Unique pharmacological properties of etrasimod among S1P receptor modulators.

Etrasimod (ADP334) is an oral, once-daily, selective sphingosine 1-phosphate (S1P) receptor modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of immune-mediated inflammatory diseases. Interaction between S1P and its five receptor subtypes (S1P-S1P) plays a role in several physiologic systems, including the cardiovascular and immune systems. Since differences in S1PR binding and downstream intracellular signaling could contribute to distinct profiles of drug efficacy and safety, we directly compared the S1P selectivity profile of etrasimod to three marketed S1PR modulators: fingolimod, ozanimod, and siponimod.

Relative Impact of Values-Oriented and Mindset-Oriented Interventions on Academic Success of Introductory Biology Students Attending 2-Year or 4-Year Institutions.

Diversifying the STEM workforce is a national priority, yet white males continue to dominate the ranks of professional scientists and engineers in the United States. This is partly due to disparities in academic success for women and minoritized students in prerequisite introductory STEM courses, leading to higher attrition from B.S.

Stimulation of a subset of natural killer T cells by CD103 DC is required for GM-CSF and protection from pneumococcal infection.

Innate-like T cells, including invariant natural killer T cells, mucosal-associated invariant T cells, and γδ T cells, are present in various barrier tissues, including the lung, where they carry out protective responses during infections. Here, we investigate their roles during pulmonary pneumococcal infection. Following infection, innate-like T cells rapidly increase in lung tissue, in part through recruitment, but T cell antigen receptor activation and cytokine production occur mostly in interleukin-17-producing NKT17 and γδ T cells.

Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae.

Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole-genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters.

Tissue-specific functions of invariant natural killer T cells.

Invariant natural killer T cells (iNKT cells) are an innate-like T cell subset that expresses an invariant T cell receptor (TCR) α-chain and recognizes lipids presented on CD1d. They secrete diverse cytokines and can influence many types of immune responses. Despite having highly similar TCR specificities, iNKT cells differentiate in the thymus into distinct subsets that are analogous to T helper 1 (T1), T2 and T17 cell subsets.

Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer.

Background: Human species C adenovirus serotype 5 (Ad5) is the archetype oncolytic adenovirus and has been used in the vast majority of preclinical and clinical tests. While Ad5 can be robust, species C Ad6 has lower seroprevalence, side effects, and appears to be more potent as a systemic therapy against a number of tumors than Ad5. Historically, there have only been four species C human adenoviruses: serotypes 1, 2, 5, and 6.

Comparison of Liver Detargeting Strategies for Systemic Therapy with Oncolytic Adenovirus Serotype 5.

Oncolytic viruses would ideally be of use for systemic therapy to treat disseminated cancer. To do this safely, this may require multiple layers of cancer specificity. The pharmacology and specificity of oncolytic adenoviruses can be modified by (1) physical retargeting, (2) physical detargeting, (3) chemical shielding, or (4) by modifying the ability of viral early gene products to selectively activate in cancer versus normal cells.

Transgene Expression and Host Cell Responses to Replication-Defective, Single-Cycle, and Replication-Competent Adenovirus Vectors.

Most adenovirus (Ad) vectors are E1 gene deleted replication defective (RD-Ad) vectors that deliver one transgene to the cell and all expression is based on that one gene. In contrast, E1-intact replication-competent Ad (RC-Ad) vectors replicate their DNA and their transgenes up to 10,000-fold, amplifying transgene expression markedly higher than RD-Ad vectors. While RC-Ad are more potent, they run the real risk of causing adenovirus infections in vector recipients and those that administer them.

Replicating Single-Cycle Adenovirus Vectors Generate Amplified Influenza Vaccine Responses.

Unlabelled: Head-to-head comparisons of conventional influenza vaccines with adenovirus (Ad) gene-based vaccines demonstrated that these viral vectors can mediate more potent protection against influenza virus infection in animal models. In most cases, Ad vaccines are engineered to be replication-defective (RD-Ad) vectors. In contrast, replication-competent Ad (RC-Ad) vaccines are markedly more potent but risk causing adenovirus diseases in vaccine recipients and health care workers.

Invariant natural killer T cells: front line fighters in the war against pathogenic microbes.

Invariant natural killer T (iNKT) cells constitute a unique subset of innate-like T cells that have been shown to have crucial roles in a variety of immune responses. iNKT cells are characterized by their expression of both NK cell markers and an invariant T cell receptor (TCR) α chain, which recognizes glycolipids presented by the MHC class I-like molecule CD1d. Despite having a limited antigen repertoire, the iNKT cell response can be very complex, and participate in both protective and harmful immune responses.

Evaluation of polymer shielding for adenovirus serotype 6 (Ad6) for systemic virotherapy against human prostate cancers.

Oncolytic viruses hold promise as "self-amplifying" cancer therapies wherein a virally killed cell can produce thousands of new viral "drugs" that can kill more cancer cells. Adenoviruses (Ads) are one family of oncolytic viruses. Most human studies have used human Ad serotype 5 (Ad5).

A Novel Codon-optimized SIV Gag-pol Immunogen for Gene-based Vaccination.

Simian immunodeficiency virus (SIV) is a robust pathogen used in non-human primates to model HIV vaccines. SIV encodes a number of potential vaccine targets. By far the largest and most conserved protein target in SIV is its gag-pol protein that bears many epitopes to drive multivalent immune T cell responses.

Mucosal vaccination by adenoviruses displaying reovirus sigma 1.

We developed adenovirus serotype 5 (Ad5) vectors displaying the sigma 1 protein from reovirus as mucosal vaccines. Ad5-sigma retargets to JAM-1 and sialic acid, but has 40-fold reduced gene delivery when compared to Ad5. While weaker at transduction, Ad5-sigma generates stronger T cell responses than Ad5 when used for mucosal immunization.

Amplified and persistent immune responses generated by single-cycle replicating adenovirus vaccines.

Unlabelled: Replication-competent adenoviral (RC-Ad) vectors generate exceptionally strong gene-based vaccine responses by amplifying the antigen transgenes they carry. While they are potent, they also risk causing adenovirus infections. More common replication-defective Ad (RD-Ad) vectors with deletions of E1 avoid this risk but do not replicate their transgene and generate markedly weaker vaccine responses.

IIIa deleted adenovirus as a single-cycle genome replicating vector.

Replication competent adenovirus (RC-Ad) vectors mediate robust transgene expression by virtue of amplifying transgenes by replication but also put patients at a risk of frank adenovirus infection. In contrast, E1-deleted replication defective Ad (RD-Ad) vectors are safer but produce substantially less transgene product. To generate a robust, but safer adenoviral vector, we created a "single cycle" adenovirus (SC-Ad) vector that replicates its genome and transgene, but that does not cause adenovirus infections by deleting the capsid cement protein IIIa in low seroprevalence adenovirus serotype 6.

Cerebrospinal fluid aβ to tau ratio and postoperative cognitive change.

Objective: Determination of biomarker and neuropathogenesis of postoperative cognitive change (POCC) or postoperative cognitive dysfunction.

Background: POCC is one of the most common postoperative complications in elderly patients. Whether preoperative cerebrospinal fluid (CSF) β-amyloid protein (Aβ) to tau ratio, an Alzheimer disease biomarker, is a biomarker for risk of POCC remains unknown.

Functional consequences of T-stem mutations in E. coli tRNAThrUGU in vitro and in vivo.

The binding affinities between Escherichia coli EF-Tu and 34 single and double base-pair changes in the T stem of E. coli tRNA(Thr)(UGU) were compared with similar data obtained previously for several aa-tRNAs binding to Thermus thermophilus EF-Tu. With a single exception, the two proteins bound to mutations in three T-stem base pairs in a quantitatively identical manner.

Arrestin orchestrates crosstalk between G protein-coupled receptors to modulate the spatiotemporal activation of ERK MAPK.

Rationale: G protein-coupled receptors (GPCRs) respond to diversified extracellular stimuli to modulate cellular function. Despite extensive studies investigating the regulation of single GPCR signaling cascades, the effects of concomitant GPCR activation on downstream signaling and cellular function remain unclear.

Objective: We aimed to characterize the cellular mechanism by which GPCR crosstalk regulates mitogen-activated protein kinase (MAPK) activation.

Spatial memory performance 2 weeks after general anesthesia in adult rats.

We have previously demonstrated that general anesthesia with 1.2% isoflurane-70% nitrous oxide impairs acquisition of a radial arm maze task in both young and aged rats when testing begins 2 days after anesthesia and in aged rats when testing begins 2 wk later. We designed this study to examine whether postanesthesia learning impairment is persistent in young rats.

Impaired acquisition of spatial memory 2 weeks after isoflurane and isoflurane-nitrous oxide anesthesia in aged rats.

Aged rats are impaired on a spatial memory task for at least 24-48 h after isoflurane-nitrous oxide anesthesia. In this study, we tested how long the impairment lasts and investigated the role of nitrous oxide. Eighteen-month-old rats were randomized to anesthesia for 2 h with 1.