bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Meta-Analytic Single-Cell Atlas of Mouse Bone Marrow Hematopoietic Development
Authors: Harris Benjamin D. , Lee John , Gillis Jesse 
Published: August 2021

AbstractThe clinical importance of the hematopoietic system makes it one of the most heavily studied lineages in all of biology. A clear understanding of the cell types and functional programs during hematopoietic development is central to research in aging, cancer, and infectious diseases. Known cell types are traditionally identified by the expression of proteins on the surface of the cells. Stem and progenitor cells defined based on these markers are assigned functions based on their lineage potential. The rapid growth of single cell RNA sequencing technologies (scRNAseq) provides a new modality for evaluating the cellular and functional landscape of hematopoietic stem and progenitor cells. The popularity of this technology among hematopoiesis researchers enables us to conduct a robust meta-analysis of mouse bone marrow scRNAseq data. Using over 300,000 cells across 12 datasets, we evaluate the classification and function of cell types based on discrete clustering,in silicoFACS sorting, and a continuous trajectory. We identify replicable signatures that define cell types based on genes and known cellular functions. Additionally, we evaluate the conservation of signatures associated with erythroid and monocyte lineage development across species using co-expression networks. The co-expression networks predict the effectiveness of the signature at identifying erythroid and monocyte cells in zebrafish and human scRNAseq data. Together, this analysis provides a robust reference, particularly marker genes and functional annotations, for future experiments in hematopoietic development.Key PointsMeta-analysis of 9 mouse bone marrow scRNAseq identifies markers for cell types and hematopoietic developmentCharacterize a replicable functional landscape of cell types by exploiting co-expression
Tissue-wide metabolomics reveals wide impact of gut microbiota on mice metabolite composition
Authors: Zarei Iman , Koistinen Ville M. , Kokla Marietta , Klåvus Anton , Babu Ambrin Farizah , Lehtonen Marko , Auriola Seppo , Hanhineva Kati 
Published: August 2021

AbstractThe essential role of gut microbiota in health and disease is well-recognized, but the biochemical details underling beneficial impact remain largely undefined. Dysbiosis of gut bacteria results in the alteration of certain microbial and host metabolites, and identifying these markers could enhance the early detection of certain diseases. We report LC-MS based non-targeted metabolic profiling to demonstrate a large effect of gut microbiota on mammalian tissue metabolites. It was hypothesized that gut microbiota influences the overall biochemistry of the host metabolome and this effect is tissue-specific. Thirteen different tissues from germ-free and conventional mice were selected and their metabolic differences were analyzed. Our study demonstrated a large effect of the microbiome on mammalian biochemistry at different tissue levels and resulted in significant modulation of metabolites from multiple metabolic pathway (p ≤ 0.05). A vast metabolic response of host to metabolites generated by the microbiota was observed, Hundreds of molecular features were detected exclusively in one mouse group, with the majority of these being unique to specific tissue, suggesting direct impact gut microbiota on host metabolism.
Identification and validation of E3 ubiquitin ligase XIAP as a novel substrate of deubiquitinase USP7 (HAUSP) - Implication towards oncogenesis
Authors: Saha Gouranga , Sarkar Sibani , Mohanta Partha S , Kumar Krishna , Chakraborty Saikat , Ghosh Mrinal K 
Published: August 2021

AbstractThe induction of apoptosis upon USP7 (HAUSP) inhibition is established in cancers that contain a wild-type p53 (p53Wt) through the ‘USP7-Mdm2-p53’ axis, but no clear explanation has yet been reported for the same to occur in cancers containing mutant 53 (p53Mut) or even p53 null (p53Null) systems. Instead of this ‘USP7-Mdm2-p53’ axis USP7 also works through an alternative new pathway identified in this study. Here in this study, we observed that the magnitude of apoptosis induction in response to USP7 inhibition was remarkably similar between cancer cells showing p53Nullor p53Mutand those with p53Wt. Through a proteomics-based approach, we were able to identify XIAP as a novel interacting partner for USP7. XIAP is a potent and well-characterized member of the inhibitor of apoptosis proteins (IAPs), which function through caspase inhibition. We successfully identified USP7 as a positive regulator of XIAP at post-translational but not at its transcriptional level. Using molecular modelling coupled with domain deletion studies, we show that the first three Ubl domains in association with the catalytic domain of USP7 interact with the BIR2 and the linker region between BIR2 and BIR3 domains of XIAP. Modulation of expression and catalytic activity of USP7 in multiple type of cancer cell lines showed that USP7 stabilizes XIAP through its deubiquitinase activity. We have also observed that USP7 sensitizes cells against chemotherapeutic drugs through stabilization of XIAP. Thus, USP7 promotes tumorigenesis in multiple cancers,viastabilization of XIAP that results in apoptosis inhibition in caspase dependent pathway. Moreover, we observed that combinatorial inhibition of USP7 and XIAP can induce cellular apoptosis in a higher magnitude than their individual inhibition. Additionally, our results indicates that nanoformulated P5091 and P22077 showed higher potency for killing C6 cells in comparison to normal drugs. To the best of our knowledge, this is the first report on identification and validation of XIAP, a crucial E3 ubiquitin ligase, as a novel substrate of the deubiquitinase USP7 and they together involve in empowerment of the tumorigenic potential of cancer cells.
Structurally distinct polymorphs of Tau aggregates revealed by nanoscale infrared spectroscopy
Authors: Banerjee Siddhartha , Ghosh Ayanjeet 
Published: August 2021

AbstractAggregation of the tau protein plays a central role in several neurodegenerative diseases collectively known as tauopathies, including Alzheimer’s and Parkinson’s disease. Tau misfolds into fibrillar beta sheet structures that constitute the paired helical filaments found in Neurofibrillary tangles. It is known that there can be significant structural heterogeneities in tau aggregates associated with different diseases. However, while structures of mature fibrils have been studied, the structural distributions in early stage tau aggregates is not well understood. In the present study, we use AFM-IR to investigate nanoscale spectra of individual tau fibrils at different stages of aggregation and demonstrate the presence of multiple fibrillar polymorphs that exhibit different secondary structures. We further show that mature fibrils contain significant amounts of antiparallel beta sheets. Our results are the very first application of nanoscale infrared spectroscopy to tau aggregates and underscore the promise of spatially resolved infrared spectroscopy for investigating protein aggregation.
A-GHN: Attention-based Fusion of Multiple GraphHeat Networks for Structural to Functional Brain Mapping
Authors: Oota Subba Reddy , Yadav Archi , Dash Arpita , Bapi Raju S. , Sharma Avinash 
Published: August 2021

AbstractOver the last decade, there has been growing interest in learning the mapping from structural connectivity (SC) to functional connectivity (FC) of the brain. The spontaneous fluctuations of the brain activity during the restingstate as captured by functional MRI (rsfMRI) contain rich non-stationary dynamics over a relatively fixed structural connectome. Among the modeling approaches, graph diffusion-based methods with single and multiple diffusion kernels approximating static or dynamic functional connectivity have shown promise in predicting the FC given the SC. However, these methods are computationally expensive, not scalable, and fail to capture the complex dynamics underlying the whole process. Recently, deep learning methods such as GraphHeat networks along with graph diffusion have been shown to handle complex relational structures while preserving global information. In this paper, we propose a novel attention-based fusion of multiple GraphHeat networks (A-GHN) for mapping SC-FC. A-GHN enables us to model multiple heat kernel diffusion over the brain graph for approximating the complex Reaction Diffusion phenomenon. We argue that the proposed deep learning method overcomes the scalability and computational inefficiency issues but can still learn the SC-FC mapping successfully. Training and testing were done using the rsfMRI data of 100 participants from the human connectome project (HCP), and the results establish the viability of the proposed model. Furthermore, experiments demonstrate that A-GHN outperforms the existing methods in learning the complex nature of human brain function.
Sclerostin Small Molecule Inhibitors Promote Osteogenesis by Activating Canonical Wnt and BMP Pathways
Authors: Sangadala Sreedhara , Kim Chi Heon , Fernandes Lorenzo M. , Makkar Pooja , Boden Scott D. , Beck George R. , Drissi Hicham , Presciutti Steven M. 
Published: August 2021

