Insulin Resistance in Women Correlates with Chromatin Histone Lysine Acetylation, Inflammatory Signaling, and Accelerated Aging.

BACKGROUND: Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top "hit" was chromatin opening at H3K9ac. METHODS: Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women. RESULTS: ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women. CONCLUSIONS: This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer.

Diversity and potential functional role of phyllosphere-associated actinomycetota isolated from cupuassu (Theobroma grandiflorum) leaves: implications for ecosystem dynamics and plant defense strategies.

Exploring the intricate relationships between plants and their resident microorganisms is crucial not only for developing new methods to improve disease resistance and crop yields but also for understanding their co-evolutionary dynamics. Our research delves into the role of the phyllosphere-associated microbiome, especially Actinomycetota species, in enhancing pathogen resistance in Theobroma grandiflorum, or cupuassu, an agriculturally valuable Amazonian fruit tree vulnerable to witches' broom disease caused by Moniliophthora perniciosa. While breeding resistant cupuassu genotypes is a possible solution, the capacity of the Actinomycetota phylum to produce beneficial metabolites offers an alternative approach yet to be explored in this context. Utilizing advanced long-read sequencing and metagenomic analysis, we examined Actinomycetota from the phyllosphere of a disease-resistant cupuassu genotype, identifying 11 Metagenome-Assembled Genomes across eight genera. Our comparative genomic analysis uncovered 54 Biosynthetic Gene Clusters related to antitumor, antimicrobial, and plant growth-promoting activities, alongside cutinases and type VII secretion system-associated genes. These results indicate the potential of phyllosphere-associated Actinomycetota in cupuassu for inducing resistance or antagonism against pathogens. By integrating our genomic discoveries with the existing knowledge of cupuassu's defense mechanisms, we developed a model hypothesizing the synergistic or antagonistic interactions between plant and identified Actinomycetota during plant-pathogen interactions. This model offers a framework for understanding the intricate dynamics of microbial influence on plant health. In conclusion, this study underscores the significance of the phyllosphere microbiome, particularly Actinomycetota, in the broader context of harnessing microbial interactions for plant health. These findings offer valuable insights for enhancing agricultural productivity and sustainability.

In vivo AAV-SB-CRISPR screens of tumor-infiltrating primary NK cells identify genetic checkpoints of CAR-NK therapy.

Natural killer (NK) cells have clinical potential against cancer; however, multiple limitations hinder the success of NK cell therapy. Here, we performed unbiased functional mapping of tumor-infiltrating NK (TINK) cells using in vivo adeno-associated virus (AAV)-SB (Sleeping Beauty)-CRISPR (clustered regularly interspaced short palindromic repeats) screens in four solid tumor mouse models. In parallel, we characterized single-cell transcriptomic landscapes of TINK cells, which identified previously unexplored subpopulations of NK cells and differentially expressed TINK genes. As a convergent hit, CALHM2-knockout (KO) NK cells showed enhanced cytotoxicity and tumor infiltration in mouse primary NK cells and human chimeric antigen receptor (CAR)-NK cells. CALHM2 mRNA reversed the CALHM2-KO phenotype. CALHM2 KO in human primary NK cells enhanced their cytotoxicity, degranulation and cytokine production. Transcriptomics profiling revealed CALHM2-KO-altered genes and pathways in both baseline and stimulated conditions. In a solid tumor model resistant to unmodified CAR-NK cells, CALHM2-KO CAR-NK cells showed potent in vivo antitumor efficacy. These data identify endogenous genetic checkpoints that naturally limit NK cell function and demonstrate the use of CALHM2 KO for engineering enhanced NK cell-based immunotherapies.

JUN mRNA translation regulation is mediated by multiple 5' UTR and start codon features.

