Assessment of Emissions from Cement Plants Using AERMOD Modeling

Coal combustion generates many gases and emissions which are harmful to public health and the environment. So, it is necessary to assess the health risks for the people living in the nearby cement plants that use coal as a fuel. In this article, a health risk assessment HRA was carried out concerning the air emissions from a cement plant in the heavy industry area located at Beni Suef governorate - Egypt. The article handles the assessment of the health risks for pollutants classified as non-carcinogenic i.e. sulfur dioxide - mercury and the health risks for pollutants classified as carcinogenic i.e. arsenic – chromium VI. An Air dispersion modeling program AERMOD is used to measure and evaluate long and short terms health impacts to expect the concentration of pollutants at the ground level within 30 km radius of the studied cement plant. The emissions measurements findings are used as input to the model in addition to some factors such as meteorology and surrounding terrain. Consequently, the program can implement simulations for the emissions concentration level of the mentioned pollutants and their effects on the population at Jazirat Abu Salih village, which is 10 km far from the studied cement plant. The results for mentioned pollutants concentrations levels matched with acceptance and safe levels of ambient air quality standards. In addition, the increment lifetime cancer risk ILCR by inhalation was calculated for arsenic and chromium and all results conformed with the safe and accepted limits

Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

BACKGROUND: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. METHODS: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. RESULTS: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. CONCLUSIONS: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders"

Clinical and molecular spectrum of a large Egyptian cohort with ALS2‐related disorders of infantile‐onset of clinical continuum IAHSP/JPLS

This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation

Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy

Purpose Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder. Methods Exome sequencing and rare variant family-based genomics was performed as a part of the Baylor-Hopkins Center for Mendelian Genomics Initiative. Additional families were identified via GeneMatcher. Results We identified six patients from three unrelated families with homozygous loss-of-function variants in NSRP1. Clinical features include developmental delay, epilepsy, variable microcephaly (Z-scores -0.95 to -5.60), hypotonia, and spastic cerebral palsy. Brain abnormalities included simplified gyral pattern, underopercularization, and/or vermian hypoplasia. Molecular analysis identified three pathogenic NSRP1 predicted loss-of-function variant alleles: c.1359_1362delAAAG (p.Glu455AlafsTer20), c.1272dupG (p.Lys425GlufsTer5), and c.52C>T (p.Gln18Ter). The two frameshift variants result in a premature termination codon in the last exon, and the mutant transcripts are predicted to escape nonsense mediated decay and cause loss of a C-terminal nuclear localization signal required for NSRP1 function. Conclusion We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly

The Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus since four out of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A), and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders, and microcephaly. Using structural molecular modeling and functional testing of the variants in a in a cell-based S. cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly