our understanding of the roles miRNAs play in tumorigenesis. Consequently, these investigations have facilitated the way for the development of miRNA-based approaches for breast cancer prognosis, diagnosis, and treatment. However, conducting a more extensive array of studies, particularly among diverse ethnic groups, is imperative to expand the scope of research and validate the significance of miRNAs. This study aimed to assess the expression patterns of circulating miRNAs in plasma as a prospective biomarker for breast cancer patients within a population primarily consisting of individuals from Black, Indigenous, and People of Color (BIPOC) communities. We evaluated 49 patients with breast cancer compared to 44 healthy women. All miRNAs analyzed in the plasma of patients with breast cancer were downregulated. ROC curve analysis of miR-21 (AUC = 0.798, 95% CI: 0.682-0.914, <0.0001), miR-1 (AUC = 0.742, 95% CI: 0.576-0.909, = 0.004), miR-16 (AUC = 0.721, 95% CI: 0.581-0.861, = 0.002) and miR-195 (AUC = 0.672, 95% CI: 0.553-0.792, = 0.004) showed better diagnostic accuracy in discrimination of breast cancer patients in comparison with healthy women. miR-210, miR-21 showed the highest specificities values (97.3%, 94.1%, respectively). Following, miR-10b and miR-195 showed the highest sensitivity values (89.3%, and 77.8%, respectively). The panel with a combination of four miRNAs (miR-195 + miR-210 + miR-21 + miR-16) had an AUC of 0.898 (0.765-0.970), a sensitivity of 71.4%, and a specificity of 100.0%. Collectively, our results highlight the miRNA combination in panels drastically improves the results and showed high accuracy for the diagnosis of breast cancer displaying good sensitivity and specificity.
PubMed: 38813102
DOI: 10.3389/fmolb.2024.1337706 -
Turkish Journal of Medical Sciences 2023The clinical presentation of pediatric coronavirus disease 2019 (COVID-19) is associated with a milder disease course than the adult COVID-19 syndrome. The disease...
BACKGROUND/AIM
The clinical presentation of pediatric coronavirus disease 2019 (COVID-19) is associated with a milder disease course than the adult COVID-19 syndrome. The disease course of COVID-19 has three clinicobiological phases: initiation, propagation, and complication. This study aimed to assess the pathobiological alterations affecting the distinct clinical courses of COVID-19 in pediatric age groups versus the adult population. We hypothesized that critical biogenomic marker expressions drive the mild clinical presentations of pediatric COVID-19.
MATERIALS AND METHODS
Blood samples were obtained from 72 patients with COVID-19 hospitalized at Ankara City Hospital between March and July 2021. Peripheral blood mononuclear cells were isolated using Ficoll-Paque and density-gradient sedimentation. The groups were compared using a t-test and limma analyses. Mean standardized gene expression levels were used to hierarchically cluster genes employing Euclidean Gene Cluster 3.0. The expression levels of identified genes were determined using reverse transcription-polymerase chain reaction.
RESULTS
This study found that gene expression was significantly downregulated in the pediatric group (p < 0.05, FC: 1.57) and gene expression was significantly upregulated in the adult group (p < 0.05, FC: 2.98). The study results indicated that the expression of critical biogenomic markers, such as the first-phase ( and ) and second-phase ( and ) receptor genes, was crucial in the genesis of mild clinical presentations of pediatric COVID-19. gene expression was lower in pediatric COVID-19.
CONCLUSION
The interrelationship between the and genes may prevent the progression of COVID-19 from initiation to the propagating phase in pediatric patients. High gene expression could potentially contribute to a protective effect and may be a contributing factor for the mild clinical course observed in pediatric patients.
Topics: Humans; COVID-19; Child; Male; Female; Adult; SARS-CoV-2; Child, Preschool; Adolescent; Middle Aged; Age Factors
PubMed: 38813031
DOI: 10.55730/1300-0144.5685 -
Frontiers in Genetics 2024Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors...
Genetic association and transferability for urinary albumin-creatinine ratio as a marker of kidney disease in four Sub-Saharan African populations and non-continental individuals of African ancestry.
BACKGROUND
Genome-wide association studies (GWAS) have predominantly focused on populations of European and Asian ancestry, limiting our understanding of genetic factors influencing kidney disease in Sub-Saharan African (SSA) populations. This study presents the largest GWAS for urinary albumin-to-creatinine ratio (UACR) in SSA individuals, including 8,970 participants living in different African regions and an additional 9,705 non-resident individuals of African ancestry from the UK Biobank and African American cohorts.
