Miracle-dz/UniFAR-FTUs huggingface dataset:
Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

Aldosterone may play a pivotal role in the pathophysiology of heart failure. To elucidate the beneficial cardioprotective mechanism of eplerenone, a novel selective aldosterone blocker, we hypothesized that eplerenone stimulates endothelial NO synthase (eNOS) through Akt and inhibits inducible NO synthase (iNOS) via nuclear factor &kgr;B (NF-&kgr;B) after the development of oxidative stress and activation of the lectin-like, oxidized, low-density lipoprotein receptor 1 (LOX-1) pathway in Dahl salt-sensitive rats with heart failure. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of the left ventricular hypertrophy stage (11 weeks) to the failing stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship was evaluated using a conductance catheter. Decreased percentage of fractional shortening by echocardiography and end-systolic pressure-volume relationship in failing rats was significantly ameliorated by eplerenone. Downregulated eNOS expression, eNOS and Akt phosphorylation, and NOS activity in failing rats were increased by eplerenone. Upregulated expression of the mineralocorticoid receptor aldosterone synthase (CYP11B2); NAD(P)H oxidase p22phox, p47phox, gp91phox, iNOS, and LOX-1; and activated p65 NF-&kgr;B, protein kinase C&bgr;II, c-Src, p44/p42 extracellular signal-regulated kinase, and p70S6 kinase phosphorylation were inhibited by eplerenone. Eplerenone administration resulted in significant improvement of cardiac function and remodeling and upregulation of sarcoplasmic reticulum Ca2+-ATPase expression. These findings suggest that eplerenone may have significant therapeutic potential for heart failure, and these cardioprotective mechanisms of eplerenone may be mediated in part by stimulating eNOS through Akt and inhibiting iNOS via NF-&kgr;B after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway.
MODELING EXCHANGE RATE VOLATILITIES IN CROATIA

Modeling and forecasting exchange rate volatility has important implications in a range of areas in macroeconomics and finance. A number of models have been developed in empirical finance literature to investigate this volatility across different regions and countries. Well known and frequently applied models to estimate exchange rate volatility are the autoregressive conditional heteroscedastic (ARCH) model advanced by Engle (1982) and the generalized (GARCH) model developed independently by Bollerslev (1986) and Taylor (1986). This paper examines the performance of several ARCH models for the EUR and USD against the HRK on daily data sets within the time period from 1997 to 2015. Evaluating the models through standard information criteria showed that the GARCH (2,1) is the best fitted model for the EUR/HRK and the GARCH (1,1) for the USD/HRK daily return volatility. In accordance to the estimated models there is no empirical evidence that negative and positive shocks imply a different next period volatility of the daily EUR/HRK as well as the USD/HRK exchange rate return. Keywords: GARCH model, Heteroscedasticity, Exchange rate volatility, Croatia
Systematic meta-analyses and field synopsis of genetic association studies in colorectal cancer.

BACKGROUND Colorectal cancer is a major global public health problem, with approximately 950,000 patients newly diagnosed each year. We report the first comprehensive field synopsis and creation of a parallel publicly available and regularly updated database (CRCgene) that catalogs all genetic association studies on colorectal cancer (http://www.chs.med.ed.ac.uk/CRCgene/). METHODS We performed two independent systematic reviews, reviewing 10 145 titles, then collated and extracted data from 635 publications reporting on 445 polymorphisms in 110 different genes. We carried out meta-analyses to derive summary effect estimates for 92 polymorphisms in 64 different genes. For assessing the credibility of associations, we applied the Venice criteria and the Bayesian False Discovery Probability (BFDP) test. RESULTS We consider 16 independent variants at 13 loci (MUTYH, MTHFR, SMAD7, and common variants tagging the loci 8q24, 8q23.3, 11q23.1, 14q22.2, 1q41, 20p12.3, 20q13.33, 3q26.2, 16q22.1, and 19q13.1) to have the most highly credible associations with colorectal cancer, with all variants except those in MUTYH and 19q13.1 reaching genome-wide statistical significance in at least one meta-analysis model. We identified less-credible (higher heterogeneity, lower statistical power, BFDP >0.2) associations with 23 more variants at 22 loci. The meta-analyses of a further 20 variants for which associations have previously been reported found no evidence to support these as true associations. CONCLUSION The CRCgene database provides the context for genetic association data to be interpreted appropriately and helps inform future research direction.
The effectiveness of computed tomography-guided biopsy for the diagnosis of spondylodiscitis: an analysis of variables affecting the outcome.

