Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts, such as concentration-response curves, additive effects, and predictive models, are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. Although various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors, such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA.

Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"].

BACKGROUND AND PURPOSE:

Intracranial vessel wall imaging is technically challenging to implement, given the simultaneous requirements of high spatial resolution, excellent blood and CSF signal suppression, and clinically acceptable gradient times. Herein, we present our preliminary findings on the evaluation of a deep learning–optimized sequence using T1-weighted imaging.

BACKGROUND AND PURPOSE:

Recently, artificial intelligence tools have been deployed with increasing speed in educational and clinical settings. However, the use of artificial intelligence by trainees across different levels of experience has not been well-studied. This study investigates the impact of artificial intelligence assistance on the diagnostic accuracy for intracranial hemorrhage and large-vessel occlusion by medical students and resident trainees.

The potential for more than one distinct hematolymphoid neoplasm to arise from a common mutated stem or precursor cell has been proposed based on findings in primary human malignancies. Particularly, angioimmunoblastic T-cell lymphoma (AITL), which shares a somatic mutation profile in common with other hematopoietic malignancies, has been reported to occur alongside myeloid neoplasms or clonal B-cell proliferations, with identical mutations occurring in more than one cell lineage. Here we report such a case of an elderly woman who was diagnosed over a period of 8 years with diffuse large B-cell lymphoma, polycythemia vera, and AITL, each harboring identical somatic mutations in multiple genes. Overall, at least five identical nucleotide mutations were shared across multiple specimens, with two identical mutations co-occurring at variable variant allele frequencies in all three specimen types. These findings lend credence to the theory that a common mutated stem cell could give rise to multiple neoplasms through parallel hematopoietic differentiation pathways.

Inositol 1,4,5-triphosphate receptor type 1 (ITPR1) is an endoplasmic reticulum–bound intracellular inositol triphosphate receptor involved in the regulation of intracellular calcium. Pathogenic variants in ITPR1 are associated with spinocerebellar ataxia (SCA) types 15/16 and 29 and have recently been implicated in a facial microsomia syndrome. In this report, we present a family with three affected individuals found to have a heterozygous missense c.800C > T (predicted p.Thr267Met) who present clinically with a SCA29-like syndrome. All three individuals presented with varying degrees of ataxia, developmental delay, and apparent intellectual disability, as well as craniofacial involvement—an uncommon finding in patients with SCA29. The variant was identified using clinical exome sequencing and validated with Sanger sequencing. It is presumed to be inherited via parental germline mosaicism. We present our findings to provide additional evidence for germline mosaic inheritance of SCA29, as well as to expand the clinical phenotype of the syndrome.

We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease–associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of CD79B, MyD88, TP53, TBL1XR1, and PIM1 genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of TP53 heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as PRDM1 loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of BTK and FOXO1 mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.

HBO's Casey Bloys was asked about the Game of Thrones author's spicy take on House of the Dragon season two.

A new report by the global union Education International shows that AI can degrade the quality of education, worsen working conditions for teachers and provide inferior schooling for students.

The post Artificial Intelligence can cause fake education appeared first on rabble.ca.

There must be hundreds of typewriters in the hall, their collective clacks a tidal wave of soulless automation, rising up to greet agent Kiran Estevez as she enters, pistol and flashlight in hands. Exploring rooms to the side, Alan Wake 2: The Lake House’s star finds whiteboards and documents revealing the typewriter’s purpose: to mimic Wake’s writing. Pages are graded along criteria such as ‘style’, ‘tone’, and ‘content’, then “fed into the algorithm” as references until “near-identical stories” to Wake’s can be produced.

“If Jules could simply cut the painter open and pull the painting out of him, he would,” reads one of the real Alan’s typewritten pages. That’s Jules Marmont, the obsessive head of the titular FBC centre. The Marmonts - Jules and his wife Diana - are running experiments to forcibly and synthetically create works of art, aiming to mimic creative passion convincingly enough for the paranatural entity inside Cauldron Lake to respond, as it has in the past.

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What would it take to turn Texas, a Republican stronghold, into a blue state? According to data from SurveyMonkey, just remove all the gun owners from the Lone Star State and it would have gone to Hillary Clinton in 2016. You can do the same thing in liberal California. Remove all the non-gun owners and the state would have voted for Donald Trump.

That’s how divisive the issue of gun control is in American politics.

SurveyMonkey found that no other demographic — not race, religion or gender — so perfectly divided voters. In the 2016 election, 47 percent of Trump supporters said gun control was an issue important enough to influence their vote. That’s compared to just 27 percent of voters who supported Hillary Clinton.

But what does this divide mean? How is it impacting gun control policy, and how might this issue change in light of recent mass shootings like Las Vegas, Orlando and Newtown? To discuss the data, join a PBS NewsHour-hosted Twitter chat at 1 p.m. EDT Thursday with data journalist Dante Chinni (@Dchinni), professor and chairman of political science at the University of Kansas Don Haider-Markel (@dhmarkel), and Washington Post correspondent Philip Bump (@pbump).

