Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.

KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors.

Multi-omics analysis in mouse primary cortical neurons reveals complex positive and negative biological interactions between constituent compounds in Centella asiatica.

Background: A water extract of the Ayurvedic plant (CAW) improves cognitive function in mouse models of aging and Alzheimer's disease, and affects dendritic arborization, mitochondrial activity and oxidative stress in mouse primary neurons. Triterpenes (TT) and caffeoylquinic acids (CQA) are constituents associated with these bioactivities of CAW although little is known about how interactions between these compounds contribute to the plant's therapeutic benefit.

Methods: Mouse primary cortical neurons were treated with CAW, or equivalent concentrations of four TT combined, eight CQA combined, or these twelve compounds combined (TTCQA).

Evaluating disparities in air pollution as a function of ethnicity, deprivation and sectoral emissions in England.

Macro-scale distribution of air pollution concentrations is influenced by factors including geography, weather, industry, transport and regulation. Pollution sources are unevenly distributed, with some communities disproportionately impacted by higher emissions. This study separates the effects of deprivation from ethnicity as factors that influence proximity to pollution sources.

Clinical prediction of wound re-epithelisation outcomes in non-severe burn injury using the plasma lipidome.

Whilst wound repair in severe burns has received substantial research attention, non-severe burns (<20 % total body surface area) remain relatively understudied, despite causing considerable physiological impact and constituting most of the hospital admissions for burns. Early prediction of healing outcomes would decrease financial and patient burden, and aid in preventing long-term complications from poor wound healing. Lipids have been implicated in inflammation and tissue repair and may play essential roles in burn wound healing.

Disrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis.

Macrophages are key drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of more than 70% of inducible genes in macrophages is RNA polymerase II (Pol II) promoter-proximal pause release; however, the specific role of Pol II early elongation control in inflammation, and whether it can be modulated therapeutically, is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages did not affect baseline Pol II occupancy but enhanced the transcriptional response of paused anti-inflammatory genes to lipopolysaccharide followed by secondary attenuation of inflammatory signaling in vitro and in the K/BxN serum transfer mouse model of arthritis.

Protocol for autofluorescence-driven isolation of human peripheral blood eosinophils.

Most common techniques for isolating eosinophils utilize CD16-negative selection, neglecting the CD16-positive fraction of eosinophils. Here, we present a protocol for isolating human CD16+ and CD16- eosinophils based on their autofluorescence using the MACSQuant Tyto cell sorter. We describe steps for purifying eosinophils and assessing purity, viability, and functional activity.

Activating p53 with a Mutant-Specific Small Molecule.

is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TRanscriptional Activator of p53 () due to its ability to engage mutant p53 and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription.

Validating the Quality Maternal and Newborn Care Framework Index: A Global Tool for Quality-of-Care Evaluations.

Background: Quality maternity care is known to improve a range of maternal and neonatal outcomes. The Lancet Series on Midwifery's Quality Maternal and Newborn Care (QMNC) Framework is a high-level synthesis of the global evidence on quality maternity care. Initial qualitative work demonstrated the Framework's adaptability in evaluating service user and provider perceptions of the quality of maternity care.

Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging.

Factors Influencing Meal Provision and Dietary Support Behaviour of Caregivers of People with Chronic Kidney Disease: A Cross-Sectional Study.

Background/objectives: Caregivers play an important role in supporting care recipients to navigate their health needs, including adherence to dietary recommendations, which are complex and multifaceted. This study aims to (i) describe the nutrition knowledge of caregivers of people with chronic kidney disease (CKD), and (ii) explore caregivers' perceptions of their role in providing healthy meals and nutrition support for care recipients.

Methods: A cross-sectional study design employed a multi-strategy research approach.

(Ashwagandha) Improves Spatial Memory, Anxiety and Depressive-like Behavior in the 5xFAD Mouse Model of Alzheimer's Disease.

(WS), also known as ashwagandha, is a popular botanical supplement used to treat various conditions including memory loss, anxiety and depression. Previous studies from our group showed an aqueous extract of WS root (WSAq) enhances cognition and alleviates markers for depression in . Here, we sought to confirm these effects in the 5xFAD mouse model of β-amyloid (Aβ) accumulation.

Measuring the Pupillary Light Reflex Using Portable Instruments in Applied Settings.

The early components of the pupillary light reflex (PLR) are governed by the parasympathetic nervous system. The use of cheap, portable pupillometry devices may allow for the testing of parasympathetic-system health in field settings. We examined the reliability of two portable instruments for measuring the PLR and their sensitivity to individual differences known to modulate the PLR.

Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction.

Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA).

Discovery of electrophilic degraders that exploit SAr chemistry.

Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles.

Relocalizing transcriptional kinases to activate apoptosis.

Kinases are critical regulators of cellular function that are commonly implicated in the mechanisms underlying disease. Most drugs that target kinases are molecules that inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. We synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs).

Exploration of the tunability of BRD4 degradation by DCAF16 trans-labelling covalent glues.

Chemically induced proximity modalities such as targeted protein degradation (TPD) hold promise for expanding the number of proteins that can be manipulated pharmacologically. However, current TPD strategies are often limited to proteins with preexisting ligands. Molecular glues (e.

Thorium(IV) and Uranium(IV) Thioether and Selenoether Complexes: Synthesis and An-ER (E = S, Se) Bonding Comparison.

Reactions of the rigid thioether- and selenoether-containing ligand salts [{Li(AE)}] (E = S or Se; AE = 4,5-bis(phenylchalcogenido)-2,7,9,9-tetramethylacridanide) with ThCl(dme) or UCl (for E = Se) afforded the actinide chalcogenoether complexes [(AE)ThCl] (E = S (), Se ()), and [(ASe)UCl] (). X-ray crystal structures of - revealed tetravalent actinide cations complexed to two κ-coordinated AE ligands, with Th-ER and U-ER distances below the sum of the covalent radii. Complexes - provide extremely rare examples of thorium-thioether, thorium-selenoether, and uranium-selenoether bonds, and and contain the shortest known Th-SR and Th-SeR distances.

Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics.

Targeted protein degradation and induced proximity refer to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of glues remains challenging, unbiased discovery methods are needed to unveil hidden chemical targets. Here we establish a high throughput affinity purification mass spectrometry workflow in cell lysates for the unbiased identification of molecular glue targets.

New fungal primers reveal the diversity of Mucoromycotinian arbuscular mycorrhizal fungi and their response to nitrogen application.

Background: Arbuscular mycorrhizas (AM) are the most widespread terrestrial symbiosis and are both a key determinant of plant health and a major contributor to ecosystem processes through their role in biogeochemical cycling. Until recently, it was assumed that the fungi which form AM comprise the subphylum Glomeromycotina (G-AMF), and our understanding of the diversity and ecosystem roles of AM is based almost exclusively on this group. However recent evidence shows that fungi which form the distinctive 'fine root endophyte' (FRE) AM morphotype are members of the subphylum Mucoromycotina (M-AMF), so that AM symbioses are actually formed by two distinct groups of fungi.

DCLK1 induces a pro-tumorigenic phenotype to drive gastric cancer progression.

Doublecortin-like kinase 1 (DCLK1) is a proposed driver of gastric cancer (GC) that phosphorylates serine and threonine residues. Here, we showed that the kinase activity of DCLK1 orchestrated cancer cell-intrinsic and-extrinsic processes that led to pro-invasive and pro-metastatic reprogramming of GC cells. Inhibition of the kinase activity of DCLK1 reduced the growth of subcutaneous xenograft tumors formed from MKN1 human gastric carcinoma cells in mice and decreased the abundance of the stromal markers α-Sma, vimentin, and collagen.

A Combined Computational and Experimental Approach to Studying Tropomyosin Kinase Receptor B Binders for Potential Treatment of Neurodegenerative Diseases.

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders.