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61.
Rameswari Chilamakuri Danielle C. Rouse Yang Yu Abbas S. Kabir Aaron Muth Jianhua Yang Jeffery M. Lipton Saurabh Agarwal 《Translational oncology》2022,15(1)
High-risk neuroblastoma (NB) represents a major clinical challenge in pediatric oncology due to relapse of metastatic, drug-resistant disease, and treatment-related toxicities. An analysis of 1235 primary NB patient dataset revealed significant increase in AKT1 and AKT2 gene expression with cancer stage progression. Additionally, Both AKT1 and AKT2 expression inversely correlate with poor overall survival of NB patients. AKT1 and AKT2 genes code for AKT that drive a major oncogenic cell signaling pathway known in many cancers, including NB. To inhibit AKT pathway, we repurposed an antiviral inhibitor BX-795 that inhibits PDK1, an upstream activator of AKT. BX-795 potently inhibits NB cell proliferation and colony growth in a dose-dependent manner. BX-795 significantly enhances apoptosis and blocks cell cycle progression at mitosis phase in NB. Additionally, BX-795 potently inhibits tumor formation and growth in a NB spheroid tumor model. We further tested dual therapeutic approaches by combining BX-795 with either doxorubicin or crizotinib and found synergistic and significant inhibition of NB growth, in contrast to either drug alone. Overall, our data demonstrate that BX-795 inhibits AKT pathway to inhibit NB growth, and combining BX-795 with current therapies is an effective and clinically tractable therapeutic approach for NB. 相似文献
62.
This pragmatic study examines love as a mode of communication. Our focus is on the receiver side: what makes an individual feel loved and how felt love is defined through daily interactions. Our aim is to explore everyday life scenarios in which people might experience love, and to consider people’s converging and diverging judgments about which scenarios indicate felt love. We apply a cognitive psychometric approach to quantify a receiver’s ability to detect, understand, and know that they are loved. Through crowd-sourcing, we surveyed lay participants about whether various scenarios were indicators of felt love. We thus quantify these responses to make inference about consensus judgments of felt love, measure individual levels of agreement with consensus, and assess individual response styles. More specifically, we (1) derive consensus judgments on felt love; (2) describe its characteristics in qualitative and quantitative terms, (3) explore individual differences in both (a) participant agreement with consensus, and (b) participant judgment when uncertain about shared knowledge, and (4) test whether individual differences can be meaningfully linked to explanatory variables. Results indicate that people converge towards a shared cognitive model of felt love. Conversely, respondents showed heterogeneity in knowledge of consensus, and in dealing with uncertainty. We found that, when facing uncertainty, female respondents and people in relationships more frequently judge scenarios as indicators of felt love. Moreover, respondents from smaller households tend to know more about consensus judgments of felt love, while respondents from larger households are more willing to guess when unsure of consensus. 相似文献
63.
64.
Fabian Sch?r Ulf Trostdorf Federica Giardina Virak Khieu Sinuon Muth Hanspeter Marti Penelope Vounatsou Peter Odermatt 《PLoS neglected tropical diseases》2013,7(7)
Background
The soil-transmitted threadworm, Strongyloides stercoralis, is one of the most neglected among the so-called neglected tropical diseases (NTDs). We reviewed studies of the last 20 years on S. stercoralis''s global prevalence in general populations and risk groups.Methods/Principal Findings
A literature search was performed in PubMed for articles published between January 1989 and October 2011. Articles presenting information on infection prevalence were included. A Bayesian meta-analysis was carried out to obtain country-specific prevalence estimates and to compare disease odds ratios in different risk groups taking into account the sensitivities of the diagnostic methods applied. A total of 354 studies from 78 countries were included for the prevalence calculations, 194 (62.4%) were community-based studies, 121 (34.2%) were hospital-based studies and 39 (11.0%) were studies on refugees and immigrants. World maps with country data are provided. In numerous African, Asian and South-American resource-poor countries, information on S. stercoralis is lacking. The meta-analysis showed an association between HIV-infection/alcoholism and S. stercoralis infection (OR: 2.17 BCI: 1.18–4.01; OR: 6.69; BCI: 1.47–33.8), respectively.Conclusions
Our findings show high infection prevalence rates in the general population in selected countries and geographical regions. S. stercoralis infection is prominent in several risk groups. Adequate information on the prevalence is still lacking from many countries. However, current information underscore that S. stercoralis must not be neglected. Further assessments in socio-economic and ecological settings are needed and integration into global helminth control is warranted. 相似文献65.
Bruce A. Kimball Kunio Yamazaki Dennis Kohler Richard A. Bowen Jack P. Muth Maryanne Opiekun Gary K. Beauchamp 《PloS one》2013,8(10)
Changes in body odor are known to be a consequence of many diseases. Much of the published work on disease-related and body odor changes has involved parasites and certain cancers. Much less studied have been viral diseases, possibly due to an absence of good animal model systems. Here we studied possible alteration of fecal odors in animals infected with avian influenza viruses (AIV). In a behavioral study, inbred C57BL/6 mice were trained in a standard Y-maze to discriminate odors emanating from feces collected from mallard ducks (Anas platyrhynchos) infected with low-pathogenic avian influenza virus compared to fecal odors from non-infected controls. Mice could discriminate odors from non-infected compared to infected individual ducks on the basis of fecal odors when feces from post-infection periods were paired with feces from pre-infection periods. Prompted by this indication of odor change, fecal samples were subjected to dynamic headspace and solvent extraction analyses employing gas chromatography/mass spectrometry to identify chemical markers indicative of AIV infection. Chemical analyses indicated that AIV infection was associated with a marked increase of acetoin (3-hydroxy-2-butanone) in feces. These experiments demonstrate that information regarding viral infection exists via volatile metabolites present in feces. Further, they suggest that odor changes following virus infection could play a role in regulating behavior of conspecifics exposed to infected individuals. 相似文献
66.
Positions in the 30S ribosomal subunit proximal to the 790 loop as determined by phenanthroline cleavage. 下载免费PDF全文
Positioning rRNA within the ribosome remains a challenging problem. Such positioning is critical to understanding ribosome function, as various rRNA regions interact to form suitable binding sites for ligands, such as tRNA and mRNA. We have used phenanthroline, a chemical nuclease, as a proximity probe, to help elucidate the regions of rRNA that are near neighbors of the stem-loop structure centering at nt 790 in the 16S rRNA of the Escherichia coli 30S ribosomal subunit. Using phenanthroline covalently attached to a DNA oligomer complementary to nt 787-795, we found that nt 582-584, 693-694, 787-790, and 795-797 were cleaved robustly and must lie within about 15 A of the tethered site at the 5' end of the DNA oligomer, which is adjacent to nt 795 of 16S rRNA. 相似文献
67.
Marius Muth Niklas Jänsch Aleksandra Kopranovic Andreas Krämer Nathalie Wössner Manfred Jung Frank Kirschhöfer Gerald Brenner-Weiß Franz-Josef Meyer-Almes 《Biochimica et Biophysica Acta (BBA)/General Subjects》2019,1863(3):577-585
Background
HDAC8 is an established target for T-cell lymphoma and childhood neuroblastoma. Benzothiazine-imines are promising HDAC8 inhibitors with unknown binding mechanism lacking a usual zinc binding group.Methods
In this study high-resolution and quantitative HPLC-coupled ESI-MS/MS techniques are combined with crystal structure determination and a variety of biochemical and computational methods to elucidate the reaction mechanism between benzothiazine-imine 1 and HDAC8.Results
1) 1 is a covalent inhibitor of HDAC8; 2) inhibition is reversible in the presence of reducing agents; 3) C153 in the active site and C102 are involved in the inhibition mechanism; 4) 1 modifies various cysteines in HDAC8 forming either thiocyanates or mixed disulfides with 3; 5) 1 and 5 dock in close proximity to C153 within the active site. This is supposed to accelerate covalent inactivation particularly in HDAC8 and suggested as major determinant for the observed nanomolar potency and selectivity of 1.Conclusions
1 and its analogs are interesting model compounds but unsuitable for therapeutic treatment due to their high unselective reactivity towards thiol groups. However, the postulated preceding non-covalent binding mode of 1 opens a door to optimized next generation compounds that combine potent and selective non-covalent recognition with low reactivity towards C153 at the active site of HDAC8.General significance
1 represents a completely new class of inhibitors for HDAC8. Initial non-covalent interaction at the bottom of the active site is suggested to be the key for its selectivity. Further optimization of non-covalent interaction and thiol-reactivity provides opportunities to develop therapeutic useful covalent HDAC8 inhibitors. 相似文献68.
Concepció Violan Quintí Foguet-Boreu Gemma Flores-Mateo Chris Salisbury Jeanet Blom Michael Freitag Liam Glynn Christiane Muth Jose M. Valderas 《PloS one》2014,9(7)
Introduction
Multimorbidity is a major concern in primary care. Nevertheless, evidence of prevalence and patterns of multimorbidity, and their determinants, are scarce. The aim of this study is to systematically review studies of the prevalence, patterns and determinants of multimorbidity in primary care.Methods
Systematic review of literature published between 1961 and 2013 and indexed in Ovid (CINAHL, PsychINFO, Medline and Embase) and Web of Knowledge. Studies were selected according to eligibility criteria of addressing prevalence, determinants, and patterns of multimorbidity and using a pretested proforma in primary care. The quality and risk of bias were assessed using STROBE criteria. Two researchers assessed the eligibility of studies for inclusion (Kappa = 0.86).Results
We identified 39 eligible publications describing studies that included a total of 70,057,611 patients in 12 countries. The number of health conditions analysed per study ranged from 5 to 335, with multimorbidity prevalence ranging from 12.9% to 95.1%. All studies observed a significant positive association between multimorbidity and age (odds ratio [OR], 1.26 to 227.46), and lower socioeconomic status (OR, 1.20 to 1.91). Positive associations with female gender and mental disorders were also observed. The most frequent patterns of multimorbidity included osteoarthritis together with cardiovascular and/or metabolic conditions.Conclusions
Well-established determinants of multimorbidity include age, lower socioeconomic status and gender. The most prevalent conditions shape the patterns of multimorbidity. However, the limitations of the current evidence base means that further and better designed studies are needed to inform policy, research and clinical practice, with the goal of improving health-related quality of life for patients with multimorbidity. Standardization of the definition and assessment of multimorbidity is essential in order to better understand this phenomenon, and is a necessary immediate step. 相似文献69.
Adam Hoover Anirud Singh Stephanie Fishel-Brown Eric Muth 《Biomedical signal processing and control》2012,7(4):333-341
This work presents a novel approach to detecting real-time changes in workload using heart rate variability (HRV). We propose that for a given workload state, the values of HRV vary in a sub-range of a Gaussian distribution. We describe methods to monitor a HRV signal in real-time for change points based upon sub-Gaussian fitting. We tested our method on subjects sitting at a computer performing a low workload surveillance task and a high workload video game task. The proposed algorithm showed superior performance compared to the classic CUSUM method for detecting task changes. 相似文献
70.
Felicity Muth 《Biology letters》2021,17(8)
Species’ cognitive traits are shaped by their ecology, and even within a species, cognition can reflect the behavioural requirements of individuals with different roles. Social insects have a number of discrete roles (castes) within a colony and thus offer a useful system to determine how ecological requirements shape cognition. Bumblebee queens are a critical point in the lifecycle of their colony, since its future success is reliant on a single individual''s ability to learn about floral stimuli while finding a suitable nest site; thus, one might expect particularly adept learning capabilities at this stage. I compared wild Bombus vosnesenskii queens and workers on their ability to learn a colour association and found that queens performed better than workers. In addition, queens of another species, B. insularis, a cuckoo species with a different lifecycle but similar requirements at this stage, performed equally well as the non-parasitic queens. To control for differences in foraging experience, I then repeated this comparison with laboratory-based B. impatiens and found that unmated queens performed better than workers. These results add to the body of work on how ecology shapes cognition and opens the door to further research in comparative cognition using wild bees. 相似文献