Neurotoxicidad en trabajadores petroquímicos con bajos índices de exposición a disolventes orgánicos.

OBJETIVO: Estimar el desempeño neuropsicológico y su asociación con la exposición a disolventes orgánicos (DO) en trabajadores petroquímicos en México. Material y méto-dos. Estudio transversal en 203 trabajadores: 102 expuestos a DO y 101 no expuestos. Se evaluó el desempeño neuropsi-cológico con Neurobehavioral Core Test Battery y la exposición a DO con la medición de metabolitos de exposición para tolueno, xilenos y benceno. RESULTADOS: Los trabajadores expuestos presentaron un peor desempeño en todas las pruebas (p<0.05), excepto en la prueba de Santa Ana. Esto se corroboró con modelos de regresión; los trabajadores expuestos a DO tuvieron un mayor número de errores y realizaron las pruebas en mayor tiempo (p<0.05), además de presentar mayores probabilidades de padecer síntomas de neurotoxicidad (OR: 2.93; IC95%: 0.96, 8.96). Conclusio-nes. La exposición ocupacional a disolventes orgánicos, aun a niveles permitidos por la normatividad mexicana vigente, se relacionó con un menor desempeño neuropsicológico.

Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3.

Glioblastomas remain the deadliest brain tumour, with a dismal ∼12-16-month survival from diagnosis. Therefore, identification of new diagnostic, prognostic and therapeutic tools to tackle glioblastomas is urgently needed. Emerging evidence indicates that the cellular machinery controlling the splicing process (spliceosome) is altered in tumours, leading to oncogenic splicing events associated with tumour progression and aggressiveness. Here, we identify for the first time a profound dysregulation in the expression of relevant spliceosome components and splicing factors (at mRNA and protein levels) in well characterized cohorts of human high-grade astrocytomas, mostly glioblastomas, compared to healthy brain control samples, being SRSF3, RBM22, PTBP1 and RBM3 able to perfectly discriminate between tumours and control samples, and between proneural-like or mesenchymal-like tumours versus control samples from different mouse models with gliomas. Results were confirmed in four additional and independent human cohorts. Silencing of SRSF3, RBM22, PTBP1 and RBM3 decreased aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere-formation, etc.) and induced apoptosis, especially SRSF3. Remarkably, SRSF3 was correlated with patient survival and relevant tumour markers, and its silencing in vivo drastically decreased tumour development and progression, likely through a molecular/cellular mechanism involving PDGFRB and associated oncogenic signalling pathways (PI3K-AKT/ERK), which may also involve the distinct alteration of alternative splicing events of specific transcription factors controlling PDGFRB (i.e. TP73). Altogether, our results demonstrate a drastic splicing machinery-associated molecular dysregulation in glioblastomas, which could potentially be considered as a source of novel diagnostic and prognostic biomarkers as well as therapeutic targets for glioblastomas. Remarkably, SRSF3 is directly associated with glioblastoma development, progression, aggressiveness and patient survival and represents a novel potential therapeutic target to tackle this devastating pathology.

Audiometric findings of printing press workers exposed to noise and organic solvents.

OBJECTIVE: To determine if exposure to organic solvents and noise is associated with audiometric results among workers from a printing press in Mexico City. DESIGN: Cross-sectional study. STUDY SAMPLE: One hundred and seventy-six male workers at a printing press in Mexico City exposed to noise and organic solvents, including xylene, and 103 non-exposed male workers as reference group. Hearing thresholds were assessed with pure-tone audiometry. RESULTS: Poorer hearing thresholds were observed among printing workers than non-exposed controls, particularly among groups with over 5 years of exposure. Hearing thresholds differences were observed in the frequencies above 500 Hz, especially in 4000 Hz in all exposure groups compared to the reference. Adjusted models for age and previous exposure to noise and organic solvents showed worse hearing thresholds as years of seniority increased -ß coefficients (95% CI): ≤5 years: 3.06 dB (0.01, 6.10); >5-10 years: 4.51 dB (1.13, 7.89); >10 years: 4.58 dB (1.20, 7.96). Further analyses showed no interaction between noise and organic solvents on hearing thresholds, considering both current and previous occupational exposures. CONCLUSION: Exposure to noise levels that were below recommended exposure limits and organic solvents were associated with poorer hearing thresholds than those observed among non-exposed study participants. This suggests that workers exposed to solvents should be included in hearing conservation programmes, even when noise exposures are below 85 dB. If only noise levels were taken into consideration in the risk assessment of this worker population, the risk of hearing effects could have been overlooked.

Commute times and audiometric findings among adult population in Mexico City.

INTRODUCTION: Long commute times are common in big cities. OBJECTIVE: To determine hearing thresholds and their association with commute time in Mexico City. METHODS: Cross-sectional study that included 177 healthy adults from 2009 to 2011. Demographic information and commute times were recorded. Hearing was assessed by audiometry. Regression models were constructed to determine the predictors of hearing thresholds. RESULTS: There were 101 men (53%) and 76 women (43%). Mean commute time was 43 minutes (1-150 minutes). A hearing threshold drop was observed at 4000 Hz, with recovery at 8000 Hz in both ears when patients were stratified by gender and age groups. A commute time > 40 min/day increased the hearing threshold at 4000 Hz (ß = 2.96 dB HL, p < 0.01). Men had higher thresholds (ß = 2.6 dB HL), as older subjects also did: 25-34 years, ß = 2.2 dB HL; 35-44 years, ß = 5.2 dB HL; and ≥ 45 years, ß = 8.3 dB HL. CONCLUSION: The hearing pattern, although normal, resembled that of noise-induced hearing loss, associated with long commute times.

INTRODUCCIÓN: Los tiempos prolongados de traslado son comunes en las ciudades grandes. OBJETIVO: Determinar los umbrales auditivos y su asociación con el tiempo de traslado al trabajo en la Ciudad de México. MÉTODOS: Estudio transversal que incluyó a 177 adultos sanos de 2009 a 2011. Se registró información demográfica y tiempo de traslado al trabajo. La audición se evaluó mediante audiometría. Se realizaron modelos de regresión para determinar los predictores de los umbrales auditivos. RESULTADOS: Se trató de 101 hombres (53 %) y 76 mujeres (43 %). El tiempo promedio de traslado fue 43 minutos (1 a 150 minutos). Se observó una caída del umbral auditivo en 4000 Hz, con recuperación en 8000 Hz en ambos oídos al estratificar por sexo y grupos de edad. Un tiempo de traslado > 40 minutos/día incrementó el umbral auditivo en 4000 Hz (b = 2.96 dB HL, p < 0.01). Los hombres presentaron umbrales mayores (b = 2.6 dB HL), al igual que los sujetos de edad más avanzada: 25 a 34 años, b = 2.2 dB HL; 35 a 44 años, b = 5.2 dB HL y ≥ 45 años, b = 8.3 dB HL. CONCLUSIÓN: El patrón auditivo, aunque normal, se asemejó a la pérdida auditiva por ruido asociada a tiempo prolongado de traslado al trabajo.

Neuropsychological effects among workers exposed to organic solvents.

OBJECTIVE: To assess neuropsychological performance among workers at a paint factory in Mexico City. MATERIALS AND METHODS: During 2004 and 2005 we assessed the neuropsychological performance of 208 workers who were exposed to organic solvents at a paint factory, mainly toluene and xylene. We categorized workers into low and high exposure groups using a cumulative index for toluene, based on times spent in different tasks. We evaluated cognitive and motor functions with 13 neuropsychological tests. RESULTS: We found lower attention, longer time to complete the test ß=5.5 (R2=12.3%), and a lower score in the motor-cognitive test ß=-15.7 (R2=19.5%) in the high exposure group through multiple linear regression model analysis, with adjustment for age and education. CONCLUSIONS: Our results are similar to the ones reported in the literature, but the effects are less severe, probably due to lower exposure to organic solvents.

