A 3D Self-Assembly Platform Integrating Decellularized Matrix Recapitulates In Vivo Tumor Phenotypes and Heterogeneity.

Three-dimensional (3D) in vitro cell culture models are invaluable tools for investigating the tumor microenvironment (TME). However, analyzing the impact of critical stromal elements, such as extracellular matrix (ECM), remains a challenge. Here, we developed a hydrogel-free self-assembly platform to establish ECM-rich 3D "MatriSpheres" to deconvolute cancer cell-ECM interactions.

Proton-Transfer Dynamics Regulates CO Electroreduction Products via Hydrogen Coverage.

Electrochemical conversion of CO to hydrocarbons is a promising approach to carbon neutrality and energy storage. The formation of reaction intermediates involves crucial steps of proton transfer, making it essential to understand the role of protons in the electrochemical process to control the product selectivity and elucidate the underlying catalytic reaction mechanism of the CO electrochemical reduction (CORR). In this work, we proposed a strategy to regulate product selectivities by tuning local proton transport rates through a surface resin layer over cuprous oxides.

and Are Colinear Genes That Are Highly Coexpressed in Most Cancers and Exhibit Parallel Cancer-Specific Correlations with Survival.

An association between high CD47 expression and poor cancer survival has been attributed to its function on malignant cells to inhibit phagocytic clearance. However, CD47 mRNA expression in some cancers lacks correlation or correlates with improved survival. encodes an essential primary cilium component and is colinear with across amniote genomes, suggesting coregulation of these genes.

Differential regulation by CD47 and thrombospondin-1 of extramedullary erythropoiesis in mouse spleen.

Extramedullary erythropoiesis is not expected in healthy adult mice, but erythropoietic gene expression was elevated in lineage-depleted spleen cells from mice. Expression of several genes associated with early stages of erythropoiesis was elevated in mice lacking CD47 or its signaling ligand thrombospondin-1, consistent with previous evidence that this signaling pathway inhibits expression of multipotent stem cell transcription factors in spleen. In contrast, cells expressing markers of committed erythroid progenitors were more abundant in spleens but significantly depleted in spleens.

A replication-deficient gammaherpesvirus vaccine protects mice from lytic disease and reduces latency establishment.

Gammaherpesviruses are oncogenic viruses that establish lifelong infections and are significant causes of morbidity and mortality. Vaccine strategies to limit gammaherpesvirus infection and disease are in development, but there are no FDA-approved vaccines for Epstein-Barr or Kaposi sarcoma herpesvirus. As a new approach to gammaherpesvirus vaccination, we developed and tested a replication-deficient virus (RDV) platform, using murine gammaherpesvirus 68 (MHV68), a well-established mouse model for gammaherpesvirus pathogenesis studies and preclinical therapeutic evaluations.

Innate protection against intrarectal SIV acquisition by a live SHIV vaccine.

Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies.

Engineering Tumor Stroma Morphogenesis Using Dynamic Cell-Matrix Spheroid Assembly.

The tumor microenvironment consists of resident tumor cells organized within a compositionally diverse, three-dimensional (3D) extracellular matrix (ECM) network that cannot be replicated in vitro using bottom-up synthesis. We report a new self-assembly system to engineer ECM-rich 3D MatriSpheres wherein tumor cells actively organize and concentrate microgram quantities of decellularized ECM dispersions which modulate cell phenotype. 3D colorectal cancer (CRC) MatriSpheres were created using decellularized small intestine submucosa (SIS) as an orthotopic ECM source that had greater proteomic homology to CRC tumor ECM than traditional ECM formulations such as Matrigel.

Effects of a humanized CD47 antibody and recombinant SIRPα proteins on triple negative breast carcinoma stem cells.

Signal regulatory protein-α (SIRPα, SHPS-1, CD172a) expressed on myeloid cells transmits inhibitory signals when it engages its counter-receptor CD47 on an adjacent cell. Elevated CD47 expression on some cancer cells thereby serves as an innate immune checkpoint that limits phagocytic clearance of tumor cells by macrophages and antigen presentation to T cells. Antibodies and recombinant SIRPα constructs that block the CD47-SIRPα interaction on macrophages exhibit anti-tumor activities in mouse models and are in ongoing clinical trials for treating several human cancers.

Metabolism-focused CRISPR screen unveils mitochondrial pyruvate carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer.

Homologous recombination (HR) and poly ADP-ribosylation are partially redundant pathways for the repair of DNA damage in normal and cancer cells. In cell lines that are deficient in HR, inhibition of poly (ADP-ribose) polymerase (poly (ADP-ribose) polymerase [PARP]1/2) is a proven target with several PARP inhibitors (PARPis) currently in clinical use. Resistance to PARPi often develops, usually involving genetic alterations in DNA repair signaling cascades, but also metabolic rewiring particularly in HR-proficient cells.

Acetamide Electrosynthesis from CO and Nitrite in Water.

Renewable electricity driven electrocatalytic CO reduction reaction (CO RR) is a promising solution to carbon neutralization, which mainly generate simple carbon products. It is of great importance to produce more valuable C-N chemicals from CO and nitrogen species. However, it is challenging to co-reduce CO and NO /NO to generate aldoxime an important intermediate in the electrocatalytic C-N coupling process.

Multifaceted roles for STAT3 in gammaherpesvirus latency revealed through B cell knockout models.

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor signal transducer and activator of transcription 3 (STAT3). To better understand the role of STAT3 during gammaherpesvirus latency and the B cell response to infection, we used the model pathogen murine gammaherpesvirus 68 (MHV68). Genetic deletion of STAT3 in B cells of mice reduced peak MHV68 latency approximately sevenfold.

