Surface Tension Driven Convection Experiment Completed

The Surface Tension Driven Convection Experiment (STDCE) was designed to study basic fluid mechanics and heat transfer on thermocapillary flows generated by temperature variations along the free surfaces of liquids in microgravity. STDCE first flew on the USML-1 mission in July 1992 and was rebuilt for the USML-2 mission that was launched in October 1995. This was a collaborative project with principal investigators from Case Western Reserve University (CWRU), Professors Simon Ostrach and Yasuhiro Kamotani, along with a team from the NASA Lewis Research Center composed of civil servants and contractors from Aerospace Design & Fabrication, Inc. (ADF), Analex, and NYMA, Inc

DISC1 Pathway in Brain Development: Exploring Therapeutic Targets for Major Psychiatric Disorders

Genetic risk factors for major psychiatric disorders play key roles in neurodevelopment. Thus, exploring the molecular pathways of risk genes is important not only for understanding the molecular mechanisms underlying brain development, but also to decipher how genetic disturbances affect brain maturation and functioning relevant to major mental illnesses. During the last decade, there has been significant progress in determining the mechanisms whereby risk genes impact brain development. Nonetheless, given that the majority of psychiatric disorders have etiological complexities encompassing multiple risk genes and environmental factors, the biological mechanisms of these diseases remain poorly understood. How can we move forward to our research for discovery of the biological markers and novel therapeutic targets for major mental disorders? Here we review recent progress in the neurobiology of disrupted in schizophrenia 1 (DISC1), a major risk gene for major mental disorders, with a particular focus on its roles in cerebral cortex development. Convergent findings implicate DISC1 as part of a large, multi-step pathway implicated in various cellular processes and signal transduction. We discuss links between the DISC1 pathway and environmental factors, such as immune/inflammatory responses, which may suggest novel therapeutic targets. Existing treatments for major mental disorders are hampered by a limited number of pharmacological targets. Consequently, elucidation of the DISC1 pathway, and its association with neuropsychiatric disorders, may offer hope for novel treatment interventions

The structural ensemble of a Holliday junction determined by X-ray scattering interference

The DNA four-way (Holliday) junction is the central intermediate of genetic recombination, yet key aspects of its conformational and thermodynamic properties remain unclear. While multiple experimental approaches have been used to characterize the canonical X-shape conformers under specific ionic conditions, the complete conformational ensemble of this motif, especially at low ionic conditions, remains largely undetermined. In line with previous studies, our single-molecule Förster resonance energy transfer (smFRET) measurements of junction dynamics revealed transitions between two states under high salt conditions, but smFRET could not determine whether there are fast and unresolvable transitions between distinct conformations or a broad ensemble of related states under low and intermediate salt conditions. We therefore used an emerging technique, X-ray scattering interferometry (XSI), to directly probe the conformational ensemble of the Holliday junction across a wide range of ionic conditions. Our results demonstrated that the four-way junction adopts an out-of-plane geometry under low ionic conditions and revealed a conformational state at intermediate ionic conditions previously undetected by other methods. Our results provide critical information to build toward a full description of the conformational landscape of the Holliday junction and underscore the utility of XSI for probing conformational ensembles under a wide range of solution conditions

Study of the Hot-Spot Temperature During Quench in the Nonplanar Coils of W7-X

The quench protection system of the nonplanar coils of the Wendelstein 7-X stellarator was laid out over 15 years ago. At that time, the assessment of the hot-spot temperature by a basic adiabatic model was done using design values for material and operation parameters. After the operating experience in 2016, the hot-spot temperature is reassessed with the thermal-hydraulic program THEA, using the actual values for delay and dump time. The electrical resistivity of the conduit alloy ismeasured over the whole range of temperatures and in magnetic fields on relevant samples of a conductor, exposed to the hardening heat treatment after winding. The results were fed into THEA. Parametric variations are studied in the calculations, e.g., testing the effect of the quench initiation zone, delay time, and dump resistor. The results suggest that the hot-spot temperature of the conduit in the case of quench is safely within the allowable values even when the dump voltage is reduced compared to the initial design value

Morbidity and mortality in adults with congenital heart defects in the third and fourth life decade

