Summary: Shigellosis is the second leading cause of diarrheal death in children under 5 years globally, yet no licensed vaccine exists, partly due to poor understanding of protective immunity in young children, especially in endemic settings. Here, we applied a functional antibody-profiling approach to define Shigella -specific antibody responses in young children versus older individuals with culture-confirmed shigellosis in Bangladesh. We found that higher baseline O-specific polysaccharide (OSP)-specific and protein-specific IgG and FcγR binding levels correlated with less severe disease regardless of age. We also found that over time, individuals under 5 years of age developed a less functional and durable response against OSP than older individuals. We demonstrate that OSP-specific IgG increased uptake of live Shigella by monocytes and macrophages in an Fc-dependent mechanism. Our findings suggest that young children develop limited OSP-specific functional antibody responses that fail to maximally involve innate immune cells. Innate cell clearance may be important in protecting against Shigella .
Summary: Obesity is a heterogeneous disease with a substantial genetic component. Rare pathogenic variants in genes of the leptin-melanocortin pathway can cause monogenic obesity and support targeted therapies such as setmelanotide, a melanocortin 4 receptor agonist. Pathogenic variants in NCOA1 , encoding the nuclear receptor co-activator SRC-1, have recently been proposed as a cause of monogenic obesity through impaired leptin-induced POMC activation, leading to the inclusion of NCOA1 variant carriers in the EMANATE setmelanotide trial. However, despite biological rationale, the contribution of NCOA1 variants to human obesity remains elusive. Here, we assess NCOA1 variants with case-control analyses in adults and children from the RaDiO study, combined with in vitro assays and replication in the UK Biobank. We find no association between pathogenic NCOA1 variants and obesity or body mass index.
Summary: Recent studies indicate that injury-induced dedifferentiation generates transient regenerative progenitors (TRPs), which support tissue repair across multiple organs, including the liver. In vivo partial reprogramming using Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc; OSKM) produces intestinal TRPs closely resembling those arising from injury-induced dedifferentiation, but transgenic or viral approaches raise safety concerns because of prolonged expression. Here, we show that transient OSKM induction generates two distinct liver progenitor-like cell (LPLC) populations without injury and with limited activation of injury-associated immune responses. Single-nucleus RNA sequencing shows that one population resembles injury-induced LPLCs observed in acetaminophen-injured mouse and human livers. To develop a temporally controlled regenerative strategy, we establish a liver-targeted lipid nanoparticle system for OSKM mRNA delivery. OSKM mRNA-LNP treatment induces hepatocyte dedifferentiation and Sox9 + LPLC-like cell formation and is associated with enhanced regeneration after acetaminophen-induced injury. Together, these findings identify transient hepatic reprogramming as a strategy for inducing regenerative plasticity and support liver-targeted OSKM mRNA delivery as a potential approach for acute liver injury.
Summary: While advances in immunotherapy have revolutionized care for cancer patients, most approaches still fail to mount a robust anti-cancer effect. To address this challenge, the field has turned to combination immunotherapies, but systemic administration of potent combination therapies has resulted in severe immune-related adverse effects. Here, we use an injectable polymer-nanoparticle (PNP) hydrogel to rationally localize immunotherapeutic cytokines (IL-12 and IL-2) intratumorally and antibodies (OX40a) peritumorally. We hypothesize that selectively altering the biodistribution of these cargo enables tolerable and synergistic anti-cancer combinations. Using in vivo imaging, we demonstrate that administration sites are critical for redistributing cargo to either the tumor or tumor-draining lymph node (tdLN). Further, we demonstrate that this approach synergistically improved treatment efficacy in the B16F10 and MC38 tumor models and alters cellular phenotypes, resulting in significant tumor clearance in both single and double tumor models.
