Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures.

The Alzheimer disease-associated multifunctional low-density lipoprotein receptor-related protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knock-out (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The low-density lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic low-density lipoprotein receptor-related protein-1 for glutamatergic signaling in the context of neuron-glia interactions and stage this receptor as a contributing factor for epilepsy.

Intrinsic cellular and molecular properties of in vivo hippocampal synaptic plasticity are altered in the absence of key synaptic matrix molecules.

Hippocampal synaptic plasticity comprises a key cellular mechanism for information storage. In the hippocampus, both long-term potentiation (LTP) and long-term depression (LTD) are triggered by synaptic Ca2+ -elevations that are typically mediated by the opening of voltage-gated cation channels, such as N-methyl-d-aspartate receptors (NMDAR), in the postsynaptic density. The integrity of the post-synaptic density is ensured by the extracellular matrix (ECM). Here, we explored whether synaptic plasticity is affected in adult behaving mice that lack the ECM proteins brevican, neurocan, tenascin-C, and tenascin-R (KO). We observed that the profiles of synaptic potentiation and depression in the dentate gyrus (DG) were profoundly altered compared to plasticity profiles in wild-type littermates (WT). Specifically, synaptic depression was amplified in a frequency-dependent manner and although late-LTP (>24 hr) was expressed following strong afferent tetanization, the early component of LTP (<75 min post-tetanization) was absent. LTP (>4 hr) elicited by weaker tetanization was equivalent in WT and KO animals. Furthermore, this latter form of LTP was NMDAR-dependent in WT but not KO mice. Scrutiny of DG receptor expression revealed significantly lower levels of both the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor, of the metabotropic glutamate receptor, mGlu5 and of the L-type calcium channel, Cav 1.3 in KO compared to WT animals. Homer 1a and of the P/Q-type calcium channel, Cav 1.2 were unchanged in KO mice. Taken together, findings suggest that in mice that lack multiple ECM proteins, synaptic plasticity is intact, but is fundamentally different.

High prevalence of pelvic floor muscle dysfunction in hospitalized elderly women with urinary incontinence.

INTRODUCTION AND HYPOTHESIS: The purpose of this study was to determine pelvic floor muscle (PFM) function in hospitalized elderly women with urinary incontinence (UI). METHODS: A cross-sectional study was performed using data of 704 patients, routinely collected by means of a clinical UI assessment. RESULTS: Only 25.5% of the patients were able to perform normal PFM contractions (Oxford grading scale score ≥3); 74.5% were unable to contract their PFM or showed weak PFM activity without circular contraction or elevation of the vagina. Vulvovaginal mucosal dystrophy was noted in 84% of the patients. A significant positive correlation of PFM function was found to cognitive status (MMSE score), mobility (Tinetti performance score), and history of previous PFM training; a negative correlation of PFM function was found to patients' age and vulvovaginal mucosal dystrophy, and no significant correlation to body mass index, parity, or history of hysterectomy. CONCLUSIONS: Targeted clinical UI assessment including digital vaginal palpation should be performed in all incontinent elderly women in order to detect PFM dysfunction and to optimize therapeutic measures.

Injuries of the sternoclavicular region indicate concomitant lesions and need distinguished imaging.

PURPOSE: To evaluate injuries of the sternoclavicular region as indicator injury for relevant concomitant injuries and to evaluate the modalities of initial imaging. We hypothesised a high incidence of concomitant injuries as well as a deficiency of X-ray as the initial gold standard. METHODS: We retrospectively analysed patients suffering from injuries of the sternoclavicular region between 2002 and 2017. We analysed amongst injury type and severity, initial imaging (X-ray vs. CT scan of the sternoclavicular region vs. whole-body scan), and complement of imaging with regard to defined concomitant injury localisations and the resulting necessity and urgency of surgery. RESULTS: We included n = 61 patients. The mean ISS was 13.5 ± 17, n = 13 (21.3%) cases were classified as "severely injured" (ISS ≥ 16). N = 29 (47.5%) achieved an initial X-ray, n = 10 (16.4%) an initial CT scan of the sternoclavicular region, and n = 22 (36%) an initial whole-body CT scan. Initial imaging correlated significantly with ISS. In n = 21 (72.4%) cases of the X-ray group a significant complement from X-ray to CT scan of the sternoclavicular region was indicated (p ≤ 0.001). N = 31 (50.8%) patients suffered from concomitant injuries. N = 39 (63.9%) of all patients underwent any kind of surgery, thereof n = 23 (37.7%) related to their sternoclavicular injuries. CONCLUSION: Injuries of the sternoclavicular complex are indicators for the presence of multiple injuries. A CT scan of the sternoclavicular region including ipsilateral apex of the lung and upper rib cage comprised a large proportion of concomitant injuries. Mapping those injuries during initial imaging improves treatment process, avoids underdiagnostic, and decreases uncertainties.

CombAlign: a protein sequence comparison algorithm considering recombinations.

The basic linear treatment of sequence comparisons limits the ability of contemporary sequence alignment algorithms to detect non-order-conserving recombinations. Here, we introduce the algorithm combAlign which addresses the assessment of pairwise sequence similarity on non-order-conserving recombinations on a large scale. Emphasizing a two-level approach, combAlign first detects locally well conserved subsequences in a target and a source sequence. Subsequently, the relative placement of alignments is mapped to a graph. Concatenating local alignments to reassemble the target sequence to the fullest extent, the maximum scoring path through the graph denotes the best attainable combAlignment. Parameters influencing this process can be set to meet the user's specific demands. combAlign is applied to examples demonstrating the possibility to reflect evolutionary kinship of proteins even if their domains and motifs are strongly rearranged.