OBJECTIVE To analyze: (i) the effectiveness of CT-guided biopsy for the diagnosis of suspected spinal infections (spondylodiscitis); (ii) identify common causative microorganisms and assess factors that could affect the diagnostic yield. PATIENTS AND METHODS Forty-five patients undergoing CT-guided biopsy for suspected spinal infection between November 2012 and October 2014 were analyzed. The time from presentation to diagnosis, administration of antibiotics before biopsy, blood culture results, admission C-reactive protein (CRP)/white cell count, presence of fever or neurological deficits, and soft tissue collections on MRI were analyzed. Multivariable logistic regression was performed to determine variables independently associated with a positive biopsy. RESULTS Eleven (24.4%) patients had positive blood cultures. The first biopsy was positive in 19 (42.2%) patients. Thirty-eight (84.4%) patients had a single biopsy, while seven (15.5%) patients underwent repeat biopsy with a positive yield in one (14.2%) patient. Overall, causative microorganisms were identified in 26 (57.8%) cases. Admission CRP was significantly associated with isolating the causative pathogen from CT-guided biopsy (p<0.001). A soft tissue collection on MRI was associated with identification of a microorganism in blood cultures (p=0.001). CRP was the only independent variable associated with a positive yield on CT-guided biopsy (p=0.007, OR 1.042) and was more likely in patients with CRP>50 (p<0.001). Administration of empirical antibiotics before biopsy did not affect the yield (p=0.572). CONCLUSIONS A high CRP was a strong predictor of isolation of the causative organism. Repeat CT-guided biopsy was found to have limited value with a low positive yield (14.2%) in our study.
Minimally Invasive Interbody Fusion for Revision Lumbar Surgery: Technical Feasibility and Safety

Study Design Retrospective chart review of one surgeon's practice. Objective We evaluate the perioperative morbidity of 43 patients undergoing minimally invasive lumbar interbody fusion to differentiate risks between primary and revision surgery candidates. Summary of Background Data Minimally invasive approaches to the lumbar spine have rapidly evolved and the technical feasibility and safety of minimally invasive interbody fusion is well established. Revision surgery is technically more challenging and may cause avoidance of such approaches because of altered anatomy and absent bony landmarks. Description of minimally invasive surgery approaches among revision patients and the feasibility of such techniques demands clarification. Methods Forty-three consecutive minimally invasive transforaminal lumbar interbody fusions (TLIFs) and posterior lumbar interbody fusions (PLIFs) were reviewed. Estimated blood loss, operative time, and complication rates were compared between primary and revision patients using Student t tests. Results Seventeen revision surgery cases (40%) were compared with 26 primary surgeries (60%) to elucidate differences in operative time, estimated blood loss, and complications. Demographic variables were similar in both groups. Estimated blood loss trended higher among the PLIF group and among revision cases, though no statistical significance was observed. A higher rate of complications, most notably incidental durotomy, was observed among revision cases in both PLIF and TLIF patients. One patient undergoing primary surgery had an intraoperative pedicle fracture, and 1 patient undergoing revision surgery had an asymptomatic screw malposition. No patients had a major complication, nerve injury, infection, or conversion to an open procedure. Conclusions Minimally invasive lumbar interbody fusion by revision surgery is technically feasible and is not associated with more blood loss or neurologic morbidity. However, revision surgery has a higher minor perioperative complication rate, particularly of incidental durotomy. These outcomes demand significant experience before attempting minimally invasive revision surgery in the lumbar spine.
Technical complications of implant-supported fixed partial dentures in partially edentulous cases after an average observation period of 5 years.

