Changes in left ventricular geometry during spontaneous breathing

The purpose of these experiments was to determine the effects of a spontaneously generated inspiration on the size and shape of the left ventricle (LV) in anesthetized supine dogs. We implanted markers in the LV to establish three perpendicular axes and recorded the motion of these markers using biplane cinefluoroscopy at 60 Hz. The primary changes in LV size that accompanied inspiration occurred at end diastole (ED). The largest change in LVED dimension was a 2.46-mm narrowing of the septal-lateral wall dimension, but the apex-base dimension decreased also, by 0.74 mm. The anteroposterior dimension actually widened by 1.07 mm. The septal-lateral narrowing was caused by both a 1.0-mm narrowing of the distance between the septal marker and the apex-base axis, as well as by a 1.4-mm narrowing between the apex-base axis and the lateral wall marker. Narrowing of the septal portion seemed expected because of presumed enhanced right ventricular filling during inspiration. Narrowing of the lateral portion of the LV, while the anteroposterior dimension widened, was surprising because a change in LVEDV shape is implied. Assuming ventricular homogeneity, this change in LVED shape implies that the forces applied to the epicardial surface were not uniform. There must have been a retraction on the anterior and posterior surface that was not experienced by the lateral LV wall. The net effect of these dimensional changes of the LV at end diastole (estimated from the product of the three ED axes) was a 3.5-cm3 reduction in LVED volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nuclear magnetic resonance and thermal studies of drug doped dipalmitoyl phosphatidyl choline-H2O systems

The influence of the sulfone drugs, diamino diphenyl sulfone and diamino monophenyl sulfone on the phase transitions and dynamics of dipalmitoyl phosphatidyl choline-H₂O/D₂O vesicles have been investigated using differential scanning calorimetry and nuclear magnetic resonance. Our results show that diamino diphenyl sulfone interacts quite strongly with the headgroups of dipalmitoyl phosphatidyl choline whereas the diamino monophenyl sulfone-dipalmitoyl phosphatidyl choline interaction is quite weak. This is attributed to the difference in the structure and hydrophobic character of the two drugs.     

Anonymous nuclear DNA markers in the American oyster and their implications for the heterozygote deficiency phenomenon in marine bivalves

A puzzling population-genetic phenomenon widely reported in allozyme surveys of marine bivalves is the occurrence of heterozygote deficits relative to Hardy-Weinberg expectations. Possible explanations for this pattern are categorized with respect to whether the effects should be confined to protein-level assays or are genomically pervasive and expected to be registered in both protein- and DNA-level assays. Anonymous nuclear DNA markers from the American oyster were employed to reexamine the phenomenon. In assays based on the polymerase chain reaction (PCR), two DNA-level processes were encountered that can lead to artifactual genotypic scorings: (a) differential amplification of alleles at a target locus and (b) amplification from multiple paralogous loci. We describe symptoms of these complications and prescribe methods that should generally help to ameliorate them. When artifactual scorings at two anonymous DNA loci in the American oyster were corrected, Hardy-Weinberg deviations registered in preliminary population assays decreased to nonsignificant values. Implications of these findings for the heterozygote-deficit phenomenon in marine bivalves, and for the general development and use of PCR-based assays, are discussed.      

Monocarbonyl Analogs of Curcumin with Potential to Treat Colorectal Cancer

Curcumin has a plethora of biological properties, making this compound potentially effective in the treatment of several diseases, including cancer. However, curcumin clinical use is compromised by its poor pharmacokinetics, being crucial to find novel analogs with better pharmacokinetic and pharmacological properties. Here, we aimed to evaluate the stability, bioavailability and pharmacokinetic profiles of monocarbonyl analogs of curcumin. A small library of monocarbonyl analogs of curcumin 1a–q was synthesized. Lipophilicity and stability in physiological conditions were both assessed by HPLC-UV, while two different methods assessed the electrophilic character of each compound monitored by NMR and by UV-spectroscopy. The potential therapeutic effect of the analogs 1a–q was evaluated in human colon carcinoma cells and toxicity in immortalized hepatocytes. Our results showed that the curcumin analog 1e is a promising agent against colorectal cancer, with improved stability and efficacy/safety profile.     

