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The processing of metaphors and idioms has been the subject of neuroscientific research for several decades. However, results are often contradictory, which can be traced back to inconsistent terminology and stimulus control. In this systematic review of research methods, we analyse linguistic aspects of 116 research papers which used EEG, fMRI, PET, MEG, or NIRS to investigate the neural processing of the two figurative subtypes metaphor and idiom. We critically examine the theoretical foundations as well as stimulus control by performing a systematic literature synthesis according to the PRISMA guidelines. We explicitly do not analyse the findings of the studies but instead focus on four primary aspects: definitions of figurative language and its subtypes, linguistic theory behind the studies, control for factors influencing figurative language processing, and the relationship between theoretical and operational definitions. We found both a lack and a broad variety in existing definitions and operationalisation, especially in regard to familiarity and conventionality. We identify severe obstacles in the comparability and validation potential of the results of the papers in our review corpus. We propose the development of a consensus in fundamental terminology and more transparency in the reporting of stimulus design in the research on figurative language processing. [ABSTRACT FROM AUTHOR]

Pancreatic beta cell death is a hallmark of type 1 and 2 diabetes (T1D/T2D), but the underlying molecular mechanisms are incompletely understood. Key proteins of the DNA damage response (DDR), including tumor protein P53 (P53, also known as TP53 or TRP53 in rodents) and Ataxia Telangiectasia Mutated (ATM), a kinase known to act upstream of P53, have been associated with T2D. Here we test and compare the effect of ATM and P53 ablation on beta cell survival in the rat beta cell line Ins1E. We demonstrate that ATM and P53 differentially regulate beta cell apoptosis induced upon fundamentally different types of diabetogenic beta cell stress, including DNA damage, inflammation, lipotoxicity and endoplasmic reticulum (ER) stress. DNA damage induced apoptosis by treatment with the commonly used diabetogenic agent streptozotocin (STZ) is regulated by both ATM and P53. We show that ATM is a key STZ induced activator of P53 and that amelioration of STZ induced cell death by inhibition of ATM mainly depends on P53. While both P53 and ATM control lipotoxic beta cell apoptosis, ATM but not P53 fails to alter inflammatory beta cell death. In contrast, tunicamycin induced (ER stress associated) apoptosis is further increased by ATM knockdown or inhibition, but not by P53 knockdown. Our results reveal differential roles for P53 and ATM in beta cell survival in vitro in the context of four key pathophysiological types of diabetogenic beta cell stress, and indicate that ATM can use P53 independent signaling pathways to modify beta cell survival, dependent on the cellular insult. [ABSTRACT FROM AUTHOR]

Human aggression can be differentiated into reactive aggression (RA), displayed in face of a real or perceived threat and associated with high levels of anxiety, and proactive aggression (PA), displayed to achieve a certain goal and linked to lower anxiety levels. To study the origins of these aggression subtypes and their relation to anxiety, we tested if both subtypes can be distinguished in a nonhuman primate species, characterized their occurrence within the study group, and examined the link between aggression subtype and anxiety. Data were collected on 29 individuals of a semi-free ranging group of Barbary macaques (Macaca sylvanus) at Affenberg Salem, Germany, via focal animal (303 hr) and event sampling (1,222 agonistic events). Using a priori definitions, each aggressive event was classified as either reactive or proactive. We found both aggression types in our study population as well as individual differences in the proportion at which they occurred. The predominant use of one subtype of aggression was linked to the individual's dominance rank, age and sex, but not related to standard behavioral and physiological measures of anxiety. Our results suggest that reactive and proactive subtypes of aggression also exist in Barbary macaques, indicating a deeper evolutionary history of these aggression types observed in humans. [ABSTRACT FROM AUTHOR]

