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This article is oriented to the degradation of nickel in an ionic state at laboratory level from synthetic water made with nickel sulfate, using the electrocoagulation process with aluminum cathodes and modifying this process by the addition of the Fenton reagent, which results from the combination of hydrogen peroxide (H2O2) and ferrous sulfate (FeSO4) being this reagent a catalyst and oxo-coagulant agent, The efficiency of this reagent will be compared with the typical treatment with aluminum sulfate, which is a typical process based on ion exchange/coagulation at the same percentage concentrations as the Fenton reagent. For this purpose, the optimum conditions of the advanced electrocoagulation process were determined, which consisted of determining the concentrations of Fenton’s reagent at concentrations of 150 ppm, 300 ppm, and 450 ppm, in addition to the operating variables such as pH of 8 and 10, voltage of 17.5 V and 19 V and their reaction time, which were compared with aluminum sulfate at 300 ppm, 600 ppm, and 900 ppm. The results obtained with respect to the typical treatment were 0% nickel degradation. However, with the advanced oxidation treatment, an average reduction of 97.5% was found at the conditions of 19 V, pH 10, and Fenton 150 ppm in a time of 30 min.

IntroductionMaternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Maternal reproductive history is associated with differential risk of pregnancy complications. The molecular phenotypes and roles of these distinct monocyte/macrophage populations and the influence of gravidity on these phenotypes has not been systematically investigated.MethodsHere, we used RNA sequencing to study the transcriptional profiles of MIMs and HBCs in normal term pregnancies.ResultsOur analyses revealed distinct transcriptomes of MIMs and HBCs. Genes involved in differentiation and cell organization pathways were more highly expressed in MIMs vs. HBCs. In contrast, HBCs had higher expression of genes involved in inflammatory responses and cell surface receptor signaling. Maternal gravidity influenced monocyte programming, as expression of pro-inflammatory molecules was significantly higher in MIMs from multigravidae compared to primigravidae. In HBCs, multigravidae displayed enrichment of gene pathways involved in cell-cell signaling and differentiation.DiscussionOur results demonstrated that MIMs and HBCs have highly divergent transcriptional signatures, reflecting their distinct origins, locations, functions, and roles in inflammatory responses. Furthermore, maternal gravidity influences the gene signatures of MIMs and HBCs, potentially modulating the interplay between tolerance and trained immunity. The phenomenon of reproductive immune memory may play a novel role in the differential susceptibility of primigravidae to pregnancy complications.

Resumen: La columna vertebral es la tercera ubicación más frecuente para la enfermedad metastásica, después del pulmón y el hígado. Por otra parte, los tumores óseos más recurrentes son las metástasis, siendo la columna su principal lugar de localización. En este trabajo se realiza una revisión de las diferentes técnicas de imagen disponibles, tanto radiológicas como de medicina nuclear, y de la apariencia morfológica de las metástasis de columna en cada una de ellas. La resonancia magnética (RM) es la mejor modalidad de imagen para la detección de metástasis en la columna. Es importante efectuar el diagnóstico diferencial entre fractura vertebral de causa osteoporótica y patológica. La compresión medular es una complicación grave de la enfermedad metastásica y su valoración mediante imagen a través de escalas objetivas es determinante para la estimación de la estabilidad de la columna y, por consiguiente, para establecer el tratamiento. Por último, se comentan brevemente las técnicas de intervencionismo percutáneo. Abstract: The spine is the third most frequent location for metastatic disease, after the lung and liver. On the other hand, the most frequent bone tumors are metastases and the spine is the main location. A review of the different imaging techniques available, both radiological and nuclear medicine, and the morphological appearance of spinal metastases in each of them is performed. Magnetic resonance imaging is the best imaging modality for detection of spinal metastases. It is important to make the differential diagnosis between vertebral fracture of osteoporotic and pathological cause. Spinal cord compression is a serious complication of metastatic disease and its assessment by imaging through objective scales is decisive for estimating spinal stability and therefore establishing treatment. Lastly, percutaneous intervention techniques are briefly discussed.

