bluuebunny/crossref_metadata_2025 huggingface dataset:
From Mobile Workers to Fellow Citizens and Back Again? The Future Status of EU Citizens in the UK
Authors: D'Angelo Alessio , Kofman Eleonore
Published: January 2018

Growing concerns and hostility towards continuing large-scale flows of immigrants following the two rounds of EU enlargement and high levels of net migration played a major part in the Brexit referendum result for the UK to leave the EU. So too had welfare chauvinism, or the belief that welfare benefits should be restricted to citizens, come to the fore in negative attitudes to EU immigration, reflecting a rejection of EU migrants as fellow citizens. As the article shows, proposals as of summer 2017 for the status of current EU citizens in the UK indicate a desire by the UK government to incorporate current EU citizens within the far more restrictive British immigration rules, thereby curtailing some of their basic free movement rights, especially in relation to future family members. Leaked proposals for future EU citizens post-Brexit are to bring them within a single overall immigration system covering EU and non-EU migrants and applying differential rights of residence to skilled and less skilled, thereby stratifying EU migrants according to educational level and labour market sector. This would represent a return to the status of mobile workers with conditional rights of residence and social entitlements similar to those faced by non-EU migrants.
The Strud crustacean fauna (Late Devonian, Belgium): updated review and palaeoecology of an early continental ecosystem
Authors: Gueriau Pierre , Rabet Nicolas , Du Tien Hat Eva
Published: January 2018

Arthropods were the first known animals to colonise land habitats, with myriapods and arachnids having done so at least by the Silurian. Much later, several lineages of Pancrustacea (hexapods and the paraphyletic crustaceans) also ventured onto land; the hexapods by the Early Devonian, and later at least four other groups of crustaceans, namely isopods, amphipods, ostracods and decapods, most of which generally colonised the continental water bodies. All faced a series of challenges (in particular: gas exchange; desiccation; reproduction; osmoregulation; and exposure to ultraviolet radiation), resulting in many morphological, physiological and ecological adaptations. Nonetheless, whether they reached land via saltwater or freshwater remains poorly documented, mainly because relevant localities are few. The Famennian (Late Devonian) Strud locality in Belgium provided an exceptional source of information on early aquatic continental ecosystems and their plant, vertebrate and arthropod colonisers at a crucial step in the terrestrialisation process. Here, we review and update its crustacean fauna, which inhabited floodplain and temporary pool waters. New anatomical details of the notostracanStrudops goldenbergiLagebroet al., 2015, as well as a new genus and species of spinicaudatan, are described. We also discuss the ecology of this unique, early continental ecosystem and the insights it gives into the terrestrialisation process.
Amberground pholadid bivalve borings and inclusions in Burmese amber: implications for proximity of resin-producing forests to brackish waters, and the age of the amber
Authors: Smith Ru D. A. , Ross Andrew J.
Published: January 2018

Clavate (club-shaped) structures rimming mid-Cretaceous Burmese amber from Myanmar, previously misdiagnosed as fungal sporocarps, are shown to be domichnia (crypts) of martesiine bivalves (Pholadidae: Martesiinae). They are similar in form toTeredolites clavatusLeymerie, 1842 andGastrochaenolites lapidicusKelly & Bromley, 1984; however, the former identification is preferable, given that they are martesiine crypts in amber as opposed to a lithic substrate. Cross-cutting relationships between the clavate features and inclusions in the amber demonstrate that the features post-date hardening of the resin. The fills of the crypts are variable, including sand grade sediment of very fine to coarse sand grainsize, and sparry calcite cements. In some cases, the articulated valves of the pholadid bivalve responsible are visible inside the borings. However, one remarkable specimen contains two pairs of articulated shells ‘floating’ in amber, not associated with crypts; an observation that suggests that the resin was still liquid or soft when the bivalves were trapped in the resin. One individual is associated with an irregular sediment-filled feature and shows shell breakage. Formation of a solid rim around a liquid central volume has been documented in subaqueous bodies of resin in modern swamp forests, and argues for a close proximity between the amber-producing trees and a brackish water habitat for the bivalves. The presence of pyrite as thin films and crystal groups within Burmese amber is further consistent with such a depositional environment. Comparison of the size of pholadid body fossils with growth rates of modern equivalents allows the duration of boring activities to be estimated and suggests that small fossil pholadids in Burmese amber became trapped and died within 1–2 weeks of having settled on the resin. Larger examples present within well-formed domichnia formed in hardened resin. Since ‘hardground’ describes early lithified sediment as a substrate and ‘woodground’ describes wood as a substrate, the term ‘amberground’ is used here to described borings in an amber substrate.
Formula derived Maillard reaction products in post-weaning intrauterine growth-restricted piglets induce developmental programming of hepatic oxidative stress independently of microRNA-21 and microRNA-155
Authors: Firmin S. , Elmhiri G. , Crepin D. , Souidi M. , Taouis M. , Abdennebi-Najar L.
Published: January 2018

We recently reported augmentation of lipid peroxidation products in the liver of intrauterine growth-restricted (IUGR) piglets fed a high load of Maillard reaction products (MRPs) during suckling period. The underlying mechanisms of MRPs effects remain unknown. Here, we studied the long-term impact of MRPs exposure on liver oxidative status of IUGR juvenile pigs. Livers of 54-day-old pigs suckled with formula containing either a high (HHF,n=8) or a low (LHF:n=8) load of MRPs were analyzed for protein carbonylation levels , activities and messenger RNA (mRNA) expression of glutathione (GSH) and main antioxidant regulators of redox homeostasis [Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured. In addition, mRNA levels of miRNA-21 and miRNA-155 were measured. The liver of HHF group exhibited a high level of lipid peroxidation with significantly increased expression and activity of SOD. Further in liver of HHF group, CAT activity was decreased as compared with LHF group, though with comparable total protein carbonyl contents, GSH contents, and expression of GPx and microRNAs (miRNA-21 and miRNA-155). Our findings suggest that the potential mechanism of MRPs-mediated oxidative stress programming in liver of IUGR piglets may occur via impairment of antioxidant defenses.
Lack of pronounced changes in the expression of fatty acid handling proteins in adipose tissue and plasma of morbidly obese humans
Authors: Grzegorczyk Ewa Anna , Harasim-Symbor Ewa , Lukaszuk Bartlomiej , Harasiuk Dorota , Choromanska Barbara , Mysliwiec Piotr , Zendzian-Piotrowska Malgorzata , Chabowski Adrian
Published: January 2018

Background/Objectives

Fatty acid handling proteins are involved in the process of accumulation of lipids in different fat tissue depots. Thus, the aim of the study was to estimate the expression of both fatty acid transport and binding proteins in the subcutaneous (SAT) and visceral adipose tissue (VAT) of patients with morbid obesity without metabolic syndrome, as well as the plasma concentrations of these transporters.

Subjects/Methods

Protein (Western blotting) and mRNA (Real-time PCR) expression of selected fatty acid handling proteins was assessed in the visceral and subcutaneous adipose tissue of 30 patients with morbid obesity. The control group consisted of 10 lean age-matched patients. Plasma levels of fatty acid protein transporters were also evaluated using ELISA method. Moreover, total plasma fatty acid composition and concentration was determined by gas-liquid chromatography (GLC).

Results

Significant increase in fatty acid translocase (FAT/CD36) mRNA (P = 0.03) and plasmalemmal (P = 0.01) expression was observed in VAT of patients with morbid obesity vs. lean subjects together with elevation of lipoprotein lipase (LPL), as well as peroxisome proliferator-activated receptor γ (PPARγ) in both examined compartments of adipose tissue. Moreover, in obese subjects plasma concentration of RBP4 was markedly elevated (P = 0.04) and sCD36 level presented a tendency for an increase (P = 0.08) with concomitant lack of changes in FABP4 concentration (P > 0.05).

Conclusions

Fatty acid transport into adipocytes may be, at least in part, related to the increased expression of FAT/CD36 in the VAT of morbidly obese patients, which is accompanied by augmented expression of LPL, as well as PPARγ. Probably, alternations in plasma concentrations of RBP4 and sCD36 in obese patients are associated with “unhealthy” fat distribution.
Exposure to famine in early life and chronic kidney diseases in adulthood
Authors: Wang Ningjian , Ning Zhiyuan , Xia Fangzhen , Chen Chi , Cheng Jing , Chen Yi , Lu Yingli
Published: January 2018

Objective

Chronic kidney disease (CKD) is an increasing contributor to the global disease burden. Previous findings indicated that exposure to famine in early life was associated with various metabolic diseases and urinary protein levels. We aimed to assess whether the exposure to China’s Great Famine 1959–1962 during fetal or childhood period was associated with glomerular filtration rate (GFR) and risk of CKD (eGFR<60 mL/min per 1.73 m2) in adulthood.

Materials and methods

SPECT-China was a population-based observational study in 2014–2015. Totally, 5124 women were included from SPECT-China study. Based on the birth year, they were divided into fetal-exposed (1959–1962), childhood-exposed (1949–1958), adolescence/young adult-exposed (1921–1948), and non-exposed (1963–1974, reference). The estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation. CKD was defined as eGFR less than 60 mL/min per 1.73 m2.

Results

Compared with the non-exposed, fetal exposure to famine was significantly associated with lower eGFR (B −1.47, 95%CI −2.81, −1.13) and greater risk of having CKD (OR 2.85, 95%CI 1.25, 6.50) in the crude model adjusting age. Further adjustments for demographic variables, body mass index, diabetes, and blood pressure did not qualitatively change the association (eGFR B −1.35, 95%CI −2.67, −0.04; CKD OR 2.42, 95%CI 1.05, 5.58). This association was not found in childhood-exposed and adolescence/young adult-exposed individuals.

Conclusions

Prenatal exposure to famine may have long-term effects on declined GFR and the development of CKD in humans. thus, fetal stage may be an important time window to prevent CKD in later life.
The stage of soil development modulates rhizosphere effect along a High Arctic desert chronosequence
Authors: Mapelli Francesca , Marasco Ramona , Fusi Marco , Scaglia Barbara , Tsiamis George , Rolli Eleonora , Fodelianakis Stilianos , Bourtzis Kostas , Ventura Stefano , Tambone Fulvia , Adani Fabrizio , Borin Sara , Daffonchio Daniele
Published: January 2018

In mature soils, plant species and soil type determine the selection of root microbiota. Which of these two factors drives rhizosphere selection in barren substrates of developing desert soils has, however, not yet been established. Chronosequences of glacier forelands provide ideal natural environments to identify primary rhizosphere selection factors along the changing edaphic conditions of a developing soil. Here, we analyze changes in bacterial diversity in bulk soils and rhizospheres of a pioneer plant across a High Arctic glacier chronosequence. We show that the developmental stage of soil strongly modulates rhizosphere community assembly, even though plant-induced selection buffers the effect of changing edaphic factors. Bulk and rhizosphere soils host distinct bacterial communities that differentially vary along the chronosequence. Cation exchange capacity, exchangeable potassium, and metabolite concentration in the soil account for the rhizosphere bacterial diversity. Although the soil fraction (bulk soil and rhizosphere) explains up to 17.2% of the variation in bacterial microbiota, the soil developmental stage explains up to 47.7% of this variation. In addition, the operational taxonomic unit (OTU) co-occurrence network of the rhizosphere, whose complexity increases along the chronosequence, is loosely structured in barren compared with mature soils, corroborating our hypothesis that soil development tunes the rhizosphere effect.
The emergence of metabolic heterogeneity and diverse growth responses in isogenic bacterial cells
Authors: Şimşek Emrah , Kim Minsu
Published: January 2018

Microorganisms adapt to frequent environmental changes through population diversification. Previous studies demonstrated phenotypic diversity in a clonal population and its important effects on microbial ecology. However, the dynamic changes of phenotypic composition have rarely been characterized. Also, cellular variations and environmental factors responsible for phenotypic diversity remain poorly understood. Here, we studied phenotypic diversity driven by metabolic heterogeneity. We characterized metabolic activities and growth kinetics of starved Escherichia coli cells subject to nutrient upshift at single-cell resolution. We observed three subpopulations with distinct metabolic activities and growth phenotypes. One subpopulation was metabolically active and immediately grew upon nutrient upshift. One subpopulation was metabolically inactive and non-viable. The other subpopulation was metabolically partially active, and did not grow upon nutrient upshift. The ratio of these subpopulations changed dynamically during starvation. A long-term observation of cells with partial metabolic activities indicated that their metabolism was later spontaneously restored, leading to growth recovery. Further investigations showed that oxidative stress can induce the emergence of a subpopulation with partial metabolic activities. Our findings reveal the emergence of metabolic heterogeneity and associated dynamic changes in phenotypic composition. In addition, the results shed new light on microbial dormancy, which has important implications in microbial ecology and biomedicine.
Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics
Authors: Liu Duan , Ray Balmiki , Neavin Drew R. , Zhang Jiabin , Athreya Arjun P. , Biernacka Joanna M. , Bobo William V. , Hall-Flavin Daniel K. , Skime Michelle K. , Zhu Hongjie , Jenkins Gregory D. , Batzler Anthony , Kalari Krishna R. , Boakye-Agyeman Felix , Matson Wayne R. , Bhasin Swati S. , Mushiroda Taisei , Nakamura Yusuke , Kubo Michiaki , Iyer Ravishankar K. , Wang Liewei , Frye Mark A. , Kaddurah-Daouk Rima , Weinshilboum Richard M.
Published: January 2018

Major depressive disorder (MDD) is a heterogeneous disease. Efforts to identify biomarkers for sub-classifying MDD and antidepressant therapy by genome-wide association studies (GWAS) alone have generally yielded disappointing results. We applied a metabolomics-informed genomic research strategy to study the contribution of genetic variation to MDD pathophysiology by assaying 31 metabolites, including compounds from the tryptophan, tyrosine, and purine pathways, in plasma samples from 290 MDD patients. Associations of metabolite concentrations with depressive symptoms were determined, followed by GWAS for selected metabolites and functional validation studies of the genes identified. Kynurenine (KYN), the baseline plasma metabolite that was most highly associated with depressive symptoms, was negatively correlated with severity of those symptoms. GWAS for baseline plasma KYN concentrations identified SNPs across the beta-defensin 1 (DEFB1) and aryl hydrocarbon receptor (AHR) genes that were cis-expression quantitative trait loci (eQTLs) forDEFB1andAHRmRNA expression, respectively. Furthermore, theDEFB1locus was associated with severity of MDD symptoms in a larger cohort of 803 MDD patients. Functional studies demonstrated that DEFB1 could neutralize lipopolysaccharide-stimulated expression of KYN-biosynthesizing enzymes in monocytic cells, resulting in altered KYN concentrations in the culture media. In addition, we demonstrated that AHR was involved in regulating the expression of enzymes in the KYN pathway and altered KYN biosynthesis in cell lines of hepatocyte and astrocyte origin. In conclusion, these studies identified SNPs that were cis-eQTLs forDEFB1andAHRand, which were associated with variation in plasma KYN concentrations that were related to severity of MDD symptoms.
Epigenetics and cerebral organoids: promising directions in autism spectrum disorders
Authors: Forsberg Sheena Louise , Ilieva Mirolyuba , Maria Michel Tanja
Published: January 2018

Autism spectrum disorders (ASD) affect 1 in 68 children in the US according to the Centers for Disease Control and Prevention (CDC). It is characterized by impairments in social interactions and communication, restrictive and repetitive patterns of behaviors, and interests. Owing to disease complexity, only a limited number of treatment options are available mainly for children that alleviate but do not cure the debilitating symptoms. Studies confirm a genetic link, but environmental factors, such as medications, toxins, and maternal infection during pregnancy, as well as birth complications also play a role. Some studies indicate a set of candidate genes with different DNA methylation profiles in ASD compared to healthy individuals. Thus epigenetic alterations could help bridging the gene–environment gap in deciphering the underlying neurobiology of autism. However, epigenome-wide association studies (EWAS) have mainly included a very limited number of postmortem brain samples. Hence, cellular models mimicking brain development in vitro will be of great importance to study the critical epigenetic alterations and when they might happen. This review will give an overview of the state of the art concerning knowledge on epigenetic changes in autism and how new, cutting edge expertise based on three-dimensional (3D) stem cell technology models (brain organoids) can contribute in elucidating the multiple aspects of disease mechanisms.
DNA methylome variation in a perinatal nurse-visitation program that reduces child maltreatment: a 27-year follow-up
Authors: O’Donnell Kieran J. , Chen Li , MacIsaac Julia L. , McEwen Lisa M. , Nguyen Thao , Beckmann Katherine , Zhu Yuecai , Chen Lawrence Ming , Brooks-Gunn Jeanne , Goldman David , Grigorenko Elena L. , Leckman James F. , Diorio Josie , Karnani Neerja , Olds David L. , Holbrook Joanna D. , Kobor Michael S. , Meaney Michael J.
Published: January 2018

This study reveals the influence of child maltreatment on DNA methylation across the genome and provides the first evidence that a psychosocial intervention program, the Nurse Family Partnership (NFP), which targets mothers at risk for abusive parenting, associates with variation in the DNA methylome in adult offspring. The 188 participants were born to women randomly assigned to control (n = 99) or nurse-visited intervention groups (n = 89) and provided blood samples and a diagnostic interview at age 27 years. Interindividual variation in the blood DNA methylome was described using principal components (PC) scores derived from principal component analysis and showed that the NFP program (PC10: p = 0.029) and a history of abuse/neglect (PC1: p = 0.029, PC2: p = 0.009) significantly associated with DNA methylome variation at 27 years of age independent of gender, ancestry, cellular heterogeneity, and a polygenic risk index for major psychiatric disorders. The magnitude of the association between child maltreatment and DNA methylation was reduced when accounting for lifestyle factors, including smoking. These findings reflect the sustained impact of both childhood adversity as well as intervention programs that target such adversity on the epigenome but highlight the need for prospective longitudinal studies of DNA methylome variation in the context of early intervention programs.
Metabotropic glutamate receptor 5 binding in male patients with alcohol use disorder
Authors: Akkus Funda , Mihov Yoan , Treyer Valerie , Ametamey Simon M. , Johayem Anass , Senn Smeralda , Rösner Susanne , Buck Alfred , Hasler Gregor
Published: January 2018

Glutamate signaling plays a major role in addiction. Preclinical research strongly suggests an implication of G-protein-coupled metabotropic glutamate receptor subtype 5 (mGluR5) in nicotine addiction and alcohol use disorder. In humans, smoking is related to a global reduction in mGluR5 availability. In the present study, we investigated mGluR5 in vivo in patients with alcohol use disorder without the confounding effects of smoking. A total of 14 male subjects with alcohol use disorder and at least a 25-day abstinence and 14 matched male non-smoking healthy controls were included in the study. We employed positron emission tomography (PET) with the mGluR5-specific radiotracer [11C]ABP688, using a bolus/infusion protocol. We found increased mGluR5 DVR in several regions within the temporal lobe in patients, as compared to controls. The largest between-group difference was in the amygdala. There was a marked positive relation between mGluR5 DVR in the anterior cingulate and mGluR5 DVR in the orbitofrontal cortex in patients, but not in controls. In patients, lower temptation to drink was related to higher amygdala mGluR5 DVR. We did not find altered mGluR5 DVR in the basal ganglia of subjects recovering from alcohol use disorder. In conclusion, our study provides clinical evidence for altered mGluR5 signaling in the amygdala in alcohol use disorder. This alteration was associated with the temptation to drink. In addition, this study suggests abnormal mGluR5 signaling in a network underlying reward-related behavioral flexibility. These findings strengthen the case for pharmacological agents acting on mGluR5 as promising candidates for the treatment of alcohol use disorder.
Preliminary evidence for genetic overlap between body mass index and striatal reward response
Authors: Lancaster T. M. , Ihssen I. , Brindley L. M. , Linden D. E.
Published: January 2018

The reward-processing network is implicated in the aetiology of obesity. Several lines of evidence suggest obesity-linked genetic risk loci (such as DRD2 and FTO) may influence individual variation in body mass index (BMI) through neuropsychological processes reflected in alterations in activation of the striatum during reward processing. However, no study has tested the broader hypotheses that (a) the relationship between BMI and reward-related brain activation (measured through the blood oxygenation-dependent (BOLD) signal) may be observed in a large population study and (b) the overall genetic architecture of these phenotypes overlap, an assumption critical for the progression of imaging genetic studies in obesity research. Using data from the Human Connectome Project (N = 1055 healthy, young individuals: average BMI = 26.4), we first establish a phenotypic relationship between BMI and ventral striatal (VS) BOLD during the processing of rewarding (monetary) stimuli (β = 0.44, P = 0.013), accounting for potential confounds. BMI and VS BOLD were both significantly influenced by additive genetic factors (H2r = 0.57; 0.12, respectively). Further decomposition of this variance suggested that the relationship was driven by shared genetic (ρg = 0.47, P = 0.011), but not environmental (ρE = −0.07, P = 0.29) factors. To validate the assumption of genetic pleiotropy between BMI and VS BOLD, we further show that polygenic risk for higher BMI is also associated with increased VS BOLD response to appetitive stimuli (calorically high food images), in an independent sample (N = 81; PFWE−ROI < 0.005). Together, these observations suggest that the genetic factors link risk to obesity to alterations within key nodes of the brain's reward circuity. These observations provide a basis for future work exploring the mechanistic role of genetic loci that confer risk for obesity using the imaging genetics approach.
Glucose-6-phosphate dehydrogenase is indispensable in embryonic development by modulation of epithelial-mesenchymal transition via the NOX/Smad3/miR-200b axis
Authors: Wu Yi-Hsuan , Lee Ying-Hsuan , Shih Hung-Yu , Chen Shih-Hsiang , Cheng Yi-Chuan , Tsun-Yee Chiu Daniel
Published: January 2018

Glucose-6-phosphate dehydrogenase (G6PD) is a housekeeping enzyme involved in the pentose phosphate shunt for producing nicotinamide adenine dinucleotide phosphate (NADPH). Severe G6PD deficiency leads to embryonic lethality, but the underlying mechanism is unclear. In the current study, the effects of G6PD on epithelial–mesenchymal transition (EMT), especially during embryonic development, were investigated. The knockdown of G6PD induced morphological changes, accompanied by the suppression of epithelial markers, E-cadherin and β-catenin, in A549 and MDCK cells. Such modulation of EMT was corroborated by the enhancement of migration ability in G6PD-knockdown A549 cells. Zebrafish embryos with g6pd knockdown exhibited downregulation of the E-cadherin/β-catenin adhesion molecules and impaired embryonic development through reduction in epiboly rate and increase in cell shedding at the embryo surface. The dysregulation in zebrafish embryonic development caused by g6pd knockdown could be rescued through human G6PD or CDH1 (E-cadherin gene) cRNA coinjection. The Smad3/miR-200b axis was dysregulated upon G6PD knockdown, and the reconstitution of SMAD3 in G6PD-knockdown A549 cells restored the expression of E-cadherin/β-catenin. The inhibition of NADPH oxidase (NOX) activation through the loss of p22phox signaling was involved in the dysregulation of the Smad3/miR-200b axis upon G6PD knockdown. The reconstitution of G6PD led to the recovery of the regulation of NOX/Smad3/miR-200b signaling and increased the expression of E-cadherin/β-catenin in G6PD-knockdown cells. Thus, these results suggest that in the EMT process, G6PD plays an important regulatory role as an integral component of the NOX/Smad3/miR-200b axis.
miRNA-3473b contributes to neuroinflammation following cerebral ischemia
Authors: Wang Xiaoyu , Chen Shuangshuang , Ni Jingshu , Cheng Jian , Jia Jia , Zhen Xuechu
Published: January 2018

MicroRNAs play an essential role in stroke pathology. Here, we investigated the role of a newly identified microRNA, miR-3473b, in stroke pathology. The expression of miR-3473b was upregulated in the cortex and striatum in mice following transient middle cerebral artery occlusion (MCAO). Intracerebroventricular injection of the miR-3473b antagomir prior to MCAO remarkably attenuated ischemia-induced expression of miR-3473b and pro-inflammatory factors in the ischemic brain and decreased infarct volumes in mice following MCAO. Using in vitro approaches, we showed that the miR-3473b antagomir reduced the mRNA and protein levels of pro-inflammatory factors (iNOS, COX-2, TNF-α, and IL-6) in BV2 microglial cells subjected to LPS stimulation. The miR-3473b antagomir also decreased the expression of pro-inflammatory factors in BV2 cells activated with conditioned medium collected from oxygen-glucose deprivation (OGD)-treated neurons. Suppressor of cytokine signaling 3 (SOCS3), a physiological regulator of innate and adaptive immunity, was predicted to be a potential target of miR-3473b. We verified that the miR-3473b mimic decreased SOCS3 expression in BV2 cells. Meanwhile, the miR-3473b antagomir significantly increased both SOCS3 mRNA and protein levels in the BV2 cells treated with LPS as well as in the ischemic brain. By using the dual luciferase assay, we further showed that the 3′-untranslational region of SOCS3 was directly targeted by miR-3473b. In conclusion, induction of miR-3473b, which is likely targeted to SOCS3, contributes to stroke pathogenesis by enhancing post-stroke neuroinflammation injury.
NF-κB/miR-223-3p/ARID1A axis is involved in Helicobacter pylori CagA-induced gastric carcinogenesis and progression
Authors: Yang Fenghua , Xu Yugang , Liu Chao , Ma Cunying , Zou Shuiyan , Xu Xia , Jia Jihui , Liu Zhifang
Published: January 2018

Infection with Helicobacter pylori (H. pylori) and the resulting gastric inflammation is regarded as the strongest risk factor for gastric carcinogenesis and progression. NF-κB plays an important role in linking H. pylori-mediated inflammation to cancer. However, the underlying mechanisms are poorly understood. In this study, we find that H. pylori infection induces miR-223-3p expression in H. pylori CagA-dependent manner. NF-κB stimulates miR-223-3p expression via directly binding to the promoter of miR-223-3p and is required for H. pylori CagA-mediated upregulation of miR-223-3p. miR-223-3p promotes the proliferation and migration of gastric cancer cells by directly targeting ARID1A and decreasing its expression. Furthermore, miR-223-3p/ARID1A axis is involved in CagA-induced cell proliferation and migration. In the clinical setting, the level of miR-223-3p is upregulated, while ARID1A is downregulated significantly in human gastric cancer tissues compared with the corresponding noncancerous tissues. The expression level of miR-223-3p is significantly higher in H. pylori-positive gastric cancer tissues than that in H. pylori-negative tissues. Moreover, a negative correlation between miR-223-3p and ARID1A expression is found in the gastric cancer tissues. Taken together, our findings suggested NF-κB/miR-223-3p/ARID1A axis may link the process of H. pylori-induced chronic inflammation to gastric cancer, thereby providing a new insight into the mechanism underlying H. pylori-associated gastric diseases.
Author Correction: Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent
Authors: Wang Pengju , Li Xiaozhu , Wang Jiwei , Gao Dongling , Li Yuenan , Li Haoze , Chu Yongchao , Zhang Zhongxian , Liu Hongtao , Jiang Guozhong , Cheng Zhenguo , Wang Shengdian , Dong Jianzeng , Feng Baisui , Chard Louisa S , Lemoine Nicholas R , Wang Yaohe
Published: January 2018

The originally published version of this Article contained errors in Figure 4. In panel b, the square and diamond labels associated with the uppermost survival curve were incorrectly displayed as ‘n’ and ‘u’, respectively. These errors have now been corrected in both the PDF and HTML versions of the Article.
Author Correction: Myoblasts and macrophages are required for therapeutic morpholino antisense oligonucleotide delivery to dystrophic muscle
Authors: Novak James S. , Hogarth Marshall W. , Boehler Jessica F. , Nearing Marie , Vila Maria C. , Heredia Raul , Fiorillo Alyson A. , Zhang Aiping , Hathout Yetrib , Hoffman Eric P. , Jaiswal Jyoti K. , Nagaraju Kanneboyina , Cirak Sebahattin , Partridge Terence A.
Published: January 2018

In the original version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include support from the CRI Light Microscopy and Image Analysis Core.
Brain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects
Authors: Eimon Peter M. , Ghannad-Rezaie Mostafa , De Rienzo Gianluca , Allalou Amin , Wu Yuelong , Gao Mu , Roy Ambrish , Skolnick Jeffrey , Yanik Mehmet Fatih
Published: January 2018

Neurological drugs are often associated with serious side effects, yet drug screens typically focus only on efficacy. We demonstrate a novel paradigm utilizing high-throughput in vivo electrophysiology and brain activity patterns (BAPs). A platform with high sensitivity records local field potentials (LFPs) simultaneously from many zebrafish larvae over extended periods. We show that BAPs from larvae experiencing epileptic seizures or drug-induced side effects have substantially reduced complexity (entropy), similar to reduced LFP complexity observed in Parkinson’s disease. To determine whether drugs that enhance BAP complexity produces positive outcomes, we used light pulses to trigger seizures in a model of Dravet syndrome, an intractable genetic epilepsy. The highest-ranked compounds identified by BAP analysis exhibit far greater anti-seizure efficacy and fewer side effects during subsequent in-depth behavioral assessment. This high correlation with behavioral outcomes illustrates the power of brain activity pattern-based screens and identifies novel therapeutic candidates with minimal side effects.
Author Correction: Intensification of terrestrial carbon cycle related to El Niño–Southern Oscillation under greenhouse warming
Authors: Kim Jin-Soo , Kug Jong-Seong , Jeong Su-Jong
Published: January 2018

In the original version of this Article, the affiliation for Su-Jon Jeong was incorrectly given as ‘Southern University of Science and Technology of China (SUSTECH)’, instead of ‘Southern University of Science and Technology (SUSTECH)’. This has now been corrected in both the PDF and HTML versions of the Article.
Stratospheric ozone loss over the Eurasian continent induced by the polar vortex shift
Authors: Zhang Jiankai , Tian Wenshou , Xie Fei , Chipperfield Martyn P. , Feng Wuhu , Son Seok-Woo , Abraham N. Luke , Archibald Alexander T. , Bekki Slimane , Butchart Neal , Deushi Makoto , Dhomse Sandip , Han Yuanyuan , Jöckel Patrick , Kinnison Douglas , Kirner Ole , Michou Martine , Morgenstern Olaf , O’Connor Fiona M. , Pitari Giovanni , Plummer David A. , Revell Laura E. , Rozanov Eugene , Visioni Daniele , Wang Wuke , Zeng Guang
Published: January 2018

The Montreal Protocol has succeeded in limiting major ozone-depleting substance emissions, and consequently stratospheric ozone concentrations are expected to recover this century. However, there is a large uncertainty in the rate of regional ozone recovery in the Northern Hemisphere. Here we identify a Eurasia-North America dipole mode in the total column ozone over the Northern Hemisphere, showing negative and positive total column ozone anomaly centres over Eurasia and North America, respectively. The positive trend of this mode explains an enhanced total column ozone decline over the Eurasian continent in the past three decades, which is closely related to the polar vortex shift towards Eurasia. Multiple chemistry-climate-model simulations indicate that the positive Eurasia-North America dipole trend in late winter is likely to continue in the near future. Our findings suggest that the anticipated ozone recovery in late winter will be sensitive not only to the ozone-depleting substance decline but also to the polar vortex changes, and could be substantially delayed in some regions of the Northern Hemisphere extratropics.
Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing
Authors: Nahar Rahul , Zhai Weiwei , Zhang Tong , Takano Angela , Khng Alexis J. , Lee Yin Yeng , Liu Xingliang , Lim Chong Hee , Koh Tina P. T. , Aung Zaw Win , Lim Tony Kiat Hon , Veeravalli Lavanya , Yuan Ju , Teo Audrey S. M. , Chan Cheryl X. , Poh Huay Mei , Chua Ivan M. L. , Liew Audrey Ann , Lau Dawn Ping Xi , Kwang Xue Lin , Toh Chee Keong , Lim Wan-Teck , Lim Bing , Tam Wai Leong , Tan Eng-Huat , Hillmer Axel M. , Tan Daniel S. W.
Published: January 2018

EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.
AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis
Authors: Teater Matt , Dominguez Pilar M. , Redmond David , Chen Zhengming , Ennishi Daisuke , Scott David W. , Cimmino Luisa , Ghione Paola , Chaudhuri Jayanta , Gascoyne Randy D. , Aifantis Iannis , Inghirami Giorgio , Elemento Olivier , Melnick Ari , Shaknovich Rita
Published: January 2018

Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases.
Heliconical smectic phases formed by achiral molecules
Authors: Abberley Jordan P. , Killah Ross , Walker Rebecca , Storey John M. D. , Imrie Corrie T. , Salamończyk Mirosław , Zhu Chenhui , Gorecka Ewa , Pociecha Damian
Published: January 2018

Chiral symmetry breaking in soft matter is a hot topic of current research. Recently, such a phenomenon was found in a fluidic phase showing orientational order of molecules—the nematic phase; although built of achiral molecules, the phase can exhibit structural chirality—average molecular direction follows a short-pitch helix. Here, we report a series of achiral asymmetric dimers with an odd number of atoms in the spacer, which form twisted structures in nematic as well as in lamellar phases. The tight pitch heliconical nematic (NTB) phase and heliconical tilted smectic C (SmCTB) phase are formed. The formation of a variety of helical structures is accompanied by a gradual freezing of molecular rotation. In the lowest temperature smectic phase, HexI, the twist is expressed through the formation of hierarchical structure: nanoscale helices and mesoscopic helical filaments. The short-pitch helical structure in the smectic phases is confirmed by resonant X-ray measurements.
Raman enhancement on ultra-clean graphene quantum dots produced by quasi-equilibrium plasma-enhanced chemical vapor deposition
Authors: Liu Donghua , Chen Xiaosong , Hu Yibin , Sun Tai , Song Zhibo , Zheng Yujie , Cao Yongbin , Cai Zhi , Cao Min , Peng Lan , Huang Yuli , Du Lei , Yang Wuli , Chen Gang , Wei Dapeng , Wee Andrew Thye Shen , Wei Dacheng
Published: January 2018

Graphene is regarded as a potential surface-enhanced Raman spectroscopy (SERS) substrate. However, the application of graphene quantum dots (GQDs) has had limited success due to material quality. Here, we develop a quasi-equilibrium plasma-enhanced chemical vapor deposition method to produce high-quality ultra-clean GQDs with sizes down to 2 nm directly on SiO2/Si, which are used as SERS substrates. The enhancement factor, which depends on the GQD size, is higher than conventional graphene sheets with sensitivity down to 1 × 10−9 mol L−1 rhodamine. This is attributed to the high-quality GQDs with atomically clean surfaces and large number of edges, as well as the enhanced charge transfer between molecules and GQDs with appropriate diameters due to the existence of Van Hove singularities in the electronic density of states. This work demonstrates a sensitive SERS substrate, and is valuable for applications of GQDs in graphene-based photonics and optoelectronics.
Phosphorylation-induced conformation of β2-adrenoceptor related to arrestin recruitment revealed by NMR
Authors: Shiraishi Yutaro , Natsume Mei , Kofuku Yutaka , Imai Shunsuke , Nakata Kunio , Mizukoshi Toshimi , Ueda Takumi , Iwaï Hideo , Shimada Ichio
Published: January 2018

The C-terminal region of G-protein-coupled receptors (GPCRs), stimulated by agonist binding, is phosphorylated by GPCR kinases, and the phosphorylated GPCRs bind to arrestin, leading to the cellular responses. To understand the mechanism underlying the formation of the phosphorylated GPCR-arrestin complex, we performed NMR analyses of the phosphorylated β2-adrenoceptor (β2AR) and the phosphorylated β2AR–β-arrestin 1 complex, in the lipid bilayers of nanodisc. Here we show that the phosphorylated C-terminal region adheres to either the intracellular side of the transmembrane region or lipids, and that the phosphorylation of the C-terminal region allosterically alters the conformation around M2155.54 and M2796.41, located on transemembrane helices 5 and 6, respectively. In addition, we found that the conformation induced by the phosphorylation is similar to that corresponding to the β-arrestin-bound state. The phosphorylation-induced structures revealed in this study propose a conserved structural motif of GPCRs that enables β-arrestin to recognize dozens of GPCRs.
Abnormal phase transition between two-dimensional high-density liquid crystal and low-density crystalline solid phases
Authors: Li Wenbin , Kong Longjuan , Feng Baojie , Fu Huixia , Li Hui , Zeng Xiao Cheng , Wu Kehui , Chen Lan
Published: January 2018

Some two-dimensional liquid systems are theoretically predicted to have an anomalous phase transition due to unique intermolecular interactions, for example the first-order transition between two-dimensional high-density water and low-density amorphous ice. However, it has never been experimentally observed, to the best of our knowledge. Here we report an entropy-driven phase transition between a high-density liquid crystal and low-density crystalline solid, directly observed by scanning tunneling microscope in carbon monoxide adsorbed on Cu(111). Combined with first principle calculations, we find that repulsive dipole–dipole interactions between carbon monoxide molecules lead to unconventional thermodynamics. This finding of unconventional thermodynamics in two-dimensional carbon monoxide not only provides a platform to study the fundamental principles of anomalous phase transitions in two-dimensional liquids at the atomic scale, but may also help to design and develop more efficient copper-based catalysis.
Au@Nb@H
x
K1-xNbO3 nanopeapods with near-infrared active plasmonic hot-electron injection for water splitting
Authors: Chen Ying-Chu , Hsu Yu-Kuei , Popescu Radian , Gerthsen Dagmar , Lin Yan-Gu , Feldmann Claus
Published: January 2018

Full-spectrum utilization of diffusive solar energy by a photocatalyst for environmental remediation and fuel generation has long been pursued. In contrast to tremendous efforts in the UV-to-VIS light regime of the solar spectrum, the NIR and IR areas have been barely addressed although they represent about 50% of the solar flux. Here we put forward a biomimetic photocatalyst blueprint that emulates the growth pattern of a natural plant—a peapod—to address this issue. This design is exemplified via unidirectionally seeding core-shell Au@Nb nanoparticles in the cavity of semiconducting H
x
K1−xNbO3 nanoscrolls. The biomimicry of this nanopeapod (NPP) configuration promotes near-field plasmon–plasmon coupling between bimetallic Au@Nb nanoantennas (the peas), endowing the UV-active H
x
K1−xNbO3 semiconductor (the pods) with strong VIS and NIR light harvesting abilities. Moreover, the characteristic 3D metal-semiconductor junction of the Au@Nb@H
x
K1−xNbO3 NPPs favors the transfer of plasmonic hot carriers to trigger dye photodegradation and water photoelectrolysis as proofs-of-concept. Such broadband solar spectral response renders the Au@Nb@H
x
K1−xNbO3 NPPs highly promising for widespread photoactive devices.
Deubiquitinase USP13 dictates MCL1 stability and sensitivity to BH3 mimetic inhibitors
Authors: Zhang Shengzhe , Zhang Meiying , Jing Ying , Yin Xia , Ma Pengfei , Zhang Zhenfeng , Wang Xiaojie , Di Wen , Zhuang Guanglei
Published: January 2018

MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.
Author Correction: Successful amplification of DNA aboard the International Space Station
Authors: Boguraev Anna-Sophia , Christensen Holly C. , Bonneau Ashley R. , Pezza John A. , Nichols Nicole M. , Giraldez Antonio J. , Gray Michelle M. , Wagner Brandon M. , Aken Jordan T. , Foley Kevin D. , Copeland D. Scott , Kraves Sebastian , Saavedra Ezequiel Alvarez
Published: January 2018

A correction to this article has been published and is linked from the HTML version of this article.
Relationship between spectrotemporal modulation detection and music perception in normal-hearing, hearing-impaired, and cochlear implant listeners
Authors: Choi Ji Eun , Won Jong Ho , Kim Cheol Hee , Cho Yang-Sun , Hong Sung Hwa , Moon Il Joon
Published: January 2018

The objective of this study was to examine the relationship between spectrotemporal modulation (STM) sensitivity and the ability to perceive music. Ten normal-hearing (NH) listeners, ten hearing aid (HA) users with moderate hearing loss, and ten cochlear Implant (CI) users participated in this study. Three different types of psychoacoustic tests including spectral modulation detection (SMD), temporal modulation detection (TMD), and STM were administered. Performances on these psychoacoustic tests were compared to music perception abilities. In addition, psychoacoustic mechanisms involved in the improvement of music perception through HA were evaluated. Music perception abilities in unaided and aided conditions were measured for HA users. After that, HA benefit for music perception was correlated with aided psychoacoustic performance. STM detection study showed that a combination of spectral and temporal modulation cues were more strongly correlated with music perception abilities than spectral or temporal modulation cues measured separately. No correlation was found between music perception performance and SMD threshold or TMD threshold in each group. Also, HA benefits for melody and timbre identification were significantly correlated with a combination of spectral and temporal envelope cues though HA.