Gender dimorphism in regulation of plasma proteins in streptozotocin‐induced diabetic rats

In the present study, we examined differentially regulated plasma proteins between healthy control and streptozotocin (STZ)‐induced male and female diabetic rats by 2DE‐based proteomic analysis. Animal experiments revealed that significantly lower plasma insulin levels were observed in female diabetic rats, consequently resulting in higher blood glucose levels in female diabetic rats. Importantly, plasma levels of sex hormones were significantly altered in a gender‐dependent manner before and after STZ treatment. Results of the animal experiment indicated the existence of sexual dimorphism in the regulation of plasma proteins between healthy control and diabetic rats. Plasma proteome analysis enabled us to identify a total of 38 proteins showing sexual dimorphic regulation patterns. In addition, for the first time, we identified several differentially regulated plasma proteins between healthy control and diabetic rats, including apolipoprotein E, fetuin B, α‐1‐acid glycoprotein, β‐2‐glycoprotein 1, 3‐hydroxyanthranilate 3,4‐dioxygenase, and serum amyloid P‐component. To the best of our knowledge, this is the first proteomic approach to address sexual dimorphism in diabetic animals. These proteomic data on gender‐dimorphic regulation of plasma proteins provide valuable information that can be used for evidence‐based gender‐specific clinical treatment of diabetes.     

How do rice seedlings of landrace Pokkali survive in saline fields after transplantation? Physiology,biochemistry, and photosynthesis

Photosynthesis Research - Rice, one of the most important staple food crops in the world, is highly sensitive to soil salinity at the seedling stage. The ultimate yield of this crop is a function...     

Lumbopelvic control and pitching performance of professional baseball pitchers

This study assessed the correlation between lumbopelvic control during a single-leg balancing task and in-game pitching performance in Minor-League baseball pitchers. Seventy-five healthy professional baseball pitchers performed a standing lumbopelvic control test during the last week of spring training for the 2008 and 2009 seasons while wearing a custom-designed testing apparatus, the "Level Belt." With the Level Belt secured to the waist, subjects attempted to transition from a 2-leg to a single-leg pitching stance and balance while maintaining a stable pelvic position. Subjects were graded on the maximum sagittal pelvic tilt from a neutral position during the motion. Pitching performance, number of innings pitched (IP), and injuries were compared for all subjects who pitched at least 50 innings during a season. The median Level Belt score for the study group was 7°. Two-sample t-tests with equal variances were used to determine if pitchers with a Level Belt score <7° or ≥7° were more likely to perform differently during the baseball season, and chi-square analysis was used to compare injuries between groups. Subjects scoring <7° on the Level Belt test had significantly fewer walks plus hits per inning than subjects scoring ≥7° (walks plus hits per inning pitched, 1.352 ± 0.251 vs. 1.584 ± 0.360, p = 0.013) and significantly more IP during the season (IP, 78.89 ± 38.67 vs. 53.38 ± 42.47, p = 0.043). There was no significant difference in the number of pitchers injured between groups. These data suggest that lumbopelvic control influences overall performance for baseball pitchers and that a simple test of lumbopelvic control can potentially identify individuals who have a better chance of pitching success.     

An evolutionary genomic approach to identify genes involved in human birth timing

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.     

Comparative genomics of cell envelope components in mycobacteria

Mycobacterial cell envelope components have been a major focus of research due to their unique features that confer intrinsic resistance to antibiotics and chemicals apart from serving as a low-permeability barrier. The complex lipids secreted by Mycobacteria are known to evoke/repress host-immune response and thus contribute to its pathogenicity. This study focuses on the comparative genomics of the biosynthetic machinery of cell wall components across 21-mycobacterial genomes available in GenBank release 179.0. An insight into survival in varied environments could be attributed to its variation in the biosynthetic machinery. Gene-specific motifs like 'DLLAQPTPAW' of ufaA1 gene, novel functional linkages such as involvement of Rv0227c in mycolate biosynthesis; Rv2613c in LAM biosynthesis and Rv1209 in arabinogalactan peptidoglycan biosynthesis were detected in this study. These predictions correlate well with the available mutant and coexpression data from TBDB. It also helped to arrive at a minimal functional gene set for these biosynthetic pathways that complements findings using TraSH.     

In-Vivo Efficacy of Compliant 3D Nano-Composite in Critical-Size Bone Defect Repair: a Six Month Preclinical Study in Rabbit

Bone defects above critical size do not heal completely by itself and thus represent major clinical challenge to reconstructive surgery. Numerous bone substitutes have already been used to promote bone regeneration, however their use, particularly for critical-sized bone defects along with their long term in vivo safety and efficacy remains a concern. The present study was designed to obtain a complete healing of critical-size defect made in the proximal tibia of New Zealand White rabbit, using nano-hydroxyapatite/gelatin and chemically carboxymethylated chitin (n-HA/gel/CMC) scaffold construct. The bone-implant interfaces and defect site healing was evaluated for a period up to 25 weeks using radiography, micro-computed tomography, fluorescence labeling, and histology and compared with respective SHAM (empty contra lateral control). The viscoelastic porous scaffold construct allows easy surgical insertion and post-operatively facilitate oxygenation and angiogenesis. Radiography of defect treated with scaffold construct suggested expedited healing at defect edges and within the defect site, unlike confined healing at edges of the SHAM sites. The architecture indices analyzed by micro-computed tomography showed a significant increase in percentage of bone volume fraction, resulted in reconciled cortico-trabecular bone formation at n-HA/gel/CMC constructs treated site (15.2% to 52.7%) when compared with respective SHAM (10.2% to 31.8%). Histological examination and fluorescence labeling revealed that the uniformly interconnected porous surface of scaffold construct enhanced osteoblasts’ activity and mineralization. These preclinical data suggest that, n-HA/gel/CMC construct exhibit stimulation of bone''s innate regenerative capacity, thus underscoring their use in guided bone regeneration.     

