Therapeutics against coronavirus disease 2019 (COVID-19) are urgently needed. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a myelopoietic growth factor and pro-inflammatory cytokine, ...plays a critical role in alveolar macrophage homeostasis, lung inflammation and immunological disease. Both administration and inhibition of GM-CSF are currently being therapeutically tested in COVID-19 clinical trials. This Perspective discusses the pleiotropic biology of GM-CSF and the scientific merits behind these contrasting approaches.
Over the past decade, great progress has been made in understanding the complexity of adipose tissue biology and its role in metabolism. This includes new insights into the multiple layers of adipose ...tissue heterogeneity, not only differences between white and brown adipocytes, but also differences in white adipose tissue at the depot level and even heterogeneity of white adipocytes within a single depot. These inter- and intra-depot differences in adipocytes are developmentally programmed and contribute to the wide range of effects observed in disorders with fat excess (overweight/obesity) or fat loss (lipodystrophy). Recent studies also highlight the underappreciated dynamic nature of adipose tissue, including potential to undergo rapid turnover and dedifferentiation and as a source of stem cells. Finally, we explore the rapidly expanding field of adipose tissue as an endocrine organ, and how adipose tissue communicates with other tissues to regulate systemic metabolism both centrally and peripherally through secretion of adipocyte-derived peptide hormones, inflammatory mediators, signaling lipids, and miRNAs packaged in exosomes. Together these attributes and complexities create a robust, multidimensional signaling network that is central to metabolic homeostasis.
The mechanisms that instruct the assembly of fine-scale features of synaptic connectivity in neural circuits are only beginning to be understood. Using whole-cell electrophysiology, two-photon ...calcium imaging, and glutamate uncaging in hippocampal slices, we discovered a functional coupling between NMDA receptor activation and ryanodine-sensitive intracellular calcium release that dominates the spatiotemporal dynamics of activity-dependent calcium signals during synaptogenesis. This developmentally regulated calcium amplification mechanism was tuned to detect and bind spatially clustered and temporally correlated synaptic inputs and enacted a local cooperative plasticity rule between coactive neighboring synapses. Consistent with the hypothesis that synapse maturation is spatially regulated, we observed clustering of synaptic weights in developing dendritic arbors. These results reveal developmental features of NMDA receptor-dependent calcium dynamics and local plasticity rules that are suited to spatially guide synaptic connectivity patterns in emerging neural networks.
•Synaptic NMDAR activation triggers CICR during early postnatal synapse formation•NMDAR-CICR coupling controls Ca2+ dynamics in space and time•Correlated inputs drive local cooperative spine plasticity via NMDAR-CICR coupling•Synapse maturation is clustered along dendrites of CA1 pyramidal cells
Lee et al. show that NMDAR activation triggers CICR exclusively during spine synapse development in CA1 pyramidal cells. This calcium amplification mechanism selects for specific input features along dendrites and spatially regulates synaptic plasticity, likely to shape microscale connectivity patterns of emerging neural circuits.
The cytokine, interleukin-23 (IL-23), can be critical for the progression of inflammatory diseases, including arthritis, and is often associated with T lymphocyte biology. We previously showed that ...certain lymphocyte-independent, inflammatory arthritis and pain models have a similar requirement for tumour necrosis factor (TNF), granulocyte macrophage-colony stimulating factor (GM-CSF), and C-C motif ligand 17 (CCL17). Given this correlation in cytokine requirements, we explored whether IL-23 might interact with this cytokine cluster in the control of arthritic and inflammatory pain.
The role of IL-23 in the development of pain-like behaviour was investigated using mouse arthritis models (zymosan-induced arthritis and GM-CSF-, TNF-, and CCL17-driven monoarticular arthritis) and inflammatory pain models (intraplantar zymosan, GM-CSF, TNF, and CCL17). Additionally, IL-23-induced inflammatory pain was measured in GM-CSF
, Tnf
, and Ccl17
mice and in the presence of indomethacin. Pain-like behaviour and arthritis were assessed by relative weight distribution in hindlimbs and histology, respectively. Cytokine mRNA expression in knees and paw skin was analysed by quantitative PCR. Blood and synovial cell populations were analysed by flow cytometry.
We report, using Il23p19
mice, that innate immune (zymosan)-driven arthritic pain-like behaviour (herein referred to as pain) was completely dependent upon IL-23; optimal arthritic disease development required IL-23 (P < 0.05). Zymosan-induced inflammatory pain was also completely dependent on IL-23. In addition, we found that exogenous TNF-, GM-CSF-, and CCL17-driven arthritic pain, as well as inflammatory pain driven by each of these cytokines, were absent in Il23p19
mice; optimal disease in these mBSA-primed models was dependent on IL-23 (P < 0.05). Supporting this cytokine connection, it was found conversely that IL-23 (200 ng) can induce inflammatory pain at 4 h (P < 0.0001) with a requirement for each of the other cytokines as well as cyclooxygenase activity.
These findings indicate a role for IL-23 in innate immune-mediated arthritic and inflammatory pain with potential links to TNF, GM-CSF, CCL17, and eicosanoid function.
Current techniques in biological resurfacing of cartilage defects require an open arthrotomy or arthroscopy and involve the direct transplantation of isolated cells and/or scaffolds or whole tissue ...grafts with chondrogenic potential onto the cartilage defect. Our study investigates the possibility of direct intra‐articular injection of mesenchymal stem cells suspended in hyaluronic acid (HA) as an alternative to the much more invasive methods currently available. A partial‐thickness (without penetration of the subchondral bone) cartilage defect was created in the medial femoral condyle of an adult minipig. Mesenchymal stem cells from the iliac crest marrow of the same pig harvested in a separate procedure and suspended in 2 milliliters of hylan G‐F 20 (Synvisc) were injected intra‐articularly after the creation of the defect. This was followed by two more injections of hylan G‐F 20 (HA) at weekly intervals. Either saline or HA was injected into the knees of the controls. The pigs were sacrificed at 6 and 12 weeks for morphological and histological analysis. The cell‐treated groups showed improved cartilage healing both histologically and morphologically at 6 and 12 weeks compared with both controls. The use of intra‐articular injections of mesenchymal stem cells suspended in HA is a viable option for treating large cartilage defects. This would be further explored in clinical trials.
Disclosure of potential conflicts of interest is found at the end of this article.
One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune ...surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), was firstly identified as being able to induce in vitro the proliferation and differentiation of bone marrow progenitors into ...granulocytes and macrophages. Much preclinical data have indicated that GM-CSF has a wide range of functions across different tissues in its action on myeloid cells, and GM-CSF deletion/depletion approaches indicate its potential as an important therapeutic target in several inflammatory and autoimmune disorders, for example, rheumatoid arthritis. In this review, we discuss briefly the biology of GM-CSF, raise some current issues and questions pertaining to this biology, summarize the results from preclinical models of a range of inflammatory and autoimmune disorders and list the latest clinical trials evaluating GM-CSF blockade in such disorders.
Current understanding of IL-23 biology, with its link to other pro-inflammatory cytokines, for example, IL-17 and granulocyte macrophage-colony stimulating factor (GM-CSF), is primarily focused on T ...lymphocyte-mediated inflammation/autoimmunity. Pain is a significant symptom associated with many musculoskeletal conditions leading to functional impairment and poor quality of life. While the role of IL-23 in arthritis has been studied in mouse models of adaptive immune-mediated arthritis using targeted approaches (e.g., monoclonal antibody (mAb) neutralization), the literature on IL-23 and arthritis pain is limited. Encouragingly, the anti-IL-23p19 mAb, guselkumab, reduces pain in psoriatic arthritis patients. Recent evidence has suggested a new biology for IL-23, whereby IL-23 is required in models of innate immune-mediated arthritis and its associated pain with its action being linked to a GM-CSF-dependent pathway (the so-called GM-CSF➔CCL17 pathway). This Commentary discusses the current understanding of potential cytokine networks involving IL-23 in arthritis pain and provides a rationale for future clinical studies targeting IL-23p19 in arthritis pain.
Sleep apnea (SA) is a common disorder involving the cessation of breathing during sleep. It can cause daytime hypersomnia, accidents, and, if allowed to progress, serious, chronic conditions. ...Continuous positive airway pressure is an effective SA treatment. However, long waitlists impede timely diagnosis; overnight sleep studies involve trained technicians scoring a polysomnograph, which comprises multiple physiological signals including multi-channel electroencephalography (EEG). Therefore, it is important to develop simplified and automated approaches to detect SA. In the present study, we have developed an explainable convolutional neural network (CNN) to detect SA events from single-channel EEG recordings which generalizes across subjects. The network architecture consisted of three convolutional layers. We tuned hyperparameters using the Hyperband algorithm, optimized parameters using Adam, and quantified network performance with subjectwise 10-fold cross-validation. Our CNN performed with an accuracy of 69.9%, and a Matthews correlation coefficient (MCC) of 0.38. To explain the mechanisms of our trained network, we used critical-band masking (CBM): after training, we added bandlimited noise to test recordings; we parametrically varied the noise band center frequency and noise intensity, quantifying the deleterious effect on performance. We reconciled the effects of CBM with lesioning, wherein we zeroed the trained network’s 1st-layer filter kernels in turn, quantifying the deleterious effect on performance. These analyses indicated that the network learned frequency-band information consistent with known SA biomarkers, specifically, delta and beta band activity. Our results indicate single-channel EEG may have clinical potential for SA diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Questions have arisen around new metrics for organ procurement organizations (OPO) due to the perception that low‐performing OPOs may be limited by local centers’ acceptance of marginal organs. We ...reviewed 2013–2019 Organ Procurement and Transplantation Network (OTPN) and National Centers for Health Statistics (NCHS) data to explore the relationship between objectively measured OPO performance and utilization of deceased donor kidneys. We found that although donor recovery declined with rising age and kidney donor profile index (KDPI), OPO performance differences were evident within each age/KDPI group. By contrast, the number of discards per donor did not vary with OPO performance. Centers in donor service areas (DSAs) with lower‐performing OPOs had higher local utilization and greater import of high‐KDPI kidneys than did those with higher‐performing OPOs. Lower rates of donor availability relative to waitlist additions may contribute to observed center acceptance behavior. Differences in center‐level performance were highly visible in Scientific Registry of Transplant Recipients (SRTR) organ acceptance metrics, while SRTR OPO metrics did not detect large or persistent variation in procurement performance. Cumulatively, our findings suggest that objective measures of procurement performance can inform discussions of organ utilization, allowing for alignment of metrics in all elements of the procurement‐transplantation system.
Kidney transplant centers in areas with low organ procurement rates display more aggressive utilization and import of deceased donor kidneys.
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