bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Type 2 Diabetes Risk Stratification in the Qatar Biobank Cohort by Ensemble Learning Classifier Incorporating Multi-Trait, Population-Specific, Polygenic Risk Scores
Authors: Ahmed Ikhlak , Ziab Mubarak , Taheri Shahrad , Chagoury Odette , Hussain Sura A. , Lakshmi Jyothi , Bhat Ajaz A. , Fakhro Khalid A. , Al-Shabeeb Akil Ammira S. 
Published: June 2023

ABSTRACTBackgroundType 2 Diabetes (T2D) is a pervasive chronic disease influenced by a complex interplay of environmental and genetic factors. To enhance T2D risk prediction, leveraging genetic information is essential, with polygenic risk scores (PRS) offering a promising tool for assessing individual genetic risk. Our study focuses on the comparison between multi-trait and single-trait PRS models and demonstrates how the incorporation of multi-trait PRS into risk prediction models can significantly augment T2D risk assessment accuracy and effectiveness.MethodsWe conducted genome-wide association studies (GWAS) on 12 distinct T2D-related traits within a cohort of 14,278 individuals, all sequenced under the Qatar Genome Programme (QGP). This in-depth genetic analysis yielded several novel genetic variants associated with T2D, which served as the foundation for constructing multiple weighted PRS models. To assess the cumulative risk from these predictors, we applied machine learning (ML) techniques, which allowed for a thorough risk assessment.ResultsOur research identified genetic variations tied to T2D risk and facilitated the construction of ML models integrating PRS predictors for an exhaustive risk evaluation. The top-performing ML model demonstrated a robust performance with an accuracy of 0.8549, AUC of 0.92, AUC-PR of 0.8522, and an F1 score of 0.757, reflecting its strong capacity to differentiate cases from controls. We are currently working on acquiring independent T2D cohorts to validate the efficacy of our final model.ConclusionOur research underscores the potential of PRS models in identifying individuals within the population who are at elevated risk of developing T2D and its associated complications. The use of multi-trait PRS and ML models for risk prediction could inform early interventions, potentially identifying T2D patients who stand to benefit most based on their individual genetic risk profile. This combined approach signifies a stride forward in the field of precision medicine, potentially enhancing T2D risk prediction, prevention, and management.
PINK1 Deficiency Alters Muscle Stem Cell Fate Decision and Muscle Regenerative Capacity
Authors: Cairns George , Thumiah-Mootoo Madhavee , Abassi Mah Rukh , Racine Jeremy , Larionov Nikita , Prola Alexandre , Khacho Mireille , Burelle Yan 
Published: June 2023

ABSTRACTMaintenance of optimal mitochondrial function plays a crucial role in the regulation of muscle stem cell (MuSC) behavior, but the underlying maintenance mechanisms remain ill defined. In this study, we explored the importance of mitophagy, as a mitochondrial quality control regulator, in MuSCs and the role this process plays in maintaining optimal muscle regenerative capacity. Here we show that MuSCs exhibit dynamic alterations in mitophagy under different physiological myogenic states. In particular, quiescent MuSCs exhibit high levels of PINK1/Parkin-dependent mitophagy, which is rapidly decreased upon transition to an early activation state. Genetic disruption of this pathway usingPink1knockout mice reduced mitophagy in quiescent MuSCs, which was accompanied by increased mitochondrial ROS release and mitochondrial network fragmentation. These abnormalities led to hampered self-renewal of MuSCs which ultimately translated in a progressive loss of muscle regeneration following repetitive injury. However, proliferation and differentiation capacity were unaltered in the absence of PINK1, indicating that altered fate decisions is the main mechanism underlying impaired muscle regeneration. Impaired fate decisions in PINK1 deficient MuSCs could be restored by scavenging excess mitochondrial ROS. Together, these data shed new light on the regulation of mitophagy during MuSC state transitions and position the PINK1-dependent pathway as an important regulator of MuSC mitochondrial properties and fate decisions.
Biomimetic Artificial Bone Marrow Niches for the Scale Up of Hematopoietic Stem Cells
Authors: Bosch-Fortea Minerva , Marciano Daniele , Gautrot Julien E. 
Published: June 2023

AbstractHematopoietic stem cell (HSC) transplantation to treat haematological disorders is greatly restricted by poor cell availability.Ex vivoexpansion of HSCs as a strategy to overcome this limitation has shown limited success so far, due to the loss of stem cell properties in culture. Therefore, engineering of culture platforms that mimic the physiological properties of the bone marrow (BM) in a scalable format is an important target to enable the translation of HSC therapies. Here, we report the design of biomimetic BM niches that enable the culture of HSCs in a scalable 3D platform. Beyond cellular and biochemical components (e.g., matrix and growth factors), an important element of the BM microenvironment is its architecture, dense in adipocytes, with relatively limited matrix and anisotropic mechanical properties. To capture this context, we propose the use of bioemulsions1,2in which oil microdroplets and associated mechanical anisotropy recreate important architectural features of the hematopoietic niche. Mesenchymal stem cells (MSCs) grown at the surface of such bioemulsion remodelled this environment, assembling an interstitial matrix mimicking that of the BM microenvironment composition. In addition, MSCs secreted important factors underpinning the crosstalk between stromal cells and HSCs in the native environment. HSCs cultured in the resulting artificial BM niches maintained stemness whilst expanding significantly (> 33-fold compared to HSCs cultured in suspension) and enabling scale up of expansion in conical flask bioreactors, to produce 2M cells in a single batch. This platform therefore harnesses engineered BM microenvironments and the processability of bioemulsions and microdroplet technologies to produce HSCs in a scalable format, for application in cell-based therapies.
Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation
Authors: Radvanyi Zsuzsa , Yoo Eun Jin , Kandasamy Palanivel , Salas-Bastos Adrian , Monnerat Sophie , Refardt Julie , Christ-Crain Mirjam , Hayashi Himeka , Kondo Yasuhiko , Jantsch Jonathan , Rubio-Aliaga Isabel , Sommer Lukas , Wagner Carsten A. , Hediger Matthias A. , Kwon Hyug Moo , Loffing Johannes , Pathare Ganesh 
Published: June 2023

ABSTRACTFibroblast growth factor-23 (FGF23) is a bone-derived hormone that has recently received much attention due to its association with the progression of chronic kidney disease, cardiovascular disease, and associated mortality. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (low serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (−20 mM) increased FGF23 synthesis in the osteoblast-like cell line UMR-106. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. On the other hand, arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+] revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that human hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.SIGNIFICANCE STATEMENTFibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls phosphate and vitamin D metabolism. Excess FGF23 is postulated to cause left ventricular hypertrophy, while FGF23 deficiency reduces life span and mimics age-related diseases in mice. FGF23 is also a potential biomarker for chronic kidney disease and cardiovascular disorders, but its role in disease progression is unclear. Therefore, it is important to explore the regulation of FGF23 production, which is incompletely understood. Our paper identifies extracellular-sodium-NFAT5 signaling as a key regulator of FGF23 formation.
Study on Vibrational Behavior of Cytoskeletons Modeled by Cylindrical Tensegrity Structure
Authors: Nouchi Eiji , Oka Tomoteru , Kataoka Noriyuki , Kawano Yoshihisa , Gan Buntara Sthenly 
Published: June 2023

AbstractThe dynamic mechanism of a cellular cytoskeleton is essential for the role of the cell, and its accurate characterization has been a long-standing problem for cell scientists. A cytoskeleton’s vibrations are highly influenced by interactions of filamentous proteins mediated by axial vibration of the stiff microtubules (compressive member) and lateral vibration of F-actin (tensile member). Among various structures in a cell, the cytoplasmic contractile bundles, lamellipodia, and filipodia cells can be modeled by a symmetrical cylinder-shaped self-equilibrium tensegrity structure with different radii at the top and bottom of the cylinder. The truncated conelike cylinder model is made to be small in height compared to both radii. This study investigates the tensegrity self-vibrational behavior of the cellular cytoskeleton to calculate its natural frequencies, composed of the individual vibration of microtubules and F-actins from measured data. The spectral element method is adopted based on the Wittrick–Williams procedure to solve the vibrational behaviors of the cellular cytoskeleton. Various n-polygon cylindrical truncated cone-shaped tensegrity structures to mimic the cellular cytoskeletons are presented to demonstrate the robustness of the present study.
Improving accuracy and precision of heritability estimation in twin studies: Reassessing the measurement error assumption
Authors: Chen Gang , Moraczewski Dustin , Taylor Paul A. 
Published: June 2023

AbstractIn this study, we demonstrate the need for improvement in the conventional ACE model used for estimating heritability when applied to trait data with measurement errors. The critical issue revolves around an assumption concerning measurement errors in twin studies. In cases where traits are measured using samples, data is aggregated during preprocessing, with only a centrality measure (e.g., mean) being used for modeling. Additionally, measurement errors resulting from sampling are assumed to be part of the nonshared environment and are thus overlooked in heritability estimation. Consequently, the presence of intra-individual variability remains concealed. Moreover, recommended sample sizes (e.g., 600 twin pairs) are typically based on the assumption of no measurement errors.We argue that measurement errors in the form of intra-individual variability are an intrinsic limitation of finite sampling and should not be considered as part of the nonshared environment. Previous studies have shown that the intra-individual variability of psychometric effects is significantly larger than the inter-individual counterpart. Here, to demonstrate the appropriateness and advantages of our hierarchical modeling approach in heritability estimation, we utilize simulations as well as a real dataset from the ABCD (Adolescent Brain Cognitive Development) study. Moreover, we showcase the following analytical insights for data containing non-negligible measurement errors:The conventional ACE model may underestimate heritability.A hierarchical model provides a more accurate assessment of heritability.Large samples, exceeding 100 observations or thousands of twins, may be necessary to reduce ambiguity. In summary, our study sheds light on the impact of measurement errors on heritability estimation and proposes a hierarchical model as a more accurate alternative. These findings have important implications for understanding individual differences and for the design and analysis of twin studies.
Intrarenal myeloid subsets associated with kidney injury are comparable in mice and patients with lupus nephritis
Authors: Hoover Paul J. , Lieb David J. , Kang Joyce , Li Stephen , Peters Michael , Raparia Chirag , Arazi Arnon , Eisenhaure Thomas , Gurajala Saisram S. , Xiao Qian , Mishra Rakesh , Spurrell Max , Menon Rajasree , Kretzler Matthias , Chen Jonathan , Nieman Linda , Sonny Abraham , Demeke Dawit , Hodgin Jeffrey , Guthridge Joel , Fava Andrea , Clancy Robert , Putterman Chaim , Izmirly Peter , Belmont H. Michael , Kalunian Kenneth , Kamen Diane , Wofsy David , Buyon Jill , James Judith A. , Petri Michelle , Diamond Betty , Raychaudhuri Soumya ,   The Kidney Precision Medicine Project,   The Accelerating Medicines Partnership: RA/SLE network, Hacohen Nir , Davidson Anne ,   Co-senior
Published: June 2023

AbstractResident macrophages and infiltrating monocytes in kidneys of patients with lupus nephritis are altered both in frequency and function relative to their counterparts in healthy kidneys. The extent to which mouse models might be useful in developing approaches to target these cells for treating lupus nephritis is poorly understood. Here, we studied four common lupus mouse models that share clinical, serologic, and histopathologic kidney changes with humans. Using single-cell profiling and multiplex spatial imaging to analyze the intrarenal myeloid compartment with the onset of clinical disease in these models, we identified monocyte and macrophage subsets that expand or contract in kidneys with clinical nephritis. A unique subset of classical monocytes expanded with the onset of disease and expressed genes such asCD9, Spp1, Ctsd, Cd63, Apoe,andTrem2that were previously shown to be induced by tissue injury and play a role in inflammation, lipid metabolism and tissue repair in other organs. Resident macrophages transitioned from a pro-inflammatory to a similar injury-associated state with onset of disease. To test whether these findings in mouse models were also observed in humans, we re-analyzed monocytes and macrophages in a single-cell RNAseq dataset of kidney biopsies from 155 patients with lupus nephritis and 30 healthy donors, collected by the NIH AMP RA/SLE consortium. Human monocytes and macrophages showed conserved changes in gene expression programs associated with lupus nephritis disease indices, and localized to similar kidney microenvironments as in mice. By identifying myeloid subsets and disease-associated alterations in biological processes that are conserved across species, we provide a strong rationale for functional studies of these cells and pathways in mice to uncover mechanisms and find targets relevant to human lupus nephritis.One sentence summaryThis study characterizes intrarenal myeloid cells from four lupus mouse models and 155 patients with lupus nephritis using single-cell RNA-seq and imaging, and identifies novel infiltrating and resident myeloid subsets that are conserved between mouse and human lupus nephritis, thus providing a map and strong rationale for functional studies in mice with relevance to human disease.
Manipulation of encapsulated artificial phospholipid membranes using sub-micellar lysolipid concentrations
Authors: Dimitriou Pantelitsa , Li Jin , Jamieson William D. , Schneider Johannes J. , Castell Oliver K. , Barrow David A. 
Published: June 2023

AbstractDroplet Interface Bilayers (DIBs) constitute a commonly used model of artificial membranes for molecular biology studies with applications in synthetic biology research. However, these model membranes have limited accessibility due to their requirement to be surrounded by an oil environment. Here, we demonstrate in-situ bilayer manipulation of submillimeter, free-standing, encapsulated droplet interface bilayers (eDIBs) in hydrogel capsules formed using dual-material, 3D-printed microfluidic devices. These microfluidic devices required no post-fabrication assembly, nor surface treatment to achieve the high-order emulsification, required for the formation of robust eDIBs. The eDIB capsules were exposed to various concentrations of lysophosphatidylcholine (LPC), in order to investigate the interaction of lysolipids with three-dimensional, encapsulated droplet bilayer networks. Micellar LPC concentrations trigger the bursting of the eDIB droplets, while at concentrations below the critical micelle concentration (CMC), the encapsulated aqueous inner droplet networks endure structural changes, precisely affecting the DIB contact angles and bilayer area. Manipulation of these enclosed, 3D-orchestrated membrane mimics facilitates the exploration of readily accessible compartmentalized artificial cellular machinery. Collectively, the multi-compartmentalized capsules and the lysolipid-mediated membrane modulation, introduce a chemical approach to control the properties and mechanics of artificial cellular membranes, toward responsive soft material developments.
A mitochondrial surveillance mechanism activated bySRSF2mutations in hematologic malignancies
Authors: Liu Xiaolei , Devadiga Sudhish A. , Stanley Robert F. , Morrow Ryan , Janssen Kevin , Quesnel-Vallières Mathieu , Pomp Oz , Moverley Adam A. , Li Chenchen , Skuli Nicolas , Carroll Martin P. , Huang Jian , Wallace Douglas C. , Lynch Kristen W. , Abdel-Wahab Omar , Klein Peter S. 
Published: June 2023

AbstractSplicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenicSRSF2P95H/+mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activatorPINK1to remove a poison intron, increasing the stability and abundance ofPINK1mRNA and protein.SRSF2P95H-induced mitochondrial dysfunction increasedPINK1expression through this mechanism, which is essential for survival ofSRSF2P95H/+cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis inSRSF2P95H/+cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress throughPINK1splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability inSRSF2P95Hmutant MDS and AML.
IRF8 configures enhancer landscape in postnatal microglia and directs microglia specific transcriptional programs
Authors: Saeki Keita , Pan Richard , Lee Eunju , Kurotaki Daisuke , Ozato Keiko 
Published: June 2023

AbstractMicroglia are innate immune cells in the brain. Transcription factor IRF8 is highly expressed in microglia. However, its role in postnatal microglia development is unknown. We demonstrate that IRF8 binds stepwise to enhancer regions of postnatal microglia along with Sall1 and PU.1, reaching a maximum after day 14. IRF8 binding correlated with a stepwise increase in chromatin accessibility, which preceded the initiation of microglia-specific transcriptome. Constitutive and postnatalIrf8deletion led to a loss of microglia identity and gain of disease-associated microglia-like genes. Combined analysis of scRNA-seq and scATAC-seq revealed a correlation between chromatin accessibility and transcriptome at a single-cell level. IRF8 was also required for microglia-specific DNA methylation patterns. Lastly, in the 5xFAD model, constitutive and postnatalIrf8deletion reduced the interaction of microglia with Aβ plaques and the size of plaques, lessening neuronal loss. Together, IRF8 sets the epigenetic landscape, which is required for postnatal microglia gene expression.
A comparison analysis on forward error correction technology: a future perspective for GNSS
Authors: Süzer Ahmet Esat , Oktal Hakan 
Published: June 2023

Purpose
The main aim of this study is to elaborately examine the error correction technology for global navigation satellite system (GNSS) navigation messages and to draw a conceptual decision support framework related to the modernization of the GNSS and other systems.

Design/methodology/approach
The extensive simulation model developed in Matrix Laboratory (MATLAB) is used to evaluate the performance of forward error correction (FEC) codes such as Hamming, Bose–Chaudhuri–Hocquenghem, convolutional, turbo, low-density parity check (LDPC) and polar codes under different levels of noise.

Findings
The performance and robustness of the aforementioned algorithms are compared based on the bit length, complexity and execution time of the GNSS navigation message. In terms of bit error rate, LDPC coding exhibits more ability in the robustness of the navigation message, while polar code gives better results according to the execution time.

Practical implications
In view of future new GNSS signals and message design, the findings of this paper may provide significant insight into navigation message modernization and design as an important part of GNSS modernization.

Originality/value
To the best of the authors’ knowledge, this is the first study that conducts a direct comparison of various FEC algorithms on GNSS navigation message performance against noise, taking into consideration turbo and newly developed polar codes.
Design, manufacturing and testing of pull-out and shear-out insert allowable for sandwich applications
Authors: Pelin Cristina-Elisabeta , Axenie Alexandra-Raluca , Gaz Adrian , Pelin George , Stefan Adriana , Moisei Cristian , Arnau Cubillo Albert 
Published: June 2023

Purpose
This paper aims to present the procedures necessary to determine the insert allowable for a composite sandwich, considering that the inserts were the most commonly used means to install equipment on the composite structure of Clean Sky 2 (CS2)-RACER compound helicopter.

Design/methodology/approach
The installation of the equipment inside of the airframe shall comply with the certification regulations, especially in relation to the inertial factors. Establishing of the needed number of inserts to fix the equipment is directly linked to the allowable coming from coupon tests. The materials and test procedures to which they were subjected are part of the process qualification used in the development of the CS2-RACER Main Fuselage. The samples were tested in two different static mechanical loadings, consisting of pull-out insert and shear-out insert tests. The mechanical behaviour and failure mechanism of the materials were evaluated using optical and scanning electron microscopy.

Findings
The insert installation on the sandwich structure influences the behaviour and mechanical properties during pull-out and shear-out testing.

Research limitations/implications
The limited data available in standardized documents related to insert testing makes it difficult to compare results with certified baseline values.

Practical implications
To reduce the effort of selecting the optimized insert system, specific parameters are included in analytical pre-sizing, i.e. type of loads, geometry, materials, failure modes, special conditions such as manufacturing and testing.

Originality/value
The results of the study presenting the design, manufacturing and mechanical testing of pull-out and shear-out inserts used in composite materials sandwich-type coupons provide valuable information regarding the insert allowable determination.