bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing alternative cascades from internalizing and externalizing symptoms to adolescent alcohol use and alcohol use disorder through co-occurring symptoms and peer delinquency
Authors: Scalco Matthew D. , Colder Craig R. , Read Jennifer P. , Lengua Liliana J. , Wieczorek William F. , Hawk Larry W.
Published: April 2020

Given the equivocal literature on the relationship between internalizing symptoms and early adolescent alcohol use (AU) and AU disorder (AUD), the present study took a developmental perspective to understand how internalizing and externalizing symptoms may operate together in the etiology of AU and AUD. We pit the delayed onset and rapid escalation hypothesis (Hussong et al., 2011) against a synthesis of the dual failure model and the stable co-occurring hypothesis (Capaldi, 1992; Colder et al., 2013, 2018) to test competing developmental pathways to adolescent AU and AUD involving problem behavior, peer delinquency, and early initiation of AU. A latent transactional and mediational framework was used to test pathways to AUD spanning developmental periods before AU initiation (Mage = 11) to early and high risk for AUD (Mage = 14–15 and Mage = 17–18). The results supported three pathways to AUD. The first started with “pure” externalizing symptoms in early childhood and involved multiple mediators, including the subsequent development of co-occurring symptoms and peer delinquency. The second pathway involved stable co-occurring symptoms. Interestingly, chronically elevated pure internalizing symptoms did not figure prominently in pathways to AUD. Selection and socialization effects between early AU and peer delinquency constituted a third pathway.
Outcomes of closure of doubly committed subarterial ventricular septal defects in adults
Authors: Chen Zhaoyang , Chen Wanhua , Chen Hang , Liao Zhenmei , Chen Qiang , Chen Lianglong
Published: April 2020

Background:

Outcome data of doubly committed subarterial ventricular septal defect closure in adults are limited.

Methods:

A review was made of the inpatients >18 years of age who underwent doubly committed subarterial ventricular septal defect closure between June 2010 and June 2017.

Results:

The patients were categorised into two groups: The valve intervention group consisted of 31 patients who underwent aortic valvuloplasty, aortic valve replacement, or repair of sinus Valsalva aneurysm in addition to doubly committed subarterial ventricular septal defect closure; non-valvular intervention group comprised 58 patients who underwent only doubly committed subarterial ventricular septal defect closure. The groups did not differ by sex and age. Patients in the valve intervention group, with a larger ventricular septal defect size, were shorter and tended to be lighter. The valve intervention group had more patients with pneumonia perioperatively. No infective endocarditis and reoperation were noted during the study period. At last follow-up, 91 and 96.6% of the studied patients were free from left ventricle dilation and pulmonary hypertension. In patients without pre-operative aortic regurgitation, 12 developed new mild aortic regurgitation during the follow-up.

Conclusions:

About 34.8% of adult patients with doubly committed subarterial ventricular septal defect required concurrent intervention on aortic valve or sinus Valsalva aneurysm. The midterm results of doubly committed subarterial ventricular septal defect closure in adult patients were favourable. However, the incidence of new mild aortic regurgitation after ventricular septal defect closure was high (27.3%). Long-term follow-up of aortic regurgitation progression is needed.
Influenza associated with circulatory collapse and atrioventricular block in an unvaccinated child with repaired CHD
Authors: Akam-Venkata Jyothsna , Aggarwal Sanjeev , Karpawich Peter P.
Published: April 2020

Symptomatic, circulatory collapse occurred in an unvaccinated child with repaired congenital heart and a backup pacemaker during an Influenza B viral infection with complete atrioventricular block and pacemaker non-capture. Ventricular arrhythmias occurred during her collapse. Atrioventricular conduction recovered within 24 hours. Influenza-associated cardiac inflammation can adversely affect patients with repaired CHD. Proactive immunisation is strongly recommended.
A pilot study on the association between the blood oxygen level-dependent signal in the reward system and dopamine transporter availability in adults with attention deficit hyperactivity disorder
Authors: Lin Shih-Hsien , Chi Mei Hung , Lee I Hui , Chen Kao Chin , Tai Ying Chun , Yao Wei Jen , Chiu Nan Tsing , Yang Dong-Yu , Lin Chun-Yu , Chen Po See , Yang Yen Kuang
Published: April 2020

Background

It is well-known that attention deficit hyperactivity disorder (ADHD) is associated with changes in the dopaminergic system. However, the relationship between central dopaminergic tone and the blood oxygen level-dependent (BOLD) signal during receipt of rewards and penalties in the corticostriatal pathway in adults with ADHD is unclear.

Methods

Single-photon emission computed tomography with [99mTC]TRODAT-1 was used to assess striatal dopamine transporter (DAT) availability. Event-related functional magnetic resonance imaging was conducted on subjects performing the Iowa Gambling Test.

Result

DAT availability was found to be associated with the BOLD response, which was a covariate of monetary loss, in the medial prefrontal cortex (r= 0.55,P= .03), right ventral striatum (r= 0.69,P= .003), and right orbital frontal cortex (r= 0.53,P= .03) in adults with ADHD. However, a similar correlation was not found in the controls.

Conclusions

The results confirmed that dopaminergic tone may play a different role in the penalty-elicited response of adults with ADHD. It is plausible that a lower neuro-threshold accompanied by insensitivity to punishment could be exacerbated by the hypodopaminergic tone in ADHD.
Impact of 2 Weeks of Monitored Abstinence on Cognition in Adolescent and Young Adult Cannabis Users
Authors: Wallace Alexander L. , Wade Natasha E. , Lisdahl Krista M.
Published: April 2020

Objectives:

Previous research suggests recovery from cannabis-related deficits in verbal learning and memory functioning after periods of cannabis abstinence in adolescents. Here, we examine how cannabis cessation affects cognitive performance over 2 weeks of monitored abstinence compared to controls in adolescents and young adults.

Methods:

Seventy-four participants (35 cannabis users) aged 16–26 ceased all cannabis, alcohol, and other illicit substance consumption for a 2-week period; abstinence was monitored via weekly urinalysis, breath, and sweat patch testing. Starting at baseline, participants completed weekly abbreviated neuropsychological batteries. Measures included tests of attention, inhibition, verbal working memory, and learning. Repeated measures assessed within and between subject effects for time and group status, while controlling for past year alcohol and nicotine use.

Results:

Cannabis users showed increased performance compared to controls on sustained attention tasks after 2 weeks of cannabis use.

Conclusions:

Deficits in attention, but not verbal learning and memory, recovered after 2 weeks of monitored abstinence. This differs from previous literature, suggesting that other cognitive domains may show signs of recovery after periods of cannabis cessation in adolescents and young adults.
Breast boost vector: a new metric proposed to optimise isocentre location in an fIMRT–VMAT hybrid technique for a simultaneous integrated boost in breast radiotherapy
Authors: de la Llana Víctor , del Castillo Ángel , Andrés Carlos , Gómez Laura , Agulla Manuel , del Valle María Luisa , Iglesias María , Torres Ricardo
Published: April 2020

Purpose:

Evaluating the improvements of placing the treatment isocentre at the boost centre of mass (CoM) in a hybrid treatment for breast cancer radiotherapy.

Material and methods:

Twenty-two patients were planned in two isocentre locations with two forward intensity-modulated radiation therapy (fIMRT) tangentials to the breast and a volumetric-modulated arc therapy (VMAT) to the boost. A simultaneous integrated boost technique was used. Breast Boost (BB) Vector was investigated as a criterion for selecting an appropriate isocentre placement. Various metrics for boost, breast and hybrid plans were analysed using analysis of variance statistics.

Results:

Comparing hybrid plans at the boost CoM vs. hybrid plans at the breast CoM, no significant differences were found. Analysis of relative variations of planning target volume (PTV) boost coverage vs. BB Vector indicated an upgrade in boost CoM isocentre strategy. Dose to organs at risk was comparable: V5Gy (26·24 vs. 25·69%, p = 0·8), V20Gy (14·66 vs. 14·58%, p = 0·959) and the mean dose (7·37 Gy vs. 7·26 Gy, p = 0·879) to ipsilateral lung; V5Gy (15·60 vs. 15·22%, p = 0·903), and the mean dose (4·91 Gy vs. 4·86 Gy, p = 0·950) to heart and dose to free breast of boost (46·71 Gy vs. 46·62 Gy, p = 0·408).

Findings:

The hybrid fIMRT–VMAT technique centred at the boost CoM resulted equivalent to plans centred at the breast CoM, while benefiting from an enhancement in PTV boost coverage for patients with BB Vector superior to 5.
Deutschdidaktisches Wissen angehender Sekundarstufenlehrkräfte
Authors: König Johannes , Bremerich-Vos Albert
Published: April 2020

Zusammenfassung. Das fachdidaktische Wissen ist eine zentrale Facette professionellen Lehrerwissens. Im Gegensatz zu mathematisch-naturwissenschaftlichen Fächern existieren bislang nur wenige fachdidaktische Wissenstests für sprachliche Fächer. Vorgestellt wird ein standardisierter Test zur Erfassung von fachdidaktischem Wissen angehender Deutschlehrkräfte der Sekundarstufen I und II, der im Rahmen des Projekts PlanvoLL-D entwickelt wurde. Datenbasis bilden die Testdaten von 378 Referendarinnen und Referendaren (Stichprobe 1) sowie 150 Lehramtsstudierenden (Stichprobe 2) im Bachelor ( n = 114) bzw. Master ( n = 36). Zudem liegen für 85 dieser Studierenden eine Wiederholungstestung nach einem Jahr vor, für 27 Referendarinnen bzw. Referendare Befragungsdaten zur Unterrichtsqualität aus Sicht von 564 Schülerinnen und Schülern. Fragen zur Reliabilität des Tests an Stichprobe 1 und Stichprobe 2 sowie Fragen zur Kriteriumsvalidität werden geprüft. Die Ergebnisse zeigen, dass der Test eine reliable Messung an allen Stichproben erlaubt, die Retest-Stabilität ist hoch. Die Kriteriumsvalidität lässt sich hinsichtlich Übereinstimmungsvalidität, Methode der bekannten Gruppen und Vorhersagevalidität belegen.
All‐Sky Tracking of Sporadic Field‐Aligned Irregularities as a Novel Probe of Thermospheric Winds
Authors: Helmboldt J. F. , Taylor G. B.
Published: April 2020

This paper presents the results of an analysis of a unique observing campaign that tracks groups of irregularities associated with sporadic
(
) via their coherent backscattering of a very high frequency transmitter of opportunity (an analog TV station). The unique all‐sky imaging capability of the first station of the Long Wavelength Array used in this campaign, allowed for the identification and tracking of multiple groups of irregularities, or “clouds,” over the entire visible sky. This all‐sky tracking yielded horizontal wind measurements from 75 distinct clouds observed within 18, 1‐hr collections from May–September 2014 within the
90‐ to 150‐km altitude range. While unusually strong winds of 100–200 m s
or more were observed, the winds generally agree with predictions from the updated Horizontal Wind Model. The exception to this was an offset in premidnight zonal winds, which the Long Wavelength Array observations indicated were systematically more westerly than predicted by the Horizontal Wind Model. We postulate that this may be due to a local excess in mountain waves, which is partially supported by tropospheric and stratospheric wind data from the National Oceanic and Atmospheric Administration North American Regional Reanalysis. In three out of the 18 collections, we also observe evidence of significant horizontal zonal wind shears (positive and negative) with magnitudes on the order of 1 m
s
km
.
Statistical Characteristics and Synoptic Situations of Long‐Duration Heavy Rainfall Events Over North China
Authors: Kang Yanzhen , Peng Xindong , Wang Shigong , Dong Chunqing , Shang Kezheng , Zhao Yang
Published: April 2020

The spatiotemporal characteristics of long‐duration heavy rainfall (LDHR) events are statistically analyzed using hourly surface observations over central‐southern North China during the warm seasons of 2011–2018, revealing pronounced variabilities in the frequency and amount of LDHR. Two accumulated rainfall peaks are found in the western (WHRR) and eastern (EHRR) regions of central‐southern North China. The LDHR occurrence frequency decreases westward, and the peaks of the LDHR amount, frequency and intensity in the WHRR and EHRR are observed at nighttime (2100–0200 Beijing Standard Time) or in the early morning (0300–0700 Beijing Standard Time). The rainfall amount exhibits a bimodal diurnal variation in the WHRR (determined mainly by the rainfall intensity), whereas a single rainfall frequency‐related peak is found in the EHRR. Four types of LDHR events corresponding to different flow patterns, synoptic systems, and moisture transport mechanisms are classified according to their locations. The first is heavy rainfall in the WHRR with an upper‐level jet favorable for an ascending motion near Taihang Mountain; topographic blocking of southerly flow is crucial for heavy rainfall formation. The second describes heavy rainfall in the EHRR attributable to the favorable configurations of upper‐ and lower‐level systems. Heavy rainfall occurs over both the WHRR and the EHRR in the third type, including topographic blocking and convergence associated with low‐pressure systems or shear lines and a mesoscale low vortex or shear line related to topographic effects and positive vorticity advection in front of a westerly trough. The fourth shows a scattered distribution of LDHR stations and is generally not comparable to the first three types.
Seismic Characteristics of the Eastern North American Crust With Ps Converted Waves: Terrane Accretion and Modification of Continental Crust
Authors: Li Cong , Gao Haiying , Williams Michael L.
Published: April 2020

The impact of past tectonic events on the formation and modification of continental lithosphere remains as an open question of fundamental importance. Eastern North America provides a complete record of supercontinent assembly and breakup over the past 1.3 Ga, serving as a natural laboratory for our understanding of continental crust and mantle lithosphere and for integrating geologic and geophysical observations. In this study, we used teleseismic Ps receiver functions to image the detailed distribution of crustal thickness beneath eastern North America. The radial‐component receiver functions were calculated from seismic waveforms recorded by a total of 659 broadband stations during 2010–2017, yielding a high‐resolution image of Moho depth distribution. The depths of the Moho and intracrustal layers vary within and across the major tectonic units. Specifically, there are distinct differences in crustal thickness between the northern and southern Grenville Province. A dipping intracrustal feature can be seen within the central Grenville Province, with the depth increasing eastward from 5 to 27 km. The Moho depth decreases southeastward across the Grenville‐Appalachian boundary, with a sharp Moho offset of up to 12–15 km in the central segment and a more gradual variation to the north and south. The thickness difference between the southern and northern Grenville‐aged crusts suggests different tectonic and/or exhumation histories during and after the Grenville Orogeny. The low‐angle eastward dipping crustal feature is interpreted to be a Grenville‐aged collisional structure. Differences in the steepness of the Moho offset along the strike of Appalachians probably reflect variation of the steepness of the subsurface boundary between Laurentia and accreted terranes with different intensities of postorogenic modification. The observed spatial relation between the geologically defined tectonic boundaries and crustal thickness variations provides new constraints on the depth extent of the tectonic units within the crust.
Energy Transfers and Reflection of Infragravity Waves at a Dissipative Beach Under Storm Waves
Authors: Bertin Xavier , Martins Kévin , de Bakker Anouk , Chataigner Teddy , Guérin Thomas , Coulombier Thibault , de Viron Olivier
Published: April 2020

This study presents unpublished field observations of infragravity waves, collected at the dissipative beach of Saint‐Trojan (Oléron Island, France) during the storm Kurt (3 February 2017), characterized by incident short waves of significant heights reaching 9.5 m and peak periods reaching 22 s. Data analysis reveals the development of exceptionally large infragravity waves, with significant heights reaching 1.85 m close to shore. Field observations are complemented by numerical modeling with XBeach, which well reproduces the development of such infragravity waves. Model results reveal that infragravity waves were generated mainly through the bound wave mechanism, enhanced by the development of a phase lag with the shortwave energy envelope. Spectral analysis of the free surface elevation shows the generation of superharmonic and subharmonic infragravity waves, the latter dominating the free surface elevation variance close to shore. Modeling results suggest that subharmonic infragravity waves result, at least partly, from infragravity‐wave merging, promoted by the combination of free and bound infragravity waves propagating across a several kilometer‐wide surf zone. Due to the steeper slope of the upper part of the beach profile, observed and modeled reflection coefficients under moderate‐energy show a strong tidal modulation, with a weak reflection at low tide (R2<0.2) and a full reflection at high tide (R2∼1.0). Under storm waves, the observed reflection coefficients remain unusually high for a dissipative beach (R2∼0.5−1.0), which is explained by the development of subharmonic infragravity waves with frequencies around 0.005 Hz, too long to suffer a substantial dissipation.
Homogenizing GPS Integrated Water Vapor Time Series: Benchmarking Break Detection Methods on Synthetic Data Sets
Authors: Van Malderen R. , Pottiaux E. , Klos A. , Domonkos P. , Elias M. , Ning T. , Bock O. , Guijarro J. , Alshawaf F. , Hoseini M. , Quarello A. , Lebarbier E. , Chimani B. , Tornatore V. , Zengin Kazancı S. , Bogusz J.
Published: April 2020

We assess the performance of different break detection methods on three sets of benchmark data sets, each consisting of 120 daily time series of integrated water vapor differences. These differences are generated from the Global Positioning System (GPS) measurements at 120 sites worldwide, and the numerical weather prediction reanalysis (ERA‐Interim) integrated water vapor output, which serves as the reference series here. The benchmark includes homogeneous and inhomogeneous sections with added nonclimatic shifts (breaks) in the latter. Three different variants of the benchmark time series are produced, with increasing complexity, by adding autoregressive noise of the first order to the white noise model and the periodic behavior and consecutively by adding gaps and allowing nonclimatic trends. The purpose of this “complex experiment” is to examine the performance of break detection methods in a more realistic case when the reference series are not homogeneous. We evaluate the performance of break detection methods with skill scores, centered root mean square errors (CRMSE), and trend differences relative to the trends of the homogeneous series. We found that most methods underestimate the number of breaks and have a significant number of false detections. Despite this, the degree of CRMSE reduction is significant (roughly between 40% and 80%) in the easy to moderate experiments, with the ratio of trend bias reduction is even exceeding the 90% of the raw data error. For the complex experiment, the improvement ranges between 15% and 35% with respect to the raw data, both in terms of RMSE and trend estimations.
Large‐Scale Circulation Environment and Microphysical Characteristics of the Cloud Systems Over the Tibetan Plateau in Boreal Summer
Authors: Chen Jinghua , Wu Xiaoqing , Yin Yan , Lu Chunsong
Published: April 2020

The Tibetan Plateau (TP) experiences a particular dynamical and thermal environment due to its unique topography, which could affect the generation and development of its cloud and precipitation. Statistical results of 52‐year daily precipitation (1961 to 2012) show that the most frequent daily precipitation is about 3 mm day−1 over the eastern TP (ETP) in the warm season while it is less than 1 mm day−1 over the western TP (WTP). Circulation patterns for rainy and rainless conditions over both the ETP and WTP are investigated. The results show that the rainy weather over the TP is usually related to the moisture transported from the warm ocean by the southerly flow. Moreover, rainy weather in WTP can only appear when the strong southerly flow prevails over the Indian subcontinent. When the south flow is weak, the rainy weather can still develop in ETP under favorable conditions due to the local madid environment. CloudSat observations show that the strong convective system can extend to a level as high as 16 km above the sea level with a favorable dynamical and thermal environment. However, the depth of most precipitating convective clouds over the TP is in a range of 6–9 km. Due to the wetter condition, the precipitating convective cloud holds a lower cloud base in August in ETP than WTP. Compared with other regions, the precipitating convective clouds in both the ETP and WTP are thinner in cloud depth, smaller in cloud particles and weaker in precipitation capacity.
AE, DST, and Their SuperMAG Counterparts: The Effect of Improved Spatial Resolution in Geomagnetic Indices
Authors: Bergin A. , Chapman S. C. , Gjerloev J. W.
Published: April 2020

For decades, geomagnetic indices have been used extensively to parameterize space weather events, as input to various models and as space weather specifications. The auroral electrojet (AE) index and disturbance storm time index (DST) are two such indices that span multiple solar cycles and have been widely studied. The production of improved spatial coverage analogs to AE and DST is now possible using the SuperMAG collaboration of ground‐based magnetometers. SME is an electrojet index that shares methodology with AE. SMR is a ring current index that shares methodology with DST. As the number of magnetometer stations in the SuperMAG network increases over time, so does the spatial resolution of SME and SMR. Our statistical comparison between the established indices and their new SuperMAG counterparts finds that, for large excursions in geomagnetic activity, AE systematically underestimates SME for later cycles. The difference between distributions of recorded AE and SME values for a single solar maximum can be of the same order as changes in activity seen from one solar cycle to the next. We demonstrate that DST and SMR track each other but are subject to an approximate linear shift as a result of the procedure used to map stations to the magnetic equator. We explain the observed differences between AE and SME with the assistance of a simple model, based on the construction methodology of the electrojet indices. We show that in the case of AE and SME, it is not possible to simply translate between the two indices.
Hydrologically Induced Deformation in Long Valley Caldera and Adjacent Sierra Nevada
Authors: Silverii F. , Montgomery-Brown E. K. , Borsa A. A. , Barbour A. J.
Published: April 2020

Vertical and horizontal components of GNSS displacements in the Long Valley Caldera and adjacent Sierra Nevada range show a clear correlation with hydrological trends at both multiyear and seasonal time scales. We observe a clear vertical and horizontal seasonal deformation pattern primarily attributable to the solid earth response to hydrological surface loading at large‐to‐regional (Sierra Nevada range) scales. Several GNSS sites, located at the eastern edge of the Sierra Nevada along the southwestern rim of Long Valley Caldera, also show significant horizontal deformation that cannot be explained by elastic deformation from surface loading. Due to the location of these sites and the strong correlation between their horizontal displacements and spring discharge, we hypothesize that this deformation reflects poroelastic processes related to snowmelt runoff water infiltrating into the Sierra Nevada slopes around Long Valley Caldera. Interestingly, this is also an area where water infiltrates to feed the local hydrothermal system, and where snowmelt‐induced earthquake swarms have been recently detected.
miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR
Authors: Ji Lin , Lin Zhongjie , Wan Zhe , Xia Shunjie , Jiang Shi , Cen Dong , Cai Liuxin , Xu Junjie , Cai Xiujun
Published: April 2020

HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advanced-stage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.
Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells
Authors: Edwards Genea , Perkins Guy A. , Kim Keun-Young , Kong YeEun , Lee Yonghoon , Choi Soo-Ho , Liu Yujia , Skowronska-Krawczyk Dorota , Weinreb Robert N. , Zangwill Linda , Strack Stefan , Ju Won-Kyu
Published: April 2020

Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases in CaN and total Drp1 levels, as well as a decrease in Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.
Measurement and models accounting for cell death capture hidden variation in compound response
Authors: Bae Song Yi , Guan Ning , Yan Rui , Warner Katrina , Taylor Scott D. , Meyer Aaron S.
Published: April 2020

Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes, including changes in cell growth, apoptosis, and non-apoptotic cell death. These outcomes have divergent effects on the tumor microenvironment, immune response, and resistance mechanisms. Here, we show that quantifying cell viability alone is insufficient to distinguish between these compound responses. Using an alternative assay and drug-response analysis amenable to high-throughput measurement, we find that compounds with identical viability outcomes can have very different effects on cell growth and death. Moreover, additive compound pairs with distinct growth/death effects can appear synergistic when only assessed by viability. Overall, these results demonstrate an approach to incorporating measurements of cell death when characterizing a pharmacologic response.
HSD11B1 is upregulated synergistically by IFNγ and TNFα and mediates TSG-6 expression in human UC-MSCs
Authors: Huang Peiqing , Li Yinghong , Xu Chenchang , Melino Gerry , Shao Changshun , Shi Yufang
Published: April 2020

Inflammatory factors such as IFNγ and TNFα could endow mesenchymal stem cells (MSCs) a potent immunomodulatory property, a process called licensing, but the mechanisms are not fully understood. We here found that glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive cortisone to the active cortisol and thereby regulates tissue glucocorticoid (GC) levels, was greatly upregulated by IFNγ and TNFα in human umbilical cord-derived MSCs (UC-MSCs) in a synergistic manner. While IFNγ alone was not able to induce HSD11B1, it could increase the activity of NF-kB and thus augment the upregulation of HSD11B1 by TNFα. Interestingly, the upregulation of HSD11B1 by IFNγ and TNFα also required glucocorticoid receptor. Furthermore, HSD11B1 was shown to be required for the expression of TNF-stimulated gene 6 (TSG-6), an important anti-inflammatory effector molecule of MSCs. Therefore, the inflammatory factors IFNγ and TNFα can promote GC metabolism and thereby drive the expression of anti-inflammatory factor TSG-6 in human UC-MSCs, forming a potential negative feedback loop. These findings help to understand the relationship between inflammation and GC metabolism.
Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells
Authors: Alim Md Abdul , Grujic Mirjana , Ackerman Paul W. , Kristiansson Per , Eliasson Pernilla , Peterson Magnus , Pejler Gunnar
Published: April 2020

Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate–glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate–glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.
Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes
Authors: Omar-Hmeadi Muhmmad , Lund Per-Eric , Gandasi Nikhil R. , Tengholm Anders , Barg Sebastian
Published: April 2020

Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cells of T2D donors, without changes in voltage-dependent ion currents or granule trafficking. Dispersed α-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits α-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect α-cell insensitivity to paracrine inhibition at hyperglycemia.
Aquaculture at the crossroads of global warming and antimicrobial resistance
Authors: Reverter Miriam , Sarter Samira , Caruso Domenico , Avarre Jean-Christophe , Combe Marine , Pepey Elodie , Pouyaud Laurent , Vega-Heredía Sarahi , de Verdal Hugues , Gozlan Rodolphe E.
Published: April 2020

In many developing countries, aquaculture is key to ensuring food security for millions of people. It is thus important to measure the full implications of environmental changes on the sustainability of aquaculture. We conduct a double meta-analysis (460 articles) to explore how global warming and antimicrobial resistance (AMR) impact aquaculture. We calculate a Multi-Antibiotic Resistance index (MAR) of aquaculture-related bacteria (11,274 isolates) for 40 countries, of which mostly low- and middle-income countries present high AMR levels. Here we show that aquaculture MAR indices correlate with MAR indices from human clinical bacteria, temperature and countries’ climate vulnerability. We also find that infected aquatic animals present higher mortalities at warmer temperatures. Countries most vulnerable to climate change will probably face the highest AMR risks, impacting human health beyond the aquaculture sector, highlighting the need for urgent action. Sustainable solutions to minimise antibiotic use and increase system resilience are therefore needed.
Dual functionality of the amyloid protein TasA in Bacillus physiology and fitness on the phylloplane
Authors: Cámara-Almirón Jesús , Navarro Yurena , Díaz-Martínez Luis , Magno-Pérez-Bryan María Concepción , Molina-Santiago Carlos , Pearson John R. , de Vicente Antonio , Pérez-García Alejandro , Romero Diego
Published: April 2020

Bacteria can form biofilms that consist of multicellular communities embedded in an extracellular matrix (ECM). InBacillus subtilis, the main protein component of the ECM is the functional amyloid TasA. Here, we study further the roles played by TasA inB. subtilisphysiology and biofilm formation on plant leaves and in vitro. We show that ΔtasAcells exhibit a range of cytological symptoms indicative of excessive cellular stress leading to increased cell death. TasA associates to the detergent-resistant fraction of the cell membrane, and the distribution of the flotillin-like protein FloT is altered in ΔtasAcells. We propose that, in addition to a structural function during ECM assembly and interactions with plants, TasA contributes to the stabilization of membrane dynamics as cells enter stationary phase.
Doping-free complementary WSe2 circuit via van der Waals metal integration
Authors: Kong Lingan , Zhang Xiaodong , Tao Quanyang , Zhang Mingliang , Dang Weiqi , Li Zhiwei , Feng Liping , Liao Lei , Duan Xiangfeng , Liu Yuan
Published: April 2020

Two-dimensional (2D) semiconductors have attracted considerable attention for the development of ultra-thin body transistors. However, the polarity control of 2D transistors and the achievement of complementary logic functions remain critical challenges. Here, we report a doping-free strategy to modulate the polarity of WSe2 transistors using same contact metal but different integration methods. By applying low-energy van der Waals integration of Au electrodes, we observed robust and optimized p-type transistor behavior, which is in great contrast to the transistors fabricated on the same WSe2 flake using conventional deposited Au contacts with pronounced n-type characteristics. With the ability to switch majority carrier type and to achieve optimized contact for both electrons and holes, a doping-free logic inverter is demonstrated with higher voltage gain of 340, at the bias voltage of 5.5 V. Furthermore, the simple polarity control strategy is extended for realizing more complex logic functions such as NAND and NOR.
The chloroalkaloid (−)-acutumine is biosynthesized via a Fe(II)- and 2-oxoglutarate-dependent halogenase in Menispermaceae plants
Authors: Kim Colin Y. , Mitchell Andrew J. , Glinkerman Christopher M. , Li Fu-Shuang , Pluskal Tomáš , Weng Jing-Ke
Published: April 2020

Plant halogenated natural products are rare and harbor various interesting bioactivities, yet the biochemical basis for the involved halogenation chemistry is unknown. While a handful of Fe(II)- and 2-oxoglutarate-dependent halogenases (2ODHs) have been found to catalyze regioselective halogenation of unactivated C–H bonds in bacteria, they remain uncharacterized in the plant kingdom. Here, we report the discovery of dechloroacutumine halogenase (DAH) from Menispermaceae plants known to produce the tetracyclic chloroalkaloid (−)-acutumine. DAH is a 2ODH of plant origin and catalyzes the terminal chlorination step in the biosynthesis of (−)-acutumine. Phylogenetic analyses reveal that DAH evolved independently in Menispermaceae plants and in bacteria, illustrating an exemplary case of parallel evolution in specialized metabolism across domains of life. We show that at the presence of azide anion, DAH also exhibits promiscuous azidation activity against dechloroacutumine. This study opens avenues for expanding plant chemodiversity through halogenation and azidation biochemistry.
Observation of an unpaired photonic Dirac point
Authors: Liu Gui-Geng , Zhou Peiheng , Yang Yihao , Xue Haoran , Ren Xin , Lin Xiao , Sun Hong-xiang , Bi Lei , Chong Yidong , Zhang Baile
Published: April 2020

At photonic Dirac points, electromagnetic waves are governed by the same equations as two-component massless relativistic fermions. However, photonic Dirac points are known to occur in pairs in “photonic graphene” and other similar photonic crystals, which necessitates special precautions to excite only one valley state. Systems hosting unpaired photonic Dirac points are significantly harder to realize, as they require broken time-reversal symmetry. Here, we report on the observation of an unpaired Dirac point in a planar two-dimensional photonic crystal. The structure incorporates gyromagnetic materials, which break time-reversal symmetry; the unpaired Dirac point occurs when a parity-breaking parameter is fine-tuned to a topological transition between a photonic Chern insulator and a conventional photonic insulator phase. Evidence for the unpaired Dirac point is provided by transmission and field-mapping experiments, including a demonstration of strongly non-reciprocal reflection. This unpaired Dirac point may have applications in valley filters and angular selective photonic devices.
Connecting concepts in the brain by mapping cortical representations of semantic relations
Authors: Zhang Yizhen , Han Kuan , Worth Robert , Liu Zhongming
Published: April 2020

In the brain, the semantic system is thought to store concepts. However, little is known about how it connects different concepts and infers semantic relations. To address this question, we collected hours of functional magnetic resonance imaging data from human subjects listening to natural stories. We developed a predictive model of the voxel-wise response and further applied it to thousands of new words. Our results suggest that both semantic categories and relations are represented by spatially overlapping cortical patterns, instead of anatomically segregated regions. Semantic relations that reflect conceptual progression from concreteness to abstractness are represented by cortical patterns of activation in the default mode network and deactivation in the frontoparietal attention network. We conclude that the human brain uses distributed networks to encode not only concepts but also relationships between concepts. In particular, the default mode network plays a central role in semantic processing for abstraction of concepts.
Reactions of CO2 and ethane enable CO bond insertion for production of C3 oxygenates
Authors: Xie Zhenhua , Xu Yuanguo , Xie Meng , Chen Xiaobo , Lee Ji Hoon , Stavitski Eli , Kattel Shyam , Chen Jingguang G.
Published: April 2020

Reacting CO2 and ethane to synthesize value-added oxygenate molecules represents opportunities to simultaneously reduce CO2 emissions and upgrade underutilized ethane in shale gas. Herein, we propose a strategy to produce C3 oxygenates using a tandem reactor. This strategy is achieved with a Fe3Ni1/CeO2 catalyst (first reactor at 600–800 °C) for CO2-assisted dehydrogenation and reforming of ethane to produce ethylene, CO, and H2, and a RhCox/MCM-41 catalyst (second reactor at 200 °C) enabling CO insertion for the production of C3 oxygenates (propanal and 1-propanol) via the heterogeneous hydroformylation reaction at ambient pressure. In-situ characterization using synchrotron spectroscopies and density functional theory (DFT) calculations reveal the effect of Rh–Co bimetallic formation in facilitating the production of C3 oxygenates. The proposed strategy provides an opportunity for upgrading light alkanes in shale gas by reacting with CO2 to produce aldehydes and alcohols.
Recapitulating kidney development in vitro by priming and differentiating mouse embryonic stem cells in monolayers
Authors: Chow Theresa , Wong Frances T. M. , Monetti Claudio , Nagy Andras , Cox Brian , Rogers Ian M.
Published: April 2020

In order to harness the potential of pluripotent stem cells, we need to understand how to differentiate them to our target cell types. Here, we developed a protocol to differentiate mouse embryonic stem cells (ESCs) to renal progenitors in a step-wise manner. Microarrays were used to track the transcriptional changes at each stage of differentiation and we observed that genes associated with metanephros, ureteric bud, and blood vessel development were significantly upregulated as the cells differentiated towards renal progenitors. Priming the ESCs and optimizing seeding cell density and growth factor concentrations helped improve differentiation efficiency. Organoids were used to determine the developmental potential of the renal progenitor cells. Aggregated renal progenitors gave rise to organoids consisting of LTL+/E-cadherin+ proximal tubules, cytokeratin+ ureteric bud-derived tubules, and extracellular matrix proteins secreted by the cells themselves. Over-expression of key kidney developmental genes, Pax2, Six1, Eya1, and Hox11 paralogs, during differentiation did not improve differentiation efficiency. Altogether, we developed a protocol to differentiate mouse ESCs in a manner that recapitulates embryonic kidney development and showed that precise gene regulation is essential for proper differentiation to occur.
Including water quality monitoring in rural water services: why safe water requires challenging the quantity versus quality dichotomy
Authors: Nowicki Saskia , Koehler Johanna , Charles Katrina J.
Published: April 2020

The need to increase drinking water quality monitoring in rural sub-Saharan Africa is widely recognised. Rural water service providers (RWSPs) may be positioned to include water quality monitoring in their activities; however, it is important that water safety activities do not compromise cooperation between the RWSP, bureaucracy, and communities. Using dilemma analysis, drawing on an institutional experiment engaging 76 stakeholders, we find that conceptualising water quality versus quantity as a dichotomy delays progress on safe water. This false dichotomy makes it more difficult to deliver water safety improvements due to contrasting assumptions about the importance of quality; risks associated with not being able to act; and unclear divisions of responsibility. Monitoring water quality can be a threat to stakeholders and stakeholder cooperation; however, this may be mitigated by including supported water safety planning in the technical and institutional design of rural water projects at their conception.