Systematically exploring repurposing effects of antihypertensives.

With availability of voluminous sets of observational data, an empirical paradigm to screen for drug repurposing opportunities (i.e., beneficial effects of drugs on nonindicated outcomes) is feasible.

Opportunities, Technology, and the Joy of Discovery.

My grandparents were immigrants. My paternal grandfather was illiterate. Yet my parents were able to complete college and to become teachers.

Distinct genomic subclasses of high-grade/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic.

Background: Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date.

Lipophilic antioxidants and lipid peroxidation in yellow perch subjected to various anthropogenic influences along the St. Lawrence River (QC, Canada).

In Lake Saint-Pierre (LSP), the last great widening of the St. Lawrence River (province of Québec, Canada), the yellow perch has been experiencing a significant decline since the mid-1990s. The combined effect of several stressors (deterioration of habitats appropriate for reproduction and growth, invasive species and poor water quality) seems to exert considerable influence on the yellow perch population in LSP, characterized by low recruitment.

Relationships between polybrominated diphenyl ethers and transcription and activity of type 1 deiodinase in a gull highly exposed to flame retardants.

Deca-brominated diphenyl ether (deca-BDE), composed mainly of BDE-209, is subject to usage restrictions in North America and Europe, although global action on its continued use has yet to be undertaken. Relatively large concentrations of polybrominated diphenyl ethers (PBDEs), especially BDE-209 and its higher brominated degradation products, have been reported in tissues of ring-billed gulls (Larus delawarensis) breeding near the densely populated city of Montreal (QC, Canada). There is limited knowledge of BDE-209 biotransformation and toxicokinetics in birds.

Ccdc11 is a novel centriolar satellite protein essential for ciliogenesis and establishment of left-right asymmetry.

The establishment of left-right (L-R) asymmetry in vertebrates is dependent on the sensory and motile functions of cilia during embryogenesis. Mutations in CCDC11 disrupt L-R asymmetry and cause congenital heart disease in humans, yet the molecular and cellular functions of the protein remain unknown. Here we demonstrate that Ccdc11 is a novel component of centriolar satellites-cytoplasmic granules that serve as recruitment sites for proteins destined for the centrosome and cilium.

A double-hotdog with a new trick: structure and mechanism of the trans-acyltransferase polyketide synthase enoyl-isomerase.

Many polyketide natural products exhibit invaluable medicinal properties, yet much remains to be understood regarding the machinery responsible for their biosynthesis. The recently discovered trans-acyltransferase polyketide synthases employ processing enzymes that catalyze modifications unique from those of the classical cis-acyltransferase polyketide synthases. The enoyl-isomerase domains of these megasynthases shift double bonds and are well-represented by an enzyme that helps forge the triene system within the antibiotic produced by the prototypical bacillaene synthase.

Consequences of metal exposure on retinoid metabolism in vertebrates: a review.

What we generally refer to as 'vitamin A' is a group of naturally-occurring molecules structurally similar to retinol that are capable of exerting biological activity. These retinoids are essential to diverse physiological functions including vision, immune response, bone mineralization, reproduction, cell differentiation, and growth. As well, some retinoids have antioxidant properties.

ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain.

NKG2D ligands as therapeutic targets.

The Natural Killer Group 2D (NKG2D) receptor plays an important role in protecting the host from infections and cancer. By recognizing ligands induced on infected or tumor cells, NKG2D modulates lymphocyte activation and promotes immunity to eliminate ligand-expressing cells. Because these ligands are not widely expressed on healthy adult tissue, NKG2D ligands may present a useful target for immunotherapeutic approaches in cancer.

Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors.

Conditioning strategies that deplete host lymphocytes have been shown to enhance clinical responses to some adoptive T-cell therapies. However, host T cells are capable of eliminating tumor cells upon the relief of immunosuppression, indicating that lymphodepletion prior to T-cell transfer may reduce optimal tumor protection elicited by cell treatments that are capable of shaping host immunity. In this study, we show that adoptively transferred T cells bearing a chimeric antigen receptor (CAR) harness endogenous T cells for optimal tumor elimination and the development of a tumor-specific memory T cell response.

Thermally assisted quantum annealing of a 16-qubit problem.

Efforts to develop useful quantum computers have been blocked primarily by environmental noise. Quantum annealing is a scheme of quantum computation that is predicted to be more robust against noise, because despite the thermal environment mixing the system's state in the energy basis, the system partially retains coherence in the computational basis, and hence is able to establish well-defined eigenstates. Here we examine the environment's effect on quantum annealing using 16 qubits of a superconducting quantum processor.

NKG2D CAR T-cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors.

Tumor heterogeneity presents a substantial barrier to increasing clinical responses mediated by targeted therapies. Broadening the immune response elicited by treatments that target a single antigen is necessary for the elimination of tumor variants that fail to express the targeted antigen. In this study, it is shown that adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) inhibited the growth of target-expressing and -deficient tumor cells within ovarian and lymphoma tumors.

The fusion loops and membrane proximal region of Epstein-Barr virus glycoprotein B (gB) can function in the context of herpes simplex virus 1 gB when substituted individually but not in combination.

Among the herpesvirus glycoprotein B (gB) fusion proteins, the hydrophobic content of fusion loops and membrane proximal regions (MPRs) are inversely correlated with each other. We examined the functional importance of the hydrophobicity of these regions by replacing them in herpes simplex virus type 1 gB with corresponding regions from Epstein-Barr virus gB. We show that fusion activity is dependent on the structural context in which the specific loops and MPR sequences exist, rather than a simple hydrophobic relationship.

Evidence for metabolic imbalance of vitamin A2 in wild fish chronically exposed to metals.

In a recent study on indigenous yellow perch chronically exposed to metals, we reported a negative correlation between liver metal concentration and liver transcription levels of genes encoding for enzymes involved in the metabolism of retinoids. We therefore speculated that metals, and especially the non-essential metal Cd, could alter the metabolism of retinoids in wild fish. Thus the present field study investigates the impact of in situ metal exposure on retinoid storage.

Apical movement during interkinetic nuclear migration is a two-step process.

Neural progenitor cells in the pseudostratified neuroepithelium in vertebrates undergo interkinetic nuclear migration, which results in mitotic cells localized to the apical surface. Interphase nuclei are distributed throughout the rest of the epithelium. How mitosis is coordinated with nuclear movement is unknown, and the mechanism by which the nucleus migrates apically is controversial.

Chimeric antigen receptor T cells shape myeloid cell function within the tumor microenvironment through IFN-γ and GM-CSF.

The infiltration of suppressive myeloid cells into the tumor microenvironment restrains anti-tumor immunity. However, cytokines may alter the function of myeloid lineage cells to support tumor rejection, regulating the balance between pro- and anti-tumor immunity. In this study, it is shown that effector cytokines secreted by adoptively transferred T cells expressing a chimeric Ag receptor (CAR) shape the function of myeloid cells to promote endogenous immunity and tumor destruction.

Interkinetic nuclear migration: a mysterious process in search of a function.

During interkinetic nuclear migration (INM), the nuclei in many epithelial cells migrate between the apical and basal surfaces, coordinating with the cell cycle, and undergoing cytokinesis at the apical surface. INM is observed in a wide variety of tissues and species. Recent advances in time-lapse microscopy have provided clues about the mechanisms and functions of INM.

Oxidation of retinoic acids in hepatic microsomes of wild bullfrogs Lithobates catesbeianus environmentally-exposed to a gradient of agricultural contamination.

Agricultural contaminants are suspected of contributing to the increased incidence of deformities and the decline of amphibians populations worldwide. Many authors have further suggested that a retinoid effect could be implicated in teratogenic mechanisms since the reported deformities resemble those caused by abnormal levels of retinoic acid (RA). We previously reported altered retinoid concentrations in male bullfrogs from the Yamaska River basin (Québec, Canada) associated with moderate-to-high agricultural activity, and the findings were consistent with a possible effect on hepatic RA oxidation.

Generation of neutralizing aptamers against herpes simplex virus type 2: potential components of multivalent microbicides.

The prophylactic use of topical antiviral agents has recently been validated by the reduction in human immunodeficiency virus (HIV) type 1 infection incidence seen using tonofovir-containing microbicides. In order to develop a wide-spectrum microbicide to prevent infection with a wide range of sexually transmitted viruses, we have previously reported the development of HIV-neutralizing aptamers and here report the isolation and characterization of aptamers that neutralize herpes simplex virus type 2 (HSV-2). These aptamers bind the envelope glycoprotein (gD), are potent (IC(50) of 20-50 nM) and are able to block infection pathways dependent on both major entry receptors, Nectin1 and HVEM.

Functional interaction between herpes simplex virus type 2 gD and HVEM transiently dampens local chemokine production after murine mucosal infection.

Herpes virus entry mediator (HVEM) is one of two principal receptors mediating herpes simplex virus (HSV) entry into murine and human cells. It functions naturally as an immune signaling co-receptor, and may participate in enhancing or repressing immune responses depending on the natural ligand used. To investigate whether engagement of HVEM by HSV affects the in vivo response to HSV infection, we generated recombinants of HSV-2(333) that expressed wild-type gD (HSV-2/gD) or mutant gD able to bind to nectin-1 (the other principal entry receptor) but not HVEM.

Insertion mutations in herpes simplex virus 1 glycoprotein H reduce cell surface expression, slow the rate of cell fusion, or abrogate functions in cell fusion and viral entry.

Of the four required herpes simplex virus (HSV) entry glycoproteins, the precise role of gH-gL in fusion remains the most elusive. The heterodimer gH-gL has been proposed to mediate hemifusion after the interaction of another required glycoprotein, gD, with a receptor. To identify functional domains of HSV-1 gH, we generated 22 randomized linker-insertion mutants.

T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.

The inhibitory cosignaling pathway formed between the TNF receptor herpesvirus entry mediator (HVEM, TNFRSF14) and the Ig superfamily members, B and T lymphocyte attenuator (BTLA) and CD160, limits the activation of T cells. However, BTLA and CD160 can also serve as activating ligands for HVEM when presented in trans by adjacent cells, thus forming a bidirectional signaling pathway. BTLA and CD160 can directly activate the HVEM-dependent NF-kappaB RelA transcriptional complex raising the question of how NF-kappaB activation is repressed in naive T cells.

Binding of herpes simplex virus glycoprotein B (gB) to paired immunoglobulin-like type 2 receptor alpha depends on specific sialylated O-linked glycans on gB.

Paired immunoglobulin-like type 2 receptor alpha (PILRalpha) is an inhibitory receptor expressed on both hematopoietic and nonhematopoietic cells. Its binding to a cellular ligand, CD99, depends on the presence of sialylated O-linked glycans on CD99. Glycoprotein B (gB) of herpes simplex virus type 1 (HSV-1) binds to PILRalpha, and this association is involved in HSV-1 infection.

Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1.

Multiple entry receptors can mediate infection of cells by herpes simplex virus (HSV), permitting alternative pathways for infection and disease. We investigated the roles of two known entry receptors, herpesvirus entry mediator (HVEM) and nectin-1, in infection of neurons in the CNS and the development of encephalitis. Wild-type, HVEM KO, nectin-1 KO, and HVEM/nectin-1 double KO mice were inoculated with HSV into the hippocampus.