bluuebunny/crossref_metadata_2025 huggingface dataset:
NEDDylation promotes stress granule assembly
Authors: Jayabalan Aravinth Kumar , Sanchez Anthony , Park Ra Young , Yoon Sang Pil , Kang Gum-Yong , Baek Je-Hyun , Anderson Paul , Kee Younghoon , Ohn Takbum
Published: July 2016

Stress granules (SGs) harbour translationally stalled messenger ribonucleoproteins and play important roles in regulating gene expression and cell fate. Here we show that neddylation promotes SG assembly in response to arsenite-induced oxidative stress. Inhibition or depletion of key components of the neddylation machinery concomitantly inhibits stress-induced polysome disassembly and SG assembly. Affinity purification and subsequent mass-spectrometric analysis of Nedd8-conjugated proteins from translationally stalled ribosomal fractions identified ribosomal proteins, translation factors and RNA-binding proteins (RBPs), including SRSF3, a previously known SG regulator. We show that SRSF3 is selectively neddylated at Lys85 in response to arsenite. A non-neddylatable SRSF3 (K85R) mutant do not prevent arsenite-induced polysome disassembly, but fails to support the SG assembly, suggesting that the neddylation pathway plays an important role in SG assembly.
Envelope-specific B-cell populations in African green monkeys chronically infected with simian immunodeficiency virus
Authors: Zhang Ruijun , Martinez David R. , Nguyen Quang N. , Pollara Justin , Arifin Trina , Stolarchuk Christina , Foulger Andrew , Amos Josh D. , Parks Robert , Himes Jonathon E. , Wang Minyue , Edwards Regina W. , Trama Ashley M. , Vandergrift Nathan , Colvin Lisa , Dewar Ken , Juretic Nikoleta , Wasserscheid Jessica , Ferrari Guido , Liao Hua-Xin , Permar Sallie R.
Published: July 2016

African green monkeys (AGMs) are natural primate hosts of simian immunodeficiency virus (SIV). Interestingly, features of the envelope-specific antibody responses in SIV-infected AGMs are distinct from that of HIV-infected humans and SIV-infected rhesus monkeys, including gp120-focused responses and rapid development of autologous neutralization. Yet, the lack of genetic tools to evaluate B-cell lineages hinders potential use of this unique non-human primate model for HIV vaccine development. Here we define features of the AGM Ig loci and compare the proportion of Env-specific memory B-cell populations to that of HIV-infected humans and SIV-infected rhesus monkeys. AGMs appear to have a higher proportion of Env-specific memory B cells that are mainly gp120 directed. Furthermore, AGM gp120-specific monoclonal antibodies display robust antibody-dependent cellular cytotoxicity and CD4-dependent virion capture activity. Our results support the use of AGMs to model induction of functional gp120-specific antibodies by HIV vaccine strategies.
Synthetic hydrogel supports the function and regeneration of artificial ovarian tissue in mice
Authors: Kim Jiwon , Perez Amanda S , Claflin Jake , David Anu , Zhou Hong , Shikanov Ariella
Published: July 2016

Many prepubertal girls and young women suffer from premature ovarian insufficiency induced by chemotherapy given for treatment of cancer and autoimmune diseases. Autotransplantation of cryopreserved ovarian tissue could restore the lost ovarian endocrine function and fertility. Unfortunately, tissue ischemia, inconsistent graft quality and the risk of reintroducing malignant cells may stand in the way of the clinical translation of this approach. To address these risks and limitations, we engineered an artificial ovarian tissue from immature follicles using a synthetic hydrogel, poly(ethylene glycol) vinyl sulfone (PEG-VS), as a supportive matrix. Enzymatically isolated follicles from 6–7-day-old mice ovaries were encapsulated in 7% PEG-VS hydrogels modified with 0.5 mmol/l RGD and crosslinked with a trifunctional matrix metalloproteinase-sensitive peptide. PEG hydrogels with the encapsulated follicles were orthotopically implanted into ovariectomised mice to investigate whether PEG hydrogel supports folliculogenesis and steroidogenesis in vivo. After 30 days, grafts revealed multiple fully developed antral follicles and corpora lutea, which corresponded with regular ovulation cycles and follicle-stimulating hormone (FSH) levels. The elevated levels of FSH, caused by bilateral ovariectomy, were reversed by the implanted follicles and maintained at physiological levels for 60 days. Importantly, primordial and primary follicles still represented 60% of the follicular pool, demonstrating selective recruitment of primordial follicles into the growing pool. Functioning blood vessels in the grafts 30 and 60 days after implantation proved the capability of PEG hydrogels to undergo graft remodelling and revascularisation. Our results demonstrate that PEG hydrogels with encapsulated immature ovarian follicles successfully functioned as an artificial ovarian tissue for 60 days in vivo.
Upregulation of MicroRNA-214 Contributes to the Development of Vascular Remodeling in Hypoxia-induced Pulmonary Hypertension Via Targeting CCNL2
Authors: Liu HaiTao , Tao Yin , Chen Mai , Yu Jin , Li Wei-Jie , Tao Ling , Li Yan , Li Fei
Published: July 2016

