Spontaneous neuronal activity is spatiotemporally structured, influencing brain computations. Nevertheless, the neuronal interactions underlying these spontaneous activity patterns, and their ...biological relevance, remain elusive. Here, we addressed these questions using two-photon calcium imaging of intact zebrafish larvae to monitor the neuron-to-neuron spontaneous activity fine structure in the tectum, a region involved in visual spatial detection. Spontaneous activity was organized in topographically compact assemblies, grouping functionally similar neurons rather than merely neighboring ones, reflecting the tectal retinotopic map despite being independent of retinal drive. Assemblies represent all-or-none-like sub-networks shaped by competitive dynamics, mechanisms advantageous for visual detection in noisy natural environments. Notably, assemblies were tuned to the same angular sizes and spatial positions as prey-detection performance in behavioral assays, and their spontaneous activation predicted directional tail movements. Therefore, structured spontaneous activity represents “preferred” network states, tuned to behaviorally relevant features, emerging from the circuit’s intrinsic non-linear dynamics, adapted for its functional role.
•Spontaneous functional assemblies reflect the tectal retinotopic map•Assemblies can be spontaneously engaged independently of retinal drive•Assemblies are all-or-none preferred states shaped by inhibitory competition•Assemblies are tuned to features relevant for a tectal-dependent vital behavior
The brain spontaneously produces activity patterns. Romano et al. show that this ongoing activity in a sensory brain area reflects neuronal mechanisms that assure robust circuit functioning for the extraction of behaviorally relevant sensory information.
Multicomponent reactions have become increasingly popular as tools for the rapid generation of small‐molecule libraries. However, to ensure sufficient molecular diversity and complexity, there is a ...continuous need for novel reactions. Although serendipity has always played an important role in the discovery of novel (multicomponent) reactions, rational design strategies have become much more important over the past decade. In this Review, we present an overview of general strategies that allow the design of novel multicomponent reactions. The challenges and opportunities for the future will be discussed.
MCRs à la carte: Multicomponent reactions have become essential tools for the rapid generation of molecular complexity and diversity in chemical biology and drug discovery. These reactions are often discovered by serendipity, but rational design strategies are now playing an increasing role. Several such strategies are discussed in this Review.
Isocyanides have been important building blocks in organic synthesis since the discovery of the Ugi reaction and related isocyanide‐based multicomponent reactions. In the past decade isocyanides have ...found a new application as versatile C1 building blocks in palladium catalysis. Palladium‐catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen‐containing fine chemicals. This Minireview discusses all the achievements in this emerging field.
R you in? Isocyanides (R‐NC) have recently gained attention as novel, versatile C1 building blocks in palladium catalysis. This Minireview highlights the recent progress in palladium‐catalyzed reactions involving isocyanide insertion (imidoylative cross‐couplings), thus illustrating their potential for the rapid construction of a variety of heterocycles and functional groups.
Monoterpenoid indole alkaloids are the major class of tryptamine‐derived alkaloids found in nature. Together with their structural complexity, this has attracted great interest from synthetic organic ...chemists. In this Review, the syntheses of Aspidosperma and Strychnos alkaloids through dearomatization of indoles are discussed.
Dearomatization strategy: Aspidosperma‐ and Strychnos‐type alkaloids have been attractive targets for natural product synthesis due to their challenging structures. Inspired by nature, many dearomatization strategies have been reported over the past seven decades. Nevertheless, this field has maintained substantial interest and, therefore, it is important to provide a comprehensive historical perspective, which presents an essential guideline for the future of this field.
Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test ...concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity.
The development of new imaging and optogenetics techniques to study the dynamics of large neuronal circuits is generating datasets of unprecedented volume and complexity, demanding the development of ...appropriate analysis tools. We present a comprehensive computational workflow for the analysis of neuronal population calcium dynamics. The toolbox includes newly developed algorithms and interactive tools for image pre-processing and segmentation, estimation of significant single-neuron single-trial signals, mapping event-related neuronal responses, detection of activity-correlated neuronal clusters, exploration of population dynamics, and analysis of clusters' features against surrogate control datasets. The modules are integrated in a modular and versatile processing pipeline, adaptable to different needs. The clustering module is capable of detecting flexible, dynamically activated neuronal assemblies, consistent with the distributed population coding of the brain. We demonstrate the suitability of the toolbox for a variety of calcium imaging datasets. The toolbox open-source code, a step-by-step tutorial and a case study dataset are available at https://github.com/zebrain-lab/Toolbox-Romano-et-al.
Base Metal Catalyzed Isocyanide Insertions Collet, Jurriën W.; Roose, Thomas R.; Ruijter, Eelco ...
Angewandte Chemie International Edition,
January 7, 2020, Letnik:
59, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Isocyanides are diverse C1 building blocks considering their potential to react with nucleophiles, electrophiles, and radicals. Therefore, perhaps not surprisingly, isocyanides are highly valuable as ...inputs for multicomponent reactions (MCRs) and other one‐pot cascade processes. In the field of organometallic chemistry, isocyanides typically serve as ligands for transition metals. The coordination of isocyanides to metal centers alters the electronic distribution of the isocyano moiety, and reaction pathways can therefore be accessed that are not possible in the absence of the metal. The tunable reactivity of the isocyanide functional group by transition metals has evolved into numerous useful applications. Especially palladium‐catalyzed isocyanide insertion processes have emerged as powerful reactions in the past decade. However, reports on the use of earth‐abundant and cheap base metals in these types of transformations are scarce and have received far less attention. In this Minireview, we focus on these emerging base metal catalyzed reactions and highlight their potential in synthetic organic chemistry. Although mechanistic studies are still scarce, we discuss distinct proposed catalytic cycles and categorize the literature according to 1) the (hetero)atom bound to and 2) the type of bonding with the transition metal in which the (formal) insertion occurs.
Back to basics: Base metal catalyzed processes involving isocyanide insertion have recently evolved as promising cross‐coupling reactions. While mechanistic studies are still scarce, proposed catalytic cycles are discussed in this Minireview and the literature is categorized accordingly. This should facilitate the development of new processes to efficiently assemble high added‐value compounds.
Positron emission tomography (PET) is an important driver for present day healthcare. Fluorine-18 is the most widely used radioisotope for PET imaging and a thorough overview of the available ...radiochemistry methodology is a prerequisite for selection of a synthetic approach for new fluorine-18 labelled PET tracers. These PET tracers can be synthesised either by late-stage radiofluorination, introducing fluorine-18 in the last step of the synthesis, or by a building block approach (also called modular build-up approach), introducing fluorine-18 in a fast and efficient manner in a building block, which is reacted further in one or multiple reaction steps to form the PET tracer. This review presents a comprehensive overview of the synthesis and application of fluorine-18 labelled building blocks since 2010.
Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in ...the liver to trimethylamine-N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA-producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans.
Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and increased trimethylamine N-oxide (TMAO) levels have been causally linked with CVD development. This work identifies members of the human gut microbiota responsible for both the accumulation of trimethylamine (TMA), the precursor of the proatherogenic compound TMAO, and subsequent decreased choline bioavailability to the host. Understanding how to manipulate the representation and function of choline-consuming, TMA-producing species in the intestinal microbiota could potentially lead to novel means for preventing or treating atherosclerosis and choline deficiency-associated diseases.
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