Immunomodulatory activity of itraconazole in lung

Purpose: To evaluate the in vivo effects of ITC as an immunomodulator on various immunological mediators, including cytokines, chemokines and growth factors in pulmonary homogenates.Methods: Two experimental groups consisting of 25 BALB/c mice each were used: (a) PBS-treated mice and (b) ITC-treated mice (1 mg/mouse/day). The animals were treated daily via gavage for 8 weeks. Five mice from each group were sacrificed at 0, 4, 8, and 12 weeks and cytokine levels assessed in the supernatants of lung macerates using the Bio-Plex system. Five lungs from each experimental group, after 8 weeks of treatment, were used for histopathological analysis.Results: Compared with the control group, ITC-treated mice showed significant changes in the pulmonary levels of 50 % of the molecules evaluated: IL-4, IL-10, IL-12p70, IL-13, TNF-α, eotaxin, MIP- 1α, MIP-2, and LIF were significantly upregulated. In contrast, IL-1β, IL-15, IL-2, IL-1α, and VEGF were downregulated.Conclusion: Although histopathological examination did not show changes in lung cell infiltrates, ITC exerted a marked immunomodulatory effect at the pulmonary level in healthy BALB/c mice.Keywords: Immunomodulation, Itraconazole, Antifungal drug, Histopathological examinatio

The in-plane electrodynamics of the superconductivity in Bi2Sr2CaCu2O8+d: energy scales and spectral weight distribution

The in-plane infrared and visible (3 meV-3 eV) reflectivity of Bi2Sr2CaCu2O8+d (Bi-2212) thin films is measured between 300 K and 10 K for different doping levels with unprecedented accuracy. The optical conductivity is derived through an accurate fitting procedure. We study the transfer of spectral weight from finite energy into the superfluid as the system becomes superconducting. In the over-doped regime, the superfluid develops at the expense of states lying below 60 meV, a conventional energy of the order of a few times the superconducting gap. In the underdoped regime, spectral weight is removed from up to 2 eV, far beyond any conventional scale. The intraband spectral weight change between the normal and superconducting state, if analyzed in terms of a change of kinetic energy is ~1 meV. Compared to the condensation energy, this figure addresses the issue of a kinetic energy driven mechanism.Comment: 13 pages with 9 figures include

Generalization of entropy based divergence measures for symbolic sequence analysis

Entropy based measures have been frequently used in symbolic sequence analysis. A symmetrized and smoothed form of Kullback-Leibler divergence or relative entropy, the Jensen-Shannon divergence (JSD), is of particular interest because of its sharing properties with families of other divergence measures and its interpretability in different domains including statistical physics, information theory and mathematical statistics. The uniqueness and versatility of this measure arise because of a number of attributes including generalization to any number of probability distributions and association of weights to the distributions. Furthermore, its entropic formulation allows its generalization in different statistical frameworks, such as, non-extensive Tsallis statistics and higher order Markovian statistics. We revisit these generalizations and propose a new generalization of JSD in the integrated Tsallis and Markovian statistical framework. We show that this generalization can be interpreted in terms of mutual information. We also investigate the performance of different JSD generalizations in deconstructing chimeric DNA sequences assembled from bacterial genomes including that of E. coli, S. enterica typhi, Y. pestis and H. influenzae. Our results show that the JSD generalizations bring in more pronounced improvements when the sequences being compared are from phylogenetically proximal organisms, which are often difficult to distinguish because of their compositional similarity. While small but noticeable improvements were observed with the Tsallis statistical JSD generalization, relatively large improvements were observed with the Markovian generalization. In contrast, the proposed Tsallis-Markovian generalization yielded more pronounced improvements relative to the Tsallis and Markovian generalizations, specifically when the sequences being compared arose from phylogenetically proximal organisms.publishedVersionFil: Ré, Miguel Ángel. Universidad Tecnológica Nacional. Facultad Regional Córdoba. Centro de Investigación en Informática para la Ingeniería. Departamento de Ciencias Básicas; Argentina.Fil: Ré, Miguel Ángel. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Azad, Rajeev K. University of North Texas. College of Science. Department of Biological Sciences; Estados Unidos de América.Fil: Azad, Rajeev K. University of North Texas. College of Science. Department of Mathematics; Estados Unidos de América.Ciencias de la Información y Bioinformática (desarrollo de hardware va en 2.2 "Ingeniería Eléctrica, Electrónica y de Información" y los aspectos sociales van en 5.8 "Comunicación y Medios"

Endochondral Bone Regeneration by Non-autologous Mesenchymal Stem Cells

Mimicking endochondral bone formation is a promising strategy for bone regeneration. To become a successful therapy, the cell source is a crucial translational aspect. Typically, autologous cells are used. The use of non-autologous mesenchymal stromal cells (MSCs) represents an interesting alternative. Nevertheless, non-autologous, differentiated MSCs may trigger an undesired immune response, hampering bone regeneration. The aim of this study was to unravel the influence of the immune response on endochondral bone regeneration, when using xenogeneic (human) or allogeneic (Dark Agouti) MSCs. To this end, chondrogenically differentiated MSCs embedded in a collagen carrier were implanted in critical size femoral defects of immunocompetent Brown Norway rats. Control groups were included with syngeneic/autologous (Brown Norway) MSCs or a cell-free carrier. The amount of neo-bone formation was proportional to the degree of host-donor relatedness, as no full bridging of the defect was observed in the xenogeneic group whereas 2/8 and 7/7 bridges occurred in the allogeneic and the syngeneic group, respectively. One week post-implantation, the xenogeneic grafts were invaded by pro-inflammatory macrophages, T lymphocytes, which persisted after 12 weeks, and anti-human antibodies were developed. The immune response toward the allogeneic graft was comparable to the one evoked by the syngeneic implants, aside from an increased production of alloantibodies, which might be responsible for the more heterogeneous bone formation. Our results demonstrate for the first time the feasibility of using non-autologous MSC-derived chondrocytes to elicit endochondral bone regeneration in vivo. Nevertheless, the pronounced immune response and the limited bone formation observed in the xenogeneic group undermine the clinical relevance of this group. On the contrary, although further research on how to achieve robust bone formation with allogeneic cells is needed, they may represent an alternative to autologous transplantation

Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.</p

Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer\u27s disease

The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer\u27s disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p.Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P=1.29 _ 10?12; NPHP1, rs10173717, P=1.74 _ 10?12; CADPS2, rs3757536, P=1.54 _ 10?10; GREM2, rs12129547, P=1.69 _ 10?13, among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions

Structural and Topographic Dynamics of Pulmonary Histopathology and Local Cytokine Profiles in Paracoccidioides brasiliensis Conidia-Infected Mice

Paracoccidioidomycosis (PCM), an endemic fungal infection of pulmonary origin resulting in severe disseminated disease, occurs in rural areas of most South American countries and presents several clinical forms. The infection is acquired by inhalation of specific fungal propagules, called conidia. Considering the difficulties encountered when studying the infection in humans, this work was done in mice infected by inhalation of infective fungal conidia thus mimicking the human natural infection. The lungs of mice were sequentially studied by histopathological and multiplex cytokine methods from 2 h to 16 weeks after infection to verify the course of the disease. The mycosis presented different morphologic aspects during the course of time, affecting several pulmonary compartments. Otherwise and based on the analysis of 30 cytokines, the immune response also showed heterogeneous responses, which were up or down regulated depending on the time of infection. By recognizing the different stages that correspond to the evolution of pulmonary lesions, the severity (benign, chronic or fibrotic) of the disease could be predicted and the probable prognosis of the illness be inferred

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

Background: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.Q2Q2Antecedentes La población colombiana, así como la de otras regiones latinoamericanas, surgió de una mezcla tricontinental reciente entre los nativos americanos, los invasores españoles y los africanos esclavizados, todos los cuales pasaron por un cuello de botella poblacional debido a enfermedades infecciosas generalizadas que dejaron a pequeños aislados. asentamientos locales. Como resultado, la población actual refleja múltiples efectos fundadores derivados de diversas ascendencias. Métodos Caracterizamos el papel de la mezcla y los efectos fundadores en el origen del paisaje mutacional que condujo a trastornos neurodegenerativos en estas circunstancias históricas. Genomas de 900 individuos colombianos con enfermedad de Alzheimer (EA) [n = 376], continuo degeneración lobar frontotemporal-enfermedad de la motoneurona (FTLD-MND) [n = 197], demencia de inicio temprano no especificada (EOD) [n = 73 ], y participantes sanos [n = 254] fueron analizados. Examinamos sus proporciones de ascendencia global y local y examinamos esta cohorte en busca de variantes nocivas en los genes que causan enfermedades y confieren riesgos. Resultados Identificamos 21 variantes patogénicas en genes relacionados con AD-FTLD, y PSEN1 albergaba la mayoría (11 variantes patogénicas). Se identificaron variantes de las tres ascendencias continentales. Las variantes heterocigotas y homocigotas de TREM2 fueron las más comunes entre los genes de riesgo de EA (102 portadores), un punto de interés porque el riesgo de enfermedad conferido por estas variantes difería según la ascendencia. Varias variantes genéticas que tienen una asociación conocida con MND en poblaciones europeas tenían fenotipos FTLD en un haplotipo nativo americano. De acuerdo con los efectos del fundador, la identidad por descendencia entre portadores de la misma variante fue frecuente. Conclusiones La demografía colombiana con múltiples mini-cuellos de botella probablemente mejoró la detección de eventos fundadores y dejó una frecuencia proporcionalmente más alta de variantes raras derivadas de las poblaciones ancestrales. Estos hallazgos demuestran el papel de la ascendencia definida genómicamente en la expresión fenotípica de la enfermedad, un rango fenotípico de diferentes mutaciones raras en el mismo gen, y enfatizan aún más la importancia de la inclusión en los estudios genéticos.https://orcid.org/0000-0001-6529-7077https://scholar.google.com/citations?hl=es&user=kaGongoAAAAJ&view_op=list_works&sortby=pubdatehttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000055000&lang=esRevista Internacional - Indexad