bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering of human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia and solid tumor metastasis
Authors: Grigoryan Ani , Zacharaki Dimitra , Balhuizen Alexander , Côme Christophe RM , Frank Anne-Katrine , Garcia Garcia Alejandro , Aaltonen Kristina , Mañas Adriana , Esfandyari Javanshir , Kalantari Nasim , Kjellman Pontus , Prithiviraj Sujeethkumar , Englund Emelie , Madsen Chris D , Porse Bo , Bexell Daniel , Bourgine Paul E 
Published: September 2021

AbstractThe bone marrow microenvironment provides indispensable factors to sustain blood production throughout life. It is also a hotspot for the progression of hematologic disorders and the most frequent site of solid tumor metastasis. Pre-clinical research relies on xenograft mouse models, precluding the human-specific functional interactions of stem cells with their bone marrow microenvironment. Human mesenchymal cells can be exploited for the in vivo engineering of humanized ossicles (hOss). Those mini-bones provide a human niche conferring engraftment of human healthy and malignant blood samples, yet suffering from major reproducibility issue. Here, we report the standardized generation of hOss by developmental priming of a custom-designed human mesenchymal cell line. We demonstrate superior engraftment of cord blood hematopoietic cells and primary acute myeloid leukemia samples, but also validate our hOss as metastatic site for breast cancer cells. Finally, we report the first engraftment of neuroblastoma patient-derived xenograft cells in a humanized model, recapitulating clinically reported osteolytic lesions. Collectively, our hOss constitute a powerful standardized and malleable platform to model normal hematopoiesis, leukemia and solid tumor metastasis.
Rapid and parallel adaptive mutations in spike S1 drive clade success in SARS-CoV-2
Authors: Kistler Kathryn E. , Huddleston John , Bedford Trevor 
Published: September 2021

AbstractGiven the importance of variant SARS-CoV-2 viruses with altered receptor-binding or antigenic phenotypes, we sought to quantify the degree to which adaptive evolution is driving accumulation of mutations in the SARS-CoV-2 genome. Here we assessed adaptive evolution across genes in the SARS-CoV-2 genome by correlating clade growth with mutation accumulation as well as by comparing rates of nonsynonymous to synonymous divergence, clustering of mutations across the SARS-CoV-2 phylogeny and degree of convergent evolution of individual mutations. We find that spike S1 is the focus of adaptive evolution, but also identify positively-selected mutations in other genes that are sculpting the evolutionary trajectory of SARS-CoV-2. Adaptive changes in S1 accumulated rapidly, resulting in a remarkably high ratio of nonsynonymous to synonymous divergence that is 2.5X greater than that observed in HA1 at the beginning of the 2009 H1N1 pandemic.
Cold shock induces a terminal investment reproductive response in C. elegans
Authors: Gulyas Leah , Powell Jennifer R. 
Published: September 2021

AbstractChallenges from environmental stressors have a profound impact on many life-history traits of an organism, including reproductive strategy. Examples across multiple taxa have demonstrated that maternal reproductive investment resulting from stress can improve offspring survival; a form of matricidal provisioning when death appears imminent is known as terminal investment. Here we report a reproductive response in the nematode Caenorhabditis elegans upon exposure to acute cold shock at 2°C, whereby vitellogenic lipid movement from the soma to the germline appears to be massively upregulated at the expense of parental survival. This response is dependent on functional TAX-2;TAX-4 cGMP-gated channels that are part of canonical thermosensory mechanisms in worms and can be prevented in the presence of activated SKN-1/Nrf2, the master stress regulator. Increased maternal provisioning promotes improved embryonic cold shock survival, which is notably suppressed in animals with impaired vitellogenesis. These findings suggest that cold shock in C. elegans triggers terminal investment to promote progeny fitness at the expense of parental survival and may serve as a tractable model for future studies of stress-induced progeny plasticity.
Mitochondrial ATP production is required for endothelial cell control of vascular tone
Authors: Wilson Calum , Lee Matthew D. , Buckley Charlotte , Zhang Xun , McCarron John G. 
Published: September 2021

