Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2

The hypoxia-inducible factor (HIF) prolyl-hydroxylases (human PHD1-3) catalyze prolyl hydroxylation in oxygen-dependent degradation (ODD) domains of HIFα isoforms, modifications that signal for HIFα proteasomal degradation in an oxygen-dependent manner. PHD inhibitors are used for treatment of anemia in kidney disease. Increased erythropoietin (EPO) in patients with familial/idiopathic erythrocytosis and pulmonary hypertension is associated with mutations in EGLN1 (PHD2) and EPAS1 (HIF2α); a drug inhibiting HIF2α activity is used for clear cell renal cell carcinoma (ccRCC) treatment. We report crystal structures of PHD2 complexed with the C-terminal HIF2α-ODD in the presence of its 2-oxoglutarate cosubstrate or N-oxalylglycine inhibitor. Combined with the reported PHD2.HIFα-ODD structures and biochemical studies, the results inform on the different PHD.HIFα-ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform-selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment

Scalable SCPPM Decoder

A decoder was developed that decodes a serial concatenated pulse position modulation (SCPPM) encoded information sequence. The decoder takes as input a sequence of four bit log-likelihood ratios (LLR) for each PPM slot in a codeword via a XAUI 10-Gb/s quad optical fiber interface. If the decoder is unavailable, it passes the LLRs on to the next decoder via a XAUI 10-Gb/s quad optical fiber interface. Otherwise, it decodes the sequence and outputs information bits through a 1-GB/s Ethernet UDP/IP (User Datagram Protocol/Internet Protocol) interface. The throughput for a single decoder unit is 150-Mb/s at an average of four decoding iterations; by connecting a number of decoder units in series, a decoding rate equal to that of the aggregate rate is achieved. The unit is controlled through a 1-GB/s Ethernet UDP/IP interface. This ground station decoder was developed to demonstrate a deep space optical communication link capability, and is unique in the scalable design to achieve real-time SCPP decoding at the aggregate data rate

Carbon-Rich Mira Variables: Radial Velocities and Distances

Optical radial velocities have been measured for 38 C-type Mira variables. These data together with others in the literature are used to study the differences between optical and CO mm observations for C-Miras and the necessary corrections to the optical velocities are derived in order to obtain the true radial velocities of the variables. The difference between absorption and emission line velocities is also examined. A particularly large difference (+30 km\s) is found in the case of the H-alpha emission line. A catalogue is given of 177 C-Miras with estimated distances and radial velocities. The distances are based on bolometric magnitudes derived in Paper I using SAAO observations or (for 60 of the stars) using non-SAAO photometry. In the latter case the necessary transformations to the SAAO system are derived. These data will be used in paper III to study the kinematics of the C-Miras.Comment: 11 pages, accepted for publication in MNRA

Disparities of Care for African-Americans and Caucasians with Community-Acquired Pneumonia: A Retrospective Cohort Study

Background\ud African-Americans admitted to U.S. hospitals with community-acquired pneumonia (CAP) are more likely than Caucasians to experience prolonged hospital length of stay (LOS), possibly due to either differential treatment decisions or patient characteristics.\ud \ud Methods\ud We assessed associations between race and outcomes (Intensive Care Unit [ICU] variables, LOS, 30-day mortality) for African-American or Caucasian patients over 65 years hospitalized in the Veterans Health Administration (VHA) with CAP (2002-2007). Patients admitted to the ICU were analyzed separately from those not admitted to the ICU. VHA patients who died within 30 days of discharge were excluded from all LOS analyses. We used chi-square and Fisher's exact statistics to compare dichotomous variables, the Wilcoxon Rank Sum test to compare age by race, and Cox Proportional Hazards Regression to analyze hospital LOS. We used separate generalized linear mixed-effect models, with admitting hospital as a random effect, to examine associations between patient race and the receipt of guideline-concordant antibiotics, ICU admission, use of mechanical ventilation, use of vasopressors, LOS, and 30-day mortality. We defined statistical significance as a two-tailed p ≤ 0.0001.\ud \ud Results\ud Of 40,878 patients, African-Americans (n = 4,936) were less likely to be married and more likely to have a substance use disorder, neoplastic disease, renal disease, or diabetes compared to Caucasians. African-Americans and Caucasians were equally likely to receive guideline-concordant antibiotics (92% versus 93%, adjusted OR = 0.99; 95% CI = 0.81 to 1.20) and experienced similar 30-day mortality when treated in medical wards (adjusted OR = 0.98; 95% CI = 0.87 to 1.10). African-Americans had a shorter adjusted hospital LOS (adjusted HR = 0.95; 95% CI = 0.92 to 0.98). When admitted to the ICU, African Americans were as likely as Caucasians to receive guideline-concordant antibiotics (76% versus 78%, adjusted OR = 0.99; 95% CI = 0.81 to 1.20), but experienced lower 30-day mortality (adjusted OR = 0.82; 95% CI = 0.68 to 0.99) and shorter hospital LOS (adjusted HR = 0.84; 95% CI = 0.76 to 0.93).\ud \ud Conclusions\ud Elderly African-American CAP patients experienced a survival advantage (i.e., lower 30-day mortality) in the ICU compared to Caucasians and shorter hospital LOS in both medical wards and ICUs, after adjusting for numerous baseline differences in patient characteristics. There were no racial differences in receipt of guideline-concordant antibiotic therapies

A Distinct Metabolite Signature in Military Personnel Exposed to Repetitive Low-Level Blasts