Regulation of mRNA translation by eukaryotic initiation factors (eIFs) is crucial for cell survival. In humans, eIF3 stimulates translation of the JUN mRNA which encodes the transcription factor JUN, an oncogenic transcription factor involved in cell cycle progression, apoptosis, and cell proliferation. Previous studies revealed that eIF3 activates translation of the JUN mRNA by interacting with a stem loop in the 5' untranslated region (5' UTR) and with the 5' -7-methylguanosine cap structure. In addition to its interaction site with eIF3, the JUN 5' UTR is nearly one kilobase in length, and has a high degree of secondary structure, high GC content, and an upstream start codon (uAUG). This motivated us to explore the complexity of JUN mRNA translation regulation in human cells. Here we find that JUN translation is regulated in a sequence and structure-dependent manner in regions adjacent to the eIF3-interacting site in the JUN 5' UTR. Furthermore, we identify contributions of an additional initiation factor, eIF4A, in JUN regulation. We show that enhancing the interaction of eIF4A with JUN by using the compound Rocaglamide A (RocA) represses JUN translation. We also find that both the upstream AUG (uAUG) and the main AUG (mAUG) contribute to JUN translation and that they are conserved throughout vertebrates. Our results reveal additional layers of regulation for JUN translation and show the potential of JUN as a model transcript for understanding multiple interacting modes of translation regulation.

JUN mRNA Translation Regulation is Mediated by Multiple 5' UTR and Start Codon Features.

Regulation of mRNA translation by eukaryotic initiation factors (eIFs) is crucial for cell survival. In humans, eIF3 stimulates translation of the JUN mRNA which encodes the transcription factor JUN, an oncogenic transcription factor involved in cell cycle progression, apoptosis, and cell proliferation. Previous studies revealed that eIF3 activates translation of the JUN mRNA by interacting with a stem loop in the 5' untranslated region (5' UTR) and with the 5'-7-methylguanosine cap structure. In addition to its interaction site with eIF3, the JUN 5' UTR is nearly one kilobase in length, and has a high degree of secondary structure, high GC content, and an upstream start codon (uAUG). This motivated us to explore the complexity of JUN mRNA translation regulation in human cells. Here we find that JUN translation is regulated in a sequence and structure-dependent manner in regions adjacent to the eIF3-interacting site in the JUN 5' UTR. Furthermore, we identify contributions of an additional initiation factor, eIF4A, in JUN regulation. We show that enhancing the interaction of eIF4A with JUN by using the compound Rocaglamide A (RocA) represses JUN translation. We also find that both the upstream AUG (uAUG) and the main AUG (mAUG) contribute to JUN translation and that they are conserved throughout vertebrates. Our results reveal additional layers of regulation for JUN translation and show the potential of JUN as a model transcript for understanding multiple interacting modes of translation regulation.

Enfermedad renal crónica en la región oriente del Estado de México: implicación de los determinantes sociales de la salud

Fundamento: la enfermedad renal crónica mantiene a quienes la padecen inmersos en un contexto de dependencia física, psicológica y social que demanda una atención única en su tipo. Objetivo: analizar los determinantes sociales de la salud presentes en el entorno de la atención del paciente con enfermedad renal crónica. Métodos: se realizó un estudio cualitativo en la región oriente del Estado de México en el que participaron 27 pacientes con enfermedad renal crónica quienes respondieron una entrevista semiestructurada. Se utilizó el software Iramuteq v0.7alpha2 para codificar los discursos. Resultados: la voz de la enfermedad está relegada a ser devastadora en su atención y forma de vivir; el ingreso debido a los constantes desplazamientos, costos de atención médica y el desempleo conjuga una trampa mortal que condiciona la fragmentación económica del paciente; las políticas públicas son inalcanzables -referido al programa de transplantes-; la cultura, muestra un simbolismo religioso de protección a la salud unido a la estigmatización social por padecer enfermedad renal crónica; el sistema de salud transita en falta de garantías del servicio -diálisis, hemodiálisis, falta de insumos-; el género muestra equidad en la atención pero sobrecarga de la mujer en el cuidado del paciente. Conclusiones: por su impacto en la forma de vivir y atender la enfermedad renal crónica los determinantes sociales de la salud deben incluirse transdisciplinarmente en las politicas públicas de salud, donde no solo la epidemiología dicte el abordaje del paciente renal, en esta época los modelos matemáticos no son aplicables a los colectivos, pues las conductas sociales, culturales y los determinantes sociales de la salud marcan las pautas del comportamiento de los seres humanos.

Background: chronic kidney disease keeps the person who suffers from it immersed in a context of physical, psychological and social dependence that demands unique attention of its kind. Objective: to analyze the social determinants of health present in the care setting for patients with chronic kidney disease. Methods: a qualitative study was carried out in the eastern part of the State of Mexico in which 27 patients with chronic kidney disease participated who answered a semi-structured interview, using the Iramuteq v0.7alpha2 software to code the speeches. Results: the voice of the disease is relegated to be devastating in its attention and way of living; income due to constant travel, medical care costs and unemployment conjugates a deadly trap that conditions the economic fragmentation of the patient; public policies are unattainable -referring to the transplant program-; culture shows a religious symbolism of protection to the health coupled with social stigmatization for suffering chronic kidney disease CKD; the health system transits in lack of service guarantees -dialysis, hemodialysis, lack of supplies-; gender shows equality in care but overload of women in patient care. Conclusions: due to their impact on the way of living and caring for chronic kidney disease, the social determinants of health should be included transdisciplinary in public health policies, where not only epidemiology dictates the approach to renal patients, at this time mathematical models They are not applicable to groups, because social, cultural behaviors and the social determinants of health set the behavior patterns of human beings.

Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

Perturbomics of tumor-infiltrating NK cells.

Natural killer (NK) cells are an innate immune cell type that serves at the first level of defense against pathogens and cancer. NK cells have clinical potential, however, multiple current limitations exist that naturally hinder the successful implementation of NK cell therapy against cancer, including their effector function, persistence, and tumor infiltration. To unbiasedly reveal the functional genetic landscape underlying critical NK cell characteristics against cancer, we perform perturbomics mapping of tumor infiltrating NK cells by joint in vivo AAV-CRISPR screens and single cell sequencing. We establish a strategy with AAV-SleepingBeauty(SB)- CRISPR screening leveraging a custom high-density sgRNA library targeting cell surface genes, and perform four independent in vivo tumor infiltration screens in mouse models of melanoma, breast cancer, pancreatic cancer, and glioblastoma. In parallel, we characterize single-cell transcriptomic landscapes of tumor-infiltrating NK cells, which identifies previously unexplored sub-populations of NK cells with distinct expression profiles, a shift from immature to mature NK (mNK) cells in the tumor microenvironment (TME), and decreased expression of mature marker genes in mNK cells. CALHM2, a calcium homeostasis modulator that emerges from both screen and single cell analyses, shows both in vitro and in vivo efficacy enhancement when perturbed in chimeric antigen receptor (CAR)-NK cells. Differential gene expression analysis reveals that CALHM2 knockout reshapes cytokine production, cell adhesion, and signaling pathways in CAR- NKs. These data directly and systematically map out endogenous factors that naturally limit NK cell function in the TME to offer a broad range of cellular genetic checkpoints as candidates for future engineering to enhance NK cell-based immunotherapies.

Nephrotic Syndrome in Adult Patients With COVID-19 Infection or Post COVID-19 Vaccine: A Systematic Review.

