Blastocystis is a genetically diverse intestinal protist colonizing both human and non-human hosts. By 2013, 17 subtypes had been acknowledged. Since then, nine more subtypes have been proposed. We ...argue that several recently proposed subtypes are invalid. We also revisit recommendations regarding the requirements for annotating sequences as new subtypes.
Allergen immunotherapy (AIT) has been in use for the treatment of allergic disease for more than 100 years. Asthma treatment relies mainly on corticosteroids and other controllers recommended to ...achieve and maintain asthma control, prevent exacerbations, and improve quality of life. AIT is underused in asthma, both in children and in adults. Notably, patients with allergic asthma not adequately controlled on pharmacotherapy (including biologics) represent an unmet health need. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence‐based recommendations for the use of house dust mites (HDM) AIT as add‐on treatment for HDM‐driven allergic asthma. This guideline was developed by a multi‐disciplinary working group using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. HDM AIT was separately evaluated by route of administration and children and adults: subcutaneous (SCIT) and sublingual AIT (SLIT), drops, and tablets. Recommendations were formulated for each. The important prerequisites for successful treatment with HDM AIT are (a) selection of patients most likely to respond to AIT and (b) use of allergen extracts and desensitization protocols of proven efficacy. To date, only AIT with HDM SLIT‐tablet has demonstrated a robust effect in adults for critical end points (exacerbations, asthma control, and safety). Thus, it is recommended as an add‐on to regular asthma therapy for adults with controlled or partially controlled HDM‐driven allergic asthma (conditional recommendation, moderate‐quality evidence). HDM SCIT is recommended for adults and children, and SLIT drops are recommended for children with controlled HDM‐driven allergic asthma as the add‐on to regular asthma therapy to decrease symptoms and medication needs (conditional recommendation, low‐quality evidence).
Light-controllable tools provide powerful means to manipulate and interrogate brain function with relatively low invasiveness and high spatiotemporal precision. Although optogenetic approaches permit ...neuronal excitation or inhibition at the network level, other technologies, such as optopharmacology (also known as photopharmacology) have emerged that provide molecular-level control by endowing light sensitivity to endogenous biomolecules. In this Review, we discuss the challenges and opportunities of photocontrolling native neuronal signalling pathways, focusing on ion channels and neurotransmitter receptors. We describe existing strategies for rendering receptors and channels light sensitive and provide an overview of the neuroscientific insights gained from such approaches. At the crossroads of chemistry, protein engineering and neuroscience, optopharmacology offers great potential for understanding the molecular basis of brain function and behaviour, with promises for future therapeutics.
Abstract Despite Blastocystis being one of the most widespread and prevalent intestinal eukaryotes, its role in health and disease remains elusive. DNA-based detection methods have led to a ...recognition that the organism is much more common than previously thought, at least in some geographic regions and some groups of individuals. Molecular methods have also enabled us to start categorizing the vast genetic heterogeneity that exists among Blastocystis isolates, wherein the key to potential differences in the clinical outcome of Blastocystis carriage may lie. In this review we summarize some of the recent developments and advances in Blastocystis research, including updates on diagnostic methods, molecular epidemiology, genetic diversity, host specificity, clinical significance, taxonomy, and genomics. As we are now in the microbiome era, we also review some of the steps taken towards understanding the place of Blastocystis in the intestinal microbiota.
γ-aminobutyric acid-mediated (GABAergic) inhibition plays a critical role in shaping neuronal activity in the neocortex. Numerous experimental investigations have examined perisomatic inhibitory ...synapses, which control action potential output from pyramidal neurons. However, most inhibitory synapses in the neocortex are formed onto pyramidal cell dendrites, where theoretical studies suggest they may focally regulate cellular activity. The precision of GABAergic control over dendritic electrical and biochemical signaling is unknown. By using cell type-specific optical stimulation in combination with two-photon calcium (Ca²⁺) imaging, we show that somatostatin-expressing interneurons exert compartmentalized control over postsynaptic Ca²⁺ signals within individual dendritic spines. This highly focal inhibitory action is mediated by a subset of GABAergic synapses that directly target spine heads. GABAergic inhibition thus participates in localized control of dendritic electrical and biochemical signaling.
