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Recent studies indicate that astrocytes show heterogeneity in morphology and physiological function. They integrate synaptic signals and release calcium in reaction to active neurons. These calcium signals are not yet fully understood as they are highly dependent on the cell's morphology, which can vary across and within brain regions. We found structural heterogeneity among mouse hippocampal CA1 astrocytes based on geometric features, clustering 741 cells into six classes. Of those, we selected 84 cells and reconstructed their morphology based on confocal microscope images and converted them into multi-compartment models with a high detailedness. We applied a computational biophysical model simulating the intracellular ion and IP3 signaling and diffusion in those 3D cell geometries. The cells were stimulated with three different glutamate stimuli. Calcium mainly oscillated in the stimulated and the neighboring compartment but not in the soma. Significant differences were found in the peak width, mean prominence, and mean peak amplitude of the calcium signal when comparing the signals in the stimulated and neighboring compartments. Overall, this study highlights the influence of the complex morphology of astrocytes on intracellular ionic signaling.

Biosensing techniques are progressing rapidly, promising the emergence of sophisticated virtual reality (VR) headsets with versatile biosensing enabling an objective, yet unobtrusive way to monitor the user’s physiology. Additionally, modern artificial intelligence (AI) methods provide interpretations of multimodal data to obtain personalised estimations of the users’ oculomotor behaviour, visual perception, and cognitive state, and their possibilities extend to controlling, adapting, and even creating the virtual audiovisual content in real-time. This article proposes a visionary approach for personalised virtual content adaptation via novel and precise oculomotor feature extraction from a freely moving user and sophisticated AI algorithms for cognitive state estimation. The approach is presented with an example use-case of a VR flight simulation session explaining in detail how cognitive workload, decrease in alertness level, and cybersickness symptoms could be modified in real-time by using the methods and embedded stimuli. We believe the envisioned approach will lead to significant cost savings and societal impact and will thus be a necessity in future VR setups. For instance, it will increase the efficiency of a VR training session by optimizing the task difficulty based on the user’s cognitive load and decrease the probability of human errors by guiding visual perception via content adaptation.

Hepsin, a type II transmembrane serine protease, is commonly overexpressed in prostate and breast cancer. The hepsin protein is stabilized by the Ras‐MAPK pathway, and, downstream, this protease regulates the degradation of extracellular matrix components and activates growth factor pathways, such as the hepatocyte growth factor (HGF) and transforming growth factor beta (TGFβ) pathway. However, how exactly active hepsin promotes cell proliferation machinery to sustain tumor growth is not fully understood. Here, we show that genetic deletion of the gene encoding hepsin (Hpn) in a WAP‐Myc model of aggressive MYC‐driven breast cancer inhibits tumor growth in the primary syngrafted sites and the growth of disseminated tumors in the lungs. The suppression of tumor growth upon loss of hepsin was accompanied by downregulation of TGFβ and EGFR signaling together with a reduction in epidermal growth factor receptor (EGFR) protein levels. We further demonstrate in 3D cultures of patient‐derived breast cancer explants that both basal TGFβ signaling and EGFR protein expression are inhibited by neutralizing antibodies or small‐molecule inhibitors of hepsin. The study demonstrates a role for hepsin as a regulator of cell proliferation and tumor growth through TGFβ and EGFR pathways, warranting consideration of hepsin as a potential indirect upstream target for therapeutic inhibition of TGFβ and EGFR pathways in cancer.

Abstract The immunoglobulin (Ig) superfamily members are involved in cell adhesion and migration, complex multistep processes that play critical roles in embryogenesis, wound healing, tissue formation, and many other processes, but their specific functions during embryonic development remain unclear. Here, we have studied the function of the immunoglobulin superfamily member 3 (IGSF3) by generating an Igsf3 knockout (KO) mouse model with CRISPR/Cas9-mediated genome engineering. By combining RNA and protein detection methodology, we show that during development, IGSF3 localizes to the neural crest and a subset of its derivatives, suggesting a role in normal embryonic and early postnatal development. Indeed, inactivation of Igsf3 impairs the ability of the vagal neural crest cells to migrate and normally innervate the intestine. The small intestine of Igsf3 KO mice shows reduced thickness of the muscularis externa and diminished number of enteric neurons. Also, misalignment of neurons and smooth muscle cells in the developing intestinal villi is detected. Taken together, our results suggest that IGSF3 functions contribute to the formation of the enteric nervous system. Given the essential role of the enteric nervous system in maintaining normal gastrointestinal function, our study adds to the pool of information required for further understanding the mechanisms of gut innervation and etiology behind bowel motility disorders.

