Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer.

Background: The goal of precision oncology is to find effective therapeutics for every patient. Through the inclusion of emerging therapeutics in a high-throughput drug screening platform, our functional genomics pipeline inverts the common paradigm to identify patient populations that are likely to benefit from novel therapeutic strategies.

Approach: Utilizing drug screening data across a panel of 46 cancer cell lines from 11 tumor lineages, we identified an ovarian cancer-specific sensitivity to the first-in-class CRL4 inhibitors KH-4-43 and 33-11.

Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease.

Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity strongly influences circulating protein levels, we investigated proteins mediating the effects of obesity on coronary artery disease, stroke and type 2 diabetes. By integrating two-step proteome-wide Mendelian randomization, colocalization, epigenomics and single-cell RNA sequencing, we identified five mediators and prioritized collagen type VI α3 (COL6A3).

Transposon mediated functional genomic screening for BRAF inhibitor resistance reveals convergent Hippo and MAPK pathway activation events.

Genotype-informed anticancer therapies such as BRAF inhibitors can show remarkable clinical efficacy in BRAF-mutant melanoma; however, drug resistance poses a major hurdle to successful cancer treatment. Many resistance events to targeted therapies have been identified, suggesting a complex path to improve therapeutics. Here, we showed the utility of a piggyBac transposon activation mutagenesis screen for the efficient identification of genes that are resistant to BRAF inhibition in melanoma.

COFcap2, a recyclable tandem catalysis reactor for nitrogen fixation and conversion to chiral amines.

Two or more catalysts conducting multistep reactions in the same reactor, concurrent tandem catalysis, could enable (bio)pharmaceutical and fine chemical manufacturing to become much more sustainable. Herein we report that co-immobilization of metal nanoparticles and a biocatalytic system within a synthetic covalent organic framework capsule, COFcap-2, functions like an artificial cell in that, whereas the catalysts are trapped within 300-400 nm cavities, substrates/products can ingress/egress through ca. 2 nm windows.

One-Pot Regioselective Synthesis of Spiroimidazolidinones via a Sequential Ugi 4CR/Azide-Isocyanide Coupling/Cyclization/Rearrangement/Hydroxylation Reaction.

Herein a novel and robust methodology to spiroimidazolidinones has been developed under a mild reaction. The reaction of (Z)-2-azido-3-phenylacrylic acids , aldehydes , amines , isocyanides , and isocyanides produced regioselectively spiroimidazolidinones in 71-88% yields via a sequential Ugi 4CR/Pd(0) catalyzed azide-isocyanide coupling/cyclization/rearrangement/hydroxylation reaction. Furthermore, the easily accessible starting materials, high bond-forming efficiency, and broad substituent tolerance make this strategy useful in synthetic and medicinal chemistry.

A framework for ecologically and socially informed risk reduction before and after outbreaks of wildlife-borne zoonoses.

Despite increasing emphasis being placed on the inclusion of upstream ecological and social perspectives for zoonotic disease control, few guidelines exist for practitioners and decision makers to work with communities in identifying suitable, locally relevant interventions and integrating these into public health action plans. With an interdisciplinary group of Kenyan stakeholders, we designed and tested a comprehensive framework for the co-design, evaluation, and prioritisation of beneficiary-oriented, ecologically and socially informed interventions for preventing and controlling outbreaks of wildlife-borne zoonoses. Our approach used four globally important wildlife-borne pathogens-Rift Valley fever virus, Congo-Crimean haemorrhagic fever virus, and the causative agents of anthrax and rabies-enabling stakeholders to develop a shared understanding of complex transmission pathways, identify a broad array of measures targeting ecological, biological, and social processes governing outbreaks of these pathogens, and explore trade-offs for specific interventions.

Active starch-based film using polyvinyl alcohol and chlorogenic acid for strawberry preservation: A comparative analysis of mechanical, barrier, and antibacterial properties.

The broad application of starch films has been significantly limited by their insufficient hydrophobicity and antibacterial activity. To overcome these challenges, this study developed a new starch film by incorporating polyvinyl alcohol (PVA) and chlorogenic acid. The study explored the impact of PVA polymerization on the physical and functional characteristics of the resulting films, with particular emphasis on enhancing antimicrobial functionality by incorporating chlorogenic acid.

Cropland associated with risk of Parkinson's disease in the northern Great Plains.

