bluuebunny/crossref_metadata_2025 huggingface dataset:
Label-free detection of cellular drug responses by high-throughput bright-field imaging and machine learning
Authors: Kobayashi Hirofumi , Lei Cheng , Wu Yi , Mao Ailin , Jiang Yiyue , Guo Baoshan , Ozeki Yasuyuki , Goda Keisuke
Published: September 2017

In the last decade, high-content screening based on multivariate single-cell imaging has been proven effective in drug discovery to evaluate drug-induced phenotypic variations. Unfortunately, this method inherently requires fluorescent labeling which has several drawbacks. Here we present a label-free method for evaluating cellular drug responses only by high-throughput bright-field imaging with the aid of machine learning algorithms. Specifically, we performed high-throughput bright-field imaging of numerous drug-treated and -untreated cells (N = ~240,000) by optofluidic time-stretch microscopy with high throughput up to 10,000 cells/s and applied machine learning to the cell images to identify their morphological variations which are too subtle for human eyes to detect. Consequently, we achieved a high accuracy of 92% in distinguishing drug-treated and -untreated cells without the need for labeling. Furthermore, we also demonstrated that dose-dependent, drug-induced morphological change from different experiments can be inferred from the classification accuracy of a single classification model. Our work lays the groundwork for label-free drug screening in pharmaceutical science and industry.
Radiation alters the cargo of exosomes released from squamous head and neck cancer cells to promote migration of recipient cells
Authors: Mutschelknaus Lisa , Azimzadeh Omid , Heider Theresa , Winkler Klaudia , Vetter Marcus , Kell Rosemarie , Tapio Soile , Merl-Pham Juliane , Huber Stephan M. , Edalat Lena , Radulović Vanja , Anastasov Nataša , Atkinson Michael J. , Moertl Simone
Published: September 2017

Radiation is a highly efficient therapy in squamous head and neck carcinoma (HNSCC) treatment. However, local recurrence and metastasis are common complications. Recent evidence shows that cancer-cell-derived exosomes modify tumour cell movement and metastasis. In this study, we link radiation-induced changes of exosomes to their ability to promote migration of recipient HNSCC cells. We demonstrate that exosomes isolated from irradiated donor cells boost the motility of the HNSCC cells BHY and FaDu. Molecular data identified enhanced AKT-signalling, manifested through increased phospho-mTOR, phospho-rpS6 and MMP2/9 protease activity, as underlying mechanism. AKT-inhibition blocked the pro-migratory action, suggesting AKT-signalling as key player in exosome-mediated migration. Proteomic analysis of exosomes isolated from irradiated and non-irradiated BHY donor cells identified 39 up- and 36 downregulated proteins. In line with the observed pro-migratory effect of exosomes isolated from irradiated cells protein function analysis assigned the deregulated exosomal proteins to cell motility and AKT-signalling. Together, our findings demonstrate that exosomes derived from irradiated HNSCC cells confer a migratory phenotype to recipient cancer cells. This is possibly due to radiation-regulated exosomal proteins that increase AKT-signalling. We conclude that exosomes may act as driver of HNSCC progression during radiotherapy and are therefore attractive targets to improve radiation therapy strategies.
Inverse Resolution Limit of Partition Density and Detecting Overlapping Communities by Link-Surprise
Authors: Lee Juyong , Zhang Zhong-Yuan , Lee Jooyoung , Brooks Bernard R. , Ahn Yong-Yeol
Published: September 2017

Finding overlapping communities of complex networks remains a challenge in network science. To address this challenge, one of the widely used approaches is finding the communities of links by optimizing the objective function, partition density. In this study, we show that partition density suffers from inverse resolution limit; it has a strong preference to triangles. This resolution limit makes partition density an improper objective function for global optimization. The conditions where partition density prefers triangles to larger link community structures are analytically derived and confirmed with global optimization calculations using synthetic and real-world networks. To overcome this limitation of partition density, we suggest an alternative measure, Link Surprise, to find link communities, which is suitable for global optimization. Benchmark studies demonstrate that global optimization of Link Surprise yields meaningful and more accurate link community structures than partition density optimization.
The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity
Authors: Wang Yu-Shi , Lin Yingjia , Li He , Li Yang , Song Zhiguang , Jin Ying-Hua
Published: September 2017

The 20S ginsenoside Rh2 (G-Rh2) effectively inhibits cancer cell growth and survival in both animal models and cell lines. However, its molecular targets and mechanism of action remain largely unknown. By screening for molecules that interact with (20S)G-Rh2 in a phage display assay, we have identified Annexin A2 as a potential target that mediates its anti-cancer activity. Isothermal titration calorimetry and a cellular thermal shift assay demonstrated that (20S)G-Rh2 directly bound to either recombinant or intracellular Annexin A2. This binding inhibited the interaction between Annexin A2 and the NF-кB p50 subunit, which attenuated the nuclear translocations of NF-кB p50 subunit and reduced the transactivation activity of NF-кB. Correspond to this result, (20S)G-Rh2 treatment significantly down-regulated the expression of IAPs (inhibitors of apoptosis), the well-established NF-кB targets that promote cell survival. Moreover, (20S)G-Rh2 synergized with Annexin A2 inactivation to promote apoptosis. Taken together, this study for the first time suggests a cellular target and a molecular pathway by which (20S)G-Rh2 inhibits cancer cell growth. As over-expression of Annexin A2 was evident in human hepatoma, (20S)G-Rh2 might be a promising natural compound for targeted liver cancer therapy.
Development of persistent gastrointestinal S. aureus carriage in mice
Authors: Flaxman Amy , van Diemen Pauline M. , Yamaguchi Yuko , Allen Elizabeth , Lindemann Claudia , Rollier Christine S. , Milicic Anita , Wyllie David H.
Published: September 2017

One fifth to one quarter of the human population is asymptomatically, naturally and persistently colonised by Staphylococcus aureus. Observational human studies indicate that although the whole population is intermittently exposed, some individuals lose S. aureus rapidly. Others become persistent carriers, as assessed by nasal cultures, with many individuals colonised for decades. Current animal models of S. aureus colonisation are expensive and normally require antibiotics. Importantly, these animal models have not yet contributed to our poor understanding of the dichotomy in human colonisation status. Here, we identify a single strain of S. aureus found to be persistently colonising the gastrointestinal tract of BALB/c mice. Phylogenetic analyses suggest it diverged from a human ST15 lineage in the recent past. We show that murine carriage of this organism occurs in the bowel and nares, is acquired early in life, and can persist for months. Importantly, we observe the development of persistent and non-persistent gastrointestinal carriage states in genetically identical mice. We developed a needle- and antibiotic-free model in which we readily induced S. aureus colonisation of the gastrointestinal tract experimentally by environmental exposure. Using our experimental model, impact of adaptive immunity on S. aureus colonisation could be assessed. Vaccine efficacy to eliminate colonisation could also be investigated using this model.
Valence Change Bipolar Resistive Switching Accompanied With Magnetization Switching in CoFe2O4 Thin Film
Authors: Munjal Sandeep , Khare Neeraj
Published: September 2017

Resistive Switching in oxides has offered new opportunities for developing resistive random access memory (ReRAM) devices. Here we demonstrated bipolar Resistive Switching along with magnetization switching of cobalt ferrite (CFO) thin film using Al/CFO/FTO sandwich structure, which makes it a potential candidate for developing future multifunctional memory devices. The device shows good retention characteristic time (>104 seconds) and endurance performance, a good resistance ratio of high resistance state (HRS) and low resistance state (LRS) ~103. Nearly constant resistance values in LRS and HRS confirm the stability and non-volatile nature of the device. The device shows different conduction mechanisms in the HRS and LRS i.e. Schottky, Poole Frenkel and Ohmic. Magnetization of the device is also modulated by applied electric field which has been attributed to the oxygen vacancies formed/annihilated during the voltage sweep and indicates the presence of valence change mechanism (VCM) in our device. It is suggested that push/pull of oxygen ions from oxygen diffusion layer during voltage sweep is responsible for forming/rupture of oxygen vacancies conducting channels, leading to switching between LRS and HRS and for switching in magnetization in CFO thin film. Presence of VCM in our device was confirmed by X-ray Photoelectron Spectroscopy at Al/CFO interface.
Somatic Arc protein expression in hippocampal granule cells is increased in response to environmental change but independent of task-specific learning
Authors: Cleland J. P. , Willis E. F. , Bartlett P. F. , Vukovic J.
Published: September 2017

Activated neurons express immediate-early genes, such as Arc. Expression of Arc in the hippocampal granule cell layer, an area crucial for spatial learning and memory, is increased during acquisition of spatial learning; however, it is unclear whether this effect is related to the task-specific learning process or to nonspecific aspects of the testing procedure (e.g. exposure to the testing apparatus and exploration of the environment). Herein, we show that Arc-positive cells numbers are increased to the same extent in the granule cell layer after both acquisition of a single spatial learning event in the active place avoidance task and exploration of the testing environment, as compared to naïve (i.e. caged) mice. Repeated exposure the testing apparatus and environment did not reduce Arc expression. Furthermore, Arc expression did not correlate with performance in both adult and aged animals, suggesting that exploration of the testing environment, rather than the specific acquisition of the active place avoidance task, induces Arc expression in the dentate granule cell layer. These findings thus suggest that Arc is an experience-induced immediate-early gene.
Establishing a method of short-term rainfall forecasting based on GNSS-derived PWV and its application
Authors: Yao Yibin , Shan Lulu , Zhao Qingzhi
Published: September 2017

Abstarct

Global Navigation Satellite System (GNSS) can effectively retrieve precipitable water vapor (PWV) with high precision and high-temporal resolution. GNSS-derived PWV can be used to reflect water vapor variation in the process of strong convection weather. By studying the relationship between time-varying PWV and rainfall, it can be found that PWV contents increase sharply before raining. Therefore, a short-term rainfall forecasting method is proposed based on GNSS-derived PWV. Then the method is validated using hourly GNSS-PWV data from Zhejiang Continuously Operating Reference Station (CORS) network of the period 1 September 2014 to 31 August 2015 and its corresponding hourly rainfall information. The results show that the forecasted correct rate can reach about 80%, while the false alarm rate is about 66%. Compared with results of the previous studies, the correct rate is improved by about 7%, and the false alarm rate is comparable. The method is also applied to other three actual rainfall events of different regions, different durations, and different types. The results show that the method has good applicability and high accuracy, which can be used for rainfall forecasting, and in the future study, it can be assimilated with traditional weather forecasting techniques to improve the forecasted accuracy.
Proteomic mapping of differentially vulnerable pre-synaptic populations identifies regulators of neuronal stability in vivo
Authors: Llavero Hurtado Maica , Fuller Heidi R. , Wong Andrew M. S. , Eaton Samantha L. , Gillingwater Thomas H. , Pennetta Giuseppa , Cooper Jonathan D. , Wishart Thomas M.
Published: September 2017

