bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative simulation for complex transposition of great arteries using a three-dimensional model
Authors: Yokoyama Shinya , Fukuba Ryohei , Mitani Kazuhiro , Uemura Hideki
Published: December 2019

We utilised a cast preoperatively prepared on the basis of the patient’s computed tomography data to clarify unusual orientation of the great arteries (transposition of great arteries, coarctation of the aorta, and abnormally branching central pulmonary arteries) in a 2.2-kg neonate. The three-dimensional model was very useful for designing the surgical procedure – being easy to handle for real and precise simulation of the reparative manoeuvres.
Risk of Parkinson’s disease among patients with herpes zoster: a nationwide longitudinal study
Authors: Cheng Chih-Ming , Bai Ya-Mei , Tsai Chia-Fen , Tsai Shih-Jen , Wu Yi-Hui , Pan Tai-Long , Chen Tzeng-Ji , Chen Mu-Hong
Published: December 2019

Objective

Several studies suggested a potential role of viral infection in the pathophysiology of Parkinson’s disease (PD). However, the association between herpes zoster and PD was not investigated well till now.

Methods

Using the Taiwan National Health Insurance Research Database, 13 083 patients aged ≥45 years with herpes zoster and 52 332 (1:4) age-/sex-matched controls were enrolled between 1998 and 2008 and followed to the end of 2011. Those who developed PD during the follow-up period were identified.

Results

The Cox regression analysis with adjustment of demographic characteristics, health system utilization, and comorbidities demonstrated that patients with herpes zoster had an increased risk (hazard ratio [HR]: 1.80, 95% confidence interval [CI]: 1.43-2.28) of developing PD in later life compared to the control group. Sensitivity tests after excluding the first year (HR: 1.50, 95% CI: 1.16-1.93) and first 2-year (HR: 1.44, 95% CI: 1.10-1.88) observation periods showed consistent results.

Conclusions

Patients with herpes zoster were more likely to develop PD in later life compared to the controls. Additional studies are necessary for validating our results and to clarify the underlying pathophysiology between herpes zoster and PD.
SENSITIVITY, SAFETY, AND THE LAW: A REPLY TO PARDO
Authors: Enoch David , Spectre Levi
Published: December 2019

In a recent paper, Michael Pardo argues that the epistemic property that is legally relevant is the one called Safety, rather than Sensitivity. In the process, he argues against our Sensitivity-related account of statistical evidence. Here we revisit these issues, partly in order to respond to Pardo, and partly in order to make general claims about legal epistemology. We clarify our account, we show how it adequately deals with counterexamples and other worries, we raise suspicions about Safety's value here, and we revisit our general skepticism about the role that epistemological considerations should play in determining legal policy.
The Relation Between Personality and Biomarkers in Sensitivity and Conversion to Alzheimer-Type Dementia
Authors: Duchek Janet M. , Aschenbrenner Andrew J. , Fagan Anne M. , Benzinger Tammie L.S. , Morris John C. , Balota David A.
Published: December 2019

Objectives:

The present study explored relationships among personality, Alzheimer’s disease (AD) biomarkers, and dementia by addressing the following questions: (1) Does personality discriminate healthy aging and earliest detectable stage of AD? (2) Does personality predict conversion from healthy aging to early-stage AD? (3) Do AD biomarkers mediate any observed relationships between personality and dementia status/conversion?

Methods:

Both self- and informant ratings of personality were obtained in a large well-characterized longitudinal sample of cognitively normal older adults (N= 436) and individuals with early-stage dementia (N= 74). Biomarkers included amyloid imaging, hippocampal volume, cerebral spinal fluid (CSF) Aβ42, and CSF tau.

Results:

Higher neuroticism, lower conscientiousness, along with all four biomarkers strongly discriminated cognitively normal controls from early-stage AD individuals. The direct effects of neuroticism and conscientiousness were only mediated by hippocampal volume. Conscientiousness along with all biomarkers predicted conversion from healthy aging to early-stage AD; however, none of the biomarkers mediated the relationship between conscientiousness and conversion. Conscientiousness predicted conversion as strongly as the biomarkers, with the exception of hippocampal volume.

Conclusions:

Conscientiousness and to a lesser extent neuroticism serve as important independent behavioral markers for AD risk.
Evaluating the impact of Chile’s marketing regulation of unhealthy foods and beverages: pre-school and adolescent children’s changes in exposure to food advertising on television
Authors: Dillman Carpentier Francesca R , Correa Teresa , Reyes Marcela , Taillie Lindsey Smith
Published: December 2019

Objective:

To evaluate the effects of Chile’s 2016 regulation restricting child-directed marketing of products high in energy, saturated fats, sodium and sugars on reducing children’s exposure to ‘high-in’ television food advertising.

Design:

Television use by pre-schoolers and adolescents was assessed via surveys in the months prior to implementation and a year after implementation. Hours and channels of television use were linked with the amount of high-in food advertising observed in corresponding content analyses of food advertisements (ads) from popular broadcast and cable channels to estimate changes in exposure to food ads from these channels.

Setting:

Middle-lower and lower-income neighbourhoods in Santiago, Chile.

