bluuebunny/crossref_metadata_2025_split huggingface dataset:
RUNX2-modifying enzymes: therapeutic targets for bone diseases
Authors: Kim Woo-Jin , Shin Hye-Lim , Kim Bong-Soo , Kim Hyun-Jung , Ryoo Hyun-Mo 
Published: August 2020

AbstractRUNX2 is a master transcription factor of osteoblast differentiation. RUNX2 expression in the bone and osteogenic front of a suture is crucial for cranial suture closure and membranous bone morphogenesis. In this manner, the regulation of RUNX2 is precisely controlled by multiple posttranslational modifications (PTMs) mediated by the stepwise recruitment of multiple enzymes. Genetic defects in RUNX2 itself or in its PTM regulatory pathways result in craniofacial malformations. Haploinsufficiency in RUNX2 causes cleidocranial dysplasia (CCD), which is characterized by open fontanelle and hypoplastic clavicles. In contrast, gain-of-function mutations in FGFRs, which are known upstream stimulating signals of RUNX2 activity, cause craniosynostosis (CS) characterized by premature suture obliteration. The identification of these PTM cascades could suggest suitable drug targets for RUNX2 regulation. In this review, we will focus on the mechanism of RUNX2 regulation mediated by PTMs, such as phosphorylation, prolyl isomerization, acetylation, and ubiquitination, and we will summarize the therapeutics associated with each PTM enzyme for the treatment of congenital cranial suture anomalies.
The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis
Authors: Sun Zicheng , Jiang Qiwei , Li Jie , Guo Jianping 
Published: August 2020

AbstractSalt-inducible kinases (SIKs) belong to AMP-activated protein kinase (AMPK) family, and functions mainly involve in regulating energy response-related physiological processes, such as gluconeogenesis and lipid metabolism. However, compared with another well-established energy-response kinase AMPK, SIK roles in human diseases, especially in diabetes and tumorigenesis, are rarely investigated. Recently, the pilot roles of SIKs in tumorigenesis have begun to attract more attention due to the finding that the tumor suppressor role of LKB1 in non-small-cell lung cancers (NSCLCs) is unexpectedly mediated by the SIK but not AMPK kinases. Thus, here we tend to comprehensively summarize the emerging upstream regulators, downstream substrates, mouse models, clinical relevance, and candidate inhibitors for SIKs, and shed light on SIKs as the potential therapeutic targets for cancer therapies.
Costello syndrome model mice with a Hras G12S mutation are susceptible to develop house dust mite-induced atopic dermatitis
Authors: Katata Yu , Inoue Shin-ichi , Asao Atsuko , Kobayashi Shuhei , Terui Hitoshi , Inoue-Shibui Aya , Abe Taiki , Niihori Tetsuya , Aiba Setsuya , Ishii Naoto , Kure Shigeo , Aoki Yoko 
Published: August 2020

AbstractCostello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an Hras G12S mutation (HrasG12S/+ mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (Dermatophagoides farinae, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of HrasG12S/+ mice compared with Hras+/+ mice. Cultured HrasG12S/+ keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in HrasG12S/+ mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of HrasG12S/+ mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of HrasG12S/+ mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.
Venetoclax causes metabolic reprogramming independent of BCL-2 inhibition
Authors: Roca-Portoles Alba , Rodriguez-Blanco Giovanny , Sumpton David , Cloix Catherine , Mullin Margaret , Mackay Gillian M. , O’Neill Katelyn , Lemgruber Leandro , Luo Xu , Tait Stephen W. G. 
Published: August 2020

