Multi-omics approaches reveal that diffuse midline gliomas present altered DNA replication and are susceptible to replication stress therapy.

Background: The fatal diffuse midline gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3.

Binding site maturation modulated by molecular density underlies Ndc80 binding to kinetochore receptor CENP-T.

Macromolecular assembly depends on tightly regulated pairwise binding interactions that are selectively favored at assembly sites while being disfavored in the soluble phase. This selective control can arise due to molecular density-enhanced binding, as recently found for the kinetochore scaffold protein CENP-T. When clustered, CENP-T recruits markedly more Ndc80 complexes than its monomeric counterpart, but the underlying molecular basis remains elusive.

Conferring non-strain-specific resistance to a potyvirus via overexpression of mutant potyviral coat proteins in soybean.

Transgenic soybean (Glycine max) plants expressing mutant potyviral coat proteins that disrupt virion assembly exhibited non-strain-specific resistance against soybean mosaic virus.

Essential Considerations for Free Energy Calculations of RNA-Small Molecule Complexes: Lessons from the Theophylline-Binding RNA Aptamer.

Alchemical free energy calculations are widely used to predict the binding affinity of small molecule ligands to protein targets; however, the application of these methods to RNA targets has not been deeply explored. We systematically investigated how modeling decisions affect the performance of absolute binding free energy calculations for a relatively simple RNA model system: theophylline-binding RNA aptamer with theophylline and five analogs. The goal of this investigation was 2-fold: (1) understanding the performance levels we can expect from absolute free energy calculations for a simple RNA complex and (2) learning about practical modeling considerations that impact the success of RNA-binding predictions, which may be different from the best practices established for protein targets.

ModBind, a Rapid Simulation-Based Predictor of Ligand Binding and Off-Rates.

In rational drug discovery, both free energy of binding and the binding half-life () are important factors in determining the efficacy of drugs. Numerous computational methods have been developed to predict these important properties, many of which rely on molecular dynamics (MD) simulations. While binding free-energy methods (thermodynamic equilibrium predictions) have been well validated and have demonstrated the ability to drive daily synthesis decisions in a commercial drug discovery setting, the prediction of (kinetics predictions) has had limited validation, and predictive methods have largely not been deployed in drug discovery settings.

De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly.

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15).

Discovery of the Cytocapsular Membrane as Hallmark of Malignant Tumors.

While optimizing cancer cell growth conditions, we discovered that cancer stem cells can generate second membranes outside the plasma membranes forming compartments separated from the extracellular matrix. The encapsulating membranes can extend and generate long cytocapsular tubes, wherein multiple cells can migrate. SILAC proteomics of the second cytocapsular membranes identified 400 membrane proteins, and a small subset of them are highly upregulated in cytocapsular cancers compared to normal tissues.

Study design and the sampling of deleterious rare variants in biobank-scale datasets.

One key component of study design in population genetics is the "geographic breadth" of a sample (i.e., how broad a region across which individuals are sampled).

QClus: a droplet filtering algorithm for enhanced snRNA-seq data quality in challenging samples.

Single-nuclei RNA sequencing remains a challenge for many human tissues, as incomplete removal of background signal masks cell-type-specific signals and interferes with downstream analyses. Here, we present Quality Clustering (QClus), a droplet filtering algorithm targeted toward challenging samples. QClus uses additional metrics, such as cell-type-specific marker gene expression, to cluster nuclei and filter empty and highly contaminated droplets, providing reliable filtering of samples with varying number of nuclei and contamination levels.

Polyphonia: detecting inter-sample contamination in viral genomic sequencing data.

Summary: In viral genomic research and surveillance, inter-sample contamination can affect variant detection, analysis of within-host evolution, outbreak reconstruction, and detection of superinfections and recombination events. While sample barcoding methods exist to track inter-sample contamination, they are not always used and can only detect contamination in the experimental pipeline from the point they are added. The underlying genomic information in a sample, however, carries information about inter-sample contamination occurring at any stage.

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.

Gene editing the BCL11A erythroid enhancer is a validated approach to fetal hemoglobin (HbF) induction for β-hemoglobinopathy therapy, though heterogeneity in edit allele distribution and HbF response may impact its safety and efficacy. Here, we compare combined CRISPR-Cas9 editing of the BCL11A +58 and +55 enhancers with leading gene modification approaches under clinical investigation. Dual targeting of the BCL11A +58 and +55 enhancers with 3xNLS-SpCas9 and two single guide RNAs (sgRNAs) resulted in superior HbF induction, including in sickle cell disease (SCD) patient xenografts, attributable to simultaneous disruption of core half E-box/GATA motifs at both enhancers.

The energetic landscape of CH-π interactions in protein-carbohydrate binding.

CH-π interactions between carbohydrates and aromatic amino acids play an essential role in biological systems that span all domains of life. Quantifying the strength and importance of these CH-π interactions is challenging because these interactions involve several atoms and can exist in many distinct orientations. To identify an orientational landscape of CH-π interactions, we constructed a dataset of close contacts formed between β-d-galactose residues and the aromatic amino acids, tryptophan, tyrosine, and phenylalanine, across crystallographic structures deposited in the Protein Data Bank.

Toward Dose Prediction at Point of Design.

Human dose prediction (HDP) is a useful tool for compound optimization in preclinical drug discovery. We describe here our exclusively in silico HDP strategy to triage compound designs for synthesis and experimental profiling. Our goal is a model that provides a preliminary estimate of the dose for a given exposure target based on chemical structure.

analysis of gas dependent redistribution kinetics in bimetallic Au-Pd nanoparticles.

The catalytic and plasmonic properties of bimetallic gold-palladium (Au-Pd) nanoparticles (NPs) critically depend on the distribution of the Au and Pd atoms inside the nanoparticle bulk and at the surface. Under operating conditions, the atomic distribution is highly dynamic. Analyzing gas induced redistribution kinetics at operating temperatures is therefore key in designing and understanding the behavior of Au-Pd nanoparticles for applications in thermal and light-driven catalysis, but requires advanced characterization strategies.

Ordinal Confidence Level Assignments for Regression Model Predictions.

We present a simple method for assigning accurate confidence levels to molecular property predictions from regression models. These confidence levels are easy to interpret and useful for making decisions in drug discovery programs. We demonstrate their performance using time-split validation with assay data from the Relay Therapeutics internal database.

Saccharibacteria deploy two distinct Type IV pili, driving episymbiosis, host competition, and twitching motility.

All cultivated Patescibacteria, or CPR, exist as obligate episymbionts on other microbes. Despite being ubiquitous in mammals and environmentally, molecular mechanisms of host identification and binding amongst ultrasmall bacterial episymbionts are largely unknown. Type 4 pili (T4P) are well conserved in this group and predicted to facilitate symbiotic interactions.

Long-Range Surface Forces in Salt-in-Ionic Liquids.

Ionic liquids (ILs) are a promising class of electrolytes with a unique combination of properties, such as extremely low vapor pressures and nonflammability. Doping ILs with alkali metal salts creates an electrolyte that is of interest for battery technology. These salt-in-ionic liquids (SiILs) are a class of superconcentrated, strongly correlated, and asymmetric electrolytes.

An integrative TAD catalog in lymphoblastoid cell lines discloses the functional impact of deletions and insertions in human genomes.

The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as compartments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes from outside regulatory elements' aberrant regulation.

Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation.

Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post-cardiac arrest (CA) neurological injury. Here, we analyzed circulating immune cells from a large cohort of patients with OHCA, finding that lymphopenia independently associated with poor neurological outcomes.

Remodeling of cytoskeleton, chromatin, and gene expression during mechanical rejuvenation of aged human dermal fibroblasts.

Aging is associated with a progressive decline in cellular function. To reset the aged cellular phenotype, various reprogramming approaches, including mechanical routes, have been explored. However, the epigenetic mechanisms underlying cellular rejuvenation are poorly understood.

Integrating Machine Learning and Large Language Models to Advance Exploration of Electrochemical Reactions.

Electrochemical C-H oxidation reactions offer a sustainable route to functionalize hydrocarbons, yet identifying suitable substrates and optimizing synthesis remain challenging. Here, we report an integrated approach combining machine learning and large language models to streamline the exploration of electrochemical C-H oxidation reactions. Utilizing a batch rapid screening electrochemical platform, we evaluated a wide range of reactions, initially classifying substrates by their reactivity, while LLMs text-mined literature data to augment the training set.

Robust and Versatile Biodegradable Unclonable Anti-Counterfeiting Labels with Multi-Mode Optical Encoding Using Protein-Mediated Luminescent Calcite Signatures.

Physical unclonable functions (PUFs) are emerging as a cutting-edge technology for enhancing information security by providing robust security authentication and non-reproducible cryptographic keys. Incorporating renewable and biocompatible materials into PUFs ensures safety for handling, compatibility with biological systems, and reduced environmental impact. However, existing PUF platforms struggle to balance high encoding capacity, diversified encryption signatures, and versatile functionalities with sustainability and biocompatibility.