Miracle-dz/UniFAR-FTUs huggingface dataset:
Prostaglandin E2 Induces Matrix Metalloproteinase 9 Expression in Dendritic Cells through Two Independent Signaling Pathways Leading to Activator Protein 1 (AP-1) Activation

Background: The signaling mechanisms involved in PGE2-induced MMP-9 expression in DCs are unknown. Results: PGE2-induced MMP-9 expression is mediated through the EP2/EP4 → cAMP → PKA/PI3K → ERK signaling pathway. Conclusion: PGE2-induced ERK activation is required for the binding of AP-1 to the MMP-9 promoter. Significance: ERK inhibitors can be used to regulate DC migration. Dendritic Cells (DCs) play an important role in the initiation of the immune response by migrating to regional lymph nodes and presenting antigen processed at the inflammatory site to antigen-specific naïve T cells. Prostaglandin E2 (PGE2) has been reported to play an essential role in DC migration. We reported previously that PGE2 induces matrix metalloproteinase 9 (MMP-9) expression in DCs and that PGE2-induced MMP-9 is required for DC migration in vivo and in vitro. In this study, we investigated the signaling mechanisms involved in PGE2-induced MMP-9 expression in DCs. We show that PGE2-induced MMP-9 expression is mediated primarily through the EP2/EP4 → cAMP → protein kinase A (PKA)/PI3K → ERK signaling pathway, leading to c-Fos expression, and through JNK-mediated activation of c-Jun in a PKA/PI3K/ERK-independent manner. EP2 and EP4 receptor agonists, as well as cAMP analogs, mimic the up-regulation of MMP-9 by PGE2. PKA, PI3K, and ERK inhibitors abolished PGE2- and cAMP-induced c-Fos and MMP-9 up-regulation, and ERK activation was required for the binding of activator protein 1 (AP-1) transcription factor to the MMP-9 promoter. Our results describe a new molecular mechanism for the effect of PGE2 on MMP-9 production in DCs that could lead to future therapeutic approaches using ERK inhibitors to regulate DC migration.
Mean Curvature Flow of Mean Convex Hypersurfaces

In the last 15 years, White and Huisken‐Sinestrari developed a far‐reaching structure theory for the mean curvature flow of mean convex hypersurfaces. Their papers provide a package of estimates and structural results that yield a precise description of singularities and of high‐curvature regions in a mean convex flow.
Brain Imaging and Cognitive Predictors of Stroke and Alzheimer Disease in the Framingham Heart Study

Background and Purpose— Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer disease (AD) risk. Methods— A cognitive battery was administered to 1679 dementia and stroke-free Framingham offspring (age, >55 years; mean, 65.7±7.0) between 1999 and 2004; participants were also free of other neurological conditions that could affect cognition and >90% also had brain MRI examination. We related cognitive and MRI measures to risks of incident stroke and AD ⩽10 years of follow-up. As a secondary analysis, we explored these associations in The Framingham Heart Study original cohort (mean age, 67.5±7.3 and 84.8±3.3 years at the cognitive assessment and MRI examination, respectively). Results— A total of 55 Offspring participants sustained strokes and 31 developed AD. Offspring who scored <1.5 SD below predicted mean scores, for age and education, on an executive function test, had a higher risk of future stroke (hazard ratio [HR], 2.27; 95% confidence interval [CI], 1.06–4.85) and AD (HR, 3.60; 95% CI, 1.52–8.52); additional cognitive tests also predicted AD. Participants with low (<20 percentile) total brain volume and high (>20 percentile) white matter hyperintensity volume had a higher risk of stroke (HR, 1.97; 95% CI, 1.03–3.77 and HR, 2.74; 95% CI, 1.51–5.00, respectively) but not AD. Hippocampal volume at the bottom quintile predicted AD in the offspring and original cohorts (HR, 4.41; 95% CI, 2.00–9.72 and HR, 2.37; 95% CI, 1.12–5.00, respectively). A stepwise increase in stroke risk was apparent with increasing numbers of these cognitive and imaging markers. Conclusions— Specific patterns of cognitive and brain structural measures observed even in early aging predict stroke risk and may serve as biomarkers for risk prediction.
Effects of N-Nitrosodiethylamine, a Potent Carcinogen, on Sexual Development, Gametogenesis, and Oocyte Maturation

N-Nitrosodiethylamine (DEN), a well-known hepatocarcinogen, is found in certain food products as such or as a metabolic byproduct. This study investigated the effects of DEN on sexual development, gametogenesis, and oocyte maturation in Japanese medaka (Oryzias latipes). DEN reduced the germ cell number dose-dependently during early stages of sexual differentiation in XX larvae, resulting in underdeveloped ovaries in adulthood at low doses. This effect was sex-specific as no such changes were seen in XY larvae. Furthermore, XX and XY larvae that were exposed at a low dose during early life showed a significant reduction in body weight in adulthood. Gonads in sexually immature adult medaka males and females exposed to DEN were in advanced stages in comparison to that of the controls. Gonado-somatic indices were significantly high in treated males and females. DEN induced oocyte maturation in vitro, which was inhibited by cordycepin, demonstrating that it stimulated oocyte maturation through polyadenylation of cyclin B mRNA as in the case of the endogenous maturation-inducing hormone. Altogether, our results have proven that DEN could disrupt or mimic the signaling pathways involved in germ cell development, proliferation, and maturation.
Comparative genomic analysis of upstream miRNA regulatory motifs in Caenorhabditis

MicroRNAs (miRNAs) comprise a class of short noncoding RNA molecules that play diverse developmental and physiological roles by controlling mRNA abundance and protein output of the vast majority of transcripts. Despite the importance of miRNAs in regulating gene function, we still lack a complete understanding of how miRNAs themselves are transcriptionally regulated. To fill this gap, we predicted regulatory sequences by searching for abundant short motifs located upstream of miRNAs in eight species of Caenorhabditis nematodes. We identified three conserved motifs across the Caenorhabditis phylogeny that show clear signatures of purifying selection from comparative genomics, patterns of nucleotide changes in motifs of orthologous miRNAs, and correlation between motif incidence and miRNA expression. We then validated our predictions with transgenic green fluorescent protein reporters and site-directed mutagenesis for a subset of motifs located in an enhancer region upstream of let-7. We demonstrate that a CT-dinucleotide motif is sufficient for proper expression of GFP in the seam cells of adult C. elegans, and that two other motifs play incremental roles in combination with the CT-rich motif. Thus, functional tests of sequence motifs identified through analysis of molecular evolutionary signatures provide a powerful path for efficiently characterizing the transcriptional regulation of miRNA genes.
Pigmented Villonodular Synovitis: A Retrospective Multicenter Study of 237 Cases

Purpose To review clinical characteristics of pigmented villonodular synovitis (PVNS) in China. Methods Electronic medical records (EMR) of four Chinese institutes were queried for patients with histologically proven PVNS between January 2005 and February 2014. Their data were collected including gender, age at diagnosis, clinical presentation, affected site, symptom duration, comorbidities, treatment strategy, recurrence and routine laboratories. Results A total of 237 patients with biopsy-proven PVNS were investigated. The gender ratio was 1.35 for a female predominance (101 males and 136 females). The average age was 36 years (range, 2 to 83 years). The median delay from initial clinical symptom to diagnosis was 18 months. Main affected areas were the knee (73.84%) and the hip (18.14%). Forty patients had a clear history of joint trauma. Six patients were concurrently diagnosed with PVNS and avascular necrosis (AVN). Five patients suffered from PVNS following implantation of orthopaedic devices including artificial prosthesis, plate and wire. One hundred and twenty-nine patients underwent arthroscopic synovectomy and 108 open synovectomy. Altogether 48 patients (26 males and 22 females) had recurrence of disease. The relapse rate was 24% (knee) and 6.98% (hip), 20.93% (open surgery) and 19.44% (arthroscopy), respectively. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) rate were elevated in 45.83% and 38.41% of the patients respectively. Conclusions To our knowledge, this study is the largest sample size of PVNS patients reported as well as the largest sample of PVNS with concurrent AVN reported to date. Our outcomes suggest that PVNS shows a female predominance, occurs mostly between 20–40 years and favors the knee and hip. Recurrence is frequent, particularly in the knee. Serum ESR and CRP may be elevated in some patients. Additionally, the present study supports the theory of an association between PVNS and orthopedic surgery, which is not limited to joint replacement.
Directed Evolution Reveals Unexpected Epistatic Interactions That Alter Metabolic Regulation and Enable Anaerobic Xylose Use by Saccharomyces cerevisiae

The inability of native Saccharomyces cerevisiae to convert xylose from plant biomass into biofuels remains a major challenge for the production of renewable bioenergy. Despite extensive knowledge of the regulatory networks controlling carbon metabolism in yeast, little is known about how to reprogram S. cerevisiae to ferment xylose at rates comparable to glucose. Here we combined genome sequencing, proteomic profiling, and metabolomic analyses to identify and characterize the responsible mutations in a series of evolved strains capable of metabolizing xylose aerobically or anaerobically. We report that rapid xylose conversion by engineered and evolved S. cerevisiae strains depends upon epistatic interactions among genes encoding a xylose reductase (GRE3), a component of MAP Kinase (MAPK) signaling (HOG1), a regulator of Protein Kinase A (PKA) signaling (IRA2), and a scaffolding protein for mitochondrial iron-sulfur (Fe-S) cluster biogenesis (ISU1). Interestingly, the mutation in IRA2 only impacted anaerobic xylose consumption and required the loss of ISU1 function, indicating a previously unknown connection between PKA signaling, Fe-S cluster biogenesis, and anaerobiosis. Proteomic and metabolomic comparisons revealed that the xylose-metabolizing mutant strains exhibit altered metabolic pathways relative to the parental strain when grown in xylose. Further analyses revealed that interacting mutations in HOG1 and ISU1 unexpectedly elevated mitochondrial respiratory proteins and enabled rapid aerobic respiration of xylose and other non-fermentable carbon substrates. Our findings suggest a surprising connection between Fe-S cluster biogenesis and signaling that facilitates aerobic respiration and anaerobic fermentation of xylose, underscoring how much remains unknown about the eukaryotic signaling systems that regulate carbon metabolism.
The nephropathy of non-insulin-dependent diabetes: predictors of outcome relative to diverse patterns of renal injury.

Nephropathy of non-insulin-dependent diabetes mellitus (NIDDM) is the most common cause of end-stage renal failure (ESRF) in Western countries. This study investigates the clinical and histologic putative predictors of disease progression, with the final goal to identify patients at risk who may benefit from early diagnosis and intervention. It examines by repeated measurements of BP, blood glucose, serum creatinine, and urinary protein excretion rate 65 consecutive NIDDM patients with clinical, persistent proteinuria and biopsy-documented typical diabetic glomerulopathy (class I; n = 30), predominant nephroangiosclerosis (class II; n = 23), or nondiabetic type glomerulopathy (class III; n = 12), whose severity of renal tissue involvement was precisely quantified by a global histologic score. Baseline parameters and progression to renal end points, i.e., doubling of baseline serum creatinine, dialysis, or transplantation, were univariately and multivariately correlated by proportional hazards regression models. The median kidney survival time in the overall study population was 3.07 yr. Thirty-seven percent of patients reached an end point during a median (range) follow-up of 1.8 yr (0.4 to 5.7 yr). By univariate and multivariate analysis, kidney survival significantly correlated with baseline urinary protein excretion rate (P = 0.04 and P = 0.04, respectively) and renal tissue injury score (P = 0.0001 and P = 0.02, respectively), but not with the histologic classes. Patients with a urinary protein excretion rate < or = 2 g/24 h, or > 2 g/24 h with a histologic score < 7, never reached an end point. All patients with urinary protein excretion > 2 g/24 h and a histologic score > 13 progressed to ESRF over a median of 1.6 yr. No differences in other baseline parameters or in BP and diabetes control during follow-up accounted for these different outcomes. In NIDDM as well as in nondiabetic chronic renal disease, quantification of urinary protein excretion rate--independent of the pattern of underlying glomerular involvement--reliably discriminates progressors from nonprogressors and, combined with precise quantification of renal tissue injury, reliably predicts risk of ESRF. This information may be used to set guidelines for early diagnosis and appropriate intervention to reduce the number of diabetic patients who will need renal replacement therapy in years to come.
Judgements of relative direction: The effect of task instructions on spatial recall

One of the most widely used tasks in the spatial memory literature is the judgement of relative direction (JRD) test. The present investigation examined the hypothesis that standard JRD task demands bias spatial recall. In two experiments, participants' recall of small-scale layouts as measured by standard JRD tests (in which the relationship between objects was employed to establish imagined orientations within the learned scene) was compared with recall as measured by novel JRD tasks. The novel tasks emphasized either the internal front/back and left/right axes of individual objects (Experiment 1) or extrinsic spatial cues (Experiment 2). Spatial recall was found to reflect the reference cues emphasized by the JRD task in Experiment 1 and by the novel task in Experiment 2. The finding that directional judgements tended to reflect a frame of reference aligned with the set of cues emphasized by task demands suggests that the nature of the task employed to test knowledge can have an effect on spatial recall.
C2P: Clustering based on Closest Pairs

In this paper we present C 2 P, a new clustering algorithm for large spatial databases, which exploits spatial access methods for the determination of closest pairs. Several extensions are presented for scalable clustering in large databases that contain clusters of various shapes and outliers. Due to its characteristics, the proposed algorithm attains the advantages of hierarchical clustering and graphtheoretic algorithms providing both efficiency and quality of clustering result. The superiority of C 2 P is verified both with analytical and experimental results.
A cross-sectional study on the development of foot arch function of 2715 Chinese children

A cross-sectional study was conducted to investigate the foot arch function of Chinese children. A total of 2715 children, 1246 girls, and 1369 boys, 4–18 years of age were recruited from kindergartens, primary, and secondary schools. The dynamic footprints of the children were collected using a portable pressure-sensing mat. The Contact Force Ratio (CFR, i.e. the ratio of the mid-foot loading to the total loading of the contacted foot, with the toes ignored) of each age group was calculated. In general, the CFR decreased from 4 to 10 years and plateaued at 10–12 years and then increased until 15–16 years. An abnormal low arch foot was defined as the foot that had a CFR value larger than the corresponding age mean plus one standard deviation. The cut-off CFR values of each age group were calculated. With the exception of the 17 years age group, which consisted of a relatively small number of subjects, the percentage of low arch subjects of all the other age groups ranged from 15 to 20%.
Influence of residue management on soil chemical properties and nutrient flux in forests harvested for woody biomass

Altered soil solution chemistry and nutrient flux within forests harvested for woody biomass may result from disturbance, slash removals, slash decomposition, and mineralization. Because of the potential adverse effects of woody biomass harvest to soil nutrient pools and overall soil quality, the Missouri Department of Conservation (MDC) has developed Best Management Practices (BMPs) to retain coarse woody residues associated with biomass harvesting to retain nutrient capital and sustain forest productivity. However, these BMPs remain untested. To investigate the potential impacts of woody biomass harvest and use of BMPs to mitigate deleterious effects, this study examined soil nutrient concentrations and nutrient flux in Missouri Ozark forest soils immediately following harvest to 1.5 years post-harvest. The eight treatments investigated were Missouri’s 1/3 harvest residue retention BMP for thinning and commercial biomass harvests and alternative harvest scenarios. Chemical properties of soils within the harvest treatments were quantified immediately after harvest and one year post-harvest, and analysis of variance results are presented. Total organic carbon (TOC) was the only dependent variable that was affected by harvest treatment (p-value = 0.0467); where TOC content for clearcut A (Missouri’s BMP) and clearcut B (removal of all biomass) were significantly greater than for clearcut C (alternative BMP). Changes in nutrient flux were monitored using Plant Root Simulator (PRS) ion exchange membrane probes provided by Western Ag Innovations. Nutrient flux dynamics differed for the nutrients measured within harvest treatments and at two different depths. Results indicate greater nutrient flux in the clearcut treatments compared to the intermediate
Hsp27 Inhibition with OGX-427 Sensitizes Non–Small Cell Lung Cancer Cells to Erlotinib and Chemotherapy

Non–small cell lung cancer (NSCLC) is the most frequent cause of death from cancer worldwide. Despite the availability of active chemotherapy regimens and EGFR tyrosine kinase inhibitors, all advanced patients develop recurrent disease after first-line therapy. Although Hsp27 is a stress-induced chaperone that promotes acquired resistance in several cancers, its relationship to treatment resistance in NSCLC has not been defined. Understanding adaptive responses of acquired resistance will help guide new strategies to control NSCLC. Hsp27 levels were evaluated in an HCC827 erlotinib-resistant–derived cell line (HCC-827Resistant), and sensitivity to erlotinib was examined in Hsp27-overexpressing A549 cells. The role of Hsp27 in both erlotinib and cytotoxic treatment resistance was evaluated in HCC-827 and A549 NSCLC cells using the Hsp27 antisense drug OGX-427. The effect of OGX-427 in combination with erlotinib was also assessed in mice bearing A549 xenografts. Hsp27 is induced by erlotinib and protects NSCLC cells from treatment-induced apoptosis, whereas OGX-427 sensitizes NSCLC cells to erlotinib. Interestingly, increased resistance to erlotinib was observed when Hsp27 was increased either in HCC827 erlotinib-resistant or overexpressing A549 cells. Combining OGX-427 with erlotinib significantly enhanced antitumor effects in vitro and delayed A549 xenograft growth in vivo. OGX-427 also significantly enhanced the activity of cytotoxic drugs used for NSCLC. These data indicate that treatment-induced Hsp27 contributes to the development of resistance, and provides preclinical proof-of-principle that inhibition of stress adaptive pathways mediated by Hsp27 enhances the activity of erlotinib and chemotherapeutics. Mol Cancer Ther; 14(5); 1107–16. ©2015 AACR.
Associations of body fat percent and body mass index with childhood asthma by age and gender

High body mass index (BMI) has been shown to be associated with asthma, but the pattern of this association is still unclear and may differ by gender or stage of puberty. BMI is only a proxy of adiposity, whereas estimation of body fat percent (BF%) by the bioimpedance technique is considered an accurate measure of adiposity. We investigated whether BMI and BF% behave differently in their association with asthma between genders, before and during adolescence.
Harnessing RNA sequencing for global, unbiased evaluation of two new adjuvants for dendritic-cell immunotherapy

Effective stimulation of immune cells is crucial for the success of cancer immunotherapies. Current approaches to evaluate the efficiency of stimuli are mainly defined by known flow cytometry-based cell activation or cell maturation markers. This method however does not give a complete overview of the achieved activation state and may leave important side effects unnoticed. Here, we used an unbiased RNA sequencing (RNA-seq)-based approach to compare the capacity of four clinical-grade dendritic cell (DC) activation stimuli used to prepare DC-vaccines composed of various types of DC subsets; the already clinically applied GM-CSF and Frühsommer meningoencephalitis (FSME) prophylactic vaccine and the novel clinical grade adjuvants protamine-RNA complexes (pRNA) and CpG-P. We found that GM-CSF and pRNA had similar effects on their target cells, whereas pRNA and CpG-P induced stronger type I interferon (IFN) expression than FSME. In general, the pathways most affected by all stimuli were related to immune activity and cell migration. GM-CSF stimulation, however, also induced a significant increase of genes related to nonsense-mediated decay, indicating a possible deleterious effect of this stimulus. Taken together, the two novel stimuli appear to be promising alternatives. Our study demonstrates how RNA-seq based investigation of changes in a large number of genes and gene groups can be exploited for fast and unbiased, global evaluation of clinical-grade stimuli, as opposed to the general limited evaluation of a pre-specified set of genes, by which one might miss important biological effects that are detrimental for vaccine efficacy.