bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advancing our understanding of skeletal muscle across the lifecourse: protocol for the MASS_Lifecourse study and characteristics of the first 80 participants
Authors: Dodds R M , Hurst C , Hillman S J , Davies K , Aspray T J , Granic A , Sayer A A 
Published: October 2021

AbstractIntroductionSarcopenia, the age-related loss of skeletal muscle strength and mass, carries a significant burden for affected individuals. There has been little investigation of sarcopenia using experimental medicine techniques to study human muscle tissue in detail. The aim of the Muscle Ageing Sarcopenia Studies Lifecourse (MASS_Lifecourse) study is to recruit up to 160 participants, equally divided between females and males between ages 45 and 85 years for detailed phenotyping of skeletal muscle health. Here we describe the protocol for the study and the characteristics of the first 80 participants.MethodsWe are recruiting participants from three sources in the north-east of England. Study fieldwork comprises a home visit (or videocall) for consent and assessment of health, cognition, lifestyle, and wellbeing. This is followed by a visit to a clinical research facility for assessment of sarcopenia status and collection of samples including a vastus lateralis muscle biopsy. We produced descriptive statistics for the first 80 participants, including expressing their grip strength relative to normative data in the form of Z-scores.ResultsThe first 80 participants (53.8% female) covered the target ages, ranging from 48 to 84 years. They were regularly physically active, reported good physical function and had a prevalence sarcopenia (including probable sarcopenia) of 11.3% based on the revised European consensus. Their grip strength was similar to that in the general population, with a mean Z-score of 0.09 standard deviations (95% CI: -1.64, 1.83) above that expected.ConclusionsThe MASS_Lifecourse study combines comprehensive health and lifestyle data with a range of biological samples including skeletal muscle. The findings from planned analyses should contribute to improvements in the diagnosis, treatment, and prevention of sarcopenia.
ERα-LBD, a novel isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance
Authors: Strillacci Antonio , Sansone Pasquale , Rajasekhar Vinagolu K , Turkekul Mesruh , Boyko Vitaly , Meng Fanli , Houck-Loomis Brian , Brown David , Berger Michael F , Hendrickson Ronald C , Chang Qing , de Stanchina Elisa , Pareja Fresia , Reis-Filho Jorge S , Rajappachetty Ramya Segu , Liu Bo , Penson Alex , Mastroleo Chiara , Berishaj Marjan , Borsetti Francesca , Spisni Enzo , Lyden David , Chandarlapaty Sarat , Bromberg Jacqueline 
Published: October 2021

ABSTRACTEstrogen receptor alpha (ERα) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of a novel ERα isoform, ERα-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ERα-LBD is found to promote breast cancer growth and resistance to the ERα antagonist fulvestrant. ERα-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ERα-LBD expression and function does not appear to be restricted to cancers that express full length ERα but also promotes growth of triple negative breast cancers and ERα-LBD transcript (ESR1-LBD) is also present in BC samples from both ERα(+) and ERα(−) human tumors. These findings point to ERα-LBD as a potential mediator of breast cancer progression and therapy resistance.SIGNIFICANCE STATEMENTEndocrine resistant and metastatic breast cancer (BC) is a clinically significant problem. Our study of fulvestrant resistant cancer cells led to the discovery of a novel ERα isoform which we call ERα-LBD. Encoded by a truncated transcript variant (ESR1-LBD) and lacking the N-terminal domains (activation of transcription and DNA binding), ERα-LBD displays a unique role in BC tumorigenesis and progression by mechanisms that may involve metabolic and cell growth advantages, stemness and therapy resistance. Importantly, ESR1-LBD is preferentially expressed in human breast tumor tissues and may be used as prognostic marker in BC.
Structure-based Design of CDC42 Effector Interaction Inhibitors For the Treatment of Cancer
Authors: Jahid Sohail , Ortega Jose A. , Vuong Linh M. , Acquistapace Isabella Maria , Hachey Stephanie J. , Flesher Jessica L. , La Serra Maria Antonietta , Brindani Nicoletta , La Sala Giuseppina , Manigrasso Jacopo , Arencibia Jose M. , Bertozzi Sine Mandrup , Summa Maria , Bertorelli Rosalia , Armirotti Andrea , Jin Rongsheng , Liu Zheng , Chen Chi-Fen , Edwards Robert , Hughes Christopher C.W. , Vivo Marco De , Ganesan Anand K. 
Published: October 2021

SUMMARYCDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here we use computer-aided drug design to discover a new chemical entity (ARN22089) that targets CDC42 GTPases and blocks CDC42 effector interactions without affecting the binding between closely related GTPases (RAC1, RAS, RAL) and their downstream effectors. Our lead compound has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in three-dimensional vascularized microtumor models (VMT)in vitro. In addition, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenograftsin vivo. Taken together, this work identifies a promising new class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.
Nucleocapsid mutations in SARS-CoV-2 augment replication and pathogenesis
Authors: Johnson Bryan A. , Zhou Yiyang , Lokugamage Kumari G. , Vu Michelle N. , Bopp Nathen , Crocquet-Valdes Patricia A. , Kalveram Birte , Schindewolf Craig , Liu Yang , Scharton Dionna , Plante Jessica A. , Xie Xuping , Aguilar Patricia , Weaver Scott C. , Shi Pei-Yong , Walker David H. , Routh Andrew L. , Plante Kenneth S. , Menachery Vineet D. 
Published: October 2021

AbstractWhile SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203-205 in the SARS-CoV-2 nucleocapsid protein. Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. The R203K+G204R mutant corresponds with increased viral RNA and protein both in vitro and in vivo. Importantly, the R203K+G204R mutation increases nucleocapsid phosphorylation and confers resistance to inhibition of the GSK-3 kinase, providing a molecular basis for increased virus replication. Notably, analogous alanine substitutions at positions 203+204 also increase SARS-CoV-2 replication and augment phosphorylation, suggesting that infection is enhanced through ablation of the ancestral ‘RG’ motif. Overall, these results demonstrate that variant mutations outside spike are key components in SARS-CoV-2’s continued adaptation to human infection.Author SummarySince its emergence, SARS-CoV-2 has continued to adapt for human infection resulting in the emergence of variants with unique genetic profiles. Most studies of genetic variation have focused on spike, the target of currently available vaccines, leaving the importance of variation elsewhere understudied. Here, we characterize a highly variable motif at residues 203-205 in nucleocapsid. Recreating the prominent nucleocapsid R203K+G204R mutation in an early pandemic background, we show that this mutation is alone sufficient to enhance SARS-CoV-2 replication and pathogenesis. We also link augmentation of SARS-CoV-2 infection by the R203K+G204R mutation to its modulation of nucleocapsid phosphorylation. Finally, we characterize an analogous alanine double substitution at positions 203-204. This mutant was found to mimic R203K+G204R, suggesting augmentation of infection occurs by disrupting the ancestral sequence. Together, our findings illustrate that mutations outside of spike are key components of SARS-CoV-2’s adaptation to human infection.
Deep learning based on stacked sparse autoencoder applied to viral genome classification of SARS-CoV-2 virus
Authors: Coutinho Maria G. F. , Câmara Gabriel B. M. , Barbosa Raquel de M. , Fernandes Marcelo A. C. 
Published: October 2021

AbstractSince December 2019, the world has been intensely affected by the COVID-19 pandemic, caused by the SARS-CoV-2 virus, first identified in Wuhan, China. In the case of a novel virus identification, the early elucidation of taxonomic classification and origin of the virus genomic sequence is essential for strategic planning, containment, and treatments. Deep learning techniques have been successfully used in many viral classification problems associated with viral infections diagnosis, metagenomics, phylogenetic, and analysis. This work proposes to generate an efficient viral genome classifier for the SARS-CoV-2 virus using the deep neural network (DNN) based on stacked sparse autoencoder (SSAE) technique. We performed four different experiments to provide different levels of taxonomic classification of the SARS-CoV-2 virus. The confusion matrix presented the validation and test sets and the ROC curve for the validation set. In all experiments, the SSAE technique provided great performance results. In this work, we explored the utilization of image representations of the complete genome sequences as the SSAE input to provide a viral classification of the SARS-CoV-2. For that, a dataset based onk-mers image representation, withk= 6, was applied. The results indicated the applicability of using this deep learning technique in genome classification problems.
An archaeal histone-like protein regulates gene expression in response to salt stress
Authors: Sakrikar Saaz , Schmid Amy 
Published: October 2021

