Search

A key pathological hallmark of most neurodegenerative diseases is the misfolding of a particular protein, leading to deposition of toxic protein aggregates in brain tissue. Recent data provide compelling evidence that pathogenic protein aggregates have prion-like properties-they self-replicate by templated misfolding of monomeric proteins and spread between individual cells. Studies in genetic model organisms have expanded our understanding of how prion-like pathogenic aggregates propagate in vivo, revealing potential roles for spreading along neural networks and key cellular processes in both neurons and glial cells. These findings and future studies in genetic models will help guide the development of novel therapeutic strategies that directly target the molecular mechanisms underlying these devastating diseases., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: The purpose of this study was to characterize the urinary microbiota in women who are planning treatment for urgency urinary incontinence and to describe clinical associations with urinary symptoms, urinary tract infection, and treatment outcomes., Study Design: Catheterized urine samples were collected from multisite randomized trial participants who had no clinical evidence of urinary tract infection; 16S ribosomal RNA gene sequencing was used to dichotomize participants as either DNA sequence-positive or sequence-negative. Associations with demographics, urinary symptoms, urinary tract infection risk, and treatment outcomes were determined. In sequence-positive samples, microbiotas were characterized on the basis of their dominant microorganisms., Results: More than one-half (51.1%; 93/182) of the participants' urine samples were sequence-positive. Sequence-positive participants were younger (55.8 vs 61.3 years old; P = .0007), had a higher body mass index (33.7 vs 30.1 kg/m(2); P = .0009), had a higher mean baseline daily urgency urinary incontinence episodes (5.7 vs 4.2 episodes; P < .0001), responded better to treatment (decrease in urgency urinary incontinence episodes, -4.4 vs -3.3; P = .0013), and were less likely to experience urinary tract infection (9% vs 27%; P = .0011). In sequence-positive samples, 8 major bacterial clusters were identified; 7 clusters were dominated not only by a single genus, most commonly Lactobacillus (45%) or Gardnerella (17%), but also by other taxa (25%). The remaining cluster had no dominant genus (13%)., Conclusion: DNA sequencing confirmed urinary bacterial DNA in many women with urgency urinary incontinence who had no signs of infection. Sequence status was associated with baseline urgency urinary incontinence episodes, treatment response, and posttreatment urinary tract infection risk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

While cell signaling devotees tend to think of the endoplasmic reticulum (ER) as a Ca(2+) store, those who study protein synthesis tend to see it more as site for protein maturation, or even degradation when proteins do not fold properly. These two worldviews collide when inositol 1,4,5-trisphosphate (IP(3)) receptors are activated, since in addition to acting as release channels for stored ER Ca(2+), IP(3) receptors are rapidly destroyed via the ER-associated degradation (ERAD) pathway, a ubiquitination- and proteasome-dependent mechanism that clears the ER of aberrant proteins. Here we review recent studies showing that activated IP(3) receptors are ubiquitinated in an unexpectedly complex manner, and that a novel complex composed of the ER membrane proteins SPFH1 and SPFH2 (erlin 1 and 2) binds to IP(3) receptors immediately after they are activated and mediates their ERAD. Remarkably, it seems that the conformational changes that underpin channel opening make IP(3) receptors resemble aberrant proteins, which triggers their binding to the SPFH1/2 complex, their ubiquitination and extraction from the ER membrane and finally, their degradation by the proteasome. This degradation of activated IP(3) receptors by the ERAD pathway serves to reduce the sensitivity of ER Ca(2+) stores to IP(3) and may protect cells against deleterious effects of over-activation of Ca(2+) signaling pathways.