bluuebunny/crossref_metadata_2025_split huggingface dataset:
A synthesis of pathways linking diet, metabolic risk and cardiovascular disease: a framework to guide further research and approaches to evidence-based practice
Authors: Lima do Vale Marjorie Rafaela , Buckner Luke , Mitrofan Claudia Gabriela , Tramontt Claudia Raulino , Kargbo Sento Kai , Khalid Ali , Ashraf Sammyia , Mouti Saad , Dai Xiaowu , Unwin David , Bohn Jeffrey , Goldberg Lisa , Golubic Rajna , Ray Sumantra 
Published: November 2021

AbstractCardiovascular disease (CVD) is the most common non-communicable disease occurring globally. Although previous literature has provided useful insights into the important role that diet plays in CVD prevention and treatment, understanding the causal role of diets is a difficult task considering inherent and introduced weaknesses of observational (e.g. not properly addressing confounders and mediators) and experimental research designs (e.g. not appropriate or well designed). In this narrative review, we organised current evidence linking diet, as well as conventional and emerging physiological risk factors, with CVD risk, incidence and mortality in a series of diagrams. The diagrams presented can aid causal inference studies as they provide a visual representation of the types of studies underlying the associations between potential risk markers/factors for CVD. This may facilitate the selection of variables to be considered and the creation of analytical models. Evidence depicted in the diagrams was systematically collected from studies included in the British Nutrition Task Force report on diet and CVD and database searches, including Medline and Embase. Although several markers and disorders linked to conventional and emerging risk factors for CVD were identified, the causal link between many remains unknown. There is a need to address the multifactorial nature of CVD and the complex interplay between conventional and emerging risk factors with natural and built environments, while bringing the life course into the spotlight.
Not-negation revisited: variation betweenaandanyin verb complements in contemporary spoken American English
Authors: TOTTIE GUNNEL 
Published: November 2021

Innot-negated English sentences with indefinite expressions following the verb, there is variation between the indefinite article andanyas determiners of nouns. The standard view is that singular count nouns take the indefinite article and singular non-count and plural nouns takeany.However, it is possible to encounter examples likeit isn'tany threat,there isn'tany lockorI don't haveany problem.The article studies variation between the indefinite article andanyas post-verbal determiners of singular nouns in 21,084not-negated sentences in the spoken component ofThe Corpus of Contemporary American English, COCA SPOK. The indefinite article is dominant with 90 per cent of the tokens. Variation is extremely rare in sentences with copularbeand much more frequent in sentences with existentialbeandhave. Among the reasons for variation between verb types is the use ofdo-support withhave(but not withbe). Expressions such ashave a job/car/homeorthere's not a/anwith uncontractednotmay also prevent the use ofany.Variation occurs mostly with abstract nouns such asproblem,choice,way,place,reason. This finding is surprising as abstract nouns have rarely been discussed in the literature on varying countability of nouns.
Economic freedom improves income mobility: evidence from Canadian provinces, 1982–2018
Authors: Dean James , Geloso Vincent 
Published: November 2021

AbstractEconomic freedom is robustly associated with income growth, but does this association extend to the poorest in a society? In this paper, we employ Canada's longitudinal cohorts of income mobility between 1982 and 2018 to answer this question. We find that economic freedom, as measured by the Fraser Institute's Economic Freedom of North America (EFNA) index, is positively associated with multiple measures of income mobility for people in the lowest income deciles, including (a) absolute income gain; (b) the percentage of people with rising income; and (c) average decile mobility. For the overall population, economic freedom has weaker effects.
Regulation of MDM2 E3 ligase-dependent vascular calcification by MSX1/2
Authors: Kwon Duk-Hwa , Choe Nakwon , Shin Sera , Ryu Juhee , Kim Nacksung , Eom Gwang Hyeon , Nam Kwang-Il , Kim Hyung Seok , Ahn Youngkeun , Kim Young-Kook , Park Woo Jin , Mendrysa Susan M. , Kook Hyun 
Published: November 2021

