Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐Lyase

This is the peer reviewed version of the following article: Discovery of a Histidine‐Based Scaffold as an Inhibitor of Gut Microbial Choline Trimethylamine‐Lyase, which has been published in final form at https://doi.org/10.1002/cmdc.202000571. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Anaerobic choline metabolism by human gut microbiota to produce trimethylamine (TMA) has recently evolved as a potential therapeutic target because of its association with chronic kidney disease and increased cardiovascular risks. Limited examples of choline analogues have been reported as inhibitors of bacterial enzyme choline TMA‐lyase (CutC), a key enzyme regulating choline anaerobic metabolism. We used a new workflow to discover CutC inhibitors based on focused screening of a diversified library of small molecules for intestinal metabolic stability followed by in vitro CutC inhibitory assay. This workflow identified a histidine‐based scaffold as a CutC inhibitor with an IC50 value of 1.9±0.2 μM. Remarkably, the identified CutC inhibitor was able to reduce the production of TMA in whole‐cell assays using various bacterial strains as well as in complex gut microbiota environment. The improved efficiency of the new scaffold identified in this study in comparison to previously reported CutC inhibitors would enable optimization of potential leads for in vivo screening and clinical translation. Finally, docking studies and molecular‐dynamic simulations were used to predict putative interactions created between inhibitor and CutC

Imaging of hydrothermal altered zones in Wadi Al-Bana, in southern Yemen, using remote sensing techniques and very low frequency–electromagnetic data

© 2019, Saudi Society for Geosciences. Economic mineralization and hydrothermally altered zones are areas of great economic interests. This study focusses on hydrothermal altered zones of high mineralization potentials in Wadi Al-Bana, in southern Yemen. An azimuthal very low frequency–electromagnetic (AVLF-EM) data acquisition was conducted in search for mineralization in the study area. The study integrated observations from geophysical field data with others extracted from object-oriented principal component analysis (PCA) to better map and understand mineralization in the investigated area. This technique was applied to two data sets, ASTER and Landsat 8 Operational Land Imager (OLI) imagery. The results of PCA revealed high accuracy in detecting alteration minerals and for mapping zones of high concentration of these minerals. The PCA-based distribution of selected alteration zones correlated spatially with high conductivity anomalies in the subsurface that were detected by VLF measurements. Finally, a GIS model was built and successfully utilized to categorize the resulted altered zones, into three levels. [Figure not available: see fulltext.]

Ongoing Secondary Degeneration of the Limbic System in Patients With Ischemic Stroke: A Longitudinal MRI Study

Purpose: Ongoing post-stroke structural degeneration and neuronal loss preceding neuropsychological symptoms such as cognitive decline and depression are poorly understood. Various substructures of the limbic system have been linked to cognitive impairment. In this longitudinal study, we investigated the post-stroke macro- and micro-structural integrity of the limbic system using structural and diffusion tensor magnetic resonance imaging.Materials and Methods: Nineteen ischemic stroke patients (11 men, 8 women, average age 53.4 ± 12.3, range 18–75 years), with lesions remote from the limbic system, were serially imaged three times over 1 year. Structural and diffusion-tensor images (DTI) were obtained on a 3.0 T MRI system. The cortical thickness, subcortical volume, mean diffusivity (MD), and fractional anisotropy (FA) were measured in eight different regions of the limbic system. The National Institutes of Health Stroke Scale (NIHSS) was used for clinical assessment. A mixed model for multiple factors was used for statistical analysis, and p-values <0.05 was considered significant.Results: All patients demonstrated improved NIHSS values over time. The ipsilesional subcortical volumes of the thalamus, hippocampus, and amygdala significantly decreased (p < 0.05) and MD significantly increased (p < 0.05). The ipsilesional cortical thickness of the entorhinal and perirhinal cortices was significantly smaller than the contralesional hemisphere at 12 months (p < 0.05). The cortical thickness of the cingulate gyrus at 12 months was significantly decreased at the caudal and isthmus regions as compared to the 1 month assessment (p < 0.05). The cingulum fibers had elevated MD at the ipsilesional caudal-anterior and posterior regions compared to the corresponding contralesional regions.Conclusion: Despite the decreasing NIHSS scores, we found ongoing unilateral neuronal loss/secondary degeneration in the limbic system, irrespective of the lesion location. These results suggest a possible anatomical basis for post stroke psychiatric complications

Association of Glomerular Filtration Rate with High-Sensitivity Cardiac Troponin T in a Community-Based Population Study in Beijing

BACKGROUND: Reduced renal function is an independent risk factor for cardiovascular disease mortality, and persistently elevated cardiac troponin T (cTnT) is frequently observed in patients with end-stage renal disease. In the general population the relationship between renal function and cTnT levels may not be clear because of the low sensitivity of the assay. In this study, we investigated the level of cTnT using a highly sensitive assay (hs-cTnT) and evaluated the association of estimated glomerular filtration rate (eGFR) with detectable hs-cTnT levels in a community-based population. METHODS: The serum hs-cTnT levels were measured in 1365 community dwelling population aged ≥45 years in Beijing, China. eGFR was determined by the Chinese modifying modification of diet in renal disease (C-MDRD) equation. RESULTS: With the highly sensitive assay, cTnT levels were detectable (≥3pg/mL) in 744 subjects (54.5%). The result showed that eGFR was associated with Log hs-cTnT (r = -0.14, P<0.001). After adjustment for the high predicted Framingham Coronary Heart Disease (CHD) risk (10-year risk >20%) and other prognostic indicators, moderate to severe reduced eGFR was independently associated with detectable hs-cTnT, whereas normal to mildly reduced eGFR was not independently associated with detectable hs-cTnT. In addition, after adjustment for other risk factors, the high predicted Framingham CHD risk was associated with detectable hs-cTnT in the subjects with different quartile levels of eGFR. CONCLUSION: The levels of hs-cTnT are detectable in a community-based Chinese population and low eGFR is associated with detectable hs-cTnT. Moreover, eGFR and high predicted Framingham CHD risk are associated with detectable hs-cTnT in subjects with moderate-to-severe reduced renal function

Novi kopolimerni zwitterionski matriksi za polagano oslobađanje verapamil hidroklorida

Stable co-polymer [vinyl acetate-co-3-dimethyl(methacryloyloxyethyl)ammonium propane sulfоnate, p(VA-co-DMAPS)] latex of different compositions has been synthesized for the first time by emulsifier-free emulsion copolymerization. The unusual “overshooting” behavior of the co-polymer tablets has been explained by the formation of specific clusters from the opposite oriented dipoles zwitterionic species. The change of their concentration with the DMAPS unit fraction (mDMAPS), pH and ionic strength has been considered responsible for the differences observed in the swelling kinetics. The results obtained prove that mDMAPS and ionic strength could be used to control the swelling degree of the p(VA-co-DMAPS) matrices. In this way, p(VA-co-DMAPS) matrices could be effectively used to control the sustained release of drugs with basic properties like verapamil hydrochloride from model tablets.Metodom emulzijske polimerizacije sintetiziran je novi stabilni kopolimer [vinil acetat-ko-3-dimetil(metakriloiloksietill)amonijev propan sulfоnat, p(VA-co-DMAPS)] lateks promjenjivog sastava. Neobično “overshooting” ponašanje tableta pripravljenih iz tog kopolimera objašnjava se stvaranjem specifičnih klastera suprotno rijentiranih dipola zwitterionskih specija. Proučavan je utjecaj udjela DMAPS jedinica (mDMAPS), pH i ionske jakosti na kinetiku bubrenja. Dobiveni rezultati dokazuju da se promjenom mDMAPS i ionske jakosti može kontrolirati stupanj bubrenja p(VA-co-DMAPS) matriksa i oslobađanje verapamil hidroklorida iz tableta pa se ti matriksi mogu upotrijebiti za polagano oslobađanje bazičnih lijekova srodnih verapamilu

SPARC 2017 retrospect & prospects : Salford postgraduate annual research conference book of abstracts

Welcome to the Book of Abstracts for the 2017 SPARC conference. This year we not only celebrate the work of our PGRs but also the 50th anniversary of Salford as a University, which makes this year’s conference extra special. Once again we have received a tremendous contribution from our postgraduate research community; with over 130 presenters, the conference truly showcases a vibrant PGR community at Salford. These abstracts provide a taster of the research strengths of their works, and provide delegates with a reference point for networking and initiating critical debate. With such wide-ranging topics being showcased, we encourage you to exploit this great opportunity to engage with researchers working in different subject areas to your own. To meet global challenges, high impact research inevitably requires interdisciplinary collaboration. This is recognised by all major research funders. Therefore engaging with the work of others and forging collaborations across subject areas is an essential skill for the next generation of researchers

Skeletal abnormalities of acrogeria, a progeroid syndrome

We report the skeletal abnormalities in a 4 1/2-year-old boy with acrogeria, a progeroid syndrome of premature aging of the skin without the involvement of internal organs seen in Hutchinson-Gilford progeria syndrome. Acro-osteolysis of the distal phalanges, delayed cranial suture closure with wormian bones, linear lucent defects of the metaphyses, and antegonial notching of the mandible are the predominant skeletal features of the disorder. The skeletal features described in 21 other reported cases of acrogeria are summarized.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46786/1/256_2004_Article_BF00350541.pd

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin