bluuebunny/crossref_metadata_2025 huggingface dataset:
Nocturnal Hypoxia Activation of the Hedgehog Signaling Pathway Affects Pediatric Nonalcoholic Fatty Liver Disease Severity
Authors: Sundaram Shikha S. , Swiderska‐Syn Marzena , Sokol Ronald J. , Halbower Ann C. , Capocelli Kelley E. , Pan Zhaoxing , Robbins Kristen , Graham Brian , Diehl Anna Mae
Published: April 2019

Chronic intermittent hypoxia and hedgehog (Hh) pathway dysregulation are associated with nonalcoholic fatty liver disease (NAFLD) progression. In this study, we determined the relationship between obstructive sleep apnea (OSA)/nocturnal hypoxia and Hh signaling in pediatric NAFLD. Adolescents with histologic NAFLD (n = 31) underwent polysomnogram testing, laboratory testing, and Sonic Hh (SHh), Indian hedgehog (IHh), glioblastoma‐associated oncogene 2 (Gli2), keratin 7 (K7), α‐smooth muscle actin (α‐SMA), and hypoxia‐inducible factor 1α (HIF‐1α) immunohistochemistry. Aspartate aminotransferase (AST) correlated with SHh, r = 0.64; Gli2, r = 0.4; α‐SMA, r = 0.55; and K7, r = 0.45 (P < 0.01), as did alanine aminotransferase (ALT) (SHh, r = 0.51; Gli2, r = 0.43; α‐SMA, r = 0.51; P < 0.02). SHh correlated with NAFLD activity score (r = 0.39), whereas IHh correlated with inflammation (r = −0.478) and histologic grade (r = −0.43); P < 0.03. Subjects with OSA/hypoxia had higher SHh (4.0 ± 2.9 versus 2.0 ± 1.5), Gli2 (74.2 ± 28.0 versus 55.8 ± 11.8), and α‐SMA (6.2 ± 3.3 versus 4.3 ± 1.2); compared to those without (P < 0.03). OSA severity correlated with SHh (r = 0.31; P = 0.09) and Gli2 (r = 0.37; P = 0.04) as did hypoxia severity, which was associated with increasing SHh (r = −0.53), Gli2 (r = −0.52), α‐SMA (r = −0.61), and K7 (r = −0.42); P < 0.02. Prolonged O2 desaturations <90% also correlated with SHh (r = 0.55) and Gli2 (r = 0.61); P < 0.05. Conclusion: The Hh pathway is activated in pediatric patients with NAFLD with nocturnal hypoxia and relates to disease severity. Tissue hypoxia may allow for functional activation of HIF‐1α, with induction of genes important in epithelial‐mesenchymal transition, including SHh, and NAFLD progression.
Design, Synthesis, and Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer Agents
Authors: Abdelgawad Nancy , Ismail Mahmoud F. , Hekal Mohamed H. , Marzouk Magda I.
Published: April 2019

1,3‐Diphenylpyrazole‐4‐carboxylaldehyde and o‐hydroxyacetophenone were exploited as starting materials for the synthesis of novel substituted chalconated pyrazole derivative. The proclivity of this compound towards carbon and nitrogen nucleophiles such as malononitrile, diethyl malonate, ethyl cyanoacetate, ethyl acetoacetate, semicarbazide, thiosemicarbazide, and hydroxylamine has been investigated. The structures of all synthesized compounds were ascertained by analytical and spectral data. The antitumor activity of the target synthesized compounds was tested against a panel of two human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2 and mammary gland breast MCF‐7.
Organic Electrosynthesis as a New Facile and Green Method for One‐pot Synthesis of Nanosized Particles of Octahydro‐imidazo[1,2‐a]quinolin‐6‐one Derivatives via a Multicomponent Reaction
Authors: Sayyar Rana , Makarem Somayeh , Mirza Behrooz
Published: April 2019

Organic electrosynthesis as a new facile and green method was applied for one‐pot synthesis of octahydro‐imidazo[1,2‐a]quinolin‐6‐one derivatives, via a three component condensation of a dimedone, an aldehyde and 2‐(nitromethylene)imidazolidine in propanol in an undivided cell in the presence of sodium bromide as an electrolyte at room temperature. In this study, the anion of dimedone that was produced on the cathode reacted with aromatic aldehydes through the Knoevenagel reaction and then the product condensed with 2‐(nitromethylene)imidazolidine that resulted in a highly efficient formation of octahydro‐imidazo[1,2‐a]quinolin‐6‐one with 50–96% substance yields.
Impact of fertilization on cover crops and microbial community on a bauxite‐mined soil undergoing reclamation
Authors: Teixeira Rafael S. , Souza Ivan F. , Santos Rafael S. , Gomes Lucas C. , Borges Silvano R. , Vergütz Leonardus , Silva Ivo R.
Published: April 2019

