The -aminobutyric acid type A (GABA_A) receptor is modulated by a number of neuroactive steroids. Sulfated steroids and 3β-hydroxy steroids inhibit, while 3α-hydroxy steroids typically potentiate the receptor. Here, we have investigated inhibition of the α1β32L GABA_A receptor by the endogenous neurosteroid 3α-hydroxy-5β-pregnan-20-one (3α5βP) and the synthetic neuroactive steroid 3α-hydroxy-5α-androstane-17β-carbonitrile (ACN). The receptors were expressed in Xenopus oocytes. All experiments were done using two-electrode voltage-clamp electrophysiology. In the presence of low concentrations of GABA, 3α5βP and ACN potentiate the GABA_A receptor. To reveal inhibition, we conducted the experiments on receptors activated by the combination of a saturating concentration of GABA and propofol to fully activate the receptors and mask potentiation, or on mutant receptors in which potentiation is ablated. Under these conditions, both steroids inhibited the receptor with IC₅₀s of ~13 μM and maximal inhibitory effects of 70–90%. Receptor inhibition by 3α5βP was sensitive to substitution of the α1 transmembrane domain (TM) 2-2' residue, previously shown to ablate inhibition by pregnenolone sulfate. However, results of coapplication studies and the apparent lack of state dependence suggest that pregnenolone sulfate and 3α5βP inhibit the GABA_A receptor independently and through distinct mechanisms. Mutations to the neurosteroid binding sites in the α1 and β3 subunits statistically significantly, albeit weakly and incompletely, reduced inhibition by 3α5βP and ACN.

G protein–coupled receptors (GPCRs) couple to heterotrimeric G proteins, comprised of α and β subunits, to convert extracellular signals into activation of intracellular signaling pathways. Canonically, GPCR-mediated activation results in the exchange of GDP for GTP on G protein α subunits (Gα) and the dissociation of Gα-GTP and G protein β subunits (Gβ), both of which can regulate a variety of signaling pathways. Hydrolysis of bound GTP by Gα returns the protein to Gα-GDP and allows reassociation with Gβ to reform the inactive heterotrimer. Naturally occurring mutations in Gα have been found at conserved glutamine and arginine amino acids that disrupt the canonical G protein cycle by inhibiting GTP hydrolysis, rendering these mutants constitutively active. Interestingly, these dysregulated Gα mutants are found in many different cancers due to their ability to sustain aberrant signaling without a need for activation by GPCRs. This review will highlight an increased recognition of the prevalence of such constitutively activating Gα mutations in cancers and the signaling pathways activated. In addition, we will discuss new knowledge regarding how these constitutively active Gα are regulated, how different mutations are biochemically distinct, and how mutationally activated Gα are unique compared with GPCR-activated Gα. Lastly, we will discuss recent progress in developing inhibitors directly targeting constitutively active Gα mutants.

ABSTRACTDespite global consensus on the importance of male involvement in family planning, disparities persist in low- and middle-income countries, where women continue to bear the responsibility for these initiatives. The Philippines, with a high fertility rate and unmet family planning needs, exemplifies this challenge. We present the experiences and lessons learned from implementing the no-scalpel vasectomy (NSV) program in Davao City, showcasing its potential for increasing male engagement in family planning decisions. Launched in 2008, the program aimed to address gender disparity by promoting NSV as a safe and effective contraceptive alternative to female-centric methods. Through the use of culturally sensitive information campaigns and couple-focused counseling, the program challenged traditional notions of masculinity and encouraged shared decision-making. Strong local government commitment and public-private partnerships played key roles in driving the program’s success. Results showed an average annual increase of 80% in NSV clients over the past 3 years compared to before the COVID-19 pandemic, underscoring its effectiveness. The program presents a compelling intervention model for similar initiatives, highlighting how overcoming cultural barriers, infrastructure limitations, and budgetary constraints through policy advocacy, strategic partnerships, and tailored approaches can significantly boost male involvement in family planning and improve reproductive health outcomes within communities.

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential.

