El defensor ‘embajador’ destacó la ventaja que tiene el DIM con el punto invisible.

En diálogo en exclusiva con Caracol Radio, el comandante Jerónimo, líder político de las AGG, afirmó que este grupo no tiene relación alguna con Salvatore Mancuso y no será su vocero en un eventual diálogo de paz.

En Caracol Radio estuvo Cielo Rusinque, superintendente de Industria y Comercio, conversando sobre las visitas de la SIC a las instalaciones de la Registraduría, y de la firma Thomas Greg.

En 10AM Hoy por Hoy, Vanessa Ortega, una colombiana naturalizada mexicana, compartió su experiencia, donde denunció abusos por parte de las autoridades migratorias en México.

Iván Velásquez se refirió a la propuesta del presidente Gustavo Petro de establecer este viernes 19 de abril como n día cívico con el propósito de promover el ahorro del agua y la energía eléctrica

Juan Pablo Montoya en 6AM

Concejal, Cristina Calderón en 6AM

Carlos Fernando Galán, alcalde de Bogotá, hizo hincapié en cuáles son las principales causas de las inundaciones en la Autopista Norte 

Rodrigo Negrete, director de la ANLA, aseguró que una vez subsanen los problemas actuales, esta organización tomará una nueva decisión dentro de tres meses

En 6AM de Caracol Radio estuvo Juan Manuel Mariño, Gerente general de la Concesión Ruta Bogotá Norte, quien habló sobre la ampliación de la Autopista norte de Bogotá.

Rockstar Games released the first trailer for the newest version of Grand Theft Auto on Monday, giving fans a glimpse of what’s likely to rank as one of the industry’s top-selling titles.

[Written by Anya Thompson] At Cedarbridge Academy, some students shine not just in academics but also in practical, hands-on fields. Terry Charlemagne, a dedicated student with a passion for mechanics, is one of them. From turbocharged car projects to mastering vehicle operation, Terry has cultivated a distinctive skill set that distinguishes him from his peers. […]

Party the absolute hardest you can imaginably party!

This website is using a security service to protect itself from online attacks. The action you just performed triggered the security solution. There are several actions that could trigger this block including submitting a certain word or phrase, a SQL command or malformed data. You can email the…

Having your email automatically or continually signed in to can be a security risk in some situations, but very convenient in others.

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Two projects — one that maps the function of the brain’s neuronal network in unprecedented detail and another that combines robotics and light-based computer circuits to create safe self-driving vehicles — have been awarded funding through Princeton’s Eric and Wendy Schmidt Transformative Technology Fund.

We have finally completed the renovation of our tools interfaces. Improved and unified layouts across all of our content generators and posters. And today it’s time to introduce updated WordPress and Blogger posters. These brand new content sharing tools will make a process of automated blog posting work like a charm. WordPress Poster User Guide […]

The post Meet New Automated WordPress and Blogger Posters appeared first on RSSground.com.

We have already shared our thoughts on why people do blog and why blogging is still afloat despite the rise of social media. We have also reasoned the help of automated blogging and even its necessity. And after RSS Ground has updated all of its automated posters we would like to dwell in more detail […]

The post Smart Way To Set Up Automated Blog Posting appeared first on RSSground.com.

Now you can specify a pool of hashtags, and random hashtags from your pool will be added to your posts.

The post Advanced Hashtags Feature Will Enhance Your Automated Posting appeared first on RSSground.com.

We have developed our own WordPress plugin which will help connect to your blog avoiding the use of XML-RPC.

The post Our own WordPress plugin for automated posting campaigns appeared first on RSSground.com.

According to your numerous requests, we made posting automation more flexible. Now you can set your posting campaigns to make posts only on weekdays, or to skip posting at night. Also you can change a time zone for your posting campaigns if needed. All existing posting campaigns will keep running and no need to update […]

The post Posting Automation Was Improved appeared first on RSSground.com.

We have prepared a major update for one of the most popular automated posters in RSS Ground – LinkedIn Poster. LinkedIn poster can make continuous posts to your LinkedIn personal feed or LinkedIn company pages. And now you can control what content you wish to post. Find a list of new Advanced settings in the […]

The post LinkedIn Automated Poster Major Update appeared first on RSSground.com.

In the digital age, content is king. But managing and distributing content efficiently across various channels can be a royal pain without the right tools. RSS Ground has made another giant leap for content automation by integrating first with IFTTT,  now Zapier and soon Pabbly Connect.  Thousands of third-party apps and services are now ready to enhance your content […]

The post Full Zapier Experience + Other Automation Platforms appeared first on RSSground.com.

Not so long ago, RSS Ground became “compatible” with automation platforms such as Zapier, IFTTT, and Pabbly Connect. You can use RSS Ground Posting Campaigns and Personal Feeds as “triggers,” and utilize Personal Feeds as “actions.” But many of our customers have been inquiring about compatibility with other automation platforms or even their proprietary software, […]

The post Automate posting to anywhere via webhooks appeared first on RSSground.com.

