The effect of halogen atom on the molecular quadratic nonlinearity of half sandwich complexes in the presence of an acceptor

Half sandwich complexes of the type [CpM(CO)_nX] {X = Cl, Br, I; If, M = Fe, Ru; n = 2 and if M = Mo; n = 3} and [CpNiPPh₃X] {X = Cl, Br, I} have been synthesized and their second order molecular nonlinearity (β) measured at 1064 nm in CHCl₃ by the hyper-Rayleigh scattering technique. Iron complexes consistently display larger β values than ruthenium complexes while nickel complexes have marginally larger β values than iron complexes. In the presence of an acceptor ligand such as CO or PPh₃, the role of the halogen atom is that of a π donor. The better overlap of Cl orbitals with Fe and Ni metal centres make Cl a better π donor than Br or I in the respective complexes. Consequently, M-π interaction is stronger in Fe/Ni-Cl complexes. The value of β decreases as one goes down the halogen group. For the complexes of 4d metal ions where the metal-ligand distance is larger, the influence of π orbital overlap appears to be less important, resulting in moderate changes in β as a function of halogen substitution.     

NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging

Molecular and Cellular Biochemistry - The nicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor, involved in various physiological and molecular processes, including energy...     

A Pd-mediated new strategy to functionalized 2-aminochromenes: their in vitro evaluation as potential anti tuberculosis agents

A multi component based synthesis involving palladium catalyzed C-C bond forming reaction has been developed as a new strategy to access systematically modified functionalized 2-aminochromenes. This MCR involves the use of bromobenzaldehyde as a key component and is highlighted by generating a new compound library. Many of these compounds showed Mycobacterium tuberculosis H37Rv chorismate mutase inhibiting properties in vitro representing the lead example of chorismate mutase inhibition by heteroarene based compounds.     

Anthranilate derivatives as TACE inhibitors: Docking based CoMFA and CoMSIA analyses

Anthranilic acid based derivatives (ANTs) have been identified as a novel class of potent tumor necrosis factor-α converting enzyme (TACE) inhibitors. A computational strategy based on molecular docking studies, followed by CoMFA and CoMSIA analyses has been performed to elucidate the atomic details of the TACE/ANT interactions and also to identify the most important features impacting TACE inhibitory activity of ANTs. The CoMSIA model resulted to be slightly more predictive than CoMFA model, and gave conventional r² 0.991, r_cv² 0.793, q² 0.777, SEE 0.050, F-value 655.610, and r_test² 0.871. The 3D-QSAR field contributions and the structural features of the TACE binding site showed a good correlation. These studies will be useful to design new TACE inhibitors with improved potency.     

Characterizing the normal proteome of human ciliary body

Background

The ciliary body is the circumferential muscular tissue located just behind the iris in the anterior chamber of the eye. It plays a pivotal role in the production of aqueous humor, maintenance of the lens zonules and accommodation by changing the shape of the crystalline lens. The ciliary body is the major target of drugs against glaucoma as its inhibition leads to a drop in intraocular pressure. A molecular study of the ciliary body could provide a better understanding about the pathophysiological processes that occur in glaucoma. Thus far, no large-scale proteomic investigation has been reported for the human ciliary body.

Results

In this study, we have carried out an in-depth LC-MS/MS-based proteomic analysis of normal human ciliary body and have identified 2,815 proteins. We identified a number of proteins that were previously not described in the ciliary body including importin 5 (IPO5), atlastin-2 (ATL2), B-cell receptor associated protein 29 (BCAP29), basigin (BSG), calpain-1 (CAPN1), copine 6 (CPNE6), fibulin 1 (FBLN1) and galectin 1 (LGALS1). We compared the plasma proteome with the ciliary body proteome and found that the large majority of proteins in the ciliary body were also detectable in the plasma while 896 proteins were unique to the ciliary body. We also classified proteins using pathway enrichment analysis and found most of proteins associated with ubiquitin pathway, EIF2 signaling, glycolysis and gluconeogenesis.

Conclusions

More than 95% of the identified proteins have not been previously described in the ciliary body proteome. This is the largest catalogue of proteins reported thus far in the ciliary body that should provide new insights into our understanding of the factors involved in maintaining the secretion of aqueous humor. The identification of these proteins will aid in understanding various eye diseases of the anterior segment such as glaucoma and presbyopia.     

FE65 as a link between VLDLR and APP to regulate their trafficking and processing

Background

Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) have been linked to familial Parkinson??s disease, but the underlying pathogenic mechanism remains unclear. We previously reported that loss of PINK1 impairs mitochondrial respiratory activity in mouse brains.