Introduction: We sought to identify regional associations between cropland density and crop types and PD in the U.S.

Methods: We conducted a population-based study of 21,639,190 Medicare beneficiaries, 89,790 with incident PD in 2009.

Megoura crassicauda promote the ability of Vicia faba L. to remediate cadmium pollution of water and soil.

With the increasing severity of heavy metal pollution in soil and water, phytoremediation is becoming increasingly popular because of its low cost, high returns, and environmental friendliness. The use of leguminous plants such as the broad bean for heavy metal remediation is becoming a research hotspot because of their symbiotic relationship with rhizobia. This study investigated the cadmium (Cd) remediation ability of fava beans by M.

Paediatric strategy forum for medicinal product development in diffuse midline gliomas in children and adolescents ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments.

Regioselective 1,4-Addition of P(O)-H Species to In SituFormed 1-Benzopyrylium Ion from C3-Substituted 2-Chromene Hemiketals to Construct C3-Functionalized C4-Phosphorylated 4-Chromenes.

Herein, we report the first example that P(O)-H species including -phosphonates and -phosphine oxides could participate in a highly regioselective 1,4-addition to in situ generated 1-benzopyrylium ion from C3-substituted 2-chromene hemiketals, which provides a brand-new and effective approach for the synthesis of C4-phosphorylated 4-chromenes with diverse C3-functionality (ketone, ester, sulfonyl, aryl, and alkyl groups). In total, the reaction features the use of inexpensive Zn(ClO)·6HO as a catalyst, low catalyst loading (only 5 mol %), mild reaction conditions (60 °C, 10 min to 24 h), and broad substrate scope (46 examples) as well as good to high yields (>90% yield on average). More importantly, mechanistic experiments demonstrated the essential role of the C3-substituent on 2-chromene hemiketals in stabilizing the in situ generated 1-benzopyrylium ion and the regioselective 1,4-addition control.

Low-Cost Preparation of Wafer-Scale Au(111) Single Crystals for the Epitaxy of Two-Dimensional Layered Materials.

Single-crystal Au(111), renowned for its chemically inert surface, long-range "herringbone" reconstruction, and high electrical conductivity, has long served as an exemplary template in diverse fields, , crystal epitaxy, electronics, and electrocatalysis. However, commercial Au(111) products are high-priced and limited to centimeter sizes, largely restricting their broad applications. Herein, a low-cost, high-reproducible method is developed to produce 4 in.

Genotype x environment interaction effect on grain yield of cowpea (Vigna unguiculata (L.) Walp) in Deciduous forest and Sudan savanna ecologies of Ghana.

Cowpea is deemed as a food security crop due to its ability to produce significant yields under conditions where other staples fail. Its resilience in harsh environments; such as drought, heat and marginal soils; along with its nitrogen-fixing capabilities and suitability as livestock feed make cowpea a preferred choice in many farming systems across sub-Saharan Africa (SSA). Despite its importance, Cowpea yields in farmers' fields remain suboptimal, primarily due to biotic and abiotic factors and the use of either unimproved varieties or improved varieties that are not well-suited to local conditions.

Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy.

Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded CD8 cytotoxic T lymphocytes with in vitro specificity for patient-matched AML.

Regioselective Suzuki-Miyarua Cross-Coupling for Substituted 2,4-Dibromopyridines Catalyzed by -Symmetric Tripalladium Clusters.

Multipalladium clusters possess peculiar structures and synergistic effects for reactivity and selectivity. Herein, -symmetric tripalladium clusters (, 0.5 mol %) afford C-regioselective SMCC of 2,4-dibromopyridine with phenylboronic acids or pinacol esters (C:C up to 98:1), in contrast to Pd(OAc) in ligand-free conditions.

An alternatively translated isoform of PPARG proposes AF-1 domain inhibition as an insulin sensitization target.

PPARγ is the pharmacological target of thiazolidinediones (TZDs), potent insulin sensitizers that prevent metabolic disease morbidity but are accompanied by side effects such as weight gain, in part due to non-physiological transcriptional agonism. Using high throughput genome engineering, we targeted nonsense mutations to every exon of PPARG, finding an ATG in Exon 2 (chr3:12381414, CCDS2609 c.A403) that functions as an alternative translational start site.

Scalable Fabrication of Freestanding Jammed Nanoparticle Films via Pickering Emulsion-Mediated Interfacial Assembly.

Freestanding networked nanoparticle (NP) films hold substantial potential due to their high surface areas and customizable porosities. However, NPs with high surface energies and heterogeneous sizes or shapes present considerable challenges as they tend to aggregate, compromising their structural integrities. In this study, we report the scalable fabrication of ultrathin, bicontinuous, and densely packed carbon NP films via Pickering emulsion-mediated interfacial assembly.

Regulatory and retrograde signaling networks in the chlorophyll biosynthetic pathway.

Plants, algae and photosynthetic bacteria convert light into chemical energy by means of photosynthesis, thus providing food and energy for most organisms on Earth. Photosynthetic pigments, including chlorophylls (Chls) and carotenoids, are essential components that absorb the light energy necessary to drive electron transport in photosynthesis. The biosynthesis of Chl shares several steps in common with the biosynthesis of other tetrapyrroles, including siroheme, heme and phycobilins.

The exceptionally rare phenomenon of well-differentiated colon neuroendocrine tumors.

Colonic neuroendocrine tumors (NETs), excluding rectal NETs, are often described as relatively common and aggressive, with inferior median survival compared with other gastrointestinal (GI) primary sites. However, epidemiological databases may conflate well-differentiated NETs with poorly differentiated neuroendocrine carcinomas (NECs), leading to a lack of precise data on the prevalence, clinical behavior, and prognosis of well-differentiated colonic NETs. We analyzed a large institutional database to identify patients with well-differentiated NETs originating in the colon, excluding rectal NETs.

Reference-Based Multiple Imputation for Longitudinal Binary Data.

Introduction: In clinical trials, a treatment policy strategy is often used to handle treatment nonadherence. However, estimation in this context is complicated when data are missing after treatment deviation. Reference-based multiple imputation has been developed for the analysis of a longitudinal continuous outcome in this setting.

Realistic total-body J-PET geometry optimization: Monte Carlo study.

Background: Total-body (TB) Positron Emission Tomography (PET) is one of the most promising medical diagnostics modalities, opening new perspectives for personalized medicine, low-dose imaging, multi-organ dynamic imaging or kinetic modeling. The high sensitivity provided by total-body technology can be advantageous for novel tomography methods like positronium imaging, demanding the registration of triple coincidences. Currently, state-of-the-art PET scanners use inorganic scintillators.

METTL3: a multifunctional regulator in diseases.

N6-methyladenosine (mA) methylation is the most prevalent and abundant internal modification of mRNAs and is catalyzed by the methyltransferase complex. Methyltransferase-like 3 (METTL3), the best-known mA methyltransferase, has been confirmed to function as a multifunctional regulator in the reversible epitranscriptome modulation of mA modification according to follow-up studies. Accumulating evidence in recent years has shown that METTL3 can regulate a variety of functional genes, that aberrant expression of METTL3 is usually associated with many pathological conditions, and that its expression regulatory mechanism is related mainly to its methyltransferase activity or mRNA posttranslational modification.

Two case reports of biliary stent infections by extensively drug-resistant Escherichia coli carrying bla at a tertiary-care hospital in West Bengal, India.

Background: Rising antimicrobial resistance (AMR) is an acute public health emergency impeding the clinical efficacy of surgical interventions. Biliary stent placement is one of the routine surgical procedures that rarely lead to infections that are empirically managed by broad-spectrum β-lactams and fluoroquinolones. Critical priority pathogens, such as carbapenem-resistant Escherichia coli challenge treatment outcomes and infection prevention.

Academic motivation-achievement cycle and the behavioural pathways: A short-timeframe experiment with manipulated perceived achievement.

Background: The purported reciprocity between motivation and academic achievement in education has largely been supported by correlational data.

Aims: Our first aim was to determine experimentally whether motivation and achievement are reciprocally related. The second objective was to investigate a potential behavioural mediation pathway between motivation and achievement by measuring the objective effort expended on learning.

The Esthetic Use of Botulinum Toxins in Cancer Patients: Providing a Foundation for Future Indications.

Advances in oncological treatments have improved the survival rates of cancer patients but have often resulted in significant physical changes that negatively impact their self-esteem and psychological well-being. Cancer patients frequently ask esthetic practitioners to perform procedures to address such changes. However, practitioners often hesitate to satisfy such requests due to lacking guidelines or recommendations.