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As the demographic change progresses, dementia is going to become a prevalent condition in many countries. In order to keep the Quality of Life (QoL) of People with Dementia (PwD) on a steady level, Assistive Technologies (AT) implemented on table-sized Surface Computers (SC) that promote playful and/or reminiscence-triggering activities turn out to be valuable tools for dementia care. This article gives an overview over two similar multimedia-based AT systems implemented on Microsoft PixelSense SCs and field-tested in dementia care institutions. The observations indicate that both systems can trigger positive emotions and activities as well as memories. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex ( MHC) plays an important role in the immune response and may thus crucially affect an individual's fitness, relevant also for studies on evolutionary ecology and wildlife conservation. Detailed knowledge on the genomic organization, polymorphism and diversity of the MHC has a narrow taxonomic focus though and among macaques is only available for rhesus and long-tailed macaques-the species most commonly kept for biomedical research. The lack of data on wild populations is largely due to the difficulty of obtaining blood or tissue samples necessary for genotyping approaches. Here, we aimed at analyzing MHC-DRB from non-invasively collected fecal samples in wild Assamese macaques ( Macaca assamensis), utilizing the MHC-DRB-STR ( D6S2878) microsatellite marker. Due to the fecal DNA source incomplete genotypes occurred, which may be improved in the future by method refinement. We detected 28 distinct DRB-STR lengths in 43 individuals with individual genotypes containing 1-9 MHC-DRB-STRs and defined four haplotypes segregating between families in Mendelian fashion. Our results indicate that variability and diversity of MHC-DRB in Assamese macaques is comparable to that of other macaque species and importantly, that fecal samples can be used for non-invasive analysis of MHC genes after refinement of the applied methods, opening a number of opportunities for MHC research on natural populations. Am. J. Primatol. 9999:1-9, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The purpose of this study was to examine the effect of immunohistochemical (IHC) staining of sentinel (SLN) and non sentinel lymph nodes (NSLN) on the detection of additional metastases in patients with endometrial cancer. Patients and methods: Between April 2004 and March 2006, 25 patients with endometrial cancer were operated on. A new method for labelling SLNs with Patent Blue® was used. One additional slice was cut out of each lymph node and immunohistochemically stained (IHC). Sentinel and NSLN nodes were re-evaluated. Results: 673 lymph nodes from 21 patients were available for re-evaluation. With IHC staining significantly more metastases were detected compared to H&E staining. Though more patients with metastases were discovered this was not significant on the basis of affected SLNs or NSLNs. In the conventional evaluation 7 metastases were found in 3 patients. Applying re-evaluation and IHC 6 additional metastases in 5 patients were detected. These additional metastases were evenly distributed among the pelvic and para-aortic area, and among the SLNs or NSLNs. This had an impact on the diagnostic accuracy of the sentinel concept. Sensitivity reduced from 66.7% to 33.3% and the negative predictive value (NPV) fell from 94.7% to 79.0% only if the NSLNs were additionally IHC stained. On the contrary, if the SLNs were also IHC stained, the sensitivity rose to 83.3%, the NPV rose to 93.8%. Conclusion: Our results indicate that additional immunohistochemistry staining of one additional block of SLNs improves the validity of sensitivity and the NPV in the sentinel concept. [Copyright &y& Elsevier]

Stepwise oxidation of the epigenetic mark 5-methylcytosine and base excision repair (BER) of the resulting 5-formylcytosine (5-fC) and 5-carboxycytosine (5-caC) may provide a mechanism for reactivation of epigenetically silenced genes; however, the functions of 5-fC and 5-caC at defined gene elements are scarcely explored. We analyzed the expression of reporter constructs containing either 2′-deoxy-(5-fC/5-caC) or their BER-resistant 2′-fluorinated analogs, asymmetrically incorporated into CG-dinucleotide of the GC box cis-element (5′-TGGGCGGAGC) upstream from the RNA polymerase II core promoter. In the absence of BER, 5-caC caused a strong inhibition of the promoter activity, whereas 5-fC had almost no effect, similar to 5-methylcytosine or 5-hydroxymethylcytosine. BER of 5-caC caused a transient but significant promoter reactivation, succeeded by silencing during the following hours. Both responses strictly required thymine DNA glycosylase (TDG); however, the silencing phase additionally demanded a 5′-endonuclease (likely APE1) activity and was also induced by 5-fC or an apurinic/apyrimidinic site. We propose that 5-caC may act as a repressory mark to prevent premature activation of promoters undergoing the final stages of DNA demethylation, when the symmetric CpG methylation has already been lost. Remarkably, the downstream promoter activation or repression responses are regulated by two separate BER steps, where TDG and APE1 act as potential switches. [ABSTRACT FROM AUTHOR]

Purpose Of Review: This review presents the latest experimental and clinical research focussing on the relationship between the intake of tomato products and lycopene supplementation and carcinogenesis, with the aim of drawing conclusions for concepts of clinical nutritional support.Recent Findings: Apart from the preventative role of tomato products/lycopene intake there is evidence that oral supplementation of these compounds in cancer patients may also improve the biomarkers of carcinogenesis and reduce tumour growth. New experimental studies in animal models provide insights concerning the potential mechanism(s).Summary: Although the first clinical trials are promising, it is too early to make final recommendations for nutritional therapy in cancer patients. Whether the bioactive compound in tomatoes is lycopene or whether other substrates contribute to the beneficial physiological effects is still unclear. [ABSTRACT FROM AUTHOR]

BackgroundMobile savings and payment systems have been widely adopted to store money and pay for a variety of services, including health care. However, the possible implications of these technologies on financing and payment for maternal health care services—which commonly require large 1-time out-of-pocket payments—have not yet been systematically assessed in low-resource settings. ObjectiveThe aim of this study was to determine the structural, contextual, and experiential characteristics of a mobile phone–based savings and payment platform, the Mobile Health Wallet (MHW), for skilled health care during pregnancy among women in Madagascar. MethodsWe used a 2-stage cluster random sampling scheme to select a representative sample of women utilizing either routine antenatal (ANC) or routine postnatal care (PNC) in public sector health facilities in 2 of 8 urban and peri-urban districts of Antananarivo, Madagascar (Atsimondrano and Renivohitra districts). In a quantitative structured survey among 412 randomly selected women attending ANC or PNC, we identified saving habits, mobile phone use, media consumptions, and perception of an MHW with both savings and payment functions. To confirm and explain the quantitative results, we used qualitative data from 6 semistructured focus group discussions (24 participants in total) in the same population. Results59.3% (243/410, 95% CI 54.5-64.1) saved toward the expected costs of delivery and, out of those, 64.4% (159/247, 95% CI 58.6-70.2) used household cash savings for this purpose. A total of 80.3% (331/412, 95% CI 76.5-84.1) had access to a personal or family phone and 35.7% (147/412, 95% CI 31.1-40.3) previously used Mobile Money services. Access to skilled health care during pregnancy was primarily limited because of financial obstacles such as saving difficulties or unpredictability of costs. Another key barrier was the lack of information about health benefits or availability of services. The general concept of an MHW for saving toward and payment of pregnancy-related care, including the restriction of payments, was perceived as beneficial and practicable by the majority of participants. In the discussions, several themes pointed to opportunities for ensuring the success of an MHW through design features: (1) intuitive technical ease of use, (2) clear communication and information about benefits and restrictions, and (3) availability of personal customer support. ConclusionsFinancial obstacles are a major cause of limited access to skilled maternal health care in Madagascar. An MHW for skilled health care during pregnancy was perceived as a useful and desirable tool to reduce financial barriers among women in urban Madagascar. The design of this tool and the communication strategy will likely be the key to success. Particularly important dimensions of design include technical user friendliness and accessible and personal customer service.

The objective of the present paper is to develop a validated numerical model of a water vortex power plant that serves as a digital twin for further studies such as assessments of the ethohydraulic characteristics or the performance of such devices. The reference for the validation process is a large-scale hydraulic installation equipped with a full-scale water vortex power plant prototype installed in Dresden (Germany), where flow field measurements were carried out using three-dimensional Acoustic Doppler Velocimetry. The numerical model was implemented within the software package Star-CCM+. The unsteady, two-phase flow was solved with the Reynolds-Averaged Navier–Stokes equations in a Eulerian Multiphase approach, deploying a Volume of Fluid method to describe the free-surface flow. Water level and flow velocities were systematically compared in key areas of the device, demonstrating that the simulation is in good agreement with experimental observations. Relative differences are limited to at most 4% regarding water height in the system, and even the much more challenging velocity fields are reproduced with typical relative errors of roughly 10%. This validates the ability of the model to model the challenging flow conditions found in a water vortex power plant, enabling subsequent studies of the characteristics of this power plant concerning fish migration. [ABSTRACT FROM AUTHOR]

