331 research outputs found
Maximum levels of hepatitis C virus lipoviral particles are associated with early and persistent infection
Background & Aims: Hepatitis C virus (HCV) is bound to plasma lipoproteins and circulates as an infectious lipoviral particle (LVP). Experimental evidence indicates that LVPs have decreased susceptibility to antibody-mediated neutralisation and higher infectivity. This study tested the hypothesis that LVPs are required to establish persistent infection, and conversely, low levels of LVP in recent HCV infection increase the probability of spontaneous HCV clearance. Methods: LVP in non-fasting plasma was measured using the concentration of HCV RNA bound to large >100 nm sized lipoproteins after ex vivo addition of a lipid emulsion, that represented the maximum concentration of LVP (maxi-LVP). This method correlated with LVP in fasting plasma measured using iodixanol density gradient ultracentrifugation. Maxi-LVP was measured in a cohort of 180 HCV participants with recent HCV infection and detectable HCV RNA from the Australian Trial in Acute Hepatitis C (ATAHC) and Hepatitis C Incidence and Transmission Study in prison (HITS-p) cohorts. Results: Spontaneous clearance occurred in 15% (27 of 180) of individuals. In adjusted analyses, low plasma maxi-LVP level was independently associated with spontaneous HCV clearance (â¤827 IU/ml; adjusted odds ratio 3.98, 95% CI: 1.02, 15.51, P = 0.047), after adjusting for interferon lambda-3 rs8099917 genotype, estimated duration of HCV infection and total HCV RNA level. Conclusions: Maxi-LVP is a biomarker for the maximum concentration of LVP in non-fasting samples. Low maxi-LVP level is an independent predictor of spontaneous clearance of acute HCV
PCSK9, apolipoprotein E and lipoviral particles in chronic hepatitis C genotype 3: evidence for genotype-specific regulation of lipoprotein metabolism.
BACKGROUND & AIMS: Hepatitis C virus (HCV) associates with lipoproteins to form "lipoviral particles" (LVPs) that can facilitate viral entry into hepatocytes. Initial attachment occurs via heparan sulphate proteoglycans and low-density lipoprotein receptor (LDLR); CD81 then mediates a post-attachment event. Proprotein convertase subtilisin kexin type 9 (PCSK9) enhances the degradation of the LDLR and modulates liver CD81 levels. We measured LVP and PCSK9 in patients chronically infected with HCV genotype (G)3. PCSK9 concentrations were also measured in HCV-G1 to indirectly examine the role of LDLR in LVP clearance. METHODS: HCV RNA, LVP (d1.07g/ml) fractions, were quantified in patients with HCV-G3 (n=39) by real time RT-PCR and LVP ratios (LVPr; LVP/(LVP+non-LVP)) were calculated. Insulin resistance (IR) was assessed using the homeostasis model assessment of IR (HOMA-IR). Plasma PCSK9 concentrations were measured by ELISA in HCV-G3 and HCV-G1 (n=51). RESULTS: In HCV-G3 LVP load correlated inversely with HDL-C (r=-0.421; p=0.008), and apoE (r=-0.428; p=0.013). The LVPr varied more than 35-fold (median 0.286; range 0.027 to 0.969); PCSK9 was the strongest negative predictor of LVPr (R(2)=16.2%; p=0.012). HOMA-IR was not associated with LVP load or LVPr. PCSK9 concentrations were significantly lower in HCV-G3 compared to HCV-G1 (p<0.001). PCSK9 did not correlate with LDL-C in HCV-G3 or G1. CONCLUSIONS: The inverse correlation of LVP with apoE in HCV-G3, compared to the reverse in HCV-G1 suggests HCV genotype-specific differences in apoE mediated viral entry. Lower PCSK9 and LDL concentrations imply upregulated LDLR activity in HCV-G3
Resveratrol-Based Nanoformulations as an Emerging Therapeutic Strategy for Cancer
Resveratrol is a polyphenolic stilbene derivative widely present in grapes and red wine. Broadly known for its antioxidant effects, numerous studies have also indicated that it exerts anti-inflammatory and antiaging abilities and a great potential in cancer therapy. Regrettably, the oral administration of resveratrol has pharmacokinetic and physicochemical limitations such as hampering its effects so that effective administration methods are demanding to ensure its efficiency. Thus, the present review explores the published data on the application of resveratrol nanoformulations in cancer therapy, with the use of different types of nanodelivery systems. Mechanisms of action with a potential use in cancer therapy, negative effects, and the influence of resveratrol nanoformulations in different types of cancer are also highlighted. Finally, the toxicological features of nanoresveratrol are also discussed.CR would like to acknowledge the UID/EQU/00511/2020 ProjectâLaboratory of Process Engineering, Environment, Biotechnology and Energy (LEPABE), financed by national funds through FCT/MCTES (PIDDAC). NC-M acknowledges the Portuguese Foundation for Science and Technology under the Horizon 2020 Program (PTDC/PSI-GER/28076/2017). Some of the components of the illustrations are taken from freepik and flaticon
