136 HIV-1 Nef regulates activity of endoplasmic reticulum chaperone calnexin

HIV-1 Nef promotes viral replication by downmodulating a number of cell surface transmembrane proteins, such as CD4, MHC-I and MHC-II, which are targeted by Nef to various degradation pathways. Nef is also responsible for downregulation of cellular cholesterol transporter ABCA1, and this effect contributes to development of atherosclerosis in HIV infected patients. Surprisingly, in contrast to CD4 and MHC I, to which Nef has to bind to exert downregulation, binding to ABCA1 turned out to be unnecessary for inactivation of ABCA1 by Nef. Here, we identified a novel mechanism by which Nef influences activity of host cell and viral proteins. We show that Nef interacts with an endoplasmic reticulum chaperone calnexin, which is essential for folding and maturation of glycosylated proteins. Nef disrupts calnexin interaction with ABCA1, thus impairing functionality of this protein, but increases affinity and enhances interaction of calnexin with gp160, promoting maturation and functionality of viral Env proteins. Knock-down of calnexin lead to reduced fusion activity of HIV-1 envelope and reduced virion infectivity, as well as to defective cholesterol efflux, which is mediated by ABCA1. However, gp160 and ABCA1 interacted with calnexin differently: while gp160 binding to calnexin was dependent on glycosylation, interaction of ABCA1 with calnexin was glycosylation-independent. Therefore, Nef binds to calnexin and stimulates interaction between calnexin and gp160 at the expense of ABCA1 and probably other ER proteins. These results provide a mechanistic explanation for previously unexplained effect of Nef on functionality of ABCA1, and suggest a mechanism for upregulation of HIV infectivity by Nef through stimulation of Env maturation

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential.

BackgroundMetastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning > 300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome.MethodsPNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000 and 2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121).ResultsThe CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene "metastasis" signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression.ConclusionsMeasuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis

Recurrent 8q13.2-13.3 microdeletions associated with Branchio-oto-renal syndrome are mediated by human endogenous retroviral (HERV) sequence blocks

Background: Human endogenous retroviral (HERV) sequences are the remnants of ancient retroviral infection and comprise approximately 8% of the human genome. The high abundance and interspersed nature of homologous HERV sequences make them ideal substrates for genomic rearrangements. A role for HERV sequences in mediating human disease-associated rearrangement has been reported but is likely currently underappreciated. Methods and Results: In the present study, two independent de novo 8q13.2-13.3 microdeletion events were identified in patients with clinical features of Branchio-Oto-Renal (BOR) syndrome. Nucleotide-level mapping demonstrated the identical breakpoints, suggesting a recurrent microdeletion including multiple genes such as EYA1, SULF1, and SLCO5A1, which is mediated by HERV1 homologous sequences. Conclusions: These findings raise the potential that HERV sequences may more commonly underlie recombination of dosage sensitive regions associated with recurrent syndromes

George Crumb and Makrokosmos, Volume 1

In the words of David Burge, George Crumb provided his listeners with something of the sensation of awe, wonder, and enigmatic beauty that he himself felt concerning the \u27mysteries.\u27 He named movements after geological eras, referred to images as coming from \u27the dark land,\u27 invented visual symbols for his scores, and concocted numerological schemes. For many listeners these extra musical trappings provided an avenue into the music itself, allowing them to listen to it openly and with interest rather than with resistance and skepticism (Burge, 1990, p. 212)

Suicide in older adults : helping case managers engage in difficult conversations : a project based upon an independent investigation in collaboration the producer of the film Talking with Dolores , Darlene O\u27Connor

Suicide among older adults is an increasing mental health concern in the United States, and yet depression and other signs of suicide often go unnoticed. The film and discussion guide Talking with Dolores was funded by the Massachusetts Department of Public Health to increase awareness of warnings of depression and suicide in the elderly and demonstrate ways of conversing with them about suicide. Because of their unique contact with older individuals in their own homes, geriatric case managers are positioned as a gateway to necessary psychosocial support for elders, yet may not be receiving adequate training for the initial detection of severe depression and suicide risk. Professional social workers are frequently put into the position of providing training related to the psychosocial needs of clients who are cared for by geriatric case managers. Thus, case managers and social workers alike may benefit from training tools which might increase capabilities of case managers to confront these emotionally charged issues. This study explores whether geriatric case managers think this film/discussion would be a useful training tool for increasing their awareness and comfort in discussing depression and suicide with clients. The data from two focus groups of geriatric case managers in Boston, MA indicated that they perceived that the Talking with Dolores training effectively reminded them of their important role in providing psychosocial support to their clients and helped them identify signs of suicide, but did not sufficiently provide them with concrete skills in the management of suicidal ideation. The qualitative data revealed some speculation that Talking with Dolores would increase their comfort in discussing depression and suicide with clients. Participants thought it could be a helpful training tool for geriatric case managers. They reported a lack of knowledge and training on the subject was the inhibiting factor for not discussing suicide with their clients. Additional quantitative data showed that the sample\u27s exposure to the Dolores training increased knowledge about suicide risk in the elderly but did not increase their comfort level in discussing suicide with clients

Concert recording 2021-04-22a

[Track 1]. Sicilienne and rigaudon in the style of Francoeur / Kriesler -- [Track 2]. Suite for violin and orchestra in A minor, op. 10. I. Presto ; [Track 3]. II. Adadio / Sinding -- [Track 4]. Concerto for violin no. 1 in A minor. I. Allegro ; II. Adagio / J.S. Bach -- [Track 5]. Violin concerto in B minor opus 35. I. Allegro moderato ; II. Andante ; III. Alegro moderato / Rieding

Interactions and Mechanisms of Respiratory Tract Biofilms Involving Streptococcus Pneumoniae and Nontypeable Haemophilus Influenzae

The pathology associated with human respiratory tract bacterial agents that exist as opportunistic commensals in the nasopharynx cause infections. This is particularly true for the middle ear disease otitis media (OM) and exacerbations of chronic obstructive pulmonary disease (COPD). Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) are a commonly recurrent combination and the formation of bacterial biofilms by these pathogens in the bronchial airway or middle ear contributes significantly to the chronic nature of these diseases. While S. pneumoniae and NTHi have been extensively studied in mono-culture, our knowledge about how they exist together, either in their free-living (planktonic) form or as a biofilm, or indeed the implication of co-infection is still limited. Several key elements are believed to contribute or are induced: (1) a set of sugar metabolic pathways; (2) surface structures in S. pneumoniae and NTHi when they are able to co-exist equally; (3) epithelial cell contact that dramatically increases the rate of biofilm formation; (4) chemical modifications of NTHi surface structures involved in host cell interactions; and (5) transcription factors that regulate particular surface molecules and the switch to a biofilm state. There appears to be multiple mechanisms involved and that these are active under specific conditions