OBJECTIVES The purpose of this prospective long-term study was to evaluate the incidence of the most common technical problems, namely screw loosening, screw fracture, fracturing of veneering porcelain and framework fracture in implant-supported fixed partial dentures (FPDs), and assess the survival and success rate (event-free survival) after 5 years of function. MATERIALS AND METHODS In 76 partially edentulous patients, a total of 205 3i-implants (machined surface) were placed and restored with 112 implant-supported FPDs (46 single crowns, 81 splinted crowns, seven FPD bridges and 23 FPDs with cantilevers). The survival rate of FPDs supported by implants was 94.5% (CI-95: 90.1-98.8) after an average observation period of 5 years. The success rate (event-free survival) of the FPDs was 80% (CI-95: 87.3-72.7). After an observation period of 5 years the cumulative incidence of screw loosening was 6.7% (CI-95: 1.8-11.5), the cumulative incidence for screw fracture was 3.9% (CI-95: 0.1-7.7). Fracture of the veneering porcelain occurred in 5.7% (CI-95: 1.2-10.2) of all FPDs. Fracturing of the suprastructure framework was rare (1%; CI-95: 0-2.9). The overall complication incidence after 5 years was highest in the group of FPDs with cantilever, which showed the lowest success rate 68.6% (CI-95: 50-87.3), followed by single crowns (77.6%; CI-95: 53.3-100) and splinted crowns (86.1%; CI-95: 59.5-100). No complication occurred in FPD bridges. CONCLUSION Fixed partial dentures supported by 3i-implants showed low technical complications rates, the most common being loosening of the abutment screw. Managing these complications can cause extra amount of chair-side time and patient dissatisfaction.
Contributions of Indian Ocean Sea Surface Temperatures to Enhanced East African Rainfall

Abstract Links between extreme wet conditions over East Africa and Indian Ocean sea surface temperatures (SST) are investigated during the core of the so-called short rain season in October–November. During periods of enhanced East African rainfall, Indian Ocean SST anomalies reminiscent of a tropical Indian Ocean dipole (IOD) event are observed. Ensemble simulations with an atmospheric general circulation model are used to understand the relative effect of local and large-scale Indian Ocean SST anomalies on above-average East African precipitation. The importance of the various tropical and subtropical IOD SST poles, both individually and in combination, is quantified. In the simulations, enhanced East African “short rains” are predominantly driven by the local warm SST anomalies in the western equatorial Indian Ocean, while the eastern cold pole of the tropical IOD is of lesser importance. The changed East African rainfall distribution can be explained by a reorganization of the atmospheric circulation .
Cone deactivation kinetics and GRK1/GRK7 expression in enhanced S cone syndrome caused by mutations in NR2E3.

PURPOSE To determine the relationship between cone deactivation kinetics in patients with the enhanced S cone syndrome (ESCS) caused by mutations in NR2E3 and the immunoreactivity to G-protein-coupled receptor kinase 1 (GRK1) and GRK7. METHODS Electroretinogram (ERG) photoresponses were used to investigate activation kinetics of cones with a model of cone phototransduction. Deactivation kinetics of cones after bright flashes was quantified with a paired-flash ERG paradigm. Immunocytochemistry was performed with antibodies against cone opsins and kinases GRK1 and GRK7 in postmortem normal and ESCS retinal tissue. RESULTS Activation kinetics of long/middle-wavelength-sensitive (L/M) cone-mediated responses in patients with ESCS were similar to those of normal L/M cones. Activation kinetics of ESCS short-wavelength-sensitive (S) cones, when compared with normal L/M cone responses evoked by the same stimulus, were slower by an amount consistent with the expected differences in spectral sensitivities. After bright flashes chosen to evoke identical activation kinetics, ESCS S cones deactivated much more slowly than ESCS or normal L/M cones. Normal human retina revealed strongly labeled cone outer segments with anti-GRK1 and anti-GRK7. In an ESCS retina, outer segments positive for L/M opsin were strongly labeled with anti-GRK1, whereas outer segments positive for S opsin showed no detectable GRK1 reactivity. GRK7 labeling was absent in all photoreceptors of the ESCS retina. CONCLUSIONS The cone-dominant human retina resulting from NR2E3 mutations affords greater understanding of the physiological roles of GRK1 and GRK7 in human cone photoreceptors. Normal deactivation kinetics in human L/M cones can occur without GRK7 when GRK1 is present in ESCS, but does not occur when GRK7 is present but GRK1 is deficient in Oguchi disease. Lack of both GRK1 and GRK7 in S cones of patients with ESCS results in a more pronounced abnormality in deactivation kinetics and suggests the existence of partial compensation by either GRK when the other is deficient.
Realistic modeling of the denatured states of proteins allows accurate calculations of the pH dependence of protein stability.

Computational techniques based on continuum electrostatics treatments have been successful in predicting and interpreting the pKa values of ionizable amino acids in folded proteins. Despite this progress, efforts to reproduce the pH-dependence of protein stability have met with only limited success: agreement with experimental results has been only qualitative. It has been argued previously that the most likely reason for discrepancies is the presence of residual electrostatic interactions in the unfolded state, which cause pKa values to be shifted from their model compound values. Here we show that by constructing atomistic models of the unfolded state with a simple molecular mechanics protocol that uses the native state as a starting point, much improved reproduction of pH effects on protein stability can be obtained. In contrast, when a fully extended model of the unfolded state is used, no such improvement is obtained, a result that suggests that local interactions with residues nearby in the sequence are not sufficient to properly account for the pKa shifts in the unfolded state. In comparison to model compound values, the pKa values of acidic residues in "native-like" unfolded states are typically found to be shifted downwards by approximately 0.3 pH unit, in good agreement with the average downward shift deduced from experimental measurements. Given its success in the present situation, the protocol employed here for developing simple models of the unfolded state may prove useful in other computer simulation applications.
Characterization of a Novel β-Glucosidase from a Compost Microbial Metagenome with Strong Transglycosylation Activity*

Background: There is an ongoing search for a β-glucosidase that has insensitivity to product inhibition. Results: A β-glucosidase, Td2F2, was isolated from a metagenomic library and has high glucose tolerance, and its activity is enhanced by various monosaccharides. Conclusion: The high glucose tolerance of Td2F2 is related to high transglycosylation activity. Significance: This is the first report of a β-glucosidase having high glucose tolerance and high transglycosylation activity. The β-glucosidase encoded by the td2f2 gene was isolated from a compost microbial metagenomic library by functional screening. The protein was identified to be a member of the glycoside hydrolase family 1 and was overexpressed in Escherichia coli, purified, and biochemically characterized. The recombinant β-glucosidase, Td2F2, exhibited enzymatic activity with β-glycosidic substrates, with preferences for glucose, fucose, and galactose. Hydrolysis occurred at the nonreducing end and in an exo manner. The order of catalytic efficiency for glucodisaccharides and cellooligosaccharides was sophorose > cellotetraose > cellotriose > laminaribiose > cellobiose > cellopentaose > gentiobiose, respectively. Intriguingly, the p-nitrophenyl-β-d-glucopyranoside hydrolysis activity of Td2F2 was activated by various monosaccharides and sugar alcohols. At a d-glucose concentration of 1000 mm, enzyme activity was 6.7-fold higher than that observed in the absence of d-glucose. With 31.3 mm d-glucose, Td2F2 catalyzed transglycosylation to generate sophorose, laminaribiose, cellobiose, and gentiobiose. Transglycosylation products were detected under all activated conditions, suggesting that the activity enhancement induced by monosaccharides and sugar alcohols may be due to the transglycosylation activity of the enzyme. These results show that Td2F2 obtained from a compost microbial metagenome may be a potent candidate for industrial applications.
Cytological features of cervical smears in serous adenocarcinoma of the endometrium.

OBJECTIVE Serous adenocarcinoma (SAC) of the endometrium has a poor prognosis compared with that of typical endometrioid adenocarcinoma (EAC). The objective of this study was to determine whether SAC can be distinguished from EAC preoperatively by cervical or endometrial cytology. STUDY DESIGN Cervical smears and endometrial smears obtained from 128 patients with endometrial carcinoma were reviewed. Histological types included 117 cases of EAC and 11 cases of SAC. The positive rates of cervical smears and those of endometrial smears in SAC and EAC cases were compared. Papillary clusters and bare nuclei of malignant cells in positive cervical smears were also investigated for their diagnostic significance in discriminating between EAC and SAC. RESULTS The positive rate of cervical smears in SAC was significantly higher than that in EAC (72.7 vs 27.4%, P < 0.05). Among cases with positive cervical smears, there were significantly more cases with papillary clusters and/or bare nuclei in cases of SAC than in cases of EAC. CONCLUSION When endometrial carcinoma is clinically suspected and a cervical smear is positive, the predominance of either papillary clusters or features of bare nuclei of malignant cells in the smear may indicate the presence of SAC.
Leukocyte Mitochondrial DNA Alteration in Systemic Lupus Erythematosus and Its Relevance to the Susceptibility to Lupus Nephritis

