bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired ERK MAPK activation in mature osteoblasts enhances bone formation via the mTOR pathway
Authors: Kim Jung-Min , Yang Yeon-Suk , Hong Jaehyoung , Chaugule Sachin , Chun Hyonho , van der Meulen Marjolein C. H. , Xu Ren , Greenblatt Matthew B. , Shim Jae-Hyuck 
Published: January 2022

AbstractEmerging evidence supports that osteogenic differentiation of skeletal stem cells (SSCs) is a key determinant of overall bone formation and bone mass. Despite extensive studies showing mitogen-activated protein kinase (MAPK) function in osteoblast differentiation, none of these studies properly show in vivo evidence of impacting post-lineage commitment and subsequent maturation. Here, we describe how the extracellular signal-regulated kinase (ERK) pathway in osteoblasts controls bone formation by suppressing the mechanistic target of rapamycin (mTOR) pathway. We also show that, while ERK inhibition blocks the differentiation of osteogenic precursors when initiated at an early stage, ERK inhibition surprisingly promotes the later stages of osteoblast differentiation. Accordingly, inhibition of the ERK pathway using a small compound inhibitor or conditional deletion of the MAP2Ks Mek1 and Mek2, in mature osteoblasts and osteocytes (Mek1/2Dmp1), markedly increased bone formation due to augmented osteoblast differentiation. Mice with inducible deletion of the ERK pathway in mature osteoblasts (Mek1/2Ocn-Ert) also displayed similar phenotypes, demonstrating that this phenotype reflects continuous postnatal inhibition of late-stage osteoblast maturation. Mechanistically, ERK inhibition increases mitochondrial function and SGK1 phosphorylation via mTOR2 activation, which leads to osteoblast differentiation and production of angiogenic and osteogenic factors to promote bone formation. This phenotype was partly reversed by inhibiting mTOR. Our study uncovers a surprising dichotomy of ERK pathway functions in osteoblasts, whereby ERK activation promotes the early differentiation of osteoblast precursors, but inhibits the subsequent differentiation of committed osteoblasts via mTOR-mediated regulation of mitochondrial function and SGK1.
Mechano-signaling feedback underlies precise inner hair cell patterning in the organ of Corti
Authors: Cohen Roie , Taiber Shahar , Loza Olga , Kasirer Shahar , Woland Shiran , Sprinzak David 
Published: January 2022

AbstractThe mammalian hearing organ, the organ of Corti, is one of the most organized tissues in the mammalian body plan. It contains precisely positioned array of alternating sensory hair cells (HC) and non-sensory supporting cells that emerge during embryonic development from an initially disordered pro-sensory domain. While much is known on the genetics and biochemistry underlying this process, it is still unclear how such precise alternating patterns emerge during embryonic development. Here, we combine live imaging of mouse inner ear explants with hybrid mechano-regulatory models to elucidate the mechanisms underlying the formation of a single row of inner HC (IHC). We show that a narrow strip of initially disordered salt-and-pepper pattern, generated by Notch-mediated lateral inhibition, is dynamically refined by coordinated intercalations, delaminations, and differential adhesion. We identify a new morphological transition, termed ‘hopping intercalation’, that allows nascent IHC to ‘hop’ under the apical plane into their final position. We further show that IHC patterning is associated with boundary localization of the cell adhesion molecules, Nectin-3 and Nectin-1. Our experimental results and modeling support a mechanism for precise patterning based on a feedback between Notch-mediated differentiation and mechanically driven cellular reorganization that is likely relevant for many developmental processes.
Multiomics analysis integrating pyroptosis-related signatures for building a prognostic prediction model in hepatocellular carcinoma
Authors: Huang Jiahao , Li Yan , Chu Ming , Wang Yuedan 
Published: January 2022

AbstractHepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide and has a poor prognosis. Pyroptosis, which is programmed cell necrosis mediated by gasdermin, participates in the progression of tumors. Recently, multiple omics analysis has been applied frequently to provide comprehensive and more precise conclusions. However, multiomics analysis combining pyroptosis-related signatures in HCC and their correlations with prognosis remain unclear. Here, we identified 42 pyroptosis genes that were differentially expressed between HCC and normal hepatocellular tissues. According to these differentially expressed genes (DEGs), all HCC cases could be divided into two heterogeneous subtypes. Then, we evaluated the prognostic value of differential pyroptosis-related genes to construct a multigene model using The Cancer Genome Atlas (TCGA) cohort. A 22-gene model was built and classified HCC patients in the TCGA cohort into low-risk and high-risk groups by the least absolute shrinkage and selection operator (LASSO) Cox regression method. HCC patients belonging to the low-risk group had significantly higher survival possibilities than those belonging to the high-risk group (p<0.001). Furthermore, the related genes and two groups were analyzed with multiple omics in different molecular layers. The pyroptosis-related gene model was validated with HCC patients from the Gene Expression Omnibus (GEO) cohort, and the low-risk group in GEO showed increased overall survival (OS) time (P=0.018). The risk score was an independent factor for predicting the OS of HCC patients. In conclusion, pyroptosis-related genes in HCC are correlated with tumor immunity and could be used to predict the prognosis of HCC patients.
Ligand-independent modulation of GIPR signaling by splice variants
Authors: Hang Kaini , Shao Lijun , Zhou Qingtong , Zhao Fenghui , Dai Antao , Cai Xiaoqing , Stevens Raymond C. , Yang Dehua , Wang Ming-Wei 
Published: January 2022

AbstractGlucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 7 reported (EMBL-EBI, 2022; NCBI, 2022a, 2022b) splice variants (SVs) with previously undefined functions. To explore their roles in endogenous peptide mediated GIPR signaling, we investigated the outcome of co-expressing each of the four SVs in question with GIPR in terms of ligand binding, cAMP accumulation, Gs activation, β-arrestin recruitment and cell surface localization. The effects of these SVs on intracellular cAMP responses modulated by receptor activity-modifying proteins (RAMPs) were also studied. It was found that while SVs of GIPR neither bound to the hormone nor affected its signal transduction per se, they differentially regulated GIPR-mediated cAMP and β-arrestin responses. Specifically, SV1 and SV4 were preferable to Gs signaling, SV3 was biased towards β-arrestin recruitment, whereas SV2 was inactive on both pathways. In the presence of RAMPs, only SV1 and SV4 synergized the repressive action of RAMP3 on GIP-elicited cAMP production. The results suggest a new form of signal bias that is constitutive and ligand-independent, thereby expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-dependent (e.g., SV1 of the growth hormone-releasing hormone receptor).
Impact of decision and action outcomes on subsequent decision and action behaviors
Authors: Saleri Lunazzi Clara , Thura David , Reynaud Amélie J. 
Published: January 2022

AbstractSpeed-accuracy tradeoff adjustments in decision-making have been mainly studied separately from those in motor control. In the wild however, animals coordinate their decision and action, freely investing time in choosing versus moving given specific contexts. Recent behavioral studies support this view, indicating that humans trade decision time for movement time to maximize their global rate of reward during experimental sessions. Besides, it is established that choice outcomes impact subsequent decisions. Crucially though, whether and how a decision also influences the subsequent motor behavior, and whether and how a motor error influences the next decision is unknown. Here we address these questions by analyzing trial-to-trial changes of choice and motor behaviors in healthy human participants instructed to perform successive perceptual decisions expressed with reaching movements whose duration was either bounded or unconstrained in separate tasks. Results indicate that after a bad decision, subjects who were not constrained in their action duration decided more slowly and more accurately. Interestingly, they also shortened their subsequent movement duration by moving faster. Conversely, we found that movement errors not only influenced the speed and the accuracy of the following movement, but those of the decision as well. If the movement had to be slowed down, the decision that precedes that movement was accelerated, and vice versa. Together, these results indicate that from one trial to the next, humans are primarily concerned about determining a behavioral duration as a whole instead of optimizing each of the decision and action speed-accuracy trade-offs independently of each other.
A sparse set of spikes corresponding to reliable correlations is highly informative of visual stimulus on single trials
Authors: Levy Maayan , Guo Jeff K. , MacLean Jason N. 
Published: January 2022

AbstractSpike trains in cortical neuronal populations vary in number and timing trial-to-trial, rendering a viable single trial coding scheme for sensory information elusive. Correlations between pairs of neocortical neurons can be segmented into either sensory or noise according to their stimulus specificity. Here we show that pairs of spikes, corresponding to reliable sensory correlations in imaged populations in layer 2/3 of mouse visual cortex are particularly informative of visual stimuli. This set of spikes is sparse and exhibits comparable levels of trial-to-trial variance relative to the full spike train. Despite this, correspondence of pairs of spikes to a specific set of sensory correlations identifies spikes that carry more information per spike about the visual stimulus than the full set or any other matched set of spikes. Moreover, this sparse subset is more accurately decoded, regardless of the decoding algorithm employed. Our findings suggest that consistent pairwise correlations between neurons, rather than first-order statistical features of spike trains, may be an organizational principle of a single trial sensory coding scheme.
Decoding the IGF1 Signaling Gene Regulatory Network Behind Alveologenesis from A Mouse Model of Bronchopulmonary Dysplasia
Authors: Gao F , Li C , Smith SM , Peinado N , Kohbodi G , Tran E , Loh E , Li W , Borok Z , Minoo P 
Published: January 2022

SummaryLung development is precisely controlled by underlying Gene Regulatory Networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD)–a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization.Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin’s development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird’s-eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD.Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.
Dissecting Mutational Allosteric Effects in Alkaline Phosphatases Associated with Different Hypophosphatasia Phenotypes: An Integrative Computational Investigation
Authors: Xiao Fei , Zhou Ziyun , Song Xingyu , Gan Mi , Long Jie , Verkhivker Gennady M , Hu Guang 
Published: January 2022

AbstractHypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone mineralization, is highly variable in its clinical phenotype. The disease occurs due to various loss-of-function mutations in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). In this work, a data-driven and biophysics-based approach for large-scale analysis of ALPL mutations – from nonpathogenic to severe HPPs is proposed. Allosteric molecular signatures of ALPL mutations were determined using an integrated pipeline of synergistic approaches including sequence and energetic-based analysis, structural topology network modeling and elastic network models. Statistical analysis of molecular features computed for the ALPL mutations showed a significant difference between the control and mild and severe HPP phenotypes, and the developed machine learning model suggested that the topological network parameters could serve as is a robust indicator for severe mutations. Molecular dynamics simulations coupled with protein structure network was employed to analyze the effect of single-residue variation on conformational dynamics of TNSALP dimers, and we found that severe disease-associated mutations have a significantly greater effect on allosteric communications. The results of this study suggested that ALPL mutations associated with mild and severe HPPs tend to have different effects on protein stability on local scale and long-range communications caused by network rewiring. By linking disease phenotypes with allosteric molecular signatures, the proposed integrative computational approach elucidates the complex sequence-structure-allostery relationships of ALPL mutations and dissects the role of allosteric effects in the pathogenesis of HPPs.Author SummaryThe understanding of mutational genotype- disease phenotype relationship is a fundamental step for enabling precision medicine. It remains a challenging task to assess the molecular principle of the genotype- phenotype relationship. By focusing on Hypophosphatasia, a rare inherited disorder, as an example, we performed comprehensive analysis of single-amino-acid mutations in the encoded protein of Tissue Nonspecific Alkaline Phosphatase associated in terms of their sequence, structure, and dynamics properties. We further developed a machine learning -based method to classify different disease phenotypes, and the interpretability of the classification model was addressed by the structural-functional analysis of network topological important mutations. Our results highlighted the allosteric propensity of severe mutations, and show the potential allosteric principle of genotype- phenotype relationship.
Defects in DNA double-strand break repair re-sensitise antibiotic-resistant Escherichia coli to multiple bactericidal antibiotics
Authors: Revitt-Mills Sarah A. , Wright Elizabeth K. , Vereker Madaline , O’Flaherty Callum , McPherson Fairley , Dawson Catherine , van Oijen Antoine M. , Robinson Andrew 
Published: January 2022

AbstractAntibiotic resistance is becoming increasingly prevalent amongst bacterial pathogens and there is an urgent need to develop new types of antibiotics with novel modes of action. One promising strategy is to develop resistance-breaker compounds, which inhibit resistance mechanisms and thus re-sensitise bacteria to existing antibiotics. In the current study, we identify bacterial DNA double-strand break repair as a promising target for the development of resistance-breaking co-therapies. We examined genetic variants of Escherichia coli that combined antibiotic-resistance determinants with DNA repair defects. We observed that defects in the double-strand break repair pathway led to significant re-sensitisation towards five bactericidal antibiotics representing different functional classes. Effects ranged from partial to full re-sensitisation. For ciprofloxacin and nitrofurantoin, sensitisation manifested as a reduction in the minimum inhibitory concentration. For kanamycin and trimethoprim, sensitivity manifested through increased rates of killing at high antibiotic concentrations. For ampicillin, repair defects dramatically reduced antibiotic tolerance. Ciprofloxacin, nitrofurantoin, and trimethoprim induce the pro-mutagenic SOS response. Disruption of double-strand break repair strongly dampened the induction of SOS by these antibiotics. Our findings suggest that if break-repair inhibitors can be developed they could re-sensitise antibiotic-resistant bacteria to multiple classes of existing antibiotics and may supress the development of de novo antibiotic-resistance mutations.
Derivation of lump solutions to a variety of Boussinesq equations with distinct dimensions
Authors: Wazwaz Abdul-Majid 
Published: January 2022

Purpose
This study aims to introduce a variety of integrable Boussinesq equations with distinct dimensions.

Design/methodology/approach
The author formally uses the simplified Hirota’s method and lump schemes for exploring lump solutions, which are rationally localized in all directions in space.

Findings
The author confirms the lump solutions for every model illustrated by some graphical representations.

Research limitations/implications
The author examines the features of the obtained lumps solutions.

Practical implications
The author presents a variety of lump solutions via using a variety of numerical values of the included parameters.

Social implications
This study formally furnishes useful algorithms for using symbolic computation with Maple for the determination of lump solutions.

Originality/value
This paper introduces an original work with newly useful findings of lump solutions.
Determining public’s attitude toward medical tourism development: a scale proposal
Authors: Sağ Ilhan , Zengul Ferhat Devrim , Avcı Keziban 
Published: January 2022

Purpose
This paper aims to explore the public’s attitude toward medical tourism activities by developing a measurement instrument in Turkey, an emerging medical tourism destination.

Design/methodology/approach
During the development phase of the scale, 24 question pools were created. After the pilot study, data from a 20-question survey were collected from a study group consisting of Turkish citizens who received services from hospitals in the city of Ankara. Data were collected through convenience sampling of 221 study participants as they were walking in the Square of Kızılay, one of the most important centers and junction points in Turkey, between November 25, 2017, and December 27, 2017.

Findings
The content validity of the scale was assessed by expert opinion. The scale reliability is high with Cronbach’s α (0.908). A factor analysis was performed to assess the factor structure of the scale. The Kaiser–Meyer–Olkin measure of sampling adequacy (0.895) and Bartlett’s test (χ2 = 2,020.967; p = 0.001) were applied to determine the conformity of the scale of factor analysis. Exploratory factor analysis with Varimax rotation was performed to determine the factor structure of the scale. The 20 questions loaded under three factors: “contribution to the country,” “anxiety in getting services” and “service justice”. These factors explained approximately 55% of the total variance. Confirmatory factor analysis was performed with goodness-of-fit index (0.877), Bentler comparative fit index (0.909) and root mean square error of approximation index (0.069) to determine the validity of the factor structure, and the results indicated that the three-factor model is an acceptable level. All the results show that this new scale is valid and reliable in measuring the public’s attitude toward the development of medical tourism in Turkey.

Originality/value
The public’s attitudes on the medical tourism scale show that, as a measurement tool, it can be used validly and reliably in determining the public’s attitudes toward medical tourism.
Tribological behaviors of HfC coating prepared on 45 steel via double glow plasma surface metallurgy technique
Authors: Zang Kai , Chen Wenxin , Liang Wenping , Miao Qiang , Yao Wei , Li Jingli , Ma Yaoyao 
Published: January 2022

Purpose
45 steel is a common material for the manufacture of various components such as shafts or gears. However, its poor surface properties often limit its applications. The purpose of this paper is to find a way to enhance the surface performance of 45 steel, which is expected to improve the wear resistance of 45 steel.

Design/methodology/approach
Double glow plasma surface metallurgy technique was used to prepare hafnium carbide (HfC) coatings on the surface of the 45 steel with two preparation process; one is to diffuse two elements together, while the other is to diffuse step by step. The scanning electronic microscopy and the X-ray diffraction were used to analyze the morphology and phase of the HfC coatings. And then the wear tests were carried out for this coating.

Findings
Coating diffused step by step shows better performance; it has a 15-µm alloyed layer which is uniform and dense and its hardness can reach up to 1326.5 Vickers-hardness (HV). While the coating fabricated by diffusing elements together owns a 10-µm alloyed layer and its hardness is 1204.1 HV. According to the wear test results, both coatings have a protective effect on the substrate and the coating prepared by step-by-step diffusion process has less wear volume, indicating that it possesses better friction reduction.

Originality/value
A new method which diffuses elements together was successfully used to prepare compound HfC coating, which can reduce the cost of coating preparation and improve the efficiency of coating preparation.