bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGR5 targeting molecules as therapeutic agents for multiple cancer types
Authors: Chen Hung-Chang , Mueller Nico , Stott Katherine , Rivers Eilidh , Kapeni Chrysa , Sauer Carolin M , Beke Flavio , Walsh Stephen , Ashman Nicola , O’Brien Louise , Fard Amir Rafati , Godsinia Arman , Joud Fadwa , Giger Olivier , Zlobec Inti , Olan Ioana , Aitken Sarah J. , Hoare Matthew , Mair Richard , Serrao Eva , Brenton James D , Garcia-Gimenez Alicia , Richardson Simon E. , Huntly Brian , Spring David R. , Skjødt Mikkel-Ole , Skjødt Karsten , de la Roche Marc , de la Roche Maike 
Published: September 2022

AbstractLeucine-rich repeat-containing G-protein receptor 5 (LGR5) has been characterised as a stem cell and cancer stem cell marker. Previous analyses of LGR5 transcript levels indicate high level expression discriminates malignancies such as colorectal cancer (CRC) and pre-B acute lymphoblastic leukaemia (pre-B ALL) from healthy tissues suggesting LGR5 protein expression may provide a molecular handle for prognosis and treatment.We have developed highly specific, high affinity antibodies to the extracellular domain of human LGR5 (α-LGR5) that detect high LGR5 protein levels in colorectal cancer (CRC), hepatocellular carcinoma (HCC), and pre-B ALL. In contrast, there is low to undetectable levels of LGR5 protein in normal colon and rectal epithelia, liver, ovarian tissues, brain and immune cell types.LGR5 is rapidly internalised from the plasma membrane and trafficked to intracellular vesicular compartments including lysosomes. Treatment of high LGR5-expressing CRC and pre-B ALL cancer cell lines with an antibody-drug conjugate version of α-LGR5 (α-LGR5-ADC) lead to effective cell killing at nanomolar concentrations. Interventional treatment of pre-B ALL tumours with α-LGR5-ADC in vivo led to rapid tumour attrition. We further demonstrated the therapeutic utility of humanised α-LGR5 by using the corresponding scFv fragment for the generation of α-LGR5 chimeric antigen receptors (CARs) and a Bispecific T cell Engager (BiTE). α-LGR5-CAR-NK cells were effective at killing LGR5-expressing cells while α-LGR5/α-CD3 BiTEs induce T cell activation and killing of NALM6 cells by cytotoxic CD8+ T cells.Taken together, this study establishes α-LGR5-based therapeutic modalities that effectively discriminate and target CRC, HCC and pre-B ALL tumour cells.One Sentence SummaryWe generated novel antibodies against the cancer cell marker LGR5, validated diagnostic use in prioritizing specific cancer types for targeting, and developed antibody-based therapeutics.
Rapid intralacustrine evolution of an invasive pelagic three-spined stickleback (Gasterosteus aculeatus) ecotype in Lake Constance
Authors: Dahms Carolin , Roch Samuel , Elmer Kathryn R. , Ros Albert , Brinker Alexander , Jacobs Arne 
Published: September 2022

AbstractThe rapid invasion of the pelagic zone in Lake Constance by three-spined sticklebacks (Gasterosteus aculeatus) since 2012 and their subsequent drastic population growth has had stark ecosystem-wide effects, such as food-web shifts and declines in native biodiversity, including commercially important fish species. Yet, the origin of this invasive pelagic ecotype remains unclear. This study aims to determine if the pelagic ecotype arosein situfrom the existing littoral population or following external colonisation, identify potential phenotypic differences between individuals from different habitats, and assess genomic signals of selection. Integrating RAD-sequencing of Lake Constance individuals and whole-genome sequence data for European outgroup populations, this study shows that the pelagic Lake Constance population likely arose recently within the lake from the littoral population, with only weak genome-wide differentiation between individuals from different habitats. This is further supported by minimal differences in meristic and morphometric traits, with shape differences only found between pelagic/inflow sticklebacks and littoral sticklebacks. Using genome scans, we identified multiple outlier loci between littoral and pelagic ecotypes across the genome, potentially suggesting early signs of sympatric speciation despite high connectivity. Furthermore, increased differentiation between pelagic and littoral sticklebacks for body shape-associated loci and the overlap of outlier loci with quantitative trait loci for ecologically relevant traits points toward a driving role of selection in this pelagic invasion. This study provides an important example of rapid ecological diversification from standing genetic variation and a rare case of littoral-pelagic ecotype divergence under high gene flow in a large oligotrophic lake. Ultimately, the results of this study will have major implications for the management of the invasive pelagic ecotype, and the entire stickleback population as a whole.
Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype
Authors: Daniels Deborah E , Ferrer-Vicens Ivan , Hawksworth J , Andrienko Tatyana N , Finnie Elizabeth M , Ferguson Daniel C J , Oliveira A. Sofia F. , Szeto Jenn-Yeu A. , Wilson Marieangela C , Frayne Jan 
Published: September 2022

Abstractβ-thalassemia is a prevalent genetic disorder causing severe anemia due to defective erythropoiesis, with few treatment options. Studying the underlying molecular defects is impeded by paucity of suitable patient material. In this study we created human disease cellular model systems for β-thalassemia, which accurately recapitulate the phenotype of patient erythroid cells. We also developed a high throughput compatible fluorometric-based assay for evaluating severity of disease phenotype and utilised the assay to demonstrate positive response of lines to verified reagents, providing validation for such applications.TMT-based comparative proteomics confirmed the same profile of proteins previously reported, whilst providing new insights into the altered molecular mechanisms in β-thalassemia erythroid cells, with upregulation of a wide range of biological pathways and processes observed.Overall, the lines provide a sustainable supply of disease cells as novel research tools, for identifying new therapeutic targets, and as screening platforms for novel drugs and therapeutic reagents.
Dissecting aneuploidy phenotypes by constructing Sc2.0 chromosome VII and SCRaMbLEing synthetic disomic yeast
Authors: Shen Yue , Gao Feng , Wang Yun , Wang Yuerong , Zheng Ju , Gong Jianhui , Zhang Jintao , Luo Zhouqing , Schindler Daniel , Deng Yang , Ding Weichao , Lin Tao , Swidah Reem , Zhao Hongcui , Jiang Shuangying , Zeng Cheng , Chen Shihong , Chen Tai , Wang Yong , Luo Yisha , Mitchell Leslie , Bader Joel S. , Zhang Guojie , Shen Xia , Wang Jian , Fu Xian , Dai Junbiao , Boeke Jef D. , Yang Huanming , Xu Xun , Cai Yizhi 
Published: September 2022

AbstractAneuploidy compromises genomic stability, often leading to embryo inviability, and is frequently associated with tumorigenesis and aging. Different aneuploid chromosome stoichiometries lead to distinct transcriptomic and phenotypic changes, making it helpful to study aneuploidy in tightly controlled genetic backgrounds. By deploying the engineered SCRaMbLE system to the newly synthesized Sc2.0 megabase chromosome VII (synVII), we constructed a synthetic disomic yeast and screened hundreds of SCRaMbLEd derivatives with diverse chromosomal rearrangements. Phenotypic characterization and multi-omics analysis revealed that fitness defects associated with aneuploidy could be restored by i) removing most of the chromosome content, or ii) modifying specific regions in the duplicated chromosome. These findings indicate that both chromosome copy number and chromosomal regions contribute to the aneuploidy-related phenotypes, and the synthetic yeast resource opens new paradigms in studying aneuploidy.In briefUse of SCRaMbLE and newly synthesized Mb-scale Sc2.0 chromosome VII enables insights into genotype/phenotype relationships associated with aneuploidyHighlightsDe novo design and synthesis of a Mb-scale synthetic yeast chromosome VII, carrying 11.8% sequence modifications and representing nearly 10% of the yeast genome.A disomic yeast (n + synVII) is constructed for dissecting the aneuploidy phenotypeSCRaMbLE enables systematic exploration of regions causing aneuploidy phenotypesChromosomal copy number and content both contribute to aneuploidy phenotypesA 20 Kb deletion on the right arm of synVII leads to fitness improvement linked to up-regulation of protein synthesis
When two’s a crowd - Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3/Crk signaling
Authors: Roy Michael J. , Surudoi Minglyanna G. , Kropp Ashleigh , Hou Jianmei , Dai Weiwen , Hardy Joshua M. , Liang Lung-Yu , Cotton Thomas R. , Lechtenberg Bernhard C. , Dite Toby A. , Ma Xiuquan , Daly Roger J. , Patel Onisha , Lucet Isabelle S. 
Published: September 2022

AbstractPEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. Despite lacking catalytic activity, alteration in their expression level is associated with several aggressive cancers. Here, we elucidate new molecular details of key PEAK signaling interactions with the adapter proteins CrkII and Grb2 and the scaffold protein 14-3-3. Our findings rationalize why the dimerization of PEAK proteins has a crucial function in signal transduction and provide biophysical and structural data to unravel binding specificity within the PEAK interactome. We identify a conserved high affinity 14-3-3 motif on PEAK3 and demonstrate its role as a molecular switch to regulate CrkII binding. Together, our studies provide a detailed structural snapshot of PEAK interaction networks and further elucidate how PEAK proteins, especially PEAK3, act as dynamic scaffolds that exploit adapter proteins to control signal transduction in cell growth/motility and cancer.
Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
Authors: Torosyan Hayarpi , Paul Michael D. , Forget Antoine , Lo Megan , Diwanji Devan , Pawłowski Krzysztof , Krogan Nevan J. , Jura Natalia , Verba Kliment A. 
Published: September 2022

AbstractThe three members of the PEAK family of pseudokinases (PEAK1, PEAK2, and PEAK3) are molecular scaffolds that have recently emerged as important regulatory nodes in signaling pathways that control cell migration, morphology, and proliferation, and they are increasingly found to be mis-regulated in human cancers. While no structures of PEAK3 have been solved to date, crystal structures of the PEAK1 and PEAK2 pseudokinase domains revealed their dimeric organization. It remains unclear how dimerization plays a role in PEAK scaffolding functions, as no structures of PEAK family members in complex with their binding partners have been solved. Here, we report the cryo-EM structure of the PEAK3 pseudokinase, also adopting a dimeric state, and in complex with an endogenous 14-3-3 heterodimer purified from mammalian cells. Our structure reveals an asymmetric binding mode between PEAK3 and 14-3-3 stabilized by one pseudokinase domain and the Split HElical Dimerization (SHED) domain of the PEAK3 dimer. The binding interface is comprised of a canonical primary interaction involving two phosphorylated 14-3-3 consensus binding sites located in the N-terminal domains of the PEAK3 monomers docked in the conserved amphipathic grooves of the 14-3-3 dimer, and a unique secondary interaction between 14-3-3 and PEAK3 that has not been observed in any previous structures of 14-3-3/client complexes. Disruption of these interactions results in the relocation of PEAK3 to the nucleus and changes its cellular interactome. Lastly, we identify Protein Kinase D as the regulator of the PEAK3/14-3-3 interaction, providing a mechanism by which the diverse functions of the PEAK3 scaffold might be fine-tuned in cells.
Melaninization Reduces Cryptococcus neoformans Susceptibility to Mechanical Stress
Authors: Mattoon Ellie Rose , Cordero Radames JB , Casadevall Arturo 
Published: September 2022

AbstractMelanin is a complex pigment found in various fungal species that is associated with a multitude of protective functions against environmental stresses. In Cryptococcus neoformans, melanin is synthesized from exogenous substrate and deposited in the cell wall. Although melanin is often cited as a protector against mechanical stress, there is a paucity of direct experimental data supporting this claim. To probe whether melanin enhances cellular strength, we used ultrasonic cavitation and French pressure cell press to stress cryptococcal cells and then measured changes in cellular morphology and survival for melanized and non-melanized C. neoformans. Melanized yeast exhibited lower rates of fragmentation and lower decreases in cell area when compared to non-melanized yeast after sonication and French press conditions. Our results indicate that melanization protects against some of the morphologic changes initiated by mechanical energy derived from either sonic cavitation or French press, thus supporting the notion that this pigment provides mechanical strength to fungal cell walls.ImportanceMelanin has been shown from prior experiments in microbiology to be associated with protection against environmental stressors and has often been cited as being associated with mechanical stress protection. However, there is a lack of direct experimentation to confirm this claim. By examining the response of melanized and non-melanized C. neoformans to sonication and French press, we report differences in outcomes dependent not only based on melanization status but also culture age. Such findings have important implications in the design and interpretation of laboratory experiments involving C. neoformans. In addition, uncovering some of melanin’s mechanical properties promotes further research into fungal melanin’s applications in healthcare and industry.
Volatile aroma compound production is affected by growth rate inS. cerevisiae
Authors: Visinoni Federico , Zhang Penghan , Hollywood Katherine A. , Carlin Silvia , Vrhovsek Urska , Winterburn James , Delneri Daniela 
Published: September 2022

