Brodersennewton3944

The axonal degeneration of the sciatic nerves was observed in Optn (-/-) mice. However, we could not observe significant differences in survival time, body weight, and motor functions, at 24 months. Our findings suggest that homozygous OPTN deletion or mutations might result in autophagic dysfunction and TAR-DNA binding protein 43 mislocalization, thereby leading to neurodegeneration of motor neurons. These findings indicate that the Optn (-/-) mice recapitulate both common and specific pathogenesis of amyotrophic lateral sclerosis associated with autophagic abnormalities. Optn (-/-) mice could serve as a mouse model for the development of therapeutic strategies.Fetal alcohol spectrum disorders (FASD) are a spectrum of developmental disorders caused by prenatal alcohol exposure. Neuronal loss or neurodegeneration in the central nervous system (CNS) is one of the most devastating features in FASD. It is imperative to delineate the underlying mechanisms to facilitate the treatment of FASD. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases, including ethanol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) responds to ER stress and has been identified as a protein upregulated in response to ethanol exposure during the brain development. To investigate the role of MANF in ethanol-induced neurodegeneration and its association with ER stress regulation, we established a CNS-specific Manf knockout mouse model and examined the effects of MANF deficiency on ethanol-induced neuronal apoptosis and ER stress using a third-trimester equivalent mouse model. We found MANF deficiency exacerbated ethanol-induced neuronal apoptosis and ER stress and that blocking ER stress abrogated the harmful effects of MANF deficiency on ethanol-induced neuronal apoptosis. Moreover, using an animal model of ER-stress-induced neurodegeneration, we demonstrated that MANF deficiency potentiated tunicamycin (TM)-induced ER stress and neurodegeneration. A whole transcriptome RNA sequencing also supported the functionality of MANF in ER stress modulation and revealed targets that may mediate the ER stress-buffering capacity of MANF. Collectively, these results suggest that MANF is a neurotrophic factor that can protect neurons against ethanol-induced neurodegeneration by ameliorating ER stress.Parkinson's disease (PD) is the second most common neurodegenerative disease. Pathologically, PD is characterized by the formation of Lewy bodies (LBs) in the brain, which mainly comprises phosphorylated and aggregated α-synuclein (α-syn). The aberrant aggregation of α-syn is believed to play a key role in the pathogenesis of PD. While α-syn expression can be reduced by antisense oligonucleotides (ASOs), the challenge to deliver ASOs safely and effectively into the neurons remains unresolved. Here, we developed a safe and highly effective ASO delivery method by using exosomes. We first identified the ASO sequence that selectively reduced α-syn expression ASO4. Exosome-mediated delivery of ASO4 (exo-ASO4) showed high cellular uptake and low toxicity in primary neuronal cultures. Exo-ASO4 also significantly attenuated α-syn aggregation induced by pre-formed α-syn fibrils in vitro. Exo-ASO4 intracerebroventricular injection into the brains of α-syn A53T mice, a transgenic model of PD, significantly decreased the expression of α-syn and attenuated its aggregation. Furthermore, exo-ASO4 ameliorated the degeneration of dopaminergic neurons in these mice. Finally, the α-syn A53T mice showed significantly improved locomotor functions after exo-ASO4 injection. Overall, this study demonstrates that exosome-mediated ASO4 delivery may be an effective treatment option for PD.

To (i) investigate the proportion of overweight/obesity in a cohort of young adults with patellofemoral pain (PFP) and (ii) explore the association of body mass index (BMI), body fat, and lean mass with functional capacity and hip and knee strength in people with PFP.

We included a mixed-sex sample of young adults (18-35 years old) with PFP (n = 100). Measurements for BMI, percentage of body fat, and lean mass (assessed by bioelectrical impedance) were obtained. Functional capacity was assessed by the Anterior Knee Pain Scale, plank test, and single-leg hop test. Strength of the knee extensors, knee flexors, and hip abductors was evaluated isometrically using an isokinetic dynamometer. The proportion of overweight/obesity was calculated based on BMI. Alpelisib nmr The association between BMI, body fat, and lean mass and functional capacity and strength was investigated using partial correlations, followed by hierarchical regression analysis, adjusted for covariates (sex, bilateral pain, and current pain level).

A total of 38% of our cohort had their BMI categorized as overweight/obese. Higher BMI was associated with poor functional capacity (ΔR

 = 0.06-0.12, p ≤ 0.001) and with knee flexion strength only (ΔR

 = 0.04, p = 0.030). Higher body fat was associated with poor functional capacity (ΔR

 = 0.05-0.15, p ≤ 0.015) and reduced strength (ΔR

 = 0.15-0.23, p < 0.001). Lower lean mass was associated with poor functional capacity (ΔR

 = 0.04-0.13, p ≤ 0.032) and reduced strength (ΔR

 = 0.29- 0.31, p < 0.001).

BMI, body fat, and lean mass should be considered in the assessment and management of young people with PFP because it may be detrimental to function and strength.