By Ireland Owens Toyota’s North American Chief Operating Officer (COO) Jack Hollis criticized U.S. policies promoting electric vehicle adoption (EV) on Friday, according to Bloomberg. The Toyota COO said that electric vehicle policies are “de facto mandates” that are not in sync with consumer demand, according to Bloomberg. Hollis also said that EV mandates such as […]

The post Major Automaker Exec Flatly Says Liberals’ EV ‘Mandates’ Are ‘Impossible’ To Meet appeared first on Liberty Unyielding.

"I think they say they want autonomy. I think their actions don't say the same thing," Airbnb CEO Brian Chesky recently said in an interview.

Morgan Stanley analysts say Tesla will surge if it can expand to be an AI giant, which may be more likely if Elon Musk exerts influence in a second Trump term.

A Minnessota maker named Caleb Olson built the Poopcopter, an autonomous drone that seeks out dog-doo and retrieves it for disposal.

He describes it as the "world's first aerial bound self-guided dog poop removal system." See it in action below.

"The Poopcopter is capable of scanning areas defined by a user, your backyard for example, and as it scans it's performing real-time computer vision using the camera which is inside the drone," Olson says. — Read the rest

The post The Poopcopter is a DIY autonomous drone that finds and collects dog-doo appeared first on Boing Boing.

Víctor González-Aguilera, Alvaro Liendo, Pedro Montero and Roberto Villaflor Loyola
Trans. Amer. Math. Soc. 377 (), 5483-5511.
Abstract, references and article information

P. Lochak
St. Petersburg Math. J. 35 (), 477-535.
Abstract, references and article information

Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance.

Visual Abstract

Xiao-Ting Wen
Dec 17, 2020; 0:RA120.002119v1-mcp.RA120.002119
Research

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

Autophagy plays critical roles in the maintenance of endothelial cells in response to cellular stress caused by blood flow. There is growing evidence that both cell adhesion and cell detachment can modulate autophagy, but the mechanisms responsible for this regulation remain unclear. Immunoglobulin and proline-rich receptor-1 (IGPR-1) is a cell adhesion molecule that regulates angiogenesis and endothelial barrier function. In this study, using various biochemical and cellular assays, we demonstrate that IGPR-1 is activated by autophagy-inducing stimuli, such as amino acid starvation, nutrient deprivation, rapamycin, and lipopolysaccharide. Manipulating the IκB kinase β activity coupled with in vivo and in vitro kinase assays demonstrated that IκB kinase β is a key serine/threonine kinase activated by autophagy stimuli and that it catalyzes phosphorylation of IGPR-1 at Ser220. The subsequent activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase, which leads to phosphorylation of the major pro-autophagy proteins ULK1 and Beclin-1 (BECN1), increased LC3-II levels, and accumulation of LC3 punctum. Thus, our data demonstrate that IGPR-1 is activated by autophagy-inducing stimuli and in response regulates autophagy, connecting cell adhesion to autophagy. These findings may have important significance for autophagy-driven pathologies such cardiovascular diseases and cancer and suggest that IGPR-1 may serve as a promising therapeutic target.

Elevated levels of fasting insulin release and insufficient glucose-stimulated insulin secretion (GSIS) are hallmarks of diabetes. Studies have established cross-talk between integrin signaling and insulin activity, but more details of how integrin-dependent signaling impacts the pathophysiology of diabetes are needed. Here, we dissected integrin-dependent signaling pathways involved in the regulation of insulin secretion in β-cells and studied their link to the still debated autocrine regulation of insulin secretion by insulin/insulin-like growth factor (IGF) 2–AKT signaling. We observed for the first time a cooperation between different AKT isoforms and focal adhesion kinase (FAK)–dependent adhesion signaling, which either controlled GSIS or prevented insulin secretion under fasting conditions. Indeed, β-cells form integrin-containing adhesions, which provide anchorage to the pancreatic extracellular matrix and are the origin of intracellular signaling via FAK and paxillin. Under low-glucose conditions, β-cells adopt a starved adhesion phenotype consisting of actin stress fibers and large peripheral focal adhesion. In contrast, glucose stimulation induces cell spreading, actin remodeling, and point-like adhesions that contain phospho-FAK and phosphopaxillin, located in small protrusions. Rat primary β-cells and mouse insulinomas showed an adhesion remodeling during GSIS resulting from autocrine insulin/IGF2 and AKT1 signaling. However, under starving conditions, the maintenance of stress fibers and the large adhesion phenotype required autocrine IGF2-IGF1 receptor signaling mediated by AKT2 and elevated FAK-kinase activity and ROCK-RhoA levels but low levels of paxillin phosphorylation. This starved adhesion phenotype prevented excessive insulin granule release to maintain low insulin secretion during fasting. Thus, deregulation of the IGF2 and adhesion-mediated signaling may explain dysfunctions observed in diabetes.

