The Deep Western Boundary Current east of the Grand Banks has been observed during 1999–2005 by moored current‐meter stations and shipboard current profiling sections. These recent observations can ...be compared with those of a WOCE moored array deployed during 1993–95 at the same location. Overall, the observations of Deep Water currents east of the Grand Banks reported here do not support suggestions of a basin‐wide "slowdown" of the Atlantic Meridional Overturning Circulation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
BACKGROUND
The application of personalized vaccines has shown to be effective in patients with newly diagnosed glioblastoma in phase 1 clinical trials. Responses of CD8 T cells directed ...against the glioma-associated antigen Neuroligin-4, X-linked (NLGN4X) were reported in multipeptide vaccine trials in patients with glioblastoma. Here, we characterized the functional status of NLGN4X TCR transgenic T cells in vitro and assessed their therapeutic capacity in vivo.
METHODS
TCR encoding sequences were delivered by lentiviral transduction to activated T cells from healthy donors. After confirmation of TCR surface expression T cells were used for a functional in vitro characterization. For in vivo assessment of NLGN4X-specific TCR transgenic T cells, NLGN4X-expressing U87 glioma cells were injected into the flank of NSG MHCI/MHC II knockout mice, which do not develop graft versus host disease. TCR transgenic T cells were injected intravenously on day 11 and day 18 and tumor size was monitored.
RESULTS
TCR transgenic T cells depicted stable surface expression for at least 11 days in vitro after transduction. Thereby, murine TCR beta constant region positive T cells featured a polyfunctional phenotype demonstrated by a significant increase of Interferon-γ and TNF-α and remained reactive to the NLGN4X epitope for at least 7 days. Additionally, NLGN4X TCR transgenic T cells showed significantly increased antigen-specific production of the cytolytic protein granzyme B and elevated levels of perforin. In a novel xenograft mouse model NLGN4X TCR transgenic T cells slowed the tumor growth compared to the initial tumor size until day 25 after tumor inoculation.
DISCUSSION
We demonstrate that NLGN4X TCR transgenic T cells specifically and consistently recognize their corresponding immunogenic sequence and target antigen-overexpressing glioma cells. We present first evidence of in vivo reactivity, while further experiments are required to assess the full therapeutic potential of NLGN4X-TCR-transgenic T cell therapy for glioma patients.
Epstein-Barr virus (EBV) is a latent and oncogenic human herpesvirus. Lytic viral protein expression plays an important role in EBV-associated malignancies. The EBV envelope glycoprotein 350 (gp350) ...is expressed abundantly during EBV lytic reactivation and sporadically on the surface of latently infected cells. Here we tested T cells expressing gp350-specific chimeric antigen receptors (CARs) containing scFvs derived from two novel gp350-binding, highly neutralizing monoclonal antibodies. The scFvs were fused to CD28/CD3ζ signaling domains in a retroviral vector. The produced gp350CAR-T cells specifically recognized and killed gp350+ 293T cells in vitro. The best-performing 7A1-gp350CAR-T cells were cytotoxic against the EBV+ B95-8 cell line, showing selectivity against gp350+ cells. Fully humanized Nod.Rag.Gamma mice transplanted with cord blood CD34+ cells and infected with the EBV/M81/fLuc lytic strain were monitored dynamically for viral spread. Infected mice recapitulated EBV-induced lymphoproliferation, tumor development, and systemic inflammation. We tested adoptive transfer of autologous CD8+gp350CAR-T cells administered protectively or therapeutically. After gp350CAR-T cell therapy, 75% of mice controlled or reduced EBV spread and showed lower frequencies of EBER+ B cell malignant lymphoproliferation, lack of tumor development, and reduced inflammation. In summary, CD8+gp350CAR-T cells showed proof-of-concept preclinical efficacy against impending EBV+ lymphoproliferation and lymphomagenesis.
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EBV is an oncogenic virus, and lytic infection has been shown to promote malignancies. Slabik et al. showed that CAR-T cells targeting the gp350 envelope protein can react against EBV-infected cells. Humanized mice infected with EBV and treated with gp350CAR-T cells controlled EBV spread and EBV+ lymphoproliferative disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Metal oxides are considered as stable and low‐cost photoelectrode candidates for hydrogen production by photoelectrochemical solar water splitting. However, their power conversion efficiencies ...usually suffer from poor transport of photogenerated charge carriers, which has been attributed previously to a variety of effects occurring on different time and length scales. In search for common understanding and for a better photo‐conducting metal oxide photoabsorber, CuFeO2, α‐SnWO4, BaSnO3, FeVO4, CuBi2O4, α‐Fe2O3, and BiVO4 are compared. Their kinetics of thermalization, trapping, localization, and recombination are monitored continuously 100 fs–100 µs and mobilities are determined for different probing lengths by combined time‐resolved terahertz and microwave spectroscopy. As common issue, we find small mobilities < 3 cm2V‐1s‐1. Partial carrier localization further slows carrier diffusion beyond localization lengths of 1–6 nm and explains the extraordinarily long conductivity tails, which should not be taken as a sign of long diffusion lengths. For CuFeO2, the localization is attributed to electrostatic barriers that enclose the crystallographic domains. The most promising novel material is BaSnO3, which exhibits the highest mobility after reducing carrier localization by annealing in H2. Such overcoming of carrier localization should be an objective of future efforts to enhance charge transport in metal oxides.
The charge carrier transport in many metal oxides including α‐Fe2O3, CuFeO2, α‐SnWO4, FeVO4, BaSnO3, and CuBi2O4, is limited by partial carrier localization. This localization slows carrier diffusion beyond localization lengths of 1–6 nm and explains low TRMC mobilities and the extraordinarily long conductivity tails, which should not necessarily be taken as a sign of long diffusion lengths.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Arginine (ARG) derivatives and thyroid function independently influence atherosclerotic processes. Since thyroid hormones may mediate the association between ARG derivatives and atherosclerosis, this ...study investigated whether asymmetric and symmetric dimethylarginines (ADMA and SDMA, respectively) as well as homoarginine (hARG) are associated with parameters of thyroid function in the general population.
Cross-sectional data from 3689 individuals aged 20-81 years from the population-based Study of Health in Pomerania (SHIP-0) were analyzed. Thyroid function was defined according to serum concentrations of thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4). Low and high serum TSH were defined by the cutoffs 0.3 mIU/L and 3 mIU/L, respectively. Serum concentrations of ARG, ADMA, SDMA, and hARG were measured using liquid chromatography-tandem mass spectrometry. ARG, ADMA, SDMA, and hARG were associated with serum concentrations of TSH, fT3, and fT4 by median regression and with categorized TSH values by multinomial logistic regression adjusted for age, sex, smoking status, physical activity, body mass index, and estimated glomerular filtration rate.
Levels of ADMA (relative risk RR = 5.40 confidence interval (CI) 1.96-14.86) and SDMA (RR = 3.55 CI 1.01-12.70) were associated with low TSH. In addition, ADMA (β = 0.38 CI 0.23-0.45) was positively associated with fT3, while both ADMA (β = 0.98 CI 0.43-1.54) and SDMA (β = 1.19 CI 0.50-1.88) were positively associated with fT4. No consistent associations of ARG and hARG with thyroid function were detected.
The positive associations of ADMA and SDMA with low TSH, fT3, and fT4 argue for a relationship of arginine derivatives with increased thyroid function. This suggests that the atherogenic properties of ADMA and SDMA may be partially mediated by thyroid function.
Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it ...is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Long term mooring observations show a substantial warming of the Deep Labrador Current (DLC) during the last decade. In this paper we address the question of whether these water mass changes are ...accompanied by comparable changes in the deep western boundary current. Individual estimates of alongshore current from moored instruments and transports from Lowered ADCP sections indicate a systematic increase of the boundary current strength on the order of 15% of the mean from the period prior to 1999 to the period thereafter. A combination of these measurements allows the indexing of DLC intensity over the last decade.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Pandemics like SARS-Cov-2 very frequently have their origin in different animals and in particular herds of camels could be a source of zoonotic diseases. This study took advantage on a highly ...sensitive and adaptable method for the fast and reliable detection of viral antibodies in camels using low-cost equipment. Magnetic nanoparticles (MNP) have high variability in their functionalization with different peptides and proteins. We confirm that 3-aminopropyl triethoxysilane (APTES)-coated MNP could be functionalized with viral proteins. The protein loading could be confirmed by simple loading controls using FACS-analysis (
p
< 0.05). Complementary combination of antigen and antibody yields in a significant signal increase could be proven by both FACS and COMPASS. However, COMPASS needs only a few seconds for the measurement. In COMPASS, the phase
φ
n
on selected critical point of the fifth higher harmonic (
n
= 5th). Here, positive sera display highly significant signal increase over the control or negative sera. Furthermore, a clear distinction could be made in antibody detection as an immune response to closely related viruses (SARS-CoV2 and MERS). Using modified MNPs along with COMPASS offers a fast and reliable method that is less cost intensive than current technologies and offers the possibility to be quickly adapted in case of new occurring viral infections.
Key points
• COMPASS (critical offset magnetic particle spectroscopy) allows the fast detection of antibodies.
• Magnetic nanoparticles can be adapted by exchange of the linked bait molecule.
• Antibodies could be detected in camel sera without washing steps within seconds.
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CEKLJ, DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In dystrophic mdx skeletal muscle, aberrant Ca2+ homeostasis and fibre degeneration are found. The absence of dystrophin in models of Duchenne muscular dystrophy (DMD) has been connected to altered ...ion channel properties e.g. impaired L-type Ca2+ currents. In regenerating mdx muscle, 'revertant' fibres restore dystrophin expression. Their functionality involving DHPR-Ca2+-channels is elusive.
We developed a novel 'in-situ' confocal immuno-fluorescence and imaging technique that allows, for the first time, quantitative subcellular dystrophin-DHPR colocalization in individual, non-fixed, muscle fibres. Tubular DHPR signals alternated with second harmonic generation signals originating from myosin. Dystrophin-DHPR colocalization was substantial in wt fibres, but diminished in most mdx fibres. Mini-dystrophin (MinD) expressing fibres successfully restored colocalization. Interestingly, in some aged mdx fibres, colocalization was similar to wt fibres. Most mdx fibres showed very weak membrane dystrophin staining and were classified 'mdx-like'. Some mdx fibres, however, had strong 'wt-like' dystrophin signals and were identified as 'revertants'. Split mdx fibres were mostly 'mdx-like' and are not generally 'revertants'. Correlations between membrane dystrophin and DHPR colocalization suggest a restored putative link in 'revertants'. Using the two-micro-electrode-voltage clamp technique, Ca2+-current amplitudes (i(max)) showed very similar behaviours: reduced amplitudes in most aged mdx fibres (as seen exclusively in young mdx mice) and a few mdx fibres, most likely 'revertants', with amplitudes similar to wt or MinD fibres. Ca2+ current activation curves were similar in 'wt-like' and 'mdx-like' aged mdx fibres and are not the cause for the differences in current amplitudes. i(max) amplitudes were fully restored in MinD fibres.
We present evidence for a direct/indirect DHPR-dystrophin interaction present in wt, MinD and 'revertant' mdx fibres but absent in remaining mdx fibres. Our imaging technique reliably detects single isolated 'revertant' fibres that could be used for subsequent physiological experiments to study mechanisms and therapy concepts in DMD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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