The dorsal horn of the spinal cord is critical to processing distinct modalities of noxious and innocuous sensation, but little is known of the neuronal subtypes involved, hampering efforts to deduce ...principles governing somatic sensation. Here we used single-cell RNA sequencing to classify sensory neurons in the mouse dorsal horn. We identified 15 inhibitory and 15 excitatory molecular subtypes of neurons, equaling the complexity in cerebral cortex. Validating our classification scheme in vivo and matching cell types to anatomy of the dorsal horn by spatial transcriptomics reveals laminar enrichment for each of the cell types. Neuron types, when combined, define a multilayered organization with like neurons layered together. Employing our scheme, we find that heat and cold stimuli activate discrete sets of both excitatory and inhibitory neuron types. This work provides a systematic and comprehensive molecular classification of spinal cord sensory neurons, enabling functional interrogation of sensory processing.
Abstract
The excellent optoelectronic performance of lead halide perovskites has generated great interest in their fundamental properties. The polar nature of the perovskite lattice means that ...electron-lattice coupling is governed by the Fröhlich interaction. Still, considerable ambiguity exists regarding the phonon modes that participate in this crucial mechanism. Here, we use multiphonon Raman scattering and THz time-domain spectroscopy to investigate Fröhlich coupling in CsPbBr
3
. We identify a longitudinal optical phonon mode that dominates the interaction, and surmise that this mode effectively defines exciton-phonon scattering in CsPbBr
3
, and possibly similar materials. It is additionally revealed that the observed strength of the Fröhlich interaction is significantly higher than the expected intrinsic value for CsPbBr
3
, and is likely enhanced by carrier localization in the colloidal perovskite nanocrystals. Our experiments also unearthed a dipole-related dielectric relaxation mechanism which may impact transport properties.
Relative abundances of bacterial species in the gut microbiome have been linked to many diseases. Species of gut bacteria are ecologically differentiated by their abilities to metabolize different ...glycans, making glycan delivery a powerful way to alter the microbiome to promote health. Here, we study the properties and therapeutic potential of chemically diverse synthetic glycans (SGs). Fermentation of SGs by gut microbiome cultures results in compound-specific shifts in taxonomic and metabolite profiles not observed with reference glycans, including prebiotics. Model enteric pathogens grow poorly on most SGs, potentially increasing their safety for at-risk populations. SGs increase survival, reduce weight loss, and improve clinical scores in mouse models of colitis. Synthetic glycans are thus a promising modality to improve health through selective changes to the gut microbiome.
The gut microbiota (GM) consists of resident commensals and transient microbes conveyed by the diet but little is known about the role of the latter on GM homeostasis. Here we show, by a conjunction ...of quantitative metagenomics, in silico genome reconstruction and metabolic modeling, that consumption of a fermented milk product containing dairy starters and Bifidobacterium animalis potentiates colonic short chain fatty acids production and decreases abundance of a pathobiont Bilophila wadsworthia compared to a milk product in subjects with irritable bowel syndrome (IBS, n = 28). The GM changes parallel improvement of IBS state, suggesting a role of the fermented milk bacteria in gut homeostasis. Our data challenge the view that microbes ingested with food have little impact on the human GM functioning and rather provide support for beneficial health effects.
Rationale
The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on ...which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets.
Objective
The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms.
Method
Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions.
Results
The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity.
Conclusions
ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.
As supply chain risks refer to the risks transmitted among supply chain members and supply chain management (SCM) is concerned with close collaboration among chain members to enhance the chain׳s ...overall performance, we argue that we need to use an SCM perspective in supply chain risk management (SCRM). We identify risk information sharing and risk sharing mechanism as two important joint SCRM practices. Drawing on the literature on agency theory and collaborative relationships, we argue that the effectiveness of these two joint practices in improving financial performance can be strengthened by collaborative relationship characteristics including relationship length, supplier trust, and shared SCRM understanding. We empirically test our conceptual model using the data collected from 350 manufacturing firms in China. The results suggest that both risk information sharing and risk sharing mechanism improve financial performance, and the effectiveness of the former is strengthened by relationship length and supplier trust, while that of the latter is strengthened by shared SCRM understanding. We contribute to research and practice by identifying two useful joint SCRM practices and ascertaining the conditions under which each of the practices is particularly effectively.
Establishment of a proper chromatin landscape is central to genome function. Here, we explain H3 variant distribution by specific targeting and dynamics of deposition involving the CAF-1 and HIRA ...histone chaperones. Impairing replicative H3.1 incorporation via CAF-1 enables an alternative H3.3 deposition at replication sites via HIRA. Conversely, the H3.3 incorporation throughout the cell cycle via HIRA cannot be replaced by H3.1. ChIP-seq analyses reveal correlation between HIRA-dependent H3.3 accumulation and RNA pol II at transcription sites and specific regulatory elements, further supported by their biochemical association. The HIRA complex shows unique DNA binding properties, and depletion of HIRA increases DNA sensitivity to nucleases. We propose that protective nucleosome gap filling of naked DNA by HIRA leads to a broad distribution of H3.3, and HIRA association with Pol II ensures local H3.3 enrichment at specific sites. We discuss the importance of this H3.3 deposition as a salvage pathway to maintain chromatin integrity.
