Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in β-adrenergic signaling and enhances apoptosis

The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks of cardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typically progresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development of cardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles in both cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellular processes downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application to isolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts following myocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating the β-adrenergic pathway, where preferential β1- and β2-adrenoceptor (β1AR and β2AR) direct inhibition is combined with Giα-2 targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, we demonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygen species generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. In conclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30 overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotective and anti-tumorigenic strategy for anthracyclines

Assessment of the Linkages and Leakages in a Cloud-Based Computing Collaboration among Construction Stakeholders

The uniqueness of the construction industry can be understood in the large volumes of information in terms of paper works, processes, and communication disseminated daily. The voluminous information requires close coordination which cloud based systems offer. The aim of this research is to assess the linkages and leakages in a cloud-based computing collaboration among construction stakeholders. A purposive sampling technique was used in selecting the participants of the study. A questionnaire based instrument was distributed to eighty (80) construction stakeholder in Lagos State, Nigeria. The data collected was analyzed using SPSS v.21. Statistical tools such as frequencies, stacked bars, mean scores, factor analysis, and analysis of variance (ANOVA) were used in the study. The result of the study revealed that construction stakeholders rarely utilize cloud-based technologies for their construction processes. Construction professionals that access cloud based technologies, do so with their smart mobile phones, laptops, and tablet. The study classified the leakages that exist in the use of cloud-based technologies as securitybased factors, cloud-based infrastructure factors, and cloud-based benefits deficiency based factors. In conclusion, the study revealed that the linkages in the use of cloudbased technologies include knowledge sharing, remote access of back-office activities and engendering collaboration among construction stakeholders. It was recommended that construction stakeholders should leverage on the benefits cloud-based technologies has to offer in today’s competitive economy. Construction stakeholdersshould be adequately informed on the available cloud-based computing technologies and the additions it can bring into the construction process. Cloud computing technology vendors should improve on the security and privacy features of the platform for adequate protection of building data

How does the polymer architecture and position of cationic charges affect cell viability?

Polymer chemistry, composition and molar mass are factors that are known to affect cytotoxicity however the influence of polymer architecture has not been investigated systematically. In this study the influence of the position of the cationic charges along the polymer chain on cytotoxicity was investigated while keeping constant the other polymer characteristics. Specifically, copolymers of various architectures, based on a cationic pH responsive monomer, 2-(dimethylamino)ethyl methacrylate (DMAEMA) and a non-ionic hydrophilic monomer, oligo(ethylene glycol)methyl ether methacrylate (OEGMA) were engineered and their toxicity towards a panel of cell lines investigated. Of the seven different polymer architectures examined, the block-like structures were less cytotoxic than statistical or gradient/tapered architectures. These findings will assist in developing future vectors for nucleic acid delivery

Hexameric oligomerization of mitochondrial peroxiredoxin PrxIIF and formation of an ultrahigh affinity complex with its electron donor thioredoxin Trx-o

Mitochondria from plants, yeast, and animals each contain at least one peroxiredoxin (Prx) that is involved in peroxide detoxification and redox signalling. The supramolecular dynamics of atypical type II Prx targeted to the mitochondrion was addressed in pea. Microcalorimetric (ITC) titrations identified an extremely high-affinity binding between the mitochondrial PsPrxIIF and Trx-o with a KD of 126±14 pM. Binding was driven by a favourable enthalpy change (ΔH= –60.6 kcal mol−1) which was counterbalanced by unfavourable entropy changes (TΔS= –47.1 kcal mol−1). This is consistent with the occurrence of large conformational changes during binding which was abolished upon site-directed mutaganesis of the catalytic C59S and C84S. The redox-dependent interaction was confirmed by gel filtration of mitochondrial extracts and co-immunoprecipitation from extracts. The heterocomplex of PsPrxIIF and Trx-o reduced peroxide substrates more efficiently than free PsPrxIIF suggesting that Trx-o serves as an efficient and specific electron donor to PsPrxIIF in vivo. Other Trx-s tested by ITC analysis failed to interact with PsPrxIIF indicating a specific recognition of PsPrxIIF by Trx-o. PsPrxIIF exists primarily as a dimer or a hexamer depending on the redox state. In addition to the well-characterized oligomerization of classical 2-Cys Prx the results also show that atypical Prx undergo large structural reorganization with implications for protein–protein interaction and function

Analysis of Virion Structural Components Reveals Vestiges of the Ancestral Ichnovirus Genome

Many thousands of endoparasitic wasp species are known to inject polydnavirus (PDV) particles into their caterpillar host during oviposition, causing immune and developmental dysfunctions that benefit the wasp larva. PDVs associated with braconid and ichneumonid wasps, bracoviruses and ichnoviruses respectively, both deliver multiple circular dsDNA molecules to the caterpillar. These molecules contain virulence genes but lack core genes typically involved in particle production. This is not completely unexpected given that no PDV replication takes place in the caterpillar. Particle production is confined to the wasp ovary where viral DNAs are generated from proviral copies maintained within the wasp genome. We recently showed that the genes involved in bracovirus particle production reside within the wasp genome and are related to nudiviruses. In the present work we characterized genes involved in ichnovirus particle production by analyzing the components of purified Hyposoter didymator Ichnovirus particles by LC-MS/MS and studying their organization in the wasp genome. Their products are conserved among ichnovirus-associated wasps and constitute a specific set of proteins in the virosphere. Strikingly, these genes are clustered in specialized regions of the wasp genome which are amplified along with proviral DNA during virus particle replication, but are not packaged in the particles. Clearly our results show that ichnoviruses and bracoviruses particles originated from different viral entities, thus providing an example of convergent evolution where two groups of wasps have independently domesticated viruses to deliver genes into their hosts

MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors

BACKGROUND MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers

Plasma‐derived biomarkers of Alzheimer\u27s disease and neuropsychiatric symptoms: A community‐based study

INTRODUCTION: We examined associations between plasma-derived biomarkers of Alzheimer\u27s disease (AD) and neuropsychiatric symptoms (NPS) in community-dwelling older adults. METHODS: Cross-sectional study involving 1005 persons ≥50 years of age (mean 74 years, 564 male, 118 cognitively impaired), who completed plasma-derived biomarker (amyloid beta 42 [Aβ42]/Aβ40, phosphorylated tau 181 [p-tau181], p-tau217, total tau [t-tau], neurofilament light [NfL]), and NPS assessment. RESULTS: P-tau181 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.41–3.00, p < 0.001), p-tau217 (OR 1.70, 95% CI 1.10–2.61, p = 0.016), and t-tau (OR 1.44, 95% CI 1.08–1.92, p = 0.012) were associated with appetite change. We also found that p-tau181 and p-tau217 were associated with increased symptoms of agitation (OR 1.93, 95% CI 1.20–3.11, p = 0.007 and OR 2.04, 95% CI 1.21–3.42, p = 0.007, respectively), and disinhibition (OR 2.39, 95% CI 1.45–3.93, p = 0.001 and OR 2.30, 95% CI 1.33–3.98, p = 0.003, respectively). Aβ42/Aβ40 and NfL were not associated with NPS. CONCLUSION: Higher plasma-derived p-tau181 and p-tau217 levels are associated with increased symptoms of appetite change, agitation, and disinhibition. These findings may support the validity of plasma tau biomarkers for predicting behavioral symptoms that often accompany cognitive impairment. HIGHLIGHTS - We studied 1005 community-dwelling persons aged ≥ 50 years - Higher plasma tau levels are associated with increased neuropsychiatric symptoms - Aβ42/Aβ40 and NfL are not associated with neuropsychiatric symptoms - Clinicians should treat neuropsychiatric symptoms in persons with high plasma-derived ta

Management of chemotherapy-associated febrile neutropenia

The development of febrile neutropenia during a course of chemotherapy is not only a life-threatening complication, it can also lead to a decision to reduce chemotherapy intensity in subsequent treatment cycles, thus putting patient outcomes at risk. Although there are strategies available for the primary prevention of febrile neutropenia, these are not widely used in the UK management of breast cancer. It is, therefore, paramount to have a well thought out and rigorously implemented care protocol for febrile neutropenia, involving patients, family/carers and health-care professionals in both primary and secondary care, to ensure early detection and effective management