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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.

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.

Persistent hypoxia in bone metastases induces an immunosuppressive environment, limiting the effectiveness of immunotherapies. To address chronic hypoxia, we have developed manganese dioxide (MnO2) nanoparticles with tunable oxygen production kinetics for sustained oxygenation in bone metastases lesions. Using polyethylene glycol (PEG)-stabilized MnO2or poly(lactic[50]-co-glycolic[50] acid) (50:50 PLGA), poly(lactic[75]-co-glycolic[25] acid) (75:25 PLGA), and polylactic acid (PLA)-encapsulated MnO2NPs, we demonstrate that polymer hydrophobicity attenuates burst oxygen production and enables tunable oxygen production kinetics. The PEG-MnO2NPs resulted in rapid hypoxia reduction in spheroids, which was rapidly attenuated, while the PLA-MnO2NPs exhibited delayed hypoxia control in cancer spheroids. The 50:50 PLGA-MnO2NPs exhibited the best short- and long-term control of hypoxia in cancer spheroids, resulting in sustained regulation of the expression of HIF-1α and immunosuppressive genes. The sustained control of hypoxia by the 50:50 PLGA-MnO2NPs enhanced the cytotoxicity of natural killer cells against cancer spheroids. In vivo, 50:50 PLGA-MnO2showed greater accumulation in the long bones and pelvis, common sites for bone metastases. The NPs decreased hypoxia in bone metastases and decreased regulatory T cell levels, resulting in enhanced survival of mice with established bone metastases.

Rising feed cost challenges due to expensive conventional protein sources continue to make headlines in Africa causing drops in profit margins. We assessed the impact of insect (Hermetia illucensLinnaeus larvae meal, HILM) protein as a substitute for soybean meal and sunflower seed cake on layer chicken performance and profitability. Our results showed that apart from the growers, chicks (12.37 g/bird) and layer hens (2.02 g/bird) fed diets with 75% HILM inclusion levels had significantly higher average daily weight gain. The average daily feed intake (ADFI) and feed conversion ratio (FCR) varied significantly when the chicks and layer hens were provided with the HILM-based diets. For the chicks and layer hens, the lowest ADFI and FCR were observed in birds subjected to diets with 75% and 100% HILM compared to the growers fed diets with 50% HILM. Significantly higher egg production was observed for layer hens fed diets containing 75% of HILM throughout the first (87.41%) and second (83.05%) phase production cycles. Layer hens fed HILM-based diets had a 3–10% increase in egg laying percentage. There was higher profit margins when birds were fed diets containing 75% of HILM (~1.83 and 5.98 US$ per bird), which mirrored the return on investment estimated at 63.95% and 33.36% for the pullets (growers) and laying hen, respectively. Our findings demonstrate that diets with 75% HILM provided optimum growth performance, reduced feeding costs, increased weight gain and egg production as well as improved economic returns for commercial on-farm poultry production systems.

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 WSe2layers 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.

Premature failure of transmission towers due to extreme weather conditions and inadequate design methods have severe socio-economic implications. This study presents a state-of-the-art review of the research work related to failure of self-supported lattice steel transmission towers. Selected articles from literature were divided into broad categories namely—failure analysis techniques, joint slippage effects, retrofitting and investigations of failure due to earthquakes and high intensity winds. The former three aspects mentioned above are chosen for review in this paper since the latter two are very broad aspects by themselves. A systematic literature review has been conducted based 76 research articles after filtering from reputed journals. Advanced analysis involving computational models based on nonlinear formulations and modern finite element software and their potential to reduce the need for full-scale prototype testing have been highlighted. A description of the studies available on retrofitting techniques for transmission towers for intervention against impending tower failures—diaphragm and leg member retrofitting techniques and studies on retrofitting connections are also discussed. Key conclusions from the study that highlight the most useful findings from the various studies, limitations of the current study and directions for future research have been established.

Moiré superlattices formed by twisting trilayers of graphene are a useful model for studying correlated electron behaviour and offer several advantages over their formative bilayer analogues, including a more diverse collection of correlated phases and more robust superconductivity. Spontaneous structural relaxation alters the behaviour of moiré superlattices considerably and has been suggested to play an important role in the relative stability of superconductivity in trilayers. Here we use an interferometric four-dimensional scanning transmission electron microscopy approach to directly probe the local graphene layer alignment over a wide range of trilayer graphene structures. Our results inform a thorough understanding of how reconstruction modulates the local lattice symmetries crucial for establishing correlated phases in twisted graphene trilayers, evincing a relaxed structure that is markedly different from that proposed previously.

Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11C-MGX-10Sand 11C-MGX-11Sviacarbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitroexperiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivoassessment of each radiotracer viaPET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11C-MGX-10Scompared to 11C-MGX-11S. Subsequent use of 11C-MGX-10Sto image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivospecificity of 11C-MGX-10Sfor GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713─an existing radiotracer used to image innate immune activation in clinical research studies─11C-MGX-10Shas multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11C-MGX-10Sduring inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11C-MGX-10Sfor imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.

Over the past decade, numerous reports have focused on the development and applications of Cu-mediated C–H functionalization reactions; however, to date, little is known about the Cu intermediates involved in these transformations. This paper details the observation and characterization of CuIIand CuIIIintermediates in aminoquinoline-directed C(sp2)–H functionalization of a fluoroarene substrate. An initial C(sp2)–H activation at CuIIoccurs at room temperature to afford an isolable anionic cyclometalated CuIIcomplex. This complex undergoes single-electron oxidation with ferrocenium or AgIsalts under mild conditions (5 min at room temperature) to afford C(sp2)–C(sp2) or C(sp2)–NO2coupling products. Spectroscopic studies implicate the formation of a transient diamagnetic CuIII-σ-aryl intermediate that undergoes either (i) a second C(sp2)–H activation at CuIIIfollowed by C–C bond-forming reductive elimination or (ii) reaction with a NO2–nucleophile and C(sp2)–NO2coupling.

Sports-related concussion is now in public awareness more than ever before. Investigations into underlying pathophysiology and methods of assessment have correspondingly increased at an exponential rate. In this review, we aim to highlight some of the evidence supporting emerging techniques in the fields of neurophysiology, neuroimaging, vestibular, oculomotor, autonomics, head sensor, and accelerometer technology in the setting of the current standard: clinical diagnosis and management. In summary, the evidence we reviewed suggests that (1) head impact sensors and accelerometers may detect possible concussions that would not otherwise receive evaluation; (2) clinical diagnosis may be aided by sideline vestibular, oculomotor, and portable EEG techniques; (3) clinical decisions on return-to-play eligibility are currently not sensitive at capturing the neurometabolic, cerebrovascular, neurophysiologic, and microstructural changes that biomarkers have consistently detected days and weeks after clinical clearance. Such biomarkers include heart rate variability, quantitative electroencephalography, as well as functional, metabolic, and microstructural neuroimaging. The current challenge is overcoming the lack of consistency and replicability of any one particular technique to reach consensus.

Pathogen infection causes a stereotyped state of sickness that involves neuronally orchestrated behavioural and physiological changes1,2. On infection, immune cells release a ‘storm’ of cytokines and other mediators, many of which are detected by neurons3,4; yet, the responding neural circuits and neuro–immune interaction mechanisms that evoke sickness behaviour during naturalistic infections remain unclear. Over-the-counter medications such as aspirin and ibuprofen are widely used to alleviate sickness and act by blocking prostaglandin E2 (PGE2) synthesis5. A leading model is that PGE2 crosses the blood–brain barrier and directly engages hypothalamic neurons2. Here, using genetic tools that broadly cover a peripheral sensory neuron atlas, we instead identified a small population of PGE2-detecting glossopharyngeal sensory neurons (petrosal GABRA1 neurons) that are essential for influenza-induced sickness behaviour in mice. Ablating petrosal GABRA1 neurons or targeted knockout of PGE2 receptor 3 (EP3) in these neurons eliminates influenza-induced decreases in food intake, water intake and mobility during early-stage infection and improves survival. Genetically guided anatomical mapping revealed that petrosal GABRA1 neurons project to mucosal regions of the nasopharynx with increased expression of cyclooxygenase-2 after infection, and also display a specific axonal targeting pattern in the brainstem. Together, these findings reveal a primary airway-to-brain sensory pathway that detects locally produced prostaglandins and mediates systemic sickness responses to respiratory virus infection.

The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3–5. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniaeand Streptococcus agalactiae. S.pneumoniaeactivated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP–RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.

Two-dimensional (2D) magnetic crystals hold promise for miniaturized and ultralow power electronic devices that exploit spin manipulation. In these materials, large, controllable magnetocrystalline anisotropy (MCA) is a prerequisite for the stabilization and manipulation of long-range magnetic order. In known 2D magnetic crystals, relatively weak MCA typically results in soft ferromagnetism. Here, we demonstrate that ferromagnetic order persists down to the thinnest limit of FexTaS2(Fe-intercalated bilayer 2H-TaS2) with giant coercivities up to 3 T. We prepare Fe-intercalated TaS2by chemical intercalation of van der Waals-layered 2H-TaS2crystals and perform variable-temperature transport, transmission electron microscopy, and confocal Raman spectroscopy measurements to shed new light on the coupled effects of dimensionality, degree of intercalation, and intercalant order/disorder on the hard ferromagnetic behavior of FexTaS2. More generally, we show that chemical intercalation gives access to a rich synthetic parameter space for low-dimensional magnets, in which magnetic properties can be tailored by the choice of the host material and intercalant identity/amount, in addition to the manifold distinctive degrees of freedom available in atomically thin, van der Waals crystals.

Transition metal dichalcogenides (TMDs) intercalated with spin-bearing transition metal centers are a diverse class of magnetic materials where the spin density and ordering behavior can be varied by the choice of host lattice, intercalant identity, level of intercalation, and intercalant disorder. Each of these degrees of freedom alters the interplay between several key magnetic interactions to produce disparate collective electronic and magnetic phases. The array of magnetic and electronic behavior typified by these systems renders them distinctive platforms for realizing tunable magnetism in solid-state materials and promising candidates for spin-based electronic devices. This Perspective provides an overview of the rich magnetism displayed by transition metal-intercalated TMDs by considering Fe- and Cr-intercalated NbS2and TaS2. These four exemplars of this large family of materials exhibit a wide range of magnetic properties, including sharp switching of magnetic states, current-driven magnetic switching, and chiral spin textures. An understanding of the fundamental origins of the resultant magnetic/electronic phases in these materials is discussed in the context of composition, bonding, electronic structure, and magnetic anisotropy in each case study.

Over the last 2 decades, many African countries have undergone dietary and nutrition transitions fueled by globalization, rapid urbanization, and development. These changes have altered African food environments and, subsequently, dietary behaviors, including food acquisition and consumption. Dietary patterns associated with the nutrition transition have contributed to Africa's complex burden of malnutrition—obesity and other diet-related noncommunicable diseases (DR-NCDs)—along with persistent food insecurity and undernutrition. Available evidence links unhealthy or obesogenic food environments (including those that market and offer energy-dense, nutrient-poor foods and beverages) with suboptimal diets and associated adverse health outcomes. Elsewhere, governments have responded with policies to improve food environments. However, in Africa, the necessary research and policy action have received insufficient attention. Contextual evidence to motivate, enable, and create supportive food environments in Africa for better population health is urgently needed. In November 2020, the Measurement, Evaluation, Accountability, and Leadership Support for Noncommunicable Diseases Prevention Project (MEALS4NCDs) convened the first Africa Food Environment Research Network Meeting (FERN2020). This 3-d virtual meeting brought researchers from around the world to deliberate on future directions and research priorities related to improving food environments and nutrition across the African continent. The stakeholders shared experiences, best practices, challenges, and opportunities for improving the healthfulness of food environments and related policies in low- and middle-income countries. In this article, we summarize the proceedings and research priorities identified in the meeting to advance the food environment research agenda in Africa, and thus contribute to the promotion of healthier food environments to prevent DR-NCDs, and other forms of malnutrition.Statement of Significance: In Africa, research and policy action to improve food environments, to reduce intake of suboptimal diets, and associated adverse health outcomes have received insufficient attention. This paper articulates previously unpublished priorities to advance the food environment research agenda, and to generate contextually relevant, fit-for-local purpose evidence to confront unhealthy food environments in Africa.

Over the last 2 decades, many African countries have undergone dietary and nutrition transitions fueled by globalization, rapid urbanization, and development. These changes have altered African food environments and, subsequently, dietary behaviors, including food acquisition and consumption. Dietary patterns associated with the nutrition transition have contributed to Africa's complex burden of malnutrition—obesity and other diet-related noncommunicable diseases (DR-NCDs)—along with persistent food insecurity and undernutrition. Available evidence links unhealthy or obesogenic food environments (including those that market and offer energy-dense, nutrient-poor foods and beverages) with suboptimal diets and associated adverse health outcomes. Elsewhere, governments have responded with policies to improve food environments. However, in Africa, the necessary research and policy action have received insufficient attention. Contextual evidence to motivate, enable, and create supportive food environments in Africa for better population health is urgently needed. In November 2020, the Measurement, Evaluation, Accountability, and Leadership Support for Noncommunicable Diseases Prevention Project (MEALS4NCDs) convened the first Africa Food Environment Research Network Meeting (FERN2020). This 3-d virtual meeting brought researchers from around the world to deliberate on future directions and research priorities related to improving food environments and nutrition across the African continent. The stakeholders shared experiences, best practices, challenges, and opportunities for improving the healthfulness of food environments and related policies in low- and middle-income countries. In this article, we summarize the proceedings and research priorities identified in the meeting to advance the food environment research agenda in Africa, and thus contribute to the promotion of healthier food environments to prevent DR-NCDs, and other forms of malnutrition.

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 icipeHugel, Tanga, and Gryllus bimaculatusDe 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.

Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF). Intrathecal administration of edema toxin (ET (PA + EF)) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan or nerve injury. Analgesia depended on ANTXR2 expressed by Nav1.8+or Advillin+neurons. ET modulated protein kinase A signaling in mouse sensory and human induced pluripotent stem cell-derived sensory neurons, and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors, which may lead to the development of new pain therapeutics.

At the time this inaugural issue of Avar: A Journal of Life and Society in the Ancient Near East heads to press, we are keenly aware of the fact that the number of new journals in the fields of Biblical Studies, Egyptology, and broader Ancient Near Eastern Studies have proliferated in the last decade. Yet, we hope to demonstrate to our readers that Avar fills an important lacuna in the academic study of the ancient past. The title of the journal, Avar, centers interdisciplinarity as the primary framework for illuminating life and society in the ancient Near East. In what follows, we will introduce our vision for such interdisciplinarity.

Tailoring electron transfer dynamics across solid–liquid interfaces is fundamental to the interconversion of electrical and chemical energy. Stacking atomically thin layers with a small azimuthal misorientation to produce moiré superlattices enables the controlled engineering of electronic band structures and the formation of extremely flat electronic bands. Here, we report a strong twist-angle dependence of heterogeneous charge transfer kinetics at twisted bilayer graphene electrodes with the greatest enhancement observed near the ‘magic angle’ (~1.1°). This effect is driven by the angle-dependent tuning of moiré-derived flat bands that modulate electron transfer processes with the solution-phase redox couple. Combined experimental and computational analysis reveals that the variation in electrochemical activity with moiré angle is controlled by a structural relaxation of the moiré superlattice at twist angles of <2°, and ‘topological defect’ AA stacking regions, where flat bands are localized, produce a large anomalous local electrochemical enhancement that cannot be accounted for by the elevated local density of states alone.

Bidirectional communication between the peripheral nervous system (PNS) and the immune system is a crucial part of an effective but balanced mammalian response to invading pathogens, tissue damage and inflammatory stimuli. Here, we review how somatosensory and autonomic neurons regulate immune cellular responses at barrier tissues and in peripheral organs. Immune cells express receptors for neuronal mediators, including neuropeptides and neurotransmitters, allowing neurons to influence their function in acute and chronic inflammatory diseases. Distinct subsets of peripheral sensory, sympathetic, parasympathetic and enteric neurons are able to signal to innate and adaptive immune cells to modulate their cellular functions. In this Review, we highlight recent studies defining the molecular mechanisms by which neuroimmune signalling mediates tissue homeostasis and pathology. Understanding the neural circuitry that regulates immune responses can offer novel targets for the treatment of a wide array of diseases.

Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple alphavirus receptors have been described1–3, most are not shared among vertebrate and invertebrate hosts. Here we identify the very low-density lipoprotein receptor (VLDLR) as a receptor for the prototypic alphavirus Semliki forest virus. We show that the E2 and E1 glycoproteins (E2–E1) of Semliki forest virus, eastern equine encephalitis virus and Sindbis virus interact with the ligand-binding domains (LBDs) of VLDLR and apolipoprotein E receptor 2 (ApoER2), two closely related receptors. Ectopic expression of either protein facilitates cellular attachment, and internalization of virus-like particles, a VLDLR LBD–Fc fusion protein or a ligand-binding antagonist block Semliki forest virus E2–E1-mediated infection of human and mouse neurons in culture. The administration of a VLDLR LBD–Fc fusion protein has protective activity against rapidly fatal Semliki forest virus infection in mouse neonates. We further show that invertebrate receptor orthologues from mosquitoes and worms can serve as functional alphavirus receptors. We propose that the ability of some alphaviruses to infect a wide range of hosts is a result of their engagement of evolutionarily conserved lipoprotein receptors and contributes to their pathogenesis.

Inflammation early in life can prime the local immune milieu of peripheral tissues, which can cause lasting changes in immunological tone that confer disease protection or susceptibility1. The cellular and molecular mechanisms that prompt changes in immune tone in many nonlymphoid tissues remain largely unknown. Here we find that time-limited neonatal inflammation induced by a transient reduction in neonatal regulatory T cells causes a dysregulation of subcutaneous tissue in mouse skin. This is accompanied by the selective accumulation of type 2 helper T (TH2) cells within a distinct microanatomical niche. TH2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as TH2-interacting fascial fibroblasts (TIFFs), which expand in response to TH2 cytokines to form subcutaneous fibrous bands. Activation of the TH2–TIFF niche due to neonatal inflammation primes the skin for altered reparative responses to wounding. Furthermore, we identify fibroblasts in healthy human skin that express the TIFF transcriptional signature and detect these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a previously unidentified TH2 cell niche in skin and functionally characterize a disease-associated fibroblast population. The results also suggest a mechanism of immunological priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells to establish an immunological set-point in tissues that is maintained throughout life.

Periodontitis is induced by periodontal dysbiosis characterized by the predominance of anaerobic species. TLRs constitute the classical pathway for cell activation by infection. Interestingly, the Toll/IL-1 receptor homology domain adapters initiate signaling events, leading to the activation of the expression of the genes involved in the host immune response. The aim of this study was to evaluate the effects of Porphyromonas gingivalison the expression and protein-protein interactions among five TIR adapters (MAL, MyD88, TRIF, TRAM and SARM) in gingival epithelial cells and endothelial cells. It was observed that P. gingivalisis able to modulate the signaling cascades activated through its recognition by TLR4/2 in gingival epithelial cells and endothelial cells. Indeed, MAL-MyD88 protein-protein interactions associated with TLR4 was the main pathway activated by P. gingivalisinfection. When transient siRNA inhibition was performed, cell viability, inflammation, and cell death induced by infection decreased and such deleterious effects were almost absent when MAL or TRAM were targeted. This study emphasizes the role of such TIR adapter proteins in P. gingivaliselicited inflammation and the precise evaluation of TIR adapter protein interactions may pave the way for future therapeutics in both periodontitis and systemic disease with a P. gingivalisinvolvement, such as atherothrombosis.

The gastrointestinal tract is densely innervated by a complex network of neurons that coordinate critical physiological functions. Here, we summarize recent studies investigating the crosstalk between gut-innervating neurons, resident immune cells, and epithelial cells at homeostasis and during infection, food allergy, and inflammatory bowel disease. We introduce the neuroanatomy of the gastrointestinal tract, detailing gut-extrinsic neuron populations from the spinal cord and brain stem, and neurons of the intrinsic enteric nervous system. We highlight the roles these neurons play in regulating the functions of innate immune cells, adaptive immune cells, and intestinal epithelial cells. We discuss the consequences of such signaling for mucosal immunity. Finally, we discuss how the intestinal microbiota is integrated into the neuro-immune axis by tuning neuronal and immune interactions. Understanding the molecular events governing the intestinal neuro-immune signaling axes will enhance our knowledge of physiology and may provide novel therapeutic targets to treat inflammatory diseases.

The gastrointestinal tract is densely innervated by a complex network of neurons that coordinate critical physiological functions. Here, we summarize recent studies investigating the crosstalk between gut-innervating neurons, resident immune cells, and epithelial cells at homeostasis and during infection, food allergy, and inflammatory bowel disease. We introduce the neuroanatomy of the gastrointestinal tract, detailing gut-extrinsic neuron populations from the spinal cord and brain stem, and neurons of the intrinsic enteric nervous system. We highlight the roles these neurons play in regulating the functions of innate immune cells, adaptive immune cells, and intestinal epithelial cells. We discuss the consequences of such signaling for mucosal immunity. Finally, we discuss how the intestinal microbiota is integrated into the neuro-immune axis by tuning neuronal and immune interactions. Understanding the molecular events governing the intestinal neuro-immune signaling axes will enhance our knowledge of physiology and may provide novel therapeutic targets to treat inflammatory diseases.

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 NiIIprecyclometalation intermediate as well as in the speciation of the NiIIproducts of C–H activation. Both mono- and binuclear cyclometalated NiIIspecies are observed and interconvert, depending on the reaction conditions. Cyclic voltammetry reveals that the NiII/IIIredox 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/IVpathway for this transformation.