bluuebunny/crossref_metadata_2025 huggingface dataset:
How banks and other financial institutions think
Authors: Thompson M.
Published: January 2018

Conventional diagnoses of the 2007/8 Global Financial Crisis see it as “abnormal”, and then resort to explanations in terms of “irrational exuberance”, “animal spirits”, “herding behaviour” and so on. The prescription – “better regulation” – then follows automatically, as it has done after every such crisis, all the way back to tulipmania 400 years ago. But if there are different “seasons of risk”, and if financial sector actors are able to latch onto different risk-handling strategies, each appropriate to one of those seasons and inappropriate to the others, then we have a very different explanation: one in which, in contrast to both neoclassical and behavioural economics, rationality is no longer singular. This “anthropological” hypothesis has its roots in Mary Douglas’s book “How Institutions Think”, and the paper shows how it is well supported by historical evidence, agent-based modelling, and fieldwork among both financial sector firms and their regulators, as well as by parallels from ecology, organisation theory and evolutionary (i.e. Schumpeterian) economics.
Weed Management in Common Cottonwood (Populus deltoides) Nursery Plantation
Authors: Kaur H. , Kaur Navneet , Gill R. I. S. , Bhullar Makhan S. , Singh A.
Published: January 2018

Common cottonwood-based agroforestry system is widely adopted in Indian Indo-Gangetic plains. The stem cuttings of common cottonwood are raised in a nursery 10 to 12 months in rows spaced 0.5 mx0.5 m, before re-planting in the field. The longer duration of 10 to 12 months and wider spacing of stem cuttings in the nursery makes the entire transplants highly vulnerable to weed competition, especially during early establishment stages. The efficacy of preemergence herbicides and plastic and straw mulches for weed management in common cottonwood nursery was investigated at two sites in years 2014 and 2015. The major weed flora in the experimental field consisted of three grass weeds (crowfootgrass, feather lovegrass, and southern crabgrass), and four broadleaf weeds (scarlet pimpernel, garden spurge, niruri, and lesser swinecress). The integrated use of pendimethalin or alachlor applied PRE with paddy straw mulch significantly reduced density and biomass of both grass and broadleaf weeds compared to herbicide or straw mulch used alone, and provided similar level of weed control to hand weeding at both locations. Spreading of plastic mulch in the whole field after punching holes for common cottonwood stem cuttings, or in row spaces recorded similar weed control to hand-weeding. The integrated use of herbicides with straw mulch, and or plastic mulch alone significantly improved plant height, stem diameter, below- and above-ground biomass of common cottonwood plants compared to unweeded check. The study concluded that integrated use of herbicides plus paddy straw mulch or plastic mulch alone could be adopted for weed management in common cottonwood nursery plantations.
Dropping the Beat with Some Geoscience Data
Authors: Cartier Kimberly
Published: January 2018

Listen to the music of the ice, the turning of the planets, the ringing of rings, the rockin’ of quakes, and the mournful tones of global warming.
Computational Seismology Workshop Trains Early-Career Scientists
Authors: Rodgers Arthur , Hwang Lorraine , Kellogg Louise
Published: January 2018

2017 CIG–LLNL Computational Seismology Workshop; Livermore, California, 18–22 September 2017
Age-associated microbiome shows the giant panda lives on hemicelluloses, not on cellulose
Authors: Zhang Wenping , Liu Wenbin , Hou Rong , Zhang Liang , Schmitz-Esser Stephan , Sun Huaibo , Xie Junjin , Zhang Yunfei , Wang Chengdong , Li Lifeng , Yue Bisong , Huang He , Wang Hairui , Shen Fujun , Zhang Zhihe
Published: January 2018

The giant panda feeds almost exclusively on bamboo, a diet highly enriched in lignin and cellulose, but is characterized by a digestive tract similar to carnivores. It is still large unknown if and how the giant panda gut microbiota contributes to lignin and cellulose degradation. Here we show the giant pandas’ gut microbiota does not significantly contribute to cellulose and lignin degradation. We found that no operational taxonomic unit had a nearest neighbor identified as a cellulolytic species or strain with a significant higher abundance in juvenile than cubs, a very low abundance of putative lignin and cellulose genes existed in part of analyzing samples but a significant higher abundance of genes involved in starch and hemicellulose degradation in juveniles than cubs. Moreover, a significant lower abundance of putative cellulolytic genes and a significant higher abundance of putative α-amylase and hemicellulase gene families were present in giant pandas than in omnivores or herbivores.
Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway
Authors: Wang Lihui , Dong Xiaoyu , Ren Yong , Luo Juanjuan , Liu Pei , Su Dongsheng , Yang Xiaojun
Published: January 2018

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Epigenetic alterations have been shown to be involved in NSCLC oncogenesis; however, their function in EGFR-TKI resistance remains uncharacterized. Here, we found that an EHMT2 inhibitor, UNC0638, can significantly inhibit cell growth and induce apoptosis in EGFR-TKI-resistant NSCLC cells. Additionally, we also found that EHMT2 expression and enzymatic activity levels were elevated in EGFR-TKI-resistant NSCLC cells. Moreover, we determined that genetic or pharmacological inhibition of EHMT2 expression enhanced TKI sensitivity and suppressed migration and tumor sphere formation in EGFR-TKI-resistant NSCLC cells. Further investigation revealed that EHMT2 contributed to PTEN transcriptional repression and thus facilitated AKT pathway activation. The negative relationship between EHMT2 and PTEN was confirmed by our clinical study. Furthermore, we determined that combination treatment with the EHMT2 inhibitor and Erlotinib resulted in enhanced antitumor effects in a preclinical EGFR-TKI-resistance model. We also found that high EHMT2 expression along with low PTEN expression can predict poor overall survival in patients with NSCLC. In summary, our findings showed that EHMT2 facilitated EGFR-TKI resistance by regulating the PTEN/AKT pathway in NSCLC cells, suggesting that EHMT2 may be a target in the clinical treatment of EGFR-TKI-resistant NSCLC.
microRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway
Authors: Zhang Yi , Wei Yangchao , Li Xuan , Liang Xingsi , Wang Liming , Song Jun , Zhang Xiuzhong , Zhang Chong , Niu Jian , Zhang Pengbo , Ren Zeqiang , Tang Bo
Published: January 2018

The δ opioid receptor (DOR) is involved in the regulation of malignant transformation and tumor progression of hepatocellular carcinoma (HCC). However, regulation of the DOR in HCC remains poorly defined. We found that miR-874 was identified as a negative regulator of the DOR, which is a direct and functional target of miR-874 via its 3′ untranslated region (UTR). Moreover, miR-874 was downregulated in HCC and its expression was inversely correlated with DOR expression. Downregulation of miR-874 was also associated with larger tumor size, more vascular invasion, a poor TNM stage, poor tumor differentiation, and inferior patient outcomes. Functionally, overexpression of miR-874 in the HCC cell line SK-hep-1 inhibited cell growth, migration, in vitro invasion, and in vivo tumorigenicity. Furthermore, miR-874 overexpression suppressed the DOR, resulting in a downregulated epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) phosphorylation. The EGFR activator—epidermal growth factor (EGF)—can rescue the proliferation and migration suppression induced by miR-874 overexpression, and the rescue effects of the EGF were blocked by an ERK inhibitor. Our study results suggest that miRNA-874 is a negative regulator of the DOR that can suppress tumor proliferation and metastasis in HCC by targeting the DOR/EGFR/ERK pathway, which may be a potential target for HCC treatment.
iPSC modeling of severe aplastic anemia reveals impaired differentiation and telomere shortening in blood progenitors
Authors: Melguizo-Sanchis Dario , Xu Yaobo , Taheem Dheraj , Yu Min , Tilgner Katarzyna , Barta Tomas , Gassner Katja , Anyfantis George , Wan Tengfei , Elango Ramu , Alharthi Sameer , El-Harouni Ashraf A. , Przyborski Stefan , Adam Soheir , Saretzki Gabriele , Samarasinghe Sujith , Armstrong Lyle , Lako Majlinda
Published: January 2018

Aplastic Anemia (AA) is a bone marrow failure (BMF) disorder, resulting in bone marrow hypocellularity and peripheral pancytopenia. Severe aplastic anemia (SAA) is a subset of AA defined by a more severe phenotype. Although the immunological nature of SAA pathogenesis is widely accepted, there is an increasing recognition of the role of dysfunctional hematopoietic stem cells in the disease phenotype. While pediatric SAA can be attributable to genetic causes, evidence is evolving on previously unrecognized genetic etiologies in a proportion of adults with SAA. Thus, there is an urgent need to better understand the pathophysiology of SAA, which will help to inform the course of disease progression and treatment options. We have derived induced pluripotent stem cell (iPSC) from three unaffected controls and three SAA patients and have shown that this in vitro model mimics two key features of the disease: (1) the failure to maintain telomere length during the reprogramming process and hematopoietic differentiation resulting in SAA-iPSC and iPSC-derived-hematopoietic progenitors with shorter telomeres than controls; (2) the impaired ability of SAA-iPSC-derived hematopoietic progenitors to give rise to erythroid and myeloid cells. While apoptosis and DNA damage response to replicative stress is similar between the control and SAA-iPSC-derived-hematopoietic progenitors, the latter show impaired proliferation which was not restored by eltrombopag, a drug which has been shown to restore hematopoiesis in SAA patients. Together, our data highlight the utility of patient specific iPSC in providing a disease model for SAA and predicting patient responses to various treatment modalities.
Human papillomavirus E7 induces p63 expression to modulate DNA damage response
Authors: Eldakhakhny Sahar , Zhou Qing , Crosbie Emma J. , Sayan Berna S.
Published: January 2018

Cervical cancer is the third most common malignancy diagnosed in women worldwide. The major aetiological factor underlying the malignant transformation of cervical cells is the persistent infection with high-risk human papillomaviruses (HR-HPV), with more than 99% of cases expressing viral sequences. Here, we report a previously unknown mechanism driven by high-risk human papillomavirus E7 protein to modulate response to DNA damage in cervical cancer cells. Our data shows that HR-HPV E7 oncoprotein induces the transcription of the p53-family member p63, which modulates DNA damage response pathways, to facilitate repair of DNA damage. Based on our findings, we proposed a model, where HR-HPV could interfere with the sensitivity of transformed cells to radiation therapy by modulating DNA damage repair efficiency. Importantly, we have shown for the first time a critical role for p63 in response to DNA damage in cervical cancer cells.
FLI1 and PKC co-activation promote highly efficient differentiation of human embryonic stem cells into endothelial-like cells
Authors: Zhao Hao , Zhao Yan , Li Zili , Ouyang Qi , Sun Yi , Zhou Di , Xie Pingyuan , Zeng Sicong , Dong Lingfeng , Wen Hua , Lu Guangxiu , Lin Ge , Hu Liang
Published: January 2018

Rationale-endothelial cells (ECs) play important roles in various regeneration processes and can be used in a variety of therapeutic applications, such as cardiac regeneration, gene therapy, tissue-engineered vascular grafts and prevascularized tissue transplants. ECs can be acquired from pluripotent and adult stem cells. To acquire ECs from human embryonic stem cells (hESCs) in a fast, efficient and economic manner. We established a conditional overexpression system in hESCs based on 15 transcription factors reported to be responsible for hematopoiesis lineage. Among them, only overexpression of FLI1 could induce hESCs to a hematopoietic lineage. Moreover, simultaneous overexpression of FLI1 and activation of PKC rapidly and efficiently induced differentiation of hESCs into induced endothelial cells (iECs) within 3 days, while neither FLI1 overexpression nor PKC activation alone could derive iECs from hESCs. During induction, hESCs differentiated into spindle-like cells that were consistent in appearance with ECs. Flow cytometric analysis revealed that 92.2–98.9% and 87.2–92.6% of these cells were CD31+ and CD144+, respectively. Expression of vascular-specific genes dramatically increased, while the expression of pluripotency genes gradually decreased during induction. iECs incorporated acetylated low-density lipoproteins, strongly expressed vWF and bound UEA-1. iECs also formed capillary-like structures both in vitro and in vivo. RNA-seq analysis verified that these cells closely resembled their in vivo counterparts. Our results showed that co-activation of FLI1 and PKC could induce differentiation of hESCs into iECs in a fast, efficient and economic manner.
Downregulation of MCL-1 and upregulation of PUMA using mTOR inhibitors enhance antitumor efficacy of BH3 mimetics in triple-negative breast cancer
Authors: Li Haolong , Liu Lei , Chang Haocai , Zou Zhengzhi , Xing Da
Published: January 2018

Triple-negative breast cancer (TNBC) shows a higher malignant and poorer clinical outcome compared with other breast cancer subtypes. Albeit that chemotherapy is the first choice for TNBC treatment, rapid emergence of chemoresistance and variability of chemotherapeutic responses in TNBC patients call for novel therapeutic strategies. Here, we reported evidences highlighting that combination of BH3 mimetics and mTOR inhibitors could be a promising therapeutic strategy to improve TNBC treatment. Our results showed that combination of the BH3 mimetic ABT263 and typical mTOR inhibitors, BEZ235 or AZD8055, leads to efficient apoptosis in vitro. Tumor regression was significantly improved by combination therapy compared with either drug alone in the xenograft model. Further mechanistic investigations revealed that mTOR inhibitors induced the suppression of MCL-1; concomitantly, the expression level of PUMA was significantly upregulated in a FOXO3a-dependent manner. The specific changes of MCL-1 and PUMA facilitated the release of the apoptotic regulators, such as BIM, BAX, and BAK, to induce the activation of mitochondrial apoptotic pathway, thereby sensitizing the ABT263 activity in TNBC. Therefore, our findings provided evidences that mTOR inhibitors can enhance antitumor efficacy of BH3 mimetics via downregulating MCL-1 and upregulating PUMA in TNBC; it could be a promising therapeutic strategy to treat TNBC.
Synergistic effect of a novel autophagy inhibitor and Quizartinib enhances cancer cell death
Authors: Ouchida Amanda Tomie , Li Yingbo , Geng Jiefei , Najafov Ayaz , Ofengeim Dimitry , Sun Xiaoxiao , Yu Qiang , Yuan Junying
Published: January 2018

Drug combinations have been increasingly applied in chemotherapy as a strategy to enhance the efficacy of anti-cancer treatment. The appropriate drug combinations may achieve synergistic effects beyond monotherapies alone. AC220 (Quizartinib), an FLT3 receptor tyrosine kinase inhibitor, developed for the treatment of AML, has been tested in phase II human clinical trials. However, AC220 as a monotherapy is not efficacious enough. In this study, we performed a small-molecule screening of 12 640 compounds in order to find a compound that increase the AC220 efficacy in chemotherapy. We identified that TAK-165, a HER2 inhibitor, even when used at low nanomolar doses in combination with AC220, was able to induce cell death in different cancer cells, but not in non-cancer cell lines. We showed that TAK-165 and AC220 act synergistically to downregulate key signaling pathways and potently induce cancer cell death. Furthermore, we demonstrated that TAK-165 inhibited autophagy in a HER2-independent manner. Finally, we showed that the combination of TAK-165 and AC220 induced cell death in cancer cells through the activation of chaperone-mediated autophagy. Overall, these findings support the strategy for using AC220 and an autophagy inhibitor such as TAK-165 in a combinatorial treatment to enhance the efficacy of cancer therapies.
Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings
Authors: Feng Qiyi , Liu Yanping , Huang Jian , Chen Ke , Huang Jinxing , Xiao Kai
Published: January 2018

Iron oxide nanoparticles (IONPs) have been increasingly used in biomedical applications, but the comprehensive understanding of their interactions with biological systems is relatively limited. In this study, we systematically investigated the in vitro cell uptake, cytotoxicity, in vivo distribution, clearance and toxicity of commercially available and well-characterized IONPs with different sizes and coatings. Polyethylenimine (PEI)-coated IONPs exhibited significantly higher uptake than PEGylated ones in both macrophages and cancer cells, and caused severe cytotoxicity through multiple mechanisms such as ROS production and apoptosis. 10 nm PEGylated IONPs showed higher cellular uptake than 30 nm ones, and were slightly cytotoxic only at high concentrations. Interestingly, PEGylated IONPs but not PEI-coated IONPs were able to induce autophagy, which may play a protective role against the cytotoxicity of IONPs. Biodistribution studies demonstrated that all the IONPs tended to distribute in the liver and spleen, and the biodegradation and clearance of PEGylated IONPs in these tissues were relatively slow (>2 weeks). Among them, 10 nm PEGylated IONPs achieved the highest tumor uptake. No obvious toxicity was found for PEGylated IONPs in BALB/c mice, whereas PEI-coated IONPs exhibited dose-dependent lethal toxicity. Therefore, it is crucial to consider the size and coating properties of IONPs in their applications.
Design and synthesis of coumarin-based organoselenium as a new hit for myeloprotection and synergistic therapeutic efficacy in adjuvant therapy
Authors: Patra Arup Ranjan , Roy Somnath Singha , Basu Abhishek , Bhuniya Avishek , Bhattacharjee Arin , Hajra Subhadip , Sk Ugir Hossain , Baral Rathindranath , Bhattacharya Sudin
Published: January 2018

A newly designed organoselenium compound, methyl substituted umbelliferone selenocyanate (MUS), was synthesized as a primary hit against the myelotoxic activity of carboplatin. MUS was administered at 6 mg/kg b.wt, p.o. in concomitant and pretreatment schedules with carboplatin (12 mg/kg b.wt, i.p. for 10 days) in female Swiss albino mouse. MUS treatment reduced (P < 0.001) the percentage of chromosomal aberrations, micronuclei formation, DNA damage and apoptosis in murine bone marrow cells and also enhanced (P < 0.001) the bone marrow cell proliferation of the carboplatin-treated mice. These activities cumulatively restored the viable bone marrow cell count towards normalcy. Myeloprotection by MUS was achieved, in part, due to a significant reduction in the ROS/RNS formation and restoration of glutathione redox pool. Additionally, MUS synergistically enhanced the cytotoxicity of carboplatin against two human cancer cell lines (MCF-7 and Colo-205). Furthermore, MUS can effectively potentiate the antitumour activity of carboplatin against two murine cancers (Dalton’s Lymphoma and Sarcoma-180) in vivo. These preclinical findings clearly indicate that MUS can improve the therapeutic index of carboplatin and ensures more effective therapeutic strategy against cancer for clinical development.
The paxillin-plectin-EPLIN complex promotes apical elimination of RasV12-transformed cells by modulating HDAC6-regulated tubulin acetylation
Authors: Kasai Nobuhiro , Kadeer Ailijiang , Kajita Mihoko , Saitoh Sayaka , Ishikawa Susumu , Maruyama Takeshi , Fujita Yasuyuki
Published: January 2018

Recent studies have revealed that newly emerging RasV12-transformed cells are often apically extruded from the epithelial layer. During this cancer preventive process, cytoskeletal proteins plectin and Epithelial Protein Lost In Neoplasm (EPLIN) are accumulated in RasV12 cells that are surrounded by normal cells, which positively regulate the apical elimination of transformed cells. However, the downstream regulators of the plectin-EPLIN complex remain to be identified. In this study, we have found that paxillin binds to EPLIN specifically in the mix culture of normal and RasV12-transformed cells. In addition, paxillin is accumulated in RasV12 cells surrounded by normal cells. Paxillin, plectin and EPLIN mutually influence their non-cell-autonomous accumulation, and paxillin plays a crucial role in apical extrusion of RasV12 cells. We also demonstrate that in RasV12 cells surrounded by normal cells, acetylated tubulin is accumulated. Furthermore, acetylation of tubulin is promoted by paxillin that suppresses the activity of histone deacetylase (HDAC) 6. Collectively, these results indicate that in concert with plectin and EPLIN, paxillin positively regulates apical extrusion of RasV12-transformed cells by promoting microtubule acetylation. This study shed light on the unexplored events occurring at the initial stage of carcinogenesis and would potentially lead to a novel type of cancer preventive medicine.
Magnesium prevents vascular calcification in vitro by inhibition of hydroxyapatite crystal formation
Authors: ter Braake Anique D. , Tinnemans Paul T. , Shanahan Catherine M. , Hoenderop Joost G. J. , de Baaij Jeroen H. F.
Published: January 2018

Magnesium has been shown to effectively prevent vascular calcification associated with chronic kidney disease. Magnesium has been hypothesized to prevent the upregulation of osteoblastic genes that potentially drives calcification. However, extracellular effects of magnesium on hydroxyapatite formation are largely neglected. This study investigated the effects of magnesium on intracellular changes associated with transdifferentiation and extracellular crystal formation. Bovine vascular smooth muscle cells were calcified using β-glycerophosphate. Transcriptional analysis, alkaline phosphatase activity and detection of apoptosis were used to identify transdifferentiation. Using X-ray diffraction and energy dispersive spectroscopy extracellular crystal composition was investigated. Magnesium prevented calcification in vascular smooth muscle cells. β-glycerophosphate increased expression of osteopontin but no other genes related to calcification. Alkaline phosphatase activity was stable and apoptosis was only detected after calcification independent of magnesium. Blocking of the magnesium channel TRPM7 using 2-APB did not abrogate the protective effects of magnesium. Magnesium prevented the formation of hydroxyapatite, which formed extensively during β-glycerophosphate treatment. Magnesium reduced calcium and phosphate fractions of 68% and 41% extracellular crystals, respectively, without affecting the fraction of magnesium. This study demonstrates that magnesium inhibits hydroxyapatite formation in the extracellular space, thereby preventing calcification of vascular smooth muscle cells.
A highly efficient murine model of experimental myopia
Authors: Jiang Xiaoyan , Kurihara Toshihide , Kunimi Hiromitsu , Miyauchi Maki , Ikeda Shin-ichi , Mori Kiwako , Tsubota Kinya , Torii Hidemasa , Tsubota Kazuo
Published: January 2018

Despite the global pandemic of myopia, the precise molecular mechanism of the onset of myopia remains largely unknown. This is partially because of the lack of efficient murine myopic models that allow genetic manipulation at low cost. Here we report a highly practical and reproducible lens-induced myopia model by specially designed frames and lenses for mice. A lens power dependent myopic induction in mice was shown until minus 30 diopter lenses. The phenotype was significantly stronger than form-deprivation myopia. We presented the protocol for precise evaluations of the state of myopia, including refraction, corneal curvature and axial length using up-to-date devices. We also found that myopic mouse eyes showed decreased visual acuity on optokinetic response examination. Finally, we confirmed the anti-myopic effect of 1% atropine using this model, which showed its potential in drug screening. The strong phenotype, stable evaluation and the potential for gene manipulation utilizing the presented method in mice will accelerate the translational research of myopia.
Orbital-anisotropic electronic structure in the nonmagnetic state of BaFe2(As1−xP
x
)2 superconductors
Authors: Sonobe T. , Shimojima T. , Nakamura A. , Nakajima M. , Uchida S. , Kihou K. , Lee C. H. , Iyo A. , Eisaki H. , Ohgushi K. , Ishizaka K.
Published: January 2018

High-temperature superconductivity in iron-pnictides/chalcogenides arises in balance with several electronic and lattice instabilities. Beside the antiferromagnetic order, the orbital anisotropy between Fe 3d
xz
and 3d
yz
occurs near the orthorhombic structural transition in several parent compounds. However, the extent of the survival of orbital anisotropy against the ion-substitution remains to be established. Here we report the composition (x) and temperature (T) dependences of the orbital anisotropy in the electronic structure of a BaFe2(As1−xP
x
)2 system by using angle-resolved photoemission spectroscopy. In the low-x regime, the orbital anisotropy starts to evolve on cooling from high temperatures above both antiferromagnetic and orthorhombic transitions. By increasing x, it is gradually suppressed and survives in the optimally doped regime. We find that the in-plane orbital anisotropy persists in a large area of the nonmagnetic phase, including the superconducting dome. These results suggest that the rotational symmetry-broken electronic state acts as the stage for superconductivity in BaFe2(As1−xP
x
)2.
Evaluating upper limb impairments in multiple sclerosis by exposure to different mechanical environments
Authors: Pellegrino Laura , Coscia Martina , Muller Margit , Solaro Claudio , Casadio Maura
Published: January 2018

Multiple sclerosis is a chronic, autoimmune and neurodegenerative disease affecting multiple functional systems and resulting in motor impairments associated with muscle weakness and lack of movement coordination. We quantified upper limb motor deficits with a robot-based assessment including behavioral and muscle synergy analysis in 11 multiple sclerosis subjects with mild to moderate upper limb impairment (9 female; 50 ± 10 years) compared to 11 age- and gender- matched controls (9 female; 50 ± 9 years). All subjects performed planar reaching tasks by moving their upper limb or applying force while grasping the handle of a robotic manipulandum that generated four different environments: free space, assistive or resistive forces, and rigid constraint. We recorded the activity of 15 upper body muscles. Multiple sclerosis subjects generated irregular trajectories. While activities in isolated arm muscles appeared generally normal, shoulder muscle coordination with arm motions was impaired and there was a marked co-activation of the biceps and triceps in extension movements. Systematic differences in timing and organization of muscle synergies have also been observed. This study supports the definition of new biomarkers and rehabilitative treatments for improving upper limb motor coordination in multiple sclerosis.
‘Cold shock’ increases the frequency of homology directed repair gene editing in induced pluripotent stem cells
Authors: Guo Q. , Mintier G. , Ma-Edmonds M. , Storton D. , Wang X. , Xiao X. , Kienzle B , Zhao D. , Feder John N.
Published: January 2018

Using CRISPR/Cas9 delivered as a RNA modality in conjunction with a lipid specifically formulated for large RNA molecules, we demonstrate that homology directed repair (HDR) rates between 20–40% can be achieved in induced pluripotent stem cells (iPSC). Furthermore, low HDR rates (between 1–20%) can be enhanced two- to ten-fold in both iPSCs and HEK293 cells by ‘cold shocking’ cells at 32 °C for 24–48 hours following transfection. This method can also increases the proportion of loci that have undergone complete sequence conversion across the donor sequence, or ‘perfect HDR’, as opposed to partial sequence conversion where nucleotides more distal to the CRISPR cut site are less efficiently incorporated (‘partial HDR’). We demonstrate that the structure of the single-stranded DNA oligo donor can influence the fidelity of HDR, with oligos symmetric with respect to the CRISPR cleavage site and complementary to the target strand being more efficient at directing ‘perfect HDR’ compared to asymmetric non-target strand complementary oligos. Our protocol represents an efficient method for making CRISPR-mediated, specific DNA sequence changes within the genome that will facilitate the rapid generation of genetic models of human disease in iPSCs as well as other genome engineered cell lines.
MtNRLK1, a CLAVATA1-like leucine-rich repeat receptor-like kinase upregulated during nodulation in Medicago truncatula
Authors: Laffont Carole , De Cuyper Carolien , Fromentin Justine , Mortier Virginie , De Keyser Annick , Verplancke Christa , Holsters Marcelle , Goormachtig Sofie , Frugier Florian
Published: January 2018

Peptides are signaling molecules regulating various aspects of plant development, including the balance between cell division and differentiation in different meristems. Among those, CLAVATA3/Embryo Surrounding Region-related (CLE-ESR) peptide activity depends on leucine-rich-repeat receptor-like-kinases (LRR-RLK) belonging to the subclass XI. In legume plants, such as the Medicago truncatula model, specific CLE peptides were shown to regulate root symbiotic nodulation depending on the LRR-RLK SUNN (Super Numeric Nodules). Amongst the ten M. truncatula LRR-RLK most closely related to SUNN, only one showed a nodule-induced expression, and was so-called MtNRLK1 (Nodule-induced Receptor-Like Kinase 1). MtNRLK1 expression is associated to root and nodule vasculature as well as to the proximal meristem and rhizobial infection zone in the nodule apex. Except for the root vasculature, the MtNRLK1 symbiotic expression pattern is different than the one of MtSUNN. Functional analyses either based on RNA interference, insertional mutagenesis, and overexpression of MtNRLK1 however failed to identify a significant nodulation phenotype, either regarding the number, size, organization or nitrogen fixation capacity of the symbiotic organs formed.
Spatial and temporal evolution of natural and anthropogenic dust events over northern China
Authors: Wang Xin , Liu Jun , Che Huizheng , Ji Fei , Liu Jingjing
Published: January 2018

Mineral dust interacts with radiation and cloud microphysics in East Asia can affect local and regional climate. In this study, we found that the occurrences of dust storms, blowing dust, and floating dust over northern China has decreased 76.7%, 68.5%, and 64.5% considerably since the beginning of this century. Based on a multi-dimensional ensemble empirical mode decomposition (MEEMD) method, a steady decrease in zonal maximum wind speed (up to −0.95 m/s) in the Northern Hemisphere was largely responsible for this recent decline in dust event occurrences. Then, a new detection technique that combines multi-satellite datasets with surface observations of dust events is developed to estimate the contribution of anthropogenic dust column burden from disturbed soils to the observed total dust. It is found that the percentage of the anthropogenic dust column burdens to total mineral dust is up to 76.8% by human activities during 2007–2014 in eastern China, but only less than 9.2% near desert source regions in northwestern China. However, we note that the anthropogenic effects on the dust loading for both regions are non-negligible.
Obtaining high-quality draft genomes from uncultured microbes by cleaning and co-assembly of single-cell amplified genomes
Authors: Kogawa Masato , Hosokawa Masahito , Nishikawa Yohei , Mori Kazuki , Takeyama Haruko
Published: January 2018

Single-cell genomics is a straightforward approach to obtain genomes from uncultured microbes. However, sequence reads from a single-cell amplified genome (SAG) contain significant bias and chimeric sequences. Here, we describe Cleaning and Co-assembly of a Single-Cell Amplified Genome (ccSAG), a novel analytical workflow to obtain composite single-cell genomes with elimination of sequence errors. By the integration of ccSAG with a massively parallel single-cell genome amplification platform based on droplet microfluidics, we can generate multiple SAGs and effectively integrate them into the composite genomes quality equivalent to the data obtained from bulk DNA. We obtained two novel draft genomes from single gut microbial cells with high completeness (>96.6%) and extremely low contamination (<1.25%). Moreover, we revealed the presence of single nucleotide polymorphisms in the specific gene by sequence comparison at the single-cell level. Thus, the workflow yields near-complete genomes from uncultured microbes, and enables analyses of genetic heterogeneity within identical strains.
First in situ evidence of wakes in the far field behind offshore wind farms
Authors: Platis Andreas , Siedersleben Simon K. , Bange Jens , Lampert Astrid , Bärfuss Konrad , Hankers Rudolf , Cañadillas Beatriz , Foreman Richard , Schulz-Stellenfleth Johannes , Djath Bughsin , Neumann Thomas , Emeis Stefan
Published: January 2018

More than 12 GW of offshore wind turbines are currently in operation in European waters. To optimise the use of the marine areas, wind farms are typically clustered in units of several hundred turbines. Understanding wakes of wind farms, which is the region of momentum and energy deficit downwind, is important for optimising the wind farm layouts and operation to minimize costs. While in most weather situations (unstable atmospheric stratification), the wakes of wind turbines are only a local effect within the wind farm, satellite imagery reveals wind-farm wakes to be several tens of kilometres in length under certain conditions (stable atmospheric stratification), which is also predicted by numerical models. The first direct in situ measurements of the existence and shape of large wind farm wakes by a specially equipped research aircraft in 2016 and 2017 confirm wake lengths of more than tens of kilometres under stable atmospheric conditions, with maximum wind speed deficits of 40%, and enhanced turbulence. These measurements were the first step in a large research project to describe and understand the physics of large offshore wakes using direct measurements, together with the assessment of satellite imagery and models.
Deep brain stimulation induces sparse distributions of locally modulated neuronal activity
Authors: Xiao YiZi , Agnesi Filippo , Bello Edward M. , Zhang Simeng , Vitek Jerrold L. , Johnson Matthew D.
Published: January 2018

Deep brain stimulation (DBS) therapy is a potent tool for treating a range of brain disorders. High frequency stimulation (HFS) patterns used in DBS therapy are known to modulate neuronal spike rates and patterns in the stimulated nucleus; however, the spatial distribution of these modulated responses are not well understood. Computational models suggest that HFS modulates a volume of tissue spatially concentrated around the active electrode. Here, we tested this theory by investigating modulation of spike rates and patterns in non-human primate motor thalamus while stimulating the cerebellar-receiving area of motor thalamus, the primary DBS target for treating Essential Tremor. HFS inhibited spike activity in the majority of recorded cells, but increasing stimulation amplitude also shifted the response to a greater degree of spike pattern modulation. Modulated responses in both categories exhibited a sparse and long-range spatial distribution within motor thalamus, suggesting that stimulation preferentially affects afferent and efferent axonal processes traversing near the active electrode and that the resulting modulated volume strongly depends on the local connectome of these axonal processes. Such findings have important implications for current clinical efforts building predictive computational models of DBS therapy, developing directional DBS lead technology, and formulating closed-loop DBS strategies.
Accuracy of fetal fibronectin for the prediction of preterm birth in symptomatic twin pregnancies: a pilot study
Authors: Fuchs Florent , Lefevre Clémentine , Senat Marie-Victoire , Fernandez Hervé
Published: January 2018

Our goal was to evaluate the performance of fetal fibronectin (fFN) test alone or combined with cervical length (CL), to predict spontaneous preterm birth (PTB) in symptomatic twin pregnancies. We carry out a short pilot study including all uncomplicated diamniotic twin pregnancies with symptoms of preterm labor (PTL) and intact membranes at 24–33 weeks + 6 days of gestation. Studied outcome were spontaneous delivery within 7 and 14 days of testing and spontaneous PTB at <34 and <37 weeks of gestation. Among 40 women, fFN test was positive in 3 of them (7.5%). Regardless of the outcome studied CL did not significantly predict PTB. Performance of fFN was sensitivity (66.7%), specificity (97.2%), positive predictive value (66.7%), negative predictive value (97.2%), positive likelihood ratio (LR) (24.0), and negative LR (0.3) to predict spontaneous PTB within 7 days (p = 0.01). Thus, 66.1% of patients with a positive fFN test would deliver within 7 days versus 2.4% if negative testing; starting with a pre-test probability of 7.5%. Combining CL and fFN did not enable to increase enough positive LR or decrease significantly negative LR. In conclusion, fFN test alone might have a better ability to detect spontaneous delivery within 7 days among symptomatic twin pregnancies.
Arrhythmogenicity of fibro-fatty infiltrations
Authors: De Coster Tim , Claus Piet , Kazbanov Ivan V. , Haemers Peter , Willems Rik , Sipido Karin R. , Panfilov Alexander V.
Published: January 2018

The onset of cardiac arrhythmias depends on electrophysiological and structural properties of cardiac tissue. One of the most important changes leading to arrhythmias is characterised by the presence of a large number of non-excitable cells in the heart, of which the most well-known example is fibrosis. Recently, adipose tissue was put forward as another similar factor contributing to cardiac arrhythmias. Adipocytes infiltrate into cardiac tissue and produce in-excitable obstacles that interfere with myocardial conduction. However, adipose infiltrates have a different spatial texture than fibrosis. Over the course of time, adipose tissue also remodels into fibrotic tissue. In this paper we investigate the arrhythmogenic mechanisms resulting from the presence of adipose tissue in the heart using computer modelling. We use the TP06 model for human ventricular cells and study how the size and percentage of adipose infiltrates affects basic properties of wave propagation and the onset of arrhythmias under high frequency pacing in a 2D model for cardiac tissue. We show that although presence of adipose infiltrates can result in the onset of cardiac arrhythmias, its impact is less than that of fibrosis. We quantify this process and discuss how the remodelling of adipose infiltrates affects arrhythmia onset.
Understanding non-linear effects from Hill-type dynamics with application to decoding of p53 signaling
Authors: Shi Xiaomin , Reimers Jeffrey R.
Published: January 2018

Analytical equations are derived depicting four possible scenarios resulting from pulsed signaling of a system subject to Hill-type dynamics. Pulsed Hill-type dynamics involves the binding of multiple signal molecules to a receptor and occurs e.g., when transcription factor p53 orchestrates cancer prevention, during calcium signaling, and during circadian rhythms. The scenarios involve: (i) enhancement of high-affinity binders compared to low-affinity ones, (ii) slowing reactions involving high-affinity binders, (iii) transfer of the clocking of low-affinity binders from the signal molecule to the products, and (iv) a unique clocking process that produces incremental increases in the activity of high-affinity binders with each signal pulse. In principle, these mostly non-linear effects could control cellular outcomes. An applications to p53 signaling is developed, with binding to most gene promoters identified as category (iii) responses. However, currently unexplained enhancement of high-affinity promoters such as CDKN1a (p21) by pulsed signaling could be an example of (i). In general, provision for all possible scenarios is required in the design of mathematical models incorporating pulsed Hill-type signaling as some aspect.
Reducing acquisition time for MRI-based forensic age estimation
Authors: Neumayer Bernhard , Schloegl Matthias , Payer Christian , Widek Thomas , Tschauner Sebastian , Ehammer Thomas , Stollberger Rudolf , Urschler Martin
Published: January 2018

Radiology-based estimation of a living person’s unknown age has recently attracted increasing attention due to large numbers of undocumented immigrants entering Europe. To avoid the application of X-ray-based imaging techniques, magnetic resonance imaging (MRI) has been suggested as an alternative imaging modality. Unfortunately, MRI requires prolonged acquisition times, which potentially represents an additional stressor for young refugees. To eliminate this shortcoming, we investigated the degree of reduction in acquisition time that still led to reliable age estimates. Two radiologists randomly assessed original images and two sets of retrospectively undersampled data of 15 volunteers (N = 45 data sets) applying an established radiological age estimation method to images of the hand and wrist. Additionally, a neural network-based age estimation method analyzed four sets of further undersampled images from the 15 volunteers (N = 105 data sets). Furthermore, we compared retrospectively undersampled and acquired undersampled data for three volunteers. To assess reliability with increasing degree of undersampling, intra-rater and inter-rater agreement were analyzed computing signed differences and intra-class correlation. While our findings have to be confirmed by a larger prospective study, the results from both radiological and automatic age estimation showed that reliable age estimation was still possible for acquisition times of 15 seconds.
Optimising the glaucoma signal/noise ratio by mapping changes in spatial summation with area-modulated perimetric stimuli
Authors: Rountree Lindsay , Mulholland Pádraig J. , Anderson Roger S. , Garway-Heath David F. , Morgan James E. , Redmond Tony
Published: January 2018

Identification of glaucomatous damage and progression by perimetry are limited by measurement and response variability. This study tested the hypothesis that the glaucoma damage signal/noise ratio is greater with stimuli varying in area, either solely, or simultaneously with contrast, than with conventional stimuli varying in contrast only (Goldmann III, GIII). Thirty glaucoma patients and 20 age-similar healthy controls were tested with the Method of Constant Stimuli (MOCS). One stimulus modulated in area (A), one modulated in contrast within Ricco’s area (CR), one modulated in both area and contrast simultaneously (AC), and the reference stimulus was a GIII, modulating in contrast. Stimuli were presented on a common platform with a common scale (energy). A three-stage protocol minimised artefactual MOCS slope bias that can occur due to differences in psychometric function sampling between conditions. Threshold difference from age-matched normal (total deviation), response variability, and signal/noise ratio were compared between stimuli. Total deviation was greater with, and response variability less dependent on defect depth with A, AC, and CR stimuli, compared with GIII. Both A and AC stimuli showed a significantly greater signal/noise ratio than the GIII, indicating that area-modulated stimuli offer benefits over the GIII for identifying early glaucoma and measuring progression.
Potential benefits of mesenchymal stem cells and electroacupuncture on the trophic factors associated with neurogenesis in mice with ischemic stroke
Authors: Kim Yu Ri , Ahn Sung Min , Pak Malk Eun , Lee Hong Ju , Jung Da Hee , Shin Yong-Il , Shin Hwa Kyoung , Choi Byung Tae
Published: January 2018

The beneficial effects of mesenchymal stem cells (MSCs) and electroacupuncture (EA) on neurogenesis and related trophic factors remain unclear. Bone marrow MSCs (mBMSC) were transplanted into the striatum of mice with middle cerebral artery occlusion (MCAO), and EA stimulation was applied at two acupoints, Baihui and Dazhui. EA treatment significantly improved motor function, and a synergistic effect of combined mBMSC and EA treatment was observed. Combined mBMSC and EA treatment reduced prominent atrophic changes in the striatum and led to proliferation of neural progenitor cells in the subventricular zone (SVZ) and the surrounding areas of the striatum (SVZ + striatum) of MCAO mice. The mBMSC and EA treatment markedly enhanced mature brain-derived neurotrophic factor (mBDNF) expression in the SVZ + striatum and hippocampus of mice with MCAO, and combined treatment enhanced neurotrophin-4 (NT4) expression. The number of mBDNF- and NT4-positive neurons in the SVZ + striatum and hippocampus increased following EA treatment. Combined treatment led to an increase in the expression levels of phosphorylated cAMP response element binding protein in the neuroblasts of the striatum. Our results indicate that combined MSC and EA treatment may lead to a better therapeutic effect via co-regulation of neurotrophic factors in the brain, by regulating neurogenesis more than single therapy.
Neurophysiological mechanisms of interval timing dissociate inattentive and combined ADHD subtypes
Authors: Bluschke Annet , Schuster Jacqueline , Roessner Veit , Beste Christian
Published: January 2018

It is far from conclusive what distinguishes the inattentive (ADD) and the combined (ADHD-C) subtype of ADHD on the neuronal level. Theoretical considerations suggest that especially interval timing processes may dissociate these subtypes from each other. Combining high-density EEG recordings with source localization analyses, we examine whether there are ADHD-subtype specific modulations of neurophysiological processes subserving interval timing in matched groups of ADD (n = 16), ADHD-C (n = 16) and controls (n = 16). Patients with ADD and ADHD-C show deficits in interval timing, which was correlated with the degree of inattention in ADD patients. Compared to healthy controls, patients with ADHD-C display a somewhat weaker, yet consistent response preparation process (contingent negative variation, CNV). In patients with ADD, the early CNV is interrupted, indicating an oscillatory disruption of the interval timing process. This is associated with activations in the supplemental motor areas and the middle frontal gyrus. Patients with ADD display adequate feedback learning mechanisms (feedback-related negativity, FRN), which is not the case in patients with ADHD-C. The results suggest that altered pacemaker-accumulation processes in medial frontal structures distinguish the ADD from the ADHD-C subtype. Particularly in patients with ADD phasic interruptions of preparatory neurophysiological processes are evident, making this a possible diagnostic feature.