Miracle-dz/UniFAR-FTUs huggingface dataset:
Detection of Novel Reactive Metabolites of Trazodone: Evidence for CYP2D6-Mediated Bioactivation of m-Chlorophenylpiperazine

Several new glutathione adducts (M3–M7) of trazodone were tentatively identified in human liver microsomal incubations using liquid chromatography-tandem mass spectrometry (LC/MS/MS). Following incubations with trazodone in the presence of glutathione, 1-(3′-chlorophenyl)piperazine (m-CPP), a major circulating and pharmacologically active metabolite of several antidepressants including trazodone, nefazodone, and etoperidone, was trapped with glutathione to afford the corresponding quinone imine-sulfydryl adducts M4 and M5. Two novel glutathione adducts of deschloro-m-CPP and deschloro-trazodone, M3 and M6, were also detected by tandem mass spectrometry. The identities of these m-CPP-derived glutathione adducts were further confirmed by LC/MS/MS analyses of microsomal incubations of m-CPP. To investigate the bioactivation mechanism, a regioisomer of m-CPP, 1-(4′-chlorophenyl)piperazine, was incubated in human liver microsomes. Blockage of bioactivation by 4′-chloro-substitution at least partially suggested that formation of m-CPP-derived glutathione adducts M3, M4, and M5 is mediated by a common quinone imine intermediate. A tentative pathway states that upon formation of the trazodone- and m-CPP-1′,4′-quinone imine intermediates through initial 4′-hydroxylation, glutathione attacks at the chlorine position by an ipso substitution, resulting in 4′-hydroxy-3′-glutathion-deschloro-trazodone (M6) and 4′-hydroxy-3′-glutathion-deschloro-m-CPP (M3), respectively. In contrast to CYP3A4-dependent bioactivation of trazodone itself, formation of M4 was mediated specifically by CYP2D6, as evidenced by cDNA-expressed CYP2D6-catalyzing formation of M4 from m-CPP, strong inhibition of formation of M4 by quinidine, a specific CYP2D6 inhibitor, in both incubations of trazodone and m-CPP with human liver microsomes, and concentration-dependent inhibition of M4 formation by quinidine.
StructBoost: Boosting Methods for Predicting Structured Output Variables

Boosting is a method for learning a single accurate predictor by linearly combining a set of less accurate weak learners. Recently, structured learning has found many applications in computer vision. Inspired by structured support vector machines (SSVM), here we propose a new boosting algorithm for structured output prediction, which we refer to as StructBoost. StructBoost supports nonlinear structured learning by combining a set of weak structured learners. As SSVM generalizes SVM, our StructBoost generalizes standard boosting approaches such as AdaBoost, or LPBoost to structured learning. The resulting optimization problem of StructBoost is more challenging than SSVM in the sense that it may involve exponentially many variables and constraints. In contrast, for SSVM one usually has an exponential number of constraints and a cutting-plane method is used. In order to efficiently solve StructBoost, we formulate an equivalent 1-slack formulation and solve it using a combination of cutting planes and column generation. We show the versatility and usefulness of StructBoost on a range of problems such as optimizing the tree loss for hierarchical multi-class classification, optimizing the Pascal overlap criterion for robust visual tracking and learning conditional random field parameters for image segmentation.
Short‐term effects of treatment‐induced hormonal changes on cognitive function in breast cancer patients

It is suspected that estrogen depletion resulting from treatment may contribute to cognitive compromise in patients with breast cancer. However, the evidence for estrogen effects on cognition is inconclusive, and the consequences of hormonal changes for cognitive function in patients with cancer rarely have been investigated. In this study, the authors investigated the effects of treatment‐induced menopause and antiestrogen therapy with tamoxifen and aromatase inhibitors (AIs) on cognitive function.
CD8+ Regulatory T Cells, and Not CD4+ T Cells, Dominate Suppressive Phenotype and Function after In Vitro Live Mycobacterium bovis-BCG Activation of Human Cells

Mycobacterium bovis bacillus Calmette-Guérin (M. bovis BCG), the only currently available vaccine against tuberculosis, has been reported to induce regulatory T cells in humans. The activity of regulatory T cells may not only dampen immunogenicity and protective efficacy of tuberculosis-vaccines, but also hamper diagnosis of infection of tuberculosis, when using immune (e.g. IFNγ-release) assays. Still, in settings of infectious diseases and vaccination, most studies have focused on CD4+ regulatory T cells, and not CD8+ regulatory T-cells. Here, we present a comparative analysis of the suppressive phenotype and function of CD4+ versus CD8+ T cells after in vitro live BCG activation of human cells. Moreover, as BCG is administered as a (partly) live vaccine, we also compared the ability of live versus heatkilled BCG in activating CD4+ and CD8+ regulatory T cell responses. BCG-activated CD8+ T cells consistently expressed higher levels of regulatory T cell markers, and after live BCG activation, density and (co-)expression of markers were significantly higher, compared to CD4+ T cells. Furthermore, selection on CD25-expression after live BCG activation enriched for CD8+ T cells, and selection on co-expression of markers further increased CD8+ enrichment. Ultimately, only T cells activated by live BCG were functionally suppressive and this suppressive activity resided predominantly in the CD8+ T cell compartment. These data highlight the important contribution of live BCG-activated CD8+ Treg cells to immune regulation and emphasize their possible negative impact on immunity and protection against tuberculosis, following BCG vaccination.
Rumors, False Flags, and Digital Vigilantes: Misinformation on Twitter after the 2013 Boston Marathon Bombing

The Boston Marathon bombing story unfolded on every possible carrier of information available in the spring of 2013, including Twitter. As information spread, it was filled with rumors (unsubstantiated information), and many of these rumors contained misinformation. Earlier studies have suggested that crowdsourced information flows can correct misinformation, and our research investigates this proposition. This exploratory research examines three rumors, later demonstrated to be false, that circulated on Twitter in the aftermath of the bombings. Our findings suggest that corrections to the misinformation emerge but are muted compared with the propagation of the misinformation. The similarities and differences we observe in the patterns of the misinformation and corrections contained within the stream over the days that followed the attacks suggest directions for possible research strategies to automatically detect misinformation.
Exploring living-learning communities through students' experiences: An interpretative phenomenological analysis

This study was designed to explore the lived experiences of students at a private university during their first year of college while members of a Living-Learning Community (LLC). Interpretative Phenomenological Analysis was used to examine the experiences of eight students which sets the study apart from the larger context quantitative studies which have focused on the outcomes of LLC membership. Social Identity Theory served as the theoretical framework. The findings suggest a close link between the development of the LLC group identity and the personal growth each participant experienced throughout the year with reference to that group. While participants had various levels of connection to the larger LLC group, the group served as the catalyst for every student’s individual personal and intellectual growth. Participants constructed both emotional and intellectual families within the LLC which were able to fulfill the individual needs of each member, connecting them to the LLC as well as to the larger university environment. Recommendations for practice include ways in which the connections forged through LLC membership could be applied to other students within the university environment. First generation students, students struggling academically, as well as students beyond their freshman year of school could all benefit from the intellectual and emotional family generated through LLC membership.
The Docking Protein HEF1 Is an Apoptotic Mediator at Focal Adhesion Sites

ABSTRACT HEF1 (human enhancer of filamentation 1) is a member of a docking protein family that includes p130Cas and Efs. Through assembly of multiple protein interactions at focal adhesion sites, these proteins activate signaling cascades in response to integrin receptor binding of the extracellular matrix. The HEF1 protein is cell cycle regulated, with full-length forms cleaved in mitosis at a caspase consensus site to generate an amino-terminal 55-kDa form that localizes to the mitotic spindle. The identification of a caspase cleavage site in HEF1 led us to investigate whether HEF1 belongs to a select group of caspase substrates cleaved in apoptosis to promote the morphological changes characteristic of programmed cell death. Significantly, inducing expression of HEF1 in MCF-7 or HeLa cells causes extensive apoptosis, as assessed by multiple criteria. Endogenous HEF1 is cleaved into 65- and 55-kDa fragments and a newly detected 28-kDa form in response to the induction of apoptosis, paralleling cleavage of poly(ADP-ribose) polymerase and focal adhesion kinase (FAK); the death-promoting activity of over-expressed HEF1 is associated with production of the 28-kDa form. While the generation of the cleaved HEF1 forms is caspase dependent, the accumulation of HEF1 forms is further regulated by the proteasome, as the proteasome inhibitorsN-acetyl-l-leucinyl-l-leucinyl-l-norleucinyl and lactacystin enhance their stability. Finally, the induction of HEF1 expression also increases Jun N-terminal protein kinase (JNK) activation, and activated JNK colocalizes with HEF1, implicating this pathway in HEF1 action. Based on these results, we propose that dysregulation of HEF1 and its family members along with FAK may signal the destruction of focal adhesion sites and regulate the onset of apoptosis.
Recurrence after Mastectomy for Ductal Carcinoma in Situ

Mastectomy has long been a standard option for patients with ductal carcinoma in situ (DCIS). It is preferentially chosen by some women and may be suggested for individuals with recurrent, multifocal, or multicentric disease. We chose to evaluate our recent experience with mastectomy for DCIS. A retrospective review was conducted of 83 patients (87 breasts) from 1995 to 2006 who underwent mastectomy for DCIS. Mastectomy for DCIS was performed in 49 postmenopausal, 33 premenopausal, and one male patient. The average age was 53 years and the mean follow up was 4.5 years. Sentinel lymph node (SLN) biopsy was performed on 44 cases; positive nodes were identified in two. Intraoperative analyses of SLN were all negative. Only one patient had ipsilateral recurrence of the skin (1.1%). DCIS with microinvasion was noted in 32 per cent of the patients; none of these patients had ipsilateral recurrence. Three patients had positive microscopic margins; none have recurred to date. These results confirm the usefulness of mastectomy for patients with DCIS. We recommend SLN biopsy without intraoperative touch prep analysis. Additional treatment may not be required in patients with microinvasion, positive or close margins because our series shows no local recurrence in these patients.
Internetworking Assortativity in Facebook

The role of assortativity in real-world and on-line social networks has been largely investigated in the literature, in which several forms of assortativity have been analyzed. However, all these forms are not able to capture some pieces of knowledge that are strategic when moving from a single-social-network to a multiple-social-network perspective. The relevance of such a point of view is strongly increasing, due to the interaction among users, applications, information flows of different social networks. This interaction is the key feature of a new emerging paradigm called social internetworking scenario. Here, all the knowledge concerning information crossing different social networks assumes high importance. This stimulates the study of assortativity under the social internetworking scenario perspective. In this paper, we propose a new notion of assortativity that captures some important aspects concerning the above issue. Furthermore, we give an effective methodology for its computation. A deep experimental analysis has been performed aimed to measure the new form of assortativity for Facebook w.r. t. other seven (top-level) on-line social networks.
Tsukamurella paurometabola Lipoglycan, a New Lipoarabinomannan Variant with Pro-inflammatory Activity*

The genus Tsukamurella is a member of the phylogenetic group nocardioform actinomycetes and is closely related to the genus Mycobacterium. The mycobacterial cell envelope contains lipoglycans, and of particular interest is lipoarabinomannan, one of the most potent mycobacterial immunomodulatory molecules. We have investigated the presence of lipoglycans in Tsukamurella paurometabola and report here the isolation and structural characterization of a new lipoarabinomannan variant, designated TpaLAM. Matrix-assisted laser desorption ionization-mass spectrometric analysis revealed that TpaLAM had an average molecular mass of 12.5 kDa and consequently was slightly smaller than Mycobacterium tuberculosis lipoarabinomannan. Using a range of chemical degradations, NMR experiments, capillary electrophoresis, and mass spectrometry analyses, TpaLAM revealed an original carbohydrate structure. Indeed, TpaLAM contained a mannosylphosphatidyl-myo-inositol (MPI) anchor glycosylated by a linear (α1→6)-Manp mannan domain, which is further substituted by an (α1→5)-Araf chain. Half of the Araf units are further substituted at the O-2 position by a Manp-(α1→2)-Manp-(α1→ dimannoside motif. Altogether, TpaLAM appears to be the most elaborated non-mycobacterial LAM molecule identified to date. TpaLAM was found to induce the pro-inflammatory cytokine tumor necrosis factor (TNF)-α when tested with either human or murine monocyte/macrophage cell lines. This induction was completely abrogated in the presence of an anti-toll-like receptor-2 (TLR-2) antibody, suggesting that TLR-2 participates in the mediation of TNF-α production in response to TpaLAM. Moreover, we established that the lipomannan core of TpaLAM is the primary moiety responsible for the observed TNF-α-inducing activity. This conclusively demonstrates that a linear (α1→6)-Manp chain, linked to the MPI anchor, is sufficient in providing pro-inflammatory activity.
Control Benefits and CEO Discipline in Automatic Bankruptcy Auctions

We argue that the existence of CEO private control benefits complements managerial reputation in counteracting costly shareholder risk-shifting incentives during severe financial distress, when job-loss may be imminent. We examine this argument empirically using bankruptcy filings in Sweden, where a filing automatically terminates CEO employment and requires the firm to be sold in an open auction. The median CEO income loss is a dramatic 40%, suggesting that bankruptcy filing damages CEO reputation. Empirical proxies for both CEO reputation and control benefits are significant determinants of the probability of the CEO being rehired by the buyer in the auction, as predicted. Moreover, we find that the rehired CEOs generate a post-bankruptcy accounting performance at par with industry rivals. The surprisingly strong survival characteristics of the reorganized firms are consistent with managerial conservatism ex ante, and help alleviate creditor concern with costly asset substitution designed to delay filing in an automatic bankruptcy auction system.
Quantitative genetics of sleep in inbred mice

The timing and the organization of sleep architecture are mainly controlled by the circadian system, while sleep need and intensity are regulated by a homeostatic process. How independent these two systems are in regulating sleep is not well understood. In contrast to the impressive progress in the molecular genetics of circadian rhythms, little is known about the molecular basis of sleep. Nevertheless, as summarized here, phenotypic dissection of sleep into its most basic aspects can be used to identify both the single major genes and small effect quantitative trait loci involved. Although experimental models such as the mouse are more readily amenable to genetic analysis of sleep, similar approaches can be applied to humans.
A parochial lost cause?: The micro-politics of language revitalization initiatives in Jersey (Channel Islands)

The patois still understood, written and occasionally spoken in the island of Jersey has both an illustrious history as the linguistic signifier of this “piece of France thrown into the sea and picked up by England” (Hugo 1866), and a twenty-first-century relevance as a case study for sociolinguistic obsolescence, even irrelevance. This paper aims to investigate its status, form and expression in popular literature. The method employed is principally documentary analysis, in an attempt to situate jèrriais in the current debate about endangered languages and the effects on a minority (insular) language of its contact with two competing high-status world languages, although personal experience of living on the island in the 1980s is also drawn upon. In the author’s view, the crucial factor in the obsolescence of jèrriais is the widely held belief – even among scholars, see Jones (2001) – in its normative difference from ‘proper’ French and an unquestioning acceptance by Jersey residents of their own position in the Anglophone world. Historically speaking, it is the centuries (since 1204) of political isolation from the French-speaking Normandy peninsula that has in his view led to the terminal decline of jèrriais. Le patois normand qui est encore compris, écrit et même parlé de temps en temps sur l’île de Jersey recèle non seulement une illustre histoire en tant que signifiant linguistique de ce « morceau de France tombé dans la mer et ramassé par l’Angleterre » (Hugo 1866), mais aussi une importance bien contemporaine en tant qu’exemple d’un déclin, voire d’une disparition sociolinguistique. L’article vise à étudier l’état, la forme et l’expression dans la littérature populaire de ce parler, principalement au moyen d’une analyse documentaire qui tente de situer le jèrriais dans le débat actuel sur les langues en danger de disparition et les effets sur une langue minoritaire et insulaire d’un contact prolongé avec deux langues concurrentes de prestige mondial. L’auteur fait également référence à son séjour sur l’île dans les années 80. À son avis l’obsolescence du jèrriais s’explique par la conviction largement répandue – même parmi les linguistes comme Jones (2001) – de la différence normative entre celui-ci et le français « correct », aussi bien de l’acceptation aveugle des habitants de l’île de leur place dans le monde anglophone. D’un point de vue historique, ce sont les siècles (depuis 1204) de séparation politique de la Normandie continentale qui ont provoqué, selon l’auteur, le déclin irrémediable du jèrriais.
Location based Applications for Mobile Augmented Reality

In this work we investigate building indoor location based applications for a mobile augmented reality system. We believe that augmented reality is a natural interface to visualize spacial information such as position or direction of locations and objects for location based applications that process and present information based on the user's position in the real world. To enable such applications we construct an indoor tracking system that covers a substantial part of a building. It is based on visual tracking of fiducial markers enhanced with an inertial sensor for fast rotational updates. To scale such a system to a whole building we introduce a space partitioning scheme to reuse fiducial markers throughout the environment. Finally we demonstrate two location based applications built upon this facility, an indoor navigation aid and a library search application.
Developing a social practice‐based typology of British drinking culture in 2009–2011: implications for alcohol policy analysis

Abstract Background and aims The concept of national drinking culture is well established in research and policy debate, but rarely features in contemporary alcohol policy analysis. We aim to demonstrate the value of the alternative concept of social practices for quantitatively operationalizing drinking culture. We discuss how a practice perspective addresses limitations in existing analytical approaches to health‐related behaviour before demonstrating its empirical application by constructing a statistical typology of British drinking occasions. Design Cross‐sectional latent class analysis of drinking occasions derived from retrospective 1‐week drinking diaries obtained from quota samples of a market research panel. Occasions are periods of drinking with no more than 2 hours between drinks. Setting Great Britain, 2009–11. Cases A total of 187 878 occasions nested within 60 215 nationally representative adults (aged 18 + years). Measurements Beverage type and quantity per occasion; location, company and gender composition of company; motivation and reason for occasion; day, start‐time and duration of occasion; and age, sex and social grade. Findings Eight occasion types are derived based primarily on parsimony considerations rather than model fit statistics. These are mixed location heavy drinking (10.4% of occasions), heavy drinking at home with a partner (9.4%), going out with friends (11.1%), get‐together at someone's house (14.4%), going out for a meal (8.6%), drinking at home alone (13.6%), light drinking at home with family (12.8%) and light drinking at home with a partner (19.6%). Conclusions An empirical model of drinking culture, comprising a typology of drinking practices, reveals the dominance of moderate drinking practices in Great Britain. The model demonstrates the potential for a practice perspective to be used in evaluation of how and why drinking cultures change in response to public health interventions.
Cyclooxygenase-2 Expression Does Not Correlate With Outcome in Osteosarcoma or Rhabdomyosarcoma

Purpose To determine if expression of cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity, correlates with outcome in pediatric sarcomas. COX-2 overexpression correlates with more aggressive disease in a variety of adult solid tumors. Methods Archived human osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma tumors were retrospectively evaluated, blinded to outcome, for COX-2 expression by immunohistochemistry and correlated with patient characteristics and survival. Results COX-2 expression was detected in 94 of 142 (66%) tumors (osteosarcoma, 66/99 [67%]; rhabdomyosarcoma, 21/35 [60%]; Ewing sarcoma, 7/8 [88%]) and 51 of 85 (60%) diagnostic biopsies (osteosarcoma, 26/45 [58%]; rhabdomyosarcoma, 21/35 [60%]; Ewing sarcoma, 4/5 [80%]). COX-2 expression did not vary with clinicopathologic features and was not predictive of prognosis in these cases. Conclusions This study does not support the use of COX-2 expression as an upfront prognostic variable in patients with osteosarcoma or rhabdomyosarcoma.Results from the small number of patients studied with Ewing sarcoma suggest a similar lack of predictive value for COX-2 expression. However, COX-2 inhibitors are not entirely dependent upon enzyme expression for their antitumor effects; this study does not necessarily preclude the use of COX-2 inhibitors for the treatment of pediatric sarcomas.