Search

The article discusses research that examined the unusual cooling of the ocean and the formation of dense waters in the North Atlantic in 2013-2014. Topics covered include extreme winter heat loss in the mid- and high latitude North Atlantic, the impact of the anomalously strong northerly airflows that originated in the Nordic seas, and the north-east Atlantic cold sea surface temperature (SST) anomaly co-located with the strong losses in late winter.

Restrictive dermopathy is a lethal autosomal recessive disease characterized by tightly adherent skin, distinctive facial dysmorphisms, arthrogryposis, and pulmonary hypoplasia. While clinical findings are unique, histopathology and genetic analysis are critical for early diagnostic confirmation and to initiate appropriate management for this lethal disease. We report on a preterm Hutterite male neonate with biallelic ZMPSTE24 mutations to highlight the clinical and histopathological features of restrictive dermopathy and share our skin-directed management strategies., (© 2024 Wiley Periodicals LLC.)

Deep-water formation in the eastern Subpolar North Atlantic Ocean (eSPNA) and Nordic Seas is crucial for maintaining the lower limb of the Atlantic Meridional Overturning Circulation (AMOC), of consequence for global climate. However, it is still uncertain which processes determine the deep-water formation and how much Atlantic and Arctic waters respectively contribute to the lower limb. To address this, here we used Lagrangian trajectories to diagnose a global eddy-resolving ocean model that agrees well with recent observations highlighting the eSPNA as a primary source of the AMOC lower limb. Comprised of 72% Atlantic waters and 28% Arctic waters, the density and depth of the AMOC lower limb is critically dependent on Atlantic-Arctic mixing, primarily in the vicinity of Denmark Strait. In contrast, Atlantic waters gaining density through air-sea interaction along the eastern periphery of Nordic Seas and not entering the Arctic Ocean make a negligible contribution to the lower limb., (© 2024. The Author(s).)

Retinoic acid receptor β2 (RARβ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARβ agonist drug, C286, that modulates neuron-glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-α9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve-injured rats. We also found that other clinically available retinoids, that are not RARβ specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARβ specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARβ2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions., Competing Interests: MG and JC have a matter of composition patent for KCL-286. JT was employed by Richmond Pharmacology Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Goncalves, Wu, Clarke, Grist, Moehlin, Mendoza-Parra, Hobbs, Kalindjian, Fok, Mander, Hassanin, Bendel, Täubel, Mant, Carlstedt, Jack and Corcoran.)

Objectives: Uganda adapted its policy for prevention of vertical transmission (VT) of HIV transmission as the World Health Organization released Options A, B and B+. We assessed trends in diagnostic testing, breastfeeding practices, maternal and infant antiretroviral therapy (ART), mortality, VT and HIV-free survival (HFS) among Ugandan infants born to women living with HIV during this period of successive guideline changes., Methods: This is is a retrospective observational study of infants attending early infant diagnosis clinics at two Ugandan hospitals., Results: A total of 1885 infants (48% female) were managed from 2009 to 2017. DNA polymerase chain reaction (PCR) for early infant diagnosis was performed on 1719 infants (92%, one or more PCR tests) and 676 infants (36%, two PCR tests). HIV serology was performed on 90 infants (4.8%). Testing increased over the study period but remained suboptimal, due to high loss to follow-up (LTFU). A total of 93% of infants were breastfed, for a median of 9.5 months. The duration of breast milk exposure increased over the study period, consistent with guidelines that increasingly encouraged breastfeeding. Nine cases (0.48%) of suspected breast milk transmission were observed. The use of ART increased significantly over the study period. Mortality (3.5%, 2.7% and 1.1%; p = 0.0076) and VT (17%, 12% and 7.4%; p < 0.0001) decreased over the study period (2008-2010, 2011-2012 and 2013-2017, respectively). LTFU values were 31%, 49% and 59% at 6, 12 and 18 months of age, respectively, with only modest improvements over time. HFS could only be conclusively documented in 532 infants (28%) because of LTFU., Conclusions: From 2009 to 2017, outcomes improved among HIV-exposed infants in Uganda. LTFU remains a barrier to optimal care., (© 2022 British HIV Association.)

The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of which (T cell interferon-gamma ELISpot, N-specific antibody) wane over time, while others (spike-specific antibody, B cell memory ELISpot) are stable. We use integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling OverNight) to explore this heterogeneity. We identify a subgroup of participants with higher antibody responses and interferon-gamma ELISpot T cell responses, and a robust trajectory for longer term immunity associates with higher levels of neutralising antibodies against the infecting (Victoria) strain and also against variants B.1.1.7 (alpha) and B.1.351 (beta). These variable trajectories following early priming may define subsequent protection from severe disease from novel variants., (© 2022. The Author(s).)

Measurements of water diffusion with MRI have been used as a biomarker of tissue microstructure and heterogeneity. In this study, diffusion kurtosis tensor imaging (DKTI) of the brain was undertaken in 10 healthy volunteers at a clinical field strength of 3 T. Diffusion and kurtosis metrics were measured in regions-of-interest on the resulting maps and compared with quantitative analysis of normal post-mortem tissue histology from separate age-matched donors. White matter regions showed low diffusion (0.60 ± 0.04 × 10 -3 mm 2 /s) and high kurtosis (1.17 ± 0.06), consistent with a structured heterogeneous environment comprising parallel neuronal fibres. Grey matter showed intermediate diffusion (0.80 ± 0.02 × 10 -3 mm 2 /s) and kurtosis (0.82 ± 0.05) values. An important finding is that the subcortical regions investigated (thalamus, caudate and putamen) showed similar diffusion and kurtosis properties to white matter. Histological staining of the subcortical nuclei demonstrated that the predominant grey matter was permeated by small white matter bundles, which could account for the similar kurtosis to white matter. Quantitative histological analysis demonstrated higher mean tissue kurtosis and vector standard deviation values for white matter (1.08 and 0.81) compared to the subcortical regions (0.34 and 0.59). Mean diffusion on DKTI was positively correlated with tissue kurtosis (r = 0.82, p < 0.05) and negatively correlated with vector standard deviation (r = -0.69, p < 0.05). This study demonstrates how DKTI can be used to study regional structural variations in the cerebral tissue microenvironment and could be used to probe microstructural changes within diseased tissue in the future.

In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARβ) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARβ agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2 + cells) in a decorin-mediated neuron-glia cross talk. Decorin promoted the activation of RARα in NG2 + cells by increasing the availability of the endogenous ligand RA. NG2 + cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR-calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARβ and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination. SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARβ) and RARα in NG2 + cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARβ agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin-Ca 2+ pathway. Although RARβ has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARβ and RARα in remyelination., Competing Interests: The authors declare no competing financial interests., (Copyright © 2019 Goncalves et al.)

Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARβ agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Stimulation of retinoic acid (RA) mediated signalling pathways following neural injury leads to regeneration in the adult nervous system and numerous studies have shown that the specific activation of the retinoic acid receptor β (RARβ) is required for this process. Here we identify a novel mechanism by which neuronal RARβ activation results in the endogenous synthesis of RA which is released in association with exosomes and acts as a positive cue to axonal/neurite outgrowth. Using an established rodent model of RARβ induced axonal regeneration, we show that neuronal RARβ activation upregulates the enzymes involved in RA synthesis in a cell specific manner; alcohol dehydrogenase7 (ADH7) in neurons and aldehyde dehydrogenase 2 (Raldh2) in NG2 expressing cells (NG2+ cells). These release RA in association with exosomes providing a permissive substrate to neurite outgrowth. Conversely, deletion of Raldh2 in the NG2+ cells in our in vivo regeneration model is sufficient to compromise axonal outgrowth. This hitherto unidentified RA paracrine signalling is required for axonal/neurite outgrowth and is initiated by the activation of neuronal RARβ signalling., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Following peripheral axon injury, dysregulation of non-coding microRNAs (miRs) occurs in dorsal root ganglia (DRG) sensory neurons. Here we show that DRG neuron cell bodies release extracellular vesicles, including exosomes containing miRs, upon activity. We demonstrate that miR-21-5p is released in the exosomal fraction of cultured DRG following capsaicin activation of TRPV1 receptors. Pure sensory neuron-derived exosomes released by capsaicin are readily phagocytosed by macrophages in which an increase in miR-21-5p expression promotes a pro-inflammatory phenotype. After nerve injury in mice, miR-21-5p is upregulated in DRG neurons and both intrathecal delivery of a miR-21-5p antagomir and conditional deletion of miR-21 in sensory neurons reduce neuropathic hypersensitivity as well as the extent of inflammatory macrophage recruitment in the DRG. We suggest that upregulation and release of miR-21 contribute to sensory neuron-macrophage communication after damage to the peripheral nerve.

