Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure.

Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.

The influence of role models in undergraduate nurse education.

Aims And Objectives: To explore the concept of role modelling in undergraduate nurse education and its effect on the personal and professional development of student nurses.

Background: Effective educative strategies are important for student nurses, who have to cope with learning in both clinical and university settings. Given the contemporary issues facing nurse education and practice in the United Kingdom (UK), it is timely and important to undertake pedagogical research into the concept of role modelling as an effective educative method.

The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.

Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-[9-39] (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist.

Multiple Hip Intra-Articular Steroid Injections Increase Risk of Periprosthetic Joint Infection Compared With Single Injections.

Background: Patients with hip osteoarthritis often temporize their symptoms with multiple intra-articular steroid hip injections (IASHIs) before undergoing total hip arthroplasty (THA). Although there is recent evidence to suggest that IASHI can lead to an increased risk of future periprosthetic joint infection (PJI), the potential increase in risk of PJI after multiple IASHIs compared with single IASHI remains largely unknown. The aim of the study was to evaluate whether multiple IASHIs are associated with increased risk of PJI compared with single IASHI in THA patients.

Compound speckle model detects anti-angiogenic tumor response in preclinical nonlinear contrast-enhanced ultrasonography.

Purpose: This paper proposes a method for analyzing the first-order speckle statistics of nonlinear contrast-enhanced ultrasound images from tumors.

Methods: Contrast signal intensity is modeled as a compound distribution of exponential probability density functions with a gamma weighting function. The gamma probability weighting function serves as an approximation for log-normally distributed flow velocities in a vascular network.

The role of sleep in cognitive processing: focusing on memory consolidation.

Research indicates that sleep promotes various cognitive functions, such as decision-making, language, categorization, and memory. Of these, most work has focused on the influence of sleep on memory, with ample work showing that sleep enhances memory consolidation, a process that stores new memories in the brain over time. Recent psychological and neurophysiological research has vastly increased understanding of this process.

Protocol for Standardizing High-to-Moderate Abundance Protein Biomarker Assessments Through an MRM-with-Standard-Peptides Quantitative Approach.

Quantitative mass spectrometry (MS)-based approaches are emerging as a core technology for addressing health-related queries in systems biology and in the biomedical and clinical fields. In several 'omics disciplines (proteomics included), an approach centered on selected or multiple reaction monitoring (SRM or MRM)-MS with stable isotope-labeled standards (SIS), at the protein or peptide level, has emerged as the most precise technique for quantifying and screening putative analytes in biological samples. To enable the widespread use of MRM-based protein quantitation for disease biomarker assessment studies and its ultimate acceptance for clinical analysis, the technique must be standardized to facilitate precise and accurate protein quantitation.

Premature and multiple births in IVF are associated with pretreatment circulating LH/hCG receptor concentration.

The luteinizing hormone (LH) and pregnancy hormone, human chorionic gonadotrophin (hCG), share a common receptor: LH/hCG-R or LHCGR. In this prospective study involving 290 patients undergoing in vitro fertilization (IVF) and embryo transfer, we have examined whether pretreatment circulating LHCGR (sLHCGR) influences the course of pregnancy and perinatal outcome after embryo transfer. The blood samples were collected before the fertility treatment began and sLHCGR concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) test.

MRI surveillance of cancer cell fate in a brain metastasis model after early radiotherapy.

Purpose: Incidence of brain metastasis attributed to breast cancer is increasing and prognosis is poor. It is thought that disseminated dormant cancer cells persist in metastatic organs and may evade treatments, thereby facilitating a mechanism for recurrence. Radiotherapy is used to treat brain metastases clinically, but assessment has been limited to macroscopic tumor volumes detectable by clinical imaging.

Peroxy Pyruvic Acid-Containing Topical Anti-Infective: A Potential Candidate for a Wound Instillation Solution.

Evaluate the therapeutic properties of a peroxy pyruvic acid (PPA)-containing topical anti-infective in a human model that replicates the natural conditions of a human chronic wound. Wound material was extracted from patients with nonhealing diabetic ulcers, venous stasis ulcers, and arterial wounds. Microbial species were identified, and wound colonization was quantified.

Persistent Thalamic Sound Processing Despite Profound Cochlear Denervation.

Neurons at higher stages of sensory processing can partially compensate for a sudden drop in peripheral input through a homeostatic plasticity process that increases the gain on weak afferent inputs. Even after a profound unilateral auditory neuropathy where >95% of afferent synapses between auditory nerve fibers and inner hair cells have been eliminated with ouabain, central gain can restore cortical processing and perceptual detection of basic sounds delivered to the denervated ear. In this model of profound auditory neuropathy, auditory cortex (ACtx) processing and perception recover despite the absence of an auditory brainstem response (ABR) or brainstem acoustic reflexes, and only a partial recovery of sound processing at the level of the inferior colliculus (IC), an auditory midbrain nucleus.

Interactions across Multiple Stimulus Dimensions in Primary Auditory Cortex.

Although sensory cortex is thought to be important for the perception of complex objects, its specific role in representing complex stimuli remains unknown. Complex objects are rich in information along multiple stimulus dimensions. The position of cortex in the sensory hierarchy suggests that cortical neurons may integrate across these dimensions to form a more gestalt representation of auditory objects.

