Miracle-dz/UniFAR-FTUs huggingface dataset:
BAY 11-7085 induces glucocorticoid receptor activation and autophagy that collaborate with apoptosis to induce human synovial fibroblast cell death

Inhibition of proapoptotic pathways in synovial fibroblasts is one of the major causes of synovial proliferation and hyperplasia in rheumatic diseases. We have shown previously that NF-κB inhibitor BAY 11-7085, through inactivation of PPAR-γ, induces apoptosis in human synovial fibroblasts. In this work we showed that BAY 11-7085 induced autophagy that preceded BAY 11-7085-induced apoptosis. Of interest, BAY 11-7085 induced Serine 211 phosphorylation and degradation of glucocorticoid receptor (GR). Glucocorticoid prednisolone induced both activation and degradation of GR, as well as autophagy in synovial fibroblasts. BAY 11-7085-induced cell death was significantly decreased with glucocorticoid inhibitor mifepristone and with inhibitors of autophagy. Both BAY 11-7085-induced autophagy and GR activation were down regulated with PPAR-γ agonist, 15d-PGJ2 and MEK/ERK inhibitor UO126. Inhibition of autophagy markedly decreased endogenous and BAY 11-7085-induced ERK phosphorylation, suggesting a positive feed back loop between ERK activation and autophagy in synovial fibroblasts. Co-transfection of MEK1 with PPAR-γ1 in HEK293 cells caused known inhibitory phosphorylation of PPAR-γ1 (Serine 112) and enhanced GR degradation, in the absence or presence of prednisolone. Furthermore, GR was both phosphorylated on Serine 211 and down regulated in synovial fibroblasts during serum starvation induced autophagy. These results showed that GR activation and PPAR-γ inactivation mediated BAY 11-7085-induced autophagy.
Stepping Back to Move Forward: Evaluating the Effectiveness of a Diabetes Prevention Program Within a Large Integrated Healthcare Delivery System

Objective: To evaluate the short-term effectiveness of the Intermountain Healthcare (IH) Diabetes Prevention Program (DPP) for patients with prediabetes (preDM) deployed within primary care clinics. Study Design: A quasi-experimental study design was used to deploy the DPP within the IH system to identify patients with preDM and target a primary goal of a 5% weight loss within 6–12 months of enrollment. Study Population: Adults (aged 18–75 years) who met the American Diabetes Association criteria for preDM were included for study. Patients who attended DPP counseling between August 2013 and July 2014 were considered as the intervention (or DPP) group. The DPP group was matched using propensity scores at a 1:4 ratio with a control group of patients with preDM who did not participate in DPP. Results: Of the 17,142 patients who met the inclusion criteria for preDM, 40% had an in-person office visit with their provider. On average, patients were 58 years old, and greater than 60% were women. Based on multivariate logistic regression, the DPP group was more likely to achieve a 5% weight loss within 6–12 months after enrollment (OR = 1.70; 95% CI = 1.29–2.25; p < .001) when compared with the no-DPP group. Conclusions: Diabetes Prevention Program–based lifestyle interventions demonstrated significant reduction in body weight and incident Type 2 diabetes mellitus when compared with nonenrollees.
Recovery of Chicken Growth Plate by Heat-Shock Protein 90 Inhibitors Epigallocatechin-3-Gallate and Apigenin in Thiram-Induced Tibial Dyschondroplasia

SUMMARY Tibial dyschondroplasia (TD) is an important tibiotarsal bone disorder characterized by an avascular and nonmineralized growth plate; it is attributed to abnormal differentiation of chondrocytes and causes lameness. Heat-shock protein 90 (Hsp90) is a proangiogenic factor in animal tissues; however, its gene expression increases in cases of chicken TD. The objective of this study was to evaluate the efficacy of epigallocatechin-3-gallate (EGCG) and apigenin in thiram-induced TD birds; these substances were used because of their Hsp90 inhibitory activities. The histologic study of growth plates was carried out with hematoxylin and eosin staining, and the Hsp90 gene expression was examined by reverse transcription quantitative real-time PCR. Results showed that as compared to a control group, TD-affected birds displayed changes in chondrocyte differentiation, with lack of blood vessels, and an increased expression of Hsp90 was observed significantly (P < 0.05). However, on administering the EGCG and apigenin to TD-affected birds, the normal chondrocyte columnar organization was restored with vascularization and decreased Hsp90 expression activity (P < 0.05), which ultimately abrogated the lameness. Our results suggested that Hsp90 is the key factor in the development of TD, and EGCG and apigenin have a novel effect on Hsp90 inhibition properties, thus reducing the lameness and leg deformity in chicken broilers.
THE GENETIC BASIS OF ADAPTIVE POPULATION DIFFERENTIATION: A QUANTITATIVE TRAIT LOCUS ANALYSIS OF FITNESS TRAITS IN TWO WILD BARLEY POPULATIONS FROM CONTRASTING HABITATS

