Structural Features Underlying Raloxifene’s Biophysical Interaction with Bone Matrix

Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell- and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure–activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiophene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen

Metabolomics to unveil and understand phenotypic diversity between pathogen populations

Visceral leishmaniasis is caused by a parasite called Leishmania donovani, which every year infects about half a million people and claims several thousand lives. Existing treatments are now becoming less effective due to the emergence of drug resistance. Improving our understanding of the mechanisms used by the parasite to adapt to drugs and achieve resistance is crucial for developing future treatment strategies. Unfortunately, the biological mechanism whereby Leishmania acquires drug resistance is poorly understood. Recent years have brought new technologies with the potential to increase greatly our understanding of drug resistance mechanisms. The latest mass spectrometry techniques allow the metabolome of parasites to be studied rapidly and in great detail. We have applied this approach to determine the metabolome of drug-sensitive and drug-resistant parasites isolated from patients with leishmaniasis. The data show that there are wholesale differences between the isolates and that the membrane composition has been drastically modified in drug-resistant parasites compared with drug-sensitive parasites. Our findings demonstrate that untargeted metabolomics has great potential to identify major metabolic differences between closely related parasite strains and thus should find many applications in distinguishing parasite phenotypes of clinical relevance

Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21

Meta-AnalysisThis is the final version of the article. Available from the American Diabetes Association via the DOI in this record.Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.The major funding for this work comes from Council for Scientific and Industrial Research, Government of India, in the form of the grant “Diabetes mellitus—New drug discovery R&D, molecular mechanisms, and genetic and epidemiological factors” (NWP0032-19). R.T. received a postdoctoral fellowship from the Fogarty International Center and the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health (D43-HD-065249)

Dual Band Circular Polarized Design of Rectangular Microstrip Antenna For GPS L-band and Galileo E-band Applications

Design of rectangular microstrip antenna employing three rectangular slots of unequal lengths on one of the patch edges, is presented to achieve dual band and dual sense circular polarized characteristics. Circular polarized response in the two bands is attributed to the optimum inter-spacing in between the rectangular patch’s TM10, TM11 and TM12 resonant modes. For axial ratio less than 3 dB, an optimum design offers axial ratio bandwidth of 26 MHz (2.05%) and 73 MHz (4.59%) in the dual bands, bearing frequency ratio of 1.25. This circular polarized bandwidth lies inside the VSWR &lt; 2 bandwidth of 665 MHz (49.83%). Antenna offers radiation pattern maximum in the broadside direction across axial ratio and VSWR bandwidth, with a gain of more than 6 dBic. For the obtained antenna characteristics, the three rectangular slot cut design is suitable in variety of applications like, GPS L1 &amp; L2 bands, and Galileo E1 &amp; E6 bands. The experimental verification has been carried out for the proposed configuration that shows close agreement against the simulated results

Implementing the ‘Frozen Potential’ Approach on ADEPT to Analyze Thin Film Solar Cells

Thin film solar cells have higher absorption coefficients than traditional Silicon solar cells. This means that lesser material is required to produce the same power output for a given intensity of solar illumination. As a result, they are less expensive, easier to install and have a wider range of applications. Analyzing the performance of cells requires separating the current into the photocurrent and the injection current based on the ‘Superposition Principle’. For thin film solar cells, this cannot be done using the conventional method. This is because these components are interdependent, and so modeling one’s behavior requires understanding the other. We address this issue by implementing a new modeling approach. This novel ‘Frozen Potential’ Approach separates the photocurrent and injection current from the total current. The currents are then plotted individually. This method is implemented on a rigorous simulation tool called ADEPT 2.0, which is readily available on nanoHUB.org – the premier platform for research and simulation in nanotechnology. Equipped with this new modelling approach, a useful framework is provided for ADEPT 2.0 by tying in a traditional understanding of solar cells to a new class of materials, geometries and illumination profiles relevant for the solar cell community

Bifacial Si heterojunction-perovskite organic-inorganic tandem to produce highly efficient (η T * ~ 33%) solar cell

As single junction photovoltaic (PV) technologies both Si heterojunction (HIT) and perovskite based solar cells promise high efficiencies at low cost. Intuitively a traditional tandem cell design with these cells connected in series is expected to improve the efficiency further. Using a self-consistent numerical modeling of optical and transport characteristics however we find that a traditional series connected tandem design suffers from low JSC due to band-gap mismatch and current matching constraints. Specifically a traditional tandem cell with state-of-the-art HIT ( η=24% ) and perovskite ( η=20% ) sub-cells provides only a modest tandem efficiency of ηT~ 25%. Instead we demonstrate that a bifacial HIT/perovskite tandem design decouples the optoelectronic constraints and provides an innovative path for extraordinary efficiencies. In the bifacial configuration the same state-of-the-art sub-cells achieve a normalized output of η∗T  = 33% exceeding the bifacial HIT performance at practical albedo reflections. Unlike the traditional design this bifacial design is relatively insensitive to perovskite thickness variations which may translate to simpler manufacture and higher yield