The spine is the third most frequent location for metastatic disease, after the lung and liver. On the other hand, the most frequent bone tumours are metastases and the spine is the main location. A review of the different imaging techniques available, both radiological and nuclear medicine, and the morphological appearance of spinal metastases in each of them is performed. Magnetic resonance imaging is the best imaging modality for detection of spinal metastases. It is important to make the differential diagnosis between vertebral fracture of osteoporotic and pathological cause. Spinal cord compression is a serious complication of metastatic disease and its assessment by imaging through objective scales is decisive for estimating spinal stability and therefore establishing treatment. Lastly, percutaneous intervention techniques are briefly discussed. Resumen: La columna vertebral es la tercera ubicación más frecuente para la enfermedad metastásica, después del pulmón y el hígado. Por otra parte, los tumores óseos más recurrentes son las metástasis, siendo la columna su principal lugar de localización. En este trabajo se realiza una revisión de las diferentes técnicas de imagen disponibles, tanto radiológicas como de medicina nuclear, y de la apariencia morfológica de las metástasis de columna en cada una de ellas. La resonancia magnética es la mejor modalidad de imagen para la detección de metástasis en la columna. Es importante efectuar el diagnóstico diferencial entre fractura vertebral de causa osteoporótica y patológica. La compresión medular es una complicación grave de la enfermedad metastásica y su valoración mediante imagen a través de escalas objetivas es determinante para la estimación de la estabilidad de la columna y, por consiguiente, para establecer el tratamiento. Por último, se comentan brevemente las técnicas de intervencionismo percutáneo.

Por primera vez se analizan para la Sabana de Bogotá algunas de las características de la turbulencia y la estabilidad atmosférica como son: la escala de Monin – Obuckov, la temperatura de escala, la velocidad de fricción y el flujo de calor sensible de acuerdo con la teoría de similaridad de Monin – Obuckov. Debido a que esta teoría es poco conocida también se presenta la derivación de estos parámetros usando el método energético e igualmente la manera como estos parámetros pueden ser incluidos dentro de un modelo de dispersión. El cálculo de estos parámetros se llevó a cabo con ayuda de mediciones de la temperatura del aire a 2 y 10 m y del viento a 10 m. En general se destaca la relación entre el calentamiento diurno y el incremento de la turbulencia así: hacia las horas del mediodía y comienzos de la tarde se incrementan; la velocidad de fricción, el flujo de calor sensible y la inestabilidad atmosférica representada por valores negativos de la escala de Monin – Obuckov. A estas horas del día también se observa el máximo de la velocidad del viento. También se hace notoria la relación entre el incremento de la turbulencia y el desarrollo de la convección y formación de tormentas eléctricas en la Sabana de Bogotá. Durante las horas de la noche el viento se torna mínimo, el flujo de calor negativo y la escala de Monin – Obuckov positiva indican condiciones estables y neutrales. Estos resultados pueden ser de interés en estudios de dispersión de contaminantes atmosféricos. La relación encontrada entre la turbulencia y el desarrollo de la convección atmosférica, después de una confirmación más detallada, puede servir como un indicativo para el pronóstico de tormentas eléctricas en lugares donde no se poseen datos de radisondeo.

IntroductionImmune checkpoint inhibitors (ICIs) only benefit a subset of cancer patients, underlining the need for predictive biomarkers for patient selection. Given the limitations of tumor tissue availability, flow cytometry of peripheral blood mononuclear cells (PBMCs) is considered a noninvasive method for immune monitoring. This study explores the use of spectrum flow cytometry, which allows a more comprehensive analysis of a greater number of markers using fewer immune cells, to identify potential blood immune biomarkers and monitor ICI treatment in non-small-cell lung cancer (NSCLC) patients.MethodsPBMCs were collected from 14 non-small-cell lung cancer (NSCLC) patients before and after ICI treatment and 4 healthy human donors. Using spectrum flow cytometry, 24 immune cell markers were simultaneously monitored using only 1 million PBMCs. The results were also compared with those from clinical flow cytometry and bulk RNA sequencing analysis. ResultsOur findings showed that the measurement of CD4+ and CD8+ T cells by spectrum flow cytometry matched well with those by clinical flow cytometry (Pearson R ranging from 0.75 to 0.95) and bulk RNA sequencing analysis (R=0.80, P=1.3 x 10-4). A lower frequency of CD4+ central memory cells before treatment was associated with a longer median progression-free survival (PFS) [Not reached (NR) vs. 5 months; hazard ratio (HR)=8.1, 95% confidence interval (CI) 1.5–42, P=0.01]. A higher frequency of CD4-CD8- double-negative (DN) T cells was associated with a longer PFS (NR vs. 4.45 months; HR=11.1, 95% CI 2.2–55.0, P=0.003). ICIs significantly changed the frequency of cytotoxic CD8+PD1+ T cells, DN T cells, CD16+CD56dim and CD16+CD56- natural killer (NK) cells, and CD14+HLDRhigh and CD11c+HLADR + monocytes. Of these immune cell subtypes, an increase in the frequency of CD16+CD56dim NK cells and CD14+HLADRhigh monocytes after treatment compared to before treatment were associated with a longer PFS (NR vs. 5 months, HR=5.4, 95% CI 1.1-25.7, P=0.03; 7.8 vs. 3.8 months, HR=5.7, 95% CI 169 1.0-31.7, P=0.04), respectively. ConclusionOur preliminary findings suggest that the use of multicolor spectrum flow cytometry helps identify potential blood immune biomarkers for ICI treatment, which warrants further validation.