Objectives: The population of adults with congenital heart defects (ACHD) is continuously growing. Data on morbidity and mortality of ACHD are limited. This longitudinal observational study examined a group of ACHD with surgically corrected or palliated congenital heart defects (CHD) during a 15-year period. Methods: ACHD that had participated in the initial study were invited for a follow-up examination. Mortality and hospitalization data were compared with a healthy control group. Results: From 05/2017 to 04/2019 a total of 249/364 (68%) ACHD participated in the follow-up study: 21% had mild, 60% moderate and 19% severe CHD. During the observational period, 290 health incidents occurred (cardiac catheterization 37%, cardiovascular surgery 27%, electrophysiological study/ablation 20%, catheter interventional treatment 14%, non-cardiac surgery 3%). Events were more frequent in ACHD with moderate (53%) and severe (87%) compared to those with mild CHD (p \u3c 0.001). 24 individuals died at a median age of 43 years during the observation period. 29% of them had moderate and 71% severe CHD corresponding to a mortality rate of 0%, 0.29% and 1.68% per patient-year in ACHD with mild, moderate and severe CHD. Long-term survival was significantly reduced in patients with severe CHD in comparison to individuals with mild and moderate CHD (p \u3c 0.001). Conclusion: After correction or palliation of CHD, there was remarkable ongoing morbidity and mortality in ACHD patients over the 15-year observation period, particularly in individuals with moderate and severe CHD when compared with the general population. Thus, life-long special care is required for all surgically corrected or palliated ACHD patients. Graphical abstract: [Figure not available: see fulltext.

Co-occurrence of photochemical and microbiological transformation processes in open-water unit process wetlands

The fate of anthropogenic trace organic contaminants in surface waters can be complex due to the occurrence of multiple parallel and consecutive transformation processes. In this study, the removal of five antiviral drugs (abacavir, acyclovir, emtricitabine, lamivudine and zidovudine) via both bio- and phototransformation processes, was investigated in laboratory microcosm experiments simulating an open-water unit process wetland receiving municipal wastewater effluent. Phototransformation was the main removal mechanism for abacavir, zidovudine, and emtricitabine, with half-lives (t1/2,photo) in wetland water of 1.6, 7.6, and 25 h, respectively. In contrast, removal of acyclovir and lamivudine was mainly attributable to slower microbial processes (t1/2,bio = 74 and 120 h, respectively). Identification of transformation products revealed that bio- and phototransformation reactions took place at different moieties. For abacavir and zidovudine, rapid transformation was attributable to high reactivity of the cyclopropylamine and azido moieties, respectively. Despite substantial differences in kinetics of different antiviral drugs, biotransformation reactions mainly involved oxidation of hydroxyl groups to the corresponding carboxylic acids. Phototransformation rates of parent antiviral drugs and their biotransformation products were similar, indicating that prior exposure to microorganisms (e.g., in a wastewater treatment plant or a vegetated wetland) would not affect the rate of transformation of the part of the molecule susceptible to phototransformation. However, phototransformation strongly affected the rates of biotransformation of the hydroxyl groups, which in some cases resulted in greater persistence of phototransformation products

Cerebral expression of metabotropic glutamate receptor subtype 5 in idiopathic autism spectrum disorder and fragile X syndrome: A pilot study

Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGlu

Small Molecule Inhibition of HIV-1–Induced MHC-I Down-Regulation Identifies a Temporally Regulated Switch in Nef Action

Nef assembles a multi-kinase complex triggering MHC-I down-regulation. We identify an inhibitor that blocks MHC-I down-regulation, identifying a temporally regulated switch in Nef action from directing MHC-I endocytosis to blocking cell surface delivery. These findings challenge current dogma and reveal a regulated immune evasion program

Reduced expression of cerebral metabotropic glutamate receptor subtype 5 in men with fragile X syndrome

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu

Discovery of a diaminoquinoxaline benzenesulfonamide antagonist of HIV-1 Nef function using a yeast-based phenotypic screen

Background: HIV-1 Nef is a viral accessory protein critical for AIDS progression. Nef lacks intrinsic catalytic activity and binds multiple host cell signaling proteins, including Hck and other Src-family tyrosine kinases. Nef binding induces constitutive Hck activation that may contribute to HIV pathogenesis by promoting viral infectivity, replication and downregulation of cell-surface MHC-I molecules. In this study, we developed a yeast-based phenotypic screen to identify small molecules that inhibit the Nef-Hck complex. Results: Nef-Hck interaction was faithfully reconstituted in yeast cells, resulting in kinase activation and growth arrest. Yeast cells expressing the Nef-Hck complex were used to screen a library of small heterocyclic compounds for their ability to rescue growth inhibition. The screen identified a dihydrobenzo-1,4-dioxin-substituted analog of 2-quinoxalinyl-3-aminobenzene-sulfonamide (DQBS) as a potent inhibitor of Nef-dependent HIV-1 replication and MHC-I downregulation in T-cells. Docking studies predicted direct binding of DQBS to Nef which was confirmed in differential scanning fluorimetry assays with recombinant purified Nef protein. DQBS also potently inhibited the replication of HIV-1 NL4-3 chimeras expressing Nef alleles representative of all M-group HIV-1 clades.Conclusions: Our findings demonstrate the utility of a yeast-based growth reversion assay for the identification of small molecule Nef antagonists. Inhibitors of Nef function discovered with this assay, such as DQBS, may complement the activity of current antiretroviral therapies by enabling immune recognition of HIV-infected cells through the rescue of cell surface MHC-I. © 2013 Trible et al.; licensee BioMed Central Ltd