The ambient metric Fefferman, Charles; Graham, C. Robin
2012., 20111114, 2011, 2012-01-01, Volume:
178
eBook
This book develops and applies a theory of the ambient metric in conformal geometry. This is a Lorentz metric in n+2 dimensions that encodes a conformal class of metrics in n dimensions. The ambient ...metric has an alternate incarnation as the Poincaré metric, a metric in n+1 dimensions having the conformal manifold as its conformal infinity. In this realization, the construction has played a central role in the AdS/CFT correspondence in physics.
Conspectus Light has been instrumental in the study of living cells since its use helped in their discovery in the late 17th century. Further, combining chemical technology with light microscopy was ...an essential part of the Nobel Prize for Physiology in 1906. Such landmark scientific findings involved passive observation of cells. However, over the past 50 years, a “second use” of light has emerged in cell physiology, namely one of rational control. The seminal method for this emerged in late 1970s with the invention of caged compounds. This was the point when “caged compounds” were defined as optical probes in which the active functionality of a physiological signaling molecule was blocked with a photochemical protecting group. Caged compounds are analogous to prodrugs; in both, the activity of the effector is latent. However, caged compounds, unlike prodrugs, use a trigger that confers the power of full temporal and spatial manipulation of the effects of release of its latent biological cargo. Light is distinct because it is bio-orthogonal, passes through living tissue (even into the cell interior), and initiates rapid release of the “caged” biomolecule. Further, because light can be directed to broad areas or focused to small points, caged compounds offer an array of timing scenarios for physiologists to dissect virtually any type of cellular process. The collaborative interaction between chemists and physiologists plays a fundamental role in the development of caged compounds. First, the physiologists must define the problem to be addressed; then, with the help of chemists, decide if a caged compound would be useful. For this, structure–activity relationships of the potential optical probe and receptor must be determined. If rational targets seem feasible, synthetic organic chemistry is used to make the caged compound. The crucial property of prephotolysis bio-inertness relies on physiological or biochemical assays. Second, detailed optical characterization of the caged compound requires the skill of photochemists because the rate and efficiency of uncaging are also crucial properties for a useful caged compound. Often, these studies reveal limitations in the caged compound which has been developed; thus, chemists and physiologists use their abilities for iterative development of even more powerful optical probes. A similar dynamic will be familiar to scientists in the pharmaceutical industry. Therefore, caged compound development provides an excellent training framework for (young) chemists both intellectually and professionally. In this Account, I draw on my long experience in the field of making useful caged compounds for cell physiology by showing how each probe I have developed has been defined by an important physiological problem. Fundamental to this process has been my initial training by the pioneers in aromatic photochemistry, Derek Bryce-Smith and Andrew Gilbert. I discuss making a range of “caged calcium” probes, ones which went on to be the most widely used of all caged compounds. Then, I describe the development of caged neurotransmitters for two-photon uncaging microscopy. Finally, I survey recent work on making new photochemical protecting groups for wavelength orthogonal, two-color, and ultraefficient two-photon uncaging.
Light passes through biological tissue, and so it is used for imaging biological processes in situ. Such observation is part of the very essence of science, but mechanistic understanding requires ...intervention. For more than 50 years a “second function” for light has emerged; namely, that of photochemical control. Caged compounds are biologically inert signaling molecules that are activated by light. These optical probes enable external instruction of biological processes by stimulation of an individual element in complex signaling cascades in its native environment. Cause and effect are linked directly in spatial, temporal, and frequency domains in a quantitative manner by their use. I provide a guide to the basic properties required to make effective caged compounds for the biological sciences.
Caged compounds are optical probes in which biological signaling molecules are rendered inert by attachment of a photosensitive protecting group (PPG). Following Wittgenstein's dictum “Meaning is use”, the key features of such probes are deduced by consideration of the properties of the most widely used caged compounds that have been successfully applied to test numerous biological hypotheses.
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