(1) Background: Epidermolysis bullosa (EB) comprises a group of rare skin diseases. We assessed diagnostic procedures, comorbidity profiles, length of hospital stay (LOHS), costs, and in-hospital mortality (IHM) associated with EB. (2) Methods: A retrospective, population-based observational study was performed using the Spanish National Hospital Discharge Database. Hospitalized patients with EB in Spain were identified for the period 2016 to 2021. (3) Results: A total of 677 hospitalizations were identified among 342 patients with a diagnosis of EB. Fifty percent of patients had at least one readmission during the 6-year follow-up. Notably, rehospitalizations were more common among patients aged 2–17 years. The most prevalent comorbidity was digestive disorders, which were associated with the frequency of esophageal dilatation procedures and percutaneous endoscopic gastrostomy. The longest LOHS was recorded for the 0- to 1-year age group. IHM increased with age, and the difference was statistically significant. The prevalence of malignant neoplasm was 36.88%, with cutaneous squamous cell carcinoma being the most frequent. The overall cost per hospitalized patient was estimated to be EUR 10,895.22 (SD EUR 13,394.81), with significant variations between age groups. (4) Conclusions: Readmissions are very frequent among people with EB. We observed a higher LOHS in the 0- to 1-year age group, while the highest rates of IHM were observed in patients older than 50 years. There was a substantial prevalence of comorbidities, namely, digestive disorders, infectious diseases, and especially cancer.

Information on immune receptor repertoire provides important insights on disease progression and therapy development, but can be expensive and time-consuming to obtain. Here the authors report ImReP, a computational method that can extract detailed immune repertoire information from existing tissue-specific RNA sequencing data.

Introduction: Laparoscopic sleeve gastrectomy (LSG) is the most widely performed bariatric surgery worldwide but complications and failed procedures are on the rise. Aims: To determine the reasons for failed LSGs and report the results of conversion to gastric bypass surgery, comparing the outcomes with those of primary gastric bypass surgery. Materials and methods: Patients with failed LSG that underwent conversion to gastric bypass surgery through a robotic-assisted and laparoscopic (hybrid) technique were evaluated. Outcomes and follow-up related to weight loss failure (WLF) were compared with those in patients that underwent primary laparoscopic gastric bypass (pLGB) surgery. Results: Revisional surgery was performed on 13 patients due to WLF, on 3 patients because of refractory gastroesophageal reflux disease, and on 2 patients due to gastric stricture. There were no differences between the preoperative characteristics of the patients with WLF before undergoing conversion to gastric bypass and the patients that underwent pLGB surgery. At postoperative month 36, the percentage of excess weight loss (%EWL) was greater in the patients that underwent pLGB surgery, than in those with WLF that underwent conversion to gastric bypass (69.17 ± 23.73 vs. 54.17 ± 12.48, respectively; p

Resumen: Introducción y objetivo: La manga gástrica laparoscópica (MGL) es la cirugía bariátrica más realizada en el mundo. Sin embargo, sus complicaciones y fallas del procedimiento están aumentado. Objetivos: Determinar los motivos de falla de MGL y observar los resultados de conversión a bypass gástrico, comparándolos con bypass gástrico primario. Material y métodos: Se consultaron pacientes con falla de MGL, operados de cirugía de conversión a bypass gástrico asistido por robot y laparoscópico (técnica híbrida). Los resultados y el seguimiento por falla de pérdida de peso (FPP) se compararon con pacientes operados de bypass gástrico laparoscópico primario (BGLp). Resultados: Trece pacientes se operaron de conversión por FPP, 3 por enfermedad de reflujo gastroesofágico (ERGE) intratable y 2 por estenosis gástrica. No hubo diferencias entre las características preoperatorias de los pacientes con FPP y BGLp antes del bypass gástrico. Treinta y seis meses después de la cirugía, el porcentaje de exceso de peso perdido fue mayor en BGLp que en FPP (54.17 ± 12.48 vs. 69.17 ± 23.73, respectivamente; p =

