University of Texas Southwestern Medical Center

About: University of Texas Southwestern Medical Center is a healthcare organization based out in Dallas, Texas, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 39107 authors who have published 75242 publications receiving 4497256 citations. The organization is also known as: UT Southwestern & UT Southwestern Medical School.

The continuing value of the Apgar score for the assessment of newborn infants.

Abstract: Background The 10-point Apgar score has been used to assess the condition and prognosis of newborn infants throughout the world for almost 50 years. Some investigators have proposed that measurement of pH in umbilical-artery blood is a more objective method of assessing newborn infants. Methods We carried out a retrospective cohort analysis of 151,891 live-born singleton infants without malformations who were delivered at 26 weeks of gestation or later at an inner-city public hospital between January 1988 and December 1998. Paired Apgar scores and umbilical-artery blood pH values were determined for 145,627 infants to assess which test best predicted neonatal death during the first 28 days after birth. Results For 13,399 infants born before term (at 26 to 36 weeks of gestation), the neonatal mortality rate was 315 per 1000 for infants with five-minute Apgar scores of 0 to 3, as compared with 5 per 1000 for infants with five-minute Apgar scores of 7 to 10. For 132,228 infants born at term (37 weeks of gest...

Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion

Abstract: Cholesterol and other sterols exit the body primarily by secretion into bile. In patients with sitosterolemia, mutations in either of two ATP-binding cassette (ABC) half-transporters, ABCG5 or ABCG8, lead to reduced secretion of sterols into bile, implicating these transporters in this process. To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, we disrupted Abcg5 and Abcg8 in mice (G5G8−/−). The G5G8−/− mice had a 2- to 3-fold increase in the fractional absorption of dietary plant sterols, which was associated with an ≈30-fold increase in plasma sitosterol. Biliary cholesterol concentrations were extremely low in the G5G8−/− mice when compared with wild-type animals (mean = 0.4 vs. 5.5 μmol/ml) and increased only modestly with cholesterol feeding. Plasma and liver cholesterol levels were reduced by 50% in the chow-fed G5G8−/− mice and increased 2.4- and 18-fold, respectively, after cholesterol feeding. These data indicate that ABCG5 and ABCG8 are required for efficient secretion of cholesterol into bile and that disruption of these genes increases dramatically the responsiveness of plasma and hepatic cholesterol levels to changes in dietary cholesterol content.

How nucleotide excision repair protects against cancer

Abstract: Eukaryotic cells can repair many types of DNA damage. Among the known DNA repair processes in humans, one type — nucleotide excision repair (NER) — specifically protects against mutations caused indirectly by environmental carcinogens. Humans with a hereditary defect in NER suffer from xeroderma pigmentosum and have a marked predisposition to skin cancer caused by sunlight exposure. How does NER protect against skin cancer and possibly other types of environmentally induced cancer in humans?

Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2

Abstract: RIG-I is an RNA helicase containing caspase activation and recruitment domains (CARDs). RNA binding and signaling by RIG-I are implicated in pathogen recognition and triggering of IFN-alpha/beta immune defenses that impact cell permissiveness for hepatitis C virus (HCV). Here we evaluated the processes that control RIG-I signaling. RNA binding studies and analysis of cells lacking RIG-I, or the related MDA5 protein, demonstrated that RIG-I, but not MDA5, efficiently binds to secondary structured HCV RNA to confer induction of IFN-beta expression. We also found that LGP2, a helicase related to RIG-I and MDA5 but lacking CARDs and functioning as a negative regulator of host defense, binds HCV RNA. In resting cells, RIG-I is maintained as a monomer in an autoinhibited state, but during virus infection and RNA binding it undergoes a conformation shift that promotes self-association and CARD interactions with the IPS-1 adaptor protein to signal IFN regulatory factor 3- and NF-kappaB-responsive genes. This reaction is governed by an internal repressor domain (RD) that controls RIG-I multimerization and IPS-1 interaction. Deletion of the RIG-I RD resulted in constitutive signaling to the IFN-beta promoter, whereas RD expression alone prevented signaling and increased cellular permissiveness to HCV. We identified an analogous RD within LGP2 that interacts in trans with RIG-I to ablate self-association and signaling. Thus, RIG-I is a cytoplasmic sensor of HCV and is governed by RD interactions that are shared with LGP2 as an on/off switch controlling innate defenses. Modulation of RIG-I/LGP2 interaction dynamics may have therapeutic implications for immune regulation.

Acylation targets endothelial nitric oxide synthase to plasmalemmal caveolae

Abstract: Endothelial nitric-oxide synthase (eNOS) generates the key signaling molecule nitric oxide in response to intralumenal hormonal and mechanical stimuli We designed studies to determine whether eNOS is localized to plasmalemmal microdomains implicated in signal transduction called caveolae Using immunoblot analysis, eNOS protein was detected in caveolar membrane fractions isolated from endothelial cell plasma membranes by a newly developed detergent-free method; eNOS protein was not found in noneaveolar plasma membrane Similarly, NOS enzymatic activity was 94-fold enriched in caveolar membrane versus whole plasma membrane, whereas it was undetectable in non-caveolar plasma membrane 51-86% of total NOS activity in postnuclear supernatant was recovered in plasma membrane, and 57-100% of activity in plasma membrane was recovered in caveolae Immunoelectron microscopy showed that eNOS heavily decorated endothelial caveolae, whereas coated pits and smooth plasma membrane were devoid of gold particles Furthermore, eNOS was targeted to caveolae in COS-7 cells transfected with wild-type eNOS cDNA Studies with eNOS mutants revealed that both myristoylation and palmitoylation are required to target the enzyme to caveolae and that each acylation process enhances targeting by 10-fold Thus, acylation targets eNOS to plasmalemmal caveolae Localization to this microdomain is likely to optimize eNOS activation and the extracellular release of nitric oxide