ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy.

Only one in five patients respond to immune checkpoint inhibitors, which primarily target adaptive immunity. Ectonucleotide pyrophosphatase/phophodiesterase 1 (ENPP1), the dominant hydrolase of 2'3'-cyclic-GMP-AMP (cGAMP) that suppresses downstream stimulator of interferon genes (STING) signaling, has emerged as a promising innate immunotherapy target. However, existing ENPP1 inhibitors have been optimized for prolonged systemic residence time rather than effective target inhibition within tumors.

A 17-Year Experience of Valvular Heart Surgery in Rwanda.

Background: The advanced presentation of rheumatic heart disease in Rwanda often necessitates surgical intervention. We summarize the outcomes of valvular heart operations in Rwanda between 2006 and 2023.

Methods: The study included 366 patients in the Rwandan cardiac surgery registry who underwent valvular surgery.

ENPP1 inhibitor with ultralong drug-target residence time as an innate immune checkpoint blockade cancer therapy.

Only one in five patients is estimated to respond to immune checkpoint inhibitors, which primarily target adaptive immunity. To date, no FDA-approved immunotherapies directly activate the innate anti-cancer immunity-an essential driver of lymphocyte recruitment and potentiator of responses to existing cancer immunotherapies. ENPP1, the dominant hydrolase that degrades extracellular cGAMP and suppresses downstream STING-mediated innate immune signaling, has emerged as a promising therapeutic target.

Cost-Effectiveness Analysis of Surgical Strategies Versus Medical Management for Rheumatic Heart Disease in Rwanda.

Background: One-third of the global rheumatic heart disease burden lies in sub-Saharan Africa, where 17% of patients with severe rheumatic heart disease die within 3 years without valve surgery. Surgery is often considered uneconomical, although this assumption is not grounded in cost-effectiveness analyses.

Methods: We evaluated the cost-effectiveness of mechanical valve replacement, bioprosthetic valve replacement, and valve repair compared with medical management for patients with severe rheumatic heart disease in Rwanda.

Comparative Analysis of (Crustacea: Decapoda: Grapsidae) Mitochondrial Genome Reveals Gene Rearrangement and Phylogeny.

The taxonomy of the genus is still a matter of debate because its species have limited morphological differences. Mitochondrial genomes, which are highly informative and easily accessible genetic markers, have been widely used to study molecular evolution and clarify relationships among species. This study aims to investigate the mitochondrial genome of , a species with unique ecological and evolutionary significance.

2-5A is an immunotransmitter that fuels RNase L immunity.

cGAS-cGAMP-STING and OAS-2-5A-RNase L are evolutionarily convergent innate immune pathways. cGAMP acts as an immunotransmitter; what about 2-5A? In this issue of Immunity, Huai et al. map the transfer of 2-5A between cells, establishing it as a bona fide immunotransmitter.

Pilot Implementation of a Simulation-Based Surgical Curriculum for Rwandan Medical Interns.

Objectives: Develop and implement a standardized surgical training curriculum for Rwandan medical interns to better prepare them for general practice at district hospitals. Assess the curriculum's impact on participants surgical knowledge and technical skills and identify areas for iterative improvement.

Design: A 2-day surgical curriculum combining theory-based didactics and hands-on, simulation-based skills training was developed and implemented.

Cost-effectiveness analysis of valvular surgery in high- and low- to middle-income countries: A scoping review.

Background: Global disparities in valvular surgery services exist. Cost-effectiveness analysis (CEA) and cost-utility analysis can be used to guide national investment decisions. This scoping review aims to synthesize economic evaluations for valvular surgery by income settings and provide recommendations.

Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint.

2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only other metazoan cGAMP hydrolase under homeostatic conditions.

Identification of extracellular membrane protein ENPP3 as a major cGAMP hydrolase, cementing cGAMP's role as an immunotransmitter.

cGAMP is a second messenger that is synthesized in the cytosol upon detection of cytosolic dsDNA and passed between cells to facilitate downstream immune signaling. ENPP1, an extracellular enzyme, was the only metazoan cGAMP hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and only other metazoan cGAMP hydrolase under homeostatic conditions.

ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway.

ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary breast tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling.

Critical Roles of Translation Initiation and RNA Uridylation in Endogenous Retroviral Expression and Neural Differentiation in Pluripotent Stem Cells.

Previous studies have suggested that the loss of the translation initiation factor eIF4G1 homolog NAT1 induces excessive self-renewability of naive pluripotent stem cells (PSCs); yet the role of NAT1 in the self-renewal and differentiation of primed PSCs is still unclear. Here, we generate a conditional knockout of NAT1 in primed PSCs and use the cells for the functional analyses of NAT1. Our results show that NAT1 is required for the self-renewal and neural differentiation of primed PSCs.

Hypoxia and matrix viscoelasticity sequentially regulate endothelial progenitor cluster-based vasculogenesis.

Vascular morphogenesis is the formation of endothelial lumenized networks. Cluster-based vasculogenesis of endothelial progenitor cells (EPCs) has been observed in animal models, but the underlying mechanism is unknown. Here, using O-controllabe hydrogels, we unveil the mechanism by which hypoxia, co-jointly with matrix viscoelasticity, induces EPC vasculogenesis.

Copper-Catalyzed Radical Selenodifluoromethylation of Alkenes: Access to CF-Containing γ-Lactams.

Herein, a practical Cu-catalyzed selenodifluoromethylation protocol was developed, using readily available diselenides as the selenium source under external-oxidant-free conditions. Various structurally diverse 4-seleno-substituted α,α-difluoro-γ-lactams were obtained in moderate to excellent yields. Easy scaleup and the potential for product derivatization make this method attractive for the preparation of other valuable fIuorinated γ-lactams.

Regiospecific Cleavage of S-N Bonds in Sulfonyl Azides: Sulfonyl Donors.

Sulfonyl azides have been widely used as sulfonamido, diazo, and azido donors, as well as all-nitrogen 1,3-dipoles donors in synthetic chemistry. Here, the sulfonyl azides were used as efficient sulfonyl donors, which is very unusual. Trifluoromethanesulfonic acid-induced formation of the sulfonyl cation reactive species from sulfonyl azides was developed and used for the first time to couple various inactivated arenes to prepare sulfones at ambient temperature.

Revealing the Semantic Association between Perception of Scenes and Significant Objects by Representational Similarity Analysis.

'Significant' objects contribute greatly to scene recognition. The lateral occipital complex (LOC), parahippocampal place area (PPA), and retrosplenial cortex (RSC) play a crucial role in the cognitive processing of objects and scenes. However, the associated mechanism between objects and scenes remains unclear.

Transcriptional Landscape of Cardiomyocyte Maturation.

Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of the CM maturation that is subsequently required to generate adult myocytes remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation.

Combination of Optimization and Metalated-Ligand Exchange: An Effective Approach to Functionalize UiO-66(Zr) MOFs for CO2 Separation.

The strategy to functionalize water-stable metal-organic frameworks (MOFs) in order to improve their CO2 uptake capacities for efficient CO2 separation remains limited and challenging. We herein present an effective approach to functionalize a prominent water-stable MOF, UiO-66(Zr), by a combination of optimization and metalated-ligand exchange. In particular, by systematic optimization, we have successfully obtained UiO-66(Zr) of the highest BET surface area reported so far (1730 m(2)  g(-1) ).