Crystal structure and structural mechanism of a novel anti-human immunodeficiency virus and D-amino acid-containing chemokine

Chemokines and their receptors play important roles in normal physiological functions and the pathogeneses of a wide range of human diseases, including the entry of human immunodeficiency virus type 1 (HIV-1). However, the use of natural chemokines to probe receptor biology or to develop therapeutic drugs is limited by their lack of selectivity and the poor understanding of mechanisms in ligand-receptor recognition. We addressed these issues by combining chemical and structural biology in research into molecular recognition and inhibitor design. Specifically, the concepts of chemical biology were used to develop synthetically and modularly modified (SMM) chemokines that are unnatural and yet have properties improved over those of natural chemokines in terms of receptor selectivity, affinity, and the ability to explore receptor functions. This was followed by using structural biology to determine the structural basis for synthetically perturbed ligand-receptor selectivity. As a proof-of-principle for this combined chemical and structural-biology approach, we report a novel D-amino acid-containing SMM-chemokine designed based on the natural chemokine called viral macrophage inflammatory protein II (vMIP-II). The incorporation of unnatural D-amino acids enhanced the affinity of this molecule for CXCR4 but significantly diminished that for CCR5 or CCR2, thus yielding much more selective recognition of CXCR4 than wild-type vMIP-II. This D-amino acid-containing chemokine also showed more potent and specific inhibitory activity against HIV-1 entry via CXCR4 than natural chemokines. Furthermore, the high-resolution crystal structure of this D-amino acid-containing chemokine and a molecular-modeling study of its complex with CXCR4 provided the structure-based mechanism for the selective interaction between the ligand and chemokine receptors and the potent anti-HIV activity of D-amino acid-containing chemokines.     

Floret-like multinucleated giant cells in neurofibroma

Cotyledonoid dissecting leiomyoma of the uterus is a recently described rare variant of benign uterine leiomyoma. We report a case of cotyledonoid dissecting leiomyoma in a 52 year old woman who presented with menorrhagia and abdominal pain. An ultrasound scan showed a bulky uterus and a cystic heterogenous mass near the left ovary. At hysterectomy, the left broad ligament mass was removed. This was continuous with an ill-defined nodular area in the myometrial fundus. Microscopy revealed a benign smooth muscle proliferation in the myometrium that extended beyond the uterus and into the broad ligament. The lesion appeared to be dissecting the myometrial fibres and showed areas of oedema, hyalinisation and perinodular hydropic change. Cellular atypia, mitoses and coagulative necrosis were absent. The patient is alive and well 18 months after surgery. It is important to recognize this benign and unusual appearing variant of leiomyoma in order to prevent inappropriate treatment.     

Molecular cloning and analysis of zebrafish voltage-gated sodium channel beta subunit genes: implications for the evolution of electrical signaling in vertebrates

Background  

Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. In mammals, sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Although alpha subunit genes have been cloned from diverse metazoans including flies, jellyfish, and humans, beta subunits have not previously been identified in any non-mammalian species. To gain further insight into the evolution of electrical signaling in vertebrates, we investigated beta subunit genes in the teleost Danio rerio (zebrafish).     

In-vitro antimicrobial and anticancer properties of green synthesized gold nanoparticles using Anacardium occidentale leaves extract

The aqueous cashew leaves extract obtained was investigated for the preparation of gold nanoparticle (AuNPs). The obtained AuNPs were characterized by UV–Visible spectroscopy, FTIR and XRD analysis. Results indicated that the green synthesized AuNPs showed good antibacterial effect against Escherichia coli and Bacillus subtilis and exhibited 74.47% viability on PBMC and 23.56% viability on MCF-7 cell lines at a maximum concentration of 100?µg/ml. Therefore, future studies on antibacterial application in food packing, wound dressing and antihelmintic applications will be studied.     

Abiotic stress-related genes governing signal transduction cascades in wild plants with emphasis to those in Hordeum spontaneum

The study aims at discussing abiotic stress-related genes and metabolites in the crosstalking signal transduction pathways with emphasis to those in leaves of wild barley Hordeum spontaneum. Selected pathways involve tryptophan and target of rapamycin (or TOR) complex as core metabolites. In H. spontaneum, route towards tryptophan production seems to be mediated via anthranilate synthase acting as a master switch. Downstream auxin-related factors and proteins can secure plant’s ability to maintain proper growth rates and stress tolerance. Detected TOR in H. spontaneum participates in several signal transduction related pathways with a central role in nutrient starvation, ribosome biogenesis and protein synthesis and in standing oxidative and other abiotic stresses. TOR also participates as a master regulator of lifespan, aging and autophagy in H. spontaneum to regulate growth and maintain plant yield and its attributes under stress conditions. In conclusion, the present study emphasizes some mechanisms by which wild plant species, e.g., H. spontaneum, utilize to cope with abiotic stresses.

     

A new frog species from the central western Ghats of India, and its phylogenetic position

Tropical evergreen forests of Indian subcontinent, especially of the Western Ghats, are known hot spots of amphibian diversity, where many new anuran species await to be identified. Here we describe from the Sharavathi River basin of central Western Ghats a new shrub-frog taxon related to the anuran family Rhacophoridae. The new frog possesses the characteristic features of rhacophorids (dilated digit tips with differentiated pads circumscribed by a complete groove, intercalary cartilages on digits, T-shaped terminal phalanges and granular belly, the adaptive characters for arboreal life forms), but also a suite of unique features that distinguish it from all known congeners in the region. Morphogenetic analysis based on morphological characteristics and diversity in the mitochondrial 12S and 16S rRNA genes revealed it to be a new Philautus species that we named Philautus neelanethrus sp. nov. The phylogenetic analysis suggests the new frog to represent a relatively early Philautus species lineage recorded from the region. The distribution pattern of the species suggests its importance as a bioindicator of habitat health. In general, this relatively widespread species was found distributed only in non-overlapping small stretches, which indirectly indicates the fragmentation of the evergreen to moist deciduous forests that characterize the Western Ghats. Thus the discovery of the new rhacophorid species described here not only further reinforces the significance of the Western Ghats as a major hotspot of amphibian biodiversity, but also brings into focus the deterioration of forest habitats in the region and the need for prioritization of their conservation.     

Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance

Hypertension commonly occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome. Insulin resistance plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. There is accumulating evidence that insulin resistance occurs in cardiovascular and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue). Activation of the renin-angiotensin-aldosterone system and subsequent elevations in angiotensin II and aldosterone, as seen in cardiometabolic syndrome, contribute to altered insulin/IGF-1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular disease. This review examines currently understood mechanisms underlying the development of resistance to the metabolic actions of insulin in cardiovascular as well as skeletal muscle tissue.     

The disruption of prenylation leads to pleiotropic rearrangements in cellular behavior in Staphylococcus aureus

Prenylation is the addition of prenyl groups to peptide chains or metabolites via the condensation of geranyl‐ or isopentenyl‐diphosphate moieties by geranyltranstransferases. Although this process is extensively studied in eukaryotes, little is known about the influence of prenylation in prokaryotic species. To explore the role of this modification in bacteria, we generated a mutation in the geranyltranstransferase (IspA) of Staphylococcus aureus. Quite strikingly, the ispA mutant completely lacked pigment and exhibited a previously undescribed small colony variant‐like phenotype. Further pleiotropic defects in cellular behavior were noted, including impaired growth, decreased ATP production, increased sensitivity to oxidative stress, increased resistance to aminoglycosides and cationic antimicrobial peptides, and decreased resistance to cell wall‐targeting antibiotics. These latter effects appear to result from differences in envelope composition as ispA mutants have highly diffuse cell walls (particularly at the septum), marked alterations in fatty acid composition and increased membrane fluidity. Taken together, these data present an important characterization of prokaryotic prenylation and demonstrate that this process is central to a wealth of pathways involved in mediating cellular homeostasis in S. aureus.     

Abiotic stress induces change in Cinnamoyl CoA Reductase (CCR) protein abundance and lignin deposition in developing seedlings of Leucaena leucocephala

Aboitic stress such as drought and salinity are class of major threats, which plants undergo through their lifetime. Lignin deposition is one of the responses to such abiotic stresses. The gene encoding Cinnamoyl CoA Reductase (CCR) is a key gene for lignin biosynthesis, which has been shown to be over-expressed under stress conditions. In the present study, developing seedlings of Leucaena leucocephala (Vernacular name: Subabul, White popinac) were treated with 1 % mannitol and 200 mM NaCl to mimic drought and salinity stress conditions, respectively. Enzyme linked immunosorbant assay (ELISA) based expression pattern of CCR protein was monitored coupled with Phlorogucinol/HCl activity staining of lignin in transverse sections of developing L. leucocephala seedlings under stress. Our result suggests a differential lignification pattern in developing root and stem under stress conditions. Increase in lignification was observed in mannitol treated stems and corresponding CCR protein accumulation was also higher than control and salt stress treated samples. On the contrary CCR protein was lower in NaCl treated stems and corresponding lignin deposition was also low. Developing root tissue showed a high level of CCR content and lignin deposition than stem samples under all conditions tested. Overall result suggested that lignin accumulation was not affected much in case of developing root however developing stems were significantly affected under drought and salinity stress condition.Keyword: Abiotic stress, Cinnamoyl CoA reductase, Developing seedlings, Leucaena leucocephala