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.

Kir2.1, a strong inward rectifier potassium channel encoded by the KCNJ2 gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in KCNJ2 result in inheritable cardiac diseases in humans, e.g. the type-1 Andersen-Tawil syndrome (ATS1). Understanding the molecular mechanisms that govern the regulation of inward rectifier potassium currents by Kir2.1 in both normal and disease contexts should help uncover novel targets for therapeutic intervention in ATS1 and other Kir2.1-associated channelopathies. The information available to date on protein-protein interactions involving Kir2.1 channels remains limited. Additional efforts are necessary to provide a comprehensive map of the Kir2.1 interactome. Here we describe the generation of a comprehensive map of the Kir2.1 interactome using the proximity-labeling approach BioID. Most of the 218 high-confidence Kir2.1 channel interactions we identified are novel and encompass various molecular mechanisms of Kir2.1 function, ranging from intracellular trafficking to cross-talk with the insulin-like growth factor receptor signaling pathway, as well as lysosomal degradation. Our map also explores the variations in the interactome profiles of Kir2.1^WT versus Kir2.1^314-315, a trafficking deficient ATS1 mutant, thus uncovering molecular mechanisms whose malfunctions may underlie ATS1 disease. Finally, using patch-clamp analysis, we validate the functional relevance of PKP4, one of our top BioID interactors, to the modulation of Kir2.1-controlled inward rectifier potassium currents. Our results validate the power of our BioID approach in identifying functionally relevant Kir2.1 interactors and underline the value of our Kir2.1 interactome as a repository for numerous novel biological hypotheses on Kir2.1 and Kir2.1-associated diseases.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

A black bear with a sweet tooth visited the front porch of a Connecticut home to raid a bowl of Halloween candy and steal a pumpkin.

The first step to saving nature is the rewilding of our own minds, says conservationist and former Patagonia CEO Kristine McDivitt Tompkins. With an unwavering commitment to protecting ecosystems, she and her late husband Douglas Tompkins created vast conservation parks across South America that allowed ancient flora and fauna to flourish once again. Now, she's carrying that legacy and mission forward with a bold plan to connect parks across geographic boundaries, creating a system of continental-scale wildlife corridors — before it's too late.

Klapka has seen five games with the Flames this season

Travis Gienger, who nicknamed his prize-winning pumpkin "Rudy," has been growing gourds for nearly 30 years

A century on, the country’s most beloved Thursday spectacle reaches new heights

Team ETHOS Uses SolidWorks Design and Simulation for Punkin’ Chunkin’ World Championship

The planned action signals growing regulatory scrutiny of Walmart-owned Flipkart and Amazon when their sales are rapidly growing in India's $70 billion (roughly Rs. 5,93,614 crore) e-commerce market. An Indian antitrust investigation also found the two companies breached laws by favouring select sellers,

Hi,

I'm searching for a way to get a quick overview of too low cpk-values after a montecarlo sim. The non-MC results have the spec and thus the easy/understandable red/green/(yellow) colorcoding, but for MC sims I don't get a highlight for high variations inside the limits.

Is this possible (besides copying each expression into avg()+3*std()) and ..-..)?

It would be really handy to scan through finished sims...

(My final application is then to export the table for my reports and documentation...)

Regards,

leo

Netflix's new Biblical epic is on the way, with a trailer for "Mary" landing today. Watch.

Kiernan Shipka reflects on playing Sally Draper: 'I knew what was going on'Kiernan Shipka, who played Sally Draper on Mad Men, has fond memories of her time on the show. Appearing on the Dinner's On Me podcast, Shipka shared her experiences as a child actor on the hit series."I don't know if...

Chris kink-shames Red XIII. Kelley violates the time space continuum with cat cafes. Josh is better at keeping things afloat than Embracer Group. Robert fails at being family friendly.

The post RPG Cast – Episode 711: “I’ve Always Wanted a Gaming Napkin” appeared first on RPGamer.

