bluuebunny/crossref_metadata_2025_split huggingface dataset:
The TrkA agonist gambogic amide augments skeletal adaptation to mechanical loading through actions on sensory nerves and osteoblasts
Authors: Fioravanti Gabriella , Hua Phuong Q. , Tomlinson Ryan E. 
Published: August 2020

ABSTRACTThe periosteal and endosteal surfaces of mature bone are densely innervated by sensory nerves expressing TrkA, the high-affinity receptor for nerve growth factor (NGF). In previous work, we demonstrated that administration of exogenous NGF significantly increased load-induced bone formation through the activation of Wnt signaling. However, the translational potential of NGF is limited by the induction of substantial mechanical and thermal hyperalgesia in mice and humans. Here, we tested the effect of gambogic amide (GA), a recently identified robust small molecule agonist for TrkA, on hyperalgesia and load-induced bone formation. Behavioral analysis was used to assess pain up to one week after axial forelimb compression. Contrary to our expectations, GA treatment was not associated with diminished use of the loaded forelimb or sensitivity to thermal stimulus. Furthermore, dynamic histomorphometry revealed a significant increase in relative periosteal bone formation rate as compared to vehicle treatment. Additionally, we found that GA treatment was associated with an increase in the number of osteoblasts per bone surface in loaded limbs as well as a significant upregulation ofWnt1, Wnt7b, andNgfin loaded bones. To determine if these effects were exclusively mediated by NGF-TrkA signaling in sensory nerves, we cultured MC3T3-E1 cells for 7 or 14 days in osteogenic differentiation media containing NGF (50 ng/mL), GA (5, 50, or 500 nM), or vehicle (DMSO). After 7 days of culture, we observed increases in osteoblastic differentiation markersRunx2, Bglap2, andSp7in response to GA, whereas treatment with NGF was not different than vehicle. Only cells treated with the highest dose of GA (500 nM) had significantly impaired cell proliferation. In conclusion, our study indicates GA may be useful for augmenting skeletal adaptation to mechanical forces without inducing hyperalgesia through actions on both sensory nerves and osteoblasts.
LPAandAPOEare associated with statin selection in the UK Biobank
Authors: Lavertu Adam , McInnes Gregory , Tanigawa Yosuke , Altman Russ B , Rivas Manuel A. 
Published: August 2020

AbstractGenetics plays a key role in drug response, affecting efficacy and toxicity. Pharmacogenomics aims to understand how genetic variation influences drug response and develop clinical guidelines to aid clinicians in personalized treatment decisions informed by genetics. Although pharmacogenomics has not been broadly adopted into clinical practice, genetics influences treatment decisions regardless. Physicians adjust patient care based on observed response to medication, which may occur as a result of genetic variants harbored by the patient. Here we seek to understand the genetics of drug selection in statin therapy, a class of drugs widely used for high cholesterol treatment. Genetics are known to play an important role in statin efficacy and toxicity, leading to significant changes in patient outcome. We performed genome-wide association studies (GWAS) on statin selection among 59,198 participants in the UK Biobank and found that variants known to influence statin efficacy are significantly associated with statin selection. Specifically, we find that carriers of variants inAPOEandLPAthat are known to decrease efficacy of treatment are more likely to be on atorvastatin, a stronger statin. Additionally, carriers of theAPOEandLPAvariants are more likely to be on a higher intensity dose (a dose that reduces low-density lipoprotein cholesterol by greater than 40%) of atorvastatin than non-carriers (APOE:p(high intensity)= 0.16, OR = 1.7,P= 1.64 × 10−4,LPA:p(high intensity)= 0.17, OR = 1.4,P= 1.14 × 10−2). These findings represent the largest genetic association study of statin selection and statin dose association to date and provide evidence for the role ofLPAandAPOEin statin response, furthering the possibility of personalized statin therapy.
Pathogenic Mechanisms Underlying Stargardt Macular Degeneration Linked to Mutations in the Transmembrane Domains of ABCA4
Authors: Garces Fabian A. , Scortecci Jessica F. , Molday Robert S. 
Published: August 2020

AbstractABCA4 is an ATP-binding cassette (ABC) transporter predominantly expressed in photoreceptors where it transports the substrate N-retinylidene-phosphatidylethanolamine across disc membranes thereby facilitating the clearance of retinal compounds from photoreceptor outer segments. Loss of function mutations in ABCA4 cause the accumulation of bisretinoids leading to Stargardt disease (STGD1) and other retinopathies. In this study, we examined the expression and functional properties of ABCA4 harboring disease-causing missense mutations in the two transmembrane domains (TMDs) of ABCA4. Our results indicate that these mutations lead to protein misfolding, loss in substrate binding, decreased ATPase activity or a combination of these properties. Additionally, we identified an arginine (R653) in transmembrane segment 2 of ABCA4 as a residue essential for substrate binding and substrate-stimulated ATPase activity. The expression and functional activity of the TMD variants correlate well with the severity of STGD1. Our studies provide a basis for developing and evaluating novel treatments for STGD1.
G-quadruplex-forming sequences as potential drivers of genetic diversity in primate protein coding genes
Authors: Jara-Espejo Manuel , Line Sergio Roberto Peres 
Published: August 2020

ABSTRACTWhile non-coding G-quadruplexes (G4s) act as conserved regulatory elements when located in gene promoter and splice sites, the G4 evolutionary conservation in protein coding regions have been low explored. To address the evolutionary dynamics acting on coding G4, we mapped and characterized potential G4-forming sequences across twenty-four primate’s gene orthologous. We found that potentially more stable G4 motifs exist in coding regions following a species-specific trend. Moreover, these motifs depicted the least conserved sites across primates at both the DNA and amino acid levels and are characterized by an indel-rich mutational pattern. This trend was not observed for less stable G4 motifs. A deeper analysis revealed that [G>=3N1]4motifs, depicting potentially most stable G4s, were associated with the lowest conservation and highest indel frequencies. This mutational pattern was more evident when G4-associated amino acid regions were analyzed. We discuss the possibility of an overall conservation of less/moderate stability G4, while more stable G4 may be preserved or arises in a species-specific manner, which may explain their low conservation. Since structure-prone motifs, including G4, have the potential to induce genomic instability, this evolutionary trend may contribute to avoid broad deleterious effects driven by stable G4 on protein function while promoting genetic diversity across close-related species.
Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer
Authors: Chang Che-wei Anderson , Jen Jayu , Jiang Shaowen , Sayad Azin , Mer Arvind Singh , Brown Kevin R. , Nixon Allison , Dhabaria Avantika , Tang Kwan Ho , Venet David , Sotiriou Christos , Deng Jiehue , Wong Kwok-kin , Adams Sylvia , Meyn Peter , Heguy Adriana , Skok Jane , Tsirigos Aristotelis , Ueberheide Beatrix , Moffat Jason , Singh Abhyudai , Haibe-Kains Benjamin , Khodadadi-Jamayran Alireza , Neel Benjamin G. 
Published: August 2020

ABSTRACTResistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. “Drug-tolerant persisters” (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single cell RNA-sequencing reveal that HER2+ breast cancer cells cycle stochastically through a “pre-DTP” state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting show that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction ofSGK3,leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.STATEMENT OF SIGNIFICANCEDTPs are implicated in resistance to TKIs, other targeted therapies, and chemotherapy, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells (“pre-DTPs”) that preferentially engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and identify potential therapeutic vulnerabilities.
The limits of Thai hospitality – perceived impact of tourism development on residents’ well-being in Chiang Mai
Authors: Koh Edward , Fakfare Pipatpong , Pongwat Arunotai 
Published: August 2020

Purpose
This paper aims to assess the various impacts of tourism development in Chiang Mai on the local populace’s sense of well-being. The moderating effect of employment in and affiliation with the tourism industry on perception of tourism development is also examined.

Design/methodology/approach
A sequential explanatory mixed method design is adopted, beginning with the development of a conceptual model that links residents’ perceived impact of tourism development with their general and life domain-specific well-beings. The model is tested with a survey of 567 respondents who are long-term residents of Chiang Mai. The findings are subsequently used in the semi-structured in-depth interviews with selected tourism stakeholders to provide qualitative explanation and meaning to the data.

Findings
The results suggest a reciprocal relationship between perceived economic, cultural and environmental impact of tourism development and Chiang Mai residents’ general sense of well-being. It also revealed that community well-being and material well-being accounted the most and the least, respectively, on overall well-being for Chiang Mai residents. Another interesting observation was that Chiang Mai residents feel the same way about the various perceived impact of tourism development on overall sense of well-being, regardless of whether they are employed or affiliated with the tourism industry or otherwise.

Originality/value
With limited literature on the perceived impact of tourism development by residents in Asia, this research provides a Thai perspective of the said impact on general well-being. A sequential explanatory mixed method provides an added lens to induce insights and explain the results deduced from the earlier quantitative study.
Characteristics of Japanese patients with eosinophilic fasciitis: A brief multicenter study
Authors: Yamamoto Toshiyuki , Ito Takashi , Asano Yoshihide , Sato Shinichi , Motegi Sei‐ichiro , Ishikawa Osamu , Matsushita Takashi , Takehara Kazuhiko , Makino Takamitsu , Okiyama Naoko , Fujimoto Manabu , Jinnin Masatoshi , Ihn Hironobu 
Published: August 2020

AbstractEosinophilic fasciitis is a relatively rare cutaneous fibrotic condition affecting the deep fascia of the extremities, with or without peripheral blood eosinophilia. To examine the characteristics of Japanese patients with eosinophilic fasciitis, we conducted a brief, multicenter, retrospective survey at seven university hospitals. In total, 31 patients were identified as having eosinophilic fasciitis, among whom 30 patients fulfilled the Japanese diagnostic criteria. The male : female ratio was 2.3:1, and the mean age was 47.7 years. Three of the patients were under 20 years old. The possible triggering factors included muscle training, sports, walking or sitting for a long time, physical work, insect bite and drug. Co‐occurrence of morphea was observed in nine cases (29%), and malignancies were associated in three (two hematological malignancies and one internal malignancy). Immunological abnormalities in the serum showed positive antinuclear antibody, positive rheumatoid factor, increased aldolase levels and increased immunoglobulin G levels. The patients were treated with either monotherapy or combination therapy by oral prednisolone (20–80 mg/day), methotrexate (6–10 mg/week), cyclosporin (100–150 mg/day), mizoribine, infliximab and phototherapy. Methylprednisolone pulse therapy was performed in six cases. By contrast, spontaneous improvement due to resting only was observed in two cases, and skin hardening was improved by withdrawal of the anticancer drug in one case. This study suggests several characteristics of Japanese patients with eosinophilic fasciitis, namely male predominance, rare pediatric occurrence, immunological abnormalities and coexistence with morphea. Systemic prednisolone is the first‐line therapy, but pulse therapy is occasionally required for severe cases. The triggering events of physical stress are not so frequent as have previously been reported, and various factors or even unknown factors may be associated with the induction of eosinophilic fasciitis.
Severe eczematoid and lichenoid eruption with full‐thickness epidermal necrosis developing from metastatic urothelial cancer treated with enfortumab vedotin
Authors: Sasaki Rui , Fujimura Taku , Lyu Chunbing , Aiba Setsuya 
Published: August 2020

