Miracle-dz/UniFAR-FTUs huggingface dataset:
2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

The oncometabolite 2-hydroxyglutarate renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors. Target 2HG or not 2HG, that is the question Mutations in isocitrate dehydrogenase 1 and 2, which result in overproduction of 2-hydroxyglutarate (2HG), are observed in multiple tumor types, including gliomas and acute myelogenous leukemia. An additional form of 2HG is produced under hypoxia, which is also frequent in tumors. 2HG is considered to be an oncometabolite, or a metabolite that promotes carcinogenesis, and inhibitors of mutant isocitrate dehydrogenase are in development to target this process. However, Sulkowski et al. found that it may be possible to take advantage of 2HG overproduction instead. The authors discovered that 2HG overproduction impairs homologous recombination used in DNA repair and sensitizes cancer cells to treatment with PARP inhibitors, another class of cancer drugs that are already in clinical use. 2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)–dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibitors. This “BRCAness” phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1–dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.
Identification of Primary Transcriptional Regulation of Cell Cycle-Regulated Genes upon DNA Damage

The changes in global gene expression in response to DNA damage may derive from either direct induction or repression by transcriptional regulation or indirectly by synchronization of cells to specific cell cycle phases, such as G1 or G2. We developed a model that successfully estimated the expression levels of >400 cell-cycle-regulated genes in normal human fibroblasts based on the proportions of cells in each phase of the cell cycle. By isolating effects on the gene expression associated with the cell cycle phase redistribution after genotoxin treatment, the direct transcriptional target genes were distinguished from genes for which expression changed secondary to cell synchronization. Application of this model to ionizing radiation (IR)-treated normal human fibroblasts identified 150 of 406 cycle-regulated genes as putative direct transcriptional targets of IR-induced DNA damage. Changes in expression of these genes after IR treatment derived from both direct transcriptional regulation and cell cycle synchronization.
Canonical Transient Receptor Potential 5 Channel in Conjunction with Orai1 and STIM1 Allows Sr2+ Entry, Optimal Influx of Ca2+, and Degranulation in a Rat Mast Cell Line1

Degranulation of mast cells in response to Ag or the calcium mobilizing agent, thapsigargin, is dependent on emptying of intracellular stores of Ca2+ and the ensuing influx of external Ca2+, also referred to as store-operated calcium entry. However, it is unlikely that the calcium release-activated calcium channel is the sole mechanism for the entry of Ca2+ because Sr2+ and other divalent cations also permeate and support degranulation in stimulated mast cells. In this study we show that influx of Ca2+ and Sr2+ as well as degranulation are dependent on the presence of the canonical transient receptor potential (TRPC) channel protein TRPC5, in addition to STIM1 and Orai1, as demonstrated by knock down of each of these proteins by inhibitory RNAs in a rat mast cell (RBL-2H3) line. Overexpression of STIM1 and Orai1, which are known to be essential components of calcium release-activated calcium channel, allows entry of Ca2+ but not Sr2+, whereas overexpression of STIM1 and TRPC5 allows entry of both Ca2+ and Sr2+. These and other observations suggest that the Sr2+-permeable TRPC5 associates with STIM1 and Orai1 in a stoichiometric manner to enhance entry of Ca2+ to generate a signal for degranulation.
Fusion framework for color image retrieval based on bag-of-words model and color local Haar binary patterns

Abstract. Recently, global and local features have demonstrated excellent performance in image retrieval. However, there are some problems in both of them: (1) Local features particularly describe the local textures or patterns. However, similar textures may confuse these local feature extraction methods and get irrelevant retrieval results. (2) Global features delineate overall feature distributions in images, and the retrieved results often appear alike but may be irrelevant. To address problems above, we propose a fusion framework through the combination of local and global features, and thus obtain higher retrieval precision for color image retrieval. Color local Haar binary patterns (CLHBP) and the bag-of-words (BoW) of local features are exploited to capture global and local information of images. The proposed fusion framework combines the ranking results of BoW and CLHBP through a graph-based fusion method. The average retrieval precision of the proposed fusion framework is 83.6% on the Corel-1000 database, and its average precision is 9.9% and 6.4% higher than BoW and CLHBP, respectively. Extensive experiments on different databases validate the feasibility of the proposed framework.
Effects of electroconvulsive therapy on amygdala function in major depression – a longitudinal functional magnetic resonance imaging study

Background Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, little is known regarding brain functional processes mediating ECT effects. Method In a non-randomized prospective study, functional magnetic resonance imaging data during the automatic processing of subliminally presented emotional faces were obtained twice, about 6 weeks apart, in patients with major depressive disorder (MDD) before and after treatment with ECT (ECT, n = 24). Additionally, a control sample of MDD patients treated solely with pharmacotherapy (MED, n = 23) and a healthy control sample (HC, n = 22) were obtained. Results Before therapy, both patient groups equally showed elevated amygdala reactivity to sad faces compared with HC. After treatment, a decrease in amygdala activity to negative stimuli was discerned in both patient samples indicating a normalization of amygdala function, suggesting mechanisms potentially unspecific for ECT. Moreover, a decrease in amygdala activity to sad faces was associated with symptomatic improvements in the ECT sample (r spearman = −0.48, p = 0.044), and by tendency also for the MED sample (r spearman = −0.38, p = 0.098). However, we did not find any significant association between pre-treatment amygdala function to emotional stimuli and individual symptom improvement, neither for the ECT sample, nor for the MED sample. Conclusions In sum, the present study provides first results regarding functional changes in emotion processing due to ECT treatment using a longitudinal design, thus validating and extending our knowledge gained from previous treatment studies. A limitation was that ECT patients received concurrent medication treatment.
Cancers attributable to infections among adults with HIV in the United States

Objective:HIV-infected people are at increased risk of cancers of infectious origin. We estimated the burden of cancer attributable to infections among HIV-infected people in the United States in 2008. Design:Incidence rates for cancer sites associated with infections were estimated from record linkage between HIV/AIDS registries and cancer registries. Methods:Rates were applied to estimates of the population living with diagnosed HIV in the United States in 2008 to obtain the number of incident cancer cases. Site-specific attributable fractions and corresponding 95% confidence intervals (CIs) were estimated from infection prevalence among cancer cases. Infection prevalence data were derived from literature review of case series. Results:Of an estimated 6200 incident cancer cases (95% CI 6000–6500), 2500 (95% CI 2400–2700) were attributable to infection (attributable fraction = 40%, 95% CI 39–42). The most important infections were Kaposi sarcoma herpes virus, Epstein–Barr virus, and human papillomavirus, which together were responsible for 2200 new cancer cases (95% CI 2100–2400), mainly Kaposi sarcoma, lymphomas, and ano-genital cancers. The attributable fraction in HIV-infected people was highest in the age group 20–29 years (69%, 95% CI 65–72). MSM were the HIV transmission group with the highest attributable fraction (48%, 95% CI 46–50), due to the high incidence of both Kaposi sarcoma and anal cancer. Conclusion:The very high fraction of cancer attributable to infection in HIV-infected people points to special opportunities to prevent these cancers, that is, avoidance, detection, and early treatment of cancer-associated infections, and universal early detection and uninterrupted treatment of HIV infection to avoid immunosuppression.
What does it take to be a good GP?

[Figure][1] Once in a while I refer to myself as a GP. Of course, in Canada we call ourselves family physicians. Although the term general practitioner was considered outmoded when I first started medical school back in the 1970s,[1][2] it continues to be the term used by many member
The Influence of Guided Discovery Learning Model on Biology Result Study at SMA N 2 Sukoharjo Academic Year 2013/2014

The aim of the research is to find out the effect of Guided Discovery Learning on the Biology learning outcome of the students in SMA Negeri 2 Sukoharjo in the school year of 2013/2014. This research employed Quasi-experimental research with Posttest Only with Nonequivalent Control Group Design. The population of research was the even semester XI IPA graders of SMA Negeri 2 Sukoharjo in the school year of 2013/2014. The sample of research was taken using Cluster Sampling. Techniques of collecting data used were test and non-test method. Test method included essay of biological learning outcome in knowledge domain, while the non-test one included observation, questionnaire, and documentation. The hypothesis testing was conducted using t-test with SPSS version 17 help. The result of research showed that H 0 was not supported, meaning that there was an effect of the Guided Discovery Learning toward the Biology learning outcome of the students in SMA Negeri 2 Sukoharjo in the school year of 2013/2014. The mean score of biological learning outcome in experiment class was higher than that in control class with the highest mean occurred in attitude domain, and the lowest one occurred in skill domain. Based on result, it could be concluded that Guided Discovery Learning affected the improvement of biological learning outcome in the students of SMA Negeri 2 Sukoharjo in the school year of 2013/2014. Keywords: Guided Discovery Learning, GDL, biological learning outcome.
The Vibrio cholerae cytolysin promotes activation of mast cell (T helper 2) cytokine production

Many strains of Vibrio cholerae produce a cytolysin (VCC) that forms oligomeric transmembrane pores responsible for vacuolization of several cell types in culture. Here we suggest that VCC could contribute to the T helper 2 (Th2) response seen in the natural infection; acting through TLR2, VCC enhances mast cells secretion of IL‐4, IL‐6 and TNF‐α by 330‐, 290‐ and 550‐fold respectively. Moreover, VCC‐induced cytokine production is dependent on increased cytosolic Ca2+ and on the presence of the Src family kinases Lyn and Fyn, known to be required for FcεRI‐dependent activation of mast cells. These findings strongly suggest that VCC has a pro‐inflammatory activity promoting a Th2‐type immune profile.
Evidence for changes in beta‐ and gamma‐actin proportions during inner ear hair cell life

Cytoplasmic actin isoforms beta (β‐) and gamma (γ‐) perform crucial physiological roles in inner ear hair cells (HC). The stereocilium, which is structured by parallel actin filaments composed of both isoforms, is the responsive organelle to mechanical stimuli such as sound, gravity and head movements. Modifications in isoform proportions affect the function of the stereocilia as previously shown in genetic studies of mutant mice. Here, immunogold labeling TEM studies in mice showed that both β‐ and γ‐actin isoforms colocalize throughout stereocilia actin filaments, adherens junctions and cuticular plates as early as embryonic stage 16.5. Gold‐particle quantification indicated that there was 40% more γ‐ actin than β‐actin at E16.5. In contrast, β‐ and γ‐actin were equally concentrated in adult stereocilia of cochlear and vestibular HC. Interestingly, all actin‐based structures presented almost five‐fold more β‐actin than γ‐actin in 22 month‐ old mice, suggesting that γ‐actin is probably under‐expressed during the aging process. These data provide evidence of dynamic modifications of the actin isoforms in stereocilia, cuticular plates and cell junctions during the whole HC life. © 2015 Wiley Periodicals, Inc.
Establishment of a novel quantum dots‐encoded microbead‐based flow cytometric method for quantification of soluble FcεRIα in serum

The soluble form of the transmembrane glycoprotein, FcεRIα which corresponds to the high‐affinity receptor for IgE, is found in serum. Growing evidence suggests the pathogenic role of IgE and FcεRI in systemic lupus erythematosus (SLE). The goal of this study is to develop a sensitive and standardized cytometric assay for quantification of sFcεRIα. A membrane emulsification technique was utilized to incorporate CuInS2/ZnS quantum dots and Fe3O4 nanoparticles into poly (styrene‐co‐maleic anhydride) microbeads. The beads were then carboxylated and coated with capture antibody monoclonal anti‐human FcεRIα. This antibody binds to FcεRIα but does not block the binding of FcεRIα to IgE. After incubation with standards or serum samples, the microbeads were incubated with excessive native human IgE, followed by incubation with Phycoerythrin (PE) conjugated anti‐human IgE. The resulting quantum dot microbeads were gated, and sFcεRIα quantification was analyzed based on PE fluorescence intensity. The method exhibited good linearity (R2 > 0.99), and the limit of detection was established at 0.29 ng/mL with the dynamic range of up to 200 ng/mL. The precision of the assay validated by intra‐ and inter‐assay variability met the acceptance criteria with the mean recovery falling within 80–110% of the theoretical concentration and a corresponding CV < 20%. We tested 149 serum samples which 89 were from SLE patients and 60 were from healthy volunteers. For the first time, we detected an increased sFcεRIα level in the serum of SLE patients, which was confirmed by a commercial ELISA kit. Compared to ELISA, this novel method is more sensitive and efficient. It allows for the simple comparative analysis of sFcεRIα levels in health and disease. © 2017 International Society for Advancement of Cytometry
Induction of glutathione-dependent DNA double-strand breaks by the novel anticancer drug brostallicin

Brostallicin is a DNA minor groove binder in phase II clinical trials. Here, we show that brostallicin induces γ-H2AX nuclear foci that colocalize with 53BP1 and are dependent on glutathione, as shown by inhibition of those γ-H2AX foci by l-buthionine sulfoximine. To differentiate brostallicin from the clinically approved minor groove binder trabectedin (ecteinascidin 743), we tested whether the brostallicin-induced γ-H2AX and antiproliferative responses were dependent on nucleotide excision repair and found that, unlike trabectedin, they are not. Additionally, brostallicin retained activity in the trabectedin-resistant HCT116-ER5 cell line. Induction of γ-H2AX foci by brostallicin was partially dependent on the repair nuclease Mre11. Pretreatment with aphidicolin partially reduced brostallicin-induced γ-H2AX foci, suggesting that brostallicin induces both replication-associated and replication-independent DNA damage. Replication-associated DNA damage was further shown by the colocalization of γ-H2AX foci with replication foci and by the rapid inhibition of DNA synthesis and accumulation of cells in S phase in response to brostallicin. In addition, brostallicin was able to induce lower intensity γ-H2AX foci in human circulating lymphocytes. Together, our results indicate that brostallicin induces DNA double-strand breaks and suggest γ-H2AX as a pharmacodynamic biomarker for brostallicin. [Mol Cancer Ther 2009;8(7):1985–94]
Hemin binding by Porphyromonas gingivalis strains is dependent on the presence of A‐LPS

Porphyromonas gingivalis is a Gram‐negative black pigmenting anaerobe that is unable to synthesize heme [Fe(II)‐protoporphyrin IX] or hemin [Fe(III)‐protoporphyrin IX‐Cl], which are important growth/virulence factors, and must therefore derive them from the host. Porphyromonas gingivalis expresses several proteinaceous hemin‐binding sites, which are important in the binding/transport of heme/hemin from the host. It also synthesizes several virulence factors, namely cysteine‐proteases Arg‐ and Lys‐gingipains and two lipopolysaccharides (LPS), O‐LPS and A‐LPS. The gingipains are required for the production of the black pigment, μ‐oxo‐bisheme {[Fe(III)PPIX]2 O}, which is derived from hemoglobin and deposited on the bacterial cell‐surface leading to the characteristic black colonies when grown on blood agar. In this study we investigated the role of LPS in the deposition of μ‐oxo‐bisheme on the cell‐surface. A P. gingivalis mutant defective in the biosynthesis of Arg‐gingipains, namely rgpA/rgpB, produces brown colonies on blood agar and mutants defective in Lys‐gingipain (kgp) and LPS biosynthesis namely porR, waaL, wzy, and pg0129 (α‐1, 3‐mannosyltransferase) produce non‐pigmented colonies. However, only those mutants lacking A‐LPS showed reduced hemin‐binding when cells in suspension were incubated with hemin. Using native, de‐O‐phosphorylated and de‐lipidated LPS from P. gingivalis W50 and porR strains, we demonstrated that hemin‐binding to O‐polysaccharide (PS) and to the lipid A moiety of LPS was reduced compared with hemin‐binding to A‐PS. We conclude that A‐LPS in the outer‐membrane of P. gingivalis serves as a scaffold/anchor for the retention of μ‐oxo‐bisheme on the cell surface and pigmentation is dependent on the presence of A‐LPS.
Fusion of Head and Full-Body Detectors for Multi-object Tracking

In order to track all persons in a scene, the tracking-by-detection paradigm has proven to be a very effective approach. Yet, relying solely on a single detector is also a major limitation, as useful image information might be ignored. Consequently, this work demonstrates how to fuse two detectors into a tracking system. To obtain the trajectories, we propose to formulate tracking as a weighted graph labeling problem, resulting in a binary quadratic program. As such problems are NP-hard, the solution can only be approximated. Based on the Frank-Wolfe algorithm, we present a new solver that is crucial to handle such difficult problems. Evaluation on pedestrian tracking is provided for multiple scenarios, showing superior results over single detector tracking and standard QP-solvers. Finally, our tracker ranks 2nd on the MOT16 benchmark and 1st on the new MOT17 benchmark, outperforming over 90 trackers.
Employment Status of Depressed Individuals in an 11-Year Follow-up: Results From the Finnish Health 2011 Survey

Objectives: The aim of this study was to describe the employment and mental health status of persons with depressive disorders after an 11-year follow-up, and identify individual and work-related factors that predict adverse outcomes. Methods: Two nationally representative health surveys, Health 2000 and its follow-up, Health 2011 were used, and persons with depressive disorders at baseline (n = 275) were re-interviewed after 11 years. Results: Information on employment status was available for all 263 participants in 2011. About 15.7% had been granted disability pension by 2011, while 55.5% were employed and 18.2% on old-age pension. High job control was the only statistically significant predictor of lower probability of disability pension (adjusted odds ratio 0.42, 95% confidence interval [95% CI] 0.23 to 0.77). Being unmarried (adjusted odds ratio 2.99, 95% CI 1.19 to 7.52) was associated with persistent depressive disorder. Conclusions: Job control emerged as an important predictor of long-term employment outcomes among depressed individuals.
Bivariate shrinkage using undecimated dual-tree complex wavelet transform for image denoising

In this paper, we present a bivariate shrinkage method for denoising of images corrupted with additive white Gaussian noise. The proposed method first employs undecimated dual-tree complex wavelet transform on noisy image, which can keep a direct one-to-one relationship between the co-located complex wavelet coefficients at all scales. After that, it estimates the wavelet coefficients by taking into account the parent-child dependency under the non-Gaussian bivariate model, and completes the denoising procedure. Experimental results on test images show that our method can not only eliminate different levels of noise but also obtain fine structures preservation.