OBJETIVO: Evaluar el desempeño neuropsicológico de los trabajadores de una fábrica de pintura en la Ciudad de México. MATERIAL Y MÉTODOS: Se evaluó el desempeño neuropsicológico de 208 trabajadores expuestos a disolventes orgánicos, principalmente tolueno y xileno, en una fábrica de pintura en la Ciudad de México durante 2004 y 2005. Se categorizaron en grupos de baja y alta exposición con un índice acumulado de tolueno con base en el tiempo empleado por actividad. Se evaluaron funciones motoras y cognitivas con 13 pruebas neuropsicológicas. RESULTADOS: Se registró un tiempo más largo para completar la prueba ß=5.5 (R2=12.3%) y una puntuación baja en la prueba motor-cognitiva de ß=- 15.7 (R2=19.5%) en el grupo de alta exposición en los modelos de regresión lineal múltiple, ajustados por confusores. CONCLUSIONES: Los presentes resultados son similares a los reportados en la literatura, aunque los efectos son menos graves, probablemente debido a la baja exposición.

Economic and financial viability of a pig farm in central semi-tropical Mexico: 2022-2026 prospective.

To estimate the economic and financial viability of a pig farm in central sub-tropical Mexico within a 5-year planning horizon, a Monte Carlo simulation model was utilized. Net returns were projected using simulated values for the distribution of input and product processes, establishing 2021 as base scenario. A stochastic modelling approach was employed to determine the economic and financial outlook. The findings reveal a panorama of economic and financial viability. Net income increased by 555%, return on assets rose from 3.36% in 2022 to 11.34% in 2026, and the probability of decapitalization dropped from 58% to 13%, respectively in the aforesaid periods. Similarly, the probability of obtaining negative net income decreased from 40% in 2022 to 18% in 2026. The technological, productive, and economic management of the production unit allowed for a favorable scenario within the planning horizon. There is a growing interest in predicting the economic sectors worth investing in and supporting, considering their economic and development performance. This research offers both methodological and scientific evidence to demonstrate the feasibility of establishing a planning schedule and validating the suitability of the pork sector for public investment and support.

Assessment of cognitive performance in multiple sclerosis using smartphone-based training games: a feasibility study.

BACKGROUND: Cognitive impairment occurs in up to 70% of people with MS (pwMS) and has a large impact on quality of life and working capacity. As part of the development of a smartphone-app (dreaMS) for monitoring MS disease activity and progression, we assessed the feasibility and acceptance of using cognitive games as assessment tools for cognitive domains. METHODS: We integrated ten cognitive games in the dreaMS app. Participants were asked to play these games twice a week for 5 weeks. All subjects underwent a battery of established neuropsychological tests. User feedback on acceptance was obtained via a five-point Likert-scale questionnaire. We correlated game performance measures with predetermined reference tests (Spearman's rho) and analyzed differences between pwMS and Healthy Controls (rank biserial correlation). RESULTS: We included 31 pwMS (mean age 43.4 ± 12.0 years; 68% females; median Expanded Disability Status Scale score 3.0, range 1.0-6.0) and 31 age- and sex-matched HC. All but one game showed moderate-strong correlations with their reference tests, (|rs|= 0.34-0.77). Performance improved in both groups over the 5 weeks. Average ratings for overall impression and meaningfulness were 4.6 (range 4.2-4.9) and 4.7 (range 4.5-4.8), respectively. CONCLUSION: Moderate-strong correlations with reference tests suggest that adaptive cognitive games may be used as measures of cognitive domains. The practice effects observed suggest that game-derived measures may capture change over time. All games were perceived as enjoyable and meaningful, features crucial for long-term adherence. Our results encourage further validation of adaptive cognitive games as monitoring tools for cognition in larger studies of longer duration. STUDY REGISTER: ClinicalTrials.gov: NCT04413032.

Smartwatch-derived sleep and heart rate measures complement step counts in explaining established metrics of MS severity.

BACKGROUND: Passive remote monitoring of patients with MS (PwMS) with sensor-based wearable technologies promises near-continuous evaluation with high ecological validity. Step counts correlate strongly with traditional measures of MS severity. We hypothesized that remote monitoring of sleep and heart rate will yield complementary information. METHODS: We recruited 31 PwMS and 31 age- and sex-matched healthy volunteers (HV) as part of the dreaMS feasibility study (NCT04413032). Fitbit Versa 2 smartwatches were worn for 6 weeks and provided a total of 25 features for activity, heart rate, and sleep. Features were selected based on their pairwise intercorrelation (Pearson |r| < 0.6), test-retest reliability (intraclass correlation coefficient ≥ 0.6 or median coefficient of variation < 0.2) and group comparisons between HV and PwMS with moderate disability (expanded disability status scale (EDSS) ≥ 3.5) (rank-biserial |r| ≥ 0.5). These selected features were correlated with clinical reference tests (EDSS, timed 25-foot walk (T25FW), MS-walking scale (MSWS-12)) in PwMS, and multivariate models adjusted for age, sex, and disease duration were compared. RESULTS: We analyzed 28 PwMS (68% female, mean age 44 years, median EDSS 3.0) and 26 HV in our primary analysis. The objectively selected features discriminated well between HV and PwMS with moderate disability with rank-biserial r = 0.83 for Total number of steps, 0.51 for Deep sleep proportion, -0.51 for Median heart rate, 0.85 for Proportion very active, and 0.65 for Total number of floors. In PwMS they correlated strongly with the three clinical reference tests EDSS (strongest Spearman ρ = -0.75 for Proportion very active), T25FW (-0.75 for Total number of floors), and MSWS-12 (-0.72 for Total number of floors). Deep sleep proportion and Median heart rate complemented Total number of steps in explaining the variance of reference tests. CONCLUSIONS: Activity, deep sleep and heart rate measures can be derived reliably from smartwatches and contain independent clinically meaningful information about MS severity, highlighting their potential for continuous passive monitoring in both clinical trials and clinical care of PwMS.

Reliability and acceptance of dreaMS, a software application for people with multiple sclerosis: a feasibility study.

BACKGROUND: There is an unmet need for reliable and sensitive measures for better monitoring people with multiple sclerosis (PwMS) to detect disease progression early and adapt therapeutic measures accordingly. OBJECTIVE: To assess reliability of extracted features and meaningfulness of 11 tests applied through a smartphone application ("dreaMS"). METHODS: PwMS (age 18-70 and EDSS ≤ 6.5) and matched healthy volunteers (HV) were asked to perform tests installed on their smartphone once or twice weekly for 5 weeks. Primary outcomes were test-retest reliability of test features (target: intraclass correlation [ICC] ≥ 0.6 or median coefficient of variation [mCV] < 0.2) and reported meaningfulness of the tests by PwMS. Meaningfulness was self-assessed for each test on a 5-point Likert scale (target: mean score of > 3) and by a structured interview. CLINICALTRIALS: gov Identifier: NCT04413032. RESULTS: We included 31 PwMS (21 [68%] female, mean age 43.4 ± 12.0 years, median EDSS 3.0 [range 1.0-6.0]) and 31 age- and sex-matched healthy volunteers. Out of 133 features extracted from 11 tests, 89 met the preset reliability criteria. All 11 tests were perceived as highly meaningful to PwMS. CONCLUSION: The dreaMS app reliably assessed features reflecting key functional domains meaningful to PwMS. More studies with longer follow-up are needed to prove validity of these measures as digital biomarkers in PwMS.

Mucosal Leishmaniasis of the lip: Report of an Exuberant case in a Young man.

BACKGROUND: Leishmaniasis is a tropical disease caused by protozoan parasites of the genus Leishmania. Mucosal leishmaniasis has been described as secondary to the cutaneous form; however, isolated mucosal involvement can also occur. Specifically, mucosal leishmaniasis of the lip is poorly described and its diagnosis challenges clinicians. METHODS: We herein report a case of mucosal leishmaniasis affecting the lower lip without cutaneous involvement in a 20-year-old Venezuelan man. The patient had no relevant past medical history. Clinically, a mass-like lesion with ulcerations and crusts was observed. RESULTS: Microscopically, the lesion was composed of granulomatous inflammation along with macrophages containing intracytoplasmic inclusions similar to round-shaped Leishmania. The species Leishmania (Viannia) braziliensis was confirmed. Treatment with meglumine antimonate was effective. The lesion healed satisfactorily, and no side effects or recurrences were observed. CONCLUSION: Clinicians should be aware of isolated forms of mucosal leishmaniasis of the lip, even in cases where the cutaneous lesion is undetected or clinically manifests as self-limiting. Knowing the endemic areas in the scenario of the dynamics of the ecoepidemiology of leishmaniasis is also essential for surveillance and counselling of the population.

Spliceosomic dysregulation unveils NOVA1 as a candidate actionable therapeutic target in pancreatic neuroendocrine tumors.

Dysregulation of the splicing machinery is emerging as a hallmark in cancer due to its association with multiple dysfunctions in tumor cells. Inappropriate function of this machinery can generate tumor-driving splicing variants and trigger oncogenic actions. However, its role in pancreatic neuroendocrine tumors (PanNETs) is poorly defined. In this study we aimed to characterize the expression pattern of a set of splicing machinery components in PanNETs, and their relationship with aggressiveness features. A qPCR-based array was first deployed to determine the expression levels of components of the major (n = 13) and minor spliceosome (n = 4) and associated splicing factors (n = 27), using a microfluidic technology in 20 PanNETs and non-tumoral adjacent samples. Subsequently, in vivo and in vitro models were applied to explore the pathophysiological role of NOVA1. Expression analysis revealed that a substantial proportion of splicing machinery components was altered in tumors. Notably, key splicing factors were overexpressed in PanNETs samples, wherein their levels correlated with clinical and malignancy features. Using in vivo and in vitro assays, we demonstrate that one of those altered factors, NOVA1, is tightly related to cell proliferation, alters pivotal signaling pathways and interferes with responsiveness to drug treatment in PanNETs, suggesting a role for this factor in the aggressiveness of these tumors and its suitability as therapeutic target. Altogether, our results unveil a severe alteration of the splicing machinery in PanNETs and identify the putative relevance of NOVA1 in tumor development/progression, which could provide novel avenues to develop diagnostic biomarkers and therapeutic tools for this pathology.

Convolutional neural networks for the automatic diagnosis of melanoma: An extensive experimental study.

Melanoma is the type of skin cancer with the highest levels of mortality, and it is more dangerous because it can spread to other parts of the body if not caught and treated early. Melanoma diagnosis is a complex task, even for expert dermatologists, mainly due to the great variety of morphologies in moles of patients. Accordingly, the automatic diagnosis of melanoma is a task that poses the challenge of developing efficient computational methods that ease the diagnostic and, therefore, aid dermatologists in decision-making. In this work, an extensive analysis was conducted, aiming at assessing and illustrating the effectiveness of convolutional neural networks in coping with this complex task. To achieve this objective, twelve well-known convolutional network models were evaluated on eleven public image datasets. The experimental study comprised five phases, where first it was analyzed the sensitivity of the models regarding the optimization algorithm used for their training, and then it was analyzed the impact in performance when using different techniques such as cost-sensitive learning, data augmentation and transfer learning. The conducted study confirmed the usefulness, effectiveness and robustness of different convolutional architectures in solving melanoma diagnosis problem. Also, important guidelines to researchers working on this area were provided, easing the selection of both the proper convolutional model and technique according the characteristics of data.

Plump endothelial cells integrated into pre-existing venules contribute to the formation of 'mother' and 'daughter' vessels in pyogenic granuloma: possible role of galectin-1, -3 and -8.

