Вокалист SHINEDOWN Brent Smith опубликовал в своём аккаунте в Инстаграм фрагмент с выступления группы и написал:

«Я так же сильно, как и любой из вас, хочу, чтобы такие моменты, как этот, вернулись. Я люблю выступать, и я люблю #massgatherings или, как я люблю называть их, #familyreunions. Так что, сказав это, я хотел бы воспользоваться моментом, чтобы поделиться чем-нибудь со всеми вами по всему миру.

Такие моменты, как этот, обязательно вернутся. Все мы сможем пойти и посмотреть на выступление нашего любимого артиста вживую, на соревнования наших любимых спортивных команд, и да — это будет безопасно.

В течение последних 72 часов я наблюдал, как части #usa начинают открываться заново, а также другие страны за рубежом начинают процесс снятия некоторых ограничений, и я наблюдаю, как много взволнованных и благодарных людей, готовых вырваться в мир, который они так любят, но, я также вижу, что есть люди, которые имеют серьёзные опасения из-за открытия различных регионов.

С самого начала блокировки я сделал одну вещь, которая действительно помогла мне лично сориентироваться в этой #pandemic, и это просвещает меня.

Мы должны уважать не только друг друга, но и позволять людям, которые работают круглосуточно и без выходных, обеспечивать нашу #safety и наше #future.

Я знаю, что мы все #Anxious и хотим вернуться к #Life, но я прошу всех нас быть уважительными друг к другу и не быть эгоистичными.

Я знаю, что это трудно, но, я обещаю вам, что если мы все будем работать #together, то и сможем #riseuptogether.

У всех нас в @shinedown — меня, @zmyersofficial, @bkerchofficial и @ebassprod есть поговорка, которая дорога нашим сердцам... И она звучит так: "Дело не в художнике, дело в картине".

Мы #love всех вас, и мы скоро будем вместе. #westandtall #atlasfalls #directrelief #shinedown #shinedownnation #shinedowncrew #shinedownfamily #respect». #Shinedown #AlternativeRock #Alternative_Rock #GrungeRock #Grunge_Rock

Посмотреть эту публикацию в Instagram

“FULL DISCLOSURE” This is MY opinion 👇 I want moments like this back just as much as anyone. I love performing, and I LOVE #massgatherings or as I like to call them #familyreunions 🤗. So that being said, I wanted to take a moment to share something with all of you around the world. Moments like this WILL happen again. All of us will be able to go, and see our favorite artist perform live, our favorite sports teams compete, and yes it will be safe to do so. For the last 72 hours, I have watched parts of the #usa begin to reopen, and also other countries abroad begin the process of lifting certain lockdown restrictions, and I can see so many people excited, and grateful, and running out into the world they love so much but, I am also seeing that there are people that have serious concerns in their eyes, as parts of the world begin to open back up. Since the very beginning of the lockdown, I have done one thing that has truly helped me personally navigate through this #pandemic, and that is educate myself. We must be respectful of not only each other, but also allowing the people that are working 24/7 around the clock to insure our #safety and our #future. I know we are all #Anxious and we want to get back to living #Life , but I ask all of us to be respectful of each other, and to not be selfish. I know this is difficult but, I promise you if we all work #together we will #riseuptogether. All of us in @shinedown myself, @zmyersofficial @bkerchofficial and @ebassprod have a saying that we hold dear to our hearts... And that is “It’s not about the painter, it’s about the painting 🌎”. We #love you ALL, and we will be together soon. ❤️⚠️❤️. #westandtall #atlasfalls #directrelief #shinedown #shinedownnation #shinedowncrew #shinedownfamily #respect Moving pictures by THE MAN!!! @sanjayparikhphoto

Публикация от @ thebrentsmith 3 Май 2020 в 2:10 PDT

The AFP’s media raid warrant gets slapped down by the High Court.  Plus, Trump and the media’s latest bout, Boris Johnson gets released from “prison”, the Daily Mail find a bogus Barnsey, and an angry shop keeper flips the bird.

IBM y Red Hat, líder mundial de software de nube de código abierto, anunciaron un acuerdo en el que IBM adquirirá todas las acciones comunes emitidas y en circulación de Red Hat por USD$190.00 por acción en efectivo, lo que representa un valor total para la empresa de aproximadamente USD$34 mil millones.

At the beginning of June Probert and I taught Doga as a fundraiser for One Tail at a Time rescue in Chicago. We had an awesome time with a full class and the Fido to Go dog food truck even showed up at the end of class so the Dogis could get  treat!

Here are some pictures:

The 'Curtain of Distraction' is well known at Arizona State University as a hilarious sports tactic. This time Michael Phelps came out Magic Mike style to prevent a few free throws. Just look at those sweet moves, the opposing team was bound to miss. 

Something old, something new, something gifted, and a couple things green. READ MORE...

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PotterCast 273 is the first of our episodes from LeakyCon Dublin! And this time we have Evanna Lynch (Luna Lovegood), Katie Leung (Cho Chang), Alfie Enoch (Dean Thomas), and Afshan Azad (Padma Patil), here to tell us all about life as the Harry Potter films' Dumbledore's Army. Great stories from their time filming - a must-listen!

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Warner Bros. systematically abused an automated takedown system provided by Hotfile, the file host claims in a countersuit against the studio. The claims made by Hotfile include information on the behind-the-scenes actions taken by Hollywood to enforce its rights against file sharing on cloud file hosts. Continue reading on NewTeeVee.

