Fat-induced hepatic insulin resistance plays a key role in the pathogenesis of type 2 diabetes in obese individuals. Although PKC and inflammatory pathways have been implicated in fat-induced hepatic ...insulin resistance, the sequence of events leading to impaired insulin signaling is unknown. We used Wistar rats to investigate whether PKCδ and oxidative stress play causal roles in this process and whether this occurs via IKKβ- and JNK-dependent pathways. Rats received a 7-h infusion of Intralipid plus heparin (IH) to elevate circulating free fatty acids (FFA). During the last 2 h of the infusion, a hyperinsulinemic-euglycemic clamp with tracer was performed to assess hepatic and peripheral insulin sensitivity. An antioxidant, N-acetyl-L-cysteine (NAC), prevented IH-induced hepatic insulin resistance in parallel with prevention of decreased IκBα content, increased JNK phosphorylation (markers of IKKβ and JNK activation, respectively), increased serine phosphorylation of IRS-1 and IRS-2, and impaired insulin signaling in the liver without affecting IH-induced hepatic PKCδ activation. Furthermore, an antisense oligonucleotide against PKCδ prevented IH-induced phosphorylation of p47(phox) (marker of NADPH oxidase activation) and hepatic insulin resistance. Apocynin, an NADPH oxidase inhibitor, prevented IH-induced hepatic and peripheral insulin resistance similarly to NAC. These results demonstrate that PKCδ, NADPH oxidase, and oxidative stress play a causal role in FFA-induced hepatic insulin resistance in vivo and suggest that the pathway of FFA-induced hepatic insulin resistance is FFA → PKCδ → NADPH oxidase and oxidative stress → IKKβ/JNK → impaired hepatic insulin signaling.
Data provenance refers to the origin, processing, and movement of data. Reliable and precise knowledge about data provenance has great potential to improve reproducibility as well as quality in ...biomedical research and, therefore, to foster good scientific practice. However, despite the increasing interest on data provenance technologies in the literature and their implementation in other disciplines, these technologies have not yet been widely adopted in biomedical research.
The aim of this scoping review was to provide a structured overview of the body of knowledge on provenance methods in biomedical research by systematizing articles covering data provenance technologies developed for or used in this application area; describing and comparing the functionalities as well as the design of the provenance technologies used; and identifying gaps in the literature, which could provide opportunities for future research on technologies that could receive more widespread adoption.
Following a methodological framework for scoping studies and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines, articles were identified by searching the PubMed, IEEE Xplore, and Web of Science databases and subsequently screened for eligibility. We included original articles covering software-based provenance management for scientific research published between 2010 and 2021. A set of data items was defined along the following five axes: publication metadata, application scope, provenance aspects covered, data representation, and functionalities. The data items were extracted from the articles, stored in a charting spreadsheet, and summarized in tables and figures.
We identified 44 original articles published between 2010 and 2021. We found that the solutions described were heterogeneous along all axes. We also identified relationships among motivations for the use of provenance information, feature sets (capture, storage, retrieval, visualization, and analysis), and implementation details such as the data models and technologies used. The important gap that we identified is that only a few publications address the analysis of provenance data or use established provenance standards, such as PROV.
The heterogeneity of provenance methods, models, and implementations found in the literature points to the lack of a unified understanding of provenance concepts for biomedical data. Providing a common framework, a biomedical reference, and benchmarking data sets could foster the development of more comprehensive provenance solutions.
The ATLAS experiment is going to replace the current Inner Detector with an all new inner tracker (ITk) in the ATLAS detector for HL-LHC at CERN. Silicon strip detectors cover the outer layers of the ...barrel and the endcap sections. We have designed and fabricated a prototype single-sided n+-in-p AC-coupled silicon strip sensor for the outer barrel layer with long strips (LS), ATLAS17LS. It is of the maximum allowable size to fit in a 6-in. silicon wafer, with an outer dimension of 9.80(width)×9.76(length)cm2. The sensor features two rows of LS strip segments, 4.83 cm strip length per segment, a strip pitch of 75.5 μm, and a slim edge design. We have implemented technology for high voltage operation of up to 1000V, with a good signal collection after irradiation fluence of 5.6 × 1014neq∕cm2at the end of HL-LHC operation.
We had two objectives for the ATLAS17LS fabrication: qualification of the sensor design and fabrication quality, and providing an adequate number of the sensors for prototyping the building blocks of the strip detector. The sensors were fabricated in 3 batches by HPK with standard wafers from the foundry (320 μm physical thickness). Additional 10 sensors were fabricated with a thinner active thickness of 240 μm to investigate the influence of active thickness on charge collection. Another additional 5 sensors, with special passivation to investigate the influence of passivation on humidity sensitivity. The visual inspection of fabricated sensors revealed an inadequacy that the designed metal width of 10 μm was too narrow. The initial measurements by the vendor showed that the sensors fulfilled the specifications: onset voltages of Microdischarge VMD above the operation voltage VOP (700V for the 1st and 2nd batches; 500V for the 3rd batch, which has improved the yield), leakage currents of < 0.1μA/cm2 at VOP, full depletion voltages VFD< 330V, and rates of bad strips <<1%.
Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated ...with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake tracer-determined disappearance rate (Rd), control 41.2 +/- 1.7 vs. HG 32.4 +/- 1.9 mg. kg-1. min-1, P < 0.05, which was prevented by NAC (HG + NAC 45.9 +/- 3.5 mg. kg-1. min-1). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.
Precision medicine relies on molecular and systems biology methods as well as bidirectional association studies of phenotypes and (high-throughput) genomic data. However, the integrated use of such ...data often faces obstacles, especially in regards to data protection. An important prerequisite for research data processing is usually informed consent. But collecting consent is not always feasible, in particular when data are to be analyzed retrospectively. For phenotype data, anonymization, i.e. the altering of data in such a way that individuals cannot be identified, can provide an alternative. Several re-identification attacks have shown that this is a complex task and that simply removing directly identifying attributes such as names is usually not enough. More formal approaches are needed that use mathematical models to quantify risks and guide their reduction. Due to the complexity of these techniques, it is challenging and not advisable to implement them from scratch. Open software libraries and tools can provide a robust alternative. However, also the range of available anonymization tools is heterogeneous and obtaining an overview of their strengths and weaknesses is difficult due to the complexity of the problem space. We therefore performed a systematic review of open anonymization tools for structured phenotype data described in the literature between 1990 and 2021. Through a two-step eligibility assessment process, we selected 13 tools for an in-depth analysis. By comparing the supported anonymization techniques and further aspects, such as maturity, we derive recommendations for tools to use for anonymizing phenotype datasets with different properties.
The mechanisms of the impairment in hepatic glucose metabolism induced by free fatty acids (FFAs) and the importance of FFA oxidation in these mechanisms remain unclear. FFA-induced peripheral ...insulin resistance has been linked to membrane translocation of novel protein kinase C (PKC) isoforms, but the role of PKC in hepatic insulin resistance has not been assessed. To investigate the biochemical pathways that are induced by FFA in the liver and their relation to glucose metabolism in vivo, we determined endogenous glucose production (EGP), the hepatic content of citrate (product of acetyl-CoA derived from FFA oxidation and oxaloacetate), and hepatic PKC isoform translocation after 2 and 7 h Intralipid + heparin (IH) or SAL in rats. Experiments were performed in the basal state and during hyperinsulinemic clamps (insulin infusion rate, 5 mU. kg(-1). min(-1)). IH increased EGP in the basal state (P < 0.001) and during hyperinsulinemia (P < 0.001) at 2 and 7 h. Also, 7-h infusion of IH induced resistance to the suppressive effect of insulin on EGP (P < 0.05). Glycerol infusion (resulting in plasma glycerol levels similar to IH infusion) did not have any effect on EGP. IH increased hepatic citrate content by twofold, independent of the insulin levels and the duration of IH infusion. IH induced hepatic PKC-delta translocation from the cytosolic to membrane fraction in all groups. PKC-delta translocation was greater at 7 compared with 2 h (P < 0.05). In conclusion, 1) increased FFA oxidation may contribute to the FFA-induced increase in EGP in the basal state and during hyperinsulinemia but is not associated with FFA-induced hepatic insulin resistance, and 2) the progressive insulin resistance induced by FFA in the liver is associated with a progressive increase in hepatic PKC-delta translocation.
