While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible ...for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.
Abstract Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare ...variants have been identified in Amyloid Precursor Protein ( APP ), Triggering Receptor Expressed On Myeloid Cells 2 ( TREM2 ) and Unc-5 Netrin Receptor C ( UNC5C ) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.
OSNR monitoring using two fiber interferometers Flood, E; Guo, W H; Reid, D ...
2010 Conference on Optical Fiber Communication (OFC/NFOEC), collocated National Fiber Optic Engineers Conference,
2010-March
Conference Proceeding
In-band OSNR from 5 to 30 dB of a single 10 G NRZ-OOK channel was measured by two fiber interferometers within an accuracy of ±0.5 dB without requirement for knowledge of the noise-free extinction ...ratio of the signal.
Pharmaceutical contamination of contiguous groundwater is a substantial concern in wastewater-impacted streams, due to ubiquity in effluent, high aqueous mobility, designed bioactivity, and to ...effluent-driven hydraulic gradients. Wastewater treatment facility (WWTF) closures are rare environmental remediation events; offering unique insights into contaminant persistence, long-term wastewater impacts, and ecosystem recovery processes. The USGS conducted a combined pre/post-closure groundwater assessment adjacent to an effluent-impacted reach of Fourmile Creek, Ankeny, Iowa, USA. Higher surface-water concentrations, consistent surface-water to groundwater concentration gradients, and sustained groundwater detections tens of meters from the stream bank demonstrated the importance of WWTF effluent as the source of groundwater pharmaceuticals as well as the persistence of these contaminants under effluent-driven, pre-closure conditions. The number of analytes (110 total) detected in surface water decreased from 69 prior to closure down to 8 in the first post-closure sampling event approximately 30 d later, with a corresponding 2 order of magnitude decrease in the cumulative concentration of detected analytes. Post-closure cumulative concentrations of detected analytes were approximately 5 times higher in proximal groundwater than in surface water. About 40% of the 21 contaminants detected in a downstream groundwater transect immediately before WWTF closure exhibited rapid attenuation with estimated half-lives on the order of a few days; however, a comparable number exhibited no consistent attenuation during the year-long post-closure assessment. The results demonstrate the potential for effluent-impacted shallow groundwater systems to accumulate pharmaceutical contaminants and serve as long-term residual sources, further increasing the risk of adverse ecological effects in groundwater and the near-stream ecosystem.
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•Pre/post-closure groundwater pharmaceutical fate in wastewater-facility-impacted stream system•Consistent groundwater pharmaceutical profiles under effluent-driven, pre-closure conditions•88% reduction in surface-water pharmaceutical detections post-closure•40% of groundwater pharmaceutical contaminants still detected one year post-closure•Subsurface pharmaceutical accumulation and persistence increases risk of adverse effects.
Observations of the pulsations of stars can be used to infer their interior structure and test theoretical models. The main-sequence γ Doradus (Dor) and δ Scuti (Sct) stars with masses 1.2-2.5 M ...SUBsun/SUB are particularly useful for these studies. The γ Dor stars pulsate in high-order g-modes with periods of order 1 day, driven by convective blocking at the base of their envelope convection zone. The δ Sct stars pulsate in low-order g- and p-modes with periods of order 2 hr, driven by the κ mechanism operating in the He II ionization zone. Theory predicts an overlap region in the Hertzsprung-Russell diagram between instability regions, where "hybrid" stars pulsating in both types of modes should exist. The two types of modes with properties governed by different portions of the stellar interior provide complementary model constraints. Among the known γ Dor and δ Sct stars, only four have been confirmed as hybrids. Now, analysis of combined Quarter 0 and Quarter 1 Kepler data for hundreds of variable stars shows that the frequency spectra are so rich that there are practically no pure δ Sct or γ Dor pulsators, i.e., essentially all of the stars show frequencies in both the δ Sct and the γ Dor frequency range. A new observational classification scheme is proposed that takes into account the amplitude as well as the frequency and is applied to categorize 234 stars as δ Sct, γ Dor, δ Sct/γ Dor or γ Dor/δ Sct hybrids.
We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and ...histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.
Two Michelson fibre interferomters were used to measure the in-band OSNR of a noisy signal between 5 and 30 dB within ±0.5 dB without prior knowledge of the noise-free extinction ratio of the signal.
In a recent experiment at the Trident laser facility, a laser-driven beam of quasimonoenergetic aluminum ions was used to heat solid gold and diamond foils isochorically to 5.5 and 1.7 eV, ...respectively. Here theoretical calculations are presented that suggest the gold and diamond were heated uniformly by these laser-driven ion beams. According to calculations and SESAME equation-of-state tables, laser-driven aluminum ion beams achievable at Trident, with a finite energy spread of ΔE/E∼20%, are expected to heat the targets more uniformly than a beam of 140-MeV aluminum ions with zero energy spread. The robustness of the expected heating uniformity relative to the changes in the incident ion energy spectra is evaluated, and expected plasma temperatures of various target materials achievable with the current experimental platform are presented.
Conventional classification of patients with lower urinary tract symptoms into diagnostic categories based on a predefined symptom complex or predominant symptom appears inadequate. This is due to ...the frequent presentation of patients with multiple urinary symptoms which could not be perfectly categorized into traditional diagnostic groups. We used a novel clustering method to identify subtypes of male patients with lower urinary tract symptoms based on detailed multisymptom information.
We analyzed baseline data on 503 care seeking men in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Observational Cohort Study. Symptoms and symptom severity were assessed using the LUTS (Lower Urinary Tract Symptoms) Tool and the AUA SI (American Urological Association Symptom Index), which include a total of 52 questions. We used a resampling based consensus clustering algorithm to identify patient subtypes with distinct symptom signatures.
Four distinct symptom clusters were identified. The 166 patients in cluster M1 had predominant symptoms of frequency, nocturia, hesitancy, straining, weak stream, intermittency and incomplete bladder emptying suggestive of bladder outlet obstruction. The 93 patients in cluster M2 mainly endorsed post-micturition symptoms (eg post-void dribbling and post-void leakage) with some weak stream. The 114 patients in cluster M3 reported mostly urinary frequency without incontinence. The 130 patients in cluster M4 reported severe frequency, urgency and urgency incontinence. Most other urinary symptoms statistically differed between cluster pairs. Patient reported outcomes of bowel symptoms, mental health, sleep dysfunction, erectile function and urological pain significantly differed across the clusters.
We identified 4 data derived clusters among men seeking care for lower urinary tract symptoms. The clusters differed from traditional diagnostic categories. Further subtype refinement will be done to incorporate clinical data and nonurinary patient reported outcomes.
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