While there is now an established recognition of microplastic pollution in the oceans, and the detrimental effects this may have on marine animals, the ocean depth at which such contamination is ...ingested by organisms has still not been established. Here, we detect the presence of ingested microplastics in the hindguts of Lysianassoidea amphipod populations, in six deep ocean trenches from around the Pacific Rim (Japan, Izu-Bonin, Mariana, Kermadec, New Hebrides and the Peru-Chile trenches), at depths ranging from 7000 m to 10 890 m. This illustrates that microplastic contaminants occur in the very deepest reaches of the oceans. Over 72% of individuals examined (65 of 90) contained at least one microparticle. The number of microparticles ingested per individual across all trenches ranged from 1 to 8. The mean and standard error of microparticles varied per trench, from 0.9 ± 0.4 (New Hebrides Trench) to 3.3 ± 0.7 (Mariana Trench). A subsample of microfibres and fragments analysed using FTIR were found to be a collection of plastic and synthetic materials (Nylon, polyethylene, polyamide, polyvinyl alcohol, polyvinylchloride, often with inorganic filler material), semi-synthetic (rayon and lyocell) and natural fibre (ramie). Notwithstanding, this study reports the deepest record of microplastic ingestion, indicating that anthropogenic debris is bioavailable to organisms at some of the deepest locations in the Earth's oceans.
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal disorder that can be caused by mutations in the superoxide dismutase 1 (SOD1) gene. Although ALS is currently incurable, CRISPR base ...editors hold the potential to treat the disease through their ability to create nonsense mutations that can permanently disable the expression of the mutant SOD1 gene. However, the restrictive carrying capacity of adeno-associated virus (AAV) vectors has limited their therapeutic application. In this study, we establish an intein-mediated trans-splicing system that enables in vivo delivery of cytidine base editors (CBEs) consisting of the widely used Cas9 protein from Streptococcus pyogenes. We show that intrathecal injection of dual AAV particles encoding a split-intein CBE engineered to trans-splice and introduce a nonsense-coding substitution into a mutant SOD1 gene prolonged survival and markedly slowed the progression of disease in the G93A-SOD1 mouse model of ALS. Adult animals treated by this split-intein CRISPR base editor had a reduced rate of muscle atrophy, decreased muscle denervation, improved neuromuscular function, and up to 40% fewer SOD1 immunoreactive inclusions at end-stage mice compared to control mice. This work expands the capabilities of single-base editors and demonstrates their potential for gene therapy.
Lim et al. establish a trans-splicing system to deliver CRISPR base editors in vivo that enables treatment of a mouse model of ALS. They show that base editing can increase survival and slow the progression of disease.
Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and ...patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE).
All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561-726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations.
We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations.
FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and approximately 4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.
Clear cell renal cell carcinoma (ccRCC) is the predominant RCC subtype, but even within this classification, the natural history is heterogeneous and difficult to predict. A sophisticated ...understanding of the molecular features most discriminatory for the underlying tumor heterogeneity should be predicated on identifiable and biologically meaningful patterns of gene expression. Gene expression microarray data were analyzed using software that implements iterative unsupervised consensus clustering algorithms to identify the optimal molecular subclasses, without clinical or other classifying information. ConsensusCluster analysis identified two distinct subtypes of ccRCC within the training set, designated clear cell type A (ccA) and B (ccB). Based on the core tumors, or most well-defined arrays, in each subtype, logical analysis of data (LAD) defined a small, highly predictive gene set that could then be used to classify additional tumors individually. The subclasses were corroborated in a validation data set of 177 tumors and analyzed for clinical outcome. Based on individual tumor assignment, tumors designated ccA have markedly improved disease-specific survival compared to ccB (median survival of 8.6 vs 2.0 years, P = 0.002). Analyzed by both univariate and multivariate analysis, the classification schema was independently associated with survival. Using patterns of gene expression based on a defined gene set, ccRCC was classified into two robust subclasses based on inherent molecular features that ultimately correspond to marked differences in clinical outcome. This classification schema thus provides a molecular stratification applicable to individual tumors that has implications to influence treatment decisions, define biological mechanisms involved in ccRCC tumor progression, and direct future drug discovery.
Neutrino-induced coherent charged pion production on nuclei νμA→μ(±)π(∓)A is a rare, inelastic interaction in which a small squared four-momentum |t| is transferred to the recoil nucleus, leaving it ...intact in the reaction. In the scintillator tracker of MINERvA, we remove events with evidence of particles from nuclear breakup and reconstruct |t| from the final-state pion and muon. We select low |t| events to isolate a sample rich in coherent candidates. By selecting low |t| events, we produce a model-independent measurement of the differential cross section for coherent scattering of neutrinos and antineutrinos on carbon. We find poor agreement with the predicted kinematics in neutrino generators used by current oscillation experiments.
The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in ...acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data.
We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251).
In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen’s d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients.
The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.
Better tools are needed for risk assessment of Type B aortic dissection (TBAD) to determine optimal treatment for patients with uncomplicated disease. Magnetic resonance imaging (MRI) has the ...potential to inform computational fluid dynamics (CFD) simulations for TBAD by providing individualised quantification of haemodynamic parameters, for assessment of complication risks. This systematic review aims to present an overview of MRI applications for CFD studies of TBAD.
Following PRISMA guidelines, a search in Medline, Embase, and the Scopus Library identified 136 potentially relevant articles. Studies were included if they used MRI to inform CFD simulation in TBAD.
There were 20 articles meeting the inclusion criteria. 19 studies used phase contrast MRI (PC-MRI) to provide data for CFD flow boundary conditions. In 12 studies, CFD haemodynamic parameter results were validated against PC-MRI. In eight studies, geometric models were developed from MR angiography. In three studies, aortic wall or intimal flap motion data were derived from PC/cine MRI.
MRI provides complementary patient-specific information in CFD haemodynamic studies for TBAD that can be used for personalised care. MRI provides structural, dynamic and flow data to inform CFD for pre-treatment planning, potentially advancing its integration into clinical decision-making. The use of MRI to inform CFD in TBAD surgical planning is promising, however further validation and larger cohort studies are required.
•A systematic review of integrating magnetic resonance imaging (MRI) and computational fluid dynamics (CFD) in Type B aortic dissection (TBAD).•MRI plays roles in providing flow data for CFD boundary conditions, validating simulation results, and giving wall motion information.•Proposal of incorporating multiple MRI modalities to provide patient-specific data and improve the computational modelling of TBAD.
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