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Acta Neuropathologica Jun 2023Neuronal TDP-43-positive inclusions are neuropathological hallmark lesions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathogenic missense...
Neuronal TDP-43-positive inclusions are neuropathological hallmark lesions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Pathogenic missense variants in TARDBP, the gene encoding TDP-43, can cause ALS and cluster in the C-terminal prion-like domain (PrLD), where they modulate the liquid condensation and aggregation properties of the protein. TDP-43-positive inclusions are also found in rimmed vacuole myopathies, including sporadic inclusion body myositis, but myopathy-causing TDP-43 variants have not been reported. Using genome-wide linkage analysis and whole exome sequencing in an extended five-generation family with an autosomal dominant rimmed vacuole myopathy, we identified a conclusively linked frameshift mutation in TDP-43 producing a C-terminally altered PrLD (TDP-43) (maximum multipoint LOD-score 3.61). Patient-derived muscle biopsies showed TDP-43-positive sarcoplasmic inclusions, accumulation of autophagosomes and transcriptomes with abnormally spliced sarcomeric genes (including TTN and NEB) and increased expression of muscle regeneration genes. In vitro phase separation assays demonstrated that TDP-43 does not form liquid-like condensates and readily forms solid-like fibrils indicating increased aggregation propensity compared to wild-type TDP-43. In Drosophila TDP-43 behaved as a partial loss-of-function allele as it was able to rescue the TBPH (fly ortholog of TARDBP) neurodevelopmental lethal null phenotype while showing strongly reduced toxic gain-of-function properties upon overexpression. Accordingly, TDP-43 showed reduced toxicity in a primary rat neuron disease model. Together, these genetic, pathological, in vitro and in vivo results demonstrate that TDP-43 is an aggregation-prone partial loss-of-function variant that causes autosomal dominant vacuolar myopathy but not ALS/FTD. Our study genetically links TDP-43 proteinopathy to myodegeneration, and reveals a tissue-specific role of the PrLD in directing pathology.
Topics: Animals; Rats; Amyotrophic Lateral Sclerosis; DNA-Binding Proteins; Frameshift Mutation; Frontotemporal Dementia; Mutation; Pick Disease of the Brain; Humans
PubMed: 37000196
DOI: 10.1007/s00401-023-02565-1 -
Brain : a Journal of Neurology Sep 2023Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid...
Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.
Topics: Child; Humans; Young Adult; Anoctamin-1; Chloride Channels; Moyamoya Disease; Neoplasm Proteins
PubMed: 37253099
DOI: 10.1093/brain/awad172 -
BMC Chemistry Aug 2023This study aims to develop an effective and sensitive HPLC (High Performance Liquid Chromatography) method to determine the nitrate concentration in fruits and...
This study aims to develop an effective and sensitive HPLC (High Performance Liquid Chromatography) method to determine the nitrate concentration in fruits and vegetables (F & V) using a C column (ZORBAX Eclipse XDB-C, 80Å, 250 × 4.6 mm, 5 μm (Agilent Technologies)) maintained at 40 C, a mobile phase made up of methanol and buffer (pentane sulfonic acid sodium salt solution), and a Photo Diode Array Detector (PDA) at 225 nm. The developed method is validated in terms of selectivity, linearity, accuracy, precision, suitability, the limit of detection (LOD), and the limit of quantification (LOQ) according to the European Union Decision 2002/657/EC. The result revealed that a ratio of 30: 70 of the organic modifier methanol and buffer with pH 2.8 shows the highest efficiency. The calibration curve shows linearity with a correlation coefficient (r) of 0.9985. The LOD and LOQ were found to be 2.26 mg/kg and 7.46 mg/kg. The recovery was in the range of 98.96-100.21%. Moreover, the greenness assessment scores of different approaches (eco-scale score of 76, AGREE score of 0.71, and few red shades in GAPI portray) were at a very excellent level. Thus, our developed method is fully validated and can determine the nitrate content in F & V.
PubMed: 37620944
DOI: 10.1186/s13065-023-01008-y -
Clinica Chimica Acta; International... Aug 2023The Enhanced Liver Fibrosis (ELF) Test comprises 3 direct serum markers of fibrosis-hyaluronic acid (HA), amino-terminal pro-peptide of type III procollagen (PIIINP),...
BACKGROUND
The Enhanced Liver Fibrosis (ELF) Test comprises 3 direct serum markers of fibrosis-hyaluronic acid (HA), amino-terminal pro-peptide of type III procollagen (PIIINP), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1)-whose results are combined in an algorithm to generate the ELF score. Outside the U.S., the ELF Test and score are CE marked for assessment of liver fibrosis severity in patients with signs, symptoms, or risk factors of chronic liver disease to support diagnosis of fibrosis staging or prognosis for likelihood of progression to cirrhosis and liver-related clinical events. In the U.S., the FDA granted de novo marketing authorization to aid prognostic evaluation of disease progression (to cirrhosis and liver-related clinical events) in nonalcoholic steatohepatitis patients with advanced liver fibrosis. We describe the analytical performance of the ELF analytes and score on the Atellica® IM Analyzer.
METHODS
Clinical and Laboratory Standards Institute protocols were followed for detection capability (limits of blank [LoB], detection [LoD], and quantitation [LoQ]), precision, interference, linearity, hook effect, and ELF reference interval.
RESULTS
All parameters met predetermined requirements: HA (LoB 1.00 ng/mL, LoD 2.00 ng/mL, LoQ 3.00 ng/mL); PIIINP (LoB 0.50 ng/mL, LoD 0.75 ng/mL, LoQ 1.00 ng/mL); TIMP-1 (LoB 3.0 ng/mL, LoD 4.0 ng/mL, LoQ 5.0 ng/mL). Across the 3 assays, repeatability was ≤5.4% CV; within-lab precision was ≤8.5% CV. ELF score repeatability was ≤0.6% CV, within-lab precision ≤1.3% CV, and reproducibility ≤1.1% CV. Good correlation was obtained between the Atellica IM ELF and ADVIA Centaur ELF Tests (y = 1.01x - 0.22, r = 0.997). Assays were linear across analytical measuring ranges.
CONCLUSIONS
Analytical performance validation results for the ELF Test and ELF score were excellent making the test acceptable for routine clinical use.
Topics: Humans; Tissue Inhibitor of Metalloproteinase-1; Reproducibility of Results; Liver Cirrhosis; Fibrosis; Liver; Biomarkers; Hyaluronic Acid
PubMed: 37390944
DOI: 10.1016/j.cca.2023.117461 -
International Journal of Molecular... Nov 2023Rice plant height is an agricultural trait closely related to biomass, lodging tolerance, and yield. Identifying quantitative trait loci (QTL) regions related to plant...
Rice plant height is an agricultural trait closely related to biomass, lodging tolerance, and yield. Identifying quantitative trait loci (QTL) regions related to plant height regulation and developing strategies to screen potential candidate genes can improve agricultural traits in rice. In this study, a double haploid population (CNDH), derived by crossing 'Cheongcheong' and 'Nagdong' individuals, was used, and a genetic map was constructed with 222 single-sequence repeat markers. In the RM3482-RM212 region on chromosome 1, , , , , and were identified for five consecutive years. The phenotypic variance explained ranged from 9.3% to 13.1%, and the LOD score ranged between 3.6 and 17.6. , a candidate gene related to plant height regulation, was screened in RM3482-RM212. is an ortholog of gibberellin 20 oxidase 2, and its haplotype was distinguished by nine SNPs. Plants were divided into two groups based on their height, and tall and short plants were distinguished and clustered according to the expression level of . QTLs and candidate genes related to plant height regulation, and thus, biomass regulation, were screened and identified in this study, but the molecular mechanism of the regulation remains poorly known. The information obtained in this study will help develop molecular markers for marker-assisted selection and breeding through rice plant height control.
Topics: Humans; Quantitative Trait Loci; Chromosome Mapping; Oryza; Plant Breeding; Phenotype
PubMed: 38069217
DOI: 10.3390/ijms242316895 -
Indian Journal of Ophthalmology Jun 2023This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients.
PURPOSE
This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients.
METHODS
A case-control study was done on 42 keratoconus cases, 127 family member controls, and 96 normal controls.
RESULTS
Three gene variants, p.A182A, p.P237P, and p.R217H showed significant associations with keratoconus (P < 0.05). While p.A182A and p.P227P were more prevalent than in the family and normal controls (OR 3.14-4.05), the reverse was observed with p.R217H (OR 0.086-1.59). With Haploview analysis, p.A182A and p.P237P were shown to be in linkage disequilibrium (LD) (LOD (logarithm of the odds score) score of 2.0, r2 of 0.957, and 95% confidence interval (CI) of 0.96-1.00).
CONCLUSION
The study results suggest that the p.A182A and p.P237P variants could have contributed to the development of keratoconus in some Malaysians and that these two variants are likely to be co-inherited. In contrast, the p.R217H variant appeared to confer some protection against the development of keratoconus.
Topics: Humans; Asian People; Case-Control Studies; Eye Proteins; Homeodomain Proteins; Keratoconus
PubMed: 37322657
DOI: 10.4103/IJO.IJO_2894_22 -
Psychology Research and Behavior... 2023Late-onset depression (LOD) with poor treatment response has high incidence and mortality in the China's aged people, this study aims to explore the correlation between...
PURPOSE
Late-onset depression (LOD) with poor treatment response has high incidence and mortality in the China's aged people, this study aims to explore the correlation between health-promoting lifestyle, meaning in life, interleukin-6 (IL-6) and LOD for providing scientific basis of LOD prevention and rehabilitation.
