Synthesis of metal-binding amino acids.

The ability for amino acid residues to bind metals underpins the functions of metalloproteins to conduct a plethora of critical processes in living organisms as well as unnatural applications in the fields of catalysis, sensing and medicinal chemistry. The capability to access metal-binding peptides heavily relies on the ability to generate appropriate building blocks. This review outlines recently developed strategies for the synthesis of metal binding non-proteinogenic amino acids.

-Mediated Antigen-Independent Activation of CD8 T Cells Promotes Salt-Sensitive Hypertension.

Background: CD8 T cells (CD8Ts) have been implicated in hypertension. However, the specific mechanisms are not fully understood. In this study, we explore the contribution of the P2X7 (purinergic receptor P2X7) receptor to CD8T activation and subsequent promotion of sodium retention in the kidney.

The link between immunity and hypertension in the kidney and heart.

Hypertension is the primary cause of cardiovascular disease, which is a leading killer worldwide. Despite the prevalence of this non-communicable disease, still between 90% and 95% of cases are of unknown or multivariate cause ("essential hypertension"). Current therapeutic options focus primarily on lowering blood pressure through decreasing peripheral resistance or reducing fluid volume, but fewer than half of hypertensive patients can reach blood pressure control.

IFN- Contributes to the Immune Mechanisms of Hypertension.

Hypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For more than half a century, researchers have demonstrated that immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that proinflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension.

The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension.

Background: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated.

Mechanism of ice nucleation in liquid water on alkali feldspars.

Crystallization of supercooled liquid water in most natural environments starts with heterogeneous nucleation of ice induced by a nucleation site. Mineral surfaces, which form the majority of aqueous interfaces in Earth's ecosystem, possess a plethora of surface morphological and chemical features that can serve as ice nucleation sites. The nature of surface sites responsible for ice nucleation from supersaturated water vapor have been recently identified for alkali feldspar, a family of rock-building minerals constituting 60% of the Earth's crust.

Dysregulation of the sensory and regulatory pathways controlling cellular iron metabolism in unilateral obstructive nephropathy.

Chronic kidney disease involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in and mice, we asked if iron regulatory proteins (IRPs), the central regulators of cellular iron metabolism and suppressors of EPO production, contribute to the etiology of anemia in kidney failure.

Tetrodotoxin for Chemotherapy-Induced Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Dose Finding Trial.

Tetrodotoxin (TTX) has emerged as a potentially efficacious agent for chemotherapy-induced neuropathic pain (CINP), a prevalent, debilitating condition often resistant to analgesics. This randomized, double-blind, dose-finding study was undertaken to explore safety and trends in efficacy of four TTX doses and to identify a dose for further study. One hundred and twenty-five patients with taxane- or platinum-related CINP received subcutaneous placebo or TTX (7.

A Human IRE1 Inhibitor Blocks the Unfolded Protein Response in the Pathogenic Fungus Aspergillus fumigatus and Suggests Noncanonical Functions within the Pathway.

The unfolded protein response (UPR) is a signaling network that maintains homeostasis of the endoplasmic reticulum (ER). In the human-pathogenic fungus , the UPR is initiated by activation of an endoribonuclease (RNase) domain in the ER transmembrane stress sensor IreA, which splices the downstream mRNA into its active form, encoding the master transcriptional regulator of the pathway. Small-molecule inhibitors against IRE1, the human ortholog of IreA, have been developed for anticancer therapy, but their effects on the fungal UPR are unexplored.

Determining if nurses are involved in political action or politics: A scoping literature review.

Background: There is much current as well as long-standing concern that nurses need to be more involved in and also more adept at politics and political action for the advancement of the profession, and for the health and wellbeing of the public.

Objectives: An historical scoping literature review was carried out to identify if, as well as why, when, and how nurses become involved in government or meso-level political action or politics, and what is or has been gained through this involvement.

Design: Scoping literature review.

Safety and Efficacy of Bupivacaine HCl Collagen-Matrix Implant (INL-001) in Open Inguinal Hernia Repair: Results from Two Randomized Controlled Trials.

Introduction: Surgical site infiltration with bupivacaine results in short-lived analgesia. The MATRIX-1 and MATRIX-2 studies examined the efficacy and safety of the bioresorbable bupivacaine HCl collagen-matrix implant (INL-001) for postsurgical pain after open inguinal hernia repair. INL-001, designed to provide early and extended delivery of bupivacaine, provides prolonged duration of perioperative analgesia.

A synergistic role of IRP1 and FBXL5 proteins in coordinating iron metabolism during cell proliferation.

Iron-regulatory protein 1 (IRP1) belongs to a family of RNA-binding proteins that modulate metazoan iron metabolism. Multiple mechanisms are employed to control the action of IRP1 in dictating changes in the uptake and metabolic fate of iron. Inactivation of IRP1 RNA binding by iron primarily involves insertion of a [4Fe-4S] cluster by the cytosolic iron-sulfur cluster assembly (CIA) system, converting it into cytosolic aconitase (c-acon), but can also involve iron-mediated degradation of IRP1 by the E3 ligase FBXL5 that also targets IRP2.

Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study.

Background: Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection.

Methods: We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study.

Seven temperate terrestrial planets around the nearby ultracool dwarf star TRAPPIST-1.

One aim of modern astronomy is to detect temperate, Earth-like exoplanets that are well suited for atmospheric characterization. Recently, three Earth-sized planets were detected that transit (that is, pass in front of) a star with a mass just eight per cent that of the Sun, located 12 parsecs away. The transiting configuration of these planets, combined with the Jupiter-like size of their host star-named TRAPPIST-1-makes possible in-depth studies of their atmospheric properties with present-day and future astronomical facilities.

An international study comparing conventional versus mRNA level testing (TargetPrint) for ER, PR, and HER2 status of breast cancer.

To compare results from messenger RNA (mRNA)-based TargetPrint testing with those from immunohistochemistry (IHC) and in situ hybridization (ISH) conducted according to local standard procedures at hospitals worldwide. Tumor samples were prospectively obtained from 806 patients at 22 hospitals. The mRNA level of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was assessed by TargetPrint quantitative gene expression readouts.

Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells.

Collagen is the most abundant protein in animals. Its overproduction is associated with fibrosis and cancer metastasis. The stability of collagen relies on post-translational modifications, the most prevalent being the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases (CP4Hs).

A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer.

Background: The 4Kscore combines measurement of four kallikreins in blood with clinical information as a measure of the probability of significant (Gleason ≥7) prostate cancer (PCa) before prostate biopsy.

Objective: To perform the first prospective evaluation of the 4Kscore in predicting Gleason ≥7 PCa in the USA.

Design, Setting, And Participants: Prospective enrollment of 1012 men scheduled for prostate biopsy, regardless of prostate-specific antigen level or clinical findings, was conducted at 26 US urology centers between October 2013 and April 2014.

Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria.

Mitochondrial iron is essential for the biosynthesis of heme and iron-sulfur ([Fe-S]) clusters in mammalian cells. In developing erythrocytes, iron is imported into the mitochondria by MFRN1 (mitoferrin-1, SLC25A37). Although loss of MFRN1 in zebrafish and mice leads to profound anemia, mutant animals showed no overt signs of porphyria, suggesting that mitochondrial iron deficiency does not result in an accumulation of protoporphyrins.

Stellar spin-orbit misalignment in a multiplanet system.

Stars hosting hot Jupiters are often observed to have high obliquities, whereas stars with multiple coplanar planets have been seen to have low obliquities. This has been interpreted as evidence that hot-Jupiter formation is linked to dynamical disruption, as opposed to planet migration through a protoplanetary disk. We used asteroseismology to measure a large obliquity for Kepler-56, a red giant star hosting two transiting coplanar planets.

Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials.

Background: Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.

Methods: A total of 13 centers contributed 148 patients with breast cancer.

The IRP1-HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption.

Red blood cell production is a finely tuned process that requires coordinated oxygen- and iron-dependent regulation of cell differentiation and iron metabolism. Here, we show that translational regulation of hypoxia-inducible factor 2α (HIF-2α) synthesis by iron regulatory protein 1 (IRP1) is critical for controlling erythrocyte number. IRP1-null (Irp1(-/-)) mice display a marked transient polycythemia.

Comparison of molecular subtyping with BluePrint, MammaPrint, and TargetPrint to local clinical subtyping in breast cancer patients.

Purpose: To compare breast cancer subtyping with the three centrally assessed microarray-based assays BluePrint, MammaPrint, and TargetPrint with locally assessed clinical subtyping using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).

Methods: BluePrint, MammaPrint, and TargetPrint were all performed on fresh tumor samples. Microarray analysis was performed at Agendia Laboratories, blinded for clinical and pathological data.