Exploring kidney allograft rejection: A proof-of-concept study using spatial transcriptomics.

In this proof-of-concept study, spatial transcriptomics combined with public single-cell ribonucleic acid-sequencing data were used to explore the potential of this technology to study kidney allograft rejection. We aimed to map gene expression patterns within diverse pathologic states by examining biopsies classified across nonrejection, T cell-mediated acute rejection, interstitial fibrosis, and tubular atrophy. Our results revealed distinct immune cell signatures, including those of T and B lymphocytes, monocytes, mast cells, and plasma cells, and their spatial organization within the renal interstitium. We also mapped chemokine receptors and ligands to study immune cell migration and recruitment. Finally, our analysis demonstrated differential spatial enrichment of transcription signatures associated with kidney allograft rejection across various biopsy regions. Interstitium regions displayed higher enrichment scores for rejection-associated gene expression patterns than tubular areas, which had negative scores. This implies that these signatures are primarily driven by processes unfolding in the renal interstitium. Overall, this study highlights the value of spatial transcriptomics for revealing cellular heterogeneity and immune signatures in renal transplant biopsies and demonstrates its potential for studying the molecular and cellular mechanisms associated with rejection. However, certain limitations must be borne in mind regarding the development and future applications of this technology.

SMORES: a simple microfluidic operating room for the examination and surgery of Stentor coeruleus.

Ciliates are powerful unicellular model organisms that have been used to elucidate fundamental biological processes. However, the high motility of ciliates presents a major challenge in studies using live-cell microscopy and microsurgery. While various immobilization methods have been developed, they are physiologically disruptive to the cell and incompatible with microscopy and/or microsurgery. Here, we describe a Simple Microfluidic Operating Room for the Examination and Surgery of Stentor coeruleus (SMORES). SMORES uses Quake valve-based microfluidics to trap, compress, and perform surgery on Stentor as our model ciliate. Compared with previous methods, immobilization by physical compression in SMORES is more effective and uniform. The mean velocity of compressed cells is 24 times less than that of uncompressed cells. The compression is minimally disruptive to the cell and is easily applied or removed using a 3D-printed pressure rig. We demonstrate cell immobilization for up to 2 h without sacrificing cell viability. SMORES is compatible with confocal microscopy and is capable of media exchange for pharmacokinetic studies. Finally, the modular design of SMORES allows laser ablation or mechanical dissection of a cell into many cell fragments at once. These capabilities are expected to enable biological studies previously impossible in ciliates and other motile species.

Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) leads to endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR). When sustained, this response may trigger the inflammation and tubular cell death that acts to aggravate the damage. Here, we show that knockdown of the BET epigenetic reader BRD4 reduces the expression of ATF4 and XBP1 transcription factors under ER stress activation. BRD4 is recruited to the promoter of these highly acetylated genes, initiating gene transcription. Administration of the BET protein inhibitor, JQ1, one hour after renal damage induced by bilateral IRI, reveals reduced expression of ATF4 and XBP1 genes, low KIM-1 and NGAL levels and recovery of the serum creatinine and blood urea nitrogen levels. To determine the molecular pathways regulated by ATF4 and XBP1, we performed stable knockout of both transcription factors using CRISPR-Cas9 and RNA sequencing. The pathways triggered under ER stress were mainly XBP1-dependent, associated with an adaptive UPR, and partially regulated by JQ1. Meanwhile, treatment with JQ1 downmodulated most of the pathways regulated by ATF4 and related to the pathological processes during exacerbated UPR activation. Thus, BRD4 inhibition could be useful for curbing the maladaptive UPR activation mechanisms, thereby ameliorating the progression of renal disease.

SMORES: A Simple Microfluidic Operating Room for the Examination and Surgery of Stentor coeruleus.

Ciliates are powerful unicellular model organisms that have been used to elucidate fundamental biological processes. However, the high motility of ciliates presents a major challenge in studies using live-cell microscopy and microsurgery. While various immobilization methods have been developed, they are physiologically disruptive to the cell and incompatible with microscopy and/or microsurgery. Here, we describe a Simple Microfluidic Operating Room for the Examination and Surgery of Stentor coeruleus (SMORES). SMORES uses Quake valve-based microfluidics to trap, compress, and perform surgery on Stentor as our model ciliate. Compared with previous methods, immobilization by physical compression in SMORES is more effective and uniform. The mean velocity of compressed cells is 24 times less than that of uncompressed cells. The compression is minimally disruptive to the cell and is easily applied or removed using a 3D-printed pressure rig. We demonstrate cell immobilization for up to 2 hours without sacrificing cell viability. SMORES is compatible with confocal microscopy and is capable of media exchange for pharmacokinetic studies. Finally, the modular design of SMORES allows laser ablation or mechanical dissection of a cell into many cell fragments at once. These capabilities are expected to enable biological studies previously impossible in ciliates and other motile species.

