Tolerance without clonal expansion: Self-antigen-expressing B cells program self-reactive T cells for future deletion

B cells have been shown in various animal models to induce immunological tolerance leading to reduced immune responses and protection from autoimmunity. We show that interaction of B cells with naive T cells results in T cell triggering accompanied by the expression of negative costimulatory molecules such as PD-1, CTLA-4, B and T lymphocyte attenuator, and CD5. Following interaction with B cells, T cells were not induced to proliferate, in a process that was dependent on their expression of PD-1 and CTLA-4, but not CD5. In contrast, the T cells became sensitive to Ag-induced cell death. Our results demonstrate that B cells participate in the homeostasis of the immune system by ablation of conventional self-reactive T cells

Aeroelastic Design of the oLAF Reference Aircraft Configuration

One of the main aims of the EU Flightpath 2050 is to significantly reducet he fuel consumption of upcoming designs for transport aircraft. To achieve this challenging goal, new technologies have to be investigated. In this context, the development of the 'optimally load adaptive aircraft' (oLAF) for a conventional design is one of the main goals of the DLR project oLAF. Since the lift-to-drag ration, the structural mass and the thrust specific fuel consumption are the main drivers of the aircraft's fuel consumption, an improvement in all three topics seems to be a promising approach to fulfill the intended aims of the European Union. That's why the design of the new oLAF configuration is equipped with a next generation three shaft geared turbofan engine with an ultra-high bypass-ration and an optimized aerodynamic performance combined with aggressive loadalleviation (LA) techniques to lighten the load-carrying structure of the aircraft significantly compared to a conventional state-of-the-art aircraft. Multiple design cycles with different degree of fidelity and LA approaches are planned to be performed within oLAF. At the current state of the project, three different designs are available. On the one hand, there is the more basic configuration of the overall aircraft design (OAD) further called 'oLAF_SLv1'. On the other hand, there are configurations with more mature aerodynamic characteristics further called the oLAF_ASv0 configuration as start design for a multidisciplinary-design-optimization (MDO) process and the 'oLAF_ASv1' as the optimized result of the MDO. All configurations have been analyzed and evaluated using the aeroelastic structural design tool cpacs-MONA. The optimized 'oLAF_ASv1' configuration has furthermore been checked on aeroelastic stability. Conclusively, the stiffness of the structural pylon model has been adapted to shift a hump-mode of the new generation engine to higher airspeeds, so that the instability occurs outside of the flight envelope

Prevalence, Enabling Factors, and Clinical Outcome

Background: Striatocapsular infarcts (SCIs) are defined as large subcortical infarcts involving the territory of more than one lenticulostriate artery. SCI without concomitant ischemia in the more distal middle cerebral artery (MCA) territory [isolated SCI (iSCI)] has been described as a rare infarct pattern. The purpose of this study was to assess the prevalence of iSCI in patients treated with endovascular thrombectomy (ET), to evaluate baseline and procedural parameters associated with this condition, and to describe the clinical course of iSCI patients. Methods: A retrospective analysis of 206 consecutive patients with an isolated MCA occlusion involving the lenticulostriate arteries and treated with ET was performed. Baseline patient and procedural characteristics and ischemic involvement of the striatocapsular and distal MCA territory [iSCI, as opposed to non-isolated SCI (niSCI)] were analyzed using multivariate logistic regression models. Prevalence of iSCI was assessed, and clinical course was determined with the rates of substantial neurological improvement and good functional short- and mid-term outcome (discharge/day 90 Modified Rankin Scale ≤2). Results: iSCI was detected in 53 patients (25.7%), and niSCI was detected in 153 patients (74.3%). Successful reperfusion [thrombolysis in cerebral infarction (TICI) 2b/3] [adjusted odds ration (aOR) 8.730, 95% confidence interval (95% CI) 1.069–71.308] and good collaterals (aOR 2.100, 95% CI 1.119–3.944) were associated with iSCI. In successfully reperfused patients, TICI 3 was found to be an additional factor associated with iSCI (aOR 5.282, 1.759–15.859). Patients with iSCI had higher rates of substantial neurological improvement (71.7 vs. 37.9%, p < 0.001) and higher rates of good functional short- and mid-term outcome (58.3 vs. 23.7%, p < 0.001 and 71.4 vs. 41.7%, p < 0.001). However, while iSCI patients, in general, had a more favorable outcome, considerable heterogeneity in outcome was observed. Conclusion: High rates of successful reperfusion (TICI 2b/3) and in particular, complete reperfusion (TICI 3) are associated with iSCIs. The high prevalence of iSCI in successfully reperfused patients with good collaterals corroborates previous concepts of iSCI pathogenesis. iSCI, once considered a rare pattern of cerebral ischemia, is likely to become more prevalent with increases in endovascular stroke therapy. This may have implications for patient rehabilitation and pathophysiological analyses of ischemic damage confined to subcortical regions of the MCA territory

Isolated Striatocapsular Infarcts after Endovascular Treatment of Acute Proximal middle Cerebral Artery Occulusion: Prevalence, Enabling Factors, and Clinical Outcomes

Background: Striatocapsular infarcts (SCIs) are defined as large subcortical infarcts involving the territory of more than one lenticulostriate artery. SCI without concomitant ischemia in the more distal middle cerebral artery (MCA) territory [isolated SCI (iSCI)] has been described as a rare infarct pattern. The purpose of this study was to assess the prevalence of iSCI in patients treated with endovascular thrombectomy (ET), to evaluate baseline and procedural parameters associated with this condition, and to describe the clinical course of iSCI patients. Methods: A retrospective analysis of 206 consecutive patients with an isolated MCA occlusion involving the lenticulostriate arteries and treated with ET was performed. Baseline patient and procedural characteristics and ischemic involvement of the striatocapsular and distal MCA territory [iSCI, as opposed to non-isolated SCI (niSCI)] were analyzed using multivariate logistic regression models. Prevalence of iSCI was assessed, and clinical course was determined with the rates of substantial neurological improvement and good functional short-and mid-term outcome (discharge/day 90 Modified Rankin Scale <= 2). Results: iSCI was detected in 53 patients (25.7%), and niSCI was detected in 153 patients (74.3%). Successful reperfusion [thrombolysis in cerebral infarction (TICI) 2b/3] [adjusted odds ration (aOR) 8.730, 95% confidence interval (95% CI) 1.069-71.308] and good collaterals (aOR 2.100, 95% CI 1.119-3.944) were associated with iSCI. In successfully reperfused patients, TICI 3 was found to be an additional factor associated with iSCI (aOR 5.282, 1.759-15.859). Patients with iSCI had higher rates of substantial neurological improvement (71.7 vs. 37.9%, p < 0.001) and higher rates of good functional short-and mid-term outcome (58.3 vs. 23.7%, p < 0.001 and 71.4 vs. 41.7%, p < 0.001). However, while iSCI patients, in general, had a more favorable outcome, considerable heterogeneity in outcome was observed. Conclusion: High rates of successful reperfusion (TICl 2b/3) and in particular, complete reperfusion (TICl 3) are associated with iSCls. The high prevalence iSCl in successfully reperfused patients with good collaterals corroborates previous concepts of iSCl partho-genesis. iSCl, once considered a rare pattern of cerebral ischemia, is likely to become more prevalent with increase in endovascular stroke therapy. This may have implications for patient rehabilitation and pathophysiological analysis of ischemic damage confind to subcortical regions of the MCA territory

Cell-Type-Specific Complement Expression in the Healthy and Diseased Retina

Complement dysregulation is a feature of many retinal diseases, yet mechanistic understanding at the cellular level is limited. Given this knowledge gap about which retinal cells express complement, we performed single-cell RNA sequencing on similar to 92,000 mouse retinal cells and validated our results in five major purified retinal cell types. We found evidence for a distributed cell-type-specific complement expression across 11 cell types. Notably, Muller cells are the major contributor of complement activators c1s, c3, c4, and cfb. Retinal pigment epithelium (RPE) mainly expresses cfh and the terminal complement components, whereas cfi and cfp transcripts are most abundant in neurons. Aging enhances c1s, cfb, cfp, and cfi expression, while cfh expression decreases. Transient retinal ischemia increases complement expression in microglia, Muller cells, and RPE. In summary, we report a unique complement expression signature for murine retinal cell types suggesting a well-orchestrated regulation of local complement expression in the retinal microenvironment

Early Thrombectomy Protects the Internal Capsule in Patients With Proximal Middle Cerebral Artery Occlusion.

BACKGROUND AND PURPOSE Proximal middle cerebral artery (MCA) occlusions impede blood flow to the noncollateralized lenticulostriate artery territory. Previous work has shown that this almost inevitably leads to infarction of the dependent gray matter territories in the striate even if perfusion is restored by mechanical thrombectomy. Purpose of this analysis was to evaluate potential sparing of neighboring fiber tracts, ie, the internal capsule. METHODS An observational single-center study of patients with proximal MCA occlusions treated with mechanical thrombectomy and receiving postinterventional high-resolution diffusion-weighted imaging was conducted. Patients were classified according to internal capsule ischemia (IC+ versus IC-) at the postero-superior level of the MCA lenticulostriate artery territory (corticospinal tract correlate). Associations of IC+ versus IC- with baseline variables as well as its clinical impact were evaluated using multivariable logistic or linear regression analyses adjusting for potential confounders. RESULTS Of 92 included patients with proximal MCA territory infarctions, 45 (48.9%) had an IC+ pattern. Longer time from symptom-onset to groin-puncture (adjusted odds ratio, 2.12 [95% CI, 1.19-3.76] per hour), female sex and more severe strokes were associated with IC+. Patients with IC+ had lower rates of substantial neurological improvement and functional independence (adjusted odds ratio, 0.26 [95% CI, 0.09-0.81] and adjusted odds ratio, 0.25 [95% CI, 0.07-0.86]) after adjustment for confounders. These associations remained unchanged when confining analyses to patients without ischemia in the corona radiata or the motor cortex and here, IC+ was associated with higher National Institutes of Health Stroke Scale motor item scores (β, +2.8 [95% CI, 1.5 to 4.1]) without a significant increase in nonmotor items (β, +0.8 [95% CI, -0.2 to 1.9). CONCLUSIONS Rapid mechanical thrombectomy with successful reperfusion of the lenticulostriate arteries often protects the internal capsule from subsequent ischemia despite early basal ganglia damage. Salvage of this eloquent white matter tract within the MCA lenticulostriate artery territory seems strongly time-dependent, which has clinical and pathophysiological implications

Impact of time to endovascular reperfusion on outcome differs according to the involvement of the proximal MCA territory.

BACKGROUND The time interval between symptom onset and reperfusion is a major determinant of the benefit of endovascular therapy (ET) and patients' outcome. The impact of time may be attenuated in patients with robust collaterals. However, not all regions in the middle cerebral artery (MCA) territory have access to collaterals. PURPOSE To evaluate if the involvement of the poorly collateralized proximal MCA territory has an impact on the degree of time dependency of patients' outcome. METHODS Patients with MCA occlusions treated with ET and involvement/sparing of the proximal striatocapsular MCA territory (SC+/SC-, each n=97) were matched according to their symptom onset to reperfusion times (SORTs). Correlation and impact of time on outcome was evaluated with strata of SC+/SC- using multivariate logistic regression models (LRMs), including interaction terms. Discharge National Institute of Health Stroke Scale (NIHSS-DIS) score <5 and discharge modified Rankin Scale (mRS-DIS) score ≤2 were prespecified outcome measures. RESULTS A stronger correlation between all outcome measures (NIHSS-DIS/ΔNIHSS/mRS-DIS) and SORTs was found for SC+ patients than for SC-patients. SORTs were significant variables in LRMs for mRS-DIS score ≤2 and NIHSS-DIS score <5 in SC+ but not in SC- patients. Interaction of SC+ and SORTs was significant in LRMs for both endpoints. CONCLUSION Time dependency of outcome after ET is more pronounced if parts of the proximal MCA territory are affected. This may reflect the lack of collateralization in the striatocapsular region and a more stringent cell death with time. If confirmed, this finding may affect the selection of patients based on different time windows according to the territory at risk

BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella

The X‐linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor, best known for its anti‐apoptotic function in cancer. During apoptosis, XIAP is antagonized by SMAC, which is released from the mitochondria upon caspase‐mediated activation of BID. Recent studies suggest that XIAP is involved in immune signaling. Here, we explore XIAP as an important mediator of an immune response against the enteroinvasive bacterium Shigella flexneri, both in vitro and in vivo. Our data demonstrate for the first time that Shigella evades the XIAP‐mediated immune response by inducing the BID‐dependent release of SMAC from the mitochondria. Unlike apoptotic stimuli, Shigella activates the calpain‐dependent cleavage of BID to trigger the release of SMAC, which antagonizes the inflammatory action of XIAP without inducing apoptosis. Our results demonstrate how the cellular death machinery can be subverted by an invasive pathogen to ensure bacterial colonization