Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster.

Sequence variants in cis-acting enhancers are important for polygenic disease, but their role in Mendelian disease is poorly understood. Redundancy between enhancers that regulate the same gene is thought to mitigate the pathogenic impact of enhancer mutations. Recent findings, however, have shown that loss-of-function mutations in a single enhancer near PTF1A cause pancreas agenesis and neonatal diabetes. Using mouse and human genetic models, we show that this enhancer activates an entire PTF1A enhancer cluster in early pancreatic multipotent progenitors. This leading role, therefore, precludes functional redundancy. We further demonstrate that transient expression of PTF1A in multipotent progenitors sets in motion an epigenetic cascade that is required for duct and endocrine differentiation. These findings shed insights into the genome regulatory mechanisms that drive pancreas differentiation. Furthermore, they reveal an enhancer that acts as a regulatory master key and is thus vulnerable to pathogenic loss-of-function mutations

Characteristics of clinical trials of influenza and respiratory syncytial virus registered in ClinicalTrials.gov between 2014 and 2021

The randomized clinical trial (RCT) is the ideal and mandatory type of study to verify the effect and safety of a drug. Our aim is to examine the fundamental characteristics of interventional clinical trials on influenza and respiratory syncytial virus (RSV). This is a cross-sectional study of RCTs on influenza and RSV in humans between 2014 and 2021 registered in ClinicalTrials.gov. A total of 516 studies were identified: 94 for RSV, 423 for influenza, and 1 for both viruses. There were 51 RCTs of RSV vaccines (54.3%) and 344 (81.3%) for influenza virus vaccines (p < 0.001). Twelve (12.8%) RCTs for RSV were conducted only with women, and 6 were conducted only with pregnant women; for RCTs for influenza, 4 (0.9%) and 3, respectively. For RSV, 29 (31%) of the RCTs were exclusive to people under 5 years of age, and 21 (5%) for influenza virus (p < 0.001). For RSV, there are no RCTs exclusively for people older than or equal to 65 years and no phase 4 trials. RCTs on influenza virus and RSV has focused on vaccines. For the influenza virus, research has been consolidated, and for RSV, research is still in the development phase and directed at children and pregnant women

Rupture and distribution causes of carbonate chimneys in the Guadalquivir Ridge and Cadiz Channel (Sub Portugual Continental Margin)

A lo largo del Canal y Dorsal de Cádiz se ha observado la existencia de numerosas chimeneas carbonatadas con evidencias de rotura por flexo-tracción en su base. Este trabajo aborda el análisis de la distribución espacial y las características mecánicas de las chimeneas con el objeto de determinar la causa de la rotura. Se han considerado como posibles causas de la rotura el empuje debido a la Corriente Mediterránea de Salida que se canaliza a través del Canal de Cádiz o la inercia asociada al movimiento del terreno debido a un evento sísmico. La orientación preferente de caída de las chimeneas, así como el resultado del cálculo de la velocidad del flujo y de la aceleración del terreno necesaria para provocar la rotura en base a las características mecánicas de las mismas sugiere que su rotura pudo ser causada por un terremoto de Mw entre 5,7 a 7,0.The existence of carbonate chimneys with evidence of basal flexo-traction crack has been observed along the Cadiz Contourite Channel and Cadiz Diapiric Ridge. This research aims the study of spatial distribution and the mechanical characteristics of the chimneys for determining their rupture cause. The Mediterranean Outflow Water along the Cadiz Channel or inertia force due to ground oscillatory movement related to a seismic event could be responsible for the chimneys rupture. Considering the preferential orientation of the broken chimneys and the results obtained from estimating flow speed and ground acceleration, according to their mechanical behaviour, the occurrence of a Mw 5,7-7,0 earthquake can be suggested as the most probable cause.Depto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasTRUEEurocore-EuromarginsCONSOLIDER-INGENIOpu

The OTELO survey: faint end of the luminosity function of [O_(II)]3727 emitters at ‹z›=1.43

