bluuebunny/crossref_metadata_2025 huggingface dataset:
MET amplification and epithelial-to-mesenchymal transition exist as parallel resistance mechanisms in erlotinib-resistant, EGFR-mutated, NSCLC HCC827 cells
Authors: Jakobsen K R , Demuth C , Madsen A T , Hussmann D , Vad-Nielsen J , Nielsen A L , Sorensen B S
Published: April 2017

Although many epidermal growth factor receptor (EGFR)-mutated lung cancer patients initially benefit from the EGFR-inhibitor erlotinib, all acquire resistance. So far, several mechanisms implicated in resistance have been identified, but the existence of multiple resistance mechanisms in parallel have only been sparsely investigated. In this study, we investigated parallel resistance mechanisms acquired by HCC827, an EGFR-mutated adenocarcinoma cell line dependent on EGFR activity and sensitive to erlotinib. The cell line was treated with erlotinib by stepwise escalation of the drug-concentration and erlotinib-resistant (HCC827ER) cells created. HCC827ER cells depicted a mixed epithelial and mesenchymal phenotype. To clarify potential parallel resistance mechanisms, 14 resistant subclones were established by limited dilution. Interestingly, all HCC827ER subclones harbored either a MET-amplification (6/14) or underwent EMT (8/14), mechanisms both found in previous studies, but not in co-occurrence. Both subclone-types were resistant to erlotinib, but only MET-subclones responded to the MET-inhibitors crizotinib and capmatinib. EMT-subclones on the other hand had markedly increased FGFR1 expression and responded to the FGFR-inhibitor AZD4547, whereas MET-subclones did not. Monitoring gene expression through the development of HCC827ER revealed upregulation of FGFR1 expression as an early response to erlotinib. In addition, FGFR1 expression increased upon short-term erlotinib treatment (48 h) identifying a physiological role immediately after erlotinib exposure. The high FGFR1 expression seen in EMT-subclones was stable even after five passages without erlotinib. Here we show, that parallel resistance mechanisms appear during erlotinib-resistance development in EGFR-mutated NSCLC cells and highlight a role for FGFR1 expression changes as an early response to erlotinib as well as a bypass-signaling mechanism.
Characterizing rare fluctuations in soft particulate flows
Authors: Rahbari S.H.E. , Saberi A.A. , Park Hyunggyu , Vollmer J.
Published: April 2017

Soft particulate media include a wide range of systems involving athermal dissipative particles both in non-living and biological materials. Characterization of flows of particulate media is of great practical and theoretical importance. A fascinating feature of these systems is the existence of a critical rigidity transition in the dense regime dominated by highly intermittent fluctuations that severely affects the flow properties. Here, we unveil the underlying mechanisms of rare fluctuations in soft particulate flows. We find that rare fluctuations have different origins above and below the critical jamming density and become suppressed near the jamming transition. We then conjecture a time-independent local fluctuation relation, which we verify numerically, and that gives rise to an effective temperature. We discuss similarities and differences between our proposed effective temperature with the conventional kinetic temperature in the system by means of a universal scaling collapse.
Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma
Authors: Reuben Alexandre , Spencer Christine N. , Prieto Peter A. , Gopalakrishnan Vancheswaran , Reddy Sangeetha M. , Miller John P. , Mao Xizeng , De Macedo Mariana Petaccia , Chen Jiong , Song Xingzhi , Jiang Hong , Chen Pei-Ling , Beird Hannah C. , Garber Haven R. , Roh Whijae , Wani Khalida , Chen Eveline , Haymaker Cara , Forget Marie-Andrée , Little Latasha D. , Gumbs Curtis , Thornton Rebecca L. , Hudgens Courtney W. , Chen Wei-Shen , Austin-Breneman Jacob , Sloane Robert Szczepaniak , Nezi Luigi , Cogdill Alexandria P. , Bernatchez Chantale , Roszik Jason , Hwu Patrick , Woodman Scott E. , Chin Lynda , Tawbi Hussein , Davies Michael A. , Gershenwald Jeffrey E. , Amaria Rodabe N. , Glitza Isabella C. , Diab Adi , Patel Sapna P. , Hu Jianhua , Lee Jeffrey E. , Grimm Elizabeth A. , Tetzlaff Michael T. , Lazar Alexander J. , Wistuba Ignacio I. , Clise-Dwyer Karen , Carter Brett W. , Zhang Jianhua , Futreal P. Andrew , Sharma Padmanee , Allison James P. , Cooper Zachary A. , Wargo Jennifer A.
Published: April 2017

Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine.
Restoring heart function and electrical integrity: closing the circuit
Authors: Monteiro Luís Miguel , Vasques-Nóvoa Francisco , Ferreira Lino , Pinto-do-Ó Perpétua , Nascimento Diana Santos
Published: April 2017

Cardiovascular diseases are the main cause of death in the world and are often associated with the occurrence of arrhythmias due to disruption of myocardial electrical integrity. Pathologies involving dysfunction of the specialized cardiac excitatory/conductive tissue are also common and constitute an added source of morbidity and mortality since current standard therapies withstand a great number of limitations. As electrical integrity is essential for a well-functioning heart, innovative strategies have been bioengineered to improve heart conduction and/or promote myocardial repair, based on: (1) gene and/or cell delivery; or (2) conductive biomaterials as tools for cardiac tissue engineering. Herein we aim to review the state-of-art in the area, while briefly describing the biological principles underlying the heart electrical/conduction system and how this system can be disrupted in heart disease. Suggestions regarding targets for future studies are also presented.
Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120
Authors: Allsopp Rebecca C. , Dayl Sudad , Schmid Ralf , Evans Richard J.
Published: April 2017