The Amateur Traveler talks to Christine Cantera about her time living in the Languedoc region of France in the city Montpellier. Montpellier is sometimes called the San Francisco of France. Christine shares with us a few thoughts about cafes, bars, which museums are worth it (and which aren’t), beaches, fortified cities, when to visit, and the one day of the year when nobody in France gets any work done. She discusses what are her favorite 3 places to see in Languedoc including one seaside town that still has jousts but with a very nautical twist.

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Show Notes

France Travel Guide
Montpellier
Languedoc
Jardin des plantes de Montpellier
Le Petit Train Touristique du Centre Historique
Languedoc wine
Le Jardin du Champs de Mars
Paparazzi
La Dolce Vita
Aigues-Mortes
Carcassonne
Parc naturel régional de Camargue
Musee Fabre
Antigone District
Palavas-les-Flots
Sète
Nîmes
Beaujolais nouveau
Bar le Saint-Roch
MissExpatria’s photostream

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The Amateur Traveler talks to Photographer Ralph Velasco about two of his favorite cities in Spain, Toledo and Segovia. Both Toledo and Segovia are a short distance from Madrid and both offer interesting and historically significant cities with UNESCO World Heritage sites.

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The following article, Legal Immigrant in Michigan Sends a Message to MI Gov Whitmer and Media Criticizing Freedom-Loving Protesters, was first published on 100PercentFedUp.com.

The media and even some governors are trying to paint the Americans who are protesting to open businesses up as racists and even Nazis. The Governor of Michigan recently made a derogatory statement about the protesters implying they are racists. Painting a negative picture of the people who want their freedom and businesses demonizes our […]

Continue reading: Legal Immigrant in Michigan Sends a Message to MI Gov Whitmer and Media Criticizing Freedom-Loving Protesters ...

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.

Invitation Only

Event participants

Leandro Prados de la Escosura, Professor, Economic History, Universidad Carlos III de Madrid 

1 February 2014

Substantial gains in world human development have been achieved since 1870, but research shows that the main improvement actually occurred between the First World War and 1970.

Under 35s Forum

Event participants

Research Event

Event participants

Sherif Elsayed-Ali, Head of Technology and Human Rights, Amnesty International
Professor David Kaye, UN Special Rapporteur on the Promotion and Protection of the Right to Freedom of Opinion and Expression
Chair: Sonya Sceats, Associate Fellow, International Law Programme, Chatham House

The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H₂S has been shown to persulfidate redox sensitive cysteine residues resulting in an H₂S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H₂S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTS^GS). We propose that the RTS^GS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

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.

Carla Farsi, Laura Scull and Jordan Watts
Proc. Amer. Math. Soc. 148 (2020), 2717-2737.
Abstract, references and article information

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

Xing-Huang Gao
May 1, 2020; 19:852-870
Research

Background: ⁶⁸Ga PSMA PET CT (PSMA) is increasingly used in men with biochemical recurrence (BCR) post radical prostatectomy (RP), but its longer term prognostic / predictive potential in these men is unknown. The aim of this study was to evaluate the predictive value of PSMA PET for 3 year freedom from progression (FFP) in men with BCR post RP undergoing salvage radiotherapy (sRT). Methods: This prospective multi-center study enrolled 260 men between 2015 and 2017. Eligible patients were referred for PSMA with rising PSA following RP. Management following PSMA was recorded but not mandated. PSMA protocols were standardised across sites and reported prospectively. Clinical, pathological and surgical information, sRT, timing and duration of androgen deprivation (ADT), 3 year PSA results and clinical events were documented. FFP was defined as a PSA rise ≤ 0.2ng/mL above nadir post sRT, with no additional treatment. Results: The median PSA was 0.26ng/mL (IQR 0.15 - 0.59) and follow-up 38 months (IQR 31-43). PSMA was negative in 34.6% (90/260), confined to prostate fossa 21.5% (56/260), pelvic nodes 26.2% (68/260), and distant disease 17.7% (46/260). 71.5% (186/260) received sRT, 38.2% (71/186) to the fossa only, 49.4% (92/186) fossa + pelvic nodes and 12.4% (23/186) nodes alone/SBRT. PSMA was highly predictive of FFP at 3 years following sRT. Overall, FFP was achieved in 64.5% (120/186) of those who received sRT, 81% (81/100) with negative/fossa confined vs. 45% (39/86) for extra fossa disease (p<0.0001). On logistic regression PSMA was more independently predictive of FFP than established clinical predictors, including PSA, T-stage, surgical margin status or Gleason score (P < 0.002). 32% of men with a negative PSMA PET did not receive treatment. Of these, 66% (19/29) progressed, with a mean rise in PSA of 1.59ng/mL over the 3 years. Conclusion: PSMA PET result is highly predictive of FFP at 3 years in men undergoing sRT for BCR following RP. In particular, men with negative PSMA PET or disease identified as still confined to the prostate fossa demonstrate high FFP, despite receiving less extensive radiotherapy and lower rates of additional ADT than those with extra fossa disease.

Research Event

Event participants

Jon Temin, Director, Africa Programs, Freedom House
Chair: Rachael Jolley, Editor-in-chief, Index on Censorship 

The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H₂S has been shown to persulfidate redox sensitive cysteine residues resulting in an H₂S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H₂S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTS^GS). We propose that the RTS^GS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.