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Zwitterionic capsular polysaccharides (ZPS) of commensal bacteria are characterized by having both positive and negative charged substituents on each repeating unit of a highly repetitive structure that has an alpha-helix configuration. In this paper we look at the immune response of CD8(+) T cells to ZPSs. Intraperitoneal application of the ZPS Sp1 from Streptococcus pneumoniae serotype 1 induces CD8(+)CD28(-) T cells in the spleen and peritoneal cavity of WT mice. However, chemically modified Sp1 (mSp1) without the positive charge and resembling common negatively charged polysaccharides fails to induce CD8(+)CD28(-) T lymphocytes. The Sp1-induced CD8(+)CD28(-) T lymphocytes are CD122(low)CTLA-4(+)CD39(+). They synthesize IL-10 and TGF-beta. The Sp1-induced CD8(+)CD28(-) T cells exhibit immunosuppressive properties on CD4(+) T cells in vivo and in vitro. Experimental approaches to elucidate the mechanism of CD8(+) T cell activation by Sp1 demonstrate in a dimeric MHC class I-Ig model that Sp1 induces CD8(+) T cell activation by enhancing crosslinking of TCR. The expansion of CD8(+)CD28(-) T cells is independent, of direct antigen-presenting cell/T cell contact and, to the specificity of the T cell receptor (TCR). In CD8(+)CD28(-) T cells, Sp1 enhances Zap-70 phosphorylation and increasingly involves NF-kappaB which ultimately results in protection versus apoptosis and cell death and promotes survival and accumulation of the CD8(+)CD28(-) population. This is the first description of a naturally occurring bacterial antigen that is able to induce suppressive CD8(+)CD28(-) T lymphocytes in vivo and in vitro. The underlying mechanism of CD8(+) T cell activation appears to rely on enhanced TCR crosslinking. The data provides evidence that ZPS of commensal bacteria play an important role in peripheral tolerance mechanisms and the maintenance of the homeostasis of the immune system.

There are several differential diagnoses of unilateral sinus disease. One of these is inverted papilloma (IP) of the maxillary sinus, which is a common benign tumor with a substantial rate of malignant transformation. In general, endoscopic endonasal techniques for addressing the tumor are favored nowadays instead of classical external approaches. The aim of this retrospective study was to investigate the long-term outcome of inverted papilloma treated endoscopically via the prelacrimal approach. We reviewed 17 patients with primary or recurrent IP of the maxillary sinus that were treated via the prelacrimal endoscopic endonasal technique. After a median follow-up period of 45.9 months (3.8 years), none of the 17 included patients showed signs of recurrent disease and no serious complications were reported. Hypoesthesia of the incisors was reported by four patients and was resolved with time in one. All of the maxillary sinuses could be fully visualized with the flexible endoscope. IP is an important differential diagnosis in the clinical finding of unilateral nasal polypoid lesions. The prelacrimal approach is an effective and safe method in the treatment of IP with limited patient morbidity.

Zwitterionic capsular polysaccharides (ZPS) of commensal bacteria are characterized by having both positive and negative charged substituents on each repeating unit of a highly repetitive structure that has an α-helix configuration. In this paper we look at the immune response of CD8+ T cells to ZPSs. Intraperitoneal application of the ZPS Sp1 from Streptococcus pneumoniae serotype 1 induces CD8+CD28− T cells in the spleen and peritoneal cavity of WT mice. However, chemically modified Sp1 (mSp1) without the positive charge and resembling common negatively charged polysaccharides fails to induce CD8+CD28− T lymphocytes. The Sp1-induced CD8+CD28− T lymphocytes are CD122lowCTLA-4+CD39+. They synthesize IL-10 and TGF-β. The Sp1-induced CD8+CD28− T cells exhibit immunosuppressive properties on CD4+ T cells in vivo and in vitro. Experimental approaches to elucidate the mechanism of CD8+ T cell activation by Sp1 demonstrate in a dimeric MHC class I-Ig model that Sp1 induces CD8+ T cell activation by enhancing crosslinking of TCR. The expansion of CD8+CD28− T cells is independent, of direct antigen-presenting cell/T cell contact and, to the specificity of the T cell receptor (TCR). In CD8+CD28− T cells, Sp1 enhances Zap-70 phosphorylation and increasingly involves NF-κB which ultimately results in protection versus apoptosis and cell death and promotes survival and accumulation of the CD8+CD28− population. This is the first description of a naturally occurring bacterial antigen that is able to induce suppressive CD8+CD28− T lymphocytes in vivo and in vitro. The underlying mechanism of CD8+ T cell activation appears to rely on enhanced TCR crosslinking. The data provides evidence that ZPS of commensal bacteria play an important role in peripheral tolerance mechanisms and the maintenance of the homeostasis of the immune system. One of the most difficult challenges for the mammalian immune system is to protect its host from pathogens and cancer while at the same time avoiding a self-destructive or overwhelming immune response. In addition to so-called central tolerance induced in the thymus, the immune system relies on peripheral control mechanisms. One of the most important brakes of the peripheral tolerance system is constituted by so-called regulatory T lymphocytes. The predominately investigated regulatory T lymphocytes belong to the CD4+ subset but CD8+ regulatory T lymphocytes are now also believed to play a major role in controlling immune responses. Herein, we describe for the first time a natural occurring saccharide antigen from a commensal bacterium which induces the accumulation of a defined population of CD8+ regulatory T lymphocytes. These CD8+ regulatory lymphocytes suppress inflammatory immune responses in vivo and in in vitro assays. We also describe how the bacterial antigen induces the activation of CD8+ T cells. Our findings not only describe a novel mechanism of saccharide-mediated T cell activation but also provide evidence that commensal bacteria play an important role in the induction of peripheral tolerance and maintenance of the mammalian immune system.