AbstractArteries and veins are lined by non-proliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis to fuel each of these energy-demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells in angiogenesis, and little is known about energy production in endothelial cells within the fully-formed vascular wall. Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial oxidative phosphorylation disrupts endothelial control of vascular tone. The role for endothelial cell energy production is independent of species, sex, or vascular bed. Basal, mechanically-activated, and agonist-evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. This effect is mimicked by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. These data show that mitochondrial ATP is necessary for calcium-dependent, nitric oxide mediated endothelial control of vascular tone, and identifies the critical role of endothelial mitochondrial energy production in fueling perfused blood vessel function.
Co-variation of viral recombination with single nucleotide variants during virus evolution revealed by CoVaMa
Authors: Wang Shiyi , Sotcheff Stephanea L. , Gallardo Christian M. , Jaworski Elizabeth , Torbett Bruce E. , Routh Andrew L. 
Published: September 2021

AbstractAdaptation of viruses to their environments occurs through the acquisition of both novel Single-Nucleotide Variants (SNV) and recombination events including insertions, deletions, and duplications. The co-occurrence of SNVs in individual viral genomes during their evolution has been well-described. However, unlike covariation of SNVs, studying the correlation between recombination events with each other or with SNVs has been hampered by their inherent genetic complexity and a lack of bioinformatic tools. Here, we expanded our previously reported CoVaMa pipeline (v0.1) to measure linkage disequilibrium between recombination events and SNVs within both short-read and long-read sequencing datasets. We demonstrate this approach using long-read nanopore sequencing data acquired from Flock House virus (FHV) serially passaged in vitro. We found SNVs that were either correlated or anti-correlated with large genomic deletions generated by nonhomologous recombination that give rise to Defective-RNAs. We also analyzed NGS data from longitudinal HIV samples derived from a patient undergoing antiretroviral therapy who proceeded to virological failure. We found correlations between insertions in the p6Gag and mutations in Gag cleavage sites. This report confirms previous findings and provides insights on novel associations between SNVs and specific recombination events within the viral genome and their role in viral evolution.
COVID-19 vaccine effectiveness against hospitalizations and ICU admissions in the Netherlands, April- August 2021
Authors: de Gier Brechje , Kooijman Marjolein , Kemmeren Jeanet , de Keizer Nicolette , Dongelmans Dave , van Iersel Senna C.J.L. , van de Kassteele Jan , Andeweg Stijn P. ,   the RIVM COVID-19 epidemiology and surveillance team, de Melker Hester E. , Hahné Susan J. M. , Knol Mirjam J. , van den Hof Susan 
Published: September 2021

AbstractThe objective of this study was to estimate vaccine effectiveness (VE) against COVID-19 hospitalization and ICU admission, per period according to dominating SARS-CoV-2 variant (Alpha and Delta), per vaccine and per time since vaccination. To this end, data from the national COVID-19 vaccination register was added to the national register of COVID-19 hospitalizations. For the study period 4 April – 29 August 2021, 15,571 hospitalized people with COVID-19 were included in the analysis, of whom 887 (5.7%) were fully vaccinated. Incidence rates of hospitalizations and ICU admissions per age group and vaccination status were calculated, and VE was estimated as 1-incidence rate ratio, adjusted for calendar date and age group in a negative binomial regression model. VE against hospitalization for full vaccination was 94% (95%CI 93-95%) in the Alpha period and 95% (95%CI 94-95%) in the Delta period. The VE for full vaccination against ICU admission was 93% (95%CI 87-96%) in the Alpha period and 97% (95%CI 97-98%) in the Delta period. VE was high in all age groups and did not show waning with time since vaccination up to 20 weeks after full vaccination.
Uterus-specific transcriptional regulation underlies eggshell pigment production in Japanese quail
Authors: Ishishita Satoshi , Kitahara Shumpei , Takahashi Mayuko , Iwasaki Sakura , Tatsumoto Shoji , Hara Izumi , Kaneko Yoshiki , Kinoshita Keiji , Yamaguchi Katsushi , Harada Akihito , Ohmori Yasushige , Ohkawa Yasuyuki , Go Yasuhiro , Shigenobu Shuji , Matsuda Yoichi , Suzuki Takayuki 
Published: September 2021

AbstractThe precursor of heme, protoporphyrin IX (PPIX), accumulates abundantly in the uterus of birds, such as Japanese quail, Coturnix japonica, resulting in brown-speckled eggshells. The molecular basis of PPIX production in the uterus remains largely unknown. Here, we investigated the cause of low PPIX production in a classical Japanese quail mutant exhibiting white eggshells by comparing its gene expression in the uterus with that of the wild type using transcriptome analysis and performed genetic linkage mapping to identify the causative genomic region of the white eggshell phenotype. We showed that 11 genes, including the 5-aminolevulinic acid synthase 1 (ALAS1) and ferroxidase hephaestin-like 1 (HEPHL1) genes, were specifically upregulated in the wild-type uterus and downregulated in the mutant. We mapped the 172 kb candidate genomic region on chromosome 6, which contains several genes, including a part of the paired-like homeodomain 3 (PITX3), which encodes a transcription factor. ALAS1, HEPHL1, and PITX3 were expressed in the apical cells of the luminal epithelium and lamina propria cells of the uterine mucosa of the wild-type quail, and their expression was downregulated in these cells of the mutant quail. Biochemical analysis using uterine homogenates indicated that the restricted availability of 5-aminolevulinic acid is the main cause of low PPIX production. These results suggest that uterus-specific transcriptional regulation of heme-biosynthesis-related genes is an evolutionarily acquired mechanism of eggshell pigment production in Japanese quail.
Genome-wide identification of genes important for growth of Dickeya dadantii and D. dianthicola in potato (Solanum tuberosum) tubers
Authors: Helmann Tyler C. , Filiatrault Melanie J. , Stodghill Paul V. 
Published: September 2021

AbstractDickeya species are causal agents of soft rot diseases in many economically important crops, including soft rot disease of potato (Solanum tuberosum). Using random barcode transposon-site sequencing (RB-TnSeq), we generated genome-wide mutant fitness profiles of Dickeya dadantii 3937, Dickeya dianthicola ME23, and Dickeya dianthicola 67-19 isolates collected after passage through several in vitro and in vivo conditions. Tubers from the potato cultivars “Atlantic”, “Dark Red Norland”, and “Upstate Abundance” provided highly similar conditions for bacterial growth. Using the homolog detection software PyParanoid, we matched fitness values for orthologous genes in the three bacterial strains. Direct comparison of fitness among the strains highlighted shared and variable traits important for growth. Bacterial growth in minimal medium required many metabolic traits that were also essential for competitive growth in planta, such as amino acid, carbohydrate, and nucleotide biosynthesis. Growth in tubers specifically required the pectin degradation gene kduD. Disruption in three putative DNA-binding proteins had strain-specific effects on competitive fitness in tubers. Though the Soft Rot Pectobacteriaceae can cause disease with little host specificity, it remains to be seen the extent to which strain-level variation impacts virulence.
Regulating expression of mistranslating tRNAs by readthrough RNA polymerase II transcription
Authors: Berg Matthew D. , Isaacson Joshua R. , Cozma Ecaterina , Genereaux Julie , Lajoie Patrick , Villén Judit , Brandl Christopher J. 
Published: September 2021

