There is compelling evidence that the elevated plasma lipoprotein(a) Lp(a) levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low‐density ...lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL‐cholesterol (LDL‐C) is significantly elevated since birth. FH‐causing mutations in the LDL receptor gene demonstrate a clear gene‐dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30‐50% of patients with HeFH. The cumulative burden of two genetically determined pro‐atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA‐based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)‐lowering therapies prove to be safe and cost‐effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high‐risk patients even more than currently achieved with LDL‐C lowering alone.
Corticotropin-releasing hormone (CRH)-containing neurons in the paraventricular nucleus of the hypothalamus (PVN) initiate and control neuroendocrine responses to psychogenic and physical stress. ...Investigations into the physiology of CRH neurons, however, have been hampered by the lack of tools for adequately targeting or visualizing this cell population. Here we characterize CRH neurons in the PVN of mice that express tdTomato fluorophore, generated by crosses of recently developed Crh-IRES-Cre driver and Ai14 Cre-reporter mouse strains. tdTomato containing PVN neurons in Crh-IRES-Cre;Ai14 mice are readily visualized without secondary-detection methods. These neurons are predominantly neuroendocrine and abundantly express CRH protein, but not other PVN phenotypic neuropeptides. After an acute stress, a large majority of tdTomato cells express neuronal activation marker c-Fos. Finally, tdTomato PVN neurons exhibit homogenous intrinsic biophysical and synaptic properties, and can be optogenetically manipulated by viral Cre-driven expression of channelrhodopsin. These observations highlight basic cell-type characteristics of CRH neurons in a mutant mouse, providing validation for its future use in probing neurophysiology of endocrine stress responses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A review of Boundary and defect conformal field theory: open problems and applications, following a workshop held at Chicheley Hall, Buckinghamshire, UK, 7-8 Sept. 2017. We attempt to provide a ...broad, bird's-eye view of the latest progress in boundary and defect conformal field theory in various sub-fields of theoretical physics, including the renormalization group, integrability, conformal bootstrap, topological field theory, supersymmetry, holographic duality, and more. We also discuss open questions and promising research directions in each of these sub-fields, and combinations thereof.
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The high occurrence of atherosclerotic cardiovascular disease (ASCVD) events is still a major public health issue. Although a major determinant of ASCVD event reduction is the ...absolute change of low-density lipoprotein-cholesterol (LDL-C), considerable residual risk remains and new therapeutic options are required, in particular, to address triglyceride-rich lipoproteins and lipoprotein(a) Lp(a). In the era of Genome Wide Association Studies and Mendelian Randomization analyses aimed at increasing the understanding of the pathophysiology of ASCVD, RNA-based therapies may offer more effective treatment options. The advantage of oligonucleotide-based treatments is that drug candidates are targeted at highly specific regions of RNA that code for proteins that in turn regulate lipid and lipoprotein metabolism. For LDL-C lowering, the use of inclisiran - a silencing RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis - has the advantage that a single s.c. injection lowers LDL-C for up to 6 months. In familial hypercholesterolemia, the use of the antisense oligonucleotide (ASO) mipomersen, targeting apolipoprotein (apoB) to reduce LDL-C, has been a valuable therapeutic approach, despite unquestionable safety concerns. The availability of specific ASOs lowering Lp(a) levels will allow rigorous testing of the Lp(a) hypothesis; by dramatically reducing plasma triglyceride levels, Volanesorsen (APOC3) and angiopoietin-like 3 (ANGPTL3)-LRx will further clarify the causality of triglyceride-rich lipoproteins in ASCVD. The rapid progress to date heralds a new dawn in therapeutic lipidology, but outcome, safety and cost-effectiveness studies are required to establish the role of these new agents in clinical practice.
ABSTRACTThe purpose of this study was to determine if there was a relationship between tennis serve speed and isometric mid-thigh pull (IMTP) kinetic variables; countermovement jump height (CMJ ...Height), shoulder internal and external rotation strength and anthropometric measures in elite adolescent tennis players. Twenty-one elite junior tennis players from the Tennis Australia National Academy were recruited for this study (male, n = 12, female, n = 9). Correlations between the performance variables and peak tennis serve speed were calculated using a Pearson’s product-moment correlation coefficient. A significant positive correlation was found between peak serve speed and body height (r = 0.80, p < 0.01), IMTP peak force (r = 0.87, p < 0.01), CMJ Height (r = 0.77, p = < 0.01) and impulse at 300ms (r = 0.71, p = < 0.01). A significant, strong correlation was found between peak serve speed and impulse at 100ms (r = 0.58, p = < 0.01), impulse at 200ms (r = 0.64, p = < 0.01), internal rotation <90 (r = 0.63, p = < 0.01) and external rotation <90 (r = 0.63, p = < 0.01). Due to the significant positive correlations between IMTP variables, CMJ Height and peak serve speed, strength and conditioning coaches with access to a force plate should consider using the isometric mid-thigh pull in order to athletically profile athletes in regards to their strength, power and injury risk.