NSun2 is an RNA methyltransferase introducing 5-methylcytosine into tRNAs, mRNAs, and noncoding RNAs, thereby influencing the levels or function of these RNAs. Autotaxin (ATX) is a secreted glycoprotein and is recognized as a key factor in converting lysophosphatidylcholine into lysophosphatidic acid (LPA). The ATX-LPA axis exerts multiple biological effects in cell survival, migration, proliferation, and differentiation. Here, we show that NSun2 is involved in the regulation of cell migration through methylating ATX mRNA. In the human glioma cell line U87, knockdown of NSun2 decreased ATX protein levels, whereas overexpression of NSun2 elevated ATX protein levels. However, neither overexpression nor knockdown of NSun2 altered ATX mRNA levels. Further studies revealed that NSun2 methylated the 3'-UTR of ATX mRNA at cytosine 2756 in vitro and in vivo. Methylation by NSun2 enhanced ATX mRNA translation. In addition, NSun2-mediated 5-methylcytosine methylation promoted the export of ATX mRNA from nucleus to cytoplasm in an ALYREF-dependent manner. Knockdown of NSun2 suppressed the migration of U87 cells, which was rescued by the addition of LPA. In summary, we identify NSun2-mediated methylation of ATX mRNA as a novel mechanism in the regulation of ATX.

Natalie Bruiners
Dec 1, 2020; 61:1617-1628
Research Articles

Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody–based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.

The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin’s anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets.

Ankylosing Spondylitis (AS) is a common, inflammatory rheumatic disease, which primarily affects the axial skeleton and is associated with sacroiliitis, uveitis and enthesitis. Unlike other autoimmune rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus, autoantibodies have not yet been reported to be a feature of AS. We therefore wished to determine if plasma from patients with AS contained autoantibodies and if so, characterize and quantify this response in comparison to patients with Rheumatoid Arthritis (RA) and healthy controls. Two high-density nucleic acid programmable protein arrays expressing a total of 3498 proteins were screened with plasma from 25 patients with AS, 17 with RA and 25 healthy controls. Autoantigens identified were subjected to Ingenuity Pathway Analysis in order to determine patterns of signalling cascades or tissue origin. 44% of patients with Ankylosing Spondylitis demonstrated a broad autoantibody response, as compared to 33% of patients with RA and only 8% of healthy controls. Individuals with AS demonstrated autoantibody responses to shared autoantigens, and 60% of autoantigens identified in the AS cohort were restricted to that group. The AS patients autoantibody responses were targeted towards connective, skeletal and muscular tissue, unlike those of RA patients or healthy controls. Thus, patients with AS show evidence of systemic humoral autoimmunity and multispecific autoantibody production. Nucleic Acid Programmable Protein Arrays constitute a powerful tool to study autoimmune diseases.

To identify novel autoantibodies of Takayasu arteritis (TAK) using HuProt array-based approach. A two-phase approach was adopted. In Phase I, serum samples collected from 40 TAK patients, 15 autoimmune disease patients, and 20 healthy subjects were screened to identify TAK-specific autoantibodies using human protein (HuProt) arrays. In Phase II, the identified candidate autoantibodies were validated with TAK-focused arrays using an additional cohort comprised of 109 TAK patients, 110 autoimmune disease patients, and 96 healthy subjects. Subsequently, the TAK-specific autoantibodies validated in Phase II were further confirmed using Western blot analysis. We identified and validated eight autoantibodies as potential TAK-specific diagnostic biomarkers, including anti-SPATA7, -QDPR, -SLC25A2, -PRH2, -DIXDC1, -IL17RB, -ZFAND4, and -NOLC1 antibodies, with AUC of 0.803, 0.801, 0.780, 0.696, 0.695, 0.678, 0.635 and 0.613, respectively. SPATA7 could distinguish TAK from healthy and disease controls with 73.4% sensitivity at 85.4% specificity, while QDPR showed 71.6% sensitivity at 86.4% specificity. SLC25A22 showed the highest sensitivity of 80.7%, but at lower specificity of 67.0%. In addition, PRH2, IL17RB and NOLC1 showed good specificities of 88.3%, 85.9% and 86.9%, respectively, but at lower sensitivities (<50%). Finally, DIXDC1 and ZFAND4 showed moderate performance as compared with the other autoantibodies. Using a decision tree model, we could reach a specificity of 94.2% with AUC of 0.843, a significantly improved performance as compared to that by each individual biomarker. The performance of three autoantibodies, namely anti-SPATA7, -QDPR and -PRH2, were successfully confirmed with Western blot analysis. Using this two-phase strategy, we identified and validated eight novel autoantibodies as TAK–specific biomarker candidates, three of which could be readily adopted in a clinical setting.