Lineage specific transcription factors and epigenetic regulators mediate TGFß-dependent enhancer activation.

During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFß signaling. Genome-wide experiments demonstrate that the proneural factor ASCL1 assists SMAD3 in the binding to a subset of enhancers. Once located at the enhancers, SMAD3 recruits the histone demethylase JMJD3 and the remodeling factor CHD8, creating the appropriate chromatin landscape to allow enhancer transcription and posterior gene activation. Finally, to analyze the phenotypical traits owed to cis-regulatory regions, we use CRISPR-Cas9 technology to demonstrate that the TGFß-responsive Neurog2 enhancer is essential for proper neuronal polarization.

Characteristics and mortality of elderly patients admitted to the Intensive Care Unit of a district hospital.

AIM: To study all the elderly patients (≥75 years) who were admitted in an Intensive Care Unit (ICU) of a Spanish hospital and identify factors associated with mortality. PATIENTS AND METHODS: A retrospective, observational data collected prospectively in patients ≥75 years recruited from the ICU in the period of January 2004 to December 2010. RESULTS: During the study period, 1661 patients were admitted to our unit, of whom 553 (33.3%) were older than 75 years. The mean age was 79.9 years, 317 (57.3%) were male, and the overall in-hospital mortality was 94 patients (17% confidence interval 14-20.3%). When comparing patients who survived to those who died, we found significant differences in mean age (P = 0.001), Acute Physiologic Assessment and Chronic Health Evaluation II and Simplified Acute Physiology Scoring II (SAPS II) on admission (P < 0.0001, postoperative patients (P = 0.001), and need for mechanical ventilation (P < 0.0001). Comparing age groups, we found statistically significant differences in SAPS II (P = 0.007), diagnosis of non-ST-segment elevation myocardial infarction (P = 0.014), complicated postoperative period (P = 0.001), and pacemaker (P = 0.034). Mortality between the groups was statistically significant (P = 0.004). The survival between the group of 65 and 74 years and patients >75 years was not significant (P = 0.1390). CONCLUSIONS: The percentage of elderly patients in our unit is high, with low mortality rates. The age itself is not the sole determinant for admission to the ICU and other factors should be taken into account.

Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

Overexpression of Canonical Prefoldin Associates with the Risk of Mortality and Metastasis in Non-Small Cell Lung Cancer.

Canonical prefoldin is a protein cochaperone composed of six different subunits (PFDN1 to 6). PFDN1 overexpression promotes epithelial-mesenchymal transition (EMT) and increases the growth of xenograft lung cancer (LC) cell lines. We investigated whether this putative involvement of canonical PFDN in LC translates into the clinic. First, the mRNA expression of 518 non-small cell LC (NSCLC) cases from The Cancer Genome Atlas (TCGA) database was evaluated. Patients with PFDN1 overexpression had lower overall survival (OS; 45 vs. 86 months; p = 0.034). We then assessed the impact of PFDN expression on outcome in 58 NSCLC patients with available tumor tissue samples. PFDN1, 3, and 5 overexpression were found in 38% (n = 22), 53% (n = 31), and 41% (n = 24) of tumor samples. PFDN1, 3, and 5 overexpression were significantly associated with lower OS, lower disease-free survival (DFS), and lower distant metastasis-free survival (DMFS) for PFDN1 and 3 with a trend for PFDN5. In multivariate analysis, PFDN5 retained significance for OS (hazard ratio (HR) 2.56; p = 0.007) and PFDN1 for DFS (HR 2.53; p = 0.010) and marginally for DMFS (HR 2.32; p = 0.053). Our results indicate that protein response markers, such as PFDN1, 3, and 5, may complement mRNA signatures and be useful for determining the most appropriate therapy for NSCLC patients.

The glutathione/glutaredoxin system is essential for arsenate reduction in Synechocystis sp. strain PCC 6803.

Arsenic resistance in Synechocystis sp. strain PCC 6803 is mediated by an operon of three genes in which arsC codes for an arsenate reductase with unique characteristics. Here we describe the identification of two additional and nearly identical genes coding for arsenate reductases in Synechocystis sp. strain PCC 6803, which we have designed arsI1 and arsI2, and the biochemical characterization of both ArsC (arsenate reductase) and ArsI. Functional analysis of single, double, and triple mutants shows that both ArsI enzymes are active arsenate reductases but that their roles in arsenate resistance are essential only in the absence of ArsC. Based on its biochemical properties, ArsC belongs to a family that, though related to thioredoxin-dependent arsenate reductases, uses the glutathione/glutaredoxin system for reduction, whereas ArsI belongs to the previously known glutaredoxin-dependent family. We have also analyzed the role in arsenate resistance of the three glutaredoxins present in Synechocystis sp. strain PCC 6803 both in vitro and in vivo. Only the dithiolic glutaredoxins, GrxA (glutaredoxin A) and GrxB (glutaredoxin B), are able to donate electrons to both types of reductases in vitro, while GrxC (glutaredoxin C), a monothiolic glutaredoxin, is unable to donate electrons to either type. Analysis of glutaredoxin mutant strains revealed that only those lacking the grxA gene have impaired arsenic resistance.

Biochemical methane potential of oil-extracted microalgae and glycerol in co-digestion with chicken litter.

The objective of this work was to evaluate the technical feasibility of using both oil-extracted microalgae (M) and glycerol (G) in co-digestion with chicken litter (CL), thereby improving biochemical methane potential (BMP). Different feedstock ratios of M (0-30%), G (0-3%) and CL (67-100%) were investigated to determine the best co-digestion condition under mesophilic conditions. According to the modified Gompertz model, the best BMP (131.1mLCH4gVSfed-1) was obtained with the triple co-digestion (M:G:CL) in a proportion of 30:3:67. This yielded a methane production rate (µm) of 3.3mLCH4gVSfed-1d-1 and a lag time (λ) of 17.4d. This treatment reduced chemical oxygen demand (COD) by 91.02% and increased the methane yield 15.8% with respect to the CL control.

[Cost analysis and economic impact of anterior cruciate ligament reconstruction]. / Análisis de costo e impacto económico de la reconstrucción de ligamento cruzado anterior (LCA).

INTRODUCTION: Health economics studies play an important role in all healthcare systems. The purpose of the latter is to offer effective and low-cost treatments. OBJECTIVE: Analyze the costs and the economic impact of the comprehensive ACL treatment. MATERIAL AND METHODS: An average cost study was done of primary ACL reconstruction. We studied 104 patients during 2005, 79 males and 25 females, with mean age 31.5 years. The assessment of the preoperative, operative and postoperative costs was related to each patient's socioeconomic stratum (SES). RESULTS: The hamstrings were the most frequently used graft (71%) versus the bone-patellar tendon-bone graft (BTB) (29%). Socioeconomic strata 2 and 3 were predominant. The following were the most frequent hamstrings implants used: Rigidfix/Intrafix and Endobutton/Xtralok, while the most frequent BTB grafts used were the metallic interference screws. No difference was found between the types of grafts and the SES in the preoperative and postoperative costs, including imaging studies, hospital say and rehabilitation. However, differences were found among the different groups in the cost of surgery, resulting from the type of implant used. The mean cost for SES 1 and 2 was $6475.20, for SES 3 and 4, $8057.51, and for SES 5 and 6, $16,242.5. The vulnerable population (SES 1) needs 7.34-fold its monthly income to pay for the comprehensive treatment, while the middle stratum (SES 3) needs 3.27-fold its monthly income. CONCLUSIONS: The comprehensive cost of treatment is proportionally higher than the patients' income. It is important to point out that the systems using state-of-the-art technology, which in another setting would be inaccessible, have significant advantages when compared with the less expensive systems. Thus the economically vulnerable SES benefit from the subsidy granted by the National Institutes of Health.

Integracion, docencia, servicios e investigacion en el area de la salud / A project for developing a comprehensive teaching, research and service program for health care delivery

Partiendo del concepto de salud utilizada por los organismos internacionales, se llevó a cabo un análisis de las posibilidades de integración académica de las escuelas del área de la salud de la Universidad Autónoma de Puebla y el Hospital Universitario, estableciendo una propuesta basada en las necesidades sociales en salud de la población en nuestro pais en lo general y del estado de Puebla en particular. Para tal efecto se revisaron diversos reglamentos, leyes y programas de salud y educativos nacionales, presentándose un Modelo de Integración Docencia, Servicio de Investigación como alternativa educativa frente al diagnóstico académico de esa institución

Uso prolongado de colírios antiglaucomatosos e eficácia da trabeculectomia / Long-term use of antiglaucoma eye-drops and trabeculectomy efficacy

Retrospectivamente, foram analisadas 284 trabeculectomias realizadas em glaucomas primários com o objetivo de avaliar a influência do tratamento pré-operatório prolongado com colírios antiglaucomatosos na eficácia do procedimento. 176 pacientes fizeram uso de medicaçäo tópica por 26,5 + ou - 20 meses e 45 por um período näo superior a um mês. Constatou-se uma maior proporçäo de sucesso estatisticamente significante (96,29 por cento) no grupo sem medicaçäo em relaçäo ao do grupo com medicaçäo (83,91 por cento). Os resultados sugerem que o uso prolongado de antiglaucomatosos tópicos pode predispor ao insucesso da cirurgia