Mechanism of action of probiotics

The modern diet doesn't provide the required amount of beneficial bacteria. Maintenance of a proper microbial ecology in the host is the main criteria to be met for a healthy growth. Probiotics are one such alternative that are supplemented to the host where by and large species of Lactobacillus, Bifidobacterium and Saccharomyces are considered as main probiotics. The field of probiotics has made stupendous strides though there is no major break through in the identification of their mechanism of action. They exert their activity primarily by strengthening the intestinal barrier and immunomodulation. The main objective of the study was to provide a deep insight into the effect of probiotics against the diseases, their applications and proposed mechanism of action

Discovery of XL01126:A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

[Image: see text] Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s disease. LRRK2-targeting strategies have primarily focused on type 1 kinase inhibitors, which, however, have limitations as the inhibited protein can interfere with natural mechanisms, which could lead to undesirable side effects. Herein, we report the development of LRRK2 proteolysis targeting chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2-targeting strategy. Initial designs and screens of PROTACs based on ligands for E3 ligases von Hippel–Lindau (VHL), Cereblon (CRBN), and cellular inhibitor of apoptosis (cIAP) identified the best degraders containing thioether-conjugated VHL ligand VH101. A second round of medicinal chemistry exploration led to qualifying XL01126 as a fast and potent degrader of LRRK2 in multiple cell lines, with DC(50) values within 15–72 nM, D(max) values ranging from 82 to 90%, and degradation half-lives spanning from 0.6 to 2.4 h. XL01126 exhibits high cell permeability and forms a positively cooperative ternary complex with VHL and LRRK2 (α = 5.7), which compensates for a substantial loss of binary binding affinities to VHL and LRRK2, underscoring its strong degradation performance in cells. Remarkably, XL01126 is orally bioavailable (F = 15%) and can penetrate the blood–brain barrier after either oral or parenteral dosing in mice. Taken together, these experiments qualify XL01126 as a suitable degrader probe to study the noncatalytic and scaffolding functions of LRRK2 in vitro and in vivo and offer an attractive starting point for future drug development

An informatics supported web-based data annotation and query tool to expedite translational research for head and neck malignancies

<p>Abstract</p> <p>Background</p> <p>The Specialized Program of Research Excellence (SPORE) in Head and Neck Cancer neoplasm virtual biorepository is a bioinformatics-supported system to incorporate data from various clinical, pathological, and molecular systems into a single architecture based on a set of common data elements (CDEs) that provides semantic and syntactic interoperability of data sets.</p> <p>Results</p> <p>The various components of this annotation tool include the Development of Common Data Elements (CDEs) that are derived from College of American Pathologists (CAP) Checklist and North American Association of Central Cancer Registries (NAACR) standards. The Data Entry Tool is a portable and flexible Oracle-based data entry device, which is an easily mastered web-based tool. The Data Query Tool helps investigators and researchers to search de-identified information within the warehouse/resource through a "point and click" interface, thus enabling only the selected data elements to be essentially copied into a data mart using a multi dimensional model from the warehouse's relational structure.</p> <p>The SPORE Head and Neck Neoplasm Database contains multimodal datasets that are accessible to investigators via an easy to use query tool. The database currently holds 6553 cases and 10607 tumor accessions. Among these, there are 965 metastatic, 4227 primary, 1369 recurrent, and 483 new primary cases. The data disclosure is strictly regulated by user's authorization.</p> <p>Conclusion</p> <p>The SPORE Head and Neck Neoplasm Virtual Biorepository is a robust translational biomedical informatics tool that can facilitate basic science, clinical, and translational research. The Data Query Tool acts as a central source providing a mechanism for researchers to efficiently find clinically annotated datasets and biospecimens that are relevant to their research areas. The tool protects patient privacy by revealing only de-identified data in accordance with regulations and approvals of the IRB and scientific review committee.</p

Measurement of Charged Pion Production Yields off the NuMI Target

The fixed-target MIPP experiment, Fermilab E907, was designed to measure the production of hadrons from the collisions of hadrons of momenta ranging from 5 to 120 GeV/c on a variety of nuclei. These data will generally improve the simulation of particle detectors and predictions of particle beam fluxes at accelerators. The spectrometer momentum resolution is between 3 and 4%, and particle identification is performed for particles ranging between 0.3 and 80 GeV/c using $dE/dx$, time-of-flight and Cherenkov radiation measurements. MIPP collected $1.42 \times10^6$ events of 120 GeV Main Injector protons striking a target used in the NuMI facility at Fermilab. The data have been analyzed and we present here charged pion yields per proton-on-target determined in bins of longitudinal and transverse momentum between 0.5 and 80 GeV/c, with combined statistical and systematic relative uncertainties between 5 and 10%.Comment: 15 pages, 13 figure

Promiscuous prediction and conservancy analysis of CTL binding epitopes of HCV 3a viral proteome from Punjab Pakistan: an In Silico Approach