AbstractThe initial growth rate of a yeast strain is a key parameter in the production of fermented beverages. Fast growth is linked with higher fermentative capacity and results in less slow and stuck fermentations unable to reach the expected final gravity. As concentrations of metabolites are in constant state of flux, quantitative data on how growth rate affects the production of aromatic compounds becomes an important factor for brewers. Chemostats allow to set and keep a specific dilution rate throughout the fermentation and are ideal system to study the effect of growth on aroma production. In this study, we run chemostats alongside batch and fed-batch cultures, compared volatile profiles detected at different growth rates, and identified those affected by the different feeding profiles. Specifically, we quantified six abundant aroma compounds produced in anaerobic glucose-limited continuous cultivations ofS. cerevisiaeat different dilution rates. We found that volatile production was affected by the growth rate in four out of six compounds assayed, with higher alcohols and esters following opposite trends. Batch and fed-batch fermentations were devised to study the extent by which the final concentration of volatile compounds is influenced by glucose availability. When compared to the batch system, fed-batch fermentations, where the yeast growth was artificially limited by a slow constant release of nutrients in the media, resulted in a significant increase in concentration of higher alcohols, mirroring the results obtained in continuous fermentations. This study paves the way to further process development optimization for the production of fermented beverages.ImportanceThe production of fermentation beverages will need to quickly adapt to changes in both the climate and in customer demands, requiring the development of new strains and processes. Breakthroughs in the field are hindered by the limited knowledge on the physiological role of aroma compounds production in yeast. No quantitative data on how growth rate affects aroma profile is available in the literature to guide optimisation of the complex flavours in fermented beverages. In this study, we exploited the chemostat system, alongside with batch and fed-batch cultures to compare volatile profiles at different growth rates. We identified the aromatic compounds affected by the different feeding profiles and nutrient limitations. Moreover, we uncovered the correlation between yeast growth, esters and higher alcohols production. This study showcases the potential of the application of feeding profiles for the manipulation of aroma in the craft beverage industry.
Insomnia and risk of sepsis: A Mendelian randomization study
Authors: Thorkildsen Marianne S. , Gustad Lise T. , Mohus Randi M. , Nilsen Tom I.L. , Damås Jan K. , Rogne Tormod 
Published: September 2022

AbstractImportanceInsomnia has been associated with reduced immune function and increased risk of infections and sepsis in observational studies. These studies are prone to bias, such as residual confounding. To further understand the causal relation between insomnia and sepsis risk we used a two-sample Mendelian randomization (MR) approach.ObjectiveIs genetically predicted insomnia associated with risk of sepsis?DesignTwo-sample MR was performed to estimate the causal effect of genetically predicted insomnia on sepsis risk. Data was obtained from a genome-wide association study (GWAS) identifying 556 independent genetic variants (R2<0.01) strongly associated with insomnia (P< 5e-8). We conducted sensitivity analyses to address bias due to pleiotropy and sample overlap, along with mediation analyses.SettingObservational study using genetic variants as instrumental variables in large populations.ParticipantsFor insomnia, 2.4 million subjects of European ancestry from the UK Biobank and 23andMe. For sepsis, 462,918 subjects of European ancestry from the UK Biobank.ExposureGenetically predicted insomnia.Main Outcome and MeasureSepsis.ResultsA doubling in the population prevalence of genetically predicted insomnia was associated with an odds ratio of 1.42 (95% CI 1.23–1.63,P= 9.1e-7) for sepsis. Sensitivity analyses supported this observation. Three quarters of the effect was mediated through body mass index.Conclusions and RelevanceThe concordance between our findings and previous observational studies support of a causal role of genetically predicted insomnia in the risk of sepsis.
Preterm birth rates among twins during the Danish COVID-19 lockdown and mitigation period
Authors: Hedley Paula L , Bækvad-Hansen Marie , Hedermann Gitte , Hjalgrim Henrik , Hougaard David M. , Melbye Mads , Breindahl Morten , Krebs Lone , Hviid Anders , Lausten-Thomsen Ulrik , Christiansen Michael 
Published: September 2022

AbstractDenmark’s response to the COVID-19 pandemic was to issue guidelines on containment, isolation, and surveillance. Subsequently, Denmark entered a period with variable mitigation measures including closures of schools and workplaces, travel restrictions, and restrictions on public gatherings. A Danish study covering the lockdown period (March 12 – April 14, 2020) as well as a period of mitigation measures (February 27 – September 30, 2020) showed that the reduction in extremely preterm births was not associated with an increase in singleton stillbirth rate. Subsequent studies examining the impacts of COVID-19 mitigation measures on preterm birth have combined singleton with multifetal pregnancies. However, multifetal pregnancies have a different set of risk factors for preterm birth, as well as, increased risk of adverse outcomes, and a shorter expected pregnancy length. We assessed the impact of the Danish lockdown period, or the mitigation period on multifetal births and found no significant difference in the proportion of preterm twin births among all twin births, either within gestational age groups or in total, for either period.
Risk factors for gallstone disease onset in Japan: findings from the Shizuoka Study, a population-based cohort study
Authors: Higashizono Kazuya , Nakatani Eiji , Hawke Philip , Fujimoto Shuhei , Oba Noriyuki 
Published: September 2022

AbstractIn the research literature on factors associated with gallstones, large population-based cohort studies are rare. We carried out a study of this type to explore risk factors for the onset of gallstones. This study included Japanese participants aged 40-107 years who were followed prospectively from January 2012 to September 2020 using a dataset composed of two individually linked databases, one containing annual health checkup records and the other containing medical claims for beneficiaries of the National Health Insurance System and the Medical Care System for Elderly in the Latter Stage of Life in Shizuoka Prefecture, Japan. Among the 611,930 participants in the analysis set, 23,843 (3.9%) were diagnosed with gallstones during the observational period (median [max]: 5.68 [7.5] years). Multivariate analysis revealed that risk of gallstone disease was increased by male sex, cerebrovascular disease, any malignancy, dementia, rheumatic disease, chronic pulmonary disease, hypertension, and H. pylori-infected gastritis. These findings provide essential insights into the etiology of cholelithiasis and may contribute to efforts to reduce the incidence of the disease.
Plasma Level of ATPase Inhibitory Factor 1 (IF1) and intrinsic capacity in community-dwelling older adults: Prospective data from the MAPT Study
Authors: da Silva Jaqueline Aragoni , Martinez Laurent O. , Rolland Yves , Najib Souad , Croyal Mikaël , Perret Bertrand , Jabrane-Ferrat Nabila , Costa Hicham El , Guyonnet Sophie , Vellas Bruno , de Souto Barreto Philipe ,   the MAPT/DSA group
Published: September 2022

ABSTRACTBackgroundIntrinsic capacity (IC) is a function-related concept that reflects healthy aging. Identifying IC biomarkers is an essential step to slow down functional declines at early stages. ATPase inhibitory factor 1 (IF1) is a multifaceted protein that regulates mitochondrial oxidative phosphorylation (OXPHOS), thereby affecting cellular energy production.ObjectiveTo investigate the association between plasma levels of IF1 and IC changes over four years in community-dwelling older adults.MethodsCommunity-dwelling older adults aged over 70 years at risk of cognitive decline from the Multidomain Alzheimer Preventive Trial (MAPT Study) were enrolled in this study. A composite IC score was calculated (ranging from 0 to 100; higher is better) over time using data on the following IC domains: locomotion, psychological dimension, cognition, vitality, and sensory ability (vision and hearing; assessed over one year only). Plasma levels of IF1 were assessed one year after the beginning of the study. Mixed-model linear regression adjusted for confounders was performed.ResultsA total of 1090 participants had usable IF1 values (mean age 75.3 ± 4.4 years; 64% females). The mean values of plasma IF1 and IC (4 domains) were 565.62 ± 251.92 ng/mL and 74.85 ± 8.43, respectively. Compared to the lowest quartile, low- and high-intermediate IF1 quartiles were cross-sectionally associated with greater composite IC scores of four domains (βlow-intermediate, 1.33; 95% CI 0.06– 2.60 and βhigh-intermediate, 1.78; 95% CI 0.49–3.06), and the highest quartile associated with a slower decline in composite IC scores of five domains over one year (βhigh 1.60; 95% CI 0.06– 3.15). The low- and high-intermediate IF1 quartiles were cross-sectionally associated with greater locomotion (βlow-intermediate, 2.72; 95% CI 0.36–5.08) and vitality scores (βhigh-intermediate, 1.59; 95% CI 0.06–3.12), respectively.ConclusionThis study is the first to report circulating IF1 levels as a mitochondrial-related biomarker associated with IC composite scores in cross-sectional and prospective analyses in community-dwelling older adults. Further research is needed to confirm these findings, in particular, to determine a potential cut-off defining optimal plasma IF1 levels and to unravel the potential mechanisms that can explain these associations.