ABSTRACTTransfer RNA (tRNA) variants that alter the genetic code increase protein diversity and have many applications in synthetic biology. Since the tRNA variants can cause a loss of proteostasis, regulating their expression is necessary to achieve high levels of novel protein. Mechanisms to positively regulate transcription with exogenous activator proteins like those often used to regulate RNA polymerase II (RNAP II) transcribed genes are not applicable to tRNAs as their expression by RNA polymerase III requires elements internal to the tRNA. Here, we show that tRNA expression is repressed by overlapping transcription from an adjacent RNAP II promoter. Regulating the expression of the RNAP II promoter allows inverse regulation of the tRNA. Placing either Gal4 or TetR-VP16 activated promoters downstream of a mistranslating tRNASer variant that mis-incorporates serine at proline codons in Saccharomyces cerevisiae allows mistranslation at a level not otherwise possible because of the toxicity of the unregulated tRNA. Using this inducible tRNA system, we explore the proteotoxic effects of mistranslation on yeast cells. High levels of mistranslation cause cells to arrest in G1 phase. These cells are impermeable to propidium iodide, yet growth is not restored upon repressing tRNA expression. High levels of mistranslation increase cell size and alter cell morphology. This regulatable tRNA expression system can be applied to study how native tRNAs and tRNA variants affect the proteome and other biological processes. Variations of this inducible tRNA system should be applicable to other eukaryotic cell types.
FGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes
Authors: Yanucil Christopher , Kentrup Dominik , Li Xueyi , Grabner Alexander , Schramm Karla , Martinez Eliana C. , Li Jinliang , Campos Isaac , Czaya Brian , Heitman Kylie , Westbrook David , Wende Adam , Sloan Alexis , Roche Johanna M. , Fornoni Alessia , Kapiloff Michael S. , Faul Christian 
Published: September 2021

AbstractFibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling constitutes a novel mechanism promoting T2D-associated HFpEF and that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.
Unlabeled salivary gland organoids have distinct Raman signatures following FGF2-induced proacinar cell differentiation
Authors: Tubbesing Kate , Moskwa Nicholas , Khoo Ting Chean , Nelson Deirdre A. , Sharikova Anna , Larsen Melinda , Khmaladze Alexander 
Published: September 2021

AbstractOrganoids are self-organized three-dimensional (3D) tissue cultures that model the structure and function of organs to provide insights into signaling during organ formation and have translational applications in disease modeling and assessing drug responses. Due to their heterogeneity, there is a need for non-destructive methods to identify the differentiation state, or the phenotype, of organoids. As organoids often contain complex mixtures of basement membrane and/or extracellular matrix proteins, which are often highly auto-fluorescent, it typically makes low-resolution Raman measurements a challenge. We developed Raman confocal micro-spectroscopy methods to avoid and minimize the matrix signal and define specific Raman signatures for growth factor-differentiated and non-differentiated organoids. In complex, branched salivary gland organoids derived from mouse embryonic epithelial and stromal cells embedded within the laminin-rich basement membrane matrix, Matrigel, we identified specific Raman spectral signatures for organoids in different differentiation states. We report that either comparison of spectral signatures or multivariate SVD analysis can be used to distinguish between organoids treated with FGF2, organoids treated with EGF, and non-treated controls. Raman spectral signatures can be used to non-invasively distinguish between different phenotypes in the 3D context of unlabeled organoids.HighlightsFGF2-dependent proacinar cell differentiation in salivary organoids have unique Raman signatures detected with a novel confocal-based Raman imaging approach.These signatures can be used in unlabeled salivary organoids to monitor proacinar cell differentiation.Confocal-based Raman imaging may be applicable to monitoring differentiation state of other types of organoids.
Structural transitions permitting ligand entry and exit in bacterial fatty acid binding proteins
Authors: Gullett Jessica M. , Cuypers Maxime G. , Grace Christy R. , Pant Shashank , Subramanian Chitra , Tajkhorshid Emad , Rock Charles O. , White Stephen W. 
Published: September 2021