Abstract Background Acute Myeloid Leukemia (AML) is a malignancy of myeloid precursor cells that arise from genomic alterations in the expression of key growth regulatory genes causing cells to assume an undifferentiated state and continue to proliferate. Recent efforts have focused on developing therapies that target specific protein products of aberrantly expressed genes. However, many of the identified proteins are difficult to target and thought to be “undrugable” because of structural challenges, protein overexpression, or mutations that confer resistance to therapy. A novel technology that circumvents some of these issues is the use of small molecules that stabilize secondary DNA structures present in the promoters of many potential oncogenes and modulate their transcription. Methods This study characterizes the in vitro activity of the G-quadruplex-stabilizing small molecule GQC-05 in AML cells. The effect of GQC-05 on three AML cell lines was analyzed using viability and apoptosis assays. GQC-05 has been shown to down-regulate MYC through G-quadruplex stabilization in Burkitt’s lymphoma cell lines. MYC expression was evaluated through qPCR and immunoblotting in the three AML cell lines following the treatment of GQC-05. In order to identify other therapeutic agents that potentiate the activity of GQC-05, combination drug screening was performed. The drug combinations were validated using in vitro cytotoxicity assays and compared to other commonly used chemotherapeutic agents. Results GQC-05 treatment of KG-1a, CMK and TF-1 cells decreased cell viability and resulted in increased DNA damage and apoptosis. Additionally, treatment of KG-1a, CMK and TF-1 with GQC-05 resulted in decreased expression of MYC mRNA and protein, with a more pronounced effect in KG-1a cells. Combination drug screening identified the Bcl-2/Bcl-XL inhibitor Navitoclax as a compound that potentiated GQC-05 activity. Co-treatment with GQC-05 and Navitoclax showed a synergistic decrease in cell viability of AML cells as determined by Chou-Talalay analysis, and induced more DNA damage, apoptosis, and rapid cytotoxicity. The cytotoxicity induced by GQC-05 and Navitoclax was more potent than that of Navitoclax combined with either cytarabine or doxorubicin. Conclusion These results suggest that the G-quadruplex stabilizing small molecule GQC-05 induces down regulated MYC expression and DNA damage in AML cells. Treatment with both GQC-05 with a Bcl-2/Bcl-XL inhibitor Navitoclax results in increased cytotoxic activity, which is more pronounced than Navitoclax or GQC-05 alone, and more significant than Navitoclax in combination with cytarabine and doxorubicin that are currently being used clinically.

Background: The mitochondrial protein import complexes arose early in eukaryogenesis. Most of the components of the protein import pathways predate the last eukaryotic common ancestor. For example, the carrier-insertase TIM22 complex comprises the widely conserved Tim22 channel core. However, the auxiliary components of fungal and animal TIM22 complexes are exceptions to this ancient conservation. Methods: Using comparative genomics and phylogenetic approaches, we identified precisely when each TIM22 accretion occurred. Results: In animals, we demonstrate that Tim29 and Tim10b arose early in the holozoan lineage. Tim29 predates the metazoan lineage being present in the animal sister lineages, choanoflagellate and filastereans, whereas the erroneously named Tim10b arose from a duplication of Tim9 at the base of metazoans. In fungi, we show that Tim54 has representatives present in every holomycotan lineage including microsporidians and fonticulids, whereas Tim18 and Tim12 appeared much later in fungal evolution. Specifically, Tim18 and Tim12 arose from duplications of Sdh3 and Tim10, respectively, early in the Saccharomycotina. Surprisingly, we show that Tim54 is distantly related to AGK suggesting that AGK and Tim54 are extremely divergent orthologues and the origin of AGK/Tim54 interaction with Tim22 predates the divergence of animals and fungi. Conclusions: We argue that the evolutionary history of the TIM22 complex is best understood as the neutral structural divergence of an otherwise strongly functionally conserved protein complex. This view suggests that many of the differences in structure/subunit composition of multi-protein complexes are non-adaptive. Instead, most of the phylogenetic variation of functionally conserved molecular machines, which have been under stable selective pressures for vast phylogenetic spans, such as the TIM22 complex, is most likely the outcome of the interplay of random genetic drift and mutation pressure.

