Exploring CRISPR-Cas9 HNH-Domain-Catalyzed DNA Cleavage Using Accelerated Quantum Mechanical Molecular Mechanical Free Energy Simulation.

The target DNA (tDNA) cleavage catalyzed by the CRISPR Cas9 enzyme is a critical step in the Cas9-based genome editing technologies. Previously, the tDNA cleavage from an active SpyCas9 enzyme conformation was modeled by Palermo and co-workers (Nierzwicki et al., , 912) using ab initio quantum mechanical molecular mechanical (ai-QM/MM) free energy simulations, where the free energy barrier was found to be more favorable than that from a pseudoactive enzyme conformation.

Inositol Hexaphosphate (InsP6) Activates the HDAC1/3 Epigenetic Axis to Maintain Intestinal Barrier Function.

HDACs (histone deacetylase) play a crucial role in regulating gene expression, and the inhibition of these enzymes is gaining attention as a promising therapeutic approach for cancer treatment. Despite their significant physiological and clinical importance, the mechanisms of HDAC activation remain poorly understood. This study reveals that inositol polyphosphate multikinase (IPMK) is essential for activating HDAC1 and HDAC3 in cell lines and mice.

Expansion of tumor-reactive CD8 T cell clonotypes occurs in the spleen in response to immune checkpoint blockade.

Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8 T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population in the white pulp of the spleen that underwent substantial expansion in response to ICB and gave rise to tumor-infiltrating clonotypes.

Implementing an integrated family approach in mental health care for families experiencing complex and multiple problems: a case example in Amsterdam.

For youth care professionals who work with families with complex needs, we implemented an interagency, family-focused approach involving child and adult mental health care services and child protection services. The primary objective of the collaboration was to minimize fragmentation in service delivery and to improve practitioners' self-efficacy in supporting families. A total of 50 families were enrolled between 2020 and 2023.