Mechanism of co-operation of mutant α and mutant in acute lymphoblastic leukemia: role of MYC.

Acute lymphoblastic leukemia (ALL) is an aggressive leukemia which can be derived from either T-cell or B-cell precursors. With current treatments, the survival rate is high, but the treatments are highly toxic with severe side effects. Individual mutations in IL7Ra and RAS pathways have been previously shown to be prevalent in ALL, and especially in relapsed patients.

Differential regulation by CD47 and thrombospondin-1 of extramedullary erythropoiesis in mouse spleen.

Extramedullary erythropoiesis is not expected in healthy adult mice, but erythropoietic gene expression was elevated in lineage-depleted spleen cells from mice. Expression of several genes associated with early stages of erythropoiesis was elevated in mice lacking CD47 or its signaling ligand thrombospondin-1, consistent with previous evidence that this signaling pathway inhibits expression of multipotent stem cell transcription factors in spleen. In contrast, cells expressing markers of committed erythroid progenitors were more abundant in spleens but significantly depleted in spleens.

Molecular Self-Assembly in Conductive Covalent Networks for Selective Nitrate Electroreduction to Ammonia.

Electrochemical nitrate (NO) reduction in aqueous media provides a useful approach for ammonia (NH) synthesis. While efforts are focused on developing catalysts, the local microenvironment surrounding the catalyst centers is of great importance for controlling electrocatalytic performance. Here, we demonstrate that a self-assembled molecular iron catalyst integrated in a free-standing conductive hydrogel is capable of selective production of NH from NO at efficiencies approaching unity.

Multiscale CO Electrocatalysis to C Products: Reaction Mechanisms, Catalyst Design, and Device Fabrication.

Electrosynthesis of value-added chemicals, directly from CO, could foster achievement of carbon neutral through an alternative electrical approach to the energy-intensive thermochemical industry for carbon utilization. Progress in this area, based on electrogeneration of multicarbon products through CO electroreduction, however, lags far behind that for C products. Reaction routes are complicated and kinetics are slow with scale up to the high levels required for commercialization, posing significant problems.

Tumors produce glucocorticoids by metabolite recycling, not synthesis, and activate Tregs to promote growth.

Glucocorticoids are steroid hormones with potent immunosuppressive properties. Their primary source is the adrenals, where they are generated via de novo synthesis from cholesterol. In addition, many tissues have a recycling pathway in which glucocorticoids are regenerated from inactive metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by Hsd11b1).

IFN-γ and androgens disrupt mitochondrial function in murine myocytes.

The effect of cytokines on non-traditional immunological targets under conditions of chronic inflammation is an ongoing subject of study. Fatigue is a symptom often associated with autoimmune diseases. Chronic inflammatory response and activated cell-mediated immunity are associated with cardiovascular myopathies which can be driven by muscle weakness and fatigue.

B cell-intrinsic STAT3-mediated support of latency and interferon suppression during murine gammaherpesvirus 68 infection revealed through an competition model.

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor STAT3. To better understand the role of STAT3 during gammaherpesvirus latency and immune control, we utilized murine gammaherpesvirus 68 (MHV68) infection. Genetic deletion of STAT3 in B cells of mice reduced peak latency approximately 7-fold.

Selective CO Photoreduction to Acetate at Asymmetric Ternary Bridging Sites.

Photoreduction of CO is a promising strategy to synthesize value-added fuels or chemicals and realize carbon neutralization. Noncopper catalysts are seldom reported to generate C products, and the selectivity over these catalysts is low. Here, we design rich-interface, heterostructured InO/InP (r-InO/InP) for highly competitive photocatalytic CO-to-CHCOOH conversion with a productivity of 96.

CD47-Dependent Regulation of Immune Checkpoint Gene Expression and MYCN mRNA Splicing in Murine CD8 and Jurkat T Cells.

Elevated expression of CD47 in some cancers is associated with poor survival related to its function as an innate immune checkpoint when expressed on tumor cells. In contrast, elevated CD47 expression in cutaneous melanomas is associated with improved survival. Previous studies implicated protective functions of CD47 expressed by immune cells in the melanoma tumor microenvironment.

Asymmetrical electrohydrogenation of CO to ethanol with copper-gold heterojunctions.

Copper is distinctive in electrocatalyzing reduction of CO into various energy-dense forms, but it often suffers from limited product selectivity including ethanol in competition with ethylene. Here, we describe systematically designed, bimetallic electrocatalysts based on copper/gold heterojunctions with a faradaic efficiency toward ethanol of 60% at currents in excess of 500 mA cm. In the modified catalyst, the ratio of ethanol to ethylene is enhanced by a factor of 200 compared to copper catalysts.

A quantitative model of charge injection by ruthenium chromophores connecting femtosecond to continuous irradiance conditions.

A kinetic framework for the ultrafast photophysics of tris(2,2-bipyridine)ruthenium(II) phosphonated and methyl-phosphonated derivatives is used as a basis for modeling charge injection by ruthenium dyes into a semiconductor substrate. By including the effects of light scattering, dye diffusion, and adsorption kinetics during sample preparation and the optical response of oxidized dyes, quantitative agreement with multiple transient absorption datasets is achieved on timescales spanning femtoseconds to nanoseconds. In particular, quantitative agreement with important spectroscopic handles-the decay of an excited state absorption signal component associated with charge injection in the UV region of the spectrum and the dynamical redshift of a ∼500 nm isosbestic point-validates our kinetic model.