bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases
Authors: Sun Jing , Wang Cheng , Zhang Yi , Xu Lingyan , Fang Weijia , Zhu Yuping , Zheng Yi , Chen Xiaofeng , Xie Xiju , Hu Xinhua , Hu Weidong , Zheng Jingyu , Li Ping , Yu Jian , Mei Zhu , Cai Xiaomin , Wang Biao , Hu Zhibin , Shu Yongqian , Shen Hongbing , Gu Yanhong
Published: July 2019

Brain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue. Compared with primary CRC, BM exhibits elevated mutational signatures of homologous recombination deficiency (HRD) and mismatch repair deficiency (MMRD). Further analysis reveals two DNA damage response (DDR) signatures could emerge early and are enhanced in BM tissues but are eliminated eventually in matched primary CRC tissues. BM-specific mutations in DDR genes and elevated microsatellite instability (MSI) levels support the importance of DDR in the brain metastasis of CRC. We also identify BM-related genes (e.g., SCN7A, SCN5A, SCN2A, IKZF1, and PDZRN4) that carry frequent BM-specific mutations. These results provide a better understanding of the BM mutational landscape and insights into treatment.
Multicenter study demonstrates radiomic features derived from magnetic resonance perfusion images identify pseudoprogression in glioblastoma
Authors: Elshafeey Nabil , Kotrotsou Aikaterini , Hassan Ahmed , Elshafei Nancy , Hassan Islam , Ahmed Sara , Abrol Srishti , Agarwal Anand , El Salek Kamel , Bergamaschi Samuel , Acharya Jay , Moron Fanny E. , Law Meng , Fuller Gregory N. , Huse Jason T. , Zinn Pascal O. , Colen Rivka R.
Published: July 2019

Pseudoprogression (PsP) is a diagnostic clinical dilemma in cancer. In this study, we retrospectively analyse glioblastoma patients, and using their dynamic susceptibility contrast and dynamic contrast-enhanced perfusion MRI images we build a classifier using radiomic features obtained from both Ktrans and rCBV maps coupled with support vector machines. We achieve an accuracy of 90.82% (area under the curve (AUC) = 89.10%, sensitivity = 91.36%, 67 specificity = 88.24%, p = 0.017) in differentiating between pseudoprogression (PsP) and progressive disease (PD). The diagnostic performances of the models built using radiomic features from Ktrans and rCBV separately were equally high (Ktrans: AUC = 94%, 69 p = 0.012; rCBV: AUC = 89.8%, p = 0.004). Thus, this MR perfusion-based radiomic model demonstrates high accuracy, sensitivity and specificity in discriminating PsP from PD, thus provides a reliable alternative for noninvasive identification of PsP versus PD at the time of clinical/radiologic question. This study also illustrates the successful application of radiomic analysis as an advanced processing step on different MR perfusion maps.
Mechanism of superconductivity and electron-hole doping asymmetry in κ-type molecular conductors
Authors: Watanabe Hiroshi , Seo Hitoshi , Yunoki Seiji
Published: July 2019

Unconventional superconductivity in molecular conductors is observed at the border of metal-insulator transitions in correlated electrons under the influence of geometrical frustration. The symmetry as well as the mechanism of the superconductivity (SC) is highly controversial. To address this issue, we theoretically explore the electronic properties of carrier-doped molecular Mott system κ-(BEDT-TTF)2X. We find significant electron-hole doping asymmetry in the phase diagram where antiferromagnetic (AF) spin order, different patterns of charge order, and SC compete with each other. Hole-doping stabilizes AF phase and promotes SC with dxy-wave symmetry, which has similarities with high-Tc cuprates. In contrast, in the electron-doped side, geometrical frustration destabilizes the AF phase and the enhanced charge correlation induces another SC with extended-s + $$d_{x^2 - y^2}$$

d

x

2

-

y

2

wave symmetry. Our results disclose the mechanism of each phase appearing in filling-control molecular Mott systems, and elucidate how physics of different strongly-correlated electrons are connected, namely, molecular conductors and high-Tc cuprates.
Multifunctional cationic nanosystems for nucleic acid therapy of thoracic aortic dissection
Authors: Xu Chen , Zhang Yanzhenzi , Xu Ke , Nie Jing-Jun , Yu Bingran , Li Sijin , Cheng Gang , Li Yulin , Du Jie , Xu Fu-Jian
Published: July 2019

Thoracic aortic dissection (TAD) is an aggressive vascular disease that requires early diagnosis and effective treatment. However, due to the particular vascular structure and narrowness of lesion location, there are no effective drug delivery systems for the therapy of TAD. Here, we report a multifunctional delivery nanosystem (TP-Gd/miRNA-ColIV) composed of gadolinium-chelated tannic acid (TA), low-toxic cationic PGEA (ethanolamine-aminated poly(glycidyl methacrylate)) and type IV collagen targeted peptide (ColIV) for targeted nucleic acid therapy, early diagnosis and noninvasive monitoring of TAD. Such targeted therapy with miR-145 exhibits impressive performances in stabilizing the vascular structures and preventing the deterioration of TAD. After the treatment with TP-Gd/miR-145-ColIV, nearly no dissection occurs in the thoracic aortic arches of the mice with TAD model. Moreover, TP-Gd/miRNA-ColIV also demonstrates good magnetic resonance imaging (MRI) ability and can be used to noninvasively monitor the development conditions of TAD.
Structural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP
Authors: Abdul Azeez Kamal R. , Chatterjee Sneha , Yu Channing , Golub Todd R. , Sobott Frank , Elkins Jonathan M.
Published: July 2019

Aurora kinases B and C (AURKB/AURKC) are activated by binding to the C-terminal domain of INCENP. Full activation requires phosphorylation of two serine residues of INCENP that are conserved through evolution, although the mechanism of this activation has not been explained. Here we present crystal structures of the fully active complex of AURKC bound to INCENP, consisting of phosphorylated, activated, AURKC and INCENP phosphorylated on its TSS motif, revealing the structural and biochemical mechanism of synergistic activation of AURKC:INCENP. The structures show that TSS motif phosphorylation stabilises the kinase activation loop of AURKC. The TSS motif phosphorylations alter the substrate-binding surface consistent with a mechanism of altered kinase substrate selectivity and stabilisation of the protein complex against unfolding. We also analyse the binding of the most specific available AURKB inhibitor, BRD-7880, and demonstrate that the well-known Aurora kinase inhibitor VX-680 disrupts binding of the phosphorylated INCENP TSS motif.
Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life
Authors: Pineault Kyriel M. , Song Jane Y. , Kozloff Kenneth M. , Lucas Daniel , Wellik Deneen M.
Published: July 2019

Multipotent mesenchymal stromal cells (MSCs) are required for skeletal formation, maintenance, and repair throughout life; however, current models posit that postnatally arising long-lived adult MSCs replace transient embryonic progenitor populations. We previously reported exclusive expression and function of the embryonic patterning transcription factor, Hoxa11, in adult skeletal progenitor-enriched MSCs. Here, using a newly generated Hoxa11-CreERT2 lineage-tracing system, we show Hoxa11-lineage marked cells give rise to all skeletal lineages throughout the life of the animal and persist as MSCs. Hoxa11 lineage-positive cells give rise to previously described progenitor-enriched MSC populations marked by LepR-Cre and Osx-CreER, placing them upstream of these populations. Our studies establish that Hox-expressing cells are skeletal stem cells that arise from the earliest stages of skeletal development and self-renew throughout the life of the animal.
Controls of soil organic matter on soil thermal dynamics in the northern high latitudes
Authors: Zhu Dan , Ciais Philippe , Krinner Gerhard , Maignan Fabienne , Jornet Puig Albert , Hugelius Gustaf
Published: July 2019

Permafrost warming and potential soil carbon (SOC) release after thawing may amplify climate change, yet model estimates of present-day and future permafrost extent vary widely, partly due to uncertainties in simulated soil temperature. Here, we derive thermal diffusivity, a key parameter in the soil thermal regime, from depth-specific measurements of monthly soil temperature at about 200 sites in the high latitude regions. We find that, among the tested soil properties including SOC, soil texture, bulk density, and soil moisture, SOC is the dominant factor controlling the variability of diffusivity among sites. Analysis of the CMIP5 model outputs reveals that the parameterization of thermal diffusivity drives the differences in simulated present-day permafrost extent among these models. The strong SOC-thermics coupling is crucial for projecting future permafrost dynamics, since the response of soil temperature and permafrost area to a rising air temperature would be impacted by potential changes in SOC.
Empirical mean-noise fitness landscapes reveal the fitness impact of gene expression noise
Authors: Schmiedel Jörn M. , Carey Lucas B. , Lehner Ben
Published: July 2019

The effects of cell-to-cell variation (noise) in gene expression have proven difficult to quantify because of the mechanistic coupling of noise to mean expression. To independently quantify the effects of changes in mean expression and noise we determine the fitness landscapes in mean-noise expression space for 33 genes in yeast. For most genes, short-lived (noise) deviations away from the expression optimum are nearly as detrimental as sustained (mean) deviations. Fitness landscapes can be classified by a combination of each gene’s sensitivity to protein shortage or surplus. We use this classification to explore evolutionary scenarios for gene expression and find that certain landscape topologies can break the mechanistic coupling of mean and noise, thus promoting independent optimization of both properties. These results demonstrate that noise is detrimental for many genes and reveal non-trivial consequences of mean-noise-fitness topologies for the evolution of gene expression systems.
Divergent synthesis of chiral cyclic azides via asymmetric cycloaddition reactions of vinyl azides
Authors: Thirupathi Nuligonda , Wei Fang , Tung Chen-Ho , Xu Zhenghu
Published: July 2019

Vinyl azides, bearing conjugated azide and alkene functional groups, have been recognized as versatile building blocks in organic synthesis. In general vinyl azides act as 3-atom (CCN) synthons through the fast release of molecular nitrogen and have been extensively utilized in the construction of structurally diverse N-heterocycles. Keeping the azide moiety intact in organic transformations to synthesis chiral azides is an important but challenging task. Herein, we report an enantioselective copper(II)/BOX-catalyzed cycloaddition of vinyl azides, generating diverse chiral cyclic azides. α-Aryl substituted vinyl azides react with unsaturated keto esters through an inverse-electron-demand hetero-Diels-Alder reaction to afford chiral azido dihydropyrans with excellent enatioselectivities. In contrast, cyclohexenyl azides undergo a diastereo- and enantio-selective Diels-Alder reaction giving important azido octahydronaphthalenes with three continuous stereogenic centers. Notable features of these reactions include a very broad scope, mild reaction conditions and 100% atom economy.
Multifunctional and biodegradable self-propelled protein motors
Authors: Pena-Francesch Abdon , Giltinan Joshua , Sitti Metin
Published: July 2019

A diversity of self-propelled chemical motors, based on Marangoni propulsive forces, has been developed in recent years. However, most motors are non-functional due to poor performance, a lack of control, and the use of toxic materials. To overcome these limitations, we have developed multifunctional and biodegradable self-propelled motors from squid-derived proteins and an anesthetic metabolite. The protein motors surpass previous reports in performance output and efficiency by several orders of magnitude, and they offer control of their propulsion modes, speed, mobility lifetime, and directionality by regulating the protein nanostructure via local and external stimuli, resulting in programmable and complex locomotion. We demonstrate diverse functionalities of these motors in environmental remediation, microrobot powering, and cargo delivery applications. These versatile and degradable protein motors enable design, control, and actuation strategies in microrobotics as modular propulsion sources for autonomous minimally invasive medical operations in biological environments with air-liquid interfaces.
Detecting topology freezing transition temperature of vitrimers by AIE luminogens
Authors: Yang Yang , Zhang Shuai , Zhang Xiqi , Gao Longcheng , Wei Yen , Ji Yan
Published: July 2019

Vitrimers are one kind of covalently crosslinked polymers that can be reprocessed. Topology freezing transition temperature (Tv) is vitrimer’s upper limit temperature for service and lower temperature for recycle. However, there has been no proper method to detect the intrinsic Tv till now. Even worse, current testing methods may lead to a misunderstanding of vitrimers. Here we provide a sensitive and universal method by doping or swelling aggregation-induced-emission (AIE) luminogens into vitrimers. The fluorescence of AIE-luminogens changes dramatically below and over Tv, providing an accurate method to measure Tv without the interference of external force. Moreover, according to this method, Tv is independent of catalyst loading. The opposite idea has been kept for a long time. This method not only is helpful for the practical application of vitrimers so as to reduce white wastes, but also may facilitate deep understanding of vitrimers and further development of functional polymer materials.
A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases
Authors: Wang Zhen , Liu Ziheng , Chen Xing , Li Jingyu , Yao Weiyi , Huang Shijing , Gu Aihong , Lei Qun-Ying , Mao Ying , Wen Wenyu
Published: July 2019

HECT E3 ligases control the degradation and functioning of numerous oncogenic/tumor-suppressive factors and signaling proteins, and their activities must be tightly regulated to prevent cancers and other diseases. Here we show that the Nedd4 family HECT E3 WWP1 adopts an autoinhibited state, in which its multiple WW domains sequester HECT using a multi-lock mechanism. Removing WW2 or WW34 led to a partial activation of WWP1. The structure of fully inhibited WWP1 reveals that many WWP1 mutations identified in cancer patients result in a partially active state with increased E3 ligase activity, and the WWP1 mutants likely promote cell migration by enhancement of ∆Np63α degradation. We further demonstrate that WWP2 and Itch utilize a highly similar multi-lock autoinhibition mechanism as that utilized by WWP1, whereas Nedd4/4 L and Smurf2 utilize a slightly variant version. Overall, these results reveal versatile autoinhibitory mechanisms that fine-tune the ligase activities of the HECT family enzymes.
mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4
Authors: Castets Perrine , Rion Nathalie , Théodore Marine , Falcetta Denis , Lin Shuo , Reischl Markus , Wild Franziska , Guérard Laurent , Eickhorst Christopher , Brockhoff Marielle , Guridi Maitea , Ibebunjo Chikwendu , Cruz Joseph , Sinnreich Michael , Rudolf Rüdiger , Glass David J. , Rüegg Markus A.
Published: July 2019

Loss of innervation of skeletal muscle is a determinant event in several muscle diseases. Although several effectors have been identified, the pathways controlling the integrated muscle response to denervation remain largely unknown. Here, we demonstrate that PKB/Akt and mTORC1 play important roles in regulating muscle homeostasis and maintaining neuromuscular endplates after nerve injury. To allow dynamic changes in autophagy, mTORC1 activation must be tightly balanced following denervation. Acutely activating or inhibiting mTORC1 impairs autophagy regulation and alters homeostasis in denervated muscle. Importantly, PKB/Akt inhibition, conferred by sustained mTORC1 activation, abrogates denervation-induced synaptic remodeling and causes neuromuscular endplate degeneration. We establish that PKB/Akt activation promotes the nuclear import of HDAC4 and is thereby required for epigenetic changes and synaptic gene up-regulation upon denervation. Hence, our study unveils yet-unknown functions of PKB/Akt-mTORC1 signaling in the muscle response to nerve injury, with important implications for neuromuscular integrity in various pathological conditions.
Co-option of neurotransmitter signaling for inter-organismal communication in C. elegans
Authors: Chute Christopher D. , DiLoreto Elizabeth M. , Zhang Ying K. , Reilly Douglas K. , Rayes Diego , Coyle Veronica L. , Choi Hee June , Alkema Mark J. , Schroeder Frank C. , Srinivasan Jagan
Published: July 2019

Biogenic amine neurotransmitters play a central role in metazoan biology, and both their chemical structures and cognate receptors are evolutionarily conserved. Their primary roles are in cell-to-cell signaling, as biogenic amines are not normally recruited for communication between separate individuals. Here, we show that in the nematode C. elegans, a neurotransmitter-sensing G protein-coupled receptor, TYRA-2, is required for avoidance responses to osas#9, an ascaroside pheromone that incorporates the neurotransmitter, octopamine. Neuronal ablation, cell-specific genetic rescue, and calcium imaging show that tyra-2 expression in the nociceptive neuron, ASH, is necessary and sufficient to induce osas#9 avoidance. Ectopic expression in the AWA neuron, which is generally associated with attractive responses, reverses the response to osas#9, resulting in attraction instead of avoidance behavior, confirming that TYRA-2 partakes in the sensing of osas#9. The TYRA-2/osas#9 signaling system represents an inter-organismal communication channel that evolved via co-option of a neurotransmitter and its cognate receptor.
HARCI-EU, a harmonized gridded dataset of critical infrastructures in Europe for large-scale risk assessments
Authors: Batista e Silva Filipe , Forzieri Giovanni , Marin Herrera Mario Alberto , Bianchi Alessandra , Lavalle Carlo , Feyen Luc
Published: July 2019

Critical infrastructures (CIs) are assets, systems, or parts thereof that are essential for the maintenance of socioeconomic functions, health, safety and well-being of people. The exposure of CIs to natural and man-made hazards poses a risk to the economy and society. The spatial distribution of CIs and their economic value are a prerequisite for quantifying risk and planning suitable protection and adaptation measures. However, the incompleteness and inconsistency of existing information on CIs hamper their integration into large-scale risk frameworks. We present here the ‘HARmonized grids of Critical Infrastructures in EUrope’ (HARCI-EU) dataset. It represents major CIs in the transport, energy, industry and social sectors at 1 km2 expressed in sector-specific, economically-relevant units. The HARCI-EU grids were produced by integrating geospatial and statistical data from multiple sources. Correlation analysis performed against independent metrics corroborates the approach showing average Pearson coefficients ranging between 0.61 and 0.95 across the sectors. HARCI-EU provides a consistent mapping of CIs in key sectors that can serve as exposure information for large-scale risk assessments in Europe.
The Young-Feynman controlled double-slit electron interference experiment
Authors: Tavabi Amir H. , Boothroyd Chris B. , Yücelen Emrah , Frabboni Stefano , Gazzadi Gian Carlo , Dunin-Borkowski Rafal E. , Pozzi Giulio
Published: July 2019

The key features of quantum mechanics are vividly illustrated by the Young-Feynman two-slit thought experiment, whose second part discusses the recording of an electron distribution with one of the two slits partially or totally closed by an aperture. Here, we realize the original Feynman proposal in a modern electron microscope equipped with a high brightness gun and two biprisms, with one of the biprisms used as a mask. By exciting the microscope lenses to conjugate the biprism plane with the slit plane, observations are carried out in the Fraunhofer plane with nearly ideal control of the covering of one of the slits. A second, new experiment is also presented, in which interference phenomena due to partial overlap of the slits are observed in the image plane. This condition is obtained by inserting the second biprism between the two slits and the first biprism and by biasing it in order to overlap their images.
Pneumatic actuator and flexible piezoelectric sensor for soft virtual reality glove system
Authors: Song Kahye , Kim Sung Hee , Jin Sungho , Kim Sohyun , Lee Sunho , Kim Jun-Sik , Park Jung-Min , Cha Youngsu
Published: July 2019

The desire to directly touch and experience virtual objects led to the development of a tactile feedback device. In this paper, a novel soft pneumatic actuator for providing tactile feedback is proposed and demonstrated. The suggested pneumatic actuator does not use an external air compressor but it is operated by internal air pressure generated by an electrostatic force. By using the actuator, we designed a glove to interact with virtual reality. The finger motions are detected by attached flexible piezoelectric sensors and transmitted to a virtual space through Bluetooth for interconnecting with a virtual hand. When the virtual finger touches the virtual object, the actuators are activated and give the tactile feedback to the real fingertip. The glove is made of silicone rubber material and integrated with the sensors and actuators such that users can wear them conveniently with light weight. This device was tested in a virtual chess board program, wherein the user picked up virtual chess pieces successfully.
Androgen receptor signalling in the male adrenal facilitates X-zone regression, cell turnover and protects against adrenal degeneration during ageing
Authors: Gannon Anne-Louise , O’Hara Laura , Mason J. Ian , Jørgensen Anne , Frederiksen Hanne , Milne Laura , Smith Sarah , Mitchell Rod T. , Smith Lee B.
Published: July 2019

Androgens are known to be an essential regulator of male health. Androgen receptor (AR) is widely expressed throughout the adrenal cortex, yet the wider role for androgen signalling in the adrenal remains underexplored. To investigate AR-dependent and AR-independent androgen signalling in the adrenal, we used a novel mouse model with a specific ablation of androgen receptor in the adrenal cortex with or without reduction of circulating androgen levels by castration. Our results describe AR expression in the human and mouse adrenal and highlight that the mouse is a viable model to investigate androgen signalling in the adrenal cortex. We show androgen signalling via AR is required for X-zone regression during puberty. Furthermore, cortex measurements define differences in X-zone morphology depending on whether circulating androgens or AR have been removed. We show androgens promote both cortical cell differentiation and apoptosis but are dispensable for the formation of the definitive cortex. Additionally, investigation of aged mice with AR ablation reveals severe cortex disruption, spindle cell hyperplasia and X-zone expansion. The data described herein demonstrates AR-signalling is required to facilitate X-zone regression, cell clearance and to protect against adrenal degeneration during ageing.
Anti-apoptotic activity of ETB receptor agonist, IRL-1620, protects neural cells in rats with cerebral ischemia
Authors: Briyal Seema , Ranjan Amaresh K. , Hornick Mary G. , Puppala Anupama K. , Luu Thanh , Gulati Anil
Published: July 2019

Endothelin-B receptor agonist, IRL-1620, provides significant neuroprotection following cerebral ischemia in rats. Whether this neuroprotection is due to inhibition of apoptosis is unknown. IRL-1620-treated rats following permanent middle cerebral artery occlusion (MCAO) showed significant improvement in neurological and motor functions along with a decrease in infarct volume at 24 h (−81.3%) and day 7 (−73.0%) compared to vehicle group. Cerebral blood flow (CBF) significantly improved in IRL-1620-treated animals compared to vehicle by day 7 post MCAO. IRL-1620-treated rats showed an increase in phospho-Akt and decrease in Bad level 7 h post-occlusion compared to vehicle, while Akt and Bad expression was similar in cerebral hemispheres at 24 h post-MCAO. The phospho-Bad level was lower in vehicle- but not in IRL-1620-treated rats at 24 h. Anti-apoptotic Bcl-2 expression decreased, while pro-apoptotic Bax expression increased in vehicle-treated MCAO rats, these changes were attenuated (P < 0.01) by IRL-1620. Mitochondrial membrane-bound Bax intensity significantly decreased in IRL-1620 compared to vehicle-treated MCAO rats. IRL-1620 treatment reduced (P < 0.001) the number of TUNEL-positive cells compared to vehicle at 24 h and day 7 post MCAO. The results demonstrate that IRL-1620 is neuroprotective and attenuates neural damage following cerebral ischemia in rats by increasing CBF and reducing apoptosis.
Actin depolymerization is able to increase plant resistance against pathogens via activation of salicylic acid signalling pathway
Authors: Leontovyčová Hana , Kalachova Tetiana , Trdá Lucie , Pospíchalová Romana , Lamparová Lucie , Dobrev Petre I. , Malínská Kateřina , Burketová Lenka , Valentová Olga , Janda Martin
Published: July 2019

The integrity of the actin cytoskeleton is essential for plant immune signalling. Consequently, it is generally assumed that actin disruption reduces plant resistance to pathogen attack. Here, we demonstrate that actin depolymerization induced a dramatic increase in salicylic acid (SA) levels in Arabidopsis thaliana. Transcriptomic analysis showed that the SA pathway was activated due to the action of isochorismate synthase (ICS). The effect was also confirmed in Brassica napus. This raises the question of whether actin depolymerization could, under particular conditions, lead to increased resistance to pathogens. Thus, we explored the effect of pretreatment with actin-depolymerizing drugs on the resistance of Arabidopsis thaliana to the bacterial pathogen Pseudomonas syringae, and on the resistance of an important crop Brassica napus to its natural fungal pathogen Leptosphaeria maculans. In both pathosystems, actin depolymerization activated the SA pathway, leading to increased plant resistance. To our best knowledge, we herein provide the first direct evidence that disruption of the actin cytoskeleton can actually lead to increased plant resistance to pathogens, and that SA is crucial to this process.
Endothelial tip cells in vitro are less glycolytic and have a more flexible response to metabolic stress than non-tip cells
Authors: Yetkin-Arik B. , Vogels I. M. C. , Neyazi N. , van Duinen V. , Houtkooper R. H. , van Noorden C. J. F. , Klaassen I. , Schlingemann R. O.
Published: July 2019

Formation of new blood vessels by differentiated endothelial tip cells, stalk cells, and phalanx cells during angiogenesis is an energy-demanding process. How these specialized endothelial cell phenotypes generate their energy, and whether there are differences between these phenotypes, is unknown. This may be key to understand their functions, as (1) metabolic pathways are essentially involved in the regulation of angiogenesis, and (2) a metabolic switch has been associated with angiogenic endothelial cell differentiation. With the use of Seahorse flux analyses, we studied metabolic pathways in tip cell and non-tip cell human umbilical vein endothelial cell populations. Our study shows that both tip cells and non-tip cells use glycolysis as well as mitochondrial respiration for energy production. However, glycolysis is significantly lower in tip cells than in non-tip cells. Additionally, tip cells have a higher capacity to respond to metabolic stress. Finally, in non-tip cells, blocking of mitochondrial respiration inhibits endothelial cell proliferation. In conclusion, our data demonstrate that tip cells are less glycolytic than non-tip cells and that both endothelial cell phenotypes can adapt their metabolism depending on microenvironmental circumstances. Our results suggest that a balanced involvement of metabolic pathways is necessary for both endothelial cell phenotypes for proper functioning during angiogenesis.
Identifying potential drug targets in hepatocellular carcinoma based on network analysis and one-class support vector machine
Authors: Tong Zhan , Zhou Yuan , Wang Juan
Published: July 2019

Hepatocellular carcinoma (HCC) is one major cause of cancer-related death worldwide. But now, the systematic therapy for the advanced stages of HCC is rather limited. Thus, the discovery of novel drug targets and thereafter targeted drugs against HCC is continuously needed. In this study, we combined clinical association data, gene expression profiles and manually collected drug target genes with the human protein-protein interaction (PPI) network to establish an in-silico HCC drug target predictor. First, we found drug target genes (DTGs), disease-associated genes (DAGs), prognostic unfavorable genes (PUGs) and cancer up-regulated genes (URGs) have higher degree, betweenness, closeness centrality, while cancer down-regulated genes (DRGs), prognostic favorable genes (PFGs) have lower degrees, in comparison with background genes. Moreover, DTG nodes were shown to be closer to DAG, PUG and URG nodes, but farther away from PFG and DRG nodes. Compared to the background, PFGs and DRGs were shown to have relatively bigger genetic dependency scores, while PUGs and URGs have smaller genetic dependency scores. Finally, based on the observed features of DTGs, we constructed a drug target predictor using one-class support vector machine (one-class SVM). Performance evaluation results suggested our predictor could effectively identify putative drug target genes for further research.
Atomic scale study of stress-induced misaligned subsurface layers in KDP crystals
Authors: Hu Yue , Zhu Zhen , Xiao Jiamin , Shao Hezhu , Zhao Li , Xu Min , Zhuang Jun
Published: July 2019

We carried out ab initio calculations to study the atomic configuration, band structure and optical absorption of the lattice misalignment structure (LMS) in a subsurface layer of a machined KH2PO4 (KDP) crystal. By varying the different degrees of misalignment, the changes in the corresponding atomic position and bond and energy are obtained, and their correlations are analysed in detail. The results indicate that in the LMS evolution, the variation in the proton distribution around the oxygen atoms plays an important role, and many local stable LMSs appear. Interestingly, at a certain misalignment value, the total system energy of the local stable LMS is near that of a perfect KDP crystal. For some local stable LMSs, the electronic and optical properties related to the laser damage threshold (LDT) of KDP are further studied. The results show that in comparison with a perfect KDP crystal, the band gaps of local stable LMSs at some certain misalignment values become narrow, and their optical absorption curves produce an obvious redshift. These facts demonstrate that the emergence of the LMS could have a significant impact on the optical absorption of the KDP material and thus affect the LDT of KDP under certain working conditions.
Speech perception is similar for musicians and non-musicians across a wide range of conditions
Authors: Madsen Sara M. K. , Marschall Marton , Dau Torsten , Oxenham Andrew J.
Published: July 2019

It remains unclear whether musical training is associated with improved speech understanding in a noisy environment, with different studies reaching differing conclusions. Even in those studies that have reported an advantage for highly trained musicians, it is not known whether the benefits measured in laboratory tests extend to more ecologically valid situations. This study aimed to establish whether musicians are better than non-musicians at understanding speech in a background of competing speakers or speech-shaped noise under more realistic conditions, involving sounds presented in space via a spherical array of 64 loudspeakers, rather than over headphones, with and without simulated room reverberation. The study also included experiments testing fundamental frequency discrimination limens (F0DLs), interaural time differences limens (ITDLs), and attentive tracking. Sixty-four participants (32 non-musicians and 32 musicians) were tested, with the two groups matched in age, sex, and IQ as assessed with Raven’s Advanced Progressive matrices. There was a significant benefit of musicianship for F0DLs, ITDLs, and attentive tracking. However, speech scores were not significantly different between the two groups. The results suggest no musician advantage for understanding speech in background noise or talkers under a variety of conditions.
Validation of quantum adiabaticity through non-inertial frames and its trapped-ion realization
Authors: Hu Chang-Kang , Cui Jin-Ming , Santos Alan C. , Huang Yun-Feng , Li Chuan-Feng , Guo Guang-Can , Brito Frederico , Sarandy Marcelo S.
Published: July 2019

Validity conditions for the adiabatic approximation are useful tools to understand and predict the quantum dynamics. Remarkably, the resonance phenomenon in oscillating quantum systems has challenged the adiabatic theorem. In this scenario, inconsistencies in the application of quantitative adiabatic conditions have led to a sequence of new approaches for adiabaticity. Here, by adopting a different strategy, we introduce a validation mechanism for the adiabatic approximation by driving the quantum system to a non-inertial reference frame. More specifically, we begin by considering several relevant adiabatic approximation conditions previously derived and show that all of them fail by introducing a suitable oscillating Hamiltonian for a single quantum bit (qubit). Then, by evaluating the adiabatic condition in a rotated non-inertial frame, we show that all of these conditions, including the standard adiabatic condition, can correctly describe the adiabatic dynamics in the original frame, either far from resonance or at a resonant point. Moreover, we prove that this validation mechanism can be extended for general multi-particle quantum systems, establishing the conditions for the equivalence of the adiabatic behavior as described in inertial or non-inertial frames. In order to experimentally investigate our method, we consider a hyperfine qubit through a single trapped Ytterbium ion 171Yb+, where the ion hyperfine energy levels are used as degrees of freedom of a two-level system. By monitoring the quantum evolution, we explicitly show the consistency of the adiabatic conditions in the non-inertial frame.
Microanatomy of the stem-turtle Pappochelys rosinae indicates a predominantly fossorial mode of life and clarifies early steps in the evolution of the shell
Authors: Schoch Rainer R. , Klein Nicole , Scheyer Torsten M. , Sues Hans-Dieter
Published: July 2019

Unlike any other tetrapod, turtles form their dorsal bony shell (carapace) not from osteoderms, but by contribution of the ribs and vertebrae that expand into the dermis to form plate-like shell components. Although this was known from embryological studies in extant turtles, important steps in this evolutionary sequence have recently been highlighted by the Triassic taxa Pappochelys, Eorhynchochelys and Odontochelys, and the Permian Eunotosaurus. The discovery of Pappochelys shed light on the origin of the ventral bony shell (plastron), which formed from enlarged gastralia. A major question is whether the turtle shell evolved in the context of a terrestrial or aquatic environment. Whereas Odontochelys was controversially interpreted as aquatic, a terrestrial origin of turtles was proposed based on evidence of fossorial adaptations in Eunotosaurus. We report palaeohistological data for Pappochelys, a taxon that exemplifies earlier evolutionary stages in the formation of the bony shell than Odontochelys. Bone histological evidence reveals (1) evolutionary changes in bone microstructure in ribs and gastralia approaching the turtle condition and (2) evidence for a predominantly amphibious or fossorial mode of life in Pappochelys, which support the hypothesis that crucial steps in the evolution of the shell occurred in a terrestrial rather than fully aquatic environment.
Metabolic property of acetaldehyde production from ethanol and glucose by oral Streptococcus and Neisseria
Authors: Tagaino Ryo , Washio Jumpei , Abiko Yuki , Tanda Naoko , Sasaki Keiichi , Takahashi Nobuhiro
Published: July 2019

Acetaldehyde is known to be carcinogenic and produced by oral bacteria. Thus, bacterial acetaldehyde production might contribute to oral cancer. Therefore, we examined bacterial acetaldehyde production from ethanol and glucose under various conditions mimicking the oral cavity and clarified the metabolic pathways responsible for bacterial acetaldehyde production. Streptococcus mitis, S. salivarius, S. mutans, Neisseria mucosa and N. sicca were used. The bacterial metabolism was conducted at pH 5.0–8.0 under aerobic and anaerobic conditions. The production of acetaldehyde and organic acids was measured with gas chromatography and HPLC, respectively. Bacterial enzymes were also assessed. All of the bacteria except for S. mutans exhibited their greatest acetaldehyde production from ethanol at neutral to alkaline pH under aerobic conditions. S. mutans demonstrated the greatest acetaldehyde from glucose under anaerobic conditions, although the level was much lower than that from ethanol. Alcohol dehydrogenase and NADH oxidase were detected in all of the bacteria. This study revealed that oral indigenous bacteria, Streptococcus and Neisseria can produce acetaldehyde, and that such acetaldehyde production is affected by environmental conditions. It was suggested that alcohol dehydrogenase and NADH oxidase are involved in ethanol-derived acetaldehyde production and that the branched-pathway from pyruvate is involved in glucose-derived acetaldehyde production.
A novel mouse tail lymphedema model for observing lymphatic pump failure during lymphedema development
Authors: Weiler Michael J. , Cribb Matthew T. , Nepiyushchikh Zhanna , Nelson Tyler S. , Dixon J. Brandon
Published: July 2019

It has been suggested that many forms of secondary lymphedema in humans are driven by a progressive loss of lymphatic pump function after an initial risk-inducing event. However, the link between pump failure and disease progression has remained elusive due to experimental challenges in the clinical setting and a lack of adequate animal models. Using a novel surgical model of lymphatic injury, we track the adaptation and functional decline of the lymphatic network in response to surgery. This model mimics the histological hallmarks of the typical mouse tail lymphedema model while leaving an intact collecting vessel for analysis of functional changes during disease progression. Lymphatic function in the intact collecting vessel negatively correlated with swelling, while a loss of pumping pressure generation remained even after resolution of swelling. By using this model to study the role of obesity in lymphedema development, we show that obesity exacerbates acquired lymphatic pump failure following lymphatic injury, suggesting one mechanism through which obesity may worsen lymphedema. This lymphatic injury model will allow for future studies investigating the molecular mechanisms leading to lymphedema development.
Risk of Kidney Dysfunction from Polypharmacy among Older Patients: A Nested Case-Control Study of the South Korean Senior Cohort
Authors: Kang Hyeonjin , Hong Song Hee
Published: July 2019

Polypharmacy, the concurrent use of multiple medicines, could increase the risk of kidney dysfunction among older adults because it likely burdens the aging kidneys to excrete multiple pharmaceutical ingredients and their metabolites. This study aimed to examine the relation between polypharmacy and kidney dysfunction among older patients. A nested case-control study was conducted using the National Health Insurance Service – Senior Cohort (NHIS-SC, 2009–2013), representative of the Korean senior population. It consisted of all health insurance claims linked to records of mandatory health examination. Kidney dysfunction was defined as having an eGFR lower than 60, with a decline rate of 10% or more compared to the baseline eGFR. Polypharmacy was defined based on daily counts of pharmaceutical ingredients during one year prior to the case’s event date. It was classified into polypharmacy (five to 10 ingredients) and excessive polypharmacy (10 or more ingredients). After matching case and control groups based on a range of potential confounders, conditional logistic regression was performed incorporating adjustments on disease-specific, medication-specific, and lifestyle-related risk factors. The matching resulted in 14,577 pairs of cases and controls. Exposure to polypharmacy was significantly associated with increase in the risk of kidney dysfunction; i.e., crude model (polypharmacy: OR = 1.572, 95% CI = 1.492–1.656; excessive polypharmacy: OR = 2.069, 95% CI = 1.876–2.283) and risk adjustment model (polypharmacy: OR = 1.213, 95% CI = 1.139–1.292; excessive polypharmacy: OR = 1.461, 95% CI = 1.303–1.639). The significant associations were robust across different definitions of kidney dysfunction. These findings inform healthcare providers and policy makers of the importance of polypharmacy prevention to protect older adults from kidney dysfunction.
Prevalence and risk factors of chronic kidney disease and diabetic kidney disease in Chinese rural residents: a cross-sectional survey
Authors: Duan Jiayu , Wang Chongjian , Liu Dongwei , Qiao Yingjin , Pan Shaokang , Jiang Dengke , Zhao Zihao , Liang Lulu , Tian Fei , Yu Pei , Zhang Yu , Zhao Huanhuan , Liu Zhangsuo
Published: July 2019

We conducted a cross-sectional survey including 23869 participants and aimed to measure the prevalences of and risk factors for chronic kidney disease (CKD) and diabetic kidney disease (DKD) in a Chinese rural population. CKD and DKD status was defined according to the combination of estimated glomerular filtration rate (eGFR) and presence of albuminuria Participant completed a questionnaire involving life-style and relevant medical history, and the blood and urinary specimen were taken. The age- and gender- adjusted prevalences of CKD and DKD were calculated and risk factors associated with the presence of CKD and DKD were analyzed by logistic regression. The overall prevalence of CKD was 16.4% (15.9–16.8%) and of DKD was 2.9% (2.7–3.1%). In participants with diabetes, the overall prevalence of CKD was 35.5% (95% CI = 33.7–37.3%). Factors independently associated with renal damage were age, gender, education, personal income, alcohol consumption, overweight, obesity, diabetes, hypertension and dyslipidemia. Our study shows current prevalences of CKD and DKD in Chinese rural residents. Further researches could identify potential factors explaining the observed differences and implement the interventions to relieve the high burden of CKD and DKD in rural population.
Metabolic signatures of germination triggered by kinetin in Medicago truncatula
Authors: Araújo Susana , Pagano Andrea , Dondi Daniele , Lazzaroni Simone , Pinela Eduardo , Macovei Anca , Balestrazzi Alma
Published: July 2019

In the present work, non-targeted metabolomics was used to investigate the seed response to kinetin, a phytohormone with potential roles in seed germination, still poorly explored. The aim of this study was to elucidate the metabolic signatures of germination triggered by kinetin and explore changes in metabolome to identify novel vigor/stress hallmarks in Medicago truncatula. Exposure to 0.5 mM kinetin accelerated seed germination but impaired seedling growth. Metabolite composition was investigated in seeds imbibed with water or with 0.5 mM kinetin collected at 2 h and 8 h of imbibition, and at the radicle protrusion stage. According to Principal Component Analysis, inositol pentakisphosphate, agmatine, digalactosylglycerol, inositol hexakisphosphate, and oleoylcholine were the metabolites that mostly contributed to the separation between 2 h, 8 h and radicle protrusion stage, irrespective of the treatment applied. Overall, only 27 metabolites showed significant changes in mean relative contents triggered by kinetin, exclusively at the radicle protrusion stage. The observed metabolite depletion might associate with faster germination or regarded as a stress signature. Results from alkaline comet assay, highlighting the occurrence of DNA damage at this stage of germination, are consistent with the hypothesis that prolonged exposure to kinetin induces stress conditions leading to genotoxic injury.
Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma
Authors: Jin Yu , Wong Ye Shen , Goh Brian K. P. , Chan Chung Yip , Cheow Peng Chung , Chow Pierce K. H. , Lim Tony K. H. , Goh George B. B. , Krishnamoorthy Thinesh Lee , Kumar Rajneesh , Ng Tze Pin , Chong Samuel S. , Tan Hwee Huang , Chung Alexander Y. F. , Ooi London Lucien P. J. , Chang Jason P. E. , Tan Chee Kiat , Lee Caroline G. L.
Published: July 2019

Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3rd cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.