INTRODUCTION: Pyogenic granuloma (PG) is a reactive inflammatory vascular lesion of the skin and mucous membranes, characterised by the presence of enlarged venules and seamed and seamless capillaries with plump endothelial cells (EC), and numerous macrophages. EC activation upregulates the synthesis of galectins and induces their translocation to the EC surface promoting angiogenesis and lymphangiogenesis, particularly galectin-1 (Gal-1), Gal-3 and Gal-8. However, the presence and distribution of Gal-1, -3 and -8, as well as their implications in the pathogenesis of PG, has not been considered. MATERIALS AND METHODS: Eight biopsies from patients diagnosed with PG were selected. The presence of PECAM-1/CD31, IL-1ß, VEGF-C, VEGFR-2, VEGFR-3, integrin ß1, CD44, fibronectin and Gal-1, -3 and -8 was assessed by immunofluorescence staining using confocal laser scanning microscopy. RESULTS AND DISCUSSION: Immunostaining revealed that these molecules were present in the enlarged venules with plump ECs, in some macrophages and other immune cells. We propose that macrophages release VEGF-A and VEGF-C inducing VEGFR-2/VEGFR-3 expression and activation, leading macrophages to transdifferentiate into plump ECs that might integrate into pre-existing venules, contributing to the formation of enlarged venules with transluminal bridges and capillaries. EC activation, induced by certain cytokines, has been shown to stimulate galectin expression and changes in the cellular localisation through association and activation of specific EC surface glycoproteins. Therefore, it is plausible that Gal-1, -3 and -8, acting in a concerted manner, could be mediating the transdifferentiation of macrophages into plump ECs and facilitating their migration and incorporation into the new vessels. LAY SUMMARY: In this study, immunostaining of pyogenic granuloma (PG) tissue sections showed immunoreactivity for PECAM-1/CD31, IL-1ß, VEGF-C, VEGFR-2 and VEGFR-3, and galectin-1, -3 and -8 in enlarged venules with plump endothelial cells (EC), as well as in some macrophages and other immune cells. Interestingly, enlarged and thin-walled transient vessels lined by PECAM-1/CD31 and VEGFR-2 immunopositive ECs that form from pre-existing normal venules in response to VEGF-A (called 'mother' vessels [MV]) and that undergo intraluminal bridging evolving into various types of capillaries (called 'daughter' vessels [DV]) have been observed in benign and malignant tumours, in physiological and pathological angiogenesis as well as in vascular malformations, suggesting an important role for VEGF-A and VEGFR-2 in such a process. However, it is not only the mechanisms by which the MVs evolve in different types of DVs that remains to be elucidated, but also whether the cells that form intraluminal bridges proceed from locally activated ECs or whether they are derived from bone marrow precursors or from resident macrophages.Given that the formation of homodimers by Gal-1 and Gal-8 and pentamers by Gal-3 to generate gal-glycan lattices at the cell surface and in the extracellular space has been shown, it is possible that in PG tissue Gal-1, -3 and -8, through their binding partners, form a supramolecular structure at the surface of ECs and plump ECs, macrophages and in the extracellular space that might be mediating the transdifferentiation of macrophages into plump ECs and facilitating the migration and incorporation of these cells into the pre-existing venules, thus contributing to the formation of MVs and DVs.

Both Chloroquine and Lopinavir/Ritonavir Are Ineffective for COVID-19 Treatment and Combined Worsen the Pathology: A Single-Center Experience with Severely Ill Patients.

The off-label use of antiviral and antimalarial drugs has been considered by many researchers as a fast and relatively safe alternative to provide therapeutic options to treat COVID-19, but the assessment of such drug-specific effectiveness in this regard is far from complete. Especially, the current body of knowledge about COVID-19 therapeutics needs more data regarding drug effectiveness and safety in the severely ill patients with comorbidities. In the present article, we retrospectively analyze data from 61 patients that received treatment with chloroquine, lopinavir/ritonavir, both drugs administered together, or a standard treatment with no antiviral drugs, and the study was carried in severely ill patients. We found that either drug is ineffective at treating COVID-19, as they are not able to reduce hospitalization length, mortality, C-reactive protein (CRP), lactate dehydrogenase (LDH), d-Dimer, or ferritin, or to enhance gasometric parameters, lymphocytes, total leukocytes, and neutrophil levels, whereas both drugs administered together decrease circulating lymphocytes, increase LDH and ferritin levels, and more importantly, enhance mortality. In this way, our results show that both drugs are ineffective and even potentially harmful alternatives against SARS-CoV-2.

Tocilizumab reduces COVID-19 mortality and pathology in a dose and timing-dependent fashion: a multi-centric study.

