SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer

Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that pro-senescence therapies could be employed against SWI/SNF-mutated cancers

See-saw neutrino masses and large mixing angles in the vortex background on a sphere

In the vortex background on a sphere, a single 6-dimensional fermion family gives rise to 3 zero-modes in the 4-dimensional point of view, which may explain the replication of families in the Standard Model. Previously, it had been shown that realistic hierarchical mass and mixing patterns can be reproduced for the quarks and the charged leptons. Here, we show that the addition of a single heavy 6-dimensional field that is gauge singlet, unbound to the vortex, and embedded with a bulk Majorana mass enables to generate 4D Majorana masses for the light neutrinos through the see-saw mechanism. The scheme is very predictive. The hierarchical structure of the fermion zero-modes leads automatically to an inverted pseudo-Dirac mass pattern, and always predicts one maximal angle in the neutrino see-saw matrix. It is possible to obtain a second large mixing angle from either the charged lepton or the neutrino sector, and we demonstrate that this model can fit all observed data in neutrino oscillations experiments. Also, U_{e3} is found to be of the order ~0.1.Comment: 23 pages, 1 figur

Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries

PMCID: PMC3570554This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Non-resonant leptogenesis in seesaw models with an almost conserved B-L

We review the motivations and some results on leptogenesis in seesaw models with an almost conserved lepton number. The paper is based on a talk given at the 5th International Symposium on Symmetries in Subatomic Physics, SSP2012.Comment: 8 pages, 1 figure. Published in the proceedings of the 5th International Symposium on Symmetries in Subatomic Physics, SSP201

Association of VAV2 and VAV3 polymorphisms with cardiovascular risk factors

Hypertension, diabetes and obesity are cardiovascular risk factors closely associated to the development of renal and cardiovascular target organ damage. VAV2 and VAV3, members of the VAV family proto-oncogenes, are guanosine nucleotide exchange factors for the Rho and Rac GTPase family, which is related with cardiovascular homeostasis. We have analyzed the relationship between the presence of VAV2 rs602990 and VAV3 rs7528153 polymorphisms with cardiovascular risk factors and target organ damage (heart, vessels and kidney) in 411 subjects. Our results show that being carrier of the T allele in VAV2 rs602990 polymorphism is associated with an increased risk of obesity, reduced levels of ankle-brachial index and diastolic blood pressure and reduced retinal artery caliber. In addition, being carrier of T allele is associated with increased risk of target organ damage in males. On the other hand, being carrier of the T allele in VAV3 rs7528153 polymorphism is associated with a decreased susceptibility of developing a pathologic state composed by the presence of hypertension, diabetes, obesity or cardiovascular damage, and with an increased risk of developing altered basal glycaemia. This is the first report showing an association between VAV2 and VAV3 polymorphisms with cardiovascular risk factors and target organ damage

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

Comparison of flipped learning and traditional lecture method for teaching digestive system diseases in undergraduate medicine: A prospective non-randomized controlled trial

Introduction: This study examined the effects of a large-scale flipped learning (FL) approach in an undergraduate course of Digestive System Diseases. Methods: This prospective non-randomized trial recruited 404 students over three academic years. In 2016, the course was taught entirely in a Traditional Lecture (TL) style, in 2017 half of the course (Medical topics) was replaced by FL while the remaining half (Surgical topics) was taught by TL and in 2018, the whole course was taught entirely by FL. Academic performance, class attendance and student’s satisfaction surveys were compared between cohorts. Results: Test scores were higher in the FL module (Medical) than in the TL module (Surgical) in the 2017 cohort but were not different when both components were taught entirely by TL (2016) or by FL (2018). Also, FL increased the probability of reaching superior grades (scores >7.0) and improved class attendance and students’ satisfaction. Conclusion: The holistic FL model is more effective for teaching undergraduate clinical gastroenterology compared to traditional teaching methods and has a positive impact on classroom attendances

Helicitogenesis: WIMPy baryogenesis with sterile neutrinos and other realizations

We propose a mechanism for baryogenesis from particle decays or annihilations that can work at the TeV scale. Some heavy particles annihilate or decay into a heavy sterile neutrino N (with M ≳ 0.5 TeV) and a ¿light¿ one ν (with m ≪ 100 GeV), generating an asymmetry among the two helicity degrees of freedom of ν. This asymmetry is partially transferred to Standard Model leptons via fast Yukawa interactions and reprocessed into a baryon asymmetry by the electroweak sphalerons. We illustrate this mechanism in a WIMPy baryogenesis model where the helicity asymmetry is generated in the annihilation of dark matter. This model connects the baryon asymmetry, dark matter, and neutrino masses. Moreover it also complements previous studies on general requirements for baryogenesis from dark matter annihilation. Finally we discuss other possible realizations of this helicitogenesis mechanism