Assessing the Performance of Peptide Force Fields for Modeling the Solution Structural Ensembles of Cyclic Peptides.

Molecular dynamics simulation is a powerful tool for characterizing the solution structural ensembles of cyclic peptides. However, the ability of simulation to recapitulate experimental results and make accurate predictions largely depends on the force fields used. In our work here, we evaluate the performance of seven state-of-the-art force fields in recapitulating the experimental NMR results in water of 12 benchmark cyclic peptides, consisting of 6 cyclic pentapeptides, 4 cyclic hexapeptides, and 2 cyclic heptapeptides.

Effect of pooling family oral fluids on the probability of PRRSV RNA detection by RT-rtPCR.

Family oral fluids (FOFs) are an aggregate sample type shown to be a cost-efficient and convenient option for determining the porcine reproductive and respiratory syndrome virus (PRRSV) status of weaning age pigs. This study investigates the effect of pooling PRRSV-positive FOF samples with PRRSV-negative FOF samples at different levels (1/3, 1/5, 1/10, 1/20) on the probability of PRRSV RNA detection by reverse-transcription real-time polymerase chain reaction (RT-rtPCR). Mathematical models were built to assess how much the probability of RT-rtPCR PRRSV detection changed with increasing proportion of PRRSV-positive samples present within pools and how partially sampling a farrowing room influenced the probability of RT-rtPCR detection of PRRSV RNA in pooled samples at different prevalence scenarios.

Computational investigations of B-dependent enzymatic reactions.

Nature employs two biologically active forms of vitamin B, adenosylcobalamin (or coenzyme B) and methylcobalamin, as cofactors in molecular transformations both in bacteria and mammals. Computational chemistry, guided by experimental data, has been used to explore fundamental characteristics of these enzymatic reactions. In particular, the quantum mechanics/molecular mechanics (QM/MM) method has proven to be a powerful tool in elucidating important characteristics of B-dependent enzymatic reactions.

Photolytic properties of B-dependent enzymes: A theoretical perspective.

The biologically active vitamin B derivates, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), are ubiquitous organometallic cofactors. In addition to their key roles in enzymatic catalysis, B cofactors have complex photolytic properties which have been the target of experimental and theoretical studies. With the recent discovery of B-dependent photoreceptors, there is an increased need to elucidate the underlying photochemical mechanisms of these systems.

Methyl transfer reactions catalyzed by cobalamin-dependent enzymes: Insight from molecular docking.

Methyl transfer reactions, mediated by methyltransferases (MeTrs), such as methionine synthase (MetH) or monomethylamine: CoM (MtmBC), constitute one of the most important classes of vitamin B-dependent reactions. The challenge in exploring the catalytic function of MeTrs is related to their modular structure. From the crystallographic point of view, the structure of each subunit has been determined, but there is a lack of understanding of how each subunit interacts with each other.

A Markovian influence graph formed from utility line outage data to mitigate large cascades.

We use observed transmission line outage data to make a Markovian influence graph that describes the probabili- ties of transitions between generations of cascading line outages. Each generation of a cascade consists of a single line outage or multiple line outages. The new influence graph defines a Markov chain and generalizes previous influence graphs by including multiple line outages as Markov chain states.

Aerobic photolysis of methylcobalamin: structural and electronic properties of the Cbl-O-O-CH intermediate.

Photolysis of methylcobalamin (MeCbl) in the presence of molecular oxygen (O) has been investigated using density functional theory (DFT) and time-dependent DFT (TD-DFT). The key step involves the formation of the Cbl-O-O-CH intermediate as a result of triplet O insertion in the Co-C bond in the presence of light. Analysis of low-lying excited states shows that the presence of light is only needed to activate the Co-C bond via the formation of the ligand field (LF) state.

Clinicopathological and Immunological Profile of Patients with Cutaneous Manifestations and their Relationship with Organ Involvement in Systemic Lupus Erythematosus Attending a Tertiary Care Center of Eastern India.

Background: Lupus erythematosus (LE) is an autoimmune disorder with diverse clinical manifestations ranging from mild cutaneous disorder to life-threatening systemic illness and associated with varying immunological parameters.

Aim: We conducted a study in a tertiary care center of eastern India to determine the clinical pattern, immunological profile of patients with cutaneous manifestations of systemic LE (SLE) and their relationship with organ involvement.

Materials And Methods: Fifty-five consecutive patients attending dermatology OPD having features consistent with cutaneous LE and fulfilling the criteria of SLE were included.

14-3-3 proteins protect AMPK-phosphorylated ten-eleven translocation-2 (TET2) from PP2A-mediated dephosphorylation.

Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes and has been implicated in cancer and aging because of its role as a global epigenetic modifier. TET2 has a large N-terminal domain and a catalytic C-terminal region. Previous reports have demonstrated that the TET2 catalytic domain remains active independently of the N-terminal domain.

How does the mutation in the cap domain of methylcobalamin-dependent methionine synthase influence the photoactivation of the Co-C bond?

