p27Kip1 regulates alpha-synuclein expression.

Alpha-synuclein (α-SYN) is the main component of anomalous protein aggregates (Lewy bodies) that play a crucial role in several neurodegenerative diseases (synucleinopathies) like Parkinson's disease and multiple system atrophy. However, the mechanisms involved in its transcriptional regulation are poorly understood. We investigated here the role of the cyclin-dependent kinase (Cdk) inhibitor and transcriptional regulator p27Kip1 (p27) in the regulation of α-SYN expression. We observed that selective deletion of p27 by CRISPR/Cas9 technology in neural cells resulted in increased levels of α-SYN. Knock-down of the member of the same family p21Cip1 (p21) also led to increased α-SYN levels, indicating that p27 and p21 collaborate in the repression of α-SYN transcription. We demonstrated that this repression is mediated by the transcription factor E2F4 and the member of the retinoblastoma protein family p130 and that it is dependent of Cdk activity. Chromatin immunoprecipitation analysis revealed specific binding sites for p27, p21 and E2F4 in the proximal α-SYN gene promoter. Finally, luciferase assays revealed a direct action of p27, p21 and E2F4 in α-SYN gene expression. Our findings reveal for the first time a negative regulatory mechanism of α-SYN expression, suggesting a putative role for cell cycle regulators in the etiology of synucleinopathies.

Findings from the Initial Use of the Healthy Homes Rating System (HHRS) in Three American Cities.

HUD's Healthy Homes Rating System (HHRS) is a modification of the English version, using scoring values developed in England. The goal of the HUD Three-City Healthy Homes Rating System (HHRS) study was to create a baseline of the prevalence and severity of 29 home health hazards in three cities-Detroit, MI; Greensboro, NC; and Alameda County, CA-and to compare the results to the prevalence and severity found in England. We analyzed 978 housing assessments over 3 years. Hygrothermal hazards (e.g., excess cold) were the most prevalent across the sites. However, significant differences in the type and severity of hazards across communities were found and were more severe in US sample homes than in their English counterparts. The results suggest that the tool shows promise in its ability to identify home health hazards.

p27Kip1, PCAF and PAX5 cooperate in the transcriptional regulation of specific target genes.

The cyclin-dependent kinase inhibitor p27Kip1 (p27) also behaves as a transcriptional repressor. Data showing that the p300/CBP-associated factor (PCAF) acetylates p27 inducing its degradation suggested that PCAF and p27 could collaborate in the regulation of transcription. However, this possibility remained to be explored. We analyzed here the transcriptional programs regulated by PCAF and p27 in the colon cancer cell line HCT116 by chromatin immunoprecipitation sequencing (ChIP-seq). We identified 269 protein-encoding genes that contain both p27 and PCAF binding sites being the majority of these sites different for PCAF and p27. PCAF or p27 knock down revealed that both regulate the expression of these genes, PCAF as an activator and p27 as a repressor. The double knock down of PCAF and p27 strongly reduced their expression indicating that the activating role of PCAF overrides the repressive effect of p27. We also observed that the transcription factor Pax5 interacts with both p27 and PCAF and that the knock down of Pax5 induces the expression of p27/PCAF target genes indicating that it also participates in the transcriptional regulation mediated by p27/PCAF. In summary, we report here a previously unknown mechanism of transcriptional regulation mediated by p27, Pax5 and PCAF.

Identifying Virtual 3D Geometric Shapes with a Vibrotactile Glove.

The emergence of off-screen interaction devices is bringing the field of virtual reality to a broad range of applications where virtual objects can be manipulated without the use of traditional peripherals. However, to facilitate object interaction, other stimuli such as haptic feedback are necessary to improve the user experience. To enable the identification of virtual 3D objects without visual feedback, a haptic display based on a vibrotactile glove and multiple points of contact gives users an enhanced sensation of touching a virtual object with their hands. Experimental results demonstrate the capacity of this technology in practical applications.

Insuficiencia renal aguda asociada al tratamiento con colistín en unidad de cuidados intensivos / Acute renal failure associated with colistin treatment in the intensive care unit

Introducción: La asociación de colistín e injuria renal aguda ha mostrado resultados muy diversos en diferentes estudios desde la reintroducción de esta droga en la práctica habitual. Métodos: Se realizó un estudio prospectivo y observacional de pacientes que recibieron tratamiento con colistín por al menos 48 horas en una Unidad de Cuidados Críticos (UCI). Resultados: Ingresaron al estudio 104 pacientes, de los cuales 47% (49) desarrollaron injuria renal aguda asociada a colistín (IRA-C). Estos pacientes fueron agrupados según la clasificación RIFLE en: pacientes con Riesgo (10); pacientes con Injuria (13); pacientes con Falla renal (26). Requirieron hemodiálisis 6 pacientes. El score de Charlson y la presencia de shock se asociaron al desarrollo de IRA-C. No se asociaron al desarrollo de IRA-C la edad, APACHE, creatininemia basal, ni dosis acumulada de colistín. La IRA-C se asoció a mayor mortalidad intrahospitalaria (p=0.003). Conclusión: La IRA-C es una entidad frecuente, y que se asocia a mayor mortalidad intrahospitalaria. La implementación de estrategias de nefroprotección en pacientes que reciban colistín, y el desarrollo de nuevos antibióticos con menor toxicidad, podrán mejorar la evolución de estos pacientes.

Background: The association of colistin and acute kidney injury has shown different results in several studies since the reintroduction of this drug in the common practice. Methods: A prospective and observational study of patients that received treatment with colistin for at least 48 hours in the Intensive Care Unit (ICU) was performed. Results: 104 patients participated in the study, of which 47 % (49) developed acute kidney injury associated to colistin (AKI-C). These patients were grouped according to the RIFLE classification: patients with Risk (10); patients with Injury (13); patients with kidney Failure (26). 6 patients required hemodialysis. The Charlson'™s score and the presence of shock were associated to the development of AKI-C. Neither age, APACHE, basal serum creatinine nor accumulated doses of colestin were associated to the development of AKI-C. The AKI-C was associated to a greater in-hospital mortality (p=0.003). Conclusion: The AKI-C is a frequent condition and its associated to a greater in-hospital mortality. The implementation of nephroprotection strategies in patients that receive colestin and the development of new antibiotics with less toxicity could improve the evolution of these patients.

Chitosan microparticles loaded with yeast-derived PCV2 virus-like particles elicit antigen-specific cellular immune response in mice after oral administration.

BACKGROUND: Porcine circovirus type 2 (PCV2)-associated diseases are a major problem for the swine industry worldwide. In addition to improved management and husbandry practices, the availability of several anti-PCV2 vaccines provides an efficient immunological option for reducing the impact of these diseases. Most anti-PCV2 vaccines are marketed as injectable formulations. Although these are effective, there are problems associated with the use of injectable products, including laborious and time-consuming procedures, the induction of inflammatory responses at the injection site, and treatment-associated stress to the animals. Oral vaccines represent an improvement in antigen delivery technology; they overcome the problems associated with injection management and facilitate antigen boosting when an animals' immunity falls outside the protective window. METHODS: Chitosan microparticles were used as both a vehicle and mucosal adjuvant to deliver yeast-derived PCV2 virus-like particles (VLPs) in an attempt to develop an oral vaccine. The physical characteristics of the microparticles, including size, Zeta potential, and polydispersity, were examined along with the potential to induce PCV2-specific cellular immune responses in mice after oral delivery. RESULTS: Feeding mice with PCV2 VLP-loaded, positively-charged chitosan microparticles with an average size of 2.5 µm induced the proliferation of PCV2-specific splenic CD4+/CD8+ lymphocytes and the subsequent production of IFN-γ to levels comparable with those induced by an injectable commercial formulation. CONCLUSION: Chitosan microparticles appear to be a safe, simple system on which to base PCV2 oral vaccines. Oral chitosan-mediated antigen delivery is a novel strategy that efficiently induces anti-PCV2 cellular responses in a mouse model. Further studies in swine are warranted.