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Abstract Frontal and parietal brain regions are involved in attentional control and prospective memory. It is debated, however, whether increased or decreased activity in those regions is beneficial for older adults’ task performance. We therefore aimed to systematically modulate activity in those regions using high-definition transcranial direct current stimulation. We included n = 106 healthy adults (60–75 years old, 58% female) in a randomized, double-blind, and sham-controlled study. We evaluated task performance twice in the laboratory and at home and additionally assessed heart rates. Participants received cathodal, anodal, or sham stimulation of the left or right inferior frontal lobe, or the right superior parietal lobe (1 mA for 20 min). Performance improved at visit two in laboratory tasks but declined in at-home tasks. Stimulation did not modulate performance change in laboratory tasks but prevented decline in at home-tasks. Heart rates increased at visit two but only when right inferior frontal lobe activity was inhibited. Repeating a task seems more beneficial than stimulation for laboratory tasks. This might be different for at-home tasks. Inhibiting right frontal brain function increases heart rates, possibly due to a modulation of the frontal-vagal brain-heart axis.

Abstract Background Prospective memory is important for our health and independence but declines with age. Hence, interventions to enhance prospective memory, for example by providing an incentive, may promote healthy ageing. The neuroanatomical correlates of prospective memory and the processing of incentive-related prospective memory changes in older adults are not fully understood. In an fMRI study, we will therefore test whether incentives improve prospective memory in older adults and how prospective memory is processed in the brain in general, and when incentives are provided. Since goals and interests change across adulthood, avoiding losses is becoming more important for older adults than achieving gains. We therefore posit that loss-related incentives will enhance prospective memory, which will be subserved by increased prefrontal and midbrain activity. Methods We will include n = 60 healthy older adults (60–75 years of age) in a randomized, single-blind, and parallel-group study. We will acquire 7T fMRI data in an incentive group and a control group (n = 30 each, stratified by education, age, and sex). Before and after fMRI, all participants will complete questionnaires and cognitive tests to assess possible confounders (e.g., income, personality traits, sensitivity to reward or punishment). Discussion The results of this study will clarify whether loss-related incentives can enhance prospective memory and how any enhancement is processed in the brain. In addition, we will determine how prospective memory is processed in the brain in general. The results of our study will be an important step towards a better understanding of how prospective memory changes when we get older and for developing interventions to counteract cognitive decline.

Abstract Background The influence of both individual factors and, in particular, the regional labour market on the return to work after medical rehabilitation is to be analyzed based on comprehensive administrative data from the German Pension Insurance and Employment Agencies. Method For rehabilitation in 2016, pre- and post-rehabilitation employment was determined from German Pension Insurance data for 305,980 patients in 589 orthopaedic rehabilitation departments and 117,386 patients in 202 psychosomatic rehabilitation departments. Labour market data was linked to the district of residence and categorized into 257 labour market regions. RTW was operationalized as the number of employment days in the calendar year after medical rehabilitation. Predictors are individual data (socio-demographics, rehabilitation biography, employment biography) and contextual data (regional unemployment rate, rehabilitation department level: percentage of patients employed before). The estimation method used was fractional logit regression in a cross-classified multilevel model. Results The effect of the regional unemployment rate on RTW is significant yet small. It is even smaller (orthopaedics) or not significant (psychosomatics) when individual employment biographies (i.e., pre-rehabilitation employment status) are inserted into the model as the most important predictors. The interaction with pre-rehabilitation employment status is not substantial. Conclusions Database and methods are of high quality, however due to the nonexperimental design, omitted variables could lead to bias and limit causal interpretation. The influence of the labour market on RTW is small and proxied to a large extent by individual employment biographies. However, if no (valid) employment biographies are available, the labour market should be included in RTW analyses.

PEX19 binding sites are essential parts of the targeting signals of peroxisomal membrane proteins (mPTS). In this study, we characterized PEX19 binding sites of PEX11, the most abundant peroxisomal and glycosomal membrane protein from Trypanosoma brucei and Saccharomyces cerevisiae. TbPEX11 contains two PEX19 binding sites, one close to the N-terminus (BS1) and a second in proximity to the first transmembrane domain (BS2). The N-terminal BS1 is highly conserved across different organisms and is required for maintenance of the steady-state concentration and efficient targeting to peroxisomes and glycosomes in both baker’s yeast and Trypanosoma brucei. The second PEX19 binding site in TbPEX11 is essential for its glycosomal localization. Deletion or mutations of the PEX19 binding sites in TbPEX11 or ScPEX11 results in mislocalization of the proteins to mitochondria. Bioinformatic analysis indicates that the N-terminal region of TbPEX11 contains an amphiphilic helix and several putative TOM20 recognition motifs. We show that the extreme N-terminal region of TbPEX11 contains a cryptic N-terminal signal that directs PEX11 to the mitochondrion if its glycosomal transport is blocked.

The amyloid precursor protein (APP) is a key molecular component of Alzheimer’s disease (AD) pathogenesis. Proteolytic APP processing generates various cleavage products, including extracellular amyloid beta (Aβ) and the cytoplasmic APP intracellular domain (AICD). Although the role of AICD in the activation of kinase signaling pathways is well established in the context of full-length APP, little is known about intracellular effects of the AICD fragment, particularly within discrete neuronal compartments. Deficits in fast axonal transport (FAT) and axonopathy documented in AD-affected neurons prompted us to evaluate potential axon-autonomous effects of the AICD fragment for the first time. Vesicle motility assays using the isolated squid axoplasm preparation revealed inhibition of FAT by AICD. Biochemical experiments linked this effect to aberrant activation of selected axonal kinases and heightened phosphorylation of the anterograde motor protein conventional kinesin, consistent with precedents showing phosphorylation-dependent regulation of motors proteins powering FAT. Pharmacological inhibitors of these kinases alleviated the AICD inhibitory effect on FAT. Deletion experiments indicated this effect requires a sequence encompassing the NPTY motif in AICD and interacting axonal proteins containing a phosphotyrosine-binding domain. Collectively, these results provide a proof of principle for axon-specific effects of AICD, further suggesting a potential mechanistic framework linking alterations in APP processing, FAT deficits, and axonal pathology in AD.

Abstract Background Noise levels on intensive care units (ICUs) are typically elevated. While many studies reported negative effects of ICU ambient sounds on patients, only few investigated noise as a factor to influence well-being or performance in healthcare professionals. Methods An online survey in the German-speaking part of Switzerland was conducted to assess how ICU soundscapes are subjectively perceived by healthcare professionals. The questionnaire was answered by 348 participants. Additionally, effects of noise on working memory performance were evaluated in an experimental noise exposure setting. Twenty-six healthcare professionals and 27 healthy controls performed a 2-back object-location task while being exposed to either ICU or pink noise. Results Survey results demonstrate that a majority of participants was aware of heightened noise levels. Participants reported that mostly well-being, performance, and attention could be reduced, along with subjective annoyance and fatigue by ICU ambient sounds. Although no significant effects of noise exposure on working memory performance was observed, self-assessments revealed significantly higher stress levels, increased annoyance and distraction ratings as well as decreased confidence in performance after ICU-noise exposure. Conclusion Subjective assessments indicate that heightened noise levels on ICUs induce annoyance, with heightened stress levels, impaired well-being, and reduced performance being potential consequences. Empirical evidence with objective and physiological measures is warranted.

BackgroundVoltage-gated potassium (Kv) channels, especially Kv7 channels, are major potassium channels identified in vascular smooth muscle cells with a great, albeit differential functional impact in various vessels. Vascular smooth muscle Kv7 channels always coexist with other K channels, in particular with BK channels. BK channels differ in the extent to which they influence vascular contractility. Whether this difference also causes the variability in the functional impact of Kv7 channels is unknown. Therefore, this study addressed the hypothesis that the functional impact of Kv7 channels depends on BK channels.Experimental ApproachExperiments were performed on young and adult rat gracilis and saphenous arteries using real-time PCR as well as pressure and wire myography.Key ResultsSeveral subfamily members of Kv7 (KCNQ) and BK channels were expressed in saphenous and gracilis arteries: the highest expression was observed for BKα, BKβ1 and KCNQ4. Arterial contractility was assessed with methoxamine-induced contractions and pressure-induced myogenic responses. In vessels of adult rats, inhibition of Kv7 channels or BK channels by XE991 or IBTX, respectively enhanced arterial contractility to a similar degree, whereas activation of Kv7 channels or BK channels by retigabine or NS19504, respectively reduced arterial contractility to a similar degree. Further, IBTX increased both the contractile effect of XE991 and the anticontractile effect of retigabine, whereas NS19504 reduced the effect of retigabine and impaired the effect of XE991. In vessels of young rats, inhibition of Kv7 channels by XE991 enhanced arterial contractility much stronger than inhibition of BK channels by IBTX, whereas activation of Kv7 by retigabine reduced arterial contractility to a greater extent than activation of BK channels by NS19504. Further, IBTX increased the anticontractile effect of retigabine but not the contractile effect of XE991, whereas NS19504 reduced the effect of retigabine and impaired the effect of XE991.ConclusionKv7 and BK channels are expressed in young and adult rat arteries and function as negative feedback modulators in the regulation of contractility of these arteries. Importantly, BK channels govern the extent of functional impact of Kv7 channels. This effect depends on the relationship between the functional activities of BK and Kv7 channels.

Introduction Aphasia is a common language disorder acquired after stroke that reduces the quality of life of affected patients. The impairment is frequently accompanied by a deficit in cognitive functions. The state-of-the-art therapy is speech and language therapy but recent findings highlight positive effects of high-frequency therapy. Telerehabilitation has the potential to enable high-frequency therapy for patients at home. This study investigates the effects of high-frequency telerehabilitation speech and language therapy (teleSLT) on language functions in outpatients with aphasia compared with telerehabilitative cognitive training. We hypothesise that patients training with high-frequency teleSLT will show higher improvement in language functions and quality of life compared with patients with high-frequency tele-rehabilitative cognitive training (teleCT).Methods and analysis This study is a randomised controlled, evaluator-blinded multicentre superiority trial comparing the outcomes following either high-frequency teleSLT or teleCT. A total of 100 outpatients with aphasia will be recruited and assigned in a 1:1 ratio stratified by trial site and severity of impairment to one of two parallel groups. Both groups will train over a period of 4 weeks for 2 hours per day. Patients in the experimental condition will devote 80% of their training time to teleSLT and the remaining 20% (24 min/day) to teleCT, vice versa for patients in the control condition. The primary outcome measure is the understandability of verbal communication on the Amsterdam Nijmegen Everyday Language Test and secondary outcome measures are intelligibility of the verbal communication, impairment of receptive and expressive language functions, confrontation naming. Other outcomes measures are quality of life and acceptance (usability and subjective experience) of the teleSLT system.Ethics and dissemination This study is approved by the Ethics Committee Bern (ID 2016-01577). Results will be submitted to a peer-reviewed journal.Trial registration number NCT03228264.

Abstract Several species of the Gram-negative genus Bordetella are the cause of respiratory infections in mammals and birds, including whooping cough (pertussis) in humans. Very recently, a novel atypical species, Bordetella pseudohinzii, was isolated from laboratory mice. These mice presented no obvious clinical symptoms but elevated numbers of neutrophils in bronchoalveolar lavage fluid and inflammatory signs in histopathology. We noted that this species can occur at high prevalence in a mouse facility despite regular pathogen testing according to the FELASA-recommendations. Affected C57BL/6 J mice had, in addition to the reported pulmonary alterations, tracheal inflammation with reduced numbers of ciliated cells, slower ciliary beat frequency, and largely (>50%) compromised cilia-driven particle transport speed on the mucosal surface, a primary innate defence mechanism. In an in vitro-model, Bordetella pseudohinzii attached to respiratory kinocilia, impaired ciliary function within 4 h and caused epithelial damage within 24 h. Regular testing for this ciliotropic Bordetella species and excluding it from colonies that provide mice for lung research shall be recommended. On the other hand, controlled colonization and infection with Bordetella pseudohinzii may serve as an experimental model to investigate mechanisms of mucociliary clearance and microbial strategies to escape from this primary innate defence response.

Abstract The principal virulence factor of Shiga toxin (Stx)-producing Escherichia coli (STEC), the eponymous Stx, modulates cellular immune responses in cattle, the primary STEC reservoir. We examined whether immunization with genetically inactivated recombinant Shiga toxoids (rStx1MUT/rStx2MUT) influences STEC shedding in a calf cohort. A group of 24 calves was passively (colostrum from immunized cows) and actively (intra-muscularly at 5th and 8th week) vaccinated. Twenty-four calves served as unvaccinated controls (fed with low anti-Stx colostrum, placebo injected). Each group was divided according to the vitamin E concentration they received by milk replacer (moderate and high supplemented). The effective transfer of Stx-neutralizing antibodies from dams to calves via colostrum was confirmed by Vero cell assay. Serum antibody titers in calves differed significantly between the vaccinated and the control group until the 16th week of life. Using the expression of activation marker CD25 on CD4+CD45RO+ cells and CD8αhiCD45RO+ cells as flow cytometry based read-out, cells from vaccinated animals responded more pronounced than those of control calves to lysates of STEC and E. coli strains isolated from the farm as well as to rStx2MUT in the 16th week. Summarized for the entire observation period, less fecal samples from vaccinated calves were stx 1 and/or stx 2 positive than samples from control animals when calves were fed a moderate amount of vitamin E. This study provides first evidence, that transfer to and induction in young calves of Stx-neutralizing antibodies by Shiga toxoid vaccination offers the opportunity to reduce the incidence of stx-positive fecal samples in a calf cohort.

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

New ecological trends and changes in consumer behavior are known to favor biofilm formation in household appliances, increasing the need for new antimicrobial materials and surfaces. Their development requires laboratory-cultivated biofilms, or biofilm model systems (BMS), which allow for accelerated growth and offer better understanding of the underlying formation mechanisms. Here, we identified bacterial strains in wildtype biofilms from a variety of materials from domestic appliances using matrix-assisted laser desorption/ionization-time of flight mass spectroscopy (MALDI-TOF-MS). Staphylococci and pseudomonads were identified by MALDI-TOF-MS as the main genera in the habitats and were analyzed for biofilm formation using various in vitro methods. Standard quantitative biofilm assays were combined with scanning electron microscopy (SEM) to characterize biofilm formation. While Pseudomonas putida, a published lead germ, was not identified in any of the collected samples, Pseudomonas aeruginosa was found to be the most dominant biofilm producer. Water-born Pseudomonads were dominantly found in compartments with water contact only, such as in detergent compartment and detergent enemata. Furthermore, materials in contact with the washing load are predominantly colonized with bacteria from the human.

The Th2 cytokine IL-13 is involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. The aim of this study was to investigate IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an Abcb4-knockout mouse model (Abcb4−/−). Lack of IL-13 protected Abcb4−/− mice transiently from cholestasis. This decrease in serum bile acids was accompanied by an enhanced excretion of bile acids and a normalization of fecal bile acid composition. In Abcb4−/−/IL-13−/− double knockout mice, bacterial translocation to the liver was significantly reduced and the intestinal microbiome resembled the commensal composition in wild type animals. In addition, 52-week-old Abcb4−/−IL-13−/− mice showed significantly reduced hepatic fibrosis. Abcb4−/− mice devoid of IL-13 transiently improved cholestasis and converted the composition of the gut microbiota towards healthy conditions. This highlights IL-13 as a potential therapeutic target in biliary diseases.

The low-density lipoprotein receptor-related protein 1, LRP1, interacts with APP and affects its processing. This is assumed to be mostly caused by the impact of LRP1 on APP endocytosis. More recently, also an interaction of APP and LRP1 early in the secretory pathway was reported whereat retention of LRP1 in the ER leads to decreased APP cell surface levels and in turn, to reduced Aβ secretion. Here, we extended the biochemical and immunocytochemical analyses by showing via live cell imaging analyses in primary neurons that LRP1 and APP are transported only partly in common (one third) but to a higher degree in distinct fast axonal transport vesicles. Interestingly, co-expression of LRP1 and APP caused a change of APP transport velocities, indicating that LRP1 recruits APP to a specific type of fast axonal transport vesicles. In contrast lowered levels of LRP1 facilitated APP transport. We further show that monomeric and dimeric APP exhibit similar transport characteristics and that both are affected by LRP1 in a similar way, by slowing down APP anterograde transport and increasing its endocytosis rate. In line with this, a knockout of LRP1 in CHO cells and in primary neurons caused an increase of monomeric and dimeric APP surface localization and in turn accelerated shedding by meprin β and ADAM10. Notably, a choroid plexus specific LRP1 knockout caused a much higher secretion of sAPP dimers into the cerebrospinal fluid compared to sAPP monomers. Together, our data show that LRP1 functions as a sorting receptor for APP, regulating its cell surface localization and thereby its processing by ADAM10 and meprin β, with the latter exhibiting a preference for APP in its dimeric state.

Abstract Protein levels within signal transduction pathways vary strongly from cell to cell. Here, we analysed how signalling pathways can still process information quantitatively despite strong heterogeneity in protein levels. We systematically perturbed the protein levels of Erk, the terminal kinase in the MAPK signalling pathway in a panel of human cell lines. We found that the steady‐state phosphorylation of Erk is very robust against perturbations of Erk protein level. Although a multitude of mechanisms exist that may provide robustness against fluctuating protein levels, we found that one single feedback from Erk to Raf‐1 accounts for the observed robustness. Surprisingly, robustness is provided through a fast post‐translational mechanism although variation of Erk levels occurs on a timescale of days.

Predicted climate change will affect agricultural water resources. Particularly vegetable crops will be concerned due to high water demand and high vulnerability to water scarcity. Present vegetable production already requires irrigation water. To assess future irrigation demand, the impact of climate change needs to be revealed region- and crop-specifically. For robust predictions, a wide range of scenarios has to be simulated using different climate models. The aim of this study is to identify the climate change impact on water availability, precipitation-free periods and irrigation demand of onion crops cultivated in a German model region. Focus is on crop-specific climatic water balance, considering soil characteristics and temperature-driven plant growth. Simulated climate parameters vary between four climate models. However, in all scenarios climate parameters indicate an increasing water demand until 2100. While amount of irrigation water will not increase tremendously, occurrence and duration of dry periods will require efficient irrigation infrastructure and management.

Low levels of 25-hydroxy vitamin D (25(OH)D) are associated with cardiovascular diseases. Herein, we tested the hypothesis that vitamin D deficiency could be a causal factor in atherosclerotic vascular changes and vascular calcification. Aortic root sections of vitamin D receptor knockout (VDR(-/-)) mice that were stained for vascular calcification and immunostained for osteoblastic differentiation factors showed more calcified areas and a higher expression of the osteogenic key factors Msx2, Bmp2, and Runx2 than the wild-type mice (P