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Background Pericytes and endothelial cells are critical cellular components of the blood-brain barrier (BBB) and play an important role in neuroinflammation. To date, the majority of inflammation-related studies in endothelia and pericytes have been carried out using immortalised cell lines or non-human-derived cells. Whether these are representative of primary human cells is unclear and systematic comparisons of the inflammatory responses of primary human brain-derived pericytes and endothelia has yet to be performed. Methods To study the effects of neuroinflammation at the BBB, primary brain endothelial cells and pericytes were isolated from human biopsy tissue. Culture purity was examined using qPCR and immunocytochemistry. Electrical cell-substrate impedance sensing (ECIS) was used to determine the barrier properties of endothelial and pericyte cultures. Using immunocytochemistry, cytometric bead array, and ECIS, we compared the responses of endothelia and pericytes to a panel of inflammatory stimuli (IL-1β, TNFα, LPS, IFN-γ, TGF-β 1 , IL-6, and IL-4). Secretome analysis was performed to identify unique secretions of endothelia and pericytes in response to IL-1β. Results Endothelial cells were pure, moderately proliferative, retained the expression of BBB-related junctional proteins and transporters, and generated robust TEER. Both endothelia and pericytes have the same pattern of transcription factor activation in response to inflammatory stimuli but respond differently at the secretion level. Secretome analysis confirmed that endothelia and pericytes have overlapping but distinct secretome profiles in response to IL-1β. We identified several cell-type specific responses, including G-CSF and GM-CSF (endothelial-specific), and IGFBP2 and IGFBP3 (pericyte-specific). Finally, we demonstrated that direct addition of IL-1β, TNFα, LPS, and IL-4 contributed to the loss of endothelial barrier integrity in vitro. Conclusions Here, we identify important cell-type differences in the inflammatory response of brain pericytes and endothelia and provide, for the first time, a comprehensive profile of the secretions of primary human brain endothelia and pericytes which has implications for understanding how inflammation affects the cerebrovasculature.

The origin and nature of extreme energy cosmic rays (EECRs), which have energies above the 5 ⋅ 10 19 eV —the Greisen-Zatsepin-Kuzmin (GZK) energy limit, is one of the most interesting and complicated problems in modern cosmic-ray physics. Existing ground-based detectors have helped to obtain remarkable results in studying cosmic rays before and after the GZK limit, but have also produced some contradictions in our understanding of cosmic ray mass composition. Moreover, each of these detectors covers only a part of the celestial sphere, which poses problems for studying the arrival directions of EECRs and identifying their sources. As a new generation of EECR space detectors, TUS (Tracking Ultraviolet Set-up), KLYPVE and JEM-EUSO, are intended to study the most energetic cosmic-ray particles, providing larger, uniform exposures of the entire celestial sphere. The TUS detector, launched on board the Lomonosov satellite on April 28, 2016 from Vostochny Cosmodrome in Russia, is the first of these. It employs a single-mirror optical system and a photomultiplier tube matrix as a photo-detector and will test the fluorescent method of measuring EECRs from space. Utilizing the Earth’s atmosphere as a huge calorimeter, it is expected to detect EECRs with energies above 10 20 eV . It will also be able to register slower atmospheric transient events: atmospheric fluorescence in electrical discharges of various types including precipitating electrons escaping the magnetosphere and from the radiation of meteors passing through the atmosphere. We describe the design of the TUS detector and present results of different ground-based tests and simulations.

The ejecta composition is an open question in gamma-ray burst (GRB) physics 1 . Some GRBs possess a quasi-thermal spectral component in the time-resolved spectral analysis 2 , suggesting a hot fireball origin. Others show a featureless non-thermal spectrum known as the Band function 3 – 5 , consistent with a synchrotron radiation origin 5 , 6 and suggesting that the jet is Poynting-flux dominated at the central engine and probably in the emission region as well 7 , 8 . There are also bursts showing a sub-dominant thermal component and a dominant synchrotron component 9 , suggesting a probable hybrid jet composition 10 . Here, we report an extraordinarily bright GRB 160625B, simultaneously observed in gamma-ray and optical wavelengths, whose prompt emission consists of three isolated episodes separated by long quiescent intervals, with the durations of each sub-burst being approximately 0.8 s, 35 s and 212 s, respectively. Its high brightness (with isotropic peak luminosity L p,iso  ≈ 4 × 10 53  erg s −1 ) allows us to conduct detailed time-resolved spectral analysis in each episode, from precursor to main burst and to extended emission. The spectral properties of the first two sub-bursts are distinctly different, allowing us to observe the transition from thermal to non-thermal radiation between well-separated emission episodes within a single GRB. Such a transition is a clear indication of the change of jet composition from a fireball to a Poynting-flux-dominated jet. The extremely bright GRB 160625B, consisting of three sub-bursts separated by quiescent intervals, shows a transition from thermal to non-thermal radiation that indicates a change of jet composition from a fireball to a Poynting-flux-dominated jet.

Amyotrophic lateral sclerosis (ALS) is the most common adult onset motoneuron disease. The etiology and precise pathogenic mechanisms of the disease remain unknown, and there is no effective treatment. Vascular endothelial growth factor (VEGF) has recently been shown to exert direct neurotrophic and neuroprotective effects in animal models of ALS. Here we show that intrathecal transplantation of immortalized human neural stem cells (NSCs) overexpressing human VEGF gene (HB1.F3.VEGF) significantly delayed disease onset and prolonged the survival of the SOD1G93A mouse model of ALS. At 4 weeks, post-transplantation grafted cells were found within the gray matter of the spinal cord. Furthermore, transplanted F3.VEGF cells that express neuronal phenotype (MAP2+) were found in the anterior horn of the spinal cord gray matter indicating that the transplanted human NSCs migrated into the gray matter, took the correct structural position, integrated into the spinal cord anterior horn and differentiated into motoneurons. Intrathecal transplantation of F3.VEGF cells provides a neuroprotective effect in the diseased spinal cord by concomitant downregulation of proapoptotic proteins and upregulation of antiapoptotic proteins. Our results suggest that this treatment modality of intrathecal transplantation of human NSCs genetically modified to overexpress neurotrophic factor(s) might be of value in the treatment of ALS patients without significant adverse effects.

Purpose This multi-center, randomized, phase III study was conducted to demonstrate the non-inferiority of DA-3031 compared with daily filgrastim in patients during the first cycle of chemotherapy for breast cancer in terms of the duration of severe neutropenia (DSN). Methods Seventy-four patients with breast cancer who were receiving combination chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC) were enrolled. All participants were randomized to receive either daily subcutaneous injections of filgrastim 100 μg/m 2 /day for up to 10 days or a single subcutaneous injection of DA-3031 at fixed doses of 6 mg on day 2 of each chemotherapy cycle. Results The mean duration of grade 4 (G4) neutropenia in cycle 1 was 2.08 ± 0.85 days for the filgrastim group and 2.28 ± 1.14 days for the DA-3031 group. The difference between groups was 0.2 ± 1.10 days (95 % confidence interval (CI) = −0.26, 0.66), which supported non-inferiority. No statistically significant differences were observed in nadir absolute neutrophil count (ANC) (154.34/mm 3 and 161.75/mm 3 for the filgrastim and DA-3031 groups, respectively; P  = 0.8414) or in time to ANC recovery (10.03 ± 0.75 and 9.83 ± 1.56 days in the filgrastim and DA-3031 groups, respectively; P  = 0.0611) during cycle 1. Serious AEs occurred in six (15.8 %) patients receiving filgrastim and in ten (27.8 %) patients receiving DA-3031; however, none was determined to be related to the study drug. Conclusions DA-3031 and daily filgrastim are similar in regard to DSN and safety in breast cancer patients receiving TAC chemotherapy.

Background Brain pericytes ensheathe the endothelium and contribute to formation and maintenance of the blood–brain-barrier. Additionally, pericytes are involved in several aspects of the CNS immune response including scarring, adhesion molecule expression, chemokine secretion, and phagocytosis. In vitro cultures are routinely used to investigate these functions of brain pericytes, however, these are highly plastic cells and can display differing phenotypes and functional responses depending on their culture conditions. Here we sought to investigate how two commonly used culture media, high serum containing DMEM/F12 and low serum containing Pericyte Medium (ScienCell), altered the phenotype of human brain pericytes and neuroinflammatory responses. Methods Pericytes were isolated from adult human brain biopsy tissue and cultured in DMEM/F12 (D-pericytes) or Pericyte Medium (P-pericytes). Immunocytochemistry, qRT-PCR, and EdU incorporation were used to determine how this altered their basal phenotype, including the expression of pericyte markers, proliferation, and cell morphology. To determine whether culture media altered the inflammatory response in human brain pericytes, immunocytochemistry, qRT-PCR, cytometric bead arrays, and flow cytometry were used to investigate transcription factor induction, chemokine secretion, adhesion molecule expression, migration, phagocytosis, and response to inflammatory-related growth factors. Results P-pericytes displayed elevated proliferation and a distinct bipolar morphology compared to D-pericytes. Additionally, P-pericytes displayed lower expression of pericyte-associated markers NG2, PDGFRβ, and fibronectin, with notably lower αSMA, CD146, P4H and desmin, and higher Col-IV expression. Nuclear NF-kB translocation in response to IL-1β stimulation was observed in both cultures, however, P-pericytes displayed elevated expression of the transcription factor C/EBPδ, and lower expression of the adhesion molecule ICAM-1. P-pericytes displayed elevated phagocytic and migratory ability. Both cultures responded similarly to stimulation by the growth factors TGFβ 1 and PDGF-BB. Conclusions Despite differences in their phenotype and magnitude of response, both P-pericytes and D-pericytes responded similarly to all examined functions, indicating that the neuroinflammatory phenotype of these cells is robust to culture conditions.

Summary Backgrounds A pegylated form of recombinant granulocyte-colony stimulating factor (G-CSF) was developed for prophylactic use in breast cancer. The aim of this study was to evaluate the efficacy and safety of once-per-cycle DA-3031 in patients receiving chemotherapy for breast cancer. Methods A total of 61 patients receiving docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy were randomized in cycle 1 to receive daily injections of filgrastim (100 μg/m 2 ) or a single subcutaneous injection of pegylated filgrastim DA-3031 at a dose of either 3.6 mg or 6 mg. Results The mean duration of grade 4 neutropenia in cycle 1 was comparable among the treatment groups (2.48, 2.20, and 2.05 days for filgrastim, DA-3031 3.6 mg and 6 mg, respectively; P  = 0.275). No statistically significant differences were observed in the incidence of febrile neutropenia between the treatment groups (9.5 %, 15.0 %, and 5.0 % for filgrastim, DA-3031 3.6 mg and 6 mg, respectively; P  = 0.681) in cycle 1. The incidences of adverse events attributable to G-CSF were similar among the treatment groups. Conclusions Fixed doses of 3.6 mg or 6 mg DA-3031 have an efficacy comparable to that of daily injections of filgrastim in ameliorating grade 4 neutropenia in patients receiving TAC chemotherapy.

A stellar interferometry has been recently proposed for the detection of gravitational waves in the frequency range of 10 - 6 ∼ 10 - 4 Hz . Intensity interferometry using two satellites would be a viable experimental approach for this space based stellar interferometer. When gravitational waves pass near separated two detectors constituting the intensity interferometry, photons that travel from the stellar source to each detector are experiencing the distortion of space-time, and this effect can change the number of detected photons in given detection time interval and also the value of the second-order correlation function g ( 2 ) . We present the effect of gravitational waves onto stellar intensity interferometry in terms of variation of g ( 2 ) and the sensitivity of stellar interferometry system for gravitational wave detection with two independent detection system.

Background Transforming growth factor beta 1 (TGFβ 1 ) is strongly induced following brain injury and polarises microglia to an anti-inflammatory phenotype. Augmentation of TGFβ 1 responses may therefore be beneficial in preventing inflammation in neurological disorders including stroke and neurodegenerative diseases. However, several other cell types display immunogenic potential and identifying the effect of TGFβ 1 on these cells is required to more fully understand its effects on brain inflammation. Pericytes are multifunctional cells which ensheath the brain vasculature and have garnered recent attention with respect to their immunomodulatory potential. Here, we sought to investigate the inflammatory phenotype adopted by TGFβ 1 -stimulated human brain pericytes. Methods Microarray analysis was performed to examine transcriptome-wide changes in TGFβ 1 -stimulated pericytes, and results were validated by qRT-PCR and cytometric bead arrays. Flow cytometry, immunocytochemistry and LDH/Alamar Blue® viability assays were utilised to examine phagocytic capacity of human brain pericytes, transcription factor modulation and pericyte health. Results TGFβ 1 treatment of primary human brain pericytes induced the expression of several inflammatory-related genes ( NOX4 , COX2 , IL6 and MMP2 ) and attenuated others ( IL8 , CX3CL1 , MCP1 and VCAM1 ). A synergistic induction of IL-6 was seen with IL-1β/TGFβ 1 treatment whilst TGFβ 1 attenuated the IL-1β-induced expression of CX3CL1, MCP-1 and sVCAM-1. TGFβ 1 was found to signal through SMAD2/3 transcription factors but did not modify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) translocation. Furthermore, TGFβ 1 attenuated the phagocytic ability of pericytes, possibly through downregulation of the scavenger receptors CD36, CD47 and CD68. Whilst TGFβ did decrease pericyte number, this was due to a reduction in proliferation, not apoptotic death or compromised cell viability. Conclusions TGFβ 1 attenuated pericyte expression of key chemokines and adhesion molecules involved in CNS leukocyte trafficking and the modulation of microglial function, as well as reduced the phagocytic ability of pericytes. However, TGFβ 1 also enhanced the expression of classical pro-inflammatory cytokines and enzymes which can disrupt BBB functioning, suggesting that pericytes adopt a phenotype which is neither solely pro- nor anti-inflammatory. Whilst the effects of pericyte modulation by TGFβ 1 in vivo are difficult to infer, the reduction in pericyte proliferation together with the elevated IL-6, MMP-2 and NOX4 and reduced phagocytosis suggests a detrimental action of TGFβ 1 on neurovasculature.

Recent studies have reported that glial cell line-derived growth factor (GDNF) has neurotrophic effects on the central nervous system, and the neural stem cells (NSCs) engrafted in animal models of stroke survive and ameliorate the neurological deficits. In this study, a stable human NSC line overexpressing GDNF (F3.GDNF) was transplanted next to the intracerebral hemorrhage (ICH) lesion site and a possible therapeutic effect was investigated. F3.GDNF human NSC line was transplanted into the cortex overlying the striatal ICH lesion. ICH was induced in adult mice by the unilateral injection of bacterial collagenase into the striatum. The animals were evaluated for 8 weeks with rotarod and limb placement tests. Transplanted NSCs were detected by β-gal immunostaining with double labeling of neurofilament, microtubule associated protein-2, glial fibrillary acidic protein or human nuclear matrix antigen (HuNuMA). F3.GDNF human NSCs produced a four times higher amount of GDNF over parental F3 cells in vitro , induced behavioral improvement in ICH mice after brain transplantation and two- to threefold increase in cell survival of transplanted NSCs at 2 and 8 weeks post-transplantation. In F3.GDNF-grafted ICH brain, a significant increase in the antiapoptotic protein and cell survival signal molecules, and a marked reduction in proapoptotic proteins were found as compared with control group. Brain transplantation of human NSCs overexpressing GDNF in ICH animals provided functional recovery in ICH animals, and survival and differentiation of grafted human NSCs. These results indicate that the F3.GDNF human NSCs should be of a great value as a cellular source for the cellular therapy in animal models of human neurological disorders including ICH.