bluuebunny/crossref_metadata_2025 huggingface dataset:
An audit of the dietary intake of Australian children with type 1 diabetes
Authors: Gilbertson Heather R. , Reed Kristen , Clark Sarah , Francis Kate L. , Cameron Fergus J.
Published: April 2018

To understand what children with type 1 diabetes in a representative tertiary hospital clinic are eating compared to their peers and explore dietary intake impact on HbA1c outcome. An open cross-sectional dietary audit of children and adolescents with diabetes aged 2–17 years attending the Royal Children’s Hospital, Melbourne was conducted using an age-appropriate validated Food Frequency Questionnaire. Total energy, macronutrient intake and diet quality were calculated and compared to dietary advice provided and national intake data. Body weight, and dietary intake influences on glycaemic control were investigated. Overall, 785 patients were recruited, from which 429 dietary surveys were completed. Dietary intakes were overall nutritionally adequate with macronutrient distribution (% total energy intake) being lower carbohydrate (48.6%), higher total sugars (22.4%), fat (32.9%), saturated fat (14.9%) and protein intake (19.1%) than recommendations, but similar to their peers. Energy intakes were excessive compared to their peers in the 4–13 year olds. Rates of overweight (30%) were significantly higher than national data (18%). Overall, 43% achieved optimal glycaemic control (HbA1c < 7.5%; <58 mmol/mol). HbA1c prediction via linear regression indicated that the following factors were associated with lower HbA1c values: being male, on pump regimen, lower rates of insulin per kg, shorter duration of disease. This audit has identified areas requiring targeted education/support to improve health outcomes including dietary adherence, rates of overweight/obesity, appropriate energy intakes and optimal glycaemic targets. Furthermore, it provides baseline data to evaluate efficacy of future interventions.
RETRACTED ARTICLE: CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7
Authors: Zeng Kaixuan , Chen Xiaoxiang , Xu Mu , Liu Xiangxiang , Hu Xiuxiu , Xu Tao , Sun Huiling , Pan Yuqin , He Bangshun , Wang Shukui
Published: April 2018

Mounting evidences indicate that circular RNAs (circRNAs) have a vital role in human diseases, especially cancers. More recently, circHIPK3, a particularly abundant circRNA, was proposed to be involved in tumorigenesis. However, its role in colorectal cancer (CRC) has not been explored. In this study, we found circHIPK3 was significantly upregulated in CRC tissues and cell lines, at least in part, due to c-Myb overexpression and positively correlated with metastasis and advanced clinical stage. Moreover, Cox multivariate survival analysis showed that high-level expression of circHIPK3 was an independent prognostic factor of poor overall survival (OS) in CRC (hazard ratio [HR] = 2.75, 95% confidence interval [CI] 1.74–6.51, p = 0.009). Functionally, knockdown of circHIPK3 markedly inhibited CRC cells proliferation, migration, invasion, and induced apoptosis in vitro and suppressed CRC growth and metastasis in vivo. Mechanistically, by using biotinylated-circHIPK3 probe to perform RNA pull-down assay in CRC cells, we identified miR-7 was the only one microRNA that was abundantly pulled down by circHIPK3 in both HCT116 and HT29 cells and these interactions were also confirmed by biotinylated miR-7 pull-down and dual-luciferase reporter assays. Overexpression of miR-7 mimicked the effect of circHIPK3 knockdown on CRC cells proliferation, migration, invasion, and apoptosis. Furthermore, ectopic expression of circHIPK3 effectively reversed miR-7-induced attenuation of malignant phenotypes of CRC cells by increasing the expression levels of miR-7 targeting proto-oncogenes (FAK, IGF1R, EGFR, YY1). Remarkably, the combination of circHIPK3 silencing and miR-7 overexpression gave a better effect on tumor suppression both in vitro and in vivo than did circHIPK3 knockdown or miR-7 overexpression alone. Taken together, our data indicate that circHIPK3 may have considerable potential as a prognostic biomarker in CRC, and support the notion that therapeutic targeting of the c-Myb/circHIPK3/miR-7 axis may be a promising treatment approach for CRC patients.
PIWIL2 suppresses Siah2-mediated degradation of HDAC3 and facilitates CK2α-mediated HDAC3 phosphorylation
Authors: Zhang Yingying , Zheng Xulei , Tan Hao , Lu Yilu , Tao Dachang , Liu Yunqiang , Ma Yongxin
Published: April 2018

HDAC3 is involved in deacetylation of histone and non-histone proteins, having a key role in the regulation of gene transcription and also in the process of tumorgenesis. However, how HDAC3 is regulated in cancer remains largely unclear. Here, we showed that PIWIL2 can interact with HDAC3, leading to stabilization of HDAC3 from ubiquitin-mediated degradation by competitive association with E3 ubiquitin ligase Siah2. Furthermore, we found that expression of PIWIL2 enhanced HDAC3 activity via CK2α. PIWIL2 facilitated the interaction between HDAC3 and CK2α, thus exhibiting a promotion on the HDAC3 phosphorylation by CK2α. Further work showed that PIWIL2 could promote cell proliferation and suppress cell apoptosis via regulating HDAC3. Our present study firstly revealed that PIWIL2 can play a role in HDAC3-mediated epigenetic regulation on cancer cell proliferation and apoptosis. These findings provide a novel insight into the roles of PIWIL2 in tumorigenesis.
Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma
Authors: Zhao Yuanyuan , Yi Jun , Tao Leilei , Huang Guichun , Chu Xiaoyuan , Song Haizhu , Chen Longbang
Published: April 2018

