The maintenance of immune homeostasis requires regulatory T cells (Tregs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report ...that impaired expression of the transcription factor (TF) Helios by FoxP3+ CD4 and Qa-1–restricted CD8 Tregs results in defective regulatory activity and autoimmunity in mice. Helios-deficient Tregs develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 Tregs also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. The definition of Helios as a key transcription factor that stabilizes Tregs in the face of inflammatory responses provides a genetic explanation for a core property of Tregs.
Highlights • Glibenclamide reduced brain edema by 15% 24 h after CCI injury in rats. • Glibenclamide diminished contusion volumes assessed by MRI imaging (8 h–7 d post CCI). • Glibenclamide-treated ...rats showed reduced number and duration of epileptic seizures. • Mikrodialyses showed a positive correlation between glutamate and epileptic seizures.
We aim to summarize the available evidence on the diagnostic accuracy of imaging (index test) compared to surgery (reference test) for identifying lumbar disc herniation (LDH) in adult patients.For ...this systematic review we searched MEDLINE, EMBASE and CINAHL (June 2017) for studies that assessed the diagnostic accuracy of imaging for LDH in adult patients with low back pain and surgery as the reference standard. Two review authors independently selected studies, extracted data and assessed risk of bias. We calculated summary estimates of sensitivity and specificity using bivariate analysis, generated linked ROC plots in case of direct comparison of diagnostic imaging tests and assessed the quality of evidence using the GRADE-approach.We found 14 studies, all but one done before 1995, including 940 patients. Nine studies investigated Computed Tomography (CT), eight myelography and six Magnetic Resonance Imaging (MRI). The prior probability of LDH varied from 48.6 to 98.7%. The summary estimates for MRI and myelography were comparable with CT (sensitivity: 81.3% (95%CI 72.3-87.7%) and specificity: 77.1% (95%CI 61.9-87.5%)). The quality of evidence was moderate to very low.
The diagnostic accuracy of CT, myelography and MRI of today is unknown, as we found no studies evaluating today's more advanced imaging techniques. Concerning the older techniques we found moderate diagnostic accuracy for all CT, myelography and MRI, indicating a large proportion of false positives and negatives.
Spin accumulation is generated by passing a charge current through a ferromagnetic layer and sensed by other ferromagnetic layers downstream. Pure spin currents can also be generated in which spin ...currents flow and are detected as a nonlocal resistance in which the charge current is diverted away from the voltage measurement point. Here, we report nonlocal spin-transport on two-dimensional surface-conducting SrTiO3 (STO) without a ferromagnetic spin-injector via the spin Hall effect (and inverse spin Hall effect). By applying magnetic fields to the Hall bars at different angles to the nonlocal spin-diffusion, we demonstrate an anisotropic spin-signal that is consistent with a Hanle precession of a pure spin current. We extract key transport parameters for surface-conducting STO, including: a spin Hall angle of γ ≈ (0.25 ± 0.05), a spin lifetime of τ ∼ 49 ps, and a spin diffusion length of λs ≈ (1.23 ± 0.7) μm at 2 K.
Members of the International Skeletal Society compiled a glossary of terms for musculoskeletal radiology. The authors also represent national radiology or pathology societies in Asia, Australia, ...Europe, and the USA. We provide brief descriptions of musculoskeletal structures, disease processes, and syndromes and address their imaging features. Given the abundance of musculoskeletal disorders and derangements, we chose to omit most terms relating to neoplasm, spine, intervention, and pediatrics. Consensus agreement was obtained from 19 musculoskeletal radiology societies worldwide.
The aim of this follow-up study was to demonstrate the effect of percutaneous interventional treatment on local microcirculation of peripheral vascular malformations using CEUS and TIC analysis.
...Retrospective analysis of 197 patients (136 female; 61 male; 3-86 years) with 135 venous (VM), 39 arterio-venous (AVM), 8 lymphatic and 15 veno-lymphatic peripheral vascular malformations before and after the first percutaneous treatment.CEUS was performed after i.v. injection of 1-2.4 ml of sulfur hexafluoride microbubbles (SonoVue®) using a 6-9 MHz linear probe. Digitally stored cine loops (starting in the early arterial phase for 60 sec) were read by independent readers in consensus. Regions of interest (ROI) were defined in the center and at the margins of the malformation, as well as in the healthy surrounding tissue. TIC analyses with Time to Peak (TTP) and Area under the Curve (AUC) were calculated using integrated perfusion software.
After the treatment there was a significant decrease for median AUC in VM in the center from 297.8 (14.5-2167.6) rU down to 243.3 (0.1-1678.8) rU (p = 0.043) and in the surrounding tissue down to 107.7 (20.2-660.2) rU (p = 0.018). For the other malformations AUC decreased in the center and the margins as well. TTP rose, however these changes did not reach the level of significance.
Analyzing the capillary microcirculation TICs offer a possibility of monitoring therapy-induced capillary changes of vascular malformations.
IONIS‐FXIRX (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI (FXI) and has been investigated in healthy volunteers and patients with end‐stage renal ...disease (ESRD). FXI‐LICA (BAY2976217) shares the same RNA sequence as IONIS‐FXIRX but contains a GalNAc‐conjugation that facilitates asialoglycoprotein receptor (ASGPR)‐mediated uptake into hepatocytes. FXI‐LICA has been studied in healthy volunteers and is currently investigated in patients with ESRD on hemodialysis. We present a model‐informed bridging approach that facilitates the extrapolation of the dose‐exposure‐FXI relationship from IONIS‐FXIRX to FXI‐LICA in patients with ESRD and, thus, supports the selection of FX‐LICA doses being investigated in patients with ESRD. A two‐compartment pharmacokinetic (PK) model, with mixed first‐ and zero‐order subcutaneous absorption and first‐order elimination, was combined with an indirect response model for the inhibitory effect on the FXI synthesis rate via an effect compartment. This PK/pharmacodynamic model adequately described the median trends, as well as the interindividual variabilities for plasma drug concentration and FXI activity in healthy volunteers of IONIS‐FXIRX and FXI‐LICA, and in patients with ESRD of IONIS‐FXIRX. The model was then used to predict dose‐dependent steady‐state FXI activity following repeat once‐monthly doses of FXI‐LICA in a virtual ESRD patient population. Under the assumption of similar ASGPR expression in patients with ESRD and healthy volunteers, doses of 40 mg, 80 mg, and 120 mg FXI‐LICA are expected to cover the target range of clinical interest for steady‐state FXI activity in the phase IIb study of FXI‐LICA in patients with ESRD undergoing hemodialysis.
To fulfill its role in protein biogenesis, the endoplasmic reticulum (ER) depends on the Hsp70-type molecular chaperone BiP, which requires a constant ATP supply. However, the carrier that catalyzes ...ATP uptake into the ER was unknown. Here, we report that our screen of gene expression datasets for member(s) of the family of solute carriers that are co-expressed with BiP and are ER membrane proteins identifies SLC35B1 as a potential candidate. Heterologous expression of SLC35B1 in E. coli reveals that SLC35B1 is highly specific for ATP and ADP and acts in antiport mode. Moreover, depletion of SLC35B1 from HeLa cells reduces ER ATP levels and, as a consequence, BiP activity. Thus, human SLC35B1 may provide ATP to the ER and was named AXER (ATP/ADP exchanger in the ER membrane). Furthermore, we propose an ER to cytosol low energy response regulatory axis (termed lowER) that appears as central for maintaining ER ATP supply.
The immunological interactions that regulate the T-cell response to chronic viral infection are insufficiently understood. Here we study a cellular interaction that may enhance the antiviral immune ...response and constrain immunopathology. We analyze the contribution of Qa-1-restricted CD8 ⁺ regulatory T cells (Treg cells) to antiviral immunity after infection by lymphocytic choriomeningitis virus. These CD8 ⁺ Treg cells recognize and eliminate target cells through an interaction with the murine class Ib MHC molecule Qa-1 (HLA-E in humans). Using Qa-1 mutant mice (B6.Qa-1-D227K B6-DK) that harbor a single mutation that abrogates binding of Qa-1 peptide to the CD8–TCR (T-cell receptor) complex, we show that disruption of immune suppression mediated by CD8 ⁺ Treg cells results in robust antiviral immune responses in both acute and chronic viral infection. Enhanced antiviral responses of B6-DK mice were accompanied by increased control of virus, reduced tissue inflammation in the acute phase, and dramatic alleviation of disease in the chronic phase. In addition, CD8 ⁺ effector T cells in B6-DK mice displayed a less exhausted phenotype characterized by decreased expression of programmed cell death 1 (PD-1), LAG3 (CD223), and 2B4 (CD244) and increased expression of NKG2D (CD314) and killer cell lectin-like receptor subfamily G member 1 (KLRG1). Enhanced antiviral immunity in B6-DK mice reflected, in part, reduced inhibition of CD8 ⁺ effector cells by CD8 ⁺ Treg cells. These findings indicate that direct inhibition of effector CD8 ⁺ T cells by Qa-1-restricted CD8 ⁺ Treg cells results in increased disease severity and delayed recovery. These data suggest that depletion or inactivation of CD8 ⁺ Treg cells represents a potentially effective strategy to enhance protective immunity to chronic viral infection.
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