bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivariate credibility modelling for usage-based motor insurance pricing with behavioural data
Authors: Denuit Michel , Guillen Montserrat , Trufin Julien
Published: February 2019

Pay-how-you-drive (PHYD) or usage-based (UB) systems for automobile insurance provide actuaries with behavioural risk factors, such as the time of the day, average speeds and other driving habits. These data are collected while the contract is in force with the help of telematic devices installed in the vehicle. They thus fall in the category of a posteriori information that becomes available after contract initiation. For this reason, they must be included in the actuarial pricing by means of credibility updating mechanisms instead of being incorporated in the score as ordinary a priori observable features. This paper proposes the use of multivariate mixed models to describe the joint dynamics of telematics data and claim frequencies. Future premiums, incorporating past experience can then be determined using the predictive distribution of claim characteristics given past history. This approach allows the actuary to deal with the variety of situations encountered in insurance practice, ranging from new drivers without telematics record to contracts with different seniority and drivers using their vehicle to different extent, generating varied volumes of telematics data.
“Safe areas”: The international legal framework
Authors: Gillard Emanuela-Chiara
Published: February 2019

In recent years there have been repeated calls for the establishment of so-called “safe areas” to protect civilians from the effects of hostilities in a number of contexts. The present article presents the international law framework relevant to the establishment and operation of such areas: the provisions of international humanitarian law on protected zones; the rules regulating resort to armed force, Security Council authorization and mandates for the establishment of such areas by multinational forces in the absence of agreement between belligerents; and the refugee and international human rights issues raised by such zones. Using the example of the “protection of civilians sites” in South Sudan, the article then highlights some of the operational challenges raised by safe areas. It concludes with some reflections on how to enhance the likelihood that belligerents will establish such protected zones in the future.
Postmodernity's Unexpected Arrival: 1968 as Breakdown in Geoculture
Authors: Derluguian Georgi M.
Published: February 2019

The year 1968 marked the apogee of High Modernity as expressed in the Old Left programs of either social-democratic reform or communist revolution. The New Left critics, in both east and west, demanded more of the same: a more “humane” socialism or less bureaucratic capitalism. Their demands, however, exceeded the limits of redistribution under each political system. Both western and eastern European power elites eventually found escape from state confines in globalization and neoliberalism. The exhaustion of modernity projects caused lasting fragmentation in the fields of ideology, culture, and politics previously structured by powerful national states and large political movements. This condition can be called “post-modern” in the simplest sense of following the breakdown of modernity without any new quality. The ex-Soviet countries serve as richly-nuanced examples of historical transformation from 1968 to 1989 and into the present morass.
First Report of Kochia (Bassia scoparia) with Cross-Resistance to Dicamba and Fluroxypyr in Western Kansas
Authors: Kumar Vipan , Currie Randall S. , Jha Prashant , Stahlman Phillip W.
Published: February 2019

Evolution and rapid spread of herbicide-resistant (HR) kochia has become a significant challenge for growers in the U.S. Great Plains. The main objectives of this research were to confirm and characterize the response of putative auxinic HR (Aux-HR) kochia accessions (designated as KS-4A, KS-4D, KS-4H, KS-10A, KS-10-G, and KS-10H) collected from two different corn fields near Garden City, KS, to dicamba and fluroxypyr and to determine the EPSPS gene copy number to detect whether those accessions were also resistant to glyphosate. Single-dose experiments indicated that putative Aux-HR kochia accessions had 78% to 100% and 85% to 100% survivors when treated with dicamba (560 g ae ha−1) and fluroxypyr (235 g ae ha−1), respectively. Whole-plant dicamba dose–response studies revealed that the selected Aux-HR accessions had 2.9- to 15.1- and 3.1- to 9.4-fold resistance to dicamba relative to two susceptible accessions (MT-SUS and KS-SUS). In a separate fluroxypyr dose–response experiment, the selected Aux-HR accessions also exhibited 3.8- to 7.3- and 3.0- to 8.6-fold resistance to fluroxypyr on the basis of shoot fresh and dry weight responses, respectively. The confirmed Aux-HR kochia accessions also had 3 to 13 EPSPS gene copies relative to MT-SUS and KS-SUS accessions (each with 1 EPSPS gene copy). These results suggest that the putative Aux-HR kochia accessions from Kansas had developed moderate to high levels of cross-resistance to dicamba and fluroxypyr and low to high levels of resistance to glyphosate. This is the first confirmation of kochia accessions with cross-resistance to dicamba and fluroxypyr in Kansas. Growers should use diverse kochia control programs, including the proper use of dicamba and fluroxypyr stewardship, use of cover crops, occasional tillage, diversified crop rotations, and alternative effective herbicides to prevent further evolution and spread of Aux-HR kochia on their fields.
Integrating Behavioral Science With Mobile (mHealth) Technology to	Optimize Health Behavior Change Interventions
Authors: Walsh Jane C. , Groarke Jenny M.
Published: February 2019