The role of mitochondrial DNA (mtDNA) alterations in the pathophysiology of systemic lupus erythematosus (SLE) remains unclear. We investigated sequence variations in the D310 region and copy number change of mtDNA in 85 SLE patients and 45 normal subjects. Leukocyte DNA and RNA were extracted from leukocytes of the peripheral venous blood. The D310 sequence variations and copy number of mtDNA, and mRNA expression levels of mtDNA-encoded genes in leukocytes were determined by quantitative real-time polymerase chain reaction (Q-PCR) and PCR-based direct sequencing, respectively. We found that leukocyte mtDNA in SLE patients exhibited higher frequency of D310 heteroplasmy (69.4% vs. 48.9%, p = 0.022) and more D310 variants (2.2 vs. 1.7, p = 0.014) than those found in controls. Among normal controls and patients with low, medium or high SLE disease activity index (SLEDAI), an ever-increasing frequency of D310 heteroplasmy was observed (p = 0.021). Leukocyte mtDNA copy number tended to be low in patients of high SLEDAI group (p = 0.068), especially in those harboring mtDNA with D310 heteroplasmy (p = 0.020). Moreover, the mtDNA copy number was positively correlated with the mRNA level of mtDNA-encoded ND1 (NADH dehydrogenase subunit 1) (p = 0.041) and ATPase 6 (ATP synthase subunit 6) (p = 0.030) genes. Patients with more D310 variants were more susceptible to lupus nephritis (p = 0.035). Taken together, our findings suggest that decrease in the mtDNA copy number and increase in D310 heteroplasmy of mtDNA are related to the development and progression of SLE, and that the patients harboring more D310 variants of mtDNA are more susceptible to lupus nephritis.
Compensatory response ‘defends’ energy levels but not growth trajectories in brown trout, Salmo trutta L.

Compensatory growth is an organism's reaction to buffer deviations from targeted trajectories. We explored the compensatory patterns of juvenile brown trout under field and laboratory conditions. Divergence of size and condition trajectories was induced by manipulating food levels in the laboratory and then releasing the trout into a river. In the stream, the length trajectories of food-restricted and control fish were parallel, but food-restricted fish exhibited partial compensation for mass and rapid recovery of condition. A laboratory experiment on similar sized fish did not provide evidence for compensatory growth in length or mass. In contrast, data matched the compensatory patterns shown in the stream: length trajectories were parallel and the convergence of mass trajectories ceased as soon as food-restricted fish recovered condition to the level of controls. These results show that (i) brown trout did not compensate for depression in structural growth and (ii) mass recovery was targeted to reinstate condition or energy reserves, but not size at a given age. This does not support the common view that compensatory growth can be a general response to growth depression. Rather, compensation in other salmonids could be related to size thresholds associated with developmental switches at the onset of sexual maturation and migration.
The importance of delayed images in gastrointestinal bleeding scintigraphy

Although radionuclide methods for the detection of gastrointestinal (GI) bleeding have been available for more than 20 years, the value of delayed images in GI bleeding scintigraphy is still regarded controversially. The aim of this study was to determine the value of delayed images in a group of patients with predominantly low-grade intermittent bleeding. Eighty-nine consecutive GI bleeding scintigraphies of 75 patients were analysed retrospectively. All patients were referred to our department after other diagnostic methods had failed to identify the localization of GI bleeding. After the dynamic study, delayed images were acquired for up to 24 h until a bleeding site was identified. Data on the clinical outcome were available in all but five patients. No patient with a negative scan died from GI bleeding. A positive result was found in 41 patients (55%). The scans of 11 of these 41 patients (27%) became positive during dynamic imaging. Four required immediate surgery and, in another patient, surgery was not performed because of diffuse bleeding of the entire GI tract. One patient died without surgical intervention. Thirty-three scans of 30 of these 41 patients (73%) were positive on delayed imaging only, leading to surgery in 12 individuals. Our findings demonstrate the importance of delayed images in GI bleeding scintigraphy. Many of our patients who required surgery had scans that did not become positive for several hours.