Morphological diversification and functional maturation of human astrocytes in glia-enriched cortical organoid transplanted in mouse brain.

Astrocytes, the most abundant glial cell type in the brain, are underrepresented in traditional cortical organoid models due to the delayed onset of cortical gliogenesis. Here we introduce a new glia-enriched cortical organoid model that exhibits accelerated astrogliogenesis. We demonstrated that induction of a gliogenic switch in a subset of progenitors enabled the rapid derivation of astroglial cells, which account for 25-31% of the cell population within 8-10 weeks of differentiation. Intracerebral transplantation of these organoids reliably generated a diverse repertoire of cortical neurons and anatomical subclasses of human astrocytes. Spatial transcriptome profiling identified layer-specific expression patterns among distinct subclasses of astrocytes within organoid transplants. Using an in vivo acute neuroinflammation model, we identified a subpopulation of astrocytes that rapidly activates pro-inflammatory pathways upon cytokine stimulation. Additionally, we demonstrated that CD38 signaling has a crucial role in mediating metabolic and mitochondrial stress in reactive astrocytes. This model provides a robust platform for investigating human astrocyte function.

Contribution of sex steroids and prolactin to the modulation of T and B cells during autoimmunity.

In this review we discuss how sex steroids and prolactin affect regulation and responsiveness of B and T cells. Sex hormones exert profound effects on several physiological processes of non- reproductive tissues. In the immune system, several studies with experimental models for SLE have shown a noticeable pro-inflammatory role for ERα, contributing to disease development reflected in proteinuria and renal pathology. On the other hand, ERß appears to have an anti- inflammatory and immunosuppressive effect. Estrogen/ERα signaling induced an increase of Th17 cells in lymph nodes as well as the expression of its correspondent chemokine receptor CCR6 during collagen induced arthritis acute phase. High levels of anti- DNA antibodies and increased mortality was observed when given high E and prolactin doses to NZB/NZW mice, as compared with mice receiving low E and prolactin doses, or high E and low prolactin doses. Intracellular progesterone receptors have been detected in TCD4+ cells but in contrast as observed with ERs, it suppresses T cell dependent responses. Progestagen administration on female NZB/NZW mice decreased anti DNA IgG, improved survival, decreased glomerulonephritis and proteinuria.

Male genital tract immune response against Chlamydia trachomatis infection.

Chlamydia trachomatis is the most commonly reported agent of sexually transmitted bacterial infections worldwide. This pathogen frequently leads to persistent, long-term, subclinical infections, which in turn may cause severe pathology in susceptible hosts. This is in part due to the strategies that Chlamydia trachomatis uses to survive within epithelial cells and to evade the host immune response, such as subverting intracellular trafficking, interfering signaling pathways and preventing apoptosis. Innate immune receptors such as toll-like receptors expressed on epithelial and immune cells in the genital tract mediate the recognition of chlamydial molecular patterns. After bacterial recognition, a subset of pro-inflammatory cytokines and chemokines are continuously released by epithelial cells. The innate immune response is followed by the initiation of the adaptive response against Chlamydia trachomatis, which in turn may result in T helper 1-mediated protection or in T helper 2-mediated immunopathology. Understanding the molecular mechanisms developed by Chlamydia trachomatis to avoid killing and host immune response would be crucial for designing new therapeutic approaches and developing protective vaccines. In this review, we focus on chlamydial survival strategies and the elicited immune responses in male genital tract infections.