Military Breachers and Range Staff (MBRS) are subjected to repeated sub-concussive blasts, and they often report symptoms that are consistent with a mild traumatic brain injury (mTBI). Biomarkers of blast injury would potentially aid blast injury diagnosis, surveillance and avoidance. Our objective was to identify plasma metabolite biomarkers in military personnel that were exposed to repeated low-level or sub-concussive blast overpressure. A total of 37 military members were enrolled (18 MBRS and 19 controls), with MBRS having participated in 8–20 breaching courses per year, with a maximum exposure of 6 blasts per day. The two cohorts were similar except that the number of blast exposures were significantly higher in the MBRS, and the MBRS cohort suffered significantly more post-concussive symptoms and poorer health on assessment. Metabolomics profiling demonstrated significant differences between groups with 74% MBRS classification accuracy (CA). Feature reduction identified 6 metabolites that resulted in a MBRS CA of 98%, and included acetic acid (23.7%), formate (22.6%), creatine (14.8%), acetone (14.2%), methanol (12,7%), and glutamic acid (12.0%). All 6 metabolites were examined with individual receiver operating characteristic (ROC) curve analyses and demonstrated areas-under-the-curve (AUCs) of 0.82–0.91 (P ≤ 0.001) for MBRS status. Several parsimonious combinations of three metabolites increased accuracy of ROC curve analyses to AUCs of 1.00 (P \u3c 0.001), while a combination of volatile organic compounds (VOCs; acetic acid, acetone and methanol) yielded an AUC of 0.98 (P \u3c 0.001). Candidate biomarkers for chronic blast exposure were identified, and if validated in a larger cohort, may aid surveillance and care of military personnel. Future point-of-care screening could be developed that measures VOCs from breath, with definitive diagnoses confirmed with plasma metabolomics profiling

The Discovery of a Massive Cluster of Red Supergiants with GLIMPSE

We report the discovery of a previously unknown massive Galactic star cluster at l=29.22, b=-0.20. Identified visually in mid-IR images from the Spitzer GLIMPSE survey, the cluster contains at least 8 late-type supergiants, based on followup near-IR spectroscopy, and an additional 3-6 candidate supergiant embers having IR photometry consistent with a similar distance and reddening. The cluster lies at a local minimum in the 13-CO column density and 8 micron emission. We interpret this feature as a hole carved by the energetic winds of the evolving massive stars. The 13-CO hole seen in molecular maps at V_LSR ~95 km/s corresponds to near/far kinematic distances of 6.1/8.7+/-1 kpc. We calculate a mean spectrophotometric distance of 7.0^+3.7_-2.4 kpc, broadly consistent with the kinematic distances inferred. This location places it near the northern end of the Galactic bar. For the mean extinction of A_V=12.6+/-0.5 mag (A_K=1.5+/-0.1 mag), the color-magnitude diagram of probable cluster members is well fit by isochrones in the age range 18-24 Myr. The estimated cluster mass is ~20,000 Msun. With the most massive original cluster stars likely deceased, no strong radio emission is detected in this vicinity. As such, this RSG cluster is representative of adolescent massive Galactic clusters that lie hidden behind many magnitudes of dust obscuration. This cluster joins two similar red supergiant clusters as residents of the volatile region where the end of our Galaxy's bar joins the base of the Scutum-Crux piral arm, suggesting a recent episode of widespread massive star formation there.Comment: 26 pages; Accepted for publication in The Astronomical Journal 2009 March 13; Submitted 2008 November 6. Reports a concurrent discovery of the star cluster investigated by Clark et al. in arXiv:0903.175

Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation.

The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation

Neuromyelitis optica spectrum disorders in children and adolescents.

Neuromyelitis optica (NMO) is a severe autoimmune disease of the CNS characterized by recurrent inflammatory events primarily involving the optic nerves and spinal cord. NMO is infrequent in children, but early recognition is important to start adequate treatment. In this article, we review the evolving diagnostic criteria of NMO and provide an update on the clinical and neuroimaging spectrum of the disorder in pediatric patients, including current knowledge on immunopathogenesis and treatment recommendations for children with NMO.journal articlereview2016 Aug 30importe

Lignin Modification Leads to Increased Nodule Numbers in Alfalfa

Reduction of lignin levels in the forage legume alfalfa (Medicago sativa) by down-regulation of the monolignol biosynthetic enzyme hydroxycinnamoyl coenzyme A:shikimate hydroxycinnamoyl transferase (HCT) results in strongly increased digestibility and processing ability of lignocellulose. However, these modifications are often also associated with dwarfing and other changes in plant growth. Given the importance of nitrogen fixation for legume growth, we evaluated the impact of constitutively targeted lignin modification on the belowground organs (roots and nodules) of alfalfa plants. HCT down-regulated alfalfa plants exhibit a striking reduction in root growth accompanied by an unexpected increase in nodule numbers when grown in the greenhouse or in the field. This phenotype is associated with increased levels of gibberellins and certain flavonoid compounds in roots. Although HCT down-regulation reduced biomass yields in both the greenhouse and field experiments, the impact on the allocation of nitrogen to shoots or roots was minimal. It is unlikely, therefore, that the altered growth phenotype of reduced-lignin alfalfa is a direct result of changes in nodulation or nitrogen fixation efficiency. Furthermore, HCT down-regulation has no measurable effect on carbon allocation to roots in either greenhouse or 3-year field trials