Zwitterionic capsular polysaccharides (ZPS) of commensal bacteria are characterized by having both positive and negative charged substituents on each repeating unit of a highly repetitive structure that has an α-helix configuration. In this paper we look at the immune response of CD8+ T cells to ZPSs. Intraperitoneal application of the ZPS Sp1 from Streptococcus pneumoniae serotype 1 induces CD8+CD28- T cells in the spleen and peritoneal cavity of WT mice. However, chemically modified Sp1 (mSp1) without the positive charge and resembling common negatively charged polysaccharides fails to induce CD8+CD28- T lymphocytes. The Sp1-induced CD8+CD28- T lymphocytes are CD122lowCTLA-4+CD39+. They synthesize IL-10 and TGF-β. The Sp1-induced CD8+CD28- T cells exhibit immunosuppressive properties on CD4+ T cells in vivo and in vitro. Experimental approaches to elucidate the mechanism of CD8+ T cell activation by Sp1 demonstrate in a dimeric MHC class I-Ig model that Sp1 induces CD8+ T cell activation by enhancing crosslinking of TCR. The expansion of CD8+CD28- T cells is independent, of direct antigen-presenting cell/T cell contact and, to the specificity of the T cell receptor (TCR). In CD8+CD28- T cells, Sp1 enhances Zap-70 phosphorylation and increasingly involves NF-κB which ultimately results in protection versus apoptosis and cell death and promotes survival and accumulation of the CD8+CD28- population. This is the first description of a naturally occurring bacterial antigen that is able to induce suppressive CD8+CD28- T lymphocytes in vivo and in vitro. The underlying mechanism of CD8+ T cell activation appears to rely on enhanced TCR crosslinking. The data provides evidence that ZPS of commensal bacteria play an important role in peripheral tolerance mechanisms and the maintenance of the homeostasis of the immune system.

Zwitterionic capsular polysaccharides (ZPS) of commensal bacteria are characterized by having both positive and negative charged substituents on each repeating unit of a highly repetitive structure that has an a-helix configuration. In this paper we look at the immune response of CD[8.sup.+] T cells to ZPSs. Intraperitoneal application of the ZPS Spl from Streptococcus pneumoniae serotype 1 induces CD[8.sup.+]CD2[8.sup.-] T cells in the spleen and peritoneal cavity of WT mice. However, chemically modified Spl (mSpl) without the positive charge and resembling common negatively charged polysaccharides fails to induce CD[8.sup.+]CD[28.sup.-] T lymphocytes. The Spl-induced CD[8.sup.+]CD[28.sup.-] T lymphocytes are CD[122.sup.low]CTLA-[4.sup.+]CD[39.sup.+]. They synthesize IL-10 and TGF-β. The Spl-induced CD[8.sup.+]CD[28.sup.-] T cells exhibit immunosuppressive properties on CD[4.sup.+] T cells in vivo and in vitro. Experimental approaches to elucidate the mechanism of CD[8.sup.+] T cell activation by Spl demonstrate in a dimeric MHC class I-Ig model that Spl induces CD[8.sup.+] T cell activation by enhancing crosslinking of TCR. The expansion of CD[8.sup.+]CD[28.sup.-] T cells is independent, of direct antigen-presenting cell/T cell contact and, to the specificity of the T cell receptor (TCR). In CD[8.sup.+]CD[28.sup.-] T cells, Spl enhances Zap-70 phosphorylation and increasingly involves NF-κB which ultimately results in protection versus apoptosis and cell death and promotes survival and accumulation of the CD[8.sup.+]CD[28.sup.-]population. This is the first description of a naturally occurring bacterial antigen that is able to induce suppressive CD[8.sup.+]CD[28.sup.-] T lymphocytes in vivo and in vitro. The underlying mechanism of CD[8.sup.+] T cell activation appears to rely on enhanced TCR crosslinking. The data provides evidence that ZPS of commensal bacteria play an important role in peripheral tolerance mechanisms and the maintenance of the homeostasis of the immune system.

