Carbohydrates are important but challenging targets for supramolecular chemists. They possess complex, irregular and variable structures, and are strongly attracted to water, their natural ...environment. This tutorial review describes work on synthetic receptors which bind carbohydrates through non-covalent interactions, mimicking the strategies used in biology. Emphasis is placed on systems which operate in purely aqueous solution, without involvement of organic solvents. Although the problem is difficult, the careful design of complementary cavities can lead to surprisingly good results. In particular, a receptor for glucose has achieved performance which generally matches biology, and augurs well for real-world applications.
The blood–brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are ...necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, and constituents of the extracellular matrix. This intricate relationship implies the existence of a neurovascular unit (NVU). NVU cellular components can be activated in disease and contribute to dynamic remodeling of the BBB. This is especially true of microglia, the resident immune cells of the brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate that M1 pro-inflammatory microglia contribute to BBB dysfunction and vascular “leak”, while M2 anti-inflammatory microglia play a protective role at the BBB. Understanding biological mechanisms involved in microglia activation provides a unique opportunity to develop novel treatment approaches for neurological diseases. In this review, we highlight characteristics of M1 proinflammatory and M2 anti-inflammatory microglia and describe how these distinct phenotypes modulate BBB physiology. Additionally, we outline the role of other NVU cell types in regulating microglial activation and highlight how microglia can be targeted for treatment of disease with a focus on ischemic stroke and Alzheimer’s disease.
Mechanistic roles for many lncRNAs are poorly understood, in part because their direct interactions with genomic loci and proteins are difficult to assess. Using a method to purify endogenous RNAs ...and their associated factors, we mapped the genomic binding sites for two highly expressed human lncRNAs, NEAT1 and MALAT1. We show that NEAT1 and MALAT1 localize to hundreds of genomic sites in human cells, primarily over active genes. NEAT1 and MALAT1 exhibit colocalization to many of these loci, but display distinct gene body binding patterns at these sites, suggesting independent but complementary functions for these RNAs. We also identified numerous proteins enriched by both lncRNAs, supporting complementary binding and function, in addition to unique associated proteins. Transcriptional inhibition or stimulation alters localization of NEAT1 on active chromatin sites, implying that underlying DNA sequence does not target NEAT1 to chromatin, and that localization responds to cues involved in the transcription process.
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•High-resolution genomic binding sites for the human lncRNAs NEAT1 and MALAT1•NEAT1 and MALAT1 exhibit distinct colocalized binding at active chromatin•Transcription impacts NEAT1 localization patterns•CHART-MS identifies proteins associated with endogenous RNAs in vivo
NEAT1 and MALAT1 are two of the most abundant mammalian lncRNAs. West et al. map the genomic binding of NEAT1 and MALAT1 and identify interacting proteins via RNA pull-down followed by mass spectrometry, showing these RNAs play a synergistic role in nuclear organization linking active genes and nuclear subdomains.
Neuronal diversity is essential for mammalian brain function but poses a challenge to molecular profiling. To address the need for tools that facilitate cell-type-specific epigenomic studies, we ...developed the first affinity purification approach to isolate nuclei from genetically defined cell types in a mammal. We combine this technique with next-generation sequencing to show that three subtypes of neocortical neurons have highly distinctive epigenomic landscapes. Over 200,000 regions differ in chromatin accessibility and DNA methylation signatures characteristic of gene regulatory regions. By footprinting and motif analyses, these regions are predicted to bind distinct cohorts of neuron subtype-specific transcription factors. Neuronal epigenomes reflect both past and present gene expression, with DNA hyper-methylation at developmentally critical genes appearing as a novel epigenomic signature in mature neurons. Taken together, our findings link the functional and transcriptional complexity of neurons to their underlying epigenomic diversity.
•Affinity purification of nuclei in mice enables cell-type-specific epigenomics•3 neuron types adopt unique landscapes of DNA methylation and accessible chromatin•Distinct TF sets are predicted to bind neuron type-specific gene regulatory regions•A hyper-methylation signature in adult neurons captures developmental history
Mo et al. develop a broadly applicable tool to purify genetically labeled nuclei in mice and, using genome-wide maps of gene expression, DNA methylation, and chromatin accessibility, show how three neuronal subtypes adopt distinct epigenomic configurations associated with function and development.
Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms
. However, an unbiased understanding of the cellular and ...molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease
. Synaptic signalling of upper-layer excitatory neurons-which are evolutionarily expanded in humans
and linked to cognitive function
-is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.
