bluuebunny/crossref_metadata_2025 huggingface dataset:
Radio and X-ray observations of supernovae in dense environments
Authors: Chandra Poonam
Published: October 2017

Here we discuss the observational properties of supernovae exploding in extremely dense environments, namely Type IIn supernovae (SNe IIn). In SNe IIn, the surrounding environments play significant role in the supernovae energetics and evolution. Thus they are different than other classes of core collapse supernovae, whose energetics are not significantly altered by their environments. Though high density of medium is a prerequisite for radio and X-ray emission, less than 10% on SNe IIn are bright in these bands. This has important implications for their progenitor models. I will discuss the radio and X-ray observations of SNe IIn, which are crucial to unravel their complex environments. We also discuss some individual supernovae belonging to this class and discuss as to how they have refined our understanding of SNe IIn. Finally the importance of well sampled long term light curves in radio and X-ray bands cannot be stressed enough.
Cosmic ray astroparticle physics: current status and future perspectives
Authors: Donato Fiorenza
Published: October 2017

The data we are receiving from galactic cosmic rays are reaching an unprecedented precision, over very wide energy ranges. Nevertheless, many problems are still open, while new ones seem to appear when data happen to be redundant. We will discuss some paths to possible progress in the theoretical modeling and experimental exploration of the galactic cosmic radiation.
Diagnostics of the Supernova Engine
Authors: Fryer Chris L. , Ellinger Carola , Young Patrick A. , Vance Gregory
Published: October 2017

The standard engine behind core-collapse supernovae is continuously evolving with increasingly detailed models. At this time, most simulations focus on an engine invoking turbulence above the proto-neutron star, sometimes termed the “convection-enhanced” engine. Here we review this engine and why it has become the standard for normal supernovae, focusing on a wide set of observations that provide insight into the supernova engine.
Acetoclastic Methanosaeta are dominant methanogens in organic-rich Antarctic marine sediments
Authors: Carr Stephanie A , Schubotz Florence , Dunbar Robert B , Mills Christopher T , Dias Robert , Summons Roger E , Mandernack Kevin W
Published: October 2017

Despite accounting for the majority of sedimentary methane, the physiology and relative abundance of subsurface methanogens remain poorly understood. We combined intact polar lipid and metagenome techniques to better constrain the presence and functions of methanogens within the highly reducing, organic-rich sediments of Antarctica’s Adélie Basin. The assembly of metagenomic sequence data identified phylogenic and functional marker genes of methanogens and generated the first Methanosaeta sp. genome from a deep subsurface sedimentary environment. Based on structural and isotopic measurements, glycerol dialkyl glycerol tetraethers with diglycosyl phosphatidylglycerol head groups were classified as biomarkers for active methanogens. The stable carbon isotope (δ13C) values of these biomarkers and the Methanosaeta partial genome suggest that these organisms are acetoclastic methanogens and represent a relatively small (0.2%) but active population. Metagenomic and lipid analyses suggest that Thaumarchaeota and heterotrophic bacteria co-exist with Methanosaeta and together contribute to increasing concentrations and δ13C values of dissolved inorganic carbon with depth. This study presents the first functional insights of deep subsurface Methanosaeta organisms and highlights their role in methane production and overall carbon cycling within sedimentary environments.
The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion
Authors: Khunweeraphong Narakorn , Stockner Thomas , Kuchler Karl
Published: October 2017

The human ABC transporter ABCG2 (Breast Cancer Resistance Protein, BCRP) is implicated in anticancer resistance, in detoxification across barriers and linked to gout. Here, we generate a novel atomic model of ABCG2 using the crystal structure of ABCG5/G8. Extensive mutagenesis verifies the structure, disclosing hitherto unrecognized essential residues and domains in the homodimeric ABCG2 transporter. The elbow helix, the first intracellular loop (ICL1) and the nucleotide-binding domain (NBD) constitute pivotal elements of the architecture building the transmission interface that borders a central cavity which acts as a drug trap. The transmission interface is stabilized by salt-bridge interactions between the elbow helix and ICL1, as well as within ICL1, which is essential to control the conformational switch of ABCG2 to the outward-open drug-releasing conformation. Importantly, we propose that ICL1 operates like a molecular spring that holds the NBD dimer close to the membrane, thereby enabling efficient coupling of ATP hydrolysis during the catalytic cycle. These novel mechanistic data open new opportunities to therapeutically target ABCG2 in the context of related diseases.
The Efficacy and Pharmacological Mechanism of Zn7MT3 to Protect against Alzheimer’s Disease
Authors: Xu Wei , Xu Qiming , Cheng Hao , Tan Xiangshi
Published: October 2017

Alzheimer’s disease (AD) is one of the leading causes of death for people over 65 years. Worse still, no completely effective therapeutic agent is available so far. One important pathological hallmark of AD is accumulated amyloid-β (Aβ) plaques with dysregulated metal homeostasis. Human metallothionin 3 (MT3), a regulator of metal homeostasis, is downregulated at least 30% in AD brain. So far, some in vitro studies demonstrated its multiple functions related to AD. However, it is a great pity that systematic in vivo studies of MT3 on AD model animals are still a blank so far. In this study, we treated APP/PS1 mice with sustained drug release of Zn7MT3 directly to the central nervous system, and investigated the role and molecular mechanism of Zn7MT3 to protect against AD mice systematically. The results demonstrated that Zn7MT3 can significantly ameliorate cognitive deficits, regulate metal homeostasis, abolish Aβ plaque load, and reduce oxidative stress. Additionally, it has been confirmed that MT3 is penetrable to the blood brain barrier of AD mice. All these results support that Zn7MT3 is an effective AD suppressing agent and has potential for applications in Alzheimer’s disease therapy.
Identification of candidate drugs using tensor-decomposition-based unsupervised feature extraction in integrated analysis of gene expression between diseases and DrugMatrix datasets
Authors: Taguchi Y.-h.
Published: October 2017

Identifying drug target genes in gene expression profiles is not straightforward. Because a drug targets proteins and not mRNAs, the mRNA expression of drug target genes is not always altered. In addition, the interaction between a drug and protein can be context dependent; this means that simple drug incubation experiments on cell lines do not always reflect the real situation during active disease. In this paper, I applied tensor-decomposition-based unsupervised feature extraction to the integrated analysis using a mathematical product of gene expression in various diseases and gene expression in the DrugMatrix dataset, where comprehensive data on gene expression during various drug treatments of rats are reported. I found that this strategy, in a fully unsupervised manner, enables researchers to identify a combined set of genes and compounds that significantly overlap with gene and drug interactions identified in the past. As an example illustrating the usefulness of this strategy in drug discovery experiments, I considered cirrhosis, for which no effective drugs have ever been proposed. The present strategy identified two promising therapeutic-target genes, CYPOR and HNFA4; for their protein products, bezafibrate was identified as a promising candidate drug, supported by in silico docking analysis.
Resection of high frequency oscillations predicts seizure outcome in the individual patient
Authors: Fedele Tommaso , Burnos Sergey , Boran Ece , Krayenbühl Niklaus , Hilfiker Peter , Grunwald Thomas , Sarnthein Johannes
Published: October 2017

High frequency oscillations (HFOs) are recognized as biomarkers for epileptogenic brain tissue. A remaining challenge for epilepsy surgery is the prospective classification of tissue sampled by individual electrode contacts. We analysed long-term invasive recordings of 20 consecutive patients who subsequently underwent epilepsy surgery. HFOs were defined prospectively by a previously validated, automated algorithm in the ripple (80–250 Hz) and the fast ripple (FR, 250–500 Hz) frequency band. Contacts with the highest rate of ripples co-occurring with FR over several five-minute time intervals designated the HFO area. The HFO area was fully included in the resected area in all 13 patients who achieved seizure freedom (specificity 100%) and in 3 patients where seizures reoccurred (negative predictive value 81%). The HFO area was only partially resected in 4 patients suffering from recurrent seizures (positive predictive value 100%, sensitivity 57%). Thus, the resection of the prospectively defined HFO area proved to be highly specific and reproducible in 13/13 patients with seizure freedom, while it may have improved the outcome in 4/7 patients with recurrent seizures. We thus validated the clinical relevance of the HFO area in the individual patient with an automated procedure. This is a prerequisite before HFOs can guide surgical treatment in multicentre studies.
A self-feedback network based on liquid chromatography-quadrupole-time of flight mass spectrometry for system identification of β-carboline alkaloids in Picrasma quassioides
Authors: Shi Yuanyuan , Wang Ruoqi , Zhu Xiaoyu , Xu Dongge , Liu Wenyuan , Feng Feng
Published: October 2017

Profiling chemical components in herbs by mass spectrometry is a challenging work because of the lack of standard compounds, especially for position isomers. This paper provides a strategy based on a self-feedback network of mass spectra (MS) data to identify chemical constituents in herbs by liquid chromatography-quadrupole-time of flight mass spectrometry without compound standards. Components sharing same skeleton were screened and all ions were classified into a database. All candidates were connected by the selected bridging ions to establish a primary MS network. Benefited from such a network, it is feasible to characterize sequentially the structures of all diagnostic ions and candidates once single component has been de novo identified. TakingPicrasma quassioidesas an example, the primary network of β-carbolines was established with 65 ions (selected from 76 β-carbolines), each of which appeared at least in four compounds. Once an alkaloid has been identified, its logical ions could feedback into primary network to build pathways with other unknown compounds. Moreover, the position of the substituent groups could be deduced through the secondary metabolic pathways of alkaloids (plant secondary metabolism). The network therefore can be utilized for identification of unknown compounds and even their position isomers.
How aging impacts skin biomechanics: a multiscale study in mice
Authors: Lynch Barbara , Bonod-Bidaud Christelle , Ducourthial Guillaume , Affagard Jean-Sébastien , Bancelin Stéphane , Psilodimitrakopoulos Sotiris , Ruggiero Florence , Allain Jean-Marc , Schanne-Klein Marie-Claire
Published: October 2017

Skin aging is a complex process that strongly affects the mechanical behavior of skin. This study aims at deciphering the relationship between age-related changes in dermis mechanical behavior and the underlying changes in dermis microstructure. To that end, we use multiphoton microscopy to monitor the reorganization of dermal collagen during mechanical traction assays in ex vivo skin from young and old mice. The simultaneous variations of a full set of mechanical and microstructural parameters are analyzed in the framework of a multiscale mechanical interpretation. They show consistent results for wild-type mice as well as for genetically-modified mice with modified collagen V synthesis. We mainly observe an increase of the tangent modulus and a lengthening of the heel region in old murine skin from all strains, which is attributed to two different origins that may act together: (i) increased cross-linking of collagen fibers and (ii) loss of water due to proteoglycans deterioration, which impedes inner sliding within these fibers. In contrast, the microstructure reorganization upon stretching shows no age-related difference, which can be attributed to opposite effects of the decrease of collagen content and of the increase of collagen cross-linking in old mice.
Genetic Diversity and Phylogenetic Differentiation of Southwestern Chinese Han: a comprehensive and comparative analysis on 21 non-CODIS STRs
Authors: He Guanglin , Wang Zheng , Wang Mengge , Hou Yiping
Published: October 2017

Short tandem repeats (STRs), with high polymorphism and complex evolution information, play a significant role in genetic association studies like population genetics, molecular anthropology and human forensics. However, human genetic diversity has only been partially sampled and available for Southwest Chinese Han population, as well as the genetic architecture of this population remains uncharacterized. In this work, 368 unrelated Han individuals from Sichuan province were firstly genotyped with 21 non-CODIS autosomal STRs, and phylogenetic relationships along administrative (Han Chinese from different regions) and ethnic divisions (minority ethnic groups) were subsequently investigated. The CMP and CPE were 6.2796 × 10−20 and 0.9999999, respectively. Analysis of molecular variance (AMOVA), principal component analysis (PCA), multidimensional scaling plots (MDS) and phylogenetic analysis consistently demonstrated that the Southwest Han population had a close genetic relationship with the geographically close population (Hunan Han) and kept a distant genetic relationship with some ethnic groups, most prominently for Gansu Yugu and Fujian She. Furthermore, no significant genetic distinction between the Northern Han and Southern Han was observed. Aforementioned results suggested that these 21 STRs are highly polymorphic and informative, which are suitable for human identification and population genetics.
Role of HIV exposure and infection in relation to neonatal GBS disease and rectovaginal GBS carriage: a systematic review and meta-analysis
Authors: Cools Piet , van de Wijgert Janneke H. H. M. , Jespers Vicky , Crucitti Tania , Sanders Eduard J. , Verstraelen Hans , Vaneechoutte Mario
Published: October 2017

Streptococcus agalactiae (GBS) is the leading cause worldwide of neonatal sepsis. We sought to assess to which extent HIV exposure of neonates is associated with GBS neonatal disease. Furthermore, we assessed to which extent HIV infection in women is associated with maternal rectovaginal GBS carriage, the single most important risk factor for GBS neonatal disease. We searched Pubmed, Embase, and Web of Science for studies assessing the association between neonatal GBS disease and HIV-status of the mother and studies that assessed the association between rectovaginal GBS colonization and HIV status in women. HIV-exposed uninfected neonates were more than twice as likely to have neonatal GBS disease compared to unexposed neonates. HIV-exposed neonates were not at increased risk for early-onset neonatal disease, but were 4.43 times more likely to have late-onset neonatal GBS disease. There was no significant association between HIV infection status and rectovaginal GBS carriage. Public health interventions preventing neonatal GBS disease are urgently needed for the increasing group of HIV-exposed neonates. A framework integrating and explaining our findings highlights opportunities for the clinical practice and global health policy to prevent disease. Well-designed studies should clarify the relation between HIV-status and GBS carriage.
Toxoplasma-induced changes in host risk behaviour are independent of parasite-derived AaaH2 tyrosine hydroxylase
Authors: Afonso Cristina , Paixão Vitor B. , Klaus Andreas , Lunghi Matteo , Piro Federica , Emiliani Carla , Di Cristina Manlio , Costa Rui M.
Published: October 2017

Toxoplasma gondii infects a broad range of hosts and can establish chronic infections with the formation of brain cysts. Infected animals show altered risk behaviour which has been suggested to increase capture probability of hosts, and thus enhance parasite transmission. It has been proposed that the ability of Toxoplasma cysts to secrete tyrosine hydroxylase could mediate these behavioural alterations. We tested the involvement of secreted tyrosine hydroxylase, coded by the parasite AaaH2 gene, in the development of alterations in mouse behaviour, by generating an AaaH2 deletion mutant parasite strain and testing its influence on behaviour. We found that both mice infected with wild type or AaaH2 mutant strains showed changes in risk behaviour. We confirmed these findings using factor analysis of the behaviour, which revealed that behavioural changes happened along a single dimension, and were observed in both infected groups. Furthermore, we developed a new behavioural paradigm in which animals are unpredictably trapped, and observed that both groups of infected animals perceive trapping but fail to adjust their behaviour to avoid further trapping. These results demonstrate that parasite-secreted AaaH2 TH is neither necessary for the generation of risky behaviour nor for the increased trappability observed during chronic Toxoplasma infection.
Regiospecific Synthesis of Ring A Fused Withaferin A Isoxazoline Analogues: Induction of Premature Senescence by W-2b in Proliferating Cancer Cells
Authors: Rasool Faheem , Nayak Debasis , Katoch Archana , Faheem Mir Mohd , Yousuf Syed Khalid , Hussain Nazar , Belawal Chetan , Satti N. K. , Goswami Anindya , Mukherjee Debaraj
Published: October 2017

Induction of premature senescence represents a novel functional strategy to curb the uncontrolled proliferation of malignant cancer cells. This study unveils the regiospecific synthesis of novel isoxazoline derivatives condensed to ring A of medicinal plant product Withaferin-A. Intriguingly, the cis fused products with β-oriented hydrogen exhibited excellent cytotoxic activities against proliferating human breast cancer MCF7 and colorectal cancer HCT-116 cells. The most potent derivative W-2b triggered premature senescence along with increase in senescence-associated β-galactosidase activity, G2/M cell cycle arrest, and induction of senescence-specific marker p21Waf1/Cip1 at its sub-toxic concentration. W-2b conferred a robust increase in phosphorylation of mammalian checkpoint kinase-2 (Chk2) in cancer cells in a dose-dependent manner. Silencing of endogenous Chk2 by siRNA divulged that the amplification of p21 expression and senescence by W-2b was Chk2-dependent. Chk2 activation (either by ectopic overexpression or through treatment with W-2b) suppressed NM23-H1 signaling axis involved in cancer cell proliferation. Finally, W-2b showed excellent in vivo efficacy with 83.8% inhibition of tumor growth at a dose of 25 mg/kg, b.w. in mouse mammary carcinoma model. Our study claims that W-2b could be a potential candidate to limit aberrant cellular proliferation rendering promising improvement in the treatment regime in cancer patients.
Aquarius is required for proper CtIP expression and homologous recombination repair
Authors: Sakasai Ryo , Isono Mayu , Wakasugi Mitsuo , Hashimoto Mitsumasa , Sunatani Yumi , Matsui Tadashi , Shibata Atsushi , Matsunaga Tsukasa , Iwabuchi Kuniyoshi
Published: October 2017

Accumulating evidence indicates that transcription is closely related to DNA damage formation and that the loss of RNA biogenesis factors causes genome instability. However, whether such factors are involved in DNA damage responses remains unclear. We focus here on the RNA helicase Aquarius (AQR), a known R-loop processing factor, and show that its depletion in human cells results in the accumulation of DNA damage during S phase, mediated by R-loop formation. We investigated the involvement of Aquarius in DNA damage responses and found that AQR knockdown decreased DNA damage-induced foci formation of Rad51 and replication protein A, suggesting that Aquarius contributes to homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs). Interestingly, the protein level of CtIP, a DSB processing factor, was decreased in AQR-knockdown cells. Exogenous expression of Aquarius partially restored CtIP protein level; however, CtIP overproduction did not rescue defective HR in AQR-knockdown cells. In accordance with these data, Aquarius depletion sensitized cells to genotoxic agents. We propose that Aquarius contributes to the maintenance of genomic stability via regulation of HR by CtIP-dependent and -independent pathways.
TMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function
Authors: Gruppen Eke G. , Garcia Erwin , Connelly Margery A. , Jeyarajah Elias J. , Otvos James D. , Bakker Stephan J. L. , Dullaart Robin P. F.
Published: October 2017

Trimethylamine-N-Oxide (TMAO) is a microbiome-related metabolite that is cleared by the kidney and linked to renal function. We explored the relationship between TMAO and all-cause mortality, and determined whether this association was modified by renal function. A prospective study was performed among PREVEND participants to examine associations of plasma TMAO with all-cause mortality. After median follow-up of 8.3 years in 5,469 participants, 322 subjects died. TMAO was positively associated with age, body mass index, type 2 diabetes mellitus and inversely with estimated glomerular filtration rate (eGFRcreatcysC)(all P < 0.001). Subjects in the highest versus lowest TMAO quartile had a crude 1.86-fold higher mortality risk (Ptrend < 0.001). After adjustment for several risk factors, TMAO remained associated with all-cause mortality [HR:1.36 (95% CI, 0.97–1.91),Ptrend = 0.016]. This association was lost after further adjustment for urinary albumin excretion and eGFR [HR:1.15 (95% CI, 0.81–1.64),Ptrend = 0.22]. The association of TMAO with mortality was modified by eGFR in crude and age- and sex-adjusted analyses (interaction P = 0.002). When participants were stratified by renal function (eGFR < vs. ≥90 mL/min/1.73 m2), TMAO was associated with all-cause mortality only in subjects with eGFR <90 mL/min/1.73 m2 [adjusted HR:1.18 (95% CI, 1.02–1.36),P = 0.023]. In conclusion, TMAO is associated with all-cause mortality, particularly in subjects with eGFR <90 mL/min/1.73 m2.
Stimulation of synapse formation between stem cell-derived neurons and native brainstem auditory neurons
Authors: Hu Zhengqing , Liu Zhenjie , Li Xiaoyang , Deng Xin
Published: October 2017

Integration of stem cell-derived cells into native cellular environment remains a challenge in the field. This study developed novel methods to co-culture neural stem cell-derived spiral ganglion-like neurons (ScNs) and mouse auditory cochlear nucleus (CN) neurons to understand whether ScNs of the peripheral nervous system (PNS) synapse with CN neurons of the central nervous system (CNS). ScNs were obtained from neural stem cells that were derived from transgenic mouse pre-labeled with enhanced green fluorescent protein (EGFP), whereas CN neurons were from postnatal mouse primary cultures. ScNs and CN neurons were co-cultured  for 4–6 days in the absence or presence of astrocyte-conditioned medium (ACM). Class III β-tubulin (TUJ1)-expressing connections were found between ScNs and CN neurons. Expression of the synaptic vesicle marker SV2 was significantly increased along connections between ScNs and CN neurons in the presence of ACM. Immunodepletion and knockout studies indicated that thrombospodin-1 played an important role in ACM-exerted synaptogenic effects. Newly-generated synapse-like structures expressed glutamatergic marker VGluT1, pre- and post-synaptic proteins. Synaptic vesicle recycling studies suggested functional synaptic vesicle retrieval. These results reveal that stem cell-derived PNS neurons are able to form functional connections with native CNS neurons, which is critical for stem cell-based neural pathway regeneration.
Relationships between different types of physical activity and metabolic syndrome among Taiwanese workers
Authors: Huang Jui-Hua , Li Ren-Hau , Huang Shu-Ling , Sia Hon-Ke , Lee Su-Shiang , Wang Wei-Hsun , Tang Feng-Cheng
Published: October 2017

This study aimed to investigate the relationships between different types of physical activity (PA) and metabolic syndrome (MetS). In this cross-sectional study, 3,296 Taiwanese workers were enrolled. A self-reported questionnaire was used to assess nutritional health behavior and PA levels related to occupation, leisure time, and commuting. Anthropometric measures, blood pressure and biochemical determinations of the blood were also obtained. Multiple logistic regression was used to evaluate the adjusted odds ratios (ORs) and 95% confidence intervals (CI) of MetS and its components associated with different types of PA. The prevalence of MetS was 16.6% in workers. Compared with a low level of leisure-time PA, a high level of leisure-time PA showed a significantly lower risk of high triglycerides (OR 0.73, 95% CI 0.61–0.87) and MetS (OR 0.76, 95% CI 0.62–0.95). Compared with a low level of occupational PA, a high level of occupational PA represented a significantly lower risk of both abdominal adiposity (OR 0.64, 95% CI 0.49–0.84) and high triglycerides (OR 0.71, 95% CI 0.55–0.90). However, commuting PA levels were not significantly associated with MetS and its components. In conclusion, occupational PA as well as leisure-time PA could be important for the prevention of MetS.
An engineered vaccine of the Plasmodium vivax Duffy binding protein enhances induction of broadly neutralizing antibodies
Authors: Ntumngia Francis B. , Pires Camilla V. , Barnes Samantha J. , George Miriam T. , Thomson-Luque Richard , Kano Flora S. , Alves Jessica R. S. , Urusova Darya , Pereira Dhelio B. , Tolia Niraj H. , King Christopher L. , Carvalho Luzia H. , Adams John H.
Published: October 2017

Plasmodium vivax invasion into human reticulocytes is a complex process. The Duffy binding protein (DBP) dimerization with its cognate receptor is vital for junction formation in the invasion process. Due to its functional importance, DBP is considered a prime vaccine candidate, but variation in B-cell epitopes at the dimer interface of DBP leads to induction of strain-limited immunity. We believe that the polymorphic residues tend to divert immune responses away from functionally conserved epitopes important for receptor binding or DBP dimerization. As a proof of concept, we engineered the vaccine DEKnull to ablate the dominant Bc epitope to partially overcome strain-specific immune antibody responses. Additional surface engineering on the next generation immunogen, DEKnull-2, provides an immunogenicity breakthrough to conserved protective epitopes. DEKnull-2 elicits a stronger broadly neutralizing response and reactivity with long-term persistent antibody responses of acquired natural immunity. By using novel engineered DBP immunogens, we validate that the prime targets of protective immunity are conformational epitopes at the dimer interface. These successful results indicate a potential approach that can be used generally to improve efficacy of other malaria vaccine candidates.
Design and evaluation of the immunogenicity and efficacy of a biomimetic particulate formulation of viral antigens
Authors: Riitho Victor , Walters Adam A. , Somavarapu Satyanarayana , Lamp Benjamin , Rümenapf Till , Krey Thomas , Rey Felix A. , Oviedo-Orta Ernesto , Stewart Graham R. , Locker Nicolas , Steinbach Falko , Graham Simon P.
Published: October 2017

Subunit viral vaccines are typically not as efficient as live attenuated or inactivated vaccines at inducing protective immune responses. This paper describes an alternative ‘biomimetic’ technology; whereby viral antigens were formulated around a polymeric shell in a rationally arranged fashion with a surface glycoprotein coated on to the surface and non-structural antigen and adjuvant encapsulated. We evaluated this model using BVDV E2 and NS3 proteins formulated in poly-(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles adjuvanted with polyinosinic:polycytidylic acid (poly(I:C) as an adjuvant (Vaccine-NP). This Vaccine-NP was compared to ovalbumin and poly(I:C) formulated in a similar manner (Control-NP) and a commercial adjuvanted inactivated BVDV vaccine (IAV), all inoculated subcutaneously and boosted prior to BVDV-1 challenge. Significant virus-neutralizing activity, and E2 and NS3 specific antibodies were observed in both Vaccine-NP and IAV groups following the booster immunisation. IFN-γ responses were observed in ex vivo PBMC stimulated with E2 and NS3 proteins in both vaccinated groups. We observed that the protection afforded by the particulate vaccine was comparable to the licenced IAV formulation. In conclusion, the biomimetic particulates showed a promising immunogenicity and efficacy profile that may be improved by virtue of being a customisable mode of delivery.
Mechanistic Insights into the Cholesterol-dependent Binding of Perfringolysin O-based Probes and Cell Membranes
Authors: Johnson Benjamin B. , Breña Mariana , Anguita Juan , Heuck Alejandro P.
Published: October 2017

Cholesterol distribution in the cell is maintained by both vesicular and non-vesicular sterol transport. Non-vesicular transport is mediated by the interaction of membrane-embedded cholesterol and water-soluble proteins. Small changes to the lipid composition of the membrane that do not change the total cholesterol content, can significantly affect how cholesterol interacts with other molecules at the surface of the membrane. The cholesterol-dependent cytolysin Perfringolysin O (PFO) constitutes a powerful tool to detect cholesterol in membranes, and the use of PFO-based probes has flourished in recent years. By using a non-lytic PFO derivative, we showed that the sensitivity of the probes for cholesterol can be tuned by modifications introduced directly in the membrane-interacting loops and/or by modifying residues away from the membrane-interacting domain. Through the use of these biosensors on live RAW 264.7 cells, we found that changes in the overall cholesterol content have a limited effect on the average cholesterol accessibility at the surface of the membrane. We showed that these exquisite biosensors report on changes in cholesterol reactivity at the membrane surface independently of the overall cholesterol content in the membrane.
The role of grain boundary scattering in reducing the thermal conductivity of polycrystalline XNiSn (X = Hf, Zr, Ti) half-Heusler alloys
Authors: Schrade Matthias , Berland Kristian , Eliassen Simen N. H. , Guzik Matylda N. , Echevarria-Bonet Cristina , Sørby Magnus H. , Jenuš Petra , Hauback Bjørn C. , Tofan Raluca , Gunnæs Anette E. , Persson Clas , Løvvik Ole M. , Finstad Terje G.
Published: October 2017

Thermoelectric application of half-Heusler compounds suffers from their fairly high thermal conductivities. Insight into how effective various scattering mechanisms are in reducing the thermal conductivity of fabricated XNiSn compounds (X = Hf, Zr, Ti, and mixtures thereof) is therefore crucial. Here, we show that such insight can be obtained through a concerted theory-experiment comparison of how the lattice thermal conductivity κLat(T) depends on temperature and crystallite size. Comparing theory and experiment for a range of Hf0.5Zr0.5NiSn and ZrNiSn samples reported in the literature and in the present paper revealed that grain boundary scattering plays the most important role in bringing down κLat, in particular so for unmixed compounds. Our concerted analysis approach was corroborated by a good qualitative agreement between the measured and calculated κLat of polycrystalline samples, where the experimental average crystallite size was used as an input parameter for the calculations. The calculations were based on the Boltzmann transport equation and ab initio density functional theory. Our analysis explains the significant variation of reported κLat of nominally identical XNiSn samples, and is expected to provide valuable insights into the dominant scattering mechanisms even for other materials.
The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation
Authors: Marhäll Alissa , Kazi Julhash U. , Rönnstrand Lars
Published: October 2017

The non-receptor tyrosine kinase LCK belongs to the SRC family of kinases. SRC family kinases are proto-oncogenes that have long been known to play key roles in cell proliferation, motility, morphology and survival. Here we show that LCK regulates the function of the type III receptor tyrosine kinase FLT3 in murine pro-B cells. We observed that expression of LCK significantly enhances the colony forming capacity of the constitutively active FLT3 mutant FLT3-ITD (internal tandem duplication). Furthermore, cells expressing LCK developed tumor earlier compared to cells transfected with empty control vector. Staining of the tissues from mouse xenografts showed higher Ki67 staining in cells expressing LCK suggesting that expression of LCK enhances the FLT3-ITD-mediated proliferative capacity. LCK expression did not affect either FLT3-WT or FLT3-ITD -induced AKT, ERK1/2 or p38 phosphorylation. However, LCK expression significantly enhanced FLT3-ITD-mediated STAT5 phosphorylation. Taken together, our data suggest that LCK cooperates with oncogenic FLT3-ITD in cellular transformation.
Temperature dependent thermal conductivity and transition mechanism in amorphous and crystalline Sb2Te3 thin films
Authors: Li Qisong , Wei Jingsong , Sun Hao , Zhang Kui , Huang Zhengxing , Zhang Long
Published: October 2017

Sb2Te3 thin films are widely used in high density optical and electronic storage, high-resolution greyscale image recording, and laser thermal lithography. Thermal conductivity and its temperature dependence are critical factors that affect the application performance of thin films. This work aims to evaluate the temperature dependence of thermal conductivity of crystalline and amorphous Sb2Te3 thin films experimentally and theoretically, and explores into the corresponding mechanism of heat transport. For crystalline Sb2Te3 thin films, the thermal conductivity was found to be 0.35 ± 0.035 W m−1 K−1 and showed weak temperature dependence. The thermal conductivity of amorphous Sb2Te3 thin films at temperatures below ~450 K is about 0.23 ± 0.023 W m−1K−1, mainly arising from the lattice as the electronic contribution is negligible; at temperatures above 450 K, the thermal conductivity experiences an abrupt increase owing to the structural change from amorphous to crystalline state. The work can provide an important guide and reference to the real applications of Sb2Te3 thin films.
Nutrient Loading Fosters Seagrass Productivity Under Ocean Acidification
Authors: Ravaglioli Chiara , Lauritano Chiara , Buia Maria Cristina , Balestri Elena , Capocchi Antonella , Fontanini Debora , Pardi Giuseppina , Tamburello Laura , Procaccini Gabriele , Bulleri Fabio
Published: October 2017

The effects of climate change are likely to be dependent on local settings. Nonetheless, the compounded effects of global and regional stressors remain poorly understood. Here, we used CO2 vents to assess how the effects of ocean acidification on the seagrass, Posidonia oceanica, and the associated epiphytic community can be modified by enhanced nutrient loading. P. oceanica at ambient and low pH sites was exposed to three nutrient levels for 16 months. The response of P. oceanica to experimental conditions was assessed by combining analyses of gene expression, plant growth, photosynthetic pigments and epiphyte loading. At low pH, nutrient addition fostered plant growth and the synthesis of photosynthetic pigments. Overexpression of nitrogen transporter genes following nutrient additions at low pH suggests enhanced nutrient uptake by the plant. In addition, enhanced nutrient levels reduced the expression of selected antioxidant genes in plants exposed to low pH and increased epiphyte cover at both ambient and low pH. Our results show that the effects of ocean acidification on P. oceanica depend upon local nutrient concentration. More generally, our findings suggest that taking into account local environmental settings will be crucial to advance our understanding of the effects of global stressors on marine systems.
Spontaneous circadian rhythms in a cold-adapted natural isolate of Aureobasidium pullulans
Authors: Franco Diana L. , Canessa Paulo , Bellora Nicolás , Risau-Gusman Sebastián , Olivares-Yañez Consuelo , Pérez-Lara Rodrigo , Libkind Diego , Larrondo Luis F. , Marpegan Luciano
Published: October 2017

Circadian systems enable organisms to synchronize their physiology to daily and seasonal environmental changes relying on endogenous pacemakers that oscillate with a period close to 24 h even in the absence of external timing cues. The oscillations are achieved by intracellular transcriptional/translational feedback loops thoroughly characterized for many organisms, but still little is known about the presence and characteristics of circadian clocks in fungi other than Neurospora crassa. We sought to characterize the circadian system of a natural isolate of Aureobasidium pullulans, a cold-adapted yeast bearing great biotechnological potential. A. pullulans formed daily concentric rings that were synchronized by light/dark cycles and were also formed in constant darkness with a period of 24.5 h. Moreover, these rhythms were temperature compensated, as evidenced by experiments conducted at temperatures as low as 10 °C. Finally, the expression of clock-essential genes, frequency, white collar-1, white collar-2 and vivid was confirmed. In summary, our results indicate the existence of a functional circadian clock in A. pullulans, capable of sustaining rhythms at very low temperatures and, based on the presence of conserved clock-gene homologues, suggest a molecular and functional relationship to well-described circadian systems.
Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism
Authors: Hernández-Alvarez María Isabel , Díaz-Ramos Angels , Berdasco María , Cobb Jeff , Planet Evarist , Cooper Diane , Pazderska Agnieszka , Wanic Krzystof , O’Hanlon Declan , Gomez Antonio , de la Ballina Laura R. , Esteller Manel , Palacin Manuel , O’Gorman Donal J. , Nolan John J. , Zorzano Antonio
Published: October 2017

The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice. We document that T2D, both early and late onset, are characterized by reduced muscle expression of genes involved in branched-chain amino acids (BCAA) metabolism. Weighted Co-expression Networks Analysis provided support to idea that the BCAA genes are relevant in the pathophysiology of type 2 diabetes, and that mitochondrial BCAA management is impaired in skeletal muscle from T2D patients. In diabetic mice model we detected alterations in skeletal muscle proteins involved in BCAA metabolism but not in obese mice. Metabolomic analysis revealed increased levels of branched-chain keto acids (BCKA), and BCAA in plasma of T2D patients, which may result from the disruption of muscle BCAA management. Our data support the view that inhibition of genes involved in BCAA handling in skeletal muscle takes place as part of the pathophysiology of type 2 diabetes, and this occurs both in early-onset and in classical type 2 diabetes.
Comparative transcriptome analysis reveals host-associated differentiation in Chilo suppressalis (Lepidoptera: Crambidae)
Authors: Zhong Haiying , Li Fengbo , Chen Jianming , Zhang Juefeng , Li Fang
Published: October 2017

The striped stem borer, Chilo suppressalis Walker (Lepidoptera: Crambidae), is one of the most serious rice pests. Besides attacking rice, it also feeds on an economically important vegetable crop, water-oat Zizania latifolia. The species feeding on water-oat has higher growth and survival rate than those on rice, suggesting their success in adaptation to the new host plant. However, little is known about the molecular mechanisms of host plant adaptation. Here we investigated the midgut transcriptome responses of C. suppressalis larvae reared on rice and water-oat. A total of 1,633 differentially expressed genes were identified, with a greater number up-regulated on the more delicious new host. The up-regulation of most digestive and detoxification-related genes may be the result of adaptation to the changes in nutritional requirements and toxic chemicals during host shift. In contrast, down-regulation of ribosomal genes may be related to their better development performance when feeding on the new host. In conclusion, our results suggest that transcriptional regulation of genes related to digestion, detoxification and ribosome may play an important role in adaptation of C. suppressalis to a new host plant.
Physicochemical characterisation, immunogenicity and protective efficacy of a lead streptococcal vaccine: progress towards Phase I trial
Authors: Pandey Manisha , Powell Jessica , Calcutt Ainslie , Zaman Mehfuz , Phillips Zachary N. , Ho Mei Fong , Batzloff Michael R. , Good Michael F.
Published: October 2017

Globally, group A streptococcal infections are responsible for over 500,000 deaths per year. A safe vaccine that does not induce autoimmune pathology and that affords coverage for most GAS serotypes is highly desired. We have previously demonstrated that a vaccine based on the conserved M-protein epitope, J8 was safe and immunogenic in a pilot Phase I study. We subsequently improved vaccine efficacy by incorporation of a B-cell epitope from the IL-8 protease, SpyCEP, which protected IL-8 and enhanced neutrophil ingress to the site of infection. We have now substituted the carrier protein, diphtheria toxoid with its superior analogue, CRM197 which provides better immunogenicity and is widely used in licenced human vaccines. The new vaccine was compared with the DT conjugate vaccine to confirm that these modifications have not altered the physicochemical properties of the vaccine. This vaccine, when tested in an animal model of GAS infection, demonstrated significant reduction in systemic and local GAS burden, with comparable efficacy to the DT conjugate vaccine. The vaccine was shown to be equally effective in the presence of human plasma and in the presence of pre-existing DT-specific antibodies, thus minimising concerns regarding its potential efficacy in humans.
Effects of glucose concentration on 1,18-cis-octadec-9-enedioic acid biotransformation efficiency and lipid body formation in Candida tropicalis
Authors: Funk Irina , Sieber Volker , Schmid Jochen
Published: October 2017

The unsaturated long-chain α,ω-dicarboxylic acid 1,18-cis-octadec-9-enedioic acid (cis-ODA) is a versatile precursor of various valuable compounds, such as polymers, and can be obtained from renewable resources. This makes cis-ODA highly attractive for the chemical industry where there is a growing interest in sustainable processes. However, chemical synthesis of the cis isomers is currently not feasible. In contrast, biotechnological production allows for highly specific and selective reactions. Therefore, we developed an efficient production strategy for cis-ODA using Candida tropicalis as a whole-cell biocatalyst for the biotransformation of oleic acid, which naturally occurs in various fats and oils. Applying a bench-top system comprising eight parallel bioreactors, the production process was characterised and optimised for high productivity. Glucose feed rate was identified as the most crucial process parameter influencing product yield, with high rates inducing oleic acid incorporation into triacylglycerols and storage in lipid bodies. Conversely, application of medium-chain length fatty acid as a substrate did not show any occurrence of lipid bodies. Applying the lowest possible molar ratio of glucose to oleic acid (1.5) resulted in marginal lipid body formation, but led to a peak volumetric productivity of 0.56 g/L/h and a final titre of approximately 45 g/L with a corresponding yield of 70%.
Increased complexity of mushroom body Kenyon cell subtypes in the brain is associated with behavioral evolution in hymenopteran insects
Authors: Oya Satoyo , Kohno Hiroki , Kainoh Yooichi , Ono Masato , Kubo Takeo
Published: October 2017

In insect brains, the mushroom bodies (MBs) are a higher-order center for sensory integration and memory. Honeybee (Apis mellifera L.) MBs comprise four Kenyon cell (KC) subtypes: class I large-, middle-, and small-type, and class II KCs, which are distinguished by the size and location of somata, and gene expression profiles. Although these subtypes have only been reported in the honeybee, the time of their acquisition during evolution remains unknown. Here we performed in situ hybridization of tachykinin-related peptide, which is differentially expressed among KC subtypes in the honeybee MBs, in four hymenopteran species to analyze whether the complexity of KC subtypes is associated with their behavioral traits. Three class I KC subtypes were detected in the MBs of the eusocial hornet Vespa mandarinia and the nidificating scoliid wasp Campsomeris prismatica, like in A. mellifera, whereas only two class I KC subtypes were detected in the parasitic wasp Ascogaster reticulata. In contrast, we were unable to detect class I KC subtype in the primitive and phytophagous sawfly Arge similis. Our findings suggest that the number of class I KC subtypes increased at least twice – first with the evolution of the parasitic lifestyle and then with the evolution of nidification.
Bioprospecting on invasive plant species to prevent seed dispersal
Authors: Guzzetti Lorenzo , Galimberti Andrea , Bruni Ilaria , Magoni Chiara , Ferri Maura , Tassoni Annalisa , Sangiovanni Enrico , Dell’Agli Mario , Labra Massimo
Published: October 2017

Absract

The most anthropized regions of the world are characterized by an impressive abundance of invasive plants, which alter local biodiversity and ecosystem services. An alternative strategy to manage these species could be based on the exploitation of their fruits in a framework of bioprospecting to obtain high-added value compounds or phytocomplexes that are useful for humans. Here we tested this hypothesis on three invasive plants (Lonicera japonicaThunb.,Phytolacca americanaL., andPrunus serotinaEhrh.) in the Po plain (northern Italy) which bear fruits that are highly consumed by frugivorous birds and therefore dispersed over large distances. Our biochemical analyses revealed that unripe fruit shows high antioxidant properties due to the presence of several classes of polyphenols, which have a high benchmark value on the market. Fruit collection for phytochemical extraction could really prevent seed dispersal mediated by frugivorous animals and produce economic gains to support local management actions.