bluuebunny/crossref_metadata_2025 huggingface dataset:
Subseasonal Dispersal of Freshwater in the Northern Bay of Bengal in the 2013 Summer Monsoon Season
Authors: Sree Lekha J. , Buckley J. M. , Tandon A. , Sengupta D.
Published: July 2018

Near‐surface salinity in the north Bay of Bengal (BoB) is very low for nearly three seasons (July–January), due to freshwater input from summer monsoon rainfall and seasonal discharge from several major rivers, including the Ganga‐Brahmaputra‐Meghna and the Irrawady. The low‐salinity surface layer leads to a very shallow density mixed layer, profoundly influencing air‐sea interaction on diurnal to seasonal time scales. We use mooring and satellite observations to study the mechanisms responsible for lateral dispersal of river water in the north BoB on subseasonal time scales (days to weeks) during the summer monsoon season of 2013. A new ocean current data set, the BoB near‐surface current and advection estimation (BoBcat), is developed to account for the influence of near‐surface stratification on directly wind‐forced currents. A salt balance based on Aquarius sea surface salinity, BoBcat currents and moored observations shows that subseasonal sea surface salinity variability is mainly due to lateral advection. A shallow Ekman current, forced by enhanced wind stress during an active spell of the monsoon in mid‐August, plays a dominant role in moving freshwater from the western boundary to the interior. During subseasonal spells of weak monsoon winds, stirring by mesoscale eddies is the main mechanism of dispersal of low‐salinity water. The dispersal of river water in the BoB is very sensitive to surface wind stress.
Local Time Dependence of the Thermal Structure in the Venusian Equatorial Upper Atmosphere: Comparison of Akatsuki Radio Occultation Measurements and GCM Results
Authors: Ando Hiroki , Takagi Masahiro , Fukuhara Tetsuya , Imamura Takeshi , Sugimoto Norihiko , Sagawa Hideo , Noguchi Katsuyuki , Tellmann Silvia , Pätzold Martin , Häusler Bernd , Murata Yasuhiro , Takeuchi Hiroshi , Yamazaki Atsushi , Toda Tomoaki , Tomiki Atsushi , Choudhary Rajkumar , Kumar Kishore , Ramkumar Geetha , Antonita Maria
Published: July 2018

Temperature profiles of the Venus atmosphere obtained by the Akatsuki radio occultation measurements showed a prominent local time dependence above 65‐km altitude at low latitudes equatorward of 35°. A zonal wavenumber 2 component is predominant in the temperature field, and its phase (i.e., isothermal) surfaces descend with local time, suggesting its downward phase propagation. A general circulation model (GCM) for the Venus atmosphere, AFES‐Venus, reproduced the local time‐dependent thermal structure qualitatively consistent with the radio occultation measurements. Based on a comparison between the radio occultation measurements and the GCM results, the observed zonal wavenumber 2 structure is attributed to the semidiurnal tide. Applying the dispersion relationship for internal gravity waves to the observed wave structure, the zonally averaged zonal wind speed at 75‐ to 85‐km altitudes was found to be significantly smaller than that at the cloud top. The decrease of the zonal wind speed with altitude is attributed to the momentum deposition by the upwardly propagating semidiurnal tide excited in the cloud layer.
Ice Wedge Degradation and Stabilization Impact Water Budgets and Nutrient Cycling in Arctic Trough Ponds
Authors: Koch J. C. , Jorgenson M. T. , Wickland K. P. , Kanevskiy M. , Striegl R.
Published: July 2018

Trough ponds are ubiquitous features of Arctic landscapes and an important component of freshwater aquatic ecosystems. Permafrost thaw causes ground subsidence, creating depressions that gather water, creating ponds. Permafrost thaw also releases solutes and nutrients, which may fertilize these newly formed ponds. We measured water budget elements and chloride, ammonium, and dissolved organic nitrogen (DON) across a chronosequence of trough ponds representing different stages of ice wedge degradation and stabilization. We developed a coupled hydrologic and biogeochemical model to explore how ice wedge degradation affects hydrology and nutrient availability in trough ponds in the advanced degradation stages (DAs), which are characterized by deep troughs with warmer temperatures relative to the other stages. DAs experienced greater evaporation than the other stages, and subsurface inflows entered the DAs from a wide area. Chloride accumulated in the ponds with time since thaw, implying that subsurface fluxes are delivering solutes from the thawing permafrost. Ammonium accumulated at high rates in the initial degradation stage and was seasonally depleted over the summer in all degradation stages. Ammonium trends in the DAs were consistent with high concentration inflows and in‐pond assimilation at rates between 0.37 and 2.0 mg N m−2 day−1. Seasonal DON trends indicated that the accumulation of recalcitrant organic matter may eventually limit aquatic ecosystem production and foster pond infilling. These results provide direct evidence of nutrient release from thawing permafrost and the utilization of these nutrients by Arctic trough pond ecosystems and highlight infilling as a mechanism by which Arctic surface waters may be lost.
Ecosystem Carbon Use Efficiency Is Insensitive to Nitrogen Addition in an Alpine Meadow
Authors: Ma Fangfang , Song Bing , Zhang Fangyue , Quan Quan , Zhou Qingping , Niu Shuli
Published: July 2018

