Inhibition studies of serine hydrolases by cyclic phosphates and phosphonates

The serine hydrolase superfamily is one of the largest known enzyme families comprising approximately 1% of the predicted protein product in human genome. This family of enzymes contains a catalytic triad that is mainly consists of serine, aspartic acid/glutamic acid and histidine residues in their active sites. It has been proposed that the potential drug targets for Alzheimer’s disease and diabetes type 2 are enzymes that belong to this enzyme family. Acetylcholinesterase is an enzyme that catalyses the breakdown of acetylcholine, a neurotransmitter that helps transport information from one nerve cell to another. Breakdown of acetylcholine in Alzheimer’s disease patients enhances memory loss, which could be reduced if AChE is inhibited. Cyclophostin, a bicyclic phosphate, is a natural product inhibitor of AChE having an IC50, of 8 e-4 μM. The laboratory synthesized mono- and bicyclic analogs of phosphonate analog of cyclophostin exhibited low μM potency against human AChE. It is established that these analogs covalently modify the active site of AChE and do not dissociate from the active site upon treatment with oximes. From a comparative analysis of kinetic data it is revealed that these compounds are less toxic and milder than the existing AChE inhibitors and can be used as potential chemotherapeutic agent against Alzheimer’s disease. Hormone-sensitive lipase (HSL) is another serine hydrolase enzyme that hydrolyzes lipids in the form of triglycerides. It is a homodimer of 84 kDa subunits and is mostly found in adipose tissues. HSL is a potential drug target for diabetes type 2. The activity of HSL must be inhibited in insulin deficient patients to lower the risk of associated cardiovascular disease. Cyclipostin is a natural product inhibitor of HSL. Laboratory synthesized monocyclic phosphonate analogs of cyclipostin having varying C-chain length exhibited μM potency against rat HSL. The potency of these analogs improved upon introducing longer C-chain like C16. This class of compounds showed an aggregation property that affected their potency against the enzyme. The attachment of the C-chain at the P-center of the monocyclic phosphonate analog considerably improved the potency (almost 10 fold)

EmrE dimerization depends on membrane environment

AbstractThe small multi-drug resistant (SMR) transporter EmrE functions as a homodimer. Although the small size of EmrE would seem to make it an ideal model system, it can also make it challenging to work with. As a result, a great deal of controversy has surrounded even such basic questions as the oligomeric state. Here we show that the purified protein is a homodimer in isotropic bicelles with a monomer–dimer equilibrium constant (KMD2D) of 0.002–0.009mol% for both the substrate-free and substrate-bound states. Thus, the dimer is stabilized in bicelles relative to detergent micelles where the KMD2D is only 0.8–0.95mol% (Butler et al. 2004). In dilauroylphosphatidylcholine (DLPC) liposomes KMD2D is 0.0005–0.0008mol% based on Förster resonance energy transfer (FRET) measurements, slightly tighter than bicelles. These results emphasize the importance of the lipid membrane in influencing dimer affinity

A study of the effect of pre-radiation on healing of surgical wounds in the treatment of cancers of the head and neck