BMI, body fat, and lean mass should be considered in the assessment and management of young people with PFP because it may be detrimental to function and strength.Apicomplexans are alveolate parasites which include Plasmodium falciparum, the main cause of malaria, one of the world's biggest killers from infectious disease. Apicomplexans are characterized by a reduction in proteome size, which appears to result from metabolic and functional simplification, commensurate with their parasitic lifestyle. However, other factors may also help to explain gene loss such as population bottlenecks experienced during transmission, and the effect of reducing the overall genomic information content. The latter constitutes an 'informational constraint', which is proposed to exert a selective pressure to evolve and maintain genes involved in informational fidelity and error correction, proportional to the quantity of information in the genome (which approximates to proteome size). The dynamics of gene loss was examined in 41 Apicomplexan genomes using orthogroup analysis. We show that loss of genes involved in amino acid metabolism and steroid biosynthesis can be explained by metabolic redundancy with the host. We also show that there is a marked tendency to lose DNA repair genes as proteome size is reduced. This may be explained by a reduction in size of the informational constraint and can help to explain elevated mutation rates in pathogens with reduced genome size. Multiple Sequentially Markovian Coalescent (MSMC) analysis indicates a recent bottleneck, consistent with predictions generated using allele-based population genetics approaches, implying that relaxed selection pressure due to reduced population size might have contributed to gene loss. However, the non-randomness of pathways that are lost challenges this scenario. Lastly, we identify unique orthogroups in malaria-causing Plasmodium species that infect humans, with a high proportion of membrane associated proteins. Thus, orthogroup analysis appears useful for identifying novel candidate pathogenic factors in parasites, when there is a wide sample of genomes available.In this review, we present a summary of computer simulation studies on solute diffusion in gels carried out in the last three decades. Special attention is paid to coarse-grained simulations in which the role of steric and electrostatic interactions on the particle diffusion can be evaluated. In addition, other important characteristics of particle diffusion in gels, such as the stiffness of the gel structure and hydrodynamic interactions, can be taken into account through coarse-grained simulations. Emphasis is placed on how simulation results help to test phenomenological models and to improve the interpretation interof experimental results. Finally, coarse-grained simulations have also been employed to study the diffusion controlled release of drugs from gels. We believe that scientific advances in this line will be useful to better understand the mechanisms that control the diffusive transport of molecules in a wide variety of biological systems.

"Quantile-dependent expressivity" occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. cholesterol) is high or low relative to its distribution. We have previously shown that the effect of a 52-SNP genetic-risk score was 3-fold larger at the 90th percentile of the total cholesterol distribution than at its 10th percentile. The objective of this study is to assess quantile-dependent expressivity for total cholesterol in 7006 offspring with parents and 2112 sibships from Framingham Heart Study.

Quantile-specific heritability (h

) was estimated as twice the offspring-parent regression slope as robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples.

Quantile-specific h

increased linearly with increasing percentiles of the offspring's cholesterol distribution (P=3.0×10

), i.e. h

=0.38 at the 10th percentile, h

=0.45 at the 25th percentile, h

=0.52 at the 50th, h

=0.61 at the 75th percentile, and h

=0.65 at the 90th percentile of the total cholesterol distribution. Average h

decreased from 0.55 to 0.34 in 3564 offspring who started cholesterol-lowering medications, but this was attributable to quantile-dependent expressivity and the offspring's 0.94mmol/L average drop in total cholesterol. Quantile-dependent expressivity likely explains the reported effect of the CELSR2/PSRC1/SORT1 rs646776 and APOE rs7412 gene loci on statin efficacy. Specifically, a smaller genetic effect size at the lower (post-treatment) than higher (pre-treatment) cholesterol concentrations mandates that the trajectories of the genotypes cannot move in parallel when cholesterol is decreased pharmacologically.

Cholesterol concentrations exhibit quantile-dependent expressivity, which may provide an alternative interpretation to pharmacogenetic and nutrigenetic interactions.

Cholesterol concentrations exhibit quantile-dependent expressivity, which may provide an alternative interpretation to pharmacogenetic and nutrigenetic interactions.

Previous studies demonstrated that scar tissue assessed by late gadolinium enhancement cardiovascular magnetic resonance imaging (LGE-CMR) is associated with recovery of cardiac function after coronary artery bypass graft (CABG) in patients with a history of myocardial infarction (MI). However, information on the association between myocardial scar at baseline and long-term survival after CABG in these patients is lacking.

From April 2010 to May 2013, consecutive patients with multivessel coronary artery disease (CAD, > 70% stenosis in ≥2 vessels) and MI (> 3months) who underwent LGE-CMR within 1month prior to isolated CABG were enrolled. Left ventricular functional parameters and scar tissue were assessed by LGE-CMR before surgery. A standard 17-segment model was used for scar quantification. Predictors for cardiovascular events (CVEs) were analyzed.

Of 148 patients who met the study inclusion/exclusion criteria, 140 cases had follow-up data and were included in final analysis. Of the latter, 27 (19.