Increased Expression of Frontotemporal Dementia Risk Factor Tmem106b Alters Lysosomal and Autophagosomal Pathways

Frontotemporal lobar degeneration (FTLD) is an important cause of dementia in individuals under age 65. Common variants in the TMEM106B gene were previously discovered by genome-wide association (GWAS) to confer genetic risk for FTLD-TDP, the largest neuropathological subset of FTLD (p=1x10-11, OR=1.6). Prior to its discovery in the GWAS, TMEM106B, or Transmembrane Protein 106B, was uncharacterized. To further understand the role of TMEM106B in disease pathogenesis, we used immortalized as well as primary neurons to assess the cell biological effects of disease-relevant levels of TMEM106B overexpression and the interaction of TMEM106B with additional disease-associated proteins. We also employed immunostaining to assess its expression pattern in human brain from controls and FTLD cases. We discovered that TMEM106B is a highly glycosylated, Type II late endosomal/lysosomal transmembrane protein. We found that it is expressed by neurons, glia, and peri-vascular cells in disease-affected and unaffected regions of human brain from normal controls in a cytoplasmic, perikaryal distribution. In brain from FTLD patients, we discovered a striking loss of subcellular localization with highly disordered TMEM106B immunostaining patterns in a subset of FTLD-TDP cases. Evidence suggests that TMEM106B variants increase risk for developing FTLD-TDP by increasing TMEM106B mRNA and protein expression levels. We therefore investigated the cell biological effects of increased TMEM106B expression. Increased TMEM106B results in a decrease in the average number of late endosomes/lysosomes per cell, loss of lysosomal acidification, and impaired lysosomal degradation. In addition, lysosomal deficits are accompanied by the appearance of enlarged organelles (\u3e2-3μm) demonstrating ultrastructural characteristics of late autophagic vacuoles (autolysosomes/amphisomes). We observed these effects in both immortalized cell lines and in primary neurons overexpressing TMEM106B. Furthermore, we show that the effects of increased TMEM106B expression can be abrogated by (1) a single point mutation to a lysosomal sorting motif in TMEM106B newly identified here, or (2) knockdown of C9orf72 protein. In sum, our results suggest that TMEM106B exerts its effects on FTLD-TDP disease risk through alterations of lysosomal and autophagic pathways and that TMEM106B and C9orf72 may interact in disease pathophysiology

OrthoBoXY: A Simple Way to Compute True Self-Diffusion Coefficients from MD Simulations with Periodic Boundary Conditions Without Prior Knowledge of the Viscosity

Recently, an analytical expression for the system size dependence and direction-dependence of self-diffusion coefficients for neat liquids due to hydrodynamic interactions has been derived for molecular dynamics (MD) simulations using orthorhombic unit cells. Based on this description, we show that for systems with a ``magic'' box length ratio of $L_z/L_x\!=\!L_z/L_y\!=\!2.7933596497$ the computed self-diffusion coefficients $D_x$ and $D_y$ in $x$- and $y$-direction become system-size independent and represent the true self-diffusion coefficient $D_0\!=\!(D_x+D_y)/2$. Moreover, by using this particular box geometry, the viscosity can be determined with a reasonable degree of accuracy from the difference of components of the diffusion coefficients in $x$-,$y$- and $z$-direction using the simple expression $\eta\!=\!k_\mathrm{B}T\cdot 8.1711245653/[3\pi L_z(D_{x}+D_{y}-2D_z)]$. MD simulations of TIP4P/2005 water for various system-sizes using both orthorhombic and cubic box geometries are used to test the approach.Comment: 5 pages, 1 figure, 2 table

Validation of the Patient Health Questionnaire‐4 for longitudinal mental health evaluation in elite Para athletes

Background Despite the increasing amount of research regarding mental health in elite athletes in recent years, athletes with impairments are hardly represented. Due to this lack of data and the significant need of athlete-specific mental health screening tools, a continuous mental health monitoring program for elite Para athletes was implemented. Objective Validation of the Patient Health Questionnaire-4 (PHQ-4) as a suitable tool for continuous mental health evaluation in elite Para athletes. Design A 43-week prospective observational cohort study. Setting Online questionnaire, provided weekly via web browser and mobile app. Participants Seventy-eight Para athletes preparing for Paralympic Summer and Winter Games. Interventions Not applicable. Main Outcome Measures Weekly PHQ-4 scores, stress level, and mood. Results With a mean weekly response rate of 82.7% (SD = 8.0), 2149 PHQ-4, 2159 stress level and 2153 mood assessments were completed. Mean PHQ-4 score among all participating athletes was 1.2 (SD = 1.8; 95% confidence interval [CI], [1.1–1.3]). Individual weekly scores ranged from 0 to 12 and showed significant floor effects, with 54% of the scores being zero. PHQ-4 scores were significantly higher among female athletes and team sport members (p < .001). Internal consistency of the PHQ-4 was satisfying, Cronbach's α being 0.839. There were significant cross-sectional as well as longitudinal correlations of PHQ-4 and stress level as well as mood values (p < .001). 39.7% of all athletes (n = 31) had at least one positive screen for mental health symptoms. Conclusions The PHQ-4 was shown to be a valid tool for mental health surveillance in elite Para athletes. Significant correlations of the PHQ-4 and stress level as well as mood were shown. High weekly response rates among participating athletes indicated good acceptance of the program. The weekly monitoring allowed for the identification of individual fluctuations and could identify potential athletes at risk for mental health problems when combined with clinical follow-up

The Victoria Square Neighbourhood: Enhancing Resilience by Social Networking

Athens is climatically characterised by a Mediterranean climate with mild and rainy winters and warm summers. In the summer the average temperature is 35°C, with many days exceeding 40°C. Athens is often struck by heat waves, meaning at least 3 consecutive days with air temperatures above 36.5°C. Since the 1950s the number of heat waves has increased substantially: in 2007 14 days have been recorded in comparison to only 6 days in 1955 (FOUNDA and GIANNAKOPOULOS 2002, 229). Inappropriate building materials, the lack of green and open spaces as well as high volumes of traffic contribute to the increasing temperatures in Athens (FOUNDA and G IANNAKOPOULOS 2002, 229). Some places within the city are easily prone to high temperatures, which is called the urban heat island phenomenon. The urban heat islands describe “the excess warmth of the urban atmosphere and surfaces compared to the non-urbanized rural surroundings” (STATHOPOULOU and CARTALIS 2007, 358). The development of urban heat islands is influenced amongst others by construction material, vegetation, emissions, circulation and topography (STATHOPOULOU UND CARTALIS 2007; KATSOULIS UND THEOHARATOS 1985; HASSID et al. 2000). The vulnerability towards natural hazards and risks, including urban heat islands, are multidimensional: human, social, economic, institutional, urban or individual to stress as a result of social and environmental change, where stress refers to unexpected changes and disruption to livelihoods” (NEIL ADGER 1999, 249). It depends on various factors, such as the lack of social cohesion, social exclusion, poverty, gender, age, unemployment, housing condition and the access to health and medical services (CUTTER et al. 2003; NEIL ADGER 1999, SAPOUNTZAKI et al. 2015). Athens is especially vulnerable, as many residence do not have sufficient insulation and thus the buildings heat up in summer (BANK OF GREECE 2011). The Victoria Square neighbourhood is characterized by low-income households and various ethnic groupings. The transformation of the neighbourhood to a more resilient one towards heat islands, is not possible without major state and private investments. As the inhabitants have other, more dominant problems to cope with, than being bothered developing a sustainable neighbourhood, we have decided to use the already existing grouping to create a neighbourhood which is connected among each other, for example by creating neighbourhood gardens and making use of the roof tops among others. The idea is to develop a mobile phone app named ‘Greender’, which aims at encouraging people in the district to help each other. In the following, the neighbourhood will be analysed along social structures and the built environment. Then, the concept of neighbourhood networks will be explained in detail, which will then be applied to the idea of ‘Greender’

Visual Awareness in Binocular Rivalry Modulates Induced Pupil Fluctuations

When a visual stimulus oscillates in luminance, pupil size follows this oscillation. Recently, it has been demonstrated that such induced pupil oscillations can be used to tag which stimulus is covertly attended. Here we ask whether this “pupil frequency tagging” approach can be extended to visual awareness, specifically to inferring perceptual dominance in Binocular Rivalry between complex stimuli. We presented two distinct stimuli, a face and a house, to each eye and modulated their luminance at 1.7 Hz either in counter-phase (180° phase shift), with a 90° phase shift or in phase (0° control). In some conditions, we additionally asked observers to attend either of the stimuli. The luminance modulation was sufficiently subtle that rivalry dynamics did not differ among these conditions, and was also indistinguishable from unmodulated presentation of the stimuli. For the 180° and the 90° phase-shifted stimuli, we found that the phase of the pupil response relative to the stimuli was modulated by perceptual dominance; that is, the relative phase depended on the stimulus the observer was aware of. In turn, this perceptually dominant stimulus could be decoded from the phase of the pupil response significantly above chance. Neither percept dependence of the phase nor significant decoding was found for the 0° control condition. Our results show that visual awareness modulates pupil responses and provide proof of principle that dominance in rivalry for complex stimuli can be inferred from induced pupil fluctuations

Is the effect of precipitation on acute gastrointestinal illness in southwestern Uganda different between Indigenous and non-Indigenous communities?

