Neurodegenerative Diseases Associated with Mutations in <em>SLC25A46</em>

Neurodegenerative diseases present substantial clinical challenges. Their processes have been linked with various genetic causes, including mutations of genes encoding proteins associated with mitochondrial dynamics. Biallelic mutations in SLC25A46 have been identified as novel causes of a wide spectrum of neurological diseases with recessive inheritance, including optic atrophy, Charcot-Marie-Tooth neuropathy (CMT) type 2A neuropathy, Leigh syndrome, progressive myoclonic ataxia, and lethal congenital pontocerebellar hypoplasia. SLC25A46 (solute carrier family 25 member 46) is a membrane transit protein that is expressed in the mitochondrial outer membrane where it plays a major role in mitochondrial dynamics and cristae maintenance. This chapter presents recent findings on: (1) the clinical heterogeneity of SLC25A46-related neuropathies; (2) the SLC25A46 mutation spectrum and associated genotype-phenotype correlation; and (3) pathophysiological functions of SLC25A46 as characterized in cells and mouse models. A better understanding of the etiology of SLC25146-linked diseases will elucidate therapeutic perspectives

Research on Energy-Saving Reconstruction Technology of Hospital Buildings Based on Measured Data

In order to effectively reduce the carbon emission in the process of building operation, the energy consumption per unit area and energy consumption system of hospital buildings were analyzed and studied. The practical application shows that the energy-saving transformation of hospital buildings in hot summer and warm winter area can effectively reduce its energy consumption, it also saves at least 654 tons of carbon dioxide annually

Groundwater Arsenic-Attributable Cardiovascular Disease (CVD) Mortality Risks in India

From MDPI via Jisc Publications RouterHistory: accepted 2021-08-12, pub-electronic 2021-08-17Publication status: PublishedFunder: Natural Environment Research Council; Grant(s): NE/R003386/1Funder: Department of Science and Technology (India); Grant(s): DST/TM/INDO-UK/2K17/55(C) & 55(G)Cardiovascular diseases (CVDs) have been recognized as the most serious non-carcinogenic detrimental health outcome arising from chronic exposure to arsenic. Drinking arsenic contaminated groundwaters is a critical and common exposure pathway for arsenic, notably in India and other countries in the circum-Himalayan region. Notwithstanding this, there has hitherto been a dearth of data on the likely impacts of this exposure on CVD in India. In this study, CVD mortality risks arising from drinking groundwater with high arsenic (>10 μg/L) in India and its constituent states, territories, and districts were quantified using the population-attributable fraction (PAF) approach. Using a novel pseudo-contouring approach, we estimate that between 58 and 64 million people are exposed to arsenic exceeding 10 μg/L in groundwater-derived drinking water in India. On an all-India basis, we estimate that 0.3–0.6% of CVD mortality is attributable to exposure to high arsenic groundwaters, corresponding to annual avoidable premature CVD-related deaths attributable to chronic exposure to groundwater arsenic in India of between around 6500 and 13,000. Based on the reported reduction in life of 12 to 28 years per death due to heart disease, we calculate value of statistical life (VSL) based annual costs to India of arsenic-attributable CVD mortality of between USD 750 million and USD 3400 million

Targeting of the Human Coagulation Factor IX Gene at rDNA Locus of Human Embryonic Stem Cells

BACKGROUND: Genetic modification is a prerequisite to realizing the full potential of human embryonic stem cells (hESCs) in human genetic research and regenerative medicine. Unfortunately, the random integration methods that have been the primary techniques used keep creating problems, and the primary alternative method, gene targeting, has been effective in manipulating mouse embryonic stem cells (mESCs) but poorly in hESCs. METHODOLOGY/PRINCIPAL FINDINGS: Human ribosomal DNA (rDNA) repeats are clustered on the short arm of acrocentric chromosomes. They consist of approximately 400 copies of the 45S pre-RNA (rRNA) gene per haploid. In the present study, we targeted a physiological gene, human coagulation factor IX, into the rDNA locus of hESCs via homologous recombination. The relative gene targeting efficiency (>50%) and homologous recombination frequency (>10(-5)) were more than 10-fold higher than those of loci targeted in previous reports. Meanwhile, the targeted clones retained both a normal karyotype and the main characteristics of ES cells. The transgene was found to be stably and ectopically expressed in targeted hESCs. CONCLUSION/SIGNIFICANCE: This is the first targeting of a human physiological gene at a defined locus on the hESC genome. Our findings indicate that the rDNA locus may serve as an ideal harbor for transgenes in hESCs

Genetic and phenotypic profiling of single living circulating tumour cells from patients with microfluidics