Abstract. Recent rapid advances in technology have provided us with a golden opportunity to effect change in health-related outcomes for chronic disease by employing digital technologies to encourage and support behavior change to promote and maintain health. Behavior change theories are the bedrock to developing evidence-based mHealth interventions. Digital technologies enable researchers to empirically test behavioral theories in “real-world” contexts using behavior change techniques ( Hekler, Michie, et al., 2016 ). According to the European Commission (2014) among the world’s population of 7 billion, there are over 5 billion mobile devices and over 90% of the users have their mobile device near them 24 hr a day. This provides a huge opportunity for behavior change and one that health psychologists have already begun to address. However, while a novel and exciting area of research, many early studies have been criticized for lacking a strong evidence base in both design and implementation. The European Commission conducted a public consultation in 2016 on the issues surrounding the use of mHealth tools (e.g., apps) and found a lack of global standards was a significant barrier. Recently, the World Health Organization (WHO) mHealth Technical Evidence Review Group developed the mHealth evidence reporting and assessment (mERA) checklist for specifying the content of mHealth interventions. Health psychologists play a key role in developing mHealth interventions, particularly in the management of chronic disease. This article discusses current challenges facing widespread integration of mobile technology into self-management of chronic disease including issues around security and regulation, as well as investigating mechanisms to overcoming these barriers.
Treating Illness Distress in Chronic Illness
Authors: Hudson Joanna L. , Moss-Morris Rona
Published: February 2019

Abstract. Cognitive-behavioral therapy (CBT) is an evidence-based treatment for depression and anxiety recommended for those with and without physical long-term conditions (LTCs). However, the cognitive-behavioral mechanisms targeted in CBT protocols are based on empirical cognitive-behavioral models of depression and anxiety. In these models, emotions are conceptualized as primary mental health disorders rather than a reaction to the challenges of living with a LTC commonly referred to as illness distress. This raises important clinical questions with theoretical implications. These include: Is the experience of illness distress conceptually distinct from primary mental health diagnoses of anxiety and mood disorder? Are there unique cognitive-behavioral mechanisms related to illness self-management, which should be incorporated into CBT for illness distress? How can illness self-management interventions be embedded within existing CBT protocols for depression and anxiety? To address these questions, we distinguish between primary mental health disorders and illness distress conceptually and explore the impact of this on tailored treatment planning and engagement. Second, we review how health psychology theoretical models can help to inform modifications of existing cognitive-behavioral treatments for anxiety and depression to better support the needs of individuals experiencing illness distress. Third, we provide examples of how to embed processes important for illness self-management including, illness cognitions and adherence, alongside existing CBT techniques. The mechanisms and intervention techniques discussed may help to inform the development of integrated CBT treatments for illness distress for future hypothesis testing in comparative effectiveness trials.
The Intraseasonal Dynamics of the Mixed Layer Pump in the Subpolar North Atlantic Ocean: A Biogeochemical‐Argo Float Approach
Authors: Lacour L. , Briggs N. , Claustre H. , Ardyna M. , Dall'Olmo G.
Published: February 2019

The detrainment of organic matter from the mixed layer, a process known as the mixed layer pump (ML pump), has long been overlooked in carbon export budgets. Recently, the ML pump has been investigated at seasonal scale and appeared to contribute significantly to particulate organic carbon export to the mesopelagic zone, especially at high latitudes where seasonal variations of the mixed layer depth are large. However, the dynamics of the ML pump at intraseasonal scales remains poorly known, mainly because the lack of observational tools suited to studying such dynamics. In the present study, using a dense network of autonomous profiling floats equipped with bio‐optical sensors, we captured widespread episodic ML pump‐driven export events, during the winter and early spring period, in a large part of the subpolar North Atlantic Ocean. The intraseasonal dynamics of the ML pump exports fresh organic material to depth (basin‐scale average up to 55 mg C·m−2·day−1), providing a significant source of energy to the mesopelagic food web before the spring bloom period. This mechanism may sustain the seasonal development of overwintering organisms such as copepods with potential impact on the characteristics of the forthcoming spring phytoplankton bloom through predator‐prey interactions.
Dust Transport to the Taylor Glacier, Antarctica, During the Last Interglacial
Authors: Aarons S. M. , Aciego S. M. , McConnell J. R. , Delmonte B. , Baccolo G.
Published: February 2019

Changes in the composition of dust trapped in ice provide evidence of past atmospheric circulation and earth surface conditions. Investigations of dust provenance in Antarctic ice during glacial and interglacial periods indicate that South America is the primary dust source during both climate regimes. Here, we present results from a new ice core dust archive extracted from the Taylor Glacier in coastal East Antarctica during the deglacial transition from Marine Isotope Stage 6 to 5e. Radiogenic strontium and neodymium isotopes indicate that last interglacial dust is young and volcanic, in contrast to the observed preindustrial and Holocene (Marine Isotope Stage 1) dust composition. The dust composition differences from the last interglacial and current interglacial period at the site require a profound difference in atmospheric transport and environmental conditions. We consider several potential causes for enhanced transport of volcanic material to the site, including increased availability of volcanic material and large‐scale atmospheric circulation changes.
Climatic Factors and Their Availability in Estimating Long‐Term Variations of Fine Particle Distributions Over East China
Authors: Wang Yanyu , Duan Junyan , Xie Xin , He Qianshan , Cheng Tiantao , Mu Haizhen , Gao Wei , Li Xiang
Published: February 2019

Concerns about air pollutions in China have made fine particulate matter (PM2.5) estimation a hot research topic in recent years. Using satellite‐based PM2.5 data obtained over East China in 2000–2015, climatic factors affecting the PM2.5 variability were revealed in different seasons. Relevant climatic factors were used to estimate seasonal PM2.5 distributions by combining empirical orthogonal function with stepwise regression. The assessment results indicate a greater impact by climatic factors on PM2.5 variability in western East China than over coastal areas, and more significant influence by climatic factors on PM2.5 variability also occurs in summer and autumn than spring and winter. Our favorable results for PM2.5 estimation in 2016 further validate the capability of the estimation method for PM2.5 distributions based on climatic factors. Individual contributions of dominant climatic factors to PM2.5 variability over East China during the past 16 years range from 5% to 30%. In conclusion, climatic factors play nonnegligible roles in modulating PM2.5 concentrations, and they can feasibly be considered as predictors in the estimation of PM2.5 concentrations in East China. Our work underscores the importance of climate change impacts on air pollutions and improves air quality forecasts over East China.
Spectral Analysis of the September 2017 Solar Energetic Particle Events
Authors: Bruno A. , Christian E. R. , de Nolfo G. A. , Richardson I. G. , Ryan J. M.
Published: February 2019

An interval of exceptional solar activity was registered in early September 2017, late in the decay phase of solar cycle 24, involving the complex Active Region 12673 as it rotated across the western hemisphere with respect to Earth. A large number of eruptions occurred between 4 and 10 September, including four associated with X‐class flares. The X9.3 flare on 6 September and the X8.2 flare on 10 September are currently the two largest during cycle 24. Both were accompanied by fast coronal mass ejections and gave rise to solar energetic particle (SEP) events measured by near‐Earth spacecraft. In particular, the partially occulted solar event on 10 September triggered a ground‐level enhancement (GLE), the second GLE of cycle 24. A further, much less energetic SEP event was recorded on 4 September. In this work we analyze observations by the Advanced Composition Explorer (ACE) and the Geostationary Operational Environmental Satellites (GOES), estimating the SEP event‐integrated spectra above 300 keV and carrying out a detailed study of the spectral shape temporal evolution. Derived spectra are characterized by a low‐energy break at few/tens of MeV; the 10 September event spectrum, extending up to ∼1 GeV, exhibits an additional rollover at several hundred MeV. We discuss the spectral interpretation in the scenario of shock acceleration and in terms of other important external influences related to interplanetary transport and magnetic connectivity, taking advantage of multipoint observations from the Solar Terrestrial Relations Observatory. Spectral results are also compared with those obtained for the 17 May 2012 GLE event.
Warming Alters Hydrologic Heterogeneity: Simulated Climate Sensitivity of Hydrology‐Based Microrefugia in the Snow‐to‐Rain Transition Zone
Authors: Marshall A. M. , Link T. E. , Abatzoglou J. T. , Flerchinger G. N. , Marks D. G. , Tedrow L.
Published: February 2019

In complex terrain, drifting snow contributes to ecohydrologic landscape heterogeneity and ecological refugia. In this study, we assessed the climate sensitivity of hydrological dynamics in a semiarid mountainous catchment in the snow‐to‐rain transition zone. This catchment includes a distinct snow drift‐subsidized refugium that comprises a small portion (14.5%) of the watershed but accounts for a disproportionate amount (modeled average 56%) of hydrological flux generation. We conducted climate sensitivity experiments using a physically based hydrologic model to assess responses of a suite of hydrologic metrics across the watershed. Experiments with an imposed 3.5 °C warming showed reductions in average maximum snow water equivalent of 58–68% and deep percolation by 72%. While relative decreases were similar across the watershed, much greater absolute decreases in snowpack occurred in the drift‐subsidized site than the surrounding landscape. In drift‐subsidized locations, warming caused a shift from a regime that included both energy‐ and water‐limited evapotranspiration conditions to exclusively water‐limited conditions. Warming also resulted in altered interannual variability of hydrologic metrics. The drift‐subsidized unit was more sensitive to warming than the surrounding landscape, with reduced potential for the effects of warming to be offset by increased precipitation. Despite spatially homogeneous changes in climate, the effects of climate change on the hydrological dynamics were spatially heterogeneous in this watershed due to the presence of lateral water transport in the form of drifting snow. These findings suggest an increase in hydrologic homogeneity across the landscape and relatively large changes in snow drift‐subsidized refugia.
New Hints About How Martian Moons Formed
Authors: Underwood Emily
Published: February 2019

A new study finds that Phobos includes chunks of Martian crust.
Bruce Barkstrom (1944–2018)
Authors: Ramapriyan Hampapuram , Downs Robert , Dozier Jeff , Duerr Ruth , Folk Mike , Frew James , Hoebelheinrich Nancy , Mattmann Chris , Peng Ge
Published: February 2019

Bruce R. Barkstrom, principal investigator for NASA missions involved with understanding Earth’s radiation budget, committed his life to analyzing, interpreting, and stewarding Earth science data.
Mechanism of the natural product moracin-O derived MO-460 and its targeting protein hnRNPA2B1 on HIF-1α inhibition
Authors: Soung Nak-Kyun , Kim Hye-Min , Asami Yukihiro , Kim Dong Hyun , Cho Yangrae , Naik Ravi , Jang Yerin , Jang Kusic , Han Ho Jin , Ganipisetti Srinivas Rao , Cha-Molstad Hyunjoo , Hwang Joonsung , Lee Kyung Ho , Ko Sung-Kyun , Jang Jae-Hyuk , Ryoo In-Ja , Kwon Yong Tae , Lee Kyung Sang , Osada Hiroyuki , Lee Kyeong , Kim Bo Yeon , Ahn Jong Seog
Published: February 2019