AbstractFatty acid (FA) transfer proteins extract FA from membranes and sequester their ligand to facilitate its movement through the cytosol. While detailed views of soluble protein-FA complexes are available, how FA exchange occurs at the membrane has remained unknown. Staphylococcus aureus FakB1 is a prototypical bacterial FA transfer protein that binds palmitate within a narrow, buried tunnel. Here, we determine the conformational change from this closed state to an open state that engages the phospholipid bilayer. Upon membrane binding, a dynamic loop in FakB1 that covers the FA binding site disengages and folds into an amphipathic helix. This helix inserts below the phosphate plane of the bilayer to create a diffusion channel for the FA to exchange between the protein and the membrane. The structure of the bilayer-associated conformation of FakB1 has local similarities with mammalian FA binding proteins and provides a general conceptual framework for how these proteins interact with the membrane to promote lipid transfer.
“I thought I was prepared to do this”: an exploration of the learning and development of leadership coaches
Authors: Huggins Kristin Shawn , Klar Hans W. , Andreoli Parker M. 
Published: September 2021

PurposeThe purpose of this paper was to determine what experienced school leaders learned through participating in a three-year leadership initiative, called the Leadership Learning Community (LLC), that helped them coach less experienced leaders to lead school improvement efforts.Design/methodology/approachData were collected and analyzed using a qualitative design throughout the three-year initiative.FindingsThe findings indicate the LLC leadership coaches learned to accept and navigate the leaders' developmental and contextual needs, practiced and honed their coaching skills and recognized their own developmental needs.Originality/valueThese findings address the paucity of research on leadership coach learning and development.
Brand positioning and business performance of alcoholic beverage firms in an emerging market context: the mediation effect of brand equity
Authors: Ameyibor Leeford Edem Kojo , Anabila Peter , Saini Yvonne Kabeya 
Published: September 2021

PurposeThis study aims to investigate the relationship between brand positioning and business performance, as well as the mediation effect of brand equity between them within the context of Ghana’s alcoholic beverages industry.Design/methodology/approachA sample of 196 staff across four alcoholic beverage firms in Accra, Ghana was selected using a judgemental sampling technique. A structural equation modelling approach using partial least squares was used to conduct the analyses to answer the research hypotheses.FindingsAll the hypotheses were confirmed in line with extant literature. Specifically, the study found a positive relationship between brand positioning and business performance. The study also found that brand equity partially mediates the relationship between brand positioning and business performance.Practical implicationsThe study serves as a useful guide to strategy and policy formulation in branding in general and specifically on how brand positioning can be effectively deployed as a key strategy to enhance business performance.Originality/valueThe study has practical implications not only for the marketing and sale of alcoholic beverages in Ghana to achieve financial performance but also for lasting competitive advantage.
A novel tracking system for human following robots with fusion of MMW radar and monocular vision
Authors: Zhu Yipeng , Wang Tao , Zhu Shiqiang 
Published: September 2021

Purpose
This paper aims to develop a robust person tracking method for human following robots. The tracking system adopts the multimodal fusion results of millimeter wave (MMW) radars and monocular cameras for perception. A prototype of human following robot is developed and evaluated by using the proposed tracking system.

Design/methodology/approach
Limited by angular resolution, point clouds from MMW radars are too sparse to form features for human detection. Monocular cameras can provide semantic information for objects in view, but cannot provide spatial locations. Considering the complementarity of the two sensors, a sensor fusion algorithm based on multimodal data combination is proposed to identify and localize the target person under challenging conditions. In addition, a closed-loop controller is designed for the robot to follow the target person with expected distance.

Findings
A series of experiments under different circumstances are carried out to validate the fusion-based tracking method. Experimental results show that the average tracking errors are around 0.1 m. It is also found that the robot can handle different situations and overcome short-term interference, continually track and follow the target person.

Originality/value
This paper proposed a robust tracking system with the fusion of MMW radars and cameras. Interference such as occlusion and overlapping are well handled with the help of the velocity information from the radars. Compared to other state-of-the-art plans, the sensor fusion method is cost-effective and requires no additional tags with people. Its stable performance shows good application prospects in human following robots.