Metabolic network analysis predicts efficacy of FDA-approved drugs targeting the causative agent of a neglected tropical disease

<p>Abstract</p> <p>Background</p> <p>Systems biology holds promise as a new approach to drug target identification and drug discovery against neglected tropical diseases. Genome-scale metabolic reconstructions, assembled from annotated genomes and a vast array of bioinformatics/biochemical resources, provide a framework for the interrogation of human pathogens and serve as a platform for generation of future experimental hypotheses. In this article, with the application of selection criteria for both <it>Leishmania major </it>targets (e.g. <it>in silico </it>gene lethality) and drugs (e.g. toxicity), a method (MetDP) to rationally focus on a subset of low-toxic Food and Drug Administration (FDA)-approved drugs is introduced.</p> <p>Results</p> <p>This metabolic network-driven approach identified 15 <it>L. major </it>genes as high-priority targets, 8 high-priority synthetic lethal targets, and 254 FDA-approved drugs. Results were compared to previous literature findings and existing high-throughput screens. Halofantrine, an antimalarial agent that was prioritized using MetDP, showed noticeable antileishmanial activity when experimentally evaluated <it>in vitro </it>against <it>L. major </it>promastigotes. Furthermore, synthetic lethality predictions also aided in the prediction of superadditive drug combinations. For proof-of-concept, double-drug combinations were evaluated <it>in vitro </it>against <it>L. major </it>and four combinations involving the drug disulfiram that showed superadditivity are presented.</p> <p>Conclusions</p> <p>A direct metabolic network-driven method that incorporates single gene essentiality and synthetic lethality predictions is proposed that generates a set of high-priority <it>L. major </it>targets, which are in turn associated with a select number of FDA-approved drugs that are candidate antileishmanials. Additionally, selection of high-priority double-drug combinations might provide for an attractive and alternative avenue for drug discovery against leishmaniasis.</p

Mathematical models for immunology:current state of the art and future research directions

The advances in genetics and biochemistry that have taken place over the last 10 years led to significant advances in experimental and clinical immunology. In turn, this has led to the development of new mathematical models to investigate qualitatively and quantitatively various open questions in immunology. In this study we present a review of some research areas in mathematical immunology that evolved over the last 10 years. To this end, we take a step-by-step approach in discussing a range of models derived to study the dynamics of both the innate and immune responses at the molecular, cellular and tissue scales. To emphasise the use of mathematics in modelling in this area, we also review some of the mathematical tools used to investigate these models. Finally, we discuss some future trends in both experimental immunology and mathematical immunology for the upcoming years

Urinary Exosomal microRNA-451-5p Is a Potential Early Biomarker of Diabetic Nephropathy in Rats

Non-invasive renal signatures can help in serial monitoring of diabetic patients. We tested whether urinary exosomal (UE) microRNA (miR) analysis could non-invasively predict renal pathology in diabetic rats during the course of diabetes. Diabetes mellitus (DM) was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg body weight). Non-diabetic control (CTRL) rats were injected with vehicle. Insulin (INS) treatment (5U/d, s.c.) was provided to 50% of the DM rats. Urine samples were collected at weeks 3, 6, and 9 following injections and UE prepared. An increase in miR-451-5p and miR-16, observed by pilot small RNA sequencing of UE RNA, was confirmed by quantitative real-time polymerase chain reaction (qPCR) and selected for further study. Subsets of rats were euthanized after 3, 6, and 9 weeks of diabetes for renal pathology analysis, including determination of the tubulointerstitial fibrotic index (TFI) and glomerulosclerotic index (GI) scores. qPCR showed a substantial rise in miR-451-5p in UE from DM rats during thecourse of diabetes, with a significant rise (median fold change >1000) between 3 and 6 weeks. Moreover, UE miR-451-5p at 6 weeks predicted urine albumin at 9 weeks (r = 0.76). A delayed but significant rise was also observed for miR-16. In contrast, mean urine albumin only increased 21% between 3 and 6 weeks (non-significant rise), and renal TFI and GI were unchanged till 9 weeks. Renal expression of miR-451-5p and miR-16 (at 10 weeks) did not correlate with urine levels, and moreover, was negatively associated with indices of renal pathology (r�-0.70, p = 0.005 for TFI and r�-0.6, p�0.02 for GI). Overall, a relative elevation in renal miR-451-5p and miR-16 in diabetes appeared protective against diabetes- induced kidney fibrosis; while UE miR-451-5p may hold prognostic value as an earlyand sensitive non-invasive indicator of renal diseas