Properties and cellular uptake of photo-triggered mixed metallosurfactant vesicles intended for controlled CO delivery in gas therapy.

The scientific relevance of carbon monoxide has increased since it was discovered that it is a gasotransmitter involved in several biological processes. This fact stimulated research to find a secure and targeted delivery and lead to the synthesis of CO-releasing molecules. In this paper we present a vesicular CO delivery system triggered by light composed of a synthetized metallosurfactant (TCOL10) with two long carbon chains and a molybdenum-carbonyl complex. We studied the characteristics of mixed TCOL10/phosphatidylcholine metallosomes of different sizes. Vesicles from 80 to 800 nm in diameter are mainly unilamellar, do not disaggregate upon dilution, in the dark are physically and chemically stable at 4 °C for at least one month, and exhibit a lag phase of about 4 days before they show a spontaneous CO release at 37 °C. Internalization of metallosomes by cells was studied as function of the incubation time, and vesicle concentration and size. Results show that large vesicles are more efficiently internalized than the smaller ones in terms of the percentage of cells that show TCOL10 and the amount of drug that they take up. On balance, TCOL10 metallosomes constitute a promising and viable approach for efficient delivery of CO to biological systems.

Reoperation Rates Following Total Ankle Arthroplasty Versus Ankle Arthrodesis for Posttraumatic Indications.

AIMS: This studied aimed to compare rates of reoperation for patients who received primary ankle arthrodesis (AA) versus total ankle replacement (TAR) for posttraumatic indications between 2010 and 2016 Q2 using a nationwide claims database. METHODS: A retrospective cohort study analyzing patients who received primary AA or TAR for posttraumatic indications was performed using PearlDiver. Reoperations assessed included prosthetic joint infection (PJI), hardware removal, adjacent joint fusion, and local open reduction internal fixation (ORIF). Multivariable logistic regression was used to compare rates of reoperations at 1 and 2 years postdischarge. RESULTS: A total of 862 (74%) patients received AA and 318 (26%) patients underwent TAR for a posttraumatic indication. At 1 year, 305 (35.4%) AA patients had at least 1 reoperation compared with 55 (17.3%) TAR patients (OR 2.32; 95% CI, 1.68-3.26). At 2 years, 364 (42.2%) AA patients and 66 (20.8%) TAR patients had at least 1 reoperation (OR 2.51; 95% CI, 1.84-3.45). ORIF, hardware removal, and adjacent joint fusions were more likely for AA patients at both time intervals (all Ps < .05). CONCLUSION: Patients who received primary AA for posttraumatic indications exhibited higher rates of major reoperations in the short to medium term compared with patients who underwent TAR. LEVELS OF EVIDENCE: Level III: Retrospective cohort study.

Conducta suicida en jóvenes y adultos en la provincia Mayabeque (2018 y 2019)

Introducción: La conducta suicida incluye el intento suicida y el suicidio consumado. En Cuba ocupa la décima causa de muerte en el cuadro de mortalidad y la tercera en los adolescentes. Objetivo: Caracterizar la conducta suicida en jóvenes y adultos en la provincia Mayabeque en 2018 y 2019. Métodos: Estudio descriptivo y transversal. El universo quedó conformado por todos los casos de morbilidad por intento suicida registrados en las tarjetas de enfermedad de declaración obligatoria y los casos de mortalidad por suicidio registrados en la base de datos de la Dirección Provincial de Salud de Mayabeque entre 2018 y 2019. Entre las variables se consideraron: edad, sexo, métodos y municipios de residencia. Se calcularon las tasas de mortalidad bruta y específica calculadas por 100 000 habitantes por sexo y la razón hombre/mujer. Las variables estudiadas se expresaron en porcentajes. Resultados: Se notificaron 711 intentos suicidas. El sexo femenino exteriorizó 475 (66,8 %) casos. La razón de intento/suicidio de forma general fue de 6,8 en 2018 y de 7,7 en 2019. Se registraron 101 suicidios. El sexo masculino presentó 81 (80,2 %) casos. El método más empleado para el suicidio fue el ahorcamiento en 72 (71,2 %) casos. Conclusiones: El sexo femenino resultó el más afectado en el intento y el masculino en el suicidio. Se necesita identificar los factores de riesgo de la conducta suicida para su prevención.

