Familial Renal Glucosuria and Potential Pharmacogenetic Impact on SGLT2 Inhibitors.

Background: Renal glucosuria is a rare inheritable trait caused by loss-of-function variants in the gene that encodes SGLT2 (i.e., SLC5A2).

Identification of pathogenic genetic variants in patients with acquired early-onset bilateral cataracts using next-generation sequencing.

Background: Acquired early-onset bilateral cataracts can result from systemic etiologies or genetic disorders.

Methods: In this observational study, we analyzed individuals 18 months to 35 years of age with acquired bilateral cataracts via a next-generation sequencing panel of 66 genes to identify disease-causing genetic variants.

Results: Of 347 patients enrolled, 313 (90.

Evolution of fold switching in a metamorphic protein.

Metamorphic proteins switch between different folds, defying the protein folding paradigm. It is unclear how fold switching arises during evolution. With ancestral reconstruction and nuclear magnetic resonance, we studied the evolution of the metamorphic human protein XCL1, which has two distinct folds with different functions, making it an unusual member of the chemokine family, whose members generally adopt one conserved fold.

Structure-function guided modeling of chemokine-GPCR specificity for the chemokine XCL1 and its receptor XCR1.

Chemokines interact with their G protein-coupled receptors (GPCRs) through a two-step, two-site mechanism and, through this interaction, mediate various homeostatic and immune response mechanisms. Upon initial recognition of the chemokine by the receptor, the amino terminus of the chemokine inserts into the orthosteric pocket of the GPCR, causing conformational changes that trigger intracellular signaling. There is considerable structural and functional evidence to suggest that the amino acid composition and length of the chemokine amino terminus is critical for GPCR activation, complementing the size and amino acid composition of the orthosteric pocket.

Examination of Glycosaminoglycan Binding Sites on the XCL1 Dimer.

Known for its distinct metamorphic behavior, XCL1 interconverts between a canonical chemokine folded monomer (XCL1mon) that interacts with the receptor, XCR1, and a unique dimer (XCL1dim) that interacts with glycosaminoglycans and inhibits HIV-1 activity. This study presents the first detailed analysis of the GAG binding properties of XCL1dim. Basic residues within a conformationally selective dimeric variant of XCL1 (W55D) were mutated and analyzed for their effects on heparin binding.

Engineering Metamorphic Chemokine Lymphotactin/XCL1 into the GAG-Binding, HIV-Inhibitory Dimer Conformation.

Unlike other chemokines, XCL1 undergoes a distinct metamorphic interconversion between a canonical monomeric chemokine fold and a unique β-sandwich dimer. The monomeric conformation binds and activates the receptor XCR1, whereas the dimer binds extracellular matrix glycosaminoglycans and has been associated with anti-human immunodeficiency virus (HIV) activity. Functional studies of WT-XCL1 are complex, as both conformations are populated in solution.

Structural Determinants for the Selective Anti-HIV-1 Activity of the All-β Alternative Conformer of XCL1.

Unlabelled: HIV-1 replication is regulated in vivo by a complex network of cytokines and chemokines. XCL1/lymphotactin, a unique metamorphic chemokine, was recently identified as a broad-spectrum endogenous HIV-1 inhibitor that blocks viral entry via direct interaction with the gp120 envelope glycoprotein. HIV-1 inhibition by XCL1 requires access to the alternative all-β conformation, which interacts with glycosaminoglycans (GAGs) but not with the specific XCL1 receptor, XCR1.

Structural and agonist properties of XCL2, the other member of the C-chemokine subfamily.

Known for its unusual metamorphic native state structure, XCL1 has been the focus of most efforts to elucidate the structural, functional, and physiological properties of chemokines in the C subfamily. By comparison, its closely related paralog XCL2 remains virtually uncharacterized. Based on the importance of the chemokine N-terminus in receptor activation, it was hypothesized that two amino acid differences in XCL2 would alter its agonist activity relative to XCL1 for their shared receptor XCR1.

The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1.

CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES) are major components of the CD8-derived anti-HIV activity, evidence indicates the existence of additional, still undefined, CD8-derived HIV-suppressive factors. Here, we report the characterization of a novel anti-HIV chemokine, XCL1/lymphotactin, a member of the C-chemokine family that is produced primarily by activated CD8+ T cells and behaves as a metamorphic protein, interconverting between two structurally distinct conformations (classic and alternative).

Targeting of TGFβ signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma.

The miR-17∼92 cluster is thought to be an oncogene, yet its expression is low in glioblastoma multiforme (GBM) cell lines. This could allow unfettered expression of miR-17∼92 target genes such as connective tissue growth factor (CTGF; or CCN2), which is known to contribute to GBM pathogenesis. Indeed, microRNA-18a (but not other miR-17∼92 members) has a functional site in the CTGF 3' UTR, and its forced reexpression sharply reduces CTGF protein and mRNA levels.

p53-responsive miR-194 inhibits thrombospondin-1 and promotes angiogenesis in colon cancers.

Thrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis encoded by the THBS1 gene, whose promoter is activated by p53. In advanced colorectal cancers (CRC), its expression is sustained or even slightly increased despite frequent loss of p53. Here, we determined that in HCT116 CRC cells, p53 activates the THBS1 primary transcript, but fails to boost THBS1 mRNA or protein levels, implying posttranscriptional regulation by microRNAs (miRNA).

The myc-miR-17~92 axis blunts TGF{beta} signaling and production of multiple TGF{beta}-dependent antiangiogenic factors.

c-Myc stimulates angiogenesis in tumors through mechanisms that remain incompletely understood. Recent work indicates that c-Myc upregulates the miR-17∼92 microRNA cluster and downregulates the angiogenesis inhibitor thrombospondin-1, along with other members of the thrombospondin type 1 repeat superfamily. Here, we show that downregulation of the thrombospondin type 1 repeat protein clusterin in cells overexpressing c-Myc and miR-17∼92 promotes angiogenesis and tumor growth.

Are our investments paying off?: a study of reading level and bereavement materials.

The purpose of this article is to discuss the findings of a study that examined bereavement materials for reading level. The main research question for the study was: are printed hospice bereavement materials written at an eighth grade level or below? Readability was determined for approximately 90 individual pieces of hospice bereavement literature. The literature came from materials that were collected in a larger study and included bereavement letters to families and other educational and resource materials available to the bereaved families, the caregivers, and the public.

Effects of hormone therapy and dietary soy on myocardial ischemia/reperfusion injury in ovariectomized atherosclerotic monkeys.

Objective: Hormone therapy (HT) and dietary soy (Soy) inhibit myocardial ischemia/reperfusion (I/R) injury in nonatherosclerotic animals. The aim of this study was to determine their independent and interactive effects on I/R in monkeys previously fed an atherogenic diet for 15 months.

Design: Ovariectomized atherosclerotic monkeys (n = 40) were divided into one of four dietary treatment groups: (1) casein as the protein source, (2) casein and added HT (the equivalent of 5 mug ethinyl estradiol + 1 mg norethindrone acetate daily), (3) Soy protein providing 141 mg total isoflavones daily, or (4) Soy + HT.

A comparison of two progestins on myocardial ischemia-reperfusion injury in ovariectomized monkeys receiving estrogen therapy.

Objective: It has been reported that the progestin medroxyprogesterone acetate (MPA), but not norethindrone acetate (NETA), inhibits the beneficial vascular effects of post-menopausal estrogen therapy, but their effects on the myocardium are unclear. The goal of this study is to compare the effects of these two progestins on post-ischemic myocardial damage.

Methods: Ovariectomized monkeys were fed an atherogenic diet for 18 months while receiving, or not receiving (control, n=15), the monkey equivalent to a woman's dose of 5 mug ethinyl estradiol with either 1 mg NETA daily (n=15) or 2.

Contrasting effects of two hormone replacement therapies on the cardiovascular and mammary gland outcomes in surgically postmenopausal monkeys.

Objective: The purpose of this study was to compare the effects of two hormone replacement therapies on the intermediate end points of coronary heart disease and mammary gland hyperplasia in postmenopausal monkeys.

Study Design: Surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 12 months while receiving no treatment (control, n = 19), conjugated equine estrogens plus continuous medroxyprogesterone acetate (n = 19), or ethinyl estradiol plus norethindrone acetate (n = 21) at doses that were scaled from those doses taken by women.

Results: Quantitative coronary angiography revealed that the arteries of the control group and the conjugated equine estrogens plus continuous medroxyprogesterone acetate-treated animals constricted in response to acetylcholine (-5.

Effects of exercise on cardiovascular outcomes in monkeys with risk factors for coronary heart disease.

Objective: Exercise reduces the risk for coronary heart disease. However, the mechanisms mediating the beneficial effects of exercise remain ambiguous. In particular, it is uncertain whether exercise inhibits the development of atherosclerosis, a major pathobiologic process underlying heart disease.