An Efficient Targeted Drug Delivery through Apotransferrin Loaded Nanoparticles

BACKGROUND: Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. METHODOLOGY/PRINCIPAL FINDINGS: Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano), and showed further increase in dimension (75-95 etam) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression of hepatocellular carcinoma with negligible toxicity to kidney and liver. CONCLUSIONS: The present study thus demonstrates that the direct-nano is highly efficacious in delivery of drug in a target specific manner with lower toxicity to heart, liver and kidney

Widespread Site-Dependent Buffering of Human Regulatory Polymorphism

The average individual is expected to harbor thousands of variants within non-coding genomic regions involved in gene regulation. However, it is currently not possible to interpret reliably the functional consequences of genetic variation within any given transcription factor recognition sequence. To address this, we comprehensively analyzed heritable genome-wide binding patterns of a major sequence-specific regulator (CTCF) in relation to genetic variability in binding site sequences across a multi-generational pedigree. We localized and quantified CTCF occupancy by ChIP-seq in 12 related and unrelated individuals spanning three generations, followed by comprehensive targeted resequencing of the entire CTCF–binding landscape across all individuals. We identified hundreds of variants with reproducible quantitative effects on CTCF occupancy (both positive and negative). While these effects paralleled protein–DNA recognition energetics when averaged, they were extensively buffered by striking local context dependencies. In the significant majority of cases buffering was complete, resulting in silent variants spanning every position within the DNA recognition interface irrespective of level of binding energy or evolutionary constraint. The prevalence of complex partial or complete buffering effects severely constrained the ability to predict reliably the impact of variation within any given binding site instance. Surprisingly, 40% of variants that increased CTCF occupancy occurred at positions of human–chimp divergence, challenging the expectation that the vast majority of functional regulatory variants should be deleterious. Our results suggest that, even in the presence of “perfect” genetic information afforded by resequencing and parallel studies in multiple related individuals, genomic site-specific prediction of the consequences of individual variation in regulatory DNA will require systematic coupling with empirical functional genomic measurements

The Relative Influence of Competition and Prey Defenses on the Phenotypic Structure of Insectivorous Bat Ensembles in Southern Africa

Deterministic filters such as competition and prey defences should have a strong influence on the community structure of animals such as insectivorous bats that have life histories characterized by low fecundity, low predation risk, long life expectancy, and stable populations. We investigated the relative influence of these two deterministic filters on the phenotypic structure of insectivorous bat ensembles in southern Africa. We used null models to simulate the random phenotypic patterns expected in the absence of competition or prey defences and analysed the deviations of the observed phenotypic pattern from these expected random patterns. The phenotypic structure at local scales exhibited non-random patterns consistent with both competition and prey defense hypotheses. There was evidence that competition influenced body size distribution across ensembles. Competition also influenced wing and echolocation patterns in ensembles and in functional foraging groups with high species richness or abundance. At the same time, prey defense filters influenced echolocation patterns in two species-poor ensembles. Non-random patterns remained evident even after we removed the influence of body size from wing morphology and echolocation parameters taking phylogeny into account. However, abiotic filters such as geographic distribution ranges of small and large-bodied species, extinction risk, and the physics of flight and sound probably also interacted with biotic filters at local and/or regional scales to influence the community structure of sympatric bats in southern Africa. Future studies should investigate alternative parameters that define bat community structure such as diet and abundance to better determine the influence of competition and prey defences on the structure of insectivorous bat ensembles in southern Africa

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

<div><p>Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in <i>Trypanosoma brucei</i>. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.</p></div

Team Dynamics Theory: Nomological network among cohesion, team mental models, coordination, and collective efficacy

I put forth a theoretical framework, namely Team Dynamics Theory (TDT), to address the need for a parsimonious yet integrated, explanatory and systemic view of team dynamics. In TDT, I integrate team processes and outputs and explain their relationships within a systemic view of team dynamics. Specifically, I propose a generative nomological network linking cohesion, team mental models, coordination, collective efficacy, and team outcomes. From this nomological conceptualization, I illustrate how myriad alternative models can be derived to account for variance in different working teams, each comprised of unique members, and embedded in singular contexts. I outline TDT’s applied implications for team development, the enhancement of team functioning, and the profiling of team resilience. I conclude by discussing how TDT’s ontological and nomological propositions can be tested through various theoretical inquiries, methodological approaches, and intervention-based studies