Thermoclinic Assessment Of A Preliminary Circulation Model For Lake George In The Jefferson Project

The Jefferson Project is a collaboration between the Rensselaer Polytechnic Institute, IBM, and the FUND for Lake George aimed at understanding and managing complex factors (road salt, storm water runoff, invasive species) threatening Lake George, New York. Lake George is located about 80 km north of Albany in upstate New York and is known internationally for its water clarity. Understanding the hydrodynamics of the lake is fundamental for creation and maintenance of a research and monitoring program for the early detection of and response to adverse environmental and biological change. In this work a 3D circulation model of the lake is developed to better understand the hydro-environmental conditions of the lake; forcing is by a combination of local public survey data for the water budget and atmospheric data from the NWS (NOAA National Weather Service). The model is validated by a combination of water chemistry data collected by Darrin Fresh Water Institute (DFWI) over the last three decades, and known empirical relationships of the lake\u27s structural profile. Numerical simulations run over several years to capture the seasonal progression of thermocline depth throughout the lake, the south to north salt and surface thermal gradients and the timing of the spring and fall overturn events. Validation is by comparison with physical and chemical measurements collected over the last three decades. The study presents a novel combination of observational data, numerical modelling and empirical relationships to better understand and predict the lake circulation, and consequently the natural ecosystem

Microstructural Changes in the Striatum and Their Impact on Motor and Neuropsychological Performance in Patients with Multiple Sclerosis

Grey matter (GM) damage is a clinically relevant feature of multiple sclerosis (MS) that has been previously assessed with diffusion tensor imaging (DTI). Fractional anisotropy (FA) of the basal ganglia and thalamus might be increased in MS patients, and correlates with disability scores. Despite the established role of the striatum and thalamus in motor control, mood and cognition, the impact of DTI changes within these structures on motor and neuropsychological performance has not yet been specifically addressed in MS. We investigated DTI metrics of deep GM nuclei and their potential association with mobility and neuropsychological function. DTI metrics from 3T MRI were assessed in the caudate, putamen, and thalamus of 30 MS patients and 10 controls. Sixteen of the patients underwent neuropsychological testing. FA of the caudate and putamen was higher in MS patients compared to controls. Caudate FA correlated with Expanded Disability Status Scale score, Ambulation Index, and severity of depressive symptomatology. Putamen and thalamus FA correlated with deficits in memory tests. In contrast, cerebral white matter (WM) lesion burden showed no significant correlation with any of the disability, mobility and psychometric parameters. Our findings support evidence of FA changes in the basal ganglia in MS patients, as well as deep GM involvement in disabling features of MS, including mobility and cognitive impairment. Deep GM FA appears to be a more sensitive correlate of disability than WM lesion burden

Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.

Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections

Dynamic Range and Reproducibility of Hepatitis B Virus (HBV) DNA Detection and Quantification by Cobas Taqman HBV, a Real-Time Semiautomated Assay

The Cobas Taqman assay for hepatitis B virus (HBV) DNA showed linear detection over 7 logs for genotypes A to D. The coefficient of variation was 1.2% at ≥1,000 IU/ml and 22.0% at 10 IU/ml. In 97 clinical samples, the log HBV DNA/ml differed by 0.11 between Cobas Amplicor and Cobas Taqman (r(2) = 0.97)

Hepatitis B viral DNA decline at loss of HBeAg is mainly explained by reduced cccDNA load--down-regulated transcription of PgRNA has limited impact.

BACKGROUND: Quantification of hepatitis B virus (HBV) DNA and surface antigen (HBsAg) serum levels have become increasingly important for the assessment of clinical stage and response to treatment for chronic hepatitis B. Effective immune clearance results in reduction of viremia by 4-5 log units and HBsAg levels by 2 log, but these processes are not well understood. Thus, it is uncertain to what extent mechanisms that inhibit transcription of the pregenomic RNA (pgRNA), an RNA intermediate, contribute to suppression of viremia. Likewise, it is unclear if transcriptional regulation is important for the excessive production of surface antigen (HBsAg) that is a hallmark of HBV infection. METHODS: HBV RNA and cccDNA were quantified in 19 liver biopsies from patients with chronic HBV infection, as well as in transfected Huh7.5 cells and in PLC/PRF/5 cells carrying integrated HBV genome. RESULTS: Patients negative for HBeAg had 2.15 log lower levels of cccDNA in liver tissue, 4.84 log lower serum levels of HBV DNA and 1.45 log lower serum levels of HBsAg, than HBeAg-positive patients. The pgRNA in liver tissue correlated strongly with cccDNA (R(2) = 0.87, p<0.0001) and HBV DNA levels in serum (R(2) = 0.81, p<0.0001), whereas S-RNA correlated strongly with cccDNA (R(2) = 0.65, p<0.0001) and HBsAg levels (R(2) = 0.57, p = 0.0003). The S-RNA/pgRNA ratio was higher in HBeAg-negative patients (ratio 40 vs. 3, p = 0.01) and in PLC/PRF/5 cells, and was in transfected Huh7.5 cells not influenced by mutations in the HBV core promoter. CONCLUSION: The reduction of viremia that is observed after loss of HBeAg was mainly explained by reduced cccDNA load in the liver, whereas the contribution of down-regulation of pgRNA transcription was relatively small. Enhanced transcription of S-RNA does not explain excessive production of HBsAg

HBV DNA and RNA levels in cell cultures and liver biopsies^a.

a<p>Median values of log copy numbers, range in parentheses.</p>b<p>Three repetitive experiments under the same conditions.</p>c<p>Basal core promoter wild-type (AGG) or mutant (TGA) at 1762–1764.</p>d<p>Mann-Whitney U test (biopsies).</p><p>NA, not applicable.</p

Levels of cccDNA and HBV RNA in vivo and in vitro.

<p>The cccDNA levels (A) and pgRNA per cccDNA (B), as well as pgRNA/cccDNA ratios (C) were higher in liver tissue from HBeAg-positive as compared with HBeAg-negative patients. In PLC/PRF/5 cells, the cccDNA PCR amplifies integrated HBV DNA (a segment containing the promoter for pgRNA). In these cells which contain multiple integrations of the S region, the pgRNA/S-RNA ratio was low (C). In Huh7.5 cells, the cccDNA levels, pgRNA per cccDNA and ratio between pgRNA and S-RNA were similar in cells transfected with HBV without or with mutations in the core promoter region, indicating that these mutations have low impact on pgRNA transcription.</p