Hypoxia-inducible factor-1α (HIF-1α) mediates tumor cell adaptation to hypoxic conditions and is a potentially important anticancer therapeutic target. We previously developed a method for synthesizing a benzofuran-based natural product, (R)-(-)-moracin-O, and obtained a novel potent analog, MO-460 that suppresses the accumulation of HIF-1α in Hep3B cells. However, the molecular target and underlying mechanism of action of MO-460 remained unclear. In the current study, we identified heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a molecular target of MO-460. MO-460 inhibits the initiation of HIF-1α translation by binding to the C-terminal glycine-rich domain of hnRNPA2B1 and inhibiting its subsequent binding to the 3’-untranslated region of HIF-1α mRNA. Moreover, MO-460 suppresses HIF-1α protein synthesis under hypoxic conditions and induces the accumulation of stress granules. The data provided here suggest that hnRNPA2B1 serves as a crucial molecular target in hypoxia-induced tumor survival and thus offer an avenue for the development of novel anticancer therapies.
Development of frontoparietal connectivity predicts longitudinal symptom changes in young people with autism spectrum disorder
Authors: Lin Hsiang-Yuan , Perry Alistair , Cocchi Luca , Roberts James A. , Tseng Wen-Yih Isaac , Breakspear Michael , Gau Susan Shur-Fen
Published: February 2019

Structural neuroimaging studies suggest altered brain maturation in autism spectrum disorder (ASD) compared with typically developing controls (TDC). However, the prognostic value of whole-brain structural connectivity analysis in ASD has not been established. Diffusion magnetic imaging data were acquired in 27 high-functioning young ASD participants (2 females) and 29 age-matched TDC (12 females; age 8–18 years) at baseline and again following 3–7 years. Whole-brain structural connectomes were reconstructed from these data and analyzed using a longitudinal statistical model. We identified distinct patterns of widespread brain connections that exhibited either significant increases or decreases in connectivity over time (p < 0.001). There was a significant interaction between diagnosis and time in brain development (p < 0.001). This was expressed by a decrease in structural connectivity within the frontoparietal network—and its broader connectivity—in ASD during adolescence and early adulthood. Conversely, these connections increased with time in TDC. Crucially, stronger baseline connectivity in this subnetwork predicted a lower symptom load at follow-up (p = 0.048), independent of the expression of symptoms at baseline. Our findings suggest a clinically meaningful relationship between the atypical development of frontoparietal structural connections and the dynamics of the autism phenotype through early adulthood. These results highlight a potential marker of future outcome.
Three-dimensional alteration of neurites in schizophrenia
Authors: Mizutani Ryuta , Saiga Rino , Takeuchi Akihisa , Uesugi Kentaro , Terada Yasuko , Suzuki Yoshio , De Andrade Vincent , De Carlo Francesco , Takekoshi Susumu , Inomoto Chie , Nakamura Naoya , Kushima Itaru , Iritani Shuji , Ozaki Norio , Ide Soichiro , Ikeda Kazutaka , Oshima Kenichi , Itokawa Masanari , Arai Makoto
Published: February 2019

Psychiatric symptoms of schizophrenia suggest alteration of cerebral neurons. However, the physical basis of the schizophrenia symptoms has not been delineated at the cellular level. Here, we report nanometer-scale three-dimensional analysis of brain tissues of schizophrenia and control cases. Structures of cerebral tissues of the anterior cingulate cortex were visualized with synchrotron radiation nanotomography. Tissue constituents visualized in the three-dimensional images were traced to build Cartesian coordinate models of tissue constituents, such as neurons and blood vessels. The obtained Cartesian coordinates were used for calculating curvature and torsion of neurites in order to analyze their geometry. Results of the geometric analyses indicated that the curvature of neurites is significantly different between schizophrenia and control cases. The mean curvature of distal neurites of the schizophrenia cases was ~1.5 times higher than that of the controls. The schizophrenia case with the highest neurite curvature carried a frame shift mutation in the GLO1 gene, suggesting that oxidative stress due to the GLO1 mutation caused the structural alteration of the neurites. The differences in the neurite curvature result in differences in the spatial trajectory and hence alter neuronal circuits. It has been shown that the anterior cingulate cortex analyzed in this study has emotional and cognitive functions. We suggest that the structural alteration of neurons in the schizophrenia cases should reflect psychiatric symptoms of schizophrenia.
KIAA1199 is a secreted molecule that enhances osteoblastic stem cell migration and recruitment
Authors: Chen Li , Shi Kaikai , Andersen Thomas Levin , Qiu Weimin , Kassem Moustapha
Published: February 2019

Factors mediating mobilization of osteoblastic stem and progenitor cells from their bone marrow niche to be recruited to bone formation sites during bone remodeling are poorly known. We have studied secreted factors present in the bone marrow microenvironment and identified KIAA1199 (also known as CEMIP, cell migration inducing hyaluronan binding protein) in human bone biopsies as highly expressed in osteoprogenitor reversal cells (Rv.C) recruited to the eroded surfaces (ES), which are the future bone formation sites. In vitro, KIAA1199 did not affect the proliferation of human osteoblastic stem cells (also known as human bone marrow skeletal or stromal stem cells, hMSCs); but it enhanced cell migration as determined by scratch assay and trans-well migration assay. KIAA1199 deficient hMSCs (KIAA1199down) exhibited significant changes in cell size, cell length, ratio of cell width to length and cell roundness, together with reduction of polymerization actin (F-actin) and changes in phos-CFL1 (cofflin1), phos-LIMK1 (LIM domain kinase 1) and DSTN (destrin), key factors regulating actin cytoskeletal dynamics and cell motility. Moreover, KIAA1199downhMSC exhibited impaired Wnt signaling in TCF-reporter assay and decreased expression of Wnt target genes and these effects were rescued by KIAA1199 treatment. Finally, KIAA1199 regulated the activation of P38 kinase and its associated changes in Wnt-signaling. Thus, KIAA1199 is a mobilizing factor that interacts with P38 and Wnt signaling, and induces changes in actin cytoskeleton, as a mechanism mediating recruitment of hMSC to bone formation sites.
High mobility group box 1 promotes radioresistance in esophageal squamous cell carcinoma cell lines by modulating autophagy
Authors: Ma Hongbing , Zheng Shuyu , Zhang Xiaozhi , Gong Tuotuo , Lv Xin , Fu Shenbo , Zhang Shuqun , Yin Xiaoran , Hao Jingcan , Shan Changyou , Huang Shan
Published: February 2019

Resistance to radiotherapy results in relapse and treatment failure in locally advanced esophageal squamous cell carcinoma (ESCC). High mobility group box 1 (HMGB1) is reported to be associated with the radioresistance in bladder and breast cancer. However, the role of HMGB1 in the radiotherapy response in ESCC has not been fully elucidated. Here, we investigated the role of HMGB1 to radioresistance in ESCC clinical samples and cell lines. We found that HMGB1 expression was associated with tumor recurrence after postoperative radiotherapy in locally advanced ESCC patients. HMGB1 knockdown in ESCC cells resulted in increased radiosensitivity both in vitro and in vivo. Autophagy level was found depressed in HMGB1 inhibition cells and activation of autophagy brought back cell’s radioresistance. Our results demonstrate that HMGB1 activate autophagy and consequently promote radioresistance. HMGB1 may be used as a predictor of poor response to radiotherapy in ESCC patients. Our finding also highlights the importance of the utility of HMGB1 in ESCC radiosensitization.
A30P mutant α-synuclein impairs autophagic flux by inactivating JNK signaling to enhance ZKSCAN3 activity in midbrain dopaminergic neurons
Authors: Lei Zhinian , Cao Guangliang , Wei Gang
Published: February 2019

Mutations in α-synuclein gene have been linked to familial early-onset Parkinson’s disease (PD) with Lewy body pathology. A30P mutant α-synuclein is believed to suppress autophagic progression associated with PD pathogenesis. However, the mechanistic link between A30P mutation and autophagy inhibition in PD remains poorly understood. In this study, we identified that A30P mutant α-synuclein resulted in reduced autophagy flux through promoting the decrease of autophagosomal membrane-associated protein LC3 and the increase of SQSTM1/p62 protein levels in midbrain dopaminergic neuron, due to the transcriptional repressor ZKSCAN3 trafficking from the cytoplasm to the nucleus. Moreover, the results demonstrated that A30P mutant α-synuclein not only decreased the phospho-c-Jun N-terminal Kinase (p-JNK) levels in midbrain dopaminergic neuron but also interfered autophagy without influencing the activities of AMPK and mTOR. Collectively, the present study reveals a novel autophagy inhibition mechanism induced by A30P mutant α-synuclein via transcriptional activation of the ZKSCAN3 in a JNK-dependent manner.
ER stress sensor, glucose regulatory protein 78 (GRP78) regulates redox status in pancreatic cancer thereby maintaining “stemness”
Authors: Dauer Patricia , Sharma Nikita S. , Gupta Vineet K. , Durden Brittany , Hadad Roey , Banerjee Santanu , Dudeja Vikas , Saluja Ashok , Banerjee Sulagna
Published: February 2019

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) signaling have been shown to be dysregulated in multiple cancer types. Glucose regulatory protein 78 (GRP78), the master regulator of the UPR, plays a role in proliferation, invasion, and metastasis in cancer. Cancer stem cells (CSCs) make up a crucial component of the tumor heterogeneity in pancreatic cancer, as well as other cancers. “Stemness” in pancreatic cancer defines a population of cells within the tumor that have increased therapeutic resistance as well as survival advantage. In the current study, we investigated how GRP78 was responsible for maintaining “stemness” in pancreatic cancer thereby contributing to its aggressive biology. We determined that GRP78 downregulation decreased clonogenicity and self-renewal properties in pancreatic cancer cell lines in vitro. In vivo studies resulted in delayed tumor initiation frequency, as well as smaller tumor volume in the shGRP78 groups. Additionally, downregulation of GRP78 resulted in dysregulated fatty acid metabolism in pancreatic tumors as well as the cells. Further, our results showed that shGRP78 dysregulates multiple transcriptomic and proteomic pathways that involve DNA damage, oxidative stress, and cell death, that were reversed upon treatment with a ROS inhibitor, N-acetylcysteine. This study thus demonstrates for the first time that the heightened UPR in pancreatic cancer may be responsible for maintenance of the “stemness” properties in these cells that are attributed to aggressive properties like chemoresistance and metastasis.
LncRNA MIAT sponges miR-149-5p to inhibit efferocytosis in advanced atherosclerosis through CD47 upregulation
Authors: Ye Zi-ming , Yang Shuai , Xia Yuan-peng , Hu Rui-ting , Chen Shengcai , Li Bo-wei , Chen Shao-li , Luo Xue-ying , Mao Ling , Li Yanan , Jin Huijuan , Qin Chao , Hu Bo
Published: February 2019

Atherosclerotic cardio-cerebrovascular disease and death remain the leading cause of morbidity and mortality worldwide. Defective efferocytosis, the clearance of apoptotic cells by macrophages, is thought to lead to increased inflammation and necrotic core formation in atherosclerotic lesions. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here we show that lncRNA myocardial infarction associated transcript (MIAT) was markedly elevated in the serum of patients with symptoms of vulnerable atherosclerotic plaque and the macrophages of necrotic cores in an advanced atherosclerosis mouse model. MIAT knockdown attenuated atherosclerosis progression, reduced necrotic core size, and increased plaque stability in vivo. Furthermore, MIAT knockdown promoted clearance of apoptotic cells by macrophages in vivo and in vitro. Mechanistic studies revealed that MIAT acted as a micro RNA (miRNA) sponge to positively modulate the expression of anti-phagocytic molecule CD47 through sponging miR-149-5p. Together, these findings identified a macrophage MIAT/miR-149-5p /CD47 pathway as a key factor in the development of necrotic atherosclerotic plaques.
Hypoxia preconditioning promotes bone marrow mesenchymal stem cells survival by inducing HIF-1α in injured neuronal cells derived exosomes culture system
Authors: Luo Zucheng , Wu Fangfang , Xue Enxing , Huang Linlin , Yan Ping , Pan Xiaoyun , Zhou Yulong
Published: February 2019

Bone marrow derived stem cells (BMSCs) transplantation are viewed as a promising therapeutic candidate for spinal cord injury (SCI). However, the inflammatory microenvironment in the spinal cord following SCI limits the survival and efficacy of transplanted BMSCs. In this study, we investigate whether injured neuronal cells derived exosomes would influence the survival of transplanted BMSCs after SCI. In order to mimic the microenvironment in SCI that the neuronal cells or transplanted BMSCs suffer in vivo, PC12 cells conditioned medium and PC12 cell’s exosomes collected from H2O2-treated PC12 cell’s culture medium were cultured with BMSCs under oxidative stress in vitro. PC12 cells conditioned medium and PC12 cell’s exosomes significantly accelerated the apoptosis of BMSCs induced by H2O2. Moreover, the cleaved caspase-3, cytochrome (Cyt) C, lactate dehydrogenase (LDH) releases, and apoptotic percentage were increased, and the ratio of Bcl-2/Bax and cell viability were decreased. Inhibition of exosome secretion via Rab27a small interfering RNA prevented BMSCs apoptosis in vitro. In addition, hypoxia-preconditioned promoted the survival of BMSCs under oxidative stress both in vivo after SCI and in vitro. Our results also indicate that HIF-1α plays a central role in the survival of BMSCs in hypoxia pretreatment under oxidative stress conditions. siRNA-HIF-1α increased apoptosis of BMSCs; in contrast, HIF-1α inducer FG-4592 attenuated apoptosis of BMSCs. Taken together, we found that the injured PC12 cells derived exosomes accelerate BMSCs apoptosis after SCI and in vitro, hypoxia pretreatment or activating expression of HIF-1α to be important in the survival of BMSCs after transplantation, which provides a foundation for application of BMSCs in therapeutic potential for SCI.
Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors
Authors: Yang Yang , Wang Huanan , Kouadir Mohammed , Song Houhui , Shi Fushan
Published: February 2019

The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome has been implicated in a wide range of diseases, including Alzheimer’s disease, Prion diseases, type 2 diabetes, and some infectious diseases. It has been found that a variety of stimuli including danger-associated molecular patterns (DAMPs, such as silica and uric acid crystals) and pathogen-associated molecular patterns (PAMPs) can activate NLRP3 inflammasome, but the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Understanding the mechanisms of NLRP3 activation will enable the development of its specific inhibitors to treat NLRP3-related diseases. In this review, we summarize current understanding of the regulatory mechanisms of NLRP3 inflammasome activation as well as inhibitors that specifically and directly target NLRP3.
Direct observations of a surface eigenmode of the dayside magnetopause
Authors: Archer M. O. , Hietala H. , Hartinger M. D. , Plaschke F. , Angelopoulos V.
Published: February 2019

The abrupt boundary between a magnetosphere and the surrounding plasma, the magnetopause, has long been known to support surface waves. It was proposed that impulses acting on the boundary might lead to a trapping of these waves on the dayside by the ionosphere, resulting in a standing wave or eigenmode of the magnetopause surface. No direct observational evidence of this has been found to date and searches for indirect evidence have proved inconclusive, leading to speculation that this mechanism might not occur. By using fortuitous multipoint spacecraft observations during a rare isolated fast plasma jet impinging on the boundary, here we show that the resulting magnetopause motion and magnetospheric ultra-low frequency waves at well-defined frequencies are in agreement with and can only be explained by the magnetopause surface eigenmode. We therefore show through direct observations that this mechanism, which should impact upon the magnetospheric system globally, does in fact occur.
Structural basis of ECF-σ-factor-dependent transcription initiation
Authors: Lin Wei , Mandal Sukhendu , Degen David , Cho Min Sung , Feng Yu , Das Kalyan , Ebright Richard H.
Published: February 2019