Methionine synthase (MetH) is a methylcobalamin (MeCbl)-dependent mammalian enzyme which plays a critical role in carrying out the transfer of a methyl group from methyl tetrahydrofolate to homocysteine to generate methionine and tetrahydrofolate. This catalytic cycle proceeds via cleavage of a Co-C bond which is formally heterolytic. This cleavage results in a structural change in the MeCbl cofactor bound to an enzyme.

Trichomonas vaginalis Virus Among Women With Trichomoniasis and Associations With Demographics, Clinical Outcomes, and Metronidazole Resistance.

Background: Trichomonas vaginalis virus (TVV) is a non-segmented, 4.5-5.5 kilo-base pair (kbp), double-stranded RNA virus infecting T.

Trichomonas vaginalis virus: a review of the literature.

Trichomonas vaginalis (TV) is a parasitic protozoan responsible for the sexually transmitted infection trichomoniasis. Trichomonas vaginalis virus (TVV) is a nonsegmented, 4.5-5 kbp, double-stranded RNA virus, from the Totiviridae family, which inhabits TV.

Mechanism of the photo-induced activation of CoC bond in methylcobalamin-dependent methionine synthase.

Methylcobalamin (MeCbl)-dependent enzyme methionine synthase (MetH), plays a critical role in the catalysis of methyl group transfer from methyltetrahydrofolate (CH-Hfolate) to homocysteine. It often performs a side reaction to generate cob(II)alamin through photolysis of the organometallic CoC σ bond. A hybrid QM/MM method has been applied to explore the photochemistry of MeCbl-bound MetH.

Merging -means with hierarchical clustering for identifying general-shaped groups.

Clustering partitions a dataset such that observations placed together in a group are similar but different from those in other groups. Hierarchical and -means clustering are two approaches but have different strengths and weaknesses. For instance, hierarchical clustering identifies groups in a tree-like structure but suffers from computational complexity in large datasets while -means clustering is efficient but designed to identify homogeneous spherically-shaped clusters.

Study of the Susceptibility of Clinical Isolates of Trichomonas vaginalis to Metronidazole and Secnidazole.

Nitroimidazoles (metronidazole [MTZ] and tinidazole [TNZ]) are the only drugs recommended for treatment of infections. MTZ resistance occurs in 4% to 10% of cases of vaginal trichomoniasis (R. D.

Kinomic profiling identifies focal adhesion kinase 1 as a therapeutic target in advanced clear cell renal cell carcinoma.

The introduction of targeted therapies has caused a paradigm shift in the treatment of metastatic clear cell (cc)-renal cell carcinoma (RCC). We hypothesized that determining differential kinase activity between primary and metastatic tumor sites may identify critical drivers of progression and relevant therapeutic targets in metastatic disease. Kinomic profiling was performed on primary tumor and metastatic tumor deposits utilizing a peptide substrate microarray to detect relative tyrosine phosphorylation activity.

Point mutations of the mTOR-RHEB pathway in renal cell carcinoma.

Aberrations in the mTOR (mechanistic target of rapamycin) axis are frequently reported in cancer. Using publicly available tumor genome sequencing data, we identified several point mutations in MTOR and its upstream regulator RHEB (Ras homolog enriched in brain) in patients with clear cell renal cell carcinoma (ccRCC), the most common histology of kidney cancer. Interestingly, we found a prominent cluster of hyperactivating mutations in the FAT (FRAP-ATM-TTRAP) domain of mTOR in renal cell carcinoma that led to an increase in both mTORC1 and mTORC2 activities and led to an increased proliferation of cells.

L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.

Unlabelled: Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)-dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of-function mutations of isocitrate dehydrogenase (IDH1, IDH2) found in several different tumors.

CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress.

Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in various neurodegenerative diseases including Parkinson Disease, Alzheimer Disease and Huntington Disease. PUMA (p53 upregulated modulator of apoptosis) and BIM (BCL2 interacting mediator of cell death), pro-apoptotic BH3 domain-only, BCL2 family members, have previously been shown to regulate ER stress-induced cell death, but the upstream signaling pathways that regulate this response in neuronal cells are incompletely defined. Consistent with previous studies, we show that both PUMA and BIM are induced in response to ER stress in neuronal cells and that transcriptional induction of PUMA regulates ER stress-induced cell death, independent of p53.

Deficiency of pro-apoptotic Hrk attenuates programmed cell death in the developing murine nervous system but does not affect Bcl-x deficiency-induced neuron apoptosis.

The BCL-2 family includes both pro- and anti-apoptotic proteins, which regulate programmed cell death during development and in response to various apoptotic stimuli. The BH3-only subgroup of pro-apoptotic BCL-2 family members is critical for the induction of apoptotic signaling, by binding to and neutralizing anti-apoptotic BCL-2 family members. During embryonic development, the anti-apoptotic protein BCL-X(L) plays a critical role in the survival of neuronal populations by regulating the multi-BH domain protein BAX.