bluuebunny/crossref_metadata_2025 huggingface dataset:
Collision Chronology Along the İzmir‐Ankara‐Erzincan Suture Zone: Insights From the Sarıcakaya Basin, Western Anatolia
Authors: Mueller M. A. , Licht A. , Campbell C. , Ocakoğlu F. , Taylor M. H. , Burch L. , Ugrai T. , Kaya M. , Kurtoğlu B. , Coster P. M. C. , Métais G. , Beard K. C.
Published: September 2019

Debate persists concerning the timing and geodynamics of intercontinental collision, style of syncollisional deformation, and development of topography and fold‐and‐thrust belts along the >1,700‐km‐long İzmir‐Ankara‐Erzincan suture zone (İAESZ) in Turkey. Resolving this debate is a necessary precursor to evaluating the integrity of convergent margin models and kinematic, topographic, and biogeographic reconstructions of the Mediterranean domain. Geodynamic models argue either for a synchronous or diachronous collision during either the Late Cretaceous and/or Eocene, followed by Eocene slab breakoff and postcollisional magmatism.

We investigate the collision chronology in western Anatolia as recorded in the sedimentary archives of the 90‐km‐long Sarıcakaya Basin perched at shallow structural levels along the İAESZ. Based on new zircon U‐Pb geochronology and depositional environment and sedimentary provenance results, we demonstrate that the Sarıcakaya Basin is an Eocene sedimentary basin with sediment sourced from both the İAESZ and Söğüt Thrust fault to the south and north, respectively, and formed primarily by flexural loading from north‐south shortening along the syncollisional Söğüt Thrust. Our results refine the timing of collision between the Anatolides and Pontide terranes in western Anatolia to Maastrichtian‐Middle Paleocene and Early Eocene crustal shortening and basin formation. Furthermore, we demonstrate contemporaneous collision, deformation, and magmatism across the İAESZ, supporting synchronous collision models. We show that regional postcollisional magmatism can be explained by renewed underthrusting instead of slab breakoff. This new İAESZ chronology provides additional constraints for kinematic, geodynamic, and biogeographic reconstructions of the Mediterranean domain.
Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats
Authors: Zhao Ze-Hua , Xin Feng-Zhi , Xue Yaqian , Hu Zhimin , Han Yamei , Ma Fengguang , Zhou Da , Liu Xiao-Lin , Cui Aoyuan , Liu Zhengshuai , Liu Yuxiao , Gao Jing , Pan Qin , Li Yu , Fan Jian-Gao
Published: September 2019

Microbial metabolites have emerged as critical components that mediate the metabolic effects of the gut microbiota. Here, we show that indole-3-propionic acid (IPA), a tryptophan metabolite produced by gut bacteria, is a potent anti-non-alcoholic steatohepatitis (NASH) microbial metabolite. Here, we demonstrate that administration of IPA modulates the microbiota composition in the gut and inhibits microbial dysbiosis in rats fed a high-fat diet. IPA induces the expression of tight junction proteins, such as ZO-1 and Occludin, and maintains intestinal epithelium homeostasis, leading to a reduction in plasma endotoxin levels. Interestingly, IPA inhibits NF-κB signaling and reduces the levels of proinflammatory cytokines, such as TNFα, IL-1β, and IL-6, in response to endotoxin in macrophages to repress hepatic inflammation and liver injury. Moreover, IPA is sufficient to inhibit the expression of fibrogenic and collagen genes and attenuate diet-induced NASH phenotypes. The beneficial effects of IPA on the liver are likely mediated through inhibiting the production of endotoxin in the gut. These findings suggest a protective role of IPA in the control of metabolism and uncover the gut microbiome and liver cross-talk in regulating the intestinal microenvironment and liver pathology via a novel dietary nutrient metabolite. IPA may provide a new therapeutic strategy for treating NASH.
High-fidelity optical diffraction tomography of multiple scattering samples
Authors: Lim Joowon , Ayoub Ahmed B. , Antoine Elizabeth E. , Psaltis Demetri
Published: September 2019

We propose an iterative reconstruction scheme for optical diffraction tomography that exploits the split-step non-paraxial (SSNP) method as the forward model in a learning tomography scheme. Compared with the beam propagation method (BPM) previously used in learning tomography (LT-BPM), the improved accuracy of SSNP maximizes the information retrieved from measurements, relying less on prior assumptions about the sample. A rigorous evaluation of learning tomography based on SSNP (LT-SSNP) using both synthetic and experimental measurements confirms its superior performance compared with that of the LT-BPM. Benefiting from the accuracy of SSNP, LT-SSNP can clearly resolve structures that are highly distorted in the LT-BPM. A serious limitation for quantifying the reconstruction accuracy for biological samples is that the ground truth is unknown. To overcome this limitation, we describe a novel method that allows us to compare the performances of different reconstruction schemes by using the discrete dipole approximation to generate synthetic measurements. Finally, we explore the capacity of learning approaches to enable data compression by reducing the number of scanning angles, which is of particular interest in minimizing the measurement time.
βarrestin-1 regulates DNA repair by acting as an E3-ubiquitin ligase adaptor for 53BP1
Authors: Nieto Ainhoa , Hara Makoto R. , Quereda Victor , Grant Wayne , Saunders Vanessa , Xiao Kunhong , McDonald Patricia H. , Duckett Derek R.
Published: September 2019

Cellular DNA is constantly under threat from internal and external insults, consequently multiple pathways have evolved to maintain chromosomal fidelity. Our previous studies revealed that chronic stress, mediated by continuous stimulation of the β2-adrenergic-βarrestin-1 signaling axis suppresses activity of the tumor suppressor p53 and impairs genomic integrity. In this pathway, βarrestin-1 (βarr1) acts as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, MDM2. We sought to determine whether βarr1 plays additional roles in the repair of DNA damage. Here we demonstrate that in mice βarr1 interacts with p53-binding protein 1 (53BP1) with major consequences for the repair of DNA double-strand breaks. 53BP1 is a principle component of the DNA damage response, and when recruited to the site of double-strand breaks in DNA, 53BP1 plays an important role coordinating repair of these toxic lesions. Here, we report that βarr1 directs 53BP1 degradation by acting as a scaffold for the E3-ubiquitin ligase Rad18. Consequently, knockdown of βarr1 stabilizes 53BP1 augmenting the number of 53BP1 DNA damage repair foci following exposure to ionizing radiation. Accordingly, βarr1 loss leads to a marked increase in irradiation resistance both in cells and in vivo. Thus, βarr1 is an important regulator of double strand break repair, and disruption of the βarr1/53BP1 interaction offers an attractive strategy to protect cells against high levels of exposure to ionizing radiation.
Combining ERBB family and MET inhibitors is an effective therapeutic strategy in cutaneous malignant melanoma independent of BRAF/NRAS mutation status
Authors: Das Ishani , Wilhelm Margareta , Höiom Veronica , Franco Marquez Rodolfo , Costa Svedman Fernanda , Hansson Johan , Tuominen Rainer , Egyhàzi Brage Suzanne
Published: September 2019

Current treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival; however, relapses are common. A number of receptor tyrosine kinases (RTKs) including EGFR and MET have been reported to be involved in CMM metastasis and in the development of resistance to therapy, targeting the mitogen-activated protein kinase (MAPK pathway). IHC analysis showed that patients with higher MET protein expression had a significantly shorter overall survival. In addition, silencing of MET caused an upregulation of EGFR and p-AKT, which was abrogated by concomitant silencing of MET and EGFR in CMM cells resistant to MAPK-targeting drugs. We therefore explored novel treatment strategies using clinically approved drugs afatinib (ERBB family inhibitor) and crizotinib (MET inhibitor), to simultaneously block MET and ERBB family RTKs. The effects of the combination were assessed in cell culture and spheroid models using established CMM and patient-derived short-term cell lines, and an in vivo xenograft mouse model. The combination had a synergistic effect, promoting cell death, concomitant with a potent downregulation of migratory and invasive capacity independent of their BRAF/NRAS mutational status. Furthermore, the combination attenuated tumor growth rate, as ascertained by the significant reduction of Ki67 expression and induced DNA damage in vivo. Importantly, this combination therapy had minimal therapy-related toxicity in mice. Lastly, the cell cycle G2 checkpoint kinase WEE1 and the RTK IGF1R, non-canonical targets, were altered upon exposure to the combination. Knockdown of WEE1 abrogated the combination-mediated effects on cell migration and proliferation in BRAF mutant BRAF inhibitor-sensitive cells, whereas WEE1 silencing alone inhibited cell migration in NRAS mutant cells. In summary, our results show that afatinib and crizotinib in combination is a promising alternative targeted therapy option for CMM patients, irrespective of BRAF/NRAS mutational status, as well as for cases where resistance has developed towards BRAF inhibitors.
Structural insight into human N6amt1–Trm112 complex functioning as a protein methyltransferase
Authors: Li Wenjing , Shi Yu , Zhang Tianlong , Ye Jie , Ding Jianping
Published: September 2019

DNA methylation is an important epigenetic modification in many organisms and can occur on cytosine or adenine. N6-methyladenine (6mA) exists widespreadly in bacterial genomes, which plays a vital role in the bacterial restriction-modification system. Recently, 6mA has also been reported to exist in the genomes of a variety of eukaryotes from unicellular organisms to metazoans. There were controversial reports on whether human N6amt1, which was originally reported as a glutamine MTase for eRF1, is a putative 6mA DNA MTase. We report here the crystal structure of human N6amt1–Trm112 in complex with cofactor SAM. Structural analysis shows that Trm112 binds to a hydrophobic surface of N6amt1 to stabilize its structure but does not directly contribute to substrate binding and catalysis. The active site and potential substrate-binding site of N6amt1 are dominantly negatively charged and thus are unsuitable for DNA binding. The biochemical data confirm that the complex cannot bind DNA and has no MTase activity for DNA, but exhibits activity for the methylation of Gln185 of eRF1. Our structural and biochemical data together demonstrate that N6amt1 is a bona fide protein MTase rather than a DNA MTase.
VcFT-induced mobile florigenic signals in transgenic and transgrafted blueberries
Authors: Song Guo-qing , Walworth Aaron , Lin Tianyi , Chen Qiuxia , Han Xiumei , Irina Zaharia L. , Zhong Gan-yuan
Published: September 2019

FLOWERING LOCUS T (FT) can promote early flowering in annual species, but such role has not been well demonstrated in woody species. We produced self and reciprocal grafts involving non-transgenic blueberry (NT) and transgenic blueberry (T) carrying a 35S-driven blueberry FT (VcFT-OX). We demonstrated that the transgenic VcFT-OX rootstock promoted flowering of non-transgenic blueberry scions in the NT (scion):T (rootstock) grafts. We further analyzed RNA-Seq profiles and six groups of phytohormones in both NT:T and NT:NT plants. We observed content changes of several hormone metabolites, in a descending order, in the transgenic NT:T, non-transgenic NT:T, and non-transgenic NT:NT leaves. By comparing differential expression transcripts (DETs) of these tissues in relative to their control, we found that the non-transgenic NT:T leaves had many DETs shared with the transgenic NT:T leaves, but very few with the transgenic NT:T roots. Interestingly, a number of these shared DETs belong to hormone pathway genes, concurring with the content changes of hormone metabolites in both transgenic and non-transgenic leaves of the NT:T plants. These results suggest that phytohormones induced by VcFT-OX in the transgenic leaves might serve as part of the signals that resulted in early flowering in both transgenic plants and the non-transgenic NT:T scions.
BioExcel Building Blocks, a software library for interoperable biomolecular simulation workflows
Authors: Andrio Pau , Hospital Adam , Conejero Javier , Jordá Luis , Del Pino Marc , Codo Laia , Soiland-Reyes Stian , Goble Carole , Lezzi Daniele , Badia Rosa M. , Orozco Modesto , Gelpi Josep Ll.
Published: September 2019

In the recent years, the improvement of software and hardware performance has made biomolecular simulations a mature tool for the study of biological processes. Simulation length and the size and complexity of the analyzed systems make simulations both complementary and compatible with other bioinformatics disciplines. However, the characteristics of the software packages used for simulation have prevented the adoption of the technologies accepted in other bioinformatics fields like automated deployment systems, workflow orchestration, or the use of software containers. We present here a comprehensive exercise to bring biomolecular simulations to the “bioinformatics way of working”. The exercise has led to the development of the BioExcel Building Blocks (BioBB) library. BioBB’s are built as Python wrappers to provide an interoperable architecture. BioBB’s have been integrated in a chain of usual software management tools to generate data ontologies, documentation, installation packages, software containers and ways of integration with workflow managers, that make them usable in most computational environments.
Interstitial cells in calcified aortic valves have reduced differentiation potential and stem cell-like properties
Authors: Bogdanova Maria , Zabirnyk Arsenii , Malashicheva Anna , Enayati Katarina Zihlavnikova , Karlsen Tommy Aleksander , Kaljusto Mari-Liis , Kvitting John-Peder Escobar , Dissen Erik , Sullivan Gareth John , Kostareva Anna , Stensløkken Kåre-Olav , Rutkovskiy Arkady , Vaage Jarle
Published: September 2019

Valve interstitial cells (VICs) are crucial in the development of calcific aortic valve disease. The purpose of the present investigation was to compare the phenotype, differentiation potential and stem cell-like properties of cells from calcified and healthy aortic valves. VICs were isolated from human healthy and calcified aortic valves. Calcification was induced with osteogenic medium. Unlike VICs from healthy valves, VICs from calcified valves cultured without osteogenic medium stained positively for calcium deposits with Alizarin Red confirming their calcific phenotype. Stimulation of VICs from calcified valves with osteogenic medium increased calcification (p = 0.02), but not significantly different from healthy VICs. When stimulated with myofibroblastic medium, VICs from calcified valves had lower expression of myofibroblastic markers, measured by flow cytometry and RT-qPCR, compared to healthy VICs. Contraction of collagen gel (a measure of myofibroblastic activity) was attenuated in cells from calcified valves (p = 0.04). Moreover, VICs from calcified valves, unlike cells from healthy valves had lower potential to differentiate into adipogenic pathway and lower expression of stem cell-associated markers CD106 (p = 0.04) and aldehyde dehydrogenase (p = 0.04). In conclusion, VICs from calcified aortic have reduced multipotency compared to cells from healthy valves, which should be considered when investigating possible medical treatments of aortic valve calcification.
Incidence of Intraocular Lens Exchange after Cataract Surgery
Authors: Abdalla Elsayed Maram E. A. , Ahmad Khabir , Al-Abdullah Abdulelah A. , Malik Rizwan , Khandekar Rajiv , Martinez-Osorio Hernan , Mura Marco , Schatz Patrik
Published: September 2019

Intraocular lens (IOL) exchange after cataract surgery is unusual but may be associated with suboptimal visual outcome. The incidence of IOL exchange has not been consistently estimated. Such information is invaluable when counseling patients prior to cataract surgery. We examined the incidence of, and indications and risk factors for, IOL exchange after cataract surgery. We also assessed visual outcome of eyes that had an IOL exchange. A cohort design was used to estimate the incidence of IOL exchange and a case-control design to identify factors associated with it. All phacoemulsification surgeries with IOL (n = 17415 eyes) during 2010–2017 and those that had a subsequent IOL removal or replacement during the same time period were identified (n = 34 eyes). The incidence of IOL exchange was 2 per 1000 surgeries (95% confidence interval [CI] 1 to 3) over 8 years. Eyes that underwent subsequent IOL removal or replacement were compared with eyes that had cataract surgery only (n = 47) across demographic and clinical characteristics. In a binary logistic regression analysis, two factors were significantly associated with IOL exchange/removal: an adverse event during cataract surgery (adjusted odds ratio [aOR] 19.45; 95% CI 4.89–77.30, P < 0.001) and a pre-existing ocular comorbidity (aOR 10.70; 95% CI 1.69–67.63, P = 0.021). The effect of gender was marginally significant (P = 0.077). Eyes that underwent IOL exchange or explantation were nearly two and a half times more likely to have a final best-corrected visual acuity of <20/60 compared to those that had cataract surgery alone (adjusted RR 2.60 95% CI, 1.13–6.02; P = 0.025).
20 Years of DIEAP Flap Breast Reconstruction: A Big Data Analysis
Authors: Depypere Bernard , Herregods Sofie , Denolf Jacob , Kerkhove Louis-Philippe , Mainil Laurent , Vyncke Tom , Blondeel Phillip , Depypere Herman
Published: September 2019

With every hospital admission, a vast amount of data is collected from every patient. Big data can help in data mining and processing of this volume of data. The goal of this study is to investigate the potential of big data analyses by analyzing clinically relevant data from the immediate postoperative phase using big data mining techniques. A second aim is to understand the importance of different postoperative parameters. We analyzed all data generated during the admission of 739 women undergoing a free DIEAP flap breast reconstruction. The patients’ complete midcare nursing report, laboratory data, operative reports and drug schedule were examined (7,405,359 data points). The duration of anesthesia does not predict the need for revision. Low Red Blood cell Counts (3.53 × 106/µL versus 3.79 × 106/µL, p < 0.001) and a low MAP (MAP = 73.37 versus 76.62; p < 0.001) postoperatively are correlated with significantly more revisions. Different drugs (asthma/COPD medication, Butyrophenones) can also play a significant role in the success of the free flap. In a world that is becoming more data driven, there is a clear need for electronic medical records which are easy to use for the practitioner, nursing staff, and the researcher. Very large datasets can be used, and big data analysis allows a relatively easy and fast interpretation all this information.
The role of NaV channels in synaptic transmission after axotomy in a microfluidic culture platform
Authors: Vysokov Nickolai , McMahon Stephen B. , Raouf Ramin
Published: September 2019

Voltage gated sodium channels are key players in aberrant pain signaling and sensitization of nociceptors after peripheral nerve injury. The extent to which sodium channel activity after injury contributes to synaptic transmission at the first pain synapse however remains unclear. To investigate the effect of axotomy on synaptic transmission between dorsal root ganglia neurons and dorsal horn neurons, we reconstructed the first pain synapse in a novel microfluidic based compartmentalized cell culture system, which recapitulates the connectivity of peripheral pain signaling. We show that following axotomy of the distal axons, inhibition of NaV1.7 and NaV1.8 sodium channels in incoming presynaptic DRG axons is no longer sufficient to block activation of these axons and the resulting synaptic transmission to dorsal horn neurons. We found that blockade of NaV1.6 activity is highly effective in reducing activation of incoming axons contributing to synaptic transmission after axotomy of DRG neurons. The microfluidic culture system described here offers an in vitro platform to recapitulate and study the first pain synapse.
An Improved Method of Maintaining Primary Murine Cardiac Fibroblasts in Two-Dimensional Cell Culture
Authors: Landry Natalie M. , Rattan Sunil G. , Dixon Ian M. C.
Published: September 2019

Primary cardiac fibroblasts are notoriously difficult to maintain for extended periods of time in cell culture, due to the plasticity of their phenotype and sensitivity to mechanical input. In order to study cardiac fibroblast activation in vitro, we have developed cell culture conditions which promote the quiescent fibroblast phenotype in primary cells. Using elastic silicone substrata, both rat and mouse primary cardiac fibroblasts could be maintained in a quiescent state for more than 3 days after isolation and these cells showed low expression of myofibroblast markers, including fibronectin extracellular domain A, non-muscle myosin IIB, platelet-derived growth factor receptor-alpha and alpha-smooth muscle actin. Gene expression was also more fibroblast-like vs. that of myofibroblasts, as Tcf21 was significantly upregulated, while Fn1-EDA, Col1A1 and Col1A2 were markedly downregulated. Cell culture conditions (eg. serum, nutrient concentration) are critical for the control of temporal fibroblast proliferation. We propose that eliminating mechanical stimulus and limiting the nutrient content of cell culture media can extend the quiescent nature of primary cardiac fibroblasts for physiological analyses in vitro.
Overexpression and alternative splicing of NF-YA in breast cancer
Authors: Dolfini Diletta , Andrioletti Valentina , Mantovani Roberto
Published: September 2019

NF-Y is a CCAAT-binding trimeric transcription factor, whose regulome, interactome and oncogenic potential point to direct involvement in cellular transformation. Yet little is known about the levels of NF-Y subunits in tumors. We focused on breast carcinomas, and analyzed RNA-Seq datasets of TCGA and 54 BRCA cell lines at gene and isoforms level. We partitioned all tumors in the four major subclasses. NF-YA, but not histone-fold subunits NF-YB/NF-YC, is globally overexpressed, correlating with the proliferative Ki67 marker and a common set of 840 genes, with cell-cycle, metabolism GO terms. Their promoters are enriched in NF-Y, GC-rich and E2F sites. Surprisingly, there is an isoform switch, with the “short” isoform -NF-YAs- becoming predominant in tumors. E2F genes are also overexpressed in BRCA, but no switch in isoforms is observed. In Basal-like Claudinlow cell lines and tumors, expression of NF-YAl -long- isoform is high, together with 11 typical EMT markers and low levels of basal Keratins. Analysis of Progression-Free-Intervals indicates that tumors with unbalance of NF-YA isoforms ratios have worst clinical outcomes. The data suggest that NF-YA overexpression increases CCAAT-dependent, pro-growth genes in BRCA. NF-YAs is associated with a proliferative signature, but high levels of NF-YAl signal loss of epithelial features, EMT and acquisition of a more aggressive behavior in a subset of Claudinlow Basal-like tumors.
A high efficiency silicon nitride waveguide grating coupler with a multilayer bottom reflector
Authors: Hong Jianxun , Spring Andrew M. , Qiu Feng , Yokoyama Shiyoshi
Published: September 2019

We propose a high efficiency apodized grating coupler with a bottom reflector for silicon nitride photonic integrated circuits. The reflector consists of a stack of alternate silicon nitride and silicon dioxide quarter-wave films. The design, fabrication and optical characterization of the couplers has been presented. The measured fiber to detector insertion loss was −3.5 dB which corresponds to a peak coupling efficiency of −1.75 dB. A 3 dB wavelength bandwidth of 76.34 nm was demonstrated for the grating coupler with a 20-layer reflector. The fabrication process is CMOS-compatible and requires only a single etching step.
Resting-state brain functional connectivity in patients with chronic pain who responded to subanesthetic-dose ketamine
Authors: Motoyama Yasushi , Oshiro Yoshitetsu , Takao Yumiko , Sato Hitoaki , Obata Norihiko , Izuta Shinichiro , Mizobuchi Satoshi , Kan Shigeyuki
Published: September 2019

Ketamine has been used to treat chronic pain; however, it is still unknown as to what types of chronic pain is ketamine effective against. To identify the effect of administration of subanesthetic-dose ketamine in patients with chronic pain and to clarify the mechanism of the effect, we retrospectively investigated brain functional connectivity using resting-state functional magnetic resonance imaging (rs-fMRI). Patients were divided into responders (Group R: ≥50% improvement on Numerical Rating Scale) and non-responders (Group NR). We compared the differences in terms of brain functional connectivity by seed-to-voxel correlation analysis. Two-sample t-test revealed significant lower connectivity between the medial prefrontal cortex (mPFC) and precuneus in Group R. We also found a significant negative correlation between the improvement rate and functional connectivity strength between the mPFC and precuneus. These findings suggest that subanesthetic-dose ketamine is effective in patients with chronic pain whose brain functional connectivity between the mPFC and precuneus is low. We believe that the current study explored for the first time the correlation between brain functional connectivity and the effect of subanesthetic-dose ketamine for chronic pain and indicated the possibility of use of the predictive marker in pharmacological treatment of chronic pain.
Metagenomic analysis using next-generation sequencing of pathogens in bronchoalveolar lavage fluid from pediatric patients with respiratory failure
Authors: Takeuchi Suguru , Kawada Jun-ichi , Horiba Kazuhiro , Okuno Yusuke , Okumura Toshihiko , Suzuki Takako , Torii Yuka , Kawabe Shinji , Wada Sho , Ikeyama Takanari , Ito Yoshinori
Published: September 2019

Next-generation sequencing (NGS) has been applied in the field of infectious diseases. Bronchoalveolar lavage fluid (BALF) is considered a sterile type of specimen that is suitable for detecting pathogens of respiratory infections. The aim of this study was to comprehensively identify causative pathogens using NGS in BALF samples from immunocompetent pediatric patients with respiratory failure. Ten patients hospitalized with respiratory failure were included. BALF samples obtained in the acute phase were used to prepare DNA- and RNA-sequencing libraries. The libraries were sequenced on MiSeq, and the sequence data were analyzed using metagenome analysis tools. A mean of 2,041,216 total reads were sequenced for each library. Significant bacterial or viral sequencing reads were detected in eight of the 10 patients. Furthermore, candidate pathogens were detected in three patients in whom etiologic agents were not identified by conventional methods. The complete genome of enterovirus D68 was identified in two patients, and phylogenetic analysis suggested that both strains belong to subclade B3, which is an epidemic strain that has spread worldwide in recent years. Our results suggest that NGS can be applied for comprehensive molecular diagnostics as well as surveillance of pathogens in BALF from patients with respiratory infection.
αGlcNAc and its catalyst α4GnT are diagnostic and prognostic markers in uterine cervical tumor, gastric type
Authors: Ida Koichi , Yamanoi Kazuhiro , Asaka Shiho , Takeuchi Hodaka , Miyamoto Tsutomu , Shiozawa Tanri , Nakayama Jun
Published: September 2019

Cervical adenocarcinoma, gastric type (GAS) is not associated with human papilloma virus (HPV) infection. GAS patients prognoses are significantly worse compared with cervical adenocarcinoma associated with HPV infection, as their tumors exhibit resistance to conventional chemotherapy and radiotherapy. GAS is often associated with lobular endocervical glandular hyperplasia (LEGH), which is regarded as a precursor to GAS in the latest WHO classification. Recently, we reported that a decrease in expression of terminal α1,4-linked N-acetylglucosamine (αGlcNAc) relative to that of MUC6 was already apparent in atypical LEGH in the LEGH-GAS sequence. Here, we analyzed expression of α1,4-N-acetylglucosaminyltransferase (α4GnT), the sole enzyme catalyzing αGlcNAc biosynthesis, and that of αGlcNAc and MUC6 in cases representing non-neoplastic endocervical gland (NNEG) (11 cases), LEGH (26 cases) and GAS (12 cases). α4GnT protein was detected in a “dot-like” pattern, indicating localization in the Golgi apparatus in all 26 LEGH cases and 5 of 12 GAS cases. α4GnT- and αGlcNAc-positive cells largely overlapped, suggesting that α4GnT gene expression regulates αGlcNAc biosynthesis. Interestingly, all NNEG cases were negative for α4GnT and αGlcNAc expression, but 7 of 11 NNEG and all LEGH cases were MUC6-positive. In GAS cases, patients whose tumors were α4GnT- and αGlcNAc-positive had more favorable prognosis than others. Multivariate analysis revealed that positive expressions of α4GnT and αGlcNAc were independent prognostic indicators. These results indicate that α4GnT and αGlcNAc could serve as useful markers not only to distinguish LEGH from NNEG but to evaluate prognoses of GAS patients.
Reduction of integrin alpha 4 activity through splice modulating antisense oligonucleotides
Authors: Aung-Htut May T. , Comerford Iain , Johnsen Russell , Foyle Kerrie , Fletcher Sue , Wilton Steve D.
Published: September 2019

With recent approvals of antisense oligonucleotides as therapeutics, there is an increasing interest in expanding the application of these compounds to many other diseases. Our laboratory focuses on developing therapeutic splice modulating antisense oligonucleotides to treat diseases potentially amendable to intervention during pre-mRNA processing, and here we report the use of oligomers to down-regulate integrin alpha 4 protein levels. Over one hundred antisense oligonucleotides were designed to induce skipping of individual exons of the ITGA4 transcript and thereby reducing protein expression. Integrin alpha 4-mediated activities were evaluated in human dermal fibroblasts and Jurkat cells, an immortalised human T lymphocyte cell line. Peptide conjugated phosphorodiamidate morpholino antisense oligomers targeting ITGA4 were also assessed for their effect in delaying disease progression in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. With the promising results in ameliorating disease progression, we are optimistic that the candidate oligomer may also be applicable to many other diseases associated with integrin alpha 4 mediated inflammation. This highly specific strategy to down-regulate protein expression through interfering with normal exon selection during pre-mRNA processing should be applicable to many other gene targets that undergo splicing during expression.
Role of mineral nutrition in alleviation of heat stress in cotton plants grown in glasshouse and field conditions
Authors: Sarwar Muhammad , Saleem Muhammad Farrukh , Ullah Najeeb , Ali Shafaqat , Rizwan Muhammad , Shahid Muhammad Rizwan , Alyemeni Mohammed Nasser , Alamri Saud A. , Ahmad Parvaiz
Published: September 2019

Coincidence of high temperature with terminal reproductive pheno-stages of cotton is chief constraint to achieve yield potential. This high temperature interfere plant defensive system, physiological process, water relations and lint yield production. In this study, we modulated the detrimental outcomes of heat stress on cotton through the foliar spray of nutrients. Cotton crop was exposed to sub-optimal and supra-optimal thermal regimes for a period of one week at squaring, flowering and boll formation stages under glass house and field conditions. Foliar spray of potassium (K-1.5%), zinc (Zn-0.2%) and boron (B-0.1%) were applied at three reproductive stages one day prior to expose high temperature regimes. High temperature increased lipid membrane damage through increased malondialdehyde (MDA) contents in cotton leaves. High temperature stress also reduced leaf chlorophyll contents, net photosynthetic rate, stomatal conductance, water potential, averaged boll weight (g) and seed cotton yield per plant. Various nutrients variably influenced growth and physiology of heat-stressed cotton plants. Zinc outclassed all other nutrients in increasing leaf SOD, CAT, POX, AsA, TPC activity, chlorophyll contents, net photosynthetic rate, stomatal conductance, water potential, boll weight and seed cotton yield per plant. For example, zinc improved seed cotton yield under supra-optimal thermal regime by 17% and under sub-optimal thermal regime by 12% of glasshouse study while 19% under high temperature sowing dates of field study than the water treated plants under the same temperatures. Conclusively, increasing intensities of temperature adversely affected the recorded responses of cotton and exogenous application of Zn efficaciously alleviated heat induced perturbations. Moreover, exogenous nutrients mediated upregulations in physiochemical attributes induced heat tolerance at morphological level.
Different role of the supplementary motor area and the insula between musicians and non-musicians in a controlled musical creativity task
Authors: de Aquino Marcella Pereira Barbosa , Verdejo-Román Juan , Pérez-García Miguel , Pérez-García Purificación
Published: September 2019

The ability to compose creative musical ideas depends on the cooperation of brain mechanisms involved in multiple processes, including controlled creative cognition, which is a type of creativity that has so far been poorly researched. Therefore, the objective of this study was to examine the brain evoked activations by using fMRI, in both musicians and non-musicians, during a general task of controlled musical creativity and its relationship with general creativity. Results revealed that during a rhythmic improvisation task, musicians show greater activation of the motor supplementary area, the anterior cingulate cortex, the dorsolateral prefrontal cortex, and the insula, along with greater deactivation of the default mode network in comparison with non-musicians. For the group of musicians, we also found a positive correlation between the time improvising and the activation of the supplementary motor area, whilst in the non-musicians group improvisation time correlated with the activation of the insula. The results found for the musicians support the notion that the supplementary motor area plays a role in the representation and execution of musical behaviour, while the results in non-musicians reveal the role of the insula in the processing of novel musical information.
Transgenerational Self-Reconstruction of Disrupted Chromatin Organization After Exposure To An Environmental Stressor in Mice
Authors: Diaz-Castillo Carlos , Chamorro-Garcia Raquel , Shioda Toshi , Blumberg Bruce
Published: September 2019

Exposure to environmental stressors is known to increase disease susceptibility in unexposed descendants in the absence of detectable genetic mutations. The mechanisms mediating environmentally-induced transgenerational disease susceptibility are poorly understood. We showed that great-great-grandsons of female mice exposed to tributyltin (TBT) throughout pregnancy and lactation were predisposed to obesity due to altered chromatin organization that subsequently biased DNA methylation and gene expression. Here we analyzed DNA methylomes and transcriptomes from tissues of animals ancestrally exposed to TBT spanning generations, sexes, ontogeny, and cell differentiation state. We found that TBT elicited concerted alterations in the expression of “chromatin organization” genes and inferred that TBT-disrupted chromatin organization might be able to self-reconstruct transgenerationally. We also found that the location of “chromatin organization” and “metabolic” genes is biased similarly in mouse and human genomes, suggesting that exposure to environmental stressors in different species could elicit similar phenotypic effects via self-reconstruction of disrupted chromatin organization.
Ex situ co culturing of the sea urchin, Mespilia globulus and the coral Acropora millepora enhances early post-settlement survivorship
Authors: Craggs Jamie , Guest James , Bulling Mark , Sweet Michael
Published: September 2019

Reef restoration efforts, utilising sexual coral propagation need up-scaling to have ecologically meaningful impact. Post-settlement survival bottlenecks, in part due to competitive benthic algae interactions should be addressed, to improve productivity for these initiatives. Sea urchins are keystone grazers in reef ecosystems, yet feeding behaviour of adults causes physical damage and mortality to developing coral spat. To investigate if microherbivory can be utilised for co-culture, we quantitatively assessed how varying densities of juvenile sea urchins Mespilia globulus (Linnaeus, 1758), reared alongside the coral Acropora millepora (Ehrenberg, 1834) effected survival and growth of coral recruits. Spawning of both species were induced ex situ. A comparison of A. millepora spat reared in three M. globulus densities (low 16.67 m−2, medium 37.50 m−2, high 75.00 m−2) and a non-grazed control indicated coral survival is significantly influenced by grazing activity (p < 0.001) and was highest in the highest density treatment (39.65 ± 10.88%, mean ± s.d). Urchin grazing also significantly (p < 0.001) influenced coral size (compared to non-grazing control), with colonies in the medium and high-densities growing the largest (21.13 ± 1.02 mm & 20.80 ± 0.82, mean ± s.e.m). Increased urchin density did however have a negative influence on urchin growth, a result of limited food availability.
Defining Dysbiosis for a Cluster of Chronic Diseases
Authors: Wilkins Lamont J. , Monga Manoj , Miller Aaron W.
Published: September 2019

The prevalence of many chronic diseases has increased over the last decades. It has been postulated that dysbiosis driven by environmental factors such as antibiotic use is shifting the microbiome in ways that increase inflammation and the onset of chronic disease. Dysbiosis can be defined through the loss or gain of bacteria that either promote health or disease, respectively. Here we use multiple independent datasets to determine the nature of dysbiosis for a cluster of chronic diseases that includes urinary stone disease (USD), obesity, diabetes, cardiovascular disease, and kidney disease, which often exist as co-morbidities. For all disease states, individuals exhibited a statistically significant association with antibiotics in the last year compared to healthy counterparts. There was also a statistically significant association between antibiotic use and gut microbiota composition. Furthermore, each disease state was associated with a loss of microbial diversity in the gut. Three genera,Bacteroides, Prevotella, andRuminococcus, were the most common dysbiotic taxa in terms of being enriched or depleted in disease populations and was driven in part by the diversity of operational taxonomic units (OTUs) within these genera. Results of the cross-sectional analysis suggest that antibiotic-driven loss of microbial diversity may increase the risk for chronic disease. However, longitudinal studies are needed to confirm the causative effect of diversity loss for chronic disease risk.
Propensity score-matching analysis comparing laparoscopic and open pancreaticoduodenectomy in elderly patients
Authors: Shin Heeji , Song Ki Byung , Kim Young Il , Lee Young-Joo , Hwang Dae Wook , Lee Jae Hoon , Shin Sang Hyun , Kwon Jaewoo , Alshammary Shadi , Park Guisuk , Park Yejong , Lee Seung Jae , Kim Song Cheol
Published: September 2019

There is little evidence on the safety and benefits of laparoscopic pancreaticoduodenectomy (LPD) in elderly patients; therefore, we evaluated the feasibility and efficacy of this procedure by comparing perioperative and oncological outcomes between LPD and open pancreaticoduodenectomy (OPD) in elderly patients. We retrospectively reviewed the data of 1,693 patients who underwent PD to manage periampullary tumours at a single institution between January 2014 and June 2017. Of these patients, 326 were elderly patients aged ≥70 years, with 56 patients allocated to the LPD group and 270 to the OPD group. One-to-one propensity score matching (56:56) was used to match the baseline characteristics of patients who underwent LPD and OPD. LPD was associated with significantly fewer clinically significant postoperative pancreatic fistulas (7.1% vs. 21.4%), fewer analgesic injections (10 vs. 15.6 times; p = 0.022), and longer operative time (321.8 vs. 268.5 minutes; p = 0.001) than OPD in elderly patients. There were no significant differences in 3-year overall and disease-free survival rates between the LPD and OPD groups. LPD had acceptable perioperative and oncological outcomes compared with OPD in elderly patients. LPD is a reliable treatment option for elderly patients with periampullary tumours.
Differentiating lung cancer and infection based on measurements of extracellular pH with acidoCEST MRI
Authors: Lindeman Leila R. , Jones Kyle M. , High Rachel A. , Howison Christine M. , Shubitz Lisa F. , Pagel Mark D.
Published: September 2019

Lung cancer diagnosis via imaging may be confounded by the presence of indolent infectious nodules in imaging studies. This issue is pervasive in the southwestern US where coccidioidomycosis (Valley Fever) is endemic. AcidoCEST MRI is a noninvasive imaging method that quantifies the extracellular pH (pHe) of tissues in vivo, allowing tumor acidosis to be used as a diagnostic biomarker. Using murine models of lung adenocarcinoma and coccidoidomycosis, we found that average lesion pHe differed significantly between tumors and granulomas. Our study shows that acidoCEST MRI is a promising tool for improving the specificity of lung cancer diagnosis.
European spiny lobster recovery from overfishing enhanced through active restocking in Fully Protected Areas
Authors: Cau Alessandro , Bellodi Andrea , Cannas Rita , Fois Maurizio , Guidetti Paolo , Moccia Davide , Porcu Cristina , Pusceddu Antonio , Follesa Maria C.
Published: September 2019

Fully protected areas (FPAs) help preserving biodiversity and reversing the global decline of fishery resources. Stocks of the European spiny lobster Palinurus elephas (Fabr. 1787), among the most precious gourmet seafood worldwide, are currently facing a dramatic decline. Previous attempts of recovery based on fishery restrictions or active post-larval restocking in marine reserves provided unsuccessful outcomes. Here we present results of a 5-year restocking program carried through a Collaborative Fishery Research (CFR) project, in three ad-hoc established FPAs replenished using below-legal size wild juveniles. Results showed that Catch per Unit Effort (CPUE) in terms of both density and biomass burst (by ca. 300–700%) just 2 years since FPAs establishment, regardless of location. We also report tangible spillover effects (ca. 30–50% increase in density and biomass CPUE outside the FPAs) by the end of the program. Data from a 15-years lasting monitoring of a pilot FPA established in 1998, where the restocking protocol was conducted and protection kept in force once restocking ceased, demonstrated the persistence in time of restocking’ benefits. We foster that creation of FPAs assisted with local restocking under oriented CFR programs can represent an option for the recovery of European spiny lobster stocks from overfishing.
Influence of upscaling on identification of reservoir fluid properties using seismic-scale elastic constants
Authors: Li Shengjie , Wang Daxing , Zhang Mengbo
Published: September 2019

Elastic constants derived from seismic-scale measurements are often used to infer subsurface petrophysical properties based on rock-physics relationships established from either theoretic model or core-scale measurements. However, the spatial heterogeneity of rock physical properties at the local scale has a significant impact on this relation. To understand this problem, we built a scaled physical model comprised of artificial porous layers with different pore fluids. After conducting a two-dimensional marine seismic survey over the physical model, the physical modeling data ware then used to retrieve the elastic constants of the layered package. The seismic-scale results reveal that the identification of reservoir fluid properties is improved using elastic constants that is more sensitive to pore fluid properties. The results of numerical simulations show that Lamé moduli provide more insight into rock properties and pore-fluid contents than P-wave impedances, and that the relationship between the upscaled elastic constants and the effective fluid bulk moduli at the seismic scale is usually not perfectly preserved at the reservoir scale. To interpret seismic-scale elastic constants for petrophysical properties, the rock physics relationship need to be carefully calibrated. The findings will help us understand the upscaling of rock-physics transform, which will improve the accuracy of geological property predictions from seismic-scale elastic constants.
Optofluidic lens based on electrowetting liquid piston
Authors: Li Lin-Yang , Yuan Rong-Ying , Wang Jin-Hui , Li Lei , Wang Qiong-Hua
Published: September 2019

The conventional electrowetting lens usually has one tunable liquid-liquid (L-L) interface. The shape of L-L interface is deformed to get variable focal length due to electrowetting effect. However, contact angle saturation of the L-L interface is an unavoidable problem which prevents focal length from further changing. Here, we demonstrate an optofluidic lens based on electrowetting liquid piston. The proposed lens has two connected chambers, the piston chamber and the lens chamber to form a closed-loop fluidic system. The electrowetting liquid piston can generate clockwise and counter-clockwise liquid flows, which can make the L-L interface convex and concave. To prove the concept, we fabricate an optofluidic device whose shortest negative and positive focal lengths are ~−17.9 mm and ~18 mm with 5 mm aperture, respectively. The proposed optofluidic lens has large tunable focal length range. Widespread application of such an adaptive lens is foreseeable.
Evaluation of polypyrrole-modified bioelectrodes in a chemical absorption-bioelectrochemical reduction integrated system for NO removal
Authors: Guo Tianjiao , Zhang Chunyan , Zhao Jingkai , Ma Cunhao , Li Sujing , Li Wei
Published: September 2019

A Chemical absorption-bioelectrochemical reduction (CABER) system is based on Chemical absorption-biological reduction (CABR) system, which aims at NO removal and has been studied in many of our previous works. In this paper, we applied polypyrrole (PPy) on the electrode of bioelectrochemical reactor (BER) of CABER system, which induced a much higher current density in the cyclic voltammetry (CV) curve for the electrode itself and better NO removal rate in the system. In addition, a Microbial Electrolysis Cell (MEC) is constructed to study its strengthening mechanism. Results shows that PPy-MEC has a greater Faraday efficiency and higher reduction rate of Fe(III)EDTA and Fe(II)EDTA-NO in the solution when compared to original Carbon MEC, which confirms the advantage of PPy-modified electrode(s) in the CABER system. The results of this study are reported for illustration of potential of CABER technology and design of low-cost high-efficiency NOx control equipment in the future.