Tässä tutkimuksessa tarkastellaan varhaiskasvatuksen erityisopettajien (VEO) näkemyksiä vaativasta monialaisesta tuesta ja siihen liittyvästä yhteistyöstä. Vaativa monialainen tuki käsitteenä ja käytänteenä herättää keskustelua varhaiskasvatuskontekstissa eikä yhteneväistä määritelmää käsitteelle ole. Hyödynnämme tutkimuksessa VEOjen kirjoitelmista (N = 128) koostuvaa eläytymismenetelmäaineistoa. Kahdessa kehyskertomuksessa, joihin VAKA-TUVET-täydennyskoulutushankkeen osallistujat tuottivat vaativaa monialaista tukea koskevia kuvauksia, tuen kohteena oli joko käyttäytymisellään reagoiva lapsi tai lapsi, jolla on kehitysvamma ja autismi. Aineisto analysoitiin diskurssianalyysilla, jonka avulla tutkittiin, mitä toimijoita VEOt liittävät vaativaan monialaiseen tukeen, ja miten VEOt asemoivat itseään ja muita tuen toimijoita monialaisessa yhteistyössä. Tulosten kymmenen vaativan monialaisen tuen toimijaa asemoitiin neljällä tavalla: aktiiviset tuen toimijat, asiantuntijat, mahdollistajat sekä vastaanottajat. Tulosten perusteella vaativan monialaisen tuen yhteistyön käytänteitä ja VEO:n rooli yhteistyön koordinaattorina tulisi edelleen selkiyttää. Tulokset auttavat vaativan monialaisen tuen käytänteiden ja yhteistyön suunnittelussa.

IntroductionCurrent stress detection methods concentrate on identification of stress and non-stress states despite the existence of various stress types. The present study performs a more specific, explainable stress classification, which could provide valuable information on the physiological stress reactions.MethodsPhysiological responses were measured in the Maastricht Acute Stress Test (MAST), comprising alternating trials of cold pressor (inducing physiological stress and pain) and mental arithmetics (eliciting cognitive and social-evaluative stress). The responses in these subtasks were compared to each other and to the baseline through mixed model analysis. Subsequently, stress type detection was conducted with a comprehensive analysis of several machine learning components affecting classification. Finally, explainable artificial intelligence (XAI) methods were applied to analyze the influence of physiological features on model behavior.ResultsMost of the investigated physiological reactions were specific to the stressors, and the subtasks could be distinguished from baseline with up to 86.5% balanced accuracy. The choice of the physiological signals to measure (up to 25%-point difference in balanced accuracy) and the selection of features (up to 7%-point difference) were the two key components in classification. Reflection of the XAI analysis to mixed model results and human physiology revealed that the stress detection model concentrated on physiological features relevant for the two stressors.DiscussionThe findings confirm that multimodal machine learning classification can detect different types of stress reactions from baseline while focusing on physiologically sensible changes. Since the measured signals and feature selection affected classification performance the most, data analytic choices left limited input information uncompensated.

The aim of the current study was to compare changes in serum biomarkers, including inflammatory mediators, signaling molecules, growth factors and markers of bone turnover after a single intravenous infusion of 5 mg zoledronic acid (ZA, a long-acting bisphosphonate; n = 20) or placebo (n = 20) among patients with Modic changes (MC) and chronic low back pain in a randomized controlled design. The MCs were classified into M1, predominating M1, predominating M2, and M2. We measured the serum concentrations of 39 biomarkers at baseline, and one month and one year after treatment. After Benjamini-Hochberg (B-H) correction, we observed significant differences in three biomarkers over one year: Interferon-γ-inducible protein (IP10) had risen in the ZA group (p = 0.005), whereas alkaline phosphatase (AFOS) and intact procollagen I N-terminal propeptide (iPINP) had significantly decreased in the ZA group, but had not changed in the placebo group (p < 0.001 for both). Change in iPINP correlated with change in the volume of all MC and M1 lesions. ZA downregulated bone turnover markers as expected and, surprisingly, increased the chemokine IP-10 relative to placebo treatment. This adds to our knowledge of the effects of ZA on MC and the biomarkers that signal this process.

Abstract Background Periodontitis has been associated with inflammatory processes in arterial walls such as impairment in endothelial function and thickening of intima media. As inflammation plays a role also in arterial stiffening, an association between periodontal inflammation and arterial stiffness can be expected. So far, conflicting results of the association between periodontal disease and arterial stiffness have been reported. Many of the earlier studies were conducted in specific populations and heterogeneous measures of both arterial stiffness and periodontal status were used. In this population-based study we aimed to investigate whether periodontal pocketing and gingival bleeding are associated with ultrasound-based measures of arterial stiffness. Methods In this cross-sectional study, two sets of data based on the national Health 2000 Survey in Finland were formed. Data set I comprised never-smoking 45–64-year-old dentate (≥ 10 natural teeth), non-diabetic, non-rheumatic, non-obese (BMI ≤ 30 kg/m2), non-hypertensive subjects with no coronary artery disease or ongoing lipid-lowering medications (n = 157). Data set II was formed of an unrestricted 45–74-year-old dentate population (n = 536). Four arterial stiffness measures (carotid artery compliance, Peterson’s elastic modulus, Young’s elastic modulus and beta stiffness index) based on an ultrasound examination of the common carotid artery were used. Periodontal parameters included the number of teeth with ≥ 4 mm deep periodontal pockets and the number of sextants with gingival bleeding. β-estimates, confidence intervals, and p-values were obtained from linear regression models. Results In Data set I, the adjusted β-estimates for the association between the number of teeth with ≥ 4 mm deep periodontal pockets and Peterson’s elastic modulus and Young’s elastic modulus were 15.80 (p = 0.12) and 61.02 (p = 0.22), respectively. The respective β-estimates were 31.06 (p = 0.17) and 121.16 (p = 0.28) for the association between the number of bleeding sextants and these two stiffness measures. The results in Data set II were in line with the results in Data set I, with the exception that the adjusted β-estimates for the associations between Peterson’s elastic modulus and Young’s elastic modulus and periodontal parameters were closer to null. Conclusions This population-based study did not provide evidence of an association between periodontal condition and arterial stiffness.

Maureen George,1 Zaneta Balantac,2 Chris Gillette,3 Nabeel Farooqui,4 Tommi Tervonen,5 Caitlin Thomas,5 Ileen Gilbert,6 Hitesh Gandhi,6 Elliot Israel7 1School of Nursing, Columbia University, New York, NY, USA; 2Patient-Centered Research, Evidera, San Francisco, CA, USA; 3Department of Physician Assistant Studies, Wake Forest School of Medicine, Winston-Salem, NC, USA; 4Allergy Partners, Fishers, IN, USA; 5Patient-Centered Research, Evidera, London, UK; 6Medical Affairs-Respiratory, AstraZeneca, Wilmington, DE, USA; 7Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USACorrespondence: Maureen George, School of Nursing at CUIMC, Columbia University School of Nursing, 630 West 168th Street Mail Code 6, New York, NY, 10032, USA, Tel +1 212-305-1175 ; Tel +1 212-305-1175, Email mg3656@cumc.columbia.eduPurpose: The US National Asthma Education and Prevention Program updates and Global Initiative for Asthma report encourage considering the patient perspective to improve asthma control. The objective of the present study was to collect data about the perceptions, experiences, and concerns of adult patients and caregivers of children with asthma regarding rescue, maintenance, and oral corticosteroid treatments.Patients and Methods: In-person focus groups were conducted in three cities across the US. Participants also completed patient-reported outcome measures assessing asthma control and experiences.Results: Focus groups were conducted in demographically and clinically diverse adults with asthma (five groups, n=34), caregivers of children with asthma (five groups, n=35), and adults with a dual diagnosis of asthma and chronic obstructive pulmonary disease (one group, n=5). Only 28% of patients were well-controlled by Asthma Control Test/Asthma Control Test-Caregiver Report and 18% by Asthma Impairment and Risk Questionnaire. Forty-four percent of participants reported not following their prescribed medical plan. Four key themes emerged from the focus groups: (1) asthma symptom control and monitoring are often inadequate; (2) treatments are often used incorrectly; (3) communication between health care professionals and patients or caregivers is often ineffective; and (4) concerns related to treatment and desires to improve treatment.Conclusion: Control of asthma symptoms is suboptimal in the vast majority of patients and both patients and caregivers do not feel sufficiently informed about asthma. Health care providers should be encouraged to engage patients and caregivers in shared decision making for managing asthma and selecting treatments that integrate patient values, preferences, and lifestyles.Keywords: chronic obstructive pulmonary disease, qualitative, inhaler, maintenance therapy, rescue therapy, corticosteroid, asthma management, asthma control, shared decision-making, Asthma Control Test, ACT, Asthma Impairment and Risk Questionnaire, AIRQ, Adult Asthma Adherence Questionnaire, AAAQ, Treatment Satisfaction Questionnaire for Medication, TSQM

Sensory encounters are an essential component of the customer experience. However, most of the research conducted thus far has used self‐reported measuring techniques to address sensory experiences, which have limitations in holistically capturing the sensory encounters. Text analysis coupled with online reviews provides valuable customer experience information and at the same time, the data contains many suggestions regarding consumers' sensory experiences. Consequently, online review data can be used to gain insights into how consumers' sensory experiences—visual, olfactory, auditory, gustatory, and tactile—are represented in the dynamics of online reviews. Using a data set of 13,575 online reviews from Trustpilot and expanding upon the vocabulary of senses, we investigate how customers' sensory experiences during grocery shopping relate to online review ratings. We discover that the interaction is more complex than one might think because the review star rating rises in the presence of visual and gustatory cues, while the effects of auditory, olfactory, and tactile cues are not demonstrated. We recommend marketers to monitor eWOM related to their own brand, as it can provide indications of what kind of sensory experiences customers have encountered. [ABSTRACT FROM AUTHOR]

Abstract Background A genome‐wide association study is an analytical approach that investigates whether genetic variants across the whole genome contribute to disease progression. The aim of this study was to investigate genome-wide associations of periodontal condition measured as deepened periodontal pockets (≥ 4 mm) in Finnish adults. Methods This study was based on the data of the national Health 2000 Survey (BRIF8901) in Finland and the Northern Finland Birth Cohort 1966 Study totalling 3,245 individuals. The genotype data were analyzed using the SNPTEST v.2.4.1. The number of teeth with deepened periodontal pockets (≥ 4 mm deep) was employed as a continuous response variable in additive regression analyses performed separately for the two studies and the results were combined in a meta-analysis applying a fixed effects model. Results Genome-wide significant associations with the number of teeth with ≥ 4 mm deep pockets were not found at the p-level of

Biosensing techniques are progressing rapidly, promising the emergence of sophisticated virtual reality (VR) headsets with versatile biosensing enabling an objective, yet unobtrusive way to monitor the user's physiology. Additionally, modern artificial intelligence (AI) methods provide interpretations of multimodal data to obtain personalised estimations of the users' oculomotor behaviour, visual perception, and cognitive state, and their possibilities extend to controlling, adapting, and even creating the virtual audiovisual content in real-time. This article proposes a visionary approach for personalised virtual content adaptation via novel and precise oculomotor feature extraction from a freely moving user and sophisticated AI algorithms for cognitive state estimation. The approach is presented with an example use-case of a VR flight simulation session explaining in detail how cognitive workload, decrease in alertness level, and cybersickness symptoms could be modified in real-time by using the methods and embedded stimuli. We believe the envisioned approach will lead to significant cost savings and societal impact and will thus be a necessity in future VR setups. For instance, it will increase the efficiency of a VR training session by optimizing the task difficulty based on the user's cognitive load and decrease the probability of human errors by guiding visual perception via content adaptation. [ABSTRACT FROM AUTHOR]

