Simulation of LV pacemaker lead in marginal vein: potential risk factors for acute dislodgement

Although left ventricular (LV) coronary sinus lead dislodgement remains a problem, the risk factors for dislodgement have not been clearly defined. In order to identify potential risk factors for acute lead dislodgement, we conducted dynamic finite element simulations of pacemaker lead dislodgement in marginal LV vein. We considered factors such as mismatch in lead and vein diameters, velocity of myocardial motion, branch angle between the insertion vein and the coronary sinus, degree of slack, and depth of insertion. The results show that large lead-to-vein diameter mismatch, rapid myocardial motion, and superficial insertion are potential risk factors for lead dislodgement. In addition, the degree of slack presents either a positive or negative effect on dislodgement risk depending on the branch angle. The prevention of acute lead dislodgment can be enforced by inducing as much static friction force as possible at the lead-vein interface, while reducing the external force. If the latter exceeds the former, dislodgement will occur. The present findings underscore the major risk factors for lead dislodgment, which may improve implantation criterion and future lead design.     

Viral infection and neural stem/progenitor cell's fate: implications in brain development and neurological disorders

Viral infections in the prenatal (during pregnancy) and perinatal period have been a common cause of brain malformation. Besides the immediate neurological dysfunctions, virus infections may critically affect CNS development culminating in long-term cognitive deficits. Most of these neurotropic viruses are most damaging at a critical stage of the host, when the brain is in a dynamic stage of development. The neuropathology can be attributed to the massive neuronal loss induced by the virus as well as lack of CNS repair owing to a deficit in the neural stem/progenitor cell (NSPC) pool or aberrant formation of new neurons from NSPCs. Being one of the mitotically active populations in the post natal brain, the NSPCs have emerged as the potential targets of neurotropic viruses. The NSPCs are self-renewing and multipotent cells residing in the neurogenic niches of the brain, and, therefore, hampering the developmental fate of these cells may adversely affect the overall neurogenesis pattern. A number of neurotropic viruses utilize NSPCs as their cellular reservoirs and often establish latent and persistent infection in them. Both HIV and Herpes virus infect NSPCs over long periods of time and reactivation of the virus may occur later in life. The virus infected NSPCs either undergoes cell cycle arrest or impaired neuronal or glial differentiation, all of which leads to impaired neurogenesis. The disturbances in neurogenesis and CNS development following neurotropic virus infections have direct implications in the viral pathogenesis and long-term neurobehavioral outcome in infected individuals.     

Requirement of rRNA methylation for 80S ribosome assembly on a cohort of cellular internal ribosome entry sites

Protein syntheses mediated by cellular and viral internal ribosome entry sites (IRESs) are believed to have many features in common. Distinct mechanisms for ribosome recruitment and preinitiation complex assembly between the two processes have not been identified thus far. Here we show that the methylation status of rRNA differentially influenced the mechanism of 80S complex formation on IRES elements from the cellular sodium-coupled neutral amino acid transporter 2 (SNAT2) versus the hepatitis C virus mRNA. Translation initiation involves the assembly of the 48S preinitiation complex, followed by joining of the 60S ribosomal subunit and formation of the 80S complex. Abrogation of rRNA methylation did not affect the 48S complex but resulted in impairment of 80S complex assembly on the cellular, but not the viral, IRESs tested. Impairment of 80S complex assembly on the amino acid transporter SNAT2 IRES was rescued by purified 60S subunits containing fully methylated rRNA. We found that rRNA methylation did not affect the activity of any of the viral IRESs tested but affected the activity of numerous cellular IRESs. This work reveals a novel mechanism operating on a cohort of cellular IRESs that involves rRNA methylation for proper 80S complex assembly and efficient translation initiation.     

Loss of protease dimerization inhibition activity of darunavir is associated with the acquisition of resistance to darunavir by HIV-1

Dimerization of HIV protease is essential for the acquisition of protease's proteolytic activity. We previously identified a group of HIV protease dimerization inhibitors, including darunavir (DRV). In the present work, we examine whether loss of DRV's protease dimerization inhibition activity is associated with HIV development of DRV resistance. Single amino acid substitutions, including I3A, L5A, R8A/Q, L24A, T26A, D29N, R87K, T96A, L97A, and F99A, disrupted protease dimerization, as examined using an intermolecular fluorescence resonance energy transfer (FRET)-based HIV expression assay. All recombinant HIV(NL4-3)-based clones with such a protease dimerization-disrupting substitution failed to replicate. A highly DRV-resistant in vitro-selected HIV variant and clinical HIV strains isolated from AIDS patients failing to respond to DRV-containing antiviral regimens typically had the V32I, L33F, I54M, and I84V substitutions in common in protease. None of up to 3 of the 4 substitutions affected DRV's protease dimerization inhibition, which was significantly compromised by the four combined substitutions. Recombinant infectious clones containing up to 3 of the 4 substitutions remained sensitive to DRV, while a clonal HIV variant with all 4 substitutions proved highly resistant to DRV with a 205-fold 50% effective concentration (EC(50)) difference compared to HIV(NL4-3). The present data suggest that the loss of DRV activity to inhibit protease dimerization represents a novel mechanism contributing to HIV resistance to DRV. The finding that 4 substitutions in PR are required for significant loss of DRV's protease dimerization inhibition should at least partially explain the reason DRV has a high genetic barrier against HIV's acquisition of DRV resistance.     

A mathematical model on fractional Lotka-Volterra equations

While there are many mechanisms that may be involved in the regulation of body mass in humans and other animals, it is not so clear how much regulation is needed beyond the negative feedback effect of body mass itself. Here we model weight changes as a stochastic process, and show that it behaves approximately as an autoregressive process. Using published estimates of the energy cost of weight gain, the effect of weight on resting metabolic rate and the daily variation in intake and activity, we show that fluctuations in weight will be small. The effect of excess intake is also examined, and the assumptions and limitations of the model are discussed.     

New record of nucleopolyhedroviruses in tea looper caterpillars in India

Tea production in North-East India hit a record loss due to the widespread severe outbreak of a mixed brood of three species of looper caterpillar pests of geometrid moths (Lepidoptera) in 2008-2010. In addition to Buzura suppressaria, two newly recorded geometrids, viz., Hyposidra infixaria and Hyposidra talaca have caused widespread severe damage in recent years. In the present study we report the nucleopolyhedroviruses (NPV) isolated from the tea looper caterpillar from North-East India. We identified and characterized the NPV by cloning and sequencing a partial segment of polyhedrin gene of virus infected larvae of B. suppressaria, H. talaca and H. infixaria. A comparison of deduced amino acids of polyhedrin gene among H. talaca, H. infixaria and B. suppressaria showed that same strain was found to infect all the three loopers in India, which show high sequence identity with B. suppressaria Chinese isolates. Based on the polyhedrin sequence homology, it is predicted that a variant of B. suppressaria Chinese isolate of NPV found to infect H. talaca, H. infixaria and B. suppressaria in India.     

Direct biochemical measurements of signal relay during Dictyostelium development

Upon starvation, individual Dictyostelium discoideum cells enter a developmental program that leads to collective migration and the formation of a multicellular organism. The process is mediated by extracellular cAMP binding to the G protein-coupled cAMP receptor 1, which initiates a signaling cascade leading to the activation of adenylyl cyclase A (ACA), the synthesis and secretion of additional cAMP, and an autocrine and paracrine activation loop. The release of cAMP allows neighboring cells to polarize and migrate directionally and form characteristic chains of cells called streams. We now report that cAMP relay can be measured biochemically by assessing ACA, ERK2, and TORC2 activities at successive time points in development after stimulating cells with subsaturating concentrations of cAMP. We also find that the activation profiles of ACA, ERK2, and TORC2 change in the course of development, with later developed cells showing a loss of sensitivity to the relayed signal. We examined mutants in PKA activity that have been associated with precocious development and find that this loss in responsiveness occurs earlier in these mutants. Remarkably, we show that this loss in sensitivity correlates with a switch in migration patterns as cells transition from streams to aggregates. We propose that as cells proceed through development, the cAMP-induced desensitization and down-regulation of cAMP receptor 1 impacts the sensitivities of chemotactic signaling cascades leading to changes in migration patterns.     

MicroRNA-21 orchestrates high glucose-induced signals to TOR complex 1, resulting in renal cell pathology in diabetes

Hyperglycemia induces a wide array of signaling pathways in the kidney that lead to hypertrophy and matrix expansion, eventually culminating in progressive kidney failure. High glucose-induced reduction of the tumor suppressor protein phosphatase and tensin homolog deleted in chromosome 10 (PTEN) contributes to renal cell hypertrophy and matrix expansion. We identified microRNA-21 (miR-21) as the molecular link between high glucose and PTEN suppression. Renal cortices from OVE26 type 1 diabetic mice showed significantly elevated levels of miR-21 associated with reduced PTEN and increased fibronectin content. In renal mesangial cells, high glucose increased the expression of miR-21, which targeted the 3'-UTR of PTEN mRNA to inhibit PTEN protein expression. Overexpression of miR-21 mimicked the action of high glucose, which included a reduction in PTEN expression and a concomitant increase in Akt phosphorylation. In contrast, expression of miR-21 Sponge, to inhibit endogenous miR-21, prevented down-regulation of PTEN and phosphorylation of Akt induced by high glucose. Interestingly, high glucose-stimulated miR-21 inactivated PRAS40, a negative regulator of TORC1. Finally, miR-21 enhanced high glucose-induced TORC1 activity, resulting in renal cell hypertrophy and fibronectin expression. Thus, our results identify a previously unrecognized function of miR-21 that is the reciprocal regulation of PTEN levels and Akt/TORC1 activity that mediate critical pathologic features of diabetic kidney disease.