Nephrotic syndrome is a condition characterized by damage to podocytes that results in significant proteinuria, edema, hyperlipidemia, and hypercoagulability. Infections and malignancies are frequently associated with nephrotic syndrome. The COVID-19 virus has been associated with several atypical presentations of upper respiratory infections and acute kidney injury. Considering that COVID-19 causes systemic inflammatory changes, it seems plausible that it may also lead to nephrotic syndrome. This study aimed to investigate if an association between COVID-19 and the different types of nephrotic syndromes exists. Data were extracted into a spreadsheet. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS, IBM Corp., Armonk, NY, USA). We performed a systematic search of PubMed/Medline and Embase databases using both medical subject headings (MeSH) and regular keywords associated with COVID-19 and nephrotic syndrome, including different types of nephrotic syndromes. The search was performed on 17th December 2021. We included case reports and case series about adult patients who developed findings suggestive of nephrotic syndrome shortly after infection or vaccination. We excluded cases involving children, pregnant women, articles written in languages other than English, and those that were not retrievable. The relevance and quality of identified articles were assessed. We included 32 articles in the study, primarily case reports and case series. In our study, COVID-19 and the COVID-19 vaccine have been associated with the development of nephrotic syndrome, primarily a collapsing form of focal segmental glomerulosclerosis, although other forms have been observed as well. There was little consistency in patient histories, clinical presentations, clinical courses, or treatment regimens, although it appeared that most cases eventually resolved. More cases need to be reported and analyzed before more definitive conclusions can be reached. In conclusion, nephrotic syndrome is a possible complication of both COVID-19 infection and the COVD-19 vaccine and should be considered in patients exhibiting sudden onset edemas or deterioration in kidney function. While the majority of cases respond to standard treatment, clearer guidelines will need to be developed once more data is available.

Detection of DNA Adduct Formation in Rat Lungs by a Micro-HPLC/MS/MS Approach.

Aldehydes are abundantly present in tobacco smoke and in urban air pollution and are endogenously generated as products of the lipid peroxidation process. These molecules can react with DNA bases forming mutagenic exocyclic adducts, which have been used as biomarkers of aldehyde exposure and as potential tools for the study of inflammation, metal storage diseases, neurodegenerative disorders, and cancer. High-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS) provides a highly precise, specific and ultrasensitive method for the detection of exocyclic DNA adducts. Here we present and describe a validated micro-HPLC-Electro Spray Ionization (ESI)-MS/MS method for the quantification of 1,N2-propanodGuo, an adduct produced following the reaction between 2'-deoxyguanosine and acetaldehyde or crotonaldehyde.

Complete genome sequence and analysis of Alcaligenes faecalis strain Mc250, a new potential plant bioinoculant.

Here we present and analyze the complete genome of Alcaligenes faecalis strain Mc250 (Mc250), a bacterium isolated from the roots of Mimosa calodendron, an endemic plant growing in ferruginous rupestrian grasslands in Minas Gerais State, Brazil. The genome has 4,159,911 bp and 3,719 predicted protein-coding genes, in a single chromosome. Comparison of the Mc250 genome with 36 other Alcaligenes faecalis genomes revealed that there is considerable gene content variation among these strains, with the core genome representing only 39% of the protein-coding gene repertoire of Mc250. Mc250 encodes a complete denitrification pathway, a network of pathways associated with phenolic compounds degradation, and genes associated with HCN and siderophores synthesis; we also found a repertoire of genes associated with metal internalization and metabolism, sulfate/sulfonate and cysteine metabolism, oxidative stress and DNA repair. These findings reveal the genomic basis for the adaptation of this bacterium to the harsh environmental conditions from where it was isolated. Gene clusters associated with ectoine, terpene, resorcinol, and emulsan biosynthesis that can confer some competitive advantage were also found. Experimental results showed that Mc250 was able to reduce (~60%) the virulence phenotype of the plant pathogen Xanthomonas citri subsp. citri when co-inoculated in Citrus sinensis, and was able to eradicate 98% of juveniles and stabilize the hatching rate of eggs to 4% in two species of agricultural nematodes. These results reveal biotechnological potential for the Mc250 strain and warrant its further investigation as a biocontrol and plant growth-promoting bacterium.

Environmental Exposures during Puberty: Window of Breast Cancer Risk and Epigenetic Damage.

During puberty, a woman's breasts are vulnerable to environmental damage ("window of vulnerability"). Early exposure to environmental carcinogens, endocrine disruptors, and unhealthy foods (refined sugar, processed fats, food additives) are hypothesized to promote molecular damage that increases breast cancer risk. However, prospective human studies are difficult to perform and effective interventions to prevent these early exposures are lacking. It is difficult to prevent environmental exposures during puberty. Specifically, young women are repeatedly exposed to media messaging that promotes unhealthy foods. Young women living in disadvantaged neighborhoods experience additional challenges including a lack of access to healthy food and exposure to contaminated air, water, and soil. The purpose of this review is to gather information on potential exposures during puberty. In future directions, this information will be used to help elementary/middle-school girls to identify and quantitate environmental exposures and develop cost-effective strategies to reduce exposures.

[Influence of exercise on weight gain during pregnancy. Randomized clinical trial]. / Influencia del ejercicio físico en la evolución del peso gestacional y posparto. Ensayo clínico aleatorizado.

INTRODUCTION: Introduction: physical exercise is a good way to maintain a healthy lifestyle and its regular practice is recommended during the gestational period, favoring, among others, an adequate weight gain during pregnancy and a better recovery of pre-pregnancy weight. Objective: to analyze the evolution of weight, gestational and postpartum, in pregnant women who perform a program of moderate physical exercise in the aquatic environment. Material and methods: an intervention was carried out through a program of aquatic physical exercise designed specifically for pregnant women. The participants were randomly assigned to the exercise group (EG; n = 65) or to the control group (CG; n = 64). Participants in the EG performed three sessions per week of physical exercises, which were led by the principal investigator. CG participants received routine prenatal care. Maternal weight was measured during pregnancy at weeks 20 and 35, and postpartum at weeks 16 and 28 of the same. Results: weight gain during pregnancy shows significant differences between groups (p < 0.001). Weight retention at four months and at seven months were significant between EG and GC (p < 0.001). The weight of the newborn remained in the range of normal weight for term newborns in both groups, although with significant differences (p = 0.011). Conclusion: the Study of Water Exercise Pregnancy (SWEP) methodology during pregnancy helps control the gain of gestational weight and the recovery of pre-pregnancy weight.

INTRODUCCIÓN: Introducción: el ejercicio físico es una buena forma de mantener un estilo de vida saludable y su práctica regular es recomendable durante el periodo gestacional, favoreciendo, entre otros, una adecuada ganancia ponderal durante la gestación y una mejor recuperación del peso pregestacional. Objetivo: analizar la evolución del peso, gestacional y posparto, en mujeres embarazadas que realizan un programa de ejercicio físico moderado en el medio acuático. Material y métodos: se realizó una intervención mediante un programa de ejercicio físico acuático diseñado específicamente para mujeres embarazadas. Los participantes fueron asignados al azar al grupo de ejercicios (GE; n = 65) o al grupo de control (GC; n = 64). Los participantes en el GE realizaron tres sesiones por semana de ejercicios físicos, que fueron dirigidos por el investigador principal. Las participantes del GC recibieron atención prenatal de rutina. El peso materno se midió durante la gestación en las semanas 20 y 35 y en el posparto en las semanas 16 y 28 del mismo. Resultados: la ganancia ponderal durante la gestación presenta diferencias significativas entre grupos (p < 0,001). Las retenciones de peso a los cuatro meses y a los siete meses fueron significativas entre GE y GC (p < 0,001). El peso del recién nacido se mantuvo en el rango de peso normal para recién nacidos a término en ambos grupos, aunque con diferencias significativas (p = 0,011). Conclusión: la metodología Study of Water Exercise Pregnancy (SWEP) durante el embarazo ayuda al control de la ganancia de peso gestacional y a la recuperación del peso pregestacional.

Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer.

BACKGROUND: Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. RESULTS: MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. CONCLUSIONS: These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.

DNA Adduct Formation in the Lungs and Brain of Rats Exposed to Low Concentrations of [13C2]-Acetaldehyde.

Air pollution is a major environmental risk for human health. Acetaldehyde is present in tobacco smoke and vehicle exhaust. In this study, we show that [13C2]-acetaldehyde induces DNA modification with the formation of isotopically labeled 1, N2-propano-2'-deoxyguanosine adducts in the brain and lungs of rats exposed to concentrations of acetaldehyde found in the atmosphere of megacities. The adduct, with the addition of two molecules of isotopically labeled acetaldehyde [13C4]-1, N2-propano-dGuo, was detected in the lung and brain tissues of exposed rats by micro-HPLC/MS/MS. Structural confirmation of the products was unequivocally performed by nano-LC/ESI+-HRMS3 analyses. DNA modifications induced by acetaldehyde have been regarded as a key factor in the mechanism of mutagenesis and may be involved in the cancer risks associated with air pollution.

Association Between Proton Pump Inhibitors and Microscopic Colitis.

OBJECTIVE: Microscopic colitis (MC) is a chronic inflammatory disease of the colon that is characterized by chronic, watery, nonbloody diarrhea. Concern regarding a potential association between proton-pump inhibitors (PPIs) and MC has recently emerged. We sought to systematically review and summarize the evidence for the potential association between PPIs and MC. DATA SOURCES: We systematically searched EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Google Scholar using the terms proton-pump inhibitors (omeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, or esomeprazole), microscopic colitis, collagenous colitis, and lymphocytic colitis. STUDY SELECTION: Full-text, English-language reports of case reports/series, observational studies, experimental studies, and systematic reviews/meta-analyses published between January 2000 to August 2016 were included. Bibliographies from pertinent publications were reviewed for additional references. Outcome was defined as the development of biopsy-confirmed MC. DATA EXTRACTION/SYNTHESIS: A total of 19 publications were identified: 5 case control studies and 14 case reports/series (encompassing a total of 32 cases). All studies were limited by small sample sizes. Risk of MC by dose or specific PPI agent was not investigated in any of the studies. A review of the current body of evidence reveals a possible association between PPIs and MC. CONCLUSIONS: There is a need for large observational studies of high quality to examine the differential effect of specific PPIs and whether the magnitude of association is dose dependent. Given their widespread use, clinicians should routinely question whether patients are receiving unnecessary treatment with PPIs and discontinue therapy where appropriate.

Bmp15 Is an Oocyte-Produced Signal Required for Maintenance of the Adult Female Sexual Phenotype in Zebrafish.

Although the zebrafish is a major model organism, how they determine sex is not well understood. In domesticated zebrafish, sex determination appears to be polygenic, being influenced by multiple genetic factors that may vary from strain to strain, and additionally can be influenced by environmental factors. However, the requirement of germ cells for female sex determination is well documented: animals that lack germ cells, or oocytes in particular, develop exclusively as males. Recently, it has been determined that oocytes are also required throughout the adult life of the animal to maintain the differentiated female state. How oocytes control sex differentiation and maintenance of the sexual phenotype is unknown. We therefore generated targeted mutations in genes for two oocyte produced signaling molecules, Bmp15 and Gdf9 and here report a novel role for Bmp15 in maintaining adult female sex differentiation in zebrafish. Females deficient in Bmp15 begin development normally but switch sex during the mid- to late- juvenile stage, and become fertile males. Additionally, by generating mutations in the aromatase cyp19a1a, we show that estrogen production is necessary for female development and that the function of Bmp15 in female sex maintenance is likely linked to the regulation of estrogen biosynthesis via promoting the development of estrogen-producing granulosa cells in the oocyte follicle.

Zebrafish Germ Cell Tumors.

Germ cell tumors (GCTs) are malignant cancers that arise from embryonic precursors known as Primordial Germ Cells. GCTs occur in neonates, children, adolescents and young adults and can occur in the testis, the ovary or extragonadal sites. Because GCTs arise from pluripotent cells, the tumors can exhibit a wide range of different histologies. Current cisplatin-based combination therapies cures most patients, however at the cost of significant toxicity to normal tissues. While GWAS studies and genomic analysis of human GCTs have uncovered somatic mutations and loci that might confer tumor susceptibility, little is still known about the exact mechanisms that drive tumor development, and animal models that faithfully recapitulate all the different GCT subtypes are lacking. Here, we summarize current understanding of germline development in humans and zebrafish, describe the biology of human germ cell tumors, and discuss progress and prospects for zebrafish GCT models that may contribute to better understanding of human GCTs.

