Because of the increasing life expectancy in our society, aging-related neurodegenerative disorders are one of the main issues in global health. Most of these diseases are characterized by the ...deposition of misfolded proteins and a progressive cognitive decline. Among these diseases, Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common types of degenerative dementia. Although both show specific features, an important neuropathological and clinical overlap between them hampers their correct diagnosis. In this work, we identified molecular biomarkers aiming to improve the misdiagnosis between both diseases.
Plasma extracellular vesicles (EVs) -from DLB, AD and healthy controls- were isolated using size-exclusion chromatography (SEC) and characterized by flow cytometry, Nanoparticle Tracking Analysis (NTA) and cryo-electron microscopy. Next Generation Sequencing (NGS) and related bibliographic search was performed and a selected group of EV-associated microRNAs (miRNAs) was analysed by qPCR.
Results uncovered two miRNAs (hsa-miR-451a and hsa-miR-21-5p) significantly down-regulated in AD samples respect to DLB patients, and a set of four miRNAs (hsa-miR-23a-3p, hsa-miR-126-3p, hsa-let-7i-5p, and hsa-miR-151a-3p) significantly decreased in AD respect to controls. The two miRNAs showing decreased expression in AD in comparison to DLB provided area under the curve (AUC) values of 0.9 in ROC curve analysis, thus suggesting their possible use as biomarkers to discriminate between both diseases. Target gene analysis of these miRNAs using prediction online tools showed accumulation of phosphorylation enzymes, presence of proteasome-related proteins and genes involved in cell death among others.
Our data suggest that plasma-EV associated miRNAs may reflect a differential profile for a given dementia-related disorder which, once validated in larger cohorts of patients, could help to improve the differential diagnosis of DLB versus AD.
Kidney transplantation (KTx) is the best therapeutic approach for chronic kidney diseases leading to irreversible kidney failure. Considering the origin of the graft, several studies have reported ...differences between living (LD) and deceased donors (DD) in graft and patient survival. These differences seem to be related to multiple factors including, donor age and time of cold ischemia among others. Many of transplanted organs come from old-aged DDs, in which pre-transplant biopsy is recommended. However, kidney biopsy has several limitations, and there is a need to develop alternatives to assess the status of a kidney before transplantation. As the analysis of urinary extracellular vesicles (uEVs) rendered promising results as non-invasive biomarkers of kidney-related pathologies, this pilot study aimed to investigate whether profiling uEVs of LDs and DDs may be of help to assess the quality of the kidney before nephrectomy.
uEVs from 5 living donors and 7 deceased donors were isolated by size-exclusion chromatography, and their protein and miRNA content were analysed by liquid chromatography followed by mass spectrometry and next generation sequencing, respectively. Then, hierarchical clustering and venn diagrams were done with Perseus software and InteractiVenn tool. Specific EVs data bases were also used for Gene Ontology analysis.
Next generation sequencing revealed that uEVs from DDs contained less miRNAs than LDs, but most of the DD-expressed miRNAs were shared with LDs (96%). Only miR-326 (targeting the apoptotic-related Bcl2) was found significantly over-represented in LD. Focusing on the protein content, we detected a low intra-group correlation in both types of donors. Despite these differences, hierarchical clustering of either miRNA or protein data could not identify a differential profile between LDs and DDs. Of note, 90% of transplanted patients had a functional graft after a year from KTx.
In this pilot study we found that, in normo-functional grafts, minor differences in uEVs profile could not discriminate between LDs and DDs.
•Highest abundances of Cyclothone spp. were observed between 400–600 m and 1000–1500 m depth, both during day and night.•Smaller species were found in the mesopelagic zone than in the bathypelagic ...zone.•Oxygen consumption rates of Cyclothone spp. decreased with temperature and body mass.•Biomass and community respiration were positively associated to productivity with highest values in the eutrophic and temperate stations.•Carbon remineralisation by non-migrant fishes organisms was low compared to zooplankton and microplankton.
The organic carbon resulting from photosynthesis in the upper ocean is transferred downward through the passive sinking of organic particles, physical mixing of particulate and dissolved organic carbon as well as active flux transported by zooplanktonic and micronektonic migrants. Several meso- and bathypelagic organisms feed in shallower layers during the nighttime and respire, defecate, excrete and die at depth. Recent studies suggest that migrant micronekton transport similar amounts of carbon to migrant zooplankton. However, there is scarce information about biomass and carbon flux by non-migratory species in the mesopelagic and bathypelagic zones. The non-migratory bristlemouth fishes (Cyclothone spp.) and partial migrator (A. hemigymnus) remineralise organic carbon at depth, and knowledge about this process by this fauna is lacking despite them having been referred to as the most abundant vertebrates on Earth. Here we show the vertical distribution of biomass and respiration of non-migratory mesopelagic fishes, during day and night, using the enzymatic activity of the electron transfer system (ETS) as a proxy for respiration rates. The study is focused on five Cyclothone species (C. braueri, C. pseudopallida, C. pallida, C. livida and C. microdon) and Argyropelecus hemigymnus. The samples were taken on a transect from the oceanic upwelling off Northwest Africa (20° N, 20° W) to the south of Iceland (60° N, 20° W). Cyclothone spp. showed, by far, the largest biomass (126.90 ± 86.20 mg C·m−2) compared to A. hemigymnus (0.54 ± 0.44 mg C·m−2). The highest concentrations of Cyclothone spp. in the water column were observed between 400 and 600 m and from 1000 to 1500 m depths, both during day and night. For the different species analysed, ETS activity did not show significant differences between diurnal and nocturnal periods. The total average specific respiration of Cyclothone spp. (0.02 ± 0.01 d-1) was lower than that observed for A. hemigymnus (0.05 ± 0.02 d-1). The average carbon respiration of Cyclothone spp. was 2.22 ± 0.81 mg C·m−2·d-1, while it was much lower for A. hemigymnus (0.04 ± 0.03 mg C·m−2·d-1). The respiration of Cyclothone spp. was lower in the bathypelagic than in the mesopelagic zone (0.84 ± 0.48 vs 1.36 ± 1.01 mg C·m−2·d-1, respectively). These results, to our knowledge, provide the first account of remineralisation by this community in the meso and bathypelagic zones of the ocean.
Plasmodium vivax is the most widely distributed human malaria parasite. Previous studies have shown that circulating microparticles during P. vivax acute attacks are indirectly associated with ...severity. Extracellular vesicles (EVs) are therefore major components of circulating plasma holding insights into pathological processes. Here, we demonstrate that plasma-derived EVs from Plasmodium vivax patients (PvEVs) are preferentially uptaken by human spleen fibroblasts (hSFs) as compared to the uptake of EVs from healthy individuals. Moreover, this uptake induces specific upregulation of ICAM-1 associated with the translocation of NF-kB to the nucleus. After this uptake, P. vivax-infected reticulocytes obtained from patients show specific adhesion properties to hSFs, reversed by inhibiting NF-kB translocation to the nucleus. Together, these data provide physiological EV-based insights into the mechanisms of human malaria pathology and support the existence of P. vivax-adherent parasite subpopulations in the microvasculature of the human spleen.
The presence of P. vivax in the bone marrow was first noticed in the late 19th century 2, and examinations of sternal bone marrow aspirates were performed as an accessory to examinations of ...peripheral blood in malaria, including P. vivax 3. ...two case studies reported P. vivax infections after autologous bone marrow transplantation 56, and a third one documented an accidental P. vivax infection due to bone marrow transplantation between a malaria-infected donor and a malaria-free receptor 7. In all these reports and case studies, however, parasite loads and life stages found in the bone marrow were not investigated, and no molecular tools were available to rule out mixed infections or to characterize specific parasite stages. Description of case To gain insight into P. vivax infections in the bone marrow, we performed a morphological and molecular study of bone marrow aspirates taken from a 46-year-old man who was diagnosed with P. vivax (13,280 parasites/ML) at the tertiary hospital of Fundaçao de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil. At convalescence, 42 days after treatment, bone marrow aspirate and peripheral blood samples were obtained for comparison from this same individual. The study was approved by the Institutional Reviewing Board of the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Amazonas, Brazil and the National Committee of Ethics in Science and Technology (CONEP Process reads and to normalize gene expressions by library size. https://doi.org/10.1371/journal.pntd.0005365.s003 (TIF) References Mueller I, Galinski MR, Baird JK, Carlton JM, Kochar DK, Alonso...
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gold(I)‐catalyzed cycloisomerizations of 1,n‐enynes proceed through electrophilic intermediates that can be trapped intra‐ or intermolecularly by a variety of hetero‐ and carbon nucleophiles to form ...complex skeletons in a single step. This review covers the efforts of our group towards the development of new reactions that have been successfully applied in the total synthesis of several natural terpenoids and related carbocyclic structures, as well as for the ready access to challenging linear acenes.