Negative regulation of EGFR-Vav2 signaling axis by Cbl ubiquitin ligase controls EGF receptor-mediated epithelial cell adherens junction dynamics and cell migration

The E3 ubiquitin ligase Casitas B lymphoma protein (Cbl) controls the ubiquitin-dependent degradation of EGF receptor (EGFR), but its role in regulating downstream signaling elements with which it associates and its impact on biological outcomes of EGFR signaling are less clear. Here, we demonstrate that stimulation of EGFR on human mammary epithelial cells disrupts adherens junctions (AJs) through Vav2 and Rac1/Cdc42 activation. In EGF-stimulated cells, Cbl regulates the levels of phosphorylated Vav2 thereby attenuating Rac1/Cdc42 activity. Knockdown of Cbl and Cbl-b enhanced the EGF-induced disruption of AJs and cell motility. Overexpression of constitutively active Vav2 activated Rac1/Cdc42 and reorganized junctional actin cytoskeleton; these effects were suppressed by WT Cbl and enhanced by a ubiquitin ligase-deficient Cbl mutant. Cbl forms a complex with phospho-EGFR and phospho-Vav2 and facilitates phospho-Vav2 ubiquitinylation. Cbl can also interact with Vav2 directly in a Cbl Tyr-700-dependent manner. A ubiquitin ligase-deficient Cbl mutant enhanced the morphological transformation of mammary epithelial cells induced by constitutively active Vav2; this effect requires an intact Cbl Tyr-700. These results indicate that Cbl ubiquitin ligase plays a critical role in the maintenance of AJs and suppression of cell migration through down-regulation of EGFR-Vav2 signaling.     

Hip extension, knee flexion paradox: a new mechanism for non-contact ACL injury

Considering that an athlete performs at-risk sports activities countless times throughout the course of his or her career prior to the instance of anterior cruciate ligament (ACL) injury, one may conclude that non-contact ACL injury is a rare event. Nevertheless, the overall number of non-contact ACL injuries, both in the US and worldwide, remains alarming due to the growing number of recreational and professional athletes participating in high-risk activities. To date, numerous non-contact ACL injury mechanisms have been proposed, but none provides a detailed picture of sequence of events leading to injury and the exact cause of this injury remains elusive. In this perspective article, we propose a new conception of non-contact ACL injury mechanism that comprehensively integrates risk factors inside and outside the knee joint. The proposed mechanism is robust in the sense that it is biomechanically justifiable and addresses a number of confounding issues related to ACL injury.     

Precancerous and non-cancer disease endpoints of chronic arsenic exposure: the level of chromosomal damage and XRCC3 T241M polymorphism

Genetic variants are expected to play an important role in arsenic susceptibility. Our previous study revealed deficient DNA repair capacity to be a susceptibility factor for arsenicism. T241M polymorphism in XRCC3 (a homologous recombination repair pathway gene) is widely studied for its association with several cancers. We have investigated the association of XRCC3 T241M polymorphism with arsenic-induced precancerous and non-cancer disease outcomes. The present study evaluated the association of T241M polymorphism with arsenic-induced skin lesions, peripheral neuropathy (neurodegenerative changes), conjunctivitis and other ocular diseases. A case-control study was conducted in West Bengal, India, involving 206 cases with arsenic-induced skin lesions and 215 controls without arsenic-induced skin lesions having similar arsenic exposure. XRCC3 T241M polymorphism was determined using conventional PCR-sequencing method. Chromosomal aberration assay, arsenic-induced neuropathy and ocular diseases were also evaluated. The data revealed that presence of at least one Met allele (Met/Met or Thr/Met) was protective towards development of arsenic-induced skin lesions [OR=0.45, 95% CI: 0.30-0.67], peripheral neuropathy [OR=0.49; 95%CI: 0.30-0.82] and conjunctivitis [OR=0.60; 95%CI: 0.40-0.92]. A significant correlation was also observed between protective genotype and decreased frequency of chromosomal aberrations. Thus the results indicate the protective role of Met allele against the arsenic-induced skin lesions, chromosomal instability, peripheral neuropathy and conjunctivitis.     

An essential role of human Ada3 in p53 acetylation

The p53 tumor suppressor protein functions as a critical component of genotoxic stress response by regulating the expression of effector gene products that control the fate of a cell following DNA damage. Unstressed cells maintain p53 at low levels through regulated degradation, and p53 levels and activity are rapidly elevated upon genotoxic stress. Biochemical mechanisms that control the levels and activity of p53 are therefore of great interest. We and others have recently identified hAda3 (human homologue of yeast alteration/deficiency in activation 3) as a p53-interacting protein and enhancer of p53 activity. Here, we show that endogenous levels of p53 and Ada3 interact with each other, and by using inducible overexpression and short hairpin RNA-mediated knockdown strategies we demonstrate that hAda3 stabilizes p53 protein by promoting its acetylation. Use of a p53 mutant with mutations of known p300/CREB-binding protein acetylation sites demonstrated that hAda3-dependent acetylation is required for increase in p53 stability and target gene induction. Importantly, we demonstrate that endogenous hAda3 is essential for DNA damage-induced acetylation and stabilization of p53 as well as p53 target gene induction. Overall, our results establish hAda3, a component of coactivator complexes that include histone acetyltransferase p300/CREB-binding protein, as a critical mediator of acetylation-dependent stabilization and activation of p53 upon genotoxic stress in mammalian cells.