METHODS
Urine biomarkers and genotype data were obtained from two SSA cohorts (AWI-Gen and ARK), and two non-resident African-ancestry studies (UK Biobank and CKD-Gen Consortium). Association testing and meta-analyses were conducted, with subsequent fine-mapping, conditional analyses, and replication studies. Polygenic scores (PGS) were assessed for transferability across populations.
RESULTS
Two genome-wide significant (P < 5 × 10) UACR-associated loci were identified, one in the on chromosome 6 in the meta-analysis of resident African individuals, and another in the region on chromosome 11 in the meta-analysis of non-resident SSA individuals, as well as the combined meta-analysis of all studies. Replication of previous significant results confirmed associations in known UACR-associated regions, including , and . PGS estimated using previous studies from European ancestry, African ancestry, and multi-ancestry cohorts exhibited limited transferability of PGS across populations, with less than 1% of observed variance explained.
CONCLUSION
This study contributes novel insights into the genetic architecture of kidney disease in SSA populations, emphasizing the need for conducting genetic research in diverse cohorts. The identified loci provide a foundation for future investigations into the genetic susceptibility to chronic kidney disease in underrepresented African populations Additionally, there is a need to develop integrated scores using multi-omics data and risk factors specific to the African context to improve the accuracy of predicting disease outcomes.
PubMed: 38812969
DOI: 10.3389/fgene.2024.1372042 -
Turkish Journal of Medical Sciences 2024Calpainopathy, also known as limb-girdle muscular dystrophy recessive type 1, is a progressive muscle disorder that impacts the muscles around the hips and shoulders....
BACKGROUND AND AIM
Calpainopathy, also known as limb-girdle muscular dystrophy recessive type 1, is a progressive muscle disorder that impacts the muscles around the hips and shoulders. The disease is caused by defects in the gene and can be inherited in both recessive and dominant forms. In this retrospective study, we aimed to evaluate the clinical and molecular results of our patients with calpainopathy and to examine the variants in Turkish and global populations.
MATERIALS AND METHODS
Molecular analyses were performed using the next-generation sequencing (NGS) method. variants were identified through the examination of various databases.
RESULTS
In this retrospective study, the cohort consisted of seven patients exhibiting the (NM_000070.3) mutation and a phenotype compatible with calpainopathy at a single center in Türkiye. All patients displayed high CK levels and muscle weakness. We report a novel missense c.2437G>A variant that causes the autosomal dominant form of calpainopathy. Interestingly, the muscle biopsy report for the patient with the novel mutation indicated sarcoglycan deficiency. Molecular findings for the remaining individuals in the cohort included a compound heterozygous variant (frameshift and missense), one homozygous nonsense, one homozygous intronic deletion, and three homozygous missense variants. The most common variant in the Turkish population was c.550del. In both populations, pathogenic variants were most frequently located in exon 21, according to exon length. Variants were stochastically distributed based on consequences in CAPN3 domains.
CONCLUSION
Therefore, the NGS method proves highly effective in diagnosing rare diseases characterized by clinical heterogeneity. Assessing variants based on ethnicity holds significance in the development of precise therapies.
Topics: Humans; Retrospective Studies; Muscular Dystrophies, Limb-Girdle; Turkey; Male; Calpain; Female; Muscle Proteins; Adult; Young Adult; Adolescent; Mutation; Middle Aged; Child; Cohort Studies; High-Throughput Nucleotide Sequencing
PubMed: 38812636
DOI: 10.55730/1300-0144.5769 -
IScience Jun 2024Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cellular heterogeneity by characterizing cell types across tissues and species. While several...
Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cellular heterogeneity by characterizing cell types across tissues and species. While several mouse retinal scRNA-seq datasets exist, each dataset is either limited in cell numbers or focused on specific cell classes, thereby hindering comprehensive gene expression analysis across all retina types. To fill the gap, we generated the largest retinal scRNA-seq dataset to date, comprising approximately 190,000 single cells from C57BL/6J mouse retinas, enriched for rare population cells via antibody-based magnetic cell sorting. Integrating this dataset with public datasets, we constructed the Mouse Retina Cell Atlas (MRCA) for wild-type mice, encompassing over 330,000 cells, characterizing 12 major classes and 138 cell types. The MRCA consolidates existing knowledge, identifies new cell types, and is publicly accessible via CELLxGENE, UCSC Cell Browser, and the Broad Single Cell Portal, providing a user-friendly resource for the mouse retina research community.
PubMed: 38812536
DOI: 10.1016/j.isci.2024.109916