Summary Background As the epidemic of Zika virus expands in the Americas, countries across Africa and the Asia-Pacific region are becoming increasingly susceptible to the importation and possible ...local spread of the virus. To support public health readiness, we aim to identify regions and times where the potential health, economic, and social effects from Zika virus are greatest, focusing on resource-limited countries in Africa and the Asia-Pacific region. Methods Our model combined transportation network analysis, ecological modelling of mosquito occurrences, and vector competence for flavivirus transmission, using data from the International Air Transport Association, entomological observations from Zika's primary vector species, and climate conditions using WorldClim. We overlaid monthly flows of airline travellers arriving to Africa and the Asia-Pacific region from areas of the Americas suitable for year-round transmission of Zika virus with monthly maps of climatic suitability for mosquito-borne transmission of Zika virus within Africa and the Asia-Pacific region. Findings An estimated 2·6 billion people live in areas of Africa and the Asia-Pacific region where the presence of competent mosquito vectors and suitable climatic conditions could support local transmission of Zika virus. Countries with large volumes of travellers arriving from Zika virus-affected areas of the Americas and large populations at risk of mosquito-borne Zika virus infection include India (67 422 travellers arriving per year; 1·2 billion residents in potential Zika transmission areas), China (238 415 travellers; 242 million residents), Indonesia (13 865 travellers; 197 million residents), Philippines (35 635 travellers; 70 million residents), and Thailand (29 241 travellers; 59 million residents). Interpretation Many countries across Africa and the Asia-Pacific region are vulnerable to Zika virus. Strategic use of available health and human resources is essential to prevent or mitigate the health, economic, and social consequences of Zika virus, especially in resource-limited countries. Funding Canadian Institutes of Health Research and the US Centers for Disease Control and Prevention.
This review will examine our current knowledge of a fundamental property of CRH neuroendocrine neurons: how the major endpoint of the HPA axis—adrenal glucocorticoids—interacts with the mechanisms ...controlling the expression of the genes that encode ACTH secretogogues. A great deal of work over the past 25 years has led to the notion that this question has an ostensibly simple answer: glucocorticoids inhibit peptide gene expression using “negative feedback” at the CRH neuron and elsewhere. However, closely examining how glucocorticoids act in different physiological circumstances reveals a much more complex set of answers, particularly if we consider how the processes that control peptide synthesis and release are coupled. Out of this examination emerges a more flexible and complex framework for examining the integrative mechanisms controlling the CRH neuron. Although we will mostly focus on the
Crh gene, relevant aspects of the vasopressin (
Avp) and pro-enkephalin (
pEnk) gene regulatory mechanisms will also be discussed.
Abstract Glucose is the primary fuel for the vast majority of cells, and animals have evolved essential cellular, autonomic, endocrine, and behavioral measures to counteract both hypo- and ...hyperglycemia. A central component of these counterregulatory mechanisms is the ability of specific sensory elements to detect changes in blood glucose and then use that information to produce appropriate counterregulatory responses. Here we focus on the organization of the neural systems that are engaged by glucosensing mechanisms when blood glucose concentrations fall to levels that pose a physiological threat. We employ a classic sensory–motor integrative schema to describe the peripheral, hindbrain, and hypothalamic components that make up counterregulatory mechanisms in the brain. We propose that models previously developed to describe how the forebrain modulates autonomic reflex loops in the hindbrain offer a reasoned framework for explaining how counterregulatory neural mechanisms in the hypothalamus and hindbrain are structured.
A high-resolution spatial distribution analysis of hypothalamic neurons expressing melanin-concentrating hormone or hypocretin/orexin was performed in adult male rats with in situ hybridization ...cytochemistry. For the analysis, a new parcellation of the lateral zone with some two-dozen regions was used, and distributions were plotted on 15 transverse reference levels through the hypothalamus. Qualitatively the results confirm earlier, much lower resolution mapping studies, although some discrepancies are clarified. Previous work indicates that each of these cell populations is far from homogeneous, and the present results should help establish a framework for clarifying more precisely how they are differentiated and organized in terms of axonal input–output relationships and gene expression patterns, and for defining precise relationships with other hypothalamic neuron populations.
Competitive intelligence (CI) activities open new opportunities for firms to acquire and disclose information. We show that disclosure depends on the relative usefulness of information to the ...competing firms and is generally less (more) likely with Cournot (Bertrand) competition and when firms adopt product differentiation strategies. When CI costs are independent of information characteristics, each firm seeks. information solely useful to itself and discloses it unless it is a Bertrand competitor with customer information. Only when the cost advantage is sufficiently great does each firm seek information useful to itself and its rival.
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