La información referida a fertilización de pasturas perennes en base a alfalfa es escasa, principalmente respecto a fertilización combinada con nitrógeno (N), fósforo (P) y azufre (S). En un suelo (Haplustol éntico) degradado se implantó una pastura con base alfalfa (Medicago sativa) y se realizaron dos ensayos de fertilización con N, P YS. Los objetivos de este trabajo fueron: a) evaluar el efecto de la dosis, la frecuencia y la combinación de elementos de la fertilización con N, P Y S sobre la producción, calidad y composición botánica en pasturas asociadas con alfalfa. b) evaluar el efecto de las pasturas y la fertilización sobre las características físicas y químicas de un suelo degradado. e) evaluar el efecto residual del fertilizante fosforado según distintas dosis de aplicación. En un ensayo se midió el efecto de la fertilización con distintas dosis y la combinación de los tres elementos. En el otro ensayo se fertilizó a la siembra y al primer año (fertilización postergada y refertilización) con 70 k/ha de Sulfato de Amonio (SA) y 100 Y 300 kg/ha de Super Fosfato Triple de Calcio (STF). Se efectuaron determinaciones de suelo (N total, MO, P Bray 1, DTA, EEH) Y planta (rendimiento de MS, composición botánica y N total). No se encontraron cambios significativos en las propiedades físicas ni en las químicas. Tanto estas propiedades como el desarrollo de la pastura, se vieron limitados por las condiciones climáticas desfavorables, impidiendo la acción recuperadora de la pastura. Se encontraron diferencias en el contenido de P asimilable, entre los tratamientos testigo sin fertilizar y los refertilizados con las dosis más altas de P. Esto indicarla que para alcanzar niveles satisfactorios de P es necesario no sólo fertilizar con altas dosis sino también refertilizar. Los mayores rendimientos en MS se encontraron en los tratamientos que incluyeron los tres elementos (N, P y S) en altas dosis, tanto para alfalfa como para gramíneas. Con fertilización a la siembra y refertilización con SA dosis medias y altas de SFT se duplicó la producción del testigo. La fertilización combinada favoreció el equilibrio en la composición botánica de la pastura. La fertilización fosfatada a la siembra favoreció la implantación de la alfalfa, teniendo mayor participación en la pastura. La proporción de malezas varió en forma inversa a la de alfalfa. Director: Ing. Agr. Daniel Buschiazzo e lng, Agr. Alberto Quiroga. Cátedra: Edafología, Manejo y Conservación de Suelo.

Ammonium salts such as ammonium nitrate and ammonium sulfate constitute an important fraction of the total fine particulate matter (PM2.5) mass. While the conversion of inorganic gases into particulate-phase sulfate, nitrate, and ammonium is now well understood, there is considerable uncertainty over interactions between gas-phase ammonia and secondary organic aerosols (SOAs). Observations have confirmed that ammonia can react with carbonyl compounds in SOA, forming nitrogen-containing organic compounds (NOCs). This chemistry consumes gas-phase NH3 and may therefore affect the amount of ammonium nitrate and ammonium sulfate in particulate matter (PM) as well as particle acidity. In order to investigate the importance of such reactions, a first-order loss rate for ammonia onto SOA was implemented into the Community Multiscale Air Quality (CMAQ) model based on the ammonia uptake coefficients reported in the literature. Simulations over the continental US were performed for the winter and summer of 2011 with a range of uptake coefficients (10−3–10−5). Simulation results indicate that a significant reduction in gas-phase ammonia may be possible due to its uptake onto SOA; domain-averaged ammonia concentrations decrease by 31.3 % in the winter and 67.0 % in the summer with the highest uptake coefficient (10−3). As a result, the concentration of particulate matter is also significantly affected, with a distinct spatial pattern over different seasons. PM concentrations decreased during the winter, largely due to the reduction in ammonium nitrate concentrations. On the other hand, PM concentrations increased during the summer due to increased biogenic SOA (BIOSOA) production resulting from enhanced acid-catalyzed uptake of isoprene-derived epoxides. Since ammonia emissions are expected to increase in the future, it is important to include NH3 + SOA chemistry in air quality models.

The effect of relative humidity (RH) on the chemical composition of secondary organic aerosol (SOA) formed from low-NOx toluene oxidation in the absence of seed particles was investigated. SOA samples were prepared in an aerosol smog chamber at x toluene SOA. The volatility distributions of the SOA compounds, estimated from the distribution of molecular formulas using the molecular corridor approach, confirmed that low-NOx toluene SOA became more volatile on average under high-RH conditions. In contrast, the effect of RH on SOA mass loading was found to be much smaller for high-NOx toluene SOA. The observed increase in the oligomer fraction and particle mass loading under dry conditions were attributed to the enhancement of condensation reactions, which produce water and oligomers from smaller compounds in low-NOx toluene SOA. The reduction in the fraction of oligomeric compounds under humid conditions is predicted to partly counteract the previously observed enhancement in the toluene SOA yield driven by the aerosol liquid water chemistry in deliquesced inorganic seed particles.