Proceso penal, privacidad y autodeterminación informativa en la persecución penal de la delincuencia organizada. Un análisis desde la perspectiva del derecho procesal penal alemán / Criminal action, privacy and informative self-determination in the criminal prosecution of organized crime. An analysis from the perspective of German criminal procedural law / Processo penal, privacidade e auto-determinação informativa na perseguição penal da delinquência organizada. Uma análise desde a perspectiva do direito processual penal alemão

El surgimiento y fortalecimiento de la delincuencia organizada en las últimas décadas del siglo XX determinan un cambio en las herramientas de investigación penal y su regulación en muchos sistemas jurídicos. Estos instrumentos, apoyados en el desarrollo de nuevas tecnologías, poseen características que los diferencian de las clásicas medidas de investigación. En el presente artículo se describe esta transformación en el proceso penal alemán (I), analizando el contexto en que se ha originado la regulación de estos nuevos instrumentos de investigación penal de la delincuencia organizada (A), estudiando sus características especiales (B) y deduciendo las características generales (C). Posteriormente se reseña, desde la perspectiva de la doctrina y jurisprudencia alemanas, el significado de dos libertades fundamentales afectadas con la ejecución de tales mecanismos (II): el derecho a la privacidad (A) y el derecho a la autodeterminación informativa (B). Cómo conciliar el uso de estas medidas de investigación y su afectación a las garantías fundamentales mencionadas, constituye el tercer apartado del artículo (III). En este se examinan los diferentes presupuestos desarrollados por la doctrina y la jurisprudencia alemanas, para legitimar este tipo de intervenciones. Seguidamente (IV) se describe, de manera general, la estructura desarrollada por el legislador alemán para la regulación de las medidas de investigación aquí tratadas, teniendo en cuenta los presupuestos señalados en el acápite precedente. Finalmente, las conclusiones están dirigidas a reflexionar acerca de la importancia de una regulación estructurada de aquellas medidas de investigación, de carácter secreto y utilizadas en la persecución penal de determinados tipos de criminalidad, como la delincuencia organizada, cuyo empleo acarrea graves injerencias en derechos fundamentales.

The emergence and invigoration of organized crime in the past few decades of the 20th century have imposed a change in criminal investigation tools and regulation in many juridical aspects. The features of these instruments, as supported by the development of new technologies, make them different from the classical investigative measures. In this article, the transformation of the German legal procedure is described by: I) analyzing the context from which the regulation of these new criminal investigation of organized crime instruments have emerged (A), studying their particular features (B), and deducting the general characteristics (C). Subsequently, from the perspective of German doctrine and jurisprudence, a review is made of the meaning of two fundamental freedoms affected with the enforcement of these mechanisms: II) the right to privacy (A), and the right to informational self determination (B). How is it possible to reconcile the use of these investigative measures and the way they adversely affect the above-mentioned fundamental liberties or guarantees makes part of the third item (III) in this article, where the different assumptions developed by German doctrine and jurisprudence are examined as to legitimize this type of interventions. Then (IV), in a general manner, the structure developed by the German legislator concerning the regulation of the investigative measures analyzed herein, by taking into account the above assumptions seen in the foregoing section. Finally, the conclusions are aimed at reflecting about the importance of a structured regulation for any such investigation measures of secret nature and used in the prosecution of particular types of criminality like organized crime, the use of which entails very serious interference in fundamental rights.