AbstractEnfortumab vedotin (EV) is a novel, fully humanized monoclonal antibody–drug conjugate composed of an anti‐Nectin‐4 antibody joined to monomethyl auristatin E. In this report, we described a case of a severe eczematoid and lichenoid eruption with full‐thickness epidermal necrosis developing in patients with metastatic urothelial cancer treated with EV. Because phase II and phase III clinical studies are ongoing, in the future, substantial amounts of EV are expected to be used for the treatment of metastatic urothelial cancer. Therefore, understanding the mechanisms of drug eruption caused by EV is important for oncologists as well as dermatologists.
A multidimensional approach to the expression of phenotypic plasticity
Authors: Morel‐Journel Thibaut , Thuillier Virginie , Pennekamp Frank , Laurent Estelle , Legrand Delphine , Chaine Alexis S. , Schtickzelle Nicolas 
Published: August 2020

AbstractPhenotypic plasticity is increasingly recognized as a key element of eco‐evolutionary dynamics, but it remains challenging to assess because of its multidimensional nature. Indeed, organisms live in complex environments where numerous factors can impact the phenotypic expression of traits (inter‐environment axis), possess multiple traits that can influence each other's expression (inter‐trait axis) and differ in their genetic background (inter‐genotype axis), which can not only impact the traits' values but also their plasticity.We addressed six questions related to phenotypic plasticity: (a) do different environmental gradients show similar effects on a given trait? (b) Are the effects of two environmental gradients on a trait additive? (c) Do different traits show similar plastic response to a given environmental gradient? (d) Do the (co)variances between traits vary across environmental gradients? (e) Do genotypes differ in their plastic response to a given environmental gradient? (f) Are some genotypes more plastic than others across all traits?We designed a microcosm experiment using the protistTetrahymena thermophilaaimed at encompassing all these aspects of phenotypic plasticity. We exposed 15 distinct genotypes to 25 combinations of temperature and nutrient availability and assessed the plasticity of five phenotypic traits.Our results show strong differences in the plastic response depending on the environmental gradient, not only regarding the shape of the reaction norm of the different traits tested, but also in the overall plasticity of the organisms. We did not find any covariance between traits that was consistent across all environments.Overall, our results suggest independent impacts of the environmental dimension considered on the observed plastic response. These results underline potential difficulties in generalizing findings about plasticity to all environments and all traits.A freePlain Language Summarycan be found within the Supporting Information of this article.
Climate change and defoliation interact to affect root length across northern temperate grasslands
Authors: Ma Zilong , Chang Scott X. , Bork Edward W. , Steinaker Diego F. , Wilson Scott D. , White Shannon R. , Cahill James F. 
Published: August 2020

Abstract

Grassland plants, especially their root systems, are dynamic and can buffer changes resulting from exposure to multiple stressors; however, the interactive stressor effects on root dynamics and associated above‐ground growth are poorly understood.

Here, we examine the effects of changed precipitation and air temperature, and defoliation intensity on root length dynamics and above‐ground biomass using the third year data from a multifactor experiment conducted across three northern temperate grasslands.

We found that root length was more sensitive to the changes in environmental and management conditions than root mass, demonstrating the importance of root length as an indicator of rapid root system changes. Across all sites, warming, altered precipitation and defoliation intensity interacted to affect root length while above‐ground biomass was only affected by defoliation intensity, indicating that the root system was more responsive than above‐ground biomass when climatic conditions change. Overall, drought reduced root length, particularly under low defoliation intensity, as well as in combination with warming and heavy defoliation, highlighting the risk of additive effects of such environmental stresses. Across unclipped plots, above‐ground biomass was positively associated with total root length, the latter of which further interacted with precipitation, to affect above‐ground biomass. Compared to defoliated communities, non‐defoliated plant communities exhibited a greater ability to maintain above‐ground biomass under drought conditions via increases in root system efficiency (the amount of above‐ground biomass produced per unit of root length invested).

Our results highlight the rapid change of root length in the face of interactive stressors. We postulate that the degree of stability in above‐ground biomass is driven by the altered root system dynamics or species turnover. Future studies are warranted that more directly assess how root length responses under climate change impact other important plant traits in grasslands.

A free Plain Language Summary can be found within the Supporting Information of this article.
Convolutional neural networks for automated microseismic detection in downhole distributed acoustic sensing data and comparison to a surface geophone array
Authors: Binder Gary , Tura Ali 
Published: August 2020

ABSTRACTDistributed acoustic sensing is a growing technology that enables affordable downhole recording of strain wavefields from microseismic events with spatial sampling down to ∼1 m. Exploiting this high spatial information density motivates different detection approaches than typically used for downhole geophones. A new machine learning method using convolutional neural networks is described that operates on the full strain wavefield. The method is tested using data recorded in a horizontal observation well during hydraulic fracturing in the Eagle Ford Shale, Texas, and the results are compared to a surface geophone array that simultaneously recorded microseismic activity. The neural network was trained using synthetic microseismic events injected into real ambient noise, and it was applied to detect events in the remaining data. There were 535 detections found and no false positives. In general, the signal‐to‐noise ratio of events recorded by distributed acoustic sensing was lower than the surface array and 368 of 933 surface array events were found. Despite this, 167 new events were found in distributed acoustic sensing data that had no detected counterpart in the surface array. These differences can be attributed to the different detection threshold that depends on both magnitude and distance to the optical fibre. As distributed acoustic sensing data quality continues to improve, neural networks offer many advantages for automated, real‐time microseismic event detection, including low computational cost, minimal data pre‐processing, low false trigger rates and continuous performance improvement as more training data are acquired.
Adaptive differentiation of growth, energetics and behaviour between piscivore and insectivore juvenile rainbow trout along the Pace‐of‐Life continuum
Authors: Monnet Gauthier , Rosenfeld Jordan S. , Richards Jeffrey G. 
Published: August 2020

Abstract

Adaptive trade‐offs are fundamental mechanisms underlying phenotypic diversity, but the presence of generalizable patterns in multivariate adaptation and their mapping onto environmental gradients remain unclear.

To understand how life history affects multivariate trait associations, we examined relationships among growth, metabolism, anatomy and behaviour in rainbow trout juveniles from piscivore versus insectivore ecotypes along an experimental gradient of food availability. We hypothesized that (a) selection for larger size in piscivorous adults would select for higher juvenile growth at the cost of lower active metabolism; (b) elevated growth of piscivores would be supported by a greater productivity of their natal stream and more proactive foraging behaviours and (c) general patterns of multivariate trait associations would match the predictions of the Pace‐Of‐Life Syndrome.

Relative to insectivores, piscivorous fry showed a pattern of higher growth (+63%), maximum food intake (+33%), growth efficiency (+41%) and standard metabolic rate (SMR; +47%), but lower active metabolic capacity (maximum metabolic rate [MMR; −17%], aerobic scope [AS; −48%]), suggesting that faster piscivore growth is supported by greater food intake and digestive capacity but is traded‐off against lower scope for active metabolism. A similar trade‐off appeared among organ systems, with piscivorous fry exhibiting an 83% greater investment in average mass of organs associated with food consumption and processing (i.e. stomach and intestine), but an apparently smaller relative investment in organs involved in cardiovascular or cognitive activities (heart and brain, respectively). Higher invertebrate drift in their natal rearing habitat, quicker behavioural transition to a novel food source and lower anxiety after a frightening event in piscivorous fry suggest that faster growth requires both proactive foraging behaviours and higher prey availability in the environment. Finally, the sampling of replicate insectivore populations confirmed their lower juvenile growth (−73% on average) and reduced environmental productivity of their natal streams (−45% lower drift abundance) relative to the piscivore ecotype.

Our results suggest that selection for large adult body size influences selection on high juvenile growth, high basal metabolism and proactive behaviours, and that the intense phenotypic divergence between piscivorous and insectivorous rainbow trout may be constrained by environmental productivity.