Background: Radiation therapy is an established modality in the treatment of head and neck cancer patients. It is used alone or in combination with surgery and chemotherapy. Although radiotherapy is useful to affect tumour death, it also exerts a deleterious effect on surrounding normal tissues. These effects are either acute or can manifest months or years after the treatment. The chronic wounds are a result of impaired wound healing. Compromised wound healing in irradiated tissues is a common and challenging clinical problem.Methods: A prospective observational study was done in a tertiary care teaching institute, Kolkata. The effect of radiation on surgery of cancers of head and neck was studied in 50 patients. The patients were divided into 2 groups of 25 each. The cases in the first group were irradiated prior to surgery and those on the second group were operated upon without any pre-radiation.Results: The highest incidence of wound complications in those patients who were operated upon within 2 weeks to 6 months of completion of RT (83.33%). Patients who had their blood Hb level at or above 11 gm% developed less number of wound complications (34.78%) as compared to those who had their blood Hb level between 8-11 gm% where complication rate was 48.15%. Those patients who had their oral cavity or pharynx opened during surgery had a much higher incidence of wound complications (54.54%) than whose oral cavity or pharynx were not interfered with (17.64%). Wound infection was 36% in the irradiated group and 12% in the non-irradiated group. Separation of wound edges or skin necrosis followed in 28% cases in the pre-radiated group and in 8% cases in the non-pre-radiated group.Conclusions: Radiotherapy is an integral modality of head and neck cancer therapy. Compromised wound healing is an important side effect of radiation therapy. All sorts of local complications as wound infection and necrosis, or ocutaneous fistulae, carotid artery perforation etc. are more pronounced in patients, who received prior radiotherapy. The complication of surgery after radiotherapy was found to be more pronounced between 2 weeks to 6 months in this series

Modelling proteins’ hidden conformations to predict antibiotic resistance

AbstractTEM β-lactamase confers bacteria with resistance to many antibiotics and rapidly evolves activity against new drugs. However, functional changes are not easily explained by differences in crystal structures. We employ Markov state models to identify hidden conformations and explore their role in determining TEM’s specificity. We integrate these models with existing drug-design tools to create a new technique, called Boltzmann docking, which better predicts TEM specificity by accounting for conformational heterogeneity. Using our MSMs, we identify hidden states whose populations correlate with activity against cefotaxime. To experimentally detect our predicted hidden states, we use rapid mass spectrometric footprinting and confirm our models’ prediction that increased cefotaxime activity correlates with reduced Ω-loop flexibility. Finally, we design novel variants to stabilize the hidden cefotaximase states, and find their populations predict activity against cefotaxime in vitro and in vivo. Therefore, we expect this framework to have numerous applications in drug and protein design.</jats:p

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Measurement of nuclear modification factors of gamma(1S)), gamma(2S), and gamma(3S) mesons in PbPb collisions at root s(NN)=5.02 TeV

The cross sections for ϒ(1S), ϒ(2S), and ϒ(3S) production in lead-lead (PbPb) and proton-proton (pp) collisions at √sNN = 5.02 TeV have been measured using the CMS detector at the LHC. The nuclear modification factors, RAA, derived from the PbPb-to-pp ratio of yields for each state, are studied as functions of meson rapidity and transverse momentum, as well as PbPb collision centrality. The yields of all three states are found to be significantly suppressed, and compatible with a sequential ordering of the suppression, RAA(ϒ(1S)) > RAA(ϒ(2S)) > RAA(ϒ(3S)). The suppression of ϒ(1S) is larger than that seen at √sNN = 2.76 TeV, although the two are compatible within uncertainties. The upper limit on the RAA of ϒ(3S) integrated over pT, rapidity and centrality is 0.096 at 95% confidence level, which is the strongest suppression observed for a quarkonium state in heavy ion collisions to date. © 2019 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP3.Peer reviewe

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

Peer reviewe

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe

Measurement of the Splitting Function in &ITpp &ITand Pb-Pb Collisions at root&ITsNN&IT=5.02 TeV

Data from heavy ion collisions suggest that the evolution of a parton shower is modified by interactions with the color charges in the dense partonic medium created in these collisions, but it is not known where in the shower evolution the modifications occur. The momentum ratio of the two leading partons, resolved as subjets, provides information about the parton shower evolution. This substructure observable, known as the splitting function, reflects the process of a parton splitting into two other partons and has been measured for jets with transverse momentum between 140 and 500 GeV, in pp and PbPb collisions at a center-of-mass energy of 5.02 TeV per nucleon pair. In central PbPb collisions, the splitting function indicates a more unbalanced momentum ratio, compared to peripheral PbPb and pp collisions.. The measurements are compared to various predictions from event generators and analytical calculations.Peer reviewe