Epidermal stem cells and skin tissue engineering in hair follicle regeneration

The reconstitution of a fully organized and functional hair follicle from dissociated cells propagated under defined tissue culture conditions is a challenge still pending in tissue engineering. The loss of hair follicles caused by injuries or pathologies such as alopecias not only affects the patients´ psychological well-being, but also endangers certain inherent functions of the skin. It is then of great interest to find different strategies aiming to regenerate or neogenerate the hair follicle under conditions proper of an adult individual. Based upon current knowledge of the epithelial and dermal cells involved in embryonic hair generation and adult hair cycling, and of the epithelial-mesenchymal interactions among them, many researchers have tried to obtain mature hair follicles using different strategies and approaches depending on the causes of hair loss. This review summarizes current advances in the different experimental strategies to regenerate or neogenerate hair follicles, with emphasis on those involving neogenesis of hair follicles in adults from isolated cells and tissue engineering. Most of these experiments were performed using rodent cells, particularly from embryonic or newborn origin. However, no successful strategy to generate human hair follicles from adult cells has yet been reported. This review identifies several issues that should be considered to achieve this objective. Perhaps the most important challenge is to provide the cells with three-dimensional culture conditions mimicking the structure of living tissue. Improving culture conditions that allow the expansion of specific cells without losing their inductive properties, as well as methods of selecting populations of epithelial stem cells should give us the necessary tools to overcome the difficulties that constrain human hair follicle neogenesis. An analysis of patents trends shows that the number of patent applications aiming to hair follicle regeneration and neogenesis has been growing during the last decade, and this field is attractive not only to academic researchers but also to the companies that own almost half of the patents in this field.Fil: Balaña, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencias y Tecnología "Dr. Cesar Milstein"; ArgentinaFil: Charreau, Hernán Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Clarke, Modet & C°. Technology Intelligence Unit; ArgentinaFil: Leiros, Gustavo Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencias y Tecnología "Dr. Cesar Milstein"; Argentin

Study on a multi-brand auto distribution network serving multiple cities to minimize the total distribution cost

The current research project consists of minimizing the total cost of an auto dealership supply chain management system that provides two auto brands for five major industrial cities in the Great Lake Area of the United States. The two auto brands are Ford and Chrysler. The five major cities are Chicago, Detroit, Indianapolis, St. Louis, and Cincinnati. The total cost includes transportation cost from auto assembly plants to individual cities, along with warehouse cost and/or transshipment cost depending on the supply chain management configuration. Concerning the auto delivery schemes, both centralized and decentralized alternatives are considered. For either the centralized or decentralized alternatives, trucks and/or trains could be adopted. Each brand may utilize an independent delivery scheme. The objective is to find the best combination of the delivery schemes for both brands that could achieve the minimized total cost while meeting the demand of each city. The proposed study includes literature review, proposed methodology, and methodology applications using real world data. Finally, the report has a summary and some concluding remarks, as well as future direction of extended research to implement the research products.Outgoin

Androgens and androgen receptor action in skin and hair follicles

Beyond sexual functions, androgens exert their action in skin physiology andpathophysiology. Skin cells are able to synthesize most of active androgens from gonadal or adrenal precursors and the enzymes involved in skin steroidogenesis are implicated both in normal or pathological processes. Even when the role of androgens and androgen receptor (AR) in skin pathologies has been studied for decades, their molecular mechanisms in skin disorders remain largely unknown. Here, we go over recent studies of androgens and AR roles in several skin-related disorders, focusing in the current understanding of its molecular mechanisms in androgenetic alopecia (AGA). We review on the molecular pathophysiology of type 2 5α-reductase, AR coactivators, the paracrinefactors deregulated in dermal papilla (such as TGF-β, IGF 1, WNTs and DKK-1) and the crosstalk between AR and Wnt signaling in order to shed some light on new promising treatments.Fil: Ceruti, Julieta María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: Leiros, Gustavo Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: Balaña, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; Argentin

La vila de Montblanc: agricultura, urbanisme i societat segons el cadastre de 1731

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Gene disruption of the DNA topoisomerase IB small subunit induces a non-viable phenotype in the hemoflagellate Leishmania major

<p>Abstract</p> <p>Background</p> <p>The unusual heterodimeric leishmanial DNA topoisomerase IB consists of a large subunit containing the phylogenetically conserved "core" domain, and a small subunit harboring the C-terminal region with the characteristic tyrosine residue in the active site. RNAi silencing of any of both protomers induces a non-viable phenotype in the hemoflagelate <it>Trypanosoma brucei</it>. Unfortunately, this approach is not suitable in <it>Leishmania </it>where gene replacement with an antibiotic marker is the only approach to generate lack-of-function mutants. In this work, we have successfully generated null mutants in the small subunit of the <it>L. major </it>DNA topoisomerase IB using two selection markers, each conferring resistance to hygromycin B and puromycin, respectively.</p> <p>Results</p> <p>We have successfully replaced both <it>topS </it>loci with two selection markers. However, to achieve the second transfection round, we have had to rescue the null-homozygous with an episomal vector carrying the <it>Leishmania major topS </it>gene. Phenotypic characterization of the <it>L. major </it>rescued strain and a <it>L. major </it>strain, which co-overexpresses both subunits, shows few differences in DNA relaxation and camptothecin cytotoxicity when it was compared to the wild-type strain. Studies on phosphatidylserine externalization show a poor incidence of camptothecin-induced programmed cell death in <it>L. major</it>, but an effective cell-cycle arrest occurs within the first 24 h. S-Phase delay and G₂/M reversible arrest was the main outcome at lower concentrations, but irreversible G₂arrest was detected at higher camptothecin pressure.</p> <p>Conclusion</p> <p>Results obtained in this work evidence the essentiality of the <it>topS </it>gene encoding the <it>L. major </it>DNA topoisomerase IB small subunit. Reversibility of the camptothecin effect points to the existence of effective checkpoint mechanisms in <it>Leishmania </it>parasites.</p

Androgens downregulate BMP2 impairing the inductive role of dermal papilla cells on hair follicle stem cells differentiation

Hair follicle cyclical regeneration is regulated by epithelial-mesenchymal interactions. During androgenetic alopecia (AGA), hair follicle stem cells (HFSC) differentiation is impaired by deregulation of dermal papilla cells (DPC) secreted factors. We analyzed androgen influence on BMPs expression in DPC and their effect on HFSC differentiation to hair lineage. Androgens downregulated BMP2 and BMP4 in DPC spheroids. Addition of BMP2 restored alkaline phosphatase activity, marker of hair-inductivity in DPC, and DPC-induced HFSC differentiation, both inhibited by androgens. Concomitantly, in differentiating HFSC, an upregulation of BMPRIa and BMPRII receptors and nuclear β-catenin accumulation, indicative of Wnt/β-catenin pathway activation, were detected. Our results present BMP2 as an androgen-downregulated paracrine factor that contributes to DPC inductivity and favors DPC-induced HFSC differentiation to hair lineage, possibly through a crosstalk with Wnt/β-catenin pathway. A comprehensive understanding of androgen-deregulated DPC factors and their effects on differentiating HFSC would help to improve treatments for AGA.Fil: Ceruti, Julieta María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: Oppenheimer, Florencia Maia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: Leiros, Gustavo Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; ArgentinaFil: Balaña, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Ciencia y Tecnología "Dr. César Milstein". Fundación Pablo Cassará. Instituto de Ciencia y Tecnología "Dr. César Milstein"; Argentin

Zoonotic implications of onchocerca species on human health

The genus Onchocerca includes several species associated with ungulates as hosts, although some have been identified in canids, felids, and humans. Onchocerca species have a wide geographical distribution, and the disease they produce, onchocerciasis, is generally seen in adult individuals because of its large prepatency period. In recent years, Onchocerca species infecting animals have been found as subcutaneous nodules or invading the ocular tissues of humans; the species involved are O. lupi, O. dewittei japonica, O. jakutensis, O. gutturosa, and O. cervicalis. These findings generally involve immature adult female worms, with no evidence of being fertile. However, a few cases with fertile O. lupi, O. dewittei japonica, and O. jakutensis worms have been identified recently in humans. These are relevant because they indicate that the parasite's life cycle was completed in the new host-humans. In this work, we discuss the establishment of zoonotic Onchocerca infections in humans, and the possibility of these infections to produce symptoms similar to human onchocerciasis, such as dermatitis, ocular damage, and epilepsy. Zoonotic onchocerciasis is thought to be an emerging human parasitic disease, with the need to take measures such as One Health Strategies, in order to identify and control new cases in humans

Revisión sobre las técnicas de Biofeedback y sus aplicaciones

The emergence of biofeedback techniques has been one of the most important phenomena that has taken place in the last century in the field of clinical psychology. It has been proved the possibilities of applying operant techniques not only to the learning of autonomous and visceral functions, but also to apply them for therapeutic purposes in many psychosomatic dysfunctions. This article purports to offer a historical and general perspective of the outset and technical evolution of the biofeedback, until today by means of an intemized bibliographical review of the main clinical applications in different disorders such as stress, migraine, headache, pains, hypertension, sickness of Raynaud, etc.ResumenEl surgimiento de las técnicas de biofeedback, ha sido uno de los fenómenos más importantes ocurridos en este siglo en el campo de la psicología clínica. No sólo se ha demostrado la posibilidad de aplicar las técnicas operantes al aprendizaje de funciones autonómicas y viscerales, sino también la posibilidad de aplicar estas técnicas, con fines de intervención terapéutica en multitud de trastornos psicosomáticos. Este artículo pretende ofrecer una visión histórica general sobre los inicios y evolución de las técnicas de biofeeback, hasta la actualidad, aportando una revisión bibliográfica sobre las diferentes técnicas de biofeedback y sus aplicaciones clínicas en distintos trastornos: estrés, migrañas, cefaleas tensionales, dolores, hipertensión, enfermedad de Rainaud, etc.AbstractThe emergence of biofeedback techniques has been one of the most important phenomena that has taken place in the last century in the field of clinical psychology. It has been proved the possibilities of applying operant techniques not only to the learning of autonomous and visceral functions, but also to apply them for therapeutic purposes in many psychosomatic dysfunctions. This article purports to offer a historical and general perspective of the outset and technical evolution of the biofeedback, until today by means of an intemized bibliographical review of the main clinical applications in different disorders such as stress, migraine, headache, pains, hypertension, sickness of Raynaud, etc

Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery

AbstractThe Trypanosomatidae family, composed of unicellular parasites, causes severe vector-borne diseases that afflict human populations worldwide. Chagas disease, sleeping sickness, as well as different sorts of leishmaniases are amongst the most important infectious diseases produced by Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively. All these infections are closely related to weak health care services in low-income populations of less developed and least economically developed countries. Search for new therapeutic targets in order to hit these pathogens is of paramount priority, as no effective vaccine is currently in use against any of these parasites. Furthermore, present-day chemotherapy comprises old-fashioned drugs full of important side effects. Besides, they are prone to produce tolerance and resistance as a consequence of their continuous use for decades. DNA topoisomerases (Top) are ubiquitous enzymes responsible for solving the torsional tensions caused during replication and transcription processes, as well as in maintaining genomic stability during DNA recombination. As the inhibition of these enzymes produces cell arrest and triggers cell death, Top inhibitors are among the most effective and most widely used drugs in both cancer and antibacterial therapies. Top relaxation and decatenation activities, which are based on a common nicking–closing cycle involving one or both DNA strands, have been pointed as a promising drug target. Specific inhibitors that bind to the interface of DNA-Top complexes can stabilize Top-mediated transient DNA breaks. In addition, important structural differences have been found between Tops from the Trypanosomatidae family members and Tops from the host. Such dissimilarities make these proteins very interesting for drug design and molecular intervention. The present review is a critical update of the last findings regarding trypanosomatid’s Tops, their new structural features, their involvement both in the physiology and virulence of these parasites, as well as their use as promising targets for drug discovery

Lack of Benefit of Extending Temozolomide Treatment in Patients with High Vascular Glioblastoma with Methylated MGMT

[EN] Despite the complete treatment with surgery, chemotherapy and radiotherapy, patients with glioblastoma have a devasting prognosis. Although the role of extending temozolomide treatment has been explored, the results are inconclusive. Recent evidence suggested that tumor vascularity may be a modulating factor in combination with methylation of O6-methylguanine-DNA methyltransferase (MGMT) promotor gene on the effect of temozolomide-based therapies, opening new possibilities for personalized treatments. Before proposing a prospective interventional clinical study, it is necessary to confirm the beneficial effect of the combined effect of MGMT methylation and moderate tumor vascularity, as well as the lack of benefit of temozolomide in patients with a highly vascular tumor.In this study, we evaluated the benefit on survival of the combination of methylation of O6-methylguanine-DNA methyltransferase (MGMT) promotor gene and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity and MGMT methylation status. We found that patients included in the moderate-vascular group had longer survival when MGMT is methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on the MGMT methylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation of MGMT methylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of extending temozolomide treatment for patients with high vascular glioblastomas, even presenting MGMT methylation. Preliminary results suggest that patients with moderate vascularity and methylated MGMT glioblastomas would benefit more from prolonged adjuvant chemotherapy.M.A-T was supported by DPI2016-80054-R (Programa Estatal de Promocion del Talento y su Empleabilidad en I+D+i). This work was partially supported by the ALBATROSS project (National Plan for Scientific and Technical Research and Innovation 2017-2020, No. PID2019-104978RB-I00). This study was partially funded by the Fundacio La Marato TV3 (665/C/2013) (http://www.ccma.cat/tv3/marato/projectes-financats/2012/231/ Accessed on 8th September 2021). (JMGG); H2020-SC1-2016-CNECT Project (No. 727560) (JMGG), and H2020-SC1-BHC-2018-2020 (No. 825750) (JMGG). EFG was supported by the European Unions Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 844646 and South-Eastern Norway Regional Health Authority Grant 2021057.Álvarez-Torres, MDM.; Fuster García, E.; Balaña, C.; Puig, J.; Garcia-Gomez, JM. (2021). Lack of Benefit of Extending Temozolomide Treatment in Patients with High Vascular Glioblastoma with Methylated MGMT. Cancers. 13(21):1-14. https://doi.org/10.3390/cancers13215420S114132