STAT3 suppresses Wnt/β-catenin signaling during the induction phase of primary Myf5+ brown adipogenesis.

Thermogenic fat is a promising target for new therapies in diabetes and obesity. Understanding how thermogenic fat develops is important to develop rational strategies to treat obesity. Previously, we have shown that Tyk2 and STAT3, part of the JAK-STAT pathway, are necessary for proper development of classical brown fat.

Chromosome Translocations and Cosmic Radiation Dose in Male U.S. Commercial Airline Pilots.

Background: Chromosome translocations are a biomarker of cumulative exposure to ionizing radiation. We examined the relation between the frequency of translocations and cosmic radiation dose in 83 male airline pilots.

Methods: Translocations were scored using fluorescence in situ hybridization chromosome painting.

Reassessing the chronology of the archaeological site of Anzick.

Found in 1968, the archaeological site of Anzick, Montana, contains the only known Clovis burial. Here, the partial remains of a male infant, Anzick-1, were found in association with a Clovis assemblage of over 100 lithic and osseous artifacts-all red-stained with ochre. The incomplete, unstained cranium of an unassociated, geologically younger individual, Anzick-2, was also recovered.

Karrikin-KAI2 signalling provides Arabidopsis seeds with tolerance to abiotic stress and inhibits germination under conditions unfavourable to seedling establishment.

The control of seed germination in response to environmental conditions is important for plant success. We investigated the role of the karrikin receptor KARRIKIN INSENSITIVE2 (KAI2) in the response of Arabidopsis seeds to osmotic stress, salinity and high temperature. Germination of the kai2 mutant was examined in response to NaCl, mannitol and elevated temperature.

ABCC1-Exported Sphingosine-1-phosphate, Produced by Sphingosine Kinase 1, Shortens Survival of Mice and Patients with Breast Cancer.

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. Previously, we observed that S1P is exported out of human breast cancer cells by ATP-binding cassette (ABC) transporter ABCC1, but not by ABCB1, both known multidrug resistance proteins that efflux chemotherapeutic agents. However, the pathologic consequences of these events to breast cancer progression and metastasis have not been elucidated.

Protective effects of the angiotensin II AT receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach.

Significant neuroprotective effects of angiotensin II type 2 (AT) receptor (AT receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT receptor agonists are blood-brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke.

Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia.

Stroke-induced immune suppression predisposes the host to infections and can contribute to high morbidity and mortality in stroke patients. Because ischemic stroke has a profound effect on the systemic immune response, which may explain the increased susceptibility of stroke patients to infection, an urgent need persists for a better understanding of mechanisms associated with immune suppression; new and effective treatments for stroke can then be identified. NK cells play a key role in early host defense against pathogens by killing infected cells and/or producing cytokines such as IFN-γ.

Translating genomics into practice for real-time surveillance and response to carbapenemase-producing Enterobacteriaceae: evidence from a complex multi-institutional KPC outbreak.

Background: Until recently, carbapenemase (KPC)-producing Enterobacteriaceae were rarely identified in Australia. Following an increase in the number of incident cases across the state of Victoria, we undertook a real-time combined genomic and epidemiological investigation. The scope of this study included identifying risk factors and routes of transmission, and investigating the utility of genomics to enhance traditional field epidemiology for informing management of established widespread outbreaks.

N-Gemini peptides: cytosolic protease resistance via N-terminal dimerization of unstructured peptides.

Herein we describe a synthetically simple strategy for increasing the lifetime of unstructured peptides in cytosolic environment via dimerization at the N-terminus to block threading into the catalytic cleft of cytosolic proteases. We establish this approach with kinase substrates, allowing for phosphorylation in cells as a demonstration of protease resistance.

Interleukin-13 receptor alpha 2 cooperates with EGFRvIII signaling to promote glioblastoma multiforme.

The interleukin-13 receptor alpha2 (IL-13Rα2) is a cancer-associated receptor overexpressed in human glioblastoma multiforme (GBM). This receptor is undetectable in normal brain which makes it a highly suitable target for diagnostic and therapeutic purposes. However, the pathological role of this receptor in GBM remains to be established.

A study of 2-component i, i + 3 peptide stapling using thioethers.

Peptides are promising scaffolds for use as therapeutics, targeting interactions previously considered to be "undruggable" by small molecules. While short peptides are generally unstructured in solution and rapidly degraded by proteases in the cell cytosol, peptide stapling offers an effective method to both stabilize peptides in a helical structure and increase resistance to proteolytic degradation. Most studies of peptide stapling have focused on residues with i, i + 4 and i, i + 7 spacing, while stapling of residues with i, i + 3 spacing has been understudied.

Investigation of Trimethyllysine Binding by the HP1 Chromodomain via Unnatural Amino Acid Mutagenesis.

Trimethyllysine (Kme3) reader proteins are targets for inhibition due to their role in mediating gene expression. Although all such reader proteins bind Kme3 in an aromatic cage, the driving force for binding may differ; some readers exhibit evidence for cation-π interactions whereas others do not. We report a general unnatural amino acid mutagenesis approach to quantify the contribution of individual tyrosines to cation binding using the HP1 chromodomain as a model system.

Keratin biomaterials augment anti-inflammatory macrophage phenotype in vitro.

Unlabelled: Tissue regeneration following injury is mediated by macrophage recruitment and differentiation in response to environmental signals. In general, macrophages adopt either a classically M1 (M[IFN-γ, LPS]) or alternatively activated M2 (M[IL-4, IL-13] or M[IL-10]) phenotype. Recent studies have highlighted the importance of alternatively activated macrophages in tissue remodeling and repair as well as the contribution of an imbalance of classically and alternatively activated macrophages to tissue degeneration and disease progression.

BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands.

Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth.

A growth hormone receptor SNP promotes lung cancer by impairment of SOCS2-mediated degradation.

Both humans and mice lacking functional growth hormone (GH) receptors are known to be resistant to cancer. Further, autocrine GH has been reported to act as a cancer promoter. Here we present the first example of a variant of the GH receptor (GHR) associated with cancer promotion, in this case lung cancer.

Clinico-serologic features of statin-induced necrotising autoimmune myopathy in a single-centre cohort.

Statin-induced necrotising autoimmune myopathy (NAM) is a rare but disabling complication of statin therapy. Data regarding treatment and outcomes in these patients is sparse. We retrospectively identified those patients with a diagnosis of statin-induced NAM who were managed in a single-tertiary referral centre from January 2014 to January 2017.

Optimization of a synthetic receptor for dimethyllysine using a biphenyl-2,6-dicarboxylic acid scaffold: insights into selective recognition of hydrophilic guests in water.

In the design of small molecule receptors for polar guests, much inspiration has been taken from proteins that have adapted effective ways to selectively bind polar molecules in aqueous environments. Nonetheless, molecular recognition of hydrophilic guests in water by synthetic receptors remains a challenging task. Here we report a new synthetic receptor, A2I, with improved affinity and selectivity for a biologically important polar guest, dimethyllysine (Kme2).

Effect of thixotropic agents as additives on the mechanical properties of maxillofacial silicone elastomers.

Statement Of Problem: The incorporation of thixotropic agents to prevent slumping during the silicone packing procedure may alter some favorable mechanical properties of the silicone elastomers and could possibly influence the success of the prosthesis.

Purpose: The purpose of this in vitro study was to evaluate the effect of adding thixotropic agents on the mechanical properties of 3 commonly used silicone elastomers.

Material And Methods: Specimens of 3 maxillofacial silicones (M511, Z004; Technovent Ltd, and A2000; Factor II Inc) were prepared according to the manufacturers' instructions.

Stroke Hospital Characteristics in the Florida-Puerto Rico Collaboration to Reduce Stroke Disparities Study.

Objectives: Although disparities in stroke care and outcomes have been well documented nationally, state-based registries to monitor acute stroke care in Florida (FL) and Puerto Rico (PR) have not been established. The FL-PR Collaboration to Reduce Stroke Disparities (CReSD) was developed to evaluate race-ethnicity and regional disparities in stroke care performance. The objective of this study was to assess and compare hospital characteristics within a large quality improvement registry to identify characteristics associated with better outcomes for acute ischemic stroke care.

Nutrient availability affects floral scent much less than other floral and vegetative traits in Lithophragma bolanderi.

Background And Aims: Many plant-pollinator interactions are mediated by floral scents that can vary among species, among populations within species and even among individuals within populations. This variation could be innate and unaffected by the environment, but, because many floral volatiles have amino-acid precursors, scent variation also could be affected by differences in nutrient availability among environments. In plants that have coevolved with specific pollinators, natural selection is likely to favour low phenotypic plasticity in floral scent even under different conditions of nutrient availability if particular scents or scent combinations are important for attracting local pollinators.

Development of a 3D printable maxillofacial silicone: Part II. Optimization of moderator and thixotropic agent.

Statement Of Problem: Conventionally, maxillofacial prostheses are fabricated by hand carving the missing anatomic defect in wax and creating a mold into which pigmented silicone elastomer is placed. Digital technologies such as computer numerical control milling and 3-dimensional (3D) printing have been used to prepare molds, directly or indirectly, into which a biocompatible pigmented silicone elastomer can be placed.

Purpose: The purpose of this in vitro study was to develop a silicone elastomer that could be 3D printed directly without a mold to create facial or body prostheses by varying its composition.

A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.

The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.

Fluorogenic sensor platform for the histone code using receptors from dynamic combinatorial libraries.

Post-translational modifications (PTMs) on histone tails act in diverse combinations in the 'histone code' to control gene expression, with dysregulation observed in a variety of diseases. However, detection and sensing methods are limited, expensive, and/or low-throughput, including MS and antibody based detection. We found that by combining four synthetic receptors developed by dynamic combinatorial chemistry (DCC) in an indicator displacement system, we are able to create a pattern-based sensor platform that can discriminate single PTMs such as methylation and acetylation on a representative histone peptide with 100% accuracy as well as peptides bearing both dimethyl and trimethyl lysine in the presence of arginine methylation, which has not previously been demonstrated, and can even correctly distinguish the position of lysine methylation individually or in the presence of other PTMs.