Hypoxia-induced pulmonary hypertension (PH), which is characterized by vascular remodeling of blood vessels, is a significant complication of chronic obstructive pulmonary disease (COPD). In this study, we screened 13 candidate miRNAs in pulmonary artery smooth muscle cells (PASMCs) harvested from COPD patients with PH (n = 18) and normal controls (n = 15) and found that the expression of miR-214 was differentially expressed between these two groups. Additionally, cyclin L2 (CCNL2) was validated as a target of miR-214 in PASMCs using a luciferase assay. Based on real-time PCR, immunohistochemistry and western blot, the expression of CCNL2 was substantially downregulated in PASMCs from COPD patients with PH compared with those from normal controls. Moreover, the relationship between miRNA and mRNA expression was confirmed using real-time PCR and western blot in PASMCs transfected with miR-214 mimics. Furthermore, the introduction of miR-214 significantly promoted the proliferation of PASMCs by suppressing cell apoptosis and this effect was mediated by the downregulation of CCNL2. Exposure of PASMCs to hypoxia significantly increased the expression of miR-214, decreased the expression of CCNL2 and promoted cell proliferation. However, these effects were significantly attenuated by the introduction of miR-214 inhibitors, which significantly downregulated miR-214 expression and upregulated CCNL2 expression.
Noble metal-free bifunctional oxygen evolution and oxygen reduction acidic media electro-catalysts
Authors: Patel Prasad Prakash , Datta Moni Kanchan , Velikokhatnyi Oleg I. , Kuruba Ramalinga , Damodaran Krishnan , Jampani Prashanth , Gattu Bharat , Shanthi Pavithra Murugavel , Damle Sameer S. , Kumta Prashant N.
Published: July 2016

Identification of low cost, highly active, durable completely noble metal-free electro-catalyst for oxygen reduction reaction (ORR) in proton exchange membrane (PEM) fuel cells, oxygen evolution reaction (OER) in PEM based water electrolysis and metal air batteries remains one of the major unfulfilled scientific and technological challenges of PEM based acid mediated electro-catalysts. In contrast, several non-noble metals based electro-catalysts have been identified for alkaline and neutral medium water electrolysis and fuel cells. Herein we report for the very first time, F doped Cu1.5Mn1.5O4, identified by exploiting theoretical first principles calculations for ORR and OER in PEM based systems. The identified novel noble metal-free electro-catalyst showed similar onset potential (1.43 V for OER and 1 V for ORRvsRHE) to that of IrO2and Pt/C, respectively. The system also displayed excellent electrochemical activity comparable to IrO2for OER and Pt/C for ORR, respectively, along with remarkable long term stability for 6000 cycles in acidic media validating theory, while also displaying superior methanol tolerance and yielding recommended power densities in full cell configurations.
Self-assembly of c-myc DNA promoted by a single enantiomer ruthenium complex as a potential nuclear targeting gene carrier
Authors: Wu Qiong , Mei Wenjie , Zheng Kangdi , Ding Yang
Published: July 2016

Gene therapy has long been limited in the clinic, due in part to the lack of safety and efficacy of the gene carrier. Herein, a single enantiomer ruthenium(II) complex, Λ-[Ru(bpy)2(p-BEPIP)](ClO4)2 (Λ-RM0627, bpy = 4,4′-bipyridine, p-BEPIP = 2-(4-phenylacetylenephenyl)imidazole [4,5f][1, 10] phenanthroline), has been synthesized and investigated as a potential gene carrier that targets the nucleus. In this report, it is shown that Λ-RM0627 promotes self-assembly of c-myc DNA to form a nanowire structure. Further studies showed that the nano-assembly of c-myc DNA that induced Λ-RM0627 could be efficiently taken up and enriched in the nuclei of HepG2 cells. After treatment of the nano-assembly of c-myc DNA with Λ-RM0627, over-expression of c-myc in HepG2 cells was observed. In summary, Λ-RM0627 played a key role in the transfer and release of c-myc into cells, which strongly indicates Λ-RM0627 as a potent carrier of c-myc DNA that targets the nucleus of tumor cells.
Efficient nucleic acid delivery to murine regulatory T cells by gold nanoparticle conjugates
Authors: Gamrad Lisa , Rehbock Christoph , Westendorf Astrid M. , Buer Jan , Barcikowski Stephan , Hansen Wiebke
Published: July 2016

Immune responses have to be tightly controlled to guarantee maintenance of immunological tolerance and efficient clearance of pathogens and tumorigenic cells without induction of unspecific side effects. CD4+ CD25+ regulatory T cells (Tregs) play an important role in these processes due to their immunosuppressive function. Genetic modification of Tregs would be helpful to understand which molecules and pathways are involved in their function, but currently available methods are limited by time, costs or efficacy. Here, we made use of biofunctionalized gold nanoparticles as non-viral carriers to transport genetic information into murine Tregs. Confocal microscopy and transmission electron microscopy revealed an efficient uptake of the bioconjugates by Tregs. Most importantly, coupling eGFP-siRNA to those particles resulted in a dose and time dependent reduction of up to 50% of eGFP expression in Tregs isolated from Foxp3eGFP reporter mice. Thus, gold particles represent a suitable carrier for efficient import of nucleic acids into murine CD4+ CD25+ Tregs, superior to electroporation.
Dual-channel microcantilever heaters for volatile organic compound detection and mixture analysis
Authors: Jahangir Ifat , Koley Goutam
Published: July 2016

We report on novel microcantilever heater sensors with separate AlGaN/GaN heterostructure based heater and sensor channels to perform advanced volatile organic compound (VOC) detection and mixture analysis. Operating without any surface functionalization or treatment, these microcantilevers utilize the strong surface polarization of AlGaN, as well as the unique heater and sensor channel geometries, to perform selective detection of analytes based on their latent heat of evaporation and molecular dipole moment over a wide concentration range with sub-ppm detection limit. The dual-channel microcantilevers have demonstrated much superior sensing behavior compared to the single-channel ones, with the capability to not only identify individual VOCs with much higher specificity, but also uniquely detect them in a generic multi-component mixture of VOCs. In addition, utilizing two different dual channel configurations and sensing modalities, we have been able to quantitatively determine individual analyte concentration in a VOC mixture. An algorithm for complete mixture analysis, with unique identification of components and accurate determination of their concentration, has been presented based on simultaneous operation of an array of these microcantilever heaters in multiple sensing modalities.
Elevated Preoperative Serum Gamma-glutamyltranspeptidase Predicts Poor Prognosis for Hepatocellular Carcinoma after Liver Transplantation
Authors: Fu Shun-Jun , Zhao Qiang , Ji Fei , Chen Mao-Gen , Wu Lin-Wei , Ren Qing-Qi , Guo Zhi-Yong , He Xiao-Shun
Published: July 2016

Gamma-glutamyltransferase (γ-GGT) is a membrane-bound enzyme that is involved in biotransformation, nucleic acid metabolism, and tumourigenesis. Elevated serum γ-GGT levels are related to an increased cancer risk and worse prognosis in many cancers. In the present study, we evaluated the prognostic value of preoperative serum γ-GGT in patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT). A total of 130 HCC patients after LT were included in the study. The optimal cut-off value of γ-GGT was 128U/L by receiver operating characteristic analysis, with a sensitivity and specificity of 60.0% and 72.9%, respectively. Elevated preoperative serum γ-GGT was significantly associated with high alpha-fetoprotein (AFP), large tumor size, and macro- and micro-vascular invasion. The 1-, 3-, 5-year disease-free survival (DFS) and overall survival (OS) rates of HCC patients in the γ-GGT > 128U/L group were poorer than those in the γ-GGT ≤ 128U/L group. Stratification analysis revealed that γ-GGT exhibited a greater predictive value for DFS and OS in HCC patients beyond the Milan criteria and no macro-vascular invasion. In conclusion, elevated preoperative serum γ-GGT was significantly associated with advanced tumor stage and aggressive tumor behaviors, and serum γ-GGT can be considered as a prognostic factor for HCC patients after LT, especially for patients beyond the Milan criteria or without macro-vascular invasion.
Quantum-enhanced multiparameter estimation in multiarm interferometers
Authors: Ciampini Mario A. , Spagnolo Nicolò , Vitelli Chiara , Pezzè Luca , Smerzi Augusto , Sciarrino Fabio
Published: July 2016

Quantum metrology is the state-of-the-art measurement technology. It uses quantum resources to enhance the sensitivity of phase estimation over that achievable by classical physics. While single parameter estimation theory has been widely investigated, much less is known about the simultaneous estimation of multiple phases, which finds key applications in imaging and sensing. In this manuscript we provide conditions of useful particle (qudit) entanglement for multiphase estimation and adapt them to multiarm Mach-Zehnder interferometry. We theoretically discuss benchmark multimode Fock states containing useful qudit entanglement and overcoming the sensitivity of separable qudit states in three and four arm Mach-Zehnder-like interferometers - currently within the reach of integrated photonics technology.
Destabilizing an interacting motif strengthens the association of a designed ankyrin repeat protein with tubulin
Authors: Ahmad Shoeb , Pecqueur Ludovic , Dreier Birgit , Hamdane Djemel , Aumont-Nicaise Magali , Plückthun Andreas , Knossow Marcel , Gigant Benoît
Published: July 2016

Affinity maturation by random mutagenesis and selection is an established technique to make binding molecules more suitable for applications in biomedical research, diagnostics and therapy. Here we identified an unexpected novel mechanism of affinity increase upon in vitro evolution of a tubulin-specific designed ankyrin repeat protein (DARPin). Structural analysis indicated that in the progenitor DARPin the C-terminal capping repeat (C-cap) undergoes a 25° rotation to avoid a clash with tubulin upon binding. Additionally, the C-cap appears to be involved in electrostatic repulsion with tubulin. Biochemical and structural characterizations demonstrated that the evolved mutants achieved a gain in affinity through destabilization of the C-cap, which relieves the need of a DARPin conformational change upon tubulin binding and removes unfavorable interactions in the complex. Therefore, this specific case of an order-to-disorder transition led to a 100-fold tighter complex with a subnanomolar equilibrium dissociation constant, remarkably associated with a 30% decrease of the binding surface.
Genome-wide analysis of DNA methylation during antagonism of DMOG to MnCl2-induced cytotoxicity in the mouse substantia nigra
Authors: Yang Nannan , Wei Yang , Wang Tan , Guo Jifeng , Sun Qiying , Hu Yacen , Yan Xinxiang , Zhu Xiongwei , Tang Beisha , Xu Qian
Published: July 2016

Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson’s disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy.
An emerging zoonotic clone in the Netherlands provides clues to virulence and zoonotic potential of Streptococcus suis
Authors: Willemse N. , Howell K. J. , Weinert L. A. , Heuvelink A. , Pannekoek Y. , Wagenaar J. A. , Smith H. E. , van der Ende A. , Schultsz C.
Published: July 2016

Streptococcus suis is a zoonotic swine pathogen and a major public health concern in Asia, where it emerged as an important cause of bacterial meningitis in adults. While associated with food-borne transmission in Asia, zoonotic S. suis infections are mainly occupational hazards elsewhere. To identify genomic differences that can explain zoonotic potential, we compared whole genomes of 98 S. suis isolates from human patients and pigs with invasive disease in the Netherlands, and validated our observations with 18 complete and publicly available sequences. Zoonotic isolates have smaller genomes than non-zoonotic isolates, but contain more virulence factors. We identified a zoonotic S. suis clone that diverged from a non-zoonotic clone by means of gene loss, a capsule switch, and acquisition of a two-component signalling system in the late 19th century, when foreign pig breeds were introduced. Our results indicate that zoonotic potential of S. suis results from gene loss, recombination and horizontal gene transfer events.
3D map of the human corneal endothelial cell
Authors: He Zhiguo , Forest Fabien , Gain Philippe , Rageade Damien , Bernard Aurélien , Acquart Sophie , Peoc’h Michel , Defoe Dennis M. , Thuret Gilles
Published: July 2016

Corneal endothelial cells (CECs) are terminally differentiated cells, specialized in regulating corneal hydration and transparency. They are highly polarized flat cells that separate the cornea from the aqueous humor. Their apical surface, in contact with aqueous humor is hexagonal, whereas their basal surface is irregular. We characterized the structure of human CECs in 3D using confocal microscopy of immunostained whole corneas in which cells and their interrelationships remain intact. Hexagonality of the apical surface was maintained by the interaction between tight junctions and a submembraneous network of actomyosin, braced like a drum. Lateral membranes, which support enzymatic pumps, presented complex expansions resembling interdigitated foot processes at the basal surface. Using computer-aided design and drafting software, we obtained a first simplified 3D model of CECs. By comparing their expression with those in epithelial, stromal and trabecular corneal cells, we selected 9 structural or functional proteins for which 3D patterns were specific to CECs. This first 3D map aids our understanding of the morphologic and functional specificity of CECs and could be used as a reference for characterizing future cell therapy products destined to treat endothelial dysfunctions.
Integrated hollow microneedle-optofluidic biosensor for therapeutic drug monitoring in sub-nanoliter volumes
Authors: Ranamukhaarachchi Sahan A. , Padeste Celestino , Dübner Matthias , Häfeli Urs O. , Stoeber Boris , Cadarso Victor J.
Published: July 2016

Therapeutic drug monitoring (TDM) typically requires painful blood drawn from patients. We propose a painless and minimally-invasive alternative for TDM using hollow microneedles suitable to extract extremely small volumes (<1 nL) of interstitial fluid to measure drug concentrations. The inner lumen of a microneedle is functionalized to be used as a micro-reactor during sample collection to trap and bind target drug candidates during extraction, without requirements of sample transfer. An optofluidic device is integrated with this microneedle to rapidly quantify drug analytes with high sensitivity using a straightforward absorbance scheme. Vancomycin is currently detected by using volumes ranging between 50–100 μL with a limit of detection (LoD) of 1.35 μM. The proposed microneedle-optofluidic biosensor can detect vancomycin with a sample volume of 0.6 nL and a LoD of <100 nM, validating this painless point of care system with significant potential to reduce healthcare costs and patients suffering.
Multifaceted anti-amyloidogenic and pro-amyloidogenic effects of C-reactive protein and serum amyloid P component in vitro
Authors: Ozawa Daisaku , Nomura Ryo , Mangione P. Patrizia , Hasegawa Kazuhiro , Okoshi Tadakazu , Porcari Riccardo , Bellotti Vittorio , Naiki Hironobu
Published: July 2016

C-reactive protein (CRP) and serum amyloid P component (SAP), two major classical pentraxins in humans, are soluble pattern recognition molecules that regulate the innate immune system, but their chaperone activities remain poorly understood. Here, we examined their effects on the amyloid fibril formation from Alzheimer’s amyloid β (Aβ) (1-40) and on that from D76N β2-microglobulin (β2-m) which is related to hereditary systemic amyloidosis. CRP and SAP dose-dependently and substoichiometrically inhibited both Aβ(1-40) and D76N β2-m fibril formation in a Ca2+-independent manner. CRP and SAP interacted with fresh and aggregated Aβ(1-40) and D76N β2-m on the fibril-forming pathway. Interestingly, in the presence of Ca2+, SAP first inhibited, then significantly accelerated D76N β2-m fibril formation. Electron microscopically, the surface of the D76N β2-m fibril was coated with pentameric SAP. These data suggest that SAP first exhibits anti-amyloidogenic activity possibly via A face, followed by pro-amyloidogenic activity via B face, proposing a model that the pro- and anti-amyloidogenic activities of SAP are not mutually exclusive, but reflect two sides of the same coin, i.e., the B and A faces, respectively. Finally, SAP inhibits the heat-induced amorphous aggregation of human glutathione S-transferase. A possible role of pentraxins to maintain extracellular proteostasis is discussed.
Changes in the plasma proteome at asymptomatic and symptomatic stages of autosomal dominant Alzheimer’s disease
Authors: Muenchhoff Julia , Poljak Anne , Thalamuthu Anbupalam , Gupta Veer B. , Chatterjee Pratishtha , Raftery Mark , Masters Colin L. , Morris John C. , Bateman Randall J. , Fagan Anne M. , Martins Ralph N. , Sachdev Perminder S.
Published: July 2016

The autosomal dominant form of Alzheimer’s disease (ADAD) is far less prevalent than late onset Alzheimer’s disease (LOAD), but enables well-informed prospective studies, since symptom onset is near certain and age of onset is predictable. Our aim was to discover plasma proteins associated with early AD pathology by investigating plasma protein changes at the asymptomatic and symptomatic stages of ADAD. Eighty-one proteins were compared across asymptomatic mutation carriers (aMC, n = 15), symptomatic mutation carriers (sMC, n = 8) and related noncarriers (NC, n = 12). Proteins were also tested for associations with cognitive measures, brain amyloid deposition and glucose metabolism. Fewer changes were observed at the asymptomatic than symptomatic stage with seven and 16 proteins altered significantly in aMC and sMC, respectively. This included complement components C3, C5, C6, apolipoproteins A-I, A-IV, C-I and M, histidine-rich glycoprotein, heparin cofactor II and attractin, which are involved in inflammation, lipid metabolism and vascular health. Proteins involved in lipid metabolism differed only at the symptomatic stage, whereas changes in inflammation and vascular health were evident at asymptomatic and symptomatic stages. Due to increasing evidence supporting the usefulness of ADAD as a model for LOAD, these proteins warrant further investigation into their potential association with early stages of LOAD.
Fully integrated multi-optoelectronic synthesizer for THz pumping source in wireless communications with rich backup redundancy and wide tuning range
Authors: Xu Junjie , Hou Lianping , Deng Qiufang , Han Liangshun , Liang Song , Marsh John H. , Zhu Hongliang
Published: July 2016

We report a monolithic photonic integrated circuit (PIC) for THz communication applications. The PIC generates up to 4 optical frequency lines which can be mixed in a separate device to generate THz radiation, and each of the optical lines can be modulated individually to encode data. Physically, the PIC comprises an array of wavelength tunable distributed feedback lasers each with its own electro-absorption modulator. The lasers are designed with a long cavity to operate with a narrow linewidth, typically <4 MHz. The light from the lasers is coupled via an multimode interference (MMI) coupler into a semiconductor optical amplifier (SOA). By appropriate selection and biasing of pairs of lasers, the optical beat signal can be tuned continuously over the range from 0.254 THz to 2.723 THz. The EAM of each channel enables signal leveling balanced between the lasers and realizing data encoding, currently at data rates up to 6.5 Gb/s. The PIC is fabricated using regrowth-free techniques, making it economic for volume applications, such for use in data centers. The PIC also has a degree of redundancy, making it suitable for applications, such as inter-satellite communications, where high reliability is mandatory.
Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients
Authors: Kato Kikuya , Uchida Junji , Kukita Yoji , Kumagai Toru , Nishino Kazumi , Inoue Takako , Kimura Madoka , Oba Shigeyuki , Imamura Fumio
Published: July 2016

Monitoring of disease/therapeutic conditions is an important application of circulating tumor DNA (ctDNA). We devised numerical indices, based on ctDNA dynamics, for therapeutic response and disease progression. 52 lung cancer patients subjected to the EGFR-TKI treatment were prospectively collected and ctDNA levels represented by the activating and T790M mutations were measured using deep sequencing. Typically, ctDNA levels decreased sharply upon initiation of EGFR-TKI, however this did not occur in progressive disease (PD) cases. All 3 PD cases at initiation of EGFR-TKI were separated from other 27 cases in a two-dimensional space generated by the ratio of the ctDNA levels before and after therapy initiation (mutation allele ratio in therapy, MART) and the average ctDNA level. For responses to various agents after disease progression, PD/stable disease cases were separated from partial response cases using MART (accuracy, 94.7%; 95% CI, 73.5–100). For disease progression, the initiation of ctDNA elevation (initial positive point) was compared with the onset of objective disease progression. In 11 out of 28 eligible patients, both occurred within ±100 day range, suggesting a detection of the same change in disease condition. Our numerical indices have potential applicability in clinical practice, pending confirmation with designed prospective studies.
Neural substrates predicting short-term improvement of tinnitus loudness and distress after modified tinnitus retraining therapy
Authors: Kim Shin Hye , Jang Ji Hye , Lee Sang-Yeon , Han Jae Joon , Koo Ja-Won , Vanneste Sven , De Ridder Dirk , Song Jae-Jin
Published: July 2016

Although tinnitus retraining therapy (TRT) is efficacious in most patients, the exact mechanism is unclear and no predictor of improvement is available. We correlated the extent of improvement with pre-TRT quantitative electroencephalography (qEEG) findings to identify neural predictors of improvement after TRT. Thirty-two patients with debilitating tinnitus were prospectively enrolled, and qEEG data were recorded before their initial TRT sessions. Three months later, these qEEG findings were correlated with the percentage improvements in the Tinnitus Handicap Inventory (THI) scores, and numeric rating scale (NRS) scores of tinnitus loudness and tinnitus perception. The THI score improvement was positively correlated with the pre-treatment activities of the left insula and the left rostral and pregenual anterior cingulate cortices (rACC/pgACC), which control parasympathetic activity. Additionally, the activities of the right auditory cortices and the parahippocampus, areas that generate tinnitus, negatively correlated with improvements in loudness. Improvements in the NRS scores of tinnitus perception correlated positively with the pre-TRT activities of the bilateral rACC/pgACC, areas suggested to form the core of the noise-canceling system. The current study supports both the classical neurophysiological and integrative models of tinnitus; our results serve as a milestone in the development of precision medicine in the context of TRT.
Dynamic Contrast-enhanced MR Imaging in Renal Cell Carcinoma: Reproducibility of Histogram Analysis on Pharmacokinetic Parameters
Authors: Wang Hai-yi , Su Zi-hua , Xu Xiao , Sun Zhi-peng , Duan Fei-xue , Song Yuan-yuan , Li Lu , Wang Ying-wei , Ma Xin , Guo Ai-tao , Ma Lin , Ye Hui-yi
Published: July 2016

Pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have been increasingly used to evaluate the permeability of tumor vessel. Histogram metrics are a recognized promising method of quantitative MR imaging that has been recently introduced in analysis of DCE-MRI pharmacokinetic parameters in oncology due to tumor heterogeneity. In this study, 21 patients with renal cell carcinoma (RCC) underwent paired DCE-MRI studies on a 3.0 T MR system. Extended Tofts model and population-based arterial input function were used to calculate kinetic parameters of RCC tumors. Mean value and histogram metrics (Mode, Skewness and Kurtosis) of each pharmacokinetic parameter were generated automatically using ImageJ software. Intra- and inter-observer reproducibility and scan–rescan reproducibility were evaluated using intra-class correlation coefficients (ICCs) and coefficient of variation (CoV). Our results demonstrated that the histogram method (Mode, Skewness and Kurtosis) was not superior to the conventional Mean value method in reproducibility evaluation on DCE-MRI pharmacokinetic parameters (Ktrans & Ve) in renal cell carcinoma, especially for Skewness and Kurtosis which showed lower intra-, inter-observer and scan-rescan reproducibility than Mean value. Our findings suggest that additional studies are necessary before wide incorporation of histogram metrics in quantitative analysis of DCE-MRI pharmacokinetic parameters.
Preserved antiviral adaptive immunity following polyclonal antibody immunotherapy for severe murine influenza infection
Authors: Stevens Natalie E. , Hatjopolous Antoinette , Fraser Cara K. , Alsharifi Mohammed , Diener Kerrilyn R. , Hayball John D.
Published: July 2016

Passive immunotherapy may have particular benefits for the treatment of severe influenza infection in at-risk populations, however little is known of the impact of passive immunotherapy on the formation of memory responses to the virus. Ideally, passive immunotherapy should attenuate the severity of infection while still allowing the formation of adaptive responses to confer protection from future exposure. In this study, we sought to determine if administration of influenza-specific ovine polyclonal antibodies could inhibit adaptive immune responses in a murine model of lethal influenza infection. Ovine polyclonal antibodies generated against recombinant PR8 (H1N1) hemagglutinin exhibited potent prophylactic capacity and reduced lethality in an established influenza infection, particularly when administered intranasally. Surviving mice were also protected against reinfection and generated normal antibody and cytotoxic T lymphocyte responses to the virus. The longevity of ovine polyclonal antibodies was explored with a half-life of over two weeks following a single antibody administration. These findings support the development of an ovine passive polyclonal antibody therapy for treatment of severe influenza infection which does not affect the formation of subsequent acquired immunity to the virus.
Phase diagram of quantum critical system via local convertibility of ground state
Authors: Liu Si-Yuan , Quan Quan , Chen Jin-Jun , Zhang Yu-Ran , Yang Wen-Li , Fan Heng
Published: July 2016

We investigate the relationship between two kinds of ground-state local convertibility and quantum phase transitions in XY model. The local operations and classical communications (LOCC) convertibility is examined by the majorization relations and the entanglement-assisted local operations and classical communications (ELOCC) via Rényi entropy interception. In the phase diagram of XY model, LOCC convertibility and ELOCC convertibility of ground-states are presented and compared. It is shown that different phases in the phase diagram of XY model can have different LOCC or ELOCC convertibility, which can be used to detect the quantum phase transition. This study will enlighten extensive studies of quantum phase transitions from the perspective of local convertibility, e.g., finite-temperature phase transitions and other quantum many-body models.
Inhibitory effect of 2-methyl-naphtho[1,2,3-de]quinolin-8-one on melanosome transport and skin pigmentation
Authors: Park Jong il , Lee Ha Yeon , Lee Ji Eun , Myung Cheol hwan , Hwang Jae Sung
Published: July 2016

Melanosomes are lysosome-related organelles with specialized capabilities of melanin synthesis and movement mediated by the Rab27a-Melanophilin-MyosinVa protein complex. In this study, we found that 2-methyl-naphtho[1,2,3-de]quinolin-8-one (MNQO) induced melanosome aggregation around the nucleus in melan-a melanocytes and in melan-a melanocytes/SP-1 keratinocyte co-cultures without inducing toxicity or changing the melanin content. Western blot and real-time PCR analyses showed that MNQO decreased expression of the Rab27a, Melanophilin and MyosinVa proteins and mRNAs, respectively, in melan-a melanocytes. In a reconstituted human epidermis model, treatment with 0.001% MNQO reduced skin pigmentation. Also, MNQO reduced skin pigmentation in brown guinea pigs induced by UVB irradiation. These results indicated that regulation of melanosome transport may serve as a good target for new skin depigmenting agents and MNQO itself could be a candidate.
Thioredoxin interacting protein (TXNIP) regulates tubular autophagy and mitophagy in diabetic nephropathy through the mTOR signaling pathway
Authors: Huang Chunling , Zhang Yuan , Kelly Darren J. , Tan Christina Y. R. , Gill Anthony , Cheng Delfine , Braet Filip , Park Jin-Sung , Sue Carolyn M. , Pollock Carol A. , Chen Xin-Ming
Published: July 2016

Hyperglycemia upregulates thioredoxin interacting protein (TXNIP) expression, which in turn induces ROS production, inflammatory and fibrotic responses in the diabetic kidney. Dysregulation of autophagy contributes to the development of diabetic nephropathy. However, the interaction of TXNIP with autophagy/mitophagy in diabetic nephropathy is unknown. In this study, streptozotocin-induced diabetic rats were given TXNIP DNAzyme or scrambled DNAzyme for 12 weeks respectively. Fibrotic markers, mitochondrial function and mitochondrial reactive oxygen species (mtROS) were assessed in kidneys. Tubular autophagy and mitophagy were determined in kidneys from both human and rats with diabetic nephropathy. TXNIP and autophagic signaling molecules were examined. TXNIP DNAzyme dramatically attenuated extracellular matrix deposition in the diabetic kidneys compared to the control DNAzyme. Accumulation of autophagosomes and reduced autophagic clearance were shown in tubular cells of human diabetic compared to non-diabetic kidneys, which was reversed by TXNIP DNAzyme. High glucose induced mitochondrial dysfunction and mtROS production and inhibited mitophagy in proximal tubular cells, which was reversed by TXNIP siRNA. TXNIP inhibition suppressed diabetes-induced BNIP3 expression and activation of the mTOR signaling pathway. Collectively, hyperglycemia-induced TXNIP contributes to the dysregulation of tubular autophagy and mitophagy in diabetic nephropathy through activation of the mTOR signaling pathway.
Associations of self-reported height loss and kyphosis with vertebral fractures in Japanese women 60 years and older: a cross-sectional survey
Authors: Kamimura Mikio , Nakamura Yukio , Sugino Noriyuki , Uchiyama Shigeharu , Komatsu Masatoshi , Ikegami Shota , Kato Hiroyuki , Taguchi Akira
Published: July 2016

Some vertebral fractures come to clinical attention but most do not. This cross-sectional survey aimed to clarify the associations of self-reported height loss and kyphosis with vertebral fractures. We enrolled 407 women aged 60–92 years who visited our orthopaedic clinic between June and August 2014 in our study. Inclusion criteria were lateral radiography followed by completion of a structured questionnaire in this study. The primary outcome was vertebral fracture diagnosed on lateral radiography and graded using a semiquantitative grading method, from SQ0 (normal) to SQ3 (severe). Self-reported kyphosis was defined as none, mild to moderate, severe. Self-reported height loss was defined as <4 cm or ≥4 cm. Number of SQ1 fracture was associated only with kyphosis. Self-reported severe kyphosis was significantly associated with increased numbers of ≥SQ2 vertebral fractures (p = 0.007). Height loss ≥4 cm was significantly associated with increased ≥SQ2 grade fractures (p < 0.001). Odds ratios (ORs) for fractures associated with mild-to-moderate and severe kyphosis were 2.1 [95% confidence interval 1.4 to 3.3) and 4.2 (1.8 to 9.5), respectively. OR for fractures associated with height loss ≥4 cm was 2.3 (1.4 to 3.7). Self-reported kyphosis may be useful for identifying Japanese women aged ≥60 years who have undetected vertebral fractures.
Penternary chalcogenides nanocrystals as catalytic materials for efficient counter electrodes in dye-synthesized solar cells
Authors: Özel Faruk , Sarılmaz Adem , İstanbullu Bilal , Aljabour Abdalaziz , Kuş Mahmut , Sönmezoğlu Savaş
Published: July 2016

The penternary chalcogenides Cu2CoSn(SeS)4 and Cu2ZnSn(SeS)4 were successfully synthesized by hot-injection method and employed as a catalytic materials for efficient counter electrodes in dye-synthesized solar cells (DSSCs). The structural, compositional, morphological and optical properties of these pentenary semiconductors were characterized by X-ray diffraction (XRD), Raman spectroscopy, transmission electron microscopy (TEM), energy-dispersive spectrometer (EDS) and ultraviolet-visible (UV–Vis) spectroscopy. The Cu2CoSn(SeS)4 and Cu2ZnSn(SeS)4 nanocrystals had a single crystalline, kesterite phase, adequate stoichiometric ratio, 18–25 nm particle sizes which are forming nanospheres and band gap energy of 1.18 and 1.45 eV, respectively. Furthermore, the electrochemical impedance spectroscopy and cyclic voltammograms indicated that Cu2CoSn(SeS)4 nanocrystals as counter electrodes exhibited better electrocatalytic activity for the reduction of iodine/iodide electrolyte than that of Cu2ZnSn(SeS)4 nanocrystals and conventional platinum (Pt). The photovoltaic results demonstrated that DSSC with a Cu2CoSn(SeS)4 nanocrystals-based counter electrode achieved the best efficiency of 6.47%, which is higher than the same photoanode employing a Cu2ZnSn(SeS)4 nanocrystals (3.18%) and Pt (5.41%) counter electrodes. These promising results highlight the potential application of penternary chalcogen Cu2CoSn(SeS)4 nanocrystals in low-cost, high-efficiency, Pt-free DSSCs.
Quantitative Study of Elasticity of Rabbit VX2 Liver Tumor with Alternated Cooling and Heating Treatment based on ARFI Ultrasound Imaging Technique
Authors: Sun Di , Wei Cong , Shen E. , Ying Tao , Hu Bing
Published: July 2016

Acoustic radiation force impulse (ARFI) ultrasound imaging technique is used to quantitatively evaluate the elasticity of rabbit VX2 liver tumor with alternated cooling and heating treatment (ACHT). ACHT was performed on fifteen VX2 liver tumor models established in fifteen male New Zealand white rabbits with open tumor plant. ARFI was performed on day 0, 1, 7 and 14 after ACHT and shear wave velocity (SWV) in ARFI was recorded to evaluate the elasticity of the treated area. The SWV value of the lesion on day 0, 1, 7 and 14 was 2.33 ± 0.19 m/s, 3.09 ± 0.40 m/s, 2.64 ± 0.37 m/s and 2.26 ± 0.24 m/s, respectively, indicating the treated areas get stiffer on day 1 and then get softer gradually by day. All the difference between adjacent time points was statistically significant. The SWV value of different parts on day 7 approved that the hardness of the treated area is heterogenous: the treated area in the center >the peripheral strip-shaped area >normal liver tissues, consistent with pathological changes. Meanwhile, ARFI combined with conventional US imaging can qualitatively and quantitatively exam the healing process of rabbit VX2 liver tumor after ACHT, and corresponds well to the pathological results.
Proteome-wide analysis of lysine acetylation in the plant pathogen Botrytis cinerea
Authors: Lv Binna , Yang Qianqian , Li Delong , Liang Wenxing , Song Limin
Published: July 2016

Lysine acetylation is a dynamic and reversible post-translational modification that plays an important role in diverse cellular processes. Botrytis cinerea is the most thoroughly studied necrotrophic species due to its broad host range and huge economic impact. However, to date, little is known about the functions of lysine acetylation in this plant pathogen. In this study, we determined the lysine acetylome of B. cinerea through the combination of affinity enrichment and high-resolution LC-MS/MS analysis. Overall, 1582 lysine acetylation sites in 954 proteins were identified. Bioinformatics analysis shows that the acetylated proteins are involved in diverse biological functions and show multiple cellular localizations. Several particular amino acids preferred near acetylation sites, including KacY, KacH, Kac***R, KacF, FKac and Kac***K, were identified in this organism. Protein interaction network analysis demonstrates that a variety of interactions are modulated by protein acetylation. Interestingly, 6 proteins involved in virulence of B. cinerea, including 3 key components of the high-osmolarity glycerol pathway, were found to be acetylated, suggesting that lysine acetylation plays regulatory roles in pathogenesis. These data provides the first comprehensive view of the acetylome of B. cinerea and serves as a rich resource for functional analysis of lysine acetylation in this plant pathogen.
Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands
Authors: Finamore Claudia , Festa Carmen , Renga Barbara , Sepe Valentina , Carino Adriana , Masullo Dario , Biagioli Michele , Marchianò Silvia , Capolupo Angela , Monti Maria Chiara , Fiorucci Stefano , Zampella Angela
Published: July 2016

Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and therefore the discovery of selective GPBAR1 and FXR agonists is an essential step in the medicinal chemistry optimization of bile acid scaffold. In this study, a new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPBAR1 were assayed. This speculation resulted in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity.
Improved antifouling properties and selective biofunctionalization of stainless steel by employing heterobifunctional silane-polyethylene glycol overlayers and avidin-biotin technology
Authors: Hynninen Ville , Vuori Leena , Hannula Markku , Tapio Kosti , Lahtonen Kimmo , Isoniemi Tommi , Lehtonen Elina , Hirsimäki Mika , Toppari J. Jussi , Valden Mika , Hytönen Vesa P.
Published: July 2016

A straightforward solution-based method to modify the biofunctionality of stainless steel (SS) using heterobifunctional silane-polyethylene glycol (silane-PEG) overlayers is reported. Reduced nonspecific biofouling of both proteins and bacteria onto SS and further selective biofunctionalization of the modified surface were achieved. According to photoelectron spectroscopy analyses, the silane-PEGs formed less than 10 Å thick overlayers with close to 90% surface coverage and reproducible chemical compositions. Consequently, the surfaces also became more hydrophilic, and the observed non-specific biofouling of proteins was reduced by approximately 70%. In addition, the attachment of E. coli was reduced by more than 65%. Moreover, the potential of the overlayer to be further modified was demonstrated by successfully coupling biotinylated alkaline phosphatase (bAP) to a silane-PEG-biotin overlayer via avidin-biotin bridges. The activity of the immobilized enzyme was shown to be well preserved without compromising the achieved antifouling properties. Overall, the simple solution-based approach enables the tailoring of SS to enhance its activity for biomedical and biotechnological applications.
High Thermal Gradient in Thermo-electrochemical Cells by Insertion of a Poly(Vinylidene Fluoride) Membrane
Authors: Hasan Syed Waqar , Said Suhana Mohd , Sabri Mohd Faizul Mohd , Bakar Ahmad Shuhaimi Abu , Hashim Nur Awanis , Hasnan Megat Muhammad Ikhsan Megat , Pringle Jennifer M. , MacFarlane Douglas R.
Published: July 2016

Thermo-Electrochemical cells (Thermocells/TECs) transform thermal energy into electricity by means of electrochemical potential disequilibrium between electrodes induced by a temperature gradient (ΔT). Heat conduction across the terminals of the cell is one of the primary reasons for device inefficiency. Herein, we embed Poly(Vinylidene Fluoride) (PVDF) membrane in thermocells to mitigate the heat transfer effects - we refer to these membrane-thermocells as MTECs. At a ΔT of 12 K, an improvement in the open circuit voltage (Voc) of the TEC from 1.3 mV to 2.8 mV is obtained by employment of the membrane. The PVDF membrane is employed at three different locations between the electrodes i.e. x = 2 mm, 5 mm, and 8 mm where ‘x’ defines the distance between the cathode and PVDF membrane. We found that the membrane position at x = 5 mm achieves the closest internal ∆T (i.e. 8.8 K) to the externally applied ΔT of 10 K and corresponding power density is 254 nWcm−2; 78% higher than the conventional TEC. Finally, a thermal resistivity model based on infrared thermography explains mass and heat transfer within the thermocells.