Myosin relaxation states in skeletal muscle fibers of rats and mice: Effects of sex and adiposity.

Myosin disordered- and super-relaxed states (DRX and SRX, respectively) in skeletal muscle fibers are hypothesized to play key roles in thermogenesis and basal metabolic energy expenditure, raising potential for novel therapeutic targets for obesity and other metabolic diseases. Limited studies have investigated relationships between body composition or biological sex and myosin relaxed states. Using fluorescence-based single-nucleotide turnover, we report quantitative relationships of diet-induced adiposity and sex with biochemical parameters of myosin relaxed states of rodent muscle fibers.

FFAR4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of HFpEF patients has metabolic syndrome (MetS). Mechanistically, systemic, nonresolving inflammation associated with MetS might drive HFpEF remodeling. Free fatty acid receptor 4 (Ffar4) is a GPCR for long-chain fatty acids that attenuates metabolic dysfunction and resolves inflammation.

Signaling through Free Fatty Acid Receptor 4 Attenuates Cardiometabolic Disease.

A surge in the prevalence of obesity and metabolic syndrome, which promote systemic inflammation, underlies an increase in cardiometabolic disease. Free fatty acid receptor 4 is a nutrient sensor for long-chain fatty acids, like ω3-polyunsaturated fatty acids (ω3-PUFAs), that attenuates metabolic disease and resolves inflammation. Clinical trials indicate ω3-PUFAs are cardioprotective, and this review discusses the mechanistic links between ω3-PUFAs, free fatty acid receptor 4, and attenuation of cardiometabolic disease.

Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.

Aims: Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress.

CK2 Inhibits TIMELESS Nuclear Export and Modulates CLOCK Transcriptional Activity to Regulate Circadian Rhythms.

Circadian clocks orchestrate daily rhythms in organismal physiology and behavior to promote optimal performance and fitness. In Drosophila, key pacemaker proteins PERIOD (PER) and TIMELESS (TIM) are progressively phosphorylated to perform phase-specific functions. Whereas PER phosphorylation has been extensively studied, systematic analysis of site-specific TIM phosphorylation is lacking.

Polymicrobial Sepsis Impairs Antigen-Specific Memory CD4 T Cell-Mediated Immunity.

Patients who survive sepsis display prolonged immune dysfunction and heightened risk of secondary infection. CD4 T cells support a variety of cells required for protective immunity, and perturbations to the CD4 T cell compartment can decrease overall immune system fitness. Using the cecal ligation and puncture (CLP) mouse model of sepsis, we investigated the impact of sepsis on endogenous Ag-specific memory CD4 T cells generated in C57BL/6 (B6) mice infected with attenuated (Lm) expressing the I-A-restricted 2W1S epitope (Lm-2W).

Immunomodulatory receptors are differentially expressed in B and T cell subsets relevant to autoimmune disease.

Inhibitory cell-surface receptors on lymphocytes, often called immune checkpoints, are powerful targets for cancer therapy. Despite their direct involvement in autoimmune pathology, they are currently not exploited therapeutically for autoimmune diseases. Understanding the expression pattern of these receptors in health and disease is essential for targeted drug design.

Polymicrobial Sepsis Chronic Immunoparalysis Is Defined by Diminished Ag-Specific T Cell-Dependent B Cell Responses.

Immunosuppression is one hallmark of sepsis, decreasing the host response to the primary septic pathogens and/or secondary nosocomial infections. CD4 T cells and B cells are among the array of immune cells that experience reductions in number and function during sepsis. "Help" from follicular helper (Tfh) CD4 T cells to B cells is needed for productive and protective humoral immunity, but there is a paucity of data defining the effect of sepsis on a primary CD4 T cell-dependent B cell response.

CK1α Collaborates with DOUBLETIME to Regulate PERIOD Function in the Circadian Clock.

The animal circadian timing system interprets environmental time cues and internal metabolic status to orchestrate circadian rhythms of physiology, allowing animals to perform necessary tasks in a time-of-day-dependent manner. Normal progression of circadian rhythms is dependent on the daily cycling of core transcriptional factors that make up cell-autonomous molecular oscillators. In , PERIOD (PER), TIMELESS (TIM), CLOCK (CLK), and CYCLE (CYC) are core clock proteins that function in a transcriptional-translational feedback mechanism to regulate the circadian transcriptome.

Cutting Edge: Elevated Leptin during Diet-Induced Obesity Reduces the Efficacy of Tumor Immunotherapy.

Various malignancies are reproducibly cured in mouse models, but most cancer immunotherapies show objective responses in a fraction of treated patients. One reason for this disconnect may be the use of young, lean mice lacking immune-altering comorbidities present in cancer patients. Although many cancer patients are overweight or obese, the effect of obesity on antitumor immunity is understudied in preclinical tumor models.

