Mitochondrial dysfunction is observed in both the aging brain, and as a core feature of several neurodegenerative diseases. A central mechanism mediating this dysfunction is acquired molecular damage ...to mitochondrial DNA (mtDNA). In addition, inherited stable mtDNA variation (mitochondrial haplogroups), and inherited low level variants (heteroplasmy) have also been associated with the development of neurodegenerative disease and premature neural aging respectively. Herein we review the evidence for both inherited and acquired mtDNA mutations contributing to neural aging and neurodegenerative disease. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
•We review the evidence for the development of somatic mitochondrial DNA mutations in the aging brain.•We review the nature and mechanism of development of mitochondrial DNA variants in the aged human brain.•We discuss the role of inherited homoplasmic mitochondrial DNA variants in the development of neurodegenerative disease.•We discuss the role of somatic mitochondrial DNA mutations in the development of neurodegenerative disease.
Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain ...development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.
ABSTRACTDel Monte, MJ, Opar, DA, Timmins, RG, Ross, JA, Keogh, JWL, and Lorenzen, C. Hamstring myoelectrical activity during three different kettlebell swing exercises. J Strength Cond Res ...34(7)1953–1958, 2020—Kettlebell exercises have become an increasingly popular form of resistance training and component of lower-body rehabilitative training programs, despite a lack of scientific literature illustrating internal mechanisms and effectiveness of these approaches. Participants (n = 14) performed 3 different styles of kettlebell swings (hip hinge, squat, and double knee extension) and were assessed for medial hamstrings (MHs) and biceps femoris (BF) myoelectrical activity through surface electromyography (sEMG). Bipolar pregelled Ag/AgCl sEMG electrodes (10 mm diameter, 20 mm interelectrode distance) were placed on the participantʼs dominant limb after correct skin preparation. There was a main effect for swing type (p = 0.004), where the hip hinge swing elicited a greater overall MH and BF sEMG in comparison with the squat swing (mean difference = 3.92; 95% confidence interval CI = 1.53–6.32; p = 0.002) and the double knee extension swing (mean difference = 5.32; 95% CI = 0.80–9.83; p = 0.020). Across all swing types, normalized percentage of MH sEMG was significantly higher compared with the BF (mean difference = 9.93; 95% CI = 1.67–18.19; p = 0.022). The hip hinge kettlebell swing produced the greatest amount of hamstring sEMG for the 3 styles of kettlebell swings assessed. These findings have implications for the application of kettlebell swing exercises in strength and conditioning, injury prevention, and rehabilitation programs.
Abstract
The benefits of using electronic health records (EHRs) for disease risk screening and personalized health-care decisions are being increasingly recognized. Here we present a computationally ...feasible statistical approach with which to address the methodological challenges involved in utilizing historical repeat measures of multiple risk factors recorded in EHRs to systematically identify patients at high risk of future disease. The approach is principally based on a 2-stage dynamic landmark model. The first stage estimates current risk factor values from all available historical repeat risk factor measurements via landmark-age–specific multivariate linear mixed-effects models with correlated random intercepts, which account for sporadically recorded repeat measures, unobserved data, and measurement errors. The second stage predicts future disease risk from a sex-stratified Cox proportional hazards model, with estimated current risk factor values from the first stage. We exemplify these methods by developing and validating a dynamic 10-year cardiovascular disease risk prediction model using primary-care EHRs for age, diabetes status, hypertension treatment, smoking status, systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol in 41,373 persons from 10 primary-care practices in England and Wales contributing to The Health Improvement Network (1997–2016). Using cross-validation, the model was well-calibrated (Brier score = 0.041, 95% confidence interval: 0.039, 0.042) and had good discrimination (C-index = 0.768, 95% confidence interval: 0.759, 0.777).
