Application of Deconvolution in Path Integral Simulations.

In path integral molecular dynamics (PIMD) simulations, atoms are represented by several replicas connected with harmonic springs, so additional vibrations appear beyond the physical vibrations because of the normal mode frequencies coming from the springs of the ring polymer. In harmonic approximation, the frequencies of these internal modes can be determined exactly from the physical frequencies. We show that this formal effect of the path integral simulations on the vibrations can be considered as a convolution if we use the square of the frequency as an independent variable.

Overweight and obesity significantly increase colorectal cancer risk: a meta-analysis of 66 studies revealing a 25-57% elevation in risk.

The incidence of colorectal cancer (CRC) has been steadily rising, and obesity has been identified as a significant risk factor. Numerous studies suggest a strong correlation between excess body weight and increased risk of CRC, but comprehensive quantification through pooled analysis remains limited. This study aims to systematically review and meta-analyze the existing literature to evaluate the association between obesity and CRC risk, considering variations across sex and study designs.

Beyond Traditional Synthesis: Electrochemical Approaches to Amine Oxidation for Nitriles and Imines.

The electrochemical oxidation of amines to nitriles and imines represents a critical frontier in organic electrochemistry, offering a sustainable pathway to these valuable compounds. Nitriles and amines are pivotal in various industrial applications, including pharmaceuticals, agrochemicals, and materials science. This review encapsulates the recent advancements in the electrooxidation process, emphasizing mechanistic understanding, electrode material innovations, optimization of reaction conditions, and exploration of solvent and electrolyte systems.

Seeing and Cleaving: Turn-Off Fluorophore Uncaging and Its Application in Hydrogel Photopatterning and Traceable Neurotransmitter Photocages.

The advancements in targeted drug release and experimental neuroscience have amplified the scientific interest in photolabile protecting groups (PPGs) and photouncaging. The growing need for the detection of uncaging events has led to the development of reporters with fluorescence turn-on upon uncaging. In contrast, fluorescent tags with turn-off properties have been drastically underexplored, although there are applications where they would be sought after.

Unveiling the Complexity of cis-Regulation Mechanisms in Kinases: A Comprehensive Analysis.

Protein cis-regulatory elements (CREs) are regions that modulate the activity of a protein through intramolecular interactions. Kinases, pivotal enzymes in numerous biological processes, often undergo regulatory control via inhibitory interactions in cis. This study delves into the mechanisms of cis regulation in kinases mediated by CREs, employing a combined structural and sequence analysis.

Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads.

There has been a surge of interest in covalent inhibitors for protein kinases in recent years. Despite success in oncology, the off-target reactivity of these molecules is still hampering the use of covalent warhead-based strategies. Herein, we disclose the development of precision-guided warheads to mitigate the off-target challenge.

Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold.

For mitogen-activated protein kinases (MAPKs) a shallow surface-distinct from the substrate binding pocket-called the D(ocking)-groove governs partner protein binding. Screening of broad range of Michael acceptor compounds identified a double-activated, sterically crowded cyclohexenone moiety as a promising scaffold. We show that compounds bearing this structurally complex chiral warhead are able to target the conserved MAPK D-groove cysteine via reversible covalent modification and interfere with the protein-protein interactions of MAPKs.

Autistic and schizotypal traits exhibit similarities in their impact on mentalization and adult attachment impairments: a cross-sectional study.

Background: Deficits in mentalizing and attachment occur in the autism and schizophrenia spectrum, and their extended traits in the general population. Parental attachment and the broader social environment highly influence the development of mentalizing. Given the similarities in the symptomatology and neurodevelopmental correlates of autism spectrum disorder (ASD) and schizophrenia (SCH), it is crucial to identify their overlaps and differences to support screening, differential diagnosis, and intervention.

Evaluation of an Affinity-Enhanced Anti-SARS-CoV2 Nanobody Design Workflow Using Machine Learning and Molecular Dynamics.

optimization of protein binding has received a great deal of attention in the recent years. Since prefiltering of strong binders is fast and cheap compared to library screening methods, the advent of powerful hardware and advanced machine learning algorithms has made this strategy more accessible and preferred. These advances have already impacted the global response to pandemic threats.

Proteomic Profiles of Maternal Plasma Extracellular Vesicles for Prediction of Preeclampsia.

Problem: Preeclampsia is a heterogeneous syndrome of diverse etiologies and molecular pathways leading to distinct clinical subtypes. Herein, we aimed to characterize the extracellular vesicle (EV)-associated and soluble fractions of the maternal plasma proteome in patients with preeclampsia and to assess their value for disease prediction.

Method Of Study: This case-control study included 24 women with term preeclampsia, 23 women with preterm preeclampsia, and 94 healthy pregnant controls.

An Unprecedented Tridentate-Bridging Coordination Mode of Permanganate Ions: The Synthesis of an Anionic Coordination Polymer-[Co(NH)][(K(κ-Cl)(μ-(κ-O,O',O″-MnO))]-Containing Potassium Central Ion and Chlorido and Permanganato Ligands.

A unique compound (compound ) with structural features including an unprecedented tridentate-bridging coordination mode of permanganate ions and an eight-coordinated (rhombohedral) κ-chlorido and tridentate permanganato ligand in a potassium complex containing coordination polymer (Co(NH)][(K(κ-Cl)(μ-(κ-O,O',O″-MnO))) with isolated regular octahedral hexamminecobalt(III) cation was synthesized with a yield of >90%. The structure was found to be stabilized by mono and bifurcated N-H∙∙∙Cl and N-H∙∙∙O (bridging and non-bridging) hydrogen bonds. Detailed spectroscopic (IR, far-IR, and Raman) studies and correlation analysis were performed to assign all vibrational modes.

