Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis

Human papillomaviruses (HPVs) are the most common on sexually transmitted viruses in the world. HPVs are responsible for a large spectrum of deseases, both benign and malignant. The certain types of HPV are involved in the development of cervical cancer. In attemps to find additional drugs in the treatment of cervical cancer, inhibitors of the histone deacetylases (HDAC) have received much attention due to their low cytotoxic profiles and the E6/E7 oncogene function of human papilomavirus can be completely by passed by HDAC inhibition. The histone deacetylase inhibitors can induce growth arrest, differentiation and apoptosis of cancer cells. HDAC class I and class II are considered the main targets for cancer. Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties. Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target. SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present. Hence, SAHA could be developed as potential inhibitors of class II HDACs and valuable cervical cancer drug candidate

Phenytoin versus Leviteracetam for seizure prophylaxis after brain injury - A meta analysis

Background: Current standard therapy for seizure prophylaxis in Neuro-surgical patients involves the use of Phenytoin (PHY). However, a new drug Levetiracetam (LEV) is emerging as an alternate treatment choice. We aimed to conduct a meta-analysis to compare these two drugs in patients with brain injury.Methods: An electronic search was performed in using Pubmed, Embase, and CENTRAL. We included studies that compared the use of LEV vs. PHY for seizure prophylaxis for brain injured patients (Traumatic brain injury, intracranial hemorrhage, intracranial neoplasms, and craniotomy). Data of all eligible studies was extracted on to a standardized abstraction sheet. Data about baseline population characteristics, type of intervention, study design and outcome was extracted. Our primary outcome was seizures.Results: The literature search identified 2489 unduplicated papers. Of these 2456 papers were excluded by reading the abstracts and titles. Another 25 papers were excluded after reading their complete text. We selected 8 papers which comprised of 2 RCTs and 6 observational studies. The pooled estimate\u27s Odds Ratio 1.12 (95% CI = 0.34, 3.64) demonstrated no superiority of either drug at preventing the occurrence of early seizures. In a subset analysis of studies in which follow up for seizures lasted either 3 or 7 days, the effect estimate remained insignificant with an odds ratio of 0.96 (95% CI = 0.34, 2.76). Similarly, 2 trials reporting seizure incidence at 6 months also had insignificant pooled results while comparing drug efficacy. The pooled odds ratio was 0.96 (95% CI = 0.24, 3.79).Conclusions: Levetiracetam and Phenytoin demonstrate equal efficacy in seizure prevention after brain injury. However, very few randomized controlled trials (RCTs) on the subject were found. Further evidence through a high quality RCT is highly recommended

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Distinct Roles of Jasmonates and Aldehydes in Plant-Defense Responses

BACKGROUND: Many inducible plant-defense responses are activated by jasmonates (JAs), C(6)-aldehydes, and their corresponding derivatives, produced by the two main competing branches of the oxylipin pathway, the allene oxide synthase (AOS) and hydroperoxide lyase (HPL) branches, respectively. In addition to competition for substrates, these branch-pathway-derived metabolites have substantial overlap in regulation of gene expression. Past experiments to define the role of C(6)-aldehydes in plant defense responses were biased towards the exogenous application of the synthetic metabolites or the use of genetic manipulation of HPL expression levels in plant genotypes with intact ability to produce the competing AOS-derived metabolites. To uncouple the roles of the C(6)-aldehydes and jasmonates in mediating direct and indirect plant-defense responses, we generated Arabidopsis genotypes lacking either one or both of these metabolites. These genotypes were subsequently challenged with a phloem-feeding insect (aphids: Myzus persicae), an insect herbivore (leafminers: Liriomyza trifolii), and two different necrotrophic fungal pathogens (Botrytis cinerea and Alternaria brassicicola). We also characterized the volatiles emitted by these plants upon aphid infestation or mechanical wounding and identified hexenyl acetate as the predominant compound in these volatile blends. Subsequently, we examined the signaling role of this compound in attracting the parasitoid wasp (Aphidius colemani), a natural enemy of aphids. PRINCIPAL FINDINGS: This study conclusively establishes that jasmonates and C(6)-aldehydes play distinct roles in plant defense responses. The jasmonates are indispensable metabolites in mediating the activation of direct plant-defense responses, whereas the C(6)-aldehyes are not. On the other hand, hexenyl acetate, an acetylated C(6)-aldehyde, is the predominant wound-inducible volatile signal that mediates indirect defense responses by directing tritrophic (plant-herbivore-natural enemy) interactions. SIGNIFICANCE: The data suggest that jasmonates and hexenyl acetate play distinct roles in mediating direct and indirect plant-defense responses. The potential advantage of this "division of labor" is to ensure the most effective defense strategy that minimizes incurred damages at a reduced metabolic cost

Altered Trabecular Bone Structure and Delayed Cartilage Degeneration in the Knees of Collagen VI Null Mice

Mutation or loss of collagen VI has been linked to a variety of musculoskeletal abnormalities, particularly muscular dystrophies, tissue ossification and/or fibrosis, and hip osteoarthritis. However, the role of collagen VI in bone and cartilage structure and function in the knee is unknown. In this study, we examined the role of collagen VI in the morphology and physical properties of bone and cartilage in the knee joint of Col6a1−/− mice by micro-computed tomography (microCT), histology, atomic force microscopy (AFM), and scanning microphotolysis (SCAMP). Col6a1−/− mice showed significant differences in trabecular bone structure, with lower bone volume, connectivity density, trabecular number, and trabecular thickness but higher structure model index and trabecular separation compared to Col6a1+/+ mice. Subchondral bone thickness and mineral content increased significantly with age in Col6a1+/+ mice, but not in Col6a1−/− mice. Col6a1−/− mice had lower cartilage degradation scores, but developed early, severe osteophytes compared to Col6a1+/+mice. In both groups, cartilage roughness increased with age, but neither the frictional coefficient nor compressive modulus of the cartilage changed with age or genotype, as measured by AFM. Cartilage diffusivity, measured via SCAMP, varied minimally with age or genotype. The absence of type VI collagen has profound effects on knee joint structure and morphometry, yet minimal influences on the physical properties of the cartilage. Together with previous studies showing accelerated hip osteoarthritis in Col6a1−/− mice, these findings suggest different roles for collagen VI at different sites in the body, consistent with clinical data

Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome

We report the isolation of the 5′ flanking region of GRAF (GTPase regulator associated with the focal adhesion kinase), previously described as a putative tumour suppressor gene of acute myelogenous leukaemia and myelodysplastic syndrome, and demonstrate its promoter activity in reporter gene assays. Two putative protein-binding sites are identified of which one was sensitive to CpG methylation. The suppressed GRAF expression could be restored in leukaemia cell lines by treatment with a demethylating agent and an inhibitor of histone deacetylases. In contrast to normal tissues, which tested negative for GRAF promoter methylation, 11 of 29 (38%) bone marrow samples from patients with acute myeloid leukaemia or myelodysplastic syndrome were positive

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

Biased-corrected richness estimates for the Amazonian tree flora

Amazonian forests are extraordinarily diverse, but the estimated species richness is very much debated. Here, we apply an ensemble of parametric estimators and a novel technique that includes conspecific spatial aggregation to an extended database of forest plots with up-to-date taxonomy. We show that the species abundance distribution of Amazonia is best approximated by a logseries with aggregated individuals, where aggregation increases with rarity. By averaging several methods to estimate total richness, we confirm that over 15,000 tree species are expected to occur in Amazonia. We also show that using ten times the number of plots would result in an increase to just ~50% of those 15,000 estimated species. To get a more complete sample of all tree species, rigorous field campaigns may be needed but the number of trees in Amazonia will remain an estimate for years to come

Multifrequency studies of the peculiar quasar 4C+21.35 during the 2010 flaring activity

The discovery of rapidly variable Very High Energy ( VHE; E &gt; 100 GeV). - ray emission from 4C + 21.35 ( PKS 1222+ 216) by MAGIC on 2010 June 17, triggered by the high activity detected by the Fermi Large Area Telescope ( LAT) in high energy ( HE; E &gt; 100 MeV). - rays, poses intriguing questions on the location of the. - ray emitting region in this flat spectrum radio quasar. We present multifrequency data of 4C + 21.35 collected from centimeter to VHE during 2010 to investigate the properties of this source and discuss a possible emission model. The first hint of detection at VHE was observed by MAGIC on 2010 May 3, soon after a gamma- ray flare detected by Fermi-LAT that peaked on April 29. The same emission mechanism may therefore be responsible for both the HE and VHE emission during the 2010 flaring episodes. Two optical peaks were detected on 2010 April 20 and June 30, close in time but not simultaneous with the two gamma- ray peaks, while no clear connection was observed between the X-ray and gamma- ray emission. An increasing flux density was observed in radio and mm bands from the beginning of 2009, in accordance with the increasing gamma- ray activity observed by Fermi-LAT, and peaking on 2011 January 27 in the mm regime ( 230 GHz). We model the spectral energy distributions ( SEDs) of 4C + 21.35 for the two periods of the VHE detection and a quiescent state, using a one-zone model with the emission coming from a very compact region outside the broad line region. The three SEDs can be fit with a combination of synchrotron self-Compton and external Compton emission of seed photons from a dust torus, changing only the electron distribution parameters between the epochs. The fit of the optical/UV part of the spectrum for 2010 April 29 seems to favor an inner disk radius of &lt; six gravitational radii, as one would expect from a prograde-rotating Kerr black hole.</p