ABSTRACTHistones, ubiquitous in eukaryotes as DNA-packing proteins, find their evolutionary origins in archaea. Unlike the characterized histone proteins of a number of methanogenic and themophilic archaea, previous research indicated that HpyA, the sole histone encoded in the model halophile Halobacterium salinarum, is not involved in DNA packaging. Instead, it was found to have widespread but subtle effects on gene expression and to maintain wild type cell morphology; however, its precise function remains unclear. Here we use quantitative phenotyping, genetics, and functional genomic to investigate HpyA function. These experiments revealed that HpyA is important for growth and rod-shaped morphology in reduced salinity. HpyA preferentially binds DNA at discrete genomic sites under low salt to regulate expression of ion uptake, particularly iron. HpyA also globally but indirectly activates other ion uptake and nucleotide biosynthesis pathways in a salt-dependent manner. Taken together, these results demonstrate an alternative function for an archaeal histone-like protein as a transcriptional regulator, with its function tuned to the physiological stressors of the hypersaline environment.
Cross-seeding Controls Aβ Fibril Populations and Resulting Function
Authors: Lucas Michael J. , Pan Henry S. , Verbeke Eric J. , Partipilo Gina M. , Helfman Ethan C. , Kann Leah , Keitz Benjamin K. , Taylor David W. , Webb Lauren J. 
Published: October 2021

AbstractAmyloid peptides nucleate from monomers to aggregate into fibrils through primary nucleation; pre-existing fibrils can then act as seeds for additional monomers to fibrillize through secondary nucleation. Both nucleation processes can occur simultaneously, yielding a distribution of fibril polymorphs that can generate a spectrum of neurodegenerative effects. Understanding the mechanisms driving polymorph structural distribution during both nucleation processes is important for uncovering fibril structure-function relationships, as well creating polymorph distributions in vitro that better match distributions found in vivo. Here, we explore how cross-seeding WT Aβ1-40 with Aβ1-40 mutants E22G (Arctic) and E22Δ (Osaka), as well as with WT Aβ1-42 affects the distribution of fibril structural polymorphs, and how changes in structural distribution impact toxicity. Transmission electron microscopy analysis reveals that fibril seeds derived from mutants of Aβ1-40 impart their structure to WT Aβ1-40 monomer during secondary nucleation, but WT Aβ1-40 fibril seeds do not affect the structure of fibrils assembled from mutant Aβ1-40 monomers, despite kinetics data indicating accelerated aggregation when cross-seeding of any combination of mutants. Additionally, WT Aβ1-40 fibrils seeded with mutant fibrils to produce similar structural distributions to the mutant seeds also produced similar cytotoxicity on neuroblastoma cell lines. This indicates that mutant fibril seeds not only impart their structure to growing WT Aβ1-40 aggregates, but they also impart cytotoxic properties. Our findings provide clear evidence that there is a relationship between fibril structure and phenotype on a polymorph population level, and that these properties can be passed on through secondary nucleation of succeeding generations of fibrils.
In situ Alphavirus Assembly and Budding Mechanism Revealed by Cellular CryoET
Authors: Chmielewski David , Schmid Michael F. , Simmons Graham , Jin Jing , Chiu Wah 
Published: October 2021

SummaryChikungunya virus (CHIKV) is an alphavirus and the etiological agent for debilitating arthritogenic disease in humans. Previous studies with purified virions or budding mutants have not resolved the structural mechanism of alphavirus assembly in situ. Here we used cryogenic electron tomography (cryoET) imaging of CHIKV-infected human cells and subvolume classification to resolve distinct assembly intermediate conformations. These structures revealed that particle formation is driven by the spike envelope layer. Additionally, we showed that asymmetric immature nucleocapsids (NCs) provide scaffolds to trigger assembly of the icosahedral spike lattice, which progressively transforms immature NCs into icosahedral cores during virus budding. Further, cryoET of the infected cells treated with neutralizing antibodies (NAbs) showed that NAb-induced blockage of CHIKV assembly was achieved by preventing spike-spike lateral interactions that are required to bend the plasma membrane around NC cores. These findings provide molecular mechanisms for designing antivirals targeting spike-driven assembly/budding of viruses.
Regulating Chinese education in colonial Macao: political struggle and the role of “the Chinese Educators' Association of Macau” (c. 1914–1949)
Authors: Cheong Hang 
Published: October 2021