Biochemical studies of the excitable membrane of Paramecium tetraurelia. V. effects of proteases on the ciliary membrane

The swimming behavior of Paramecium is regulated by an excitable membrane that covers the body and cilia of the protozoan. In order to obtain information on the topology and function of ciliary membrane proteins, Paramecia were treated with trypsin, chymotrypsin or pronase and the effects of these proteases were analyzed using electron microscopy, gel electrophoresis of ciliary fractions and behavioral tests. At the concentrations used, trypsin and chymotrypsin had little or no effect on the cells while pronase removed the cell surface coat, visible as fuzzy material covering the cell membrane. The same pronase treatment caused the specific removal of a high molecular weight protein (250 000), as judged by sodium dodecyl sulfate polyacrylamide gel electrophoresis. This protein, the ‘immobilization antigen’, constitutes the major protein of the ciliary membrane. Although the immobilization antigen was removed (or markedly decreased), no marked and reproducible difference was observed in the swimming behavior of the treated cells. We also determined the effects of proteases on isolated ciliary fractions to explore the sidedness of ciliary membrane proteins. A set of proteins relatively resistant to protease digestion was identified; they may be intrinsic membrane proteins.     

The Aging Metabolome—Biomarkers to Hub Metabolites

Aging biology is intimately associated with dysregulated metabolism, which is one of the hallmarks of aging. Aging‐related pathways such as mTOR and AMPK, which are major targets of anti‐aging interventions including rapamcyin, metformin, and exercise, either directly regulate or intersect with metabolic pathways. In this review, numerous candidate bio‐markers of aging that have emerged using metabolomics are outlined. Metabolomics studies also reveal that not all metabolites are created equally. A set of core “hub” metabolites are emerging as central mediators of aging. The hub metabolites reviewed here are nicotinamide adenine dinucleotide, reduced nicotinamide dinucleotide phosphate, α‐ketoglutarate, and β‐hydroxybutyrate. These “hub” metabolites have signaling and epigenetic roles along with their canonical roles as co‐factors or intermediates of carbon metabolism. Together these hub metabolites suggest a central role of the TCA cycle in signaling and metabolic dysregulation associated with aging.     

Design,Synthesis, and Biological Evaluation of 2‐(2‐Bromo‐3‐nitrophenyl)‐5‐phenyl‐1,3,4‐oxadiazole Derivatives as Possible Anti‐Breast Cancer Agents

Breast Cancer (BCa) is the most often diagnosed cancer among women who were in the late 1940’s. Breast cancer growth is largely dependent on the expression of estrogen and progesterone receptor. Breast cancer cells may have one, both, or none of these receptors. The treatment for breast cancer may involve surgery, hormonal therapy (Tamoxifen, an aromatase inhibitor, etc.) and oral chemotherapeutic drugs. The molecular docking technique reported the findings on the potential binding modes of the 2‐(2‐bromo‐3‐nitrophenyl)‐5‐phenyl‐1,3,4‐oxadiazole derivatives with the estrogen receptor (PDB ID: 3ERT). The 1,3,4‐oxadiazole derivatives 4a – 4j have been synthesized and described by spectroscopic method. 2‐(2‐Bromo‐6‐nitrophenyl)‐5‐(4‐bromophenyl)‐1,3,4‐oxadiazole ( 4c ) was reconfirmed by single‐crystal XRD. All the compounds have been tested in combination with generic Imatinib pharmaceutical drug against breast cancer cell lines isolated from Caucasian woman MCF‐7, MDA‐MB‐453 and MCF‐10A non‐cancer cell lines. The compounds with the methoxy (in 4c ) and methyl (in 4j ) substitution were shown to have significant cytotoxicity, with 4c showing dose‐dependent activation and decreased cell viability. The mechanism of action was reported by induced apoptosis and tested by a DNA enzyme inhibitor experiment (ELISA) for Methyl Transferase. Molecular dynamics simulations were made for hit molecule 4c to study the stability and interaction of the protein?ligand complex. The toxicity properties of ADME were calculated for all the compounds. All these results provide essential information for further clinical trials.