Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3

We have obtained the 1.7 Å crystal structure of FIV protease (PR) in which 12 critical residues around the active site have been substituted with the structurally equivalent residues of HIV PR (12X FIV PR). The chimeric PR was crystallized in complex with the broad-based inhibitor TL-3, which inhibits wild type FIV and HIV PRs, as well as 12X FIV PR and several drug-resistant HIV mutants [1-4]. Biochemical analyses have demonstrated that TL-3 inhibits these PRs in the order HIV PR > 12X FIV PR > FIV PR, with K(i )values of 1.5 nM, 10 nM, and 41 nM, respectively [2-4]. Comparison of the crystal structures of the TL-3 complexes of 12X FIV and wild-typeFIV PR revealed theformation of additinal van der Waals interactions between the enzyme inhibitor in the mutant PR. The 12X FIV PR retained the hydrogen bonding interactions between residues in the flap regions and active site involving the enzyme and the TL-3 inhibitor in comparison to both FIV PR and HIV PR. However, the flap regions of the 12X FIV PR more closely resemble those of HIV PR, having gained several stabilizing intra-flap interactions not present in wild type FIV PR. These findings offer a structural explanation for the observed inhibitor/substrate binding properties of the chimeric PR

CYP1B1 copy number variation is not a major contributor to primary congenital glaucoma

This article is published under a Creative Commons Attribution-NonCommercial-NoDerivatives License 3.0, or CC BY-NC-ND 3.0 (see http://creativecommons.org/licenses/by-nc-nd/3.0/ for license terms). The authors retain copyright and grant Molecular Vision an irrevocable, royalty-free, perpetual license to publish and distribute the article, in all formats now known or later developed, and to identify Molecular Vision as the original publisher.Purpose: To evaluate the prevalence and the diagnostic utility of testing for CYP1B1 copy number variation (CNV) in primary congenital glaucoma (PCG) cases unexplained by CYP1B1 point mutations in The Australian and New Zealand Registry of Advanced Glaucoma. Methods: In total, 50 PCG cases either heterozygous for disease-causing variants or with no CYP1B1 sequence variants were included in the study. CYP1B1 CNV was analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA). Results: No deletions or duplications were found in any of the cases. Conclusion: This is the first study to report on CYP1B1 CNV in PCG cases. Our findings show that this mechanism is not a major contributor to the phenotype and is of limited diagnostic utility

Reducing Decisional Conflict and Enhancing Satisfaction with Information among Women Considering Breast Reconstruction following Mastectomy: Results from the BRECONDA Randomized Controlled Trial

Background: Deciding whether or not to have breast reconstruction following breast cancer diagnosis is a complex decision process. This randomized controlled trial assessed the impact of an online decision aid [Breast RECONstruction Decision Aid (BRECONDA)] on breast reconstruction decision-making. Methods: Women (n = 222) diagnosed with breast cancer or ductal carcinoma in situ, and eligible for reconstruction following mastectomy, completed an online baseline questionnaire. They were then assigned randomly to receive either standard online information about breast reconstruction (control) or standard information plus access to BRECONDA (intervention). Participants then completed questionnaires at 1 and 6 months after randomization. The primary outcome was participants' decisional conflict 1 month after exposure to the intervention. Secondary outcomes included decisional conflict at 6 months, satisfaction with information at 1 and 6 months, and 6-month decisional regret. Results: Linear mixed-model analyses revealed that 1-month decisional conflict was significantly lower in the intervention group (27.18) compared with the control group (35.5). This difference was also sustained at the 6-month follow-up. Intervention participants reported greater satisfaction with information at 1- and 6-month follow-up, and there was a nonsignificant trend for lower decisional regret in the intervention group at 6-month follow-up. Intervention participants' ratings for BRECONDA demonstrated high user acceptability and overall satisfaction. Conclusions: Women who accessed BRECONDA benefited by experiencing significantly less decisional conflict and being more satisfied with information regarding the reconstruction decisional process than women receiving standard care alone. These findings support the efficacy of BRECONDA in helping women to arrive at their breast reconstruction decision

Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β during Dectin-1 signaling

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP

Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma

© 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND licensePurpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective, multicenter case series. Participants A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency < 4×10−5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest–derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment

The influence of tumor regression, solar elastosis, and patient age on pathologists\u27 interpretation of melanocytic skin lesions.