α-Synuclein (AS) is a small presynaptic protein that is genetically, biochemically, and neuropathologically linked to Parkinson's disease (PD) and related synucleinopathies. We present here a review of the topic of this relationship, focusing on more recent knowledge. In particular, we review the genetic evidence linking AS to familial and sporadic PD, including a number of recently identified point mutations in the SNCA gene. We briefly go over the relevant neuropathological findings, stressing the evidence indicating a correlation between aberrant AS deposition and nervous system dysfunction. We analyze the structural characteristics of the protein, in relation to both its physiologic and pathological conformations, with particular emphasis on posttranslational modifications, aggregation properties, and secreted forms. We review the interrelationship of AS with various cellular compartments and functions, with particular focus on the synapse and protein degradation systems. We finally go over the recent exciting data indicating that AS can provide the basis for novel robust biomarkers in the field of synucleinopathies, while at the same time results from the first clinical trials specifically targeting AS are being reported.

PlayStation 5 Pro is out, and with plenty of availability, scalpers are shifting the £700 console at a loss and turning their attention to a key accessory instead

The ongoing saga of the BlackCat/AlphV ransomware gang continues, with a news report that the crew has shut down its servers after a controversial hack of an American healthcare services provider. Bleeping Computer says the gang’s data leak blog shut on Friday and the sites it uses to negotiate ransom payments closed today. This comes […]

Canada will be without captain Alphonso Davies for its upcoming CONCACAF Nations League quarterfinal against Suriname. Canada Soccer says the Bayern Munich star has withdrawn as a "precautionary measure due to physical fatigue."

C'était une nouvelle attendue.

Joël McGuirk a dénoncé son retrait imprévu du dernier plateau de «Tout le monde en parle», lundi, au micro de Sophie Durocher, à QUB radio.

A review of Labor’s City of Sydney council campaign finds earlier preselections and better policies are needed.

Labor has urged Malcolm Turnbull to be more transparent about the deal reached to resettle refugees in the US.

Some 180 women were prescribed valproate, a medicine used to treat epilepsy and bipolar disorder, during their pregnancy within a 2.5 year interval, NHS data has revealed.

Groupe Renault Chairman and CEO Carlos Ghosn today announced plans for a new Alpine sports car and unveiled the Alpine Vision show car.

Компания Google DeepMind опубликовала исходные тексты системы машинного обучения AlphaFold 3, предназначенной для предсказания трёхмерной структуры белков и моделирования взаимодействия белков с другими типами молекул. За создание алгоритмов машинного обучения, реализованных во второй версии AlphaFold, в этом году присуждена Нобелевская премия по химии. Связанный с AlphaFold 3 инструментарий написан на Python и C++, и распространяется под лицензией CC BY-NC-SA 4.0. Натренированные модели предоставляются на основе пользовательского соглашения. Отдельно запущен сервер, позволяющий экспериментировать с AlphaFold 3 в online-режиме.

“This is a collapse of the Democratic Party.” Consumer advocate, corporate critic and former presidential candidate Ralph Nader comments on the reelection of Donald Trump and the failures of the Democratic challenge against him. Despite attempts by left-wing segments of the Democratic base to shift the party’s messaging toward populist, anti-corporate and progressive policies, says Nader, Democrats “didn’t listen.” Under Trump, continues Nader, “We’re in for huge turmoil.”

I recently asked the question about which Steve Jackson Games product and game is last alphabetically, which we answered here. In that earlier question, I alluded to the other question. Namely:

• What is the first item alphabetically that is currently available for sale, and . . .

• What is the first item alphabetically that is a complete game and currently available for sale?

This one is trickier for a couple of reasons. As Magesmiley noted on the forums when talking about the "Omega" question, somewhat of a software-sorting question hides here. There's also a bit of an oddity in the second question we're asking today that makes this more challenging. Still, let's see if we can't muddle toward an answer . . .

. . . Which we'll divulge sometime soon. As ever, feel free to share your answers on the forums!

– Steven Marsh

Warehouse 23 News: The City Never Sleeps Because Of All The Action

There are a million stories in the city, and they're all exciting! GURPS Action 9: The City shows how you can add GURPS City Stats to your GURPS Action campaigns. It also features six sample cities to use with your own action-packed adventures. Download it today from Warehouse 23!

It’s a Christmas miracle—Bootstrap v5.3.0-alpha1 has arrived just in time for the holiday break! This release brings new color mode support, an expanded color palette with variables and utilities, and more.