Although many articles have uncovered that Wnt signaling is involved in radioresistance, the mechanism is rarely reported. Here we generated two radioresistant cells rECA109 and rKyse150 from parental esophageal cancer cells ECA109 and Kyse150. We then found that Wnt signaling activity was higher in radioresistant cells and was further activated upon ionizing radiation (IR) exposure. In addition, radioresistant cells acquired epithelial-to-mesenchymal transition (EMT) properties and stem quality. Wnt signaling was then found to be involved in radioresistance by promoting DNA damage repair. In our present study, high-mobility group box 1 protein (HMGB1), a chromatin-associated protein, was firstly found to be transactivated by Wnt signaling and mediate Wnt-induced radioresistance. The role of HMGB1 in the regulation of DNA damage repair with the activation of DNA damage checkpoint response in response to IR was the main cause of HMGB1-induced radioresistance.
Methamphetamine alters T cell cycle entry and progression: role in immune dysfunction
Authors: Potula Raghava , Haldar Bijayesh , Cenna Jonathan M , Sriram Uma , Fan Shongshan
Published: April 2018

We and others have demonstrated that stimulants such as methamphetamine (METH) exerts immunosuppressive effects on the host’s innate and adaptive immune systems and has profound immunological implications. Evaluation of the mechanisms responsible for T-cell immune dysregulation may lead to ways of regulating immune homeostasis during stimulant use. Here we evaluated the effects of METH on T cell cycle entry and progression following activation. Kinetic analyses of cell cycle progression of T-cell subsets exposed to METH demonstrated protracted G1/S phase transition and differentially regulated genes responsible for cell cycle regulation. This result was supported by in vivo studies where mice exposed to METH had altered G1 cell cycle phase and impaired T-cell proliferation. In addition, T cells subsets exposed to METH had significant decreased expression of cyclin E, CDK2 and transcription factor E2F1 expression. Overall, our results indicate that METH exposure results in altered T cell cycle entry and progression. Our findings suggest that disruption of cell cycle machinery due to METH may limit T-cell proliferation essential for mounting an effective adaptive immune response and thus may strongly contribute to deleterious effect on immune system.
Single rhodium atoms anchored in micropores for efficient transformation of methane under mild conditions
Authors: Tang Yu , Li Yuting , Fung Victor , Jiang De-en , Huang Weixin , Zhang Shiran , Iwasawa Yasuhiro , Sakata Tomohiro , Nguyen Luan , Zhang Xiaoyan , Frenkel Anatoly I. , Tao Franklin
Published: April 2018

Catalytic transformation of CH4 under a mild condition is significant for efficient utilization of shale gas under the circumstance of switching raw materials of chemical industries to shale gas. Here, we report the transformation of CH4 to acetic acid and methanol through coupling of CH4, CO and O2 on single-site Rh1O5 anchored in microporous aluminosilicates in solution at ≤150 °C. The activity of these singly dispersed precious metal sites for production of organic oxygenates can reach about 0.10 acetic acid molecules on a Rh1O5 site per second at 150 °C with a selectivity of ~70% for production of acetic acid. It is higher than the activity of free Rh cations by >1000 times. Computational studies suggest that the first C–H bond of CH4 is activated by Rh1O5 anchored on the wall of micropores of ZSM-5; the formed CH3 then couples with CO and OH, to produce acetic acid over a low activation barrier.
Ruthenium(II)-enabled para-selective C–H difluoromethylation of anilides and their derivatives
Authors: Yuan Chunchen , Zhu Lei , Chen Changpeng , Chen Xiaolan , Yang Yong , Lan Yu , Zhao Yingsheng
Published: April 2018

Transition-metal-catalyzed direct site-selective functionalization of arene C–H bonds has emerged as an innovative approach for building the core structure of pharmaceutical agents and other versatile complex compounds. However, para-selective C–H functionalization has seldom been explored, only a few examples, such as steric-hindered arenes, electron-rich arenes, and substrates with a directing group, have been reported to date. Here we describe the development of a ruthenium-enabled para-selective C–H difluoromethylation of anilides, indolines, and tetrahydroquinolines. This reaction tolerates various substituted arenes, affording para-difluoromethylation products in moderate to good yields. Results of a preliminary study of the mechanism indicate that chelation-assisted cycloruthenation might play a role in the selective activation of para-CAr–H bonds. Furthermore, this method provides a direct approach for the synthesis of fluorinated drug derivatives, which has important application for drug discovery and development.
RING tetramerization is required for nuclear body biogenesis and PML sumoylation
Authors: Wang Pengran , Benhenda Shirine , Wu Haiyan , Lallemand-Breitenbach Valérie , Zhen Tao , Jollivet Florence , Peres Laurent , Li Yuwen , Chen Sai-Juan , Chen Zhu , de Thé Hugues , Meng Guoyu
Published: April 2018

ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Most TRIM family members bind ubiquitin E2s and many acquire ligase activity upon RING dimerization. In contrast, PML binds UBC9, the SUMO E2 enzyme. Here, using X-ray crystallography and SAXS characterization, we demonstrate that PML RING tetramerizes through highly conserved PML-specific sequences, which are required for NB assembly and PML sumoylation. Conserved residues implicated in RING dimerization of other TRIMs also contribute to PML tetramer stability. Wild-type PML rescues the ability of some RING mutants to form NBs as well as their sumoylation. Impaired RING tetramerization abolishes PML/RARA-driven leukemogenesis in vivo and arsenic-induced differentiation ex vivo. Our studies thus identify RING tetramerization as a key step in the NB macro-molecular scaffolding. They suggest that higher order RING interactions allow efficient UBC9 recruitment and thus change the biochemical nature of TRIM-facilitated post-translational modifications.
Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects
Authors: Corbet Cyril , Bastien Estelle , Draoui Nihed , Doix Bastien , Mignion Lionel , Jordan Bénédicte F. , Marchand Arnaud , Vanherck Jean-Christophe , Chaltin Patrick , Schakman Olivier , Becker Holger M. , Riant Olivier , Feron Olivier
Published: April 2018

Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro 13C-glucose and in vivo hyperpolarized 13C-pyruvate, we identify 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation. Also, while in spheroids MCT1 inhibition leads to cytostatic effects, MPC activity inhibition induces cytotoxic effects together with glycolysis stimulation and uncompensated inhibition of mitochondrial respiration. Hypoxia reduction obtained with 7ACC2 is further shown to sensitize tumor xenografts to radiotherapy. This study positions MPC as a control point for lactate metabolism and expands on the anticancer potential of MPC inhibition.
Ecological control of nitrite in the upper ocean
Authors: Zakem Emily J. , Al-Haj Alia , Church Matthew J. , van Dijken Gert L. , Dutkiewicz Stephanie , Foster Sarah Q. , Fulweiler Robinson W. , Mills Matthew M. , Follows Michael J.
Published: April 2018

Microorganisms oxidize organic nitrogen to nitrate in a series of steps. Nitrite, an intermediate product, accumulates at the base of the sunlit layer in the subtropical ocean, forming a primary nitrite maximum, but can accumulate throughout the sunlit layer at higher latitudes. We model nitrifying chemoautotrophs in a marine ecosystem and demonstrate that microbial community interactions can explain the nitrite distributions. Our theoretical framework proposes that nitrite can accumulate to a higher concentration than ammonium because of differences in underlying redox chemistry and cell size between ammonia- and nitrite-oxidizing chemoautotrophs. Using ocean circulation models, we demonstrate that nitrifying microorganisms are excluded in the sunlit layer when phytoplankton are nitrogen-limited, but thrive at depth when phytoplankton become light-limited, resulting in nitrite accumulation there. However, nitrifying microorganisms may coexist in the sunlit layer when phytoplankton are iron- or light-limited (often in higher latitudes). These results improve understanding of the controls on nitrification, and provide a framework for representing chemoautotrophs and their biogeochemical effects in ocean models.
Rescue of conformational dynamics in enzyme catalysis by directed evolution
Authors: Otten Renee , Liu Lin , Kenner Lillian R. , Clarkson Michael W. , Mavor David , Tawfik Dan S. , Kern Dorothee , Fraser James S.
Published: April 2018

Rational design and directed evolution have proved to be successful approaches to increase catalytic efficiencies of both natural and artificial enzymes. Protein dynamics is recognized as important, but due to the inherent flexibility of biological macromolecules it is often difficult to distinguish which conformational changes are directly related to function. Here, we use directed evolution on an impaired mutant of the proline isomerase CypA and identify two second-shell mutations that partially restore its catalytic activity. We show both kinetically, using NMR spectroscopy, and structurally, by room-temperature X-ray crystallography, how local perturbations propagate through a large allosteric network to facilitate conformational dynamics. The increased catalysis selected for in the evolutionary screen is correlated with an accelerated interconversion between the two catalytically essential conformational sub-states, which are both captured in the high-resolution X-ray ensembles. Our data provide a glimpse of an evolutionary trajectory and show how subtle changes can fine-tune enzyme function.
A biochemical network controlling basal myosin oscillation
Authors: Qin Xiang , Hannezo Edouard , Mangeat Thomas , Liu Chang , Majumder Pralay , Liu Jiaying , Choesmel-Cadamuro Valerie , McDonald Jocelyn A. , Liu Yiyao , Yi Bin , Wang Xiaobo
Published: April 2018

The actomyosin cytoskeleton, a key stress-producing unit in epithelial cells, oscillates spontaneously in a wide variety of systems. Although much of the signal cascade regulating myosin activity has been characterized, the origin of such oscillatory behavior is still unclear. Here, we show that basal myosin II oscillation in Drosophila ovarian epithelium is not controlled by actomyosin cortical tension, but instead relies on a biochemical oscillator involving ROCK and myosin phosphatase. Key to this oscillation is a diffusive ROCK flow, linking junctional Rho1 to medial actomyosin cortex, and dynamically maintained by a self-activation loop reliant on ROCK kinase activity. In response to the resulting myosin II recruitment, myosin phosphatase is locally enriched and shuts off ROCK and myosin II signals. Coupling Drosophila genetics, live imaging, modeling, and optogenetics, we uncover an intrinsic biochemical oscillator at the core of myosin II regulatory network, shedding light on the spatio-temporal dynamics of force generation.
Oncofetal gene SALL4 reactivation by hepatitis B virus counteracts miR-200c in PD-L1-induced T cell exhaustion
Authors: Sun Cheng , Lan Peixiang , Han Qiuju , Huang Mei , Zhang Zhihong , Xu Geliang , Song Jiaxi , Wang Jinyu , Wei Haiming , Zhang Jian , Sun Rui , Zhang Cai , Tian Zhigang
Published: April 2018

A chronic viral or tumor microenvironment can push T cells to exhaustion by promoting coinhibitory ligand expression. However, how host factors control coinhibitory ligand expression and whether viral infection breaks this control during tumor progress is unknown. Here we show a close negative correlation between SALL4 or PD-L1 and miR-200c in tumors from 98 patients with HBV-related hepatocellular carcinoma. SALL4 or PD-L1 expression correlates negatively with miR-200c expression, and patients with lower levels of SALL4 or PD-L1 and higher miR-200c survive longer. Moreover, over-expression of miR-200c antagonizes HBV-mediated PD-L1 expression by targeting 3ʹ-UTR of CD274 (encoding PD-L1) directly, and reverses antiviral CD8+ T cell exhaustion. MiR-200c transcription is inhibited by oncofetal protein SALL4, which is re-expressed through HBV-induced STAT3 activation in adulthood. We propose that an HBV-pSTAT3-SALL4-miR-200c axis regulates PD-L1. Therapeutic strategies to influence this axis might reverse virus-induced immune exhaustion.
USP52 acts as a deubiquitinase and promotes histone chaperone ASF1A stabilization
Authors: Yang Shangda , Liu Ling , Cao Cheng , Song Nan , Wang Yuejiao , Ma Shuai , Zhang Qi , Yu Na , Ding Xiang , Yang Fuquan , Tian Shanshan , Zhang Kai , Sun Tao , Yang Jie , Yao Zhi , Wu Shaoyuan , Shi Lei
Published: April 2018

Histone chaperone ASF1A has been reported to be dysregulated in multiple tumors; however, the underlying molecular mechanism that how the abundance and function of ASF1A are regulated remains unclear. Here we report that ASF1A is physically associated with USP52, which is previously identified as a pseudo-deubiquitinase. Interestingly, we demonstrate that USP52 is a bona fide ubiquitin-specific protease, and USP52 promotes ASF1A deubiquitination and stabilization. USP52-promoted ASF1A stabilization facilitates chromatin assembly and favors cell cycle progression. Additionally, we find that USP52 is overexpressed in breast carcinomas, and its level of expression correlates with that of ASF1A. Moreover, we reveal that impairment of USP52-promoted ASF1A stabilization results in growth arrest of breast cancer cells and sensitizes these cells to DNA damage. Our experiments identify USP52 as a truly protein deubiquitinase, uncover a molecular mechanism of USP52 in chromatin assembly, and reveal a potential role of USP52 in breast carcinogenesis.
Asymmetric electric field screening in van der Waals heterostructures
Authors: Li Lu Hua , Tian Tian , Cai Qiran , Shih Chih-Jen , Santos Elton J. G.
Published: April 2018

A long-standing challenge facing the combination of two-dimensional crystals into heterojunction is the unknown effect of mixing layer of different electronic properties (semiconductors, metals, insulators) on the screening features of the fabricated device platforms including their functionality. Here we use a compelling set of theoretical and experimental techniques to elucidate the intrinsic dielectric screening properties of heterostructures formed by MoS2 and graphene layers. We experimentally observed an asymmetric field screening effect relative to the polarization of the applied gate bias into the surface. Surprisingly, such behavior allows selection of the electronic states that screen external fields, and it can be enhanced with increasing of the number of layers of the semiconducting MoS2 rather than the semi-metal. This work not only provides unique insights on the screening properties of a vast amount of heterojunction fabricated so far, but also uncovers the great potential of controlling a fundamental property for device applications.
Counterregulation of cAMP-directed kinase activities controls ciliogenesis
Authors: Porpora Monia , Sauchella Simona , Rinaldi Laura , Delle Donne Rossella , Sepe Maria , Torres-Quesada Omar , Intartaglia Daniela , Garbi Corrado , Insabato Luigi , Santoriello Margherita , Bachmann Verena A. , Synofzik Matthis , Lindner Herbert H. , Conte Ivan , Stefan Eduard , Feliciello Antonio
Published: April 2018

The primary cilium emanates from the cell surface of growth-arrested cells and plays a central role in vertebrate development and tissue homeostasis. The mechanisms that control ciliogenesis have been extensively explored. However, the intersection between GPCR signaling and the ubiquitin pathway in the control of cilium stability are unknown. Here we observe that cAMP elevation promotes cilia resorption. At centriolar satellites, we identify a multimeric complex nucleated by PCM1 that includes two kinases, NEK10 and PKA, and the E3 ubiquitin ligase CHIP. We show that NEK10 is essential for ciliogenesis in mammals and for the development of medaka fish. PKA phosphorylation primes NEK10 for CHIP-mediated ubiquitination and proteolysis resulting in cilia resorption. Disarrangement of this control mechanism occurs in proliferative and genetic disorders. These findings unveil a pericentriolar kinase signalosome that efficiently links the cAMP cascade with the ubiquitin-proteasome system, thereby controlling essential aspects of ciliogenesis.
A semi-synthetic regulon enables rapid growth of yeast on xylose
Authors: Endalur Gopinarayanan Venkatesh , Nair Nikhil U.
Published: April 2018

Nutrient assimilation is the first step that allows biological systems to proliferate and produce value-added products. Yet, implementation of heterologous catabolic pathways has so far relied on constitutive gene expression without consideration for global regulatory systems that may enhance nutrient assimilation and cell growth. In contrast, natural systems prefer nutrient-responsive gene regulation (called regulons) that control multiple cellular functions necessary for cell survival and growth. Here, in Saccharomyces cerevisiae, by partially- and fully uncoupling galactose (GAL)-responsive regulation and metabolism, we demonstrate the significant growth benefits conferred by the GAL regulon. Next, by adapting the various aspects of the GAL regulon for a non-native nutrient, xylose, we build a semi-synthetic regulon that exhibits higher growth rate, better nutrient consumption, and improved growth fitness compared to the traditional and ubiquitous constitutive expression strategy. This work provides an elegant paradigm to integrate non-native nutrient catabolism with native, global cellular responses to support fast growth.
Pharmacologically induced amnesia for learned fear is time and sleep dependent
Authors: Kindt Merel , Soeter Marieke
Published: April 2018

The discovery in animal research that fear memories may change upon retrieval has sparked a wave of interest into whether this phenomenon of reconsolidation also occurs in humans. The critical conditions under which memory reconsolidation can be observed and targeted in humans, however, remain elusive. Here we report that blocking beta-adrenergic receptors in the brain, either before or after reactivation, effectively neutralizes the expression of fear memory. We show a specific time-window during which beta-adrenergic receptors are involved in the reconsolidation of fear memory. Finally, we observe intact fear memory expression 12 h after reactivation and amnesic drug intake when the retention test takes place during the same day as the intervention, but post-reactivation amnesia after a night of sleep (12 h or 24 h later). We conclude that memory reconsolidation is not simply time-dependent, but that sleep is a final and necessary link to fundamentally change the fear memory engram.
Endogenous modulation of human visual cortex activity improves perception at twilight
Authors: Cordani Lorenzo , Tagliazucchi Enzo , Vetter Céline , Hassemer Christian , Roenneberg Till , Stehle Jörg H. , Kell Christian A.
Published: April 2018

Perception, particularly in the visual domain, is drastically influenced by rhythmic changes in ambient lighting conditions. Anticipation of daylight changes by the circadian system is critical for survival. However, the neural bases of time-of-day-dependent modulation in human perception are not yet understood. We used fMRI to study brain dynamics during resting-state and close-to-threshold visual perception repeatedly at six times of the day. Here we report that resting-state signal variance drops endogenously at times coinciding with dawn and dusk, notably in sensory cortices only. In parallel, perception-related signal variance in visual cortices decreases and correlates negatively with detection performance, identifying an anticipatory mechanism that compensates for the deteriorated visual signal quality at dawn and dusk. Generally, our findings imply that decreases in spontaneous neural activity improve close-to-threshold perception.
Valence and spin states of iron are invisible in Earth’s lower mantle
Authors: Liu Jiachao , Dorfman Susannah M. , Zhu Feng , Li Jie , Wang Yonggang , Zhang Dongzhou , Xiao Yuming , Bi Wenli , Alp E. Ercan
Published: April 2018

Heterogeneity in Earth’s mantle is a record of chemical and dynamic processes over Earth’s history. The geophysical signatures of heterogeneity can only be interpreted with quantitative constraints on effects of major elements such as iron on physical properties including density, compressibility, and electrical conductivity. However, deconvolution of the effects of multiple valence and spin states of iron in bridgmanite (Bdg), the most abundant mineral in the lower mantle, has been challenging. Here we show through a study of a ferric-iron-only (Mg0.46Fe3+0.53)(Si0.49Fe3+0.51)O3Bdg that Fe3+in the octahedral site undergoes a spin transition between 43 and 53 GPa at 300 K. The resolved effects of the spin transition on density, bulk sound velocity, and electrical conductivity are smaller than previous estimations, consistent with the smooth depth profiles from geophysical observations. For likely mantle compositions, the valence state of iron has minor effects on density and sound velocities relative to major cation composition.
Linear and inverted U-shaped dose-response functions describe estrogen effects on hippocampal activity in young women
Authors: Bayer Janine , Gläscher Jan , Finsterbusch Jürgen , Schulte Laura H. , Sommer Tobias
Published: April 2018

In animals, 17-beta-estradiol (E2) enhances hippocampal plasticity in a dose-dependent, monotonically increasing manner, but this relationship can also exhibit an inverted U-shaped function. To investigate E2’s dose-response function in the human hippocampus, we pharmacologically increased E2 levels in 125 naturally cycling women (who were in their low-hormone menstruation phase) to physiological (equivalent to menstrual cycle peak) and supraphysiological (equivalent to levels during early pregnancy) concentrations in a placebo-controlled design. Twenty-four hours after first E2 intake, we measured brain activity during encoding of neutral and negative pictures and then tested recognition memory 24 h after encoding. Here we report that E2 exhibits both a monotonically increasing relationship with hippocampal activity as well as an inverted U-shaped relationship, depending on the hippocampal region. Hippocampal activity exhibiting a U-shaped relationship inflects at supraphysiological E2 levels, suggesting that while E2 within physiological ranges stimulates hippocampal activity, supraphysiological ranges show opposite effects.
Quantitative 3D determination of self-assembled structures on nanoparticles using small angle neutron scattering
Authors: Luo Zhi , Marson Domenico , Ong Quy K. , Loiudice Anna , Kohlbrecher Joachim , Radulescu Aurel , Krause-Heuer Anwen , Darwish Tamim , Balog Sandor , Buonsanti Raffaella , Svergun Dmitri I. , Posocco Paola , Stellacci Francesco
Published: April 2018

The ligand shell (LS) determines a number of nanoparticles’ properties. Nanoparticles’ cores can be accurately characterized; yet the structure of the LS, when composed of mixture of molecules, can be described only qualitatively (e.g., patchy, Janus, and random). Here we show that quantitative description of the LS’ morphology of monodisperse nanoparticles can be obtained using small-angle neutron scattering (SANS), measured at multiple contrasts, achieved by either ligand or solvent deuteration. Three-dimensional models of the nanoparticles’ core and LS are generated using an ab initio reconstruction method. Characteristic length scales extracted from the models are compared with simulations. We also characterize the evolution of the LS upon thermal annealing, and investigate the LS morphology of mixed-ligand copper and silver nanoparticles as well as gold nanoparticles coated with ternary mixtures. Our results suggest that SANS combined with multiphase modeling is a versatile approach for the characterization of nanoparticles’ LS.
Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment
Authors: Kojima Ryosuke , Bojar Daniel , Rizzi Giorgio , Hamri Ghislaine Charpin-El , El-Baba Marie Daoud , Saxena Pratik , Ausländer Simon , Tan Kelly R. , Fussenegger Martin
Published: April 2018

Exosomes are cell-derived nanovesicles (50–150 nm), which mediate intercellular communication, and are candidate therapeutic agents. However, inefficiency of exosomal message transfer, such as mRNA, and lack of methods to create designer exosomes have hampered their development into therapeutic interventions. Here, we report a set of EXOsomal transfer into cells (EXOtic) devices that enable efficient, customizable production of designer exosomes in engineered mammalian cells. These genetically encoded devices in exosome producer cells enhance exosome production, specific mRNA packaging, and delivery of the mRNA into the cytosol of target cells, enabling efficient cell-to-cell communication without the need to concentrate exosomes. Further, engineered producer cells implanted in living mice could consistently deliver cargo mRNA to the brain. Therapeutic catalase mRNA delivery by designer exosomes attenuated neurotoxicity and neuroinflammation in in vitro and in vivo models of Parkinson’s disease, indicating the potential usefulness of the EXOtic devices for RNA delivery-based therapeutic applications.
Giant optical nonlinearities from Rydberg excitons in semiconductor microcavities
Authors: Walther Valentin , Johne Robert , Pohl Thomas
Published: April 2018

The realization of exciton polaritons—hybrid excitations of semiconductor quantum well excitons and cavity photons—has been of great technological and scientific significance. In particular, the short-range collisional interaction between excitons has enabled explorations into a wealth of nonequilibrium and hydrodynamical effects that arise in weakly nonlinear polariton condensates. Yet, the ability to enhance optical nonlinearities would enable quantum photonics applications and open up a new realm of photonic many-body physics in a scalable and engineerable solid-state environment. Here we outline a route to such capabilities in cavity-coupled semiconductors by exploiting the giant interactions between excitons in Rydberg states. We demonstrate that optical nonlinearities in such systems can be vastly enhanced by several orders of magnitude and induce nonlinear processes at the level of single photons.
Massive mining of publicly available RNA-seq data from human and mouse
Authors: Lachmann Alexander , Torre Denis , Keenan Alexandra B. , Jagodnik Kathleen M. , Lee Hoyjin J. , Wang Lily , Silverstein Moshe C. , Ma’ayan Avi
Published: April 2018