The P2X7 receptor (P2X7R) for ATP is a therapeutic target for pathophysiological states including inflammation, pain management and epilepsy. This is facilitated by the predicted low side effect profile as the high concentrations of ATP required to activate the receptor are usually only found following cell damage/disease and so P2X7Rs respond to a “danger” signal and are not normally active. AZ10606120 is a selective antagonist for P2X7Rs (IC50 of ~10 nM) and ineffective at the P2X1R (at 10 μM). To determine the molecular basis of selectivity we generated a series of P2X7/1R chimeras and mutants. Two regions that are unique to the P2X7R, a loop insertion (residues 73–79) and threonine residues T90 and T94, are required for high affinity antagonist action. Point mutations ruled out an orthosteric antagonist site. Mutations and molecular modelling identified an allosteric binding site that forms at the subunit interface at the apex of the receptor. Molecular dynamics simulations indicated that unique P2X7R features regulate access of AZ10606120 to the allosteric site. The characterisation of the allosteric pocket provides a new and novel target for rational P2X7R drug development.
Elastic Anomaly and Polyamorphic Transition in (La, Ce)-based Bulk Metallic Glass under Pressure
Authors: Qi Xintong , Zou Yongtao , Wang Xuebing , Chen Ting , Welch David O. , Jiang Jianzhong , Li Baosheng
Published: April 2017

Pressure-induced polyamorphism in Ce-based metallic glass has attracted significant interest in condensed matter physics. In this paper, we discover that in association with the polyamorphism of La32Ce32Al16Ni5Cu15 bulk metallic glass, the acoustic velocities, measured up to 12.3 GPa using ultrasonic interferometry, exhibit velocity minima at 1.8 GPa for P wave and 3.2 GPa for S wave. The low and high density amorphous states are distinguished by their distinct pressure derivatives of the bulk and shear moduli. The elasticity, permanent densification, and polyamorphic transition are interpreted by the topological rearrangement of solute-centered clusters in medium-range order (MRO) mediated by the 4f electron delocalization of Ce under pressure. The precisely measured acoustic wave travel times which were used to derive the velocities and densities provided unprecedented data to document the evolution of the bulk and shear elastic moduli associated with a polyamorphic transition in La32Ce32Al16Ni5Cu15 bulk metallic glass and can shed new light on the mechanisms of polyamorphism and structural evolution in metallic glasses under pressure.
Aqueous Solution Chemistry of Ammonium Cation in the Auger Time Window
Authors: Hollas Daniel , Pohl Marvin N. , Seidel Robert , Aziz Emad F. , Slavíček Petr , Winter Bernd
Published: April 2017

We report on chemical reactions triggered by core-level ionization of ammonium ($${{\rm{NH}}}_{4}^{+}$$

NH

4

+

) cation in aqueous solution. Based on a combination of photoemission experiments from a liquid microjet and high-level ab initio simulations, we identified simultaneous single and double proton transfer occurring on a very short timescale spanned by the Auger-decay lifetime. Molecular dynamics simulations indicate that the proton transfer to a neighboring water molecule leads to essentially complete formation of H3O+ (aq) and core-ionized ammonia $${({{\rm{NH}}}_{3}^{+})}^{\ast }$$

(

NH

3

+

)

⁎

(aq) within the ~7 fs lifetime of the nitrogen 1s core hole. A second proton transfer leads to a transient structure with the proton shared between the remaining NH2 moiety and another water molecule in the hydration shell. These ultrafast proton transfers are stimulated by very strong hydrogen bonds between the ammonium cation and water. Experimentally, the proton transfer dynamics is identified from an emerging signal at the high-kinetic energy side of the Auger-electron spectrum in analogy to observations made for other hydrogen-bonded aqueous solutions. The present study represents the most pronounced charge separation observed upon core ionization in liquids so far.
Nanodiamonds as multi-purpose labels for microscopy
Authors: Hemelaar S. R. , de Boer P. , Chipaux M. , Zuidema W. , Hamoh T. , Martinez F. Perona , Nagl A. , Hoogenboom J. P. , Giepmans B. N. G. , Schirhagl R.
Published: April 2017

Nanodiamonds containing fluorescent nitrogen-vacancy centers are increasingly attracting interest for use as a probe in biological microscopy. This interest stems from (i) strong resistance to photobleaching allowing prolonged fluorescence observation times; (ii) the possibility to excite fluorescence using a focused electron beam (cathodoluminescence; CL) for high-resolution localization; and (iii) the potential use for nanoscale sensing. For all these schemes, the development of versatile molecular labeling using relatively small diamonds is essential. Here, we show the direct targeting of a biological molecule with nanodiamonds as small as 70 nm using a streptavidin conjugation and standard antibody labelling approach. We also show internalization of 40 nm sized nanodiamonds. The fluorescence from the nanodiamonds survives osmium-fixation and plastic embedding making them suited for correlative light and electron microscopy. We show that CL can be observed from epon-embedded nanodiamonds, while surface-exposed nanoparticles also stand out in secondary electron (SE) signal due to the exceptionally high diamond SE yield. Finally, we demonstrate the magnetic read-out using fluorescence from diamonds prior to embedding. Thus, our results firmly establish nanodiamonds containing nitrogen-vacancy centers as unique, versatile probes for combining and correlating different types of microscopy, from fluorescence imaging and magnetometry to ultrastructural investigation using electron microscopy.
IMGMD: A platform for the integration and standardisation of In silico Microbial Genome-scale Metabolic Models
Authors: Ye Chao , Xu Nan , Dong Chuan , Ye Yuannong , Zou Xuan , Chen Xiulai , Guo Fengbiao , Liu Liming
Published: April 2017

Genome-scale metabolic models (GSMMs) constitute a platform that combines genome sequences and detailed biochemical information to quantify microbial physiology at the system level. To improve the unity, integrity, correctness, and format of data in published GSMMs, a consensus IMGMD database was built in the LAMP (Linux + Apache + MySQL + PHP) system by integrating and standardizing 328 GSMMs constructed for 139 microorganisms. The IMGMD database can help microbial researchers download manually curated GSMMs, rapidly reconstruct standard GSMMs, design pathways, and identify metabolic targets for strategies on strain improvement. Moreover, the IMGMD database facilitates the integration of wet-lab and in silico data to gain an additional insight into microbial physiology. The IMGMD database is freely available, without any registration requirements, at http://imgmd.jiangnan.edu.cn/database.
Poynting vector analysis for wireless power transfer between magnetically coupled coils with different loads
Authors: Guo Yunsheng , Li Jiansheng , Hou Xiaojuan , Lv Xiaolong , Liang Hao , Zhou Ji , Wu Hongya
Published: April 2017

Wireless power transfer is a nonradiative type of transmission that is performed in the near-field region. In this region, the electromagnetic fields that are produced by both the transmitting and receiving coils are evanescent fields, which should not transmit energy. This then raises the question of how the energy can be transferred. Here we describe a theoretical study of the two evanescent field distributions at different terminal loads. It is shown that the essential principle of wireless energy transfer is the superposition of the two evanescent fields, and the resulting superimposed field is mediated through the terminal load. If the terminal load is either capacitive or inductive, then the superimposed field cannot transfer the energy because its Poynting vector is zero; in contrast, if the load is resistive, energy can then be conveyed from the transmitting coil to the receiving coil. The simulation results for the magnetic field distributions and the time-domain current waveforms agree very well with the results of the theoretical analysis. This work thus provides a comprehensive understanding of the energy transfer mechanism involved in the magnetic resonant coupling system.
Female rats with severe left ventricle volume overload exhibit more cardiac hypertrophy but fewer myocardial transcriptional changes than males
Authors: Beaumont Catherine , Walsh-Wilkinson Élisabeth , Drolet Marie-Claude , Roussel Élise , Arsenault Marie , Couet Jacques
Published: April 2017

Aortic valve regurgitation (AR) imposes a volume overload (VO) to the left ventricle (LV). Male rats with a pathological heart overload usually progress more quickly towards heart failure than females. We examined whether a sexual dimorphism exists in the myocardial transcriptional adaptations to AR. Adult Wistar male and female rats either underwent a sham operation or were induced with AR and then followed for 26 weeks. Female AR rats gained relatively more LV mass than males (75 vs. 42%). They had a similar increase in LV chamber dimensions compared to males but more wall thickening. On the other hand, fatty acid oxidation (FAO)-related LV enzyme activity was only decreased in AR males. The expression of genes encoding FAO-related enzymes was only reduced in AR males and not in females. A similar situation was observed for the expression of genes involved in mitochondrial biogenesis or function as well as for genes encoding for transcription factors implicated in the control of bioenergetics and mitochondrial function (Errα, Errγ or Pgc1α). Although females develop more LV hypertrophy from severe VO, their myocardial gene expression remains closer to normal. This could provide survival benefits for females with severe VO.
Exploring functions of long noncoding RNAs across multiple cancers through co-expression network
Authors: Li Suqing , Li Bin , Zheng Yuanting , Li Menglong , Shi Leming , Pu Xuemei
Published: April 2017

In contrast to protein-coding genes, long-noncoding RNAs (lncRNAs) are much less well understood, despite increasing evidence indicating a wide range of their biological functions, and possible roles in various cancers. Based on public RNA-seq datasets of four solid cancer types, we here utilize Weighted Correlation Network Analysis (WGCNA) to propose a strategy for exploring the functions of lncRNAs altered in more than two cancer types, which we call onco-lncRNAs. Results indicate that cancer-expressed lncRNAs show high tissue specificity and are weakly expressed, more so than protein-coding genes. Most of the 236 onco-lncRNAs we identified have not been reported to have associations with cancers before. Our analysis exploits co-expression network to reveal that onco-lncRNAs likely play key roles in the multistep development of human cancers, covering a wide range of functions in genome stability maintenance, signaling, cell adhesion and motility, morphogenesis, cell cycle, immune and inflammatory response. These observations contribute to a more comprehensive understanding of cancer-associated lncRNAs, while demonstrating a novel and efficient strategy for subsequent functional studies of lncRNAs.
Split-gated point-contact for electrostatic confinement of transport in MoS2/h-BN hybrid structures
Authors: Sharma Chithra H. , Thalakulam Madhu
Published: April 2017

Electrostatically defined nanoscale devices on two-dimensional semiconductor heterostructures are the building blocks of various quantum electrical circuits. Owing to its atomically flat interfaces and the inherent two-dimensional nature, van der Waals heterostructures hold the advantage of large-scale uniformity, flexibility and portability over the conventional bulk semiconductor heterostructures. In this letter we show the operation of a split-gate defined point contact device on a MoS2/h-BN heterostructure, the first step towards realizing electrostatically gated quantum circuits on van der Waals semiconductors. By controlling the voltage on the split-gate we are able to control and confine the electron flow in the device leading to the formation of the point contact. The formation of the point contact in our device is elucidated by the three characteristic regimes observed in the pinch-off curve; transport similar to the conventional FET, electrostatically confined transport and the tunneling dominated transport. We explore the role of the carrier concentration and the drain-source voltages on the pinch-off characteristics. We are able to tune the pinch-off characteristics by varying the back-gate voltage at temperatures ranging from 4 K to 300 K.
Significance of baseline and change in neutrophil-to-lymphocyte ratio in predicting prognosis: a retrospective analysis in advanced pancreatic ductal adenocarcinoma
Authors: Chen Yang , Yan Huan , Wang YanRong , Shi Yan , Dai GuangHai
Published: April 2017

The neutrophil-lymphocyte ratio (NLR) has been reported to be associated with prognosis in several cancers. The objective of our study was to evaluate the prognostic role of baseline NLR and change in NLR (ΔNLR) in advanced pancreatic cancer underwent chemotherapy. Between January 2010 and June 2015, 132 patients underwent chemotherapy were eligible for assessment. Based on our patients’ data, the cut-off value of NLR was 2.78 according to receiver operating characteristic curve. We observed that a high level of baseline NLR (NLR > 2.78) was a poor prognostic factor for overall survival (multivariable hazard ratio [HR] = 2.648, P < 0.001). Increased NLR (ΔNLR > 0) after 2 cycles of chemotherapy was associated with higher risk compared to ΔNLR ≤ 0 (multivariable HR = 1.894, P = 0.007). Combining both NLR and ΔNLR factors, multivariate analysis showed a significant higher risk (HR = 5.817, P < 0.001) for patients with high baseline NLR and increased NLR after 2 cycles of chemotherapy compared to patients with low baseline NLR and ΔNLR ≤ 0. In conclusion, both baseline NLR and ΔNLR are independent prognostic predictors for patients with advanced pancreatic cancer underwent chemotherapy.
Root anatomy and canal morphology of mandibular first premolars in a Chinese population
Authors: Dou Lei , Li Duojiao , Xu Tingting , Tang Yin , Yang Deqin
Published: April 2017

This study was to investigate root anatomy and root canal morphology of mandibular first premolars in a Chinese population. 178 human permanent mandibular first premolars extracted from a native Chinese population were collected, scanned using micro-computed tomography and reconstructed three-dimensionally. The number of roots and canals, canal configuration and radicular grooves were investigated. The root canal morphology was categorized according to Vertucci’s criteria. The radicular grooves were scored according to the Arizona State University dental anthropology scoring system (ASUDAS), and the correlation between scores for radicular grooves and root canal morphology was analyzed. Almost all the samples were single-rooted (99.4%). 64.04% of teeth possessed type I canal systems, whilst 34.27% had two canals and 1.69% had three canals. According to ASUDAS, the scores of radicualr grooves were 56.74%, 16.85%, 12.36%, 10.11%, 3.37% and 0.56% respectively from grade 0 to grade 5. The roots with radicular grooves (grade 3 or 4) were defined as Tome’s anomalous root and these roots have a high incidence of C-shape configurations (66.67%) and multiple-canal systems (100%). There is complicated variation of the root anatomy and canal morphology of mandibular first premolars in southwestern Chinese population, which needs special attention and careful assessment for endodontic treatment.
Comprehensive analysis of the association between UBAC2 polymorphisms and Behçet’s disease in a Japanese population
Authors: Yamazoe Kyoko , Meguro Akira , Takeuchi Masaki , Shibuya Etsuko , Ohno Shigeaki , Mizuki Nobuhisa
Published: April 2017

Behçet’s disease (BD) is reportedly associated with polymorphisms of the ubiquitin-associated domain containing 2 (UBAC2) gene in Turkish, Italian, and Chinese populations. Here we investigated whether UBAC2 polymorphisms were associated with BD in a Japanese population. Using data from 611 Japanese BD patients and 737 Japanese controls who participated in our previous genome-wide association study, we analyzed the 58 genotyped single-nucleotide polymorphisms (SNPs) in the region 100 kb upstream and downstream of UBAC2. We also performed imputation analysis in the region, with 562 imputed SNPs included in the statistical analyses. Association testing revealed that the T allele of rs9517723 in the lncRNA LOC107984558 was significantly associated with ocular and central nervous system (CNS) lesions and showed the strongest association under the recessive model (TT vs. CT+CC: ocular lesion, Pc = 0.0099, OR = 1.56; CNS lesion, Pc = 0.0052, OR = 3.42). Expression analysis revealed that rs9517723 TT homozygotes showed significantly increased UBAC2 expression (P < 0.05). Our findings suggest that enhanced UBAC2 expression associated with the homozygous risk allele (TT) of rs9517723 could induce overactivation of ubiquitination-related pathway, resulting in the development of ocular and CNS lesions in BD.
Chromosomal breaks at FRA18C: association with reduced DOK6 expression, altered oncogenic signaling and increased gastric cancer survival
Authors: Leong Siew Hong , Lwin Kyaw Myo , Lee Sze Sing , Ng Wai Har , Ng Kia Min , Tan Soo Yong , Ng Bee Ling , Carter Nigel P. , Tang Carol , Lian Kon Oi
Published: April 2017

Chromosomal rearrangements are common in cancer. More than 50% occur in common fragile sites and disrupt tumor suppressors. However, such rearrangements are not known in gastric cancer. Here we report recurrent 18q2 breakpoints in 6 of 17 gastric cancer cell lines. The rearranged chromosome 18, t(9;18), in MKN7 cells was flow sorted and identified by reverse chromosome painting. High-resolution tiling array hybridization mapped breakpoints to DOK6 (docking protein 6) intron 4 in FRA18C (18q22.2) and an intergenic region in 9q22.2. The same rearrangement was detected by FISH in 22% of 99 primary gastric cancers. Intron 4 truncation was associated with reduced DOK6 transcription. Analysis of The Cancer Genome Atlas stomach adenocarcinoma cohort showed significant correlation of DOK6 expression with histological and molecular phenotypes. Multiple oncogenic signaling pathways (gastrin-CREB, NGF-neurotrophin, PDGF, EGFR, ERK, ERBB4, FGFR1, RAS, VEGFR2 and RAF/MAP kinase) known to be active in aggressive gastric cancers were strikingly diminished in gastric cancers with low DOK6 expression. Median survival of patients with low DOK6-expressing tumors was 2100 days compared with 533 days in patients with high DOK6-expressing tumors (log-rank P = 0.0027). The level of DOK6 expression in tumors predicted patient survival independent of TNM stage. These findings point to new functions of human DOK6 as an adaptor that interacts with diverse molecular components of signaling pathways. Our data suggest that DOK6 expression is an integrated biomarker of multiple oncogenic signals in gastric cancer and identify FRA18C as a new cancer-associated fragile site.
Multi-compartment encapsulation of communicating droplets and droplet networks in hydrogel as a model for artificial cells
Authors: Bayoumi Mariam , Bayley Hagan , Maglia Giovanni , Sapra K. Tanuj
Published: April 2017

Constructing a cell mimic is a major challenge posed by synthetic biologists. Efforts to this end have been primarily focused on lipid- and polymer-encapsulated containers, liposomes and polymersomes, respectively. Here, we introduce a multi-compartment, nested system comprising aqueous droplets stabilized in an oil/lipid mixture, all encapsulated in hydrogel. Functional capabilities (electrical and chemical communication) were imparted by protein nanopores spanning the lipid bilayer formed at the interface of the encapsulated aqueous droplets and the encasing hydrogel. Crucially, the compartmentalization enabled the formation of two adjoining lipid bilayers in a controlled manner, a requirement for the realization of a functional protocell or prototissue.
Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells
Authors: Fontes-Oliveira Cibely C. , Steinz Maarten , Schneiderat Peter , Mulder Hindrik , Durbeej Madeleine
Published: April 2017

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients.
High-resolution RNA allelotyping along the inactive X chromosome: evidence of RNA polymerase III in regulating chromatin configuration
Authors: Hong Ru , Lin Bingqing , Lu Xinyi , Lai Lan-Tian , Chen Xin , Sanyal Amartya , Ng Huck-Hui , Zhang Kun , Zhang Li-Feng
Published: April 2017

We carried out padlock capture, a high-resolution RNA allelotyping method, to study X chromosome inactivation (XCI). We examined the gene reactivation pattern along the inactive X (Xi), after Xist (X-inactive specific transcript), a prototype long non-coding RNA essential for establishing X chromosome inactivation (XCI) in early embryos, is conditionally deleted from Xi in somatic cells (Xi∆Xist). We also monitored the behaviors of X-linked non-coding transcripts before and after XCI. In each mutant cell line, gene reactivation occurs to ~6% genes along Xi∆Xist in a recognizable pattern. Genes with upstream regions enriched for SINEs are prone to be reactivated. SINE is a class of retrotransposon transcribed by RNA polymerase III (Pol III). Intriguingly, a significant fraction of Pol III transcription from non-coding regions is not subjected to Xist-mediated transcriptional silencing. Pol III inhibition affects gene reactivation status along Xi∆Xist, alters chromatin configuration and interferes with the establishment XCI during in vitro differentiation of ES cells. These results suggest that Pol III transcription is involved in chromatin structure re-organization during the onset of XCI and functions as a general mechanism regulating chromatin configuration in mammalian cells.
Use of 3D faces facilitates facial expression recognition in children
Authors: Wang Lamei , Chen Wenfeng , Li Hong
Published: April 2017

This study assessed whether presenting 3D face stimuli could facilitate children’s facial expression recognition. Seventy-one children aged between 3 and 6 participated in the study. Their task was to judge whether a face presented in each trial showed a happy or fearful expression. Half of the face stimuli were shown with 3D representations, whereas the other half of the images were shown as 2D pictures. We compared expression recognition under these conditions. The results showed that the use of 3D faces improved the speed of facial expression recognition in both boys and girls. Moreover, 3D faces improved boys’ recognition accuracy for fearful expressions. Since fear is the most difficult facial expression for children to recognize, the facilitation effect of 3D faces has important practical implications for children with difficulties in facial expression recognition. The potential benefits of 3D representation for other expressions also have implications for developing more realistic assessments of children’s expression recognition.
Oil adsorption ability of three-dimensional epicuticular wax coverages in plants
Authors: Gorb Elena V. , Hofmann Philipp , Filippov Alexander E. , Gorb Stanislav N.
Published: April 2017

Primary aerial surfaces of terrestrial plants are very often covered with three-dimensional epicuticular waxes. Such wax coverages play an important role in insect-plant interactions. Wax blooms have been experimentally shown in numerous previous studies to be impeding locomotion and reducing attachment of insects. Among the mechanisms responsible for these effects, a possible adsorption of insect adhesive fluid by highly porous wax coverage has been proposed (adsorption hypothesis). Recently, a great decrease in insect attachment force on artificial adsorbing materials was revealed in a few studies. However, adsorption ability of plant wax blooms was still not tested. Using a cryo scanning electron microscopy approach and high-speed video recordings of fluid drops behavior, followed by numerical analysis of experimental data, we show here that the three-dimensional epicuticular wax coverage in the waxy zone of Nepenthes alata pitcher adsorbs oil: we detected changes in the base, height, and volume of the oil drops. The wax layer thickness, differing in samples with untreated two-layered wax coverage and treated one-layered wax, did not significantly affect the drop behavior. These results provide strong evidence that three-dimensional plant wax coverages due to their adsorption capability are in general anti-adhesive for insects, which rely on wet adhesion.
CNT-based saturable absorbers with scalable modulation depth for Thulium-doped fiber lasers operating at 1.9 μm
Authors: Sobon Grzegorz , Duzynska Anna , Świniarski Michał , Judek Jarosław , Sotor Jarosław , Zdrojek Mariusz
Published: April 2017

In this work, we demonstrate a comprehensive study on the nonlinear parameters of carbon nanotube (CNT) saturable absorbers (SA) as a function of the nanotube film thickness. We have fabricated a set of four saturable absorbers with different CNT thickness, ranging from 50 to 200 nm. The CNTs were fabricated via a vacuum filtration technique and deposited on fiber connector end facets. Each SA was characterized in terms of nonlinear transmittance (i.e. optical modulation depth) and tested in a Thulium-doped fiber laser. We show, that increasing the thickness of the CNT layer significantly increases the modulation depth (up to 17.3% with 200 nm thick layer), which strongly influences the central wavelength of the laser, but moderately affects the pulse duration. It means, that choosing the SA with defined CNT thickness might be an efficient method for wavelength-tuning of the laser, without degrading the pulse duration. In our setup, the best performance in terms of bandwidth and pulse duration (8.5 nm and 501 fs, respectively) were obtained with 100 nm thick CNT layer. This is also, to our knowledge, the first demonstration of a fully polarization-maintaining mode-locked Tm-doped laser based on CNT saturable absorber.
Higher glomerular filtration rate is related to insulin resistance but not to obesity in a predominantly obese non-diabetic cohort
Authors: Naderpoor Negar , Lyons Jasmine G. , Mousa Aya , Ranasinha Sanjeeva , de Courten Maximilian P. J. , Soldatos Georgia , de Courten Barbora
Published: April 2017

Glomerular hyperfiltration has been associated with obesity, insulin resistance, and systolic blood pressure (SBP). However, previous studies are limited by confounders such as pre-existing diabetes or hypertension, or have used indirect measures of adiposity and insulin sensitivity (IS). Therefore, we examined the relationship between estimated glomerular filtration rate (eGFR) and IS measured by the hyperinsulinaemic euglycaemic clamp in a healthy population on no medications. We performed oral glucose tolerance test (OGTT) and measured % body fat (DEXA), BMI, blood pressure and M-value (hyperinsulinaemic euglycaemic clamp) in 104 individuals (44 females and 60 males). The majority of the study population (n = 89, 85.6%) were classified on their BMI as overweight/obese. eGFR was related to age, BMI, M-value (IS), 2-hour glucose levels post OGTT and white blood cell count (WBC) (all p < 0.05); but not to SBP (p = 0.1) or fasting glucose levels (p = 0.2). After adjustment for gender, BMI, SBP and WBC, the inverse association between eGFR and M-value (p = 0.001), and 2-hour glucose post OGTT (p = 0.02) persisted. In conclusion, although eGFR has been associated with BMI and blood pressure in previous studies, in our healthy population, eGFR was more closely related to markers of glucose metabolism (IS and 2-hour glucose post OGTT) than to BMI and blood pressure.
Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction
Authors: Suzuki Jun , Hashimoto Ken , Xiao Ru , Vandenberghe Luk H. , Liberman M. Charles
Published: April 2017

The use of viral vectors for inner ear gene therapy is receiving increased attention for treatment of genetic hearing disorders. Most animal studies to date have injected viral suspensions into neonatal ears, via the round window membrane. Achieving transduction of hair cells, or sensory neurons, throughout the cochlea has proven difficult, and no studies have been able to efficiently transduce sensory cells in adult ears while maintaining normal cochlear function. Here, we show, for the first time, successful transduction of all inner hair cells and the majority of outer hair cells in an adult cochlea via virus injection into the posterior semicircular canal. We used a “designer” AAV, AAV2/Anc80L65, in which the main capsid proteins approximate the ancestral sequence state of AAV1, 2, 8, and 9. Our injections also transduced ~10% of spiral ganglion cells and a much larger fraction of their satellite cells. In the vestibular sensory epithelia, the virus transduced large numbers of hair cells and virtually all the supporting cells, along with close to half of the vestibular ganglion cells. We conclude that this viral vector and this delivery route hold great promise for gene therapy applications in both cochlear and vestibular sense organs.
Validation of a smartphone-based EEG among people with epilepsy: A prospective study
Authors: McKenzie Erica D. , Lim Andrew S. P. , Leung Edward C. W. , Cole Andrew J. , Lam Alice D. , Eloyan Ani , Nirola Damber K. , Tshering Lhab , Thibert Ronald , Garcia Rodrigo Zepeda , Bui Esther , Deki Sonam , Lee Liesly , Clark Sarah J. , Cohen Joseph M. , Mantia Jo , Brizzi Kate T. , Sorets Tali R. , Wahlster Sarah , Borzello Mia , Stopczynski Arkadiusz , Cash Sydney S. , Mateen Farrah J.
Published: April 2017

Our objective was to assess the ability of a smartphone-based electroencephalography (EEG) application, the Smartphone Brain Scanner-2 (SBS2), to detect epileptiform abnormalities compared to standard clinical EEG. The SBS2 system consists of an Android tablet wirelessly connected to a 14-electrode EasyCap headset (cost ~ 300 USD). SBS2 and standard EEG were performed in people with suspected epilepsy in Bhutan (2014–2015), and recordings were interpreted by neurologists. Among 205 participants (54% female, median age 24 years), epileptiform discharges were detected on 14% of SBS2 and 25% of standard EEGs. The SBS2 had 39.2% sensitivity (95% confidence interval (CI) 25.8%, 53.9%) and 94.8% specificity (95% CI 90.0%, 97.7%) for epileptiform discharges with positive and negative predictive values of 0.71 (95% CI 0.51, 0.87) and 0.82 (95% CI 0.76, 0.89) respectively. 31% of focal and 82% of generalized abnormalities were identified on SBS2 recordings. Cohen’s kappa (κ) for the SBS2 EEG and standard EEG for the epileptiform versus non-epileptiform outcome was κ = 0.40 (95% CI 0.25, 0.55). No safety or tolerability concerns were reported. Despite limitations in sensitivity, the SBS2 may become a viable supportive test for the capture of epileptiform abnormalities, and extend EEG access to new, especially resource-limited, populations at a reduced cost.
Chemical and Bandgap Engineering in Monolayer Hexagonal Boron Nitride
Authors: Ba Kun , Jiang Wei , Cheng Jingxin , Bao Jingxian , Xuan Ningning , Sun Yangye , Liu Bing , Xie Aozhen , Wu Shiwei , Sun Zhengzong
Published: April 2017

Monolayer hexagonal boron nitride (h-BN) possesses a wide bandgap of ~6 eV. Trimming down the bandgap is technically attractive, yet poses remarkable challenges in chemistry. One strategy is to topological reform the h-BN’s hexagonal structure, which involves defects or grain boundaries (GBs) engineering in the basal plane. The other way is to invite foreign atoms, such as carbon, to forge bizarre hybrid structures like hetero-junctions or semiconducting h-BNC materials. Here we successfully developed a general chemical method to synthesize these different h-BN derivatives, showcasing how the chemical structure can be manipulated with or without a graphene precursor, and the bandgap be tuned to ~2 eV, only one third of the pristine one’s.
A furoviral replicase recruits host HSP70 to membranes for viral RNA replication
Authors: Yang Jian , Zhang Fen , Cai Nian-Jun , Wu Ne , Chen Xuan , Li Jing , Meng Xiang-Feng , Zhu Tong-Quan , Chen Jian-Ping , Zhang Heng-Mu
Published: April 2017

Many host factors have been identified to be involved in viral infection. However, although furoviruses cause important diseases of cereals worldwide, no host factors have yet been identified that interact with furoviral genes or participate in the viral infection cycle. In this study, both TaHSP70 and NbHSP70 were up-regulated in Chinese wheat mosaic furovirus (CWMV)-infected plants. Their overexpression and inhibition were correlated with the accumulation of viral genomic RNAs, suggesting that the HSP70 genes could be necessary for CWMV infection. The subcellular distributions of TaHSP70 and NbHSP70 were significantly affected by CWMV infection or by infiltration of RNA1 alone. Further assays showed that the viral replicase encoded by CWMV RNA1 interacts with both TaHSP70 and NbHSP70 in vivo and vitro and that its region aa167–333 was responsible for the interaction. Subcellular assays showed that the viral replicase could recruit both TaHSP70 and NbHSP70 from the cytoplasm or nucleus to the granular aggregations or inclusion-like structures on the intracellular membrane system, suggesting that both HSP70s may be recruited into the viral replication complex (VRC) to promote furoviral replication. This is the first host factor identified to be involved in furoviral infection, which extends the list and functional scope of HSP70 chaperones.
Polymorphisms of STS gene and SULT2A1 gene and neurosteroid levels in Han Chinese boys with attention-deficit/hyperactivity disorder: an exploratory investigation
Authors: Wang Liang-Jen , Chan Wen-Ching , Chou Miao-Chun , Chou Wen-Jiun , Lee Min-Jing , Lee Sheng-Yu , Lin Pao-Yen , Yang Yi-Hsin , Yen Cheng-Fang
Published: April 2017

This study examined the relationships among polymorphisms of the STS gene and SULT2A1 gene, dehydroepiandrosterone (DHEA) and its sulfated form (DHEA-S), and characteristics of attention-deficit/hyperactivity disorder (ADHD). We used cheek swabs to obtain the genomic DNA of 200 ADHD male probands (mean age: 8.7 years), 192 patients’ mothers and 157 patients’ fathers. Three SNPs in the STS gene (rs6639786, rs2270112, and rs17268988) and one SNP in the SULT2A1 gene (rs182420) were genotyped. Saliva samples were collected from the ADHD patients to analyze DHEA and DHEA-S levels. The behavioral symptoms were evaluated with the Swanson, Nolan, and Pelham, and Version IV Scale for ADHD (SNAP-IV), and the neuropsychological function was assessed using the Conners’ Continuous Performance Tests (CPT). We found the C allele of rs2270112 within the STS gene to be over-transmitted in males with ADHD. Polymorphisms of rs182420 within the SULT2A1 gene were not associated with ADHD. In addition, the C allele carriers of rs2270112 demonstrated significantly higher DHEA-S levels than the G allele carriers. Levels of DHEA were positively correlated with attention as measured by the CPT. These findings support a potential role in the underlying biological pathogenesis of ADHD with regard to STS polymorphisms and neurosteroid levels.
Successful lichen translocation on disturbed gypsum areas: A test with adhesives to promote the recovery of biological soil crusts
Authors: Ballesteros M. , Ayerbe J. , Casares M. , Cañadas E. M. , Lorite J.
Published: April 2017

The loss of biological soil crusts represents a challenge for the restoration of disturbed environments, specifically in particular substrates hosting unique lichen communities. However, the recovery of lichen species affected by mining is rarely addressed in restoration projects. Here, we evaluate the translocation of Diploschistes diacapsis, a representative species of gypsum lichen communities affected by quarrying. We tested how a selection of adhesives could improve thallus attachment to the substrate and affect lichen vitality (as CO2 exchange and fluorescence) in rainfall-simulation and field experiments. Treatments included: white glue, water, hydroseeding stabiliser, gum arabic, synthetic resin, and a control with no adhesive. Attachment differed only in the field, where white glue and water performed best. Adhesives altered CO2 exchange and fluorescence yield. Notably, wet spoils allowed thalli to bind to the substrate after drying, revealing as the most suitable option for translocation. The satisfactory results applying water on gypsum spoils are encouraging to test this methodology with other lichen species. Implementing these measures in restoration projects would be relatively easy and cost-effective. It would help not only to recover lichen species in the disturbed areas but also to take advantage of an extremely valuable biological material that otherwise would be lost.
Nitrous Oxide Production in a Granule-based Partial Nitritation Reactor: A Model-based Evaluation
Authors: Peng Lai , Sun Jing , Liu Yiwen , Dai Xiaohu , Ni Bing-Jie
Published: April 2017

Sustainable wastewater treatment has been attracting increasing attentions over the past decades. However, the production of nitrous oxide (N2O), a potent GHG, from the energy-efficient granule-based autotrophic nitrogen removal is largely unknown. This study applied a previously established N2O model, which incorporated two N2O production pathways by ammonia-oxidizing bacteria (AOB) (AOB denitrification and the hydroxylamine (NH2OH) oxidation). The two-pathway model was used to describe N2O production from a granule-based partial nitritation (PN) reactor and provide insights into the N2O distribution inside granules. The model was evaluated by comparing simulation results with N2O monitoring profiles as well as isotopic measurement data from the PN reactor. The model demonstrated its good predictive ability against N2O dynamics and provided useful information about the shift of N2O production pathways inside granules for the first time. The simulation results indicated that the increase of oxygen concentration and granule size would significantly enhance N2O production. The results further revealed a linear relationship between N2O production and ammonia oxidation rate (AOR) (R2 = 0.99) under the conditions of varying oxygen levels and granule diameters, suggesting that bulk oxygen and granule size may exert an indirect effect on N2O production by causing a change in AOR.
Present-day heat flow model of Mars
Authors: Parro Laura M. , Jiménez-Díaz Alberto , Mansilla Federico , Ruiz Javier
Published: April 2017

Until the acquisition of in-situ measurements, the study of the present-day heat flow of Mars must rely on indirect methods, mainly based on the relation between the thermal state of the lithosphere and its mechanical strength, or on theoretical models of internal evolution. Here, we present a first-order global model for the present-day surface heat flow for Mars, based on the radiogenic heat production of the crust and mantle, on scaling of heat flow variations arising from crustal thickness and topography variations, and on the heat flow derived from the effective elastic thickness of the lithosphere beneath the North Polar Region. Our preferred model finds heat flows varying between 14 and 25 mW m−2, with an average value of 19 mW m−2. Similar results (although about ten percent higher) are obtained if we use heat flow based on the lithospheric strength of the South Polar Region. Moreover, expressing our results in terms of the Urey ratio (the ratio between total internal heat production and total heat loss through the surface), we estimate values close to 0.7–0.75, which indicates a moderate contribution of secular cooling to the heat flow of Mars (consistent with the low heat flow values deduced from lithosphere strength), unless heat-producing elements abundances for Mars are subchondritic.