AbstractBH3-mimetics are a new class of anti-cancer drugs that inhibit anti-apoptotic Bcl-2 proteins. In doing so, BH3-mimetics sensitise to cell death. Venetoclax is a potent, BCL-2 selective BH3-mimetic that is clinically approved for use in chronic lymphocytic leukaemia. Venetoclax has also been shown to inhibit mitochondrial metabolism, this is consistent with a proposed role for BCL-2 in metabolic regulation. We used venetoclax to understand BCL-2 metabolic function. Similar to others, we found that venetoclax inhibited mitochondrial respiration. In addition, we also found that venetoclax impairs TCA cycle activity leading to activation of reductive carboxylation. Importantly, the metabolic effects of venetoclax were independent of cell death because they were also observed in apoptosis-resistant BAX/BAK-deficient cells. However, unlike venetoclax treatment, inhibiting BCL-2 expression had no effect on mitochondrial respiration. Unexpectedly, we found that venetoclax also inhibited mitochondrial respiration and the TCA cycle in BCL-2 deficient cells and in cells lacking all anti-apoptotic BCL-2 family members. Investigating the basis of this off-target effect, we found that venetoclax-induced metabolic reprogramming was dependent upon the integrated stress response and ATF4 transcription factor. These data demonstrate that venetoclax affects cellular metabolism independent of BCL-2 inhibition. This off-target metabolic effect has potential to modulate venetoclax cytotoxicity.
Hederagenin potentiated cisplatin- and paclitaxel-mediated cytotoxicity by impairing autophagy in lung cancer cells
Authors: Wang Kun , Liu Xiaodong , Liu Quanmeng , Ho Idy ht , Wei Xianli , Yin Ting , Zhan Yujuan , Zhang Wenjing , Zhang Wenbo , Chen Bonan , Gu Jiangyong , Tan Yuhui , Zhang Lin , Chan Matthew Tv , Wu William Kk , Du Biaoyan , Xiao Jianyong 
Published: August 2020

AbstractAutophagy inhibition has been demonstrated to increase the efficacy of conventional chemotherapy. In this study, we identified hederagenin, a triterpenoid derived fromHedera helix, as a potent inhibitor of autophagy and then hypothesized that hederagenin might synergize with chemotherapeutic drugs (e.g., cisplatin and paclitaxel) to kill lung cancer cells. Firstly, we observed that hederagenin induced the increased autophagosomes in lung cancer cells concomitantly with the upregulation of LC3-II and p62, which indicated the impairment of autophagic flux. The colocalization assay indicated hederagenin could not block the fusion of lysosomes and autophagosomes, whereas the lysosomal acidification might be inhibited by hederagenin as revealed by the reduced staining of acidity-sensitive reagents (i.e., Lysotracker and acridine orange). The aberrant acidic environment then impaired the function of lysosome, which was evidenced by the decrease of mature cathepsin B and cathepsin D. Lastly, hederagenin, in agree with our hypothesis, promoted pro-apoptotic effect of cisplatin and paclitaxel with the accumulation of reactive oxygen species (ROS); while the synergistic effect could be abolished by the ROS scavenger, N-acetyl-L-cysteine. These data summarily demonstrated hederagenin-induced accumulation of ROS by blocking autophagic flux potentiated the cytotoxicity of cisplatin and paclitaxel in lung cancer cells.
Piezochromism in the magnetic chalcogenide MnPS3
Authors: Harms Nathan C. , Kim Heung-Sik , Clune Amanda J. , Smith Kevin A. , O’Neal Kenneth R. , Haglund Amanda V. , Mandrus David G. , Liu Zhenxian , Haule Kristjan , Vanderbilt David , Musfeldt Janice L. 
Published: August 2020

Abstractvan der Waals materials are exceptionally responsive to external stimuli. Pressure-induced layer sliding, metallicity, and superconductivity are fascinating examples. Inspired by opportunities in this area, we combined high-pressure optical spectroscopies and first-principles calculations to reveal piezochromism in MnPS3. Dramatic color changes (green → yellow → red → black) take place as the charge gap shifts across the visible regime and into the near infrared, moving systematically toward closure at a rate of approximately −50 meV/GPa. This effect is quenched by the appearance of the insulator–metal transition. In addition to uncovering an intriguing and tunable functionality that is likely to appear in other complex chalcogenides, the discovery that piezochromism can be deterministically controlled at room temperature accelerates the development of technologies that take advantage of stress-activated modification of electronic structure.
Blood levels of microRNAs associated with ischemic heart disease differ between Austrians and Japanese: a pilot study
Authors: Wakabayashi Ichiro , Eguchi Ryoji , Sotoda Yoko , von Lewinski Dirk , Sourij Harald , Daimon Takashi , Groschner Klaus , Rainer Peter P. 
Published: August 2020

AbstractMortality from ischemic heart disease (IHD) is significantly lower in Japan than in Western countries. The purpose of this study was to investigate differences in circulating microRNA (miRNA) levels related to IHD in Austrians and Japanese. Participants were middle-aged healthy male Austrians (n = 20) and Japanese (n = 20). Total miRNAs in serum from each participant were analyzed using the 3D-Gene miRNA Oligo chip. Twenty-one miRNAs, previously reported as associated with IHD, were compared between Austrians and Japanese. The expression levels of miR-106a-5p, miR-135a-3p, miR-150-3p, miR-16-5p, miR-17-5p. miR-191-5p, miR-320b, miR-451a, miR-486-5p, miR-663b, and miR-92a-3p were significantly higher, while the miR-2861 expression level was significantly lower in Austrians as compared to Japanese. Both in Austrians and Japanese, there were significant positive correlations between serum expression levels of each pair of the above miRNAs except for miR-2861. The expression level of miR-2861 showed significant positive correlations with the expression levels of miR-106a-5p, miR-150-3p, miR-17-5p, miR-486-5p, miR-663b and miR-92a-3p in Austrians but not in Japanese. In pathway analysis, proinflammatory cytokine production in foam cells and collagen synthesis in vascular smooth muscle cells were associated with differentially expressed miRNAs. Difference in miRNA levels may contribute to lower cardiovascular risk in Japan than in Western countries.
Environmental unpredictability shapes glucocorticoid regulation across populations of tree swallows
Authors: Zimmer Cedric , Taff Conor C. , Ardia Daniel R. , Rose Alexandra P. , Aborn David A. , Johnson L. Scott , Vitousek Maren N. 
Published: August 2020

AbstractThe ability to respond appropriately to challenges is an important contributor to fitness. Variation in the regulation of glucocorticoid hormones, which mediate the phenotypic response to challenges, can therefore influence the ability to persist in a given environment. We compared stress responsiveness in four populations of tree swallows (Tachycineta bicolor) breeding under different environmental conditions to evaluate support for different selective pressures in driving the evolution of glucocorticoid regulation. In accordance with the environmental unpredictability hypothesis, stronger stress responses were seen in more unpredictable environments. Contrary to the reproductive value hypothesis, the stress response was not lower in populations engaging in more valuable reproductive attempts. Populations with stronger stress responses also had stronger negative feedback, which supports a “mitigating” rather than a “magnifying” effect of negative feedback on stress responses. These results suggest that combining a robust stress response with strong negative feedback may be important for persisting in unpredictable or rapidly changing environments.
Dynamical heart beat correlations during running
Authors: Molkkari Matti , Angelotti Giorgio , Emig Thorsten , Räsänen Esa 
Published: August 2020

AbstractFluctuations of the human heart beat constitute a complex system that has been studied mostly under resting conditions using conventional time series analysis methods. During physical exercise, the variability of the fluctuations is reduced, and the time series of beat-to-beat RR intervals (RRIs) become highly non-stationary. Here we develop a dynamical approach to analyze the time evolution of RRI correlations in running across various training and racing events under real-world conditions. In particular, we introduce dynamical detrended fluctuation analysis and dynamical partial autocorrelation functions, which are able to detect real-time changes in the scaling and correlations of the RRIs as functions of the scale and the lag. We relate these changes to the exercise intensity quantified by the heart rate (HR). Beyond subject-specific HR thresholds the RRIs show multiscale anticorrelations with both universal and individual scale-dependent structure that is potentially affected by the stride frequency. These preliminary results are encouraging for future applications of the dynamical statistical analysis in exercise physiology and cardiology, and the presented methodology is also applicable across various disciplines.
Transthyretin interacts with actin regulators in a Drosophila model of familial amyloid polyneuropathy
Authors: I. Oliveira da Silva Marina , Lopes Carla S. , Liz Márcia A. 
Published: August 2020

AbstractFamilial amyloid polyneuropathy (FAP) is a neurodegenerative disorder whose major hallmark is the deposition of mutated transthyretin (TTR) in the form of amyloid fibrils in the peripheral nervous system (PNS). The exposure of PNS axons to extracellular TTR deposits leads to an axonopathy that culminates in neuronal death. However, the molecular mechanisms underlying TTR-induced neurodegeneration are still unclear, despite the extensive studies in vertebrate models. In this work we used a Drosophila FAP model, based on the expression of the amyloidogenic TTR (V30M) in the fly retina, to uncover genetic interactions with cytoskeleton regulators. We show that TTR interacts with actin regulators and induces cytoskeleton alterations, leading to axonal defects. Moreover, our study pinpoints an interaction between TTRV30M and members of Rho GTPase signaling pathways, the major actin regulators. Based on these findings we propose that actin cytoskeleton alterations may mediate the axonopathy observed in FAP patients, and highlight a molecular pathway, mediated by Rho GTPases, underlying TTR-induced neurodegeneration. We expect this work to prompt novel studies and approaches towards FAP therapy.
The control of acidity in tumor cells: a biophysical model
Authors: Piasentin Nicola , Milotti Edoardo , Chignola Roberto 
Published: August 2020

AbstractAcidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. The model takes into account the dynamic interplay between glucose and $$\hbox {O}_2$$

O
2

consumption with lactate and $$\hbox {CO}_2$$

CO
2

production and connects these processes to $$\hbox {H}^+$$

H
+

and $$\hbox {HCO}_3^-$$

HCO
3
-

fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. The simulations show a dominance of the $$\hbox {H}^+$$

H
+

exchanges in well-oxygenated regions, and of $$\hbox {HCO}_3^-$$

HCO
3
-

exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. The model also includes the activity of the enzyme Carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear $$\hbox {pH}_i$$

pH
i

equalizer at any $$\hbox {O}_2$$

O
2

level in cells that grow in acidic extracellular environments.
Identification of ultrasound imaging markers to quantify long bone regeneration in a segmental tibial defect sheep model in vivo
Authors: Tang Songyuan , Shajudeen Peer , Tasciotti Ennio , Righetti Raffaella 
Published: August 2020

AbstractThe healing of large bone defects has been investigated for decades due to its complexity and clinical relevance. Ultrasound (US) methods have shown promise in monitoring bone healing, but no quantitative method to assess regenerated bone morphology in US images has been presented yet. In this study, we investigate new US morphometric parameters to quantify bone regeneration in vivo. A segmental tibial defect was surgically created and stabilized in a sheep animal model. US and computed tomography (CT) imaging data were collected two months post-surgery. New bone was assessed, reconstructed and quantified from the US and CT data using 3 morphometric parameters: the new-bone bulk (NBB), new-bone surface (NBS) and new-bone contact (NBC). The distance (mm) between surface reconstructions from repeated US was $$0.49\pm 0.30$$

0.49
±
0.30

and from US and CT was $$0.89\pm 0.49$$

0.89
±
0.49

. In the mid-shaft of the defected tibia, US measurements of NBB, NBS and NBC were significantly higher than the corresponding CT measurements ($$p < 0.001$$

p
<
0.001

). Based on our results, we conclude that US may complement CT to reconstruct and quantify bone regrowth, especially in its early stages.
Experimental study of the nonreciprocal effective interactions between microparticles in an anisotropic plasma
Authors: Lisin E. A. , Petrov O. F. , Sametov E. A. , Vaulina O. S. , Statsenko K. B. , Vasiliev M. M. , Carmona-Reyes J. , Hyde T. W. 
Published: August 2020

AbstractThere is a variety of cases in nature when the action–reaction symmetry is broken. In particular, suitable conditions for this are realized in colloidal suspensions and complex plasmas. Since the first theories and simulations of the nonreciprocal effective interactions between microparticles in complex plasmas were published in 1995–1996, there have been hundreds of studies in the theoretical development of this theme. However, despite such a rich theoretical background, one of the important unsolved problems is a direct experimental determination of the nonreciprocal interparticle interaction forces. Here, we studied experimentally in detail the forces of the nonreciprocal effective interaction between microparticles suspended a radio-frequency produced plasma sheath. For this purpose, an experimental method based on an analysis of the spectral density of random processes in an open dissipative two-particle system was developed. In contrast to previous investigations, the proposed method takes into account random and dissipative processes in the system, does not require a special design of the experimental setup and any external perturbations, pre-measurements of external fields and any assumptions about the type of interaction. We found that even small charge changes of one particle, caused by its thermal motion in a wake field of another particle, can lead to a significant change in the effective (measurable) interaction between the particles.
Risk of shoreline hardening and associated beach loss peaks before mid-century: Oʻahu, Hawaiʻi
Authors: Tavares Kammie-Dominique , Fletcher Charles H. , Anderson Tiffany R. 
Published: August 2020

AbstractShoreline hardening, which causes beach loss globally, will accelerate with sea level rise (SLR), causing more beach loss if management practices are not changed. To improve beach conservation efforts, current and future shoreline hardening patterns on sandy beaches need deeper analysis. A shoreline change model driven by incremental SLR (0.25, 0.46, 0.74 m) is used to simulate future changes in the position of an administrative hazard zone, as a proxy for risk of hardening at all sandy beaches on the island of O‘ahu, Hawai ‘i. In Hawai ‘i, hardening can be triggered when evidence of erosion is within 6.1 m (“20 ft”) of certain structures, allowing an applicant to request emergency protection. Results show an increase in shoreline vulnerability to hardening with SLR governed by backshore land use patterns. The largest increase (+ 7.6%) occurred between modern-day and 0.25 m of SLR (very likely by year 2050) with half of all beachfront shoreline at risk by 0.74 m of SLR. Maximum risk of shoreline hardening and beach loss is projected to occur from modern-day and near-term hardening because of the heavily developed aspect of some shoreline segments. Adaptation to SLR should be considered an immediate need—not solely a future issue.
Identification of potential diagnostic gene biomarkers in patients with osteoarthritis
Authors: Wang Xinling , Yu Yang , Huang Yong , Zhu Mingshuang , Chen Rigao , Liao Zhanghui , Yang Shipeng 
Published: August 2020

AbstractThe current study was aimed to identify diagnostic gene signature for osteoarthritis (OA). The differentially expressed genes (DEGs) in synovial membrane samples and blood samples were respectively identified from the GEO dataset. The intersection DEGs between synovial membrane and blood were further screened out, followed by the functional annotation of these common DEGs. The optimal intersection gene biomarkers for OA diagnostics were determined. The GSE51588 dataset of articular cartilage was used for expression validation and further diagnostic analysis validation of identified gene biomarkers for OA diagnostics. There were 379 intersection DEGs were obtained between the synovial membrane and blood samples of OA. 22 DEGs had a diagnostic value for OA. After further screening, a total of 9 DEGs including TLR7, RTP4, CRIP1, ZNF688, TOP1, EIF1AY, RAB2A, ZNF281 and UIMC1 were identified for OA diagnostic. The identified DEGs could be considered as potential diagnostic biomarkers for OA.
Exploring the potential of TEM analysis for understanding cooking at prehistoric feasting sites
Authors: Faillace Katie E. , Foody M. George B. , Madgwick Richard 
Published: August 2020

AbstractThis study explores the utility of transmission electron microscopy (TEM) analysis of bone collagen for investigating prehistoric cooking. Approaches to cooking practices have relied principally on artefactual evidence, macroscopic bone modification, and organic residue analysis. However, direct evidence for cooking of bone has been limited. Richter and Koon successfully applied TEM analysis of collagen to determine heating to modern and medieval bones, but this method has yet to be experimentally tested using prehistoric remains. Collagen will denature at relatively low temperatures, such as during roasting, boiling, or baking. The denaturation of collagen causes predictable structural changes that can be viewed through TEM. Zooarchaeological remains of sheep and pig with minimal taphonomic modifications were analysed from four later prehistoric (c. 800–500BC) sites in Britain (n = 33). Humeri and phalanges were selected to compare elements with high and low meat yields. Samples were classified into ‘Heated’ and ‘Unheated’ groups consistent with previous studies, and variable patterns were observed between different sites and taxa. Analytical limitations have hindered the study of cooking in the past, but this study demonstrates the potential of this taphonomic method for exploring prehistoric cooking practices and provides a springboard for wider studies.