The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport

Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human “ubiquitinome” using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport

One egg per day improves inflammation compared to an oatmeal-based breakfast without increasing the risk for heart disease in diabetic patients

There is concern that egg intake may increase blood glucose in patients with type 2 diabetes mellitus (T2DM). However, we have previously shown that eggs reduce inflammation in patients at risk for T2DM, including obese subjects and those with metabolic syndrome. Thus, we hypothesized that egg intake would not alter plasma glucose in T2DM patients when compared to oatmeal intake. Our primary endpoints for this clinical intervention were plasma glucose and the inflammatory markers tumor necrosis factor (TNF)-α and interleukin 6 (IL-6). As secondary endpoints, we evaluated additional parameters of glucose metabolism, dyslipidemias, oxidative stress and inflammation. Twenty-nine subjects, 35–65 years with glycosylated hemoglobin (HbA1c) value

Safety and Immunogenicity of a Human Papillomavirus Peptide Vaccine (CIGB-228) in Women with High-Grade Cervical Intraepithelial Neoplasia: First-in-Human, Proof-of-Concept Trial

Objective. CIGB-228 is a novel therapeutic vaccine consisting of HLA-restricted HPV16 E7 epitope adjuvated with VSSP. This trial was designed to evaluate the toxicity, safety, immunogenicity, HPV clearance, and lesion regression. Methods. Seven women were entered. All were HLA-A2 positive, had biopsy-proven high-grade CIN, histologically positive for HPV16, and beared persistent postbiopsy lesions visible by digital colposcopy. HLA-A2 women with biopsy-proven high-grade CIN, HPV16-positive, and beared persistent postbiopsy lesions visible by digital colposcopy were vaccinated. One weekly injections of CIGB-228 vaccine was given for four weeks. Then, loop electrosurgical excision procedure (LEEP) of the transformation zone was performed. Study subjects were followed for 1 year after LEEP. Results. No toxicity beyond grade 1 was observed during and after the four vaccinations. Five of seven women had complete and partial regression. Cellular immune response was seen in all patients. HPV was cleared in three of the patients with complete response. Conclusion. CIGB-228 vaccination was well tolerated and capable to induce IFNγ-associated T-cell response in women with high-grade CIN. In several patients, lesion regression and HPV clearance were observed

Atypical Mg-poor Milky Way Field Stars with Globular Cluster Second-generation-like Chemical Patterns

We report the peculiar chemical abundance patterns of 11 atypical Milky Way (MW) field red giant stars observed by the Apache Point Observatory Galactic Evolution Experiment (APOGEE). These atypical giants exhibit strong Al and N enhancements accompanied by C and Mg depletions, strikingly similar to those observed in the so-called second-generation (SG) stars of globular clusters (GCs). Remarkably, we find low Mg abundances ([Mg/Fe] < 0.0) together with strong Al and N overabundances in the majority (5/7) of the metal-rich ([Fe/H] gsim −1.0) sample stars, which is at odds with actual observations of SG stars in Galactic GCs of similar metallicities. This chemical pattern is unique and unprecedented among MW stars, posing urgent questions about its origin. These atypical stars could be former SG stars of dissolved GCs formed with intrinsically lower abundances of Mg and enriched Al (subsequently self-polluted by massive AGB stars) or the result of exotic binary systems. We speculate that the stars Mg-deficiency as well as the orbital properties suggest that they could have an extragalactic origin. This discovery should guide future dedicated spectroscopic searches of atypical stellar chemical patterns in our Galaxy, a fundamental step forward to understanding the Galactic formation and evolution

Belle II Technical Design Report

The Belle detector at the KEKB electron-positron collider has collected almost 1 billion Y(4S) events in its decade of operation. Super-KEKB, an upgrade of KEKB is under construction, to increase the luminosity by two orders of magnitude during a three-year shutdown, with an ultimate goal of 8E35 /cm^2 /s luminosity. To exploit the increased luminosity, an upgrade of the Belle detector has been proposed. A new international collaboration Belle-II, is being formed. The Technical Design Report presents physics motivation, basic methods of the accelerator upgrade, as well as key improvements of the detector.Comment: Edited by: Z. Dole\v{z}al and S. Un

Physical properties of Centaur (60558) 174P/Echeclus from stellar occultations

The Centaur (60558) Echeclus was discovered on March 03, 2000, orbiting between the orbits of Jupiter and Uranus. After exhibiting frequent outbursts, it also received a comet designation, 174P. If the ejected material can be a source of debris to form additional structures, studying the surroundings of an active body like Echeclus can provide clues about the formation scenarios of rings, jets, or dusty shells around small bodies. Stellar occultation is a handy technique for this kind of investigation, as it can, from Earth-based observations, detect small structures with low opacity around these objects. Stellar occultation by Echeclus was predicted and observed in 2019, 2020, and 2021. We obtain upper detection limits of rings with widths larger than 0.5 km and optical depth of $\tau$ = 0.02. These values are smaller than those of Chariklo's main ring; in other words, a Chariklo-like ring would have been detected. The occultation observed in 2020 provided two positive chords used to derive the triaxial dimensions of Echeclus based on a 3D model and pole orientation available in the literature. We obtained $a = 37.0\pm0.6$ km, $b = 28.4 \pm 0.5$ km, and $c= 24.9 \pm 0.4$ km, resulting in an area-equivalent radius of $30.0 \pm 0.5$ km. Using the projected limb at the occultation epoch and the available absolute magnitude ($\rm{H}_{\rm{v}} = 9.971 \pm 0.031$), we calculate an albedo of $p_{\rm{v}} = 0.050 \pm 0.003$. Constraints on the object's density and internal friction are also proposed.Comment: Corrected and typeset versio

The Mexican consensus on the diagnosis, treatment, and prevention of NSAID-induced gastropathy and enteropathy

Más de 30 millones de personas consumen diariamente antiinflamatorios noesteroideos (AINE) en el mundo, y este consumo se ve incrementado anualmente. Aunque losAINE poseen propiedades analgésicas y antiinflamatorias, sus eventos adversos gastrointesti-nales son bien reconocidos. En nuestro país no existía un consenso respecto al diagnóstico,tratamiento y prevención de la gastropatía y la enteropatía por AINE, por lo que la AsociaciónMexicana de Gastroenterología reunió a un grupo de expertos para establecer recomendacionesde utilidad para la comunidad médica. En este consenso se emitieron 33 recomendaciones. Elconsenso destaca que el riesgo de toxicidad gastrointestinal de los AINE varía según el fármacoempleado y su farmacocinética, lo cual debe ser considerado al momento de su prescripción. Losfactores de riesgo de complicación gastroduodenal por AINE son: antecedente de úlcera pép-tica, edad mayor a 65 a˜nos, dosis altas del AINE, infección por Helicobacter pylori (H.pylori), ypresencia de comorbilidades graves. Los síntomas y el da˜no gastroduodenal inducido por AINEson variables ya que puede cursar asintomático o manifestarse como anemia por deficiencia dehierro, hemorragia, estenosis y perforación. La cápsula endoscópica y la enteroscopia son méto-dos diagnósticos directos en la enteropatía por AINE. Respecto a la prevención, se recomiendaprescribir la dosis mínima necesaria de un AINE para obtener el efecto deseado y durante elmenor tiempo. Finalmente, los inhibidores de la bomba de protones (IBP) representan el están-dar de oro para la profilaxis y tratamiento de los efectos gastroduodenales, mas no son útilesen la enteropatía

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected