The meninges host a unique compartment of regulatory T cells that bulwarks adult hippocampal neurogenesis.

Our knowledge about the meningeal immune system has recently burgeoned, particularly our understanding of how innate and adaptive effector cells are mobilized to meet brain challenges. However, information on how meningeal immunocytes guard brain homeostasis in healthy individuals remains sparse. This study highlights the heterogeneous and polyfunctional regulatory-T (Treg) cell compartment in the meninges. A Treg subtype specialized in controlling Th1-cell responses and another known to control responses in B-cell follicles were substantial components of this compartment, foretelling that punctual Treg-cell ablation rapidly unleashed interferon-gamma production by meningeal lymphocytes, unlocked their access to the brain parenchyma, and altered meningeal B-cell profiles. Distally, the hippocampus assumed a reactive state, with morphological and transcriptional changes in multiple glial-cell types; within the dentate gyrus, neural stem cells showed exacerbated death and desisted from further differentiation, associated with inhibition of spatial-reference memory. Thus, meningeal Treg cells are a multifaceted bulwark to brain homeostasis at steady-state. One sentence summary: A distinct population of regulatory T cells in the murine meninges safeguards homeostasis by keeping local interferon-γ-producing lymphocytes in check, thereby preventing their invasion of the parenchyma, activation of hippocampal glial cells, death of neural stem cells, and memory decay.

Shifts in receptors during submergence of an encephalitic arbovirus.

Western equine encephalitis virus (WEEV) is an arthropod-borne virus (arbovirus) that frequently caused major outbreaks of encephalitis in humans and horses in the early twentieth century, but the frequency of outbreaks has since decreased markedly, and strains of this alphavirus isolated in the past two decades are less virulent in mammals than strains isolated in the 1930s and 1940s1-3. The basis for this phenotypic change in WEEV strains and coincident decrease in epizootic activity (known as viral submergence3) is unclear, as is the possibility of re-emergence of highly virulent strains. Here we identify protocadherin 10 (PCDH10) as a cellular receptor for WEEV. We show that multiple highly virulent ancestral WEEV strains isolated in the 1930s and 1940s, in addition to binding human PCDH10, could also bind very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), which are recognized by another encephalitic alphavirus as receptors4. However, whereas most of the WEEV strains that we examined bind to PCDH10, a contemporary strain has lost the ability to recognize mammalian PCDH10 while retaining the ability to bind avian receptors, suggesting WEEV adaptation to a main reservoir host during enzootic circulation. PCDH10 supports WEEV E2-E1 glycoprotein-mediated infection of primary mouse cortical neurons, and administration of a soluble form of PCDH10 protects mice from lethal WEEV challenge. Our results have implications for the development of medical countermeasures and for risk assessment for re-emerging WEEV strains.

Physicochemical properties of edible cricket oils: Implications for use in pharmaceutical and food industries.

The prevailing global market demands locally produced, sustainable oils for biomedical applications. This study focused on evaluating the quality of cricket-derived oils and meals from Scapsipedus icipe Hugel, Tanga, and Gryllus bimaculatus De Geer common delicacy in Africa, following standard methods for physicochemical properties, fatty acid composition, and phytochemicals (oxalates, phytates, tannins, and polyphenols). The cricket oils physicochemical properties aligned with Codex Alimentarius standards for edible oils, including low solidification temperature (< 2 °C), a high refractive index (1.46), and a specific gravity of 0.88. Notably, peroxide values (1.9 to 2.5 mg mEq O2/kg), acid values (1.1 to 2.2 mg KOH/g), and saponification values (234-246 mg KOH/g) all are indicative of lightness and unsaturated fatty acids. Nutritionally, cricket powder was rich in protein (56.8-56.9% -) and fat (31.7-33.5% -of dry matter), with significant amounts of essential omega-3 and omega-6 fatty acids. Predominant saturated and monounsaturated fatty acids were palmitic (23.9-31.2 mg/100 g-) and oleic acids (10.9-11.4 mg/100 g- of oil), respectively. Antioxidant values (48.0 to 65.0 mg/100 g), inferred from total polyphenols, suggests a stable oil with long shelf-life. These results highlight the promising and sustainable potential of cricket-derived oils for applications in the food and pharmaceutical industries.

Neuroimmune Interactions in the Intestine.

Recent advances have contributed to a mechanistic understanding of neuroimmune interactions in the intestine and revealed an essential role of this cross talk for gut homeostasis and modulation of inflammatory and infectious intestinal diseases. In this review, we describe the innervation of the intestine by intrinsic and extrinsic neurons and then focus on the bidirectional communication between neurons and immune cells. First, we highlight the contribution of neuronal subtypes to the development of colitis and discuss the different immune and epithelial cell types that are regulated by neurons via the release of neuropeptides and neurotransmitters. Next, we review the role of intestinal inflammation in the development of visceral hypersensitivity and summarize how inflammatory mediators induce peripheral and central sensitization of gut-innervating sensory neurons. Finally, we outline the importance of immune cells and gut microbiota for the survival and function of different neuronal populations at homeostasis and during bacterial and helminth infection.

Elucidating the Mechanism of Efficient Eu(III) and Yb(III) Sensitisation from a Re(I) Tetrazolato Triangular Assembly.

The reaction of Re(CO)5Br with deprotonated 1H-(5-(2,2':6',2''-terpyridine)pyrid-2-yl)tetrazole yields a triangular assembly formed by tricarbonyl Re(I) vertices. Photophysical measurements reveal blue-green emission with a maximum at 520 nm, 32% quantum yield, and 2430 ns long-lived excited state decay lifetime in deaerated dichloromethane solution. Coordination of lanthanoid ions to the terpyridine units red-shifts the emission to 570 nm and also reveals efficient (90%) and fast sensitisation to both Eu(III) and Yb(III) at room temperature, with a similar rate constant kET of the order of 107 s-1. Efficient sensitisation of Eu(III) from Re(I) is unprecedented, especially when considering the close proximity in energy between the donor and acceptor excited states. On the other hand, comparative measurements at 77 K reveal that energy transfer to Yb(III) is two orders of magnitude slower than that to Eu(III). A two-step mechanism of sensitisation is therefore proposed, whereby the rate-determining step is a thermally activated energy transfer step between the Re(I) centre and the terpyridine functionality, followed by rapid energy transfer to the respective Ln(III) excited states. At 77 K, the direct Re(I) to Eu(III) energy transfer seems to proceed via a ligand-mediated superexchange Dexter-type mechanism.

Multi-response deconvolution of auditory evoked potentials in a reduced representation space.

The estimation of auditory evoked potentials requires deconvolution when the duration of the responses to be recovered exceeds the inter-stimulus interval. Based on least squares deconvolution, in this article we extend the procedure to the case of a multi-response convolutional model, that is, a model in which different categories of stimulus are expected to evoke different responses. The computational cost of the multi-response deconvolution significantly increases with the number of responses to be deconvolved, which restricts its applicability in practical situations. In order to alleviate this restriction, we propose to perform the multi-response deconvolution in a reduced representation space associated with a latency-dependent filtering of auditory responses, which provides a significant dimensionality reduction. We demonstrate the practical viability of the multi-response deconvolution with auditory responses evoked by clicks presented at different levels and categorized according to their stimulation level. The multi-response deconvolution applied in a reduced representation space provides the least squares estimation of the responses with a reasonable computational load. matlab/Octave code implementing the proposed procedure is included as supplementary material.

Speciation and Reactivity of Mono- and Binuclear Ni Intermediates in Aminoquinoline-Directed C-H Arylation and Benzylation.

This paper describes detailed organometallic studies of the aminoquinoline-directed Ni-catalyzed C-H functionalization of 2,3,4,5-tetrafluoro-N-(quinolin-8-yl)benzamide with diaryliodonium reagents. A combination of 19F NMR spectroscopy and X-ray crystallography is used to track and characterize diamagnetic and paramagnetic intermediates throughout this transformation. These provide key insights into both the cyclometalation and oxidative functionalization steps of the catalytic cycle. The reaction conditions (solvent, ligands, base, and stoichiometry) play a central role in the observation of a NiII precyclometalation intermediate as well as in the speciation of the NiII products of C-H activation. Both mono- and binuclear cyclometalated NiII species are observed and interconvert, depending on the reaction conditions. Cyclic voltammetry reveals that the NiII/III redox potentials for the cyclometalated intermediates vary by more than 700 mV depending on their coordination environments, and these differences are reflected in their relative reactivity with diaryliodonium oxidants. The oxidative functionalization reaction affords a mixture of arylated and solvent functionalization organic products, depending on the conditions and solvent. For example, conducting oxidation in toluene leads to the preferential formation of the benzylated product. A series of experiments implicate a NiII/III/IV pathway for this transformation.

B0-insensitive image navigators for prospective motion-corrected MRS with localized second-order shimming.

PURPOSE: Localized shimming in single-voxel MRS often results in large B0 inhomogeneity outside the volume-of-interest. This causes unacceptable degradation in motion navigator images. Switching back and forth between whole-brain shim and localized shim is possible for linear shims, but not for higher-order shims. Here we propose motion navigators largely insensitive to B0 inhomogeneity for prospective motion-corrected MRS with localized higher-order shimming. METHODS: A recent fast high-resolution motion navigator based on spiral-in/out k-space trajectories and multislice-to-volume registration was modified by splitting the readout into multiple shot interleaves which shortened the echo time and reduced the effect of B0 inhomogeneity. The performance of motion correction was assessed in healthy subjects in the prefrontal cortex using a sLASER sequence at 3T (N = 5) and 7T (N = 5). RESULTS: With multiple spatial interleaves, excellent quality navigator images were acquired in the whole brain in spite of large B0 inhomogeneity outside the MRS voxel. The total duration of the navigator in sLASER remained relatively short even with multiple shots (3T: 10 spatial interleaves 94 ms per slice; 7T: 15 spatial interleaves 103 ms per slice). Prospective motion correction using the multi-shot navigators yielded comparable spectral quality (water linewidth and metabolite SNR) with and without subject motion. CONCLUSION: B0-insensitive motion navigators enable prospective motion correction for MRS with all first- and second-order shims adjusted in the MRS voxel, providing optimal spectral linewidth.

Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice.

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-ß response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.

A Comprehensive Review of Ethnomedicinal Uses, Phytochemistry, Pharmacology, and Toxicity of Prunus africana (Hook. F.) Kalkman from Africa.

Prunus africana, a widely utilized medicinal plant in various African ethnic communities, continues to hold significant importance in traditional healing practices. Research has identified phytochemical compounds in this plant, exhibiting diverse pharmacological activities that offer potential for pharmaceutical development. Notably, P. africana is employed in treating various ailments such as wounds, diabetes mellitus, malaria, benign prostatic hyperplasia, chest pain, and prostate cancer. Its pharmacological properties are attributed to a spectrum of bioactive compounds, including tannins, saponins, alkaloids, flavonoids, terpenoids, phytosterols, and fatty acids. Multiple studies have documented the anti-inflammatory, antimicrobial, antiandrogenic, antiangiogenic, antioxidant, antidipeptidyl peptidase-4 activity, analgesic, and astringent properties of P. africana extracts. This review offers a comprehensive compilation of ethnomedicinal applications, phytochemical composition, pharmacological effects, and toxicity assessments of P. africana, serving as a foundation for future preclinical and clinical investigations. By understanding its traditional uses and chemical constituents, researchers can target specific medical conditions with greater precision, potentially expediting the development of safe and effective pharmaceuticals. Moreover, toxicity assessments provide crucial insights into the safety profile of P. africana extracts, ensuring the development of safe pharmaceuticals to treat various diseases.

Sensory neurons: An integrated component of innate immunity.

The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate immunity.

Rosacea Core Domain Set for Clinical Trials and Practice: A Consensus Statement.

Importance: Inconsistent reporting of outcomes in clinical trials of rosacea is impeding and likely preventing accurate data pooling and meta-analyses. There is a need for standardization of outcomes assessed during intervention trials of rosacea. Objective: To develop a rosacea core outcome set (COS) based on key domains that are globally relevant and applicable to all demographic groups to be used as a minimum list of outcomes for reporting by rosacea clinical trials, and when appropriate, in clinical practice. Evidence Review: A systematic literature review of rosacea clinical trials was conducted. Discrete outcomes were extracted and augmented through discussions and focus groups with key stakeholders. The initial list of 192 outcomes was refined to identify 50 unique outcomes that were rated through the Delphi process Round 1 by 88 panelists (63 physicians from 17 countries and 25 patients with rosacea in the US) on 9-point Likert scale. Based on feedback, an additional 11 outcomes were added in Round 2. Outcomes deemed to be critical for inclusion (rated 7-9 by ≥70% of both groups) were discussed in consensus meetings. The outcomes deemed to be most important for inclusion by at least 85% of the participants were incorporated into the final core domain set. Findings: The Delphi process and consensus-building meetings identified a final core set of 8 domains for rosacea clinical trials: ocular signs and symptoms; skin signs of disease; skin symptoms; overall severity; patient satisfaction; quality of life; degree of improvement; and presence and severity of treatment-related adverse events. Recommendations were also made for application in the clinical setting. Conclusions and Relevance: This core domain set for rosacea research is now available; its adoption by researchers may improve the usefulness of future trials of rosacea therapies by enabling meta-analyses and other comparisons across studies. This core domain set may also be useful in clinical practice.

Engineering interfacial polarization switching in van der Waals multilayers.

In conventional ferroelectric materials, polarization is an intrinsic property limited by bulk crystallographic structure and symmetry. Recently, it has been demonstrated that polar order can also be accessed using inherently non-polar van der Waals materials through layer-by-layer assembly into heterostructures, wherein interfacial interactions can generate spontaneous, switchable polarization. Here we show that deliberate interlayer rotations in multilayer van der Waals heterostructures modulate both the spatial ordering and switching dynamics of polar domains. The engendered tunability is unparalleled in conventional bulk ferroelectrics or polar bilayers. By means of operando transmission electron microscopy we show how alterations of the relative rotations of three WSe2 layers produce structural polytypes with distinct arrangements of polar domains with either a global or localized switching response. Furthermore, the presence of uniaxial strain generates structural anisotropy that yields a range of switching behaviours, coercivities and even tunable biased responses. We also provide evidence of mechanical coupling between the two interfaces of the trilayer, a key consideration for the control of switching dynamics in polar multilayer structures more broadly.

A mouse DRG genetic toolkit reveals morphological and physiological diversity of somatosensory neuron subtypes.

Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from the periphery to the CNS has been challenging with existing tools. Here, we develop and curate a mouse genetic toolkit that allows for interrogating the properties and functions of distinct cutaneous targeting DRG neuron subtypes. These tools have enabled a broad morphological analysis, which revealed distinct cutaneous axon arborization areas and branching patterns of the transcriptionally distinct DRG neuron subtypes. Moreover, in vivo physiological analysis revealed that each subtype has a distinct threshold and range of responses to mechanical and/or thermal stimuli. These findings support a model in which morphologically and physiologically distinct cutaneous DRG sensory neuron subtypes tile mechanical and thermal stimulus space to collectively encode a wide range of natural stimuli.

The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota.

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide calcitonin gene-related peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. The neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.

Basophils are important for development of allergic skin inflammation.

BACKGROUND: Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis. OBJECTIVE: We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation. METHODS: Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR. RESULTS: Basophils were important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic TH2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive TH2 polarization of naive T cells. CONCLUSION: Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice.

Justice beliefs for self and others: Associations with positive and negative affectivity in African Americans and White Americans.

Prior research has shown that a belief in personal justice (i.e., justice for self) is associated with better health and well-being, whereas a belief in justice more generally (i.e., justice for others) is unrelated. However, an emerging perspective is that racial differences may overlay the relationships between multidimensional beliefs about justice and indices of well-being. This includes that well-being among African Americans may be additionally supported by rejecting rather than endorsing some forms of believing in justice. In the present study, we consider racial similarities and differences in the links between beliefs about justice for self and others and emotional well-being. African Americans (N = 117) and White Americans (N = 188) completed measures of beliefs about justice for self and others, and also measures of dispositional tendencies towards experiencing positive and negative emotion (i.e., positive and negative affectivity). In both groups, beliefs about justice for the self were associated with greater positive affect and reduced negative affect. However, beliefs about justice for others were additionally associated with greater negative affect only among African Americans. The link between justice for others and negative affect among African Americans was not attributable to measurement or mean differences in justice beliefs across racial groups, or to socioeconomic differences. Results align with an emerging perspective that simultaneously endorsing and rejecting justice beliefs may be vital to preserving well-being for some racial minorities.