It is not known whether patient age or tumor characteristics such as tumor regression or solar elastosis influence pathologists\u27 interpretation of melanocytic skin lesions (MSLs). We undertook a study to determine the influence of these factors, and to explore pathologist\u27s characteristics associated with the direction of diagnosis. To meet our objective, we designed a cross-sectional survey study of pathologists\u27 clinical practices and perceptions. Pathologists were recruited from diverse practices in 10 states in the United States. We enrolled 207 pathologist participants whose practice included the interpretation of MSLs. Our findings indicated that the majority of pathologists (54.6%) were influenced toward a less severe diagnosis when patients were70 years of age, or by the presence of tumor regression or solar elastosis (58.5%, 71.0%, and 57.0%, respectively). Generally, pathologists with dermatopathology board certification and/or a high caseload of MSLs were more likely to be influenced, whereas those with more years\u27 experience interpreting MSL were less likely to be influenced. Our findings indicate that the interpretation of MSLs is influenced by patient age, tumor regression, and solar elastosis; such influence is associated with dermatopathology training and higher caseload, consistent with expertise and an appreciation of lesion complexity

​Residential mobility:Towards progress in mobility health research

Research into health disparities has long recognized the importance of residential mobility as a crucial factor in determining health outcomes. However, a lack of connectivity between the health and mobility literatures has led to a stagnation of theory and application on the health side, which lacks the detail and temporal perspectives now seen as critical to understanding residential mobility decisions. Through a critical re-think of mobility processes with respect to health outcomes and an exploitation of longitudinal analytical techniques, we argue that health geographers have the potential to better understand and identify the relationship that residential mobility has with health.“The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 615159 (ERC Consolidator Grant DEPRIVEDHOODS, Socio-spatial inequality, deprived neighbourhoods, and neighbourhood effects)”OLD Urban Renewal and Housin

Histological features of melanoma associated with CDKN2A genotype

Background: Inherited susceptibility genes have been associated with histopathologic characteristics of tumors. Objective: We sought to identify associations between histology of melanomas and CDKN2A genotype. Methods: This was a case-control study design comparing 28 histopathologic tumor features among individuals with sporadic melanomas (N = 81) and cases from melanoma families with (N = 123) and without (N = 120) CDKN2A germline mutations. Results: Compared with CDKN2A− cases, mutation carriers tended to have histologic features of superficial spreading melanoma subtype including higher pigmentation (Ptrend = .02) and increased pagetoid scatter (Ptrend = .07) after adjusting for age at diagnosis, sex, and American Joint Committee on Cancer thickness category. Similar associations were observed when comparing mutation carriers with a combined group of CDKN2A− (wild type) and sporadic melanomas. The presence of spindle cell morphology in the vertical growth phase was also an important predictor of genotype. Of the 15 cases with this phenotype, none were observed to harbor a CDKN2A mutation. Limitations: Our study examined rare mutations and may have been underpowered to detect small, but biologically significant associations between histology and genotype. Conclusion: Familial melanomas with CDKN2A mutations preferentially express a histologic phenotype of dense pigmentation, high pagetoid scatter, and a non-spindle cell morphology in the vertical growth phase

The nature of slow dynamics in a minimal model of frustration-limited domains

We present simulation results for the dynamics of a schematic model based on the frustration-limited domain picture of glass-forming liquids. These results are compared with approximate theoretical predictions analogous to those commonly used for supercooled liquid dynamics. Although model relaxation times increase by several orders of magnitude in a non-Arrhenius manner as a microphase separation transition is approached, the slow relaxation is in many ways dissimilar to that of a liquid. In particular, structural relaxation is nearly exponential in time at each wave vector, indicating that the mode coupling effects dominating liquid relaxation are comparatively weak within this model. Relaxation properties of the model are instead well reproduced by the simplest dynamical extension of a static Hartree approximation. This approach is qualitatively accurate even for temperatures at which the mode coupling approximation predicts loss of ergodicity. These results suggest that the thermodynamically disordered phase of such a minimal model poorly caricatures the slow dynamics of a liquid near its glass transition