Subtype B and subtype C HIV type 1 recombinants in the northeastern state of Manipur, India

The predominant HIV-1 strain circulating in India is subtype C. However, subtype A and B strains of HIV-1 have also been reported in India. In 1999, the first A/C recombinant strain was reported from Pune in India. Intravenous drug users (IVDUs) from the northeastern region of India have a high HIV-1 seroprevalence. Studies carried out in intravenous drug users in the northeastern region of India have shown that HIV-1 subtype C is the predominant strain infecting IVDUs. Fourteen blood samples were collected from HIV-1-infected individuals from the northeastern region of India and screened by env and gag heteroduplex mobility assays (HMA). Where the env and gag HMA results from a sample yielded different subtypes, sequencing of env and gag PCR products was carried out to confirm the presence of HIV-1 recombinants. Of the 14 samples subtyped, nine samples belonged HIV-1 subtype C (gag C/env C), one to HIV-1 subtype B (gag B/env B), and the remaining were B/C recombinants (gag C/env B). This is the first report of HIV-1 B/C recombinants from India.     

Preliminary analysis testing the accuracy of radiographic visibility of root pulp in the mandibular first molars as a maturity marker at age threshold of 18 years

International Journal of Legal Medicine - Forensic age estimation, after completion of third molar mineralization, regressive features such as apposition of secondary dentin, which is seen as...     

Does pure robotic partial nephrectomy provide similar perioperative outcomes when compared to the combined laparoscopic–robotic approach?

Laparoscopic and robotic partial nephrectomy have become the preferred option for surgical management of incidentally discovered small renal tumors. Currently there is no consensus on which aspects of the procedure should be performed laparoscopically versus robotically. We believe that combining a laparoscopic exposure and hilar dissection followed by tumor extirpation and renorrhaphy with robotic assistance provides improved perioperative outcomes compared to a pure robotic approach alone. We performed a comparison of perioperative outcomes between combined laparoscopic–robotic partial nephrectomy—or hybrid procedure—and pure robotic partial nephrectomy (RPN). A multi-center retrospective analysis of patients undergoing RPN and hybrid PN using the da Vinci S system^® was performed. Patient data were reviewed for demographic and perioperative variables. Statistical analysis was performed using the Welch t test and linear regression, and nonparametric tests with similar significance results. Thirty-one patients underwent RPN while 77 patients underwent hybrid PN between 2007 and 2011. Preoperative variables were comparable in both groups with the exception of lesion size and nephrometry score which were significantly higher in patients undergoing hybrid PN. Length of surgery, estimated blood loss and morphine used were significantly less in the hybrid group, while warm ischemia time was significantly longer. The difference in WIT was accounted for in this data by adjusting for nephrometry score. In our multi-center series, the hybrid approach was associated with a shorter operative time, reduced blood loss and lower narcotic usage. We believe this approach is a valid alternative to RPN.     

A novel site-II directed glycoprotein estimation ELISA to aid rabies vaccine manufacture for veterinary and human use

Although the World Health Organization recommends the use of in vitro techniques to qualify rabies vaccine lot release, very limited proposals have been made to arrive at a harmonized approach for wide scale usage. The present study proposed and evaluated the use of a novel avidin–biotin ELISA as an alternative to these in vivo tests in rabies vaccine manufacture. This assay utilized a neutralizing pan reactive monoclonal antibody (mAb) reactive with the conserved site-II of the natively folded rabies glycoprotein. Linear regression analysis of the in vitro glycoprotein estimates with the in vivo potency values, showed a good correlation (r² = 0.8) with veterinary vaccines, but a poor correlation (r² = 0.2) with human vaccines. However, we could qualitatively arrive at cut-off glycoprotein estimates from the ELISA, above which all the vaccines were declared to be protective by mouse challenge studies (>2.5 IU/dose).     