Carbon use efficiency (CUE) is an important variable in carbon cycling and a key parameter in biogeochemical models, which is expected to increase with N availability. However, how CUE changes with N input rate remains elusive and lacks field evidence. We implemented a field manipulative experiment to examine effects of N addition with six levels of rate (0, 2, 4, 8, 16, and 32 g·N·m−2·year−1) on canopy CUE (the ratio of net primary productivity [NPP] to gross primary productivity [GPP]) and ecosystem CUE (the ratio of net ecosystem productivity [NEP] to GPP) in an alpine meadow on the Tibetan Plateau in 2014–2016. Over the 3 years, nitrogen addition treatments did not change canopy CUE or ecosystem CUE in comparing with the control, although it significantly increased GPP, NPP, and NEP; those components of CUE had the same response patterns to N addition rates, which shifted from linear responses in the first year to saturation responses thereafter. Moreover, GPP showed a positive linear relationship with NEP, NPP, ecosystem respiration, and autotrophic respiration under each N addition treatment with no changes in slope. The inherent coupling between GPP and ecosystem respiration, as well as GPP and autotrophic respiration, made CUE less sensitive to N addition than carbon fluxes themselves. The conclusions challenge the widely held hypothesis that ecosystem CUE increases with N addition. This study provides the first empirical evidences on the proposition that CUE is insensitive to N availability, which is of importance in model construction and parameterization.
Spatiotemporal Distribution of Microearthquakes and Implications Around the Seismic Gap Between the Wenchuan and Lushan Earthquakes
Authors: Wang Chaoliang , Liang Chuntao , Deng Kai , Huang Yanling , Zhou Lu
Published: July 2018

The mechanism of why the rupture terminated sharply on both sides of the seismic gap between the Wenchuan and Lushan earthquakes is not yet known along the southwestern Longmen Shan fault zone. The accommodation modes of compressional strain and stress are still not known well in the gap subregion. Using the Match and Locate method, we obtained a detailed catalog of background microearthquakes around the seismic gap from May to December 2015. The characteristics of spatiotemporal distribution of the events is highlighted with a complete magnitude of 0.2. These small events tend to concentrate at different depth ranges on two sides of the seismic gap, indicating that the gap serves as a transition zone between the Wenchuan and Lushan source regions. Strain release through microearthquakes is an unlikely candidate for accommodating modes in the gap, because of the sustained deficit of microseismicity. A strong anticorrelation between background seismicity and monthly precipitation variation rate is observed for different magnitude scales. Enhanced seismicity may be activated by the terrestrial water storage reduction next to a precipitation peak with a time lag of 1–2 months during the summer and autumn, indicating a seasonal modulation of seismicity by the water storage cycle. The background microseismicity exhibits prominent responses to precipitation variation due to a short nucleation duration of less than one quarter.
Development of a Pediatric Psychology Practicum for Doctoral Trainees in the Context of Outpatient Pediatric Gastroenterology
Authors: Murphy Lexa K. , Stone Amanda L. , Walker Lynn S. , Acra Sari A. , Hawkins Stacy , Han Gloria T. , McLaughlin F. Joseph
Published: July 2018

This article demonstrates how the development of a practicum in pediatric psychology in a multidisciplinary clinic provides rich opportunities for doctoral trainees. The process of partnering with a pediatric gastroenterology clinic with limited behavioral health services and developing a practicum that met both clinic needs and trainee goals is described. Initial data assessing utilization, acceptability, and training effectiveness are presented. Medical providers ( N = 11) were asked to complete a brief survey to assess their experience with the trainees; graduates of the training clinic ( N = 3) were asked to retrospectively rate competencies before and after the training practicum. Preliminary data suggest that pediatric psychology services were well utilized and providers reported high levels of acceptability and satisfaction. Graduates of the training practicum reported growth in each competency. This practicum evolved into a tiered 2-year practicum experience that met core competencies in pediatric psychology across multiple domains. Lessons learned are reviewed in order to guide other graduate programs wishing to develop similar pediatric psychology practicum for advanced doctoral students with interests in pediatric psychology.

Implications for Impact Statement

This article reviews the development of a new clinical psychology training practicum in a pediatric multidisciplinary setting and discusses how this experience addressed core competencies in training in pediatric psychology. The development process is reviewed, initial utilization and acceptability data are presented, and specific lessons learned are provided for training programs interested in developing similar practicum.
Genomic profiling of four cultivated Candidatus Nitrotoga spp. predicts broad metabolic potential and environmental distribution
Authors: Boddicker Andrew M , Mosier Annika C
Published: July 2018

Nitrite-oxidizing bacteria (NOB) play a critical role in the mitigation of nitrogen pollution by metabolizing nitrite to nitrate, which is removed via assimilation, denitrification, or anammox. Recent studies showed that NOB are phylogenetically and metabolically diverse, yet most of our knowledge of NOB comes from only a few cultured representatives. Using cultivation and genomic sequencing, we identified four putative Candidatus Nitrotoga NOB species from freshwater sediments and water column samples in Colorado, USA. Genome analyses indicated highly conserved 16S rRNA gene sequences, but broad metabolic potential including genes for nitrogen, sulfur, hydrogen, and organic carbon metabolism. Genomic predictions suggested that Ca. Nitrotoga can metabolize in low oxygen or anoxic conditions, which may support an expanded environmental niche for Ca. Nitrotoga similar to other NOB. An array of antibiotic and metal resistance genes likely allows Ca. Nitrotoga to withstand environmental pressures in impacted systems. Phylogenetic analyses highlighted a deeply divergent nitrite oxidoreductase alpha subunit (NxrA), suggesting a novel evolutionary trajectory for Ca. Nitrotoga separate from any other NOB and further revealing the complex evolutionary history of nitrite oxidation in the bacterial domain. Ca. Nitrotoga-like 16S rRNA gene sequences were prevalent in globally distributed environments over a range of reported temperatures. This work considerably expands our knowledge of the Ca. Nitrotoga genus and suggests that their contribution to nitrogen cycling should be considered alongside other NOB in wide variety of habitats.
Ricolinostat (ACY-1215) suppresses proliferation and promotes apoptosis in esophageal squamous cell carcinoma via miR-30d/PI3K/AKT/mTOR and ERK pathways
Authors: Cao Jinlin , Lv Wang , Wang Luming , Xu Jinming , Yuan Ping , Huang Sha , He Zhehao , Hu Jian
Published: July 2018

Ricolinostat (ACY-1215), a first-in-class selective HDAC6 inhibitor, exhibits antitumor effects alone or in combination with other drugs in various cancers. However, its efficacy in esophageal cancer remains unclear. In this study, we found that the high expression of HDAC6 was associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) tissues. Then, we identified that ACY-1215 significantly inhibited cellular proliferation in ESCC, and caused G2/M phase arrest and apoptosis. We further demonstrated that ACY-1215 treatment reduced the expression of PI3K, P-AKT, P-mTOR, and P-ERK1/2 and increased that of Ac-H3K9 and Ac-H4K8. In addition, using miRNA microarray and bioinformatics analysis, we detected that ACY-1215 promoted miR-30d expression, and PI3K regulatory subunit 2 (PIK3R2) was a direct target of miR-30d. Anti-miR-30d partially rescued the G2/M phase arrest and apoptosis caused by ACY-1215 treatment. The reductions in PI3K, P-AKT, and P-mTOR expression were also partially reversed by miR-30d inhibitor. Furthermore, the effects of ACY-1215 inhibited ESCC proliferation were validated in a mouse xenograft model in vivo. In conclusion, our study showed that ACY-1215 suppressed proliferation and promoted apoptosis in ESCC via miR-30d/PI3K/AKT/mTOR and ERK pathways and that ACY-1215 may be a promising antitumor agent in ESCC.
Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells
Authors: Sulaiman Andrew , McGarry Sarah , Lam Ka Mien , El-Sahli Sara , Chambers Jason , Kaczmarek Shelby , Li Li , Addison Christina , Dimitroulakos Jim , Arnaout Angel , Nessim Carolyn , Yao Zemin , Ji Guang , Song Haiyan , Liu Sheng , Xie Ying , Gadde Suresh , Li Xuguang , Wang Lisheng
Published: July 2018

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. It causes the majority of breast cancer-related deaths, which has been largely associated with the plasticity of tumor cells and persistence of cancer stem cells (CSCs). Conventional chemotherapeutics enrich CSCs and lead to drug resistance and disease relapse. Development of a strategy capable of inhibiting both bulk and CSC populations is an unmet medical need. Inhibitors against estrogen receptor 1, HDACs, or mTOR have been studied in the treatment of TNBC; however, the results are inconsistent. In this work, we found that patient TNBC samples expressed high levels of mTORC1 and HDAC genes in comparison to luminal breast cancer samples. Furthermore, co-inhibition of mTORC1 and HDAC with rapamycin and valproic acid, but neither alone, reproducibly promoted ESR1 expression in TNBC cells. In combination with tamoxifen (inhibiting ESR1), both S6RP phosphorylation and rapamycin-induced 4E-BP1 upregulation in TNBC bulk cells was inhibited. We further showed that fractionated CSCs expressed higher levels of mTORC1 and HDAC than non-CSCs. As a result, co-inhibition of mTORC1, HDAC, and ESR1 was capable of reducing both bulk and CSC subpopulations as well as the conversion of fractionated non-CSC to CSCs in TNBC cells. These observations were partially recapitulated with the cultured tumor fragments from TNBC patients. Furthermore, co-administration of rapamycin, valproic acid, and tamoxifen retarded tumor growth and reduced CD44high/+/CD24low/− CSCs in a human TNBC xenograft model and hampered tumorigenesis after secondary transplantation. Since the drugs tested are commonly used in clinic, this study provides a new therapeutic strategy and a strong rationale for clinical evaluation of these combinations for the treatment of patients with TNBC.
MicroRNA-143 targets ERK5 in granulopoiesis and predicts outcome of patients with acute myeloid leukemia
Authors: Hartmann Jens-Uwe , Bräuer-Hartmann Daniela , Kardosova Miroslava , Wurm Alexander A. , Wilke Franziska , Schödel Cindy , Gerloff Dennis , Katzerke Christiane , Krakowsky Rosanna , Namasu Carolina Yaeko , Bill Marius , Schwind Sebastian , Müller-Tidow Carsten , Niederwieser Dietger , Alberich-Jorda Meritxell , Behre Gerhard
Published: July 2018

Hematopoiesis, the formation of blood cells from hematopoietic stem cells (HSC), is a highly regulated process. Since the discovery of microRNAs (miRNAs), several studies have shown their significant role in the regulation of the hematopoietic system. Impaired expression of miRNAs leads to disrupted cellular pathways and in particular causes loss of hematopoietic ability. Here, we report a previously unrecognized function of miR-143 in granulopoiesis. Hematopoietic cells undergoing granulocytic differentiation exhibited increased miR-143 expression. Overexpression or ablation of miR-143 expression resulted in accelerated granulocytic differentiation or block of differentiation, respectively. The absence of miR-143 in mice resulted in a reduced number of mature granulocytes in blood and bone marrow. Additionally, we observed an association of high miR-143 expression levels with a higher probability of survival in two different cohorts of patients with acute myeloid leukemia (AML). Overexpression of miR-143 in AML cells impaired cell growth, partially induced differentiation, and caused apoptosis. Argonaute2-RNA-Immunoprecipitation assay revealed ERK5, a member of the MAPK-family, as a target of miR-143 in myeloid cells. Further, we observed an inverse correlation of miR-143 and ERK5 in primary AML patient samples, and in CD34+ HSPCs undergoing granulocytic differentiation and we confirmed functional relevance of ERK5 in myeloid cells. In conclusion, our data describe miR-143 as a relevant factor in granulocyte differentiation, whose expression may be useful as a prognostic and therapeutic factor in AML therapy.
Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson’s disease
Authors: Milanese Chiara , Cerri Silvia , Ulusoy Ayse , Gornati Simona V. , Plat Audrey , Gabriels Sylvia , Blandini Fabio , Di Monte Donato A. , Hoeijmakers Jan H. , Mastroberardino Pier G.
Published: July 2018

The involvement of DNA damage and repair in aging processes is well established. Aging is an unequivocal risk factor for chronic neurodegenerative diseases, underscoring the relevance of investigations into the role that DNA alterations may have in the pathogenesis of these diseases. Consistently, even moderate impairment of DNA repair systems facilitates the onset of pathological features typical of PD that include derangement of the dopaminergic system, mitochondrial dysfunction, and alpha-synuclein stress. The latter establishes a connection between reduced DNA repair capacity and a cardinal feature of PD, alpha-synuclein pathology. It remains to be determined, however, whether alpha-synuclein stress activates in vivo the canonical signaling cascade associated with DNA damage, which is centered on the kinase ATM and substrates such as γH2Ax and 53BP1. Addressing these issues would shed light on age-related mechanisms impinging upon PD pathogenesis and neurodegeneration in particular. We analyzed two different synucleinopathy PD mouse models based either on intranigral delivery of AAV-expressing human alpha-synuclein, or intrastriatal injection of human alpha-synuclein pre-formed fibrils. In both cases, we detected a significant increase in γH2AX and 53BP1 foci, and in phospho-ATM immunoreactivity in dopaminergic neurons, which collectively indicate DNA damage and activation of the DNA damage response. Mechanistic experiments in cell cultures indicate that activation of the DNA damage response is caused, at least in part, by pro-oxidant species because it is prevented by exogenous or endogenous antioxidants, which also rescue mitochondrial anomalies caused by proteotoxic alpha-synuclein. These in vivo and in vitro findings reveal that the cellular stress mediated by alpha-synuclein—a pathological hallmark in PD—elicits DNA damage and activates the DNA damage response. The toxic cascade leading to DNA damage involves oxidant stress and mitochondrial dysfunction The data underscore the importance of DNA quality control for preservation of neuronal integrity and protection against neurodegenerative processes.
A positive feedback loop bi-stably activates fibroblasts
Authors: Yeo So-Young , Lee Keun-Woo , Shin Dongkwan , An Sugyun , Cho Kwang-Hyun , Kim Seok-Hyung
Published: July 2018

Although fibroblasts are dormant in normal tissue, they exhibit explosive activation during wound healing and perpetual activation in pathologic fibrosis and cancer stroma. The key regulatory network controlling these fibroblast dynamics is still unknown. Here, we report that Twist1, a key regulator of cancer-associated fibroblasts, directly upregulates Prrx1, which, in turn, increases the expression of Tenascin-C (TNC). TNC also increases Twist1 expression, consequently forming a Twist1-Prrx1-TNC positive feedback loop (PFL). Systems biology studies reveal that the Twist1-Prrx1-TNC PFL can function as a bistable ON/OFF switch and regulates fibroblast activation. This PFL can be irreversibly activated under pathologic conditions, leading to perpetual fibroblast activation. Sustained activation of the Twist1-Prrx1-TNC PFL reproduces fibrotic nodules similar to idiopathic pulmonary fibrosis in vivo and is implicated in fibrotic disease and cancer stroma. Considering that this PFL is specific to activated fibroblasts, Twist1-Prrx1-TNC PFL may be a fibroblast-specific therapeutic target to deprogram perpetually activated fibroblasts.
Brain-controlled modulation of spinal circuits improves recovery from spinal cord injury
Authors: Bonizzato Marco , Pidpruzhnykova Galyna , DiGiovanna Jack , Shkorbatova Polina , Pavlova Natalia , Micera Silvestro , Courtine Grégoire
Published: July 2018

The delivery of brain-controlled neuromodulation therapies during motor rehabilitation may augment recovery from neurological disorders. To test this hypothesis, we conceived a brain-controlled neuromodulation therapy that combines the technical and practical features necessary to be deployed daily during gait rehabilitation. Rats received a severe spinal cord contusion that led to leg paralysis. We engineered a proportional brain–spine interface whereby cortical ensemble activity constantly determines the amplitude of spinal cord stimulation protocols promoting leg flexion during swing. After minimal calibration time and without prior training, this neural bypass enables paralyzed rats to walk overground and adjust foot clearance in order to climb a staircase. Compared to continuous spinal cord stimulation, brain-controlled stimulation accelerates and enhances the long-term recovery of locomotion. These results demonstrate the relevance of brain-controlled neuromodulation therapies to augment recovery from motor disorders, establishing important proofs-of-concept that warrant clinical studies.
Transmissive silicon photonic dichroic filters with spectrally selective waveguides
Authors: Magden Emir Salih , Li Nanxi , Raval Manan , Poulton Christopher V. , Ruocco Alfonso , Singh Neetesh , Vermeulen Diedrik , Ippen Erich P. , Kolodziejski Leslie A. , Watts Michael R.
Published: July 2018

Many optical systems require broadband filters with sharp roll-offs for efficiently splitting or combining light across wide spectra. While free space dichroic filters can provide broadband selectivity, on-chip integration of these high-performance filters is crucial for the scalability of photonic applications in multi-octave interferometry, spectroscopy, and wideband wavelength-division multiplexing. Here we present the theory, design, and experimental characterization of integrated, transmissive, 1 × 2 port dichroic filters using spectrally selective waveguides. Mode evolution through adiabatic transitions in the demonstrated filters allows for single cutoff and flat-top responses with low insertion losses and octave-wide simulated bandwidths. Filters with cutoffs around 1550 and 2100 nm are fabricated on a silicon-on-insulator platform with standard complementary metal-oxide-semiconductor processes. A filter roll-off of 2.82 dB nm−1 is achieved while maintaining ultra-broadband operation. This new class of nanophotonic dichroic filters can lead to new paradigms in on-chip communications, sensing, imaging, optical synthesis, and display applications.
Linked dimensions of psychopathology and connectivity in functional brain networks
Authors: Xia Cedric Huchuan , Ma Zongming , Ciric Rastko , Gu Shi , Betzel Richard F. , Kaczkurkin Antonia N. , Calkins Monica E. , Cook Philip A. , García de la Garza Angel , Vandekar Simon N. , Cui Zaixu , Moore Tyler M. , Roalf David R. , Ruparel Kosha , Wolf Daniel H. , Davatzikos Christos , Gur Ruben C. , Gur Raquel E. , Shinohara Russell T. , Bassett Danielle S. , Satterthwaite Theodore D.
Published: July 2018

Neurobiological abnormalities associated with psychiatric disorders do not map well to existing diagnostic categories. High co-morbidity suggests dimensional circuit-level abnormalities that cross diagnoses. Here we seek to identify brain-based dimensions of psychopathology using sparse canonical correlation analysis in a sample of 663 youths. This analysis reveals correlated patterns of functional connectivity and psychiatric symptoms. We find that four dimensions of psychopathology – mood, psychosis, fear, and externalizing behavior – are associated (r = 0.68–0.71) with distinct patterns of connectivity. Loss of network segregation between the default mode network and executive networks emerges as a common feature across all dimensions. Connectivity linked to mood and psychosis becomes more prominent with development, and sex differences are present for connectivity related to mood and fear. Critically, findings largely replicate in an independent dataset (n = 336). These results delineate connectivity-guided dimensions of psychopathology that cross clinical diagnostic categories, which could serve as a foundation for developing network-based biomarkers in psychiatry.
Tailoring van der Waals dispersion interactions with external electric charges
Authors: Kleshchonok Andrii , Tkatchenko Alexandre
Published: July 2018

van der Waals (vdW) dispersion interactions strongly impact the properties of molecules and materials. Often, the description of vdW interactions should account for the coupling with pervasive electric fields, stemming from membranes, ionic channels, liquids, or nearby charged functional groups. However, this quantum-mechanical effect has been omitted in atomistic simulations, even in widely employed electronic-structure methods. Here, we develop a model and study the effects of an external charge on long-range vdW correlations. We show that a positive external charge stabilizes dispersion interactions, whereas a negative charge has an opposite effect. Our analytical results are benchmarked on a series of (bio)molecular dimers and supported by calculations with high-level correlated quantum-chemical methods, which estimate the induced dispersion to reach up to 35% of intermolecular binding energy (4 kT for amino-acid dimers at room temperature). Our analysis bridges electrostatic and electrodynamic descriptions of intermolecular interactions and may have implications for non-covalent reactions, exfoliation, dissolution, and permeation through biological membranes.
Exploring the role of stromal osmoregulation in cancer and disease using executable modelling
Authors: Shorthouse David , Riedel Angela , Kerr Emma , Pedro Luisa , Bihary Dóra , Samarajiwa Shamith , Martins Carla P. , Shields Jacqueline , Hall Benjamin A.
Published: July 2018

Osmotic regulation is a vital homoeostatic process in all cells and tissues. Cells initially respond to osmotic stresses by activating transmembrane transport proteins to move osmotically active ions. Disruption of ion and water transport is frequently observed in cellular transformations such as cancer. We report that genes involved in membrane transport are significantly deregulated in many cancers, and that their expression can distinguish cancer cells from normal cells with a high degree of accuracy. We present an executable model of osmotic regulation and membrane transport in mammalian cells, providing a mechanistic explanation for phenotype change in varied disease states, and accurately predicting behaviour from single cell expression data. We also predict key proteins involved in cellular transformation, SLC4A3 (AE3), and SLC9A1 (NHE1). Furthermore, we predict and verify a synergistic drug combination in vitro, of sodium and chloride channel inhibitors, which target the osmoregulatory network to reduce cancer-associated phenotypes in fibroblasts.
Transient marine euxinia at the end of the terminal Cryogenian glaciation
Authors: Lang Xianguo , Shen Bing , Peng Yongbo , Xiao Shuhai , Zhou Chuanming , Bao Huiming , Kaufman Alan Jay , Huang Kangjun , Crockford Peter W. , Liu Yonggang , Tang Wenbo , Ma Haoran
Published: July 2018

Termination of the terminal Cryogenian Marinoan snowball Earth glaciation (~650–635 Ma) is associated with the worldwide deposition of a cap carbonate. Modeling studies suggest that, during and immediately following deglaciation, the ocean may have experienced a rapid rise in pH and physical stratification followed by oceanic overturn. Testing these predictions requires the establishment of a high-resolution sequence of events within sedimentary records. Here we report the conspicuous occurrence of pyrite concretions in the topmost Nantuo Formation (South China) that was deposited in the Marinoan glacial deposits. Sedimentary facies and sulfur isotope data indicate pyrite precipitation in the sediments with H2S diffusing from the overlying sulfidic/euxinic seawater and Fe (II) from diamictite sediments. These observations suggest a transient but widespread presence of marine euxinia in an ocean characterized by redox stratification, high bioproductivity, and high-fluxes of sulfate from chemical weathering before the deposition of the cap carbonate.
Enhancement of adenovirus infection and adenoviral vector-mediated gene delivery by bromodomain inhibitor JQ1
Authors: Lv Baojie , Li Jingjing , Li Meng , Zhuo Yujie , Ren Ke , Li Erguang , Yang Guang
Published: July 2018

Adenovirus-based vectors are among the most commonly used platforms for gene delivery and gene therapy studies. One of the obstacles for potential application is dose-related toxicity. We show here that adenovirus infection and Ad-mediated gene delivery can be enhanced by inhibitors of bromodomain and extra-terminal (BET) family proteins. We showed that JQ1, but not its inactive enantiomer (−)-JQ1, dose-dependently promoted Ad infection and Ad-mediated gene delivery in both epithelial and lymphocyte cells. Given orally, JQ1 also enhanced transgene expression in a murine tumor model. Inhibitors of histone deacetylases (HDACi) are among the commonly reported small molecule compounds which enhance Ad-mediated gene delivery. We found that JQ1 treatment did not cause histone acetylation nor expression of Ad attachment receptor CAR. Instead, JQ1 treatment induced an increase in BRD4 association with CDK9, a subunit of P-TEFb of transcription elongation. Concurrently, we showed that CDK9 inhibition blocked Ad infection and JQ1 enhancement on the infection. The study exemplifies the potentials of BET inhibitors like JQ1 in oncolytic virotherapy.
Characterization of the APETALA2/Ethylene-responsive factor (AP2/ERF) transcription factor family in sunflower
Authors: Najafi Somayeh , Sorkheh Karim , Nasernakhaei Fatemeh
Published: July 2018

One of the most prominent families of genes in plants is the AP2/ERF which play an important role in regulating plant growth and responses to various stresses. In this research, a genome-wide survey was conducted to recognize the AP2/ERF genes in sunflower (Helianthus annuus L.), and a total of 288 HaAP2/ERF was obtained. Phylogenetic analysis divided them into four sub-families, including 248 ERF, 4 RAV and 35 AP2, and one subgroup of the Soloist family. Localization of chromosome, gene structure, the conserved motif, gene ontology, interaction networks, homology modeling, the modeling of cis-regulatory elements and the analysis of events in the duplication of genes were carried out for HaAP2/ERF genes. Finally, 9AP2/ERF genes were chosen to confirm the gene expression of the selected genes in leaf and root tissues in various abiotic stress conditions by qPCR. The results confirmed that AP2/ERFs genes could effectively resist abiotic stress. Also, proline content was studied under drought, salinity, cold and heat stress. The results indicated that proline was increased under abiotic stress. This research has been done for the first time to determine the HaAP2/ERF family, which prepared valuable data for the evolutionary and practical research regarding AP2/ERF in sunflower.
A Rho-based reaction-diffusion system governs cell wall patterning in metaxylem vessels
Authors: Nagashima Yoshinobu , Tsugawa Satoru , Mochizuki Atsushi , Sasaki Takema , Fukuda Hiroo , Oda Yoshihisa
Published: July 2018

Rho GTPases play crucial roles in cell polarity and pattern formation. ROPs, Rho of plant GTPases, are widely involved in cell wall patterning in plants, yet the molecular mechanism underlying their action remains unknown. Arabidopsis ROP11 is locally activated to form plasma membrane domains, which direct formation of cell wall pits in metaxylem vessel cells through interaction with cortical microtubules. Here, we show that the pattern formation of cell wall pits is governed by ROP activation via a reaction-diffusion mechanism. Genetic analysis and reconstructive assays revealed that ROPGEF4/7 and ROPGAP3/4, which encode ROP activators and inactivators, respectively, regulated the formation of ROP-activated domains; these in turn determined the pattern of cell wall pits. Mathematical modelling showed that ROP-activation cycle generated ROP domains by reaction-diffusion mechanism. The model predicted that a positive feedback and slow diffusion of ROP11-ROPGEF4 complex were required to generate ROP-activated domains. ROPGEF4 formed a dimer that interacted with activated ROP11 in vivo, which could provide positive feedback for ROP activation. ROPGEF4 was highly stable on the plasma membrane and inhibited ROP11 diffusion. Our study indicated that ROP-based reaction-diffusion system self-organizes ROP-activated domains, thereby determines the pit pattern of metaxylem vessels.
Rapid Quaternary subsidence in the northwestern German North Sea
Authors: Arfai Jashar , Franke Dieter , Lutz Rüdiger , Reinhardt Lutz , Kley Jonas , Gaedicke Christoph
Published: July 2018

3D and 2D seismic data reveal the base-reflection of the Quaternary in the northwestern German North Sea locally at depths of more than 1000 m. This indicates extremely fast subsidence, with a rate of up to 480 m/Ma during the Quaternary, resulting in a NNW-SSE oriented sedimentary depocentre. Distinct iceberg scour marks, identified in 3D seismic data are used to calibrate quantitative subsidence analysis and to document shallow marine conditions during the Quaternary interglacials. Previously, a number of mechanisms have been proposed to explain the Quaternary subsidence. Here we show that compaction and load-induced subsidence alone explain about 75% of the observed Quaternary subsidence. However, a certain portion of the subsidence needs additional processes to be invoked. The extensive seismic dataset interpreted here makes it possible to exclude a phase of renewed tectonic activity as the origin of the subsidence anomaly. From the orientation and extent of the depocentre, lithosphere buckling and subsidence due to salt movement are considered unlikely. Possibly a post-glacial collapse after the retreat of glaciers in the North Sea Basin, local lower crustal flow, or dynamic topography or a combination of these processes contributed to the residual subsidence.
Vinexin family (SORBS) proteins regulate mechanotransduction in mesenchymal stem cells
Authors: Kuroda Mito , Ueda Kazumitsu , Kioka Noriyuki
Published: July 2018

The stiffness of extracellular matrix (ECM) directs the differentiation of mesenchymal stem cells (MSCs) through the transcriptional co-activators Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding motif (TAZ). Although a recent study revealed the involvement of vinexin α and CAP (c-Cbl-associated proteins), two of vinexin (SORBS) family proteins that bind to vinculin, in mechanosensing, it is still unclear whether these proteins regulate mechanotransduction and differentiation of MSCs. In the present study, we show that both vinexin α and CAP are necessary for the association of vinculin with the cytoskeleton and the promotion of YAP/TAZ nuclear localization in MSCs grown on rigid substrates. Furthermore, CAP is involved in the MSC differentiation in a stiffness-dependent manner, whereas vinexin depletion suppresses adipocyte differentiation independently of YAP/TAZ. These observations reveal a critical role of vinexin α and CAP in mechanotransduction and MSC differentiation.
Characterizing the activity of abundant, diverse and active CRISPR-Cas systems in lactobacilli
Authors: Crawley Alexandra B. , Henriksen Emily D. , Stout Emily , Brandt Katelyn , Barrangou Rodolphe
Published: July 2018

CRISPR-Cas systems provide immunity against phages and plasmids in bacteria and archaea. Despite the popularity of CRISPR-Cas9 based genome editing, few endogenous systems have been characterized to date. Here, we sampled 1,262 publically available lactobacilli genomes found them to be enriched with CRISPR-Cas adaptive immunity. While CRISPR-Cas is ubiquitous in some Lactobacillus species, CRISPR-Cas content varies at the strain level in most Lactobacillus species. We identified that Type II is the most abundant type across the genus, with II-A being the most dominant sub-type. We found that many Type II-A systems are actively transcribed, and encode spacers that efficiently provide resistance against plasmid uptake. Analysis of various CRISPR transcripts revealed that guide sequences are highly diverse in terms of crRNA and tracrRNA length and structure. Interference assays revealed highly diverse target PAM sequences. Lastly, we show that these systems can be readily repurposed for self-targeting by expressing an engineered single guide RNA. Our results reveal that Type II-A systems in lactobacilli are naturally active in their native host in terms of expression and efficiently targeting invasive and genomic DNA. Together, these systems increase the possible Cas9 targeting space and provide multiplexing potential in native hosts and heterologous genome editing purpose.
Gomesin inhibits melanoma growth by manipulating key signaling cascades that control cell death and proliferation
Authors: Ikonomopoulou Maria P. , Fernandez-Rojo Manuel A. , Pineda Sandy S. , Cabezas-Sainz Pablo , Winnen Brit , Morales Rodrigo A. V. , Brust Andreas , Sánchez Laura , Alewood Paul F. , Ramm Grant A. , Miles John J. , King Glenn F.
Published: July 2018

Consistent with their diverse pharmacology, peptides derived from venomous animals have been developed as drugs to treat disorders as diverse as hypertension, diabetes and chronic pain. Melanoma has a poor prognosis due in part to its metastatic capacity, warranting further development of novel targeted therapies. This prompted us to examine the anti-melanoma activity of the spider peptides gomesin (AgGom) and a gomesin-like homolog (HiGom). AgGom and HiGom dose-dependently reduced the viability and proliferation of melanoma cells whereas it had no deleterious effects on non-transformed neonatal foreskin fibroblasts. Concordantly, gomesin-treated melanoma cells showed a reduced G0/G1 cell population. AgGom and HiGom compromised proliferation of melanoma cells via activation of the p53/p21 cell cycle check-point axis and the Hippo signaling cascade, together with attenuation of the MAP kinase pathway. We show that both gomesin peptides exhibit antitumoral activity in melanoma AVATAR-zebrafish xenograft tumors and that HiGom also reduces tumour progression in a melanoma xenograft mouse model. Taken together, our data highlight the potential of gomesin for development as a novel melanoma-targeted therapy.
Familial Ovarian Cancer Clusters with Other Cancers
Authors: Zheng Guoqiao , Yu Hongyao , Kanerva Anna , Försti Asta , Sundquist Kristina , Hemminki Kari
Published: July 2018

Familial risk of ovarian cancer is well-established but whether ovarian cancer clusters with other cancers and the clusters differ by histology remains uncertain. Using data from the Swedish Family-Cancer Database, we explored familial associations of ovarian cancer with other cancers with a novel approach; relative risk for (histology-specific) ovarian cancer was estimated in families with patients affected by other cancers, and conversely, risks for other cancers in families with (histology-specific) ovarian cancer patients. Eight discordant cancers were associated with ovarian cancer risk, of which family history of breast cancer showed a dose-response (P-trend <0.0001). Conversely, risks of eight types of cancer increased in families with ovarian cancer patients, and dose-responses were shown for risks of liver (P-trend = 0.0083) and breast cancers (P-trend <0.0001) and cancer of unknown primary (P-trend = 0.0157). Some cancers were only associated with histology-specific ovarian cancers, e.g. endometrial cancer was only associated with endometrioid type but with highest significance. Novel associations with virus-linked cancers of the nose and male and female genitals were found. The results suggest that ovarian cancer shares susceptibility with a number of other cancers. This might alert genetic counselors and challenge approaches for gene and gene-environment identification.
Comparison of Computed Tomography derived Fractional Flow Reserve to invasive Fractional Flow Reserve in Diagnosis of Functional Coronary Stenosis: A Meta-Analysis
Authors: Agasthi Pradyumna , Kanmanthareddy Arun , Khalil Charl , Egbuche Obiora , Yarlagadda Vivek , Sachdeva Rajesh , Arsanjani Reza
Published: July 2018

Computed Tomography derived Fractional Flow Reserve (CTFFR) is an emerging non-invasive imaging modality to assess functional significance of coronary stenosis. We performed a meta-analysis to compare the diagnostic performance of CTFFR to invasive Fractional Flow reserve (FFR). Electronic search was performed to identify relevant articles. Pooled Estimates of sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR−) and diagnostic odds ratio (DOR) with corresponding 95% confidence intervals (CI) were calculated at the patient level as well as the individual vessel level using hierarchical logistic regression, summary receiver operating characteristic (SROC) curve and area under the curve were estimated. Our search yielded 559 articles and of these 17 studies was included in the analysis. A total of 2,191 vessels in 1294 patients were analyzed. Pooled estimates of sensitivity, specificity, LR+, LR− and DOR with corresponding 95% CI at per-patient level were 83% (79–87), 72% (68–76), 3.0 (2.6–3.5), 0.23 (0.18–0.29) and 13 (9–18) respectively. Pooled estimates of sensitivity, specificity, LR+, LR− and DOR with corresponding 95% CI at per-vessel level were 85% (83–88), 76% (74–79), 3.6 (3.3–4.0), 0.19 (0.16–0.22) and 19 (15–24). The area under the SROC curve was 0.89 for both per patient level and at the per vessel level. In our meta-analysis, CTFFR demonstrated good diagnostic performance in identifying functionally significant coronary artery stenosis compared to the FFR.
Evidence for functional state transitions in intensively-managed soil ecosystems
Authors: Todman L. C. , Fraser F. C. , Corstanje R. , Harris J. A. , Pawlett M. , Ritz K. , Whitmore A. P.
Published: July 2018

Soils are fundamental to terrestrial ecosystem functioning and food security, thus their resilience to disturbances is critical. Furthermore, they provide effective models of complex natural systems to explore resilience concepts over experimentally-tractable short timescales. We studied soils derived from experimental plots with different land-use histories of long-term grass, arable and fallow to determine whether regimes of extreme drying and re-wetting would tip the systems into alternative stable states, contingent on their historical management. Prior to disturbance, grass and arable soils produced similar respiration responses when processing an introduced complex carbon substrate. A distinct respiration response from fallow soil here indicated a different prior functional state. Initial dry:wet disturbances reduced the respiration in all soils, suggesting that the microbial community was perturbed such that its function was impaired. After 12 drying and rewetting cycles, despite the extreme disturbance regime, soil from the grass plots, and those that had recently been grass, adapted and returned to their prior functional state. Arable soils were less resilient and shifted towards a functional state more similar to that of the fallow soil. Hence repeated stresses can apparently induce persistent shifts in functional states in soils, which are influenced by management history.
Longitudinal effects of aging on 18F-FDG distribution in cognitively normal elderly individuals
Authors: Ishibashi Kenji , Onishi Airin , Fujiwara Yoshinori , Oda Keiichi , Ishiwata Kiichi , Ishii Kenji
Published: July 2018

Previous studies of aging effects on fluorine-18-labeled fluorodeoxyglucose (18F-FDG) distribution have employed cross-sectional designs. We examined aging effects on 18F-FDG distribution using both cross-sectional and longitudinal assessments. We obtained two 18F-FDG positron emission tomography scans at two different time points from 107 cognitively normal elderly participants. The participants’ mean ages at baseline and second scans were 67.9 and 75.7, respectively. The follow-up period ranged from 4 to 11 years with a mean of 7.8 years. The voxel-wise analysis revealed significant clusters in which 18F-FDG uptake was decreased between baseline and second scans (p < 0.05, family-wise error corrected) in the anterior cingulate cortex (ACC), posterior cingulate cortex/precuneus (PCC/PC), and lateral parietal cortex (LPC). The cross-sectional analysis of 18F-FDG uptake and age showed significant correlations in the ACC (p = 0.016) but not the PCC/PC (p = 0.240) at baseline, and in the ACC (p = 0.004) and PCC/PC (p = 0.002) at the second scan. The results of longitudinal assessments suggested that 18F-FDG uptake in the ACC, PCC/PC, and LPC decreased with advancing age in cognitively normal elderly individuals, and those of the cross-sectional assessments suggested that the trajectories of age-associated 18F-FDG decreases differed between the ACC and PCC/PC.