Persistence of lymphocytic choriomeningitis virus at very low levels in immune mice

Lymphocytic choriomeningitis virus (LCMV), strain WE, is a non-cytopathic RNA virus that is highly adapted to its natural host, the mouse. Acute infection of adult mice leads to generalized virus spread, followed by cytotoxic T lymphocyte-mediated virus clearance below the detection levels of conventional assays within 2-3 weeks. Indirect evidence had suggested that virus or viral antigen might persist in the immune mouse. Here we demonstrate LCMV-WE persistence at low levels after infection with 10(2) or 10(6) plaque-forming units, shown as viral genome, viral antigen, and replicative virus using sensitive in vitro and in vivo assays. The finding that LCMV-WE persists in the face of apparently intact immune responses resembles the situation in some viral (hepatitis B and C, HIV) and bacterial (tuberculosis, leprosy) infections in humans; the results are relevant to the understanding not only of other murine and human persistent viral infections but also of protective immunological memory by "infection immunity."     

Non-linear adaptive controllers for an over-actuated pneumatic MR-compatible stepper

Pneumatics is one of the few actuation principles that can be used in an MR environment, since it can produce high forces without affecting imaging quality. However, pneumatic control is challenging, due to the air high compliance and cylinders non-linearities. Furthermore, the system’s properties may change for each subject. Here, we present novel control strategies that adapt to the subject’s individual anatomy and needs while performing accurate periodic gait-like movements with an MRI compatible pneumatically driven robot. In subject-passive mode, an iterative learning controller (ILC) was implemented to reduce the system’s periodic disturbances. To allow the subjects to intend the task by themselves, a zero-force controller minimized the interaction forces between subject and robot. To assist patients who may be too weak, an assist-as-needed controller that adapts the assistance based on online measurement of the subject’s performance was designed. The controllers were experimentally tested. The ILC successfully learned to reduce the variability and tracking errors. The zero-force controller allowed subjects to step in a transparent environment. The assist-as-needed controller adapted the assistance based on individual needs, while still challenged the subjects to perform the task. The presented controllers can provide accurate pneumatic control in MR environments to allow assessments of brain activation.     

Cortical reorganization after motor stroke: A pilot study on differences between the upper and lower limbs

Stroke patients suffering from hemiparesis may show substantial recovery in the first months poststroke due to neural reorganization. While reorganization driving improvement of upper hand motor function has been frequently investigated, much less is known about the changes underlying recovery of lower limb function. We, therefore, investigated neural network dynamics giving rise to movements of both the hands and feet in 12 well‐recovered left‐hemispheric chronic stroke patients and 12 healthy participants using a functional magnetic resonance imaging sparse sampling design and dynamic causal modeling (DCM). We found that the level of neural activity underlying movements of the affected right hand and foot positively correlated with residual motor impairment, in both ipsilesional and contralesional premotor as well as left primary motor (M1) regions. Furthermore, M1 representations of the affected limb showed significantly stronger increase in BOLD activity compared to healthy controls and compared to the respective other limb. DCM revealed reduced endogenous connectivity of M1 of both limbs in patients compared to controls. However, when testing for the specific effect of movement on interregional connectivity, interhemispheric inhibition of the contralesional M1 during movements of the affected hand was not detected in patients whereas no differences in condition‐dependent connectivity were found for foot movements compared to controls. In contrast, both groups featured positive interhemispheric M1 coupling, that is, facilitation of neural activity, mediating movements of the affected foot. These exploratory findings help to explain why functional recovery of the upper and lower limbs often develops differently after stroke, supporting limb‐specific rehabilitative strategies.     

Ischemic lesion water homeostasis after thrombectomy for large vessel occlusion stroke within the anterior circulation: The impact of age

The effect of age on lesion pathophysiology in the context of thrombectomy has been poorly investigated. We aimed to investigate the impact of age on ischemic lesion water homeostasis measured with net water uptake (NWU) within a multicenter cohort of patients receiving thrombectomy for anterior circulation large vessel occlusion (LVO) stroke. Lesion-NWU was quantified in multimodal CT on admission and 24 h for calculating Δ-NWU as their difference. The impact of age and procedural parameters on Δ-NWU was analyzed. Multivariable regression analysis was performed to identify significant predictors for Δ-NWU. Two hundred and four patients with anterior circulation stroke were included in the retrospective analysis. Comparison of younger and elderly patients showed no significant differences in NWU on admission but significantly higher Δ-NWU (p = 0.005) on follow-up CT in younger patients. In multivariable regression analysis, higher age was independently associated with lowered Δ-NWU (95% confidence interval: −0.59 to −0.16, p < 0.001). Although successful recanalization (TICI ≥ 2b) significantly reduced Δ-NWU progression by 6.4% (p < 0.001), younger age was still independently associated with higher Δ-NWU (p < 0.001). Younger age is significantly associated with increased brain edema formation after thrombectomy for LVO stroke. Younger patients might be particularly receptive targets for future adjuvant neuroprotective drugs that influence ischemic edema formation.     

A role for TASK2 channels in the human immunological synapse

The immunological synapse is a transient junction that occurs when the plasma membrane of a T cell comes in close contact with an APC after recognizing a peptide from the antigen-MHC. The interaction starts when CRAC channels embedded in the T cell membrane open, flowing calcium ions into the cell. To counterbalance the ion influx and subsequent depolarization, K_v1.3 and KCa3.1 channels are recruited to the immunological synapse, increasing the extracellular K⁺ concentration. These processes are crucial as they initiate gene expression that drives T cell activation and proliferation. The T cell-specific function of the K_2P channel family member TASK2 channels and their role in autoimmune processes remains unclear. Using mass spectrometry analysis together with epifluorescence and super-resolution single-molecule localization microscopy, we identified TASK2 channels as novel players recruited to the immunological synapse upon stimulation. TASK2 localizes at the immunological synapse, upon stimulation with CD3 antibodies, likely interacting with these molecules. Our findings suggest that, together with K_v1.3 and KCa3.1 channels, TASK2 channels contribute to the proper functioning of the immunological synapse, and represent an interesting treatment target for T cell-mediated autoimmune disorders.     

A case of homozygous familial hypercholesterolemia with an atypical phenotype and delayed clinical symptoms

We describe the casuistry of a homozygous familial hypercholesterolemia female patient with a biallelic missense variant (NM_000527.4:c.1775G>A, p.Gly592Glu) in the LDLR gene, severe hypertriglyceridemia and late manifestation of coronary heart disease not earlier than at the age of 45 years. An atypical phenotype led to a delayed diagnosis.