Human-to-human transmission of Creutzfeldt–Jakob disease (CJD) has occurred through medical procedures resulting in iatrogenic CJD (iCJD). One of the commonest causes of iCJD was the use of human ...pituitary-derived growth hormone (hGH) to treat primary or secondary growth hormone deficiency. As part of a comprehensive tissue-based analysis of the largest cohort yet collected (35 cases) of UK hGH-iCJD cases, we describe the clinicopathological phenotype of hGH-iCJD in the UK. In the 33/35 hGH-iCJD cases with sufficient paraffin-embedded tissue for full pathological examination, we report the accumulation of the amyloid beta (Aβ) protein associated with Alzheimer’s disease (AD) in the brains and cerebral blood vessels in 18/33 hGH-iCJD patients and for the first time in 5/12 hGH recipients who died from causes other than CJD. Aβ accumulation was markedly less prevalent in age-matched patients who died from sporadic CJD and variant CJD. These results are consistent with the hypothesis that Aβ, which can accumulate in the pituitary gland, was present in the inoculated hGH preparations and had a seeding effect in the brains of around 50% of all hGH recipients, producing an AD-like neuropathology and cerebral amyloid angiopathy (CAA), regardless of whether CJD neuropathology had occurred. These findings indicate that Aβ seeding can occur independently and in the absence of the abnormal prion protein in the human brain. Our findings provide further evidence for the prion-like seeding properties of Aβ and give insights into the possibility of iatrogenic transmission of AD and CAA.
An anatomic transcriptional atlas of human glioblastoma Puchalski, Ralph B; Shah, Nameeta; Miller, Jeremy ...
Science (American Association for the Advancement of Science),
05/2018, Letnik:
360, Številka:
6389
Journal Article
Recenzirano
Odprti dostop
Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for ...diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.
A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2. We hypothesized that ...negatively screened patients may harbor somatic variants in these genes.
We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years).
We identified and confirmed nine somatic variants (allele fractions: 0.2%–10.8%): two APP, five SORL1, one NCSTN, and one MARK4 variants by independent amplicon-based deep sequencing.
Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases.
Effective environmental watering programmes improve the ecological conditions of river systems. This involves identifying and managing any significant risks that may hinder programme success. We ...undertook a qualitative study exploring how environmental water managers perceive and manage these risks while planning and delivering environmental water, using the Goulburn River, south-east Australia, as a case study. We developed a risk table detailing the progression of key risk events and how environmental water managers manage these. The findings highlight that many risk management strategies are tied to different organizations and water users, making it challenging to successfully deliver environmental water.
Small RNAs (sRNAs) remain an understudied class of regulatory molecules in bacteria in general and in Gram-positive bacteria in particular. In the major human pathogen
, hundreds of sRNAs have been ...identified; however, only a few have been characterized in detail. In this study, we investigate the role of the sRNA Teg41 in
virulence. We demonstrate that Teg41, an sRNA divergently transcribed from the locus that encodes the cytolytic alpha phenol-soluble modulin (αPSM) peptides, plays a critical role in αPSM production. Overproduction of Teg41 leads to an increase in αPSM levels and a corresponding increase in hemolytic activity from
cells and cell-free culture supernatants. To identify regions of Teg41 important for its function, we performed an
RNA-RNA interaction analysis which predicted an interaction between the 3' end of Teg41 and the αPSM transcript. Deleting a 24-nucleotide region from the
genome, corresponding to the 3' end of Teg41, led to a 10-fold reduction in αPSM-dependent hemolytic activity and attenuation of virulence in a murine abscess model of infection. Restoration of hemolytic activity in the Teg41Δ3' strain was possible by expressing full-length Teg41 in
Restoration of hemolytic activity was also possible by expressing the 3' end of Teg41, suggesting that this region of Teg41 is necessary and sufficient for αPSM-dependent hemolysis. Our results show that Teg41 is positively influencing αPSM production, demonstrating for the first time regulation of the αPSM peptides by an sRNA in
The alpha phenol-soluble modulins (αPSMs) are among the most potent toxins produced by
Their biological role during infection has been studied in detail; however, the way they are produced by the bacterial cell is not well understood. In this work, we identify a small RNA molecule called Teg41 that plays an important role in αPSM production by
Teg41 positively influences αPSM production. The importance of Teg41 is highlighted by the fact that a strain containing a deletion in the 3' end of Teg41 produces significantly less αPSMs and is attenuated for virulence in a mouse abscess model of infection. As the search for new therapeutic strategies to combat
infection proceeds, Teg41 may represent a novel target.
PDF
