Die Metalloprotease Meprin beta ist eine Sheddase des triggering receptor expressed on myeloid cells type 2 (TREM2)

Diese Arbeit demonstriert, dass die Metalloprotease Meprin beta in der Lage ist den Zelloberflächenrezeptor TREM2 proteolytisch zu spalten. TREM2 wird vor allem von Monozyten/Makrophagen exprimiert und kann über Bindung von anionischen Liganden, oder nach Stimulation durch benachbarte Rezeptoren, die Immunantwort modulieren. Mikroglia, welche die Repräsentanten des Mononukleären-Phagozytären Sytems (MPS) im Zentralnervensystem sind, zeigen eine hohe Expression des TREM2. So erregte der Rezeptor Aufsehen im Kontext neurodegenerativer Erkrankungen. In der Tat konnten diverse Korrelationen zwischen Mutationen des TREM2 und neurodegenerativen Erkrankungen hergestellt werden. Die prominenteste unter diesen Erkrankungen ist die Alzheimer-Erkrankung, in welcher der Funktionsverlust des TREM2 gleich mit mehreren Prozessen der Pathogenese in Verbindung gebracht wird. In unseren Experimenten demonstrierten wir die proteolytische Spaltung des TREM2 durch Meprin beta in mehreren Zellsystemen. Ein Mausmodell, mit einem Gen-Knockout für Meprin beta, wies erhöhte Mengen an TREM2 auf monozytären Zellen auf. Um die Reduktion des TREM2 auf der Zelloberfläche auch qualitativ beurteilen zu können, bedienten wir uns des regulatorischen Einflusses des TREM2 auf die Phagozytose. Der Rezeptor ist in der Lage über Bindung extrazellulärer Liganden eine intrazelluläre Signalkaskade in Gang zu setzen, welche einen steigernden Einfluss auf die Phagozytose der Zelle hat. Die Abspaltung des TREM2 von der Zelloberfläche durch Meprin beta führte experimentell in mehreren Zellsystemen zu einer Reduktion der Phagozytoseleistung. Aus dem Knochenmark gewonnene Makrophagen der Meprin beta k.o. Mäuse veranschaulichten neben erhöhten Mengen an TREM2 ein gesteigertes Maß ihrer Phagozytoseleistung. Dies verdeutlicht, dass Meprin beta diesen Rezeptor so prozessiert, dass er seine Funktionsfähigkeit verliert. TREM2 kann neben seiner membrangebundenen Form auch als lösliches Signalmolekül vorliegen. Diese freie Form wird auch als soluble TREM2 (sTREM2) bezeichnet und entsteht entweder nach Abspaltung von der Zellmembran oder wird nach alternativem Splicing von der Zelle sekretiert. Auch Meprin beta kann von der Zelloberfläche abgespalten werden und als freie Protease im Extrazellularraum agieren. So konnten wir ebenfalls belegen, dass das sTREM2 sowohl von membrangebundenem Meprin beta, als auch von der löslichen Variante weiter gespalten werden kann. Mäuse mit einer Defizienz für Meprin beta weisen neben erhöhten Mengen des TREM2 an der Zelloberfläche höhere Mengen an sTREM2 im Extrazellularraum auf

The Professional Peer Membership of School Counselors and the Resources Used Within Their Decision-Making

Abstract The purpose of this study was to describe the demographic identity of a national sample of professional school counselors who were members of the American School Counselor Association (ASCA), understand the manner in which they conceptualized their professional peer membership, and explore what sources they use to make professional and ethical decisions. Consistent with previous research, the majority of participants were white woman, across all four regions in the sample; however, when compared to previous studies, there were a slightly higher percentage of non-white school counselors. Results suggest that there is still a significant gap between the demographics of school counselors and the students they serve. The results of this study indicate that professional school counselors hold a wide range of opinions concerning who they view are their professional peers. There were also significant differences on what resources participants’ used to make professional and ethical decisions. Implications and future directions for research are discussed

