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Hypertension During Pregnancy Risks Woman's Health Later in Life (CME/CE)

Headlines from MedPage Today® - Sun, 02/07/2016 - 2:00pm
(MedPage Today) -- Increased risk of mortality and a variety of comorbidities

FDA Turns Away New Indication for CF Drug Kalydeco

Headlines from MedPage Today® - Sun, 02/07/2016 - 1:00pm
(MedPage Today) -- Won't approve use in patients with certain CFTR mutations

Earlier May Be Better for Flu Vax in Pregnant Women

Headlines from MedPage Today® - Sun, 02/07/2016 - 12:00pm
(MedPage Today) -- Pilot study found somewhat better immune response in first trimester

Antibodies Predict RA Response to Orencia (CME/CE)

Headlines from MedPage Today® - Sun, 02/07/2016 - 11:00am
(MedPage Today) -- Patients seropositive for rheumatoid factor or ACPA less likely to stop abatacept

MERS Virus Targets Lungs (CME/CE)

Headlines from MedPage Today® - Sun, 02/07/2016 - 10:00am
(MedPage Today) -- First autopsy in fatal case increases understanding of pathogenesis

Sequential, Alternating Drug Regimens Both Effective in Myeloma (CME/CE)

Headlines from MedPage Today® - Sun, 02/07/2016 - 9:00am
(MedPage Today) -- Further optimization for newly diagnosed seniors still needed

Wired for Life: Device Short Circuits Seizures

Headlines from MedPage Today® - Sun, 02/07/2016 - 12:01am
(MedPage Today) -- When nothing else works, this device may be best option in epilepsy

Diet-responsive Gene Networks Rewire Metabolism in the Nematode Caenorhabditis elegans to Provide Robustness against Vitamin B12 Deficiency: A Dissertation

eScholarship@UMMS - Sat, 02/06/2016 - 10:21pm

Maintaining cellular homeostasis is a complex task, which involves monitoring energy states and essential nutrients, regulating metabolic fluxes to accommodate energy and biomass needs, and preventing buildup of potentially toxic metabolic intermediates and byproducts. Measures aimed at maintaining a healthy cellular economy inherently depend on the composition of nutrients available to the organism through its diet. We sought to delineate links between dietary composition, metabolic gene regulation, and physiological responses in the model organism C. elegans.

As a soil-dwelling bacterivore, C. elegans encounters diverse bacterial diets. Compared to a diet of E. coli OP50, a diet of Comamonas aquatica accelerates C. elegans developmental rate, alters egg-laying dynamics and shortens lifespan. These physiological responses are accompanied by gene expression changes. Taking advantage of this natural, genetically tractable predator-prey system, we performed genetic screens i) in C. elegans to identify regulators of diet-responsive genes, and ii) in E. coli and Comamonas to determine dietary factors driving transcriptional responses in C. elegans. We identified a C. elegans transcriptional program that regulates metabolic genes in response to vitamin B12 content in the bacterial diet. Interestingly, several B12- repressed metabolic genes of unknown function are highly activated when B12- dependent propionyl-CoA breakdown is impaired, and inactivation of these genes renders animals sensitive to propionate-induced toxicity. We provide genetic and metabolomic evidence in support of the hypothesis that these genes form a parallel, B12-independent, β-oxidation-like propionate breakdown shunt in C. elegans, similar to the pathway utilized by organisms like yeast and plants that do not use vitamin B12.

Transcriptional Regulation of the Drosophila Peptidoglycan Sensor PGRP-LC by the Steroid Hormone Ecdysone: A Masters Thesis

eScholarship@UMMS - Sat, 02/06/2016 - 10:21pm

Drosophila is host to the steroid hormone ecdysone, which regulates development and immune functions using a common group of transcription factors. Developmentally-induced ecdysone pulses activate the expression of the EcR, BR-C, HR46, Eip74EF, Eip75B, Eip78C, and Eip93F, which assume control of hundreds of other genes involved in the transition from larva to pupa stage. Many of the transcription factors are related to mammalian nuclear hormone receptors by homology. In addition to these transcription factors, the ecdysoneregulated GATA factors SRP and PNR are required for the proper expression of the peptidoglycan sensor PGRP-LC, which belongs to a conserved class of proteins in innate immunity. Although the transcriptional network has been elucidated in development, it is unclear why ecdysone control of PGRP-LC gene activity involves these nine transcription factors and how ecdysone is regulated in the context of an infection in vivo.

