The 86-year-old Supreme Court Justice repeated a regular clap back she's reserved for those who've counted her out. She isn't going anywhere.

Outside the committee room Wednesday, several lawmakers got to see and be seen.

Swift called on the White House to respond to her petition in support of the Equality Act, which would explicitly outlaw discrimination based on gender and sexual orientation.

Review of 'The Case for Nationalism: How It Made Us Powerful, United, and Free' by Rich Lowry

Who actually owns and operates the most popular and your favourite cruise lines? Be prepared for some surprises as I take a look at who the biggest cruise lines in the world are based on number of passengers carried, and then who owns and controls the lines. Although there are many cruise lines, they are all pretty much owned by three large cruise corporations. Discover who owns and operates the cruise lines you have heard of, love or considering cruising with.

Gary Bembridge's Tips For Travellers aims to help you make more of your precious travel time and money on land and when cruising the oceans or rivers of the world. To help you, in every video I draw on my first-hand tips and advice from travelling every month for over 20 years and 60+ cruises.

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No, they aren’t going to pay for themselves.

It’s been frustrating to watch more moderate positions be characterized as solely driven by political calculations.

Many of the changes are simply worse for the economy.

A framework for how Congress should be thinking about the immediate economic challenges ahead — and the tools available to address them.

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External sources link to your website with the wrong URLs, here’s how you can fix that.

Please visit Search Engine Land for the full article.

Rick Bright, head of an agency tasked with developing coronavirus drugs, has said administration ignored his warnings.

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Bollywood star, Irrfan Khan, has died after being admitted to the intensive care unit at Mumbai's Kokilaben hospital.

After a long battle with cancer, Bollywood actor Rishi Kapoor has died.

After three decades of mystery, the cold case murder of a 17-year-old Ohio teen named Barbara Blatnik has been solved thanks in part to DNA genealogical research. The last time anyone saw Blatnik alive was around midnight on Dec. 19, 1987, when a friend dropped her off in Garfield Heights, Ohio. The following day, Blatnik,…

The post 32 Years After Teen’s Body Found Strangled on Side of Road, Suspect Finally Arrested appeared first on The Western Journal.

Sen. Ted Cruz was apparently about to get into mullet territory. He hadn’t had a haircut in three months. Things were looking grim for the Texas senator. Thankfully, Shelley Luther is able to do something about that. Luther is both famous and free after a viral clip of her standing up to a judge who…

The post Ted Cruz Stops by Shelly Luther’s Salon for a Trim, ‘True Authenticity’ Leaves Her Sobbing appeared first on The Western Journal.

A year after the Obama administration changed its policy on which undocumented immigrants it would target for deportation, it's not clear who is being sent back.

It appears ISIS-allied fighters are gaining a foothold in Afghanistan, but just how similar are they to the group's branches in Iraq and Syria?

All it took was a pandemic, but the long-running joke finally became a reality: DEF CON is canceled. 

The annual hacker conference in Las Vegas, Nevada, typically draws tens of thousands of attendees to talk shop, compare notes, and generally cause delightful mischief. One element of that mischief is the constant — and until now false — yearly claim that DEF CON is canceled. The coronavirus changed that, and the organization announced Friday that the in-person conference will not take place this year. 

"The #DEFCONiscanceled meme has crossed over into real life, courtesy of #COVID19," read the announcement. "In early March we had hopes that things would be stable by August. That is no longer realistic." Read more...

Striso is a digital instrument with pressure-sensitive buttons that plays a variety of acoustic-like sounds.  Read more...

Between the infamous Peloton commercial, the wild Boyhood wannabe that ended up being a Subway ad, and the endless #girlboss marketing reminding you that even women can be part of the capitalist machine, 2019 was a year for advertising. 

But nothing quite tops this one, which was released in September but resurfaced in a viral tweet on Friday.  

The ad starts off with a bleak statistic: women hold just 10 percent of all patented inventions. Then, it pans over to a delightful montage of ambitious young women. Each one is filmed preparing for their career goals, from mixing delicate chemicals in a laboratory to carefully testing the consistency of soil.  Read more...

TL;DR: You don't have to buy a drum set to learn how to play the drums. Instead, just grab the Senstroke by Redison bluetooth drum kit for $189.95, on sale for 5% off as of May 9.