AbstractBackgroundThe healing environment within the posterolateral lumbar spine is one of the most clinically challenging bone healing environments in all of orthopaedics due to a lack of a contained space and the need to formde novobone in a non-bony environment. Our group has previously published data that suggests that sclerostin in expressed locally at high levels throughout the process of a spinal fusion mass maturing.MethodsWe computationally identified multiple FDA-approved drugs, as well as a novel drug, for their ability to disrupt the interaction between sclerostin and its receptor, LRP5/6. The drugs were tested in several in vitro biochemical assays using murine MC3T3 and MSCs, assessing their ability to (1) enhance canonical Wnt signaling, (2) promote the accumulation of the active (non-phosphorylated) form of β-catenin, and (3) enhance the intensity and signaling duration of BMP signaling. These drugs were then tested subcutaneously in rats as standalone osteoinductive agents on plain collagen sponges. Finally, the top drug candidates (called VA1 and C07) were tested in a rabbit posterolateral spine fusion model for their ability to achieve a successful fusion.ResultsWe show that by controlling GSK3b phosphorylation, these SMIs simultaneously enhance canonical Wnt signaling and potentiate canonical BMP signaling intensity and duration. We also demonstrate that the SMIs produce dose-dependent ectopic mineralizationin vivoin rats as well as significantly increase posterolateral spine fusion rates in rabbitsin vivo, both as standalone osteogenic drugs and in combination with autologous iliac crest bone graft.ConclusionsFew if any osteogenic small molecules have been described that possess the osteoinductive potency of BMP itself – that is, the ability to formde novoectopic bone as a standalone agent, particularly in stringentin vivoenvironments. Herein, we describe two such SMIs that have this unique ability and thus may have potential application as novel cost-effective biologic bone graft substitutes for achieving consistent spinal fusion or even or critical-sized fracture defects.FundingThis work was supported by a Veteran Affairs Career Development Award (IK2-BX003845).
Predicting the distributions ofPouteria adolfi-friedericiandPrunus africanaiconic tree species under current and future climate change scenarios in Ethiopia
Authors: Tadesse Zerihun , Nemomissa Sileshi , Lemessa Debissa 
Published: August 2021

AbstractThe distributions of the potential adaptive ranges of iconic plant species are not yet fully known especially in regions such as Ethiopia where high climatic variability and vegetation types are found. This study was undertaken to predict the distributions of the potential suitable habitats ofPouteria adolfi-friedericiandPrunus africanatree species under the current and two future climate scenarios (i.e., RCP 4.5 and RCP 8.5 in 2050 and 2070) using MaxEnt software (version: 3.4.4.). Eleven less correlated environmental variables (r<0.7) were identified and used to make the prediction models. Elevational shifts of the highly suitable habitats, effects of elevation, solar radiation and topographic position in relation to the current and future climatic scenarios on the habitats were statistically analyzed using independent t-test and linear model. Under all climate scenarios, we found a decrease in the proportion of areas of highly suitable habitats for both study species. High potentials of suitable habitats forPouteria adolfi-friedericiare predicted to be confined to southwest, west central and south parts of Ethiopia in fragmented moist afromontane forest patches, while it is in the southwest and west central parts of Ethiopia forPrunus africana. On basis of vegetation types of the country, potential suitable habitats forPouteria adolfi-friedericiare predicted to occur in moist evergreen forest, dry evergreen forest and grassland complex andCombretum-Terminaliawoodland vegetation types. Whereas, moist evergreen forest, dry evergreen forest and grassland complex and riverine vegetation types are predicted to comprise potential suitable habitats forPrunus africana,showing considerable spatial dynamics. Overall, our results suggest that the strategies deem to design biodiversity conservation should take into account the dynamics of the suitable niches of different species under different future climate scenarios.
Mixed selectivity in the cerebellar Purkinje-cell response during visuomotor association learning
Authors: Sendhilnathan Naveen , Ipata Anna E. , Goldberg Michael E. 
Published: August 2021

