Plasma extracellular vesicles (pEV) can harbor a diverse array of factors including active proteases and the amyloid-precursor-protein (APP) cleavage product Aβ, involved in plaque formation in ...Alzheimer`s diseases (AD). A potential role of such vesicles in AD pathology is unexplored.
In a case-control study of randomly selected patients with AD and other neurological diseases (n = 14), and healthy controls (n = 7), we systematically analyzed the content of pEV, using different assay systems. In addition, we determined their entry path into brain tissue, employing animal (mice) injection experiments with ex vivo generated EV that were similar to AD-pEV, followed by multi antigen analysis (MAA) of brain tissue (n = 4 per condition). The results were compared with an IHC staining of human brain tissue in a small cohort of AD patients (n = 3) and controls with no neurodegenerative diseases (n = 3).
We show that pEV levels are considerably upregulated in AD patients. Besides numerous inflammatory effectors, AD-pEV contained α-, β- and γ-secretases, able to cleave APP in in target cells. In vitro generated EV with similar characteristics as AD-pEV accumulated in the choroid plexus (CP) of injected animals and reached primarily hippocampal neurons. Corroborating findings were made in human brain samples. An inhibitor of hyaluronic-acid-synthetase (HAS) blocked uploading of proteases and Hyaluronan onto EV in vitro and abolished CP targeting in animal injection experiments.
We conclude that protease-containing pEV could be part of a communication axis between the periphery and the brain that could be become detrimental depending on pEV concentration and duration of target cell impact.
See the Acknowledgements section.
Abstract
With the recent widespread adoption of LED lighting in outdoor areas, numerous concerns have been raised about the potential for harmful effects on humans, animals, plants, and the night ...sky. These stem from the high blue light content of some LED bulbs and an incentive to increase lighting levels caused by higher efficiency and lower costs. While new lighting installations are often described as environmentally friendly due to their energy efficiency, factors such as light pollution are often neglected or not given enough weight. This research focuses on optimizing the design of exterior lighting for human, environmental, and economic factors using a multi-criteria decision analysis. Based on data in the literature and survey research, illuminance and spectrum alternatives were scored relative to each other using the analytic hierarchy process and multi-attribute utility theory. The findings of this study support the use of artificial illumination at levels similar to a full moon (0.01 fc) and a warm white spectrum (2700K or 2200K), with amber LED becoming a better choice if its energy efficiency and cost effectiveness improve in the future. This methodology can be used in the future as a framework for lighting design optimization in different settings.
Tumor necrosis factor (TNF) is a key cytokine in HIV replication and pathogenesis. For reasons that are not entirely clear, the cytokine remains upregulated despite anti-retroviral therapy (ART). ...Here we demonstrate that HIV Nef induces an alternative TNF secretion mechanism that remains active in chronic infection. Ingestion of Nef-containing plasma extracellular vesicles (pEV) from ART patients by primary immune cells, but also Nef expression, induced intracellular proTNF cleavage and secretion of vesicular TNF endosomes. Key event was the Nef-mediated routing of the TNF-converting enzyme ADAM17 into Rab4+ early endosomes and the Rab27+ secretory pathway. Analysis of lymph-node tissue by multi-epitope-ligand-cartography (MELC) confirmed a vesicular TNF secretion phenotype that co-localized with persistent Nef expression, and implicated Notch1 as an essential co-factor. Surprisingly Notch1 had no transcriptional effect but was required for the endosomal trafficking of ADAM17. We conclude that Nef expression and Nef-containing pEV mobilize TNF from endosomal compartments in acute and chronic infection.
•Nef/ADAM17 containing extracellular vesicles induce an endosomal TNF secretion type in primary target cells.•The mechanism required the shuttling of ADAM17 into Rab4+ endosomal compartments in a Notch1-dependent manner.•The mechanism could be demonstrated in tissue by multi-epitope-ligand-cartography (MELC) technology.
Despite antiviral therapy, plasma levels of TNF remain upregulated and likely play a role in many comorbidities seen in chronic HIV infection. We found that this is due to high levels of HIV-induced plasma extracellular vesicles (pEV) containing the TNF processing ADAM17 protease. Interestingly these vesicles induced a different TNF secretion type. Whereas TNF is usually shed from the plasma membrane, pEV mobilized intracellular TNF storage compartments, secreting endosomal vesicles. We could confirm this mechanism analyzing lymph node tissue sections by a novel immunostaining technology. Our report supports our previous publication implying ongoing viral activity despite successful antiretroviral therapy.
Purpose
To analyze cumulative pregnancy rates of subfertile couples after fertility awareness training.
Methods
A prospective observational cohort study followed 187 subfertile women, who had ...received training in self-observation of the fertile phase of the menstrual cycle with the Sensiplan method, for 8 months. The women, aged 21–47 years, had attempted to become pregnant for 3.5 years on average (range 1–8 years) before study entry. Amenorrhea, known tubal occlusion and severe male factor had been excluded. An additional seven women, who had initially been recruited, became pregnant during the cycle immediately prior to Sensiplan training: this is taken to be the spontaneous pregnancy rate per cycle in the cohort in the absence of fertility awareness training.
Results
The cumulative pregnancy rate of subfertile couples after fertility awareness training was 38% (95% CI 27–49%; 58 pregnancies) after eight observation months, which is significantly higher than the estimated basic pregnancy rate of 21.6% in untrained couples in the same cohort. For couples who had been seeking to become pregnant for 1–2 years, the pregnancy rate increased to 56% after 8 months. A female age above 35 (cumulative pregnancy rate 25%,
p
= 0.06), couples who had attempted to become pregnant for more than 2 years (cumulative pregnancy rate 17%,
p
< 0.01), all significantly reduce the chances of conceiving naturally at some point.
Conclusions
Training women to identify their fertile window in the menstrual cycle seems to be a reasonable first-line therapy in the management of subfertility.
Chronic immune activation is an important driver of human immunodeficiency virus type 1 (HIV-1) pathogenesis and has been associated with the presence of tumor necrosis factor-α converting enzyme ...(TACE) in extracellular vesicles (EVs) circulating in infected individuals. We have recently shown that activation of the Src-family tyrosine kinase hematopoietic cell kinase (Hck) by HIV-1 Nef can trigger the packaging of TACE into EVs via an unconventional protein secretion pathway. Using a panel of HIV-1 Nef mutants and natural HIV-2 and simian immunodeficiency virus (SIV) Nef alleles, we now show that the capacity to promote TACE secretion depends on the superior ability of HIV-1-like Nef alleles to induce Hck kinase activity, whereas other Nef effector functions are dispensable. Strikingly, among the numerous Src-family downstream effectors, serine/threonine kinase Raf-1 was found to be necessary and alone sufficient to trigger the secretion of TACE into EVs. These data reveal the involvement of Raf-1 in regulation of unconventional protein secretion and highlight the importance of Raf-1 as a cellular effector of Nef, thereby suggesting a novel rationale for testing pharmacological inhibitors of the Raf-MAPK pathway to treat HIV-associated immune activation.
Chronic immune activation contributes to the immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection and is associated with poor recovery of the immune system despite potent antiretroviral therapy, which is observed in 10% to 40% drug-treated patients depending on the definition of immune reconstitution. We have previously shown that the HIV pathogenicity factor Nef can promote loading of the proinflammatory protease TACE into extracellular vesicles (EVs), and the levels of such TACE-containing EVs circulating in the blood correlate with low CD4 lymphocyte counts in HIV patients receiving antiretroviral therapy. Here, we show that Nef promotes uploading of TACE into EVs by triggering unconventional secretion via activation of the Hck/Raf/mitogen-activated protein kinase (MAPK) cascade. We find that several pharmaceutical inhibitors of these kinases that are currently in clinical use for other diseases can potently suppress this pathogenic deregulation and could thus provide a novel strategy for treating HIV-associated immune activation.
Acute myeloid leukemia (AML) represents the most common acute leukemia among adults. Despite recent progress in diagnosis and treatment, long-term outcome remains unsatisfactory. The success of ...allogeneic stem cell transplantation underscores the immunoresponsive nature of AML, creating the basis for further exploiting immunotherapies. However, emerging evidence suggests that AML, similar to other malignant entities, employs a variety of mechanisms to evade immunosurveillance. In light of this, T-cell inhibitory myeloid-derived suppressor cells (MDSC) are gaining interest as key facilitators of immunoescape. Accumulation of CD14
HLA-DR
monocytic MDSCs has been described in newly diagnosed AML patients, and deciphering the underlying mechanisms could help to improve anti-AML immunity. Here, we report that conventional monocytes readily take-up AML-derived extracellular vesicles (EV) and subsequently undergo MDSC differentiation. They acquired an CD14
HLA-DR
phenotype, expressed the immunomodulatory indoleamine-2,3-dioxygenase, and upregulated expression of genes characteristic for MDSCs, such as
and
. The Akt/mTOR pathway played a critical role in the AML-EV-induced phenotypical and functional transition of monocytes. Generated MDSCs displayed a glycolytic switch, which rendered them more susceptible toward glycolytic inhibitors. Furthermore, palmitoylated proteins on the AML-EV surface activated Toll-like receptor 2 as the initiating event of Akt/mTOR-dependent induction of MDSC. Therefore, targeting protein palmitoylation in AML blasts could block MDSC accumulation to improve immune responses. SIGNIFICANCE: These findings indicate that targeting protein palmitoylation in AML could interfere with the leukemogenic potential and block MDSC accumulation to improve immunity.
Although dispensable in vitro, HIV Nef enables high-level viral replication in infected hosts by an as yet unexplained mechanism. Previously, we proposed that Nef functionally cooperates with the ...viral transactivator Tat by derepressing the viral promoter via a Nef-associated kinase complex (NAKC). Here, we demonstrate that hnRNP-K, a host factor thought to facilitate crosstalk between kinases and gene expression, interacts with Nef and, as part of NAKC, nucleates Nef-interacting kinases, including Lck, PKCdelta, and PI-3 kinase, leading to Lck and Erk1/2 activation. This strongly increased HIV transcription, which depended on Tat and the NF-kB motif in the viral promoter, but not on NF-kB activation. Depletion of hnRNP-K in a Jurkat model of HIV latency increased Erk1/2 activity and greatly augmented HIV reactivating stimuli. We conclude that hnRNP-K coordinates membrane signaling with transcriptional derepression through Erk1/2 and is targeted by HIV to enable Tat-mediated transcription.
SI.DE is an international research project at the University of Duisburg-Essen, which examines German, Russian, Turkish and Chinese auto- and heterostereotypes. Questioning for the study is made ...online and consists of two surveys; one survey based on stereotypes and a second based on the perception of each other’s foreign language. The questionnaire on stereotypes contains 140 attributes in total, while the respondents can select all of them without any limitation. The choice of these attributes is based on previous investigations, where methodologically formative surveys within the field of stereotype research had been compared with each other. Therefore, it is of high importance to take account of the transferability of the attributes to other languages, without any loss of crop-specific connotations. After the first phase of the study, the items on the attribute list have proved valuable. The construction of the questionnaire and the selected items are described in the following. Moreover, the perception in each other’s language is being researched on the basis of polarity profiles.
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