A Novel Toll-Like Receptor 2 Agonist Protects Mice in a Prophylactic Treatment Model Against Challenge With .

Current therapies for anthrax include the use of antibiotics (i.e., doxycycline, and ciprofloxacin), an anthrax vaccine (BioThrax) and -specific, monoclonal antibody (mAb) (i.

Polycarbonate Urethane Mesh: A New Material for Pelvic Reconstruction.

Objective: Polycarbonate urethane (PCU) is a new biomaterial, and its mechanical properties can be tailored to match that of vaginal tissue. We aimed to determine whether vaginal host immune and extracellular matrix responses differ after PCU versus lightweight polypropylene (PP) mesh implantation.

Methods: Hysterectomy and ovariectomy were performed on 24 Sprague-Dawley rats.

Inhibition of inositol kinase B controls acute and chronic graft-versus-host disease.

T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T cells, and can control T-cell-mediated autoimmunity.

Liver-Targeted Toll-Like Receptor 7 Agonist Combined With Entecavir Promotes a Functional Cure in the Woodchuck Model of Hepatitis B Virus.

Current therapeutics for chronic infection with hepatitis B virus (HBV) rarely induce functional cure due to the immunotolerant status of patients. Small molecule agonists targeting toll-like receptor 7 (TLR7) have been shown to elicit a functional cure in animal models of HBV but sometimes with poor tolerability due to immune-related toxicities. In an effort to increase the therapeutic window of TLR7 agonists to treat chronic hepatitis B (CHB), we developed an oral TLR7 agonist, APR002, designed to act locally in the gastrointestinal tract and liver, thus minimizing systemic exposure and improving tolerability.

Stable Nanoemulsions for the Delivery of Small Molecule Immune Potentiators.

Adjuvants are required to enhance immune responses to typically poorly immunogenic recombinant antigens. Toll-like receptor agonists (TLRa) have been widely evaluated as adjuvants because they activate the innate immune system. Currently, licensed vaccines adjuvanted with TLRa include the TLR4 agonist monophosphoryl lipid, while additional TLRa are in clinical development.

Design and Structure-Function Characterization of 3D Printed Synthetic Porous Biomaterials for Tissue Engineering.

3D printing is now adopted for use in a variety of industries and functions. In biomedical engineering, 3D printing has prevailed over more traditional manufacturing methods in tissue engineering due to its high degree of control over both macro- and microarchitecture of porous tissue scaffolds. However, with the improved flexibility in design come new challenges in characterizing the structure-function relationships between various architectures and both mechanical and biological properties in an assortment of clinical applications.

Deformation and fatigue of tough 3D printed elastomer scaffolds processed by fused deposition modeling and continuous liquid interface production.

Polyurethane (PU) based elastomers continue to gain popularity in a variety of biomedical applications as compliant implant materials. In parallel, advancements in additive manufacturing continue to provide new opportunities for biomedical applications by enabling the creation of more complex architectures for tissue scaffolding and patient specific implants. The purpose of this study was to examine the effects of printed architecture on the monotonic and cyclic mechanical behavior of elastomeric PUs and to compare the structure-property relationship across two different printing approaches.

Activin A programs the differentiation of human TFH cells.

Follicular helper T cells (TFH cells) are CD4(+) T cells specialized in helping B cells and are associated both with protective antibody responses and autoimmune diseases. The promise of targeting TFH cells therapeutically has been limited by fragmentary understanding of extrinsic signals that regulate the differentiation of human TFH cells. A screen of a human protein library identified activin A as a potent regulator of TFH cell differentiation.

Incorporation of Phosphonate into Benzonaphthyridine Toll-like Receptor 7 Agonists for Adsorption to Aluminum Hydroxide.

Small molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. Localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance colocalization of antigen and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site deposition.

Initial Outcomes of a Lung Cancer Screening Program in an Integrated Community Health System.

Purpose: Lung cancer screening with low-dose CT (LDCT) demonstrated reduced mortality in the National Lung Screening Trial, yet there is debate as to whether the reported efficacy can translate into comparable effectiveness with community-based screening. The authors' purpose is to report the baseline patient characteristics and malignancy rate in the first 18 months after implementing a lung cancer screening program in an integrated community health system.

Methods: Patients were screened at 1 of 10 participating community-based centers within a 22-hospital system from 2013 to 2015.

Compressive cyclic ratcheting and fatigue of synthetic, soft biomedical polymers in solution.

The use of soft, synthetic materials for the replacement of soft, load-bearing tissues has been largely unsuccessful due to a lack of materials with sufficient fatigue and wear properties, as well as a lack of fundamental understanding on the relationship between material structure and behavior under cyclic loads. In this study, we investigated the response of several soft, biomedical polymers to cyclic compressive stresses under aqueous conditions and utilized dynamic mechanical analysis and differential scanning calorimetry to evaluate the role of thermo-mechanical transitions on such behavior. Studied materials include: polycarbonate urethane, polydimethylsiloxane, four acrylate copolymers with systematically varied thermo-mechanical transitions, as well as bovine meniscal tissue for comparison.

Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease.

Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes.

Rational design of small molecules as vaccine adjuvants.

Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically.

Platelet-rich plasma for the treatment of chronic plantar fasciopathy in adults: a case series.

Plantar fasciopathy (PF) is a common source of pain and disability that is often refractory to conservative management. There are no uniformly effective standard-of-care treatments for chronic recalcitrant PF. Corticosteroid injection is considered a viable treatment option when traditional therapies fail, but is limited by suboptimal long-term efficacy and potential adverse effects.