Synapses are an early pathological target in many neurodegenerative diseases ranging from well-known adult onset conditions such as Alzheimer and Parkinson disease to neurodegenerative conditions of childhood such as spinal muscular atrophy (SMA) and neuronal ceroid lipofuscinosis (NCLs). However, the reasons why synapses are particularly vulnerable to such a broad range of neurodegeneration inducing stimuli remains unknown. To identify molecular modulators of synaptic stability and degeneration, we have used the Cln3−/− mouse model of a juvenile form of NCL. We profiled and compared the molecular composition of anatomically-distinct, differentially-affected pre-synaptic populations from the Cln3−/− mouse brain using proteomics followed by bioinformatic analyses. Identified protein candidates were then tested using a Drosophila CLN3 model to study their ability to modify the CLN3-neurodegenerative phenotype in vivo. We identified differential perturbations in a range of molecular cascades correlating with synaptic vulnerability, including valine catabolism and rho signalling pathways. Genetic and pharmacological targeting of key ‘hub’ proteins in such pathways was sufficient to modulate phenotypic presentation in a Drosophila CLN3 model. We propose that such a workflow provides a target rich method for the identification of novel disease regulators which could be applicable to the study of other conditions where appropriate models exist.
Selection on start codons in prokaryotes and potential compensatory nucleotide substitutions
Authors: Belinky Frida , Rogozin Igor B. , Koonin Eugene V.
Published: September 2017

Reconstruction of the evolution of start codons in 36 groups of closely related bacterial and archaeal genomes reveals purifying selection affecting AUG codons. The AUG starts are replaced by GUG and especially UUG significantly less frequently than expected under the neutral expectation derived from the frequencies of the respective nucleotide triplet substitutions in non-coding regions and in 4-fold degenerate sites. Thus, AUG is the optimal start codon that is actively maintained by purifying selection. However, purifying selection on start codons is significantly weaker than the selection on the same codons in coding sequences, although the switches between the codons result in conservative amino acid substitutions. The only exception is the AUG to UUG switch that is strongly selected against among start codons. Selection on start codons is most pronounced in evolutionarily conserved, highly expressed genes. Mutation of the start codon to a sub-optimal form (GUG or UUG) tends to be compensated by mutations in the Shine-Dalgarno sequence towards a stronger translation initiation signal. Together, all these findings indicate that in prokaryotes, translation start signals are subject to weak but significant selection for maximization of initiation rate and, consequently, protein production.
Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer’s disease-like pathologies
Authors: Kim Min Woo , Abid Noman bin , Jo Myeong Hoon , Jo Min Gi , Yoon Gwang Ho , Kim Myeong Ok
Published: September 2017

Recent studies on neurodegeneration have focused on dysfunction of CNS energy metabolism as well as proteinopathies. Adiponectin (ADPN), an adipocyte-derived hormone, plays a major role in the regulation of insulin sensitivity and glucose homeostasis in peripheral organs via adiponectin receptors. In spite of accumulating evidence that adiponectin has neuroprotective properties, the underlying role of adiponectin receptors has not been illuminated. Here, using gene therapy-mediated suppression with shRNA, we found that adiponectin receptor 1 (AdipoR1) suppression induces neurodegeneration as well as metabolic dysfunction. AdipoR1 knockdown mice exhibited increased body weight and abnormal plasma chemistry and also showed spatial learning and memory impairment in behavioural studies. Moreover, AdipoR1 suppression resulted in neurodegenerative phenotypes, diminished expression of the neuronal marker NeuN, and increased expression and activity of caspase 3. Furthermore, AD-like pathologies including insulin signalling dysfunction, abnormal protein aggregation and neuroinflammatory responses were highly exhibited in AdipoR1 knockdown groups, consistent with brain pathologies in ADPN knockout mice. Together, these results suggest that ADPN-AdipoR1 signalling has the potential to alleviate neurodegenerative diseases such as Alzheimer’s diseases.
CCK reduces the food intake mainly through CCK1R in Siberian sturgeon (Acipenser baerii Brandt)
Authors: Zhang Xin , Tang Ni , Qi Jinwen , Wang Shuyao , Hao Jin , Wu Yuanbing , Chen Hu , Tian Zhengzhi , Wang Bin , Chen Defang , Li Zhiqiong
Published: September 2017

To explore the effect of CCK on food intake in Siberian sturgeon, cck cDNA sequence of 1005 bp was obtained, and cck mRNA possessed the highest expression in brain. The expressions of cck were significantly increased after feeding 1 and 3 h, while displaying significant decrease after fasting within 15 days in brain and duodenum. Re-feeding for 3 days induced cck level returned to basic level. Acute i.p. injection experiment showed 100 and 200 ng/g BW CCK8 inhibited the food intake in 0–1 h together with the cumulative food intake within 3 h. 7 days chronic i.p. injection of 100 and 200 ng/g BW CCK8, both daily food intake and cumulative food intake were significantly decreased. In addition, chronic i.p injection of CCK8 induced the expression of feeding related factors changes including cck, ucn3, cart, apelin, pyy and npy in respective organization. Moreover, as revealed by the results, Lorglumide, the CCK1R selective antagonist, effectively reversed the inhibitory effects of CCK8 on food intake and the levels of feeding related factors. On the other hand, LY 225910, the CCK2R selective antagonist, partially reversed these effects. These results indicate CCK is a satiety factor inhibits the feeding of Siberian sturgeon primarily through CCK1R.
Interplay between 3′-UTR polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the risk of ischemic stroke
Authors: Kim Jung Oh , Park Han Sung , Ryu Chang Soo , Shin Jung-Won , Kim Jinkwon , Oh Seung Hun , Kim Ok Joon , Kim Nam Keun
Published: September 2017

Stroke incidence is a multifactorial disease and especially hyperhomocysteinemia is associated with a higher risk of stroke. Previous studies have reported a folate metabolism disorder associated with the MTHFR gene. We investigated four single nucleotide polymorphisms in the MTHFR 3′-UTR [2572 C > A (rs4846049), 4869 C > G (rs1537514), 5488 C > T (rs3737967), and 6685 T > C (rs4846048)] to elucidate associations between ischemic stroke prevalence and prognosis. We examined 511 consecutive patients with ischemic stroke. Additionally, we selected 411 sex-/age-matched control subjects from patients presenting at our hospitals during the same period. The MTHFR 2572 C > A and 6685 T > C were significantly associated with ischemic stroke prevalence in the cardioembolism subgroup (MTHFR 2572CC vs. CA + AA: AOR, 2.145; 95% CI, 1.203–3.827; P = 0.010; MTHFR 6685TT vs. CC: AOR, 10.146; 95% CI, 1.297–79.336; P = 0.027). The gene-environment combined effect was significant, with MTHFR 2572CA + AA and folate levels ≤3.45 ng/mL correlating with ischemic stroke incidence. In addition, the total homocysteine (tHcy) levels in subjects with MTHFR 2572AA were elevated compared to tHcy levels in subjects with MTHFR 2572CC. Therefore, we suggest that MTHFR 2572 C > A and 6685 T > C are associated with ischemic stroke pathogenesis. The combined effects of the MTHFR 3′-UTR polymorphisms and tHcy/folate levels may contribute to stroke prevalence.
The oxytocinergic system modulates sadistic context-dependent empathy in humans
Authors: Luo Siyang , Zhu Yiyi , Xu Ying , Kong Qianting
Published: September 2017

The oxytocinergic system is crucial for sociality and well-being and is associated with empathy. It is suggested that the oxytocinergic system exerts context- and person-dependent effects. We examined how sexual sadistic contexts influenced the effects of the oxytocinergic system on empathic-related behaviors and brain activity in healthy adults. Combining genetic neuroimaging, pharmacological techniques and a psychological paradigm of empathy, we recorded EEG neural responses in female OXTR rs53756 G/G and A/A carriers and measured subjective empathic ratings after intranasal administration of oxytocin/placebo in healthy male adults during the perception of painful facial expressions in sadistic/general social contexts. The results revealed that sadistic contexts modulate oxytocinergic effects on empathy at both behavioral and neural levels. The oxytocinergic system preferentially modulated empathic responses to sadistic contexts. These effects are moderated by individual’s trait empathy. Our combined genetic-pharmacological-imaging results provide a neurochemical mechanism for sadistic context-dependent effects of the oxytocinergic system on empathy.
Modeling the Kinetics of Integrin Receptor Binding to Hepatic Extracellular Matrix Proteins
Authors: Hudson Shanice V. , Dolin Christine E. , Poole Lauren G. , Massey Veronica L. , Wilkey Daniel , Beier Juliane I. , Merchant Michael L. , Frieboes Hermann B. , Arteel Gavin E.
Published: September 2017

The composition of the extracellular matrix (ECM) proteins and the expression of their cognate receptors dictate cell behavior and dynamics. In particular, the interactions of ECM proteins with integrin receptors are key mediators of these cellular processes, playing a crucial role in the progression of several diseases of the liver, including inflammation, fibrosis/cirrhosis and cancer. This study establishes a modeling approach combining computation and experiments to evaluate the kinetics of integrin receptor binding to hepatic ECM proteins. ECM ligand concentration was derived from LC-MS/MS quantification of the hepatic ECM from mice exposed to chronic carbon tetrachloride (CCl4); receptor density was derived from published literature. Mathematical models for ECM-integrin binding kinetics that were developed incorporate receptor divalence and an aggregation scheme to represent clustering. The computer simulations reproduced positive cooperativity in the receptor aggregation model when the aggregation equilibrium constant (Ka) was positive and greater than Keq for divalent complex formation. Importantly, the modeling projected an increase in integrin binding for several receptors for which signaling is known to be increased after CCl4 exposure in the liver. The proposed modeling approach may be of use to elucidate the kinetics of integrin receptor binding to ECM proteins for homeostatic and diseased livers.
AlphaScreen-based homogeneous assay using a pair of 25-residue artificial proteins for high-throughput analysis of non-native IgG
Authors: Senga Yukako , Imamura Hiroshi , Miyafusa Takamitsu , Watanabe Hideki , Honda Shinya
Published: September 2017

Therapeutic IgG becomes unstable under various stresses in the manufacturing process. The resulting non-native IgG molecules tend to associate with each other and form aggregates. Because such aggregates not only decrease the pharmacological effect but also become a potential risk factor for immunogenicity, rapid analysis of aggregation is required for quality control of therapeutic IgG. In this study, we developed a homogeneous assay using AlphaScreen and AF.2A1. AF.2A1 is a 25-residue artificial protein that binds specifically to non-native IgG generated under chemical and physical stresses. This assay is performed in a short period of time. Our results show that AF.2A1-AlphaScreen may be used to evaluate the various types of IgG, as AF.2A1 recognizes the non-native structure in the constant region (Fc region) of IgG. The assay was effective for detection of non-native IgG, with particle size up to ca. 500 nm, generated under acid, heat, and stirring conditions. In addition, this technique is suitable for analyzing non-native IgG in CHO cell culture supernatant and mixed with large amounts of native IgG. These results indicate the potential of AF.2A1-AlphaScreen to be used as a high-throughput evaluation method for process monitoring as well as quality testing in the manufacturing of therapeutic IgG.
Toll like receptor7 polymorphisms in relation to disease susceptibility and progression in Chinese patients with chronic HBV infection
Authors: Zhu Junping , Zhang Tong , Cao Lina , Li Aixin , Zheng Kai , Zhang Nan , Su Bin , Chen Zhiyun , Chen Ning , Wu Hao , He Qiushui
Published: September 2017

Toll-like receptors (TLRs) play a key role in innate and adaptive immunity, protecting the host from viral pathogens. We studied the effect of TLR7 polymorphisms on disease susceptibility and progression of chronic hepatitis B (CHB) infection in Chinese adults. Blood samples were taken from 612 patients with confirmed CHB, hepatitis B virus (HBV)-related liver cirrhosis (LC) or hepatocellular carcinoma (HCC) and 293 controls. TLR7 polymorphisms (rs179010-C > T, rs2074109-T > C, and rs179009-A > G) were analyzed by PCR-based sequencing. A significantly higher frequency of TLR7 rs179010 C allele was found in male CHB patients than in controls (74.8% vs 59.5%, P = 0.002). The frequency of rs179009 G allele was markedly increased with disease progression when male patients with CHB, LC and HCC were compared (P = 0.012). The haplotype CTA was significantly associated with an increased susceptibility to CHB among male patients (P = 0.000). Frequency of the haplotype CTG was higher in male patients with HCC than CHB (P = 0.005). No such differences in these allele frequencies were found between female patients and controls. Our results indicated that TLR7 polymorphisms play an important role in disease susceptibility and the progression of CHB infections in Chinese adults, and may partly explain the high incidence of HBV related diseases in Chinese men.
Supraspinal-selective TRPV1 desensitization induced by intracerebroventricular treatment with resiniferatoxin
Authors: Fukushima Akihiro , Mamada Kizuku , Iimura Aki , Ono Hideki
Published: September 2017

The transient receptor potential vanilloid type 1 (TRPV1) is a thermosensitive cation channel that triggers heat pain in the periphery. Long-term desensitization of TRPV1, which can be induced by excess amounts of agonists, has been a method for investigating the physiological relevance of TRPV1-containing neuronal circuits, and desensitization induced by various routes of administration, including systemic, intrathecal and intraganglionic, has been demonstrated in rodents. In the present study, we examined the effect of intracerebroventricular (i.c.v.) treatment with an ultrapotent TRPV1 agonist, resiniferatoxin (RTX), on nociception and the analgesic effect of acetaminophen, which is known to mediate the activation of central TRPV1. I.c.v. administration of RTX a week before the test did not affect the licking/biting response to intraplantar injection of RTX (RTX test), suggesting that such i.c.v. treatment spares the function of TRPV1 at the hindpaw. Mice that had been i.c.v.-administered RTX also exhibited normal nociceptive responses in the formalin test and the tail pressure test, but acetaminophen failed to induce analgesia in those mice in any of the tests. These results suggest that i.c.v. administration of RTX leads to brain-selective TRPV1 desensitization in mice.
A remarkable effect of the combination of probabilistic peer-punishment and coevolutionary mechanism on the evolution of cooperation
Authors: Ohdaira Tetsushi
Published: September 2017

In the previous studies, the author has proposed the probabilistic peer-punishment based on the difference of payoff, and presented that the proposed peer-punishment utilizes its mechanism for preventing antisocial punishment like retaliation of a defector on a cooperator, effectively enhances the evolution of cooperation, and greatly increases the average payoff of all players in various parameters regarding static three types of topology of connections. Here, this study introduces both activities of breaking and creating connections of every player based on his/her preference to the model of the proposed peer-punishment. Every player will keep connections with his/her preferable players, whereas he/she will frequently break connections with his/her dissatisfied other players. Therefore, the new model of this study is the combination of probabilistic peer-punishment and coevolutionary mechanism that not only strategy of players but also connections between players evolve. This study discovers new knowledge that such combination induces high-level evolution of cooperation and great increase of the average payoff of all players in the condition where cooperation is hard to evolve.
Stochastic resonance in a proton pumping Complex I of mitochondria membranes
Authors: Kaur D. , Filonenko I. , Mourokh L. , Fendler C. , Blick R. H.
Published: September 2017

We make use of the physical mechanism of proton pumping in the so-called Complex I within mitochondria membranes. Our model is based on sequential charge transfer assisted by conformational changes which facilitate the indirect electron-proton coupling. The equations of motion for the proton operators are derived and solved numerically in combination with the phenomenological Langevin equation describing the periodic conformational changes. We show that with an appropriate set of parameters, protons can be transferred against an applied voltage. In addition, we demonstrate that only the joint action of the periodic energy modulation and thermal noise leads to efficient uphill proton transfer, being a manifestation of stochastic resonance.
Evaluation of irreversible protein thermal inactivation caused by breakage of disulphide bonds using methanethiosulphonate
Authors: Futami Junichiro , Miyamoto Ai , Hagimoto Atsushi , Suzuki Shigeyuki , Futami Midori , Tada Hiroko
Published: September 2017

Many extracellular globular proteins have evolved to possess disulphide bonds in their native conformations, which aids in thermodynamic stabilisation. However, disulphide bond breakage by heating leads to irreversible protein denaturation through disulphide-thiol exchange reactions. In this study, we demonstrate that methanethiosulphonate (MTS) specifically suppresses the heat-induced disulphide-thiol exchange reaction, thus improving the heat-resistance of proteins. In the presence of MTS, small globular proteins that contain disulphides can spontaneously refold from heat-denatured states, maintaining wild-type disulphide pairing. Because the disulphide-thiol exchange reaction is triggered by the generation of catalytic amounts of perthiol or thiol, rapid and specific perthiol/thiol protection by MTS reagents prevents irreversible denaturation. Combining MTS reagents with another additive that suppresses chemical modifications, glycinamide, further enhanced protein stabilisation. In the presence of these additives, reliable remnant activities were observed even after autoclaving. However, immunoglobulin G and biotin-binding protein, which are both composed of tetrameric quaternary structures, failed to refold from heat-denatured states, presumably due to chaperon requirements. Elucidation of the chemical modifications involved in irreversible thermoinactivation is useful for the development of preservation buffers with optimum constitutions for specific proteins. In addition, the impact of disulphide bond breakage on the thermoinactivation of proteins can be evaluated using MTS reagents.
Targeted genome editing restores T cell differentiation in a humanized X-SCID pluripotent stem cell disease model
Authors: Alzubi Jamal , Pallant Celeste , Mussolino Claudio , Howe Steven J. , Thrasher Adrian J. , Cathomen Toni
Published: September 2017

The generation of T cells from pluripotent stem cells (PSCs) is attractive for investigating T cell development and validating genome editing strategies in vitro. X-linked severe combined immunodeficiency (X-SCID) is an immune disorder caused by mutations in the IL2RG gene and characterised by the absence of T and NK cells in patients. IL2RG encodes the common gamma chain, which is part of several interleukin receptors, including IL-2 and IL-7 receptors. To model X-SCID in vitro, we generated a mouse embryonic stem cell (ESC) line in which a disease-causing human IL2RG gene variant replaces the endogenous Il2rg locus. We developed a stage-specific T cell differentiation protocol to validate genetic correction of the common G691A mutation with transcription activator-like effector nucleases. While all ESC clones could be differentiated to hematopoietic precursor cells, stage-specific analysis of T cell maturation confirmed early arrest of T cell differentiation at the T cell progenitor stage in X-SCID cells. In contrast, genetically corrected ESCs differentiated to CD4 + or CD8 + single-positive T cells, confirming correction of the cellular X-SCID phenotype. This study emphasises the value of PSCs for disease modelling and underlines the significance of in vitro models as tools to validate genome editing strategies before clinical application.
Comparative Transcriptome Analysis of Mink (Neovison vison) Skin Reveals the Key Genes Involved in the Melanogenesis of Black and White Coat Colour
Authors: Song Xingchao , Xu Chao , Liu Zongyue , Yue Zhigang , Liu Linling , Yang Tongao , Cong Bo , Yang Fuhe
Published: September 2017

Farmed mink (Neovison vison) is one of the most important fur-bearing species worldwide, and coat colour is a crucial qualitative characteristic that contributes to the economic value of the fur. To identify additional genes that may play important roles in coat colour regulation, Illumina/Solexa high-throughput sequencing technology was used to catalogue the global gene expression profiles in mink skin with two different coat colours (black and white). RNA-seq analysis indicated that a total of 12,557 genes were differentially expressed in black versus white minks, with 3,530 genes up-regulated and 9,027 genes down-regulated in black minks. Significant differences were not observed in the expression of MC1R and TYR between the two different coat colours, and the expression of ASIP was not detected in the mink skin of either coat colour. The expression levels of KITLG, LEF1, DCT, TYRP1, PMEL, Myo5a, Rab27a and SLC7A11 were validated by qRT-PCR, and the results were consistent with RNA-seq analysis. This study provides several candidate genes that may be associated with the development of two coat colours in mink skin. These results will expand our understanding of the complex molecular mechanisms underlying skin physiology and melanogenesis in mink and will provide a foundation for future studies.
IL-17A induces heterogeneous macrophages, and it does not alter the effects of lipopolysaccharides on macrophage activation in the skin of mice
Authors: Nakai Kozo , He Yu-Ying , Nishiyama Fumiko , Naruse Fukiko , Haba Reiji , Kushida Yoshio , Katsuki Naomi , Moriue Tetsuya , Yoneda Kozo , Kubota Yasuo
Published: September 2017

Macrophages are central to inflammatory response and become polarized towards the M1 or M2 states upon activation by immunostimulants. In this study, we investigated the effects of lipopolysaccharides (LPS) and interleukin (IL)-17A on the activation of macrophages in in vivo mouse skin. We examined whether macrophages are activated in the skin of imiquimod (IMQ)-treated mice, a model for IL-17A-induced psoriasis-like skin inflammation, and flaky-tail (Flg
ft
) mice, a model for IL-17A-induced chronic atopic dermatitis-like skin inflammation. LPS and IL-17A independently increased the expression levels of iNOS, CX3CR1, CD206, phospho-STAT1 and phospho-STAT3 proteins in the skin of B6 mice, and the effects of LPS was not altered by IL-17A. The expression levels of these proteins were increased in the skin of IMQ-treated and Flg
ft
mice. IL-17A neutralization increased the expressions of iNOS and phospho-STAT1 in the IMQ-treated skin, but it decreased the expressions of CD206 and phospho-STAT3 proteins in the skin of Flg
ft
mice, suggesting that macrophages to change from the M2 to the M1 state in the skin of these mice. These results suggest that IL-17A is involved in the activation of macrophages that are in the process of adopting the heterogeneous profiles of both the M1 and M2 states.
Immunoprotective potential of BamA, the outer membrane protein assembly factor, against MDR Acinetobacter baumannii
Authors: Singh Ravinder , Capalash Neena , Sharma Prince
Published: September 2017

Abstarct

Acinetobacter baumannii infections are responsible for major health problems in immunocompromised patients particularly in intensive care units. Due to rapid acquisition of and also inherent drug resistance, a vaccine is an effective treatment option against this pathogen. BamA, an outer membrane β-barrel assembly protein, was identified in A. baumannii as potential vaccine candidate by in silico analysis. The immunoprotective efficacy of this highly conserved protein was investigated against a virulent multidrug resistant clinical isolate using murine pneumonia model. Recombinant BamA elicited a high IgG antibody titer (160000) in mice. Opsonophagocytic killing assay showed non-neutrilizing, opsonizing antibodies with combinatorial bactericidal activity of antibodies and complement components. Active and passive immunization protected 80 and 60% mice respectively against intranasal challenge with lethal dose (109 CFU) of virulent A. baumannii along with efficient clearance of bacteria in mice lungs and reduction in levels of pro-inflammatory cytokines viz. TNF-α, IL-6 and IL-1β in sera and lung tissue homogenate. Increase in levels of IL-10, an anti-inflammatory cytokine and reduction of neutrophils in lungs facilitated the control of infection. This study demonstrates the potential of BamA as effective vaccine candidate and a promising target for antibody-based therapy to protect against MDR A. baumannii infections.
Herbicide glufosinate inhibits yeast growth and extends longevity during wine fermentation
Authors: Vallejo Beatriz , Picazo Cecilia , Orozco Helena , Matallana Emilia , Aranda Agustín
Published: September 2017

Glufosinate ammonium (GA) is a widely used herbicide that inhibits glutamine synthetase. This inhibition leads to internal amino acid starvation which, in turn, causes the activation of different nutrient sensing pathways. GA also inhibits the enzyme of the yeast Saccharomyces cerevisiae in such a way that, although it is not used as a fungicide, it may alter yeast performance in industrial processes like winemaking. We describe herein how GA indeed inhibits the yeast growth of a wine strain during the fermentation of grape juice. In turn, GA extends longevity in a variety of growth media. The biochemical analysis indicates that GA partially inhibits the nutrient sensing TORC1 pathway, which may explain these phenotypes. The GCN2 kinase mutant is hypersensitive to GA. Hence the control of translation and amino acid biosynthesis is required to also deal with the damaging effects of this pesticide. A global metabolomics analysis under winemaking conditions indicated that an increase in amino acid and in polyamines occurred. In conclusion, GA affects many different biochemical processes during winemaking, which provides us with some insights into both the effect of this herbicide on yeast physiology and into the relevance of the metabolic step for connecting nitrogen and carbon metabolism.
Enhanced Neonatal Brain Responses To Sung Streams Predict Vocabulary Outcomes By Age 18 Months
Authors: François Clément , Teixidó Maria , Takerkart Sylvain , Agut Thaïs , Bosch Laura , Rodriguez-Fornells Antoni
Published: September 2017

Words and melodies are some of the basic elements infants are able to extract early in life from the auditory input. Whether melodic cues contained in songs can facilitate word-form extraction immediately after birth remained unexplored. Here, we provided converging neural and computational evidence of the early benefit of melodies for language acquisition. Twenty-eight neonates were tested on their ability to extract word-forms from continuous flows of sung and spoken syllabic sequences. We found different brain dynamics for sung and spoken streams and observed successful detection of word-form violations in the sung condition only. Furthermore, neonatal brain responses for sung streams predicted expressive vocabulary at 18 months as demonstrated by multiple regression and cross-validation analyses. These findings suggest that early neural individual differences in prosodic speech processing might be a good indicator of later language outcomes and could be considered as a relevant factor in the development of infants’ language skills.
Genetic elimination of dopamine vesicular stocks in the nigrostriatal pathway replicates Parkinson’s disease motor symptoms without neuronal degeneration in adult mice
Authors: Isingrini Elsa , Guinaudie Chloé , C Perret Léa , Rainer Quentin , Moquin Luc , Gratton Alain , Giros Bruno
Published: September 2017

The type 2 vesicular monoamine transporter (VMAT2), by regulating the storage of monoamines transmitters into synaptic vesicles, has a protective role against their cytoplasmic toxicity. Increasing evidence suggests that impairment of VMAT2 neuroprotection contributes to the pathogenesis of Parkinson’s disease (PD). Several transgenic VMAT2 mice models have been developed, however these models lack specificity regarding the monoaminergic system targeting. To circumvent this limitation, we created VMAT2-KO mice specific to the dopamine (DA) nigrostriatal pathway to analyze VMAT2’s involvement in DA depletion-induced motor features associated to PD and examine the relevance of DA toxicity in the pathogenesis of neurodegeneration. Adult VMAT2 floxed mice were injected in the substancia nigra (SN) with an adeno-associated virus (AAV) expressing the Cre-recombinase allowing VMAT2 removal in DA neurons of the nigrostriatal pathway solely. VMAT2 deletion in the SN induced both DA depletion exclusively in the dorsal striatum and motor dysfunction. At 16 weeks post-injection, motor symptoms were accompanied with a decreased in food and water consumption and weight loss. However, despite an accelerating death, degeneration of nigrostriatal neurons was not observed in this model during this time frame. This study highlights a non-cytotoxic role of DA in our genetic model of VMAT2 deletion exclusively in nigrostriatal neurons.
Periodically spilled-oil input as a trigger to stimulate the development of hydrocarbon-degrading consortia in a beach ecosystem
Authors: Zhang Kai , Sun Yongge , Cui Zhisong , Yu Di , Zheng Li , Liu Peng , Lv Zhenmei
Published: September 2017

In this study, time-series samples were taken from a gravel beach to ascertain whether a periodic oil input induced by tidal action at the early stage of an oil spill can be a trigger to stimulate the development of hydrocarbon-degrading bacteria under natural in situ attenuation. High-throughput sequencing shows that the microbial community in beach sediments is characterized by the enrichment of hydrocarbon-degrading bacteria, including Alcanivorax, Dietzia, and Marinobacter. Accompanying the periodic floating-oil input, dynamic successions of microbial communities and corresponding fluctuations in functional genes (alkB and RDH) are clearly indicated in a time sequence, which keeps pace with the ongoing biodegradation of the spilled oil. The microbial succession that accompanies tidal action could benefit from the enhanced exchange of oxygen and nutrients; however, regular inputs of floating oil can be a trigger to stimulate an in situ “seed bank” of hydrocarbon-degrading bacteria. This leads to the continued blooming of hydrocarbon-degrading consortia in beach ecosystems. The results provide new insights into the beach microbial community structure and function in response to oil spills.
Approaching gender equity in academic chemistry: lessons learned from successful female chemists in the UK
Authors: Miller-Friedmann Jaimie , Childs Ann , Hillier Judith
Published: September 2017

The internationally acknowledged gender gap in science continues to be an unrelenting concern to science educators; aggregate data in the UK show that both recruitment and retention of women in academic science remain relatively low. Most published research focuses on women in the broad field of science, generates correlations or predictions, or examines the reasons why women do not participate in fields like physics or engineering. Previous work has not yet addressed how women have found ways to succeed in particular fields, such as chemistry, or how successful pathways may be applied to recruitment and retention efforts in those fields. This study investigated the experiences of successful British female chemists, in order to uncover coping mechanisms and commonalities that may illuminate obstacles and solutions particular to women in chemistry. Four case study semi-structured life history interviews with highly successful British female chemists revealed common experiences that helped the women in the study to succeed. Of these, two resonated with the literature: having an integrated support network, and the ability to cope with financial and career instability; choice of subfield and adaptation of (unconscious) bias are offered as new insights. The findings suggest changes in policy and practice that would provide particular kinds of support for women in chemistry at school and university level. Implementing these changes may be the impetus needed to approach gender parity in UK academic chemistry from undergraduate to Professor.
Sphingosine and dihydrosphingosine as biomarkers for multiple sclerosis identified by metabolomic profiling using coupled UPLC-MS
Authors: Ward Sean , Page Michael I. , McHugh Patrick , Powles Nicholas T.
Published: September 2017

The project aim was to identify differences in the metabolomic profiles in the serum of patients with multiple sclerosis (MS), those with neuropathic pain (NP) and those with both MS and NP compared with controls and to identify potential biomarkers of each disease state.
Co3O4 morphology in the preferential oxidation of CO
Authors: Khasu Motlokoa , Nyathi Thulani , Morgan David J. , Hutchings Graham J. , Claeys Michael , Fischer Nico
Published: September 2017

Different morphologies of Co3O4 were synthesized and tested for their performance in the preferential oxidation (PrOx) of carbon monoxide to investigate the effect of preferentially exposed crystal planes.
Enhancing bimetallic synergy with light: the effect of UV light pre-treatment on catalytic oxygen activation by bimetallic Au–Pt nanoparticles on a TiO2support
Authors: Wong Roong Jien , Scott Jason , Kappen Peter , Low Gary K.-C. , Hart Judy N. , Amal Rose
Published: September 2017

UV pre-illumination-enhanced bimetallic synergy work-function-driven electron transfer pathway.Au;Pt;oxygen;electron.
A green route for methanol carbonylation
Authors: Ni Youming , Shi Lei , Liu Hongchao , Zhang Wenna , Liu Yong , Zhu Wenliang , Liu Zhongmin
Published: September 2017

Halide-free and noble metal-free pyridine-modified H-mordenites exhibit high stability and selectivity in methanol carbonylation to acetic acid.
A long-range emissive mega-Stokes inorganic–organic hybrid material with peripheral carboxyl functionality for As(v) recognition and its application in bioimaging
Authors: Venkateswarulu M. , Gambhir Diksha , Kaur Harpreet , Daniel P. Vineeth , Mondal Prosenjit , Koner Rik Rani
Published: September 2017

We demonstrate a strategy for the recognition of As5+ in aqueous solution using a red-emissive probe based on a perylene–Cu2+ ensemble decorated with peripheral free carboxyl functionality.