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Author Correction: Natural behaviour is learned through dopamine-mediated reinforcement
The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction
Dual-metal-doped perovskite adsorbents for efficient removal of humic acid
Cortical-limbic circuit dynamics of approach-avoidance conflict in humans
Abstract Choosing to approach or avoid is common in everyday life and excessive avoidance is a cardinal feature of anxiety disorders. We use intracranial EEG to define a prefrontal-limbic circuit supporting approach and avoidance. Presurgical epilepsy patients (n = 20) performed an approach-avoidance conflict decision-making task inspired by the arcade game Pac-Man, where patients trade off rewards against losses from ghost attack. During approach, theta power increases across a limbic circuit including the hippocampus, amygdala, orbitofrontal cortex and anterior cingulate cortex, which drops during avoidance. Theta connectivity between this circuit and lateral prefrontal cortex increases during approach and falls during avoidance. Network connectivity tracks how long patients approach, with enhanced synchronicity extending approach times. During imminent threat, the system switches to sustained increase in high-frequency activity in the lateral prefrontal cortex. The results provide evidence of a distributed prefrontal-limbic circuit, mediated by theta oscillations and high frequency activity, underlying approach-avoidance conflict in humans.
Pan-tumor activity of olomorasib, a next-generation KRAS G12C inhibitor in KRAS G12C-mutant advanced solid tumors: a first-in-human study
Abstract This multicenter, first-in-human Phase 1 study (NCT04956640) evaluated olomorasib (LY3537982), a next-generation KRAS G12C inhibitor designed to enhance target occupancy at low absolute exposures. In total, data from 195 patients are reported: Phase 1a dose escalation ( n = 112) assessed olomorasib monotherapy at 50, 100, 150 or 200 mg BID across KRAS G12C-mutant advanced solid tumors; the primary objective was to determine the recommended Phase 2 dose (RP2D) based on dose-limiting toxicities (DLTs). No DLTs occurred, and 150 mg BID was selected as the RP2D. The primary objective for the Phase 1b dose expansion ( n = 83) was to evaluate the safety and tolerability of olomorasib in specific KRAS G12C-mutant tumor types. Olomorasib was well tolerated, with predominantly grade 1–2 treatment-related adverse events (TRAEs) and infrequent grade 3 TRAEs; no grade 4/5 TRAEs occurred. Secondary objectives evaluated the antitumor activity of olomorasib. Among 168 efficacy-evaluable patients, the ORR and median PFS were both higher in non-CRC solid tumors compared to CRC, including in patients with NSCLC who previously received a KRAS G12C inhibitor. Intracranial responses were observed in patients with untreated, active brain metastases. This may support the potential of next-generation KRAS G12C inhibitors to overcome limitations of earlier agents and justify further investigation of combination therapy.
Multimodal framework for the joint analysis of single-cell RNA and T cell receptor sequencing data predicts T cell response to cancer immunotherapy
Retraction Note: NIR-light-mediated spatially selective triggering of anti-tumor immunity via upconversion nanoparticle-based immunodevices
Patterns and determinants of mitogenomic evolution in Bilateria
Genetic Variation in Clinical Cohorts
Polarity-tunable field-free room-temperature spin orbit torque switching via topological symmetry breaking in an all-vdW heterostructure for spin logic applications
Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN
A genetic toolkit for the human gut bacterium Mediterraneibacter gnavus identifies capsular polysaccharides as a competitive colonization factor
Abstract Mediterraneibacter gnavus is a human symbiotic gut bacterium whose abundance often increases in patients with various diseases, such as active inflammatory bowel disease (IBD). However, the genetic factors governing its gut colonization and pathogenicity remain elusive due to the lack of genetic modification systems. In this study, we developed several genetic tools for M. gnavu s, including a shuttle vector, an inducible promoter, fluorescent reporters, and systems for gene disruption and deletion. Using these genetic tools, we constructed mutants for six of the eight sortase-encoding genes in M. gnavus ATCC 29149 and identified those involved in the surface presentation of capsular polysaccharide (CPS) and superantigen-like proteins. We also identified a CPS biosynthetic gene cluster adjacent to the sortase gene and demonstrated that CPS production is crucial for competitive colonization in germ-free mouse intestines. Notably, CPS production was inversely correlated with inflammatory activity, and CPS cluster-positive strains were more prevalent in healthy individuals than in Crohn’s disease patients. These findings suggest that CPS contributes to the modulation of inflammation and pathogenesis. This study highlights the potential of precise gene-modification systems to uncover genetic determinants of intestinal colonization and pathogenesis in gut bacteria.