AbstractVascular calcification increases morbidity and mortality in patients with cardiovascular and renal diseases. Previously, we reported that histone deacetylase 1 prevents vascular calcification, whereas its E3 ligase, mouse double minute 2 homolog (MDM2), induces vascular calcification. In the present study, we identified the upstream regulator of MDM2. By utilizing cellular models and transgenic mice, we confirmed that E3 ligase activity is required for vascular calcification. By promoter analysis, we found that both msh homeobox 1 (Msx1) and msh homeobox 2 (Msx2) bound to the MDM2 promoter region, which resulted in transcriptional activation of MDM2. The expression levels of both Msx1 and Msx2 were increased in mouse models of vascular calcification and in calcified human coronary arteries. Msx1 and Msx2 potentiated vascular calcification in cellular and mouse models in an MDM2-dependent manner. Our results establish a novel role for MSX1/MSX2 in the transcriptional activation of MDM2 and the resultant increase in MDM2 E3 ligase activity during vascular calcification.
The effects of altered BMP4 signaling in first branchial-arch-derived murine embryonic orofacial tissues
Authors: Xu Jue , Chen Meiling , Yan Yanan , Zhao Qiaoxue , Shao Meiying , Huang Zhen 
Published: November 2021

AbstractThe first branchial arch (BA1), which is derived from cranial neural crest (CNC) cells, gives rise to various orofacial tissues. Cre mice are widely used for the determination of CNC and exploration of gene functions in orofacial development. However, there is a lack of Cre mice specifically marked BA1’s cells. Pax2-Cre allele was previously generated and has been widely used in the field of inner ear development. Here, by compounding Pax2-Cre and R26R-mTmG mice, we found a specific expression pattern of Pax2+ cells that marked BA1’s mesenchymal cells and the BA1-derivatives. Compared to Pax2-Cre; R26R-mTmG allele, GFP+ cells were abundantly found both in BA1 and second branchial arch in Wnt1-Cre;R26R-mTmG mice. As BMP4 signaling is required for orofacial development, we over-activated Bmp4 by using Pax2-Cre; pMes-BMP4 strain. Interestingly, our results showed bilateral hyperplasia between the upper and lower teeth. We also compare the phenotypes of Wnt1-Cre; pMes-BMP4 and Pax2-Cre; pMes-BMP4 strains and found severe deformation of molar buds, palate, and maxilla-mandibular bony structures in Wnt1-Cre; pMes-BMP4 mice; however, the morphology of these orofacial organs were comparable between controls and Pax2-Cre; pMes-BMP4 mice except for bilateral hyperplastic tissues. We further explore the properties of the hyperplastic tissue and found it is not derived from Runx2+ cells but expresses Msx1, and probably caused by abnormal cell proliferation and altered expression pattern of p-Smad1/5/8. In sum, our findings suggest altering BMP4 signaling in BA1-specific cell lineage may lead to unique phenotypes in orofacial regions, further hinting that Pax2-Cre mice could be a new model for genetic manipulation of BA1-derived organogenesis in the orofacial region.
Is tumour volume an independent predictor of outcome after radical prostatectomy for high-risk prostate cancer?
Authors: Raison Nicholas , Servian Pol , Patel Amit , Santhirasekaram Ainkaran , Smith Andrew , Yeung Maidie , Lloyd Josephine , Mannion Ethna , Rockall Andrea , Ahmed Hashim , Winkler Mathias 
Published: November 2021

Abstract
Background
Preoperative PSA, ISUP grade group (GG), prostate examination and multiparametric MRI (mpMRI) form the basis of prostate cancer staging. Unlike other solid organ tumours, tumour volume (TV) is not routinely used aside from crude estimates such as maximum cancer core length. The aim of this study is to assess the role of TV as a marker for oncological outcomes in high-risk non-metastatic prostate cancer.

Methods
A prospectively maintained database of patients undergoing minimally invasive (laparoscopic or robot-assisted laparoscopic) radical prostatectomy at a UK centre between 2007 and 2019 were analysed. A total of 251 patients with NCCN high or very high-risk prostate cancer were identified. Primary outcome measure was time to biochemical recurrence (BCR) and the secondary outcome was time to treatment failure (TTF). TV was measured on the pathological specimen using the stacking method. Multivariable cox regression analysis was used to identify factors predicting BCR and TFF. TV as a predictor of BCR and TFF was further analysed through time-dependent receiver operating characteristic (ROC) curves. Kaplan–Meier survival estimates were used to evaluate TV cut-off scores.

