Infectious bursal disease virus (IBDV), a member of the Birnaviridae family, is responsible for a devastating immunosuppressive disease affecting juvenile domestic chickens. IBDV particles are naked ...icosahedrons enclosing a bipartite double-stranded RNA genome harboring three open reading frames (ORF). One of these ORFs codes for VP5, a non-structural polypeptide dispensable for virus replication in tissue culture but essential for IBDV pathogenesis. Using two previously described recombinant viruses, whose genomes differ in a single nucleotide, expressing or not the VP5 polypeptide, we have analyzed the role of this polypeptide during the IBDV replication process. Here, we show that VP5 is not involved in house-keeping steps of the virus replication cycle; i.e. genome transcription/replication, protein translation and virus assembly. Although infection with the VP5 expressing and non-expressing viruses rendered similar intracellular infective progeny yields, striking differences were detected on the ability of their progenies to exiting infected cells. Experimental data shows that the bulk of the VP5-expressing virus progeny efficiently egresses infected cells during the early phase of the infection, when viral metabolism is peaking and virus-induced cell death rates are as yet minimal, as determined by qPCR, radioactive protein labeling and quantitative real-time cell death analyses. In contrast, the release of the VP5-deficient virus progeny is significantly abridged and associated to cell death. Taken together, data presented in this report show that IBDV uses a previously undescribed VP5-dependent non-lytic egress mechanism significantly enhancing the virus dissemination speed. Ultrastructural analyses revealed that newly assembled IBDV virions associate to a vesicular network apparently facilitating their trafficking from virus assembly factories to the extracellular milieu, and that this association requires the expression of the VP5 polypeptide.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
miRNAs are important regulators of gene expression that are frequently deregulated in cancer, with aberrant DNA methylation being an epigenetic mechanism involved in this process. We previously ...identified miRNA promoter regions active in normal mammary cell types and here we analyzed which of these promoters are targets of aberrant DNA methylation in human breast cancer cell lines and breast tumor specimens. Using 5-methylcytosine immunoprecipitation coupled to miRNA tiling microarray hybridization, we performed comprehensive evaluation of DNA methylation of miRNA gene promoters in breast cancer. We found almost one third (55/167) of miRNA promoters were targets for aberrant methylation in breast cancer cell lines. Breast tumor specimens displayed DNA methylation of majority of these miRNA promoters, indicating that these changes in DNA methylation might be clinically relevant. Aberrantly methylated miRNA promoters were, similar to protein coding genes, enriched for promoters targeted by polycomb in normal cells. Detailed analysis of selected miRNA promoters revealed decreased expression of miRNA linked to increased promoter methylation for mir-31, mir-130a, let-7a-3/let-7b, mir-155, mir-137 and mir-34b/mir-34c genes. The proportion of miRNA promoters we found aberrantly methylated in breast cancer is several fold larger than that observed for protein coding genes, indicating an important role of DNA methylation in miRNA deregulation in cancer.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Difficulties associated with handling H2 and CO in metal-catalyzed processes have led to the development of chemical surrogates to these species. Despite many successful examples using this strategy, ...the application of convenient hydrogen halide (HX) surrogates in catalysis has lagged behind considerably. We now report the use of ammonium halides as HX surrogates to accomplish a Pd-catalyzed hydrohalogenation of enynes. These safe and practical salts avoid many drawbacks associated with traditional HX sources including toxicity and corrosiveness. Experimental and computational studies support a reaction mechanism involving a crucial E-to-Z vinyl–Pd isomerization and a carbon–halogen bond-forming reductive elimination. Furthermore, rare examples of C(sp3)–Br and −Cl reductive elimination from Pd(II) as well as transfer hydroiodination using 1-iodobutane as an alternate HI surrogate are also presented.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Machine learning techniques combined with wearable electronics can deliver accurate short-term blood glucose level prediction models. These models can learn personalized glucose-insulin dynamics ...based on the sensor data collected by monitoring several aspects of the physiological condition and daily activity of an individual. Until now, the prevalent approach for developing data-driven prediction models was to collect as much data as possible to help physicians and patients optimally adjust therapy. The objective of this work was to investigate the minimum data variety, volume, and velocity required to create accurate person-centric short-term prediction models. We developed a series of these models using different machine learning time series forecasting techniques suitable for execution within a wearable