PurposeThe study aims to trace the history of Chinese education in Macao in the first half of the 20th century, emphasizing macro- and meso-level political influences.Design/methodology/approachThe paper reviews published works including official documents, rare books, newspapers, etc. and provides a three-part analysis: first, discussion of the colonial Government's education policy during the early 20th century and the establishment of the Chinese Educators' Association of Macau (CEAM); second, contextualization of the major upset and change in educational policy during the Sino-Japanese War (World War II in Asia); and third, considering the reinstatement of laissez-faire education policies regarding Macao's Chinese community and the CEAM's shifting political loyalties in the post-war period.FindingsThe colonial Government created a vacuum into which both the Kuomintang (KMT) and the Chinese Communist Party (CCP) muscled, seeking to manipulate education from across the border via control of the CEAM. Mainland China's shifting political landscapes thus significantly altered the political orientation of the CEAM, especially around 1949. Soon afterward, various Catholic and other schools withdrew from the CEAM, primarily separating Chinese schools in Macao into blue (Catholic et al.) and red (pro-CCP) camps.Originality/valueThe paper reviews Macao Chinese education history from 1914 to 1949 while providing better comprehension of an analogous situation in neighboring Hong Kong.
Investigating the prevalence and predictors of food insecurity: a comparison of HFSSM and EU-SILC indicators
Authors: Beacom Emma , McLaughlin Christopher , Furey Sinéad , Hollywood Lynsey Elizabeth , Humphreys Paul 
Published: October 2021

PurposeData from the Northern Ireland (NI) Health Survey 2014/15 (n = 2,231) were statistically analysed to examine the prevalence of food insecurity according to both indicators. Pearson'sX2test for association and logistic regressions were used to examine associations between food security status and predictor variables.Design/methodology/approachHousehold food insecurity has been identified as a significant societal issue in both developed and developing nations, but there exists no universal indicator to approximate its prevalence. In NI, two indicators (United States Household Food Security Survey Module [HFSSM] and the European Union Statistics on Income and Living Conditions [EU-SILC] food deprivation questions) have been used. This study examines how both indicators differ in their classification of food insecurity prevalence in a population sample and also examines the relationship between various demographic and household factors and food security status.FindingsAccording to the EU-SILC food deprivation questions, 8.3% (n = 185) were indicated to be food insecure, while according to the HFSSM, 6.5% (n = 146) were indicated to be food insecure. The HFSSM and EU-SILC regression models differed in the underlying variables they identified as significant predictors of food insecurity. Significant variables common to both modules were tenure, employment status, health status, anxiety/depression and receipt of benefits.Originality/valueFindings can inform policy action with regards to targeting the key contributors and can inform policy decisions in NI and elsewhere with regards to choosing the most appropriate food insecurity indicator.
Barriers to the use of sustainable materials in Australian building projects
Authors: Gounder Sheetal , Hasan Abid , Shrestha Asheem , Elmualim Abbas 
Published: October 2021

PurposeAlthough the adverse effects of construction activities on the environment and the need for sustainable construction practices are recognised in both research and practice, any significant shift in the selection and use of construction materials from the sustainability perspective has not taken place in many building projects. Still, conventional construction materials are widely used in building projects in both developed and developing countries. This study attempts to identify the main barriers to the use of sustainable materials in building projects in an advanced economy such as Australia.Design/methodology/approachThis study adopted a questionnaire survey approach to examine the main reasons behind the low usage of sustainable materials in building projects. Based on the relative importance index, exploratory factor analysis and multinomial logistic regression analysis, the study examined the main barrier measures and barrier factors to the use of sustainable materials in building projects.FindingsThe findings reveal that critical barriers to the use of sustainable materials are related to cost and profit considerations, the unwillingness of the key stakeholders to incorporate these materials into building projects, lack of incentives and government policies. The factor analysis reduced the critical barrier measures into three factors: techno-economic considerations, cost and delay concerns and resistance to use. Furthermore, multinomial regression analysis based on the extracted factors identified techno-economic considerations as the main barrier factor to the use of sustainable materials in building projects.Practical implicationsThe empirical results of this research can inform construction practitioners, organisations and policymakers on how to increase the use of sustainable building materials in the construction industry.Originality/valueIdentification of barriers to the use of sustainable building materials is a prerequisite to improve their uptake and use in the construction industry. The study fills a gap in the existing research on the use of sustainable materials in building projects in Australia.