Cerebrospinal fluid contacting neurons (CSF-cNs) are a specific type of neurons located around the ventricles in the brain and the central canal in the spinal cord and have been demonstrated to be intrinsic sensory neurons in the central nervous system (CNS). One of the important channels responsible for the sensory function is polycystic kidney disease 2-like 1 (PKD2L1) channel. Most of the studies concerning the distribution and function of the PKD2L1-expressing CSF-cNs in the spinal cord have previously been performed in non-mammalian vertebrates. In the present study immunohistochemistry was performed to determine the distribution of PKD2L1-immunoreactive (IR) CSF-cNs in the spinal cords of 4 mammalian species: mouse, rat, cat, and macaque monkey. Here, we found that PKD2L1-expressing CSF-cNs were present at all levels of the spinal cord in these animal species. Although the distribution pattern was similar across these species, differences existed. Mice and rats presented a clear PKD2L1-IR cell body labeling, whereas in cats and macaques the PKD2L1-IR cell bodies were more weakly labeled. Ectopic PKD2L1-IR neurons away from the ependymal layer were observed in all the animal species although the abundance and the detailed locations varied. The apical dendritic protrusions towards the lumen of the central canal were clearly seen in all the animal species, but the sizes of protrusion bulbs were different among the species. PKD2L1-IR cell bodies/dendrites were co-expressed with doublecortin, MAP2 (microtubule-associated protein 2) and aromatic L-amino acid decarboxylase, but not with NeuN (neuronal nuclear protein), indicating their immature property and ability to synthesis monoamine transmitters. In addition, in-situ hybridization performed in rats revealed PKD2L1 mRNA expression in the cells around the central canal. Our results indicate that the intrinsic sensory neurons are conserved across non-mammalian and mammalian vertebrates, and that this may play an essential role in the regulation of motor and sensory functions as well as in the maintenance of homeostasis in the CNS.

Background; Programmed death-1 (PD-1) and PD-1 ligand 1 (PD-L1) are target molecules for immunotherapy in non-small cell lung cancer. PD-L1 is expressed not only in cancer cells, but also on macrophages, and has been suggested to contribute to macrophage-mediated immune suppression. Methods; Clinical significance of PD-L1 expression on macrophages in human lung adenocarcinoma was examined. The mechanisms of PD-L1 overexpression on macrophages were investigated by means of cell culture studies. Results; High PD-L1 expression on macrophages was correlated with the presence of EGFR mutation, a lower cancer grade, and a shorter cancer-specific overall survival. In an in vitro study using lung cancer cell lines and human monocyte-derived macrophages, the conditioned medium from cancer cells was found to up-regulate PD-L1 expression on macrophages via STAT3 activation, and a cytokine array revealed that granulocyte-macrophage colony-stimulating factor (GM-CSF) was a candidate factor that induced PD-L1 expression. Culture studies using recombinant GM-CSF, neutralizing antibody, and inhibitors indicated that PD-L1 overexpression was induced via STAT3 activation by GM-CSF derived from cancer cells. Conclusions; PD-L1 overexpression on macrophages via the GM-CSF/STAT3 pathway was suggested to promote cancer progression in lung adenocarcinoma. Cancer cell-derived GM-CSF might be a promising target for anti-cancer therapy.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic myelopoietic growth factor and proinflammatory cytokine, clinically used for multiple indications and serving as a promising target for treatment of many disorders, including cancer, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, COVID-19. We have previously shown that dimeric Ca2+-bound forms of S100A6 and S100P proteins, members of the multifunctional S100 protein family, are specific to GM-CSF. To probe selectivity of these interactions, the affinity of recombinant human GM-CSF to dimeric Ca2+-loaded forms of 18 recombinant human S100 proteins was studied by surface plasmon resonance spectroscopy. Of them, only S100A4 protein specifically binds to GM-CSF with equilibrium dissociation constant, Kd, values of 0.3-2 μM, as confirmed by intrinsic fluorescence and chemical crosslinking data. Calcium removal prevents S100A4 binding to GM-CSF, whereas monomerization of S100A4/A6/P proteins disrupts S100A4/A6 interaction with GM-CSF and induces a slight decrease in S100P affinity for GM-CSF. Structural modelling indicates the presence in the GM-CSF molecule of a conserved S100A4/A6/P-binding site, consisting of the residues from its termini, helices I and III, some of which are involved in the interaction with GM-CSF receptors. The predicted involvement of the ‘hinge’ region and F89 residue of S100P in GM-CSF recognition was confirmed by mutagenesis. Examination of S100A4/A6/P ability to affect GM-CSF signaling showed that S100A4/A6 inhibit GM-CSF/S100-induced suppression of viability of monocytic THP-1 cells. The ability of the S100 proteins to modulate GM-CSF activity is relevant to progression of various neoplasms and other diseases, according to bioinformatics analysis. The direct regulation of GM-CSF signaling by extracellular forms of the S100 proteins should be taken into account in the clinical use of GM-CSF and development of the therapeutic interventions targeting GM-CSF or its receptors.

Colony-stimulating factor 1 receptor (CFS-1R) is a myeloid receptor with a crucial role in monocyte survival and differentiation. Its overexpression is associated with aggressive tumor characterized by an immunosuppressive microenvironment and poor prognosis. CSF-1R ligands, IL-34 and M-CSF, are produced by many cells in the tumor microenvironment (TME), suggesting a key role for the receptor in the crosstalk between tumor, immune and stromal cells in the TME. Recently, CSF-1R expression was reported at the cell membrane of cancer cell from different solid tumors, capturing the interest of various research group interested in investigating the role of this receptor in non-myeloid cells. This review summarizes current data available on the expression and activity of CSF-1R in different tumor types. Notably, CSF-1R+ cancer cells have been shown to produce CSF-1R ligands, indicating that CSF-1R signaling is positively regulated in autocrine manner in cancer cells. Recent research demonstrated that CSF-1R signaling enhances cell transformation by supporting tumor cell proliferation, invasion, stemness and drug resistance. In addition, this review covers recent therapeutic strategies, including monoclonal antibodies and small molecule inhibitors, targeting the CSF-1R and designed to block the pro-oncogenic role of CSF-1R in cancer cell.

Astronauts are at risk of losing 1.0 to 1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs and dietary regimens designed to preserve their musculoskeletal system. This loss is the result of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption. This review describes the ontogeny of osteoclast hematopoietic stem cells, the contributions of macrophage colony stimulating factor, activator of NFkB and the calcineurin pathways make in osteoclast differentiation, and provides details of bone formation, the osteoclast cytoskeleton, the immune regulation of osteoclasts, and osteoclast mechanotransduction on Earth, in the microgravity of space, and in conditions of simulated microgravity. The article discusses the need to better understand how osteoclasts are able to function in zero gravity and reviews current and prospective therapies that may be used to treat osteoclast-mediated bone disease.

Cerebrospinal fluid (CSF)-contacting neurons (CSF-N) located in the surface of both brain ventricles and the central canal (cc) in the spinal cord. The cc and CSF maintain a proliferative niche for neural progenitor cells and play a vital role in development of the brain. The CSF circulates in the ventricles and the subarachnoid spaces with the CSF rhythmic flow: cardiac pulsation and respiratory fluctuation. A new concept of CSF motion may be contrary to the classical one that the direction of CSF motion may vary in direction and may be dynamic in its location. The CSF pressure may also depend on the body position. Moderate music-making has been considered a potential approach for rehabilitative and restorative therapy of brain dysfunctions. Recently, we find that the CSF-Ns are present in both the interior CFS in the cc and also exterior CSF around the surface of the spinal cord. We hypothesize that CSF-N as mechanical sensors in the spinal cord could sense motion of the spinal cord. The myodural bridge is a ligament connecting a pair of deep, upper-neck muscles to the dura mater, which envelops the arachnoid mater and contains the CSF surrounding the brain and the spinal cord. We figure out the term “CSF-static compartment” and classify CSF storage location as rostral pool and caudal pool to demonstrate our hypothesis. We presume that the somatic body movement with music-making and rehabilitation-based interventions would orchestrate the CSF motion with head movement, myodural bridge stretching and puling as well as spinal bending.

Cerebrospinal fluid (CSF) viral escape has been poorly described among people with HIV-associated cryptococcal meningitis. We determined the prevalence of CSF viral escape and HIV-1 viral load (VL) trajectories in individuals treated for HIV-associated cryptococcal meningitis. A retrospective longitudinal study was performed using paired CSF and plasma collected prior to and during the antifungal treatment of 83 participants recruited at the Botswana site of the phase-3 AMBITION-cm trial (2018-2021). HIV-1 RNA levels were quantified then CSF viral escape (CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma) and HIV-1 VL trajectories were assessed. CSF viral escape occurred in 20/62 (32.3%; 95% confidence interval [CI]: 21.9%-44.6%), 13/52 (25.0%; 95% CI: 15.2%-38.2%) and 1/33 (3.0%; 95% CI: 0.16%-15.3%) participants at days 1, 7 and 14 respectively. CSF viral escape was significantly lower on day 14 compared to days 1 and 7, p=0.003 and p=0.02, respectively. HIV-1 VL de-creased significantly from day 1 to day 14 post antifungal therapy in the CSF but not in the plasma (OR, 0.56; 95% CI: 0.41-0.77; p<0.001). CSF viral escape is high among individuals presenting with HIV-associated cryptococcal meningitis; however, antifungal therapy may reverse this, highlighting the importance of rapid initiation of antifungal therapy in these patients.

Liquorpheresis (CSF filtration) comprises a therapeutical approach that has been proposed to treat several neurological conditions where antibodies, inflammatory mediators or abnormal peptides are the cause or play an important role in the pathogenesis of the disease. CSF replacement may be an alternative approach not explored so far. Here, we review previous experiences in the use of liquorpheresis in autoimmune and degenerative neurological diseases. Then we describe previous developments and provide some new technical innovations in order to design bidirectional CSF shunting systems. These systems can be complemented either with a deposit of artificial CSF or with a CSF filter, allowing CSF replacement or liquorpheresis respectively. Both options would lead to mechanical dilution of the patient’s CSF.

A total of thirty-two aerobic spore former strains were isolated from intestinal samples of healthy children and analyzed for their hemolytic and antibiotic-resistance activities. Four strains selected as non-hemolytic and sensitive to all antibiotics recommended as relevant by regulatory agencies were short-listed and evaluated for their in silico and in vitro probiotic potentials. The four selected strains were assigned to the Bacillus velenzensis (MV4 and MV11), B. subtilis (MV24) and Priestia megaterium (formerly Bacillus megaterium) (MV30) species. A genomic analysis indicated that MV4, MV11 and MV24 contained a homolog of the gene coding for the fibrinolytic enzyme nattokinase while only MV30 encoded for a glutamic acid decarboxylase essential to synthesize the neurotransmitter GABA. All four strains showed a strong antioxidant activity, formed biofilm and produced/secreted quorum sensing peptides able to induce a cytoprotective stress response in a model of human intestinal (HT29) cells. Altogether, genomic and physiological data indicate that the analyzed strains do not pose safety concerns and have in vitro probiotic potentials.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation causing progressive joint damage that can lead to lifelong disability. The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone. Involvement of the cytokines TNF- and IL-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines such as IL-17, IL-23, GM-CSF, IL-33, and IL-2 also play a role. Clarification of RA pathology has led to the development of therapeutic agents such as biological disease-modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors, and further details of the immunological background to RA are emerging. This review covers existing knowledge regarding the roles of cytokines, related immune cells and the immune system in RA, manipulation of which may offer the potential for even safer and more effective treatments in the future.

With the advent of real-time MRI, the motion and passage of cerebrospinal fluid can be visualized without gating and exclusion of low-frequency waves. This imaging modality gives insights into low-volume, rapidly oscillating cardiac-driven movement as well as sustained, high-volume, slowly oscillating inspiration-driven movement.Inspiration means a spontaneous or artificial increase in the intrathoracic dimensions independent of body position. Alterations in thoracic diameter enable the thoracic and spinal epidural venous compartments to be emptied and filled, producing an upward surge of cerebrospinal fluid inside the spine during inspiration; this surge counterbalances the downward pooling of venous blood toward the heart.Real-time MRI, as a macroscale in vivo observation method, could expand our knowledge of neurofluid dynamics, including how astrocytic fluid preloading is adjusted and how brain buoyancy and turgor are maintained in different postures and zero gravity.Along with these macroscale findings, new microscale insights into aquaporin-mediated fluid transfer, its sensing by cilia and its tuning by nitric oxide will be reviewed. By incorporating clinical knowledge spanning several disciplines, certain disorders—congenital hydrocephalus with Chiari malformation, idiopathic intracranial hypertension and adult idiopathic hydrocephalus—are interpreted and reviewed according to current concepts, from the basics of the interrelated systems to their pathology.

Neutropenia is a common adverse event during myelosuppressive oncological chemotherapy, predisposing to febrile neutropenia (FN). Patients with coexisting moderate-to-severe chronic kidney disease (CKD) have an increased risk of FN, included in the guidelines for the primary prophylaxis of FN. However, this does not include mild kidney function impairment with esti-mated glomerular filtration rate (eGFR) 60–89 ml/min/1.73m2. This prospective study analyzed the risk of neutropenia in patients on chemotherapy without indication for the primary prophy-laxis of FN. The study enrolled 38 patients starting chemotherapy, including 26 (68.4%) patients aged 65 years or more. The median duration of follow-up was 76 days. The methodology of cre-atinine assessment enabled the use of the newly recommended CKD-EPI formula for identifying patients with a mild reduction of glomerular filtration. Sixteen (42.1%) patients developed at least G2 neutropenia without episodes of FN. Only five (13.1%) patients had eGFR<60ml/min/1.73m2, while 15 (62.5%) eGFR< 90ml/min/1.73m2. The relative risk of neutro-penia in patients with impaired eGFR was over six times higher than in patients with eGFR>90 ml/min/1.73m2 (RR=6.08; 95%CI:1.45–27.29; p< 0.01). Our observation indicates that even a mild reduction in eGFR is a risk factor for the development of neutropenia and a potential risk factor for FN.

Oxidative stress (OS) is involved in the pathogenesis of retinal neurodegenerative diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR) and an important target of therapeutic treatments. New therapeutics are tested in vivo despite limits in transferability and ethical concerns. Retina cultures using human tissue can deliver critical information and significantly reduce the number of animal experiments along with increased transferability. We cultured up to 32 retina samples derived from one eye, analyzed models’ quality, induced OS, and tested efficiency of antioxidative therapeutics. Bovine, porcine, rat, and human retinae were cultured in different experimental settings for 3-14 d. OS was induced by high-glucose or hydrogen peroxide (H2O2) and treated by Scutellarin, pigment epithelium-derived factor (PEDF), and/or granulocyte macrophage-colony stimulating factor (GM-CSF). Tissue morphology, cell viability, inflammation, and glutathione level were determined. Retina samples showed only moderate necrosis (23.83±5.05 increased to 27.00±1.66 AU PI-staining over 14 d) after 14 days in culture. OS was successfully induced (reduced ATP content of 288.3±59.9 vs. 435.7±166.8 nM ATP in controls); antioxidants reduced OS-induced apoptosis (from 124.20±51.09 to 60.80±319.66 cells/image after scutellarin-treatment). Enhanced mammalian animal and human retina cultures allow reliable, highly transferable research on OS-triggered age-related diseases and pre-clinical testing during drug development.