EFFECT OF LACTOFERRIN TO INCREASE DRUG PERMEABILITY OF PRIMARY PULMONARY MYCOBACTERIAL GRANULOMAS

Despite extensive research and worldwide eradication efforts, Mycobacterium tuberculosis (Mtb) remains a major infectious pathogen to the human population with about 10 million cases of infection per year globally. The host-pathogen interaction, pulmonary granuloma formation, and Mtb adaptions result in increased complexity of the disease. Granulomas are formed by active immune responses generated during Mtb infection, and serve to contain and limit bacterial dissemination. The major mycobacterial surface mycolic acid, trehalose 6,6\u27-dimycolate (TDM), functions in multiple ways to enhance immune cell recruitment of sites of infection, to induce inflammation and granulomatous responses, and to initiate survival strategies for the organism inside macrophages. Mtb also benefits from establishment of a tightly formed granuloma, which both protects it from immune reactivity and serves as a physical boundary to limit penetration of drugs during therapeutic treatment. In order to demystify the complicated relationship between the host and pathogen, many studies have been performed around the primary Mtb-induced granuloma to combat the challenges that come with this specific immunopathology. We hypothesized that by altering the immunopathology of granulomas using lactoferrin, an immunomodulating agent, it will allow greater penetration of therapeutics into the site of focal inflammation. Our lab has reported that oral bovine lactoferrin treatments during the innate immune response leads to significant modulation of the primary Mtb granuloma response and lessen Mtb burden in mouse lungs. Here, we show that such modulation during granuloma development can also be achieved by using recombinant human lactoferrin oral treatments to increase granuloma permeability and promotes drug penetration in both TDM-induced granulomatous inflammation as well as during active Mtb-infection. Findings from this work show lactoferrin’s potential as a host-directed therapeutic that can be combined with current TB standard treatment to reduce pathological damage in the lungs post mycobacterial infection

Genetic landscape of autism spectrum disorder in Vietnamese children

Autism spectrum disorder (ASD) is a complex disorder with an unclear aetiology and an estimated global prevalence of 1%. However, studies of ASD in the Vietnamese population are limited. Here, we first conducted whole exome sequencing (WES) of 100 children with ASD and their unaffected parents. Our stringent analysis pipeline was able to detect 18 unique variants (8 de novo and 10 ×-linked, all validated), including 12 newly discovered variants. Interestingly, a notable number of X-linked variants were detected (56%), and all of them were found in affected males but not in affected females. We uncovered 17 genes from our ASD cohort in which CHD8, DYRK1A, GRIN2B, SCN2A, OFD1 and MDB5 have been previously identified as ASD risk genes, suggesting the universal aetiology of ASD for these genes. In addition, we identified six genes that have not been previously reported in any autism database: CHM, ENPP1, IGF1, LAS1L, SYP and TBX22. Gene ontology and phenotype-genotype analysis suggested that variants in IGF1, SYP and LAS1L could plausibly confer risk for ASD. Taken together, this study adds to the genetic heterogeneity of ASD and is the first report elucidating the genetic landscape of ASD in Vietnamese children

Structure and functional relevance of the Slit2 homodimerization domain

Slit proteins are secreted ligands that interact with the Roundabout (Robo) receptors to provide important guidance cues in neuronal and vascular development. Slit–Robo signalling is mediated by an interaction between the second Slit domain and the first Robo domain, as well as being dependent on heparan sulphate. In an effort to understand the role of the other Slit domains in signalling, we determined the crystal structure of the fourth Slit2 domain (D4) and examined the effects of various Slit2 constructs on chick retinal ganglion cell axons. Slit2 D4 forms a homodimer using the conserved residues on its concave face, and can also bind to heparan sulphate. We observed that Slit2 D4 frequently results in growth cones with collapsed lamellipodia and that this effect can be inhibited by exogenously added heparan sulphate. Our results show that Slit2 D4–heparan sulphate binding contributes to a Slit–Robo signalling mechanism more intricate than previously thought

Expanding HIV Testing Efforts in Concentrated Epidemic Settings: A Population-Based Survey from Rural Vietnam

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Intron Dynamics in Ribosomal Protein Genes

The role of spliceosomal introns in eukaryotic genomes remains obscure. A large scale analysis of intron presence/absence patterns in many gene families and species is a necessary step to clarify the role of these introns. In this analysis, we used a maximum likelihood method to reconstruct the evolution of 2,961 introns in a dataset of 76 ribosomal protein genes from 22 eukaryotes and validated the results by a maximum parsimony method. Our results show that the trends of intron gain and loss differed across species in a given kingdom but appeared to be consistent within subphyla. Most subphyla in the dataset diverged around 1 billion years ago, when the “Big Bang” radiation occurred. We speculate that spliceosomal introns may play a role in the explosion of many eukaryotes at the Big Bang radiation

Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Practical computational toolkits for dendrimers and dendrons structure design

Dendrimers and dendrons offer an excellent platform for developing novel drug delivery systems and medicines. The rational design and further development of these repetitively branched systems are restricted by difficulties in scalable synthesis and structural determination, which can be overcome by judicious use of molecular modelling and molecular simulations. A major difficulty to utilise in silico studies to design dendrimers lies in the laborious generation of their structures. Current modelling tools utilise automated assembly of simpler dendrimers or the inefficient manual assembly of monomer precursors to generate more complicated dendrimer structures. Herein we describe two novel graphical user interface (GUI) toolkits written in Python that provide an improved degree of automation for rapid assembly of dendrimers and generation of their 2D and 3D structures. Our first toolkit uses the RDkit library, SMILES nomenclature of monomers and SMARTS reaction nomenclature to generate SMILES and mol files of dendrimers without 3D coordinates. These files are used for simple graphical representations and storing their structures in databases. The second toolkit assembles complex topology dendrimers from monomers to construct 3D dendrimer structures to be used as starting points for simulation using existing and widely available software and force fields. Both tools were validated for ease-of-use to prototype dendrimer structure and the second toolkit was especially relevant for dendrimers of high complexity and size.Peer reviewe