MicroRNAs Associated with Metastatic Prostate Cancer

Metastasis is the most common cause of death of prostate cancer patients. Identification of specific metastasis biomarkers and novel therapeutic targets is considered essential for improved prognosis and management of the disease. MicroRNAs (miRNAs) form a class of non-coding small RNA molecules considered to be key regulators of gene expression. Their dysregulation has been shown to play a role in cancer onset, progression and metastasis, and miRNAs represent a promising new class of cancer biomarkers. The objective of this study was to identify down- and up-regulated miRNAs in prostate cancer that could provide potential biomarkers and/or therapeutic targets for prostate cancer metastasis. into NOD/SCID mice, a methodology that tends to preserve properties of the original cancers (e.g., tumor heterogeneity, genetic profiles).Differentially expressed known miRNAs, isomiRs and 36 novel miRNAs were identified. A number of these miRNAs (21/104) have previously been reported to show similar down- or up-regulation in prostate cancers relative to normal prostate tissue, and some of them (e.g., miR-16, miR-34a, miR-126*, miR-145, miR-205) have been linked to prostate cancer metastasis, supporting the validity of the analytical approach.The use of metastatic and non-metastatic prostate cancer subrenal capsule xenografts derived from one patient's cancer makes it likely that the differentially expressed miRNAs identified in this study include potential biomarkers and/or therapeutic targets for human prostate cancer metastasis

Patterns of Pain and Functional Improvement in Patients with Bone Metastases after Conventional External Beam Radiotherapy and a Telephone Validation Study

Patients experiencing lower body pain resulting from bone metastases have greater levels of functional interference than those with upper body pain. The purpose of this study was to assess the levels of interference caused by pain after treatment with conventional radiotherapy using the Brief Pain Inventory (BPI) and to validate this tool for telephone use. After radiotherapy, a total of 159, 129, and 106 patients completed the BPI over the telephone at months 1, 2, and 3, respectively. Cronbach's alpha, confirmatory factor analysis, and discriminant validity tests were performed to assess the validity of the BPI. One-way ANOVA was used to compare BPI scores. There was no statistically significant difference in functional interference among patients after treatment. Internal consistency of the BPI was high. Functional interference may be inherently higher in patients with pain in the lower body. Telephone use of the BPI is reliable and recommended in this population

Radiotherapy for Metastatic Epidural Spinal Cord Compression with Increased Doses: Final Results of the RAMSES-01 Trial

Simple Summary Patients with MESCC and favorable survival prognoses assigned to radiotherapy alone may benefit from increased doses. In a multi-center phase 2 trial, patients receiving 15 x 2.633 Gy or 18 x 2.333 Gy were evaluated and subsequently compared to a historical control group receiving 10 x 3.0 Gy. The phase 2 cohort, including 50 (of 62 planned) evaluable patients, showed promising results regarding 12-month local progression-free survival (LPFS), 12-month overall survival (OS), improvement of motor and sensory functions, post-radiotherapy ambulatory status, and relief of pain and distress. Radiotherapy with 15 x 2.633 Gy or 18 x 2.333 Gy was well tolerated and appeared more effective than 10 x 3.0 Gy with respect to LPFS and improvement of motor function.Abstract Patients with metastatic epidural spinal cord compression (MESCC) and favorable survival prognoses may benefit from radiation doses exceeding 10 x 3.0 Gy. In a multi-center phase 2 trial, patients receiving 15 x 2.633 Gy (41.6 Gy10) or 18 x 2.333 Gy (43.2 Gy10) were evaluated for local progression-free survival (LPFS), motor/sensory functions, ambulatory status, pain, distress, toxicity, and overall survival (OS). They were compared (propensity score-adjusted Cox regression) to a historical control group (n = 266) receiving 10 x 3.0 Gy (32.5 Gy10). In the phase 2 cohort, 50 (of 62 planned) patients were evaluated for LPFS. Twelve-month rates of LPFS and OS were 96.8% and 69.9%, respectively. Motor and sensory functions improved in 56% and 57.1% of patients, and 94.0% were ambulatory following radiotherapy. Pain and distress decreased in 84.4% and 78.0% of patients. Ten and two patients experienced grade 2 and 3 toxicities, respectively. Phase 2 patients showed significantly better LPFS than the control group (p = 0.039) and a trend for improved motor function (p = 0.057). Ambulatory and OS rates were not significantly different. Radiotherapy with 15 x 2.633 Gy or 18 x 2.333 Gy was well tolerated and appeared superior to 10 x 3.0 Gy