<p>Abstract</p> <p>Background</p> <p>HCV is a positive sense RNA virus affecting approximately 180 million people world wide and about 10 million Pakistani populations. HCV genotype 3a is the major cause of infection in Pakistani population. One of the major problems of HCV infection especially in the developing countries that limits the limits the antiviral therapy is the long term treatment, high dosage and side effects. Studies of antigenic epitopes of viral sequences of a specific origin can provide an effective way to overcome the mutation rate and to determine the promiscuous binders to be used for epitope based subunit vaccine design. An <it>in silico </it>approach was applied for the analysis of entire HCV proteome of Pakistani origin, aimed to identify the viral epitopes and their conservancy in HCV genotypes 1, 2 and 3 of diverse origin.</p> <p>Results</p> <p>Immunoinformatic tools were applied for the predictive analysis of HCV 3a antigenic epitopes of Pakistani origin. All the predicted epitopes were then subjected for their conservancy analysis in HCV genotypes 1, 2 and 3 of diverse origin (worldwide). Using freely available web servers, 150 MHC II epitopes were predicted as promiscuous binders against 51 subjected alleles. E2 protein represented the 20% of all the predicted MHC II epitopes. 75.33% of the predicted MHC II epitopes were (77-100%) conserve in genotype 3; 47.33% and 40.66% in genotype 1 and 2 respectively. 69 MHC I epitopes were predicted as promiscuous binders against 47 subjected alleles. NS4b represented 26% of all the MHC I predicted epitopes. Significantly higher epitope conservancy was represented by genotype 3 i.e. 78.26% and 21.05% for genotype 1 and 2.</p> <p>Conclusions</p> <p>The study revealed comprehensive catalogue of potential HCV derived CTL epitopes from viral proteome of Pakistan origin. A considerable number of predicted epitopes were found to be conserved in different HCV genotype. However, the number of conserved epitopes in HCV genotype 3 was significantly higher in contrast to its conservancy in HCV genotype 1 and 2. Despite of the lower conservancy in genotype 1 and 2, all the predicted epitopes have important implications in diagnostics as well as CTL-based rational vaccine design, effective for most population of the world and especially the Pakistani Population.</p

Inhibition of HCV 3a core gene through Silymarin and its fractions

Hepatitis C is a major health problem affecting 270 million individuals in world including Pakistan. Current treatment regimen, interferon alpha and ribavirin only cure half of patients due to side effects and high cost. In the present study Silybum marianum (Milk thistle) seeds were collected, extracted and analyzed against HCV 3a core gene by transiently transfecting the liver cells with HCV core plasmid. Our results demonstrated that Silymarin (SM) dose dependently inhibit the expression or function of HCV core gene at a non toxic concentration while the GAPDH remained constant. To identify the active ingredient, SM was fractioned by thin layer chromatography (TLC), column chromatography and HPLC. Purified fractions were tested for HCV core gene and western blotting results showed that two factions of SM (S1 and S2) inhibit HCV 3a core expression or function in liver cells Our results suggest SM and its fractions (S1 and S2) inhibit HCV core gene of 3a genotype and combination of SM and its fractions with interferon will be a better option to treat HCV infection

Search for bottom squarks in pbarp collisions at sqrt(s)=1.8 TeV

We report on a search for bottom squarks produced in pbarp collisions at sqrt(s) = 1.8 TeV using the D0 detector at Fermilab. Bottom squarks are assumed to be produced in pairs and to decay to the lightest supersymmetric particle (LSP) and a b quark with branching fraction of 100%. The LSP is assumed to be the lightest neutralino and stable. We set limits on the production cross section as a function of bottom squark mass and LSP mass.Comment: 5 pages, Latex. submitted 3-12-1999 to PRD - Rapid Communicatio

Differential Production Cross Section of Z Bosons as a Function of Transverse Momentum at sqrt{s}=1.8 TeV

We present a measurement of the transverse momentum distribution of Z bosons produced in ppbar collisions at sqrt{s}=1.8 TeV using data collected by the D0 experiment at the Fermilab Tevatron Collider during 1994--1996. We find good agreement between our data and a current resummation calculation. We also use our data to extract values of the non-perturbative parameters for a particular version of the resummation formalism, obtaining significantly more precise values than previous determinations.Comment: 10 pages, 2 figures, submitted to Phys. Rev. Letters v2 has margin error correcte

A Quasi-Model-Independent Search for New Physics at Large Transverse Momentum

We apply a quasi-model-independent strategy ("Sleuth") to search for new high p_T physics in approximately 100 pb^-1 of ppbar collisions at sqrt(s) = 1.8 TeV collected by the DZero experiment during 1992-1996 at the Fermilab Tevatron. Over thirty-two e mu X, W+jets-like, Z+jets-like, and 3(lepton/photon)X exclusive final states are systematically analyzed for hints of physics beyond the standard model. Simultaneous sensitivity to a variety of models predicting new phenomena at the electroweak scale is demonstrated by testing the method on a particular signature in each set of final states. No evidence of new high p_T physics is observed in the course of this search, and we find that 89% of an ensemble of hypothetical similar experimental runs would have produced a final state with a candidate signal more interesting than the most interesting observed in these data.Comment: 28 pages, 17 figures. Submitted to Physical Review