processor. We conducted an extensive passive patient monitoring study in real-world conditions to build an appropriate data set. The study involved a subset of type 1 diabetic subjects wearing a flash glucose monitoring system. We comparatively and quantitatively evaluated the performance of the developed data-driven prediction models and the corresponding machine learning techniques. Our results indicate that very accurate short-term prediction can be achieved by only monitoring interstitial glucose data over a very short time period and using a low sampling frequency. The models developed can predict glucose levels within a 15-min horizon with an average error as low as 15.43 mg/dL using only 24 historic values collected within a period of sex hours, and by increasing the sampling frequency to include 72 values, the average error is reduced to 10.15 mg/dL. Our prediction models are suitable for execution within a wearable device, requiring the minimum hardware requirements while at simultaneously achieving very high prediction accuracy.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Calcium signalling in astroglia Verkhratsky, Alexei; Rodríguez, José J.; Parpura, Vladimir
Molecular and cellular endocrinology,
04/2012, Volume:
353, Issue:
1-2
Journal Article
Peer reviewed
Astroglia possess excitability based on movements of Ca2+ ions between intracellular compartments and plasmalemmal Ca2+ fluxes. This “Ca2+ excitability” is controlled by several families of proteins ...located in the plasma membrane, within the cytosol and in the intracellular organelles, most notably in the endoplasmic reticulum (ER) and mitochondria. Accumulation of cytosolic Ca2+ can be caused by the entry of Ca2+ from the extracellular space through ionotropic receptors and store-operated channels expressed in astrocytes. Plasmalemmal Ca2+ ATP-ase and sodium–calcium exchanger extrude cytosolic Ca2+ to the extracellular space; the exchanger can also operate in reverse, depending of the intercellular Na+ concentration, to deliver Ca2+ to the cytosol. The ER internal store possesses inositol 1,4,5-trisphosphate receptors which can be activated upon stimulation of astrocytes through a multiple plasma membrane metabotropic G-protein coupled receptors. This leads to release of Ca2+ from the ER and its elevation in the cytosol, the level of which can be modulated by mitochondria. The mitochondrial uniporter takes up Ca2+ into the matrix, while free Ca2+ exits the matrix through the mitochondrial Na+/Ca2+ exchanger as well as via transient openings of the mitochondrial permeability transition pore. One of the prominent consequences of astroglial Ca2+ excitability is gliotransmission, a release of transmitters from astroglia which can lead to signalling to adjacent neurones.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
IMPORTANCE: Enhanced Recovery After Surgery (ERAS) care has been reported to be associated with improvements in outcomes after colorectal surgery compared with traditional care. OBJECTIVE: To ...determine the association between ERAS protocols and outcomes in patients undergoing elective colorectal surgery. DESIGN, SETTING, AND PARTICIPANTS: The Postoperative Outcomes Within Enhanced Recovery After Surgery Protocol (POWER) Study is a multicenter, prospective cohort study of 2084 consecutive adults scheduled for elective colorectal surgery who received or did not receive care in a self-declared ERAS center. Patients were recruited from 80 Spanish centers between September 15 and December 15, 2017. All patients included in this analysis had 1 month of follow-up. EXPOSURES: Colorectal surgery and perioperative management were the exposures. Twenty-two individual ERAS items were assessed in all patients, regardless of whether they were included in an established ERAS protocol. MAIN OUTCOMES AND MEASURES: The primary study outcome was moderate to severe postoperative complications within 30 days after surgery. Secondary outcomes included ERAS adherence, mortality, readmissions, reoperation rates, and hospital length of stay. RESULTS: Between September 15 and December 15, 2017, 2084 patients were included in the study. Of these, 1286 individuals (61.7%) were men; mean age was 68 years (interquartile range IQR, 59-77). A total of 879 patients (42.2%) presented with postoperative complications and 566 patients (27.2%) developed moderate to severe complications. The number of patients with moderate or severe complications was lower in the ERAS group (25.2% vs 30.3%; odds ratio OR, 0.77; 95% CI, 0.63-0.94; P = .01). The overall rate of adherence to the ERAS protocol was 63.6% (IQR, 54.5%-77.3%), and the rate for patients from hospitals self-declared as ERAS was 72.7% (IQR, 59.1%-81.8%) vs non-ERAS institutions, which was 59.1% (IQR, 50.0%-63.6%; P < .001). Adherence quartiles among patients receiving the highest and lowest ERAS components showed that the patients with the highest adherence rates had fewer moderate to severe complications (OR, 0.34; 95% CI, 0.25-0.46; P < .001), overall complications (OR, 0.33; 95% CI, 0.26-0.43; P < .001), and mortality (OR, 0.27; 95% CI, 0.07-0.97; P = .06) compared with those who had the lowest adherence rates. CONCLUSIONS AND RELEVANCE: An increase in ERAS adherence appears to be associated with a decrease in postoperative complications.
Type 1 Diabetes Mellitus (DM1) patients are used to checking their blood glucose levels several times per day through finger sticks and, by subjectively handling this information, to try to predict ...their future glycaemia in order to choose a proper strategy to keep their glucose levels under control, in terms of insulin dosages and other factors. However, recent Internet of Things (IoT) devices and novel biosensors have allowed the continuous collection of the value of the glucose level by means of Continuous Glucose Monitoring (CGM) so that, with the proper Machine Learning (ML) algorithms, glucose evolution can be modeled, thus permitting a forecast of this variable. On the other hand, glycaemia dynamics require that such a model be user-centric and should be recalculated continuously in order to reflect the exact status of the patient, i.e., an 'on-the-fly' approach. In order to avoid, for example, the risk of being disconnected from the Internet, it would be ideal if this task could be performed locally in constrained devices like smartphones, but this would only be feasible if the execution times were fast enough. Therefore, in order to analyze if such a possibility is viable or not, an extensive, passive, CGM study has been carried out with 25 DM1 patients in order to build a solid dataset. Then, some well-known univariate algorithms have been executed in a desktop computer (as a reference) and two constrained devices: a smartphone and a Raspberry Pi, taking into account only past glycaemia data to forecast glucose levels. The results indicate that it is possible to forecast, in a smartphone, a 15-min horizon with a Root Mean Squared Error (RMSE) of 11.65 mg/dL in just 16.15 s, employing a 10-min sampling of the past 6 h of data and the Random Forest algorithm. With the Raspberry Pi, the computational effort increases to 56.49 s assuming the previously mentioned parameters, but this can be improved to 34.89 s if Support Vector Machines are applied, achieving in this case an RMSE of 19.90 mg/dL. Thus, this paper concludes that local on-the-fly forecasting of glycaemia would be affordable with constrained devices.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
U.S. health inequities won’t be eliminated by abandoning the use of race and ethnicity in research and clinical practice, since these variables capture key epidemiologic information. But ...incorporating genetic ancestry, genotypes, or biomarkers requires further study.
It has become generally accepted that new neurones are added and integrated mainly in two areas of the mammalian CNS, the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus (DG) ...of the hippocampus, which is of central importance in learning and memory. The newly generated cells display neuronal morphology, are able to generate action potentials and receive functional synaptic inputs, i.e. their properties are similar to those found in mature neurones. Alzheimer's disease (AD) is the primary and widespread cause of dementia and is an age-related, progressive and irreversible neurodegenerative disease that deteriorates cognitive functions. Here, we have used male and female triple transgenic mice (3xTg-AD) harbouring three mutant genes (beta-amyloid precursor protein, presenilin-1 and tau) and their respective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and 12 months of age to establish the link between AD and neurogenesis. Using immunohistochemistry we determined the area density of proliferating cells within the SGZ of the DG, measured by the presence of phosphorylated Histone H3 (HH3), and their possible co-localisation with GFAP to exclude a glial phenotype. Less than 1% of the HH3 labeled cells co-localised with GFAP. Both non-Tg and 3xTg-AD showed an age-dependent decrease in neurogenesis. However, male 3xTg-AD mice demonstrated a further reduction in the production of new neurones from 9 months of age (73% decrease) and a complete depletion at 12 months, when compared to controls. In addition, female 3xTg-AD mice showed an earlier but equivalent decrease in neurogenesis at 4 months (reduction of 63%) with an almost inexistent rate at 12 months (88% decrease) compared to controls. This reduction in neurogenesis was directly associated with the presence of beta-amyloid plaques and an increase in the number of beta-amyloid containing neurones in the hippocampus; which in the case of 3xgTg females was directly correlated. These results suggest that 3xTg-AD mice have an impaired ability to generate new neurones in the DG of the hippocampus, the severity of which increases with age and might be directly associated with the known cognitive impairment observed from 6 months of age onwards . The earlier reduction of neurogenesis in females, from 4 months, is in agreement with the higher prevalence of AD in women than in men. Thus it is conceivable to speculate that a recovery in neurogenesis rates in AD could help to rescue cognitive impairment.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