Degrees of tenant isolation for cloud-hosted software services : a cross-case analysis
A challenge, when implementing multi-tenancy
in a cloud-hosted software service, is how to ensure that the
performance and resource consumption of one tenant does
not adversely affect other tenants. Software designers and
architects must achieve an optimal degree of tenant isolation
for their chosen application requirements. The objective
of this research is to reveal the trade-offs, commonalities,
and differences to be considered when implementing
the required degree of tenant isolation. This research uses
a cross-case analysis of selected open source cloud-hosted
software engineering tools to empirically evaluate varying
degrees of isolation between tenants. Our research reveals
five commonalities across the case studies: disk space reduction,
use of locking, low cloud resource consumption,
customization and use of plug-in architecture, and choice of
multi-tenancy pattern. Two of these common factors compromise
tenant isolation. The degree of isolation is reduced
when there is no strategy to reduce disk space and customization
and plug-in architecture is not adopted. In contrast,
the degree of isolation improves when careful consideration
is given to how to handle a high workload, locking of
data and processes is used to prevent clashes between multiple
tenants and selection of appropriate multi-tenancy pattern. The research also revealed five case study differences:
size of generated data, cloud resource consumption, sensitivity
to workload changes, the effect of the software process,
client latency and bandwidth, and type of software process.
The degree of isolation is impaired, in our results, by
the large size of generated data, high resource consumption
by certain software processes, high or fluctuating workload,
low client latency, and bandwidth when transferring multiple
files between repositories. Additionally, this research
provides a novel explanatory framework for (i) mapping tenant
isolation to different software development processes,
cloud resources and layers of the cloud stack; and (ii) explaining
the different trade-offs to consider affecting tenant
isolation (i.e. resource sharing, the number of users/requests,
customizability, the size of generated data, the scope of control
of the cloud application stack and business constraints)
when implementing multi-tenant cloud-hosted software services.
This research suggests that software architects have
to pay attention to the trade-offs, commonalities, and differences
we identify to achieve their degree of tenant isolation
requirements
The Phenotypic Radiation Resistance of CD44+/CD24âor low Breast Cancer Cells Is Mediated through the Enhanced Activation of ATM Signaling
Cancer initiating cells (CIC) are stem-like cells. CIC may contribute not only to the initiation of cancer but also to cancer recurrence because of the resistance of CIC both to chemotherapy and radiation therapy. From the MCF-7 and MDA-MB231 breast cancer cell lines and primary culture of patient breast cancer cells, we isolated by flow cytometry a CIC subset of cells with the CD44+/CD24âor low phenotype. The CD44+/CD24âor low subset showed increased sphere formation and resistance to radiation compared to the non- CD44+/CD24âor low subset. The increased radiation resistance was not dependent on the result of altered non-homologous end joining (NHEJ) DNA repair activity as both NHEJ activity and expression of the various proteins involved in NHEJ were not significantly different between the CD44+/CD24âor low and non- CD44+/CD24âor low subsets. However, activation of ATM signaling was significantly increased in CD44+/CD24âor low cells compared to non- CD44+/CD24âor low cells in both from breast cancer cell lines and primary human breast cancer cells. Application of an ATM inhibitor effectively decreased the radiation resistance of CD44+/CD24âor low subset, suggesting that targeting ATM signaling may provide a new tool to eradicate stem-like CIC and abolish the radiation resistance of breast cancer
Reconstruction of the 2014 eruption sequence of Ontake Volcano from recorded images and interviews
Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy
Post-depositional fracturing and subsidence of pumice flow deposits: Lascar Volcano, Chile
Unconsolidated pyroclastic flow deposits of the
1993 eruption of Lascar Volcano, Chile, have, with time,
become increasingly dissected by a network of deeply
penetrating fractures. The fracture network comprises
orthogonal sets of decimeter-wide linear voids that form a
pseudo-polygonal grid visible on the deposit surface. In this