RNA sequencing (RNA-seq) is the leading technology for genome-wide transcript quantification. However, publicly available RNA-seq data is currently provided mostly in raw form, a significant barrier for global and integrative retrospective analyses. ARCHS4 is a web resource that makes the majority of published RNA-seq data from human and mouse available at the gene and transcript levels. For developing ARCHS4, available FASTQ files from RNA-seq experiments from the Gene Expression Omnibus (GEO) were aligned using a cloud-based infrastructure. In total 187,946 samples are accessible through ARCHS4 with 103,083 mouse and 84,863 human. Additionally, the ARCHS4 web interface provides intuitive exploration of the processed data through querying tools, interactive visualization, and gene pages that provide average expression across cell lines and tissues, top co-expressed genes for each gene, and predicted biological functions and protein–protein interactions for each gene based on prior knowledge combined with co-expression.
The beta secretase BACE1 regulates the expression of insulin receptor in the liver
Authors: Meakin Paul J. , Mezzapesa Anna , Benabou Eva , Haas Mary E. , Bonardo Bernadette , Grino Michel , Brunel Jean-Michel , Desbois-Mouthon Christèle , Biddinger Sudha B. , Govers Roland , Ashford Michael L. J. , Peiretti Franck
Published: April 2018

Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.
A NIGT1-centred transcriptional cascade regulates nitrate signalling and incorporates phosphorus starvation signals in Arabidopsis
Authors: Maeda Yoshie , Konishi Mineko , Kiba Takatoshi , Sakuraba Yasuhito , Sawaki Naoya , Kurai Tomohiro , Ueda Yoshiaki , Sakakibara Hitoshi , Yanagisawa Shuichi
Published: April 2018

Nitrate is a nutrient signal that triggers complex regulation of transcriptional networks to modulate nutrient-dependent growth and development in plants. This includes time- and nitrate concentration-dependent regulation of nitrate-related gene expression. However, the underlying mechanisms remain poorly understood. Here we identify NIGT1 transcriptional repressors as negative regulators of the ArabidopsisNRT2.1 nitrate transporter gene, and show antagonistic regulation by NLP primary transcription factors for nitrate signalling and the NLP-NIGT1 transcriptional cascade-mediated repression. This antagonistic regulation provides a resolution to the complexity of nitrate-induced transcriptional regulations. Genome-wide analysis reveals that this mechanism is applicable to NRT2.1 and other genes involved in nitrate assimilation, hormone biosynthesis and transcription. Furthermore, the PHR1 master regulator of the phosphorus-starvation response also directly promotes expression of NIGT1 family genes, leading to reductions in nitrate uptake. NIGT1 repressors thus act in two transcriptional cascades, forming a direct link between phosphorus and nitrogen nutritional regulation.
Entropy favors heterogeneous structures of networks near the rigidity threshold
Authors: Yan Le
Published: April 2018

The dynamical properties and mechanical functions of amorphous materials are governed by their microscopic structures, particularly the elasticity of the interaction networks, which is generally complicated by structural heterogeneity. This ubiquitous heterogeneous nature of amorphous materials is intriguingly attributed to a complex role of entropy. Here, we show in disordered networks that the vibrational entropy increases by creating phase-separated structures when the interaction connectivity is close to the onset of network rigidity. The stress energy, which conversely penalizes the heterogeneity, finally dominates a smaller vicinity of the rigidity threshold at the glass transition and creates a homogeneous intermediate phase. This picture of structures changing between homogeneous and heterogeneous phases by varying connectivity provides an interpretation of the transitions observed in chalcogenide glasses.
Statistical variances of diffusional properties from ab initio molecular dynamics simulations
Authors: He Xingfeng , Zhu Yizhou , Epstein Alexander , Mo Yifei
Published: April 2018

Ab initio molecular dynamics (AIMD) simulation is widely employed in studying diffusion mechanisms and in quantifying diffusional properties of materials. However, AIMD simulations are often limited to a few hundred atoms and a short, sub-nanosecond physical timescale, which leads to models that include only a limited number of diffusion events. As a result, the diffusional properties obtained from AIMD simulations are often plagued by poor statistics. In this paper, we re-examine the process to estimate diffusivity and ionic conductivity from the AIMD simulations and establish the procedure to minimize the fitting errors. In addition, we propose methods for quantifying the statistical variance of the diffusivity and ionic conductivity from the number of diffusion events observed during the AIMD simulation. Since an adequate number of diffusion events must be sampled, AIMD simulations should be sufficiently long and can only be performed on materials with reasonably fast diffusion. We chart the ranges of materials and physical conditions that can be accessible by AIMD simulations in studying diffusional properties. Our work provides the foundation for quantifying the statistical confidence levels of diffusion results from AIMD simulations and for correctly employing this powerful technique.
Ultra-low thermal conductivity of two-dimensional phononic crystals in the incoherent regime
Authors: Xie Guofeng , Ju Zhifang , Zhou Kuikui , Wei Xiaolin , Guo Zhixin , Cai Yongqing , Zhang Gang
Published: April 2018

Two-dimensional silicon phononic crystals have attracted extensive research interest for thermoelectric applications due to their reproducible low thermal conductivity and sufficiently good electrical properties. For thermoelectric devices in high-temperature environment, the coherent phonon interference is strongly suppressed; therefore phonon transport in the incoherent regime is critically important for manipulating their thermal conductivity. On the basis of perturbation theory, we present herein a novel phonon scattering process from the perspective of bond order imperfections in the surface skin of nanostructures. We incorporate this strongly frequency-dependent scattering rate into the phonon Boltzmann transport equation and reproduce the ultra low thermal conductivity of holey silicon nanostructures. We reveal that the remarkable reduction of thermal conductivity originates not only from the impediment of low-frequency phonons by normal boundary scattering, but also from the severe suppression of high-frequency phonons by surface bond order imperfections scattering. Our theory not only reveals the role of the holey surface on the phonon transport, but also provide a computation tool for thermal conductivity modification in nanostructures through surface engineering.
Electrophysiological experiments in microgravity: lessons learned and future challenges
Authors: Wuest Simon L. , Gantenbein Benjamin , Ille Fabian , Egli Marcel
Published: April 2018

Advances in electrophysiological experiments have led to the discovery of mechanosensitive ion channels (MSCs) and the identification of the physiological function of specific MSCs. They are believed to play important roles in mechanosensitive pathways by allowing for cells to sense their mechanical environment. However, the physiological function of many MSCs has not been conclusively identified. Therefore, experiments have been developed that expose cells to various mechanical loads, such as shear flow, membrane indentation, osmotic challenges and hydrostatic pressure. In line with these experiments, mechanical unloading, as experienced in microgravity, represents an interesting alternative condition, since exposure to microgravity leads to a series of physiological adaption processes. As outlined in this review, electrophysiological experiments performed in microgravity have shown an influence of gravity on biological functions depending on ion channels at all hierarchical levels, from the cellular level to organs. In this context, calcium signaling represents an interesting cellular pathway, as it involves the direct action of calcium-permeable ion channels, and specific gravitatic cells have linked graviperception to this pathway. Multiple key proteins in the graviperception pathways have been identified. However, measurements on vertebrae cells have revealed controversial results. In conclusion, electrophysiological experiments in microgravity have shown that ion-channel-dependent physiological processes are altered in mechanically unloaded conditions. Future experiments may provide a better understanding of the underlying mechanisms.
Milestones of low-D quantum magnetism
Authors: Vasiliev Alexander , Volkova Olga , Zvereva Elena , Markina Maria
Published: April 2018

There is a long time gap between the formulation of the basic theory of low-dimensional (low-D) magnetism as advanced by Ising, Heisenberg and Bethe and its experimental verification. The latter started not long before the discovery of high-TC superconductivity in cuprates and has been boosted by this discovery result in an impressive succession of newly observed physical phenomena. Milestones on this road were the compounds which reached their quantum ground states upon lowering the temperature either gradually or through different instabilities. The gapless and gapped ground states for spin excitations in these compounds are inherent for isolated half-integer spin and integer spin chains, respectively. The same is true for the compounds hosting odd and even leg spin ladders. Some complex oxides of transition metals reach gapped ground state by means of spin-Peierls transition, charge ordering or orbital ordering mechanisms. However, the overwhelming majority of low-dimensional systems arrive to a long-range ordered magnetic state, albeit quite exotic realizations. Under a magnetic field some frustrated magnets stabilize multipolar order, e.g., showing a spin-nematic state in the simplest quadropolar case. Finally, numerous square, triangular, kagome and honeycomb layered lattices, along with Shastry–Sutherland and Nersesyan–Tsvelik patterns constitute the playground to check the basic concepts of two-dimensional magnetism, including resonating valence bond state, Berezinskii–Kosterlitz–Thouless transition and Kitaev model.
Author Correction: The epigenetic modifier Fam208a is required to maintain epiblast cell fitness
Authors: Bhargava Shohag , Cox Brian , Polydorou Christiana , Gresakova Veronika , Korinek Vladimir , Strnad Hynek , Sedlacek Radislav , Epp Trevor Allan , Chawengsaksophak Kallayanee
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Author Correction: Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes
Authors: Wiśnik Ewelina , Płoszaj Tomasz , Robaszkiewicz Agnieszka
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Author Correction: Revealing hidden complexities of genomic rearrangements generated with Cas9
Authors: Boroviak Katharina , Fu Beiyuan , Yang Fengtang , Doe Brendan , Bradley Allan
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
A Novel Platform for Evaluating the Environmental Impacts on Bacterial Cellulose Production
Authors: Basu Anindya , Vadanan Sundaravadanam Vishnu , Lim Sierin
Published: April 2018

Bacterial cellulose (BC) is a biocompatible material with versatile applications. However, its large-scale production is challenged by the limited biological knowledge of the bacteria. The advent of synthetic biology has lead the way to the development of BC producing microbes as a novel chassis. Hence, investigation on optimal growth conditions for BC production and understanding of the fundamental biological processes are imperative. In this study, we report a novel analytical platform that can be used for studying the biology and optimizing growth conditions of cellulose producing bacteria. The platform is based on surface growth pattern of the organism and allows us to confirm that cellulose fibrils produced by the bacteria play a pivotal role towards their chemotaxis. The platform efficiently determines the impacts of different growth conditions on cellulose production and is translatable to static culture conditions. The analytical platform provides a means for fundamental biological studies of bacteria chemotaxis as well as systematic approach towards rational design and development of scalable bioprocessing strategies for industrial production of bacterial cellulose.