Protective role of TIRAP functional variant against development of coronary artery disease

Coronary artery disease (CAD) is the leading cause of sudden death worldwide. Inflammation is proved to be an important player in development of the CAD. Inflammation is directly regulated by the Toll like receptors (TLRs). Susceptibility of CAD is influenced by genetic variations within TLRs and the proteins involved in its signaling cascade. The TIRAP/MAL {TIR domain containing adaptor protein / MyD88 (myeloid differentiation primary response gene 88) adaptor-like} exhibits maximum genetic variations of all adaptor proteins involved in TLR signaling cascade. Susceptibility to a number of diseases can be influenced due to presence of S180L single nucleotide polymorphism (SNP) of TIRAP/MAL. This study was conducted to investigate the functional role of this well characterized S180L polymorphism on susceptibility to CAD among Pakistani patients. A total of 146 Pakistani CAD patients and 147 controls were genotyped by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) and the data was analyzed by using 2-tailed Chi square (x²) test. The p value ≤ 0.05 was considered to be significant.Significantly high frequency of homozygous L180L genotype was observed among healthy subjects as compared to the CAD patients [24 (16%) vs 7 (5%); x² 11.85; p = 0.003]. Moreover, the allele frequency of the minor allele; 180L was observed to be significantly higher among controls than the CAD patients, having same direction of association [156 (53%) vs 131 (45%); OR (95% CI) = 0.7198 (0.520–0.996); p < 0.05).Our results indicate that protective effect of L180L; a coding variant of TIRAP/MAL against CAD is discernible.     

Fluid–structure interaction (FSI) modeling of bone marrow through trabecular bone structure under compression

Biomechanics and Modeling in Mechanobiology - The present study has sought to investigate the fluid characteristic and mechanical properties of trabecular bone using fluid–structure...     

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs.     

Cancer cell migration: integrated roles of matrix mechanics and transforming potential

Significant progress has been achieved toward elucidating the molecular mechanisms that underlie breast cancer progression; yet, much less is known about the associated cellular biophysical traits. To this end, we use time-lapsed confocal microscopy to investigate the interplay among cell motility, three-dimensional (3D) matrix stiffness, matrix architecture, and transforming potential in a mammary epithelial cell (MEC) cancer progression series. We use a well characterized breast cancer progression model where human-derived MCF10A MECs overexpress either ErbB2, 14-3-3ζ, or both ErbB2 and 14-3-3ζ, with empty vector as a control. Cell motility assays showed that MECs overexpressing ErbB2 alone exhibited notably high migration speeds when cultured atop two-dimensional (2D) matrices, while overexpression of 14-3-3ζ alone most suppressed migration atop 2D matrices (as compared to non-transformed MECs). Our results also suggest that co-overexpression of the 14-3-3ζ and ErbB2 proteins facilitates cell migratory capacity in 3D matrices, as reflected in cell migration speed. Additionally, 3D matrices of sufficient stiffness can significantly hinder the migratory ability of partially transformed cells, but increased 3D matrix stiffness has a lesser effect on the aggressive migratory behavior exhibited by fully transformed cells that co-overexpress both ErbB2 and 14-3-3ζ. Finally, this study shows that for MECs possessing partial or full transforming potential, those overexpressing ErbB2 alone show the greatest sensitivity of cell migration speed to matrix architecture, while those overexpressing 14-3-3ζ alone exhibit the least sensitivity to matrix architecture. Given the current knowledge of breast cancer mechanobiology, these findings overall suggest that cell motility is governed by a complex interplay between matrix mechanics and transforming potential.     

