bluuebunny/crossref_metadata_2025 huggingface dataset:
Enablers and determinants of the provision of written action plans to patients with asthma: a stratified survey of Canadian physicians
Authors: Djandji Fabienne , Lamontagne Alexandrine J. , Blais Lucie , Bacon Simon L. , Ernst Pierre , Grad Roland , Lavoie Kim L. , McKinney Martha L. , Desplats Eve , Ducharme Francine M.
Published: March 2017

Despite national recommendations, most patients with asthma are not given a written action plan . The objectives were to ascertain physicians’ endorsement of potential enablers to providing a written action plan, and the determinants and proportion, of physician-reported use of a written action plan. We surveyed 838 family physicians, paediatricians, and emergency physicians in Quebec. The mailed questionnaire comprised 102 questions on asthma management, 11 of which pertained to written action plan and promising enablers. Physicians also selected a case vignette that best corresponded to their practice and reported their management. The survey was completed by 421 (56%) physicians (250 family physicians, 115 paediatricians and 56 emergency physicians); 43 (5.2%) reported providing a written action plan to ≥70% of their asthmatic patients and 126 (30%) would have used a written action plan in the selected vignette. Most (>60%) physicians highly endorsed the following enablers: patients requesting a written action plan, adding a blank written action plan to the chart, receiving a copy of the written action plan completed by a consultant, receiving a monetary compensation for its completion, and having another healthcare professional explain the completed written action plan to patients. Four determinants were significantly associated with providing a written action plan: being a paediatrician (RR:2.1), treating a child (RR:2.0), aiming for long-term asthma control (RR:2.5), and being aware of national recommendations to provide a written action plan to asthmatic patients (RR:2.9). A small minority of Quebec physicians reported providing a written action plan to most of their patients, revealing a huge care gap. Several enablers to improve uptake, highly endorsed by physicians, should be prioritised in future implementation efforts.
Helping children with reading difficulties: some things we have learned so far
Authors: McArthur Genevieve , Castles Anne
Published: March 2017

A substantial proportion of children struggle to learn to read. This not only impairs their academic achievement, but increases their risk of social, emotional, and mental health problems. In order to help these children, reading scientists have worked hard for over a century to better understand the nature of reading difficulties and the people who have them. The aim of this perspective is to outline some of the things that we have learned so far, and to provide a framework for considering the causes of reading difficulties and the most effective ways to treat them.
SNPs in bone-related miRNAs are associated with the osteoporotic phenotype
Authors: De-Ugarte Laura , Caro-Molina Enrique , Rodríguez-Sanz Maria , García-Pérez Miguel Angel , Olmos José M. , Sosa-Henríquez Manuel , Pérez-Cano Ramón , Gómez-Alonso Carlos , Del Rio Luis , Mateo-Agudo Jesús , Blázquez-Cabrera José Antonio , González-Macías Jesús , Pino-Montes Javier del , Muñoz-Torres Manuel , Diaz-Curiel Manuel , Malouf Jorge , Cano Antonio , Pérez-Castrillon José Luis , Nogues Xavier , Garcia-Giralt Natalia , Diez-Perez Adolfo
Published: March 2017

Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.
A Convenient Cas9-based Conditional Knockout Strategy for Simultaneously Targeting Multiple Genes in Mouse
Authors: Chen Jiang , Du Yinan , He Xueyan , Huang Xingxu , Shi Yun S.
Published: March 2017

The most powerful way to probe protein function is to characterize the consequence of its deletion. Compared to conventional gene knockout (KO), conditional knockout (cKO) provides an advanced gene targeting strategy with which gene deletion can be performed in a spatially and temporally restricted manner. However, for most species that are amphiploid, the widely used Cre-flox conditional KO (cKO) system would need targeting loci in both alleles to be loxP flanked, which in practice, requires time and labor consuming breeding. This is considerably significant when one is dealing with multiple genes. CRISPR/Cas9 genome modulation system is advantaged in its capability in targeting multiple sites simultaneously. Here we propose a strategy that could achieve conditional KO of multiple genes in mouse with Cre recombinase dependent Cas9 expression. By transgenic construction of loxP-stop-loxP (LSL) controlled Cas9 (LSL-Cas9) together with sgRNAs targeting EGFP, we showed that the fluorescence molecule could be eliminated in a Cre-dependent manner. We further verified the efficacy of this novel strategy to target multiple sites by deleting c-Maf and MafB simultaneously in macrophages specifically. Compared to the traditional Cre-flox cKO strategy, this sgRNAs-LSL-Cas9 cKO system is simpler and faster, and would make conditional manipulation of multiple genes feasible.
A dataset of stereoscopic images and ground-truth disparity mimicking human fixations in peripersonal space
Authors: Canessa Andrea , Gibaldi Agostino , Chessa Manuela , Fato Marco , Solari Fabio , Sabatini Silvio P.
Published: March 2017

Binocular stereopsis is the ability of a visual system, belonging to a live being or a machine, to interpret the different visual information deriving from two eyes/cameras for depth perception. From this perspective, the ground-truth information about three-dimensional visual space, which is hardly available, is an ideal tool both for evaluating human performance and for benchmarking machine vision algorithms. In the present work, we implemented a rendering methodology in which the camera pose mimics realistic eye pose for a fixating observer, thus including convergent eye geometry and cyclotorsion. The virtual environment we developed relies on highly accurate 3D virtual models, and its full controllability allows us to obtain the stereoscopic pairs together with the ground-truth depth and camera pose information. We thus created a stereoscopic dataset: GENUA PESTO—GENoa hUman Active fixation database: PEripersonal space STereoscopic images and grOund truth disparity. The dataset aims to provide a unified framework useful for a number of problems relevant to human and computer vision, from scene exploration and eye movement studies to 3D scene reconstruction.
The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization
Authors: Zhang Yao V. , Hannan Shabab B. , Kern Jeannine V. , Stanchev Doychin T. , Koç Baran , Jahn Thomas R. , Rasse Tobias M.
Published: March 2017

The kinesin-3 family member KIF1A has been shown to be important for experience dependent neuroplasticity. In Drosophila, amorphic mutations in the KIF1A homolog unc-104 disrupt the formation of mature boutons. Disease associated KIF1A mutations have been associated with motor and sensory dysfunctions as well as non-syndromic intellectual disability in humans. A hypomorphic mutation in the forkhead-associated domain of Unc-104, unc-104bris, impairs active zone maturation resulting in an increased fraction of post-synaptic glutamate receptor fields that lack the active zone scaffolding protein Bruchpilot. Here, we show that the unc-104brismutation causes defects in synaptic transmission as manifested by reduced amplitude of both evoked and miniature excitatory junctional potentials. Structural defects observed in the postsynaptic compartment of mutant NMJs include reduced glutamate receptor field size, and altered glutamate receptor composition. In addition, we observed marked loss of postsynaptic scaffolding proteins and reduced complexity of the sub-synaptic reticulum, which could be rescued by pre- but not postsynaptic expression of unc-104. Our results highlight the importance of kinesin-3 based axonal transport in synaptic transmission and provide novel insights into the role of Unc-104 in synapse maturation.
Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells
Authors: Alizadeh Javad , Zeki Amir A. , Mirzaei Nima , Tewary Sandipan , Rezaei Moghadam Adel , Glogowska Aleksandra , Nagakannan Pandian , Eftekharpour Eftekhar , Wiechec Emilia , Gordon Joseph W. , Xu Fred. Y. , Field Jared T. , Yoneda Ken Y. , Kenyon Nicholas J. , Hashemi Mohammad , Hatch Grant M. , Hombach-Klonisch Sabine , Klonisch Thomas , Ghavami Saeid
Published: March 2017

The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP- and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.
The giant deep-sea octopus Haliphron atlanticus forages on gelatinous fauna
Authors: Hoving H.J.T. , Haddock S.H.D.
Published: March 2017

Feeding strategies and predator-prey interactions of many deep-sea pelagic organisms are still unknown. This is also true for pelagic cephalopods, some of which are very abundant in oceanic ecosystems and which are known for their elaborate behaviors and central role in many foodwebs. We report on the first observations of the giant deep-sea octopus Haliphron atlanticus with prey. Using remotely operated vehicles, we saw these giant octopods holding medusae in their arms. One of the medusae could be identified as Phacellophora camtschatica (the egg-yolk jelly). Stomach content analysis confirmed predation on cnidarians and gelatinous organisms. The relationship between medusae and H. atlanticus is discussed, also in comparison with other species of the Argonautoidea, all of which have close relationships with gelatinous zooplankton.
Molecular and functional heterogeneity of early postnatal porcine satellite cell populations is associated with bioenergetic profile
Authors: Miersch Claudia , Stange Katja , Hering Silvio , Kolisek Martin , Viergutz Torsten , Röntgen Monika
Published: March 2017

During postnatal development, hyperplastic and hypertrophic processes of skeletal muscle growth depend on the activation, proliferation, differentiation, and fusion of satellite cells (SC). Therefore, molecular and functional SC heterogeneity is an important component of muscle plasticity and will greatly affect long-term growth performance and muscle health. However, its regulation by cell intrinsic and extrinsic factors is far from clear. In particular, there is only minor information on the early postnatal period which is critical for muscle maturation and the establishment of adult SC pools. Here, we separated two SC subpopulations (P40/50, P50/70) from muscle of 4-day-old piglets. Our results characterize P40/50 as homogeneous population of committed (high expression of Myf5), fast-proliferating muscle progenitors. P50/70 constituted a slow-proliferating phenotype and contains high numbers of differentiated SC progeny. During culture, P50/70 is transformed to a population with lower differentiation potential that contains 40% Pax7-positive cells. A reversible state of low mitochondrial activity that results from active down-regulation of ATP-synthase is associated with the transition of some of the P50/70 cells to this more primitive fate typical for a reserve cell population. We assume that P40/50 and P50/70 subpopulations contribute unequally in the processes of myofiber growth and maintenance of the SC pool.
Derivation of Functional Human Astrocytes from Cerebral Organoids
Authors: Dezonne Rômulo Sperduto , Sartore Rafaela Costa , Nascimento Juliana Minardi , Saia-Cereda Verônica M. , Romão Luciana Ferreira , Alves-Leon Soniza Vieira , de Souza Jorge Marcondes , Martins-de-Souza Daniel , Rehen Stevens Kastrup , Gomes Flávia Carvalho Alcantara
Published: March 2017

Astrocytes play a critical role in the development and homeostasis of the central nervous system (CNS). Astrocyte dysfunction results in several neurological and degenerative diseases. However, a major challenge to our understanding of astrocyte physiology and pathology is the restriction of studies to animal models, human post-mortem brain tissues, or samples obtained from invasive surgical procedures. Here, we report a protocol to generate human functional astrocytes from cerebral organoids derived from human pluripotent stem cells. The cellular isolation of cerebral organoids yielded cells that were morphologically and functionally like astrocytes. Immunolabelling and proteomic assays revealed that human organoid-derived astrocytes express the main astrocytic molecular markers, including glutamate transporters, specific enzymes and cytoskeletal proteins. We found that organoid-derived astrocytes strongly supported neuronal survival and neurite outgrowth and responded to ATP through transient calcium wave elevations, which are hallmarks of astrocyte physiology. Additionally, these astrocytes presented similar functional pathways to those isolated from adult human cortex by surgical procedures. This is the first study to provide proteomic and functional analyses of astrocytes isolated from human cerebral organoids. The isolation of these astrocytes holds great potential for the investigation of developmental and evolutionary features of the human brain and provides a useful approach to drug screening and neurodegenerative disease modelling.
Synergistic infection of BrYV and PEMV 2 increases the accumulations of both BrYV and BrYV-derived siRNAs in Nicotiana benthamiana
Authors: Zhou Cui-Ji , Zhang Xiao-Yan , Liu Song-Yu , Wang Ying , Li Da-Wei , Yu Jia-Lin , Han Cheng-Gui
Published: March 2017

Viral synergism is caused by co-infection of two unrelated viruses, leading to more severe symptoms or increased titres of one or both viruses. Synergistic infection of phloem-restricted poleroviruses and umbraviruses has destructive effects on crop plants. The mechanism underlying this synergy remains elusive. In our study, synergism was observed in co-infections of a polerovirus Brassica yellows virus (BrYV) and an umbravirusPea enation mosaic virus 2(PEMV 2) onNicotiana benthamiana, which led to (1) increased titres of BrYV, (2) appearance of severe symptoms, (3) gain of mechanical transmission capacity of BrYV, (4) broader distribution of BrYV to non-vascular tissues. Besides, profiles of virus-derived small interfering RNAs (vsiRNAs) from BrYV and PEMV 2 in singly and doubly infected plants were obtained by small RNA deep sequencing. Our results showed that accumulation of BrYV vsiRNAs increased tremendously and ratio of positive to negative strand BrYV vsiRNAs differed between singly infected and co-infected plants. Positions to which the BrYV vsiRNAs mapped to the viral genome varied considerably during synergistic infection. Moreover, target genes of vsiRNAs were predicted and annotated. Our results revealed the synergistic characteristics during co-infection of BrYV and PEMV 2, and implied possible effects of synergism have on vsiRNAs.
Degree of functionalisation dependence of individual Raman intensities in covalent graphene derivatives
Authors: Vecera Philipp , Eigler Siegfried , Koleśnik-Gray Maria , Krstić Vojislav , Vierck Asmus , Maultzsch Janina , Schäfer Ricarda A. , Hauke Frank , Hirsch Andreas
Published: March 2017

Covalent functionalisation of graphene is a continuously progressing field of research. The optical properties of such derivatives attract particular attention. In virtually all optical responses, however, an enhancement in peak intensity with increase of sp3 carbon content, and a vanishing of the peak position shift in monolayer compared to few-layer systems, is observed. The understanding of these seemingly connected phenomena is lacking. Here we demonstrate, using Raman spectroscopy and in situ electrostatic doping techniques, that the intensity is directly modulated by an additional contribution from photoluminescent π-conjugated domains surrounded by sp3 carbon regions in graphene monolayers. The findings are further underpinned by a model which correlates the individual Raman mode intensities to the degree of functionalisation. We also show that the position shift in the spectra of solvent-based and powdered functionalised graphene derivatives originates predominantly from the presence of edge-to-edge and edge-to-basal plane interactions and is by large functionalisation independent.
Spatiotemporal expression of osteopontin in the striatum of rats subjected to the mitochondrial toxin 3-nitropropionic acid correlates with microcalcification
Authors: Riew Tae-Ryong , Kim Hong Lim , Jin Xuyan , Choi Jeong-Heon , Shin Yoo-Jin , Kim Ji Soo , Lee Mun-Yong
Published: March 2017

Our aim was to elucidate whether osteopontin (OPN) is involved in the onset of mineralisation and progression of extracellular calcification in striatal lesions due to mitochondrial toxin 3-nitropropionic acid exposure. OPN expression had two different patterns when observed using light microscopy. It was either localised to the Golgi complex in brain macrophages or had a small granular pattern scattered in the affected striatum. OPN labelling tended to increase in number and size over a 2-week period following the lesion. Ultrastructural investigations revealed that OPN is initially localised to degenerating mitochondria within distal dendrites, which were then progressively surrounded by profuse OPN on days 7–14. Electron probe microanalysis of OPN-positive and calcium-fixated neurites indicated that OPN accumulates selectively on the surfaces of degenerating calcifying dendrites, possibly via interactions between OPN and calcium. In addition, 3-dimensional reconstruction of OPN-positive neurites revealed that they are in direct contact with larger OPN-negative degenerating dendrites rather than with fragmented cell debris. Our overall results indicate that OPN expression is likely to correlate with the spatiotemporal progression of calcification in the affected striatum, and raise the possibility that OPN may play an important role in the initiation and progression of microcalcification in response to brain insults.
Towards reproducible MRM based biomarker discovery using dried blood spots
Authors: Ozcan Sureyya , Cooper Jason D. , Lago Santiago G. , Kenny Diarmuid , Rustogi Nitin , Stocki Pawel , Bahn Sabine
Published: March 2017

There is an increasing interest in the use of dried blood spot (DBS) sampling and multiple reaction monitoring in proteomics. Although several groups have explored the utility of DBS by focusing on protein detection, the reproducibility of the approach and whether it can be used for biomarker discovery in high throughput studies is yet to be determined. We assessed the reproducibility of multiplexed targeted protein measurements in DBS compared to serum. Eighty-two medium to high abundance proteins were monitored in a number of technical and biological replicates. Importantly, as part of the data analysis, several statistical quality control approaches were evaluated to detect inaccurate transitions. After implementing statistical quality control measures, the median CV on the original scale for all detected peptides in DBS was 13.2% and in Serum 8.8%. We also found a strong correlation (r = 0.72) between relative peptide abundance measured in DBS and serum. The combination of minimally invasive sample collection with a highly specific and sensitive mass spectrometry (MS) technique allows for targeted quantification of multiple proteins in a single MS run. This approach has the potential to fundamentally change clinical proteomics and personalized medicine by facilitating large-scale studies.
Activation of the mechanosensitive ion channel MscL by mechanical stimulation of supported Droplet-Hydrogel bilayers
Authors: Rosholm Kadla R. , Baker Matthew A. B. , Ridone Pietro , Nakayama Yoshitaka , Rohde Paul R. , Cuello Luis G. , Lee Lawrence K. , Martinac Boris
Published: March 2017

The droplet on hydrogel bilayer (DHB) is a novel platform for investigating the function of ion channels. Advantages of this setup include tight control of all bilayer components, which is compelling for the investigation of mechanosensitive (MS) ion channels, since they are highly sensitive to their lipid environment. However, the activation of MS ion channels in planar supported lipid bilayers, such as the DHB, has not yet been established. Here we present the activation of the large conductance MS channel of E. coli, (MscL), in DHBs. By selectively stretching the droplet monolayer with nanolitre injections of buffer, we induced quantifiable DHB tension, which could be related to channel activity. The MscL activity response revealed that the droplet monolayer tension equilibrated over time, likely by insertion of lipid from solution. Our study thus establishes a method to controllably activate MS channels in DHBs and thereby advances studies of MS channels in this novel platform.
Brain arousal regulation as response predictor for antidepressant therapy in major depression
Authors: Schmidt Frank M. , Sander Christian , Dietz Marie-Elisa , Nowak Claudia , Schröder Thomas , Mergl Roland , Schönknecht Peter , Himmerich Hubertus , Hegerl Ulrich
Published: March 2017

A tonically high level of brain arousal and its hyperstable regulation is supposed to be a pathogenic factor in major depression. Preclinical studies indicate that most antidepressants may counteract this dysregulation. Therefore, it was hypothesized that responders to antidepressants show a) a high level of EEG-vigilance (an indicator of brain arousal) and b) a more stable EEG-vigilance regulation than non-responders. In 65 unmedicated depressed patients 15-min resting-state EEGs were recorded off medication (baseline). In 57 patients an additional EEG was recorded 14 ± 1 days following onset of antidepressant treatment (T1). Response was defined as a ≥50% HAMD-17-improvement after 28 ± 1 days of treatment (T2), resulting in 29 responders and 36 non-responders. Brain arousal was assessed using the Vigilance Algorithm Leipzig (VIGALL 2.1). At baseline responders and non-responders differed in distribution of overall EEG-vigilance stages (F2,133 = 4.780, p = 0.009), with responders showing significantly more high vigilance stage A and less low vigilance stage B. The 15-minutes Time-course of EEG-vigilance did not differ significantly between groups. Exploratory analyses revealed that responders showed a stronger decline in EEG-vigilance levels from baseline to T1 than non-responders (F2,130 = 4.978, p = 0.005). Higher brain arousal level in responders to antidepressants supports the concept that dysregulation of brain arousal is a possible predictor of treatment response in affective disorders.
Transcriptome analysis of molecular mechanisms responsible for light-stress response in Mythimna separata (Walker)
Authors: Duan Yun , Gong ZhongJun , Wu RenHai , Miao Jin , Jiang YueLi , Li Tong , Wu XiaoBo , Wu YuQing
Published: March 2017

Light is an important environmental signal for most insects. The Oriental Armyworm,Mythimna separata, is a serious pest of cereal crops worldwide, and is highly sensitive to light signals during its developmental and reproductive stages. However, molecular biological studies of its response to light stress are scarce, and related genomic information is not available. In this study, we sequenced andde novoassembled the transcriptomes ofM. separataexposed to four different light conditions: dark, white light (WL), UV light (UVL) and yellow light (YL). A total of 46,327 unigenes with an average size of 571 base pairs (bp) were obtained, among which 24,344 (52.55%) matched to public databases. The numbers of genes differentially expressed between dark vs WL, dark vs UVL, dark vs YL, and UVL vs YL were 12,012, 12,950, 14,855, and 13,504, respectively. These results suggest that light exposure altered gene expression patterns inM. separata. Putative genes involved in phototransduction-fly, phototransduction, circadian rhythm-fly, olfactory transduction, and taste transduction were identified. This study thus identified a series of candidate genes and pathways potentially related to light stress inM. separata.
Early loss of subchondral bone following microfracture is counteracted by bone marrow aspirate in a translational model of osteochondral repair
Authors: Gao Liang , Orth Patrick , Müller-Brandt Kathrin , Goebel Lars K. H. , Cucchiarini Magali , Madry Henning
Published: March 2017

Microfracture of cartilage defects may induce alterations of the subchondral bone in the mid- and long-term, yet very little is known about their onset. Possibly, these changes may be avoided by an enhanced microfracture technique with additional application of bone marrow aspirate. In this study, full-thickness chondral defects in the knee joints of minipigs were either treated with (1) debridement down to the subchondral bone plate alone, (2) debridement with microfracture, or (3) microfracture with additional application of bone marrow aspirate. At 4 weeks after microfracture, the loss of subchondral bone below the defects largely exceeded the original microfracture holes. Of note, a significant increase of osteoclast density was identified in defects treated with microfracture alone compared with debridement only. Both changes were significantly counteracted by the adjunct treatment with bone marrow. Debridement and microfracture without or with bone marrow were equivalent regarding the early cartilage repair. These data suggest that microfracture induced a substantial early resorption of the subchondral bone and also highlight the potential value of bone marrow aspirate as an adjunct to counteract these alterations. Clinical studies are warranted to further elucidate early events of osteochondral repair and the effect of enhanced microfracture techniques.
Serum lactate dehydrogenase predicts prognosis and correlates with systemic inflammatory response in patients with advanced pancreatic cancer after gemcitabine-based chemotherapy
Authors: Yu Shu-Lin , Xu Li-Tao , Qi Qi , Geng Ya-Wen , Chen Hao , Meng Zhi-Qiang , Wang Peng , Chen Zhen
Published: March 2017

Serum lactate dehydrogenase (LDH) concentrations correlate with tumor progression and poor outcome. We evaluated the predictive value of serum LDH level for overall survival (OS) of patients with advanced pancreatic cancer after gemcitabine-based chemotherapy. We retrospectively enrolled 364 patients with locally advanced or metastatic pancreatic adenocarcinoma who were then allocated to training (n = 139) and validation cohorts (n = 225). We evaluated the association between serum LDH levels and OS as well as with markers of systemic inflammation, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/monocyte ratio (LMR). Kaplan–Meier analyses revealed that low serum LDH levels in the training cohort significantly correlated with longer OS. Multivariate analysis identified the serum LDH levels as an independent prognostic predictor of OS (p = 0.005). Serum LDH levels correlated positively with NLR and PLR and correlated negatively with LMR. Similar results were obtained for the validation cohort, except that multivariate analysis identified the serum LDH level as a significant prognostic predictor and only a statistical trend for OS (p = 0.059). We conclude that serum LDH levels were associated with the systemic inflammatory response and served as a significant prognostic predictor of OS. Serum LDH levels predicted OS in patients with advanced pancreatic cancer after gemcitabine-based palliative chemotherapy.
Novel 1, 4-dihydropyridines for L-type calcium channel as antagonists for cadmium toxicity
Authors: Saddala Madhu Sudhana , Kandimalla Ramesh , Adi Pradeepkiran Jangampalli , Bhashyam Sainath Sri , Asupatri Usha Rani
Published: March 2017

The present study, we design and synthesize the novel dihydropyridine derivatives, i.e., 3 (a-e) and 5 (a-e) and evaluated, anticonvulsant activity. Initially due to the lacuna of LCC, we modeled the protein through modeller 9.15v and evaluated through servers. Docking studies were performed with the synthesized compounds and resulted two best compounds, i.e.,5a, 5eshowed the best binding energies. The activity of intracellular Ca2+measurements was performed on two cell lines: A7r5 (rat aortic smooth muscle cells) and SH-SY5Y (human neuroblastoma cells). The 5a and 5e compounds was showing the more specific activity on L-type calcium channels, i.e. A7r5 (IC50 = 0.18 ± 0.02 and 0.25 ± 0.63 μg/ml, respectively) (containing only L-type channels) than SH-SY5Y (i.e. both L-type and T-type channels) (IC50 = 8 ± 0.23 and 10 ± 0.18 μg/ml, respectively) with intracellular calcium mobility similar to amlodipine. Finally, bothin silicoandin vitroresults exploring two derivatives 5a and 5e succeeded to treat cadmium toxicity.
Post-Traumatic Osteoarthritis in Mice Following Mechanical Injury to the Synovial Joint
Authors: Rai Muhammad Farooq , Duan Xin , Quirk James D. , Holguin Nilsson , Schmidt Eric J. , Chinzei Nobuaki , Silva Matthew J. , Sandell Linda J.
Published: March 2017

We investigated the spectrum of lesions characteristic of post-traumatic osteoarthritis (PTOA) across the knee joint in response to mechanical injury. We hypothesized that alteration in knee joint stability in mice reproduces molecular and structural features of PTOA that would suggest potential therapeutic targets in humans. The right knees of eight-week old male mice from two recombinant inbred lines (LGXSM-6 and LGXSM-33) were subjected to axial tibial compression. Three separate loading magnitudes were applied: 6N, 9N, and 12N. Left knees served as non-loaded controls. Mice were sacrificed at 5, 9, 14, 28, and 56 days post-loading and whole knee joint changes were assessed by histology, immunostaining, micro-CT, and magnetic resonance imaging. We observed that tibial compression disrupted joint stability by rupturing the anterior cruciate ligament (except for 6N) and instigated a cascade of temporal and topographical features of PTOA. These features included cartilage extracellular matrix loss without proteoglycan replacement, chondrocyte apoptosis at day 5, synovitis present at day 14, osteophytes, ectopic calcification, and meniscus pathology. These findings provide a plausible model and a whole-joint approach for how joint injury in humans leads to PTOA. Chondrocyte apoptosis, synovitis, and ectopic calcification appear to be targets for potential therapeutic intervention.
Sex-dependent effects on gut microbiota regulate hepatic carcinogenic outcomes
Authors: Xie Guoxiang , Wang Xiaoning , Zhao Aihua , Yan Jingyu , Chen Wenlian , Jiang Runqiu , Ji Junfang , Huang Fengjie , Zhang Yunjing , Lei Sha , Ge Kun , Zheng Xiaojiao , Rajani Cynthia , Alegado Rosanna A. , Liu Jiajian , Liu Ping , Nicholson Jeremy , Jia Wei
Published: March 2017

Emerging evidence points to a strong association between sex and gut microbiota, bile acids (BAs), and gastrointestinal cancers. Here, we investigated the mechanistic link between microbiota and hepatocellular carcinogenesis using a streptozotocin-high fat diet (STZ-HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) murine model and compared results for both sexes. STZ-HFD feeding induced a much higher incidence of HCC in male mice with substantially increased intrahepatic retention of hydrophobic BAs and decreased hepatic expression of tumor-suppressive microRNAs. Metagenomic analysis showed differences in gut microbiota involved in BA metabolism between normal male and female mice, and such differences were amplified when mice of both sexes were exposed to STZ-HFD. Treating STZ-HFD male mice with 2% cholestyramine led to significant improvement of hepatic BA retention, tumor-suppressive microRNA expressions, microbial gut communities, and prevention of HCC. Additionally the sex-dependent differences in BA profiles in the murine model can be correlated to the differential BA profiles between men and women during the development of HCC. These results uncover distinct male and female profiles for gut microbiota, BAs, and microRNAs that may contribute to sex-based disparity in liver carcinogenesis, and suggest new possibilities for preventing and controlling human obesity-related gastrointestinal cancers that often exhibit sex differences.
Location, location & size: defects close to surfaces dominate fatigue crack initiation
Authors: Serrano-Munoz Itziar , Buffiere Jean-Yves , Mokso Rajmund , Verdu Catherine , Nadot Yves
Published: March 2017

Metallic cast components inevitably contain defects such as shrinkage cavities which are inherent to the solidification process. Those defects are known to significantly alter the fatigue life of components. Yet very little is known, quantitatively, on the dangerosity of internal casting defects compared to surface ones. In this study, fatigue specimens containing controlled internal defects (shrinkage pores) are used to foster internal cracking. In situ fatigue tests monitored by X ray synchrotron tomography revealed that the internal nucleation and propagation of cracks was systematically overran by surface cracking initiated at castings defects up to ten times smaller than the internal ones. These findings indicate that the presence of internal defects in cast components can be tolerated to a larger extent than is allowed by nowadays standards
Influence of Anthropogenic Climate Change on Planetary Wave Resonance and Extreme Weather Events
Authors: Mann Michael E. , Rahmstorf Stefan , Kornhuber Kai , Steinman Byron A. , Miller Sonya K. , Coumou Dim
Published: March 2017

Persistent episodes of extreme weather in the Northern Hemisphere summer have been shown to be associated with the presence of high-amplitude quasi-stationary atmospheric Rossby waves within a particular wavelength range (zonal wavenumber 6–8). The underlying mechanistic relationship involves the phenomenon of quasi-resonant amplification (QRA) of synoptic-scale waves with that wavenumber range becoming trapped within an effective mid-latitude atmospheric waveguide. Recent work suggests an increase in recent decades in the occurrence of QRA-favorable conditions and associated extreme weather, possibly linked to amplified Arctic warming and thus a climate change influence. Here, we isolate a specific fingerprint in the zonal mean surface temperature profile that is associated with QRA-favorable conditions. State-of-the-art (“CMIP5”) historical climate model simulations subject to anthropogenic forcing display an increase in the projection of this fingerprint that is mirrored in multiple observational surface temperature datasets. Both the models and observations suggest this signal has only recently emerged from the background noise of natural variability.
Two-dimensional electronic spectra of the photosynthetic apparatus of green sulfur bacteria
Authors: Kramer Tobias , Rodriguez Mirta
Published: March 2017

Advances in time resolved spectroscopy have provided new insight into the energy transmission in natural photosynthetic complexes. Novel theoretical tools and models are being developed in order to explain the experimental results. We provide a model calculation for the two-dimensional electronic spectra of Cholorobaculum tepidum which correctly describes the main features and transfer time scales found in recent experiments. From our calculation one can infer the coupling of the antenna chlorosome with the environment and the coupling between the chlorosome and the Fenna-Matthews-Olson complex. We show that environment assisted transport between the subunits is the required mechanism to reproduce the experimental two-dimensional electronic spectra.
Dynamic Changes in Amygdala Psychophysiological Connectivity Reveal Distinct Neural Networks for Facial Expressions of Basic Emotions
Authors: Diano Matteo , Tamietto Marco , Celeghin Alessia , Weiskrantz Lawrence , Tatu Mona-Karina , Bagnis Arianna , Duca Sergio , Geminiani Giuliano , Cauda Franco , Costa Tommaso
Published: March 2017

The quest to characterize the neural signature distinctive of different basic emotions has recently come under renewed scrutiny. Here we investigated whether facial expressions of different basic emotions modulate the functional connectivity of the amygdala with the rest of the brain. To this end, we presented seventeen healthy participants (8 females) with facial expressions of anger, disgust, fear, happiness, sadness and emotional neutrality and analyzed amygdala’s psychophysiological interaction (PPI). In fact, PPI can reveal how inter-regional amygdala communications change dynamically depending on perception of various emotional expressions to recruit different brain networks, compared to the functional interactions it entertains during perception of neutral expressions. We found that for each emotion the amygdala recruited a distinctive and spatially distributed set of structures to interact with. These changes in amygdala connectional patters characterize the dynamic signature prototypical of individual emotion processing, and seemingly represent a neural mechanism that serves to implement the distinctive influence that each emotion exerts on perceptual, cognitive, and motor responses. Besides these differences, all emotions enhanced amygdala functional integration with premotor cortices compared to neutral faces. The present findings thus concur to reconceptualise the structure-function relation between brain-emotion from the traditional one-to-one mapping toward a network-based and dynamic perspective.
A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions
Authors: Noel Gaelle , Baetz Nicholas W. , Staab Janet F. , Donowitz Mark , Kovbasnjuk Olga , Pasetti Marcela F. , Zachos Nicholas C.
Published: March 2017

Integration of the intestinal epithelium and the mucosal immune system is critical for gut homeostasis. The intestinal epithelium is a functional barrier that secludes luminal content, senses changes in the gut microenvironment, and releases immune regulators that signal underlying immune cells. However, interactions between epithelial and innate immune cells to maintain barrier integrity and prevent infection are complex and poorly understood. We developed and characterized a primary human macrophage-enteroid co-culture model for in-depth studies of epithelial and macrophage interactions. Human intestinal stem cell-derived enteroid monolayers co-cultured with human monocyte-derived macrophages were used to evaluate barrier function, cytokine secretion, and protein expression under basal conditions and following bacterial infection. Macrophages enhanced barrier function and maturity of enteroid monolayers as indicated by increased transepithelial electrical resistance and cell height. Communication between the epithelium and macrophages was demonstrated through morphological changes and cytokine production. Intraepithelial macrophage projections, efficient phagocytosis, and stabilized enteroid barrier function revealed a coordinated response to enterotoxigenic and enteropathogenic E. coli infections. In summary, we have established the first primary human macrophage-enteroid co-culture system, defined conditions that allow for a practical and reproducible culture model, and demonstrated its suitability to study gut physiology and host responses to enteric pathogens.
Structure of the Cyanuric Acid Hydrolase TrzD Reveals Product Exit Channel
Authors: Bera Asim K , Aukema Kelly G. , Elias Mikael , Wackett Lawrence P.
Published: March 2017

Cyanuric acid hydrolases are of industrial importance because of their use in aquatic recreational facilities to remove cyanuric acid, a stabilizer for the chlorine. Degradation of excess cyanuric acid is necessary to maintain chlorine disinfection in the waters. Cyanuric acid hydrolase opens the cyanuric acid ring hydrolytically and subsequent decarboxylation produces carbon dioxide and biuret. In the present study, we report the X-ray structure of TrzD, a cyanuric acid hydrolase from Acidovorax citrulli. The crystal structure at 2.19 Å resolution shows a large displacement of the catalytic lysine (Lys163) in domain 2 away from the active site core, whereas the two other active site lysines from the two other domains are not able to move. The lysine displacement is proposed here to open up a channel for product release. Consistent with that, the structure also showed two molecules of the co-product, carbon dioxide, one in the active site and another trapped in the proposed exit channel. Previous data indicated that the domain 2 lysine residue plays a role in activating an adjacent serine residue carrying out nucleophilic attack, opening the cyanuric acid ring, and the mobile lysine guides products through the exit channel.
Associations of parental age with health and social factors in adult offspring. Methodological pitfalls and possibilities
Authors: Carslake David , Tynelius Per , van den Berg Gerard , Davey Smith George , Rasmussen Finn
Published: March 2017

Parental age is increasing rapidly in many countries. Analysis of this potentially important influence on offspring well-being is hampered by strong secular trends and socioeconomic patterning and by a shortage of follow-up data for adult offspring. We used Swedish national data on up to 3,653,938 offspring to consider the associations of parental age with a suite of outcomes in adult offspring, comparing the results from an array of statistical methods for optimal causal inference. The offspring of older mothers had higher BMI, blood pressure, height, intelligence, non-cognitive ability and socioeconomic position. They were less likely to smoke or to be left-handed. Associations with paternal age were strongly, but not completely, attenuated by adjustment for maternal age. Estimates from the commonly-used sibling comparison method were driven primarily by a pathway mediated by offspring date of birth when outcomes showed strong secular trends. These results suggest that the intra-uterine and early life environments provided by older mothers may be detrimental to offspring cardiovascular health, but that their greater life experience and social position may bring intellectual and social advantages to their offspring. The analysis of parental age presents particular challenges, and further methodological developments are needed.
Community temporal variability increases with fluctuating resource availability
Authors: Li Wei , Stevens M. Henry H.
Published: March 2017

An increase in the quantity of available resources is known to affect temporal variability of aggregate community properties. However, it is unclear how might fluctuations in resource availability alter community-level temporal variability. Here we conduct a microcosm experiment with laboratory protist community subjected to manipulated resource pulses that vary in intensity, duration and time of supply, and examine the impact of fluctuating resource availability on temporal variability of the recipient community. The results showed that the temporal variation of total protist abundance increased with the magnitude of resource pulses, as protist community receiving infrequent resource pulses (i.e., high-magnitude nutrients per pulse) was relatively more unstable than community receiving multiple resource pulses (i.e., low-magnitude nutrients per pulse), although the same total amounts of nutrients were added to each community. Meanwhile, the timing effect of fluctuating resources did not significantly alter community temporal variability. Further analysis showed that fluctuating resource availability increased community temporal variability by increasing the degree of community-wide species synchrony and decreasing the stabilizing effects of dominant species. Hence, the importance of fluctuating resource availability in influencing community stability and the regulatory mechanisms merit more attention, especially when global ecosystems are experiencing high rates of anthropogenic nutrient inputs.
53BP1 contributes to regulation of autophagic clearance of mitochondria
Authors: Youn Cha Kyung , Kim Hong Beum , Wu Ting Ting , Park Sanggon , Cho Sung Il , Lee Jung-Hee
Published: March 2017

Autophagy, the primary recycling pathway within cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the cellular response to stress. Here we provide evidence that 53BP1, a DNA damage response protein, is involved in regulating mitochondrial clearance from the cell via a type of autophagy termed mitophagy. We found that when either human or mouse cells were 53BP1-deficient, there was an increase in mitochondrial abnormalities, as observed through staining intensity, aggregation, and increased mass. Moreover, a 53BP1-depleted cell population included an increased number of cells with a high mitochondrial membrane potential (ΔΨm) relative to controls, suggesting that the loss of 53BP1 prevents initiation of mitophagy thereby leading to the accumulation of damaged mitochondria. Indeed, both 53BP1 and the mitophagy-associated protein LC3 translocated to mitochondria in response to damage induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP). The recruitment of parkin, an E3-ubiquitin ligase, to mitochondria in response to CCCP treatment was significantly decreased in 53BP1-deficient cells. And lastly, using p53-deficient H1299 cells, we confirmed that the role of 53BP1 in mitophagy is independent of p53. These data support a model in which 53BP1 plays an important role in modulating mitochondrial homeostasis and in the clearance of damaged mitochondria.