Abstract We used a quantitative trait locus (QTL) approach to study the genetic basis of population differentiation in wild barley, Hordeum spontaneum. Several ecotypes are recognized in this model species, and population genetic studies and reciprocal transplant experiments have indicated the role of local adaptation in shaping population differences. We derived a mapping population from a cross between a coastal Mediterranean population and a steppe inland population from Israel and assessed F3 progeny fitness in the natural growing environments of the two parental populations. Dilution of the local gene pool, estimated as the proportion of native alleles at 96 marker loci in the recombinant lines, negatively affected fitness traits at both sites. QTLs for fitness traits tended to differ in the magnitude but not in the direction of their effects across sites, with beneficial alleles generally conferring a greater fitness advantage at their native site. Several QTLs showed fitness effects at one site only, but no opposite selection on individual QTLs was observed across the sites. In a common-garden experiment, we explored the hypothesis that the two populations have adapted to divergent nutrient availabilities. In the different nutrient environments of this experiment, but not under field conditions, fitness of the F3 progeny lines increased with the number of heterozygous marker loci. Comparison of QTL-effects that underlie genotype × nutrient interaction in the common-garden experiment and genotype × site interaction in the field suggested that population differentiation at the field sites may have been driven by divergent nutrient availabilities to a limited extent. Also in this experiment no QTLs were observed with opposite fitness effects in contrasting environments. Our data are consistent with the view that adaptive differentiation can be based on selection on multiple traits changing gradually along ecological gradients. This can occur without QTLs showing opposite fitness effects in the different environments, that is, in the absence of genetic trade-offs in performance between environments.
A host-endoparasite network of Neotropical marine fish: are there organizational patterns?

SUMMARY Properties of ecological networks facilitate the understanding of interaction patterns in host-parasite systems as well as the importance of each species in the interaction structure of a community. The present study evaluates the network structure, functional role of all species and patterns of parasite co-occurrence in a host-parasite network to determine the organization level of a host-parasite system consisting of 170 taxa of gastrointestinal metazoans of 39 marine fish species on the coast of Brazil. The network proved to be nested and modular, with a low degree of connectance. Host-parasite interactions were influenced by host phylogeny. Randomness in parasite co-occurrence was observed in most modules and component communities, although species segregation patterns were also observed. The low degree of connectance in the network may be the cause of properties such as nestedness and modularity, which indicate the presence of a high number of peripheral species. Segregation patterns among parasite species in modules underscore the role of host specificity. Knowledge of ecological networks allows detection of keystone species for the maintenance of biodiversity and the conduction of further studies on the stability of networks in relation to frequent environmental changes.
Microcyst Response to High Dk/t Silicone Hydrogel Contact Lenses

Purpose To investigate the microcyst response to extended wear (EW) with high oxygen transmissible (Dk/t) silicone hydrogel lenses. Methods Microcysts were monitored for 12 months in subjects wearing low Dk/t hydrogel lenses on a 6-night EW schedule or high Dk/t hydrogel lenses on a 30-night EW schedule. Subjects wearing low Dk/t lenses transferred to the high Dk/t EW lenses and schedule after 12 months and were monitored for a further 6 months. Results The mean number of microcysts did not deviate from baseline in the high Dk/t group. Microcysts in the low Dk/t group increased over 12 months, and more microcysts were observed in low Dk/t lens wearers compared with high Dk/t lens wearers after 3 months. Microcysts increased in 50% of subjects 1 week after transfer to high Dk/t lenses and returned to baseline levels seen with high Dk/t lens wear within 3 months. Conclusions EW with high Dk/t silicone hydrogel lenses did not cause an increase in microcyst numbers. It is not necessary to discontinue lens wear with patients who transfer from low to high Dk/t lenses because the increase in microcysts is transitory. This result has implications for practitioners when fitting and assessing the success of high Dk/t hydrogel lenses.
Learning Visually Grounded Sentence Representations

We investigate grounded sentence representations, where we train a sentence encoder to predict the image features of a given caption—i.e., we try to “imagine” how a sentence would be depicted visually—and use the resultant features as sentence representations. We examine the quality of the learned representations on a variety of standard sentence representation quality benchmarks, showing improved performance for grounded models over non-grounded ones. In addition, we thoroughly analyze the extent to which grounding contributes to improved performance, and show that the system also learns improved word embeddings.
Decoding by local optimization

The maximum likelihood decoding problem for linear binary (n,k) codes is reformulated as a continuous optimization problem in a k -dimensional solid cube. We obtain a near optimum solution of this problem by use of a simple gradient local optimization algorithm. Computer simulation results are presented for the (21,11) projective geometry code and the (47,23) quadratic-residue code.
Model selection for Gaussian regression with random design

This paper is about Gaussian regression with random design, where the observations are i.i. d. , it is known from Le Cam (1973, 1975 and 1986) that the rate of convergence of optimal estimators is closely connected to the metric structure of the parameter space with respect to the Hellinger distance. In particular, this metric structure essentially determines the risk when the loss function is a power of the Hellinger distance. For random design regression, one typically uses as loss function the squared L2-distance between the estimator and the parameter. If the parameter space is bounded with respect to the L∞-norm, both distances are equivalent. Without this assumption, it may happen that there is a large distorsion between the two distances, resulting in some unusual rates of convergence for the squared L2-risk, as noticed by Baraud (2002). We shall first explain this phenomenon and then show that the use of the Hellinger distance instead of the L2-distance allows to recover the usual rates and to perform model selection in great generality. An extension to the L2-risk is given under a boundedness assumption similar to the one in Wegkamp (2003).
Prognostic Significance of E-Cadherin Protein Expression in Pathological Stage I-III Endometrial Cancer

Purpose: Decreased expression of E-cadherin in endometrial cancer cells is associated with adverse prognostic features. This study aimed to evaluate the prognostic significance of decreased E-cadherin expression in patients with endometrial cancer. Experimental Design: Between 1992 and 1999, 102 endometrial cancer patients with stage I-III disease underwent primary surgery at the University of Chicago. Representative tissue specimens were immunostained with a monoclonal antibody to E-cadherin. A semiquantitative evaluation scale was developed based on the percentage of endometrial cancer cells with membranous E-cadherin staining. Tissue sections were scored as “3” if >75%, “2” if 25–75%, “1” if 5–25%, and “0” if <5% of cells stained. E-Cadherin staining was correlated with overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and extrapelvic progression. Multivariate Cox proportional hazards modeling was used to estimate hazard ratios, controlling for clinicopathological characteristics and adjuvant treatment. Median follow-up for the study group was 58.5 months. Results: E-Cadherin staining was scored as 0, 1, 2, and 3 in 29.4%, 18.6%, 26.5%, 25.5% of cases, respectively. E-Cadherin expression was positively correlated with myometrial invasion (Kendall τ: 0.30, P < 0.01), and negatively correlated with grade (Kendall τ: −0.13, P = 0.15) and papillary serous or clear cell histology (Kendall τ: −0.14, P = 0.12). Five-year actuarial OS, CSS, PFS, and extrapelvic recurrence rates for negative (score = 0), heterogeneous (score = 1–2), and positive (score = 3) staining were as follows: OS, 69.2 versus 75.7 versus 81.0% (P = 0.64); CSS, 78.8 versus 91.2 versus 95.5% (P = 0.19); PFS, 69.1 versus 88.6 versus 92.2% (P = 0.079), and extrapelvic progression, 20.8 versus 7.3 versus 4.0% (P = 0.17). On multivariate Cox regression, a higher E-cadherin expression score was associated with decreased overall mortality [hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.34–1.03; P = 0.066), and statistically significant decreases in endometrial cancer mortality (HR, 0.23; 95% CI, 0.055–0.94; P = 0.040), disease progression (HR, 0.28; 95% CI, 0.10–0.77; P = 0.014), and extrapelvic recurrence (HR, 0.24; 95% CI, 0.062–0.97; P = 0.045). Conclusions: Decreased E-cadherin expression is an independent prognostic factor for disease progression and mortality in pathological stage I-III endometrial cancer. Evaluation of E-cadherin expression may aid in the selection of patients for more aggressive adjuvant therapy.
Audio-to-score alignment of piano music using RNN-based automatic music transcription

We propose a framework for audio-to-score alignment on piano performance that employs automatic music transcription (AMT) using neural networks. Even though the AMT result may contain some errors, the note prediction output can be regarded as a learned feature representation that is directly comparable to MIDI note or chroma representation. To this end, we employ two recurrent neural networks that work as the AMT-based feature extractors to the alignment algorithm. One predicts the presence of 88 notes or 12 chroma in frame-level and the other detects note onsets in 12 chroma. We combine the two types of learned features for the audio-to-score alignment. For comparability, we apply dynamic time warping as an alignment algorithm without any additional post-processing. We evaluate the proposed framework on the MAPS dataset and compare it to previous work. The result shows that the alignment framework with the learned features significantly improves the accuracy, achieving less than 10 ms in mean onset error.
Diagnostic accuracy and clinical utility of fine‐needle aspiration cytology in the diagnosis of clinically primary bone lesions

Optimal treatment of primary bone sarcomas requires minimal disturbance of the tumor prior to preoperative radiation and chemotherapy. Currently, carefully planned incisional or cutting needle biopsies are the favored methods for procurement of specimens. Recently, fine‐needle aspiration has gained favor as the initial diagnostic procedure at some centers. We investigated the diagnostic accuracy and the effects of errors in diagnosis and of complications on the patient's course in a series of 101 patients presenting with lesions clinically believed to have arisen in bone. We found that 29% of aspirates were insufficient for the diagnosis; 41% of aspirates yielded a correct diagnosis that had a significant favorable impact on the patient's course, while 20% of aspirates gave a correct diagnosis that did not significantly influence therapy. In 7% of cases, the aspirates were associated with an incorrect diagnosis that negatively influenced therapy, and in an additional 3% of cases an incorrect diagnosis was obtained that had no impact on patient outcome. No complications were encountered in this series of patients.
The function of the nuclear envelope in nuclear protein accumulation

The mechanism by which proteins accumulate in the cell nucleus is not yet known. Two alternative mechanisms are discussed here: (a) selective unidirectional entry of karyophilic proteins through the nuclear pores, and (b) free diffusion of all proteins through the nuclear pores and specific binding of nuclear proteins to nondiffusible components of the nucleoplasm. We present experiments designed to distinguish between these alternatives. After mechanical injury of the Xenopus oocyte nuclear envelope, nuclear proteins were detected in the cytoplasm by immunohistochemical methods. In a second approach, nuclei from X. borealis oocytes were isolated under oil, the nuclear envelopes were removed, and the pure nucleoplasm was injected into the vegetal pole of X. laevis oocytes. With immunohistochemical methods, it was found that each of five nuclear proteins rapidly diffuses out of the injected nucleoplasm into the surrounding cytoplasm. The subsequent transport and accumulation in the intact host nucleus could be shown for the nuclear protein N1 with the aid of a species-specific mAb that reacts only with X. borealis N1. Purified and iodinated nucleoplasmin was injected into the cytoplasm of Xenopus oocytes and its uptake into the nucleus was studied by biochemical methods.
Recipient‐Donor race mismatch for African American liver transplant patients with chronic hepatitis C

African American (AA) recipient‐donor race mismatch has been associated with graft loss and mortality, but studies of an association between race mismatch and hepatitis C virus (HCV) disease severity are lacking. HCV‐infected adults from 4 US centers who underwent liver transplantation for the first time (n = 1093) were followed for a median of 3.05 years to determine the rates of advanced HCV disease (bridging fibrosis or cirrhosis) and graft failure; 11% of the patients were AA. The unadjusted cumulative rate of advanced fibrosis was higher in AAs than non‐AAs (56% and 40% at 4 years, respectively, (P < 0.01), and 59% and 56% for AA recipient‐donor–matched patients and AA recipient‐donor–mismatched patients, respectively (P = 0.89). In adjusted models, both AA recipient race [hazard ratio (HR) = 1.47, 95% CI = 1.06‐2.03, P = 0.02] and AA recipient‐donor mismatch (versus match; HR = 1.48, 95% CI = 1.03‐2.12, P = 0.03) were significant predictors of advanced fibrosis; other independent predictors were donor age (HR = 1.21, P < 0.01) and cytomegalovirus infection (HR = 1.55, P < 0.01). The 4‐year unadjusted cumulative rates for HCV‐associated graft loss were 10% and 17% for non‐AAs and AAs, respectively (P < 0.01), and 0% and 21% for AA recipient‐donor–matched patients and AA recipient‐donor–mismatched patients, respectively (P < 0.01). In adjusted models, AA recipient‐donor–mismatched patients had a 62% higher rate of graft loss than non‐AA recipients (HR = 1.62, 95% CI = 1.14‐2.29, P < 0.01), and AA recipient‐donor–matched patients had a 76% lower rate of graft loss/mortality (HR = 0.24, 95% CI = 0.06‐0.97, P = 0.05). In conclusion, AA recipient‐donor–mismatched patients who are infected with HCV are at high risk for advanced HCV disease and HCV‐related graft loss and constitute a patient group that will benefit from new therapeutic strategies for preventing graft loss. Liver Transpl, 2012. © 2012 AASLD.
Impending extinctions of North American freshwater mussels (Unionoida) following the zebra mussel (Dreissena polymorpha) invasion

1. Freshwater mussels (Order Unionoida) are the most imperiled faunal group in North America; 60% of described species are considered endangered or threatened, and 12% are presumed extinct. Widespread habitat degradation (including pollution, siltation, river channelization and impoundment) has been the primary cause of extinction during this century, but a new stress was added in the last decade by the introduction of the Eurasian zebra mussel, Dreissena polymorpha, a biofouling organism that smothers the shells of other molluscs and competes with other suspension feeders for food. Since the early 1990s, it has been spreading throughout the Mississippi River basin, which contains the largest number of endemic freshwater mussels in the world. In this report, we use an exponential decay model based on data from other invaded habitats to predict the long-term impact of D. polymorpha on mussel species richness in the basin. 2. In North American lakes and rivers that support high densities (>3000 m−2) of D. polymorpha, native mussel populations are extirpated within 4–8 years following invasion. Significant local declines in native mussel populations in the Illinois and Ohio rivers, concomitant with the establishment of dense populations of D. polymorpha, suggest that induced mortality is occurring in the Mississippi River basin. 3. A comparison of species loss at various sites before and after invasion indicates that D. polymorpha has accelerated regional extinction rates of North American freshwater mussels by 10-fold. If this trend persists, the regional extinction rate for Mississippi basin species will be 12% per decade. Over 60 endemic mussels in the Mississippi River basin are threatened with global extinction by the combined impacts of the D. polymorpha invasion and environmental degradation.
Rate of Calcium Binding and Uptake in Normal Animal and Failing Human Cardiac Muscle: MEMBRANE VESICLES (RELAXING SYSTEM) AND MITOCHONDRIA

Cardiac relaxing system (CRS) and mitochondria were isolated by a modified rapid procedure from human, rabbit, and dog. Relaxing system (sarcoplasmic reticulum) was also isolated from white and red skeletal muscles for comparative purposes. Rapid kinetic measurements were made with a dual-beam spectrophotometric assay procedure. Maximum calcium binding (absence of oxalate), expressed as nmoles calcium/mg protein in 5 minutes at 25°C, for rabbit heart and red and white skeletal muscles were approximately 40, 58 and 170, respectively. The calcium binding constant for rabbit CRS was 2 × 106 M-1. The estimated initial binding rates (nmoles calcium/mg protein/minute) of cardiac, white and red skeletal muscle relaxing systems were 256, 1440 and 182, respectively. The rate constant (M-1 sec-1) of CRS was about 2400, which falls between white and red skeletal muscle preparations. Human cardiac muscle from recipients obtained at the time of transplantation yielded CRS with slower rates of accumulation of calcium and very little calcium release, compared to normal animal heart preparations. ATP was the most effective of four nucleoside triphosphates in supporting calcium binding and uptake. Calcium binding and release and calcium uptake of CRS were temperature-sensitive. The energies of activation of binding and uptake were 10.5 kcal mole-1 and 22.5 kcal mole-1, respectively. Under specific conditions, heart mitochondria accumulated calcium at a rate faster than CRS. Mitochondria could also release accumulated calcium.