bluuebunny/crossref_metadata_2025 huggingface dataset:
ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect in human stomach adenocarcinoma
Authors: Gu Zhuoyu , Wang Liping , Yao Xiaohan , Long Qian , Lee Kaping , Li Jieyao , Yue Dongli , Yang Shuangning , Liu Yanfen , Li Na , Li Yixin
Published: October 2020

Currently, only a few available targeted drugs are considered to be effective in stomach adenocarcinoma (STAD) treatment. The PARP inhibitor olaparib is a molecularly targeted drug that continues to be investigated in BRCA-mutated tumors. However, in tumors without BRCA gene mutations, particularly in STAD, the effect and molecular mechanism of olaparib are unclear, which largely restricts the use of olaparib in STAD treatment. In this study, the in vitro results showed that olaparib specifically inhibited cell growth and migration, exerting antitumor effect in STAD cell lines. In addition, a ClC-3/SGK1 regulatory axis was identified and validated in STAD cells. We then found that the down-regulation of ClC-3/SGK1 axis attenuated olaparib-induced cell growth and migration inhibition. On the contrary, the up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced cell growth and migration inhibition, and the enhancement effect could be attenuated by SGK1 knockdown. Consistently, the whole-cell recorded chloride current activated by olaparib presented the same variation trend. Next, the clinical data showed that ClC-3 and SGK1 were highly expressed in human STAD tissues and positively correlated (r = 0.276,P = 0.009). Furthermore, high protein expression of both ClC-3 (P = 0.030) and SGK1 (P = 0.006) was associated with poor survival rate in STAD patients, and positive correlations between ClC-3/SGK1 and their downstream molecules in STAD tissues were demonstrated via the GEPIA datasets. Finally, our results suggested that olaparib inhibited the PI3K/AKT pathway in STAD cells, and up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced PI3K/AKT pathway inhibition. The animal experiments indicated that olaparib also exerted antitumor effect in vivo. Altogether, our findings illustrate that olaparib exerts antitumor effect in human STAD, and ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect. Up-regulation of the ClC-3/SGK1 axis may provide promising therapeutic potential for the clinical application of olaparib in STAD treatment.
BCL11B suppresses tumor progression and stem cell traits in hepatocellular carcinoma by restoring p53 signaling activity
Authors: Yang Wen-Jing , Sun Yun-Fan , Jin An-Li , Lv Li-Hua , Zhu Jie , Wang Bei-Li , Zhou Yan , Zhang Chun-Yan , Wang Hao , Hu Bo , Wang Peng-Xiang , Te Liu , Pan Bai-Shen , Zhou Jian , Fan Jia , Yang Xin-Rong , Guo Wei
Published: October 2020

Accumulating evidence indicates that hepatocellular carcinoma (HCC) tumorigenesis, recurrence, metastasis, and therapeutic resistance are strongly associated with liver cancer stem cells (CSCs), a rare subpopulation of highly tumorigenic cells with self-renewal capacity and differentiation potential. Previous studies identified B cell leukemia/lymphoma-11b (BCL11B) as a novel tumor suppressor with impressive capacity to restrain CSC traits. However, the implications of BCL11B in HCC remain unclear. In this study, we found that low BCL11B expression was an independent indicator for shorter overall survival (OS) and time to recurrence (TTR) for HCC patients with surgical resection. In vitro and in vivo experiments confirmed BCL11B as a tumor suppressor in HCC with inhibitory effects on proliferation, cell cycle progression, apoptosis, and mobility. Furthermore, BCL11B could suppress CSC traits, as evidenced by dramatically decreased tumor spheroid formation, self-renewal potential and drug resistance. A Cignal Finder Array and dual-luciferase activity reporter assays revealed that BCL11B could activate the transcription of P73 via an E2F1-dependent manner. Thus, we concluded that BCL11B is a strong suppressor of retaining CSC traits in HCC. Ectopic expression of BCL11B might be a promising strategy for anti-HCC treatment with the potential to cure HBV-related HCC regardless of P53 mutation status.
Cancer-testis antigens, semenogelins 1 and 2, exhibit different anti-proliferative effects on human lung adenocarcinoma cells
Authors: Shuvalov Oleg , Kizenko Alyona , Petukhov Alexey , Aksenov Nickolai , Fedorova Olga , Vorobev Mikhail , Daks Alexandra , Barlev Nickolai
Published: October 2020

Сancer-testis antigens (CTAs) comprise proteins which are aberrantly expressed in various malignancies, yet under normal situation are restricted to only germ cells. Semenogelins 1 and 2 (SEMG1 and 2, respectively) belong to the family of non-X-linked (autosomal) cancer-testis antigens. They are the major protein ingredients of human semen and share 78% of similarity between them on the gene level. SEMG1/2 gene products regulate the motility and fertility of sperm, as well as provide sperm the antibacterial defense. Besides, SEMG1 and SEMG2 were detected in various malignancies including small cell lung cancer (SCLC). However, the biological role of both SEMG1 and 2 proteins in tumorigenesis has not been fully understood. We demonstrate here that SEMG1 and SEMG2 (SEMGs) exhibit different patterns of expression and sub-cellular localization in non-small cell lung cancer (NSCLC) cell lines. To elucidate the biological properties of SEMGs in NSCLC, we established H1299 cell lines that were stably transduced with either SEMGs-overexpressing or knockdown vectors, respectively. Using fluorescence-based dihydroethidium (DHE) assay we showed that both SEMGs augmented the production of reactive oxygen species (ROS) up to 2 times. Moreover, SEMGs (especially SEMG1) strongly increased the number of Annexin V–positive apoptotic cells manifesting an increased sensitivity to genotoxic drugs including doxorubicin, etoposide, and cisplatin. Taken our results together, SEMGs may arguably play a positive role in tumorigenesis by sensitizing NSCLCs to genotoxic therapy.
High-temperature ferromagnetic semiconductor with a field-tunable green fluorescent effect
Authors: Zhou Bowen , Zhao Qing , Liu Zhehong , Shen Xudong , Ye Xubin , Shi Jiangjian , Liao Zhiyu , Wang Weipeng , Hu Zhiwei , Lin Hong-Ji , Chen Chien-Te , Bian Yuecheng , Sheng Zhigao , Yu Richeng , Qiu Xianggang , Meng Qingbo , Li Zhi , Long Youwen
Published: October 2020

Ferromagnetic semiconductors with luminescent effects provide a unique platform for studying magneto-electric-optical multifunctional devices. However, little is known about such materials with spin ordering well above room temperature. By using a unique high-pressure annealing method, a Cr and Fe disordered perovskite oxide SrCr0.5Fe0.5O2.875 (SCFO) with a simple cubic structure was prepared. Magnetic measurements demonstrated the ferromagnetic behavior with a spin ordering temperature as high as 600 K. In contrast to metallic SrCrO3 and SrFeO3, SCFO, with a moderate oxygen deficiency, is a direct bandgap semiconductor with an energy gap of 2.28 eV, which is within the visible light region. As a consequence, SCFO displays a green fluorescent effect arising from the d–p bonding and anti-bonding states. Moreover, the photoluminescence intensity can be tuned by a magnetic field. This work opens up a new avenue for research on room-temperature multifunctional materials with coupled magnetic, electrical, and optical performance.
Natural antisense transcripts of MIR398 genes suppress microR398 processing and attenuate plant thermotolerance
Authors: Li Yajie , Li Xiaorong , Yang Jun , He Yuke
Published: October 2020

MicroRNAs (miRNAs) and natural antisense transcripts (NATs) control many biological processes and have been broadly applied for genetic manipulation of eukaryotic gene expression. Still unclear, however, are whether and how NATs regulate miRNA production. Here, we report that the cis-NATs of MIR398 genes repress the processing of their pri-miRNAs. Through genome-wide analysis of RNA sequencing data, we identify cis-NATs of MIRNA genes in Arabidopsis and Brassica. In Arabidopsis, MIR398b and MIR398c are coexpressed in vascular tissues with their antisense genes NAT398b and NAT398c, respectively. Knock down of NAT398b and NAT398c promotes miR398 processing, resulting in stronger plant thermotolerance owing to silencing of miR398-targeted genes; in contrast, their overexpression activates NAT398b and NAT398c, causing poorer thermotolerance due to the upregulation of miR398-targeted genes. Unexpectedly, overexpression of MIR398b and MIR398c activates NAT398b and NAT398c. Taken together, these results suggest that NAT398b/c repress miR398 biogenesis and attenuate plant thermotolerance via a regulatory loop.
Author Correction: Concerted pulsatile and graded neural dynamics enables efficient chemotaxis in C. elegans
Authors: Itskovits Eyal , Ruach Rotem , Kazakov Alexander , Zaslaver Alon
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Mode of induction of platelet-derived extracellular vesicles is a critical determinant of their phenotype and function
Authors: Ferreira P. M. , Bozbas E. , Tannetta S. D. , Alroqaiba N. , Zhou R. , Crawley J. T. B. , Gibbins J. M. , Jones C. I. , Ahnström J. , Yaqoob P.
Published: October 2020

Platelet-derived extracellular vesicles (PDEVs) are the most abundant amongst all types of EVs in the circulation. However, the mechanisms leading to PDEVs release, their role in coagulation and phenotypic composition are poorly understood. PDEVs from washed platelets were generated using different stimuli and were characterised using nanoparticle tracking analysis. Procoagulant properties were evaluated by fluorescence flow cytometry and calibrated automated thrombography. EVs from plasma were isolated and concentrated using a novel protocol involving a combination of size exclusion chromatography and differential centrifugation, which produces pure and concentrated EVs. Agonist stimulation enhanced PDEV release, but did not alter the average size of EVs compared to those produced by unstimulated platelets. Agonist stimulation led to lower negatively-charged phospholipid externalization in PDEVs, which was reflected in the lower procoagulant activity compared to those generated without agonist stimulation. Circulating EVs did not have externalized negatively-charged phospholipids. None of the 4 types of EVs presented tissue factor. The mechanism by which PDEV formation is induced is a critical determinant of its phenotype and function. Importantly, we have developed methods to obtain clean, concentrated and functional EVs derived from platelet-free plasma and washed platelets, which can be used to provide novel insight into their biological functions.
An injectable self-healing anesthetic glycolipid-based oleogel with antibiofilm and diabetic wound skin repair properties
Authors: Prasad Yadavali Siva , Miryala Sandeep , Lalitha Krishnamoorthy , Saritha Balasubramani , Maheswari C. Uma , Sridharan Vellaisamy , Srinandan C. S. , Nagarajan Subbiah
Published: October 2020

Globally, wound infections are considered as one of the major healthcare problems owing to the delayed healing process in diabetic patients and microbial contamination. Thus, the development of advanced materials for wound skin repair is of great research interest. Even though several biomaterials were identified as wound healing agents, gel-based scaffolds derived from either polymer or small molecules have displayed promising wound closure mechanism. Herein, for the first time, we report an injectable and self-healing self-assembled anesthetic oleogel derived from glycolipid, which exhibits antibiofilm and wound closure performance in diabetic rat. Glycolipid derived by the reaction of hydrophobic vinyl ester with α-chloralose in the presence of novozyme 435 undergoes spontaneous self-assembly in paraffin oil furnished an oleogel displaying self-healing behavior. In addition, we have prepared composite gel by encapsulating curcumin in the 3D fibrous network of oleogel. More interestingly, glycolipid in its native form demoed potential in disassembling methicillin-resistant Staphylococcus aureus, methicillin-susceptible Staphylococcus aureus, and Pseudomonas aeruginosa biofilms. Both oleogel and composite gel enhanced the wound skin repair in diabetic induced Wistar rats by promoting collagen synthesis, controlling free radical generation and further regulating tissue remodeling phases. Altogether, the reported supramolecular self-assembled anesthetic glycolipid could be potentially used for diabetic skin wound repair and to treat bacterial biofilm related infections.
3D reconstruction of coronary artery bifurcations from coronary angiography and optical coherence tomography: feasibility, validation, and reproducibility
Authors: Wu Wei , Samant Saurabhi , de Zwart Gijs , Zhao Shijia , Khan Behram , Ahmad Mansoor , Bologna Marco , Watanabe Yusuke , Murasato Yoshinobu , Burzotta Francesco , Brilakis Emmanouil S. , Dangas George , Louvard Yves , Stankovic Goran , Kassab Ghassan S. , Migliavacca Francesco , Chiastra Claudio , Chatzizisis Yiannis S.
Published: October 2020

The three-dimensional (3D) representation of the bifurcation anatomy and disease burden is essential for better understanding of the anatomical complexity of bifurcation disease and planning of stenting strategies. We propose a novel methodology for 3D reconstruction of coronary artery bifurcations based on the integration of angiography, which provides the backbone of the bifurcation, with optical coherence tomography (OCT), which provides the vessel shape. Our methodology introduces several technical novelties to tackle the OCT frame misalignment, correct positioning of the OCT frames at the carina, lumen surface reconstruction, and merging of bifurcation lumens. The accuracy and reproducibility of the methodology were tested in n = 5 patient-specific silicone bifurcations compared to contrast-enhanced micro-computed tomography (µCT), which was used as reference. The feasibility and time-efficiency of the method were explored in n = 7 diseased patient bifurcations of varying anatomical complexity. The OCT-based reconstructed bifurcation models were found to have remarkably high agreement compared to the µCT reference models, yielding r2values between 0.91 and 0.98 for the normalized lumen areas, and mean differences of 0.005 for lumen shape and 0.004 degrees for bifurcation angles. Likewise, the reproducibility of our methodology was remarkably high. Our methodology successfully reconstructed all the patient bifurcations yielding favorable processing times (average lumen reconstruction time < 60 min). Overall, our method is an easily applicable, time-efficient, and user-friendly tool that allows accurate and reproducible 3D reconstruction of coronary bifurcations. Our technique can be used in the clinical setting to provide information about the bifurcation anatomy and plaque burden, thereby enabling planning, education, and decision making on bifurcation stenting.
Cell-penetrating peptide-mediated cell entry of H5N1 highly pathogenic avian influenza virus
Authors: Kajiwara Naoki , Nomura Namiko , Ukaji Masako , Yamamoto Naoki , Kohara Michinori , Yasui Fumihiko , Sakoda Yoshihiro , Kida Hiroshi , Shibasaki Futoshi
Published: October 2020

H5N1 highly pathogenic avian influenza virus (HPAIV) poses a huge threat to public health and the global economy. These viruses cause systemic infection in poultry and accidental human infection leads to severe pneumonia, associated with high mortality rates. The hemagglutinin (HA) of H5N1 HPAIV possesses multiple basic amino acids, as in the sequence RERRRKKR at the cleavage site; however, the role of this motif is not fully understood. Here, we showed that a 33-amino acid long peptide derived from HA of H5N1 HPAIV (HA314-46) has the potential to penetrate various cells and lung tissue through a sialic acid-independent endocytotic pathway. Mutant peptide analyses revealed that the cysteine residue at position 318 and multiple basic amino acids were essential for the cell-penetrating activity. Moreover, reassortant viruses possessing H5 HA could enter sialic acid-deficient cells, and virus internalisation was facilitated by cleavage with recombinant furin. Thus, our findings demonstrate that the HA314-46 motif exhibits cell-penetrating activity through a sialic acid-independent cell entry mechanism.
Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome
Authors: Trevino Cristina E. , Holleman Aaron M. , Corbitt Holly , Maslen Cheryl L. , Rosser Tracie C. , Cutler David J. , Johnston H. Richard , Rambo-Martin Benjamin L. , Oberoi Jai , Dooley Kenneth J. , Capone George T. , Reeves Roger H. , Cordell Heather J. , Keavney Bernard D. , Agopian A.J. , Goldmuntz Elizabeth , Gruber Peter J. , O’Brien James E. , Bittel Douglas C. , Wadhwa Lalita , Cua Clifford L. , Moskowitz Ivan P. , Mulle Jennifer G. , Epstein Michael P. , Sherman Stephanie L. , Zwick Michael E.
Published: October 2020

Atrioventricular septal defects (AVSD) are a severe congenital heart defect present in individuals with Down syndrome (DS) at a > 2000-fold increased prevalence compared to the general population. This study aimed to identify risk-associated genes and pathways and to examine a potential polygenic contribution to AVSD in DS. We analyzed a total cohort of 702 individuals with DS with or without AVSD, with genomic data from whole exome sequencing, whole genome sequencing, and/or array-based imputation. We utilized sequence kernel association testing and polygenic risk score (PRS) methods to examine rare and common variants. Our findings suggest that the Notch pathway, particularlyNOTCH4, as well as genes involved in the ciliome includingCEP290may play a role in AVSD in DS. These pathways have also been implicated in DS-associated AVSD in prior studies. A polygenic component for AVSD in DS has not been examined previously. Using weights based on the largest genome-wide association study of congenital heart defects available (2594 cases and 5159 controls; all general population samples), we found PRS to be associated with AVSD with odds ratios ranging from 1.2 to 1.3 per standard deviation increase in PRS and corresponding liability r2values of approximately 1%, suggesting at least a small polygenic contribution to DS-associated AVSD. Future studies with larger sample sizes will improve identification and quantification of genetic contributions to AVSD in DS.
Comparative genomic and transcriptomic analyses of chemosensory genes in the citrus fruit fly Bactrocera (Tetradacus) minax
Authors: Cheng Jun-Feng , Yu Ting , Chen Zhong-Jian , Chen Shicheng , Chen Yu-Peng , Gao Lei , Zhang Wen-Hu , Jiang Bo , Bai Xue , Walker Edward D. , Liu Jun , Lu Yong-Yue
Published: October 2020

The citrus fruit fly Bactrocera (Tetradacus) minax is a major and devastating agricultural pest in Asian subtropical countries. Previous studies have shown that B. minax interacts with plant hosts via the efficient chemosensory system. However, the molecular components of the B. minax chemosensory system have not been well characterized. Herein, we identified a total of 25 putative odorant-binding receptors (OBPs), 4 single-copy chemosensory proteins (CSPs) and 53 candidate odorant receptors (ORs) using a newly generated whole-genome dataset for B. minax. This study significantly extended the chemosensation-related gene profiles (particularly, OBPs and ORs) in six other tephritid species. Comparative transcriptome analysis of adult B. minax and Bactrocera dorsalis showed that there were 14 highly expressed OBPs (FPKM > 100) in B. dorsalis and 7 highly expressed ones in B. minax. The expression level of CSP3 gene and CSP4 gene was higher in B. dorsalis than that in B. minax. Comparative genomic and transcriptomic analyses of chemosensory genes in the citrus fruit fly B. minax provided new insights for preventive control of this agriculture important pest and closely related species.
Neuroepithelial cell competition triggers loss of cellular juvenescence
Authors: Jam Faidruz Azura , Morimune Takao , Tsukamura Atsushi , Tano Ayami , Tanaka Yuya , Mori Yasuhiro , Yamamoto Takefumi , Nishimura Masaki , Tooyama Ikuo , Mori Masaki
Published: October 2020

Cell competition is a cell–cell interaction mechanism which maintains tissue homeostasis through selective elimination of unfit cells. During early brain development, cells are eliminated through apoptosis. How cells are selected to undergo elimination remains unclear. Here we aimed to identify a role for cell competition in the elimination of suboptimal cells using an in vitro neuroepithelial model. Cell competition was observed when neural progenitor HypoE-N1 cells expressing RASV12 were surrounded by normal cells in the co-culture. The elimination through apoptosis was observed by cellular changes of RASV12 cells with rounding/fragmented morphology, by SYTOX blue-positivity, and by expression of apoptotic markers active caspase-3 and cleaved PARP. In this model, expression of juvenility-associated genes Srsf7 and Ezh2 were suppressed under cell-competitive conditions. Srsf7 depletion led to loss of cellular juvenescence characterized by suppression of Ezh2, cell growth impairment and enhancement of senescence-associated proteins. The cell bodies of eliminated cells were engulfed by the surrounding cells through phagocytosis. Our data indicates that neuroepithelial cell competition may have an important role for maintaining homeostasis in the neuroepithelium by eliminating suboptimal cells through loss of cellular juvenescence.
Rescue of germ cells in dnd crispant embryos opens the possibility to produce inherited sterility in Atlantic salmon
Authors: Güralp Hilal , Skaftnesmo Kai O. , Kjærner-Semb Erik , Straume Anne Hege , Kleppe Lene , Schulz Rüdiger W. , Edvardsen Rolf B. , Wargelius Anna
Published: October 2020

Genetic introgression of escaped farmed Atlantic salmon (Salmo salar) into wild populations is a major environmental concern for the salmon aquaculture industry. Using sterile fish in commercial aquaculture operations is, therefore, a sustainable strategy for bio-containment. So far, the only commercially used methodology for producing sterile fish is triploidization. However, triploid fish are less robust. A novel approach in which to achieve sterility is to produce germ cell-free salmon, which can be accomplished by knocking out the dead-end (dnd) gene using CRISPR-Cas9. The lack of germ cells in the resulting dnd crispants, thus, prevents reproduction and inhibits subsequent large-scale production of sterile fish. Here, we report a rescue approach for producing germ cells in Atlantic salmon dnd crispants. To achieve this, we co-injected the wild-type (wt) variant of salmon dnd mRNA together with CRISPR-Cas9 constructs targeting dnd into 1-cell stage embryos. We found that rescued one-year-old fish contained germ cells, type A spermatogonia in males and previtellogenic primary oocytes in females. The method presented here opens a possibility for large-scale production of germ-cell free Atlantic salmon offspring through the genetically sterile broodstock which can pass the sterility trait on the next generation.
Ensemble transfer learning for the prediction of anti-cancer drug response
Authors: Zhu Yitan , Brettin Thomas , Evrard Yvonne A. , Partin Alexander , Xia Fangfang , Shukla Maulik , Yoo Hyunseung , Doroshow James H. , Stevens Rick L.
Published: October 2020

Transfer learning, which transfers patterns learned on a source dataset to a related target dataset for constructing prediction models, has been shown effective in many applications. In this paper, we investigate whether transfer learning can be used to improve the performance of anti-cancer drug response prediction models. Previous transfer learning studies for drug response prediction focused on building models to predict the response of tumor cells to a specific drug treatment. We target the more challenging task of building general prediction models that can make predictions for both new tumor cells and new drugs. Uniquely, we investigate the power of transfer learning for three drug response prediction applications including drug repurposing, precision oncology, and new drug development, through different data partition schemes in cross-validation. We extend the classic transfer learning framework through ensemble and demonstrate its general utility with three representative prediction algorithms including a gradient boosting model and two deep neural networks. The ensemble transfer learning framework is tested on benchmark in vitro drug screening datasets. The results demonstrate that our framework broadly improves the prediction performance in all three drug response prediction applications with all three prediction algorithms.
Direct evidence for low-energy electron emission following O LVV Auger transitions at oxide surfaces
Authors: Fairchild Alexander J. , Chirayath Varghese A. , Sterne Philip A. , Gladen Randall W. , Koymen Ali R. , Weiss Alex H.
Published: October 2020

Oxygen, the third most abundant element in the universe, plays a key role in the chemistry of condensed matter and biological systems. Here, we report evidence for a hitherto unexplored Auger transition in oxides, where a valence band electron fills a vacancy in the 2s state of oxygen, transferring sufficient energy to allow electron emission. We used a beam of positrons with kinetic energies of $$\sim 1$$

∼
1

 eV to create O 2s holes via matter-antimatter annihilation. This made possible the elimination of the large secondary electron background that has precluded definitive measurements of the low-energy electrons emitted through this process. Our experiments indicate that low-energy electron emission following the Auger decay of O 2s holes from adsorbed oxygen and oxide surfaces are very efficient. Specifically, our results indicate that the low energy electron emission following the Auger decay of O 2s hole is nearly as efficient as electron emission following the relaxation of O 1s holes in $$\hbox {TiO}_2$$

TiO
2

. This has important implications for the understanding of Auger-stimulated ion desorption, Coulombic decay, photodynamic cancer therapies, and may yield important insights into the radiation-induced reactive sites for corrosion and catalysis.
An equity-oriented rethink of global rankings with complex networks mapping development
Authors: Bellantuono Loredana , Monaco Alfonso , Tangaro Sabina , Amoroso Nicola , Aquaro Vincenzo , Bellotti Roberto
Published: October 2020

Nowadays, world rankings are promoted and used by international agencies, governments and corporations to evaluate country performances in a specific domain, often providing a guideline for decision makers. Although rankings allow a direct and quantitative comparison of countries, sometimes they provide a rather oversimplified representation, in which relevant aspects related to socio-economic development are either not properly considered or still analyzed in silos. In an increasingly data-driven society, a new generation of cutting-edge technologies is breaking data silos, enabling new use of public indicators to generate value for multiple stakeholders. We propose a complex network framework based on publicly available indicators to extract important insight underlying global rankings, thus adding value and significance to knowledge provided by these rankings. This approach enables the unsupervised identification of communities of countries, establishing a more targeted, fair and meaningful criterion to detect similarities. Hence, the performance of states in global rankings can be assessed based on their development level. We believe that these evaluations can be crucial in the interpretation of global rankings, making comparison between countries more significant and useful for citizens and governments and creating ecosystems for new opportunities for development.
A rapid and highly sensitive biomarker detection platform based on a temperature-responsive liposome-linked immunosorbent assay
Authors: Hu Runkai , Sou Keitaro , Takeoka Shinji
Published: October 2020

The enzyme-linked immunosorbent assay (ELISA) is widely used in various fields to detect specific biomarkers. However, ELISA tests have limited detection sensitivity (≥ 1 pM), which is insufficiently sensitive for the detection of small amounts of biomarkers in the early stages of disease or infection. Herein, a method for the rapid and highly sensitive detection of specific antigens, using temperature-responsive liposomes (TLip) containing a squaraine dye that exhibits fluorescence at the phase transition temperature of the liposomes, was developed. A proof-of-concept study using biotinylated TLip and a streptavidin-immobilized microwell plate showed that the TLip bound to the plate via specific molecular recognition could be distinguished from unbound TLip within 1 min because of the difference in the heating time required for the fluorescence emission of TLip. This system could be used to detect prostate specific antigen (PSA) based on a sandwich immunosorbent assay using detection and capture antibodies, in which the limit of detection was as low as 27.6 ag/mL in a 100-μL PSA solution, 0.97 aM in terms of molar concentration. The present temperature-responsive liposome-linked immunosorbent assay provides an advanced platform for the rapid and highly sensitive detection of biomarkers for use in diagnosis and biological inspections.
Incorporation of docetaxel and thymoquinone in borage nanoemulsion potentiates their antineoplastic activity in breast cancer cells
Authors: Alkhatib Mayson H. , Bawadud Raghdah S. , Gashlan Hana M.
Published: October 2020

Combining more than one anticancer agent in a nanocarrier is beneficial in producing a formula with a low dose and limited adverse side effects. The current study aimed to formulate docetaxel (DTX) and thymoquinone (TQ) in borage oil-based nanoemulsion (B-NE) and evaluate its potential in impeding the growth of breast cancer cells. The formulated B-NE and the combination (DTX + TQ) B-NE were prepared by the ultra-sonication method and physically characterized by the dynamic light scattering techniques. The cytotoxicity analyses of (DTX + TQ) B-NE in MCF-7 and MDA-MB-231 cells were evaluated in vitro by using the SRB assay. Cell death mechanisms were investigated in terms of apoptosis and autophagy pathways by flow cytometry. The optimum mean droplet sizes formulated for blank B-NE and the (DTX + TQ) B-NE were 56.04 ± 4.00 nm and 235.00 ± 10.00 nm, respectively. The determined values of the half-maximal inhibitory concentration (IC50) of mixing one-half amounts of DTX and TQ in B-NE were 1.15 ± 0.097 µM and 0.47 ± 0.091 µM in MCF-7 and MDA-MB-231 cells, respectively, which were similar to the IC50 values of the full amount of free DTX in both tested cell lines. The treatment with (DTX + TQ) B-NE resulted in a synergistic effect on both tested cells. (DTX + TQ) B-NE induced apoptosis that was integrated with the stimulation of autophagy. The produced formulation enhances the DTX efficacy against human breast cancer cells by reducing its effective dose, and thus it could have the potential to minimize the associated toxicity.
Ocean acidification disrupts the orientation of postlarval Caribbean spiny lobsters
Authors: Gravinese Philip M. , Page Heather N. , Butler Casey B. , Spadaro Angelo Jason , Hewett Clay , Considine Megan , Lankes David , Fisher Samantha
Published: October 2020

Anthropogenic inputs into coastal ecosystems are causing more frequent environmental fluctuations and reducing seawater pH. One such ecosystem is Florida Bay, an important nursery for the Caribbean spiny lobster, Panulirus argus. Although adult crustaceans are often resilient to reduced seawater pH, earlier ontogenetic stages can be physiologically limited in their tolerance to ocean acidification on shorter time scales. We used a Y-maze chamber to test whether reduced-pH seawater altered the orientation of spiny lobster pueruli toward chemical cues produced by Laurencia spp. macroalgae, a known settlement cue for the species. We tested the hypothesis that pueruli conditioned in reduced-pH seawater would be less responsive to Laurencia spp. chemical cues than pueruli in ambient-pH seawater by comparing the proportion of individuals that moved to the cue side of the chamber with the proportion that moved to the side with no cue. We also recorded the amount of time (sec) before a response was observed. Pueruli conditioned in reduced-pH seawater were less responsive and failed to select the Laurencia cue. Our results suggest that episodic acidification of coastal waters might limit the ability of pueruli to locate settlement habitats, increasing postsettlement mortality.
Zeolite water purification at Tikal, an ancient Maya city in Guatemala
Authors: Tankersley Kenneth Barnett , Dunning Nicholas P. , Carr Christopher , Lentz David L. , Scarborough Vernon L.
Published: October 2020

Evidence for the oldest known zeolite water purification filtration system occurs in the undisturbed sediments of the Corriental reservoir at the Maya city of Tikal, in northern Guatemala. The Corriental reservoir was an important source of drinking water at Tikal during the Late Preclassic to Late Classic cultural periods. X-ray diffraction analysis (XRD) and six AMS radiocarbon ages show that between ~ 2185 and 965 cal yr B.P. the drinking water in the Corriental reservoir water was filtered through a mixture of zeolite and coarse, sand-sized crystalline quartz. Zeolite is a non-toxic, three-dimensionally porous, crystalline, hydrated aluminosilicate with natural adsorbent and ion exchange properties, which removes harmful microbes as well as dispersed insoluble and soluble toxins from drinking water. The occurrence of zeolite in Corriental reservoir sediments expands our understanding of the earliest history of water purification and the long-term sustainability of an ancient Maya city.
Higher genome mutation rates of Beijing lineage of Mycobacterium tuberculosis during human infection
Authors: Hakamata Mariko , Takihara Hayato , Iwamoto Tomotada , Tamaru Aki , Hashimoto Atsushi , Tanaka Takahiro , Kaboso Shaban A. , Gebretsadik Gebremichal , Ilinov Aleksandr , Yokoyama Akira , Ozeki Yuriko , Nishiyama Akihito , Tateishi Yoshitaka , Moro Hiroshi , Kikuchi Toshiaki , Okuda Shujiro , Matsumoto Sohkichi
Published: October 2020

Mycobacterium tuberculosis (Mtb) strains of Beijing lineage have caused great concern because of their rapid emergence of drug resistance and worldwide spread. DNA mutation rates that reflect evolutional adaptation to host responses and the appearance of drug resistance have not been elucidated in human-infected Beijing strains. We tracked and obtained an original Mtb isolate of Beijing lineage from the 1999 tuberculosis outbreak in Japan, as well as five other isolates that spread in humans, and two isolates from the patient caused recurrence. Three isolates were from patients who developed TB within one year after infection (rapid-progressor, RP), and the other three isolates were from those who developed TB more than one year after infection (slow-progressor, SP). We sequenced genomes of these isolates and analyzed the propensity and rate of genomic mutations. Generation time versus mutation rate curves were significantly higher for RP. The ratio of oxidative versus non-oxidation damages induced mutations was higher in SP than RP, suggesting that persistent Mtb are exposed to oxidative stress in the latent state. Our data thus demonstrates that higher mutation rates of Mtb Beijing strains during human infection is likely to account for the higher adaptability and an emergence ratio of drug resistance.
Non-compulsory measures sufficiently reduced human mobility in Tokyo during the COVID-19 epidemic
Authors: Yabe Takahiro , Tsubouchi Kota , Fujiwara Naoya , Wada Takayuki , Sekimoto Yoshihide , Ukkusuri Satish V.
Published: October 2020

While large scale mobility data has become a popular tool to monitor the mobility patterns during the COVID-19 pandemic, the impacts of non-compulsory measures in Tokyo, Japan on human mobility patterns has been under-studied. Here, we analyze the temporal changes in human mobility behavior, social contact rates, and their correlations with the transmissibility of COVID-19, using mobility data collected from more than 200K anonymized mobile phone users in Tokyo. The analysis concludes that by April 15th (1 week into state of emergency), human mobility behavior decreased by around 50%, resulting in a 70% reduction of social contacts in Tokyo, showing the strong relationships with non-compulsory measures. Furthermore, the reduction in data-driven human mobility metrics showed correlation with the decrease in estimated effective reproduction number of COVID-19 in Tokyo. Such empirical insights could inform policy makers on deciding sufficient levels of mobility reduction to contain the disease.
Synthesis of computer simulation and machine learning for achieving the best material properties of filled rubber
Authors: Kojima Takashi , Washio Takashi , Hara Satoshi , Koishi Masataka
Published: October 2020

Molecular dynamics (MD) simulation is used to analyze the mechanical properties of polymerized and nanoscale filled rubber. Unfortunately, the computation time for a simulation can require several months’ computing power, because the interactions of thousands of filler particles must be calculated. To alleviate this problem, we introduce a surrogate convolutional neural network model to achieve faster and more accurate predictions. The major difficulty when employing machine-learning-based surrogate models is the shortage of training data, contributing to the huge simulation costs. To derive a highly accurate surrogate model using only a small amount of training data, we increase the number of training instances by dividing the large-scale simulation results into 3D images of middle-scale filler morphologies and corresponding regional stresses. The images include fringe regions to reflect the influence of the filler constituents outside the core regions. The resultant surrogate model provides higher prediction accuracy than that trained only by images of the entire region. Afterwards, we extract the fillers that dominate the mechanical properties using the surrogate model and we confirm their validity using MD.
Towards middle-up analysis of polyclonal antibodies: subclass-specific N-glycosylation profiling of murine immunoglobulin G (IgG) by means of HPLC-MS
Authors: Blöchl Constantin , Regl Christof , Huber Christian G. , Winter Petra , Weiss Richard , Wohlschlager Therese
Published: October 2020

In recent years, advanced HPLC-MS strategies based on intact protein (“top-down”) or protein subunit (“middle-up/middle-down”) analysis have been implemented for the characterization of therapeutic monoclonal antibodies. Here, we assess feasibility of middle-up/middle-down analysis for polyclonal IgGs exhibiting extensive sequence variability. Specifically, we addressed IgGs from mouse, representing an important model system in immunological investigations. To obtain Fc/2 portions as conserved subunits of IgGs, we made use of the bacterial protease SpeB. For this purpose, we initially determined SpeB cleavage sites in murine IgGs. The resulting Fc/2 portions characteristic of different subclasses were subsequently analysed by ion-pair reversed-phase HPLC hyphenated to high-resolution mass spectrometry. This enabled simultaneous relative quantification of IgG subclasses and theirN-glycosylation variants, both of which influence IgG effector functions. To assess method capabilities in an immunological context, we applied the analytical workflow to polyclonal antibodies obtained from BALB/c mice immunized with the grass pollen allergen Phl p 6. The study revealed a shift in IgG subclasses and Fc-glycosylation patterns in total and antigen-specific IgGs from different mouse cohorts, respectively. Eventually, Fc/2 characterization may reveal other protein modifications including oxidation, amino acid exchanges, and C-terminal lysine, and may thus be implemented for quality control of functional antibodies.
The soluble neurexin-1β ectodomain causes calcium influx and augments dendritic outgrowth and synaptic transmission
Authors: Wierda Keimpe D. B. , Toft-Bertelsen Trine L. , Gøtzsche Casper R. , Pedersen Ellis , Korshunova Irina , Nielsen Janne , Bang Marie Louise , Kønig Andreas B. , Owczarek Sylwia , Gjørlund Michelle D. , Schupp Melanie , Bock Elisabeth , Sørensen Jakob B.
Published: October 2020

Classically, neurexins are thought to mediate synaptic connections through trans interactions with a number of different postsynaptic partners. Neurexins are cleaved by metalloproteases in an activity-dependent manner, releasing the soluble extracellular domain. Here, we report that in both immature (before synaptogenesis) and mature (after synaptogenesis) hippocampal neurons, the soluble neurexin-1β ectodomain triggers acute Ca2+-influx at the dendritic/postsynaptic side. In both cases, neuroligin-1 expression was required. In immature neurons, calcium influx required N-type calcium channels and stimulated dendritic outgrowth and neuronal survival. In mature glutamatergic neurons the neurexin-1β ectodomain stimulated calcium influx through NMDA-receptors, which increased presynaptic release probability. In contrast, prolonged exposure to the ectodomain led to inhibition of synaptic transmission. This secondary inhibition was activity- and neuroligin-1 dependent and caused by a reduction in the readily-releasable pool of vesicles. A synthetic peptide modeled after the neurexin-1β:neuroligin-1 interaction site reproduced the cellular effects of the neurexin-1β ectodomain. Collectively, our findings demonstrate that the soluble neurexin ectodomain stimulates growth of neurons and exerts acute and chronic effects on trans-synaptic signaling involved in setting synaptic strength.
Synthesis, characterization of two matrine derivatives and their cytotoxic effect on Sf9 cell of Spodoptera frugiperda
Authors: He Huiqing , Qin Xiangjing , Dong Fangyun , Ye Jingmin , Xu Chunbao , Zhang Hanhui , Liu Zhanmei , Lv Xiaojing , Wu Yuehua , Jiang Xuhong , Cheng Xingan
Published: October 2020

The invasion ofSpodoptera frugiperdahas imposed a serious impact on global food security. Matrine is a botanical pesticide with a broad spectrum of insecticidal activity which was recommended for controllingSpodoptera frugiperda. In order to discover effective insecticide forSpodoptera frugiperda, two matrine derivatives modified with carbon disulfide and nitrogen-containing groups were systhesized. And their inhibition activities onSf9cell were evaluated. The structural configuration of compounds were characterized by IR, HPLC, MS, NMR and XRD, with yields of 52% and 65%, respectively. The IC50of the two newly synthesized compounds onSf9cell reduced to 0.648 mmol/L and 1.13 mmol/L, respectively, compared with that of matrine (5.330 mmol/L). In addition, microscopic observation ofSf9cell treated with the compounds showed that the number of adherent cells decreased, the cells shrunk, vacuolated and apoptotic bodies appeared. The two newly synthesized compounds exhibited better inhibitory effect onSf9cell than that of the parent matrine, suggesting that the positive effect of the introduction of 1-pyrrolidinecarbodithioate and diethylcarbamodithioate groups to matrine. The morphological observation ofSf9cell induced by derivatives indicated that apoptosis induction may be a mechanism that inhibits insect cell proliferation and exerts insecticidal effect.
CELF2 regulates the species-specific alternative splicing of TREM2
Authors: Yanaizu Motoaki , Washizu Chika , Nukina Nobuyuki , Satoh Jun-ichi , Kino Yoshihiro
Published: October 2020

Genetic variations of TREM2 have been implicated as a risk factor of Alzheimer’s disease (AD). Recent studies suggest that the loss of TREM2 function compromises microglial responses to the accumulation of amyloid beta. Previously, we found that exon 3 of TREM2 is an alternative exon whose skipping leads to a reduction in full-length TREM2 protein by inducing nonsense-mediated mRNA decay. Here, we aimed to identify factors regulating TREM2 splicing. Using a panel of RNA-binding proteins, we found that exon 3 skipping of TREM2 was promoted by two paralogous proteins, CELF1 and CELF2, which were both linked previously with risk loci of AD. Although the overexpression of both CELF1 and CELF2 enhanced exon 3 skipping, only CELF2 reduced the expression of full-length TREM2 protein. Notably, the TREM2 ortholog in the green monkey, but not in the mouse, showed alternative splicing of exon 3 like human TREM2. Similarly, splicing regulation of exon 3 by CELF1/2 was found to be common to humans and monkeys. Using chimeric minigenes of human and mouse TREM2, we mapped a CELF-responsive sequence within intron 3 of human TREM2. Collectively, our results revealed a novel regulatory factor of TREM2 expression and highlighted a species-dependent difference of its regulation.
Integrated stress response inhibition provides sex-dependent protection against noise-induced cochlear synaptopathy
Authors: Rouse Stephanie L. , Matthews Ian R. , Li Jiang , Sherr Elliott H. , Chan Dylan K.
Published: October 2020

Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator Integrated Stress Response InhiBitor (ISRIB) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.
Clinical manifestations and perinatal outcomes of pregnant women with COVID-19: a systematic review and meta-analysis
Authors: Yee Jeong , Kim Woorim , Han Ji Min , Yoon Ha Young , Lee Nari , Lee Kyung Eun , Gwak Hye Sun
Published: October 2020

This systematic review and meta-analysis aimed to evaluate the impact of COVID-19 on pregnant women. We searched for qualified studies in PubMed, Embase, and Web of Science. The clinical characteristics of pregnant women with COVID-19 and their infants were reported as means and proportions with 95% confidence interval. Eleven studies involving with 9032 pregnant women with COVID-19 and 338 infants were included in the meta-analysis. Pregnant women with COVID-19 have relatively mild symptoms. However, abnormal proportions of laboratory parameters were similar or even increased, compared to general population. Around 30% of pregnant women with COVID-19 experienced preterm delivery, whereas the mean birth weight was 2855.9 g. Fetal death and detection of SARS-CoV-2 were observed in about 2%, whereas neonatal death was found to be 0.4%. In conclusion, the current review will serve as an ideal basis for future considerations in the treatment and management of COVID-19 in pregnant women.