Temperature protocols to guide selective self-assembly of competing structures

Multicomponent self-assembly mixtures offer the possibility of encoding multiple target structures with the same set of interacting components. Selective retrieval of one of the stored structures has been attempted by preparing an initial state that favors the assembly of the required target, through seeding, concentration patterning, or specific choices of interaction strengths. This may not be possible in an experiment where on-the-fly reconfiguration of the building blocks to switch functionality may be required. In this paper, we explore principles of inverse design of a multicomponent, self-assembly mixture capable of encoding two competing structures that can be selected through simple temperature protocols. We design the target structures to realize the generic situation in which one of the targets has the lower nucleation barrier, while the other is globally more stable. We observe that, to avoid the formation of spurious or chimeric aggregates, the number of neighboring component pairs that occur in both structures should be minimal. Our design also requires the inclusion of components that are part of only one of the target structures. We observe, however, that to maximize the selectivity of retrieval, the component library itself should be maximally shared by the two targets, within such a constraint. We demonstrate that temperature protocols can be designed that lead to the formation of either one of the target structures with high selectivity. We discuss the important role played by secondary aggregation products in improving selectivity, which we term “vestigial aggregates.”

Self-assembly is a fundamental manufacturing mechanism of Nature. Many mesoscale cellular structures required for biological functionality, such as membranes, microtubules, actin fibrils, ribosomes, etc., are formed through self-assembly, often driven by nonequilibrium forces (1, 2). Even though the cytoplasm contains thousands of molecular components, the various cellular structures self-assemble with remarkable precision and may even share components (3). However, in rare cases, they can misassemble, leading to impaired function or even diseases (4, 5). Mechanisms for controlling synthesis in the cell, such as molecular chaperones and compartmentalization of enzymatic action (6–8), are widely studied.When designing self-assembling systems, one must contend with unwanted “off-target” structures. It is therefore important to understand what causes misassembly and how it can be avoided, both at the design stage and during assembly. On the other hand, an ability to reuse the same building blocks to assemble different structures can be extremely useful to create smart materials that can change their functionality in response to an external stimulus. Often, such materials are designed to change their shape and functionality through conformational or morphological changes of their building blocks (9–15). However, it is also possible to have multiple structures that differ in the spatial arrangement of their building blocks. Multicomponent mixtures not only allow for such a design (16–20), but can also form finite structures with arbitrary complexity (21, 22). Experiments with DNA bricks have shown a way of self-assembling complex structures with hundreds of distinct components (23, 24). Such an addressable assembly, where each component and its position in the target structure are uniquely defined, is made possible because of the complementarity of the DNA hybridization process.Here, we investigate the generic problem of designing two competing target structures of distinct shape, a feature that we show involves new nontrivial challenges. By designing the location of components and the strength of their interactions, we show that the nucleation behavior of the target structures can be tuned such that either of them can be assembled using distinct time-varying temperature protocols. Further, such a design shows that to avoid chimeric aggregation, the neighborhood of the individual components in the two structures should be maximally different. We show that the design of the competing structure requires the inclusion of components that form part of only one of the two structures. However, in order to maximize the selectivity of self-assembly, the component library should be maximally shared by the targets, within the constraints imposed by the design.We begin by noting that even with a single target structure, multicomponent systems assemble quite differently from classical nucleation, due to the fact that the components need to bind in certain specific ways to form the correct structure (25, 26). Numerical evidence and theoretical analyses have shown that multicomponent self-assembly proceeds via a nonclassical nucleation process (27–30). For successful assembly, the theories also predict a protocol that allows for slow nucleation followed by completion of growth at a lower temperature (30, 31). Due to incidental interactions between components, there may also be numerous undesired ways in which they can aggregate, which increases the probability of formation of undesired structures. Thus, the designed interactions should be made sufficiently strong, so as to offset this entropic effect (32, 33). Some studies suggested that a narrow distribution of designed interactions is required for error-free self-assembly (32, 33). However, other studies showed that variable bond strengths may improve the kinetics and diminish the competition between fragments that are incorporated at an early stage (30, 34). To avoid the formation of off-target structures, it is important that the self-assembling structure can anneal during growth. This implies that the assembly should take place under thermodynamic conditions, where the growth is almost reversible (30, 35). As a consequence, the range of thermodynamic parameters within which self-assembly can be made error-free is significantly reduced (24, 27, 36, 37).Focusing now on strategies to design multiple target structures from the same building blocks, the two most pertinent questions are: 1) how to design the targets while avoiding misaggregation; and 2) how to guide their self-assembly into specific target structures. The simplest examples of distinct targets that form from the same building blocks are objects that have the same shape, but differ in the spatial arrangement of building blocks (16–18). Components that are neighbors in any of the multiple targets are assigned attractive interactions. If the interactions are of equal strength, then the retrieval of any specific target from the mixture requires a target-specific seeding procedure or concentration pattern. Selective retrieval by strengthening a few bonds specific to the desired target has also been attempted (16, 18), in which case the system always favors the formation of one structure over others.     