Accurate prediction of the efficacy of immunotherapy for cancer patients through the characterization of both genetic and phenotypic heterogeneity in individual patient cells holds great promise in informing targeted treatments, and ultimately in improving care pathways and clinical outcomes. Here, we describe the nanoplatform for interrogating living cell host-gene and (micro-)environment (NICHE) relationships, that integrates micro- and nanofluidics to enable highly efficient capture of circulating tumor cells (CTCs) from blood samples. The platform uses a unique nanopore-enhanced electrodelivery system that efficiently and rapidly integrates stable multichannel fluorescence probes into living CTCs for in situ quantification of target gene expression, while on-chip coculturing of CTCs with immune cells allows for the real-time correlative quantification of their phenotypic heterogeneities in response to immune checkpoint inhibitors (ICI). The NICHE microfluidic device provides a unique ability to perform both gene expression and phenotypic analysis on the same single cells in situ, allowing us to generate a predictive index for screening patients who could benefit from ICI. This index, which simultaneously integrates the heterogeneity of single cellular responses for both gene expression and phenotype, was validated by clinically tracing 80 non–small cell lung cancer patients, demonstrating significantly higher AUC (area under the curve) (0.906) than current clinical reference for immunotherapy prediction

Association of low-level inorganic arsenic exposure from rice with age-standardized mortality risk of cardiovascular disease (CVD) in England and Wales

Adverse health outcomes, including death from cardiovascular disease (CVD), arising from chronic exposure to inorganic arsenic (iAs) are well documented. Consumption of rice is a major iAs exposure route for over 3 billion people, however, there is still a lack of epidemiological evidence demonstrating the association between iAs exposure from rice intake and CVD risks. We explored this potential association through an ecological study using data at local authority level across England and Wales. Local authority level daily per capita iAs exposure from rice (E-iAsing,rice) was estimated using ethnicity as a proxy for class of rice consumption. A series of linear and non-linear models were applied to estimate the association between E-iAsing,rice and CVD age-standardized mortality rate (ASMR), using Akaike's Information Criterion as the principle model selection criterion. When adjusted for significant confounders, notably smoking prevalence, education level, employment rate, overweight percentage, PM2.5, female percentage and medical and care establishments, the preferred non-linear model indicated that CVD risks increased with iAs exposure from rice at exposures above 0.3 μg/person/day. Also, the best-fitted linear model indicated that CVD ASMR in the highest quartile of iAs exposure (0.375–2.71 μg/person/day) was 1.06 (1.02, 1.11; p-trend <0.001) times higher than that in the lowest quartile (<0.265 μg/person/day). Notwithstanding the well-known limitations of ecological studies, this study further suggests exposure to iAs, including from rice intake, as a potentially important confounder for studies of the factors controlling CVD risks

Research on Energy-Saving Reconstruction Technology of Hospital Buildings Based on Measured Data

In order to effectively reduce the carbon emission in the process of building operation, the energy consumption per unit area and energy consumption system of hospital buildings were analyzed and studied. The practical application shows that the energy-saving transformation of hospital buildings in hot summer and warm winter area can effectively reduce its energy consumption, it also saves at least 654 tons of carbon dioxide annually

Clinical and genetic study of 20 patients from China with Cornelia de Lange syndrome

Abstract Background Cornelia de Lange syndrome (CdLS) is a rare congenital syndrome with no racial difference. The objective of this study is to report the clinical characteristics and genetic study of 20 CdLS cases from China. Methods This is an observational study. Suspected patients were referred for further confirmation, clinical treatment, and genetic testing under voluntary condition. Demographic data and family history, data of clinical manifestations including facial dysmorphism and developmental delay of each patient were collected. Chromosomal analysis and NIPBL/SMC1A/SMC3 gene mutational analysis were carried out by PCR, reverse transcription PCR direct sequencing in the probands, and SNP array to detect the genome-wide copy number variations. Results Twenty CdLS cases from China were included in this study. Facial dysmorphisms, feeding difficulties, and developmental delay were the major clinical manifestations. Seven patients underwent gene mutation tests. Both the SMC1A and SMC3 gene mutation tests were negative in all. A heterozygous mutation in exon 20 of the NIPBL gene in proband 2, and a heterozygous mutation in intron 38 of the NIPBL gene in proband 3 were found in 1 patient, and RT-PCR revealed a splicing mutation in exon 38, generating both normal transcript and an aberrant alternatively spliced transcript with exon 38 deletion. Conclusions Clinical manifestations of CdLS patients from China are similar to those in the other countries. Heterozygous mutations of NIPBL gene were found