Results
Median follow up was 4.50 years. Four factors were associated with BCR and TFF on multivariable analysis (TV, pathological GG, pathological T stage, positive margin >3 mm). Area under the Curve (AUC) for TV as a predictor of BCR and TTF at 5 years was 0.71 and 0.75, respectively. Including all 4 variables in the model increased AUC to 0.84 and 0.85 for BCR and TFF. A 2.50 cm TV cut off demonstrated a significance difference in time to BCR, p < 0.001.

Conclusions
Pathological tumour volume is an independent predictor of oncological outcomes in high risk prostate cancer but does not add significant prognostic value when combined with established variables. However, the option of accurate TV measurement on mpMRI raises the possibility of using TV as useful marker for preoperative risk stratification.
Nicotinamide promotes cardiomyocyte derivation and survival through kinase inhibition in human pluripotent stem cells
Authors: Meng Ya , Song Chengcheng , Ren Zhili , Li Xiaohong , Yang Xiangyu , Ai Nana , Yang Yang , Wang Dongjin , Zhan Meixiao , Wang Jiaxian , LEI Chon Lok , Liu Weiwei , Ge Wei , Lu Ligong , Chen Guokai 
Published: November 2021

AbstractNicotinamide, the amide form of Vitamin B3, is a common nutrient supplement that plays important role in human fetal development. Nicotinamide has been widely used in clinical treatments, including the treatment of diseases during pregnancy. However, its impacts during embryogenesis have not been fully understood. In this study, we show that nicotinamide plays multiplex roles in mesoderm differentiation of human embryonic stem cells (hESCs). Nicotinamide promotes cardiomyocyte fate from mesoderm progenitor cells, and suppresses the emergence of other cell types. Independent of its functions in PARP and Sirtuin pathways, nicotinamide modulates differentiation through kinase inhibition. A KINOMEscan assay identifies 14 novel nicotinamide targets among 468 kinase candidates. We demonstrate that nicotinamide promotes cardiomyocyte differentiation through p38 MAP kinase inhibition. Furthermore, we show that nicotinamide enhances cardiomyocyte survival as a Rho-associated protein kinase (ROCK) inhibitor. This study reveals nicotinamide as a pleiotropic molecule that promotes the derivation and survival of cardiomyocytes, and it could become a useful tool for cardiomyocyte production for regenerative medicine. It also provides a theoretical foundation for physicians when nicotinamide is considered for treatments for pregnant women.
MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging
Authors: Yang Yun-Fei , Yang Wu , Liao Zhi-Yin , Wu Yong-Xin , Fan Zhen , Guo Ai , Yu Jing , Chen Qiu-Nan , Wu Jiang-Hao , Zhou Jing , Xiao Qian 
Published: November 2021

AbstractAge-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by d-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.
Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy
Authors: Marcelo Adriana , Afonso Inês T. , Afonso-Reis Ricardo , Brito David V. C. , Costa Rafael G. , Rosa Ana , Alves-Cruzeiro João , Ferreira Benedita , Henriques Carina , Nobre Rui J. , Matos Carlos A. , de Almeida Luís Pereira , Nóbrega Clévio 
Published: November 2021

AbstractSpinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients’ striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.
Phase segregation in mixed-halide perovskites affects charge-carrier dynamics while preserving mobility
Authors: Motti Silvia G. , Patel Jay B. , Oliver Robert D. J. , Snaith Henry J. , Johnston Michael B. , Herz Laura M. 
Published: November 2021

AbstractMixed halide perovskites can provide optimal bandgaps for tandem solar cells which are key to improved cost-efficiencies, but can still suffer from detrimental illumination-induced phase segregation. Here we employ optical-pump terahertz-probe spectroscopy to investigate the impact of halide segregation on the charge-carrier dynamics and transport properties of mixed halide perovskite films. We reveal that, surprisingly, halide segregation results in negligible impact to the THz charge-carrier mobilities, and that charge carriers within the I-rich phase are not strongly localised. We further demonstrate enhanced lattice anharmonicity in the segregated I-rich domains, which is likely to support ionic migration. These phonon anharmonicity effects also serve as evidence of a remarkably fast, picosecond charge funnelling into the narrow-bandgap I-rich domains. Our analysis demonstrates how minimal structural transformations during phase segregation have a dramatic effect on the charge-carrier dynamics as a result of charge funnelling. We suggest that because such enhanced recombination is radiative, performance losses may be mitigated by deployment of careful light management strategies in solar cells.
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics
Authors: Tirier Stephan M. , Mallm Jan-Philipp , Steiger Simon , Poos Alexandra M. , Awwad Mohamed H. S. , Giesen Nicola , Casiraghi Nicola , Susak Hana , Bauer Katharina , Baumann Anja , John Lukas , Seckinger Anja , Hose Dirk , Müller-Tidow Carsten , Goldschmidt Hartmut , Stegle Oliver , Hundemer Michael , Weinhold Niels , Raab Marc S. , Rippe Karsten 
Published: November 2021

AbstractVirtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.
Multi-species host range of staphylococcal phages isolated from wastewater
Authors: Göller Pauline C. , Elsener Tabea , Lorgé Dominic , Radulovic Natasa , Bernardi Viona , Naumann Annika , Amri Nesrine , Khatchatourova Ekaterina , Coutinho Felipe Hernandes , Loessner Martin J. , Gómez-Sanz Elena 
Published: November 2021

AbstractThe host range of bacteriophages defines their impact on bacterial communities and genome diversity. Here, we characterize 94 novel staphylococcal phages from wastewater and establish their host range on a diversified panel of 117 staphylococci from 29 species. Using this high-resolution phage-bacteria interaction matrix, we unveil a multi-species host range as a dominant trait of the isolated staphylococcal phages. Phage genome sequencing shows this pattern to prevail irrespective of taxonomy. Network analysis between phage-infected bacteria reveals that hosts from multiple species, ecosystems, and drug-resistance phenotypes share numerous phages. Lastly, we show that phages throughout this network can package foreign genetic material enclosing an antibiotic resistance marker at various frequencies. Our findings indicate a weak host specialism of the tested phages, and therefore their potential to promote horizontal gene transfer in this environment.
Thermochemical anomalies in the upper mantle control Gakkel Ridge accretion
Authors: O’Connor John M. , Jokat Wilfried , Michael Peter J. , Schmidt-Aursch Mechita C. , Miggins Daniel P. , Koppers Anthony A. P. 
Published: November 2021

AbstractDespite progress in understanding seafloor accretion at ultraslow spreading ridges, the ultimate driving force is still unknown. Here we use40Ar/39Ar isotopic dating of mid-ocean ridge basalts recovered at variable distances from the axis of the Gakkel Ridge to provide new constraints on the spatial and temporal distribution of volcanic eruptions at various sections of an ultraslow spreading ridge. Our age data show that magmatic-dominated sections of the Gakkel Ridge spread at a steady rate of ~11.1 ± 0.9 mm/yr whereas amagmatic sections have a more widely distributed melt supply yielding ambiguous spreading rate information. These variations in spreading rate and crustal accretion correlate with locations of hotter thermochemical anomalies in the asthenosphere beneath the ridge. We conclude therefore that seafloor generation in ultra-slow spreading centres broadly reflects the distribution of thermochemical anomalies in the upper mantle.
A general strategy for C(sp3)–H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor
Authors: Leibler Isabelle Nathalie-Marie , Tekle-Smith Makeda A. , Doyle Abigail G. 
Published: November 2021

AbstractPhotoredox catalysis has provided many approaches to C(sp3)–H functionalization that enable selective oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp3)–H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an azide—to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical—a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis—enabling new site-selectivity for late-stage C(sp3)–H functionalization.
Production of hydrogen from offshore wind in China and cost-competitive supply to Japan
Authors: Song Shaojie , Lin Haiyang , Sherman Peter , Yang Xi , Nielsen Chris P. , Chen Xinyu , McElroy Michael B. 
Published: November 2021

AbstractThe Japanese government has announced a commitment to net-zero greenhouse gas emissions by 2050. It envisages an important role for hydrogen in the nation’s future energy economy. This paper explores the possibility that a significant source for this hydrogen could be produced by electrolysis fueled by power generated from offshore wind in China. Hydrogen could be delivered to Japan either as liquid, or bound to a chemical carrier such as toluene, or as a component of ammonia. The paper presents an analysis of factors determining the ultimate cost for this hydrogen, including expenses for production, storage, conversion, transport, and treatment at the destination. It concludes that the Chinese source could be delivered at a volume and cost consistent with Japan’s idealized future projections.