AbstractAlthough the cerebellum has been traditionally considered to be exclusively involved in motor control, recent anatomical and clinical studies show that it also has a role in reward-processing. However, the way in which the movement related and the reward related neural activity interact at the level of the cerebellar cortex and contribute towards learning is still unclear. Here, we studied the simple spike activity of Purkinje cells in the mid-lateral cerebellum when monkeys learned to associate a right or left-hand movement with one of two visual symbolic cues. These cells had distinctly different discharge patterns between an overtrained symbol-hand association and a novel symbol-hand association, responding in association with the movement of both hands, although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the movement kinematics, the monkeys’ reaction times or the novelty of the visual symbols. The simple spike activity changed with throughout the learning process, but the concurrent complex spikes did not instruct that change. Although these neurons also have reward-related activity, the reward-related and movement-related signals were independent. We suggest that this mixed-selectivity may facilitate the flexible learning of difficult reinforcement learning problems.
Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: the VITAL-AF Randomized Controlled Trial
Authors: Lubitz Steven A. , Atlas Steven J. , Ashburner Jeffrey M. , Lipsanopoulos Ana T. Trisini , Borowsky Leila H. , Guan Wyliena , Khurshid Shaan , Ellinor Patrick T. , Chang Yuchiao , McManus David D. , Singer Daniel E. 
Published: August 2021

ABSTRACTBackgroundUndiagnosed atrial fibrillation (AF) may cause preventable strokes. Guidelines differ regarding AF screening recommendations. We tested whether point-of-care screening with a handheld single lead electrocardiogram (ECG) at primary care practice visits increases diagnoses of AF.MethodsWe randomized 16 primary care clinics 1:1 to AF screening using a handheld single-lead ECG (AliveCor KardiaMobile) during vital sign assessments, or usual care. Patients included were aged ≥ 65 years. Screening results were provided to primary care clinicians at the encounter. All confirmatory diagnostic testing and treatment decisions were made by the primary care clinician. New AF diagnoses over one-year follow-up were ascertained electronically and manually adjudicated. Proportions and incidence rates were calculated. Effect heterogeneity was assessed.ResultsOf 30,715 patients without prevalent AF (n=15,393 screening [91% screened], n=15,322 control), 1.72% of individuals in the screening group had new AF diagnosed at one year versus 1.59% in the control group (risk difference [RD] 0.13%, 95% confidence interval [CI] −0.16–0.42, P=0.38). New AF diagnoses in the screening and control groups differed by age with the greatest effect observed for those aged ≥ 85 years (5.56% versus 3.76%, respectively, RD 1.80%, 95% CI 0.18–3.30). The difference in newly diagnosed AF between the screening period and the prior year was marginally greater in the screening versus control group (0.32% versus −0.12%, RD 0.43%, 95% CI −0.01–0.84). The proportion of individuals with newly diagnosed AF who were initiated on oral anticoagulants was similar in the screening (n=194, 73.5%) and control (n=172, 70.8%) arms (RD 2.7%, 95% CI −5.5–10.4).ConclusionsScreening for AF using a single-lead ECG at primary care visits was not associated with a significant increase in new AF diagnoses among individuals aged 65 years or older compared to usual care. However, screening may be associated with an increased likelihood of diagnosing AF among individuals aged 85 years or older and warrants further evaluation.This study is registered with ClinicalTrials.gov,NCT03515057FundingBristol Myers Squibb-Pfizer Alliance
Transcriptional profiling of early differentiation of primary human mesenchymal stem cells into chondrocytes
Authors: Schwarzl Thomas , Keogh Andrea , Shaw Georgina , Krstic Aleksandar , Clayton Elizabeth , Murphy Mary , Higgins Desmond G , Kolch Walter , Barry Frank 
Published: August 2021

AbstractArticular cartilage has only very limited regenerative capacities in humans. Tissue engineering techniques for cartilage damage repair are limited in the production of hyaline cartilage. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells and can be differentiated into mature cartilage cells, chondrocytes, which could be used for repairing damaged cartilage. Chondrogenesis is a highly complex, relatively inefficient process lasting over 3 weeks in vitro. In order to better understand chondrogenic differentiation, especially the commitment phase, we have performed transcriptional profiling of MSC differentiation into chondrocytes from early timepoints starting 15 minutes after induction to 16 hours and fully differentiated chondrocytes at 21 days. Transcriptional gene regulatory networks (GRN) were identified using time-course clustering and upstream-regulator predictions which revealed that cells start epigenetic reprogramming as early as 2 hours after induction and commit to differentiation within 4-6 hours. After that they adapt their gene expression to cater for differentiation specific protein production. These results suggest that interventions to improve the frequency and efficiency of differentiation should target early processes.
Sound sellers: musicians' strategies for marketing to industry gatekeepers
Authors: Sanders Ariel , Phillips Barbara J. , Williams David E. 
Published: August 2021

PurposeThe relationship between musicians and the music industry has often been depicted as a dichotomy between creativity and commerce with musicians conflicted between their roles as artists and their roles as marketers of sound. Recently, marketing researchers have problematized this dichotomy and suggested musicians perceive these roles as inevitable and indivisible. However, the processes of how musicians market their sound to the industry gatekeepers remain unclear. This study seeks to find the key industry gatekeepers for musicians and how musicians sell their personal sound to them.Design/methodology/approachUsing an interpretative phenomenological approach, ten interviews with professional musicians across different music genres provided insight into the strategies musicians use to market their sound to industry gatekeepers.FindingsIn total, three key gatekeepers and the five strategies that musicians use to sell their sound are identified. The gatekeepers are record labels, other musicians and consumers. Musicians sell their sound to these gatekeepers through the externally directed strategies of using social media to build relationships, defining their personal sound through genre and creating a unique sound, and through the internally directed strategies of keeping motivated through sound evolution and counting on luck.Research limitations/implicationsThe findings are limited by the small number of musicians interviewed and the heterogeneous representation of music genres.Originality/valueThe study contributes to theoretical understandings of how musicians as cultural producers market their sound in a commercial industry.
Transforming the construction sector: an institutional complexity perspective
Authors: Oti-Sarpong Kwadwo , Pärn Erika Anneli , Burgess Gemma , Zaki Mohamed 
Published: August 2021

Purpose
Government initiatives to improve construction have increasingly become more focused on introducing a repertoire of technologies to transform the sector. In the literature on construction industry transformation through policy-backed initiatives, how firms will respond to the demands to adopt and use innovative technologies and approaches is taken for granted, and there is scarcely any attention given to the institutional implications of transformation agenda. The purpose of this paper is to discuss these gaps and offer directions for future research.

Design/methodology/approach
Following a synthesis of literature on the UK’s industry transformation agenda, the authors use the concepts of institutional logics, arrangements, complexity and strategic responses to suggest seven research questions that are at the nexus of policy-backed transformation and institutional theory.

Findings
In this paper, the authors argue that increasing demands for the adoption and use of digital technologies, platforms, manufacturing approaches and other “industry-4.0”-related technologies will reconfigure existing logics and arrangements in the construction industry, creating a problem of institutional complexity for general contracting firms in particular.

Originality/value
The questions are relevant for our understanding of the nature of institutional complexities, change, strategic firm responses, field-level dynamics and implications for the construction industry in relation to the transformation agenda. This paper is positioned to spur future research towards exploring the consequences of industry transformation through the lens of institutional theory.