Geometric analysis of macronutrient selection in breeds of the domestic dog, Canis lupus familiaris.

Although many herbivores and omnivores have been shown to balance their intake of macronutrients when faced with nutritionally variable foods, study of this ability has been relatively neglected in carnivores, largely on the assumption that prey are less variable in nutrient composition than the foods of herbivores and omnivores and such mechanisms therefore unnecessary. We performed diet selection studies in 5 breeds of adult dog (Canis lupus familiaris) to determine whether these domesticated carnivores regulate macronutrient intake. Using nutritional geometry, we show that the macronutrient content of the diet was regulated to a protein:fat:carbohydrate ratio of approximately 30%:63%:7% by energy, a value that was remarkably similar across breeds.

Consistent proportional macronutrient intake selected by adult domestic cats (Felis catus) despite variations in macronutrient and moisture content of foods offered.

We investigated the ability of domestic cats to regulate the macronutrient composition of their diet when provided with foods that differed not only in macronutrient content but also in texture and moisture content, as typically found in the main forms of commercially manufactured cat foods. Cats were provided with foods in different combinations (1 wet + 3 dry; 1 dry + 3 wet; 3 wet + 3 dry) in three separate experiments. Within each experiment cats were offered the wet and dry food combinations in two (naïve and experienced) diet selection phases where all the foods were offered simultaneously, separated by a phase in which the foods were offered sequentially in 3-day cycles in pairs (1 wet with 1 dry).

Topical SMIP-7.7, a toll-like receptor 7 agonist, protects against genital herpes simplex virus type-2 disease in the guinea pig model of genital herpes.

Background: Development of more effective therapies for genital herpes simplex virus type-2 (HSV-2) infections remains a priority. The toll-like receptors (TLR) are attractive targets for the immunomodulation of primary and recurrent genital herpes infection. The guinea pig model of genital HSV-2 disease was therefore used to evaluate the efficacy of a new TLR-7 agonist, SMIP-7.

The effect of dietary starch level on postprandial glucose and insulin concentrations in cats and dogs.

A charge made against feeding dry foods to cats is that the high carbohydrate (i.e. starch) content results in high blood glucose levels which over time may have detrimental health effects.

Postprandial glucose and insulin profiles following a glucose-loaded meal in cats and dogs.

Data from intravenous (i.v.) glucose tolerance tests suggest that glucose clearance from the blood is slower in cats than in dogs.

Accuracy of the use of triaxial accelerometry for measuring daily activity as a predictor of daily maintenance energy requirement in healthy adult Labrador Retrievers.

Objective: To determine accuracy of the use of triaxial accelerometry for measuring daily activity as a predictor of maintenance energy requirement (MER) in healthy adult Labrador Retrievers.

Animals: 10 healthy adult Labrador Retrievers.

Procedures: Dogs wore an accelerometer for two 2-week periods, with data on daily activity successfully collected for 24 to 26 days.

Geometric analysis of macronutrient selection in the adult domestic cat, Felis catus.

We report feeding studies on adult domestic cats designed to disentangle the complex interactions among dietary protein, fat and carbohydrate in the control of intake. Using geometric techniques that combine mixture triangles and intake plots from the geometric framework, we: (1) demonstrate that cats balance their macronutrient intake, (2) estimate the composition of the target balance and (3) reveal the priorities given to different macronutrients under dietary conditions where the target is unachievable. Our analysis indicates that cats have a ceiling for carbohydrate intake, which limits ingestion and constrains them to deficits in protein and fat intake (relative to their target) on high-carbohydrate foods.

Tonic BCR signaling represses receptor editing via Raf- and calcium-dependent signaling pathways.

Light chain receptor editing is an important mechanism that prevents B cell self-reactivity. We have previously shown that tonic signaling through the BCR represses RAG expression at the immature B cell stage, and that initiation of light chain rearrangements occurs in the absence of these tonic signals in an in vitro model of B cell development. To further test our hypothesis we studied the effect of itpkb deficiency (itpkb(-/-) mice) or Raf hyper-activation (Raf-CAAX transgenic mice), two mutations that enhance BCR signaling, on receptor editing in an in vivo model.

Inositol 1,4,5-trisphosphate 3-kinase B is a negative regulator of BCR signaling that controls B cell selection and tolerance induction.

Inositol 1,4,5-trisphosphate 3-kinase B (or Itpkb) converts inositol 1,4,5-trisphosphate to inositol 1,3,4,5-tetrakisphosphate upon Ag receptor activation and controls the fate and function of lymphocytes. To determine the role of Itpkb in B cell tolerance, Itpkb(-/-) mice were crossed to transgenic mice that express a BCR specific for hen egg lysozyme (IgHEL). B cells from Itpkb(-/-) IgHEL mice possess an anergic phenotype, hypoproliferate in response to cognate Ag, and yet they exhibit enhanced Ag-induced calcium signaling.

Beyond IP3: roles for higher order inositol phosphates in immune cell signaling.

Nearly 25 years ago the first function of an inositol phosphate, namely Ins(1,4,5)P3, was reported to act as a "second messenger" to mobilize calcium from the endoplasmic reticulum (ER). Since this discovery, many other inositol phosphates and the kinases and phosphatases that generate these inositol phosphates have subsequently been discovered. However, the function of these "higher order" inositol phosphates in biological processes, if any, has remained a mystery.