Detecting peripheral neuropathy (PNP) is crucial in preventing complications such as foot ulceration. Clinical examinations for PNP are infrequently provided to patients at high risk due to restrictions on facilities, care providers, or time. A gamified health assessment approach combining wearable sensors holds the potential to address these challenges and provide individuals with instantaneous feedback on their health status. We aimed to develop and evaluate an application that assesses PNP through video games controlled by pressure sensor-equipped insoles. In the proof-of-concept exploratory cohort study, a complete game-based framework that allowed the study participant to play 4 video games solely by modulating plantar pressure values was established in an outpatient clinic setting. Foot plantar pressures were measured by the sensor-equipped insole and transferred via Bluetooth to an Android tablet for game control in real time. Game results and sensor data were delivered to the study server for visualization and analysis. Each session lasted about 15 minutes. In total, 299 patients with diabetes mellitus and 30 with metabolic syndrome were tested using the game application. Patients' game performance was initially assessed by hypothesis-driven key capabilities that consisted of reaction time, sensation, skillfulness, balance, endurance, and muscle strength. Subsequently, specific game features were extracted from gaming data sets and compared with nerve conduction study findings, neuropathy symptoms, or disability scores. Multiple machine learning algorithms were applied to 70% (n=122) of acquired data to train predictive models for PNP, while the remaining data were held out for final model evaluation. Overall, clinically evident PNP was present in 247 of 329 (75.1%) participants, with 88 (26.7%) individuals showing asymmetric nerve deficits. In a subcohort (n=37) undergoing nerve conduction study as the gold standard, sensory and motor nerve conduction velocities and nerve amplitudes in lower extremities significantly correlated with 79 game features (|R|>0.4, highest R value +0.65; P<.001; adjusted R =0.36). Within another subcohort (n=173) with normal cognition and matched covariates (age, sex, BMI, etc), hypothesis-driven key capabilities and specific game features were significantly correlated with the presence of PNP. Predictive models using selected game features achieved 76.1% (left) and 81.7% (right foot) accuracy for PNP detection. Multiclass models yielded an area under the receiver operating characteristic curve of 0.76 (left foot) and 0.72 (right foot) for assessing nerve damage patterns (small, large, or mixed nerve fiber damage). The game-based application presents a promising avenue for PNP screening and classification. Evaluation in expanded cohorts may iteratively optimize artificial intelligence model efficacy. The integration of engaging motivational elements and automated data interpretation will support acceptance as a telemedical application.

Gait is often impaired in people with multiple sclerosis (PwMS), but detailed assessment of gait impairment in research and care remains challenging. In a previous pilot study we reported the feasibility of visual perceptive computing (VPC) for gait assessment in PwMS using the Short Maximum Speed Walk (SMSW), which assesses gait on recording distances confined to less than 4 meters. To investigate the equivalence of SMSW to rater-based timed 25ft. walk (T25FW) in a large cohort of PwMS, and to investigate the association of SMSW-derived gait parameters with clinical disability, as well as subjective and objective gait impairment, in order to validate the SMSW as a quick and objective measure of clinical relevance possibly superior to T25FW. 95 PwMS and 60 healthy controls (HC) performed the SMSW using a VPC system with Microsoft Kinect. All participants received two immediate retests to establish test-retest-reliability. Both PwMS and HC performed the T25FW. PwMS were rated according to the Expanded Disability Status Scale (EDSS) and answered the 12-item Multiple Sclerosis Walking Scale (MSWS-12) as a measure of self-perceived walking impairment. PwMS showed reduced average speed (p<0.001) and higher mediolateral deviation (p = 0.002) during SMSW than HC. Average speed was the most reliable SMSW parameter in PwMS and HC (intra-class correlation coefficient (ICC) in PwMS = 0.985, and in HC = 0.977). Average speed declined with age in PwMS and HC (r in PwMS = -0.648, and in HC = -0.452, both p<0.001). Correlation of SMSW average speed and T25FW speed was high in both groups (r in PwMS = 0.783, and in HC = 0.747, both p<0.001) and mean difference (0.0013 m/s) between methods was below smallest detectable change. Average speed correlated well with both clinical disability based on EDSS (r = -0.586, p<0.001) and self-perceived walking impairment based on MSWS-12 (r = -0.546, p<0.001). VPC-assessed walking parameters during SMSW can reliably detect gait disturbance in PwMS over very short distance. Specifically, maximum gait speed can be obtained with high accuracy in this simple test set-up. Cross-sectional associations with disability and self-perceived walking impairment support clinical relevance. Given its objectivity in a simple test set-up, SMSW is superior to T25FW.

