Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology

BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid -peptide (A) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of A(1-42) (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal A pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsA pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, A pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2

Drama ve İşbirlikli Öğrenme Yöntemlerinin Beşinci Sınıf Öğrencilerinin Okuduğunu Anlama Becerilerine, Tutumlarına ve Bunların Kalıcılığına Etkileri

Bu araştırmanın amacı, drama ve işbirlikli öğrenme yöntemlerinin beşinci sınıf öğrencilerinin okuduğunu anlama becerilerine, tutumlarına ve bunların kalıcılığına etkilerinin incelenmesidir. Araştırmanın desenini ön-test, son-test kontrol gruplu yarı deneysel desen oluşturmuştur. Araştırmaya toplam 82 beşinci sınıf öğrencisi gönüllü olarak katılmıştır. Verilerin toplanmasında “Bilişsel Giriş Davranışları Testi”, “Okuduğunu Anlama Ölçeği”, “Okumaya İlişkin Tutum Ölçeği” ve izleme testleri kullanılmıştır. Araştırma sorularının cevaplanması amacıyla doğrulayıcı faktör analizi; kovaryans analizi ve tekrarlı ölçümler için kovaryans analizleri gerçekleştirilmiştir. Araştırmanın bulguları, işbirlikli öğrenme yönteminin uygulandığı gruptaki öğrencilerin okuduğunu anlama ve tutum son-test puanlarının, hem drama yönteminin uygulandığı gruptaki öğrencilerin hem de mevcut öğretim programının uygulandığı kontrol grubundaki öğrencilerin okuduğunu anlama son-test puanlarından anlamlı düzeyde daha yüksek olduğunu göstermiştir. Bununla birlikte,  işbirlikli öğrenme yönteminin uygulandığı gruptaki öğrencilerin okuduğunu anlama son-test ve izleme testi puanları arasında anlamlı bir farklılığın bulunmadığı, ancak drama yönteminin uygulandığı gruptaki ve kontrol grubundaki öğrencilerin okuduğunu anlama son-test ve izleme testi puanları arasında anlamlı farklılıkların bulunduğu saptanmıştır. Bulgular ayrıca, tutum son-test puan ortalamaları ve izleme testi puan ortalamaları arasındaki farklılıkların gruplara göre anlamlı olmadığını da göstermiştir. Araştırmada eğitime yönelik çıkarımlara ve gelecekte yapılacak araştırmalara ilişkin önerilere de yer verilmiştir

Establishment and Development of Academic Spin – Off Firms by Evidence from Turkey and Some Policy Recommendations

This study aims to identify the main characteristics of academic spin – off firms, which evolve from universities through commercialization of intellectual property and transfer of technology developed within academic institutions. Academic spin – off firms can be conceptualized as a subset of new technology-based firms and they emerge as important actors of the innovation system in Turkey. Despite the extensive empirical evidence pointing to the conclusion that most new technology-based firms do not grow and more importantly do not even want to grow, the dominating view of new technology-based firms is presuming rapid growth, or at least an aspiration towards it. In addition to problems associated with the liability of newness, academic spin – off firms also face two fundamentally different difficulties: Academic spin – off firms evolve from non – commercial environments, i.e. universities and research laboratories, and have to overcome substantial obstacles on the way to become a profitable organization. Moreover key stakeholders in the founding process (i.e. the academic entrepreneurs, university management, finance suppliers etc.) may have conflicting interests, which may influence the growth pattern of academic spin – off firms. Solution of these problems call for a redefinition of parent organization’s structure and mission statement. Recently emerging “third mission” paradigm puts forward entrepreneurialism as a new pillar in addition to teaching and research. This study attempts to highlight key characteristics of ASOF’s and obtained results are expected to contribute to the intellectual debate about transformation of universities with an entrepreneurial mind set. Obtained results indicate that founders of academic spin – off firms have precedent joint research experience, i.e. network of researchers and role of research group as a quasi- firm is influential in the founding process of academic spin – off firms. Moreover academic spin – off firms are embedded in networks, rather than being atomistic entities and either structure of these networks change, or academic spin – off firms partake in different networks during their development

Sulforaphane Inhibits Lipopolysaccharide-Induced Inflammation, Cytotoxicity, Oxidative Stress, and miR-155 Expression and Switches to Mox Phenotype through Activating Extracellular Signal-Regulated Kinase 1/2–Nuclear Factor Erythroid 2-Related Factor 2/Antioxidant Response Element Pathway in Murine Microglial Cells

Sulforaphane (SFN) is a natural product with cytoprotective, anti-inflammatory, and antioxidant effects. In this study, we evaluated the mechanisms of its effects on lipopolysaccharide (LPS)-induced cell death, inflammation, oxidative stress, and polarization in murine microglia. We found that SFN protects N9 microglial cells upon LPS-induced cell death and suppresses LPS-induced levels of secreted pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6. SFN is also a potent inducer of redox sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), which is responsible for the transcription of antioxidant, cytoprotective, and anti-inflammatory genes. SFN induced translocation of Nrf2 to the nucleus via extracellular signal-regulated kinase 1/2 (ERK1/2) pathway activation. siRNA-mediated knockdown study showed that the effects of SFN on LPS-induced reactive oxygen species, reactive nitrogen species, and pro-inflammatory cytokine production and cell death are partly Nrf2 dependent. Mox phenotype is a novel microglial phenotype that has roles in oxidative stress responses. Our results suggested that SFN induced the Mox phenotype in murine microglia through Nrf2 pathway. SFN also alleviated LPS-induced expression of inflammatory microRNA, miR-155. Finally, SFN inhibits microglia-mediated neurotoxicity as demonstrated by conditioned medium and co-culture experiments. In conclusion, SFN exerts protective effects on microglia and modulates the microglial activation state

MicroRNA exocytosis by large dense-core vesicle fusion

Neurotransmitters and peptide hormones are secreted into outside the cell by a vesicle fusion process. Although non-coding RNA (ncRNA) that include microRNA (miRNA) regulates gene expression inside the cell where they are transcribed, extracellular miRNA has been recently discovered outside the cells, proposing that miRNA might be released to participate in cell-to-cell communication. Despite its importance of extracellular miRNA, the molecular mechanisms by which miRNA can be stored in vesicles and released by vesicle fusion remain enigmatic. Using next-generation sequencing, vesicle purification techniques, and synthetic neurotransmission, we observe that large dense-core vesicles (LDCVs) contain a variety of miRNAs including miR-375. Furthermore, miRNA exocytosis is mediated by the SNARE complex and accelerated by Ca2+. Our results suggest that miRNA can be a novel neuromodulator that can be stored in vesicles and released by vesicle fusion together with classical neurotransmitters

Sulforaphane Inhibits Lipopolysaccharide-Induced Inflammation, Cytotoxicity, Oxidative Stress, and miR-155 Expression and Switches to Mox Phenotype through Activating Extracellular Signal-Regulated Kinase 1/2–Nuclear Factor Erythroid 2-Related Factor 2/Antioxidant Response Element Pathway in Murine Microglial Cells

Sulforaphane (SFN) is a natural product with cytoprotective, anti-inflammatory, and antioxidant effects. In this study, we evaluated the mechanisms of its effects on lipopolysaccharide (LPS)-induced cell death, inflammation, oxidative stress, and polarization in murine microglia. We found that SFN protects N9 microglial cells upon LPS-induced cell death and suppresses LPS-induced levels of secreted pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6. SFN is also a potent inducer of redox sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), which is responsible for the transcription of antioxidant, cytoprotective, and anti-inflammatory genes. SFN induced translocation of Nrf2 to the nucleus via extracellular signal-regulated kinase 1/2 (ERK1/2) pathway activation. siRNA-mediated knockdown study showed that the effects of SFN on LPS-induced reactive oxygen species, reactive nitrogen species, and pro-inflammatory cytokine production and cell death are partly Nrf2 dependent. Mox phenotype is a novel microglial phenotype that has roles in oxidative stress responses. Our results suggested that SFN induced the Mox phenotype in murine microglia through Nrf2 pathway. SFN also alleviated LPS-induced expression of inflammatory microRNA, miR-155. Finally, SFN inhibits microglia-mediated neurotoxicity as demonstrated by conditioned medium and co-culture experiments. In conclusion, SFN exerts protective effects on microglia and modulates the microglial activation state

Neuronal-Derived EV Biomarkers Track Cognitive Decline in Alzheimer’s Disease

The hallmarks of Alzheimer’s disease (AD) pathology are senile plaques containing amyloid-beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. Additional pathologies often co-exist, whereas multiple pathogenic mechanisms are involved in AD, especially synaptic degeneration, which necessitate the need for synaptic integrity-related biomarkers alongside Aβ- and tau-related biomarkers. Plasma neuron-derived Extracellular Vesicles EVs (NDEVs) provide biomarkers related to Aβ and tau and synaptic degeneration. Here, to further establish the latter as a “liquid biopsy” for AD, we examined their relationship with ante-mortem cognition in pathologically-confirmed AD cases. We immunoprecipitated NDEVs by targeting neuronal marker L1CAM from ante-mortem plasma samples from 61 autopsy-confirmed cases of pure AD or AD with additional pathologies and measured Aβ42, p181-Tau, total Tau, synaptophysin, synaptopodin and three canonical EV markers, CD63, CD81 and CD9. Higher NDEV Aβ42 levels were consistently associated with better cognitive status, memory, fluency, working memory and executive function. Higher levels of NDEV synaptic integrity-related biomarkers were associated with better performance on executive function tasks. Our findings motivate the hypothesis that releasing Aβ42-laden NDEVs may be an adaptive mechanism in AD

New hematological parameters as early diagnosis and prognostic markers in critically patients

INTRODUCTION: Nucleated red blood cells and immature granulocytes are not normally detected in the blood of healthy adults. We aimed to investigate the effect of nucleated red blood cells and immature granulocytes on mortality in order to identify critically ill patients who were admitted to the emergency department, at high risk of death, and who was not traumatic.MATERIAL AND METHODS: This study was performed retrospectively in the emergency department of a tertiary education and research hospital between January 2021 and June 2021. All patients who died out of trauma and patients who were discharged from the emergency department on the same day were included. Nucleated red blood cells and immature granulocytes parameters were compared between the two groups. The primary outcome was all-cause death in the emergency department.RESULTS: Of the 188 patients included in the study, 129 (68.6%) were male. Nucleated red blood cells (1.88 ± 6.9/μL; 0.02 ± 0.08), % immature granulocytes (2.91 ± 3.04/μL; 0.58 ± 1.63) and immature red blood cells in deceased patients’ granulocyte count (0.38 ± 0.46/μL; 0.04 ± 0.04) was significantly more significant than the control group (p < 0.001). When the area under the curve was examined, the highest value was found in nucleated red blood cells (Area under the curve = 0.920, p < 0.001). In multivariate regression analysis, high nucleated red blood cells, immature granulocyte count, and white blood cell levels were associated with all-cause mortality in the emergency department.CONCLUSIONS: High nucleated red blood cells and immature granulocyte levels may be associated with increased mortality during admission to the emergency department