Background: Rheumatoid arthritis (RA) patients frequently show weak correlations between the magnitude of pain and inflammation suggesting that mechanisms other than overt peripheral inflammation contribute to pain in RA. We assessed changes in microglial reactivity and spinal excitability and their contribution to pain-like behaviour in the early stages of collagen-induced arthritis (CIA) model., Methods: Mechanically evoked hypersensitivity, spinal nociceptive withdrawal reflexes (NWRs) and hind paw swelling were evaluated in female Lewis rats before and until 13 days following collagen immunization. In the spinal dorsal horn, microgliosis was assayed using immunohistochemistry (Iba-1/p-p38) and cyto(chemo)kine levels in the cerebrospinal fluid (CSF). Intrathecal administration of microglia-targeting drugs A-438079 (P2X7 antagonist) and LHVS (cathepsin S inhibitor) were examined upon hypersensitivity, NWRs, microgliosis and cyto(chemo)kine levels in the early phase of CIA., Results: The early phase of CIA was associated with mechanical allodynia and exaggerated mechanically evoked spinal NWRs, evident before hind paw swelling, and exacerbated with the development of swelling. Concomitant with the development of hypersensitivity was the presence of reactive spinal microgliosis and an increase of IL-1β levels in CSF (just detectable in plasma). Prolonged intrathecal administration of microglial inhibitors attenuated the development of mechanical allodynia, reduced microgliosis and attenuated IL-1β increments. Acute spinal application of either microglial inhibitor significantly diminished the sensitization of the spinal NWRs., Conclusions: Mechanical hypersensitivity in the early phase of CIA is associated with central sensitization that is dependent upon microglial-mediated release of IL-1β in the spinal cord. Blockade of these spinal events may provide pain relief in RA patients.

Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARβ-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARβ signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs., Significance Statement: Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor β (RARβ), which modulates these two aspects of the postinjury physiological response. Activation of RARβ in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation. This may open new therapeutic avenues for SCIs., (Copyright © 2015 Goncalves et al.)

Objective: To evaluate the contribution of sensory neurons in ankle joints and adjacent tissue to the development of pain in collagen-induced arthritis (CIA), and to determine the relationship between pain and the appearance of clinical signs., Methods: Mechanical and heat hypersensitivity and hind paw swelling were assessed in Lewis rats before and until 18 days following collagen immunization. We examined the effect of intrathecal administration of a calcitonin gene-related peptide (CGRP) antagonist (CGRP(8-37) ) from day 11 to day 18 postimmunization on CIA-induced hypersensitivity. During CIA development, CGRP and p-ERK immunoreactivity was quantified in lumbar dorsal root ganglia in which sensory neurons innervating the ankle joint were identified by retrograde labeling with Fluoro-Gold. Microgliosis in the lumbar dorsal horn was assessed by immunohistochemistry, and release of CGRP evoked by activity of primary afferent fibers was measured using a preparation of isolated dorsal horn with dorsal roots attached., Results: CIA was associated with mechanical hypersensitivity that was evident before hind paw swelling and that was exacerbated with the development of swelling. Heat hyperalgesia developed along with swelling. Concomitant with the development of mechanical hypersensitivity, joint innervating neurons exhibited enhanced CGRP expression and an activated phenotype (increased p-ERK expression), and significant microgliosis became evident in the dorsal horn; these peripheral and central changes were augmented further with disease progression. CGRP release evoked by dorsal root stimulation was higher in the dorsal horn on day 18 in rats with CIA compared to control rats. Prolonged intrathecal administration of CGRP(8-37) attenuated established mechanical hypersensitivity and reduced spinal microgliosis., Conclusion: Sensory neuron-derived CGRP sustains mechanical hypersensitivity and spinal microglial reactivity in CIA, suggesting that central mechanisms play critical roles in chronic inflammatory pain. Blockade of these central events may provide pain relief in rheumatoid arthritis patients., (© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

A major dose-limiting side effect associated with cancer-treating antineoplastic drugs is the development of neuropathic pain, which is not readily relieved by available analgesics. A better understanding of the mechanisms that underlie pain generation has potential to provide targets for prophylactic management of chemotherapy pain. Here, we delineate a pathway for pain that is induced by the chemotherapeutic drug vincristine sulfate (VCR). In a murine model of chemotherapy-induced allodynia, VCR treatment induced upregulation of endothelial cell adhesion properties, resulting in the infiltration of circulating CX3CR1⁺ monocytes into the sciatic nerve. At the endothelial-nerve interface, CX3CR1⁺ monocytes were activated by the chemokine CX3CL1 (also known as fractalkine [FKN]), which promoted production of reactive oxygen species that in turn activated the receptor TRPA1 in sensory neurons and evoked the pain response. Furthermore, mice lacking CX3CR1 exhibited a delay in the development of allodynia following VCR administration. Together, our data suggest that CX3CR1 antagonists and inhibition of FKN proteolytic shedding, possibly by targeting ADAM10/17 and/or cathepsin S, have potential as peripheral approaches for the prophylactic treatment of chemotherapy-induced pain.