Extracytoplasmic (ECF) σ factors, the largest class of alternative σ factors, are related to primary σ factors, but have simpler structures, comprising only two of six conserved functional modules in primary σ factors: region 2 (σR2) and region 4 (σR4). Here, we report crystal structures of transcription initiation complexes containing Mycobacterium tuberculosis RNA polymerase (RNAP), M. tuberculosis ECF σ factor σL, and promoter DNA. The structures show that σR2 and σR4 of the ECF σ factor occupy the same sites on RNAP as in primary σ factors, show that the connector between σR2 and σR4 of the ECF σ factor–although shorter and unrelated in sequence–follows the same path through RNAP as in primary σ factors, and show that the ECF σ factor uses the same strategy to bind and unwind promoter DNA as primary σ factors. The results define protein-protein and protein-DNA interactions involved in ECF-σ-factor-dependent transcription initiation.
Costimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes
Authors: Galle-Treger Lauriane , Sankaranarayanan Ishwarya , Hurrell Benjamin P. , Howard Emily , Lo Richard , Maazi Hadi , Lewis Gavin , Banie Homayon , Epstein Alan L. , Hu Peisheng , Rehan Virender K. , Gilliland Frank D. , Allayee Hooman , Soroosh Pejman , Sharpe Arlene H. , Akbari Omid
Published: February 2019

Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type 2 diabetes mellitus (T2DM). Type-2 innate lymphoid cells (ILC2s) are a recently discovered immune population secreting Th2 cytokines. While previous studies show how ILC2s can play a critical role in the regulation of metabolic homeostasis in the adipose tissue, a therapeutic target capable of modulating ILC2 activation has yet to be identified. Here, we show that GITR, a member of the TNF superfamily, is expressed on both murine and human ILC2s. Strikingly, we demonstrate that GITR engagement of activated, but not naïve, ILC2s improves glucose homeostasis, resulting in both protection against insulin resistance onset and amelioration of established insulin- resistance. Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s.
Inhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production
Authors: Waise T. M. Zaved , Rasti Mozhgan , Duca Frank A. , Zhang Song-Yang , Bauer Paige V. , Rhodes Christopher J. , Lam Tony K. T.
Published: February 2019

Glucose homeostasis is partly controlled by the energy sensor mechanistic target of rapamycin (mTOR) in the muscle and liver. However, whether mTOR in the small intestine affects glucose homeostasis in vivo remains unknown. Here, we first report that delivery of rapamycin or an adenovirus encoding the dominant negative acting mTOR-mutated protein into the upper small intestine is sufficient to inhibit small intestinal mTOR signaling and lower glucose production in rodents with high fat diet-induced insulin resistance. Second, we found that molecular activation of small intestinal mTOR blunts the glucose-lowering effect of the oral anti-diabetic agent metformin, while inhibiting small intestinal mTOR alone lowers plasma glucose levels by inhibiting glucose production in rodents with diabetes as well. Thus, these findings illustrate that inhibiting upper small intestinal mTOR is sufficient and necessary to lower glucose production and enhance glucose homeostasis, and thereby unveil a previously unappreciated glucose-lowering effect of small intestinal mTOR.
Controlling light in complex media beyond the acoustic diffraction-limit using the acousto-optic transmission matrix
Authors: Katz Ori , Ramaz François , Gigan Sylvain , Fink Mathias
Published: February 2019

Studying the internal structure of complex samples with light is an important task but a difficult challenge due to light scattering. While the complex optical distortions induced by scattering can be effectively undone if the medium’s scattering-matrix is known, this matrix generally cannot be retrieved without the presence of an invasive detector or guide-star at the target points of interest. To overcome this limitation, the current state-of-the-art approaches utilize focused ultrasound for generating acousto-optic guide-stars, in a variety of different techniques. Here, we introduce the acousto-optic transmission matrix (AOTM), which is an ultrasonically-encoded, spatially-resolved, optical scattering-matrix. The AOTM provides both a generalized framework to describe any acousto-optic based technique, and a tool for light control and focusing beyond the acoustic diffraction-limit inside complex samples. We experimentally demonstrate complex light control using the AOTM singular vectors, and utilize the AOTM framework to analyze the resolution limitation of acousto-optic guided focusing approaches.
Soil carbon sequestration accelerated by restoration of grassland biodiversity
Authors: Yang Yi , Tilman David , Furey George , Lehman Clarence
Published: February 2019

Agriculturally degraded and abandoned lands can remove atmospheric CO2 and sequester it as soil organic matter during natural succession. However, this process may be slow, requiring a century or longer to re-attain pre-agricultural soil carbon levels. Here, we find that restoration of late-successional grassland plant diversity leads to accelerating annual carbon storage rates that, by the second period (years 13–22), are 200% greater in our highest diversity treatment than during succession at this site, and 70% greater than in monocultures. The higher soil carbon storage rates of the second period (years 13–22) are associated with the greater aboveground production and root biomass of this period, and with the presence of multiple species, especially C4 grasses and legumes. Our results suggest that restoration of high plant diversity may greatly increase carbon capture and storage rates on degraded and abandoned agricultural lands.
Publisher Correction: Deacetylation of serine hydroxymethyl-transferase 2 by SIRT3 promotes colorectal carcinogenesis
Authors: Wei Zhen , Song Jinglue , Wang Guanghui , Cui Ximao , Zheng Jun , Tang Yunlan , Chen Xinyuan , Li Jixi , Cui Long , Liu Chen-Ying , Yu Wei
Published: February 2019

The original version of this Article contained an error in the Data Availability Statement. The accession code indicated ‘53V’ and should have read ‘5X3V’. This has been corrected in both PDF and HTML versions of the Article.
The (eg ⊗ eu) ⊗ Eg product Jahn–Teller effect in the neutral group-IV vacancy quantum bits in diamond
Authors: Thiering Gergő , Gali Adam
Published: February 2019

The product Jahn–Teller effect may occur for such coupled electron–phonon systems in solids where single electrons occupy double degenerate orbitals. We propose that the excited state of the neutral XV split-vacancy complex in diamond, where X and V labels a group-IV impurity atom of X = Si, Ge, Sn, Pb and the vacancy, respectively, is such a system with eg and eu double degenerate orbitals and Eg quasi-localized phonons. We develop and apply ab initio theory to quantify the strength of electron–phonon coupling for neutral XV complexes in diamond, and find a significant impact on the corresponding optical properties of these centers. Our results show good agreement with recent experimental data on the prospective SiV(0) quantum bit, and reveals the complex nature of the excited states of neutral XV color centers in diamond.
Both mass ratio effects and community diversity drive biomass production in a grassland experiment
Authors: Sonkoly Judit , Kelemen András , Valkó Orsolya , Deák Balázs , Kiss Réka , Tóth Katalin , Miglécz Tamás , Tóthmérész Béla , Török Péter
Published: February 2019

The maintenance of biodiversity is crucial for ecosystem processes such as plant biomass production, as higher species richness is associated with increased biomass production in plant communities. However, the effects of evenness and functional diversity on biomass production are understudied. We manipulated the composition of an experimental grassland by sowing various seed mixtures and examined the effects of diversity and evenness on biomass production after three years. We found that biomass production increased with greater species and functional richness but decreased with greater species and functional evenness. Standing biomass increased but species number and functional richness decreased with increasing proportion of perennial grasses. Our findings emphasise the importance of productive dominant species, as the proportion of perennial grasses had a positive effect on standing biomass, while species and functional evenness had a negative effect on it. Thus, our findings support the theory that, besides diversity, dominance effects and the so-called mass ratio hypothesis may also play a key role in explaining primary biomass production.
Novel function of PiT1/SLC20A1 in LPS-related inflammation and wound healing
Authors: Koumakis Eugénie , Millet-Botti Joëlle , Benna Jamel El , Leroy Christine , Boitez Valérie , Codogno Patrice , Friedlander Gérard , Forand Anne
Published: February 2019

PiT1/SLC20A1 is an inorganic phosphate transporter with additional functions including the regulation of TNFα-induced apoptosis, erythropoiesis, cell proliferation and insulin signaling. Recent data suggest a relationship between PiT1 and NF-κB-dependent inflammation: (i)Pit1mRNA is up-regulated in the context of NF-κB pathway activation; (ii) NF-κB target gene transcription is decreased in PiT1-deficient conditions. This led us to investigate the role of PiT1 in lipopolysaccharide (LPS)-induced inflammation. MCP-1 and IL-6 concentrations were impaired in PiT1-deficient bone marrow derived macrophages (BMDMs) upon LPS stimulation. Lower MCP-1 and IL-6 serum levels were observed inMx1-Cre;Pit1lox/loxmice dosed intraperitoneally with LPS. Lower PiT1 expression correlated with decreasedin vitrowound healing and lower reactive oxygen species levels. Reduced IκB degradation and lower p65 nuclear translocation were observed in PiT1-deficient cells stimulated with LPS. Conversely, PiT1 expression was inducedin vitroupon LPS stimulation. Addition of an NF-κB inhibitor abolished LPS-induced PiT1 expression. Furthermore, we showed that p65 expression activatedPit1promoter activity. Finally, ChIP assays demonstrated that p65 directly binds to themPit1promoter in response to LPS. These data demonstrate a completely novel function of PiT1 in the response to LPS and provide mechanistic insights into the regulation of PiT1 expression by NF-κB.
NKT Cells in Mice Originate from Cytoplasmic CD3-Positive, CD4−CD8− Double-Negative Thymocytes that Express CD44 and IL-7Rα
Authors: Hu Zhansheng , Gu Wen , Wei Yang , Liu Gang , Wu Shengli , Liu Tie
Published: February 2019

Although natural killer T cells (NKT cells) are thought to be generated from CD4+CD8+ (DP) thymocytes, the developmental origin of CD4−CD8− (DN) NKT cells has remained unclear. In this study, we found the level of NK1.1 expression was highest in DN cells, followed by CD4 and CD8 (SP) and DP cells. The level of NK1.1 expression was highest in CD44+CD25− (DN1) cells, after that CD44+CD25+ (DN2), finally, CD44−CD25− (DN3) and CD44− CD25+ (DN4) cells. Unexpectedly, cytoplasmic CD3 was not only expressed in SP and DP thymocytes but also in most DN thymocytes at various stages. The mean fluorescence of cytoplasmic and surface CD3 in DN cells was significantly lower than in mature (SP) T and NKT cells in the thymus and spleen. Interestingly, there were more NKT cells in DN-cytoplasmic CD3 expression cells was higher than in DN-surface CD3 expression cells. There were more CD3-NKT cells in DN1 thymocytes than in TCR-β-NKT cells. NKT cells expressed higher levels of IL-7Rα which was correlated with CD44 expression in the thymus. Our data suggest that T cells and NKT cells follow similar patterns of expression with respect to cytoplasmic and surface CD3. Cytoplasmic CD3 could be used as a marker for early stage T cells. Both cytoplasmic CD3 and surface CD3 were expressed in mature T cells and immature T cells, including the immature cytoplasmic CD3+ surface CD3− and surface CD3+TCR-β− cells in DN1-NKT thymocytes. CD44 could be used as an additional marker of NKT cells which may originate from cytoplasmic CD3-positive DN thymocytes that express CD44 and IL-7Rα in mice.