bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting lipid metabolism in multiple myeloma cells: Rational development of a synergistic strategy with proteasome inhibitors
Authors: Xu Gaojie , Huang Sheng , Peng Jian , Gao Xiaofang , Li Minhui , Yu Sisi , Liu Zuofeng , Qie Pengfan , Wang Yu , Yu Siqi , Liu Siyuan , Wen Hu , Su Lijuan , Li Ping , Guang Bin , Dong Renhan , Liu Jin , Yang Tai 
Published: August 2021

Background and PurposeAberrant lipid metabolism is recognized as a key feature of cancer cells. Our initial research on MS‐based analysis of lipids in a multiple myeloma (MM) cell line showed a significant accumulation of lipids in multiple myeloma cells after proteasome inhibition. This finding prompted us to hypothesize that multiple myeloma cell survival depends on the maximal utilization of abnormally accumulated lipids. Therefore, we explored whether lipid metabolism‐modulating agents would synergize with proteasome inhibitors.Experimental ApproachLipid accumulation in multiple myeloma cells was measured by MS. Synergism between lipid regulators and proteasome inhibitors was assessed by cell viability and apoptosis. A novel stable derivative of fenofibrate (FCE) was synthesized and used to treat multiple myeloma cells in vitro and in vivo along with the proteasome inhibitor ixazomib. ChIP‐seq, western blotting and RT‐qPCR were performed to explore the potential mechanism(s) underlying the increase in lipid levels in multiple myeloma cells after proteasome inhibition.Key ResultsAccumulation of lipids in multiple myeloma cells was induced by proteasome inhibition. Lipid‐lowering drugs and MG‐132 exerted a synergistic effect to kill multiple myeloma cells. FCE showed significant synergistic activity in vitro and in vivo with ixazomib. The abnormal lipid accumulation in multiple myeloma cells that was enhanced by proteasome inhibitors might be due to the elevated SREBP1/2 expression induced by ATF4.Conclusions and ImplicationsOur results provide a proof of principle and support for the further clinical evaluation of the combination of lipid‐modulating drugs with proteasome inhibitors in the treatment of multiple myeloma.
The inhibition of enkephalin catabolism by dual enkephalinase inhibitor: A novel possible therapeutic approach for opioid use disorders
Authors: Alvarez‐Perez Beltran , Poras Hervé , Maldonado Rafael 
Published: August 2021

Despite the increasing impact of opioid use disorders on society, there is a disturbing lack of effective medications for their clinical management. An interesting innovative strategy to treat these disorders consists in the protection of endogenous opioid peptides to activate opioid receptors, avoiding the classical opioid‐like side effects. Dual enkephalinase inhibitors (DENKIs) physiologically activate the endogenous opioid system by inhibiting the enzymes responsible for the breakdown of enkephalins, protecting endogenous enkephalins and increasing their half‐lives and physiological actions. The activation of opioid receptors by the increased enkephalin levels, and their well‐demonstrated safety, suggests that DENKIs could represent a novel analgesic therapy and a possible effective treatment for acute opioid withdrawal, as well as a promising alternative to opioid substitution therapy minimizing side effects. This new pharmacological class of compounds could bring effective and safe medications avoiding the major limitations of exogenous opioids, representing a novel approach to overcome the problem of opioid use disorders.LINKED ARTICLESThis article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc
Education: Optimal choice and efficient policy
Authors: Richter Wolfram F. , Schneider Kerstin 
Published: August 2021

AbstractThis paper argues that it suffices to assume distortionary wage taxation to prove the efficiency of effective subsidization of education. The paper does not rely on considerations of equity and market failure to justify subsidies. Instead, the optimal subsidy reduces the social cost of distortive wage taxation. The theoretical approach assumes a Mincer‐type earnings function, analyzes corner solutions of optimal schooling choice and derives the result of efficient subsidization in a Ramsey‐type framework. Second‐best policy is confronted with empirical evidence from OECD countries. The majority of countries are shown to subsidize tertiary education in effective terms.
Four‐implant‐supported overdenture treatment in the maxilla. Part II: Speech‐ and oral health‐related quality of life in patients with implant‐supported overdentures in the maxilla—A prospective 3‐year follow‐up
Authors: Fonteyne Ester , Burms Eline , Matthys Carine , Van Lierde Kristiane , De Bruyn Hugo 
Published: August 2021

AbstractBackgroundImplant‐supported overdentures (IOD) are becoming a more commonly used treatment in the dental practice and it risks causing speech problems.PurposeThe aim of this study was investigating the changes in speech, satisfaction with speech, and overall oral health‐related quality of life (OHRQoL) in edentulous patients during and after treatment with maxillary IODs.Materials and methodsTwenty‐one patients receiving an IOD participated in speech assessment. They were examined preoperatively with their conventional denture (CD) with full palatal coverage, after connection of the implant‐bar connected denture, without palatal coverage, and 3 years thereafter. The examination included assessment of articulation in speech, OHRQoL based on total OHIP‐14, and satisfaction with overall oral health and speech (visual analogue scale).ResultsThere was a reduction in mean number of articulation disorders from 1.00 at baseline to 0.55 at connection, although statistically insignificant (p = 0.059). Especially the /s/ sound is vulnerable. At 3 years follow‐up, still 6/16 (37.5%) of the patients suffered from this speech problem. Overall satisfaction improved from 64.05/100 at baseline to 82.95/100 at connection (p = 0.008) and remained unchanged with 81.69/100 after 3 years follow‐up. Patients' satisfaction with speech increased from 70.62/100 with CD to 82.63/100, 3 years follow‐up (p = 0.009). Total OHIP‐14 decreased from 21.45/56 with CD to 8.00/56 (p < 0.001) with IOD and 6.13/56 3 years after connection (p = 0.001). Significant improvement of all seven domains in OHRQoL was observed with IOD compared to CD.ConclusionsPatients treated with maxillary IODs show improved OHRQoL 3 years after connection of the IOD compared to the CD. Even though patients reported improvement of satisfaction and OHRQoL, articulation disorders were still present, suggesting that patients should be informed about possible speech issues.
A panel analysis of income inequality and energy use
Authors: Sonora Robert J. 
Published: August 2021

AbstractThis paper investigates the relationship between energy consumption and income inequality in an unbalanced panel of 144 countries over the period 1990–2018. Using fixed effect and instrumental variable panel methods and controlling for other determinants of inequality, I find a large and strong negative relationship between energy use and income inequality. The paper also demonstrates that results hold for models which divide the total sample into subsamples of economic blocs and regions. In addition, greater energy use reduces the income share of the top 10% and increases the share of the bottom 40%.
Emergent Goal‐Anticipatory Gaze in Infants via Event‐Predictive Learning and Inference
Authors: Gumbsch Christian , Adam Maurits , Elsner Birgit , Butz Martin V. 
Published: August 2021

AbstractFrom about 7 months of age onward, infants start to reliably fixate the goal of an observed action, such as a grasp, before the action is complete. The available research has identified a variety of factors that influence such goal‐anticipatory gaze shifts, including the experience with the shown action events and familiarity with the observed agents. However, the underlying cognitive processes are still heavily debated. We propose that our minds (i) tend to structure sensorimotor dynamics into probabilistic, generative event‐predictive, and event boundary predictive models, and, meanwhile, (ii) choose actions with the objective to minimize predicted uncertainty. We implement this proposition by means of event‐predictive learning and active inference. The implemented learning mechanism induces an inductive, event‐predictive bias, thus developing schematic encodings of experienced events and event boundaries. The implemented active inference principle chooses actions by aiming at minimizing expected future uncertainty. We train our system on multiple object‐manipulation events. As a result, the generation of goal‐anticipatory gaze shifts emerges while learning about object manipulations: the model starts fixating the inferred goal already at the start of an observed event after having sampled some experience with possible events and when a familiar agent (i.e., a hand) is involved. Meanwhile, the model keeps reactively tracking an unfamiliar agent (i.e., a mechanical claw) that is performing the same movement. We qualitatively compare these modeling results to behavioral data of infants and conclude that event‐predictive learning combined with active inference may be critical for eliciting goal‐anticipatory gaze behavior in infants.
Motivated Reasoning in an Explore‐Exploit Task
Authors: Caddick Zachary A. , Rottman Benjamin M. 
Published: August 2021

AbstractThe current research investigates how prior preferences affect causal learning. Participants were tasked with repeatedly choosing policies (e.g., increase vs. decrease border security funding) in order to maximize the economic output of an imaginary country and inferred the influence of the policies on the economy. The task was challenging and ambiguous, allowing participants to interpret the relations between the policies and the economy in multiple ways. In three studies, we found evidence of motivated reasoning despite financial incentives for accuracy. For example, participants who believed that border security funding should be increased were more likely to conclude that increasing border security funding actually caused a better economy in the task. In Study 2, we hypothesized that having neutral preferences (e.g., preferring neither increased nor decreased spending on border security) would lead to more accurate assessments overall, compared to having a strong initial preference; however, we did not find evidence for such an effect. In Study 3, we tested whether providing participants with possible functional forms of the policies (e.g., the policy takes some time to work or initially has a negative influence but eventually a positive influence) would lead to a smaller influence of motivated reasoning but found little evidence for this effect. This research advances the field of causal learning by studying the role of prior preferences, and in doing so, integrates the fields of causal learning and motivated reasoning using a novel explore‐exploit task.
Parsing as a Cue‐Based Retrieval Model
Authors: Dotlačil Jakub 
Published: August 2021

AbstractThis paper develops a novel psycholinguistic parser and tests it against experimental and corpus reading data. The parser builds on the recent research into memory structures, which argues that memory retrieval is content‐addressable and cue‐based. It is shown that the theory of cue‐based memory systems can be combined with transition‐based parsing to produce a parser that, when combined with the cognitive architecture ACT‐R, can model reading and predict online behavioral measures (reading times and regressions). The parser's modeling capacities are tested against self‐paced reading experimental data (Grodner & Gibson, 2005), eye‐tracking experimental data (Staub, 2011), and a self‐paced reading corpus (Futrell et al., 2018).
Distorting Face Representations in Newborn Brains
Authors: Wood Samantha M. W. , Wood Justin N. 
Published: August 2021

AbstractWhat role does experience play in the development of face recognition? A growing body of evidence indicates that newborn brains need slowly changing visual experiences to develop accurate visual recognition abilities. All of the work supporting this “slowness constraint” on visual development comes from studies testing basic‐level object recognition. Here, we present the results of controlled‐rearing experiments that provide evidence for a slowness constraint on the development of face recognition, a prototypical subordinate‐level object recognition task. We found that (1) newborn chicks can rapidly develop view‐invariant face recognition and (2) the development of this ability relies on experience with slowly moving faces. When chicks were reared with quickly moving faces, they built distorted face representations that largely lacked invariance to viewpoint changes, effectively “breaking” their face recognition abilities. These results provide causal evidence that slowly changing visual experiences play a critical role in the development of face recognition, akin to basic‐level object recognition. Thus, face recognition is not a hardwired property of vision but is learned rapidly as the visual system adapts to the temporal structure of the animal's visual environment.
A new composite abundance metric detects stream fish declines and community homogenization during six decades of invasions
Authors: Sleezer Logan J. , Angermeier Paul L. , Frimpong Emmanuel A. , Brown Bryan L. 
Published: August 2021

AbstractAimWe developed a new technique, utilizing species‐specific counts of individuals from historical fish community samples, to examine landscape‐level, spatio‐temporal trends in relative abundance distributions. Abundance‐based historical distribution analyses are often plagued by data comparability issues, but provide critical information about community composition trends inaccessible to those using analyses based only on species presence–absence. We established trends in native and non‐native fish abundance and community homogenization, uniqueness and diversity to help local conservation managers prioritize targets and motivate similar studies globally to support fish conservation.LocationUpper and middle New River (UMNR) basin, Appalachian Mountains, USA.MethodsWe compiled catch data from 61 years of fish community surveys (1958–2019) and tested for community homogenization by comparing data from repeatedly sampled sites (1900s versus 2000s samples) using dispersion analyses. We measured community uniqueness (site contributions to beta diversity) and species diversity (Shannon index) at sampled streams to identify potential conservation hotspots. We then used regression analyses and Wilcoxon signed‐rank tests to examine species‐specific basin‐wide and local abundance trends and identify species of potential conservation concern.ResultsDispersion of sites in species abundance space was significantly greater in the 1900s compared with the 2000s, indicating homogenization had occurred. Of 36 native species analysed, 44.4% (16) showed basin‐wide declines. Non‐native species exhibited mixed patterns; site‐level abundance increased in 2 of 15 species analysed (13%).Main conclusionsOur results indicate basin‐wide community homogenization has occurred within the UMNR, but many unique and diverse communities persist. If conserved, these could help maintain regional fish diversity. We found basin‐wide declines in four endemic species, as well as spread patterns of non‐native and native species that were not detected by a presence–absence analysis applied within the same study area. This finding illustrates the importance of considering both species’ abundance and occurrence patterns as separate dimensions of biodiversity to inform conservation planning.
Community engagement in genomic research: Proposing a strategic model for effective participation of indigenous communities
Authors: Ogunrin Olubunmi , Gabbay Mark , Woolfall Kerry , Frith Lucy 
Published: August 2021

AbstractCommunity engagement (CE) contributes to successful research. There is, however, a lack of literature on the effectiveness of different models of CE and, specifically, on CE strategies for the conduct of genomic research in sub‐Saharan Africa. There is also a need for models of CE that transcend the recruitment stage of engaging prospective individuals and communities and embed CE throughout the research process and after the research has concluded. The qualitative study reported here was designed to address these knowledge gaps and comprised of 36 key informant semi‐structured interviews and fifteen focus groups with 50 participants. We interviewed selected stakeholders in genomic research in Nigeria: biomedical researchers, community rulers, opinion leaders, community health workers, and prospective research participants. We explored these stakeholders’ views on their understanding of community engagement, their expectations, experiences, and their opinions on acceptable processes of community consultation in genomic research. The methodological design, adapted from grounded theory, used the constant comparative method of data analysis; while normative conclusions were made using the symbiotic empirical ethics approach. Data analysis revealed five main themes important for successfully engaging communities in genomic research: effective communication, diversity of community gatekeeping, trust, cultural integration of research, and conservation of the research setting. From these themes, we have developed a four‐stage model of community engagement that covers all stages of the research process; namely, the Community Approach, Intermediate phase, Collaboration and Post‐research Cordiality model (CICP). This model could be used to improve the integration of CE in genomic research among local communities.
Leibniz and Bolzano on conceptual containment
Authors: Claas Jan 
Published: August 2021

AbstractPhilosophers often rely on the notion of conceptual containment and apply mereological terminology when they talk about the parts or constituents of a complex concept. In this paper, I explore two historical approaches to this general notion. In particular, I reconstruct objections Bernard Bolzano puts forward against a criterion that played a prominent role in the history of philosophy and that was endorsed, among others, by Leibniz. According to this criterion, a concept that represents objects contains all and only the concepts that represent properties the objects must have in order to be represented by the former concept. Bolzano offers several counterexamples and arguments against the criterion. I argue that while some of them presuppose a strongly mereological understanding of containment, which Leibniz is not committed to, one of them also succeeds without relying on demanding mereological principles.
Efficacy of erlotinib and its effects on the quality of life of older patients with epidermal growth factor receptor‐mutant non‐small cell lung cancer: A prospective, multicenter, dose‐modification study
Authors: Tsubata Yukari , Masuda Takeshi , Hamai Kosuke , Taniwaki Masaya , Tanino Akari , Hotta Takamasa , Hamaguchi Megumi , Hamaguchi Shunichi , Yamasaki Masahiro , Ishikawa Nobuhisa , Fujitaka Kazunori , Sutani Akihisa , Isobe Takeshi 
Published: August 2021

AimGefitinib and erlotinib are efficacious and safe for older patients with epidermal growth factor receptor‐mutant non‐small cell lung cancer. However, prolonged use of epidermal growth factor receptor‐tyrosine kinase inhibitors in older patients is difficult, owing to potential adverse events. Hence, dose reduction or treatment discontinuation is often required. We investigated the efficacy of low‐dose first‐line erlotinib and its effects on the quality of life of older patients with lung cancer.MethodsA prospective, multicenter, phase II clinical trial was carried out in patients aged ≥75 years with epidermal growth factor receptor‐mutant non‐small cell lung cancer. Initially, 100 mg/day erlotinib was administered orally; if well tolerated, it was increased to 150 mg/day. The primary end‐point was progression‐free survival, and secondary end‐points were the response rate, overall survival and change in quality of life (“Care Notebook” questionnaire).ResultsThe median progression‐free survival was 17.8 months, response rate was 63.6% and median overall survival was 27.8 months. The change in the quality of life after 6 weeks was assessed in 72.7% of the patients. Fatigue, pain, anxiety and deterioration in daily activities were found in at least 40% of the patients. Despite the therapeutic effect of 100 mg/day erlotinib, many patients required dose reduction, and in some, the quality of life could not be maintained.ConclusionsMany older patients with epidermal growth factor receptor‐mutant non‐small cell lung cancer might require treatment dose reduction. Further studies are required to develop individualized treatments for older patients with lung cancer. Geriatr Gerontol Int 2021; 21: 881–886.
Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A
Authors: Pasi K John , Laffan Michael , Rangarajan Savita , Robinson Tara M , Mitchell Nina , Lester Will , Symington Emily , Madan Bella , Yang Xinqun , Kim Benjamin , Pierce Glenn F , Wong Wing Yen 
Published: August 2021

AbstractIntroductionValoctocogene roxaparvovec is an investigational AAV5‐based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A.AimTo report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795).MethodsMen ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti‐AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 1013 vg/kg dose, n = 7) and 4 years (4 × 1013 vg/kg dose, n = 6).ResultsOver the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was ‐0.14 (95% confidence interval [CI]: ‐.32 to .03) IU/dl/wk in the 6 × 1013 vg/kg cohort in year 5 and ‐.06 (95% CI: ‐.14 to .01) IU/dl/wk in the 4 × 1013 vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 1013 vg/kg cohort; all six Haemo‐QOL‐A domain scores increased. For the 4 × 1013 vg/kg cohort, high baseline Haemo‐QOL‐A scores persisted.ConclusionThese results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A.