bluuebunny/crossref_metadata_2025 huggingface dataset:
The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35
Authors: MONAGHAN PAUL , LENEGHAN DARREN B. , SHAW WESLEY , BELL ANGUS
Published: March 2017

FK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506–FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap –FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement ofPlasmodiumcalcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of thePlasmodium falciparumFKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.
The tension between emotive/aesthetic and analytic/scientific motifs in the work of amateur visual documenters of Antarctica's Heroic Era
Authors: Millar Pat
Published: March 2017

Visual documenters made a major contribution to the recording of the Heroic Era of Antarctic exploration. By far the best known were the professional photographers, Herbert Ponting and Frank Hurley, hired to photograph British and Australasian expeditions. But a great number of images – photographs and artworks – were also produced by amateurs on lesser known European expeditions and a Japanese one. These amateurs were sometimes designated official illustrators, often scientists recording their research. This paper offers a discursive examination of illustrations from the Belgian Antarctic Expedition (1897–1899), German Deep Sea Expedition (1898–1899), German South Polar Expedition (1901–1903), Swedish South Polar Expedition (1901–1903), French Antarctic Expedition (1903–1905) and Japanese Antarctic Expedition (1910–1912), assessing their representations of exploration in Antarctica in terms of the tension between emotive/aesthetic and systematic analytic/scientific motifs. Their depictions were influenced by their illustrative skills and their ‘ways of seeing’, produced from their backgrounds and the sponsorship needs of the expedition.
TAXONOMY OF BEGONIA ALBOMACULATA AND DESCRIPTION OF TWO NEW SPECIES ENDEMIC TO PERU
Authors: Moonlight P. W. , Hughes M. , Tebbitt M. C.
Published: March 2017

Begonia mayasiana L.B.Sm. & B.G.Schub. is shown to be synonymous with Begonia albomaculata C.DC. An emended description and lectotypification of Begonia albomaculata is provided, and the species is recorded from the Peruvian regions of Amazonas, Loreto, San Martín, Huánuco and Ucayali; the Brazilian state of Acre; and the Ecuadorian province of Pastaza. The use of the name Begonia albomaculata in the Flora of Ecuador and related publications is a misapplication, and the specimens cited there represent an undescribed taxon closely related to Begonia tiliifolia C.DC., described in a companion paper in this volume. Taxonomic study of Begonia albomaculata prompted a re-evaluation of related Andean species. As a result, two further new species were identified, and Begonia longimaculata Irmsch. and Begonia maynensis A.DC. were found to be conspecific. The two new species are described as Begonia chemillenensis Moonlight sp. nov. and Begonia scorpiocaulis Moonlight & Tebbitt sp. nov., and are known only from the Pasco and Huánuco regions and the Madre de Dios region of Peru, respectively. Begonia longimaculata Irmsch. is newly treated here as a synonym of B. maynensis A.DC.
Extender supplementation with catalase maintains the integrity of sperm plasma membrane after freezing–thawing of semen from capuchin monkey
Authors: Leão Danuza L. , Brito Adriel B. , Miranda Stefânia A. , Oliveira Karol G. , Almeida Débora V.C. , Santos Regiane R. , Domingues Sheyla F. S.
Published: March 2017

We aimed to evaluate the effect of supplementation of ACP-118® extender with the antioxidant catalase (10 and 50 µg/ml) on Sapajus apella sperm motility, vigour, and plasma membrane integrity during the processes of seminal liquefaction, cooling, and freezing. Catalase did not affect any of the evaluated parameters after semen dilution or cooling. Cryopreserved sperm in the presence of 50 µg/ml catalase presented a plasma membrane integrity similar to that fresh sperm, however.
Mitochondria during sea urchin oogenesis
Authors: Agnello Maria , Roccheri Maria Carmela , Morici Giovanni , Rinaldi Anna Maria
Published: March 2017

Sea urchin represents an ideal model for studies on fertilization and early development, but the achievement of egg competence and mitochondrial behaviour during oogenesis remain to be enlightened. Oocytes of echinoid, such as sea urchin, unlike other echinoderms and other systems, complete meiotic maturation before fertilization. Mitochondria, the powerhouse of eukaryotic cells, contain a multi-copy of the maternally inherited genome, and are involved directly at several levels in the reproductive processes, as their functional status influences the quality of oocytes and contributes to fertilization and embryogenesis. In the present paper, we report our latest data on mitochondrial distribution, content and activity duringParacentrotus lividusoogenesis. The analyses were carried out using confocal microscopy,in vivoincubating oocytes at different maturation stages with specific probes for mitochondria and mtDNA, and by immunodetection of Hsp56, a well known mitochondrial marker. Results show a parallel rise of mitochondrial mass and activity, and, especially in the larger oocytes, close to germinal vesicle (GV) breakdown, a considerable increase in organelle activity around the GV, undoubtedly for an energetic aim. In the mature eggs, mitochondrial activity decreases, in agreement with their basal metabolism. Further and significant information was achieved by studying the mitochondrial chaperonin Hsp56 and mtDNA. Results show a high increase of both Hsp56 and mtDNA. Taken together these results demonstrate that during oogenesis a parallel rise of different mitochondrial parameters, such as mass, activity, Hsp56 and mtDNA occurs, highlighting important tools in the establishment of developmental competence.
Quality of Pinzgau bull spermatozoa following different periods of cryostorage
Authors: Chrenek P. , Spaleková E. , Olexikova L. , Makarevich A. , Kubovicova E.
Published: March 2017

The aim of this work was to examine the influence of cryostorage duration of Pinzgau bull's insemination doses (IDs) on some sperm traits. The IDs were frozen by a slow freezing method and stored in liquid nitrogen for different periods: less than 8 years (group 1), 8–13 years (group 2) and 14–18 years (group 3). Motility (CASA), pathological sperm rate (Giemsa staining), apoptotic (Yo-Pro-1-positive) and necrotic (propidium iodide-positive) cell occurrence and fertilizing ability (penetration/fertilization test) of spermatozoa were evaluated post-thaw. The average post-thaw sperm motility in all examined groups was over 40%. No significant influence of storage length either on the sperm total motility or progressive movement was revealed. In each tested group the average rate of malformed spermatozoa did not exceed 20%. No effect of cryostorage length on the occurrence of apoptotic or necrotic sperm was noted. Similarly, penetrating/fertilizing ability of sperm did not differ among the groups, excepting differences in the rate of pronuclei (PN) formation. In group 1, 72.9% of eggs showed two visible PN following 20 h incubation with sperm, whilst in groups 2 and 3 only 67 and 54.5% of zygotes, respectively, had both PN at this time. These results revealed no influence of storage time on the bull spermatozoa in all parameters excepting the rate of PN formation. As high inter-male variability was observed in the susceptibility of bull sperm to cryostorage, individual differences should be taken into account when semen from individual bulls is to be stored for a long time.
Improving Data Quality in Mass-Gatherings Health Research
Authors: Guy Andrew , Prager Ross , Turris Sheila , Lund Adam
Published: March 2017

Mass gatherings attract large crowds and can strain the planning and health resources of the community, city, or nation hosting an event. Mass-Gatherings Health (MGH) is an evolving niche of prehospital care rooted in emergency medicine, emergency management, public health, and disaster medicine. To explore front-line issues related to data quality in the context of mass gatherings, the authors draw on five years of management experience with an online, mass-gathering event and patient registry, as well as clinical and operational experience amassed over several decades.

Here the authors propose underlying human, environmental, and logistical factors that may contribute to poor data quality at mass gatherings, and make specific recommendations for improvement through pre-event planning, on-site actions, and post-event follow-up. The advancement of MGH research will rely on addressing factors that influence data quality and developing strategies to mitigate or enhance those factors. This is an exciting time for MGH research as higher order questions are beginning to be addressed; however, quality research must start from the ground up to ensure optimal primary data capture and quality.

GuyA, PragerR, TurrisS, LundA. Improving data quality in mass-gatherings health research. Prehosp Disaster Med. 2017;32(3):329–332.
Same, Same But Different? Cognitive Behavioural Treatment Approaches for Paediatric CFS/ME and Depression
Authors: Loades M.E. , Chalder T.
Published: March 2017

Background: Approximately one in three children and young people with chronic fatigue syndrome (CFS/ME) also have probable depression. Cognitive behaviour therapy (CBT) has a growing evidence base as an effective treatment approach for CFS/ME and for depression in this population. Aims: Given the high degree of co-morbidity, this discussion paper aims to compare and contrast CBT for CFS/ME and CBT for depression in children and young people. Method: The existing literature on CBT for depression and CBT for CFS/ME, in relation to children and young people was reviewed. Results: Whilst there are commonalities to both treatments, the cognitive behavioural model of CFS/ME maintenance includes different factors and has a different emphasis to the cognitive behavioural model of depression, resulting in different intervention targets and strategies in a different sequence. Conclusions: A collaborative, formulation-driven approach to intervention should inform the intervention targets and treatment strategies.
The Relationship Between Atomic Structure and Strain Distribution of Misfit Dislocation Cores at Cubic Heteroepitaxial Interfaces
Authors: Wen Cai
Published: March 2017

The atomic reconstruction of a misfit dislocation (MD) core causes change in the strain distribution around the core. Several MD cores at the AlSb/GaAs (001) cubic zincblende interface, including a symmetrical glide set Lomer dislocation (LD), a left-displaced glide set LD, a glide set LD with an atomic step, a symmetrical shuffle set LD, and a 60° dislocation pair, were studied using simulated projected potential and aberration-corrected transmission electron microscope images. Image deconvolution was also used to restore structure images from nonoptimum-defocus images. The corresponding biaxial strain maps,εxx(in-plane) andεyy(out-of-plane), were obtained by geometric phase analysis using the GaAs substrate as the reference lattice. The results show that atomic structure characteristics of MD cores can be revealed by the strain maps. The strain maps should be measured from optimum-defocus images or restored structure images. Furthermore, theεxxstrain map has been found more accurate than theεyystrain map for MD cores, and the specimen thickness should be below the critical thickness due to the influence of dynamical scattering.
Airline Flight Paths over the Unmapped Ocean
Authors: Smith Walter , Marks Karen , Schmitt Thierry
Published: March 2017

An assessment of ocean depth knowledge underneath commercial airline routes shows just how much of the seafloor remains "terra incognita."
Getting to Fair: Recognizing Implicit Bias and Easing Its Impact
Authors: Holmes Mary , Mukasa Sam , Schwert Donald
Published: March 2017

Six tactics given below can counteract unconscious biases that unbeknownst to us, influence decisions such as whom we nominate and choose for honors and recognition.
An electrically actuated molecular toggle switch
Authors: Gerhard Lukas , Edelmann Kevin , Homberg Jan , Valášek Michal , Bahoosh Safa G. , Lukas Maya , Pauly Fabian , Mayor Marcel , Wulfhekel Wulf
Published: March 2017

Molecular electronics is considered a promising approach for future nanoelectronic devices. In order that molecular junctions can be used as electrical switches or even memory devices, they need to be actuated between two distinct conductance states in a controlled and reproducible manner by external stimuli. Here we present a tripodal platform with a cantilever arm and a nitrile group at its end that is lifted from the surface. The formation of a coordinative bond between the nitrile nitrogen and the gold tip of a scanning tunnelling microscope can be controlled by both electrical and mechanical means, and leads to a hysteretic switching of the conductance of the junction by more than two orders of magnitude. This toggle switch can be actuated with high reproducibility so that the forces involved in the mechanical deformation of the molecular cantilever can be determined precisely with scanning tunnelling microscopy.
Oriented graphene nanoribbons embedded in hexagonal boron nitride trenches
Authors: Chen Lingxiu , He Li , Wang Hui Shan , Wang Haomin , Tang Shujie , Cong Chunxiao , Xie Hong , Li Lei , Xia Hui , Li Tianxin , Wu Tianru , Zhang Daoli , Deng Lianwen , Yu Ting , Xie Xiaoming , Jiang Mianheng
Published: March 2017

Graphene nanoribbons (GNRs) are ultra-narrow strips of graphene that have the potential to be used in high-performance graphene-based semiconductor electronics. However, controlled growth of GNRs on dielectric substrates remains a challenge. Here, we report the successful growth of GNRs directly on hexagonal boron nitride substrates with smooth edges and controllable widths using chemical vapour deposition. The approach is based on a type of template growth that allows for the in-plane epitaxy of mono-layered GNRs in nano-trenches on hexagonal boron nitride with edges following a zigzag direction. The embedded GNR channels show excellent electronic properties, even at room temperature. Such in-plane hetero-integration of GNRs, which is compatible with integrated circuit processing, creates a gapped channel with a width of a few benzene rings, enabling the development of digital integrated circuitry based on GNRs.
MicroRNA-92a is a circadian modulator of neuronal excitability in Drosophila
Authors: Chen Xiao , Rosbash Michael
Published: March 2017

Many biological and behavioural processes of animals are governed by an endogenous circadian clock, which is dependent on transcriptional regulation. Here we address post-transcriptional regulation and the role of miRNAs in Drosophila circadian rhythms. At least six miRNAs show cycling expression levels within the pigment dispersing factor (PDF) cell-pacemaker neurons; only mir-92a peaks during the night. In vivo calcium monitoring, dynamics of PDF projections, ArcLight, GCaMP6 imaging and sleep assays indicate that mir-92a suppresses neuronal excitability. In addition, mir-92a levels within PDF cells respond to light pulses and also affect the phase shift response. Translating ribosome affinity purification (TRAP) and in vitro luciferase reporter assay indicate that mir-92a suppresses expression of sirt2, which is homologous to human sir2 and sirt3. sirt2 RNAi also phenocopies mir-92a overexpression. These experiments indicate that sirt2 is a functional mir-92a target and that mir-92a modulates PDF neuronal excitability via suppressing SIRT2 levels in a rhythmic manner.
RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans
Authors: Son Heehwa G. , Seo Mihwa , Ham Seokjin , Hwang Wooseon , Lee Dongyeop , An Seon Woo A. , Artan Murat , Seo Keunhee , Kaletsky Rachel , Arey Rachel N. , Ryu Youngjae , Ha Chang Man , Kim Yoon Ki , Murphy Coleen T. , Roh Tae-Young , Nam Hong Gil , Lee Seung-Jae V.
Published: March 2017

Long-lived organisms often feature more stringent protein and DNA quality control. However, whether RNA quality control mechanisms, such as nonsense-mediated mRNA decay (NMD), which degrades both abnormal as well as some normal transcripts, have a role in organismal aging remains unexplored. Here we show that NMD mediates longevity in C. elegans strains with mutations in daf-2/insulin/insulin-like growth factor 1 receptor. We find that daf-2 mutants display enhanced NMD activity and reduced levels of potentially aberrant transcripts. NMD components, including smg-2/UPF1, are required to achieve the longevity of several long-lived mutants, including daf-2 mutant worms. NMD in the nervous system of the animals is particularly important for RNA quality control to promote longevity. Furthermore, we find that downregulation of yars-2/tyrosyl-tRNA synthetase, an NMD target transcript, by daf-2 mutations contributes to longevity. We propose that NMD-mediated RNA surveillance is a crucial quality control process that contributes to longevity conferred by daf-2 mutations.
Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury
Authors: Rossi Maxime , Thierry Antoine , Delbauve Sandrine , Preyat Nicolas , Soares Miguel P. , Roumeguère Thierry , Leo Oberdan , Flamand Véronique , Le Moine Alain , Hougardy Jean-Michel
Published: March 2017

Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1M-KO), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1M-KO exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1M-KO mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b+ F4/80lo subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1+ CD11b+ F4/80lo myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1M-KO mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation.
Length-dependent gene misexpression is associated with Alzheimer’s disease progression
Authors: Barbash Shahar , Sakmar Thomas P.
Published: March 2017

Recent reports show transcription preference for long genes in neuronal tissues compared with non-neuronal tissues, and a gene-length dependent change in expression in the neurodevelopmental disease Rett syndrome (RTT). Whether the gene-length dependent changes in expression seen in RTT might also be seen in neurodegenerative diseases is not yet known. However, a reasonable hypothesis is that similar effects might be seen in neurodegenerative diseases as well as in RTT since a common general feature of both illnesses involves progressive dysfunction of synapses. Here, we demonstrate a clear length-dependent gene misexpression in the most prevalent neurodegenerative disease, Alzheimer’s disease. We show that the effect is associated with disease progression and can be attributed specifically to neurons. In particular, we observed gene length-dependent down regulation on the level of the whole tissue and gene length-dependent up regulation on the level of single cells. Our analysis shows that a gene-length effect on expression can be found in degenerative neurological illnesses, such as Alzheimer’s disease. Additional investigation to elucidate the precise mechanism underlying gene-length dependent changes in expression is warranted.
Considerable knock-on displacement of metal atoms under a low energy electron beam
Authors: Gu Hengfei , Li Geping , Liu Chengze , Yuan Fusen , Han Fuzhou , Zhang Lifeng , Wu Songquan
Published: March 2017

Under electron beam irradiation, knock-on atomic displacement is commonly thought to occur only when the incident electron energy is above the incident-energy threshold of the material in question. However, we report that when exposed to intense electrons at room temperature at a low incident energy of 30 keV, which is far below the theoretically predicted incident-energy threshold of zirconium, Zircaloy-4 (Zr-1.50Sn-0.25Fe-0.15Cr (wt.%)) surfaces can undergo considerable displacement damage. We demonstrate that electron beam irradiation of the bulk Zircaloy-4 surface resulted in a striking radiation effect that nanoscale precipitates within the surface layer gradually emerged and became clearly visible with increasing the irradiation time. Our transmission electron microscope (TEM) observations further reveal that electron beam irradiation of the thin-film Zircaly-4 surface caused the sputtering of surface α-Zr atoms, the nanoscale atomic restructuring in the α-Zr matrix, and the amorphization of precipitates. These results are the first direct evidences suggesting that displacement of metal atoms can be induced by a low incident electron energy below threshold. The presented way to irradiate may be extended to other materials aiming at producing appealing properties for applications in fields of nanotechnology, surface technology, and others.
Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel
Authors: Verona Guglielmo , Mangione P. Patrizia , Raimondi Sara , Giorgetti Sofia , Faravelli Giulia , Porcari Riccardo , Corazza Alessandra , Gillmore Julian D. , Hawkins Philip N. , Pepys Mark B. , Taylor Graham W. , Bellotti Vittorio
Published: March 2017

Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloid fibrillogenesis. It is modelled by exposure of the protein to non-physiological low pH in vitro and is inhibited by small molecule compounds, such as the drug tafamidis. We have recently identified a new mechano-enzymatic pathway of TTR fibrillogenesis in vitro, catalysed by selective proteolytic cleavage, which produces a high yield of genuine amyloid fibrils. This pathway is efficiently inhibited only by ligands that occupy both binding sites in TTR. Tolcapone, which is bound with similar high affinity in both TTR binding sites without the usual negative cooperativity, is therefore of interest. Here we show that TTR fibrillogenesis by the mechano-enzymatic pathway is indeed more potently inhibited by tolcapone than by tafamidis but neither, even in large molar excess, completely prevents amyloid fibril formation. In contrast, mds84, the prototype of our previously reported bivalent ligand TTR ‘superstabiliser’ family, is notably more potent than the monovalent ligands and we show here that this apparently reflects the critical additional interactions of its linker within the TTR central channel. Our findings have major implications for therapeutic approaches in TTR amyloidosis.
Variation-preserving normalization unveils blind spots in gene expression profiling
Authors: Roca Carlos P. , Gomes Susana I. L. , Amorim Mónica J. B. , Scott-Fordsmand Janeck J.
Published: March 2017

RNA-Seq and gene expression microarrays provide comprehensive profiles of gene activity, but lack of reproducibility has hindered their application. A key challenge in the data analysis is the normalization of gene expression levels, which is currently performed following the implicit assumption that most genes are not differentially expressed. Here, we present a mathematical approach to normalization that makes no assumption of this sort. We have found that variation in gene expression is much larger than currently believed, and that it can be measured with available assays. Our results also explain, at least partially, the reproducibility problems encountered in transcriptomics studies. We expect that this improvement in detection will help efforts to realize the full potential of gene expression profiling, especially in analyses of cellular processes involving complex modulations of gene expression.
Building a 5-HT3A Receptor Expression Map in the Mouse Brain
Authors: Koyama Yoshihisa , Kondo Makoto , Shimada Shoichi
Published: March 2017

Of the many serotonin receptors, the type 3 receptors (5-HT3R) are the only ionotropic ones, playing a key role in fast synaptic transmission and cognitive and emotional brain function through controlled neuronal excitation. To better understand the various functions of 5-HT3Rs, it is very important to know their expression pattern in the central nervous system (CNS). To date, many distributional studies have shown localized 5-HT3R expression in the brain and spinal cord. However, an accurate pattern of 5-HT3R expression in the CNS remains to be elucidated. To investigate the distribution of 5-HT3R in the mouse brain in detail, we performed immunofluorescent staining using 5-HT3AR-GFP transgenic mice. We found strong 5-HT3AR expression in the olfactory bulb, cerebral cortex, hippocampus, and amygdala; and partial expression in the pons, medulla, and spinal cord. Meanwhile, the thalamus, hypothalamus, and midbrain exhibited a few 5-HT3AR-expressing cells, and no expression was detected in the cerebellum. Further, double-immunostaining using neural markers confirmed that 5-HT3AR is expressed in GABAergic interneurons containing somatostatin or calretinin. In the present study, we built a 5-HT3AR expression map in the mouse brain. Our findings make significant contributions in elucidating the novel functions of 5-HT3R in the CNS.
The Final (Oral Ebola) Vaccine Trial on Captive Chimpanzees?
Authors: Walsh Peter D. , Kurup Drishya , Hasselschwert Dana L. , Wirblich Christoph , Goetzmann Jason E. , Schnell Matthias J.
Published: March 2017

Could new oral vaccine technologies protect endangered wildlife against a rising tide of infectious disease? We used captive chimpanzees to test oral delivery of a rabies virus (RABV) vectored vaccine against Ebola virus (EBOV), a major threat to wild chimpanzees and gorillas. EBOV GP and RABV GP-specific antibody titers increased exponentially during the trial, with rates of increase for six orally vaccinated chimpanzees very similar to four intramuscularly vaccinated controls. Chimpanzee sera also showed robust neutralizing activity against RABV and pseudo-typed EBOV. Vaccination did not induce serious health complications. Blood chemistry, hematologic, and body mass correlates of psychological stress suggested that, although sedation induced acute stress, experimental housing conditions did not induce traumatic levels of chronic stress. Acute behavioral and physiological responses to sedation were strongly correlated with immune responses to vaccination. These results suggest that oral vaccination holds great promise as a tool for the conservation of apes and other endangered tropical wildlife. They also imply that vaccine and drug trials on other captive species need to better account for the effects of stress on immune response.
Immunogenicity is preferentially induced in sparse dendritic cell cultures
Authors: Nasi Aikaterini , Bollampalli Vishnu Priya , Sun Meng , Chen Yang , Amu Sylvie , Nylén Susanne , Eidsmo Liv , Rothfuchs Antonio Gigliotti , Réthi Bence
Published: March 2017

We have previously shown that human monocyte-derived dendritic cells (DCs) acquired different characteristics in dense or sparse cell cultures. Sparsity promoted the development of IL-12 producing migratory DCs, whereas dense cultures increased IL-10 production. Here we analysed whether the density-dependent endogenous breaks could modulate DC-based vaccines. Using murine bone marrow-derived DC models we show that sparse cultures were essential to achieve several key functions required for immunogenic DC vaccines, including mobility to draining lymph nodes, recruitment and massive proliferation of antigen-specific CD4+ T cells, in addition to their TH1 polarization. Transcription analyses confirmed higher commitment in sparse cultures towards T cell activation, whereas DCs obtained from dense cultures up-regulated immunosuppressive pathway components and genes suggesting higher differentiation plasticity towards osteoclasts. Interestingly, we detected a striking up-regulation of fatty acid and cholesterol biosynthesis pathways in sparse cultures, suggesting an important link between DC immunogenicity and lipid homeostasis regulation.
Principal Components Analysis Based Unsupervised Feature Extraction Applied to Gene Expression Analysis of Blood from Dengue Haemorrhagic Fever Patients
Authors: Taguchi Y-h.
Published: March 2017

Dengue haemorrhagic fever (DHF) sometimes occurs after recovery from the disease caused by Dengue virus (DENV), and is often fatal. However, the mechanism of DHF has not been determined, possibly because no suitable methodologies are available to analyse this disease. Therefore, more innovative methods are required to analyse the gene expression profiles of DENV-infected patients. Principal components analysis (PCA)-based unsupervised feature extraction (FE) was applied to the gene expression profiles of DENV-infected patients, and an integrated analysis of two independent data sets identified 46 genes as critical for DHF progression. PCA using only these 46 genes rendered the two data sets highly consistent. The application of PCA to the 46 genes of an independent third data set successfully predicted the progression of DHF. A fourth in vitro data set confirmed the identification of the 46 genes. These 46 genes included interferon- and heme-biosynthesis-related genes. The former are enriched in binding sites for STAT1, STAT2, and IRF1, which are associated with DHF-promoting antibody-dependent enhancement, whereas the latter are considered to be related to the dysfunction of spliceosomes, which may mediate haemorrhage. These results are outcomes that other type of bioinformatic analysis could hardly achieve.
Widespread platinum anomaly documented at the Younger Dryas onset in North American sedimentary sequences
Authors: Moore Christopher R. , West Allen , LeCompte Malcolm A. , Brooks Mark J. , Daniel I. Randolph , Goodyear Albert C. , Ferguson Terry A. , Ivester Andrew H. , Feathers James K. , Kennett James P. , Tankersley Kenneth B. , Adedeji A. Victor , Bunch Ted E.
Published: March 2017

Previously, a large platinum (Pt) anomaly was reported in the Greenland ice sheet at the Younger Dryas boundary (YDB) (12,800 Cal B.P.). In order to evaluate its geographic extent, fire-assay and inductively coupled plasma mass spectrometry (FA and ICP-MS) elemental analyses were performed on 11 widely separated archaeological bulk sedimentary sequences. We document discovery of a distinct Pt anomaly spread widely across North America and dating to the Younger Dryas (YD) onset. The apparent synchroneity of this widespread YDB Pt anomaly is consistent with Greenland Ice Sheet Project 2 (GISP2) data that indicated atmospheric input of platinum-rich dust. We expect the Pt anomaly to serve as a widely-distributed time marker horizon (datum) for identification and correlation of the onset of the YD climatic episode at 12,800 Cal B.P. This Pt datum will facilitate the dating and correlating of archaeological, paleontological, and paleoenvironmental data between sequences, especially those with limited age control.
Simple Risk Score for Prediction of Early Recurrence of Hepatocellular Carcinoma within the Milan Criteria after Orthotopic Liver Transplantation
Authors: Feng Jiliang , Wu Jushan , Zhu Ruidong , Feng Dezhao , Yu Lu , Zhang Yan , Bu Dayu , Li Chenlei , Zhou Yuyan , Si Lianghao , Liu Yuhan , Liang Ziwei , Xu Jianing , Wu Tianjun
Published: March 2017

Ten to twenty percent of the hepatocellular carcinoma (HCC) patients fulfilling the Milan criteria (MC) recurred within three years after orthotopic liver transplantation (OLT). We therefore utilize a training cohort to develop an improved prognostic model for predicting the recurrence in these patients. By univariate and multivariate analysis, AFP level [cut-off value: 321 ng/mL, area under the curve (AUC) = 0.724, 95% confidence interval (CI) = 0.604–0.843, P < 0.001] and cytokeratin-19 (CK19) and glypican-3 (GPC3) expression pattern from nine putative prognostic factors were entered in risk factor scoring model to conjecture the tumor recurrence. In the training cohort, the AUC value of the model was 0.767 (95% CI = 0.645–0.890, P < 0.001), which was the highest among all the elements. The model’s performance was then assessed using a validation cohort. In the validation cohort, the AUC value of the model was 0.843 (95% CI = 0.720−0.966, P < 0.001) which was higher than any other elements. The results indicated that model had high performance with good discrimination ability and significantly improved the predictive capacity for the recurrence of HCC patients within MC after OLT.
Suppression of autophagy by mycophenolic acid contributes to inhibition of HCV replication in human hepatoma cells
Authors: Fang Shoucai , Su Jinming , Liang Bingyu , Li Xu , Li Yu , Jiang Junjun , Huang Jiegang , Zhou Bo , Ning Chuanyi , Li Jieliang , Ho Wenzhe , Li Yiping , Chen Hui , Liang Hao , Ye Li
Published: March 2017

Previous studies have shown that mycophenolic acid (MPA) has an anti-HCV activity. However, the mechanism of MPA-mediated inhibition of HCV replication remains to be determined. This study investigated whether MPA has an effect on autophagy, a cellular machinery required for HCV replication, thereby, inhibits HCV replication in Huh7 cells. MPA treatment of Huh7 cells could suppress autophagy, evidenced by decreased LC3B-II level and conversion of LC3B-I to LC3B-II, decreased autophagosome formation, and increased p62 level compared to MPA-untreated cells. Tunicamycin treatment or HCV infection could induce cellular autophagy, however, MPA also exhibited its inhibitory effect on tunicamycin- or HCV infection-induced autophagy. The expression of three autophagy-related genes, Atg3, Atg5, and Atg7 were identified to be inhibited by MPA treatment. Over-expression of these genes could partly recover HCV replication inhibited by MPA; however, silencing their expression by siRNAs could enhance the inhibitory effect of MPA on HCV. Collectively, these results reveal that suppression of autophagy by MPA plays a role in its anti-HCV activity. Down-regulating the expression of three autophagy-related genes by MPA involves in its antiviral mechanism.
The effect of cold priming on the fitness of Arabidopsis thaliana accessions under natural and controlled conditions
Authors: Cvetkovic Jelena , Müller Klaus , Baier Margarete
Published: March 2017

Priming improves an organism's performance upon a future stress. To test whether cold priming supports protection in spring and how it is affected by cold acclimation, we compared seven Arabidopsis accessions with different cold acclimation potentials in the field and in the greenhouse for growth, photosynthetic performance and reproductive fitness in March and May after a 14 day long cold-pretreatment at 4 °C. In the plants transferred to the field in May, the effect of the cold pretreatment on the seed yield correlated with the cold acclimation potential of the accessions. In the March transferred plants, the reproductive fitness was most supported by the cold pretreatment in the accessions with the weakest cold acclimation potential. The fitness effect was linked to long-term effects of the cold pretreatment on photosystem II activity stabilization and leaf blade expansion. The study demonstrated that cold priming stronger impacts on plant fitness than cold acclimation in spring in accessions with intermediate and low cold acclimation potential.
Comparison of human adipose stromal vascular fraction and adipose-derived mesenchymal stem cells for the attenuation of acute renal ischemia/reperfusion injury
Authors: Zhou Liuhua , Song Qun , Shen Jiangwei , Xu Luwei , Xu Zheng , Wu Ran , Ge Yuzheng , Zhu Jiageng , Wu Jianping , Dou Quanliang , Jia Ruipeng
Published: March 2017

Stem cells therapy has been suggested as a promising option for the treatment of acute kidney injury (AKI). This study was performed to compare the abilities of xenogenic transplantation of human adipose stromal vascular fraction (SVF) and adipose-derived mesenchymal stem cells (AdMSCs) to facilitate the recovery of renal function and structure in a rat model of ischemia/reperfusion (IR) induced AKI. SVF or AdMSCs were transplanted to the injured kidney through intra-parenchymal injection. Significantly improved renal function and reduced tubular injury were observed in SVF and AdMSCs groups. Administration of SVF or AdMSCs contributed to significantly improved cell proliferation and markedly reduced cell apoptosis in parallel with reduced microvascular rarefaction in injured kidney. IR injury resulted in higher levels of inflammatory cytokines, whereas xenogenic transplantation of SVF or AdMSCs reduced but not induced inflammatory cytokines expression. Additionally, in vitro study showed that administration of SVF or AdMSCs could also significantly promote the proliferation and survival of renal tubular epithelial cells underwent hypoxia/reoxygenation injury through secreting various growth factors. However, cell proliferation was significantly promoted in SVF group than in AdMSCs group. In conclusion, our study demonstrated that administration of SVF or AdMSCs was equally effective in attenuating acute renal IR injury.
Acetylation and phosphorylation control both local and global stability of the chloroplast F1 ATP synthase
Authors: Schmidt Carla , Beilsten-Edmands Victoria , Mohammed Shabaz , Robinson Carol V.
Published: March 2017

ATP synthases (ATPases) are enzymes that produce ATP and control the pH in the cell or cellular compartments. While highly conserved over different species, ATPases are structurally well-characterised but the existence and functional significance of many post-translational modifications (PTMs) is not well understood. We combined a range of mass spectrometric techniques to unravel the location and extent of PTMs in the chloroplast ATP synthase (cATPase) purified from spinach leaves. We identified multiple phosphorylation and acetylation sites and found that both modifications stabilise binding of ε and δ subunits. Comparing cross-linking of naturally modified cATPase with the in vitro deacetylated enzyme revealed a major conformational change in the ε subunit in accord with extended and folded forms of the subunit. Locating modified residues within the catalytic head we found that phosphorylated and acetylated residues are primarily on α/β and β/α interfaces respectively. By aligning along different interfaces the higher abundance acetylated residues are proximal to the regulatory sites while the lower abundance phosphorylation sites are more densely populated at the catalytic sites. We propose that modifications in the catalytic head, together with the conformational change in subunit ε, work in synergy to fine-tune the enzyme during adverse conditions.
Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype
Authors: Kamath-Loeb Ashwini S. , Zavala-van Rankin Diego G. , Flores-Morales Jeny , Emond Mary J. , Sidorova Julia M. , Carnevale Alessandra , Cárdenas-Cortés Maria del Carmen , Norwood Thomas H. , Monnat Raymond J. , Loeb Lawrence A. , Mercado-Celis Gabriela E.
Published: March 2017

Loss-of-function mutations in theWRNhelicase gene cause Werner syndrome- a progeroid syndrome with an elevated risk of cancer and other age-associated diseases. Large numbers of single nucleotide polymorphisms have been identified inWRN. We report here the organismal, cellular, and molecular phenotypes of variant rs3087425 (c. 2500C > T) that results in an arginine to cysteine substitution at residue 834 (R834C) and up to 90% reduction of WRN helicase activity. This variant is present at a high (5%) frequency in Mexico, where we identified 153 heterozygous and three homozygous individuals among 3,130 genotyped subjects. Family studies of probands identified ten additional TT homozygotes. Biochemical analysis of WRN protein purified from TT lymphoblast cell lines confirmed that the R834C substitution strongly and selectively reduces WRN helicase, but not exonuclease activity. Replication track analyses showed reduced replication fork progression in some homozygous cells following DNA replication stress. Among the thirteen TT homozygotes, we identified a previously unreported and statistically significant gender bias in favor of males (p = 0.0016), but none of the clinical findings associated with Werner syndrome. Our results indicate that WRN helicase activity alone is not rate-limiting for the development of clinical WS.
Behavioral responses to noxious stimuli shape the perception of pain
Authors: May Elisabeth S. , Tiemann Laura , Schmidt Paul , Nickel Moritz M. , Wiedemann Nina , Dresel Christian , Sorg Christian , Ploner Markus
Published: March 2017

Pain serves vital protective functions. To fulfill these functions, a noxious stimulus might induce a percept which, in turn, induces a behavioral response. Here, we investigated an alternative view in which behavioral responses do not exclusively depend on but themselves shape perception. We tested this hypothesis in an experiment in which healthy human subjects performed a reaction time task and provided perceptual ratings of noxious and tactile stimuli. A multi-level moderated mediation analysis revealed that behavioral responses are significantly involved in the translation of a stimulus into perception. This involvement was significantly stronger for noxious than for tactile stimuli. These findings show that the influence of behavioral responses on perception is particularly strong for pain which likely reflects the utmost relevance of behavioral responses to protect the body. These observations parallel recent concepts of emotions and entail implications for the understanding and treatment of pain.
B-Myb Induces APOBEC3B Expression Leading to Somatic Mutation in Multiple Cancers
Authors: Chou Wen-Cheng , Chen Wei-Ting , Hsiung Chia-Ni , Hu Ling-Yueh , Yu Jyh-Cherng , Hsu Huan-Ming , Shen Chen-Yang
Published: March 2017

The key signature of cancer genomes is the accumulation of DNA mutations, the most abundant of which is the cytosine-to-thymine (C-to-T) transition that results from cytosine deamination. Analysis of The Cancer Genome Atlas (TCGA) database has demonstrated that this transition is caused mainly by upregulation of the cytosine deaminase APOBEC3B (A3B), but the mechanism has not been completely characterized. We found that B-Myb (encoded by MYBL2) binds the A3B promoter, causing transactivation, and this is responsible for the C-to-T transitions and DNA hypermutation in breast cancer cells. Analysis of TCGA database yielded similar results, supporting that MYBL2 and A3B are upregulated and putatively promote C-to-T transitions in multiple cancer types. Moreover, blockade of EGF receptor with afatinib attenuated B-Myb–A3B signaling, suggesting a clinically relevant means of suppressing mutagenesis. Our results suggest that B-Myb–A3B contributes to DNA damage and could be targeted by inhibiting EGF receptor.
Vascular transcriptome profiling identifies Sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction
Authors: Siedlinski Mateusz , Nosalski Ryszard , Szczepaniak Piotr , Ludwig-Gałęzowska Agnieszka H. , Mikołajczyk Tomasz , Filip Magdalena , Osmenda Grzegorz , Wilk Grzegorz , Nowak Michał , Wołkow Paweł , Guzik Tomasz J.
Published: March 2017

Vascular dysfunction is an important phenomenon in hypertension. We hypothesized that angiotensin II (AngII) affects transcriptome in the vasculature in a region-specific manner, which may help to identify genes related to vascular dysfunction in AngII-induced hypertension. Mesenteric artery and aortic transcriptome was profiled using Illumina WG-6v2.0 chip in control and AngII infused (490 ng/kg/min) hypertensive mice. Gene set enrichment and leading edge analyses identified Sphingosine kinase 1 (Sphk1) in the highest number of pathways affected by AngII. Sphk1 mRNA, protein and activity were up-regulated in the hypertensive vasculature. Chronic sphingosine-1-phosphate (S1P) infusion resulted in a development of significantly increased vasoconstriction and endothelial dysfunction. AngII-induced hypertension was blunted in Sphk1−/− mice (systolic BP 167 ± 4.2 vs. 180 ± 3.3 mmHg, p < 0.05), which was associated with decreased aortic and mesenteric vasoconstriction in hypertensive Sphk1−/− mice. Pharmacological inhibition of S1P synthesis reduced vasoconstriction of mesenteric arteries. While Sphk1 is important in mediating vasoconstriction in hypertension, Sphk1−/− mice were characterized by enhanced endothelial dysfunction, suggesting a local protective role of Sphk1 in the endothelium. S1P serum level in humans was correlated with endothelial function (arterial tonometry). Thus, vascular transcriptome analysis shows that S1P pathway is critical in the regulation of vascular function in AngII-induced hypertension, although Sphk1 may have opposing roles in the regulation of vasoconstriction and endothelium-dependent vasorelaxation.
miR-193a-3p interaction with HMGB1 downregulates human endothelial cell proliferation and migration
Authors: Khoo Cheen P. , Roubelakis Maria G. , Schrader Jack B. , Tsaknakis Grigorios , Konietzny Rebecca , Kessler Benedikt , Harris Adrian L. , Watt Suzanne M.
Published: March 2017

Circulating endothelial colony forming cells (ECFCs) contribute to vascular repair where they are a target for therapy. Since ECFC proliferative potential is increased in cord versus peripheral blood and to define regulatory factors controlling this proliferation, we compared the miRNA profiles of cord blood and peripheral blood ECFC-derived cells. Of the top 25 differentially regulated miRNAs selected, 22 were more highly expressed in peripheral blood ECFC-derived cells. After validating candidate miRNAs by q-RT-PCR, we selected miR-193a-3p for further investigation. The miR-193a-3p mimic reduced cord blood ECFC-derived cell proliferation, migration and vascular tubule formation, while the miR-193a-3p inhibitor significantly enhanced these parameters in peripheral blood ECFC-derived cells. Using in silico miRNA target database analyses combined with proteome arrays and luciferase reporter assays of miR-193a-3p mimic treated cord blood ECFC-derived cells, we identified 2 novel miR-193a-3p targets, the high mobility group box-1 (HMGB1) and the hypoxia upregulated-1 (HYOU1) gene products. HMGB1 silencing in cord blood ECFC-derived cells confirmed its role in regulating vascular function. Thus, we show, for the first time, that miR-193a-3p negatively regulates human ECFC vasculo/angiogenesis and propose that antagonising miR-193a-3p in less proliferative and less angiogenic ECFC-derived cells will enhance their vasculo/angiogenic function.