Lifetime psychiatric disorders: A comparison study between offspring of parents with bipolar disorder type-I versus the offspring of community controls parents / Trastornos psiquiátricos a través de la vida: un estudio de comparación de hijos de padres con trastorno afectivo bipolar tipo I frente a hijos de padres controles de la comunidad

Abstract Introduction: Literature reports show that bipolar offspring (BO) present with a wide range of psychiatric disorders. Comparison between BO and control parent offspring (CPO) may help to identify which psychopathological findings are specific to this high-risk group. Objective: To compare the psychopathological characteristics between a group of BO type-I and a group of CPO, by identifying the presence of psychiatric disorders according the DSM-IV-TR. Methods: A descriptive-correlational, cross-sectional and comparative study was conducted with 127 offspring of parents with bipolar disorder type-I from the multimodal intervention programme (PRISMA) and with 150 CPO between 6 and 30 years of age. Subjects were evaluated with validated diagnostic interviews (K-SADS-PL and DIGS). Results: The BO group showed higher frequencies for bipolar disorder (prevalence ratio [PR] = 17.70; 95% confidence interval [CI]; 1.02-306.83), bipolar disorder not otherwise specified (PR = 23.07, 95% CI; 2.8-189.0, p = 0.0001), disorders due to psychoactive substance use (PR = 9.52,95% CI; 2.93-30.90), oppositional defiant disorder (PR = 4.10,95% CI; 1.70-9.89), posttraumatic stress disorder (PR = 3.90, 95% CI 1.30-11.66), disorder due to alcohol use (PR = 3.84, 95% CI; 1.28-11.48), attention deficit/hyperactivity disorder (PR = 2.26, 95% CI; 1.37-3.75), and major depressive disorder (PR = 2.25, 95% CI; 1.13-4.50). Statistically significant differences were also found in the CGAS and GAF functional scales, with lower scores for the BO group. Conclusion: These findings confirm previous literature reports showing that BO have higher rates of affective and non-affective psychiatric disorders than control subjects, and also a lower level of global functioning.

Resumen Introducción: Reportes en la literatura muestran que los Hijos de Padres con Trastorno Bipolar tipo I (HPTB) manifiestan un amplio rango de trastornos psiquiátricos. La comparación entre los HPTB y los Hijos de Padres Control (HPC) permite establecer cuáles hallazgos psicopatológicos son específicos de este grupo de alto riesgo. Objetivo: Comparar las características psicopatológicas entre un grupo de HPTB tipo I y un grupo de HPC, mediante la identificación de la presencia de trastornos psiquiátricos según el DSM-IV-TR. Metodología: Se realizó un estudio descriptivo-correlacional, comparativo de corte transversal con 127 Hijos de Padres con TAB tipo I (HPTB-I) dentro de un programa de intervención multimodal (PRISMA) y 150 HPC, con edades entre los seis y 30 años. Los sujetos fueron evaluados con entrevistas diagnósticas validados (K-SADS-PL y DIGS). Resultados: El grupo de HPTB mostró mayor frecuencias de trastorno bipolar (Razón de Prevalencia [RP] = 17,70; Intervalo de Confianza [IC] del 95%, 1,02-306,83), trastorno bipolar no especificado (RP = 23,07, IC 95% 2,8 -189, p = 0.0001), trastorno por uso de sustancias psi-coactivas (RP = 9,52; IC 95%, 2,93-30,90), trastorno oposicionista desafiante (RP = 4,10; IC 95%, 1,70-9,89); trastorno de estrés postraumático (RP = 3,90; IC 95%, 1,30-11,66), trastorno por uso de alcohol (RP = 3,84; IC 95%, 1,2811,48), trastorno por déficit de atención e hiperactividad (RP = 2,26; IC 95%, 1,37-3,75) y trastorno depresivo mayor (RP = 2,25; IC 95%, 1,13-4,50). También se encontraron diferencias estadísticamente significativas en las escalas de funcionalidad CGAS y GAF, con menor puntaje en el grupo de HPB. Conclusión: Estos hallazgos confirman reportes previos de la literatura que demuestran que los HPTB presentan mayores tasas de trastornos psiquiátricos afectivos y no afectivos, y una menor nivel de funcionalidad global, al ser comparados con sujetos controles de la comunidad.

[Lifetime Psychiatric Disorders: a Comparision Study Between Offspring of Parents With Bipolar Disorder Type-I Versus the Offspring of Community Controls Parents]. / Trastornos psiquiátricos a través de la vida: un estudio de comparación de hijos de padres con trastorno afectivo bipolar tipo I frente a hijos de padres controles de la comunidad.

INTRODUCTION: Literature reports show that Bipolar Offspring (BO) present with a wide range of psychiatric disorders. Comparison between BO and Control Parent Offspring (CPO) may help to identify which psychopathological findings are specific to this high-risk group. OBJECTIVE: To compare the psychopathological characteristics between a group of BO type-I and a group of CPO, by identifying the presence of psychiatric disorders according the DSM-IV-TR. METHODS: A descriptive-correlational, cross-sectional and comparative study was conducted with 127 offspring of parents with bipolar disorder type-I from the multimodal intervention program (PRISMA) and with 150 CPO between 6 and 30 years of age. Subjects were evaluated with validated diagnostic interviews (K-SADS-PL and DIGS). RESULTS: The BO group showed higher frequencies for bipolar disorder (Prevalence Ratio [PR]=17.70; 95% confidence interval [CI]; 1.02 - 306.83), bipolar disorder not otherwise specified (PR=23.07, 95% CI; 2.8 - 189.0, P=.0001), disorders due to psychoactive substance use (PR=9.52, 95% CI; 2.93 -30.90), oppositional defiant disorder (PR=4.10, 95% CI; 1.70 -9.89), posttraumatic stress disorder (PR=3.90, 95% CI 1.30 -11.66), disorder due to alcohol use (PR=3.84, 95% CI; 1.28 -11.48), attention deficit/hyperactivity disorder (PR=2.26, 95% CI; 1.37 -3.75), and major depressive disorder (PR=2.25, 95% CI; 1.13 -4.50). Statistically significant differences were also found in the CGAS and GAF functional scales, with lower scores for the BO group. CONCLUSION: These findings confirm previous literature reports showing that BO have higher rates of affective and non-affective psychiatric disorders than control subjects, and also a lower level of global functioning.

Riesgos en la salud de agricultores por uso y manejo de plaguicidas, microcuenca "La Pila" / Health risks of farmers for using and handling pesticides in the watershed "La Pila"

Introducción: El corregimiento de Cabrera del municipio de Pasto, fundamenta su economía en el sector agropecuario, actividad que demanda el uso y manejo de variados productos químicos cuyo empleo conlleva riesgos para la salud. Objetivo: Identificar los principales riesgos a los cuales están expuestos los campesinos agricultores de la microcuenca "La Pila", municipio de Pasto, por el uso y manejo inadecuado de plaguicidas en sus labores de producción. Materiales y métodos: Se comparó los resultados obtenidos en la simulación de la dispersión de plaguicidas a través del Software HYSPLIT libre y la evaluación de los riesgos por contacto inmediato identificados a través de criterios establecidos en la GTC45 de ICONTEC. Resultados: Se pudo determinar que el factor de riesgo al cual se encuentran sometidos los agricultores de la zona es de tipo químico; que la dispersión de dichos contaminantes alcanza una longitud máxima de dispersión de 250 m y que a pesar que los trabajadores conocen de la importancia de la implementación de Elementos de Protección Personal no los utilizan como barreras para atenuar e impedir la materialización de los peligros. Conclusiones: Los riesgos identificados son más latentes en los agricultores de la zona media y baja de la microcuenca.

Introduction: The village of Cabrera, in the municipality of Pasto, bases its economy on agriculture, which requires the use and handling of various chemicals that can cause health risks. Objective: To identify the main risks to which farmers are exposed for the use and improper handling of pesticides in their production work in the watershed called "La Pila" in the municipality of Pasto. Materials and Methods: The results obtained in the simulation of the dispersion of pesticides through HYSPLIT free Software and the risk assessment for immediate contact identified through established criteria in GTC45 ICONTEC were compared. Results: It was determined that the risk factor to which farmers in the area are subjected to is of chemical type; besides, the dispersion of these pollutants reaches a maximum length of dispersion of 250 m- However, despite the fact that workers are aware of the importance of the implementation of Personal Protective Equipment, they do not use them as barriers to mitigate and prevent the realization of the dangers. Conclusions: The identified risks are latent in farmers of the middle and lower area of the watershed.

[Description of Clinical and Neurocognitive Profiles in Offspring of Bipolar-Type-I Parents From a Multimodal Intervention Program: Prisma]. / Descripción de perfiles psicopatológicos y neurocognitivos de hijos de pacientes con trastorno bipolar tipo I dentro un programa de intervencion multimodal: PRISMA.

INTRODUCTION: Offspring of bipolar parents are a high risk population for the develop of mental diseases, their study allow determining the genetic risk, early symptoms, prodromes and psychopathology of bipolar disorder. OBJECTIVE: To describe the psychopathological characteristics and neurocognitives profiles of the offspring of bipolar type I parents. And to identify the presence of sub-syndromal symptoms in all the symptom domains. METHODS: A descriptive and cross-sectional study was conducted on 110 offspring between 6 and 30 years old. Semi-structured diagnostic interviews were performed. The intelectual coeficient was determined and a neuropsychological assessment was performed on 89 offspring. RESULTS: The most prevalent disorder in the offspring was ADHD (27.6%), with major depression (15.5%) and separation anxiety (14.1%) also being prevalent. Seven patients of the sample were diagnosed with bipolar disorder. There was a statistically significant difference between the age groups for ADHD prevalence. The most frequent sub-syndromal symptoms were observed in the disruptive group. Alterations in the cognitive domains: attention, verbal fluency, work memory, and speed of information processing, were observed in the group younger than 18 years. CONCLUSIONS: The offspring of bipolar parents have an elevated rate of psychopathology and cognitive alterations. They are a high risk population for the development of mental disease. These subjects also require close longitudinal observation and early and preventive therapeuthic interventions.

The late endocytic Rab39a GTPase regulates the interaction between multivesicular bodies and chlamydial inclusions.

Given their obligate intracellular lifestyle, Chlamydia trachomatis ensure that they have access to multiple host sources of essential lipids by interfering with vesicular transport. These bacteria hijack Rab6-, Rab11- and Rab14-controlled trafficking pathways to acquire sphingomyelin from the Golgi complex. Another important source of sphingolipids, phospholipids and cholesterol are multivesicular bodies (MVBs). Despite their participation in chlamydial inclusion development and bacterial replication, the molecular mechanisms mediating the interaction between MVBs and chlamydial inclusions remain unknown. In the present study, we demonstrate that Rab39a labels a subset of late endocytic vesicles - mainly MVBs - that move along microtubules. Moreover, Rab39a is actively recruited to chlamydial inclusions throughout the pathogen life cycle by a bacterial-driven process that depends on the Rab39a GTP- or GDP-binding state. Interestingly, Rab39a participates in the delivery of MVBs and host sphingolipids to maturing chlamydial inclusions, thereby promoting inclusion growth and bacterial development. Taken together, our findings indicate that Rab39a favours chlamydial replication and infectivity. This is the first report showing that a late endocytic Rab GTPase is involved in chlamydial infection development.

Descripción de perfiles psicopatológicos y neurocognitivos de hijos de pacientes con trastorno bipolar tipo I dentro un programa de intervencion multimodal: PRISMA / Description of Clinical and Neurocognitive Profiles in Offspring of Bipolar-Type-I Parents From a Multimodal Intervention Program: Prisma

Introducción: Los hijos de pacientes con trastorno bipolar (HPTB) son una población de alto riesgo de sufrir trastornos mentales; su observación permite apreciar el riesgo genético, los síntomas tempranos, los pródromos y la psicopatología del trastorno bipolar (TB). Objetivo: Describir las características psicopatológicas y los perfiles neurocognitivos de los HPTB tipo I. Métodos: Estudio descriptivo de corte transversal en el cual se incluyó a 110 HPTB de 6 a 30 arios de edad. Se hicieron entrevistas diagnósticas semiestructuradas, se determinó el coeficiente intelectual y se aplicó una valoración neuropsicológica a 49 de los HPTB. Resultados: Los diagnósticos más prevalentes entre los HPTB fueron: trastorno de déficit de atención e hiperactividad (27,6%), trastorno depresivo mayor (15,5%) y trastorno de ansiedad por separación (14,1%). A 7 HPTB se les diagnóstico TB. Los síntomas subumbrales más frecuentes, fueron los del grupo de los trastornos disruptivos. Además, en los HPTB menores de 18 años, se observaron alteraciones en los dominios cognitivos: atención, fluidez verbal, memoria de trabajo y velocidad de procesamiento de la información. Conclusiones: Los HPTB presentan una elevada tasa de psicopatologías y alteraciones cognitivas; son una población de alto riesgo de enfermedad mental que requiere estrecha observación longitudinal e intervenciones terapéuticas y preventivas tempranas.

Introduction: Offspring of bipolar parents are a high risk population for the develop of mental diseases, their study allow determining the genetic risk, early symptoms, prodromes and psychopathology of bipolar disorder. Objective: To describe the psychopathological characteristics and neurocognitives profiles of the offspring of bipolar type I parents. And to identify the presence of sub-syndromal symptoms in all the symptom domains. Methods: A descriptive and cross-sectional study was conducted on 110 offspring between 6 and 30 years old. Semi-structured diagnostic interviews were performed. The intelectual coeficient was determined and a neuropsychological assessment was performed on 89 offspring. Results:The most prevalent disorder in the offspring was ADHD (27.6%), with major depression (15.5%) and separation anxiety (14.1%) also being prevalent. Seven patients of the sample were diagnosed with bipolar disorder. There was a statistically significant difference between the age groups for ADHD prevalence. The most frequent sub-syndromal symptoms were observed in the disruptive group. Alterations in the cognitive domains: attention, verbal fluency, work memory, and speed of information processing, were observed in the group younger than 18 years. Conclusions: The offspring of bipolar parents have an elevated rate of psychopathology and cognitive alterations. They are a high risk population for the development of mental disease. These subjects also require close longitudinal observation and early and preventive therapeuthic interventions.

Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections.

Pathogens have evolved highly specialized mechanisms to infect hosts. Several microorganisms modulate the eukaryotic cell surface to facilitate their engulfment. Once internalized, they hijack the molecular machinery of the infected cell for their own benefit. At different stages of phagocytosis, particularly during invasion, certain pathogens manipulate pathways governed by small GTPases. In this review, we focus on the role of Rho proteins on curable, sexually transmitted infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Treponema pallidum. Despite the high, worldwide frequencies of these sexually-transmitted diseases, very little is known about the strategies developed by these microorganisms to usurp key eukaryotic proteins that control intracellular signaling and actin dynamics. Improved knowledge of these molecular mechanisms will contribute to the elucidation of how these clinically important pathogens manipulate intracellular processes and parasitize their hosts.

Identification of a site in Sar1 involved in the interaction with the cytoplasmic tail of glycolipid glycosyltransferases.

Glycolipid glycosyltransferases (GGT) are transported from the endoplasmic reticulum (ER) to the Golgi, their site of residence, via COPII vesicles. An interaction of a (R/K)X(R/K) motif at their cytoplasmic tail (CT) with Sar1 is critical for the selective concentration in the transport vesicles. In this work using computational docking, we identify three putative binding pockets in Sar1 (sites A, B, and C) involved in the interaction with the (R/K)X(R/K) motif. Sar1 mutants with alanine replacement of amino acids in site A were tested in vitro and in cells. In vitro, mutant versions showed a reduced ability to bind immobilized peptides with the CT sequence of GalT2. In cells, Sar1 mutants (Sar1(D198A)) specifically affect the exiting of GGT from the ER, resulting in an ER/Golgi concentration ratio favoring the ER. Neither the typical Golgi localization of GM130 nor the exiting and transport of the G protein of the vesicular stomatitis virus were affected. The protein kinase inhibitor H89 produced accumulation of Sec23, Sar1, and GalT2 at the ER exit sites; Sar1(D189A) also accumulated at these sites, but in this case GalT2 remained disperse along ER membranes. The results indicate that amino acids in site A of Sar1 are involved in the interaction with the CT of GGT for concentration at ER exiting sites.

Calsenilin and CALP interact with the cytoplasmic tail of UDP-Gal:GA2/GM2/GD2 beta-1,3-galactosyltransferase.

GalT2 (UDP-Gal:GA2/GM2/GD2 beta-1,3-galactosyltransferase) is a Golgi-resident type II membrane protein that participates in the synthesis of glycosphingolipids. The molecular determinants for traffic and localization of this and other glycosyltransferases are still poorly characterized. Considering the possibility that interactions with other proteins may influence these processes, in the present study we carried out a yeast two-hybrid screening using elements of the N-terminal domain of GalT2 as bait. In this screening, we identified calsenilin and its close homologue CALP (calsenilin-like protein), both members of the recoverin-NCS (neuronal calcium sensor) family of calcium-binding proteins. In vitro, GalT2 binds to immobilized recombinant CALP, and CALP binds to immobilized peptides with the GalT2 cytoplasmic tail sequence. GalT2 and calsenilin interact physically when co-expressed in CHO (Chinese-hamster ovary)-K1 cells. The expression of CALP or calsenilin affect Golgi localization of GalT2, and of two other glycosyltransferases, SialT2 (CMP-NeuAc:GM3 sialyltransferase) and GalNAcT (UDP-GalNAc:lactosylceramide/GM3/GD3 beta1-4 N-acetylgalactosaminyltransferase), by redistributing them from the Golgi to the ER (endoplasmic reticulum), whereas the localization of the VSV-G (G-protein of the vesicular stomatitis virus) or the Golgin GM130 was essentially unaffected. Conversely, the expression of GalT2 affects the localization of calsenilin and CALP by shifting a fraction of the molecules from being mostly diffuse in the cytosol, to clustered structures in the perinuclear region. These combined in vivo and in vitro results suggest that CALP and calsenilin are involved in the trafficking of Golgi glycosyltransferases.

Arabidopsis displays centromeric DNA hypomethylation and cytological alterations of heterochromatin upon attack by pseudomonas syringae.

Plant tissues display major alterations upon the perception of microbial pathogens. Changes of cytoplasmic and apoplastic components that sense and transduce plant defenses have been extensively characterized. In contrast, less information is available about modifications affecting the plant nuclear genome under these circumstances. Here, we investigated whether the Arabidopsis thaliana DNA methylation status is altered in tissues responding to the attack of Pseudomonas syringae pv. tomato DC3000. We applied amplified fragment length polymorphism analysis to monitor cytosine methylation at anonymous 5'-CCGG-3' and 5'-GATC-3' sites in naive and infected samples. Plant genomic fragments reducing methylation upon infection, including peri/centromeric repeats such as the 180-bp unit, Athila retrotansposon, and a portion of the nuclear insertion of mitochondrial DNA, were isolated and characterized. P. syringae pv. tomato-induced hypomethylation was detected by high-performance liquid chromatography assays and at the molecular level it did not seem to equally affect all 5-methyl cytosine (5-mC) residues. Nuclei from challenged tissues displayed structural chromatin alterations, including loosening of chromocenters, which also were stimulated by avirulent P. syringae pv. tomato, but not by the P. syringae pv. tomato hrpL- mutant. Finally, P. syringae pv. tomato-induced hypomethylation was found to occur in the absence of DNA replication, suggesting that it involves an active demethylation mechanism. All these responses occurred at 1 day postinfection, largely preceding massive plant cell death generated by pathogen attack.