Introduction: Suicidal behavior includes the suicide attempt and completed suicide. In Cuba it ranks tenth among the leading causes of death and third among adolescents according to the mortality record. Objective: To characterize the suicidal behavior in young people and adults from Mayabeque province in 2018 and 2019. Methods: A descriptive and cross-sectional study. The universe of study comprised all the morbidity cases for suicide attempt registered in the notifiable disease cards and the mortality cases for completed suicide registered in Provincial Health Department database in Mayabeque in 2018 and 2019. Among the variables studied were age, sex, suicide methods, and municipality of residence. Crude and cause-specific mortality rates were calculated per 100 000 population by sex and woman/man ratio. Variables were expressed as percentage. Results: A total of 711 suicide attempts were reported. Female sex accounted for 475 (66.8%) cases. Overall, the suicide attempt/completed suicide ratio was of 6.8 in 2018 and 7.7 in 2019. A total of 101 completed suicides were reported. There were 81 cases (80.2%) among male sex. Hanging was the most common suicide method in 72 cases (71.2 %). Conclusions: Suicide attempts are more frequent among women while completed suicide is more frequent among men. It is necessary to identify the risk factors associated to suicidal behavior for their prevention.

Insights behind the Relationship between Colorectal Cancer and Obesity: Is Visceral Adipose Tissue the Missing Link?

Colorectal cancer (CRC) is a major health problem worldwide, with an estimated 1.9 million new cases and 915,880 deaths in 2020 alone. The etiology of CRC is complex and involves both genetic and lifestyle factors. Obesity is a major risk factor for CRC, and the mechanisms underlying this link are still unclear. However, the generalized inflammatory state of adipose tissue in obesity is thought to play a role in the association between CRC risk and development. Visceral adipose tissue (VAT) is a major source of proinflammatory cytokines and other factors that contribute to the characteristic systemic low-grade inflammation associated with obesity. VAT is also closely associated with the tumor microenvironment (TME), and recent evidence suggests that adipocytes within the TME undergo phenotypic changes that contribute to tumor progression. In this review, we aim to summarize the current evidence linking obesity and CRC, with a focus on the role of VAT in tumor etiology and progression.

Dependencia endotelial del efecto de canfenol plus 3 % sobre el músculo liso vascular arterial / Endothelial dependence of the effect of 3 % camphenol plus on arterial vascular smooth muscl

RESUMEN Introducción: el canfenol plus, es un derivado clorado del fenol empleado de forma habitual como medicación intraconducto durante los tratamientos pulporradiculares en Estomatología. Son escasos los estudios en relación con sus efectos sobre el músculo liso vascular arterial y la participación del endotelio en estos. Objetivo: determinar la dependencia endotelial del efecto de canfenol plus 3 % sobre el músculo liso vascular arterial. Material y Métodos: se realizó una investigación experimental preclínica utilizando 26 anillos de carótida externa desprovistos de endotelio vascular. Las preparaciones realizadas se colocaron en baño de órganos, registrándose la tensión desarrollada por el músculo liso vascular tras la adición de acetilcolina, así como de soluciones de canfenol plus 3 % durante diferentes intervalos de tiempo. La dependencia entre ambas tensiones, se determinó a través de un modelo de regresión lineal simple. Resultados: tras la preactivación con solución Krebs concentrada de iones potasio, la adición de 10 μl de acetilcolina y canfenol plus 3 %, indujeron una discreta, pero significativa vasorrelajación de la musculatura lisa vascular. El modelo de regresión lineal elaborado, demostró la dependencia entre las variables tensión producida por acetilcolina y tensión producida por el fármaco al décimo minuto, corroborando la implicación del endotelio vascular en dicho efecto relajante. Conclusiones: el canfenol plus 3 %, produjo in vitro, un efecto vasorrelajante sobre la musculatura lisa de anillos de carótida externa, dependiente de endotelio y a partir de un factor relajante o hiperpolarizante derivado de este.

ABSTRACT Introduction: Camphenol plus is a chlorinated phenol derivative commonly used as intracanal medication during pulporradicular treatments in Dentistry. Studies in relation to its effects on arterial vascular smooth muscle and the involvement of the endothelium in them are scarce. Objective: To determine the endothelial dependence of the effect of 3 % camphenol plus on arterial vascular smooth muscle. Material and Methods: A preclinical experimental research was carried out using 26 external carotid artery rings devoid of vascular endothelium. The preparations made were placed in an organ bath, recording the tension developed by the vascular smooth muscle after the addition of acetylcholine, as well as 3 % Camphenol plus solutions during different intervals of time. The dependence between both tensions was determined through a simple linear regression model. Results: After pre-activation with Krebs concentrated potassium ion solution, the addition of 10 μl of acetylcholine and 3 % camphenol plus induced a discrete but significant vasorelaxation of the vascular smooth muscle. The linear regression model developed demonstrated the dependence between the variables tension produced by acetylcholine and tension produced by the drug at the tenth minute, corroborating the involvement of the vascular endothelium in that vasorelaxant effect. Conclusions: It is concluded that 3 % Camphenol plus in vitro, produced a vasorelaxant effect on the smooth muscle of external carotid rings dependent on endothelium and from a relaxing or hiperpolarizing factor derived from it.

Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".

Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound 9 (4-{[1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-3-yl]methyl}morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities. The identified GLP-1R PAM shows a remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. Enantioselective synthesis revealed oral efficacy for (S)-9 in animal models. Compound 9 behavior bolsters the interest of a small-molecule PAM of GLP-1R as a promising therapeutic approach for the increasingly prevalent obesity-associated diabetes.

Efecto del 4-Clorofenol sobre el músculo liso vascular de aorta abdominal de ratas Wistar / Effect of 4-Chlorophenol on the vascular smooth muscle of the abdominal aorta of Wistar rats

Introducción: Uno de los derivados de los clorofenoles más utilizado en Estomatología, lo constituye el p-clorofenol (4-clorofenol), empleado como agente antibacteriano en la desinfección del conducto radicular durante el tratamiento pulporradicular. Son escasos los reportes científicos sobre sus efectos en la musculatura lisa vascular arterial y la regulación del flujo sanguíneo local. Objetivo: Determinar el efecto del 4-clorofenol sobre el músculo liso vascular de aorta abdominal de ratas Wistar. Material y Métodos: Se realizó una investigación experimental preclínica, utilizando 30 anillos de aorta abdominal (porción superior) obtenidos de ratas Wistar adultas. Las preparaciones de unos 5 mm se colocaron en baño de órganos, registrándose la tensión desarrollada por el músculo liso vascular tras la adición de 4-clorofenol en diferentes concentraciones y durante diferentes intervalos de tiempo. Resultados: El 4-clorofenol, tras la preactivación del musculo liso vascular de anillos de aorta abdominal, indujo relajación del vaso, la que se incrementó durante todo el tiempo de estudio y al aumento de la concentración del medicamento. Existieron diferencias significativas entre los valores de tensión promedios registrados en los diferentes intervalos de tiempo con los de la tensión base inicial. Conclusiones: El p-clorofenol indujo in vitro, relajación del músculo liso vascular de aorta abdominal de ratas Wistar(AU)

Introduction: In Dentistry, p-chlorophenol (4-chlorophenol) is one of the most widely used derivatives of chlorophenols. It is used as an antibacterial agent in root canal disinfection during pulp-radicular treatment. There are few scientific reports on its effects on vascular smooth musculature and the regulation of local blood flow. Objective: To determine the effect of 4-chlorophenol on vascular smooth muscle of abdominal aorta from Wistar rats. Material and Methods: A preclinical experimental research was carried out using 30 abdominal aortic rings (upper portion) obtained from adult Wistar rats. The preparations of about 5 mm were placed in an organ bath, recording the tension developed by the vascular smooth muscle after the addition of 4-chlorophenol at different concentrations and during different time intervals. Results: The results demonstrate that 4-Chlorophenol induced vasorelaxation after the preactivation of the vascular smooth muscle of the abdominal aortic rings, which increased during the entire study time and with increased drug concentration. There were significant differences among average tension values registered at different intervals of time in relation to the initial base tension. Conclusions: It is concluded that in vitro, p-chlorophenol induced relaxation of abdominal aorta vascular smooth muscle in Wistar rats(AU)

Dinámica contráctil espontánea del músculo liso vascular de la arteria carótida externa / Spontaneous contractile dynamics of the vascular smooth muscle of the external carotid artery

Introducción: La carótida externa es una arteria muscular que irriga todos los componentes del sistema masticatorio, por lo que la regulación de la dinámica contráctil de su músculo liso vascular es imprescindible para garantizar el tono y el flujo sanguíneo tisular y modular la respuesta inflamatoria. Objetivo: Describir la dinámica contráctil espontánea del musculo liso vascular de la arteria carótida externa. Métodos: Se realizó una investigación experimental en el Instituto de Fisiología Oscar Langerdorff de la Facultad de Medicina, en la Universidad de Rostock, Alemania, de octubre a diciembre del 2018, en la cual se utilizaron 60 anillos de arterias carótidas externas obtenidas de 10 ratas Wistar adultas de ambos sexos. A dichos anillos se les practicó un corte helicoidal y fueron colocados en un baño de órganos, para registrarles, luego, la tensión espontánea desarrollada por el músculo liso vascular contra una carga de 1 gramo, durante diferentes intervalos de tiempo. Resultados: Los registros de la actividad contracción-relajación espontánea del músculo liso vascular de la arteria carótida externa fluctuaron dentro de un rango estrecho de cifras de tensión, con valores máximos de 8,48 ± 0,03 y mínimos de 8,33 ± 0,03, y una diferencia de 0,08 mN/g de músculo. Los valores promedios de tensión en cada intervalo de tiempo fueron muy cercanos, con desviaciones estándar que evidenciaron muy poca dispersión de los datos respecto a la media. La tensión promedio general registrada fue de 8,40 ± 0,032 mN/g. Conclusiones: La dinámica contráctil espontánea desarrollada por el músculo liso vascular de la arteria carótida externa mostró una progresión irregular en el tiempo, con valores promedios de tensión que oscilaron entre 5-10 mN/g de músculo.