PATIENTS AND METHODS
A total of 496 LOD patients (study group) and healthy older adults (control group) were enrolled and investigated by using the Health-promoting lifestyle Profile-II, revised (HPLP-IIR), Meaning in Life Questionnaire-Chinese Version (MLQ-C), and Hamilton Depression Scale (HAMD). The interleukin-6 (IL-6) in the circulating blood was detected by utilizing ELISA kit.
RESULTS
The results showed that the scores of all factors in HPLP-IIR and MLQ were significantly lower and IL-6 level was higher in the study group than the control group. Scores of most factors in HPLP-IIR and MLQ negatively and IL-6 positively correlated with scores of subscales and total HAMD score. Meaning in life and IL-6 partially mediated the relationship between health-promoting lifestyles and depression severity in the study group, with the mediating effect explains 15.76% and 22.64% of the total effect, respectively.
CONCLUSION
Health-promoting lifestyles, meaning in life, and IL-6 are predictors of LOD, and an unhealthy lifestyle could induce LOD through the mediating effect of meaning in life and IL-6 in older adults.
PubMed: 38146389
DOI: 10.2147/PRBM.S441277 -
The American Journal of Geriatric... Mar 2024Understanding experiences and challenges faced by persons living with Early-Onset Dementia (EOD) compared to individuals diagnosed with Late-Onset Dementia (LOD) is...
BACKGROUND
Understanding experiences and challenges faced by persons living with Early-Onset Dementia (EOD) compared to individuals diagnosed with Late-Onset Dementia (LOD) is important for the development of targeted interventions.
OBJECTIVE
Describe differences in sociodemographic, neuropsychiatric behavioral symptoms, caregiver characteristics, and psychotropic use.
DESIGN, SETTING, PARTICIPANTS
Cross-sectional, retrospective study including 908 UCLA Alzheimer's Dementia Care Program participants (177 with EOD and 731 with LOD).
MEASUREMENTS
Onset of dementia was determined using age at program enrollment, with EOD defined as age <65 years and LOD defined as age >80 years. Sociodemographic and clinical characteristics were measured once at enrollment. Behavioral symptoms were measured using the Neuropsychiatric Inventory Questionnaire (NPI-Q) severity score and caregiver distress was measured using the NPI-Q distress score. Medications included antipsychotic, antidepressant, benzodiazepines and other hypnotics, antiepileptics, and dementia medications.
RESULTS
EOD compared to LOD participants were more likely men, college graduates, married, live alone, and have fewer comorbidities. EOD caregivers were more often spouses (56% vs 26%, p <0.01), whereas LOD caregivers were more often children (57% vs 10%, p <0.01). EOD was associated with lower odds of being above the median (worse) NPI-Q severity (adjusted odds ratio [aOR], 0.58; 95% CI 0.35-0.96) and NPI-Q distress scores (aOR, 0.53; 95% CI 0.31-0.88). Psychotropic use did not differ between groups though symptoms were greater for LOD compared to EOD.
CONCLUSION
Persons with EOD compared to LOD had sociodemographic differences, less health conditions, and fewer neuropsychiatric symptoms. Future policies could prioritize counseling for EOD patients and families, along with programs to support spousal caregivers of persons with EOD.
PubMed: 38600005
DOI: 10.1016/j.jagp.2024.03.009 -
G3 (Bethesda, Md.) Dec 2023Hop production utilizes exclusively female plants, whereas male plants only serve to generate novel variation within breeding programs through crossing. Currently, hop...
Hop production utilizes exclusively female plants, whereas male plants only serve to generate novel variation within breeding programs through crossing. Currently, hop lacks a rapid and accurate diagnostic marker to determine whether plants are male or female. Without a diagnostic marker, breeding programs may take 1-2 years to determine the sex of new seedlings. Previous research on sex-linked markers was restricted to specific populations or breeding programs and therefore had limited transferability or suffered from low scalability. A large collection of 765 hop genotypes with known sex phenotypes, genotyping-by-sequencing, and genome-wide association mapping revealed a highly significant marker on the sex chromosome (LOD score = 208.7) that predicted sex within our population with 96.2% accuracy. In this study, we developed a PCR allele competitive extension (PACE) assay for the diagnostic SNP and tested three quick DNA extraction methodologies for rapid, high-throughput genotyping. Additionally, the marker was validated in a separate population of 94 individuals from 15 families from the USDA-ARS hop breeding program in Prosser, WA with 96% accuracy. This diagnostic marker is located in a gene predicted to encode the basic helix-loop-helix transcription factor protein, a family of proteins that have been previously implicated in male sterility in a variety of plant species, which may indicate a role in determining hop sex. The marker is diagnostic, accurate, affordable, and highly scalable and has the potential to improve efficiency in hop breeding.
Topics: Humans; Genome-Wide Association Study; Plant Breeding; Chromosome Mapping; Phenotype; Genotype
PubMed: 37963231
DOI: 10.1093/g3journal/jkad216