In a production experiment on German we investigated the prosodic effects of informativeness (comprising information status and contrast) on sentence-initial referents, i.e. sentence topics. While referents in sentence-final position usually receive the nuclear accent of the utterance, commonly defined as the last and information-structurally crucial pitch accent in an intonation unit, sentence topics in German often carry a prenuclear accent. However, the status of prenuclear accents is still unclear: are they just “ornamental” or do they express meaning differences? We expected to find a direct relationship between the informativeness of a sentence topic and its prosodic prominence but the hypothesis could only be confirmed to a very limited extent. Results show that informativeness does not affect the accent type of sentence-initial referents, as they are consistently marked by rising prenuclear accents, even on given items. Only the parameter duration shows a main effect of informativeness in the expected direction, since contrastive referents proved to be longer than given ones. In general, and surprisingly, however, contrastive topics are mostly produced as prosodically less prominent than non-contrastive items that are either given, accessible or new. An explanation that holds for our data set may be that the contrast is already expressed by a parallel syntactic structure, which speakers often realize prosodically by a flat hat pattern. We conclude that prenuclear accents on sentence- initial referents are consistently placed for rhythmic reasons in German and that their prosodic form is only slightly influenced by a referent’s level of informativeness.

In a production experiment on German we investigated the prosodic effects of informativeness (comprising information status and contrast) on sentence-initial referents, i.e. sentence topics. While referents in sentence-final position usually receive the nuclear accent of the utterance, commonly defined as the last and information-structurally crucial pitch accent in an intonation unit, sentence topics in German often carry a prenuclear accent. However, the status of prenuclear accents is still unclear: are they just “ornamental” or do they express meaning differences? We expected to find a direct relationship between the informativeness of a sentence topic and its prosodic prominence but the hypothesis could only be confirmed to a very limited extent. Results show that informativeness does not affect the accent type of sentence-initial referents, as they are consistently marked by rising prenuclear accents, even on given items. Only the parameter duration shows a main effect of informativeness in the expected direction, since contrastive referents proved to be longer than given ones. In general, and surprisingly, however, contrastive topics are mostly produced as prosodically less prominent than non-contrastive items that are either given, accessible or new. An explanation that holds for our data set may be that the contrast is already expressed by a parallel syntactic structure, which speakers often realize prosodically by a flat hat pattern. We conclude that prenuclear accents on sentenceinitial referents are consistently placed for rhythmic reasons in German and that their prosodic form is only slightly influenced by a referent’s level of informativeness.

Background Digital interventions for older adults may significantly extend preventive action to postpone disability and preserve health-related quality of life. However, more evidence is needed from multi-domain interventions using broad-scale objective and self-report assessments and intra-individual change data-analytical techniques. Method SMART-AGE examines the effect of an app-based multilevel treatment designed to enhance social participation, physical fitness, and health awareness. The target population comprises healthy and community-dwelling adults 67 years and older with basic digital skills in two socially diverse communities. Treatment relies on an Android-based tablet computer, on which three apps offering interventions in the core areas of social participation, physical fitness, and health awareness are pre-installed. A feedback app designed to provide participants with a feedback option at any time is also offered. Participants are randomly assigned to three intervention arms and assessed at baseline and after 3 and 6 months. Arm 1 receives the full intervention, consisting of the social participation app, the physical fitness app, the health awareness app, and the feedback app. The health awareness app is available in months 4 to 6, meaning that participants receive the full three-app intervention only in the second half of the intervention period. Arm 2 receives the social participation app and the feedback app throughout the intervention. Arm 3 serves as an active control condition in that a stand-alone tablet with a low-dose introduction to publicly available standard apps is provided. The data protocol includes assessment of three primary outcome domains: social support and loneliness, motor capacity and physical performance, and health awareness and health locus of control. Potential moderators (e.g., cognitive function, depression) as well as various technology-oriented constructs (e.g., skills, acceptance) are also assessed. App use data are automatically collected across the full intervention interval in arms 1 and 2. Data management is conducted within a cloud-based REDCap architecture. Feedback recordings via the feedback app are collected in arms 1 and 2 and undergo qualitative analysis. Discussion The SMART-AGE intervention aims to enhance core domains of health-related quality of life in community-dwelling older adults through an app-based multi-domain intervention and a user-centered approach. Trial registration German-Clinical-Trials-Register, DRKS00034316. Registered 29-May-2024, https://drks.de/search/en/trial/DRKS00034316 . The study’s design and hypotheses were also pre-registered in the Open Science Framework (OSF) prior to study enrollment ( https://doi.org/10.17605/OSF.IO/YQEBW , 2023–04-28).