The blood-brain barrier (BBB) is a critical regulator of brain homeostasis. Additionally, the BBB is the most significant obstacle to effective CNS drug delivery. It possesses specific charcteristics ...(i.e., tight junction protein complexes, influx and efflux transporters) that control permeation of circulating solutes including therapeutic agents. In order to form this "barrier," brain microvascular endothelial cells require support of adjacent astrocytes and microglia. This intricate relationship also occurs between endothelial cells and other cell types and structures of the CNS (i.e., pericytes, neurons, extracellular matrix), which implies existence of a "neurovascular unit." Ischemic stroke can disrupt the neurovascular unit at both the structural and functional level, which leads to an increase in leak across the BBB. Recent studies have identified several pathophysiological mechanisms (i.e., oxidative stress, activation of cytokine-mediated intracellular signaling systems) that mediate changes in the neurovascular unit during ischemic stroke. This review summarizes current knowledge in this area and emphasizes pathways (i.e., oxidative stress, cytokine-mediated intracellular signaling, glial-expressed receptors/targets) that can be manipulated pharmacologically for i) preservation of BBB and glial integrity during ischemic stroke and ii) control of drug permeation and/or transport across the BBB. Targeting these pathways present a novel opportunity for optimization of CNS delivery of therapeutics in the setting of ischemic stroke.
Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological ...manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-β architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids, and realizing that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing. At the conclusion of a half century since Eanes and Glenner's seminal study of amyloids in humans, this review commemorates the occasion by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology. We also discuss new challenges and opportunities to drive this interdisciplinary field moving forward.
Nanoparticles have been successfully used for cancer drug delivery since 1995. In the design of commercial nanoparticles, size and surface characteristics have been exploited to achieve efficacious ...delivery. However, the design of optimized drug delivery platforms for efficient delivery to disease sites with minimal off-target effects remains a major research goal. One crucial element of nanoparticle design influencing both pharmacokinetics and cell uptake is nanoparticle morphology (both size and shape). In this succinct review, the authors collate the recent literature to assess the current state of understanding of the influence of nanoparticle shape on the effectiveness of drug delivery with a special emphasis on cancer therapy.
This review draws on studies that have focused on the role of nonspherical nanoparticles used for cancer drug delivery. In particular, the authors summarize the influence of nanoparticle shape on biocirculation, biodistribution, cellular uptake and overall drug efficacy. By comparing spherical and nonspherical nanoparticles, they establish some general design principles to serve as guidelines for developing the next generation of nanocarriers for drug delivery.
Pioneering studies on nanoparticles show that nonspherical shapes show great promise as cancer drug delivery vectors. Filamentous or worm-like micelles together with other rare morphologies such as needles or disks may become the norm for next-generation drug carriers, though at present, traditional spherical micelles remain the dominant shape of nanocarriers described in the literature due to synthesis and testing difficulties. The few reports that do exist describing nonspherical nanoparticles show a number of favorable properties that should encourage more efforts to develop facile and versatile nanoparticle synthesis methodologies with the flexibility to create different shapes, tunable sizes and adaptable surface chemistries. In addition, the authors note that there is a current lack of understanding into the factors governing (and optimizing) the inter-relationships of size, surface characteristics and shapes of many nanoparticles proposed for use in cancer therapy.
Precise modelling of the influence of climate change on Arabica coffee is limited; there are no data available for indigenous populations of this species. In this study we model the present and ...future predicted distribution of indigenous Arabica, and identify priorities in order to facilitate appropriate decision making for conservation, monitoring and future research. Using distribution data we perform bioclimatic modelling and examine future distribution with the HadCM3 climate model for three emission scenarios (A1B, A2A, B2A) over three time intervals (2020, 2050, 2080). The models show a profoundly negative influence on indigenous Arabica. In a locality analysis the most favourable outcome is a c. 65% reduction in the number of pre-existing bioclimatically suitable localities, and at worst an almost 100% reduction, by 2080. In an area analysis the most favourable outcome is a 38% reduction in suitable bioclimatic space, and the least favourable a c. 90% reduction, by 2080. Based on known occurrences and ecological tolerances of Arabica, bioclimatic unsuitability would place populations in peril, leading to severe stress and a high risk of extinction. This study establishes a fundamental baseline for assessing the consequences of climate change on wild populations of Arabica coffee. Specifically, it: (1) identifies and categorizes localities and areas that are predicted to be under threat from climate change now and in the short- to medium-term (2020-2050), representing assessment priorities for ex situ conservation; (2) identifies 'core localities' that could have the potential to withstand climate change until at least 2080, and therefore serve as long-term in situ storehouses for coffee genetic resources; (3) provides the location and characterization of target locations (populations) for on-the-ground monitoring of climate change influence. Arabica coffee is confimed as a climate sensitivite species, supporting data and inference that existing plantations will be neagtively impacted by climate change.
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