Introduction: The external carotid is a muscle artery irrigating all components of the masticatory system, so that the regulation of the contractile dynamics of its vascular smooth muscle is important. Objective: To describe the spontaneous contractile dynamics of the vascular smooth muscle of the external carotid artery. Methods: An experimental investigation was carried out in the Oscar Langerdorff Physiology Institute from the Medicine Faculty at Rostock University, Germany, from October to December 2018, in which 60 rings of the external carotid artery obtained from 10 adult Wistar rats from both sexes. An helical cut was made to each ring and they were placed in an organ bath, to be registered, then, the spontaneous strain developed by the vascular smooth muscle against a charge of 1 g, during different time intervals was registered. Results: The records from the spontaneous contraction-relaxation of the vascular smooth muscle in the external carotid artery fluctuated within a narrow range of strain figures, with maximum values of 8.48 ± 0.03 and minimum of 8.33 ± 0.03, and a difference of 0.08 mN/g of muscle. Average strain values in each time interval were very closed, with standard deviations which evidenced a very small data dispersion regarding the mean. The average general registered strain was 8.40 ± 0.032 mN/g. Conclusions: The spontaneous contractile dynamics developed by the vascular smooth muscle of the external carotid artery showed an irregular progression in time, with average strain values fluctuating between 5-10 mN/g of muscle.

Efecto del Camphenol Plus sobre el músculo liso vascular de vena porta en ratas Wistar / Effect of Camphenol Plus on portal vein vascular smooth muscle in Wistar rats

RESUMEN Introducción: uno de los antisépticos comúnmente empleado en Estomatología desde el pasado siglo y que mantiene su uso hasta la actualidad, lo constituye el Camphenol Plus. Son escasos los reportes científicos de su efecto sobre el endotelio y la dinámica contráctil del músculo liso vascular, en especial de tejidos venosos como la vena porta hepática. Objetivo: determinar el efecto del Camphenol Plus sobre el músculo liso vascular de la vena porta. Métodos: se realizó una investigación experimental preclínica, con la utilización de 21 venas porta obtenidas de ratas Wistar. Las preparaciones realizadas se colocaron en baño de órganos, se registró la tensión desarrollada por el músculo liso vascular tras la adición de diez microlitros de Camphenol Plus, en diferentes concentraciones y durante diferentes intervalos de tiempo. Resultados: el Camphenol Plus, tras la preactivación del musculo liso vascular de la vena porta, indujo vasorelajación, la que se incrementó durante todo el tiempo de estudio y según el incremento de las concentraciones del medicamento. Existieron diferencias significativas entre los valores de tensión promedios registrados en los diferentes intervalos de tiempo con los de la tensión espontánea basal y la tensión base inicial. Conclusiones: el Camphenol Plus, indujo "in vitro", relajación de la musculatura lisa de la vena porta a través de un acoplamiento excitación-contracción de tipo farmacomecánico.

ABSTRACT Introduction: Camphenol Plus is one of the antiseptics commonly used in Dentistry since the last century and still in use today. There are few scientific reports of its effect on the endothelium and contractile dynamics of vascular smooth muscle, especially in venous tissues such as the hepatic portal vein. Objective: to determine the effect of Camphenol Plus on the vascular smooth muscle of the portal vein. Methods: a preclinical experimental investigation was carried out using 21 portal veins obtained from Wistar rats. The preparations were placed in an organ bath and the tension developed by the vascular smooth muscle was recorded after the addition of ten microliter of Camphenol Plus, at different concentrations and during different time intervals. Results: Camphenol Plus, after the preactivation of the vascular smooth muscle of the portal vein, induced relaxation, which increased throughout the study time and according to the increase in drug concentrations. There were significant differences between the average tension values recorded in the different time intervals with those of the basal spontaneous tension and the initial baseline tension. Conclusions: Camphenol Plus induced "in vitro" relaxation of portal venous smooth muscles through a pharmacomechanical excitation-contraction coupling.

Estratificación epidemiológica de riesgo del intento suicida en Cuba / Epidemiological Risk Stratification of Suicide Attempt in Cuba

Introducción: La estratificación epidemiológica de riesgo es un proceso integrado de diagnóstico-intervención-evaluación, que sirve para la toma de decisiones. El riesgo de morir por suicidio, en quienes hacen intentos es 100 veces superior a la población general. Objetivo: Estratificar epidemiológicamente el intento suicida según provincias de residencia. Métodos: Se realizó un estudio ecológico mixto. El universo fueron los registros de intento suicida, a través de las tarjetas de enfermedad de declaración obligatoria de los Registros Médicos y Estadísticas del Ministerio de Salud Pública desde 1990 hasta 2014. Las variables fueron: sexo, edad y provincias de residencia. Se calcularon las tasas de morbilidad acumuladas, brutas, ajustadas y específicas por 100 000 habitantes. La estratificación se realizó tomando como punto de corte los percentiles, quedando Muy alto riesgo por encima del 75 percentil, Alto riesgo entre 50-74; Moderado riesgo entre 25-49 y Bajo riesgo por debajo del 25 percentil. Se calculó el porcentaje de cambio relativo de la serie y los porcentajes, según variables. Resultados: Desde 1990-2014 se produjeron 291 524 intentos suicidas (20 823 intentos por año), de los cuales el 71,5 por ciento fueron mujeres, Las provincias de Muy Alto Riesgo en el periodo 1990-2014 fueron: Cienfuegos (tasa 151,9), Holguín (135,2), Santiago de Cuba (126,9) y Granma (125,2) tasas por 100 000 habitantes; y durante 2011-2014: Matanzas (tasas de 154,4), Las Tunas (154,3), Cienfuegos (148,3) y Holguín (147,3) por 100 000 hab. Conclusiones: La estratificación de riesgo a nivel provincial varió en los periodos estudiados. El sexo femenino y los adolescentes fueron los de mayor riesgo en el intento suicida(AU)

Introduction: Epidemiological risk stratification is an integrated process of diagnosis, intervention and evaluation, used for decision-making. The risk of dying by suicide in those who make attempts is a hundred times higher than in the general population. Objective: To stratify suicide attempt epidemiologically, according to province of residence. Methods: A mixed ecological study was carried out. The universe was made up of the records of suicide attempts, accessed through the files of reportable diseases from the Medical Registries and Statistics of the Ministry of Public Health from 1990 to 2014. The variables were sex, age and provinces of residence. Cumulative gross, adjusted and specific morbidity rates per 100 000 inhabitants were calculated. The stratification was carried out taking the percentiles as cut-off point, leaving very high risk above the 75th percentile, high risk between the 50th and the 74th percentiles, moderate risk between the 25th and the 49th percentiles, and low risk below the 25th percentile. The relative change percentage of the series and the percentages were calculated, according to variables. Results: From 1990 to 2014, there were 291 524 suicide attempts (20 823 attempts per year), of which 71.5 por ciento corresponded to women. The provinces with very high risk in the period 1990-2014 were Cienfuegos, Holguín, Santiago de Cuba and Granma, accounting, respectively, for rates of 151.9, 135.2, 126.9 and 125.2 per 100 000 inhabitants; and during 2011-2014, Matanzas, Las Tunas, Cienfuegos and Holguín, accounting, respectively, for rates of 154.4, 154.3, 148.3 and 147.3 per 100 000 inhabitants. Conclusions: Risk stratification at the provincial level varied in the periods studied. The female sex and adolescents were the most at risk of suicide attempt(AU)

Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia.

B7-H6, a ligand for the NK activating receptor NKp30, has been identified as a biomarker of poor prognosis in several solid cancers. However, little is known about the role of B7-H6 and the mechanisms that control its expression in acute myeloid leukemia (AML). Epigenome modulation, including epigenomic reader dysregulation, is one of the hallmarks of AML. Bromodomain-containing protein 4 (BRD4), the best-known member of the BET family of epigenetic readers, is overexpressed in AML cells and regulates the transcription of genes involved in the pathogenesis of AML, as MYC oncogene. Here, we analyze the role of BRD4 in regulating B7-H6 in AML cells. Results demonstrated that the specific inhibition of BRD4 drastically reduces the expression of B7-H6 in AML cells. Histone acetylation mediated by CBP30/P300 facilitates the binding of BRD4 to the B7-H6 promoter, which recruits the P-TEFb elongation factor that phosphorylates RNA polymerase II, thereby activating B7-H6 transcription. BRD4 also co-bounded with JMJD6 at the distal enhancer of the B7-H6 gene. Metabolic modulation with metformin modifies the acetylation pattern in the B7-H6 promoter, impairing BRD4 binding, thereby inhibiting B7-H6 expression. B7-H6 knockdown induces the apoptosis in HEL-R cell line. Moreover, a high level of B7-H6 expression in AML patients is related to increased BRD4 levels, myelodysplastic-derived AML, and del5q, the two latter being associated with poor prognosis. Our data show that BRD4 is a positive regulator of the pro-tumorigenic molecule B7-H6 and that the blockage of the B7-H6 is a potential therapeutic target for the treatment of AML.

A Versatile Peroxidase from the Fungus Bjerkandera adusta Confers Abiotic Stress Tolerance in Transgenic Tobacco Plants.

White-rot fungi are efficient lignin degraders due to the secretion of lignin peroxidase, manganese peroxidase, laccase, and versatile peroxidase (VP) on decayed wood. The VP is a high-redox-potential enzyme and could be used to detoxify reactive oxygen species (ROS), which accumulate in plants during biotic and abiotic stresses. We cloned the VP gene and expressed it via the Agrobacterium transformation procedure in transgenic tobacco plants to assay their tolerance to different abiotic stress conditions. Thirty independent T2 transgenic VP lines overexpressing the fungal Bjerkandera adustaVP gene were selected on kanamycin. The VP22, VP24, and VP27 lines showed significant manganese peroxidase (MnP) activity. The highest was VP22, which showed 10.87-fold more manganese peroxidase activity than the wild-type plants and led to a 34% increase in plant height and 28% more biomass. The VP22, VP24, and VP27 lines showed enhanced tolerance to drought, 200 mM NaCl, and 400 mM sorbitol. Also, these transgenics displayed significant tolerance to methyl viologen, an active oxygen-generating compound. The present data indicate that overproducing the VP gene in plants increases significantly their biomass and the abiotic stress tolerance. The VP enzyme is an effective biotechnological tool to protect organisms against ROS. In transgenic tobacco plants, it improves drought, salt, and oxidative stress tolerance. Thus, the VP gene represents a great potential for obtaining stress-tolerant crops.

Aplicación de herramientas de visualización de la información para la toma de decisiones en las bibliotecas: el caso de la Biblioteca Provincial Martí, de Villa Clara, Cuba / Use of information visualization tools for decision-making in libraries: the case of Martí Provincial Library in Villa Clara, Cuba

El estudio tuvo como objetivo examinar la viabilidad de la aplication de herramientas que ilustren el uso de la colección y de la institución, por parte la comunidad usuaria de la Biblioteca Provincial Martí, y contribuyan a una mejor toma de decisiones. La investigación se basó en una combinación de métodos cualitativos y cuantitativos; entre ellos, los matemáticos y estadísticos y las herramientas de visualización de la información. La muestra comprendió 1 422 usuarios, representativa del 25 por ciento del total de la población de la Biblioteca Provincial Martí, de Villa Clara. A partir de la información que se generó en el sistema de control estadístico de la institución, se recolectaron, se procesaron y se analizaron indicadores relativos al índice de captación, los servicios por usuarios, el uso de la biblioteca, el índice de circulación de la colección, el índice de rotación de la colección y el co-uso de los documentos por temáticas. Los datos revelaron aspectos esenciales de la gestión de la institución objeto de estudio y la necesidad de acometer acciones con respecto a su política de adquisición y de difusión, a fin de revertir los aspectos con incidencia negativa. El trabajo concluye con el reconocimiento de que la aplicación de esta novedosa forma de tratar los datos es una alternativa para la presentación de información en el proceso de la toma de decisiones de cualquier institución similar(AU)

The purpose of the study was to examine the viability of the application of tools that illustrate the use of the collection and the institution, by the user community of the Martí Provincial Library, which contributes to better decision-making.The research was based on a combination of qualitative and quantitative methods, among them mathematical and statistical, and information visualization tools. The sample was composed of 1 422 users representing 25 percent of the total population of Martí Provincial Library in Villa Clara. Starting from the information generated by the statistical control system of the institution, indicators were collected, processed and analyzed which had to do with the following variables: recruitment rate, services per user, use of the library, collection circulation rate, collection turnover rate, and document co-use by subject. The data revealed essential aspects of management at the study institution, as well as the need to implement actions related to their acquisition and dissemination policy with a view to improving deficient areas. The paper recognizes that application of this novel way to treat data is an alternative for the presentation of information in the decision-making process at any similar institution(AU)

Early Signs of Impaired Gut Function Affect Daily Functioning in Patients With Advanced Cancer Undergoing Chemotherapy.

BACKGROUND: Gastrointestinal symptoms are common during chemotherapy, but underlying disturbances in gut function and their impact on daily life are unclear. This study investigates gut function in a heterogenous group of cancer patients with gastrointestinal symptoms during chemotherapy and its relation to anabolic response, muscle health, and daily functioning. METHODS: In 16 patients with solid tumors (mostly stage III+IV) undergoing chemotherapy (T) and 16 healthy (H) matched controls, small-intestinal membrane integrity was measured by urine sugar tests. Protein digestion, absorption, and anabolic response to a conventional protein supplement were analyzed by stable-tracer methods. Muscle mass and strength and daily functioning were assessed. RESULTS: Eighty-one percent of T patients reported gastrointestinal symptoms. Small-intestinal membrane permeability was similar, but active glucose transport was lower in the T group (T, 35.5% ± 3.4% vs H, 48.4% ± 4.7%; P = .03). Protein digestion and absorption tended to be lower in the T group (0.67 ± 0.02 vs 0.80 ± 0.04; P = .08). Net protein anabolic response to feeding was comparable, although lower in cancer patients with recent weight loss. Gut permeability negatively correlated to hand grip strength, global health, and physical functioning, and active-transport capacity positively correlated to global health in the T group. CONCLUSION: Advanced cancer patients with gastrointestinal symptoms during chemotherapy, particularly those with recent weight loss, show signs of impaired gut function negatively affecting muscle health, daily functioning, and anabolic response to feeding.

Immune Landscape in Tumor Microenvironment: Implications for Biomarker Development and Immunotherapy.

Integration of the tumor microenvironment as a fundamental part of the tumorigenic process has undoubtedly revolutionized our understanding of cancer biology. Increasing evidence indicates that neoplastic cells establish a dependency relationship with normal resident cells in the affected tissue and, furthermore, develop the ability to recruit new accessory cells that aid tumor development. In addition to normal stromal and tumor cells, this tumor ecosystem includes an infiltrated immune component that establishes complex interactions that have a critical effect during the natural history of the tumor. The process by which immune cells modulate tumor progression is known as immunoediting, a dynamic process that creates a selective pressure that finally leads to the generation of immune-resistant cells and the inability of the immune system to eradicate the tumor. In this context, the cellular and functional characterization of the immune compartment within the tumor microenvironment will help to understand tumor progression and, ultimately, will serve to create novel prognostic tools and improve patient stratification for cancer treatment. Here we review the impact of the immune system on tumor development, focusing particularly on its clinical implications and the current technologies used to analyze immune cell diversity within the tumor.

Salud mental en la infancia y adolescencia durante la pandemia de COVID-19 / Mental health in children and adolescents during COVID-19 pandemic

Introducción: La pandemia del COVID-19 representa un impacto trascendental para la salud mental, lo que es poco abordado por su relativa invisibilidad, lo que puede comprometer especialmente a las personas más vulnerables, entre las que se encuentra la población infantojuvenil. Objetivo: Examinar los factores que influyen en la salud mental de la población infantojuvenil durante la pandemia del COVID-19. Métodos: Se realizó la revisión bibliográfica entre mayo y agosto de 2020 utilizando como fuentes de información la literatura publicada en las bases de datos de Pubmed/Medline, Science Direct, SciELO, Cumed, Lilacs. Se utilizaron las palabras clave: COVID-19, cuarentena, confinamiento, distanciamiento social, salud mental, trastornos mentales, trastornos psiquiátricos, infancia, adolescencia. Resultados: Se consideraron temáticas como estrés, afectación física, distanciamiento y aislamiento social, experiencias adversas, resiliencia, salud mental, impacto psicológico, maltrato infantil, y familia. Las experiencias adversas vividas durante las etapas de desarrollo ocupan un lugar crítico en la conformación de la salud mental. Consideraciones finales: La salud mental de la población infantojuvenil puede afectarse por las consecuencias adversas de la pandemia de la COVID-19 y estar la persona en pleno desarrollo psicológico. No todas las respuestas psicológicas podrán calificarse como enfermedades, porque la mayoría son reacciones normales ante una situación anormal. El factor protector por excelencia de los infantes y adolescentes es la familia con la presencia de adultos responsables y estables que puedan ofrecer el apoyo necesario, establecer rutinas y hábitos saludables, y promover la resiliencia(AU)

Introduction: COVID-19 pandemic represents a momentous impact for mental health which is poorly addressed due to its relative invisibility; but it can affect especially most vulnerable people, among them the children-adolescents´ population. Objective: Examine the factors impacting in children-adolescents population's mental health during COVID-19 pandemic. Methods: It was carried out a bibliographic review from May to August 2020 using literature published in PubMed/Medline, Science Direct, SciELO, Cumed, and Lilacs databases as information sources. Some keywords were used as: COVID-19, quarantine, confinement, social distancing, mental health, mental disorders, psychiatric disorders, childhood, and adolescence. Results: Themes as stress, physical impairment, social distancing and isolation, adverse experiences, resilience, mental health, psychological impact, child abuse, and family were reviewed. Adverse experiences lived during the development stages have a critical place in the composition of mental health. Final considerations: Mental health in the children-adolescents´ population can be affected by the adverse consequences of COVID-19 pandemic when the person is in the middle of the psychological development. Not all the psychological responses can be qualified as diseases because most of them are normal reactions to an abnormal situation. The ultimate protection's factor for children and adolescents is the family with presence of stable and responsible adults who can offer them the necessary support, establish routines and healthy habits, and promote resilience(AU)