Popearmstrong1219

The onset and progression of numerous protein misfolding diseases are associated with the presence of oligomers formed during the aberrant aggregation of several different proteins, including amyloid-β (Aβ) in Alzheimer's disease and α-synuclein (αS) in Parkinson's disease. These small, soluble aggregates are currently major targets for drug discovery. In this study, we show that trodusquemine, a naturally-occurring aminosterol, markedly reduces the cytotoxicity of αS, Aβ and HypF-N oligomers to human neuroblastoma cells by displacing the oligomers from cell membranes in the absence of any substantial morphological and structural changes to the oligomers. These results indicate that the reduced toxicity results from a mechanism that is common to oligomers from different proteins, shed light on the origin of the toxicity of the most deleterious species associated with protein aggregation and suggest that aminosterols have the therapeutically-relevant potential to protect cells from the oligomer-induced cytotoxicity associated with numerous protein misfolding diseases.To examine the effects of poor sanitation and hygiene on the prevalence of antimicrobial-resistant bacteria, we surveyed households in two rural and two urban communities in Guatemala (N = 196 randomly selected households). One adult (≥ 18-years old) and, when available, one child (≤ 5 years-old) provided a stool sample. Up to 48 presumptive Escherichia coli isolates were collected from each stool sample (n = 21,256 total) and were subjected to breakpoint assays for ten antibiotics. Mixed-effects logistic models were used to identify potential factors influencing the likelihood of harboring antibiotic-resistant bacteria. For nine out of ten antibiotics, the odds of detecting resistant bacteria decreased by ~ 32% (odds ratios, OR 0.53-0.8, P  1.89-9.6). Poor hygiene conditions likely obscure effects of individual antibiotic use, presumably due to enhanced microbial transmission. Consequently, efforts to improve antibiotic stewardship should be coupled with improving hygiene conditions.Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2LMW) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2LMW-/- mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. Selleckchem Cilofexor FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS+/CD206+ TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment.Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.Medical image segmentation is an important tool for current clinical applications. It is the backbone of numerous clinical diagnosis methods, oncological treatments and computer-integrated surgeries. A new class of machine learning algorithm, deep learning algorithms, outperforms the results of classical segmentation in terms of accuracy. However, these techniques are complex and can have a high range of variability, calling the reproducibility of the results into question. In this article, through a literature review, we propose an original overview of the sources of variability to better understand the challenges and issues of reproducibility related to deep learning for medical image segmentation. Finally, we propose 3 main recommendations to address these potential issues (1) an adequate description of the framework of deep learning, (2) a suitable analysis of the different sources of variability in the framework of deep learning, and (3) an efficient system for evaluating the segmentation results.Both modular and nonmodular tapered fluted titanium stems are commonly used in revision total hip arthroplasty (THA). However, which type of femoral stem is superior remains controversial. The purpose of this study was to assess the clinical and radiographic outcomes of modular and nonmodular tapered fluted titanium. The clinical data of patients undergoing primary revision THA from January 2009 to January 2013 in two institutions were retrospectively analyzed. According to the type of prosthesis used on the femoral side, the patients were divided into the modular group (108 hips; Link MP modular stem in 73 hips and AK-MR modular stem in 35 hips) and nonmodular group (110 hips; Wagner SL stem in 78 hips and AK-SL stem in 32 hips). The operative time, hospital stay, blood loss, blood transfusion volume, hip function, hip pain, limb length discrepancy, imaging data, and complications were compared between the two groups.A total of 218 patients were followed up for 78-124 months, with an average of 101.5 months.