Recent studies indicate that astrocytes show heterogeneity in morphology and physiological function. They integrate synaptic signals and release calcium in reaction to active neurons. These calcium signals are not yet fully understood as they are highly dependent on the cell’s morphology, which can vary across and within brain regions. We found structural heterogeneity among mouse hippocampal CA1 astrocytes based on geometric features, clustering 741 cells into six classes. Of those, we selected 84 cells and reconstructed their morphology based on confocal microscope images and converted them into multi-compartment models with a high detailedness. We applied a computational biophysical model simulating the intracellular ion and IP3 signaling and diusion in those 3D cell geometries. The cells were stimulated with three dierent glutamate stimuli. Calcium mainly oscillated in the stimulated and the neighboring compartment but not in the soma. Significant dierences were found in the peak width, mean prominence, and mean peak amplitude of the calcium signal when comparing the signals in the stimulated and neighboring compartments. Overall, this study highlights the influence of the complex morphology of astrocytes on intracellular ionic signalin [ABSTRACT FROM AUTHOR]

Cities and towns are critical geographies of refuge for a globally unprecedented number of forcibly displaced people. Yet urban processes also expose these groups and the local urban poor to recurrent displacements. While such experiences are shared, studies often treat these populations as distinct. Drawing on Yiftachel's notion of displaceability, this paper systematically reviews and synthesizes a global literature on diversely displaced people's placemaking in urban public space. Observing a significant analytical gap regarding cities of the so-called global South, the paper identifies a heuristic, and key analytical dimensions shaping divergent access and uses of public space by variously displaced populations. These concern: temporal patterns; powerful meta-narratives of people and place; and complex multi-scalar and multi-actor configurations of regulatory regimes governing public space. Simultaneously, acquisition and deployment of urban knowledge and a practice of (in)visibility enable differentially displaced populations' everyday claims to public space for wellbeing. [ABSTRACT FROM AUTHOR]

Objectives We aimed to quantify patient preferences for efficacy, safety and convenience features of atopic dermatitis (AD) treatments.Design and setting Online discrete choice experiment survey.Participants Adults in the UK, France and Spain who had used AD treatments during the past 2 years.Primary and secondary outcome measures Preferences for attributes were analysed using a multinomial logit model. Willingness to make trade-offs was expressed as the maximum acceptable decrease (MAD) in the probability of achieving clear/almost clear skin at week 16.Results The survey was completed by 404 patients (44.1±12.0 years; 65% women; 64% moderate/severe eczema). Most patients (68%) had no prior experience of using self-injectable treatments for AD or any other illness. Participants most valued increasing the chance of achieving a meaningful reduction in itch at week 16 from 20% to 50%, followed by reducing the risks of serious infections from 6% to 0% and of eye inflammation from 20% to 0%. Participants were willing to accept a decrease in the possibility of achieving clear/almost clear skin to obtain a treatment that can be paused (MAD=24.1%), requires occasional check-ups (MAD=16.1%) or no check-ups (MAD=20.9%) over frequent check-ups, is administered as a one time per day or two times per day oral pill versus a subcutaneous injection every 2 weeks (MAD=16.6%), has a 2-day over 2-week onset of action (MAD=11.3%), and can be used for flare management (MAD=5.8%).Conclusions Although patients with AD most valued treatment benefits and risks, they were willing to tolerate reduced efficacy to obtain a rapid onset, oral administration, less frequent monitoring and a treatment that can be paused. Understanding patients’ preferences for AD therapies, including new targeted therapies, can aid shared decision-making between clinicians and patients and support health technology assessments.