The reclamation of bauxite‐mined areas can be favored by the application of organic and/or chemical fertilization to restore the vegetation. Otherwise, the impact of fertilizations on soil microbiota or plant–microbe interactions as land reclamation progresses is less understood. To address this issue, we evaluated the impact of organic and chemical fertilization on plants and soil microbial community within the first 36 months of land reclamation in a bauxite‐mined site. The experiment was set up according to a split‐plot design in which the main plots received fertilizations [non‐fertilized control (NF), chemical fertilization (CF; NPK and rock phosphate), organic fertilization (OF; poultry litter), and CF+OF combined], and the subplots received cover crops [no cover crops (NC), grass (B; Brachiaria), legume (S, Stylosanthes), and B+S combined]. Cover crops biomass yield was assessed annually with five field campaigns per year. We used phospholipid fatty acids (PLFAs) to infer the impacts of mining and restoration practices on actinobacteria, Gram‐negative and Gram‐positive bacteria, arbuscular mycorrhizal fungi, and fungi. Accordingly, PLFAs were determined before bauxite mining (pre‐mining), six months after topsoil reconfiguration (post‐mining), and after 14 and 36 months following the application of the fertilizations and cover crops. PLFAs results indicated that in post‐mining, the living microbiota was significantly lower than in pre‐mining. Cover crops biomass yield was highest for B and B+S fertilized with CF+OF at 14 and 36 months. Both parametric and non‐parametric statistics showed a temporal variation in the response of living microbes to the treatments applied. After 14 months, living microbes showed greatest response to OF, while at 36 months their response was strongest in the treatments with highest plant biomass production (B and B+S). These results suggest that in the early stages of land reclamation, living microbial biomass benefit the most from organic fertilizers. As this initial boost decline, living microbes are more likely to thrive in areas undergoing reclamation where they can develop synergistic interactions with plants.
Graphoepitaxial Assembly of Block Copolymer for Bending Stripe Patterns
Authors: Huh June , Kim Mi‐Jeong , Park Jong‐Wan
Published: April 2019

The formation of bend patterns using block copolymer (BCP) lamellae within trench‐type groove patterned with bend geometry is simulated by using a Monte Carlo simulation and a strong segregation theory. A tolerance of curvatures at the bend corners of the guide pattern for the formation of bent lamellae is proposed. It is found from the simulation and the strong segregation theory that the tolerance for the difference in curvature radii of two bend corners for the well‐patterned lamellar bends is proportional to the inverse of the trench width in the straight region.
Universal Size and Shape Ratios for Arms in Star‐Branched Polymers: Theory and Mesoscopic Simulations
Authors: Kalyuzhnyi Ostap , Haidukivska Khristine , Blavatska Viktoria , Ilnytskyi Jaroslav
Published: April 2019

Star polymer undergoes a transformation from a group of loosely coupled chains at low number of arms to a dense hairy colloid at their high number. This change affects solubility, aggregation, and rheological behavior and is of much practical interest. The range of size and shape properties of the star molecule and of its individual arms upon this transformation are studied. Theoretical calculations are based on a continuous chain model and are performed in the first order in ε = 4 −d. Computer simulations are done by the dissipative particle dynamics and in part by Monte Carlo method and the results demonstrate very good agreement with the selected set of properties known from the previous simulations. Theory and simulations provide qualitatively similar trends upon increase of the number of arms, but higher order of approximation is required in a theory to achieve a good quantitative agreement.
Experimental and Theoretical Insights into the Optical Properties and Intermolecular Interactions in Push‐Pull Bromide Salts
Authors: Venkatesan Perumal , Cerón Margarita , Pérez‐Gutiérrez Enrique , Castillo Armando E. , Thamotharan Subbiah , Robles Fernando , Siegler Maxime A. , Percino M. Judith
Published: April 2019

Experimental and theoretical insights into the nature of intermolecular interactions and their effect on optical properties of 1‐allyl‐4‐(1‐cyano‐2‐(4‐dialkylaminophenyl)vinyl)pyridin‐1‐ium bromide salts (I and II) are reported. A comparison of optical properties in solution and in the solid‐state of the salts (I and II) with their precursors (Ia and IIa) is made. The experimental absorption maxima (λmax) in CHCl3 is at 528 nm for I and at 542 nm for II, and a strong bathochromic shift of ∼110 nm is observed for salts I and II compared with their precursors. The absorption bands in solid‐state at ∼627 nm for I and at ∼615 nm for II that are assigned to charge transfer (CT) effect. The optical properties and single crystal structural features of I and II are explored by experimental and computational tools. The calculated λmax and the CT are in good agreement with the experimental results. The intermolecular interactions existing in the crystal structures and their energies are quantified for various dimers by PIXEL, QTAIM and DFT approaches. Three types of interactions, (i) the cation⋅⋅⋅cation interactions, (ii) cation⋅⋅⋅anion interactions and (iii) anion⋅⋅⋅anion interactions are observed. The cationic moiety is mainly destabilized by C−H⋅⋅⋅N/π and π⋅⋅⋅π interactions whereas the cation and anion moiety is predominantly stabilized by strong C−H⋅⋅⋅Br− interactions in both structures. The existence of charge transfer between cation and anion moieties in these structures is established through NBO analysis.
On the Uselessness of Bond Paths Linking Distant Atoms and on the Violation of the Concept of Privileged Exchange Channels
Authors: Jabłoński Mirosław
Published: April 2019

We refer to frequently used determinants suggesting dominant interactions between distant atoms in various dimers. First of all, we show, against the still‐prevailling opinion, that, in general, bond paths have nothing in common with dominant intermolecular interactions and therefore they are useless in such cases. Quite the contrary, reliable information about dominant intermolecular interactions can be obtained by means of electrostatic potential maps, which very convincingly explain mutual orientation of molecules in a dimer. For the first time, numerous examples of interactions that violate both the concept of privileged exchange channels proposed by Pendás and his collaborators as well as inequalities obtained by Tognetti and Joubert for theβparameter related to secondary interactions are presented. The possible cause of this violation is suggested. We also show that the so‐called counterintuitive bond paths result from quite natural behavior of the electron density gradient vector, i. e. searching for those areas of space that are characterized by large values of electron density or the most expanded its distributions.
Ball‐Mill‐Exfoliated Graphene: Tunable Electrochemistry and Phenol Sensing
Authors: Li Xiaoyu , Shen Jian , Wu Can , Wu Kangbing
Published: April 2019

A simple wet ball‐milling method for exfoliating pristine graphite to graphene nanosheets is proposed. The surfactant of cetyltrimethyl ammonium bromide is utilized to greatly improve the exfoliation efficiency of graphene nanosheets. Variation of the ball‐milling time is an efficient way to control the size and thickness of graphene nanosheets, as well as the level of edge defects. With an increase of ball‐milling time, superior electrochemical reactivity is imparted owing to enlarged active area and increased catalytic ability. The obtained graphene nanosheets are sensitive for electrochemical oxidation of phenols (e.g., hydroquinone, p‐chlorophenol, and p‐nitrophenol), and thus qualified for the simultaneous sensing of trace level of phenols. The detection limits of simultaneous monitoring of hydroquinone, p‐chlorophenol, and p‐nitrophenol are as low as 0.017, 0.024, and 0.42 mg L−1, respectively. The proposed strategy thus opens up a new way to tune electrochemistry of graphene materials as well as to design their new applications.
On the typification of the lichen genus Lepra Scop.
Authors: Jørgensen Per M. , Nimis Pier L.
Published: April 2019

The first typification of Lepra Scop. by Pertusaria discoidea (Pers.) Malme (= Lepra albescens (Hudson) Hafellner), made in the Paris Code (1956), is shown to be correct after studies of the original material in the Micheli Herbarium in FI. Details of the latter are given. All later statements about this case, even in the Code, are irrelevant.
Insurance risk assessment in the face of climate change: Integrating data science and statistics
Authors: Lyubchich Vyacheslav , Newlands Nathaniel K. , Ghahari Azar , Mahdi Tahir , Gel Yulia R.
Published: April 2019

Local extreme weather events cause more insurance losses overall than large natural disasters. The evidence is provided by long‐term observations of weather and insurance records that are also a foundation for the majority of insurance products covering weather related damages. The insurers around the world are concerned, however, that the past records used to assess and price the risks underestimate the risk and incurred losses in recent years. The growing insurance risks are largely attributed to climate change that brings increasingly more alterations and permanent impact on all aspects of human life and welfare. From floods to hail to excessive wind, adverse atmospheric events are a poignant reminder of how vulnerable our society is across a broad range of threats posed by environmental extremes. Indeed, as climate change effects become more pronounced, we face a new era of risk with increasing weather related damages and losses. This in turn, coupled with challenges of massive climatic data, requires developing innovative analytic approaches that transcend traditional disciplinary boundaries of statistical, actuarial and environmental sciences. Nevertheless, the multidisciplinary nature of climate risk assessment and its impact on insurance is often overlooked and neglected. We highlight the most recent developments and interdisciplinary perspectives on diverse statistical and machine learning methodology for modeling and assessing climate risk in agricultural and home insurances, with a particular focus on noncatastrophic events.

This article is categorized under:

Applications of Computational Statistics > Computational Climate Change and Numerical Weather Forecasting

Statistical and Graphical Methods of Data Analysis > Multivariate Analysis

Data: Types and Structure > Massive Data
Respect Your Neighbor as Yourself: Neighborliness, Caste, and Community in South India
Authors: Thiranagama Sharika
Published: April 2019

This essay explores a global and existential problem—how ordinary people live and contend with historically deep subordination, humiliation, and exclusion—through an examination of the everyday lives of formerly untouchable caste Dalit communities in Kerala, India. I look at this through the lens of neighborliness: how people discuss how theylive togetherwith other castes and classes in small town and rural Kerala. Their continuing struggles with and experiences of humiliation and subordination must be placed within the historical context of Kerala, where deep inequality previously constituted every social relationship, and where the communist movement and other important social and political transformations have radically transformed living conditions and provided new languages and possibilities of equality within the official public sphere, if not the household. Drawing from the anthropology of ethics and engaging with philosophical discussions of living with others, I scrutinizeneighborlinessas an ethical landscape for Dalits living in new kinds of neighborhoods produced by political and social transformation. In doing so, I also reflect upon the ongoing conversations and interactions within which, for Dalits, respect, dignity, and worth are at stake. The essay also suggests new ways of understanding publics that are neither private nor part of the official public, but rather are networks of houses within rural neighborhoods—what I call “private-publics,” which are constituted through gendered caste relations.
The Role of Variable Slab Dip in Driving Mantle Flow at the Eastern Edge of the Alaskan Subduction Margin: Insights From Shear‐Wave Splitting
Authors: Venereau C. M. A. , Martin‐Short R. , Bastow I. D. , Allen R. M. , Kounoudis R.
Published: April 2019

Alaska provides an ideal tectonic setting for investigating the interaction between subduction and asthenospheric flow. Within the span of a few hundred kilometers along strike, the geometry of the subducting Pacific plate varies significantly and terminates in a sharp edge. Furthermore, the region documents a transition from subduction along the Aleutian Arc to strike‐slip faulting along the Pacific Northwest. To better understand mantle interactions within this subduction zone, we conduct an SKS shear‐wave splitting analysis on passive‐source seismic data collected between 2011 and 2018 at 239 broadband seismometers, including those from the Transportable Array. Anisotropic fast directions in the east of our study area parallel the Queen Charlotte and Fairweather transform faults, suggesting that the ongoing development of lithospheric anisotropy dominates the results there. However, our observed delay times (δt = 1–1.5 s) obtained across the study region may also imply an asthenospheric contribution to the splitting pattern. Our splitting observations exhibit slab‐parallel fast directions northwest of the trench and a rotation of fast directions around the northeastern slab edge. These observations suggest the presence of toroidal asthenospheric flow around the edge of the downgoing Pacific plate. We suggest that Wrangell Volcanic Field volcanism might be caused by mantle upwelling associated with this flow. Splitting observations closer to the trench can be explained by fossil anisotropy within the downgoing Pacific‐Yakutat plate combined with entrained subslab mantle. The geometry of the slab, including its variable dip and its abrupt eastern edge, thus plays an important role in governing mantle flow beneath Alaska.
Submarine Permafrost Map in the Arctic Modeled Using 1‐D Transient Heat Flux (SuPerMAP)
Authors: Overduin P. P. , Schneider von Deimling T. , Miesner F. , Grigoriev M. N. , Ruppel C. , Vasiliev A. , Lantuit H. , Juhls B. , Westermann S.
Published: April 2019

Offshore permafrost plays a role in the global climate system, but observations of permafrost thickness, state, and composition are limited to specific regions. The current global permafrost map shows potential offshore permafrost distribution based on bathymetry and global sea level rise. As a first‐order estimate, we employ a heat transfer model to calculate the subsurface temperature field. Our model uses dynamic upper boundary conditions that synthesize Earth System Model air temperature, ice mass distribution and thickness, and global sea level reconstruction and applies globally distributed geothermal heat flux as a lower boundary condition. Sea level reconstruction accounts for differences between marine and terrestrial sedimentation history. Sediment composition and pore water salinity are integrated in the model. Model runs for 450 ka for cross‐shelf transects were used to initialize the model for circumarctic modeling for the past 50 ka. Preindustrial submarine permafrost (i.e., cryotic sediment), modeled at 12.5‐km spatial resolution, lies beneath almost 2.5 ×106km2of the Arctic shelf. Our simple modeling approach results in estimates of distribution of cryotic sediment that are similar to the current global map and recent seismically delineated permafrost distributions for the Beaufort and Kara seas, suggesting that sea level is a first‐order determinant for submarine permafrost distribution. Ice content and sediment thermal conductivity are also important for determining rates of permafrost thickness change. The model provides a consistent circumarctic approach to map submarine permafrost and to estimate the dynamics of permafrost in the past.
Infrared Spectroscopy of Large, Low‐Albedo Asteroids: Are Ceres and Themis Archetypes or Outliers?
Authors: Rivkin Andrew S. , Howell Ellen S. , Emery Joshua P.
Published: April 2019

Low‐albedo, hydrated objects dominate the list of the largest asteroids. These objects have varied spectral shapes in the 3‐μm region, where diagnostic absorptions due to volatile species are found. Dawn's visit to Ceres has extended the view shaped by ground‐based observing and shown that world to be a complex one, potentially still experiencing geological activity. We present 33 observations from 2.2 to 4.0 μm of eight large (D > 200 km) asteroids from the C spectral complex, with spectra inconsistent with the hydrated minerals we see in meteorites. We characterize their absorption band characteristics via polynomial and Gaussian fits to test their spectral similarity to Ceres, the asteroid 24 Themis (thought to be covered in ice frost), and the asteroid 51 Nemausa (spectrally similar to the CM meteorites). We confirm most of the observations are inconsistent with what is seen in meteorites and require additional absorbers. We find clusters in band centers that correspond to Ceres‐ and Themis‐like spectra, but no hiatus in the distribution suitable for use to simply distinguish between them. We also find a range of band centers in the spectra that approaches what is seen on Comet 67P. Finally, variation is seen between observations for some objects, with the variation on 324 Bamberga consistent with hemispheric‐level difference in composition. Given the ubiquity of objects with 3‐μm spectra unlike what we see in meteorites, and the similarity of those spectra to the published spectra of Ceres and Themis, these objects appear much more to be archetypes than outliers.
Recurrence of Extreme Coastal Erosion in SE Australia Beyond Historical Timescales Inferred From Beach Ridge Morphostratigraphy
Authors: Tamura T. , Oliver T. S. N. , Cunningham A. C. , Woodroffe C. D.
Published: April 2019

Extreme storms present a major risk to coasts. Increasing populations worldwide, together with sea level rise, exacerbate concerns for coastal settlements, but the low frequency of extreme storms makes an assessment of risk difficult. In southeast Australia, the severest beach retreat on record relates to a series of extratropical cyclones in the 1970s, but the relatively short observational record hinders assessment of how frequent these events are. At Moruya in New South Wales, four decades of beach monitoring has provided new insights into response of beaches to extreme storms. We augment this recorded history with morphostratigraphic analysis of beach ridge evolution by using ground‐penetrating radar and optically stimulated luminescence dating. We find an episode of extreme retreat over 550 years, proving that the 1970s extreme event is a recurrent phenomenon. Our high‐precision morphostratigraphic analysis provides evidence with which to better plan coastal adaptation.
Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56
Authors: Xue Min , Zhang Kai , Mu Kun , Xu Juntao , Yang Huijie , Liu Yun , Wang Beibei , Wang Zhonghao , Li Zhongbo , Kong Qiong , Li Xiumin , Wang Hui , Zhu Jian , Zhuang Ting
Published: April 2019

Breast cancer ranks no. 1 in women cancer worldwide, while 60–70% are estrogen receptor alpha positive. The estrogen selective modulators, such as tamoxifen, become the effective drugs for controlling ER alpha breast cancer progression. However, tamoxifen resistance will develop during long-time treatment and cancer progression. Thus, further understanding of ER alpha signaling becomes necessary for the improvement of breast cancer therapy. Here, we identify TRIM56 as a novel regulatory factor in ER alpha signaling. TRIM56 expression is positively correlated with ER alpha and PR in breast cancer samples and is related to poor prognosis in endocrine therapy patients. TRIM56 depletion significantly decreases ER alpha signaling activity and ER-alpha-positive breast cancer proliferation in vitro and in vivo. TRIM56 associates with AF1 domain of ER alpha via its WD40 domain in the cytoplasm. TRIM56 prolongs ER alpha protein stability, possibly through targeting ER alpha K63-linked ubiquitination. In conclusion, our study reveals an interesting posttranslational mechanism between TRIM56 and ER alpha in breast cancer progression. Targeting TRIM56 could be a promising approach for ER-alpha-positive breast cancer.
Hippocampal–prefrontal coherence mediates working memory and selective attention at distinct frequency bands and provides a causal link between schizophrenia and its risk gene GRIA1
Authors: Bygrave Alexei M. , Jahans-Price Thomas , Wolff Amy R. , Sprengel Rolf , Kullmann Dimitri M. , Bannerman David M. , Kätzel Dennis
Published: April 2019

Increased fronto-temporal theta coherence and failure of its stimulus-specific modulation have been reported in schizophrenia, but the psychological correlates and underlying neural mechanisms remain elusive. Mice lacking the putative schizophrenia risk gene GRIA1 (Gria1–/–), which encodes GLUA1, show strongly impaired spatial working memory and elevated selective attention owing to a deficit in stimulus-specific short-term habituation. A failure of short-term habituation has been suggested to cause an aberrant assignment of salience and thereby psychosis in schizophrenia. We recorded hippocampal–prefrontal coherence while assessing spatial working memory and short-term habituation in these animals, wildtype (WT) controls, and Gria1–/– mice in which GLUA1 expression was restored in hippocampal subfields CA2 and CA3. We found that beta (20–30 Hz) and low-gamma (30–48 Hz) frequency coherence could predict working memory performance, whereas—surprisingly—theta (6–12 Hz) coherence was unrelated to performance and largely unaffected by genotype in this task. In contrast, in novel environments, theta coherence specifically tracked exploration-related attention in WT mice, but was strongly elevated and unmodulated in Gria1-knockouts, thereby correlating with impaired short-term habituation. Strikingly, reintroduction of GLUA1 selectively into CA2/CA3 restored abnormal short-term habituation, theta coherence, and hippocampal and prefrontal theta oscillations. Although local oscillations and coherence in other frequency bands (beta, gamma), and theta-gamma cross-frequency coupling also showed dependence on GLUA1, none of them correlated with short-term habituation. Therefore, sustained elevation of hippocampal–prefrontal theta coherence may underlie a failure in regulating novelty-related selective attention leading to aberrant salience, and thereby represents a mechanistic link between GRIA1 and schizophrenia.
Oxytocin receptors in the dorsolateral bed nucleus of the stria terminalis (BNST) bias fear learning toward temporally predictable cued fear
Authors: Martinon Daisy , Lis Paulina , Roman Alexandra N. , Tornesi Patricio , Applebey Sarah V. , Buechner Garrett , Olivera Valentina , Dabrowska Joanna
Published: April 2019

The inability to discriminate between threat and safety is a hallmark of stress-induced psychiatric disorders, including post-traumatic stress disorder. Dorsolateral bed nucleus of the stria terminalis (BNSTdl) is critically involved in the modulation of fear and anxiety, and has been proposed to regulate discrimination between signaled (cued, predictable) and unsignaled (unpredictable) threats. We recently showed that oxytocin receptors (OTRs) in the BNSTdl facilitate acquisition of cued fear measured in a fear-potentiated startle (FPS). In the current study, using in vivo microdialysis in awake male Sprague–Dawley rats, a double immunofluorescence approach with confocal microscopy, as well as retrograde tracing of hypothalamic BNST-projecting OT neurons, we investigated whether fear conditioning activates OT system and modulates OT release. To determine the role of OTR in fear memory formation, we also infused OTR antagonist or OT into the BNSTdl before fear conditioning and measured rats’ ability to discriminate between cued (signaled) and non-cued (unsignaled) fear using FPS. In contrast to acute stress (exposure to forced swim stress or foot shocks alone), cued fear conditioning increases OT content in BNSTdl microdialysates. In addition, fear conditioning induces moderate activation of OT neurons in the paraventricular nucleus of the hypothalamus and robust activation in the supraoptic and accessory nuclei of the hypothalamus. Application of OT into the BNSTdl facilitates fear learning toward signaled, predictable threats, whereas blocking OTR attenuates this effect. We conclude that OTR neurotransmission in the BNSTdl plays a pivotal role in strengthening fear learning of temporally predictable, signaled threats.
Influenza a virus-triggered autophagy decreases the pluripotency of human-induced pluripotent stem cells
Authors: Zahedi-Amiri Ali , Sequiera Glen L. , Dhingra Sanjiv , Coombs Kevin M.
Published: April 2019

Maternal influenza infection during pregnancy was reported multiple times as the possible cause of many defects and congenital anomalies. Apart from several cases of influenza-related miscarriage during various trimesters of pregnancy, some epidemiological data suggest a link between maternal influenza infection and genetic abnormalities in offspring. However, there are no reports yet describing how maternal influenza alters cellular pathways at early stages of development to result in congenital defects in the fetus. In the present study, using proteomic approaches, we utilized human-induced pluripotent stem cells (hiPSCs) for modeling intrablastocyst infection with influenza virus to not only investigate the vulnerability and responses of pluripotent stem cells to this virus but also to determine the possible impacts of influenza on pluripotency and signaling pathways controlling differentiation and embryogenesis. Our data indicated viral protein production in influenza A virus (IAV)-infected hiPSCs. However, viral replication was restricted in these cells, but cell viability and pluripotency were negatively affected. These events occurred simultaneously with an excessive level of IAV-induced autophagy as well as cytopathic effects. Quantitative SOMAscan screening also indicated that changes in the proteome of hiPSCs corresponded to abnormal differentiation in these cells. Taken together, our results showed that IAV-modulated reduction in hiPSC pluripotency is associated with significant activation of autophagy. Further investigations are required to explore the role of IAV-induced autophagy in leading pluripotent stem cells toward abnormal differentiation and impaired development in early stages of embryogenesis.
BRD9 binds cell type-specific chromatin regions regulating leukemic cell survival via STAT5 inhibition
Authors: Del Gaudio Nunzio , Di Costanzo Antonella , Liu Ning Qing , Conte Lidio , Migliaccio Antimo , Vermeulen Michiel , Martens Joost H. A. , Stunnenberg Hendrik G. , Nebbioso Angela , Altucci Lucia
Published: April 2019

Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer cells, which are unable to differentiate. Although genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared with CD34+ cells. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOCS3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.
Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
Authors: Kaasinen Eevi , Kuismin Outi , Rajamäki Kristiina , Ristolainen Heikki , Aavikko Mervi , Kondelin Johanna , Saarinen Silva , Berta Davide G. , Katainen Riku , Hirvonen Elina A. M. , Karhu Auli , Taira Aurora , Tanskanen Tomas , Alkodsi Amjad , Taipale Minna , Morgunova Ekaterina , Franssila Kaarle , Lehtonen Rainer , Mäkinen Markus , Aittomäki Kristiina , Palotie Aarno , Kurki Mitja I. , Pietiläinen Olli , Hilpert Morgane , Saarentaus Elmo , Niinimäki Jaakko , Junttila Juhani , Kaikkonen Kari , Vahteristo Pia , Skoda Radek C. , Seppänen Mikko R. J. , Eklund Kari K. , Taipale Jussi , Kilpivaara Outi , Aaltonen Lauri A.
Published: April 2019

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.
Basin-wide sea level coherency in the tropical Indian Ocean driven by Madden–Julian Oscillation
Authors: Rohith B. , Paul Arya , Durand Fabien , Testut Laurent , Prerna S. , Afroosa M. , Ramakrishna S. S. V. S. , Shenoi S. S. C.
Published: April 2019

Changes in sea level may be attributed either to barotropic (involving the entire water column) or baroclinic processes (governed by stratification). It has been widely accepted that barotropic sea level changes in the tropics are insignificant at intraseasonal time scales (periods of 30–80 days). Based on bottom pressure records, we present evidence for significant basin-wide barotropic sea level variability in the tropical Indian Ocean during December–April with standard deviations amounting to ∼30–60% of the standard deviation in total intraseasonal sea level variability. The origin of this variability is linked to a small patch of wind over the Eastern Indian Ocean, associated with boreal winter Madden–Julian Oscillations (MJO). These large fluctuations are likely to play a prominent role in the intraseasonal sea level and mass budgets. Because of their much faster propagation than baroclinic processes, they allow the basin to adjust to climatic perturbations much more rapidly than was previously thought.
Colossal barocaloric effects near room temperature in plastic crystals of neopentylglycol
Authors: Lloveras P. , Aznar A. , Barrio M. , Negrier Ph. , Popescu C. , Planes A. , Mañosa L. , Stern-Taulats E. , Avramenko A. , Mathur N. D. , Moya X. , Tamarit J.-Ll.
Published: April 2019

There is currently great interest in replacing the harmful volatile hydrofluorocarbon fluids used in refrigeration and air-conditioning with solid materials that display magnetocaloric, electrocaloric or mechanocaloric effects. However, the field-driven thermal changes in all of these caloric materials fall short with respect to their fluid counterparts. Here we show that plastic crystals of neopentylglycol (CH3)2C(CH2OH)2display extremely large pressure-driven thermal changes near room temperature due to molecular reconfiguration, that these changes outperform those observed in any type of caloric material, and that these changes are comparable with those exploited commercially in hydrofluorocarbons. Our discovery of colossal barocaloric effects in a plastic crystal should bring barocaloric materials to the forefront of research and development in order to achieve safe environmentally friendly cooling without compromising performance.
Hierarchical self-assembly of 3D lattices from polydisperse anisometric colloids
Authors: Luo Binbin , Kim Ahyoung , Smith John W. , Ou Zihao , Wu Zixuan , Kim Juyeong , Chen Qian
Published: April 2019

Colloids are mainly divided into two types defined by size. Micron-scale colloids are widely used as model systems to study phase transitions, while nanoparticles have physicochemical properties unique to their size. Here we study a promising yet underexplored third type: anisometric colloids, which integrate micrometer and nanometer dimensions into the same particle. We show that our prototypical system of anisometric silver plates with a high polydispersity assemble, unexpectedly, into an ordered, three-dimensional lattice. Real-time imaging and interaction modeling elucidate the crucial role of anisometry, which directs hierarchical assembly into secondary building blocks—columns—which are sufficiently monodisperse for further ordering. Ionic strength and plate tip morphology control the shape of the columns, and therefore the final lattice structures (hexagonal versus honeycomb). Our joint experiment–modeling study demonstrates potentials of encoding unconventional assembly in anisometric colloids, which can likely introduce properties and phase behaviors inaccessible to micron- or nanometer-scale colloids.
Bayesian nonparametric models characterize instantaneous strategies in a competitive dynamic game
Authors: McDonald Kelsey R. , Broderick William F. , Huettel Scott A. , Pearson John M.
Published: April 2019

Previous studies of strategic social interaction in game theory have predominantly used games with clearly-defined turns and limited choices. Yet, most real-world social behaviors involve dynamic, coevolving decisions by interacting agents, which poses challenges for creating tractable models of behavior. Here, using a game in which humans competed against both real and artificial opponents, we show that it is possible to quantify the instantaneous dynamic coupling between agents. Adopting a reinforcement learning approach, we use Gaussian Processes to model the policy and value functions of participants as a function of both game state and opponent identity. We found that higher-scoring participants timed their final change in direction to moments when the opponent’s counter-strategy was weaker, while lower-scoring participants less precisely timed their final moves. This approach offers a natural set of metrics for facilitating analysis at multiple timescales and suggests new classes of experimental paradigms for assessing behavior.
Author Correction: Solution-processed hybrid perovskite photodetectors with high detectivity
Authors: Dou Letian , Yang Yang , You Jingbi , Hong Ziruo , Chang Wei-Hsuan , Li Gang , Yang Yang
Published: April 2019

This Article contains an error in Equation 2 in that the denominator is inverted. This has not been fixed in the PDF or HTML versions of the Article but can be seen in the associated Correction.
Proteins that physically interact with the phosphatase Cdc14 in Candida albicans have diverse roles in the cell cycle
Authors: Kaneva Iliyana N. , Sudbery Ian M. , Dickman Mark J. , Sudbery Peter E.
Published: April 2019

The chromosome complement of the human fungal pathogen Candida albicans is unusually unstable, suggesting that the process of nuclear division is error prone. The Cdc14 phosphatase plays a key role in organising the intricate choreography of mitosis and cell division. In order to understand the role of Cdc14 in C. albicans we used quantitative proteomics to identify proteins that physically interact with Cdc14. To distinguish genuine Cdc14-interactors from proteins that bound non-specifically to the affinity matrix, we used a substrate trapping mutant combined with mass spectrometry analysis using Stable Isotope Labelling with Amino Acids in Cell Culture (SILAC). The results identified 126 proteins that interact with Cdc14 of which 80% have not previously been identified as Cdc14 interactors in C. albicans or S. cerevisiae. In this set, 55 proteins are known from previous research in S. cerevisiae and S. pombe to play roles in the cell cycle, regulating the attachment of the mitotic spindle to kinetochores, mitotic exit, cytokinesis, licensing of DNA replication by re-activating pre-replication complexes, and DNA repair. Five Cdc14-interacting proteins with previously unknown functions localised to the Spindle Pole Bodies (SPBs). Thus, we have greatly increased the number of proteins that physically interact with Cdc14 in C. albicans.
Lewis and AB0 blood group-phenotypes in periodontitis, cardiovascular disease, obesity and stroke
Authors: Enevold C. , Nielsen C. H. , Molbo D. , Lund R. , Bendtzen K. , Fiehn N. -E. , Holmstrup P.
Published: April 2019

The AB0 blood group has been linked to ischaemic heart disease, stroke, and periodontal disease, while the Lewis blood group has been linked to ischaemic heart disease and obesity, all of which have been associated with periodontitis. AB0 or Lewis blood group phenotype may therefore constitute common hereditary components predisposing to these disorders. In this study, we investigated if blood group phenotype associated with periodontitis in a subpopulation consisting of 702 participants from a Danish cross-sectional cohort and, secondarily, attempted to confirm their association with hypertension, ischaemic heart disease, stroke, and obesity. No significant association between blood group phenotype and periodontitis was detected, nor were previously reported associations between blood group phenotype and hypertension, ischaemic heart disease, stroke, and obesity confirmed. This may, at least partly, be attributed to differences in study type, outcome definitions, cohort sizes, and population attributable factors. However, our results suggested a strong association between self-reported stroke and the Lewis (a−b−) phenotype (P = 0.0002, OR: 22.28; CI 95: 4.72–131.63).
Whole Genome Sequencing of Extended Spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae Isolated from Hospitalized Patients in KwaZulu-Natal, South Africa
Authors: Founou Raspail Carrel , Founou Luria Leslie , Allam Mushal , Ismail Arshad , Essack Sabiha Yusuf
Published: April 2019

Extended spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae remain a critical clinical concern worldwide. The aim of this study was to characterize ESBL-producing K. pneumoniae detected within and between two hospitals in uMgungundlovu district, South Africa, using whole genome sequencing (WGS). An observational period prevalence study on antibiotic-resistant ESKAPE (i.e. Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) bacteria was carried out in hospitalized patients during a two-month period in 2017. Rectal swabs and clinical specimens were collected from patients hospitalized and were screened for ESBL-producing, Gram-negative ESKAPE bacteria using cefotaxime-containing MacConkey agar and ESBL combination disk tests. Nine confirmed ESBL-K. pneumoniae isolated from six patients and two hospitals were whole genome sequenced using an Illumina MiSeq platform. Genome sequences were screened for presence of integrons, insertion sequences, plasmid replicons, CRISPR regions, resistance genes and virulence genes using different software tools. Of the 159 resistant Gram-negative isolates collected, 31 (19.50%) were ESBL-producers, of which, nine (29.03%) were ESBL-K. pneumoniae. The nine K. pneumoniae isolates harboured several β-lactamase genes, including blaCTX-M-15, blaTEM-1b, blaSHV-1, blaOXA-1 concomitantly with many other resistance genes e.g. acc(6′)-lb-cr, aadAI6, oqxA and oqxB that confer resistance to aminoglycosides and/or fluoroquinolones, respectively. Three replicon plasmid types were detected in both clinical and carriage isolates, namely ColRNAI, IncFIB(K), IncF(II). Sequence type ST152 was confirmed in two patients (one carriage isolate detected on admission and one isolate implicated in infection) in one hospital. In contrast, ST983 was confirmed in a clinical and a carriage isolate of two patients in two different hospitals. Our data indicate introduction of ESBL-producing K. pneumoniae isolates into hospitals from the community. We also found evidence of nosocomial transmission within a hospital and transmission between different hospitals. The Clustered Regularly Interspaced Palindromic Repeats (CRISPR)-associated cas3 genes were further detected in two of the nine ESBL-KP isolates. This study showed that both district and tertiary hospital in uMgungundlovu District were reservoirs for several resistance determinants and highlighted the necessity to efficiently and routinely screen patients, particularly those receiving extensive antibiotic treatment and long-term hospitalization stay. It also reinforced the importance of infection, prevention and control measures to reduce the dissemination of antibiotic resistance within the hospital referral system in this district.
Neutrophil properties in healthy and Leishmania infantum-naturally infected dogs
Authors: Wardini Amanda Brito , Pinto-da-Silva Lucia Helena , Nadaes Natalia Rocha , Nascimento Michelle Tanny , Roatt Bruno Mendes , Reis Alexandre Barbosa , Viana Kelvinson Fernandes , Giunchetti Rodolfo Cordeiro , Saraiva Elvira Maria
Published: April 2019

Visceral leishmaniasis is a chronic disease that affects humans and dogs as well. Dogs, the domestic reservoir of Leishmania, play a central role in the transmission of visceral leishmaniasis, the most severe form of this disease. Neutrophils are the most abundant leukocytes in blood and interact with the parasite after infection. Here, we evaluate the effector properties of neutrophils from healthy and naturally Leishmania infantum-infected dogs. Our results showed that the parasite induced neutrophil extracellular trap (NET) release from neutrophils in both groups. Additionally, phagocytosis and NETs contributed differently to parasite killing by neutrophils from healthy and infected animals, and IFN-γ, IL-8, IL-4 and TNF-α production by neutrophils from both groups were differentially modulated by the parasite. Our results contribute to a better understanding of the complex role played by neutrophils in canine visceral leishmaniasis, which may favor the development of more effective therapies.