Pelé falleció este jueves 29 de diciembre en el hospital de Sao Paulo, Brasil.

La Gobernación de Antioquia y el INVÍAS se comprometieron a entregar el próximo 24 de abril, un plan con las acciones y tiempos que garanticen que estas obras sean terminadas.

El exministron del Interior se refirió en 6AM al reciente atentado terrorista en el casco urbano del municipio del Valle que dejó una persona fallecida y al menos seis heridos

Jaime Andrés Beltrán, alcalde de Bucaramanga, anunció que serán trasladados 250 detenidos en estaciones de policía a cárceles del área metropolitana.

How white-nose syndrome threatens bat colonies in California. Tracking college graduate earnings based on their major. Finally, how to address anxiety and stress after the election.

"As former governors, we support the Colorado River District’s purchase of Xcel's water rights for $99 million." -- former Govs. Roy Romer and Bill Ritter

Google представила несколько нововведений для браузера Chrome на iPhone и iPad. В частности, функция Google Lens теперь позволяет одновременно искать по изображению и тексту.

Google today announced several new features for the Chrome browser that's available on the iPhone and the iPad, with the new additions aimed at providing users with more intuitive ways for finding information and completing tasks.


Google Lens now supports searching with images and text at the same time, rather than search being limited to just an image. Users can add words to a visual query to refine results and conduct more complex searches.

Google Drive and Google Photos users can now save content from the web directly to those services from Chrome, freeing up on-device storage space. To save a file to Google Drive from Chrome, tap on the Google Drive option. Saving an image to ‌Photos‌ from Chrome can be done by long pressing on the image and then selecting the Save in Google ‌Photos‌ option.

For U.S. users, Chrome on iOS is gaining Shopping Insights, which are designed to better surface deals. If Chrome has Shopping Insights for a product that a user is searching for, there will be a "Good Deal Now" notification in the address bar. The feature requires signing into Chrome and toggling on "Make Searches and Browsing Better."

When viewing a map of an address in Chrome, users will soon be able to tap an underlined address and see a more detailed mini-map of the location directly in the browser without having to swap over to Google Maps. Google says that it is experimenting with this feature and will roll it out globally over the coming months.

Do you use Google Chrome? Do you want to look at pictures of kittens instead of Donald Trump? Install this! It doesn't work on every news site, but it's still pretty darn great. PS - If you already have the extension installed and you're trying to look at these examples, they'll all be replaced with kittens. It's magic!

The award supports independent research in the arts and humanities at the American Academy in Rome. Both Princeton recipients are undergraduate alumni.

A new update is rolling out that automatically starts Microsoft's Edge browser and prompts users to import their Chrome tabs -- a move that has sparked criticism over its invasive tactics to encourage Edge adoption. The Verge's Tom Warren reports: My colleague Richard Lawler noticed that Edge started automatically on his PC last week at boot and offered up a new prompt to "enhance your browsing experience." The pop-up has a "bring over your data from other browsers regularly" option ticked by default, and encourages people to confirm and continue with a big blue button. If you want to dismiss this prompt there's a tiny white X button that looks similar to the sparkles Microsoft is using in the background of the prompt. If you simply hit confirm and continue then Microsoft Edge will import your Chrome data and continually import your tabs if you have Chrome set as default. The prompt seems to mainly appear on PCs with Chrome installed, suggesting that Microsoft is once again targeting Chrome users. Microsoft confirmed the new "feature" to The Verge. "This is a notification giving people the choice to import data from other browsers," explains Microsoft spokesperson Caitlin Roulston. "There is an option to turn it off."

Read more of this story at Slashdot.

Rome is magnificent in every way possible, from the millennia of history made here to the deliciousness of a perfect cacio e pepe pasta. There are so many things to do in Rome, from the Colosseum to the Vatican Museums to the Trevi Fountain and the Spanish Steps. Rome is so overwhelming, in a good […]

The post 30+ Epic Things to Do in Rome, Italy appeared first on Adventurous Kate.

Plan a trip to Rome, and you’ll wish you were there for weeks! From the Colosseum to the Vatican Museums, there’s a lot in the Eternal City to check off your bucket list.  But if you can tear yourself away from Rome’s top attractions, there are plenty of excellent day trips from Rome. Rome is […]

The post 18 Fun Day Trips from Rome appeared first on Adventurous Kate.

