APOE Genotype Influences on The Brain Metabolome of Aging Mice - Role for Mitochondrial Energetics in Mechanisms of Resilience in APOE2 Genotype.

Alzheimer's disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice.

Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle.

During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is known to be activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for activation of the mtISR remain mostly unknown.

Structural Determinants of Oxantel Analogs Reveal Modulatory Selectivity of α3β2 and α4β2 Neuronal Nicotinic Acetylcholine Receptors.

Nicotinic acetylcholine receptors (nAChRs), ligand-gated ion channels involved in key physiological processes, show pharmacological diversity across receptor subtypes and species. The structurally similar anthelmintic compounds pyrantel, morantel, and oxantel differentially affect the α3β2 and α4β2 nAChR subtypes. Mutation analysis located the modulator binding sites to β(+)/α(-) interface pockets, homologous to the orthosteric agonist sites.

Exploring Possible Drug-Resistant Variants of SARS-CoV-2 Main Protease (M) with Noncovalent Preclinical Candidate, Mpro61.

SARS-CoV-2 M inhibitors, such as nirmatrelvir, have proven efficacy in clinical use. Nirmatrelvir was developed in a target-based approach against wild-type M, with the anticipation that prolonged usage may cause enrichment of drug-resistant mutations and persistence of COVID infections. Although globally prevalent drug-resistant mutations have not yet been observed, individual cases have recently been reported among patients following treatment with Paxlovid-a formulation of nirmatrelvir.

Structural Diversity of Metabotropic Glutamate Receptor/Beta-Arrestin Coupling.

Despite the widespread physiological roles of beta-arrestin (β-arr) coupling in G protein-coupled receptor (GPCR) regulation, the molecular basis of GPCR/β-arr interaction has been studied primarily in monomeric family A GPCRs. Here we take an integrative biophysical and structural approach to uncover extreme molecular diversity in β-arr coupling to the neuromodulatory metabotropic glutamate receptors (mGluRs), prototypical, dimeric family C GPCRs. Using a new single molecule pulldown assay, we find that mGluRs couple to β-arrs with a 2:1 or 2:2 stoichiometry via a combination of "tail" and "core" interactions.

Airway management in acute hematoma formation following anterior cervical spine surgery.

Anterior cervical spine surgery (ACSS) is a frequently performed procedure that enhances life quality by reducing pain and improving functionality. A rare but serious complication after ACCS is cervical hematoma, which can lead to acute airway obstruction and subsequent rapid deterioration. Effective management of cervical hematomas requires an astute awareness of the developing signs and proficiency in the techniques involved when issues arise.

On the entanglement of chromophore and solvent orbitals.

Among various types of chromophore-solvent interactions, the entanglement of chromophore and solvent orbitals, when significant, can cause the chromophore frontier orbitals to spread over to nearby solvent molecules, introducing partial charge-transfer character to the lowest excitations of the chromophore and lowering the excitation energies. While highly intuitive, the physical details of such orbital entanglement effects on the excitation energies of chromophores have yet to be fully explored. Here, using two well-known biochromophores (oxyluciferin and p-hydroxybenzyledene imidazolinone) as examples, we show that the chromophore-solvent orbital entanglements can be elucidated using two quantum mechanical embedding schemes: density matrix embedding theory and absolutely localized molecular orbitals.

Small circular RNAs as vaccines for cancer immunotherapy.

Messenger RNA vaccines have shown strong prophylactic efficacy against viral infections. Here we show that antigen-encoding small circular RNAs (circRNAs) loaded in lipid nanoparticles elicit potent and durable T cell responses for robust tumour immunotherapy after subcutaneous injection in mice, particularly when combined with immune checkpoint inhibition. The small circRNA vaccines are highly stable and show low levels of activation of protein kinase R as well as low cytotoxicity, enabling long-lasting antigen translation (longer than 1 week in cells).

Degradable thermosets via orthogonal polymerizations of a single monomer.

Crosslinked thermosets are highly durable materials, but overcoming their petrochemical origins and inability to be recycled poses a grand challenge. Many strategies to access crosslinked polymers that are bioderived or degradable-by-design have been proposed, but they require several resource-intensive synthesis and purification steps and are not yet feasible alternatives to conventional consumer materials. Here we present a modular, one-pot synthesis of degradable thermosets from the commercially available, biosourced monomer 2,3-dihydrofuran (DHF).

The effect of first intervention on cardiac parameters in patients with acromegaly: a systematic review.

Objective: Cardiovascular disease in acromegaly patients remains a major cause of morbidity and all-cause mortality. This systematic review investigates the effect of the first growth hormone-lowering intervention on cardiac parameters.

Design: Systematic review.

The Single-Cell Landscape of Peripheral and Tumor-infiltrating Immune Cells in HPV- HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. HPV-negative HNSCC, which arises in the upper airway mucosa, is particularly aggressive, with nearly half of patients succumbing to the disease within five years and limited response to immune checkpoint inhibitors compared to other cancers. There is a need to further explore the complex immune landscape in HPV-negative HNSCC to identify potential therapeutic targets.

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.