If you want to learn how to play the drums, then a quality set may cost you upwards of $1,000. Not only is this a hefty price to play for individuals who aren't fully committed to the instrument yet, but their massive size may be impossible to fit inside your space. Or at least your housemates may not appreciate it.

With the Senstroke by Redison Bluetooth Drum Kit and App Bundle, you can practice, play, and record on just about any surface for a much more affordable price — and it'll take up little to no space.  Read more...

Including a shoulder-brush with a livid Steve Waugh, Rob Houwing remembers witnessing SA's heroic finish to an otherwise stormy 2001/02 Australian tour.

The DML News App offers the best in news reporting.

The post JUST IN: Actress and leader of #MeToo movement accuses Bill Maher of sexually harassing her appeared first on Dennis Michael Lynch.

The following article, Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom, was first published on 100PercentFedUp.com.

The normalizing of pedophilia is not a far-right conspiracy theory...

Continue reading: Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom ...

Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.

Nucleoside analogues are a valuable experimental tool. Incorporation of these molecules into newly synthesized DNA (i.e. pulse-labeling) is used to monitor cell proliferation or to isolate nascent DNA. Some of the most common nucleoside analogues used for pulse-labeling of DNA in cells are the deoxypyrimidine analogues 5-ethynyl-2'-deoxyuridine (EdU) and 5-ethynyl-2'-deoxycytidine (EdC). Click chemistry enables conjugation of an azide molecule tagged with a fluorescent dye or biotin to the alkyne of the analog, which can then be used to detect incorporation of EdU and EdC into DNA. The use of EdC is often recommended because of the potential cytotoxicity associated with EdU during longer incubations. Here, by comparing the relative incorporation efficiencies of EdU and EdC during short 30-min pulses, we demonstrate significantly lower incorporation of EdC than of EdU in noninfected human fibroblast cells or in cells infected with either human cytomegalovirus or Kaposi's sarcoma-associated herpesvirus. Interestingly, cells infected with herpes simplex virus type-1 (HSV-1) incorporated EdC and EdU at similar levels during short pulses. Of note, exogenous expression of HSV-1 thymidine kinase increased the incorporation efficiency of EdC. These results highlight the limitations when using substituted pyrimidine analogues in pulse-labeling and suggest that EdU is the preferable nucleoside analogue for short pulse-labeling experiments, resulting in increased recovery and sensitivity for downstream applications. This is an important discovery that may help to better characterize the biochemical properties of different nucleoside analogues with a given kinase, ultimately leading to significant differences in labeling efficiency of nascent DNA.

Dawid Kielak
J. Amer. Math. Soc. 33 (2019), 451-486.
Abstract, references and article information

Christian Tagwerker
Apr 1, 2006; 5:737-748
Research

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.

3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.

M el-Saadani
Apr 1, 1989; 30:627-630
Articles

Reactive oxygen and nitrogen species have been implicated in many biological processes and diseases, including immune responses, cardiovascular dysfunction, neurodegeneration, and cancer. These chemical species are short-lived in biological settings, and detecting them in these conditions and diseases requires the use of molecular probes that form stable, easily detectable, products. The chemical mechanisms and limitations of many of the currently used probes are not well-understood, hampering their effective applications. Boronates have emerged as a class of probes for the detection of nucleophilic two-electron oxidants. Here, we report the results of an oxygen-18–labeling MS study to identify the origin of oxygen atoms in the oxidation products of phenylboronate targeted to mitochondria. We demonstrate that boronate oxidation by hydrogen peroxide, peroxymonocarbonate, hypochlorite, or peroxynitrite involves the incorporation of oxygen atoms from these oxidants. We therefore conclude that boronates can be used as probes to track isotopically labeled oxidants. This suggests that the detection of specific products formed from these redox probes could enable precise identification of oxidants formed in biological systems. We discuss the implications of these results for understanding the mechanism of conversion of the boronate-based redox probes to oxidant-specific products.

Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding.

euromicron AG, a medium-sized technology group and expert on the digital networking of business and production processes, has now fully placed the capital increase it resolved on July 10, 2019.

From the moment he became a trainer, Frederick Watson says his dream was to win the Derby.

A new study from University of Michigan climate researchers concludes that some of the latest-generation climate models may be overly sensitive to carbon dioxide increases and therefore project future warming that is unrealistically high.

A new way of looking at marine evolution over the past 540 million years has shown that levels of biodiversity in our oceans have remained fairly constant, rather than increasing continuously over the last 200 million years, as scientists previously thought.