Steven A. Carr
Mar 1, 2014; 13:907-917
Technological Innovation and Resources

Michal Bassani-Sternberg
Mar 1, 2015; 14:658-673
Research

Ivan Matic
Jan 1, 2008; 7:132-144
Research

Hasmik Keshishian
Dec 1, 2007; 6:2212-2229
Research

Yi Zhang
Sep 1, 2005; 4:1240-1250
Research

Leigh Anderson
Apr 1, 2006; 5:573-588
Research

Jesper V. Olsen
Dec 1, 2005; 4:2010-2021
Technology

Jorge H. Capdevila
Feb 1, 2000; 41:163-181
Reviews

Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box–driven transcription of clock-associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg-293 of CRY1, identified as a rare CRY1 SNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1−/−Cry2−/− double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared with CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg-293 and the serine loop by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.

Connexin (Cx) protein forms hemichannels and gap junctional channels, which play diverse and profound roles in human physiology and diseases. Gap junctions are arrays of intercellular channels formed by the docking of two hemichannels from adjacent cells. Each hexameric hemichannel contains the same or different Cx isoform. Although homomeric Cxs forms have been largely described functionally and structurally, the stoichiometry and arrangement of heteromeric Cx channels remain unknown. The latter, however, are widely expressed in human tissues and variation might have important implications on channel function. Investigating properties of heteromeric Cx channels is challenging considering the high number of potential subunit arrangements and stoichiometries, even when only combining two Cx isoforms. To tackle this problem, we engineered an HA tag onto Cx26 or Cx30 subunits and imaged hemichannels that were liganded by Fab-epitope antibody fragments via atomic force microscopy. For Cx26-HA/Cx30 or Cx30-HA/Cx26 heteromeric channels, the Fab-HA binding distribution was binomial with a maximum of three Fab-HA bound. Furthermore, imaged Cx26/Cx30-HA triple liganded by Fab-HA showed multiple arrangements that can be derived from the law of total probabilities. Atomic force microscopy imaging of ringlike structures of Cx26/Cx30-HA hemichannels confirmed these findings and also detected a polydisperse distribution of stoichiometries. Our results indicate a dominant subunit stoichiometry of 3Cx26:3Cx30 with the most abundant subunit arrangement of Cx26-Cx26-Cx30-Cx26-Cx30-Cx30. To our knowledge, this is the first time that the molecular architecture of heteromeric Cx channels has been revealed, thus providing the basis to explore the functional effect of these channels in biology.

Yadong Yu
Dec 1, 2020; 19:1997-2014
Research

Ji Eun Kim
Dec 20, 2020; 0:RA120.002159v1-mcp.RA120.002159
Research

Alison M. Kurimchak
Dec 1, 2020; 19:2068-2089
Research

Peter Lasch
Dec 1, 2020; 19:2125-2138
Technological Innovation and Resources

Colin T. McDowell
Nov 24, 2020; 0:RA120.002256v1-mcp.RA120.002256
Research

Congcong Lu
Nov 17, 2020; 0:R120.002257v1-mcp.R120.002257
Review

Douglas A. Andres
Dec 1, 2020; 61:1537-1537
Images in Lipid Research

Astrid M. Moerman
Dec 23, 2020; 0:jlr.RA120000974v1-jlr.RA120000974
Research Articles

Babunageswararao Kanuri
Nov 17, 2020; 0:jlr.RA120001101v1-jlr.RA120001101
Research Articles

Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N and C termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N and C terminome of the LC proteoforms in fibrils extracted from the hearts of two AL cardiomyopathy patients, using a proteomic approach based on derivatization of N- and C-terminal residues, followed by mapping of fragmentation sites on the structures of native and fibrillar relevant LCs. We provide the first high-specificity map of proteolytic cleavages in natural AL amyloid. Proteolysis occurs both on the LC variable and constant domains, generating a complex fragmentation pattern. The structural analysis indicates extensive remodeling by multiple proteases, largely taking place on poorly folded regions of the fibril surfaces. This study adds novel important knowledge on amyloid LC processing: although our data do not exclude that proteolysis of native LC dimers may destabilize their structure and favor fibril formation, the data show that LC deposition largely precedes the proteolytic events documentable in mature AL fibrils.

Mendelian randomization (MR) of lipid traits in coronary artery disease (CAD) has provided evidence for causal associations of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted (IVW) and MR-Egger methods in large (n ≥ 300,000) GWAS datasets. We found that 30% of lipid trait genetic variants have effects on metabolic syndrome traits, including body mass index (BMI), type 2 diabetes (T2D), and systolic blood pressure (SBP). Nonetheless, in multivariable MR analysis, LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, BMI, T2D, and SBP are independently associated with CAD, and each of these associations is robust to adjustment for directional pleiotropy. MR at loci linked to direct effects on HDL-C and TG suggests locus- and mechanism-specific causal effects of these factors on CAD.

Smith-Lemli-Opitz Syndrome (SLOS) is a developmental disorder (OMIM #270400) caused by autosomal recessive mutations in the Dhcr7 gene, which encodes the enzyme 3β-hydroxysterol-7 reductase. SLOS patients present clinically with dysmorphology and neurological, behavioral and cognitive defects, with characteristically elevated levels of 7-dehydrocholesterol (7-DHC) in all bodily tissues and fluids. Previous mouse models of SLOS have been hampered by postnatal lethality when Dhcr7 is knocked out globally, while a hypomorphic mouse model showed improvement in the biochemical phenotype with ageing, and did not manifest most other characteristic features of SLOS. We report the generation of a conditional knockout of Dhcr7 (Dhcr7flx/flx), validated by generating a mouse with a liver-specific deletion (Dhcr7L-KO). Phenotypic characterization of liver-specific knockout mice revealed no significant changes in viability, fertility, growth curves, liver architecture, hepatic triglyceride secretion, or parameters of systemic glucose homeostasis. Furthermore, qPCR and RNA-Seq analyses of livers revealed no perturbations in pathways responsible for cholesterol synthesis, either in male or female Dhcr7L-KO mice, suggesting hepatic disruption of post-squalene cholesterol synthesis leads to minimal impact on sterol metabolism in the liver. This validated conditional Dhcr7 knockout model may now allow us to systematically explore the pathophysiology of SLOS, by allowing for temporal, cell and tissue-specific loss of DHCR7.

Carotid atherosclerosis is a risk factor for ischemic stroke, one of the main causes of mortality and disability worldwide. The disease is characterized by plaques, heterogeneous deposits of lipids and necrotic debris in the vascular wall, which grow gradually and may remain asymptomatic for decades. However, at some point a plaque can evolve to a high-risk plaque phenotype, which may trigger a cerebrovascular event. Lipids play a key role in the development and progression of atherosclerosis, but the nature of their involvement is not fully understood. Using matrix-assisted laser desorption/ionization mass spectrometry imaging, we visualized the distribution of approximately 200 different lipid signals, originating of > 90 uniquely assigned species, in 106 tissue sections of 12 human carotid atherosclerotic plaques. We performed unsupervised classification of the mass spectrometry dataset, as well as a histology-directed multivariate analysis. These data allowed us to extract the spatial lipid patterns associated with morphological plaque features in advanced plaques from a symptomatic population, revealing spatial lipid patterns in atherosclerosis and their relation to histological tissue type. The abundances of sphingomyelin and oxidized cholesteryl ester species were elevated specifically in necrotic intima areas, while diacylglycerols and triacylglycerols were spatially correlated to areas containing the coagulation protein fibrin. These results demonstrate a clear co-localization between plaque features and specific lipid classes, as well as individual lipid species in high-risk atherosclerotic plaques.

Ion mobility separates molecules in the gas-phase based on their physico-chemical properties, providing information about their size as collisional cross-sections. The timsTOF Pro combines trapped ion mobility with a quadrupole, collision cell and a TOF mass analyzer, to probe ions at high speeds with on-the-fly fragmentation. Here, we show that on this platform ion mobility is beneficial for cross-linking MS (XL-MS). Cross-linking reagents covalently link amino acids in proximity, resulting in peptide pairs after proteolytic digestion. These cross-linked peptides are typically present at low abundance in the background of normal peptides, which can partially be resolved by using enrichable cross-linking reagents. Even with a very efficient enrichable cross-linking reagent, like PhoX, the analysis of cross-linked peptides is still hampered by the co-enrichment of peptides connected to a partially hydrolyzed reagent – termed mono-linked peptides. For experiments aiming to uncover protein-protein interactions these are unwanted byproducts. Here, we demonstrate that gas-phase separation by ion mobility enables the separation of mono-linked peptides from cross-linked peptide pairs. A clear partition between these two classes is observed at a CCS of 500 Ų and a monoisotopic mass of 2 kDa, which can be used for targeted precursor selection. A total of 50-70% of the mono-linked peptides are prevented from sequencing, allowing the analysis to focus on sequencing the relevant cross-linked peptide pairs. In applications to both simple proteins and protein mixtures and a complete highly complex lysate this approach provides a substantial increase in detected cross-linked peptides.