Participants:

Pre-schoolers (n 879; mothers reporting) and adolescents (n 753; self-reporting).

Results:

Pre-schoolers’ and adolescents’ exposure to high-in food advertising in total decreased significantly by an average of 44 and 58 %, respectively. Exposure to high-in food advertising with child-directed appeals, such as cartoon characters, decreased by 35 and 52 % for pre-schoolers and adolescents, respectively. Decreases were more pronounced for children who viewed more television. Products high in sugars were the most prevalent among the high-in ads seen by children after implementation.

Conclusions:

Following Chile’s 2016 child-directed marketing regulation, children’s exposure to high-in food advertising on popular broadcast and cable television decreased significantly but was not eliminated from their viewing. Later stages of the regulation are expected to eliminate the majority of children’s exposure to high-in food advertising from television.
Effectiveness of a primary care-based group educational intervention in the management of patients with migraine: a randomized controlled trial
Authors: Aguirrezabal Iñaki , Pérez de San Román Maria Soledad , Cobos-Campos Raquel , Orruño Estibalitz , Goicoechea Arturo , Martínez de la Eranueva Rafael , Arroniz Mercedes , Uzquiza Elena
Published: December 2019

Aim:

The aim of this study was to assess the effectiveness of a primary care-based group educational intervention about concepts of pain neuroscience for the management of migraine compared to the routine medical care delivered to patients with this condition.

Background:

The way pain is understood has been radically changed in recent decades, thanks to developments in the field of neuroscience. Thus, migraine may develop as a result of an exaggerated perception of threat that activates the pain neuromatrix, which might be modifiable, from a learning perspective, by adjusting the beliefs and behaviours that favour the onset of an attack.

Methods:

A randomised controlled trial was carried out in five primary care health centres of Vitoria-Gasteiz (Basque Country, Spain). The follow-up period was 12 months. The main outcome measure was the reduction in days lost due to migraine-related disability according to the Migraine Disability Assessment Test (MIDAS) score. Secondary outcome measures included the intensity and frequency of the pain and the number of analgesic drugs taken in the previous three months. A positive response to treatment was considered when the MIDAS score decreased by at least 50% from baseline.

Findings:

Days lost due to migraine-related disability decreased by at least 50% in 68.9% (n= 37) of patients in the intervention group and 34.6% of patients in the control group (n= 18) (P< 0.001). The intensity of the headache [odds ratio (OR) 9.116;P= 0.005] and the medication intake (OR 13.267;P< 0.001) were also significantly reduced with the intervention.

Conclusions:

The provision of suitable information through a group educational intervention delivered in primary care appears to be effective in preventing migraine attacks. Moreover, the intervention could offer a new cost-effective management alternative that seems to reduce the need for pharmacological treatment in patients with migraine.
HUME, KANT, AND FEUERBACH: WHY THE ANTHROPOMORPHIC CRITIQUE REVEALS A FALSE DILEMMA BETWEEN NATURALISTIC ATHEISM AND ANTI-NATURALISTIC THEISM
Authors: Byron Chris , Lopes Jesse
Published: December 2019

In current debates concerning atheism, two positions are considered possible: naturalistic atheism or anti-naturalistic theism. Anti-naturalistic theism is motivated by the failure of naturalism to explain the fundamental nature of reality. We, however, endorse anti-naturalistic atheism by reviving the ‘anthropomorphic critique’, arguing that theism misattributes human traits to the deity. Anti-naturalistic atheism is better suited to refute theists, since it undercuts their appeal to science's inadequacies. We trace the anthropomorphic critique from Hume's Dialogues, through Kant's epistemology, and conclude with its reception in Feuerbach. The anthropomorphic critique is an epistemological – not metaphysical – thesis, hence, it is agnostic about the fundamental nature of reality. Yet it convincingly shows that theism is not a tenable position. In essence, we aim to decouple atheism from naturalism, on the basis of a salient critique in the history of modern philosophy, in order to ameliorate current debates between atheists and theists.
Zum Einfluss von störendem Schülerverhalten im Unterricht auf Leistungsbeurteilungen: Explizite Einschätzungen und experimentelle Befunde
Authors: Krämer Sonja , Zimmermann Friederike
Published: December 2019

Zusammenfassung. Eine wichtige Aufgabe von Lehrkräften ist die Leistungsbeurteilung von Schülerinnen und Schülern. Aktuelle Befunde belegen Verzerrungen der Leistungsbeurteilung durch leistungsirrelevante Faktoren. In diesem Artikel wird störendes Schülerverhalten als weiterer möglicherweise verzerrender Faktor betrachtet. Zunächst untersuchten wir die Bedeutung, die u. a. allgemeinem Sozialverhalten im Unterricht für Fachnoten zugeschrieben wird (N = 99 Lehramtsstudierende). In der experimentellen Hauptstudie (N = 88 Lehramtsstudierende) untersuchten wir mittels eines simulierten Klassenraums, inwieweit Störverhalten in Fachnoten und prozentuale Leistungsbeurteilungen einfließt und ob der Klassenkomposition im Störverhalten eine moderierende Rolle zukommt. Im Mittel wurden Fachnoten neben schriftlichen und mündlichen Fachleistungen (53 %) sowie fachbezogenem Unterrichtsverhalten (31 %) zu 16 % aus allgemeinem Disziplin- und Sozialverhalten im Unterricht zusammengesetzt. Experimentell zeigte sich ein negativer Einfluss von Störverhalten auf Fachnoten und prozentuale Leistungsbeurteilungen jeweils unter Kontrolle der tatsächlich gezeigten Leistungen. Nicht signifikant war die Tendenz zu größeren Effekten des Störverhaltens, je weniger Kinder im Klassenraum dieses Verhalten zeigten.
The Tides They Are A‐Changin': A Comprehensive Review of Past and Future Nonastronomical Changes in Tides, Their Driving Mechanisms, and Future Implications
Authors: Haigh Ivan D. , Pickering Mark D. , Green J. A. Mattias , Arbic Brian K. , Arns Arne , Dangendorf Sönke , Hill David F. , Horsburgh Kevin , Howard Tom , Idier Déborah , Jay David A. , Jänicke Leon , Lee Serena B. , Müller Malte , Schindelegger Michael , Talke Stefan A. , Wilmes Sophie‐Berenice , Woodworth Philip L.
Published: December 2019

Scientists and engineers have observed for some time that tidal amplitudes at many locations are shifting considerably due to nonastronomical factors. Here we review comprehensively these important changes in tidal properties, many of which remain poorly understood. Over long geological time scales, tectonic processes drive variations in basin size, depth, and shape and hence the resonant properties of ocean basins. On shorter geological time scales, changes in oceanic tidal properties are dominated by variations in water depth. A growing number of studies have identified widespread, sometimes regionally coherent, positive, and negative trends in tidal constituents and levels during the 19th, 20th, and early 21st centuries. Determining the causes is challenging because a tide measured at a coastal gauge integrates the effects of local, regional, and oceanic changes. Here, we highlight six main factors that can cause changes in measured tidal statistics on local scales and a further eight possible regional/global driving mechanisms. Since only a few studies have combined observations and models, or modeled at a temporal/spatial resolution capable of resolving both ultralocal and large‐scale global changes, the individual contributions from local and regional mechanisms remain uncertain. Nonetheless, modeling studies project that sea level rise and climate change will continue to alter tides over the next several centuries, with regionally coherent modes of change caused by alterations to coastal morphology and ice sheet extent. Hence, a better understanding of the causes and consequences of tidal variations is needed to help assess the implications for coastal defense, risk assessment, and ecological change.
A Whittaker Biome‐Based Framework to Account for the Impact of Climate Change on Catchment Behavior
Authors: Deshmukh Ankit , Singh Riddhi
Published: December 2019

Rainfall‐runoff models are often used to simulate the impact of long‐term climate change on future water availability. A common assumption in most modeling frameworks is that catchment's hydrologically relevant characteristics, represented via model parameters, remain constant. However, several studies present evidence on the contrary and suggest potential biases in estimates of future streamflow due to this assumption. Regardless, there is a lack of modeling frameworks that account for the possible impact of climate on catchment's characteristics. To change model parameters with climate, we propose a method based on the Whittaker biome plot that relates biome type to the climatic setting of a catchment. We compare estimates of catchment's vulnerability to climate change obtained from fixed and changing parameters. Our analysis spanning 83 catchments across the conterminous United States shows that considering changes in catchment's representative parameters with climate significantly alters the estimated vulnerability to climate change for a majority of catchments.
Quantifying Climate and Catchment Control on Hydrological Drought in the Continental United States
Authors: Konapala Goutam , Mishra Ashok
Published: December 2019

The evolution of hydrological drought events is a result of complex (nonlinear) interactions between climate and catchment processes. To investigate such nonlinear relationship, we integrated a machine learning modeling framework based on the random forest (RF) algorithms with an interpretation framework to quantify the role of climate and catchment controls on hydrological drought. More particularly, our framework interprets a built RF machine‐learning model to identify dominant variables and visualize their functional dependence and interaction effects on hydrological drought characteristics utilizing concepts of minimal depth, interactive depth, and partial dependence. We test our proposed modeling framework based on a set of 652 continental United States catchments with minimal human interference for a period of 1979–2010. Application of this framework indicated presence of three distinct drought regimes, which includes, Regime 1: droughts with longer duration, less frequent and lesser intensity; Regime 2: droughts with moderate duration, moderate frequency, and moderate intensity; and Regime 3: droughts with shorter duration, more frequent, and more intense. RF algorithm was able to accurately model the drought characteristics (intensity, duration, and number of events) for all the three drought regimes as a function of selected variables. It was observed that the type of dominant variables as well as their nonlinear functional relationship with hydrological droughts characteristics can vary between three selected regimes. Our interpretation framework indicated that catchment characteristics have a significant role in controlling the hydrologic drought for catchments (regime 1), whereas both climate and catchment characteristics control hydrological drought in regimes 2 and 3.
Spatial Evaluation and Assimilation of SMAP, SMOS, and ASCAT Satellite Soil Moisture Products Over Africa Using Statistical Techniques
Authors: Mousa B. G. , Shu Hong
Published: December 2019

The limited number of in situ stations of surface soil moisture (SM) in Africa creates a shortage in the validation of SM satellite products. Therefore, this study investigates the performance of Soil Moisture Active Passive (SMAP), Soil Moisture and Ocean Salinity (SMOS), and the H113 product from the Advanced Scatterometer (ASCAT) on the regional scale over Africa through these goals: (1) validate of satellite SM products against in situ stations and SM data from the ERA‐Interim atmospheric reanalysis product, (2) study the spatiotemporal variability of satellite SM products on the regional scale, and (3) evaluate the regional scale error patterns and investigate regions where the assimilation of satellites SM data may add improvement to ERA‐Interim. Standard statistical metrics, hovmöller diagrams, and the Triple Collocation (TC) model were used to achieve these goals. Land cover data, Normalized Difference Vegetation Index, and precipitation data were used to interpret results. The validation results based on statistical metrics and TC indicate that over the desert and shrub, passive products showed better performance than ASCAT, while over moderate vegetation areas (grassland), SMAP had the best among SM products. Over high densely vegetated regions, ASCAT showed a high comparatively performance than passive products. The potential regions for assimilation of satellite data sets were selected to be over savannas and grassland regions for ASCAT, and over shrub and grassland regions for SMAP. In particular, SMAP and ASCAT SM data sets are considered more stable than SMOS for data assimilation and capturing the spatial distribution of SM on the regional scale over Africa.
An Explicit IMF B Dependence on Solar Wind‐Magnetosphere Coupling
Authors: Reistad J. P. , Laundal K. M. , Ohma A. , Moretto T. , Milan S. E.
Published: December 2019

Presently, all empirical coupling functions quantifying the solar wind—magnetosphere energy—or magnetic flux conversion assume that the coupling is independent of the sign of the dawn‐dusk component (B
) of the Interplanetary Magnetic Field (IMF). In this paper we present observations strongly suggesting an explicit IMF B
effect on the solar wind‐magnetosphere coupling. When the Earth's dipole is tilted in the direction corresponding to northern winter, positive IMF B
is found to on average lead to a larger polar cap than when IMF B
is negative during otherwise similar conditions. This explicit IMF B
effect is found to reverse when the Earth's dipole is inclined in the opposite direction (northern summer) and is consistently observed from both hemispheres. We interpret the different responses of the polar cap size due to the sign of IMF B
to likely be a result of differences in the dayside reconnection rate.
Jovian UV Aurora's Response to the Solar Wind: Hisaki EXCEED and Juno Observations
Authors: Kita H. , Kimura T. , Tao C. , Tsuchiya F. , Murakami G. , Yamazaki A. , Yoshioka K. , Ebert R.W. , Wilson R.J. , Allegrini F. , Clark G. , Connerney J. E. P. , Gladstone G. R. , Yoshikawa I. , Fujimoto M.
Published: December 2019

We summarize Jupiter's ultraviolet (UV) auroral response to solar wind dynamic pressure variations during Juno's approach to Jupiter in 2016. The response time of Jupiter's aurora to external drivers has thus far been unknown owing to a sparsity of upstream in situ solar wind measurements. Combining the Juno solar wind observations with continuous UV aurora data obtained by Hisaki EXCEED (Extreme Ultraviolet Spectroscope for Exospheric Dynamics) and Juno UV spectrograph, the UV aurora brightenings in response to three major shock arrivals showed time lags of 10–15 hr. These time lags are longer than the time required for ballistic propagation of the shocks by the solar wind. In addition to that puzzle, while an enhancement in the UV auroral power was observed with an increase in dynamic pressure to ~0.03 nPa, no associated brightening was observed with a dynamic pressure elevation of >0.1 nPa. These imply that internal magnetospheric aspects need to be taken into consideration to fully resolve the issue.
Significantly Enhanced Aerosol CCN Activity and Number Concentrations by Nucleation‐Initiated Haze Events: A Case Study in Urban Beijing
Authors: Zhang Fang , Ren Jingye , Fan Tianyi , Chen Lu , Xu Weiqi , Sun Yele , Zhang Renyi , Liu Jieyao , Jiang Sihui , Jin Xiaoai , Wu Hao , Li Shangze , Cribb Maureen C. , Li Zhanqing
Published: December 2019

The evolution of haze, involving multiple processes such as nucleation, coagulation, and condensation, may exert complex effects on aerosols' cloud condensation nuclei (CCN) activity and number concentration (NCCN). Based on field campaigns carried out in the winters of 2014 and 2016 in Beijing, we show that NCCN was significantly enhanced by the evolution of haze, substantially driven by the nucleation process (or new particle formation). The enhancement factor of NCCN by such nucleation‐initiated haze episodes, E_NCCN, defined as the ratio of NCCN after haze events to NCCN prior to haze events, ranged from 2.2 to 6.5 at a supersaturation (S) = 0.76% and from 4.2 to 17.3 at S = 0.23%, the magnitude of which partially depends on the severity of the haze event. The enhancements are much greater than those previously observed and those from model simulations of contribution from new particle formation. This suggests that CCN sources from new particle formation may be underestimated, needing reevaluation in polluted environments where the subsequent growth of newly formed particles can last 2–3 days, yielding more CCN‐sized particles. We further quantified that the changes in particle size and composition during the nucleation‐initiated evolution of haze are responsible for > 80% and 12–20%, respectively, of the enhancement in CCN activity. The changes in particle composition had a limited impact because most of the ambient particles were already hydrophilic, with hygroscopic parameters of 0.2–0.65.
Density Structure of the Rümker Region in the Northern Oceanus Procellarum: Implications for Lunar Volcanism and Landing Site Selection for the Chang'E‐5 Mission
Authors: Chisenga Chikondi , Yan Jianguo , Zhao Jiannan , Atekwana Estella A. , Steffen Rebekka
Published: December 2019

The Rümker region, located in the northern Oceanus Procellarum, is the candidate landing region for China's Chang'E‐5 lunar sample‐return mission. The area is geologically complex and known for its volcanic activity. To understand the volcanism of the Rümker region, we investigate the 3D crustal density structure of this region using Bouguer gravity data from the Gravity Recovery and Interior Laboratory mission. We applied derivative filters and a 3D density inversion to resolve both the shallow and deep structures in the subsurface. Results indicate that the Rümker region exhibits different modes of emplacement. The Mons Rümker volcanic complex is fed by an intrusion‐like structure at a depth of ~6–18 km and contains high‐density basaltic materials of >3,000 kg/m3. A quasi‐circular mass anomaly that was identified in a previous study with high gravity amplitude (~130 mGal) and high density (> 3,000 kg/m3) was also documented in the study region. The quasi‐circular mass anomaly feature represents deeper and thicker buried mare basalts with a bowl‐shaped geometry formed by an impact event. Based on our geophysical analysis, we propose four landing site candidates for the Chang'E‐5 mission that satisfy the geological and geophysical criteria for maximum scientific return.
Insights Into Preferential Flow Snowpack Runoff Using Random Forest
Authors: Avanzi Francesco , Johnson Ryan Curtis , Oroza Carlos A. , Hirashima Hiroyuki , Maurer Tessa , Yamaguchi Satoru
Published: December 2019

Using 12 seasons of data from a multicompartment snow lysimeter and a statistical learning algorithm (Random Forest), we investigated to what extent preferential flow snowpack runoff can be predicted from concurrent weather and snow conditions, as well as the relative importance of factors affecting this process. We found that preferential flow development can be partially predicted based on concurrent weather and snow conditions. In this case study where snow is generally wet and coarse, the most important predictors of standard and maximum deviation from mean spatial snowpack runoff are related to weather inputs and their interaction with the snowpack (rainfall, longwave radiation, and snow‐surface temperature) and to more season‐specific snow properties (number of macroscopic snow layers and snowfall days to date, the latter being a feature we included to account for microstructural heterogeneity developing at smaller scales than macroscopic layers). This combination between weather and season‐specific snow factors and the fact that several of these important features are correlated with other processes result in significant seasonal variability of the Random Forest algorithm's accuracy. All versions of the Random Forest algorithm underestimated seasonal peaks in preferential flow, which points to these peaks being either undersampled in our data set or caused by poorly understood redistribution processes acting at larger spatial scales than the size of our multicompartment lysimeter (e.g., dimples).
Host–microbiota interactions in rheumatoid arthritis
Authors: Maeda Yuichi , Takeda Kiyoshi
Published: December 2019

The gut microbiota has been proposed to be an important environmental factor in the development of rheumatoid arthritis (RA). Here, we review a growing body of evidence from human and animal studies that supports the hypothesis that intestinal microbiota play a role in RA. Previous studies from we and others showed an altered composition of the microbiota in early RA patients. A recent study demonstrated that Prevotella species are dominant in the intestine of patients in the preclinical stages of RA. In addition, Prevotella-dominated microbiota isolated from RA patients contributes to the development of Th17 cell-dependent arthritis in SKG mice. Moreover, it was reported that periodontal bacteria correlates with the pathogenesis of RA. In this review, we discuss the link between oral bacteria and the development of arthritis. However, many questions remain to be elucidated in terms of molecular mechanisms for the involvement of intestinal and oral microbiota in RA pathogenesis.
TGIF2 promotes the progression of lung adenocarcinoma by bridging EGFR/RAS/ERK signaling to cancer cell stemness
Authors: Du Renle , Shen Wenzhi , Liu Yi , Gao Wenjuan , Zhou Wei , Li Jun , Zhao Shuangtao , Chen Chong , Chen Yanan , Liu Yanhua , Sun Peiqing , Xiang Rong , Shi Yi , Luo Yunping
Published: December 2019

TGF-β-induced factor homeobox 2 (TGIF2) is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions. Aberrant expression of TGIF family proteins has been observed in several cancers, including ovarian, esophageal, and colorectal cancers. Here, we report that TGIF2 mediates the EGFR–RAS–ERK signaling pathway to enhance the stemness of lung adenocarcinoma (LUAD) cells and, therefore, promote the progression and metastasis of LUAD. We found that high TGIF2 expression was closely correlated with tumor growth, lymph node metastasis, and survival of patients with LUAD. Mice bearing TGIF2-silenced H1299 xenografts developed smaller tumors and fewer lung metastases. Importantly, silencing TGIF2 decreased the cancer stem cell (CSC)-like properties in A549 and H1299 cells. Furthermore, we identified that TGIF2 binding to the OCT4 promoter promotes its expression. In both LUAD cells and in vivo LUAD mouse models, we revealed that EGFR–RAS–ERK signaling phosphorylated TGIF2 and increased its stability, which was important for TGIF2-promoted LUAD stemness since phosphorylation-deficient TGIF2 mutants lost these functions. Thus, our study revealed that an important factor, TGIF2, bridges EGFR signaling to the CSC characteristics of LUAD cells, which can be utilized as an effective target for LUAD therapy.
KAT6B-related disorder in a patient with a novel frameshift variant (c.3925dup)
Authors: Hamaguchi Yo , Aoki Mikihiro , Watanabe Satoshi , Mishima Hiroyuki , Yoshiura Koh-ichiro , Moriuchi Hiroyuki , Dateki Sumito
Published: December 2019

Heterozygous pathogenic variants in the KAT6B gene, which encodes lysine acetyltransferase 6B, have been identified in patients with congenital rare disorders, including genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome. Herein, we report another Japanese patient with a KAT6B-related disorder and a novel de novo heterozygous variant in exon 18 of KAT6B [c.3925dup, p.(Glu1309fs*33)], providing further evidence that truncating variants in exon 17 and in the proximal region of exon 18 are associated with genitopatellar syndrome-like phenotypes.
Rap1 regulates hematopoietic stem cell survival and affects oncogenesis and response to chemotherapy
Authors: Khattar Ekta , Maung Kyaw Ze Ya , Chew Chen Li , Ghosh Arkasubhra , Mok Michelle Meng Huang , Lee Pei , Zhang Jun , Chor Wei Hong Jeff , Cildir Gökhan , Wang Chelsia Qiuxia , Mohd-Ismail Nur Khairiah , Chin Desmond Wai Loon , Lee Soo Chin , Yang Henry , Shin Yong-Jae , Nam Do-Hyun , Chen Liming , Kumar Alan Prem , Deng Lih Wen , Ikawa Masahito , Gunaratne Jayantha , Osato Motomi , Tergaonkar Vinay
Published: December 2019

Increased levels and non-telomeric roles have been reported for shelterin proteins, including RAP1 in cancers. Herein using Rap1 null mice, we provide the genetic evidence that mammalian Rap1 plays a major role in hematopoietic stem cell survival, oncogenesis and response to chemotherapy. Strikingly, this function of RAP1 is independent of its association with the telomere or with its known partner TRF2. We show that RAP1 interacts with many members of the DNA damage response (DDR) pathway. RAP1 depleted cells show reduced interaction between XRCC4/DNA Ligase IV and DNA-PK, and are impaired in DNA Ligase IV recruitment to damaged chromatin for efficient repair. Consistent with its role in DNA damage repair, RAP1 loss decreases double-strand break repair via NHEJ in vivo, and consequently reduces B cell class switch recombination. Finally, we discover that RAP1 levels are predictive of the success of chemotherapy in breast and colon cancer.
An unexpected N-dependence in the viscosity reduction in all-polymer nanocomposite
Authors: Chen Tao , Zhao Huan-Yu , Shi Rui , Lin Wen-Feng , Jia Xiang-Meng , Qian Hu-Jun , Lu Zhong-Yuan , Zhang Xing-Xing , Li Yan-Kai , Sun Zhao-Yan
Published: December 2019

Adding small nanoparticles (NPs) into polymer melt can lead to a non-Einstein-like decrease in viscosity. However, the underlying mechanism remains a long-standing unsolved puzzle. Here, for an all-polymer nanocomposite formed by linear polystyrene (PS) chains and PS single-chain nanoparticles (SCNPs), we perform large-scale molecular dynamics simulations and experimental rheology measurements. We show that with a fixed (small) loading of the SCNP, viscosity reduction (VR) effect can be largely amplified with an increase in matrix chain length$$N$$N, and that the system with longer polymer chains will have a larger VR. We demonstrate that such$$N$$N-dependent VR can be attributed to the friction reduction experienced by polymer segment blobs which have similar size and interact directly with these SCNPs. A theoretical model is proposed based on the tube model. We demonstrate that it can well describe the friction reduction experienced by melt polymers and the VR effect in these composite systems.
LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients
Authors: Ysselstein Daniel , Nguyen Maria , Young Tiffany J. , Severino Alex , Schwake Michael , Merchant Kalpana , Krainc Dimitri
Published: December 2019

Mutations in LRRK2 and GBA1 are common genetic risk factors for Parkinson’s disease (PD) and major efforts are underway to develop new therapeutics that target LRRK2 or glucocerebrosidase (GCase). Here we describe a mechanistic and therapeutic convergence of LRRK2 and GCase in neurons derived from patients with PD. We find that GCase activity was reduced in dopaminergic (DA) neurons derived from PD patients with LRRK2 mutations. Inhibition of LRRK2 kinase activity results in increased GCase activity in DA neurons with either LRRK2 or GBA1 mutations. This increase is sufficient to partially rescue accumulation of oxidized dopamine and alpha-synuclein in PD patient neurons. We have identified the LRRK2 substrate Rab10 as a key mediator of LRRK2 regulation of GCase activity. Together, these results suggest an important role of mutant LRRK2 as a negative regulator of lysosomal GCase activity.
Global urban expansion offsets climate-driven increases in terrestrial net primary productivity
Authors: Liu Xiaoping , Pei Fengsong , Wen Youyue , Li Xia , Wang Shaojian , Wu Changjiang , Cai Yiling , Wu Jianguo , Chen Jun , Feng Kuishuang , Liu Junguo , Hubacek Klaus , Davis Steven J. , Yuan Wenping , Yu Le , Liu Zhu
Published: December 2019

The global urbanization rate is accelerating; however, data limitations have far prevented robust estimations of either global urban expansion or its effects on terrestrial net primary productivity (NPP). Here, using a high resolution dataset of global land use/cover (GlobeLand30), we show that global urban areas expanded by an average of 5694 km2 per year between 2000 and 2010. The rapid urban expansion in the past decade has in turn reduced global terrestrial NPP, with a net loss of 22.4 Tg Carbon per year (Tg C year−1). Although small compared to total terrestrial NPP and fossil fuel carbon emissions worldwide, the urbanization-induced decrease in NPP offset 30% of the climate-driven increase (73.6 Tg C year−1) over the same period. Our findings highlight the urgent need for global strategies to address urban expansion, enhance natural carbon sinks, and increase agricultural productivity.
New isotope constraints on the Mg oceanic budget point to cryptic modern dolomite formation
Authors: Shalev Netta , Bontognali Tomaso R. R. , Wheat C. Geoffrey , Vance Derek
Published: December 2019

The oceanic magnesium budget is important to our understanding of Earth’s carbon cycle, because similar processes control both (e.g., weathering, volcanism, and carbonate precipitation). However, dolomite sedimentation and low-temperature hydrothermal circulation remain enigmatic oceanic Mg sinks. In recent years, magnesium isotopes (δ26Mg) have provided new constraints on the Mg cycle, but the lack of data for the low-temperature hydrothermal isotope fractionation has hindered this approach. Here we present new δ26Mg data for low-temperature hydrothermal fluids, demonstrating preferential 26Mg incorporation into the oceanic crust, on average by εsolid-fluid ≈ 1.6‰. These new data, along with the constant seawater δ26Mg over the past ~20 Myr, require a significant dolomitic sink (estimated to be 1.5–2.9 Tmol yr−1; 40–60% of the oceanic Mg outputs). This estimate argues strongly against the conventional view that dolomite formation has been negligible in the Neogene and points to the existence of significant hidden dolomite formation.
Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness
Authors: Hulpia Fabian , Mabille Dorien , Campagnaro Gustavo D. , Schumann Gabriela , Maes Louis , Roditi Isabel , Hofer Anders , de Koning Harry P. , Caljon Guy , Van Calenbergh Serge
Published: December 2019

African trypanosomiasis is a disease caused by Trypanosoma brucei parasites with limited treatment options. Trypanosoma is unable to synthesize purines de novo and relies solely on their uptake and interconversion from the host, constituting purine nucleoside analogues a potential source of antitrypanosomal agents. Here we combine structural elements from known trypanocidal nucleoside analogues to develop a series of 3’-deoxy-7-deazaadenosine nucleosides, and investigate their effects against African trypanosomes. 3’-Deoxytubercidin is a highly potent trypanocide in vitro and displays curative activity in animal models of acute and CNS-stage disease, even at low doses and oral administration. Whole-genome RNAi screening reveals that the P2 nucleoside transporter and adenosine kinase are involved in the uptake and activation, respectively, of this analogue. This is confirmed by P1 and P2 transporter assays and nucleotide pool analysis. 3’-Deoxytubercidin is a promising lead to treat late-stage sleeping sickness.
Biogenesis and functions of aminocarboxypropyluridine in tRNA
Authors: Takakura Mayuko , Ishiguro Kensuke , Akichika Shinichiro , Miyauchi Kenjyo , Suzuki Tsutomu
Published: December 2019

Transfer (t)RNAs contain a wide variety of post-transcriptional modifications, which play critical roles in tRNA stability and functions. 3-(3-amino-3-carboxypropyl)uridine (acp3U) is a highly conserved modification found in variable- and D-loops of tRNAs. Biogenesis and functions of acp3U have not been extensively investigated. Using a reverse-genetic approach supported by comparative genomics, we find here that the Escherichia coli yfiP gene, which we rename tapT (tRNA aminocarboxypropyltransferase), is responsible for acp3U formation in tRNA. Recombinant TapT synthesizes acp3U at position 47 of tRNAs in the presence of S-adenosylmethionine. Biochemical experiments reveal that acp3U47 confers thermal stability on tRNA. Curiously, the ΔtapT strain exhibits genome instability under continuous heat stress. We also find that the human homologs of tapT, DTWD1 and DTWD2, are responsible for acp3U formation at positions 20 and 20a of tRNAs, respectively. Double knockout cells of DTWD1 and DTWD2 exhibit growth retardation, indicating that acp3U is physiologically important in mammals.
Stereodivergent assembly of tetrahydro-γ-carbolines via synergistic catalytic asymmetric cascade reaction
Authors: Xu Shi-Ming , Wei Liang , Shen Chong , Xiao Lu , Tao Hai-Yan , Wang Chun-Jiang
Published: December 2019

Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.
Dendritic inhibition differentially regulates excitability of dentate gyrus parvalbumin-expressing interneurons and granule cells
Authors: Elgueta Claudio , Bartos Marlene
Published: December 2019

Fast-spiking parvalbumin-expressing interneurons (PVIs) and granule cells (GCs) of the dentate gyrus receive layer-specific dendritic inhibition. Its impact on PVI and GC excitability is, however, unknown. By applying whole-cell recordings, GABA uncaging and single-cell-modeling, we show that proximal dendritic inhibition in PVIs is less efficient in lowering perforant path-mediated subthreshold depolarization than distal inhibition but both are highly efficient in silencing PVIs. These inhibitory effects can be explained by proximal shunting and distal strong hyperpolarizing inhibition. In contrast, GC proximal but not distal inhibition is the primary regulator of their excitability and recruitment. In GCs inhibition is hyperpolarizing along the entire somato-dendritic axis with similar strength. Thus, dendritic inhibition differentially controls input-output transformations in PVIs and GCs. Dendritic inhibition in PVIs is suited to balance PVI discharges in dependence on global network activity thereby providing strong and tuned perisomatic inhibition that contributes to the sparse representation of information in GC assemblies.
Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway
Authors: Chen Sisi , Wang Qiang , Yu Hao , Capitano Maegan L. , Vemula Sasidhar , Nabinger Sarah C. , Gao Rui , Yao Chonghua , Kobayashi Michihiro , Geng Zhuangzhuang , Fahey Aidan , Henley Danielle , Liu Stephen Z. , Barajas Sergio , Cai Wenjie , Wolf Eric R. , Ramdas Baskar , Cai Zhigang , Gao Hongyu , Luo Na , Sun Yang , Wong Terrence N. , Link Daniel C. , Liu Yunlong , Boswell H. Scott , Mayo Lindsey D. , Huang Gang , Kapur Reuben , Yoder Mervin C. , Broxmeyer Hal E. , Gao Zhonghua , Liu Yan
Published: December 2019

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.
No evidence for high-pressure melting of Earth’s crust in the Archean
Authors: Smithies Robert H. , Lu Yongjun , Johnson Tim E. , Kirkland Christopher L. , Cassidy Kevin F. , Champion David C. , Mole David R. , Zibra Ivan , Gessner Klaus , Sapkota Jyotindra , De Paoli Matthew C. , Poujol Marc
Published: December 2019

Much of the present-day volume of Earth’s continental crust had formed by the end of the Archean Eon, 2.5 billion years ago, through the conversion of basaltic (mafic) crust into sodic granite of tonalite, trondhjemite and granodiorite (TTG) composition. Distinctive chemical signatures in a small proportion of these rocks, the so-called high-pressure TTG, are interpreted to indicate partial melting of hydrated crust at pressures above 1.5 GPa (>50 km depth), pressures typically not reached in post-Archean continental crust. These interpretations significantly influence views on early crustal evolution and the onset of plate tectonics. Here we show that high-pressure TTG did not form through melting of crust, but through fractionation of melts derived from metasomatically enriched lithospheric mantle. Although the remaining, and dominant, group of Archean TTG did form through melting of hydrated mafic crust, there is no evidence that this occurred at depths significantly greater than the ~40 km average thickness of modern continental crust.
Light-induced evaporative cooling of holes in the Hubbard model
Authors: Werner Philipp , Eckstein Martin , Müller Markus , Refael Gil
Published: December 2019

An elusive goal in the field of driven quantum matter is the induction of long-range order. Here, we propose a mechanism based on light-induced evaporative cooling of holes in a correlated fermionic system. Since the entropy of a filled narrow band grows rapidly with hole doping, the isentropic transfer of holes from a doped Mott insulator to such a band results in a drop of temperature. Strongly correlated Fermi liquids and symmetry-broken states could thus be produced by dipolar excitations. Using nonequilibrium dynamical mean field theory, we show that suitably designed chirped pulses may realize this cooling effect. In particular, we demonstrate the emergence of antiferromagnetic order in a system which is initially in a weakly correlated state above the maximum Néel temperature. Our work suggests a general strategy for inducing strong correlation phenomena in periodically modulated atomic gases in optical lattices or light-driven materials.
miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
Authors: Scherm Martin G. , Serr Isabelle , Zahm Adam M. , Schug Jonathan , Bellusci Saverio , Manfredini Rossella , Salb Victoria K. , Gerlach Katharina , Weigmann Benno , Ziegler Anette-Gabriele , Kaestner Klaus H. , Daniel Carolin
Published: December 2019

In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.