We’re keeping things short and simple in this blog post with deeper dives into the new color modes and more coming in future posts. For now, we want you to enjoy the holiday break and come back next year feeling refreshed and rejuvenated. Keep reading for what’s new and we’ll see you next year!

Our second alpha release of v5.3.0 has landed with a ton of enhancements and bug fixes for our new color modes! There’s still more to come, but we’ve held off shipping until we ironed out enough issues. Huzzah, we have!

This v5.3.0 release is a monumental update for Bootstrap 5. It’s big enough that it could’ve been a v6 on its own, but we wanted to do right by the community and get color modes out the door without the massive major release upgrade. We’re getting super close now, so bear with us as we continue to chip away at this.

Hot on the heels of our second alpha, we’re releasing a third (and unexpected) alpha for v5.3.0 today with some fixes for some Node Sass compilation errors. In addition, we’ve added a handful of other updates. We’re still on target to ship our stable release soon!

Once again, if you’re new to the v5.3.0 alpha releases, please read through the Migration guide for the first alpha and last month’s second alpha.

Here’s a look at what’s changed in this quick release:

Shreyas Talpade is also a brand ambassador and face of the Bombay Psychiatric Society. On the film front, the actor is also gearing up for Emergency, and Welcome To The Jungle to name a few.

Dish has made a stunning bid to buy Sprint for a cash-and -stock deal valuing Dish at $25.5 billion. Last year Softbank agreed to buy Sprint, also for a package of cash and stock. Dish claims its offer is worth 13% more.

  Incident in Jabalpur like Delhi's Kanjhawala:राजधानी दिल्ली कंझावला में हुई दिलदहला देने वाली घटना की तरह एमपी के जबलपुर में भी एक्सीडेंट हुआ। रात के वक्त 14 चक्का ने बाइक सवार मेडिकल स्टूडेंट्स को रौंदा, जिसमें फंसी शहडोल की

The UN Disengagement Observer Force warns of severe violations by Israel along the Alpha Line, risking increased tensions with Syria.

[s.l.] : Amsterdam University Press, 2023.

My Name Ijj Lakhan premieres on January 26.

India won last of their eight Olympic gold medals way back in the 1980 Moscow Games. Paris provides them a great opportunity to make history.

The annual Kalpathy Bhajanotsavam in Palakkad was composed of musicality and piety

New Brunswick : Rutgers University Press, 2024.

Cobra Kai star Ralph Macchio takes the WIRED Autocomplete Interview and answers the internet's most searched questions about himself. Who taught Ralph Macchio karate? How many languages does Ralph speak? Does he respond to fan mail? Is he from New Jersey? Why does he look so young?? Ralph answers all these questions and much more! Director: Alexandra Coccia Director of Photography: Constantine Economides Editor: Ron Douglas Talent: Ralph Macchio Line Producer: Joseph Buscemi Associate Producer: Brandon White Production Manager: Eric Martinez Production Coordinator: Fernando Davila Assistant Camera: Christopher Alfonso Audio: Rebecca O’Neill Production Assistant: Patrick Sargent Post Production Supervisor: Alexa Deutsch Post Production Coordinator: Ian Bryant Supervising Editor: Doug Larsen Director: Alexandra Coccia Director of Photography: Constantine Economides Editor: Ron Douglas Talent: Ralph Macchio Line Producer: Joseph Buscemi Associate Producer: Brandon White Production Manager: Eric Martinez Production Coordinator: Fernando Davila Assistant Camera: Christopher Alfonso Audio: Rebecca O’Neill Production Assistant: Patrick Sargent Post Production Supervisor: Alexa Deutsch Post Production Coordinator: Ian Bryant Supervising Editor: Doug Larsen Assistant Editor: Justin Symonds

AGS Entertainment is doing another movie with Pradeep Ranganathan and also produced by the production house

Marketline

Kalpen Parekh of DSP Mutual Fund on his fund house’s investment philosophy, the markets, valuation metrics and more

Continental Kings will defend its crown against PBG Alaskan Knights.

His 15th five-wicket haul results in Mumbai earning a bonus point following an innings win; Himanshu picks four as Swain, Biswal contributions go in vain

The authorities of IIM, Sambalpur announced the introduction of artificial intelligence (AI) as faculty during a programme commemorating its 10th Foundation Day