Statistical Learning Methods to Identify Nonwear Periods From Accelerometer Data

Background: Accelerometers are used to objectively measure movement in free-living individuals. Distinguishing nonwear from sleep and sedentary behavior is important to derive accurate measures of physical activity, sedentary behavior, and sleep. We applied statistical learning approaches to examine their promise in detecting nonwear time and compared the results with commonly used wear time (WT) algorithms. Methods: Fifteen children, aged 4–17, wore an ActiGraph wGT3X- BT monitor on their hip during overnight polysomnography. We applied Hidden Markov Models (HMM) and Gaussian Mixture Models (GMM) to classify states of nonwear and wear in triaxial acceleration data. Performance of methods was compared with WT algorithms across two conditions with differing amounts of consecutive nonwear. Clinical scoring of polysomnography served as the gold standard. Results: When the length of nonwear was less than or equal to WT algorithms’ predefined thresholds for consecutive nonwear time, GMM methods yielded improved classification error, specificity, positive predictive value, and negative predictive value over commonly used algorithms. HMM was superior to one algorithm for sensitivity and negative predictive value. When the length of nonwear was longer, results were mixed, with the commonly used algorithms performing better on some parameters but GMM with the greatest specificity. However, all approached the upper limits of performance for almost all metrics. Conclusions: GMM and HMM demonstrated robust, consistently strong performance across multiple conditions, surpassing or remaining competitive with commonly used WT algorithms which had marked inaccuracy when nonwear time periods were shorter. Of the two statistical learning algorithms, GMM was superior to HMM

Quantifiable Assessment of SWNT Dispersion in Polymer Composites

NASA LaRC has established a new protocol for visualizing the nanomaterials in structural polymer matrix resins. Using this new technique and reconstructing the 3D distribution of the nanomaterials allows us to compare this distribution against a theoretically perfect distribution. Additional tertiary structural information can now be obtained and quantified with the electron tomography studies. These tools will be necessary to establish the structural-functional relationships between the nano and the bulk. This will also help define the critical length scales needed for functional properties. Field ready tool development and calibration can begin by using these same samples and comparing the response. i.e. gold standards of good and bad dispersion

Ecological effects of nitrogen and sulfur air pollution in the US: what do we know?

Four decades after the passage of the US Clean Air Act, air-quality standards are set to protect ecosystems from damage caused by gas-phase nitrogen (N) and sulfur (S) compounds, but not from the deposition of these air pollutants to land and water. Here, we synthesize recent scientific literature on the ecological effects of N and S air pollution in the US. Deposition of N and S is the main driver of ecosystem acidification and contributes to nutrient enrichment in many natural systems. Although surface-water acidification has decreased in the US since 1990, it remains a problem in many regions. Perturbations to ecosystems caused by the nutrient effects of N deposition continue to emerge, although gas-phase concentrations are generally not high enough to cause phytotoxicity. In all, there is overwhelming evidence of a broad range of damaging effects to ecosystems in the US under current air-quality conditions

Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury. METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility. FINDINGS: In 2016, there were 27·08 million (95% uncertainty interval [UI] 24·30-30·30 million) new cases of TBI and 0·93 million (0·78-1·16 million) new cases of SCI, with age-standardised incidence rates of 369 (331-412) per 100 000 population for TBI and 13 (11-16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55·50 million (53·40-57·62 million) and of SCI was 27·04 million (24·98-30·15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8·4% (95% UI 7·7 to 9·2), whereas that of SCI did not change significantly (-0·2% [-2·1 to 2·7]). Age-standardised incidence rates increased by 3·6% (1·8 to 5·5) for TBI, but did not change significantly for SCI (-3·6% [-7·4 to 4·0]). TBI caused 8·1 million (95% UI 6·0-10·4 million) YLDs and SCI caused 9·5 million (6·7-12·4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82-141) per 100 000 for TBI and 130 (90-170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions. INTERPRETATION: TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments