bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploratory dietary patterns: a systematic review of methods applied in pan-European studies and of validation studies
Authors: Jannasch Franziska , Riordan Fiona , Andersen Lene F. , Schulze Matthias B.
Published: August 2018

Besides a priori approaches, using previous knowledge about food characteristics, exploratory dietary pattern (DP) methods, using data at hand, are commonly applied. This systematic literature review aimed to identify exploratory methods on DP in pan-European studies and to inform the development of the DEterminants of DIet and Physical ACtivity (DEDIPAC) toolbox of methods suitable for use in future European studies. The search was conducted in three databases on prospective studies in healthy, free-living people across the whole life span. To identify validated DP methods, an additional search without regional restrictions was conducted. Studies including at least two European countries were retained. The search resulted in six pan-European studies applying principal component/factor analysis (PC/FA) (n 5) or cluster analysis (n 2). The criteria to retain PC/factors ranged from the application of the eigenvalue>1 criterion, the scree plot and/or the interpretability criterion. Furthermore, seven validation studies were identified: DP, derived by PC/FA (n 6) or reduced rank regression (RRR) (n 1) were compared using dietary information from FFQ (n 6) or dietary history (n 1) as study instrument and dietary records (n 6) or 24-h dietary recalls (n 1) as reference. The correlation coefficients for the derived DP ranged from modest to high. To conclude, PC/FA was predominantly applied using the eigenvalue criterion and scree plot to retain DP, but a better description of the applied criteria is highly recommended to enable a standardised application of the method. Research gaps were identified for the methods cluster analysis and RRR, as well as for validation studies on DP.
Experimental murine model of neurocysticercosis: first report of cerebellum as a location for Mesocestoides corti tetrathyridia
Authors: Fabbri J. , Elissondo M.C.
Published: August 2018

Neurocysticercosis is a parasitic disease caused by encysted larvae ofTaenia soliumin the human central nervous system. Cysts mainly affect the cerebral hemispheres, although they can also be found in ventricles, basal cisterns, and subarachnoid spaces, and rarely in the cerebellum. Given the impossibility of studying the disease in human patients, Cardonaet al. (1999) developed a mouse model of neurocysticercosis, usingMesocestoides corti, a closely related cestode. This allows us to study the parasite–host relationship and the mechanisms involved in the disease, in order to improve the therapy. In this murine model of neurocysticercosis, the location of tetrathyridia in parenchyma, ventricles and meninges has already been reported. The aim of this work is to report the cerebellum as a new location forM. cortitetrathyridia in the murine model of neurocysticercosis. A murine model that reproduces the human pathology is essential to evaluate the symptomatology and response to drug treatment in experimentally infected mice.
Neurocognition and adaptive functioning in a genetic high risk model of schizophrenia
Authors: Fiksinski A. M. , Breetvelt E. J. , Lee Y. J. , Boot E. , Butcher N. , Palmer L. , Chow E. W. C. , Kahn R. S. , Vorstman J. A. S. , Bassett A. S.
Published: August 2018

Background

Identifying factors that influence the functional outcome is an important goal in schizophrenia research. The 22q11.2 deletion syndrome (22q11DS) is a unique genetic model with high risk (20–25%) for schizophrenia. This study aimed to identify potentially targetable domains of neurocognitive functioning associated with functional outcome in adults with 22q11DS.

Methods

We used comprehensive neurocognitive test data available for 99 adults with 22q11DS (n = 43 with schizophrenia) and principal component analysis to derive four domains of neurocognition (Verbal Memory, Visual and Logical Memory, Motor Performance, and Executive Performance). We then investigated the association of these neurocognitive domains with adaptive functioning using Vineland Adaptive Behavior Scales data and a linear regression model that accounted for the effects of schizophrenia status and overall intellectual level.

Results

The regression model explained 46.8% of the variance in functional outcome (p < 0.0001). Executive Performance was significantly associated with functional outcome (p = 0.048). Age and schizophrenia were also significant factors. The effects of Executive Performance on functioning did not significantly differ between those with and without psychotic illness.

Conclusion

The findings provide the impetus for further studies to examine the potential of directed (early) interventions targeting Executive Performance to improve long-term adaptive functional outcome in individuals with, or at high risk for, schizophrenia. Moreover, the neurocognitive test profiles may benefit caregivers and clinicians by providing insight into the relative strengths and weaknesses of individuals with 22q11DS, with and without psychotic illness.
ENERGY IN A MODEL OF FIRM ENTRY
Authors: Patra Soma
Published: August 2018

Nine out of the last ten recessions in the United States have been preceded by an increase in the price of oil as noted by Hamilton [Palgrave Dictionary of Economics]. Given the small share of energy in gross domestic product this phenomenon is difficult to explain using standard models. In this paper, I show that firm entry can be an important transmission and amplifying channel for energy price shocks. The results from the baseline dynamic stochastic general equilibrium (DSGE) model predict a drop in output that is two times the impact in a model without entry. The model also predicts an increase in energy prices would lead to a decline in real wages, investment, consumption, and return on investment. Additionally, using US firm level data, I demonstrate that a rise in energy prices has a negative impact on firm entry as predicted by the DSGE model. This lends further support toward endogenizing firm entry when analyzing the effects of energy price shocks.
Having a different pointing of view about the future: The effect of signs on co-speech gestures about time in Mandarin–CSL bimodal bilinguals
Authors: GU YAN , ZHENG YEQIU , SWERTS MARC
Published: August 2018

Mandarin speakers often usegesturesto represent time laterally, vertically, and sagittally. Chinese Sign Language (CSL) users also exploitsignsfor that purpose, and can differ from the gestures of Mandarin speakers in their choices of axes and direction of sagittal movements. The effects of sign language on co-speech gestures about time were investigated by comparing spontaneous temporal gestures of late bimodal bilinguals (Mandarin learners of CSL) and non-signing Mandarin speakers. Spontaneous gestures were elicited via a wordlist definition task. In addition to effects of temporal words on temporal gestures, results showed significant effects of sign. Compared with non-signers, late bimodal bilinguals (1) produced more sagittal but fewer lateral temporal gestures; and (2) exhibited a different temporal orientation of sagittal gestures, as they were more likely to gesture past events to their back. In conclusion, bodily experience of sign language can not only impact the nature of co-speech gestures, but also spatio-motoric thinking and abstract space-time mappings.
A study for the dosimetric evaluation of rotational setup error for
lung stereotactic body radiation therapy
Authors: Mossahebi Sina , Langner Ulrich , Prado Karl , Lee Minsik , Yi ByongYong
Published: August 2018

Purpose

To investigate the necessity of rotational shifts by considering dosimetric
impact of rotational errors on stereotactic body radiation therapy
(SBRT).

Materials and methods

20 lung patients with the lesion size <5 cm treated with SBRT have
been selected for dosimetric analysis. Three-dimensional dose has been
rotationally shifted (±1°, ±3°,
±5° for pitch, roll and yaw) and overlaid to the original
computed tomography images. The dose–volume histograms of
18-rotational plans of each patient were compared to those of the original
plan.

Results

No significant dosimetric differences were observed in target coverage. For
all of the cases up to 5° in any couch angle dose differences of
D99 and D95 were
<3%. Variations of conformity index were observed to be less
than 0·05. None of the organ at risk doses exceeded the dose limit.
The V20 differences of the ipsilateral and the
total lungs were less than 0·4%.

Conclusion

It has been found to be unnecessary to perform rotational shifts up to
5° for lung SBRT treatments; the translational shift is sufficient
for the cases used in this study. This method may be applied and tested
after planning and before treatment initiation to rule out exceptionally
extreme cases.
How Jupiter’s Icy Moons Got Their Bands and Grooves
Authors: Underwood Emily
Published: August 2018

Europa’s churning ice crust could reveal signs of ocean life, new study suggests.
High‐Pressure/Temperature Behavior of the Alkali/Calcium Carbonate Shortite (Na2Ca2(CO3)3): Implications for Carbon Sequestration in Earth's Transition Zone
Authors: Vennari Cara E. , Beavers Christine M. , Williams Quentin
Published: August 2018

The behavior of shortite (Na2Ca2(CO3)3) has been probed using synchrotron‐based single crystal X‐ray diffraction and Raman spectroscopy at high pressures and following laser heating to illuminate carbon retention within the deep earth, and phase equilibria of alkali/calcium carbonate‐rich systems. Above 15 GPa, a transition to the shortite‐II structure occurs at 300 K. This phase is novel as it involves a large distortion of the carbonates, with an onset of 3 + 1 coordination and near‐dimerization of carbonate groups. Above 22 GPa, shortite‐II amorphizes. Samples laser heated at pressures between 12 and 30 GPa crystallize in a new structure, shortite‐III. Below 12 GPa, this phase appears to decompose into a mixture of shortite, nyerereite (Na2Ca(CO3)2), and aragonite (CaCO3) in accord with prior phase equilibria results. The high‐pressure behavior of nyerereite using Raman spectroscopy was also investigated to 25 GPa. The structural response of shortite to pressure is modulated by the sodium cations in the structure; hence, the behavior of alkali‐rich carbonates within kimberlitic systems at depth is likely dependent on the bonding and local geometry of alkali cations. Our results show that complex, dense high‐pressure structures are generated in the shortite system, and phase equilibria of the protoliths of carbonatites and kimberlites at deep upper mantle and transition zone pressures will involve intermediate alkali‐calcium carbonate phases, including the high‐pressure phases of shortite. Moreover, 3 + 1 coordination of carbon is observed at far lower pressures than other systems: this coordination could become important in complex carbonates and possibly liquids at substantially shallower depths than previously anticipated.
Ash From the Changbaishan Qixiangzhan Eruption: A New Early Holocene Marker Horizon Across East Asia
Authors: Sun Chunqing , Wang Luo , Plunkett Gill , You Haitao , Zhu Zeyang , Zhang Lei , Zhang Bin , Chu Guoqiang , Liu Jiaqi
Published: August 2018

Prehistoric Holocene eruptions of Changbaishan volcano in Northeast China are poorly dated, with the exception of the 946 CE Millennium eruption. Poorly refined age estimates for the earlier eruptions present problems for the reconstruction of the eruptive history of the volcano. The Qixiangzhan eruption (QE) is a major controversial event in terms of its eruptive timing (ranging from ~88 to ~4 kyr) and style (effusive or explosive). As a result of the imprecise age estimates for the eruption, a geomagnetic field excursion recorded within the QE comendite has been variably correlated with a number of different excursion events observed elsewhere. In this study, a visible early Holocene tephra was identified in Yuanchi Lake, ~30 km east of the Changbaishan volcanic vent, and was dated to 8831‐8100 cal yr BP using Bayesian age modelling. Glass shard compositions enable the correlation of this tephra with the poorly dated QE, as well as with a tephra (SG14‐1058) recorded in Lake Suigetsu, in central Japan. These correlations confirm that the QE was explosive and that the ash from the QE can serve as an important early Holocene marker bed across East Asia. In addition, we propose an age of ~8100 cal yr BP for the QE based on the precise date of the Suigetsu SG14‐1058 tephra. Our results also confirm that the geomagnetic field excursion recorded in the Qixiangzhan comendite dates to ~8100 cal yr BP.
Interseismic Ground Deformation and Fault Slip Rates in the Greater San Francisco Bay Area From Two Decades of Space Geodetic Data
Authors: Xu Wenbin , Wu Songbo , Materna Kathryn , Nadeau Robert , Floyd Michael , Funning Gareth , Chaussard Estelle , Johnson Christopher W. , Murray Jessica R. , Ding Xiaoli , Bürgmann Roland
Published: August 2018

The detailed spatial variations of strain accumulation and creep on major faults in the northern San Francisco Bay Area (North Bay), which are important for seismic potential and evaluation of natural hazards, remain poorly understood. Here we combine interferometric synthetic aperture radar data from the ERS‐1/2 and Envisat satellites between 1992 and 2010 with continuous and campaign GPS data to obtain a high spatial and temporal coverage of ground deformation of the North Bay. The SAR data from both ascending and descending orbits are combined to separate horizontal and vertical components of the deformation. We jointly invert the horizontal component of the mean velocities derived from these data to infer the deep strike‐slip rates on major locked faults. We use the estimated deep rates to simulate the long‐wavelength deformation due to interseismic elastic strain accumulation along these locked faults. After removing the long‐wavelength signal from the InSAR horizontal mean velocity field, we estimate fault‐parallel surface creep rates of up to 2 mm/year along the central section of the Rodgers Creek fault and surface creep rates ranging between 2 and 4 mm/year along the Concord fault. No surface creep is geodetically resolved along the West Napa and Green Valley fault zones. We identified characteristically repeating earthquakes on the Rodgers Creek fault, the West Napa fault, the Green Valley fault, and the Concord fault. Nontectonic deformation in the Geysers geothermal field and in Late Cenozoic basins (Rohnert Park and Sonoma basins) are also observed, likely due to hydrological and sediment‐compaction processes, respectively.
Male increase in brain gene expression variability is linked to genetic risk for schizophrenia
Authors: Chen Junfang , Cao Han , Meyer-Lindenberg Andreas , Schwarz Emanuel
Published: August 2018

Schizophrenia shows substantial sex differences in age of onset, course, and treatment response, but the biological basis of these effects is incompletely understood. Here we show that during human development, males show a regionally specific decrease in brain expression similarity compared to females. The genes modulating this effect were significantly co-expressed with schizophrenia risk genes during prefrontal cortex brain development in the fetal period as well as during early adolescence. This suggests a genetic contribution to a mechanism through which developmental abnormalities manifest with psychosis during adolescence. It further supports sex differences in brain expression variability as a factor underlying the well-established sex differences in schizophrenia.
History of autoimmune conditions and lymphoma prognosis
Authors: Kleinstern Geffen , Maurer Matthew J. , Liebow Mark , Habermann Thomas M. , Koff Jean L. , Allmer Cristine , Witzig Thomas E. , Nowakowski Grzegorz S. , Micallef Ivana N. , Johnston Patrick B. , Inwards David J. , Thompson Carrie A. , Feldman Andrew L. , Link Brian K. , Flowers Christopher , Slager Susan L. , Cerhan James R.
Published: August 2018

Autoimmune conditions are strong risk factors for developing lymphoma, but their role in lymphoma prognosis is less clear. In a prospective cohort study, we evaluated self-reported history of eight autoimmune conditions with outcomes in 736 diffuse large B-cell, 703 follicular, 302 marginal zone (MZL), 193 mantle cell (MCL), 297 Hodgkin lymphoma (HL), and 186 T-cell lymphomas. We calculated event-free survival (EFS) and overall survival (OS), and estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sex, prognostic score, and treatment. History of any of the eight autoimmune conditions ranged from 7.4% in HL to 18.2% in MZL, and was not associated with EFS or OS for any lymphoma subtype. However, there was a positive association of autoimmune conditions primarily mediated by B-cell responses with inferior EFS in MCL (HR = 2.23, CI: 1.15–4.34) and HL (HR = 2.63, CI: 1.04–6.63), which was largely driven by rheumatoid arthritis. Autoimmune conditions primarily mediated by T-cell responses were not found to be associated with EFS or OS in any lymphoma subtype, although there were few events for this exposure. Our results indicate that distinguishing autoimmune conditions primarily mediated by B-cell/T-cell responses may yield insight regarding the impact of this comorbid disease, affecting ~10% of lymphoma patients, on survival.
Non-invasive monitoring of diffuse large B-cell lymphoma by cell-free DNA high-throughput targeted sequencing: analysis of a prospective cohort
Authors: Bohers Elodie , Viailly Pierre-Julien , Becker Stéphanie , Marchand Vinciane , Ruminy Philippe , Maingonnat Catherine , Bertrand Philippe , Etancelin Pascaline , Picquenot Jean-Michel , Camus Vincent , Menard Anne-Lise , Lemasle Emilie , Contentin Nathalie , Leprêtre Stéphane , Lenain Pascal , Stamatoullas Aspasia , Lanic Hélène , Libraire Julie , Vaudaux Sandrine , Pepin Louis-Ferdinand , Vera Pierre , Tilly Hervé , Jardin Fabrice
Published: August 2018

From a liquid biopsy, cell-free DNA (cfDNA) can provide information regarding basal tumoral genetic patterns and changes upon treatment. In a prospective cohort of 30 diffuse large B-cell lymphomas (DLBCL), we determined the clinical relevance of cfDNA using targeted next-generation sequencing and its correlation with PET scan imaging at the time of diagnosis and during treatment. Using a dedicated DLBCL panel, mutations were identified at baseline for 19 cfDNAs and profiles were consistent with expected DLBCL patterns. Tumor burden-related clinical and PET scan features (LDH, IPI, and metabolic tumor volume) were significantly correlated with the quantity of tumoral cfDNA. Among the four patients presenting additional mutations in their cfDNAs, three had high metabolic tumor volumes, suggesting that cfDNA more accurately reflects tumor heterogeneity than tissues biopsy itself. Mid-treatment, four patients still had basal mutations in their cfDNAs, including three in partial response according to their Deauville scores. Our study highlights the major interests in liquid biopsy, in particular in the context of bulky tumors where cfDNA allows capturing the entire tumoral mutation profile. Therefore, cfDNA analysis in DLBCL represents a complementary approach to PET scan imaging.
Berberine ameliorates blockade of autophagic flux in the liver by regulating cholesterol metabolism and inhibiting COX2-prostaglandin synthesis
Authors: Sun Haidong , Liu Qian , Hu Hai , Jiang Yisheng , Shao Wentao , Wang Qihan , Jiang Zhaoyan , Gu Aihua
Published: August 2018

Excessive cholesterol contributes to the development of cardiovascular diseases. Berberine (BBR) has been reported to regulate cholesterol homeostasis. Here, we found that BBR could ameliorate the hepatic autophagic flux blockade caused by cholesterol overloading. The underlying mechanism included lowering hepatic cholesterol level, modulating the cholesterol distribution targeting the plasma membrane by decreasing sterol carrier protein 2 expression and inhibiting cyclooxygenase 2-mediated production of prostaglandin metabolites, which decreased the phosphorylation of Akt/mTOR. Our study provides evidences that BBR could be a therapeutic agent for protecting liver under cholesterol overloading via the regulation of autophagic flux.
Double-edged sword of gonadotropin-releasing hormone (GnRH): A novel role of GnRH in the multiple beneficial functions of endometrial stem cells
Authors: Park Se-Ra , Cho Ara , Park Sung Taek , Park Chan Hum , Lim Soyi , Jin Mirim , Lee Hwa-Yong , Hong In-Sun
Published: August 2018

Gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of gonadotropins, which induce estrogen production and subsequent ovulation. Therefore, long-term GnRH exposure to regulate ovarian hyperstimulation is recognized as the gold standard for most in vitro fertilization (IVF) strategies. However, one of the most disappointing aspects of current IVF technology is relatively low rate (between 35 and 50%) of positive pregnancy outcomes, and the major reason for this high cancellation rate has not yet been revealed. Previous studies have demonstrated that resident stem cell deficiency limits the cyclic regenerative capacity of the endometrium and subsequently increases pregnancy failure rates. Therefore, we hypothesized that long-term GnRH exposure directly damages endometrial stem cells and consequently negatively affects pregnancy outcomes in GnRH-based IVF. In addition to their well-known roles in regulating the hypothalamus-pituitary-gonadal axis, GnRH and its receptors also localize in the extra-hypothalamic endometrium, suggesting a possible non-canonical role in endometrial stem cells. Consistent with our hypothesis, we show for the first time that GnRH suppresses the multiple beneficial functions of endometrial stem cells via the PI3K/Akt signaling pathway in vitro and in vivo. To the best of our knowledge, this is the first study to focus on the direct effects of GnRH on the regenerative potential of stem cells, and the findings will facilitate the development of more promising IVF strategies.
Screening for long noncoding RNAs associated with oral squamous cell carcinoma reveals the potentially oncogenic actions of DLEU1
Authors: Nishiyama Koyo , Maruyama Reo , Niinuma Takeshi , Kai Masahiro , Kitajima Hiroshi , Toyota Mutsumi , Hatanaka Yui , Igarashi Tomohiro , Kobayashi Jun-ichi , Ogi Kazuhiro , Dehari Hironari , Miyazaki Akihiro , Yorozu Akira , Yamamoto Eiichiro , Idogawa Masashi , Sasaki Yasushi , Sugai Tamotsu , Tokino Takashi , Hiratsuka Hiroyoshi , Suzuki Hiromu
Published: August 2018

Recent studies have shown that long noncoding RNAs (lncRNAs) have pivotal roles in human malignancies, although their significance in oral squamous cell carcinoma (OSCC) is not fully understood. In the present study, we identified lncRNAs functionally associated with OSCC. By analyzing RNA-seq datasets obtained from primary head and neck squamous cell carcinoma (HNSCC), we identified 15 lncRNAs aberrantly expressed in cancer tissues. We then validated their expression in 18 OSCC cell lines using qRT-PCR and identified 6 lncRNAs frequently overexpressed in OSCC. Among those, we found that knocking down DLEU1 (deleted in lymphocytic leukemia 1) strongly suppressed OSCC cell proliferation. DLEU1 knockdown also suppressed migration, invasion, and xenograft formation by OSCC cells, which is suggestive of its oncogenic functionality. Microarray analysis revealed that DLEU1 knockdown significantly affects expression of a number of cancer-related genes in OSCC cells, including HAS3, CD44, and TP63, suggesting that DLEU1 regulates HA-CD44 signaling. Expression of DLEU1 was elevated in 71% of primary OSCC tissues, and high DLEU1 expression was associated with shorter overall survival of HNSCC patients. These data suggest that elevated DLEU1 expression contributes to OSCC development, and that DLEU1 may be a useful therapeutic target in OSCC.
A gate-free monolayer WSe2 pn diode
Authors: Chen Jhih-Wei , Lo Shun-Tsung , Ho Sheng-Chin , Wong Sheng-Shong , Vu Thi-Hai-Yen , Zhang Xin-Quan , Liu Yi-De , Chiou Yu-You , Chen Yu-Xun , Yang Jan-Chi , Chen Yi-Chun , Chu Ying-Hao , Lee Yi-Hsien , Chung Chung-Jen , Chen Tse-Ming , Chen Chia-Hao , Wu Chung-Lin
Published: August 2018

Interest in bringing p- and n-type monolayer semiconducting transition metal dichalcogenides (TMD) into contact to form rectifying pn diode has thrived since it is crucial to control the electrical properties in two-dimensional (2D) electronic and optoelectronic devices. Usually this involves vertically stacking different TMDs with pn heterojunction or, laterally manipulating carrier density by gate biasing. Here, by utilizing a locally reversed ferroelectric polarization, we laterally manipulate the carrier density and created a WSe2 pn homojunction on the supporting ferroelectric BiFeO3 substrate. This non-volatile WSe2 pn homojunction is demonstrated with optical and scanning probe methods and scanning photoelectron micro-spectroscopy. A homo-interface is a direct manifestation of our WSe2 pn diode, which can be quantitatively understood as a clear rectifying behavior. The non-volatile confinement of carriers and associated gate-free pn homojunction can be an addition to the 2D electron–photon toolbox and pave the way to develop laterally 2D electronics and photonics.
Global and Arctic climate sensitivity enhanced by changes in North Pacific heat flux
Authors: Praetorius Summer , Rugenstein Maria , Persad Geeta , Caldeira Ken
Published: August 2018

Arctic amplification is a consequence of surface albedo, cloud, and temperature feedbacks, as well as poleward oceanic and atmospheric heat transport. However, the relative impact of changes in sea surface temperature (SST) patterns and ocean heat flux sourced from different regions on Arctic temperatures are not well constrained. We modify ocean-to-atmosphere heat fluxes in the North Pacific and North Atlantic in a climate model to determine the sensitivity of Arctic temperatures to zonal heterogeneities in northern hemisphere SST patterns. Both positive and negative ocean heat flux perturbations from the North Pacific result in greater global and Arctic surface air temperature anomalies than equivalent magnitude perturbations from the North Atlantic; a response we primarily attribute to greater moisture flux from the subpolar extratropics to Arctic. Enhanced poleward latent heat and moisture transport drive sea-ice retreat and low-cloud formation in the Arctic, amplifying Arctic surface warming through the ice-albedo feedback and infrared warming effect of low clouds. Our results imply that global climate sensitivity may be dependent on patterns of ocean heat flux in the northern hemisphere.
Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia
Authors: Bryois Julien , Garrett Melanie E. , Song Lingyun , Safi Alexias , Giusti-Rodriguez Paola , Johnson Graham D. , Shieh Annie W. , Buil Alfonso , Fullard John F. , Roussos Panos , Sklar Pamela , Akbarian Schahram , Haroutunian Vahram , Stockmeier Craig A. , Wray Gregory A. , White Kevin P. , Liu Chunyu , Reddy Timothy E. , Ashley-Koch Allison , Sullivan Patrick F. , Crawford Gregory E.
Published: August 2018

Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in the brain are highly enriched for schizophrenia SNP heritability. Accessible chromatin regions that overlap evolutionarily conserved regions exhibit an even higher heritability enrichment, indicating that sequence conservation can further refine functional risk variants. We identify few differences in chromatin accessibility between cases and controls, in contrast to thousands of age-related differential accessible chromatin regions. Altogether, we characterize chromatin accessibility in the human prefrontal cortex, the effect of schizophrenia and age on chromatin accessibility, and provide evidence that our dataset will allow for fine mapping of risk variants.
Dual-template engineering of triple-layered nanoarray electrode of metal chalcogenides sandwiched with hydrogen-substituted graphdiyne
Authors: Zhuo Sifei , Shi Yusuf , Liu Lingmei , Li Renyuan , Shi Le , Anjum Dalaver H. , Han Yu , Wang Peng
Published: August 2018

Hybrid nanostructures integrating electroactive materials with functional species, such as metal-organic frameworks, covalent organic frameworks, graphdiyne etc., are of significance for both fundamental research and energy conversion/storage applications. Here, hierarchical triple-layered nanotube arrays, which consist of hydrogen-substituted graphdiyne frameworks seamlessly sandwiched between an outer layer of nickel–cobalt co-doped molybdenum disulfide nanosheets and an inner layer of mixed cobalt sulfide and nickel sulfide (Co9S8/Ni3S2), are directly fabricated on conductive carbon paper. The elaborate triple-layered structure emerges as a useful hybrid electrode for energy conversion and storage, in which the organic hydrogen-substituted graphdiyne middle layer, with an extended π-conjugated system between the electroactive nanomaterials, provides built-in electron and ion channels that are crucial for performance enhancement. This dual-template synthetic method, which makes use of microporous organic networks to confine a self-template, is shown to be versatile and thus provides a promising platform for advanced nanostructure-engineering of hierarchical multi-layered nanostructures towards a wide range of electrochemical applications.
Developmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin
Authors: Hines Rochelle M. , Maric Hans Michael , Hines Dustin J. , Modgil Amit , Panzanelli Patrizia , Nakamura Yasuko , Nathanson Anna J. , Cross Alan , Deeb Tarek , Brandon Nicholas J. , Davies Paul , Fritschy Jean-Marc , Schindelin Hermann , Moss Stephen J.
Published: August 2018

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents.Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. SurvivingGabra2-1 mice show anxiety and elevations in electroencephalogramδpower, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development.
Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis
Authors: McCarthy Cormac , Lee Elinor , Bridges James P. , Sallese Anthony , Suzuki Takuji , Woods Jason C. , Bartholmai Brian J. , Wang Tisha , Chalk Claudia , Carey Brenna C. , Arumugam Paritha , Shima Kenjiro , Tarling Elizabeth J. , Trapnell Bruce C.
Published: August 2018

Pulmonary alveolar proteinosis (PAP) is a syndrome of reduced GM-CSF-dependent, macrophage-mediated surfactant clearance, dysfunctional foamy alveolar macrophages, alveolar surfactant accumulation, and hypoxemic respiratory failure for which the pathogenetic mechanism is unknown. Here, we examine the lipids accumulating in alveolar macrophages and surfactant to define the pathogenesis of PAP and evaluate a novel pharmacotherapeutic approach. In PAP patients, alveolar macrophages have a marked increase in cholesterol but only a minor increase in phospholipids, and pulmonary surfactant has an increase in the ratio of cholesterol to phospholipids. Oral statin therapy is associated with clinical, physiological, and radiological improvement in autoimmune PAP patients, and ex vivo statin treatment reduces cholesterol levels in explanted alveolar macrophages. In Csf2rb−/− mice, statin therapy reduces cholesterol accumulation in alveolar macrophages and ameliorates PAP, and ex vivo statin treatment increases cholesterol efflux from macrophages. These results support the feasibility of statin as a novel pathogenesis-based pharmacotherapy of PAP.
A mouse model reproducing the pathophysiology of neonatal group B streptococcal infection
Authors: Andrade Elva Bonifácio , Magalhães Ana , Puga Ana , Costa Madalena , Bravo Joana , Portugal Camila Cabral , Ribeiro Adília , Correia-Neves Margarida , Faustino Augusto , Firon Arnaud , Trieu-Cuot Patrick , Summavielle Teresa , Ferreira Paula
Published: August 2018

Group B streptococcal (GBS) meningitis remains a devastating disease. The absence of an animal model reproducing the natural infectious process has limited our understanding of the disease and, consequently, delayed the development of effective treatments. We describe here a mouse model in which bacteria are transmitted to the offspring from vaginally colonised pregnant females, the natural route of infection. We show that GBS strain BM110, belonging to the CC17 clonal complex, is more virulent in this vertical transmission model than the isogenic mutant BM110∆cylE, which is deprived of hemolysin/cytolysin. Pups exposed to the more virulent strain exhibit higher mortality rates and lung inflammation than those exposed to the attenuated strain. Moreover, pups that survive to BM110 infection present neurological developmental disability, revealed by impaired learning performance and memory in adulthood. The use of this new mouse model, that reproduces key steps of GBS infection in newborns, will promote a better understanding of the physiopathology of GBS-induced meningitis.
Persistent structures in a three-dimensional dynamical system with flowing and non-flowing regions
Authors: Zaman Zafir , Yu Mengqi , Park Paul P. , Ottino Julio M. , Lueptow Richard M. , Umbanhowar Paul B.
Published: August 2018

Mixing of fluids and mixing of solids are both relatively mature fields. In contrast, mixing in systems where flowing and non-flowing regions coexist remains largely unexplored and little understood. Here we report remarkably persistent mixing and non-mixing regions in a three-dimensional dynamical system where randomness is expected. A spherical shell half-filled with dry non-cohesive particles and periodically rotated about two horizontal axes generates complex structures that vary non-trivially with the rotation angles. They result from the interplay between fluid-like mixing by stretching-and-folding, and solids mixing by cutting-and-shuffling. In the experiments, larger non-mixing regions predicted by a cutting-and-shuffling model alone can persist for a range of protocols despite the presence of stretching-and-folding flows and particle-collision-driven diffusion. By uncovering the synergy of simultaneous fluid and solid mixing, we point the way to a more fundamental understanding of advection driven mixing in materials with coexisting flowing and non-flowing regions.
Critical role of CD4+ T cells and IFNγ signaling in antibody-mediated resistance to Zika virus infection
Authors: Lucas Carolina G. O. , Kitoko Jamil Z. , Ferreira Fabricio M. , Suzart Vinicius G. , Papa Michelle P. , Coelho Sharton V. A. , Cavazzoni Cecilia B. , Paula-Neto Heitor A. , Olsen Priscilla C. , Iwasaki Akiko , Pereira Renata M. , Pimentel-Coelho Pedro M. , Vale Andre M. , de Arruda Luciana B. , Bozza Marcelo T.
Published: August 2018

Protective adaptive immunity to Zika virus (ZIKV) has been mainly attributed to cytotoxic CD8+ T cells and neutralizing antibodies, while the participation of CD4+ T cells in resistance has remained largely uncharacterized. Here, we show a neutralizing antibody response, dependent on CD4+ T cells and IFNγ signaling, which we detected during the first week of infection and is associated with reduced viral load in the brain, prevention of rapid disease onset and survival. We demonstrate participation of these components in the resistance to ZIKV during primary infection and in murine adoptive transfer models of heterologous ZIKV infection in a background of IFNR deficiency. The protective effect of adoptively transferred CD4+ T cells requires IFNγ signaling, CD8+ T cells and B lymphocytes in recipient mice. Together, this indicates the importance of CD4+ T cell responses in future vaccine design for ZIKV.
Monitoring the action of redox-directed cancer therapeutics using a human peroxiredoxin-2-based probe
Authors: Langford Troy F. , Huang Beijing K. , Lim Joseph B. , Moon Sun Jin , Sikes Hadley D.
Published: August 2018

Redox cancer therapeutics target the increased reliance on intracellular antioxidant systems and enhanced susceptibility to oxidant-induced stress of some cancer cells compared to normal cells. Many of these therapeutics are thought to perturb intracellular levels of the oxidant hydrogen peroxide (H2O2), a signaling molecule that modulates a number of different processes in human cells. However, fluorescent probes for this species remain limited in their ability to detect the small perturbations induced during successful treatments. We report a fluorescent sensor based upon human peroxiredoxin-2, which acts as the natural indicator of small H2O2 fluctuations in human cells. The new probe reveals peroxide-induced oxidation in human cells below the detection limit of current probes, as well as peroxiredoxin-2 oxidation caused by two different redox cancer therapeutics in living cells. This capability will be useful in elucidating the mechanism of current redox-based therapeutics and in developing new ones.
ATP activates bestrophin ion channels through direct interaction
Authors: Zhang Yu , Kittredge Alec , Ward Nancy , Ji Changyi , Chen Shoudeng , Yang Tingting
Published: August 2018

Human Bestrophin1 (hBest1) is a Ca2+-activated Cl− channel in retinal pigment epithelium (RPE) essential for retina physiology, and its mutation results in retinal degenerative diseases that have no available treatments. Here, we discover that hBest1’s channel activity in human RPE is significantly enhanced by adenosine triphosphate (ATP) in a dose-dependent manner. We further demonstrate a direct interaction between ATP and bestrophins, and map the ATP-binding motif on hBest1 to an intracellular loop adjacent to the channel activation gate. Importantly, a disease-causing mutation of hBest1 located within the ATP-binding motif, p.I201T, diminishes ATP-dependent activation of the channel in patient-derived RPE, while the corresponding mutants in bestrophin homologs display defective ATP binding and a conformational change in the ATP-binding motif. Taken together, our results identify ATP as a critical activator of bestrophins, and reveal the molecular mechanism of an hBest1 patient-specific mutation.
Variation in bradyrhizobial NopP effector determines symbiotic incompatibility with Rj2-soybeans via effector-triggered immunity
Authors: Sugawara Masayuki , Takahashi Satoko , Umehara Yosuke , Iwano Hiroya , Tsurumaru Hirohito , Odake Haruka , Suzuki Yuta , Kondo Hitoshi , Konno Yuki , Yamakawa Takeo , Sato Shusei , Mitsui Hisayuki , Minamisawa Kiwamu
Published: August 2018

Genotype-specific incompatibility in legume–rhizobium symbiosis has been suggested to be controlled by effector-triggered immunity underlying pathogenic host-bacteria interactions. However, the rhizobial determinant interacting with the host resistance protein (e.g., Rj2) and the molecular mechanism of symbiotic incompatibility remain unclear. Using natural mutants of Bradyrhizobium diazoefficiens USDA 122, we identified a type III-secretory protein NopP as the determinant of symbiotic incompatibility with Rj2-soybean. The analysis of nopP mutations and variants in a culture collection reveal that three amino acid residues (R60, R67, and H173) in NopP are required for Rj2-mediated incompatibility. Complementation of rj2-soybean by the Rj2 allele confers the incompatibility induced by USDA 122-type NopP. In response to incompatible strains, Rj2-soybean plants activate defense marker gene PR-2 and suppress infection thread number at 2 days after inoculation. These results suggest that Rj2-soybeans monitor the specific variants of NopP and reject bradyrhizobial infection via effector-triggered immunity mediated by Rj2 protein.
Chemical genetic-based phenotypic screen reveals novel regulators of gluconeogenesis in human primary hepatocytes
Authors: Zou Haixia , Liu Qian , Meng Li , Zhou Jingye , Da Chenxiao , Wu Xikun , Jiang Lichun , Shou Jianyong , Hua Haiqing
Published: August 2018

Insulin resistance is a pathophysiological hallmark of type 2 diabetes and nonalcoholic fatty liver disease. Under the condition of fat accumulation in the liver, suppression of hepatic glucose production by insulin is diminished. In order to gain deeper understanding of dysregulation of glucose production in metabolic diseases, in the present study, we performed an unbiased phenotypic screening in primary human hepatocytes to discover novel mechanisms that regulate gluconeogenesis in the presence of insulin. To optimize phenotypic screening process, we used a chemical genetic screening approach by building a small-molecule library with prior knowledge of activity-based protein profiling. The “positive hits” result from the screen will be small molecules with known protein targets. This makes downstream deconvolution process (i.e., determining the relevant biological targets) less time-consuming. To unbiasedly decipher the molecular targets, we developed a novel statistical method and discovered a set of genes, including DDR3 and CACNA1E that suppressed gluconeogenesis in human hepatocytes. Further investigation, including transcriptional profiling and gene network analysis, was performed to understand the molecular functions of DRD3 and CACNA1E in human hepatocytes.
Radiocarbon analysis of modern olive wood raises doubts concerning a crucial piece of evidence in dating the Santorini eruption
Authors: Ehrlich Yael , Regev Lior , Boaretto Elisabetta
Published: August 2018

Charred olive wood is abundant in the archaeological record, especially around the Mediterranean. As the outermost ring closest to the bark is assumed to represent the latest time that the tree was alive, the radiocarbon date obtained from the outermost rings of an olive branch buried during the Santorini volcanic eruption is regarded as crucial evidence for the date of this cataclysmic event. The date of this eruption has far reaching consequences in the archaeology of the Aegean, Egypt and the Levant, and the understanding of their interconnections. We analyzed the radiocarbon concentrations in cross-sections from a modern olive tree trunk as well as from a living branch, and obtained near-annual resolution dates using the radiocarbon “bomb peak”. In both cases we show that radiocarbon dates of the last formed wood along the circumference are not chronologically homogenous, and can differ by up to a few decades. Thus the outermost wood layer does not necessarily represent the date of the last year of growth. These findings challenge the interpretation of the results obtained from dating the olive branch from the Santorini volcanic eruption, as it could predate the eruption by a few decades. In addition, our results are also significant for any future studies based on archaeologically preserved olive wood.
Essential role of MED1 in the transcriptional regulation of ER-dependent oncogenic miRNAs in breast cancer
Authors: Nagpal Neha , Sharma Shivani , Maji Sourobh , Durante Giorgio , Ferracin Manuela , Thakur Jitendra K. , Kulshreshtha Ritu
Published: August 2018

Mediator complex has been extensively shown to regulate the levels of several protein-coding genes; however, its role in the regulation of miRNAs in humans remains unstudied so far. Here we show that MED1, a Mediator subunit in the Middle module of Mediator complex, is overexpressed in breast cancer and is a negative prognostic factor. The levels of several miRNAs (miR-100-5p, -191-5p, -193b-3p, -205-5p, -326, -422a and -425-5p) were found to be regulated by MED1. MED1 induces miR-191/425 cluster in an estrogen receptor-alpha (ER-α) dependent manner. Occupancy of MED1 on estrogen response elements (EREs) upstream of miR-191/425 cluster is estrogen and ER-α-dependent and ER-α-induced expression of these miRNAs is MED1-dependent. MED1 mediates induction of cell proliferation and migration and the genes associated with it (JUN, FOS, EGFR, VEGF, MMP1, and ERBB4) in breast cancer, which is abrogated when used together with miR-191-inhibition. Additionally, we show that MED1 also regulates the levels of direct miR-191 target genes such as SATB1, CDK6 and BDNF. Overall, the results show that MED1/ER-α/miR-191 axis promotes breast cancer cell proliferation and migration and may serve as a novel target for therapy.
Classification and Regression Tree Approach for Prediction of Potential Hazards of Urban Airborne Bacteria during Asian Dust Events
Authors: Yoo Keunje , Yoo Hyunji , Lee Jae Min , Shukla Sudheer Kumar , Park Joonhong
Published: August 2018

Despite progress in monitoring and modeling Asian dust (AD) events, real-time public hazard prediction based on biological evidence during AD events remains a challenge. Herein, both a classification and regression tree (CART) and multiple linear regression (MLR) were applied to assess the applicability of prediction for potential urban airborne bacterial hazards during AD events using metagenomic analysis and real-time qPCR. In the present work, Bacillus cereus was screened as a potential pathogenic candidate and positively correlated with PM10 concentration (p < 0.05). Additionally, detection of the bceT gene with qPCR, which codes for an enterotoxin in B. cereus, was significantly increased during AD events (p < 0.05). The CART approach more successfully predicted potential airborne bacterial hazards with a relatively high coefficient of determination (R2) and small bias, with the smallest root mean square error (RMSE) and mean absolute error (MAE) compared to the MLR approach. Regression tree analyses from the CART model showed that the PM10 concentration, from 78.4 µg/m3 to 92.2 µg/m3, is an important atmospheric parameter that significantly affects the potential airborne bacterial hazard during AD events. The results show that the CART approach may be useful to effectively derive a predictive understanding of potential airborne bacterial hazards during AD events and thus has a possible for improving decision-making tools for environmental policies associated with air pollution and public health.
Author Correction: CREB-binding protein plays key roles in juvenile hormone action in the red flour beetle, Tribolium Castaneum
Authors: Xu Jingjing , Roy Amit , Palli Subba Reddy
Published: August 2018

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