EPK

Nathan Cleverly receives a boost in his bid for a light-heavyweight unification clash with Bernard Hopkins.

The Enforcement Directorate (ED) on Thursday conducted raids on multiple sellers across the country -- linked to e-commerce platforms including Amazon and Flipkart -- over alleged money laundering activities.

As Flipkart deepens its engagements across the country, it sees a positive ripple effect - more jobs being created, MSMEs scaling up, and technology driving easy access to goods and services.

Arne Schepker, the CEO of the popular Berlin-based language learning platform Babbel, is stepping down, and the company’s co-founder and former CEO Markus Witte is stepping back in to lead the company “into a new phase while searching for Arne’s successor with patience,” the company said. This new phase, unsurprisingly, will involve AI. Witte will not […]

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Recent investigations by the Competition Commission of India (CCI) have revealed significant antitrust violations involving major smartphone manufacturers, including Samsung and Xiaomi. According to detailed reports obtained by Reuters, these companies, along with others, have been implicated in anti-competitive practices that

As Flipkart gears up for its annual Big Billion Days sale, the company is facing an unexpected wave of controversy. Just days before the sale’s scheduled start on September 27th, customers have taken to social media platforms like X (formerly Twitter)

India's e-commerce sector is once again in the regulatory spotlight as the Enforcement Directorate (ED) shifts its focus to two of the largest players, Amazon and Flipkart. In response to allegations of foreign investment law violations, the ED is now preparing

München ; Wien : De Gruyter Oldenbourg, [2023]

Saeed, Aisha, author

Hopkinson, Deborah, author

Surinder Dehal and Pardeep Narwal were in fine form for the Bengaluru Bulls, who inflicted an ALL-OUT on the Telugu Titans, midway through the second phase.

As more platforms allow creators to earn from viewers’ purchases of featured products, YouTube also announced its Shopping affiliate programme in India

The iPhone 16 series made its debut in India in September, with the flagship iPhone 16 Pro Max starting at Rs. 1,44,900 for the 256GB variant.

Marks Nokia’s entry into the laptop segment in India

'Let It Snow' stars Kiernan Shipka and Isabela Merced take the WIRED Autocomplete Interview and answer the web's most searched questions about themselves. Is Kiernan Shipka vegan? Is Isabela Merced married? Does Kiernan do ballet? Is Isabela related to Vanessa Hudgens? Kiernan and Isabela answer all these questions and more! LET IT SNOW is now streaming on Netflix, http://www.netflix.com/letitsnow

Pumpkin carving master James Hall explains pumpkin carving in 13 spooky levels of difficulty. The 2-time 'Halloween Wars' winner breaks down a variety of pumpkin carving techniques, ranging from simple to incredibly complex.

5 acres identified for establishing the cancer care centre next to Princess Krishnarajammanni Super Speciality Hospital on KRS Road

avg more refined pro apk is a smart system supervision and marketing tool that has been installed simply by almost 60 million users. It helps you avoid lagging and remove junk files, and optimize photographs so you can enjoy your smart phone more. In addition, it helps you conserve battery power, and it will find […]

YouTube Shopping affiliate programme allows creators to earn by recommending products, across videos, shorts and live streams

Under Ella’s guidance, Bharat Biotech created several groundbreaking vaccines, including Covaxin, India’s first indigenous Covid-19 vaccine

Marketline

Not just pumpkins, but flowers such as marigold and chrysanthemum also saw a roaring business this season, to be adorned to the shopping outlets and vehicles

Montreal : National Film Board of Canada, 2012

The proposed initiative will cover the protected and unprotected sites in Karnataka, most of which lack even a fence, so as to prevent encroachment

Police have arrested one person and seized the motorcycle used to commit the crime while claiming that two other absconding persons would be caught ‘very soon’

Amazon and Flipkart have for years faced allegations from Indian brick-and-mortar retailers that they violate foreign investment rules by working with select preferred sellers