Results

In this study, we investigate how loss of PINK1 impairs mitochondrial respiration using cultured primary fibroblasts and neurons. We found that intact mitochondria in PINK1?/? cells recapitulate the respiratory defect in isolated mitochondria from PINK1?/? mouse brains, suggesting that these PINK1?/? cells are a valid experimental system to study the underlying mechanisms. Enzymatic activities of the electron transport system complexes are normal in PINK1?/? cells, but mitochondrial transmembrane potential is reduced. Interestingly, the opening of the mitochondrial permeability transition pore (mPTP) is increased in PINK1?/? cells, and this genotypic difference between PINK1?/? and control cells is eliminated by agonists or inhibitors of the mPTP. Furthermore, inhibition of mPTP opening rescues the defects in transmembrane potential and respiration in PINK1?/? cells. Consistent with our earlier findings in mouse brains, mitochondrial morphology is similar between PINK1?/? and wild-type cells, indicating that the observed mitochondrial functional defects are not due to morphological changes. Following FCCP treatment, calcium increases in the cytosol are higher in PINK1?/? compared to wild-type cells, suggesting that intra-mitochondrial calcium concentration is higher in the absence of PINK1.

Conclusions

Our findings show that loss of PINK1 causes selective increases in mPTP opening and mitochondrial calcium, and that the excessive mPTP opening may underlie the mitochondrial functional defects observed in PINK1?/? cells.     

Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes

Liver and skeletal muscle triglyceride stores are elevated in type 2 diabetes and correlate with insulin resistance. As postprandial handling of dietary fat may be a critical determinant of tissue triglyceride levels, we quantified postprandial fat storage in normal and type 2 diabetes subjects. Healthy volunteers (n = 8) and diet-controlled type 2 diabetes subjects (n = 12) were studied using a novel 13C magnetic resonance spectroscopy protocol to measure the postprandial increment in liver and skeletal muscle triglyceride following ingestion of 13C-labeled fatty acids given with a standard mixed meal. The postprandial increment in hepatic triglyceride was rapid in both groups (peak increment controls: +7.3 +/- 1.5 mmol/l at 6 h, P = 0.002; peak increment diabetics: +10.8 +/- 3.4 mmol/l at 4 h, P = 0.009). The mean postprandial incremental AUC of hepatic 13C enrichment between the first and second meals (0 and 4 h) was significantly higher in the diabetes group (6.1 +/- 1.4 vs. 1.7 +/- 0.6 mmol x l(-1) x h(-1), P = 0.019). Postprandial increment in skeletal muscle triglyceride in the control group was small compared with the diabetic group, the mean 24-h postprandial incremental AUC being 0.2 +/- 0.3 vs. 1.7 +/- 0.4 mmol x l(-1) x h(-1) (P = 0.009). We conclude that the postprandial uptake of fatty acids by liver and skeletal muscle is increased in type 2 diabetes and may underlie the elevated tissue triglyceride stores and consequent insulin resistance.     

Literature mining and database annotation of protein phosphorylation using a rule-based system

MOTIVATION: A large volume of experimental data on protein phosphorylation is buried in the fast-growing PubMed literature. While of great value, such information is limited in databases owing to the laborious process of literature-based curation. Computational literature mining holds promise to facilitate database curation. RESULTS: A rule-based system, RLIMS-P (Rule-based LIterature Mining System for Protein Phosphorylation), was used to extract protein phosphorylation information from MEDLINE abstracts. An annotation-tagged literature corpus developed at PIR was used to evaluate the system for finding phosphorylation papers and extracting phosphorylation objects (kinases, substrates and sites) from abstracts. RLIMS-P achieved a precision and recall of 91.4 and 96.4% for paper retrieval, and of 97.9 and 88.0% for extraction of substrates and sites. Coupling the high recall for paper retrieval and high precision for information extraction, RLIMS-P facilitates literature mining and database annotation of protein phosphorylation.     

Effects of thrombin,PAR-1 activating peptide and a PAR-1 antagonist on umbilical artery resistance in vitro

Background  

The non-thrombotic effects of thrombin in cardiovascular tissues, as mediated via the protease activated receptors (PARs), and particularly PAR-1, have been the focus of much recent research. The aims of this study were to evaluate the effects of thrombin, a specific PAR-1 activating peptide (PAR1-AP), and a PAR-1 antagonist on human umbilical artery tone in vitro.