work, we combine shallow surface geophysical imaging
tools with remote sensing observations and direct field
measurements of the deposit to investigate these fractures
and their underlying causal mechanisms. Based on ground
penetrating radar images, the fractures are observed to have
propagated to depths of up to 10 m. In addition, orbiting radar interferometry shows that deposit subsidence of up to
1 cm/year occurred between 1993 and 1996 with continued
subsidence occurring at a slower rate thereafter. In situ
measurements show that 1 m below the surface, the 1993
deposits remain 5°C to 15°C hotter, 18 years after
emplacement, than adjacent deposits. Based on the observed
subsidence as well as estimated cooling rates, the fractures are
inferred to be the combined result of deaeration, thermal
contraction, and sedimentary compaction in the months to
years following deposition. Significant environmental factors,
including regional earthquakes in 1995 and 2007, accelerated
settling at punctuated moments in time. The spatially variable
fracture pattern relates to surface slope and lithofacies
variations as well as substrate lithology. Similar fractures
have been reported in other ignimbrites but are generally
exposed only in cross section and are often attributed to
formation by external forces. Here we suggest that such
interpretations should be invoked with caution, and deformation
including post-emplacement subsidence and fracturing of
loosely packed ash-rich deposits in the months to years postemplacement
is a process inherent in the settling of pyroclastic
material
Preschool Teachersâ Perspectives About the Engagement of Immigrant and Non-Immigrant Parents in Their Childrenâs Early Education
The present study explores the perceptions of teachers about the engagement of immigrant and non-immigrant parents in preschool. Data were drawn from a larger evaluation study of a government initiative for preschools in Germany, which was designed to foster inclusive pedagogy and parent cooperation. In these analyses, teachersâ perceptions of the engagement of immigrant parents and non-immigrant parents were rated for each parent group, on a 10-item measure, to identify how teacher ratings varied for the different parent groups. Data from 1397 preschool teachers, employed across 203 preschools, were analyzed using multilevel modeling. This statistical approach takes account of the clustered nature of the data. Teacher ratings of engagement for immigrant and non-immigrant parent groups differed between preschools. Most variability in the ratings could be ascribed to preschool characteristics. In preschools, in which staff held a shared understanding of dealing with cultural diversity and in which the director of the preschool had a multicultural mindset, teachers perceived engagement of parents more positively, especially for immigrant parents. Overall, the findings identified the importance of self-efficacy for inclusion and more positive beliefs about multiculturalism among preschool teachers. Such qualities are important for working with all parents. However, unfavorable social structures, such as those found in disadvantaged areas, may present major challenges for parent cooperation and engagement
A case for increased private sector involvement in Ireland's national animal health services
Non-regulatory animal health issues, such as Johne's disease, infectious bovine rhinotracheitis (IBR) and mastitis will become increasing important, with ongoing globalisation of markets in animals and animal products. In response, Ireland may need to broaden the scope of its national animal health services. However, there have been concerns about the respective roles and responsibilities (both financial and otherwise) of government and industry in any such moves. This paper argues the case for increased private sector involvement in Ireland's national animal health services, based both on theoretical considerations and country case studies (the Netherlands and Australia). The Dutch and Australian case studies present examples of successful partnerships between government and industry, including systems and processes to address non-regulatory animal health issues. In each case, the roles and responsibilities of government are clear, as are the principles underpinning government involvement. Furthermore, the roles and responsibilities (financial and otherwise) of the Dutch and Australian industry are determined through enabling legislation, providing both legitimacy and accountability. There are constraints on the use of EU and national government funds to support non-regulatory animal health services in EU member states (such as Ireland and the Netherlands)
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