O surgimento e fortalecimento da delinquência organizada nas últimas décadas do século XX determinam uma mudança nas ferramentas da investigação penal e seu regulamento em muitos sistemas legais. Estes instrumentos, suportados no desenvolvimento de novas tecnologias, têm as características que os diferenciam das medidas clássicas da investigação. Neste artigo, esta transformação no processo penal alemão (I) é descrito, analisando o contexto em que o regulamento destes instrumentos novos da investigação penal da delinquência organizada (A) foi originada, estudando suas características especiais (B) e deduzindo as características gerais (C). Posteriormente resenha-se, desde a perspectiva da doutrina e da jurisprudência alemãs, o significado de duas liberdades fundamentais afetadas com a execução de tais mecanismos (II): o direito à privacidade (A) e o direito à auto-determinação informativa (B). Como conciliar o uso destas medidas da investigação e da sua afetação às garantias fundamentais mencionadas, constitui a terceira seção do artigo (III). Neste, os pressupostos diferentes desenvolvidos pela doutrina e pela jurisprudência alemãs são examinados, para legitimar este tipo de intervenções. Seguidamente (IV) descreva-se, em geral, a estrutura desenvolvida pelo legislador alemão para o regulamento das medidas da investigação tratadas aqui, considerando os pressupostos indicados no parágrafo precedente. Finalmente, as conclusões são dirigidas para refletir sobre a importância de um regulamento estruturado daquelas medidas da investigação, de caráter secreto e usadas na perseguição penal de determinados tipos de criminalidade, como a delinquência organizada, cujo uso ocasiona interferências sérias em direitos fundamentais.

Trasplantes en mmérica latina y el caribe: difusión del documento de aguascalientes / Transplants n laatin america and the caribbean: release of the aguascalientes document / Transpantes na aamérica latina e no caribe: difusão do documento de aguascaiientes

Durante el primer Foro de Bioética de la Sociedad de Trasplantes de Latinoamérica y el Caribe 2010 se redactó el Documento de Aguascalientes que busca salvaguardar la integridad del donante vivo. El artículo tiene por objeto indagar sobre el Documento de Aguascalientes entre los participantes del Congreso de la SLANH 2012. Se aplicó un cuestionario con 21 preguntas sobre temas abordados por el dicho documento. Los resultados muestran que el 36,3% acepta al donante vivo no relacionado; 36,3% considera que hay margen de crecimiento en la tasa de donantes fallecidos; 57,9% garantiza la salud con medicamentos inmunosupresores de calidad; 61,5% no conoce el documento. Se concluye que el Documento de Aguascalientes tiene recomendaciones útiles para vigilar aspectos bioéticos de trasplantes.

The Aguascalientes Document was drafted during the first 2010 Bioethics Forum of the Transplantation Society in Latin America and the Caribbean. The object of the document is to safeguard the integrity of the living donor. This article aims to investigate the Aguascalientes Document among the participants to the 2012 SLANH Congress. A questionnaire was applied, with 21 questions on topics covered by said document. The results show that 36.3% of the respondents accepts the unrelated living donor; 36.3% believes there is a margin of growth in the rate of deceased donors; 57.9% guarantees health with quality immunosuppressive drugs; 61.5% does not know the document. In view of the above, it is concluded that the Aguascalientes Document contains useful recommendations for monitoring the bioethical aspects of transplants.

Durante o primeiro Fórum de Bioética da Sociedade de Transplantes da América Latina e do Caribe 2010, redigiu-se o Documento de Aguascalientes, que pretende assegurar a integridade do doador vivo. O artigo tem por objetivo indagar sobre o Documento de Aguascalientes entre os participantes do Congresso da SLANH 2012. Aplicou-se um questionário com 21 perguntas sobre temas abordados por tal documento. Os resultados mostram que 36,3% aceitam o doador vivo não relacionado; 36,3% consideram que há margem de crescimento na taxa de doadores falecidos; 57,9% garantem a saúde com medicamentos imunossupressores de qualidade; 61,5% não conhecem o documento. Conclui-se que o Documento de Aguascalientes tem recomendações úteis para vigiar aspectos bioéticos de transplantes.