Ligand-based pharmacophore modeling and molecular dynamic simulation approaches to identify putative MMP-9 inhibitors

MMP-9 is a calcium-dependent zinc endopeptidase that plays a crucial role in various diseases and is a ubiquitous target for many classes of drugs. The availability of MMP-9 crystal structure in combination with aryl sulfonamide anthranilate hydroxamate inhibitor facilitates to accentuate the computer-aided screening of MMP-9 inhibitors with the presumed binding mode. In the current study, ligand-based pharmacophore modeling and 3D-QSAR analysis were performed using 67 reported MMP-9 inhibitors possessing pIC₅₀ in the range of 5.221 to 9.000. The established five-point hypothesis model DDHRR_1 was statistically validated using various parameters R² (0.9076), Q² (0.8170), and F value (83.5) at a partial least square of four. Hypothesis validation and enrichment analysis were performed for the generated hypothesis. Further, Y-scrambling and Xternal validation using mean-absolute error-based criteria were performed to evaluate the reliability of the model. Docking in the XP mode and binding free energy was calculated for 67 selected ligands to explore the key binding interactions and binding affinity against the MMP-9 enzyme. Additionally, high-throughput virtual screening was carried out for 2.3 million chemical molecules to explore the potential virtual hits, and their predicted activity was calculated. Thus, the results obtained aid in developing novel MMP-9 inhibitors with significant activity and binding affinity.

MMP-9 is a calcium-dependent zinc endopeptidase that plays a crucial role in various diseases and is a ubiquitous target for many classes of drugs.     

Liver transplantation from non-heart-beating donors: current status and future prospects.

Liver transplantation is the treatment of choice for many patients with acute and chronic liver failure, but its application is limited by a shortage of donor organs. Donor organ shortage is the principal cause of increasing waiting lists, and a number of patients die while awaiting transplantation. Non-heart-beating donor (NHBD) livers are a potential means of expanding the donor pool. This is not a new concept. Prior to the recognition of brainstem death, organs were retrieved from deceased donors only after cardiac arrest. Given the preservation techniques available at that time, this restricted the use of extrarenal organs for transplantation. In conclusion, after establishment of brain death criteria, deceased donor organs were almost exclusively from heart-beating donors (HBDs). To increase organ availability, there is now a resurgence of interest in NHBD liver transplantation. This review explores the basis for this and considers some of the published results.     

Gender Differences in Cardiac Arrhythmias in the Elderly

Cardiac arrhythmias are a major source of morbidity and mortality in the elderly. Gender differences have been described in the incidence and clinical course of various arrhythmias in the elderly. Gender appears to influence response to therapies such as implantable cardiac devices. The purpose of this article is to review recent advances in this area of electrophysiology. Further research is required to enhance our current knowledge of this complex subject.