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► Failure in H3.1 deposition at replication sites permits replacement by H3.3 via HIRA ► RNA pol II presence correlates with H3.3 enrichment at genes and associates with HIRA ► DNA binding ability of HIRA reveals a gap-filling mechanism for H3.3 deposition ► HIRA-dependent H3.3 deposition as a salvage pathway to maintain chromatin integrity
Land‐based enhanced rock weathering (ERW) is a biogeochemical carbon dioxide removal (CDR) strategy aiming to accelerate natural geological processes of carbon sequestration through application of ...crushed silicate rocks, such as basalt, to croplands and forested landscapes. However, the efficacy of the approach when undertaken with basalt, and its potential co‐benefits for agriculture, require experimental and field evaluation. Here we report that amending a UK clay‐loam agricultural soil with a high loading (10 kg/m2) of relatively coarse‐grained crushed basalt significantly increased the yield (21 ± 9.4%, SE) of the important C4 cereal Sorghum bicolor under controlled environmental conditions, without accumulation of potentially toxic trace elements in the seeds. Yield increases resulted from the basalt treatment after 120 days without P‐ and K‐fertilizer addition. Shoot silicon concentrations also increased significantly (26 ± 5.4%, SE), with potential benefits for crop resistance to biotic and abiotic stress. Elemental budgets indicate substantial release of base cations important for inorganic carbon removal and their accumulation mainly in the soil exchangeable pools. Geochemical reactive transport modelling, constrained by elemental budgets, indicated CO2 sequestration rates of 2–4 t CO2/ha, 1–5 years after a single application of basaltic rock dust, including via newly formed soil carbonate minerals whose long‐term fate requires assessment through field trials. This represents an approximately fourfold increase in carbon capture compared to control plant–soil systems without basalt. Our results build support for ERW deployment as a CDR technique compatible with spreading basalt powder on acidic loamy soils common across millions of hectares of western European and North American agriculture.
Amending a UK clay‐loam agricultural soil with a high loading (10 kg/m2) of relatively coarse‐grained crushed basalt significantly increased the yield (21 ± 9.4%) of the important C4 cereal Sorghum bicolor under controlled environmental conditions, without accumulation of potentially toxic trace elements in the seeds, and CO2 sequestration potential.
Systemic hypertension increases cardiac workload causing cardiomyocyte hypertrophy and increased cardiac fibrosis. An underlying feature is increased production of reactive oxygen species. ...Redox-sensitive ASK1 (apoptosis signal-regulating kinase 1) activates stress-regulated protein kinases (p38-MAPK mitogen-activated protein kinases and JNKs c-Jun N-terminal kinases) and promotes fibrosis in various tissues. Here, we determined the specificity of ASK1 signaling in the heart, with the hypothesis that ASK1 inhibitors may be used to manage fibrosis in hypertensive heart disease. Using immunoblotting, we established that moderate levels of H
O
activate ASK1 in neonatal rat cardiomyocytes and perfused rat hearts. ASK1 was activated during ischemia in adult rat hearts, but not on reperfusion, consistent with activation by moderate (not high) reactive oxygen species levels. In contrast, IL (interleukin)-1β activated an alternative kinase, TAK1 (transforming growth factor-activated kinase 1). ASK1 was not activated by IL1β in cardiomyocytes and activation in perfused hearts was due to increased reactive oxygen species. Selonsertib (ASK1 inhibitor) prevented activation of p38-MAPKs (but not JNKs) by oxidative stresses in cultured cardiomyocytes and perfused hearts. In vivo (C57Bl/6J mice with osmotic minipumps for drug delivery), selonsertib (4 mg/kg·d) alone did not affect cardiac function/dimensions (assessed by echocardiography). However, it suppressed hypertension-induced cardiac hypertrophy resulting from angiotensin II (0.8 mg/kg·d, 7d), with inhibition of
mRNA upregulation, reduced cardiomyocyte hypertrophy and, notably, significant reductions in interstitial and perivascular fibrosis. Our data identify a specific reactive oxygen species→ASK1→p38-MAPK pathway in the heart and establish that ASK1 inhibitors protect the heart from hypertension-induced cardiac remodeling. Thus, targeting the ASK1→p38-MAPK nexus has potential therapeutic viability as a treatment for hypertensive heart disease.
Abstract
The concept of ‘natural selection’, as proposed in The Origin of Species (published in 1859), refers to the better known of Charles Darwin’s two distinct theories of evolution. Darwin’s ...other theory was originally associated with his predecessor, Jean-Baptiste de Lamarck. (Darwin used the shorthand phrase, the ‘use and disuse of parts’, to characterize this alternative theory.) Lamarck’s theory was rejected (and even mocked) by many 20th century theorists, who instead adopted a gene-centred, one-way, bottom-up model of evolutionary change, called the modern synthesis. (It has also been termed neo-Darwinism.) Darwin was more receptive to Lamarck’s approach, and in his second great work, The Descent of Man (published in 1874), he applied this Lamarckian theory particularly to human evolution. He ascribed our remarkable evolutionary success to our behaviour: social cooperation, innovation (and tools), morality and cumulative culture. Neo-Darwinists called it Darwin’s biggest mistake. However, an ever-increasing body of evidence, inclusive of cultural phenomena in many other species, suggests that it was, in fact, their mistake. Often called gene–culture co-evolution theory, the reverse order (as used here) might be a better way of characterizing the underlying causal dynamics. The ‘purposeful’ behaviour (teleonomy) of living systems has exerted a major influence on the trajectory of biological evolution.
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