We present the design of a porous-core PCF with elliptical holes in the core that achieved low loss, high birefringence, and flattened dispersion for guiding terahertz waves. The finite element method is used to study the properties of the designed waveguide in detail: effective material loss, birefringence, confinement losses, and dispersion. Simulation results show that the proposed structure exhibits simultaneously high modal birefringence of 1.32 × 10-2 and a flattened dispersion over a broadband of 1.28 THz. Then, polarization splitters, based on both symmetric and asymmetric porous-core PCF structures, are designed and evaluated at 1 THz. We show that this kind of device exhibits a strong polarization-dependent coupling behavior. Numerical results show that the configuration based on dual-core waveguide with asymmetric cores can achieve a 10.9 cm long splitter with a broadband of 0.306 THz for x -polarization and 0.23 THz for y-polarization. Finally, this paper offers an effective method to design an ultrawideband polarization beam splitter to operate in the THz region, which might be relevant for future applications in technical areas, such as spectroscopy, sensing, and high-speed data transmission.

Indole is a heterocyclic compound emitted by various plant species under stressed conditions or during flowering events. The formation, optical properties, and chemical composition of secondary organic aerosol (SOA) formed by low-NOx photooxidation of indole were investigated. The SOA yield (1. 3 ± 0. 3) was estimated from measuring the particle mass concentration with a scanning mobility particle sizer (SMPS) and correcting it for wall loss effects. The high value of the SOA mass yield suggests that most oxidized indole products eventually end up in the particle phase. The SOA particles were collected on filters and analysed offline with UV–vis spectrophotometry to measure the mass absorption coefficient (MAC) of the bulk sample. The samples were visibly brown and had MAC values of ∼ 2 m2 g−1 at λ = 300 nm and ∼ 0. 5 m2 g−1 at λ = 400 nm, comparable to strongly absorbing brown carbon emitted from biomass burning. The chemical composition of SOA was examined with several mass spectrometry methods. Direct analysis in real-time mass spectrometry (DART-MS) and nanospray desorption electrospray high-resolution mass spectrometry (nano-DESI-HRMS) were both used to provide information about the overall distribution of SOA compounds. High-performance liquid chromatography, coupled to photodiode array spectrophotometry and high-resolution mass spectrometry (HPLC-PDA-HRMS), was used to identify chromophoric compounds that are responsible for the brown colour of SOA. Indole derivatives, such as tryptanthrin, indirubin, indigo dye, and indoxyl red, were found to contribute significantly to the visible absorption spectrum of indole SOA. The potential effect of indole SOA on air quality was explored with an airshed model, which found elevated concentrations of indole SOA during the afternoon hours contributing considerably to the total organic aerosol under selected scenarios. Because of its high MAC values, indole SOA can contribute to decreased visibility and poor air quality.

ABSTRACT Epidemiological evidence correlates low serum vitamin A (retinol) levels with increased susceptibility to active tuberculosis (TB); however, retinol is biologically inactive and must be converted into its bioactive form, all-trans retinoic acid (ATRA). Given that ATRA triggers a Niemann-Pick type C2 (NPC2)-dependent antimicrobial response against Mycobacterium tuberculosis, we investigated the mechanism by which the immune system converts retinol into ATRA at the site of infection. We demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived dendritic cells (DCs), but not macrophages, express enzymes in the vitamin A metabolic pathway, including aldehyde dehydrogenase 1 family, member a2 (ALDH1A2) and short-chain dehydrogenase/reductase family, member 9 (DHRS9), enzymes capable of the two-step conversion of retinol into ATRA, which is subsequently released from the cell. Additionally, mRNA and protein expression levels of ALDH1A2 and DC marker CD1B were lower in tuberculosis lung tissues than in normal lung. The conditioned medium from DCs cultured with retinol stimulated antimicrobial activity from M. tuberculosis-infected macrophages, as well as the expression of NPC2 in monocytes, which was blocked by specific inhibitors, including retinoic acid receptor inhibitor (RARi) or N,N-diethylaminobenzaldehyde (DEAB), an ALDH1A2 inhibitor. These results indicate that metabolism of vitamin A by DCs transactivates macrophage antimicrobial responses. IMPORTANCE Tuberculosis (TB) is the leading cause of death by a single infectious agent worldwide. One factor that contributes to the success of the microbe is the deficiency in immunomodulatory nutrients, such as vitamin A (retinol), which are prevalent in areas where TB is endemic. Clinical trials show that restoration of systemic retinol levels in active TB patients is ineffective in mitigating the disease; however, laboratory studies demonstrate that activation of the vitamin A pathway in Mycobacterium tuberculosis-infected macrophages triggers an antimicrobial response. Therefore, the goal of this study was to determine the link between host retinol levels and retinoic acid-mediated antimicrobial responses against M. tuberculosis. By combining established in vitro models with in situ studies of lung tissue from TB patients, this study demonstrates that the innate immune system utilizes transcellular metabolism leading to activation between dendritic cells and macrophages as a means to combat the pathogen.

Summary: To understand how the interaction between an intracellular bacterium and the host immune system contributes to outcome at the site of infection, we studied leprosy, a disease that forms a clinical spectrum, in which progressive infection by the intracellular bacterium Mycobacterium leprae is characterized by the production of type I IFNs and antibody production. Dual RNA-seq on patient lesions identifies two independent molecular measures of M. leprae, each of which correlates with distinct aspects of the host immune response. The fraction of bacterial transcripts, reflecting bacterial burden, correlates with a host type I IFN gene signature, known to inhibit antimicrobial responses. Second, the bacterial mRNA:rRNA ratio, reflecting bacterial viability, links bacterial heat shock proteins with the BAFF-BCMA host antibody response pathway. Our findings provide a platform for the interrogation of host and pathogen transcriptomes at the site of infection, allowing insight into mechanisms of inflammation in human disease. : Montoya et al. utilizes dual RNA-seq to define the bacterial burden and transcriptional state within leprosy skin lesions. These molecular measures vary across patients and provide separate but informative metrics about the pathogenesis of mycobacterial disease, revealing that the immune system responds to bacterial states and not just their abundance. Keywords: mycobacteria, immunology, systems immunology, microbiology, plasma cell, host-pathogen, tuberculosis, heat shock, humoral, translational, transcriptome, sequencing, bioinformatics, computational biology

Abstract Laboratory data interpretation for the assessment of complex biological systems remains a great challenge, as occurs in mitochondrial function research studies. The classical biochemical data interpretation of patients versus reference values may be insufficient, and in fact the current classifications of mitochondrial patients are still done on basis of probability criteria. We have developed and applied a mathematic agglomerative algorithm to search for correlations among the different biochemical variables of the mitochondrial respiratory chain in order to identify populations displaying correlation coefficients >0.95. We demonstrated that coenzyme Q10 may be a better biomarker of mitochondrial respiratory chain enzyme activities than the citrate synthase activity. Furthermore, the application of this algorithm may be useful to re-classify mitochondrial patients or to explore associations among other biochemical variables from different biological systems.

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Nitrones have a well-recognized capacity as spin-traps and are considered powerful free radical scavengers, which are two important issues in hypoxia-induced oxidative stress and cell death in brain ischemia. Consequently, nitrones have been proposed as therapeutic agents in acute ischemic stroke (AIS). In this paper, we update the biological and pharmacological characterization of ISQ-201, a previously identified cholesteronitrone hybrid with antioxidant and neuroprotective activity. This study characterizes ISQ-201 as a neuroprotective agent against the hypoxia-induced ischemic injury. Transitory four-vessel occlusion and middle cerebral artery occlusion (tMCAO) were used to induce cerebral ischemia. Functional outcomes were determined using neurofunctional tests. Infarct area, neuronal death, and apoptosis induction were evaluated. In addition, ISQ-201 reactivity towards free radicals was studied in a theoretical model. ISQ-201 significantly decreased the ischemia-induced neuronal death and apoptosis, in a dose-dependent manner, showing its therapeutic effect when administered up until 6 h after post-ischemic reperfusion onset, effects that remained after 3 months from the ischemic episode. Furthermore, ISQ-201 significantly reduced infarct volume, leading to recovery of the motor function in the tMCAO model. Finally, the theoretical study confirmed the reactivity of ISQ-201 towards hydroxyl radicals. The results reported here prompted us to suggest ISQ-201 as a promising candidate for the treatment of AIS.

Peroxisome proliferator-activated receptor (PPAR)γ is a global transcriptional regulator associated with anti-inflammatory actions. It is highly expressed in alveolar macrophages (AMs), which are unable to clear the intracellular pathogen Mycobacterium tuberculosis (M.tb). Although M.tb infection induces PPARγ in human macrophages, which contributes to M.tb growth, the mechanisms underlying this are largely unknown. We undertook NanoString gene expression analysis to identify novel PPARγ effectors that condition macrophages to be more susceptible to M.tb infection. This revealed several genes that are differentially regulated in response to PPARγ silencing during M.tb infection, including the Bcl-2 family members Bax (pro-apoptotic) and Mcl-1 (pro-survival). Apoptosis is an important defense mechanism that prevents the growth of intracellular microbes, including M.tb, but is limited by virulent M.tb. This suggested that M.tb differentially regulates Mcl-1 and Bax expression through PPARγ to limit apoptosis. In support of this, gene and protein expression analysis revealed that Mcl-1 expression is driven by PPARγ during M.tb infection in human macrophages. Further, 15-lipoxygenase (15-LOX) is critical for PPARγ activity and Mcl-1 expression. We also determined that PPARγ and 15-LOX regulate macrophage apoptosis during M.tb infection, and that pre-clinical therapeutics that inhibit Mcl-1 activity significantly limit M.tb intracellular growth in both human macrophages and an in vitro TB granuloma model. In conclusion, identification of the novel PPARγ effector Mcl-1 has determined PPARγ and 15-LOX are critical regulators of apoptosis during M.tb infection and new potential targets for host-directed therapy for M.tb.

An efficient synthesis of enantiomerically-pure β-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of β-aryl-γ-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)- and (S)-Baclofen hydrochloride.

Resumen Objetivo: describir la situación actual de los componentes de salud en los planes integrales de vida de cuatro organizaciones indígenas del departamento del Vaupés, región amazónica de Colombia. Metodología: búsqueda, recuperación, lectura crítica y análisis de contenido de los planes integrales de vida de cuatro organizaciones indígenas del departamento del Vaupés. Comparación con planes de desarrollo territorial de las entidades vigentes – municipio y departamento. Resultados: los planes integrales de vida y los planes de desarrollo territorial no desarrollan los componentes de salud de forma estratégica. Se presentan como enunciados en distintos momentos de los Planes, pero sin lograr la concreción necesaria para llevar a cabo su seguimiento y evaluación. Discusión: existen falencias en los procesos de construcción del componente salud en los instrumentos de planeación de la institucionalidad y las organizaciones indígenas. Mientras esto persista, será imposible llevar a la realidad las intervenciones necesarias para la mejoría de la situación de salud de los grupos y pueblos étnicos indígenas. Es necesaria una acción decidida y articulada de la institucionalidad, la academia y el sector no gubernamental que favorezca estos procesos./ Abstract Objective: to describe the current state of the health-related components of the comprehensive life development plans of four indigenous organizations of the Vaupés department, in the Amazon region of Colombia. Methodology: search, collection, critical reading and analysis of the contents of the comprehensive life development plans of four indigenous organizations of the Vaupés department. In addition, these plans were compared with the municipal and departmental territory development plans. Results: the comprehensive life development plans and the territory development plans fail to develop their health-related components strategically. Furthermore, the health sections of the plans are unspecific enunciations appearing in several parts of the documents, which hinders their monitoring and evaluation. Discussion: the territorial institutions and indigenous organizations have shortcomings in the planning processes used to create the health components of their plans. If this situation persists, it will be impossible to implement the interventions required to improve the health situation of the indigenous ethnic groups of the area. Governmental, non-governmental and academic institutions should take action in a decided and combined effort in order to improve this situation.

En el sistema silvopastoril de la Reserva Natural El Hatico (Rneh) en El Cerrito, Valle (Colombia), las legumbres del algarrobo (Prosopis juliflora), se utilizan como alimento para bovinos. Sin embargo, desde 2006, la polilla Eccopsis galapagana (Lepidoptera: Tortricidae), afecta el follaje y la producción de legumbres. Motivados por el brote poblacional de esta polilla, se propuso identificar las especies de parasitoides, su distribución, su densidad y relacionarlas con el hábitat y el daño del insecto sobre P. juliflora. Se capturaron himenópteros, utilizando platos amarillos ubicados en 24 árboles de algarrobo escogidos al azar, en cuatro lotes dentro del sistema silvopastoril y al interior del bosque adyacente (control). Se midió el porcentaje de herbivoría, por E. galapagana; la cobertura del dosel de cada árbol muestreado, la temperatura y se determinó la composición vegetal de cada lote. De un total de 1,376 parasitoides -pertenecientes a siete superfamilias, 18 familias y 42 morfoespecies- el 71% se identificó hasta género. La superfamilia más representativa fue Chalcidoidea, y Encyrtidae la familia más abundante. Se encontró una relación positiva entre composición, cobertura vegetal y abundancia de parasitoides; pero esto no se tradujo en una disminución de los porcentajes de herbivoría por la polilla.