The transcriptional regulator TBX3 promotes progression from non-invasive to invasive breast cancer.

Background: TBX3 is a T-box transcription factor repressor that is elevated in metastatic breast cancer and is believed to promote malignancy of tumor cells, possibly by promoting cell survival and epithelial-mesenchymal transition.

Methods: The relative expression of TBX3 was assessed in the 21T cell lines which were derived from an individual patient and represent three distinct stages of breast cancer progression: 21PT, atypical ductal hyperplasia; 21NT, ductal carcinoma in situ; and 21MT-1, invasive mammary carcinoma. Two different isoforms of TBX3 (TBX3iso1 and TBX3iso2) were overexpressed to evaluate cell survival/colony forming ability, growth, and invasion in the ductal carcinoma in situ-like 21NT cell line using an in vitro Matrigel model of cancer progression.

Relationship between Parental Feeding Practices and Neural Responses to Food Cues in Adolescents.

Social context, specifically within the family, influences adolescent eating behaviours and thus their health. Little is known about the specific mechanisms underlying the effects of parental feeding practices on eating. We explored relationships between parental feeding practices and adolescent eating habits and brain activity in response to viewing food images.

Improved Linear Contrast-Enhanced Ultrasound Imaging via Analysis of First-Order Speckle Statistics.

The linear subtraction methods commonly used for preclinical contrast-enhanced imaging are susceptible to registration errors and motion artifacts that lead to reduced contrast-to-tissue ratios. To address this limitation, a new approach to linear contrast-enhanced ultrasound (CEUS) is proposed based on the analysis of the temporal dynamics of the speckle statistics during wash-in of a bolus injection of microbubbles. In the proposed method, the speckle signal is approximated as a mixture of temporally varying random processes, representing the microbubble signal, superimposed onto spatially heterogeneous tissue backscatter in multiple subvolumes within the region of interest.

Evaluating Changes to Blood-Brain Barrier Integrity in Brain Metastasis over Time and after Radiation Treatment.

Introduction: The incidence of brain metastasis due to breast cancer is increasing, and prognosis is poor. Treatment is challenging because the blood-brain barrier (BBB) limits efficacy of systemic therapies. In this work, we develop a clinically relevant whole brain radiotherapy (WBRT) plan to investigate the impact of radiation on brain metastasis development and BBB permeability in a murine model.

Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight.

Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis.

Quantification of cancer cell extravasation in vivo.

Cancer cell 'invasiveness' is one of the main driving forces in cancer metastasis, and assays that quantify this key attribute of cancer cells are crucial in cancer metastasis research. The research goal of many laboratories is to elucidate the signaling pathways and effectors that are responsible for cancer cell invasion, but many of these experiments rely on in vitro methods that do not specifically simulate individual steps of the metastatic cascade. Cancer cell extravasation is arguably the most important example of invasion in the metastatic cascade, whereby a single cancer cell undergoes transendothelial migration, forming invasive processes known as invadopodia to mediate translocation of the tumor cell from the vessel lumen into tissue in vivo.

Primary melanoma tumor inhibits metastasis through alterations in systemic hemostasis.

Progression from a primary tumor to distant metastases requires extensive interactions between tumor cells and their microenvironment. The primary tumor is not only the source of metastatic cells but also can also modulate host responses to these cells, leading to an enhancement or inhibition of metastasis. Tumor-mediated stimulation of bone marrow can result in pre-metastatic niche formation and increased metastasis.

Effects of slip severity on muscle activation of the trailing leg during an unexpected slip.

Falls and injuries due to falls are a major health concern, and accidental slips are a leading cause of falls during gait. Understanding how the body reacts to an unexpected slip can aid in developing intervention techniques to reduce the number of injuries due to falls. In this study, muscle activation patterns, specifically those of the trailing (non-slipping) limb, were studied in unexpected slips of 24 young and 24 middle-aged adults.

Increased Depth and Breadth of Plasma Protein Quantitation via Two-Dimensional Liquid Chromatography/Multiple Reaction Monitoring-Mass Spectrometry with Labeled Peptide Standards.

Absolute quantitative strategies are emerging as a powerful and preferable means of deriving concentrations in biological samples for systems biology applications. Method development is driven by the need to establish new-and validate current-protein biomarkers of high-to-low abundance for clinical utility. In this chapter, we describe a methodology involving two-dimensional (2D) reversed-phase liquid chromatography (RPLC), operated under alkaline and acidic pH conditions, combined with multiple reaction monitoring (MRM)-mass spectrometry (MS) (also called selected reaction monitoring (SRM)-MS) and a complex mixture of stable isotope-labeled standard (SIS) peptides, to quantify a broad and diverse panel of 253 proteins in human blood plasma.

Central Gain Restores Auditory Processing following Near-Complete Cochlear Denervation.

Sensory organ damage induces a host of cellular and physiological changes in the periphery and the brain. Here, we show that some aspects of auditory processing recover after profound cochlear denervation due to a progressive, compensatory plasticity at higher stages of the central auditory pathway. Lesioning >95% of cochlear nerve afferent synapses, while sparing hair cells, in adult mice virtually eliminated the auditory brainstem response and acoustic startle reflex, yet tone detection behavior was nearly normal.