Acute gastrointestinal illness (AGI) is a global public health priority that often disproportionately effects Indigenous populations. While previous research examines the association between meteorological conditions and AGI, little is known about how socio-cultural factors may modify this relationship. This present study seeks to address this research gap by comparing AGI prevalence and determinants between an Indigenous and non-Indigenous population in Uganda. We estimate the 14-day self-reported prevalence of AGI among adults in an Indigenous Batwa population and their non-Indigenous neighbours using cross-sectional panel data collected over four periods spanning typically rainy and dry seasons (January 2013 to April 2014). The independent associations between Indigenous status, precipitation, and AGI are examined with multivariable multi-level logistic regression models, controlling for relative wealth status and clustering at the community level. Estimated prevalence of AGI among the Indigenous Batwa was greater than among the non-Indigenous Bakiga. Our models indicate that both Indigenous identity and decreased levels of precipitation in the weeks preceding the survey period were significantly associated with increased AGI, after adjusting for confounders. Multivariable models stratified by Indigenous identity suggest that Indigenous identity may not modify the association between precipitation and AGI in this context. Our results suggest that short-term changes in precipitation affect both Indigenous and non-Indigenous populations similarly, though from different baseline AGI prevalences, maintaining rather than exacerbating this socially patterned health disparity. In the context of climate change, these results may challenge the assumption that changing weather patterns will necessarily exacerbate existing socially patterned health disparities

Mental Health in German Paralympic Athletes During the 1st Year of the COVID-19 Pandemic Compared to a General Population Sample

Introduction: The COVID-19 pandemic has huge influences on daily life and is not only associated with physical but also with major psychological impacts. Mental health problems and disorders are frequently present in elite paralympic athletes. Due to the pandemic situation, new stressors (e.g., loss of routine, financial insecurity) might act upon the athletes. Therefore, the assessment of mental health in athletes during the COVID-19 pandemic is important to identify prevalence of psychological problems and propose countermeasures. Methods: The mental health of German paralympic athletes was longitudinally monitored (starting in May 2019). The athletes completed the Patient Health Questionnaire 4 (PHQ-4) on a weekly basis and reported a stress level, training hours, and training load. During the pandemic, 8 measurement time points (March 2020 to April 2021) were used to reflect the psychological health course of the athletes. In parallel, a convenience sample of the general population was questioned about their psychological distress, including the PHQ-4. To be included in the analysis, participants of both groups had to complete at least 4 measurement time points. Matching of the para-athletes and the general population sample was prioritized upon completion of the same measurement time points, gender, and age. Results: Seventy-eight paralympic athletes (40 women, 38 men, age: 29.8 ± 11.4 years) met the inclusion criteria. Seventy-eight matched pairs of the general population (40 women; 38 men; age: 30.5 ± 10.9 years) were identified. The para-athletes had a significantly (p < 0.0001; 0.39 < r < 0.48) lower PHQ-4 value at each measurement time point compared to the matched control group. No significant age or sex differences were evident regarding the symptom burden. In para-athletes, no significant and a weak positive correlation was found between decreased training load and PHQ-4 values and Mental Health in Para-Athletes During COVID-19 a stress level, respectively. Reduced physical activity was significantly (p < 0.0001) associated with higher PHQ-4 values in the general population sample. Discussion: Lower PHQ-4 values were reported by the para-athletes compared to the general population sample. However, small sample sizes must be considered while interpreting the data. Nevertheless, adequate support for individuals suffering from severe psychopathological symptoms should be provided for para-athletes as well as for the general population

Transient Tumor-Fibroblast Interactions Increase Tumor Cell Malignancy by a TGF-β Mediated Mechanism in a Mouse Xenograft Model of Breast Cancer

Carcinoma are complex societies of mutually interacting cells in which there is a progressive failure of normal homeostatic mechanisms, causing the parenchymal component to expand inappropriately and ultimately to disseminate to distant sites. When a cancer cell metastasizes, it first will be exposed to cancer associated fibroblasts in the immediate tumor microenvironment and then to normal fibroblasts as it traverses the underlying connective tissue towards the bloodstream. The interaction of tumor cells with stromal fibroblasts influences tumor biology by mechanisms that are not yet fully understood. Here, we report a role for normal stroma fibroblasts in the progression of invasive tumors to metastatic tumors. Using a coculture system of human metastatic breast cancer cells (MCF10CA1a) and normal murine dermal fibroblasts, we found that medium conditioned by cocultures of the two cell types (CoCM) increased migration and scattering of MCF10CA1a cells in vitro, whereas medium conditioned by homotypic cultures had little effect. Transient treatment of MCF10CA1a cells with CoCM in vitro accelerated tumor growth at orthotopic sites in vivo, and resulted in an expanded pattern of metastatic engraftment. The effects of CoCM on MCF10CA1a cells were dependent on small amounts of active TGF-β1 secreted by fibroblasts under the influence of the tumor cells, and required intact ALK5-, p38-, and JNK signaling in the tumor cells. In conclusion, these results demonstrate that transient interactions between tumor cells and normal fibroblasts can modify the acellular component of the local microenvironment such that it induces long-lasting increases in tumorigenicity and alters the metastatic pattern of the cancer cells in vivo. TGF-β appears to be a key player in this process, providing further rationale for the development of anti-cancer therapeutics that target the TGF-β pathway