bluuebunny/crossref_metadata_2025 huggingface dataset:
Cataloging Nature: Standardizing Fruit Varieties in the United States, 1800–1860
Authors: Pawley Emily
Published: November 2016

The forests and fields of the early American republic teemed with individually varying seedling fruit trees. American nurserymen stabilized both this chaotic landscape and their trade by promoting named fruit “varieties” gleaned from domestic orchards and from a global network of botanical gardens. Developing strategies to regulate the production of names and descriptions, they altered both texts and organisms, replacing a profusion of “wild” trees with a negotiated list of “named varieties.” Examining this process reveals intersections between commercial and scientific credibility and illuminates the alternative business forms built around living goods.
Effect of combined acetylmethionine, cyanocobalamin and α-lipoic acid on hepatic metabolism in high-yielding dairy cow
Authors: Fiore Enrico , Perillo Laura , Piccione Giuseppe , Gianesella Matteo , Bedin Silvia , Armato Leonardo , Giudice Elisabetta , Morgante Massimo
Published: November 2016

The aim of the study reported in this Research Communication was to investigate the effect of a combined acetylmethionine, cyanocobalamin and α-lipoic acid treatment, on some metabolic parameters of early lactating high-yielding dairy cows. Thirty cows were randomly divided into two groups: experimental group (EG, n = 20) and control group (CG, n = 10). EG received 20 ml of treatment and CG received 20 ml of placebo. The treatments were administered for seven times every 2 d. Blood samples were collected from all cows at 3 time points: 10 ± 2, 30 ± 2 and 50 ± 2 d postpartum. Glucose, β-hydroxybutyrate (BHB), nonesterified fatty acids (NEFA), triglycerides, total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamiltransferase (GGT), total bilirubin (TB), conjugated bilirubin (CB), total proteins (TP), globulins, albumin and urea concentrations were determined. Two-way repeated measure analysis of variance was applied. Significant differences in the values of glucose, BHB, NEFA, triglycerides, TC, AST and urea were found between EG and CG. Moreover, the increased glucose, TC, ALT, GGT, TP and globulins, and the reduced BHB, NEFA, AST, triglycerides, TB, CB and urea concentrations were evident in both groups, but the changes were more pronounced in EG. Our findings indicate that our treatment positively influenced liver metabolism in high-yielding dairy cows.
The value of pathogen information in treating clinical mastitis
Authors: Cha Elva , Smith Rebecca L , Kristensen Anders R , Hertl Julia A , Schukken Ynte H , Tauer Loren W , Welcome Frank L , Gröhn Yrjö T
Published: November 2016

The objective of this study was to determine the economic value of obtaining timely and more accurate clinical mastitis (CM) test results for optimal treatment of cows. Typically CM is first identified when the farmer observes recognisable outward signs. Further information of whether the pathogen causing CM is Gram-positive, Gram-negative or other (including no growth) can be determined by using on-farm culture methods. The most detailed level of information for mastitis diagnostics is obtainable by sending milk samples for culture to an external laboratory. Knowing the exact pathogen permits the treatment method to be specifically targeted to the causation pathogen, resulting in less discarded milk. The disadvantages are the additional waiting time to receive test results, which delays treating cows, and the cost of the culture test. Net returns per year (NR) for various levels of information were estimated using a dynamic programming model. The Value of Information (VOI) was then calculated as the difference in NR using a specific level of information as compared to more detailed information on the CM causative agent. The highest VOI was observed where the farmer assumed the pathogen causing CM was the one with the highest incidence in the herd and no pathogen specific CM information was obtained. The VOI of pathogen specific information, compared with non-optimal treatment of Staphylococcus aureus where recurrence and spread occurred due to lack of treatment efficacy, was $20.43 when the same incorrect treatment was applied to recurrent cases, and $30.52 when recurrent cases were assumed to be the next highest incidence pathogen and treated accordingly. This indicates that negative consequences associated with choosing the wrong CM treatment can make additional information cost-effective if pathogen identification is assessed at the generic information level and if the pathogen can spread to other cows if not treated appropriately.
Delayed Registration and Identifying the “Missing Girls” in China
Authors: Shi Yaojiang , Kennedy John James
Published: November 2016

In 2010, according to the sixth Chinese census, the sex ratio at birth (SRB) was 118 males for every 100 females. The global SRB average is about 105. Thus, the gap between 118 and 105 is made up of “missing girls.” Scholars present three main explanations for the skewed SRB statistic: sex-selective abortion, infanticide and delayed or late registration. Most studies take a demographic and cultural approach to explain the high SRB. However, we believe the story of the “missing girls” is also an administrative one and adopt the street-level bureaucrat theory of policy implementation to explain the pervasiveness of late registration in rural China. We use descriptive statistics derived from the 1990, 2000 and 2010 census data to identify the “missing girls.” We believe the combination of late registration and unreported births may point to a larger proportion of “missing girls” than previously reported from the SRB statistic.
Yet more on a stochastic economic model: Part 3A: stochastic interpolation: Brownian and Ornstein–Uhlenbeck (OU) bridges
Authors: Wilkie A. D. , Şahin Şule
Published: November 2016

In this paper, we develop certain properties for discrete Brownian bridges and Ornstein–Uhlenbeck bridges, which we use in the successor papers Part 3B and Part 3C to analyse real economic data series, with a view to constructing stochastic interpolation models for the Wilkie asset model.
Intranasal Oxytocin Enhances Connectivity in the Neural Circuitry Supporting Social Motivation and Social Perception in Children with Autism
Authors: Gordon Ilanit , Jack Allison , Pretzsch Charlotte M. , Vander Wyk Brent , Leckman James F. , Feldman Ruth , Pelphrey Kevin A.
Published: November 2016

Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain’s reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation—one that could, in future, be harnessed to augment behavioral treatments for ASD.
SNP discovery and genotyping using Genotyping-by-Sequencing in Pekin ducks
Authors: Zhu Feng , Cui Qian-Qian , Hou Zhuo-Cheng
Published: November 2016

Genomic selection and genome-wide association studies need thousands to millions of SNPs. However, many non-model species do not have reference chips for detecting variation. Our goal was to develop and validate an inexpensive but effective method for detecting SNP variation. Genotyping by sequencing (GBS) can be a highly efficient strategy for genome-wide SNP detection, as an alternative to microarray chips. Here, we developed a GBS protocol for ducks and tested it to genotype 49 Pekin ducks. A total of 169,209 SNPs were identified from all animals, with a mean of 55,920 SNPs per individual. The average SNP density reached 1156 SNPs/MB. In this study, the first application of GBS to ducks, we demonstrate the power and simplicity of this method. GBS can be used for genetic studies in to provide an effective method for genome-wide SNP discovery.
Characterizing the Blood Oxygen Level-Dependent Fluctuations in Musculoskeletal Tumours Using Functional Magnetic Resonance Imaging
Authors: Duan Li-Sha , Wang Meng-Jun , Sun Feng , Zhao Zhen-Jiang , Xing Mei , Zang Yu-Feng , Louis Steven , Cui Sheng-Jie , Cui Jian-Ling , Zhang Han
Published: November 2016

This study characterized the blood oxygen level-dependent (BOLD) fluctuations in benign and malignant musculoskeletal tumours via power spectrum analyses in pre-established low-frequency bands. BOLD MRI and T1-weighted imaging (T1WI) were collected for 52 patients with musculoskeletal tumours. Three ROIs were drawn on the T1WI image in the tumours’ central regions, peripheral regions and neighbouring tissue. The power spectrum of the BOLD within each ROI was calculated and divided into the following four frequency bands: 0.01–0.027 Hz, 0.027–0.073 Hz, 0.073–0.198 Hz, and 0.198–0.25 Hz. ANOVA was conducted for each frequency band with the following two factors: the location of the region of interest (LoR, three levels: tumour “centre”, “peripheral” and “healthy tissue”) and tumour characteristic (TC, two levels: “malignant” and “benign”). There was a significant main effect of LoR in the frequencies of 0.073–0.198 Hz and 0.198–0.25 Hz. These data were further processed with post-hoc pair-wise comparisons. BOLD fluctuations at 0.073–0.198 Hz were stronger in the peripheral than central regions of the malignant tumours; however, no such difference was observed for the benign tumours. Our findings provide evidence that the BOLD signal fluctuates with spatial heterogeneity in malignant musculoskeletal tumours at the frequency band of 0.073–0.198 Hz.
Systems-level chromosomal parameters represent a suprachromosomal basis for the non-random chromosomal arrangement in human interphase nuclei
Authors: Fatakia Sarosh N. , Mehta Ishita S. , Rao Basuthkar J.
Published: November 2016

Forty-six chromosome territories (CTs) are positioned uniquely in human interphase nuclei, wherein each of their positions can range from the centre of the nucleus to its periphery. A non-empirical basis for their non-random arrangement remains unreported. Here, we derive a suprachromosomal basis of that overall arrangement (which we refer to as a CT constellation), and report a hierarchical nature of the same. Using matrix algebra, we unify intrinsic chromosomal parameters (e.g., chromosomal length, gene density, the number of genes per chromosome), to derive an extrinsic effective gene density matrix, the hierarchy of which is dominated largely by extrinsic mathematical coupling of HSA19, followed by HSA17 (human chromosome 19 and 17, both preferentially interior CTs) with all CTs. We corroborate predicted constellations and effective gene density hierarchy with published reports from fluorescent in situ hybridization based microscopy and Hi-C techniques, and delineate analogous hierarchy in disparate vertebrates. Our theory accurately predicts CTs localised to the nuclear interior, which interestingly share conserved synteny with HSA19 and/or HSA17. Finally, the effective gene density hierarchy dictates how permutations among CT position represents the plasticity within its constellations, based on which we suggest that a differential mix of coding with noncoding genome modulates the same.
Serum metabolomics analysis of patients with chikungunya and dengue mono/co-infections reveals distinct metabolite signatures in the three disease conditions
Authors: Shrinet Jatin , Shastri Jayanthi S. , Gaind Rajni , Bhavesh Neel Sarovar , Sunil Sujatha
Published: November 2016

Chikungunya and dengue are arboviral infections with overlapping clinical symptoms. A subset of chikungunya infection occurs also as co-infections with dengue, resulting in complications during diagnosis and patient management. The present study was undertaken to identify the global metabolome of patient sera infected with chikungunya as mono infections and with dengue as co-infections. Using nuclear magnetic resonance (NMR) spectroscopy, the metabolome of sera of three disease conditions, namely, chikungunya and dengue as mono-infections and when co-infected were ascertained and compared with healthy individuals. Further, the cohorts were analyzed on the basis of age, onset of fever and joint involvement. Here we show that many metabolites in the serum are significantly differentially regulated during chikungunya mono-infection as well as during chikungunya co-infection with dengue. We observed that glycine, serine, threonine, galactose and pyrimidine metabolisms are the most perturbed pathways in both mono and co-infection conditions. The affected pathways in our study correlate well with the clinical manifestation like fever, inflammation, energy deprivation and joint pain during the infections. These results may serve as a starting point for validations and identification of distinct biomolecules that could be exploited as biomarker candidates thereby helping in better patient management.
Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3
Authors: Son Dong Ju , Kim Dae Hwan , Nah Seong-Su , Park Mi Hee , Lee Hee Pom , Han Sang Bae , Venkatareddy Udumula , Gann Benjamin , Rodriguez Kevin , Burt Scott R. , Ham Young Wan , Jung Yu Yeon , Hong Jin Tae
Published: November 2016

Rheumatoid arthritis (RA) is a severely debilitating chronic autoimmune disease that leads to long-term joint damage. Signal transducer and activator of transcription 3 (STAT3)-targeted small molecules have shown promise as therapeutic drugs for treating RA. We previously identified (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), a tyrosine-fructose Maillard reaction product, as a small molecule with potent anti-inflammatory and anti-arthritic properties, mediated through the inhibition of STAT3 activation. The aim of this study was to develop a novel BHPH derivative with improved anti-arthritic properties and drug-likeness. We designed and synthesised (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a novel synthetic BHPB analogue, and investigated its anti-inflammatory and anti-arthritic activities in experimentally-induced RA. We showed that MMPP strongly inhibited pro-inflammatory responses by inhibiting in vitro STAT3 activation and its downstream signalling in murine macrophages and human synoviocytes from patients with RA. Furthermore, we demonstrated that MMPP exhibited potent anti-arthritic activity in a collagen antibody-induced arthritis (CAIA) mouse model in vivo. Collectively, our results suggest that MMPP has great potential for use in the treatment of RA.
A genomic island in Vibrio cholerae with VPI-1 site-specific recombination characteristics contains CRISPR-Cas and type VI secretion modules
Authors: Labbate Maurizio , Orata Fabini D. , Petty Nicola K. , Jayatilleke Nathasha D. , King William L. , Kirchberger Paul C. , Allen Chris , Mann Gulay , Mutreja Ankur , Thomson Nicholas R. , Boucher Yan , Charles Ian G.
Published: November 2016

Cholera is a devastating diarrhoeal disease caused by certain strains of serogroup O1/O139 Vibrio cholerae. Mobile genetic elements such as genomic islands (GIs) have been pivotal in the evolution of O1/O139 V. cholerae. Perhaps the most important GI involved in cholera disease is the V. cholerae pathogenicity island 1 (VPI-1). This GI contains the toxin-coregulated pilus (TCP) gene cluster that is necessary for colonization of the human intestine as well as being the receptor for infection by the cholera-toxin bearing CTX phage. In this study, we report a GI (designated GIVchS12) from a non-O1/O139 strain of V. cholerae that is present in the same chromosomal location as VPI-1, contains an integrase gene with 94% nucleotide and 100% protein identity to the VPI-1 integrase, and attachment (att) sites 100% identical to those found in VPI-1. However, instead of TCP and the other accessory genes present in VPI-1, GIVchS12 contains a CRISPR-Cas element and a type VI secretion system (T6SS). GIs similar to GIVchS12 were identified in other V. cholerae genomes, also containing CRISPR-Cas elements and/or T6SS’s. This study highlights the diversity of GIs circulating in natural V. cholerae populations and identifies GIs with VPI-1 recombination characteristics as a propagator of CRISPR-Cas and T6SS modules.
A dual inhibition mechanism of herpesviral ICP47 arresting a conformationally thermostable TAP complex
Authors: Herbring Valentina , Bäucker Anja , Trowitzsch Simon , Tampé Robert
Published: November 2016

As a centerpiece of antigen processing, the ATP-binding cassette transporter associated with antigen processing (TAP) became a main target for viral immune evasion. The herpesviral ICP47 inhibits TAP function, thereby suppressing an adaptive immune response. Here, we report on a thermostable ICP47-TAP complex, generated by fusion of different ICP47 fragments. These fusion complexes allowed us to determine the direction and positioning in the central cavity of TAP. ICP47-TAP fusion complexes are arrested in a stable conformation, as demonstrated by MHC I surface expression, melting temperature, and the mutual exclusion of herpesviral TAP inhibitors. We unveiled a conserved region next to the active domain of ICP47 as essential for the complete stabilization of the TAP complex. Binding of the active domain of ICP47 arrests TAP in an open inward facing conformation rendering the complex inaccessible for other viral factors. Based on our findings, we propose a dual interaction mechanism for ICP47. A per se destabilizing active domain inhibits the function of TAP, whereas a conserved C-terminal region additionally stabilizes the transporter. These new insights into the ICP47 inhibition mechanism can be applied for future structural analyses of the TAP complex.
Mesoscopic packing of disk-like building blocks in calcium silicate hydrate
Authors: Yu Zechuan , Zhou Ao , Lau Denvid
Published: November 2016

At 100-nanometer length scale, the mesoscopic structure of calcium silicate hydrate (C-S-H) plays a critical role in determining the macroscopic material properties, such as porosity. In order to explore the mesoscopic structure of C-S-H, we employ two effective techniques, nanoindentation test and molecular dynamics simulation. Grid nanoindentation tests find different porosity of C-S-H in cement paste specimens prepared at varied water-to-cement (w/c) ratios. The w/c-ratio-induced porosity difference can be ascribed to the aspect ratio (diameter-to-thickness ratio) of disk-like C-S-H building blocks. The molecular dynamics simulation, with a mesoscopic C-S-H model, reveals 3 typical packing patterns and relates the packing density to the aspect ratio. Illustrated with disk-like C-S-H building blocks, this study provides a description of C-S-H structures in complement to spherical-particle C-S-H models at the sub-micron scale.
Giant suppression of phononic heat transport in a quantum magnet BiCu2PO6
Authors: Jeon Byung-Gu , Koteswararao B. , Park C. B. , Shu G. J. , Riggs S. C. , Moon E. G. , Chung S. B. , Chou F. C. , Kim Kee Hoon
Published: November 2016

Thermal transport of quantum magnets has elucidated the nature of low energy elementary excitations and complex interplay between those excited states via strong scattering of thermal carriers. BiCu2PO6 is a unique frustrated spin-ladder compound exhibiting highly anisotropic spin excitations that contain both itinerant and localized dispersion characters along the b- and a-axes respectively. Here, we investigate thermal conductivity κ of BiCu2PO6 under high magnetic fields (H) of up to 30 tesla. A dip-feature in κ, located at ~15 K at zero-H along all crystallographic directions, moves gradually toward lower temperature (T) with increasing H, thus resulting in giant suppression by a factor of ~30 near the critical magnetic field of Hc ≅ 23.5 tesla. The giant H- and T-dependent suppression of κ can be explained by the combined result of resonant scattering of phononic heat carriers with magnetic energy levels and increased phonon scattering due to enhanced spin fluctuation at Hc, unequivocally revealing the existence of strong spin-phonon coupling. Moreover, we find an experimental indication that the remaining magnetic heat transport along the b-axis becomes almost gapless at the magnetic quantum critical point realized at Hc.
Sacrificial Reducing Agent Free Photo-Generation of Platinum Nano Particle over Carbon/TiO2 for Highly Efficient Oxygen Reduction Reaction
Authors: Badam Rajashekar , Vedarajan Raman , Okaya Kazuki , Matsutani Koichi , Matsumi Noriyoshi
Published: November 2016

Electrocatalytic materials for oxygen reduction reaction, currently dominated by platinum/carbon catalyst is marred by drawbacks such as use of copious amount of Pt and use of “non-green” sacrificial reducing agent (SRA) during its synthesis. A single stroke remedy for these two problems has been achieved through an in-situ aqueous photoreduction void of even trace amounts of SRA with an enhanced activity. Reduction of PtCl62− salt to Pt nano particles on carbon substrate was achieved solely using solar spectrum as the source of energy and TiO2 as photocatalyst. Here, we demonstrate that this new procedure of photoreduction, decorates Pt over different types of conducting allotropes with the distribution and the particle size primarily depending on the conductivity of the allotrope. The Pt/C/TiO2 composite unveiled an ORR activity on par to the most efficient Pt based electrocatalyst prepared through the conventional sacrificial reducing agent aided preparation methods.
Cellulose nanofiber backboned Prussian blue nanoparticles as powerful adsorbents for the selective elimination of radioactive cesium
Authors: Vipin Adavan Kiliyankil , Fugetsu Bunshi , Sakata Ichiro , Isogai Akira , Endo Morinobu , Li Mingda , Dresselhaus Mildred S.
Published: November 2016

On 11 March 2011, the day of the unforgettable disaster of the 9 magnitude Tohoku earthquake and quickly followed by the devastating Tsunami, a damageable amount of radionuclides had dispersed from the Fukushima Daiichi’s damaged nuclear reactors. Decontamination of the dispersed radionuclides from seawater and soil, due to the huge amounts of coexisting ions with competitive functionalities, has been the topmost difficulty. Ferric hexacyanoferrate, also known as Prussian blue (PB), has been the most powerful material for selectively trapping the radioactive cesium ions; its high tendency to form stable colloids in water, however, has made PB to be impossible for the open-field radioactive cesium decontamination applications. A nano/nano combinatorial approach, as is described in this study, has provided an ultimate solution to this intrinsic colloid formation difficulty of PB. Cellulose nanofibers (CNF) were used to immobilize PB via the creation of CNF-backboned PB. The CNF-backboned PB (CNF/PB) was found to be highly tolerant to water and moreover, it gave a 139 mg/g capability and a million (106) order of magnitude distribution coefficient (Kd) for absorbing of the radioactive cesium ion. Field studies on soil and seawater decontaminations in Fukushima gave satisfactory results, demonstrating high capabilities of CNF/PB for practical applications.
Effects of behavioral patterns and network topology structures on Parrondo’s paradox
Authors: Ye Ye , Cheong Kang Hao , Cen Yu-wan , Xie Neng-gang
Published: November 2016

A multi-agent Parrondo’s model based on complex networks is used in the current study. For Parrondo’s game A, the individual interaction can be categorized into five types of behavioral patterns: the Matthew effect, harmony, cooperation, poor-competition-rich-cooperation and a random mode. The parameter space of Parrondo’s paradox pertaining to each behavioral pattern, and the gradual change of the parameter space from a two-dimensional lattice to a random network and from a random network to a scale-free network was analyzed. The simulation results suggest that the size of the region of the parameter space that elicits Parrondo’s paradox is positively correlated with the heterogeneity of the degree distribution of the network. For two distinct sets of probability parameters, the microcosmic reasons underlying the occurrence of the paradox under the scale-free network are elaborated. Common interaction mechanisms of the asymmetric structure of game B, behavioral patterns and network topology are also revealed.
Sex-specific associations of low birth weight with adult-onset diabetes and measures of glucose homeostasis: Brazilian Longitudinal Study of Adult Health
Authors: Yarmolinsky James , Mueller Noel T , Duncan Bruce B , Chor Dóra , Bensenor Isabela M , Griep Rosane H , Appel Lawrence J , Barreto Sandhi M , Schmidt Maria Inês
Published: November 2016

Emerging evidence suggests sex differences in the early origins of adult metabolic disease, but this has been little investigated in developing countries. We investigated sex-specific associations between low birth weight (LBW; <2.5 kg) and adult-onset diabetes in 12,525 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Diabetes was defined by self-reported information and laboratory measurements. In confounder-adjusted analyses, LBW (vs. 2.5–4 kg) was associated with higher prevalence of diabetes in women (Prevalence Ratio (PR) 1.54, 95% CI: 1.32–1.79), not in men (PR 1.06, 95% CI: 0.91–1.25; Pheterogeneity = 0.003). The association was stronger among participants with maternal diabetes (PR 1.60, 95% CI: 1.35–1.91), than those without (PR 1.15, 95% CI: 0.99–1.32; Pheterogeneity = 0.03). When jointly stratified by sex and maternal diabetes, the association was observed for women with (PR 1.77, 95% CI: 1.37–2.29) and without (PR 1.45, 95% CI: 1.20–1.75) maternal diabetes. In contrast, in men, LBW was associated with diabetes in participants with maternal diabetes (PR 1.45, 95% CI: 1.15–1.83), but not in those without (PR 0.92, 95% CI: 0.74–1.14). These sex-specific findings extended to continuous measures of glucose homeostasis. LBW was associated with higher diabetes prevalence in Brazilian women, and in men with maternal diabetes, suggesting sex-specific intrauterine effects on adult metabolic health.
Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways
Authors: Yan Yumei , Jiang Ke , Liu Peng , Zhang Xianbin , Dong Xin , Gao Jingchun , Liu Quentin , Barr Martin P. , Zhang Quan , Hou Xiukun , Meng Songshu , Gong Peng
Published: November 2016

Hepatocellular carcinoma (HCC) is refractory to chemotherapies, necessitating novel effective agents. The lysosome inhibitor Bafilomycin A1 (BafA1) at high concentrations displays cytotoxicity in a variety of cancers. Here we show that BafA1 at nanomolar concentrations suppresses HCC cell growth in both 2 dimensional (2D) and 3D cultures. BafA1 induced cell cycle arrest in the G1 phase and triggered Cyclin D1 turnover in HCC cells in a dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) dependent manner. Notably, BafA1 induced caspase-independent cell death in HCC cells by impairing autophagy flux as demonstrated by elevated LC3 conversion and p62/SQSTM1 levels. Moreover, genetic ablation of LC3 significantly attenuated BafA1-induced cytotoxicity of HCC cells. We further demonstrate that pharmacological down-regulation or genetic depletion of p38 MAPK decreased BafA1-induced cell death via abolishment of BafA1-induced upregulation of Puma. Notably, knockdown of Puma impaired BafA1-induced HCC cell death, and overexpression of Puma enhanced BafA1-mediated HCC cell death, suggesting a role for Puma in BafA1-mediated cytotoxicity. Interestingly, pharmacological inhibition of JNK with SP600125 enhanced BafA1-mediated cytotoxicity both in vitro and in xenografts derived from HCC cells. Taken together, our data suggest that BafA1 may offer potential as an effective therapy for HCC.
Ligand-mediated changes in conformational dynamics of NpmA: implications for ribosomal interactions
Authors: Husain Nilofer , Tulsian Nikhil Kumar , Chien Wang Loo , Suresh Sushant , Anand Ganesh Srinivasan , Sivaraman J.
Published: November 2016

Aminoglycosides are broad-spectrum antibiotics that bind to the 30S ribosomal subunit (30S) of bacteria and disrupt protein translation. NpmA, a structurally well-characterized methyltransferase identified in an E. coli clinical isolate, catalyzes methylation of 30S at A1408 of the 16S rRNA and confers aminoglycoside resistance. Using sucrose cushion centrifugation and isothermal titration calorimetry, we first confirmed the binding between NpmA and 30S. Next, we performed amide Hydrogen/Deuterium Exchange Mass Spectrometry (HDXMS) of apo NpmA and in the presence and absence of SAM/SAH. We observed that ligand binding resulted in time-dependent differences in deuterium exchange not only at the ligand-binding pocket (D25–D55 and A86–E112) but also in distal regions (F62-F82 and Y113-S144) of NpmA. These results provide insights into methylation group donor cofactor-mediated allostery in NpmA in the ligand-bound states, which could not be observed in the static endpoint crystal structures. We predict that the two distal sites in NpmA form part of the allosteric sites that importantly are part of the main 16S rRNA binding interface. Thus HDXMS helped uncover allosteric communication relays that couple SAM/SAH binding sites with the ribosome-binding site. This highlights how HDXMS together with X-ray crystallography can provide important allosteric insights in protein-ligand complexes.
Non-linear Equation using Plasma Brain Natriuretic Peptide Levels to Predict Cardiovascular Outcomes in Patients with Heart Failure
Authors: Fukuda Hiroki , Suwa Hideaki , Nakano Atsushi , Sakamoto Mari , Imazu Miki , Hasegawa Takuya , Takahama Hiroyuki , Amaki Makoto , Kanzaki Hideaki , Anzai Toshihisa , Mochizuki Naoki , Ishii Akira , Asanuma Hiroshi , Asakura Masanori , Washio Takashi , Kitakaze Masafumi
Published: November 2016

Brain natriuretic peptide (BNP) is the most effective predictor of outcomes in chronic heart failure (CHF). This study sought to determine the qualitative relationship between the BNP levels at discharge and on the day of cardiovascular events in CHF patients. We devised a mathematical probabilistic model between the BNP levels at discharge (y) and on the day (t) of cardiovascular events after discharge for 113 CHF patients (Protocol I). We then prospectively evaluated this model on another set of 60 CHF patients who were readmitted (Protocol II). P(t|y) was the probability of cardiovascular events occurring after >t, the probability on t was given as p(t|y) = −dP(t|y)/dt, and p(t|y) = pP(t|y) = αyβP(t|y), along with p = αyβ (α and β were constant); the solution was p(t|y) = αyβ exp(−αyβt). We fitted this equation to the data set of Protocol I using the maximum likelihood principle, and we obtained the model p(t|y) = 0.000485y0.24788 exp(−0.000485y0.24788t). The cardiovascular event-free rate was computed as P(t) = 1/60Σi=1,…,60 exp(−0.000485yi0.24788t), based on this model and the BNP levels yi in a data set of Protocol II. We confirmed no difference between this model-based result and the actual event-free rate. In conclusion, the BNP levels showed a non-linear relationship with the day of occurrence of cardiovascular events in CHF patients.
Scalable Synthesis of Ag Networks with Optimized Sub-monolayer Au-Pd Nanoparticle Covering for Highly Enhanced SERS Detection and Catalysis
Authors: Li Tianyu , Vongehr Sascha , Tang Shaochun , Dai Yuming , Huang Xiao , Meng Xiangkang
Published: November 2016

Highly porous tri-metallic AgxAuyPdz networks with a sub-monolayer bimetallic Au-Pd nanoparticle coating were synthesized via a designed galvanic replacement reaction of Ag nanosponges suspended in mixed solutions of HAuCl4 and K2PdCl4. The resulting networks’ ligaments have a rough surface with bimetallic nanoparticles and nanopores due to removal of Ag. The surface morphology and composition are adjustable by the temperature and mixed solutions’ concentration. Very low combined Au and Pd atomic percentage (1−x) where x is atomic percentage of Ag leads to sub-monolayer nanoparticle coverings allowing a large number of active boundaries, nanopores, and metal-metal interfaces to be accessible. Optimization of the Au/Pd atomic ratio y/z obtains large surface-enhanced Raman scattering detection sensitivity (at y/z = 5.06) and a higher catalytic activity (at y/z = 3.55) toward reduction reactions as benchmarked with 4-nitrophenol than for most bimetallic catalysts. Subsequent optimization of x (at fixed y/z) further increases the catalytic activity to obtain a superior tri-metallic catalyst, which is mainly attributed to the synergy of several aspects including the large porosity, increased surface roughness, accessible interfaces, and hydrogen absorption capacity of nanosized Pd. This work provides a new concept for scalable synthesis and performance optimization of tri-metallic nanostructures.
Terahertz molecular resonance of cancer DNA
Authors: Cheon Hwayeong , Yang Hee-jin , Lee Sang-Hun , Kim Young A , Son Joo-Hiuk
Published: November 2016

Carcinogenesis involves the chemical and structural alteration of biomolecules in cells. Aberrant methylation of DNA is a well-known carcinogenic mechanism and a common chemical modification of DNA. Terahertz waves can directly observe changes in DNA because the characteristic energies lie in the same frequency region. In addition, terahertz energy levels are not high enough to damage DNA by ionization. Here, we present terahertz molecular resonance fingerprints of DNA methylation in cancer DNA. Methylated cytidine, a nucleoside, has terahertz characteristic energies that give rise to the molecular resonance of methylation in DNA. Molecular resonance is monitored in aqueous solutions of genomic DNA from cancer cell lines using a terahertz time-domain spectroscopic technique. Resonance signals can be quantified to identify the types of cancer cells with a certain degree of DNA methylation. These measurements reveal the existence of molecular resonance fingerprints of cancer DNAs in the terahertz region, which can be utilized for the early diagnosis of cancer cells at the molecular level.
Structure and Function of Cyanobacterial DHDPS and DHDPR
Authors: Christensen Janni B. , Soares da Costa T. P. , Faou Pierre , Pearce F. Grant , Panjikar Santosh , Perugini Matthew A.
Published: November 2016

Lysine biosynthesis in bacteria and plants commences with a condensation reaction catalysed by dihydrodipicolinate synthase (DHDPS) followed by a reduction reaction catalysed by dihydrodipicolinate reductase (DHDPR). Interestingly, both DHDPS and DHDPR exist as different oligomeric forms in bacteria and plants. DHDPS is primarily a homotetramer in all species, but the architecture of the tetramer differs across kingdoms. DHDPR also exists as a tetramer in bacteria, but has recently been reported to be dimeric in plants. This study aimed to characterise for the first time the structure and function of DHDPS and DHDPR from cyanobacteria, which is an evolutionary important phylum that evolved at the divergence point between bacteria and plants. We cloned, expressed and purified DHDPS and DHDPR from the cyanobacterium Anabaena variabilis. The recombinant enzymes were shown to be folded by circular dichroism spectroscopy, enzymatically active employing the quantitative DHDPS-DHDPR coupled assay, and form tetramers in solution using analytical ultracentrifugation. Crystal structures of DHDPS and DHDPR from A. variabilis were determined at 1.92 Å and 2.83 Å, respectively, and show that both enzymes adopt the canonical bacterial tetrameric architecture. These studies indicate that the quaternary structure of bacterial and plant DHDPS and DHDPR diverged after cyanobacteria evolved.
Serotonergic Modulation Differentially Targets Distinct Network Elements within the Antennal Lobe of Drosophila melanogaster
Authors: Sizemore Tyler R. , Dacks Andrew M.
Published: November 2016

Neuromodulation confers flexibility to anatomically-restricted neural networks so that animals are able to properly respond to complex internal and external demands. However, determining the mechanisms underlying neuromodulation is challenging without knowledge of the functional class and spatial organization of neurons that express individual neuromodulatory receptors. Here, we describe the number and functional identities of neurons in the antennal lobe of Drosophila melanogaster that express each of the receptors for one such neuromodulator, serotonin (5-HT). Although 5-HT enhances odor-evoked responses of antennal lobe projection neurons (PNs) and local interneurons (LNs), the receptor basis for this enhancement is unknown. We used endogenous reporters of transcription and translation for each of the five 5-HT receptors (5-HTRs) to identify neurons, based on cell class and transmitter content, that express each receptor. We find that specific receptor types are expressed by distinct combinations of functional neuronal classes. For instance, the excitatory PNs express the excitatory 5-HTRs, while distinct classes of LNs each express different 5-HTRs. This study therefore provides a detailed atlas of 5-HT receptor expression within a well-characterized neural network, and enables future dissection of the role of serotonergic modulation of olfactory processing.
Psychiatric and neurological disorders are associated with bullous pemphigoid – a nationwide Finnish Care Register study
Authors: Försti Anna-Kaisa , Jokelainen Jari , Ansakorpi Hanna , Seppänen Allan , Majamaa Kari , Timonen Markku , Tasanen Kaisa
Published: November 2016

Bullous pemphigoid (BP) is an autoimmune blistering skin disease with increasing incidence. BP is associated with neurological disorders, but it has not been established, what subtypes of dementia and stroke are associated with BP, and what is the temporal relation between these diseases. Also, the association between BP and psychiatric disorders is controversial. We conducted a retrospective nationwide study, using the Finnish Care Register for Health Care diagnoses between 1987 and 2013. The study population of 4524 BP patients were compared with 66138 patients with basocellular carcinoma (BCC), neurological and psychiatric comorbid disorders were evaluated for both groups, and associations were estimated by Cox regression and logistic regression analyses. The strongest risk of developing BP was found after diagnosis of multiple sclerosis (MS) (OR=5.9, 95% CI 3.9–8.5). Among psychiatric diseases, the corresponding risk was strongest in schizophrenia (OR=2.7, 95% CI 2.0–3.5), and as a novel finding, also personality disorders (OR=2.2, 95% CI 1.3–3.3) preceded BP. In conclusion, many psychiatric disorders, especially schizophrenia, carry heightened risk for BP. Furthermore, several neurological diseases which cause central nervous system inflammation or degeneration were related to BP, and the association was strongest between MS and BP.
Regulating Mid-infrared to Visible Fluorescence in Monodispersed Er3+-doped La2O2S (La2O2SO4) Nanocrystals by Phase Modulation
Authors: Pan Qiwen , Yang Dandan , Kang Shiliang , Qiu Jianrong , Dong Guoping
Published: November 2016

Rare earth doped mid-infrared (MIR) fluorescent sources have been widely investigated due to their various potential applications in the fields of communication, chemical detecting, medical surgery and so forth. However, with emission wavelength extended to MIR, multiphonon relaxation process that strongly quenched the MIR emission is one of the greatest challenges for such practical applications. In our design, we have described a controllable gas-aided annealing strategy to modulate the phase, crystal size, morphology and fluorescent performance of a material simultaneously. Uniform and monodispersed Er3+-doped La2O2S and La2O2SO4 nanocrystals with a similar lattice structure, crystallinity, diameter and morphology have been introduced to investigate the impact of multiphonon relaxation on luminescence performance. Detailed spectroscopic evolutions in the region of MIR, near-infrared (NIR), visible upconversion (UC) and their corresponding decay times provide insight investigation into the fluorescent mechanism caused by multiphonon relaxation. A possible energy transfer model has also been established. Our results present direct observation and mechanistic investigation of fluorescent evolution in multiphonon relaxation process, which is conductive to design MIR fluorescent materials in the future. To the best of our knowledge, it is the first investigation on MIR fluorescent performance of La2O2S nanocrystals, which may find various applications in many photoelectronic fields.
MicroRNA-124 promotes hepatic triglyceride accumulation through targeting tribbles homolog 3
Authors: Liu Xing , Zhao Jiejie , Liu Qi , Xiong Xuelian , Zhang Zhijian , Jiao Yang , Li Xiaoying , Liu Bin , Li Yao , Lu Yan
Published: November 2016

An increase in hepatic triglyceride (TG) contents usually results in non-alcoholic fatty liver disease (NAFLD) and related metabolic diseases. However, the mechanisms underlying perturbations of hepatic TG homeostasis remain largely unknown. Here, we showed that MicroRNA-124 was up-regulated in the livers of C57BL/6 mice fed a short-term high-fat-diet (HFD). Adenoviral overexpression of miR-124 in C57BL/6 mice led to accumulation of excessive triglycerides and up-regulation of lipogenic genes in the liver. We further identified tribbles homolog 3 (TRB3) as a direct target of miR-124. AKT signaling, which is negatively regulated by TRB3, was enhanced by miR-124 overexpression. Moreover, restoration of TRB3 expression markedly abolished the effect of miR-124 on hepatic TG metabolism. Therefore, our findings revealed that miR-124 played a role in mediating high-fat-diet induced TG accumulation in the liver.
A comparative analysis and guidance for individualized chemotherapy of stage II and III colorectal cancer patients based on pathological markers
Authors: Han Yang , Lu Su , Yu Fudong , Liu Xisheng , Sun Huimin , Wang Jingtao , Zhu Xingwu , Lu Huijun , Yue Hao , Wang Jing , Lin Jun , Zhou Chongzhi , Tang Huamei , Peng Zhihai
Published: November 2016

Adjuvant chemotherapy is considered the standard of care for patients with colorectal cancer after curative resection. Although current guidelines provide clear instructions for chemotherapy for stage II high-risk and stage III colorectal cancer, it is insufficient to individualize therapy. We analyzed the outcomes of 902 patients with colorectal cancer treated with or without chemotherapy in our hospital. We found Chinese survival benefit for chemotherapy was consistent with current guidelines. Moreover, our data added to the evidence that chemotherapy might be used for elderly patients with stage II high-risk colorectal cancer. Pathological markers could predict response to individualize therapy in a convenient, fast and inexpensive way. We compared survivals of patients with stage II high-risk and stage III colorectal cancer with chemotherapy in different pathological markers expression, and furthermore used 458 colon adenocarcinoma samples from The Cancer Genome Atlas to verify our preliminary results. We confirmed TOPIIα, EGFR and P170 may be sufficiently predictive markers to individualize chemotherapy. FOLFOX was the optimal adjuvant chemotherapy for patients with stage II high-risk and stage III colorectal cancer when TOPIIα was positive or EGFR or P170 was negative.
Vibrational resonance, allostery, and activation in rhodopsin-like G protein-coupled receptors
Authors: Woods Kristina N. , Pfeffer Jürgen , Dutta Arpana , Klein-Seetharaman Judith
Published: November 2016

G protein-coupled receptors are a large family of membrane proteins activated by a variety of structurally diverse ligands making them highly adaptable signaling molecules. Despite recent advances in the structural biology of this protein family, the mechanism by which ligands induce allosteric changes in protein structure and dynamics for its signaling function remains a mystery. Here, we propose the use of terahertz spectroscopy combined with molecular dynamics simulation and protein evolutionary network modeling to address the mechanism of activation by directly probing the concerted fluctuations of retinal ligand and transmembrane helices in rhodopsin. This approach allows us to examine the role of conformational heterogeneity in the selection and stabilization of specific signaling pathways in the photo-activation of the receptor. We demonstrate that ligand-induced shifts in the conformational equilibrium prompt vibrational resonances in the protein structure that link the dynamics of conserved interactions with fluctuations of the active-state ligand. The connection of vibrational modes creates an allosteric association of coupled fluctuations that forms a coherent signaling pathway from the receptor ligand-binding pocket to the G-protein activation region. Our evolutionary analysis of rhodopsin-like GPCRs suggest that specific allosteric sites play a pivotal role in activating structural fluctuations that allosterically modulate functional signals.
A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer’s disease pathology
Authors: Paterson R W , Heywood W E , Heslegrave A J , Magdalinou N K , Andreasson U , Sirka E , Bliss E , Slattery C F , Toombs J , Svensson J , Johansson P , Fox N C , Zetterberg H , Mills K , Schott J M
Published: November 2016

Alzheimer’s disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previously validated multiplexed 10-min, targeted proteomic assay to assess 54 candidate cerebrospinal fluid (CSF) biomarkers in two independent cohorts comprising individuals with neurodegenerative dementias and healthy controls. Individuals were classified as ‘AD’ or ‘non-AD’ on the basis of their CSF T-tau and amyloid Aβ1–42 profile measured using enzyme-linked immunosorbent assay; biomarkers of interest were compared using univariate and multivariate analyses. In all, 35/31 individuals in Cohort 1 and 46/36 in Cohort 2 fulfilled criteria for AD/non-AD profile CSF, respectively. After adjustment for multiple comparisons, five proteins were elevated significantly in AD CSF compared with non-AD CSF in both cohorts: malate dehydrogenase; total APOE; chitinase-3-like protein 1 (YKL-40); osteopontin and cystatin C. In an independent multivariate orthogonal projection to latent structures discriminant analysis (OPLS-DA), these proteins were also identified as major contributors to the separation between AD and non-AD in both cohorts. Independent of CSF Aβ1–42 and tau, a combination of these biomarkers differentiated AD and non-AD with an area under curve (AUC)=0.88. This targeted proteomic multiple reaction monitoring (MRM)-based assay can simultaneously and rapidly measure multiple candidate CSF biomarkers. Applying this technique to AD we demonstrate differences in proteins involved in glucose metabolism and neuroinflammation that collectively have potential clinical diagnostic utility.