Ranging and foraging of Himalayan grey langurs (Semnopithecus ajax) in Machiara National Park, Pakistan

Grey langurs (Semnopithecus spp.) occupy a variety of habitats, ranging from lowland forests and semi-desert to alpine forests. Little is known about their foraging and ranging in alpine forests, which appear to contain less food than lowland forests. We conducted a 1-year study of Himalayan grey langurs (Semnopithecus ajax) in Machiara National Park, Pakistan, where they occur at relatively high altitudes (range 2000–4733 m). We followed three groups of different sizes and compositions and examined the effects of ecological and social factors on ranging and feeding. The home-range sizes of a small bisexual group (SBG), a large bisexual group (LBG), and an all-male group (AMG) were 2.35 ± 0.92 (mean ± SD; average of four seasons), 3.28 ± 0.55, and 3.52 ± 1.00 km², respectively, and were largest in winter for all groups. The daily path lengths of the SBG, LBG, and AMG were 1.23 ± 0.28 (mean ± SD; average of four seasons), 1.75 ± 0.34, and 1.84 ± 0.70 km, respectively; that of the LBG was longer in winter, while that of the AMG was shorter in summer. Both the home-range size and daily path length of the AMG were larger than those of the other groups, even after partialling out the effect of group size differences. The mean altitude used by the langurs and the proportion of animals seen feeding did not differ among seasons or group types. As the mean temperature increased, the altitude used by langurs significantly increased for the SBG and LBG, but not for the AMG. On the other hand, as the temperature increased, the home-range sizes significantly decreased for the SBG and AMG, but not for the LBG. Rainfall did not show any correlation with ranging or feeding in any of the groups. Our results suggested that grey langurs in Machiara National Park employ a high-cost, high-return foraging strategy in winter, and that the ranging of the AMG also reflects its reproductive strategy.     

Sulf2 gene is alternatively spliced in mammalian developing and tumour tissues with functional implications

SULF2 enzyme regulates the activities of a number of signalling pathways that in many tissues are up-regulated during development and disease. As we recently showed for avian Sulf1, the present study demonstrates that mammalian Sulf2 gene can also generate functionally distinct splice variants that would regulate normal development and tumour growth differentially. It is thus important to distinguish SULF1/SULF2 isoforms in mammalian tissues to understand their functional and clinical relevance to disease. This study demonstrates that unlike normal adult lung with little or no SULF2 expression, this enzyme is expressed at high levels in most lung tumours showing differential cellular distribution of full length and shorter SULF2 variants in such tumours. Furthermore, we show that the short SULF2 splice variants are associated with those signalling pathways that are inhibited by full length SULF1/SULF2 variants and therefore could promote growth in such lung tumours.     

Cav2.3 channels are critical for oscillatory burst discharges in the reticular thalamus and absence epilepsy

Neurons of the reticular thalamus (RT) display oscillatory burst discharges that are believed to be critical for thalamocortical network oscillations related to absence epilepsy. Ca2+-dependent mechanisms underlie such oscillatory discharges. However, involvement of high-voltage activated (HVA) Ca2+ channels in this process has been discounted. We examined this issue closely using mice deficient for the HVA Ca(v)2.3 channels. In brain slices of Ca(v)2.3?/?, a hyperpolarizing current injection initiated a low-threshold burst of spikes in RT neurons; however, subsequent oscillatory burst discharges were severely suppressed, with a significantly reduced slow afterhyperpolarization (AHP). Consequently, the lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to γ-butyrolactone-induced absence epilepsy. Local blockade of Ca(v)2.3 channels in the RT mimicked the results of Ca(v)2.3?/? mice. These results provide strong evidence that Ca(v)2.3 channels are critical for oscillatory burst discharges in RT neurons and for the expression of absence epilepsy.     

Simple synthetic toll-like receptor 2 ligands

Stimulation of toll-like receptor 2 (TLR2) by bacterial lipoproteins induces fast non-specific immune responses against pathogens followed by slow but specific adaptive immune responses. Development of synthetic TLR2 agonists/antagonists would be useful in the prevention of different infectious and immunologic disorders. The current study reports synthesis and TLR2 activity of two simple TLR2 ligands, which feature minimal structural requirement for TLR2 activity (two long lipid chains) and stimulate agonistic activity at nanomolar concentration.