Cullin-5 deficiency promotes chimeric antigen receptor T cell effector functions potentially via the modulation of JAK/STAT signaling pathway.

Chimeric antigen receptor (CAR) T cell is a promising therapy for cancer, but factors that enhance the efficacy of CAR T cell remain elusive. Here we perform a genome-wide CRISPR screening to probe genes that regulate the proliferation and survival of CAR T cells following repetitive antigen stimulations. We find that genetic ablation of CUL5, encoding a core element of the multi-protein E3 ubiquitin-protein ligase complex, cullin-RING ligase 5, enhances human CD19 CAR T cell expansion potential and effector functions, potentially via the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway.

LAG-3-An incompletely understood target in cancer therapy.

LAG-3 is a member of the immunoglobulin superfamily expressed on activated T cells, but also on other immune cells. It has significant homology to CD4. Both molecules have four extracellular Ig-like domains with similar structural motifs but the sequence identity between LAG-3 and CD4 is low.

Presolar Grains as Probes of Supernova Nucleosynthesis.

We provide an overview of the isotopic signatures of presolar supernova grains, specifically focusing on Ti-containing grains with robustly inferred supernova origins and their implications for nucleosynthesis and mixing mechanisms in supernovae. Recent technique advancements have enabled the differentiation between radiogenic (from Ti decay) and nonradiogenic Ca excesses in presolar grains, made possible by enhanced spatial resolution of Ca-Ti isotope analyses with the Cameca NanoSIMS (Nano-scale Secondary Ion Mass Spectrometer) instrument. Within the context of presolar supernova grain data, we discuss () the production of Ti in supernovae and the impact of interstellar medium heterogeneities on the galactic chemical evolution of Ca/Ca, () the nucleosynthesis processes of neutron bursts and explosive H-burning in Type II supernovae, and () challenges in identifying the progenitor supernovae for Cr-rich presolar nanospinel grains.

Fourth-Order Algebraic Diagrammatic Construction for Electron Detachment and Attachment: The IP- and EA-ADC(4) Methods.

We present a non-Dyson fourth-order algebraic diagrammatic construction formulation of the electron propagator, featuring the distinct IP- and EA-ADC(4) schemes for the treatment of ionization and electron attachment processes. The algebraic expressions have been derived automatically using the intermediate state representation approach and implemented in the Q-Chem quantum-chemical program package. The performance of the novel methods is assessed with respect to high-level reference data for ionization potentials and electron affinities of closed- and open-shell systems.

Co-stimulation of CD28/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness.

CD19 chimeric antigen receptor T (CD19CAR-T) cells have achieved promising outcomes in relapsed/refractory B cell malignancies. However, recurrences occur due to the loss of CAR-T cell persistence. We developed dual T/B cell co-stimulatory molecules (CD28 and CD40) in CAR-T cells to enhance intense tumoricidal activity and persistence.