Abstract
Several proteases are involved in the proteolytic processing of the amyloid precursor protein (APP) generating the amyloidogenic Aβ peptide, which can act as the triggering pathological ...effector of Alzheimer's disease (AD). Among these proteases, the β‐site amyloid precursor protein cleaving enzyme 2 (BACE2) is of particular interest because it was first proposed as an alternative β‐secretase to its homolog BACE1; however, accumulating evidence suggests that BACE2 acts as a non‐amyloidogenic α‐secretase and exerts neuroprotective effects. In this issue of
J Neurochem
, Katusic et al. present an interesting article reporting that BACE2 plays a role in preservation of cerebral vascular endothelial nitric oxide synthase (eNOS) function, thus exerting protective functions. Their data support that the process is mediated by the large soluble non‐amyloidogenic APP fragment sAPPα through the γ‐aminobutyric acid type B receptor 1, which enhances the expression of a major transcription factor for eNOS gene expression in endothelial cells, the Krüppel‐like factor 2. These protective functions of BACE2 contrast with the pathogenic role of BACE1 as a key player in the AD amyloidogenic pathway. Indeed, many efforts have been invested in BACE1 inhibitors as potential disease modifiers for AD. Unfortunately, the results in clinical trials have been disappointing. In this scenario, a better understanding of the functions of BACE2, as well as the selectivity of BACE1 inhibitors with respect to other β‐secretases (mainly BACE2), is crucial for the development of new therapeutic agents. Furthermore, specific cellular targeting should also be considered to improve such therapies due to the diverse balance of secretases targeting APP and the complex cross‐talk between them and the generated APP fragments.
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Down syndrome (DS) is a human genetic disease caused by trisomy of chromosome 21 and characterized by early developmental brain abnormalities. Dysfunctional endosomal pathway in neurons is an early ...event of DS and Alzheimer's disease. Recently, we have demonstrated that exosome secretion is upregulated in human DS postmortem brains, in the brain of the trisomic mouse model TsRb(12.1716)2Cje (Ts2) and by DS fibroblasts as compared with disomic controls. High levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Partially blocking exosome secretion by DS fibroblasts exacerbated a pre‐existing early endosomal pathology. We thus hypothesized that enhanced CD63 expression induces generation of intraluminal vesicles (ILVs) in late endosomes/multivesicular bodies (MVBs), increasing exosome release as an endogenous mechanism to mitigate endosomal abnormalities in DS. Herein, we show a high‐resolution electron microscopy analysis of MVBs in neurons of the frontal cortex of 12‐month‐old Ts2 mice and littermate diploid controls. Our quantitative analysis revealed that Ts2 MVBs are larger, more abundant, and contain a higher number of ILVs per neuron compared to controls. These findings were further corroborated biochemically by Western blot analysis of purified endosomal fractions showing higher levels of ILVs proteins in the same fractions containing endosomal markers in the brain of Ts2 mice compared to controls. These data suggest that upregulation of ILVs production may be a key homeostatic mechanism to alleviate endosomal dysregulation via the endosomal–exosomal pathway.
Extrachromosomal DNA amplifications in cancer Yi, Eunhee; Chamorro González, Rocío; Henssen, Anton G ...
Nature reviews. Genetics,
12/2022, Letnik:
23, Številka:
12
Journal Article
Recenzirano
Extrachromosomal DNA (ecDNA) amplification is an important driver alteration in cancer. It has been observed in most cancer types and is associated with worse patient outcome. The functional impact ...of ecDNA has been linked to its unique properties, such as its circular structure that is associated with altered chromatinization and epigenetic regulatory landscape, as well as its ability to randomly segregate during cell division, which fuels intercellular copy number heterogeneity. Recent investigations suggest that ecDNA is structurally more complex than previously anticipated and that it localizes to specialized nuclear bodies (hubs) and can act in trans as an enhancer for genes on other ecDNAs or chromosomes. In this Review, we synthesize what is currently known about how ecDNA is generated and how its genetic and epigenetic architecture affects proto-oncogene deregulation in cancer. We discuss how recently identified ecDNA functions may impact oncogenesis but also serve as new therapeutic vulnerabilities in cancer.
Pleiotropic roles are proposed for brain extracellular vesicles (EVs) in the development of Alzheimer's disease (AD). Our previous studies have suggested a beneficial role for EVs in AD, where the ...endosomal system in vulnerable neurons is compromised, contributing to the removal of accumulated material from neurons. However, the involvement of EVs in propagating AD amyloidosis throughout the brain has been considered because the amyloid‐β precursor protein (APP), APP metabolites, and key APP cleaving enzymes were identified in association with EVs. Here, we undertook to determine whether the secretase machinery is actively processing APP in EVs isolated from the brains of wild‐type and APP overexpressing Tg2576 mice. We found that full‐length APP is cleaved in EVs incubated in the absence of cells. The resulting metabolites, both α‐ and β‐APP carboxyl‐terminal fragments and APP intracellular domain accumulate in EVs over time and amyloid‐β dimerizes. Thus, EVs contribute to the removal from neurons and transport of APP‐derived neurotoxic peptides. While this is potentially a venue for propagation of the pathology throughout the brain, it may contribute to efficient removal of neurotoxic peptides from the brain.
Long-term effects of COVID-19, also called Long COVID, affect more than 10% of patients. The most severe cases (i.e. those requiring hospitalization) present a higher frequency of sequelae, but ...detailed information on these effects is still lacking. The objective of this study is to identify and quantify the frequency and outcomes associated with the presence of sequelae or persistent symptomatology (SPS) during the 6 months after discharge for COVID-19.
Retrospective observational 6-month follow-up study conducted in four hospitals of Spain. A cohort of all 969 patients who were hospitalized with PCR-confirmed SARS-CoV-2 from March 1 to April 15, 2020, was included. We collected all the SPS during the 6 months after discharge reported by patients during follow-up from primary care records. Cluster analyses were performed to validate the measures. The main outcome measures were return to the Emergency Services, hospital readmission and post-discharge death. Surviving patients' outcomes were collected through clinical histories and primary care reports. Multiple logistic regression models were applied.
The 797 (82.2%) patients who survived constituted the sample followed, while the rest died from COVID-19. The mean age was 63.0 years, 53.7% of them were men and 509 (63.9%) reported some sequelae during the first 6 months after discharge. These sequelae were very diverse, but the most frequent were respiratory (42.0%), systemic (36.1%), neurological (20.8%), mental health (12.2%) and infectious (7.9%) SPS, with some differences by sex. Women presented higher frequencies of headache and mental health SPS, among others. A total of 160 (20.1%) patients returned to the Emergency Services, 35 (4.4%) required hospital readmission and 8 (1.0%) died during follow-up. The main factors independently associated with the return to Emergency Services were persistent fever, dermatological SPS, arrythmia or palpitations, thoracic pain and pneumonia.
COVID-19 cases requiring hospitalization during the first wave of the pandemic developed a significant range of mid- to long-term SPS. A detailed list of symptoms and outcomes is provided in this multicentre study. Identification of possible factors associated with these SPS could be useful to optimize preventive follow-up strategies in primary care for the coming months of the pandemic.
Background
Cytoreductive surgery (CRS) and administration of hyperthermic intraperitoneal chemotherapy (HIPEC) have shown their efficacy in multiple malignancies and also could offer a prognostic ...benefit for patients with advanced ovarian cancer.
Methods
A prospective, single-center, parallel-group, randomized phase 3 clinical trial analyzed patients with a diagnosis of carcinomatosis from ovarian cancer treated with neoadjuvant systemic chemotherapy (NACT). In this trial, 71 patients were randomized to receive CRS alone (36 patients) or CRS with HIPEC (35 patients) using cisplatin (75 mg/m
2
for 60 min at 42 °C). The primary end point was disease-free survival (DFS). Overall survival (OS), morbidity, and quality of life (QoL) were the secondary end points.
Results
During a median follow-up period of 32 months, the median DFS was 12 months in the control group (CRS) and 18 months in the experimental group (CRS and HIPEC). The findings showed HIPEC to be an independent protective factor against the development of recurrence (hazard ratio HR, 0.12, 95 % confidence interval CI, 0.02–0.89;
p
= 0.038). The median OS was 45 months in the control group and 52 months in the experimental group. The respective morbidity rates for any grade (1 to 5) were respectively 58.3 % and 45.7 % (
p
> 0.05), with a mortality rates of 2.8 % and 2.9 % (
p
> 0.05). In the dimensions evaluated, CRS with or without HIPEC had no impact on QoL.
Conclusions
For patients who had advanced ovarian cancer treated with NACT, CRS and HIPEC was associated with better DFS and OS, but without a difference in postoperative morbidity, mortality, or in the QoL evaluation.
Objective We developed a novel non-insulin-based fasting score to evaluate insulin sensitivity validated against the euglycemic–hyperinsulinemic clamp (EHC). We also evaluated its correlation with ...ectopic fact accumulation and its capacity to predict incident type 2 diabetes mellitus (T2D). Design and methods The discovery sample was composed by 125 subjects (57 without and 68 with T2D) that underwent an EHC. We defined METS-IR as Ln((2*G0)+TG0)*BMI)/(Ln(HDL-c)) (G0: fasting glucose, TG0: fasting triglycerides, BMI: body mass index, HDL-c: high-density lipoprotein cholesterol), and compared its diagnostic performance against the M-value adjusted by fat-free mass (MFFM) obtained by an EHC. METS-IR was validated in a sample with EHC data, a sample with modified frequently sampled intravenous glucose tolerance test (FSIVGTT) data and a large cohort against HOMA-IR. We evaluated the correlation of the score with intrahepatic and intrapancreatic fat measured using magnetic resonance spectroscopy. Subsequently, we evaluated its ability to predict incident T2D cases in a prospective validation cohort of 6144 subjects. Results METS-IR demonstrated the better correlation with the MFFM (ρ = −0.622, P < 0.001) and diagnostic performance to detect impaired insulin sensitivity compared to both EHC (AUC: 0.84, 95% CI: 0.78–0.90) and the SI index obtained from the FSIVGTT (AUC: 0.67, 95% CI: 0.53–0.81). METS-IR significantly correlated with intravisceral, intrahepatic and intrapancreatic fat and fasting insulin levels (P < 0.001). After a two-year follow-up, subjects with METS-IR in the highest quartile (>50.39) had the highest adjusted risk to develop T2D (HR: 3.91, 95% CI: 2.25–6.81). Furthermore, subjects with incident T2D had higher baseline METS-IR compared to healthy controls (50.2 ± 10.2 vs 44.7 ± 9.2, P < 0.001). Conclusion METS-IR is a novel score to evaluate cardiometabolic risk in healthy and at-risk subjects and a promising tool for screening of insulin sensitivity.
The multiple protocols that have been developed to characterize river hydromorphology, partly in response to legislative drivers such as the European Union Water Framework Directive (EU WFD), make ...the comparison of results obtained in different countries challenging. Recent studies have analyzed the comparability of existing methods, with remote sensing based approaches being proposed as a potential means of harmonizing hydromorphological characterization protocols. However, the resolution achieved by remote sensing products may not be sufficient to assess some of the key hydromorphological features that are required to allow an accurate characterization. Methodologies based on high resolution aerial photography taken from Unmanned Aerial Vehicles (UAVs) have been proposed by several authors as potential approaches to overcome these limitations. Here, we explore the applicability of an existing UAV based framework for hydromorphological characterization to three different fluvial settings representing some of the distinct ecoregions defined by the WFD geographical intercalibration groups (GIGs). The framework is based on the automated recognition of hydromorphological features via tested and validated Artificial Neural Networks (ANNs). Results show that the framework is transferable to the Central-Baltic and Mediterranean GIGs with accuracies in feature identification above 70%. Accuracies of 50% are achieved when the framework is implemented in the Very Large Rivers GIG. The framework successfully identified vegetation, deep water, shallow water, riffles, side bars and shadows for the majority of the reaches. However, further algorithm development is required to ensure a wider range of features (e.g., chutes, structures and erosion) are accurately identified. This study also highlights the need to develop an objective and fit for purpose hydromorphological characterization framework to be adopted within all EU member states to facilitate comparison of results.
Physical exercise is a tool to prevent and treat some of the chronic diseases affecting the world's population. A mechanism through which exercise could exert beneficial effects in the body is by ...provoking alterations to the gut microbiota, an environmental factor that in recent years has been associated with numerous chronic diseases. Here we show that physical exercise performed by women to at least the degree recommended by the World Health Organization can modify the composition of gut microbiota. Using high-throughput sequencing of the 16s rRNA gene, eleven genera were found to be significantly different between active and sedentary women. Quantitative PCR analysis revealed higher abundance of health-promoting bacterial species in active women, including Faecalibacterium prausnitzii, Roseburia hominis and Akkermansia muciniphila. Moreover, body fat percentage, muscular mass and physical activity significantly correlated with several bacterial populations. In summary, we provide the first demonstration of interdependence between some bacterial genera and sedentary behavior parameters, and show that not only does the dose and type of exercise influence the composition of gut microbiota, but also the breaking of sedentary behavior.
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