Aims. In this paper, we aim to study the main properties and luminosity function (LF) of the [O II]3727 emitters detected in the OTELO survey in order to characterise the star formation processes in low-mass galaxies at z ∼ 1.43 and to constrain the faint-end of the LF. Methods. Here, we describe the selection method and analysis of the emitters obtained from narrow-band scanning techniques. In addition, we present several relevant properties of the emitters and discuss the selection biases and uncertainties in the determination of the LF and the star formation rate density (SFRD). Results. We confirmed a total of 60 sources from a preliminary list of 332 candidates as [O II]3727 emitters. Approximately 93% of the emitters have masses in the range of 10^(8) < M*/M⊙ < 10^(9). All of our emitters are classified as late-type galaxies, with a lower value of (u − v) when compared with the rest of the emitters of the OTELO survey. We find that the cosmic variance strongly affects the normalisation (ϕ*) of the LF and explains the discrepancy of our results when compared with those obtained from surveys of much larger volumes. However, we are able to determine the faint-end slope of the LF, namely, α = −1.42 ± 0.06, by sampling the LF down to ∼1 dex lower than in previous works. We present our calculation of the SFRD of our sample and compare it to the value obtained in previous studies from the literature

Targeted Deficiency of the Transcriptional Activator Hnf1α Alters Subnuclear Positioning of Its Genomic Targets

DNA binding transcriptional activators play a central role in gene-selective regulation. In part, this is mediated by targeting local covalent modifications of histone tails. Transcriptional regulation has also been associated with the positioning of genes within the nucleus. We have now examined the role of a transcriptional activator in regulating the positioning of target genes. This was carried out with primary β-cells and hepatocytes freshly isolated from mice lacking Hnf1α, an activator encoded by the most frequently mutated gene in human monogenic diabetes (MODY3). We show that in Hnf1a−/− cells inactive endogenous Hnf1α-target genes exhibit increased trimethylated histone H3-Lys27 and reduced methylated H3-Lys4. Inactive Hnf1α-targets in Hnf1a−/− cells are also preferentially located in peripheral subnuclear domains enriched in trimethylated H3-Lys27, whereas active targets in wild-type cells are positioned in more central domains enriched in methylated H3-Lys4 and RNA polymerase II. We demonstrate that this differential positioning involves the decondensation of target chromatin, and show that it is spatially restricted rather than a reflection of non-specific changes in the nuclear organization of Hnf1a-deficient cells. This study, therefore, provides genetic evidence that a single transcriptional activator can influence the subnuclear location of its endogenous genomic targets in primary cells, and links activator-dependent changes in local chromatin structure to the spatial organization of the genome. We have also revealed a defect in subnuclear gene positioning in a model of a human transcription factor disease

International conference on the healthy effect of virgin olive oil

Ageing represents a great concern in developed countries because the number of people involved and the pathologies related with it, like atherosclerosis, morbus Parkinson, Alzheime's disease, vascular dementia, cognitive decline, diabetes and cancer. Epidemiological studies suggest that a Mediterranean diet (which is rich in virgin olive oil) decreases the risk of cardiovascular disease. The Mediterranean diet, rich in virgin olive oil, improves the major risk factors for cardiovascular disease, such as the lipoprotein profile, blood pressure, glucose metabolism and antithrombotic profile. Endothelial function, inflammation and oxidative stress are also positively modulated. Some of these effects are attributed to minor components of virgin olive oil. Therefore, the definition of the Mediterranean diet should include virgin olive oil. Different observational studies conducted in humans have shown that the intake of monounsaturated fat may be protective against age-related cognitive decline and Alzheimer's disease. Microconstituents from virgin olive oil are bioavailable in humans and have shown antioxidant properties and capacity to improve endothelial function. Furthermore they are also able to modify the haemostasis, showing antithrombotic properties. In countries where the populations fulfilled a typical Mediterranean diet, such as Spain, Greece and Italy, where virgin olive oil is the principal source of fat, cancer incidence rates are lower than in northern European countries. The protective effect of virgin olive oil can be most important in the first decades of life, which suggests that the dietetic benefit of virgin olive oil intake should be initiated before puberty, and maintained through life. The more recent studies consistently support that the Mediterranean diet, based in virgin olive oil, is compatible with a healthier ageing and increased longevity. However, despite the significant advances of the recent years, the final proof about the specific mechanisms and contributing role of the different components of virgin olive oil to its beneficial effects requires further investigations. © 2005 Blackwell Publishing Ltd