Have questions? Tweet them using #NewsHourChats.

The post Twitter chat: How the gun control debate mirrors larger issues of partisanship in America appeared first on PBS NewsHour.

Martin Lewis has warned Tesco customers of a piece of small print that could see £18m worth of Clubcard points wasted.

Artificial intelligence has more in common with ants than humans, says Neil Lawrence. Only by taking a more nuanced view of intelligence can we see how machines will truly transform society

Certain strains of E. coli are capable of causing severe disease, by rapidly spreading through the human digestive system, wreaking havoc throughout the bloodstream, and eventually damaging the delicate kidneys. That's the situation right now during a large outbreak in Alberta, with hundreds of children now affected.

As artificial intelligence becomes more common in university classrooms, some professors are weighing the benefits — and downsides — of students using it for research projects.

People keep predicting that each wave of new technology will mean humans can put their feet up. It hasn't happened yet. Some economists and anthropologists who study the subject say even with the arrival of artificial intelligence, humans will remain integral to making the world go round.

Sedimentary mineral deposits found on the surface of Mars may have been left by an ancient sea 3.5 billion years ago.

The post Ancient Coastline Spotted in Martian Utopia Region appeared first on Sci.News: Breaking Science News.

From the busy cities to ocean waters, our need to illuminate the world has had some strange and tragic consequences

The Puerto Rican singer covers the latest issue of 'Out' magazine.

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Tickets for the event will go on sale on November 10, 2024, via BookMyShow

Peruvanam Satheesan Marar recalls his initiation into the percussion ensemble and how he gained expertise in playing different instruments

By comparing early markings used for business purposes to 'proto' cuneiform, we can say language transitioned from symbols to writing.

Williams played Arya Stark in Game of Thrones for eight seasons

C'était une nouvelle attendue.

Traverser une séquence de revers, ça n’a rien de plaisant. Surtout quand elle vous refoule jusqu’au dernier rang de la LNH.

José González is an illustrator, author and animator originally from Buenos Aires now living in English Harbour. González was selected to be one of the Artists in Residence at Business and Arts N.L. (Un)Common Threads Creativity and Innovation Summit happening on Nov. 7. In advance of the summit, González has been busy preparing for his installation, which will feature a large-scale fish tank with animated sea creatures brought to life through projections and augmented reality.

Bill MacDonnell's paintings are on display at the Military Museums in Calgary through Remembrance Day and into 2025.

Une ancienne boîte de poulet St-Hubert, retrouvée par hasard dans l’entretoit d’un chalet, a été remise à la famille Martin en échange d'un don.

Le Parti Québécois misera sur sa présidente, Catherine Gentilcore, pour tenter de ravir la circonscription de Terrebonne à la CAQ.

The Embassy of India in Iraq has extended an invitation to Indian businesses to participate in the "Medico Expo," officially known as the Erbil International Health Exhibition. This prestigious event, set to be the

The Directorate General of Trade Remedies (DGTR), under the ministry of commerce and industry, has released a list of registered interested parties regarding the ongoing Second Sunset Review anti─dumping

The Martian new year arrives with the Red Planet’s vernal equinox. Explaining why requires a deep dive into celestial mechanics and Earth’s calendrical history

Novartis recently announced the acquisition of Mariana Oncology, an emerging biotech focused on advancing a radioligand therapeutics platform, for up to $1.75 billion in upfronts and future milestones. The capstone of its three short years of operations, this acquisition represents

The post Mariana Oncology’s Radiopharm Platform Acquired By Novartis appeared first on LifeSciVC.

By Peter Tummino, CSO of Nimbus Therapeutics, as part of the From The Trenches feature of LifeSciVC  “Over the next five to 10 years, our goal is to become a company that’s leading the world in personalized medicines, a company

The post Medicinal Chemistry In The Age Of Artificial Intelligence appeared first on LifeSciVC.

Value-based care contracting is especially difficult for behavioral health providers, Taft Parsons III, chief psychiatric officer at CVS Health/Aetna, pointed out during a conference this week.

The post CVS Health Exec: Payers Need to Stop Making Behavioral Health Providers Jump Through Hoops In Order to Participate in Value-Based Care appeared first on MedCity News.

The Pew Charitable Trusts today commended Michigan Governor Gretchen Whitmer (D), state Senate Majority Leader Mike Shirkey (R), and Lee Chatfield (R)—whose term as state House Speaker ended last month—for passing and signing a bipartisan package of bills aimed at protecting public safety while reducing the number of people in county jails.

Total income for the selected regional parties in FY20 amounted to ₹803.24 crore, of which 55% was from unknown sources

In FY21, national parties and regional parties received ₹427 crore and ₹264 crore worth of funds, respectively, from unknown sources

As many as 3.32 crore voters will cast their votes in 37,809 polling stations across State

Les tendances du march� neuf

Sephora Launches Virtual Artist for the Sephora To Go App

Felicitacion Chucho Valdes