Protein kinase C (PKC) epsilon , a member of the novel PKC family, has key roles in mitogenesis and survival in normal and cancer cells. PKC epsilon is frequently overexpressed in epithelial cancers, ...particularly in lung cancer. Using a short-hairpin RNA approach, here we established that PKC epsilon is required for non-small cell lung carcinoma (NSCLC) growth in vitro as well as tumor growth when inoculated into athymic mice. Moreover, sustained delivery of a PKC epsilon -selective inhibitor peptide, epsilon V1-2, reduced xenograft growth in mice. Both RNA interference depletion and pharmacological inhibition of PKC epsilon caused a marked elevation in the number of apoptotic cells in NSCLC tumors. PKC epsilon -depleted NSCLC cells show elevated expression of pro-apoptotic proteins of the Bcl-2 family, caspase recruitment domain-containing proteins and tumor necrosis factor ligands/receptor superfamily members. Moreover, a Gene Set Enrichment Analysis revealed that a vast majority of the genes changed in PKC epsilon -depleted cells were also deregulated in human NSCLC. Our results strongly suggest that PKC epsilon is required for NSCLC cell survival and maintenance of NSCLC tumor growth. Therefore, PKC epsilon may represent an attractive therapeutic target for NSCLC.
To investigate the beneficial effect of bevacizumab injection one week prior to panretinal photocoagulation (PRP) on the occurrence of vitreous hemorrhage (VH) following PRP in high-risk ...proliferative diabetic retinopathy (PDR).
This was a case-control pilot study conducted on two groups: an anti-VEGF treatment group, treated with bevacizumab injection one week prior to the first PRP session, and a control group of treatment-naive PDR patients who underwent PRP treatment and were not given an intravitreal bevacizumab injection, consecutively recruited. In both groups, a complete ophthalmological examination was conducted prior to PRP and at 4, 9, and 16 weeks following treatment. The primary endpoint studied was the occurrence of VH.
The control group included 69 patients (mean age 63±12.3 years) with high-risk PDR who received PRP treatment only, and the anti-VEGF treatment group included 67 patients (mean age 63.13±10.3 years). None of the demographic variables or comorbidities showed any significant difference between the two groups. The number of PRP sessions was not significantly correlated to the occurrence of VH in either of the groups (P=0.167). Vitreous hemorrhage within 16 weeks following laser treatment occurred in 10 patients (14.5%) in the control group and in only 3 patients (4.5%) in the anti-VEGF group (P=0.047).
Our case-control pilot study demonstrates that a bevacizumab injection preceding the initial PRP session might be beneficial in reducing the occurrence of VH in the first 16 weeks following PRP.
Abstract Emerging research highlights the potential cognitive benefits of physical exercise (PE) programs for schizophrenia (SCZ). The few recent efficacy studies that examined augmenting cognitive ...training (CT) with PE suggest superior effects of the combination. The next step is to consider strategies to enhance adherence in real-world settings if this type of combined treatment is going to be effective. We present the first community effectiveness data for PE and CT that included a motivationally-enhancing, self-determined approach to exercise, in lieu of participant payment. Eighty-five outpatients with schizophrenia attending an intensive outpatient program were randomized to 18 h of either (A) self-determined PE regimen with choice from a menu of different activities; (B) tablet-based neurofeedback CT focused on processing speed (PS) and working memory (WM), or (C) a time-matched combination of PE and CT. Assessments were conducted at baseline, post, and follow-up (2 mo). All groups improved in WM from baseline to post, with greatest gains in the PE only group. At follow-up, cognitive gains originally observed in the PE-only group disappeared, while the PE + CT group evidenced improvements in WM and psychotic symptoms. Notably, attrition for PE was only 7%. Our data shows that combining PE and CT leads to lasting effects that are superior to those of either intervention alone. The low PE drop-out rate suggests a self-determined approach to the exercise regimen was tolerable, and may be an important component of future community implementation efforts.
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