Background: New treatment options are needed to prevent relapses following failed antibiotic therapies of Clostridium difficile infections (CDI) in humans. The concomitant therapy with an anti-C. difficile IgA containing whey protein concentrate can support the sustainable recovery of CDI patients. For 31 weeks, nine dairy cows were continuously vaccinated with several anti-C. difficile vaccines by certain routes of administration to produce anti-C. difficile IgA enriched milk. The study aimed at finding decisive differences between low responder (LR) and high responder (HR) cows (> 8.0 µg ml−1 total milk C. difficile specific IgA) concerning their immune response to vaccination on cellular and molecular biological levels. Results: The results of total and differential cell counting (DCC) in blood and milk and the outcomes of the gene expression analysis of selected immune factors were assessed relating to the usage of two vaccine batches for injection (MucoCD-I batch A and B), marking two immunization (IM) periods, and compared to a control group (Ctr). The MucoCD-I batch A caused short-term leukopenia followed by leukocytosis in the blood of LR and HR. The total somatic cell counts in milk were not altered by the treatment. The DCC revealed that the leukocytes of the treated groups were partly impaired by the treatment. The gene expression analysis exposed cumulative and sustainable differences (p < 0.05) between LR and HR for the genes encoding for lactoferrin, CXCL8, IL1β, IL2, IL6, IL12β, IFNγ, CD4 and CD163. The regulation of the epithelial IgA cell receptor PIGR was not impaired by the IM. In contrast to the vaccination with MucoCD-I batch A, the second IM period with MucoCD-I batch B resulted in mitigation and synchronization of the treated groups' immune responses. Conclusions: The inversely regulated cytokines in the blood and milk cells of the treated groups led to a variously directed, local T cell response resulting in their different production intensities of C. difficile specific IgA in milk. [ABSTRACT FROM AUTHOR]

Studying host parasite interactions and their implications for evolution and ecology recently received increasing attention, particularly with regard to host physiology and immunity. Here we assess variation of urinary neopterin (uNEO), a marker of cellular immune activation and iummunosenescence, in response to age and anthelmintic treatment in semi-free ranging Barbary macaques (Macaca sylvanus). Urinary NEO levels were measured via enzyme-immunoassay from 179 urine samples of 43 individuals between 5-29 years of age. Efficiency of treatment was assessed by Mc Master flotation on repeated faecal samples, including 18 untreated individuals as control group. We used linear mixed models with age and parasite status as main effects, controlling for sex and physical condition, assessed through urinary C-Peptide-levels, with social group and ID as random factors. Urinary NEO levels significantly increased with age, suggesting that changes in aging Barbary macaque immune responses are consistent with immunosenescence described in human and nonhuman primates and can be detected via uNEO measurements. Anthelmintic treatment, however, had no influence on uNEO levels, potentially due to quick reinfections or attenuated immune responses in repeated infections. We conclude that uNEO is a potential non-invasive marker for immune function and particularly immunosenescence in wildlife. [ABSTRACT FROM AUTHOR]

The oxidation-induced DNA modification 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) was recently implicated in the activation and repression of gene transcription. We aimed at a systematic characterisation of the impacts of 8-oxodG on the activity of a GC box placed upstream from the RNA polymerase II core promoter. With the help of reporters carrying single synthetic 8-oxodG residues at four conserved G:C base pairs (underlined) within the 5'-TGGGCGGAGC-3' GC box sequence, we identified two modes of interference of 8-oxodG with the promoter activity. Firstly, 8-oxodG in the purine-rich (but not in the pyrimidine-rich) strand caused direct impairment of transcriptional activation. In addition, and independently of the first mechanism, 8-oxodG initiated a decline of the gene expression, which was mediated by the specific DNA glycosylase OGG1. For the different 8-oxodG positions, the magnitude of this effect reflected the excision preferences of OGG1. Thus, 8-oxodG seeded in the pyrimidine-rich strand was excised with the highest efficiency and caused the most pronounced decrease of the promoter activity. Conversely, 8-oxodG in the symmetric position within the same CpG dinucleotide, was poorly excised and induced no decline of the gene expression. Of note, abasic lesions caused gene silencing in both positions. By contrast, an uncleavable apurinic lesion in the pyrimidine-rich strand enhanced the GC box activity, suggesting that the AP endonuclease step provides a switch between the active versus repressed promoter states during base excision repair., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Brain serotonin (5-HT) is involved in the control of food intake. The ingestive effects of 5-HT are mediated by various receptor subtypes, among others the 5-HT1A receptor. While the involvement of presynaptic 5-HT1A receptors is regarded as certain, the role of postsynaptic 5-HT1A receptors is rather vague. Here, we studied the role of the 5-HT1A receptor on feeding in non-food-deprived and food-deprived (young adult and adult, both sexes) wild-type NMRI mice as well as transgenic NMRI mice, which are characterized by a distinct overexpression of postsynaptic 5-HT1A receptors. The known hyperphagic effect of the 5-HT1A receptor full agonist 8-OH-DPAT ((±)-8-hydroxy-N,N-dipropyl-2-aminotetralin) in non-food-deprived animals was demonstrated in male NMRI wild-type mice and could be antagonized by the selective 5-HT1A receptor antagonist WAY100635. In transgenic mice, this hyperphagic response was induced at lower doses, with an earlier onset and even in females. However, in adult male transgenic mice, the hyperphagic effect did not occur. In food-deprived NMRI wild-type as well as transgenic mice, 8-OH-DPAT first induced a hypophagic and subsequently a hyperphagic effect. Again, in transgenic animals most responses occurred at lower doses and with an earlier onset. The results indicate that postsynaptic 5-HT1A receptors exert a modulatory function in food intake in free-feeding and fasted mice, which for the first time shows an involvement of postsynaptic 5-HT1A receptors in feeding behavior. Understanding the function of pre- and postsynaptic 5-HT1A receptors may help to achieve new insights into the regulation of food intake and foster prospective treatment strategies for eating disorders.

Myelodysplastic syndromes (MDSs) are a heterogeneous group of myeloid neoplasms with defects in hematopoietic stem and progenitor cells (HSPCs) and possibly the HSPC niche. Here, we show that patient-derived mesenchymal stromal cells (MDS MSCs) display a disturbed differentiation program and are essential for the propagation of MDS-initiating Lin(-)CD34(+)CD38(-) stem cells in orthotopic xenografts. Overproduction of niche factors such as CDH2 (N-Cadherin), IGFBP2, VEGFA, and LIF is associated with the ability of MDS MSCs to enhance MDS expansion. These factors represent putative therapeutic targets in order to disrupt critical hematopoietic-stromal interactions in MDS. Finally, healthy MSCs adopt MDS MSC-like molecular features when exposed to hematopoietic MDS cells, indicative of an instructive remodeling of the microenvironment. Therefore, this patient-derived xenograft model provides functional and molecular evidence that MDS is a complex disease that involves both the hematopoietic and stromal compartments. The resulting deregulated expression of niche factors may well also be a feature of other hematopoietic malignancies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Chromosomal abnormalities have been shown to play a major role in disease evolution of multiple myeloma. Specific changes in interphase cells can be detected by fluorescent in situ hybridization, which overcomes the problem of the lack of dividing cells required for conventional cytogenetics., Design and Methods: We analyzed the prognostic value of 12 frequent chromosomal abnormalities detected by fluorescent in situ hybridization in a series of patients (n=315) with newly diagnosed, symptomatic multiple myeloma. All patients underwent frontline autologous stem cell transplantation according to the GMMG-HD3- or GMMG-HD4-trial protocols or analogous protocols., Results: Univariate statistical analyses revealed that the presence of del(13q14), del(17p13), t(4;14), +1q21 and non-hyperdiploidy was associated with adverse progression-free and overall survival rates independently of the International Staging System (ISS) classification. Multivariate analyses showed that only t(4;14) and del(17p13) retained prognostic value for both progression-free and overall survival. According to the presence or absence of t(4;14) and del(17p13) and the patients' International Staging System classification, the cohort could be stratified into three distinct groups: a group with a favorable prognosis [absence of t(4;14)/del(17p13) and ISS I], a group with a poor prognosis [presence of t(4;14)/del(17p13) and ISS II/III] and a group with an intermediate prognosis (all remaining patients). The probabilities of overall survival at 5 years decreased from 72% in the favorable prognostic group to 62% (hazard ratio 2.4; P=0.01) in the intermediate and 41% (hazard ratio 5.6; P<0.001) in the poor prognostic groups., Conclusions: These results have implications for risk-adapted management for patients with multiple myeloma undergoing high-dose chemotherapy followed by autologous stem cell transplantation and suggest that new treatment concepts are urgently needed for patients who belong to the poor prognosis group. As targeted therapies evolve, different treatment options might have variable success, depending on the underlying genetic nature of the clone.

Myc proteins are essential regulators of cellular growth and proliferation during normal development. Activating mutations in myc genes result in excessive growth and are frequently associated with human cancers. At the same time, forced expression of Myc sensitizes vertebrate cells towards different pro-apoptotic stimuli. Recently, the ability of overexpressed Myc to induce cell-autonomous apoptosis has been shown to be evolutionarily conserved in Drosophila Myc (dMyc). Here, we show that dMyc induced apoptosis is accompanied by the induction of Drosophila p53 mRNA, but that dp53 activity is not essential for dMyc's ability to induce apoptosis. Conversely, larvae carrying a hypomorphic dmyc mutation are more resistant to the apoptosis-promoting effects of X-irradiation. These data suggest that the control of apoptosis is a physiological function of Myc and that dMyc might play a role in the response to DNA damage., ((c) 2008 Wiley-Liss, Inc.)