Eradication of Established Tumors by Chemically Self-Assembled Nanoring Labeled T Cells.

Our laboratory has developed chemically self-assembled nanorings (CSANs) as prosthetic antigen receptors (PARs) for the nongenetic modification of T cell surfaces. PARs have been successfully employed in vitro to activate T cells for the selective killing of leukemia cells. However, PAR efficacy has yet to be evaluated in vivo or against solid tumors.

Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy.

Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines.

A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies.

Renal cell carcinoma (RCC) affects > 60,000 people in the United States annually, and ~ 30% of RCC patients have multiple metastases at the time of diagnosis. Metastatic RCC (mRCC) is incurable, with a median survival time of only 18 months. Immune-based interventions (e.

Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD.

Codon usage bias is a universal feature of all genomes, but its in vivo biological functions in animal systems are not clear. To investigate the in vivo role of codon usage in animals, we took advantage of the sensitivity and robustness of the Drosophila circadian system. By codon-optimizing parts of Drosophila period (dper), a core clock gene that encodes a critical component of the circadian oscillator, we showed that dper codon usage is important for circadian clock function.

CD8 T Cell-Independent Antitumor Response and Its Potential for Treatment of Malignant Gliomas.

Malignant brain tumors continue to represent a devastating diagnosis with no real chance for cure. Despite an increasing list of potential salvage therapies, standard-of-care for these patients has not changed in over a decade. Immunotherapy has been seen as an exciting option, with the potential to offer specific and long lasting tumor clearance.

Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis.

Transient lymphopenia is one hallmark of sepsis, and emergent data indicate the CD4 T cell compartment in sepsis survivors is numerically and functionally altered (when examined at the Ag-specific level) compared with nonseptic control subjects. Previous data from our laboratory demonstrated Ag-independent, lymphopenia-induced homeostatic proliferation to be a contributing mechanism by which CD4 T cells numerically recover in sepsis survivors. However, we reasoned it is also formally possible that some CD4 T cells respond directly to Ag expressed by gut-resident microbes released during polymicrobial sepsis.

Ingestion of genetically modified yeast symbiont reduces fitness of an insect pest via RNA interference.

RNA interference has had major advances as a developing tool for pest management. In laboratory experiments, double-stranded RNA (dsRNA) is often administered to the insect by genetic modification of the crop, or synthesized in vitro and topically applied to the crop. Here, we engineered genetically modified yeast that express dsRNA targeting y-Tubulin in Drosophila suzukii.

Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma.

Renal cell carcinoma (RCC) is resistant to traditional cancer therapies, and metastatic RCC (mRCC) is incurable. The shortcomings in current therapeutic options for patients with mRCC provide the rationale for the development of novel treatment protocols. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be a potent inducer of tumor cell death in vitro and in vivo, and a number of TRAIL death receptor agonists (recombinant TRAIL or TRAIL death receptor-specific mAb) have been developed and tested clinically.

Exploiting natural anti-tumor immunity for metastatic renal cell carcinoma.

Clinical observations of spontaneous disease regression in some renal cell carcinoma (RCC) patients implicate a role for tumor immunity in controlling this disease. Puzzling, however, are findings that high levels of tumor infiltrating lymphocytes (TIL) are common to RCC. Despite expression of activation markers by TILs, functional impairment of innate and adaptive immune cells has been consistently demonstrated contributing to the failure of the immune system to control RCC.

Mosquito genomics. Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes.

Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila.

CD8+ T cell-independent tumor regression induced by Fc-OX40L and therapeutic vaccination in a mouse model of glioma.

Despite the growing number of preclinical and clinical trials focused on immunotherapy for the treatment of malignant gliomas, the prognosis for this disease remains grim. Although some promising advances have been made, the immune response stimulated as a result of immunotherapeutic protocols has been inefficient at complete tumor elimination, primarily due to our lack of understanding of the necessary effector functions of the immune system. We previously demonstrated that a tumor lysate vaccine/Fc-OX40L therapy is capable of inducing enhanced survival and tumor elimination in the GL261 mouse glioma model.

Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy.

Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are to identify likely responders to immunotherapy regimens among individuals with cancer and to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here, the immune profiles of 6 murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to 2 immunotherapy regimens.

An in vivo immunotherapy screen of costimulatory molecules identifies Fc-OX40L as a potent reagent for the treatment of established murine gliomas.

Purpose: We tested the combination of a tumor lysate vaccine with a panel of costimulatory molecules to identify an immunotherapeutic approach capable of curing established murine gliomas.

Experimental Design: Glioma-bearing mice were primed with a tumor lysate vaccine, followed by systemic administration of the following costimulatory ligands: OX40L, CD80, 4-1BBL, and GITRL, which were fused to the Fc portion of human immunoglobulin. Lymphocytes and mRNA were purified from the brain tumor site for immune monitoring studies.