An ecdysone-activated enhancer was located upstream of the PGRP-LC locus using a reporter plasmid. Female flies that lacked the enhancer had reduced PGRP-LC expression, but survived infection. Male flies did not experience these changes. Therefore, PGRP-LC enhancer appears to be a female-specific cis-regulatory element. The lack of survival phenotype could be caused by using an improper injection site. Bioinformatics software was used to identify putative individual and overlapping binding sites for some transcription factors. Site-directed mutations of the motifs reduced PGRP-LC promoter activity without abolishing the signal. These results suggest that the transcription factors assemble at multiple locations on the PGRP-LC enhancer and form strong protein-protein bonds. Septic injury led to elevated ecdysone in whole flies, which could be a neuroendocrine response to stress similar to the mammalian system. Steroid hormone regulation of immune receptors is a common theme in humans and flies, and these results could advance our understanding of the transcriptional regulation of related genes and gender differences observed in innate immune responses at the transcriptional level.

Exploring the Role of FUS Mutants from Stress Granule Incorporation to Nucleopathy in Amyotrophic Lateral Sclerosis: A Dissertation

eScholarship@UMMS - Sat, 02/06/2016 - 10:21pm

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade.

FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than 50 mutations in the FUS gene are linked to 4% of familial ALS, and many of these may disrupt the nuclear localization signal, leading to variable amounts of FUS accumulation in the cytoplasm. However, the mechanism by which FUS mutants cause motor neuron death is still unknown.

The studies presented in this dissertation focused on investigating the properties of FUS mutants in the absence and presence of stress conditions. We first examined how ALS-linked FUS mutants behaved in response to imposed stresses in both cell culture and zebrafish models of ALS. We found that FUS mutants were prone to accumulate in stress granules in proportion to their degree of cytoplasmic mislocalization under conditions of oxidative stress, ER stress, and heat shock.

However, many FUS missense mutants are retained predominantly in the nucleus, and this suggested the possibility that these mutants might also perturb one or more nuclear functions. In a human cell line expressing FUS variants and in human fibroblasts from an ALS patient, mutant FUS expression was associated with enlarged promyelocytic leukemia nuclear bodies (PML-NBs) under basal condition. Upon oxidative insult with arsenic trioxide (ATO), PML-NBs in control cells increased acutely in size and were turned over within 12-24 h, as expected. However, PML-NBs in FUS mutant cells did not progress through the expected turnover but instead continued to enlarge over 24 h. We also observed a persistent accumulation of the transcriptional repressor Daxx and the 11S proteasome regulator in association with these enlarged PML-NBs. Furthermore, the peptidase activities of the 26S proteasome were decreased in FUS mutant cells without any changes in the expression of proteasome subunits.

These results demonstrate that FUS mutant expression may alter cellular stress responses as manifested by (i) accumulation of mutant FUS into stress granules and (ii) inhibition of PML-NB dynamics. These findings suggest a novel nuclear pathology specific to mutant FUS expression that may perturb nuclear homeostasis and thereby contribute to ALS pathogenesis.

OB-GYNS: Stick With CDC Zika Guidelines

Headlines from MedPage Today® - Sat, 02/06/2016 - 3:48pm
(MedPage Today) -- Special SMFM session clarifies role of serial ultrasound, amniocentesis

Bone Marrow Lesions Common in Young Adults (CME/CE)

Headlines from MedPage Today® - Sat, 02/06/2016 - 3:00pm
(MedPage Today) -- BMLs correlate with knee symptoms, history of knee injury

How Intuition Paved the Way for One Physician

Headlines from MedPage Today® - Sat, 02/06/2016 - 2:00pm
(MedPage Today) -- Haywood Hall, MD, learned how to practice medicine differently with telemedicine

PodMed: A Medical News Roundup From Johns Hopkins (with audio)

Headlines from MedPage Today® - Sat, 02/06/2016 - 1:00pm
(MedPage Today) -- This week's topics include a Zika virus update, choice of topical agents before C-section, surgery resident hours, and rivaroxaban trial questions

Amyloid Deposits in TBI Similar to Alzheimer's (CME/CE)

Headlines from MedPage Today® - Sat, 02/06/2016 - 12:00pm
(MedPage Today) -- Distinct deposition pattern suggests shared mechanism

D.C. Week: Obama Pitches $1.1 Billion to Fight Opioid Addiction

Headlines from MedPage Today® - Sat, 02/06/2016 - 11:00am
(MedPage Today) -- House questions infamous former Turing CEO about drug price hikes

Hospitals Put Empathy in Emails

Headlines from MedPage Today® - Sat, 02/06/2016 - 10:00am
(MedPage Today) -- Automating the human touch appears effective

How to Unboil an Egg: That's Improbable!

Headlines from MedPage Today® - Sat, 02/06/2016 - 9:00am
(MedPage Today) -- Also, why hummingbirds get so hot

Insulin Out of Reach for Millions Around the Globe

Headlines from MedPage Today® - Sat, 02/06/2016 - 8:00am
(MedPage Today) -- Price and accessibility prevent many in need from getting it

'Tradeoffs for This Important Work': What We Heard This Week

Headlines from MedPage Today® - Fri, 02/05/2016 - 4:30pm
(MedPage Today) -- Quoteable quotes from MedPage Today's sources
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