bluuebunny/crossref_metadata_2025 huggingface dataset:
Graph Contextualized Attention Network for Predicting Synthetic Lethality in Human Cancers
Authors: Long Yahui , Wu Min , Liu Yong , Zheng Jie , Kwoh Chee Keong , Luo Jiawei , Li Xiaoli
Published: January 2021

Motivation

Synthetic Lethality (SL) plays an increasingly critical role in the targeted anticancer therapeutics. In addition, identifying SL interactions can create opportunities to selectively kill cancer cells without harming normal cells. Given the high cost of wet-lab experiments, in silico prediction of SL interactions as an alternative can be a rapid and cost-effective way to guide the experimental screening of candidate SL pairs. Several matrix factorization-based methods have recently been proposed for human SL prediction. However, they are limited in capturing the dependencies of neighbors. In addition, it is also highly challenging to make accurate predictions for new genes without any known SL partners.

Results

In this work, we propose a novelgraph contextualized attention networknamed GCATSL to learn gene representations for SL prediction. First, we leverage different data sources to construct multiple feature graphs for genes, which serve as the feature inputs for our GCATSL method. Second, for each feature graph, we design node-level attention mechanism to effectively capture the importance of local and global neighbors and learn local and global representations for the nodes, respectively. We further exploit multi-layer perceptron (MLP) to aggregate the original features with the local and global representations and then derive the feature-specific representations. Third, to derive the final representations, we design feature-level attention to integrate feature-specific representations by taking the importance of different feature graphs into account. Extensive experimental results on three datasets under different settings demonstrate that our GCATSL model outperforms 14 state-of-the-art methods consistently. In addition, case studies further validate the effectiveness of our proposed model in identifying novel SL pairs.

Availability

Python codes and dataset are available at:

Contact

luojiawei@hnu.edu.cnandxlli@i2r.a-star.edu.sg
A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response
Authors: Connolly Kelli A. , Kuchroo Manik , Venkat Aarthi , Khatun Achia , Wang Jiawei , William Ivana , Hornick Noah , Fitzgerald Brittany , Damo Martina , Kasmani Moujtaba Y. , Cui Can , Fagerberg Eric , Monroy Isabel , Hutchins Amanda , Cheung Julie F , Foster Gena G. , Mariuzza Dylan L. , Zhao Hongyu , Cui Weiguo , Krishnaswamy Smita , Joshi Nikhil S.
Published: January 2021

“Stem-like” TCF1+CD8+T cells (TSL) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. We found that a small number of TCF1+tumor-specific CD8+T cells were present in tumors throughout development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” to “cold”. By contrast, most tumor-specific CD8+T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSLfrom chronic LCMV infection and this population was stable over time, despite the changes in the TME. dLN T cells were the precursors of their more-differentiated intratumoral counterparts, and maintenance of TCF1 by intratumoral T cells required continuous migration from dLNs. Finally, TSLCD8 T cells were also present in LNs from lung adenocarcinoma patients, suggesting this population is also relevant in human disease. Thus, we propose that the dLN TSLreservoir has a critical function during tumor development in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.
Transcriptome profiling of human pluripotent stem cell-derived cerebellar organoids reveals faster commitment under dynamic conditions
Authors: Silva Teresa P. , Sousa-Luís Rui , Fernandes Tiago G. , Bekman Evguenia P. , Rodrigues Carlos A. V. , Vaz Sandra H. , Moreira Leonilde M. , Hashimura Yas , Jung Sunghoon , Lee Brian , Carmo-Fonseca Maria , Cabral Joaquim M. S.
Published: January 2021

Human induced pluripotent stem cells (iPSCs) have great potential for disease modeling. However, generating iPSC-derived models to study brain diseases remains a challenge. In particular, the ability to recapitulate cerebellar developmentin vitrois still limited. We presented a reproducible and scalable production of cerebellar organoids by using the novel Vertical-Wheel single-use bioreactors, in which functional cerebellar neurons were obtained. Here, we evaluate the global gene expression profiles by RNA sequencing (RNA-seq) across cerebellar differentiation, demonstrating a faster cerebellar commitment in this novel dynamic differentiation protocol. Furthermore, transcriptomic profiles suggest a significant enrichment of extracellular matrix (ECM) in dynamic-derived cerebellar organoids, which can better mimic the neural microenvironment and support a consistent neuronal network. Thus, an efficient generation of organoids with cerebellar identity was achieved for the first time in a continuous process using a dynamic system without the need of organoids encapsulation in ECM-based hydrogels, allowing the possibility of large-scale production and application in high-throughput processes. The presence of factors that favors angiogenesis onset was also detected in dynamic condition, which can enhance functional maturation of cerebellar organoids. We anticipate that large-scale production of cerebellar organoids may help developing models for drug screening, toxicological tests and studying pathological pathways involved in cerebellar degeneration.
Stimulating human prefrontal cortex increases reward learning
Authors: Juliëtte Overman Margot , Sarrazin Verena , Browning Michael , O’Shea Jacinta
Published: January 2021

Work in computational psychiatry suggests that mood disorders may stem from aberrant reinforcement learning processes. Specifically, it is proposed that depressed individuals believe that negative events are more informative than positive events, resulting in faster learning from negative outcomes (Pulcu & Browning, 2019). In this proof-of-concept study, we investigated whether learning rates for affective outcomes are malleable using transcranial direct current stimulation (tDCS). Healthy adults completed an established reinforcement learning task (Pulcu & Browning, 2017) in which the information content of reward and loss outcomes was manipulated by varying the volatility of stimulus-outcome associations. Learning rates on the tasks were quantified using computational models. Stimulation over dorsolateral prefrontal cortex (DLPFC) but not motor cortex (M1) specifically increased learning rates for reward outcomes. The effects of prefrontal tDCS were cognitive state-dependent: online stimulation increased learning rates for wins; offline stimulation decreased both win and loss learning rates. A replication study confirmed the key finding that online tDCS to DLPFC specifically increased learning rates for rewards relative to losses. Taken together, these findings demonstrate the potential of tDCS for modulating computational parameters of reinforcement learning relevant to mood disorders.

Significance statement

Disproportionate learning from negative relative to positive outcomes has been implicated in the development and maintenance of depression. The present work demonstrates that transcranial direct current stimulation (tDCS) to dorsolateral prefrontal cortex can specifically increase learning from positive events in healthy adults. Our results provide preliminary evidence that non-invasive brain stimulation can be used to shape reinforcement learning, indicating a potential novel cognitive neurostimulation intervention strategy for affective disorders.
Single-cell immune profiling reveals the impact of antiretroviral therapy on HIV-1-induced immune dysfunction, T cell clonal expansion, and HIV-1 persistencein vivo
Authors: Collora Jack A. , Pinto-Santini Delia , Pasalar Siavash , Ravindra Neal , Ganoza Carmela , Lama Javier , Alfaro Ricardo , Chiarella Jennifer , Spudich Serena , van Dijk David , Duerr Ann , Ho Ya-Chi
Published: January 2021

Despite antiretroviral therapy (ART), HIV-1 persists in proliferating T cell clones that increase over time. To understand whether early ART affects HIV-1 persistencein vivo, we performed single-cell ECCITE-seq and profiled 89,279 CD4+T cells in paired samples during viremia and after immediate versus delayed ART in six people in the randomized interventional Sabes study. We found that immediate ART partially reverted TNF responses while delayed ART did not. Antigen and TNF responses persisted despite immediate ART and shaped the transcriptional landscape of CD4+T cells, HIV-1 RNA+cells, and T cell clones harboring them (cloneHIV-1). Some HIV-1 RNA+cells reside in the most clonally expanded cytotoxic T cell populations (GZMB and GZMK Th1 cells). CloneHIV-1+were larger in clone size, persisted despite ART, and exhibited transcriptional signatures of antigen, cytotoxic effector, and cytokine responses. Using machine-learning algorithms, we identified markers for HIV-1 RNA+cells and cloneHIV-1+as potential therapeutic targets. Overall, by combining single-cell immune profiling and T cell expansion dynamics tracking, we identified drivers of HIV-1 persistencein vivo.
High contrast, moving targets in an emerging target paradigm promote fast visuomotor responses during visually guided reaching
Authors: Kozak Rebecca A. , Corneil Brian D.
Published: January 2021

Humans have a remarkable capacity to rapidly interact with the surrounding environment, often by transforming visual input into motor output on a moment-to-moment basis. But what visual features promote rapid reaching? High contrast, fast-moving targets elicit strong responses in the superior colliculus (SC), a structure associated with express saccades and implicated in rapid electromyographic (EMG) responses on upper limb muscles. To test the influence of stimulus properties on rapid reaches, we had human subjects perform visually guided reaches to moving targets varied by speed (experiment 1) or speed and contrast (experiment 2), in an emerging target paradigm which has recently been shown to robustly elicit fast visuomotor responses. Our analysis focused on stimulus-locked responses (SLRs) on upper limb muscles. SLRs appear within <100 ms of target presentation, and as the first wave of muscle recruitment, they have been hypothesized to arise from the SC. Across 32 subjects studied in both experiments, 97% expressed SLRs in the emerging target paradigm, whereas only 69% expressed SLRs in an immediate response paradigm towards static targets. Faster moving targets (experiment 1) evoked large magnitude SLRs, while high contrast fast moving targets (experiment 2) evoked short latency, large magnitude SLRs. In some instances, SLR magnitude exceeded the magnitude of movement aligned activity. Both large magnitude and short latency SLRs were correlated with short latency reach reaction times. Our results support the hypothesis that, in scenarios requiring expedited responses, a subcortical pathway originating in the SC elicits the earliest wave of muscle recruitment, expediting reaction times.

New & Noteworthy

How does the brain rapidly transform vision into action? Here, by recording upper limb muscle activity, we find that high contrast and fast moving targets are highly effective at evoking rapid visually guided reaches. We surmise that a brainstem circuit originating in the superior colliculus contributes to the most rapid reaching responses. When time is of the essence, cortical areas may serve to prime this circuit, and elaborate subsequent phases of recruitment.
2.5D geophysical model of the Gällivare mining area: An integrated study to model the top 4 km of the subsurface and guide for future exploration activities
Authors: Tavakoli Saman , Sarlus Zmar , Kronsell Ida , Bauer Tobias E.
Published: January 2021

Potential field and Slingram data alongside rock physical properties, drill‐core information and results from geological field mapping were used to investigate the geometry of the geological structures in the Gällivare area in regional scale. The main purpose of this study was to delineate the vertical and lateral extension of the Malmberget felsic volcanic rocks, the Dundret and Vassaravaara units as well as geological structures related to the crustal‐scale Nautanen deformation zone. Furthermore, we aimed at identifying new magnetite‐hematite and sulphide mineralizations and lithologies related to the mineralizations based on the results from regional‐scale potential field modelling which are delineated with rock physical properties and borehole data. The study result indicated that the dome‐shaped Dundret gabbro extends downwards to ∼4 km depth and has its maximum depth at its centre. Hematite and magnetite assemblages occur within the top 2 km of the Dundret complex. Felsic volcanic rocks in the Malmberget area extend vertically down to a maximum depth of ∼3 km and get considerably thinner towards the west. The model for the known magnetite‐rich mineralizations in Malmberget was inferred from earlier drilling activities and was integrated into the profile models, which indicates a reasonable fit to the measured data, in particular on the magnetic anomaly; whereas the small dimensions of the modelled structures make them invisible on the Bouguer anomaly data. Additional magnetite‐rich mineralizations are suggested within the Malmberget felsic rocks. High real component and low imaginary response of the Slingram data suggests conductive zones within the Nautanen deformation zone towards the NE, which given the geology of the area in the high strain zone can indicate disseminated sulphide mineralizations. Drill‐hole data at the eastern parts of W‐E profiles agreed well with the suggested model inferred from potential field data, suggesting presence of mafic intrusions within the ∼top 1 km of the subsurface. The integrated model based on geophysical, petrophysical and geological data improved earlier understanding about the regional geometry of the key structures in the Gällivare area and indicates new magnetite‐rich and sulphide mineralization prospects which can be used as a guide for future exploration activities in the area.
Analytical chemistry, formation, mitigation, and risk assessment of polycyclic aromatic hydrocarbons: From food processing to in vivo metabolic transformation
Authors: Zhang Yiju , Chen Xiaoqian , Zhang Yu
Published: January 2021

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the air, oils, water, and food products we encounter every day. Among these exposures, food consumption is a major route of PAH exposure for nonsmokers. The PAH dietary exposure levels vary among different countries; however, many studies have shown PAH exposure to be highly concerning to human health. The levels of PAH contamination in food are mainly influenced by processing procedures and cooking methods, and they could be attenuated by modifying cooking procedures and adding antioxidant‐rich marinades. Several PAHs have toxic, mutagenic, and carcinogenic properties. The PAH benzo[a]pyrene (BaP) is particularly regarded as carcinogenic. There are three major metabolism pathways for PAHs, and the final products can bind to DNA, thus exerting mutagenic effects. Biological monitoring through the use of biomarkers is necessary for comprehensive and accurate risk assessments of human PAH exposure. It is important to reduce dietary PAH exposure and to implement reasonable and effective risk management strategies to reduce PAH levels in food to improve public health.
Specific oral and maxillofacial identifiers in panoramic radiographs used for human identification
Authors: Du Han , Li Min , Li Gang , Lyu Tu , Tian Xue‐mei
Published: January 2021

Radiographically assisted dental identification is an important means for individual identification. Specific identifiers help to quickly filter some of the possible corresponding AM and PM images at the beginning. The study seeks specific oral and maxillofacial identifiers in panoramic radiographs. A total of 920 panoramic radiographs from 460 live patients were used. The most recent radiograph served as the surrogate post‐mortem (PM) record of an unidentified person, and the earliest radiograph served as the ante‐mortem (AM) record of the same person. We evaluated the following four groups of identifiers of the images: (1) dental morphology, tooth number, and position; (2) dental treatment and pathology; (3) morphological identifiers of the jaw; and (4) pathological identifiers of the jaw. The ratio of each identifier being identified simultaneously in the AM and PM databases was determined. Specific identifiers were defined as those that appeared at low frequency (ratio: 0%–0.250%). A total of 18 specific oral and maxillofacial identifiers were determined. The specific identifiers were a retained deciduous tooth (0.011%), S‐shaped deflection of a tooth root (0.012%), distal deflection of tooth root (0.017%), inverted impaction (0.018%), malposition (0.038%), supernumerary teeth (0.061%), mesial deflection of tooth root (0.092%), microdontia (0.136%), buccal/lingual impaction (0.188%), cementoma (0.002%), hypercementosis (0.002%), continuous crown (0.004%), pulp calcification (0.023%), attrition (0.030%), residual root (0.106%), root resorption (0.137%), implant (0.156%), and osteomyelitis (0.002%). Identifiers of the teeth and jaw can be used for human identification, and dental identifiers are more specific than identifiers of jaw.
Is waiver of consent for the use of health information for research acceptable to emergency department patients?
Authors: Schultz‐Swarthfigure Chase , Kelly Anne‐Maree
Published: January 2021

Some emergency medicine research, especially retrospective studies using medical records review, rely on waiver of consent for use of personal health information (PHI) contained in clinical records. This is a secondary use of PHI and waiver of consent raises ethical, legal and practical issues. Granting of a waiver of consent is often (but not always) approved by a human research ethics committee and requires separate but inter‐related consideration of the legal and ethical issues. In part, this involves a balancing of the public interest versus the risk to privacy and an evaluation of whether subjects would, mostly likely, have agreed to the use of their PHI had they been asked. To date, there are no robust data about whether use of PHI without consent for research would be acceptable to people who attend Australasian EDs for care.
New psychoactives within polydrug use trajectories—evidence from a mixed‐method longitudinal study
Authors: Higgins Kathryn , O'Neill Nina , O'Hara Leeanne , Jordan Julie‐Ann , McCann Mark , O'Neill Tara , Clarke Mike , O'Neill Tony , Kelly Grace , Campbell Anne
Published: January 2021

Aims

To provide public health‐related research evidence on types and usage patterns of new psychoactive substances (NPS), developmental pathways into NPS and decision‐making factors for, and associated harms of, NPS use.

Design

Three‐phase mixed‐methods design, including a latent class analysis (LCA) of the longitudinal Belfast Youth Development Study (BYDS), a narrative analysis of interviews with NPS users and a three‐step approach manual method modelling using regressions to reveal classes of substance use and their associated predictors and outcomes.

Setting

Northern Ireland.

Participants

A total of 2039 people who responded to the questions on ‘ever use’ of the drug variables included at wave 7 (aged 21 years) of the BYDS. Eighty‐four narrative interviews with NPS users.

Measurements

Categories of drug use identified by LCA. Predictors and outcomes included measures of family, partners, peers, substance use, school, delinquency and mental health.

Findings

A four‐class solution provided the best fit for the data: alcohol; alcohol and tobacco; alcohol, tobacco and cannabis; and polydrug (the latter including NPS). The qualitative analysis yielded a taxonomy that distinguished how NPS operate within a wider range of drug repertoires from experimental to problematic.

Conclusions

In Northern Ireland, new psychoactive substances appear to be a feature of broader polydrug use rather than a standalone class of drug use.
CDK4/6 inhibitor plus endocrine therapy for hormone receptor‐positive, HER2‐negative metastatic breast cancer: The new standard of care
Authors: Hui Rina , de Boer Richard , Lim Elgene , Yeo Belinda , Lynch Jodi
Published: January 2021

Patients presenting with hormone receptor‐positive (HR+), human epidermal growth factor receptor 2‐negative (HER2–) metastatic breast cancer (MBC) are usually treated with endocrine therapy (ET), except if there is a concern about endocrine resistance or a need to achieve rapid disease control due to visceral crisis. The combination of CDK4/6 inhibitor + ET has now replaced single‐agent ET as the standard first‐line treatment; and it can also be considered a standard option in the second‐line setting. This review briefly summarizes recently reported efficacy findings from the key phase III clinical trials of CDK4/6 inhibitor + ET in patients with HR+/HER2– MBC, including evidence that adding a CDK4/6 inhibitor to ET improves overall survival and does so without reducing patients’ quality of life. There is still much to learn regarding the use of CDK4/6 inhibitors and how they may be optimally integrated into clinical practice. In particular, there is a need for specific biomarkers that help predict the likelihood of response or resistance to CDK4/6 inhibitor therapy; and for data to guide treatment decisions when a patient's disease progresses on a CDK4/6 inhibitor.
Migrating to GBA cities in mainland China: Assessing a model of psychological distance among Hong Kong working adults
Authors: Zhu Alex Yue Feng , Mok Ka Ho , Huang Geng Hua
Published: January 2021

South–North and North–North migration patterns have received significant interest in the literature, and recently, studies have begun to investigate South–South migration. However, as yet, very few studies have addressed North–South migration or investigated the psychological facilitators and barriers that drive this growing migration pattern. With a sample from a representative group of Hong Kong adults, we evaluated the role of positive attitude in shaping the intention to migrate from Hong Kong, a more‐developed economy (a metropolitan area), to the Greater Bay Area (GBA) cities in Mainland China, considered a less‐developed economy (with less metropolitan areas). We found positive attitude toward GBA cities in Mainland China promoted migration intention both directly and indirectly, as mediated by situational concerns and experience of visiting Mainland GBA cities. The impact of a positive attitude on a field visit was found to be weaker among wealthier adults relative to their economically disadvantaged counterparts. The effect of a field visit on migration intention was found to be stronger among wealthier adults relative to their economically disadvantaged counterparts. The findings suggest that an understanding of social psychology has implications for policy makers through highlighting the different approaches and entry points that could be adopted to encourage migration by people of varying economic status.
Thermal basal regime of the Elsterian ice‐sheet marginal zone in a hilly mountain foreland, Rychleby Mts., Eastern Sudetes
Authors: Hanáček Martin , Nývlt Daniel , Jennings Stephen J. A.
Published: January 2021

The Scandinavian Ice Sheet reached the Sudetes and Carpathian Mountains during the Elsterian glaciation. A long ice‐sheet piedmont marginal zone affected by the rugged mountain foreland topography and associated slopes originated. This study focuses on the hilly Rychleby Mts. foreland (Eastern Sudetes, Czechia), which was a part of the piedmont marginal foreland zone of the ice sheet. The basal regime was reconstructed through an investigation of the sedimentology, structural features, and the nature of ice‐sheet erosion of preglacial landscapes evident at two sites located ~3–5 km inside the maximum ice‐sheet extent. These sites show a preglacial relief buried by sub‐ to supraglacial sediments. The sites were located under an ice cover of max. 200 m. Evidence of cold‐based conditions (including palaeotors with delicate structures on the bedrock, almost absent striations on clasts, originally frozen unlithified sedimentary rafts) exists at both sites. Permafrost composed of coarse‐grained sediments was subject to brittle deformation at the base of the ice sheet, whereas permafrost composed of fine‐grained sediments underwent ductile deformation. The margin of the Scandinavian Ice Sheet in the Rychleby Mts. foreland was cold‐based, therefore glacial erosion was not sufficient to significantly remodel the palaeotors into roches moutonnées. During ice‐sheet decay, the preglacial landscape was partially buried by melt‐out tills and meltwater sediments.
A conserved arginine with non‐conserved function is a key determinant of agonist selectivity in α7 nicotinic ACh receptors
Authors: Minguez‐Viñas Teresa , Nielsen Beatriz E. , Shoemark Deborah K. , Gotti Cecilia , Sessions Richard B. , Mulholland Adrian J. , Bouzat Cecilia , Wonnacott Susan , Gallagher Timothy , Bermudez Isabel , Oliveira Ana Sofia
Published: January 2021

Background and Purpose

The α7 and α4β2* (“*” denotes possibly assembly with another subunit) nicotinic acetylcholine receptors (nAChRs) are the most abundant nAChRs in the mammalian brain. These receptors are the most targeted nAChRs in drug discovery programmes for brain disorders. However, the development of subtype‐specific agonists remains challenging due to the high degree of sequence homology and conservation of function in nAChRs. We have developed C(10) variants of cytisine, a partial agonist of α4β2 nAChR that has been used for smoking cessation. The C(10) methyl analogue used in this study displays negligible affinity for α7 nAChR, while retaining high affinity for α4β2 nAChR.

Experimental Approach

The structural underpinning of the selectivity of 10‐methylcytisine for α7 and α4β2 nAChRs was investigated using molecular dynamic simulations, mutagenesis and whole‐cell and single‐channel current recordings.

Key Results

We identified a conserved arginine in the β3 strand that exhibits a non‐conserved function in nAChRs. In α4β2 nAChR, the arginine forms a salt bridge with an aspartate residue in loop B that is necessary for receptor expression, whereas in α7 nAChR, this residue is not stabilised by electrostatic interactions, making its side chain highly mobile. This lack of constrain produces steric clashes with agonists and affects the dynamics of residues involved in agonist binding and the coupling network.

Conclusion and Implications

We conclude that the high mobility of the β3‐strand arginine in the α7 nAChR influences agonist binding and possibly gating network and desensitisation. The findings have implications for rational design of subtype‐selective nAChR agents.
Developing radical innovation capabilities: Exploring the effects of training employees for creativity and innovation
Authors: Rampa Romain , Agogué Marine
Published: January 2021

The resilience of organizations is increasingly dependent on their ability to develop radical innovation capabilities. While the literature documents numerous cases of organizations that already have radical innovation capabilities, the question of organizational devices that can be used to stimulate the emergence of such capabilities remains poorly addressed. Specifically, training for innovation and creativity has been proposed as a means to foster innovation capabilities; however, there has been little empirical evidence concerning the long‐term impacts of such training. To fill this gap, this article aims to document and evaluate the efforts of the research institute of a major Canadian energy company to provide training for innovation and creativity to initiate a radical innovation capability. We rely on a longitudinal study over the span of 18 months, where we observed 128 h of training and conducted 70 semi‐structured interviews with a sample of 40 researchers. We found that training for creativity and innovation has the potential to develop individual creative skills for exploration, to catalyze and federate collective action through common methods and a shared sense of what innovation entails, and to help create a common language and vocabulary between the different groups or divisions of an organization to talk about exploration.
On stipulation
Authors: Shields Matthew
Published: January 2021

When we carry out a speech act of stipulation, it seems that we can shape our language however we see fit. This autonomy, however, also seems to make such acts arbitrary: it is unclear if there are any constraints on what counts as a "correct" or "incorrect" stipulation. In this paper, I offer a novel, detailed account of the pragmatics of stipulation and explain its crucial role in conceptual analysis and articulation. My account shows that stipulation does indeed equip us with a key tool for changing our linguistic practices, but that such acts can nonetheless count as meaningfully, normatively constrained: they are always subject to felicitous criticism and the possibility of defeat by others. I then examine the metaphilosophical implications of this account. Philosophers often describe the project of conceptual analysis as having a crucial stipulative dimension, but they rarely explain what they take this act to consist in. On my view, speech acts of stipulation are best understood as acts that generate a shared inferential entitlement for speaker and audience, an entitlement justified on the basis of its utility. In developing this account, I distinguish stipulations from more familiar speech act kinds such as assertions and commands, synthesize and criticize alternative views of stipulation in the literature, and discuss the relationship between stipulation and seemingly kindred speech acts (such as assumptions, suppositions, and proposals).
Tillage system and seeding rate effects on the performance of Brassica carinata
Authors: Iboyi Joseph E. , Mulvaney Michael J. , Balkcom Kipling S. , Seepaul Ramdeo , Bashyal Mahesh , Perondi Daniel , Leon Ramon G. , Devkota Pratap , Small Ian M. , George Sheeja , Wright David L.
Published: January 2021

Brassica carinata, a nonfood oilseed crop, is used to produce renewable fuels because of its high oil content and favorable fatty acid profile. Production in the southeastern United States is relatively new, and information on agronomic management practices to optimize growth and yield is limited. Since optimal seeding rate may depend on the land preparation method for this small‐seeded crop, a study was conducted to evaluate the effect of tillage system (conventional, no‐till, broadcast‐disc, and ripper‐roller) and seeding rate (1.12, 5.60, 10.09, and 14.57 kg seed ha−1) on the performance of B. carinata. A randomized complete block design with a strip‐plot restriction on randomization and four replications was implemented in Headland, AL, Jay, FL, and Quincy, FL, over five site‐years during the 2017–2018 and 2018–2019 growing seasons. Data were collected on soil residue cover; plant population; soil penetrometer resistance and moisture; biomass (including carbon and nitrogen); stalk diameter; yield and yield components; seed oil, protein, and glucosinolates concentration; and oil composition. Soil penetrometer resistance was significantly affected by tillage system, with the ripper‐roller consistently having the lowest penetration resistance values across all site‐years. Ripper‐roller tillage had the highest oil content and lowest protein and glucosinolate contents. Yield response to tillage system was variable. Among seeding rate treatments, yield was lowest at 1.12 kg seed ha−1 and similar among 5.60, 10.09, and 14.57 kg seed ha−1 at all site‐years. There was no tillage by seeding rate interaction for yield. Results indicate that among seeding rate treatments used, 5.6 kg seed ha−1 rate was optimal at all site‐years regardless of land preparation method and is thus the recommended seeding rate for commercial carinata production in the Southeastern United States.
Potent antitumour of the mTORC1/2 dual inhibitor AZD2014 in docetaxel‐sensitive and docetaxel‐resistant castration‐resistant prostate cancer cells
Authors: Li Senmao , Sheng Jindong , Liu Zhenhua , Fan Yu , Zhang Cuijian , Lv Tianjing , Hu Shuai , Jin Jie , Yu Wei , Song Yi
Published: January 2021

Recent studies indicate mammalian target of rapamycin (mTOR) may play an important role in PCa progression and drug resistance. Here, we investigated the effects of a novel mTORC1/C2 dual inhibitor, AZD2014, on naive and docetaxel (Doc)‐pre‐treated castration‐resistant PCa (CRPC) cells and explored its therapeutic potential in CRPCs. In the current study, AZD2014 has a greater inhibitory effect against 4EBP1 and AKT phosphorylation than rapamycin in CRPC cells and prevented the feedback activation of AKT signalling. Importantly, AZD2014 suppressed CRPC cell growth in vitro by suppressing proliferation, apoptosis, cell cycle arrest at G1 phase and autophagy to a greater extent than rapamycin. Moreover, AZD2014 was more efficacious than rapamycin in inhibiting migration, invasion and EMT progression in Doc‐sensitive and Doc‐resistant CRPC cells. Overall, AZD2014 showed significant antitumour effects. Thereby, the current study highlights a reliable theoretical basis for the clinical application of AZD2014 in both Doc‐sensitive and Doc‐resistant CRPCs.
The differences in clinical and dermoscopic features between in situ and invasive nevus‐associated melanomas and de novo melanomas
Authors: Reiter O. , Kurtansky N. , Nanda J.K. , Busam K.J. , Scope A. , Musthaq S. , Marghoob A.A.
Published: January 2021

Background

Nevus‐associated melanomas (NAM) account for 30% of all melanomas and are associated with younger age and with thinner Breslow thickness. Previous studies of NAM dermoscopy found conflicting results.

Objective

To compare the clinical and dermoscopic features of NAM and de novo melanomas (DNM), stratified by melanoma thickness, in a relatively large cohort of patients.

Methods

A cross‐sectional study of all melanomas biopsied between 2004 and 2019 at a large cancer centre. Lesions were categorized as in situ and invasive NAM or DNM. Dermoscopic images were reviewed and annotated. Associations between melanoma subtype and dermoscopic features were analysed via logistic regression modelling. Bivariate analyses were conducted using non‐parametric bootstrap and chi‐squared methods.

Results

The study included 160 NAM (86 in situ and 74 invasive) and 218 DNM (109 in situ and 109 invasive). NAM were associated with younger age, greater likelihood of being present on the torso, and thinner Breslow thickness. NAM were 2.5 times more likely to show a negative pigment network than DNM. In situ NAM were 2.1 and two times more likely to display dermoscopic area without definable structures and tan structureless areas than DNM, respectively. In situ melanomas were more likely to present a pigment network, and invasive melanomas more commonly presented scar‐like depigmentation and shiny white structures. Streaks, blotches and shiny white structures were associated with deeper Breslow depth.

Conclusions

Even though the nevus component of NAM could not be identified dermoscopically in the current series, negative pigment network, tan structureless areas and areas without definable structures are dermoscopic clues for NAM.
Efficacy of sedation with dexmedetomidine plus propofol during esophageal endoscopic submucosal dissection
Authors: Ashikari Keiichi , Nonaka Takashi , Higurashi Takuma , Takatsu Tomohiro , Yoshihara Tsutomu , Misawa Noboru , Arimoto Jun , Kanoshima Kenji , Matsuura Tetsuya , Fuyuki Akiko , Ohkubo Hidenori , Chiba Hideyuki , Nakajima Atsushi
Published: January 2021

Background and Aim

During endoscopic submucosal dissection for superficial esophageal cancer, patient body movement can sometimes occur, which may cause discontinuation of the procedure. Propofol and dexmedetomidine have recently been found to be useful sedatives for endoscopic submucosal dissection. This study investigated whether sedation using propofol plus dexmedetomidine can suppress the patient's body movements during esophageal endoscopic submucosal dissection and compared this combination with sedation using propofol alone.

Methods

This was a prospective double‐blind randomized controlled trial. Patients with superficial esophageal cancers who underwent esophageal endoscopic submucosal dissection at Yokohama City University Hospital were prospectively enrolled and were randomly assigned to the propofol and the propofol plus dexmedetomidine groups. The primary endpoint was the incidence of restlessness. The secondary endpoints were the satisfaction score, maintenance dose of propofol, and number of rescue propofol injections.

Results

Sixty‐six patients (propofol group: n = 33; combination group: n = 33) were included. The combination group had a significantly lower incidence of restlessness than the propofol group (3.0% vs 27.3%, P = 0.02). In the combination group, the satisfaction scores of the endoscopists were significantly higher, the maintenance dose of propofol was significantly lower, and the number of rescue propofol injections was lower than those in the propofol group (3.0% vs 18.2%, P < 0.001). Although the incidence of bradycardia was significantly higher in the combination group (30.3% vs 3.0%, P < 0.01), no serious adverse effects occurred.

Conclusion

The propofol plus dexmedetomidine combination provided excellent sedation that effectively suppressed the patient's body movements during esophageal endoscopic submucosal dissection.
Therapist effects on dropout in couple therapy
Authors: Willis Kwin L. , Miller Richard B. , Anderson Shayne R. , Bradford Angela B. , Johnson Lee N. , Yorgason Jeremy B.
Published: January 2021

Marriage and family therapy scholars have argued that therapists play a crucial role in successful couple therapy, yet little research has empirically documented that the therapist in couple therapy has a significant impact on outcomes. Known as the study of therapist effects, this study sought to assess the amount of variance attributed to the therapist in couple therapy outcomes. Using dropout as the outcome variable, this study analyzed data from 1,192 couples treated by 90 masters and doctoral student therapists at a university‐based training clinic. Results from multilevel analysis indicated that therapists in the sample accounted for 9.4% of the variance in couple dropout while controlling for initial couple impairment. Therapist gender and therapist experience did not significantly predict variability in therapist effects. These findings give promise to future research on therapist effects in couple therapy and encourage exploration into which therapist characteristics and behaviors contribute to successful clinical outcome.
Stress as cause of signs and symptoms of pseudo‐Cushing’s syndrome in buffy‐tufted marmosets (Callithrix aurita)
Authors: Orsini Heloísa , Castellano Viviane B. D. , Kokubun Hanna S. , Lopes Karla A. R. , Velho Nádia M. R. C.
Published: January 2021

Hyperadrenocorticism is a medical condition caused by the increase in cortisol production by the cortex of the adrenal gland. Although infrequently described in most animal species, its naturally occurring form, called Cushing's syndrome, is the most prevalent endocrinopathy in dogs. Cushing's syndrome is also present in humans and might be confused with the pseudo‐Cushing's syndrome (PCS), rarely described in animals. PCS shares many of the clinical and biochemical features of Cushing's syndrome. However, the hypercortisolemia seen is usually idiopathic and, in some circumstances, associated with psychological disruptions. This report describes PCS‐like disorder in two marmosets Callithrix aurita that were exposed to environmental changes, suggesting stress as the main cause of the process and reviewing the mechanisms involved in the pathogeny of the two syndromes.
THE INTELLECTUAL IDEAS INSIDE CENTRAL BANKS: WHAT'S CHANGED (OR NOT) SINCE THE CRISIS?
Authors: Windsor Callan
Published: January 2021

I explore how the intellectual ideas inside central banks have shifted over the first two decades of the new century. To do this I collect every research paper published by advanced economy central banks and examine them using tools from computational linguistics. The analysis points to a shift in the intellectual focus, from a relatively macroeconomic perspective towards a less aggregated view. In part, these changes seem to reflect lessons from the 2008 financial crisis – for example, that macroeconomic models can only get you so far and that microeconomic data are useful for teasing out the causes of aggregate fluctuations. There has been an increase in the amount of research dedicated to the banking and household sectors and a reduction in the amount of intellectual effort invested in modelling the macroeconomy – though some of these shifts had already begun before the crisis. Consistent with this, the similarity of central banking research to that published in top macroeconomic journals has been widening since the crisis.
Protein modification: A critical modulator in the interaction between geminiviruses and host plants
Authors: Liu Xiaoshi , Huang Wei , Zhai Zhenqian , Ye Tushu , Yang Chengwei , Lai Jianbin
Published: January 2021

Geminiviruses are a large group of single‐stranded DNA viruses that infect plants and cause severe agricultural losses worldwide. Given geminiviruses only have small genomes that encode a few proteins, viral factors have to interact with host components to establish an environment suitable for virus infection, whilst the host immunity system recognizes and targets these viral components during infection. Post‐translational protein modifications, such as phosphorylation, lipidation, ubiquitination, SUMOylation, acetylation and methylation, have been reported to be critical during the interplay between host plants and geminiviruses. Here we summarize the research progress, including phosphorylation and lipidation which usually control the activity and localization of viral factors; as well as ubiquitination and histone modification which are predominantly interfered with by viral components. We also discuss the dynamic competition on protein modifications between host defence and geminivirus efficient infection, as well as potential applications of protein modifications in geminivirus resistance. The summary and perspective of this topic will improve our understanding on the mechanism of geminivirus‐plant interaction and contribute to further protection of plants from virus infection.
Natural history and mechanisms of COPD
Authors: Lange Peter , Ahmed Engi , Lahmar Zakaria Mohamed , Martinez Fernando J. , Bourdin Arnaud
Published: January 2021

The natural history of COPD is complex, and the disease is best understood as a syndrome resulting from numerous interacting factors throughout the life cycle with smoking being the strongest inciting feature. Unfortunately, diagnosis is often delayed with several longitudinal cohort studies shedding light on the long ‘preclinical’ period of COPD. It is now accepted that individuals presenting with different COPD phenotypes may experience varying natural history of their disease. This includes its inception, early stages and progression to established disease. Several scenarios regarding lung function course are possible, but it may conceptually be helpful to distinguish between individuals with normal maximally attained lung function in their early adulthood who thereafter experience faster than normal FEV1 decline, and those who may achieve a lower than normal maximally attained lung function. This may be the main mechanism behind COPD in the latter group, as the decline in FEV1 during their adult life may be normal or only slightly faster than normal. Regardless of the FEV1 trajectory, continuous smoking is strongly associated with disease progression, development of structural lung disease and poor prognosis. In developing countries, factors such as exposure to biomass and sequelae after tuberculosis may lead to a more airway‐centred COPD phenotype than seen in smokers. Mechanistically, COPD is characterized by a combination of structural and inflammatory changes. It is unlikely that all patients share the same individual or combined mechanisms given the heterogeneity of resultant phenotypes. Lung explants, bronchial biopsies and other tissue studies have revealed important features. At the small airway level, progression of COPD is clinically imperceptible, and the pathological course of the disease is poorly described. Asthmatic features can further add confusion. However, the small airway epithelium is likely to represent a key focus of the disease, combining impaired subepithelial crosstalk and structural/inflammatory changes. Insufficient resolution of inflammatory processes may facilitate these changes. Pathologically, epithelial metaplasia, inversion of the goblet to ciliated cell ratio, enlargement of the submucosal glands and neutrophil and CD8‐T‐cell infiltration can be detected. Evidence of type 2 inflammation is gaining interest in the light of new therapeutic agents. Alarmin biology is a promising area that may permit control of inflammation and partial reversal of structural changes in COPD. Here, we review the latest work describing the development and progression of COPD with a focus on lung function trajectories, exacerbations and survival. We also review mechanisms focusing on epithelial changes associated with COPD and lack of resolution characterizing the underlying inflammatory processes.
Renewing the Auld Alliance: Marie Stuart’s poetics and the Catholic League’s politics☆
Authors: DeVos Jessica Erin
Published: January 2021

Few historical sovereigns’ political fate and posthumous image have been as influenced by creative literature as those of Marie, Queen of Scots, yet comparatively little attention has been paid to how she depicted herself in her own poetry. Most research devoted to her verse over the past two decades has been undertaken by scholars of English literature, despite the fact that Marie Stuart was neither English, nor did she write poetry in that language. Acknowledging that Marie considered France her homeland and French her mother tongue, this article examines the poems contained in Oxford MS. Add C.92, fol.22 as works of Francophone literature and situates them within a transnational historical context that has also been understudied: the intersection of the English Catholic exile cause in Paris with the politics and propaganda of France’s Catholic League, led by Marie’s cousin, Henri, Duke of Guise. It seeks to clarify not only the language and meaning of the poems themselves, but also to highlight how they draw from and contribute to a larger pool of French poetic and political discourse during the French Wars of Religion.