Feasibility and effects of cognitive training on cognition and psychosocial function in Huntington's disease: a randomised pilot trial.

Background: Huntington's disease (HD) is a rare neurodegenerative disease that causes progressive cognitive, physical, and psychiatric symptoms. Computerised cognitive training (CCT) is a novel intervention that aims to improve and maintain cognitive functions through repeated practice. The effects of CCT have yet to be established in HD.

Effects and mechanisms of computerized cognitive training in Huntington's disease: protocol for a pilot study.

Huntington's disease (HD) causes progressive cognitive decline, with no available treatments. Computerized cognitive training (CCT) has shown efficacy in other populations, but its effects in HD are largely unknown. This pilot study will explore the effects and neural mechanisms of CCT in HD.

Consuming a modified Mediterranean ketogenic diet reverses the peripheral lipid signature of Alzheimer's disease in humans.

Background: Alzheimer's disease (AD) is a major neurodegenerative disorder with significant environmental factors, including diet and lifestyle, influencing its onset and progression. Although previous studies have suggested that certain diets may reduce the incidence of AD, the underlying mechanisms remain unclear.

Method: In this post-hoc analysis of a randomized crossover study of 20 elderly adults, we investigated the effects of a modified Mediterranean ketogenic diet (MMKD) on the plasma lipidome in the context of AD biomarkers, analyzing 784 lipid species across 47 classes using a targeted lipidomics platform.

Face-to-face or face-to-screen: A quantitative comparison of conferences modalities.

The COVID-19 pandemic forced a societal shift from in-person to virtual activities, including scientific conferences. As society navigates a "new normal," the question arises as to the advantages and disadvantages of these alternative modalities. We introduce two new comprehensive datasets enabling direct comparison between virtual and in-person conferences: the first, from a series of nine small conferences, encompasses over 12,000 pairs of potential scientific collaborators across five virtual and four in-person meetings on a range of scientific topics; the expressed goal of these conferences is to create novel collaborations.

UltimateSynth: MRI Physics for Pan-Contrast AI.

Magnetic resonance imaging (MRI) is commonly used in healthcare for its ability to generate diverse tissue contrasts without ionizing radiation. However, this flexibility complicates downstream analysis, as computational tools are often tailored to specific MRI types and lack generalizability across the full spectrum of scans used in healthcare. Here, we introduce a versatile framework for the development and validation of pan-contrast AI models that can exhaustively cater to the full spectrum of scans achievable with MRI, enabling model deployment across scanner models, scan types, and age groups.

Hippo pathway activation causes multiple lipid derangements in a murine model of cardiomyopathy.

Metabolic reprogramming occurs in cardiomyopathy and heart failure contributing to progression of the disease. Activation of cardiac Hippo pathway signaling has been implicated in mediating mitochondrial dysfunction and metabolic reprogramming in cardiomyopathy, albeit influence of Hippo pathway on lipid profile is unclear. Using a dual-omics approach, we determined alterations of cardiac lipids in a mouse model of cardiomyopathy due to enhanced Hippo signaling and explored molecular mechanisms.

Personalized Profiling of Lipoprotein and Lipid Metabolism Based on 1018 Measures from Combined Quantitative NMR and LC-MS/MS Platforms.

Applications of advanced omics methodologies are increasingly popular in biomedicine. However, large-scale studies aiming at clinical translation are typically siloed to single technologies. Here, we present the first comprehensive large-scale population data combining 209 lipoprotein measures from a quantitative NMR spectroscopy platform and 809 lipid classes and species from a quantitative LC-MS/MS platform.

The Immunoregulatory Architecture of the Adult Oral Cavity.

The oral cavity is a critical barrier with immunosurveillance capabilities. A detailed understanding of its cellular, molecular, and spatial architecture is essential for advancing precision medicine across aerodigestive tissues. Here, we present the first integrated atlas of human adult oral and craniofacial tissues, derived from single-cell RNA sequencing of ~250,000 cells from 70 samples across 13 niches, including salivary glands and oral mucosae.

Microalgae - bacteria based wastewater treatment systems: Granulation, influence factors and pollutants removal.

Wastewater treatment based on microalgae and bacteria symbiosis is an environmentally friendly, sustainable technology that has attracted attention recently because of its high efficiency in treating pollutants, saving energy, and short-term biomass recovery. Among them, the granular microalgae and bacteria combination emerges with the advantages of rapid gravity settling, good resistance to adverse environmental conditions, outstanding wastewater treatment performance, and easy biomass recovery. This review aims to clarify the microalgal-bacterial granule (MBG) - based process for wastewater treatment.

From Tradition to Technology: Robotic Artificial Intelligence in Dental Implantology.

Dynamic navigation and haptic robotic systems are revolutionizing dentistry by significantly improving implant placement precision, especially in the maxillofacial region where safeguarding nerves, vessels, and vital structures is crucial. This article examines the impact of X-Guide dynamic navigation and Yomi robotics on implant surgery outcomes, comparing these technologies to traditional freehand methods. The X-Guide dynamic navigation system and Yomi robotics have both been proven to enhance accuracy, with both achieving mean deviations of around 1 mm from pre-planned positions.