Autoimmune thyroid disease--Hashimoto thyroiditis and Graves' disease--patients produce high levels of thyroid autoantibodies and contain lymphoid tissue that resembles secondary lymphoid follicles ...(LFs). We compared the specificity, structure, and function of tonsil and lymph node LFs with those of the intrathyroidal LFs to assess the latter's capability to contribute to autoimmune response. Thyroglobulin and thyroperoxidase binding to LFs indicated that most intrathyroidal LFs were committed to response to thyroid self-antigens and were associated to higher levels of antibodies to thyroglobulin, thyroperoxidase, and thyroid-stimulating hormone receptor. Intrathyroidal LFs were microanatomically very similar to canonical LFs, ie, they had well-developed germinal centers with mantle, light, and dark zones and each of these zones contained B and T lymphocytes, follicular dendritic and interdigitating dendritic cells with typical phenotypes. Careful assessment of proliferation (Ki67) and apoptosis (terminal dUTP nick-end labeling) indicators and of the occurrence of secondary immunoglobulin gene rearrangements (RAG1 and RAG2) confirmed the parallelism. Unexpected high levels of RAG expression suggested that receptor revision occurs in intrathyroidal LFs and may contribute to generate high-affinity thyroid autoantibodies. Well-formed high endothelial venules and a congruent pattern of adhesion molecules and chemokine expression in intrathyroidal LFs were also detected. These data suggest that ectopic intrathyroidal LFs contain all of the elements needed to drive the autoimmune response and also that their microenvironment may favor the expansion and perpetuation of autoimmune response.
Background
Management of asymptomatic meningiomas represents a challenge due to the absence of a solid consensus on which is the best management strategy. There are various known factors predicting ...meningiomas growth risk. However, the Asian Intracranial Meningioma Scoring System (AIMSS) is the only described score to quantify such risk thus emerging as a potential tool for management decisions. This study aims to validate this score on our series of asymptomatic meningiomas.
Method
We performed a retrospective review of asymptomatic meningiomas diagnosed at our institution between January 2008 and October 2016 and followed by an annual cerebral Magnetic Resonance Imaging (MRI). For each lesion, the AIMSS score was calculated thus classifying them in low (0–2), intermediate (3–6) or high risk (7–11) of rapid growth (>2cm
3
/year). We investigated the correlation between the expected Average Growth Rate (AGR) according to the score and the one obtained in our study. The mean growth velocity over the different risk groups was also compared.
Results
Overall, 69 asymptomatic meningiomas found incidentally in 46 patients were included in the study; 31 were assigned to the low-risk group, 34 to the intermediate-risk group and 4 to the high-risk group. Attending to the AGR, 0% showed rapid growth in the low-risk group, 12% in the intermediate-risk group, and 25% in the high-risk group. The mean growth velocity showed a significant difference over the different risk groups (
p
< 0,001).
Conclusions
According to our finding, the AIMSS score is a valid tool to estimate the risk of rapid growth of asymptomatic meningiomas. It is especially useful distinguishing between low- and intermediate-risk meningiomas. This feature would allow physicians to adjust the periodicity of radiological and clinical controls. Adding more known risk factors of rapid growth to the score might improve its predictive capabilities with the high-risk group.
Chemokines and their corresponding receptors are crucial for the recruitment of lymphocytes into the lymphoid organs and for its organization acting in a multistep process. Tissues affected by ...autoimmune disease often contain ectopic lymphoid follicles which, in the case of autoimmune thyroid disorders, are highly active and specific for thyroid Ags although its pathogenic role remains unclear. To understand the genesis of these lymphoid follicles, the expression of relevant cytokines and chemokines was assessed by real time PCR, immunohistochemistry and by in vitro assays in autoimmune and nonautoimmune thyroid glands. Lymphotoxin alpha, lymphotoxin beta, C-C chemokine ligand (CCL) 21, CXC chemokine ligand (CXCL) 12, CXCL13, and CCL22 were increased in thyroids from autoimmune patients, whereas CXCL12, CXCL13, and CCL22 levels were significantly higher in autoimmune glands with ectopic secondary lymphoid follicles than in those without follicles. Interestingly, thyroid epithelium produced CXCL12 in response to proinflammatory cytokines providing a possible clue for the understanding of how tissue stress may lead to ectopic follicle formation. The finding of a correlation between chemokines and thyroid autoantibodies further suggests that intrathyroidal germinal centers play a significant role in the autoimmune response. Unexpectedly, the percentage of circulating CXCR4(+) T cells and CCR7(+) B and T cells (but not of CXCR5) was significantly reduced in PBMCs of patients with autoimmune thyroid disease when they were compared with their intrathyroidal lymphocytes. This systemic effect of active intrathyroidal lymphoid tissue emerges as a possible new marker of thyroid autoimmune disease activity.
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