Pan-genome association study of lineage-4 revealed specific genes related to the high and low prevalence of the disease in patients from the North-Eastern area of Medellín, Colombia.

() lineage 4 is responsible for the highest burden of tuberculosis (TB) worldwide. This lineage has been the most prevalent lineage in Colombia, especially in the North-Eastern (NE) area of Medellin, where it has been shown to have a high prevalence of LAM9 SIT42 and Haarlem1 SIT62 sublineages. There is evidence that regardless of environmental factors and host genetics, differences among sublineages of strains play an important role in the course of infection and disease.

Physiological role and potential clinical interest of mycobacterial pigments.

The production of pigments by bacterial colonies has sparked interest among bacteriologists since the 19th century, whether for taxonomy or, in the case of carotenoids for their association with antibiotics resistance. Mycobacteria have gained a very special place in the bacterial world due to their clinical importance. Alone, Mycobacterium tuberculosis is responsible for about two million deaths annually worldwide making tuberculosis one of the most influential diseases in the history of mankind.

Wear behavior and in vitro cytotoxicity of wear debris generated from hydroxyapatite-carbon nanotube composite coating.

This work evaluates the effect of carbon nanotube (CNT) addition to plasma-sprayed hydroxyapatite (HA) coating on its tribological behavior, biocompatibility of the coating, and cytotoxicity of CNT-containing wear debris. Biological response of the CNT-containing wear debris is critical for osteoblasts, the bone-forming cells, and macrophages, the cells that clear up wear debris from blood stream. The addition of 4 wt % CNTs to HA coating reduces the volume of wear debris generation by 80% because of the improved elastic modulus and fracture toughness.

Boron nitride nanotube reinforced polylactide-polycaprolactone copolymer composite: mechanical properties and cytocompatibility with osteoblasts and macrophages in vitro.

Biodegradable polylactide-polycaprolactone copolymer (PLC) has been reinforced with 0, 2 and 5wt.% boron nitride nanotubes (BNNTs) for orthopedic scaffold application. Elastic modulus of the PLC-5wt.

The untranslated side of hair and skin mammalian pigmentation: Beyond coding sequences.

For several decades, tremendous advances in studying skin and hair pigmentation of mammals have been made using Mendelian genetics principles. A number of loci and their associated traits have been extensively examined, crossings performed, and phenotypes well documented. Continuously improving PCR techniques allowed the molecular cloning and sequencing of the first pigmentation genes at the end of the 20th century, a period followed by an intense effort to detect and describe polymorphisms in the coding regions and correlate allelic combinations with the observed melanogenic phenotypes.

Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse.

Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MC4R). MC4R knockout mice have been well characterized as a genetic model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs.

Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/beta-catenin signaling in keratinocytes.

The epidermis (containing primarily keratinocytes and melanocytes) overlies the dermis (containing primarily fibroblasts) of human skin. We previously reported that dickkopf 1 (DKK1) secreted by fibroblasts in the dermis elicits the hypopigmented phenotype of palmoplantar skin due to suppression of melanocyte function and growth via the regulation of two important signaling factors, microphthalmia-associated transcription factor (MITF) and beta-catenin. We now report that treatment of keratinocytes with DKK1 increases their proliferation and decreases their uptake of melanin and that treatment of reconstructed skin with DKK1 induces a thicker and less pigmented epidermis.

Involvement of dynein and spectrin with early melanosome transport and melanosomal protein trafficking.

Melanosomes are unique membrane-bound organelles specialized for the synthesis and distribution of melanin. Mechanisms involved in the trafficking of proteins to melanosomes and in the transport of mature pigmented melanosomes to the dendrites of melanocytic cells are being characterized, but details about those processes during early stages of melanosome maturation are not well understood. Early melanosomes must remain in the perinuclear area until critical components are assembled.

Sialylated core 1 O-glycans influence the sorting of Pmel17/gp100 and determine its capacity to form fibrils.

Pmel17 is a melanocyte/melanoma-specific protein that is essential for the maturation of melanosomes to form mature, fibrillar, and pigmented organelles. Recently, we reported that the less glycosylated form of Pmel17 (termed iPmel17) is sorted via the plasma membrane in a manner distinct from mature Pmel17 (termed mPmel17), which is sorted directly to melanosomes. To clarify the mechanism(s) underlying the distinct processing and sorting of Pmel17, we generated a highly specific antibody (termed alphaPEP25h) against an epitope within the repeat domain of Pmel17 that is sensitive to changes in O-glycosylation.

The effects of dickkopf 1 on gene expression and Wnt signaling by melanocytes: mechanisms underlying its suppression of melanocyte function and proliferation.

Dickkopf 1 (DKK1), which is expressed at high mRNA levels by fibroblasts in the dermis of human skin on the palms and soles, inhibits the function and proliferation of melanocytes in the epidermis of those areas via the suppression of beta-catenin and microphthalmia-associated transcription factor (MITF). In this study, we investigated the protein expression levels of DKK1 between palmoplantar and non-palmoplantar areas and the effects of DKK1 on melanocyte gene expression profiles and on Wnt signaling pathways using DNA microarray technology, reverse transcriptase-PCR, Western blot, 3-dimensional reconstructed skin, immunocytochemistry, and immunohistochemistry. DKK1-responsive genes included those encoding proteins involved in the regulation of melanocyte development, growth, differentiation, and apoptosis (including Kremen 1, G-coupled receptor 51, lipoprotein receptor-related protein 6, low-density lipoprotein receptor, tumor necrosis factor receptor super-family 10, growth arrest and DNA-damage-inducible gene 45beta, and MITF).

Regulation of constitutive and UVR-induced skin pigmentation by melanocortin 1 receptor isoforms.

Melanin synthesized by epidermal melanocytes protects the skin against UVR-induced DNA damage and skin cancer. Exposure to UVR increases the synthesis of the photoprotective eumelanin on activation of MC1R, a melanoma susceptibility gene. We studied the expression of MC1R under UVR and alpha-MSH stimulation in skin of different ethnic origins and in melanocytes of various pigmentary levels.

Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas.

Multidrug resistance mechanisms underlying the intractability of malignant melanomas remain largely unknown. In this study, we demonstrate that the development of multidrug resistance in melanomas involves subcellular sequestration of intracellular cytotoxic drugs such as cis-diaminedichloroplatinum II (cisplatin; CDDP). CDDP is initially sequestered in subcellular organelles such as melanosomes, which significantly reduces its nuclear localization when compared with nonmelanoma/KB-3-1 epidermoid carcinoma cells.

The repeat domain of the melanosomal matrix protein PMEL17/GP100 is required for the formation of organellar fibers.

Over 125 pigmentation-related genes have been identified to date. Of those, PMEL17/GP100 has been widely studied as a melanoma-specific antigen as well as a protein required for the formation of fibrils in melanosomes. PMEL17 is synthesized, glycosylated, processed, and delivered to melanosomes, allowing them to mature from amorphous round vesicles to elongated fibrillar structures.

Sorting of Pmel17 to melanosomes through the plasma membrane by AP1 and AP2: evidence for the polarized nature of melanocytes.

Adaptor proteins (AP) play important roles in the sorting of proteins from the trans-Golgi network, but how they function in the sorting of various melanosome-specific proteins such as Pmel17, an essential structural component of melanosomes, in melanocytes is unknown. We characterized the processing and trafficking of Pmel17 via adaptor protein complexes within melanocytic cells. Proteomics analysis detected Pmel17, AP1 and AP2, but not AP3 or AP4 in early melanosomes.

Regulatory elements of the melanocortin 1 receptor.

Among more than 120 genes that are now known to regulate mammalian pigmentation, one of the key genes is MC1R, which encodes the melanocortin 1 receptor, a seven transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Since the monoexonic sequence of the gene was cloned and characterized more than a decade ago, tremendous efforts have been dedicated to the extensive genotyping of mostly red-haired populations all around the world, thus providing allelic variants that may or may not account for melanoma susceptibility in the presence or absence of ultraviolet (UV) exposure. Soluble factors, such as proopiomelanocortin (POMC) derivatives, agouti signal protein (ASP) and others, regulate MC1R expression, leading to improved photoprotection via increased eumelanin synthesis or in contrast, inducing the switch to pheomelanin.

Mutations in dopachrome tautomerase (Dct) affect eumelanin/pheomelanin synthesis, but do not affect intracellular trafficking of the mutant protein.

Dopachrome tautomerase (Dct) is a type I membrane protein and an important regulatory enzyme that plays a pivotal role in the biosynthesis of melanin and in the rapid metabolism of its toxic intermediates. Dct-mutant melanocytes carrying the slaty or slaty light mutations were derived from the skin of newborn congenic C57BL/6J non-agouti black mice and were used to study the effect(s) of these mutations on the intracellular trafficking of Dct and on the pigmentation of the cells. Dct activity is 3-fold lower in slaty cells compared with non-agouti black melanocytes, whereas slaty light melanocytes have a surprisingly 28-fold lower Dct activity.

Principal expression of two mRNA isoforms (ABCB 5alpha and ABCB 5beta ) of the ATP-binding cassette transporter gene ABCB 5 in melanoma cells and melanocytes.

ATP-binding cassette (ABC) transporters play a pivotal role in physiology and pathology. We identified and cloned two novel mRNA isoforms (ABCB 5alpha and ABCB 5beta) of the ABC transporter ABCB 5 in human melanoma cells. The deduced ABCB 5alpha protein appears to be an altered splice variant containing only a putative ABC, whereas the ABCB 5beta isoform shares approximately 70% similarity with ABCB1 (MDR1) and has a deduced topological arrangement similar to that of the whole carboxyl terminal half of the ABCB1 gene product, P-glycoprotein, including an intact ABC.

MC1R and the response of melanocytes to ultraviolet radiation.

The constitutive color of our skin plays a dramatic role in our photoprotection from solar ultraviolet radiation (UVR) that reaches the Earth and in minimizing DNA damage that gives rise to skin cancer. More than 120 genes have been identified and shown to regulate pigmentation, one of the key genes being melanocortin 1 receptor (MC1R) that encodes the melanocortin 1 receptor (MC1R), a seven-transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Modulation of MC1R function regulates melanin synthesis by melanocytes qualitatively and quantitatively.

Mesenchymal-epithelial interactions in the skin: increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation.

We investigated whether or not the topographic regulation of melanocyte differentiation is determined by mesenchymal-epithelial interactions via fibroblast-derived factors. The melanocyte density in palmoplantar human skin (i.e.

Regulation of melanocortin 1 receptor expression at the mRNA and protein levels by its natural agonist and antagonist.

Five melanocortin receptors, which form a subfamily of G protein-coupled receptors, are expressed in mammalian tissues and regulate such diverse physiological processes as pigmentation, adrenal function, energy homeostasis, feeding efficiency, and sebaceous gland lipid production, as well as immune and sexual function. Pigmentation in mammals is stimulated by alpha-melanocyte stimulating hormone (MSH), which binds to the melanocortin 1 receptor (Mc1r) and induces an activation of melanogenic enzymes through stimulation of adenylate cyclase and protein kinase A. The antagonist agouti signal protein (ASP) interacts with the Mc1r and blocks its stimulation by MSH.

The Seiji memorial lecture: the melanosome: an ideal model to study cellular differentiation.

Melanosomes provide an intriguing model for study at many levels. In part this is due to their unique structure and function, but also in part to their involvement in pigmentary diseases and as a model to study basic cellular mechanisms of organelle biogenesis. Recent studies have elucidated the full proteome of the melanosome and the metabolic and molecular lesions involved in a number of pigmentary diseases have been resolved.

The inhibitory effect of androgen and sex-hormone-binding globulin on the intracellular cAMP level and tyrosinase activity of normal human melanocytes.

The effect of androgens on human melanocytes has not been well clarified. We studied the effects of androgens on normal human melanocytes in the presence or absence of sex-hormone-binding globulin (SHBG), which complexes with those hormones. Immunohistochemically, testosterone and SHBG co-localized on the cell membrane.