In Vitro Evaluation of Antipseudomonal Activity and Safety Profile of Peptidomimetic Furin Inhibitors.

Inhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence quenching studies suggested no relevant binding of the compounds to human serum albumin and α-acid glycoprotein.

Disruption of sleep macro- and microstructure in Alzheimer's disease: overlaps between neuropsychology, neurophysiology, and neuroimaging.

Alzheimer's disease (AD) is the leading cause of dementia, often associated with impaired sleep quality and disorganized sleep structure. This study aimed to characterize changes in sleep macrostructure and K-complex density in AD, in relation to neuropsychological performance and brain structural changes. We enrolled 30 AD and 30 healthy control participants, conducting neuropsychological exams, brain MRI, and one-night polysomnography.

Unlocking Oxetane Potential: Modular Synthetic Platform for the Concise Synthesis of Acyclic Oligo-Isoprenoids and Terpenoids.

Terpenes occupy a unique place among the secondary metabolites due to their broad utility and extraordinary structural diversity. Their synthesis via polyene cyclization, either biomimetic or enzymatic, represents the cutting edge of modern synthetic chemistry. However, these endeavors have been inherently tied to the availability of natural and non-natural acyclic polyene starting materials.

Target-Templated Construction of Functional Proteomimetics Using Photo-Foldamer Libraries.

Current methods for proteomimetic engineering rely on structure-based design. Here we describe a design strategy that allows the construction of proteomimetics against challenging targets without a priori characterization of the target surface. Our approach employs (i) a 100-membered photoreactive foldamer library, the members of which act as local surface mimetics, and (ii) the subsequent affinity maturation of the primary hits using systems chemistry.

Insulin receptor substrate 1 is a novel member of EGFR signaling in pancreatic cells.

Pancreatic ductal adenocarcinoma is an extremely incurable cancer type characterized by cells with highly proliferative capacity and resistance against the current therapeutic options. Our study reveals that IRS1 acts as a bridging molecule between EGFR and IGFR/InsR signalization providing a potential mechanism for the interplay between signaling pathways and bypassing EGFR-targeted or IGFR/InsR-targeted therapies. The analysis of IRS1 phosphorylation status in four pancreatic cell lines identified the impact of EGFR signaling on IRS1 activation in comparison with InsR/IGFR signaling.

Coamplified Nanozyme Cocktails for Cascade Reaction-Driven Antioxidant Treatments.

Antioxidant nanozymes are powerful tools to combat oxidative stress, which can be further improved by applying nanozyme mixtures of multiple enzymatic function. Here, cocktails of Prussian blue (PB) nanocubes and copper(II) exchanged ZSM-5 zeolites (CuZ) with enhanced reactive oxygen species (ROS) scavenging activity were developed. Surface functionalization of the particles was performed using polymers to obtain stable colloids, i.

The Immune-Related 27-Gene Signature DetermaIO Predicts Response to Neoadjuvant Atezolizumab plus Chemotherapy in Triple-Negative Breast Cancer.

Purpose: We assessed the 27-gene RT-qPCR-based DetermaIO assay and the same score calculated from RNA sequencing (RNA-seq) data as predictors of sensitivity to immune checkpoint therapy in the neoTRIPaPDL1 randomized trial that compared neoadjuvant carboplatin/nab-paclitaxel chemotherapy (CT) plus atezolizumab with CT alone in stage II/III triple-negative breast cancer. We also assessed the predictive function of the immuno-oncology (IO) score in expression data of patients treated with pembrolizumab plus paclitaxel (N = 29) or CT alone (N = 56) in the I-SPY2 trial.

Experimental Design: RNA-seq data were obtained from pretreatment core biopsies from 242 (93.

Exploring Chemical Spaces in the Billion Range: Is Docking a Computational Alternative to DNA-Encoded Libraries?

The concept of DNA-encoded libraries (DELs) enables the experimental screening of billions of compounds simultaneously, offering an unprecedented boost in the coverage of chemical space. In parallel, however, dramatically increased access to supercomputers and a number of ultrahigh throughput virtual screening (uHTVS) tools have made screening of billion-membered virtual libraries available. Here, we investigate whether current, brute-force, or AI-enabled uHTVS approaches might constitute a computational alternative to DEL screening.

Identifying Transfer Learning in the Reshaping of Inductive Biases.

Transfer learning, the reuse of newly acquired knowledge under novel circumstances, is a critical hallmark of human intelligence that has frequently been pitted against the capacities of artificial learning agents. Yet, the computations relevant to transfer learning have been little investigated in humans. The benefit of efficient inductive biases (meta-level constraints that shape learning, often referred as priors in the Bayesian learning approach), has been both theoretically and experimentally established.

Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression.

We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis.

Redox-dependent condensation and cytoplasmic granulation by human ssDNA-binding protein-1 delineate roles in oxidative stress response.

Human single-stranded DNA binding protein 1 (hSSB1/NABP2/OBFC2B) plays central roles in DNA repair. Here, we show that purified hSSB1 undergoes redox-dependent liquid-liquid phase separation (LLPS) in the presence of single-stranded DNA or RNA, features that are distinct from those of LLPS by bacterial SSB. hSSB1 nucleoprotein droplets form under physiological ionic conditions in response to treatment modeling cellular oxidative stress.