Life-threatening COVID-19 is associated with strong inflammation, where an IL-6-driven cytokine storm appears to be a cornerstone for enhanced pathology. Nonetheless, the specific inhibition of such pathway has shown mixed outcomes. This could be due to variations in the dose of tocilizumab used, the stage in which the drug is administered or the severity of disease presentation. Thus, we performed a retrospective multicentric study in 140 patients with moderate to critical COVID-19, 79 of which received tocilizumab in variable standard doses (< 400 mg, 400-800 mg or > 800 mg), either at the viral (1-7 days post-symptom onset), early inflammatory (8-15) or late inflammatory (16 or more) stages, and compared it with standard treated patients. Mortality, reduced respiratory support requirements and pathology markers were measured. Tocilizumab significantly reduced the respiratory support requirements (OR 2.71, CI 1.37-4.85 at 95%) and inflammatory markers (OR 4.82, CI 1.4-15.8) of all patients, but mortality was only reduced (4.1% vs 25.7%, p = 0.03) when the drug was administered at the early inflammatory stage and in doses ranging 400-800 mg in severely-ill patients. Despite the apparent inability of Tocilizumab to prevent the progression of COVID-19 into a critical presentation, severely-ill patients may be benefited by its use in the early inflammatory stage and moderate doses.

[Spatial and temporal distribution of physicochemical features in the habitat of whale shark Rhincodon typus (Orectolobiformes: Rhincodontidae) in the north of Mexican Caribbean]. / Distribución espacio-temporal de variables fisicoquímicas y biológicas en el hábitat del tiburón ballena Rhincodon typus (Orectolobiformes: Rhincodontidae) al norte del Caribe Mexicano.

Large groups of whale sharks (Rhincodon typus) are common in the North Mexican Caribbean and gather between May and September each year. We describe their spatial and temporal distribution, and the physicochemical (temperature, dissolved oxygen, light extinction coefficient and salinity) and biological conditions during the presence and absence seasons of R. typus. A total of 26 sampling stations were monitored to record whale shark sightings and physicochemical variables during 10 field campaigns from April 2005 to March 2006. At each station, zooplankton and water samples, for chlorophyll-a and nutrients determination, were collected. Physicochemical conditions were significantly different between presence-absence seasons (ANOSIM, Rglobal = 0.632). The R. typus season was characterized by low salinity values, and higher temperature, chlorophyll-a, dissolved oxygen and inorganic nitrogen concentrations values. Average zooplankton biomass was lower during the absence season, while recorded the maximum values during the presence one. Furthermore, these values were also observed in areas with higher species abundances, supporting the hypothesis that the site is used by R. typus primarily as a foraging area. We conclude that physicochemical conditions of the study area promote the biological productivity, which explains the spatial and temporal variability of R. typus.

A supervised machine learning-based methodology for analyzing dysregulation in splicing machinery: An application in cancer diagnosis.

Deregulated splicing machinery components have shown to be associated with the development of several types of cancer and, therefore, the determination of such alterations can help the development of tumor-specific molecular targets for early prognosis and therapy. Determining such splicing components, however, is not a straightforward task mainly due to the heterogeneity of tumors, the variability across samples, and the fat-short characteristic of genomic datasets. In this work, a supervised machine learning-based methodology is proposed, allowing the determination of subsets of relevant splicing components that best discriminate samples. The methodology comprises three main phases: first, a ranking of features is determined by means of applying feature weighting algorithms that compute the importance of each splicing component; second, the best subset of features that allows the induction of an accurate classifier is determined by means of conducting an effective heuristic search; then the confidence over the induced classifier is assessed by means of explaining the individual predictions and its global behavior. At the end, an extensive experimental study was conducted on a large collection of transcript-based datasets, illustrating the utility and benefit of the proposed methodology for analyzing dysregulation in splicing machinery.

Nanoparticle-Based Devices in the Control of Antibiotic Resistant Bacteria.

Antimicrobial resistance (AR) is one of the most important public health challenges worldwide as it represents a serious complication that is able to increase the mortality, morbidity, disability, hospital stay and economic burden related to infectious diseases. As such, the spread of AR-pathogens must be considered as an emergency, and interdisciplinary approaches must be undertaken in order to develop not only drugs, but holistic strategies to undermine the epidemic and pathogenic potentials of multi-drug resistant (MDR) pathogens. One of such approaches has focused on the use of antimicrobial nanoparticles (ANPs), as they have demonstrated to possess strong antimicrobial effects on MDR pathogens. On the other hand, the ability of bacteria to develop resistance to such agents is minimal. In this way, ANPs may seem a good choice for the development of new drugs, but there is no certainty about their safety, which may delay its translation to the clinical setting. As MDR pathogens are quickly becoming more prevalent and drug development is slow and expensive, there is an increasing need for the rapid development of new strategies to control such agents. We hereby explore the possibility of designing ANP-based devices such as surgical masks and fabrics, wound dressings, catheters, prostheses, dentifrices, water filters, and nanoparticle-coated metals to exploit the potential of such materials in the combat of MDR pathogens, with a good potential for translation into the clinical setting.

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer.

BACKGROUND: Dysregulation of splicing variants (SVs) expression has recently emerged as a novel cancer hallmark. Although the generation of aberrant SVs (e.g. AR-v7/sst5TMD4/etc.) is associated to prostate-cancer (PCa) aggressiveness and/or castration-resistant PCa (CRPC) development, whether the molecular reason behind such phenomena might be linked to a dysregulation of the cellular machinery responsible for the splicing process [spliceosome-components (SCs) and splicing-factors (SFs)] has not been yet explored. METHODS: Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinically-localized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42). FINDINGS: A profound dysregulation in the expression of multiple components of the splicing machinery (i.e. 7 SCs/19 SFs) were found in PCa compared to their non-tumor adjacent-regions. Notably, overexpression of SNRNP200, SRSF3 and SRRM1 (mRNA and/or protein) were associated with relevant clinical (e.g. Gleason score, T-Stage, metastasis, biochemical recurrence, etc.) and molecular (e.g. AR-v7 expression) parameters of aggressiveness in PCa-samples. Functional (cell-proliferation/migration) and mechanistic [gene-expression (qPCR) and protein-levels (western-blot)] assays were performed in normal prostate cells (PNT2) and PCa-cells (LNCaP/22Rv1/PC-3/DU145 cell-lines) in response to SNRNP200, SRSF3 and/or SRRM1 silencing (using specific siRNAs) revealed an overall decrease in proliferation/migration-rate in PCa-cells through the modulation of key oncogenic SVs expression levels (e.g. AR-v7/PKM2/XBP1s) and alteration of oncogenic signaling pathways (e.g. p-AKT/p-JNK). INTERPRETATION: These results demonstrate that the spliceosome is drastically altered in PCa wherein SNRNP200, SRSF3 and SRRM1 could represent attractive novel diagnostic/prognostic and therapeutic targets for PCa and CRPC.

Specific therapies proposed for the management of COVID-19. / Terapias específicas propuestas para el manejo de COVID-19.

The appearance of a new coronavirus, which has caused the collapse of health systems around the world, has led to the emergence of numerous investigations looking for the ideal treatment and proper management of this new entity, since its control has become impossible and its cure an international necessity. To date, there are hundreds of articles and clinical trials to review. For this reason, in an attempt to facilitate the reader's knowledge of the new evidence and in summary form, the different therapies studied so far are presented in this article: their antiviral and adverse effects. Without forgetting that there are still doubts to be resolved and this process of new knowledge is just beginning.

La aparición de un nuevo coronavirus, causante del colapso de los sistemas de salud de todo el mundo, ha provocado el surgimiento de cuantiosas investigaciones en busca del tratamiento ideal y un adecuado manejo a esta nueva entidad, ya que su control se ha vuelto imposible y su cura una necesidad internacional. Hasta la fecha existen cientos de artículos y ensayos clínicos por revisar. Por ello, en un intento por facilitar al lector el entendimiento de la nueva evidencia y en forma de resumen, se exponen en el presente artículo las distintas terapias estudiadas hasta el momento: sus efectos antivirales y adversos. Sin olvidar que aún quedan varias incógnitas por resolver y este proceso de nuevo conocimiento apenas comienza.