bluuebunny/crossref_metadata_2025 huggingface dataset:
Nominal licensing in caseless languages
Authors: SHEEHAN MICHELLE , VAN DER WAL JENNEKE
Published: May 2018

This paper provides evidence for a kind of nominal licensing (Vergnaud licensing) in a number of morphologically caseless languages. Recent work on Bantu languages has suggested that abstract Case or nominal licensing should be parameterised (Diercks 2012, Van der Wal 2015a). With this is mind, we critically discuss the status of Vergnaud licensing in six languages lacking morphological case. While Luganda appears to systematically lack a Vergnaud licensing requirement, Makhuwa more consistently displays evidence in favour of it, as do all of the analytic languages that we survey (Mandarin, Yoruba, Jamaican Creole and Thai). We conclude that, while it seems increasingly problematic to characterise nominal licensing in terms of uninterpretable/abstract Case features, we nonetheless need to retain a (possibly universal) notion of nominal licensing, the explanation for which remains opaque.
Omega-3 (ω-3) and social skills interventions for reactive aggression and childhood externalizing behavior problems: a randomized, stratified, double-blind, placebo-controlled, factorial trial
Authors: Raine Adrian , Ang Rebecca P. , Choy Olivia , Hibbeln Joseph R. , Ho Ringo M-H. , Lim Choon Guan , Lim-Ashworth Nikki S. J. , Ling Shichun , Liu Jean C. J. , Ooi Yoon Phaik , Tan Yi Ren , Fung Daniel S. S.
Published: May 2018

Background

While studies suggest that nutritional supplementation may reduce aggressive behavior in children, few have examined their effects on specific forms of aggression. This study tests the primary hypothesis that omega-3 (ω-3), both alone and in conjunction with social skills training, will have particular post-treatment efficacy for reducing childhood reactive aggression relative to baseline.

Methods

In this randomized, double-blind, stratified, placebo-controlled, factorial trial, a clinical sample of 282 children with externalizing behavior aged 7–16 years was randomized intoω-3 only, social skills only,ω-3 + social skills, and placebo control groups. Treatment duration was 6 months. The primary outcome measure was reactive aggression collected at 0, 3, 6, 9, and 12 months, with antisocial behavior as a secondary outcome.

Results

Children in theω-3-only group showed a short-term reduction (at 3 and 6 months) in self-report reactive aggression, and also a short-term reduction in overall antisocial behavior. Sensitivity analyses and a robustness check replicated significant interaction effects. Effect sizes (d) were small, ranging from 0.17 to 0.31.

Conclusions

Findings provide some initial support for the efficacy ofω-3 in reducing reactive aggression over and above standard care (medication and parent training), but yield only preliminary and limited support for the efficacy ofω-3 in reducing overall externalizing behavior in children. Future studies could test further whetherω-3 shows promise in reducing more reactive, impulsive forms of aggression.
Significant spike in excess mortality in England in winter 2014/15 – influenza the likely culprit
Authors: Pebody R. G. , Green H. K. , Warburton F. , Sinnathamby M. , Ellis J. , Mølbak K. , Nielsen J. , de Lusignan S. , Andrews N.
Published: May 2018

Significant increases in excess all-cause mortality, particularly in the elderly, were observed during the winter of 2014/15 in England. With influenza A(H3N2) the dominant circulating influenza A subtype, this paper determines the contribution of influenza to this excess controlling for weather. A standardised multivariable Poisson regression model was employed with weekly all-cause deaths the dependent variable for the period 2008–2015. Adjusting for extreme temperature, a total of 26 542 (95% CI 25 301–27 804) deaths in 65+ and 1942 (95% CI 1834–2052) in 15–64-year-olds were associated with influenza from week 40, 2014 to week 20, 2015. This is compatible with the circulation of influenza A(H3N2). It is the largest estimated number of influenza-related deaths in England since prior to 2008/09. The findings highlight the potential health impact of influenza and the important role of the annual influenza vaccination programme that is required to protect the population including the elderly, who are vulnerable to a severe outcome.
Food environment, social deprivation and obesity among students from Brazilian public schools
Authors: Assis Maíra Macário de , Leite Maria Alvim , Carmo Ariene Silva do , Andrade Amanda Cristina de Souza , Pessoa Milene Cristine , Netto Michele Pereira , Cândido Ana Paula Carlos , Mendes Larissa Loures
Published: May 2018

Objective

To investigate the relationship between social deprivation and the food environment. Furthermore, to evaluate if the food environment is associated with the prevalence of obesity among students in Brazilian public schools.

Design

Cross-sectional. For the classification of obesity, weight and height were measured, and the cut-off point of BMI-for-age Z-score >+2 was adopted. Social deprivation level was determined from the Health Vulnerability Index (HVI). To assess the food environment, the density of food establishments in urban residential areas was calculated. Associations between the food environment and the presence of obesity were estimated by binary logistic regression through a generalized estimating equations model.

Setting

Juiz de Fora, Minas Gerais, Brazil.

Subjects

Children and adolescents (n 661) aged 7–14 years.

Results

The lowest social deprivation level showed a higher density of all types of establishments that sold predominantly unhealthy foods. An inverse association was found between the density of supermarkets and hypermarkets and the presence of obesity (OR=0·58; 95 % CI 0·36, 0·93). For the other categories of food retailers, no significant differences were found.

Conclusions

The findings reinforce the need for public policies that promote equality in the food environments of the city. Also, further investigations into the influence of the presence of supermarkets on the nutritional status of children and adolescents are required.
Rush Skeletonweed (Chondrilla juncea) Control in Pacific Northwest Winter Wheat
Authors: Spring John F. , Thorne Mark E. , Burke Ian C. , Lyon Drew J.
Published: May 2018

Rush skeletonweed is emerging as a regionally important weed of winter wheat production in eastern Washington. Field studies were conducted during the 2016 and 2017 crop years to evaluate several auxin herbicides applied at two seasonal timings (fall or spring) for control of rush skeletonweed in winter wheat. Clopyralid (210 g ae ha-1) provided>90% visual control of rush skeletonweed in both years of the study and aminopyralid (10 g ae ha-1) provided>80% visual control. Aminocyclopyrachlor, dicamba, and 2,4-D provided<55% control of rush skeletonweed. Season of application did not meaningfully affect efficacy of any herbicide tested. Wheat yields were reduced by 39 to 69% compared to the non-treated check when aminocyclopyrachlor was applied in the spring. Clopyralid is an effective option for control of rush skeletonweed in Pacific Northwest winter wheat.
Formation and Maintenance of the GEOTRACES Subsurface‐Dissolved Iron Maxima in an Ocean Biogeochemistry Model
Authors: Pham Anh L. D. , Ito Takamitsu
Published: May 2018

Recent GEOTRACES transects revealed basin‐scale patterns of dissolved iron in the global oceans, providing a unique opportunity to test numerical models and to improve our understanding of the iron cycling. Subsurface maxima of dissolved iron in the upper ocean thermocline are observed in various transects, which can play an important role in regulating marine productivity due to their proximity to the surface euphotic layer. An ocean biogeochemistry model with refined parameterizations of iron cycling is used to examine the mechanisms controlling the formation and maintenance of these subsurface maxima. The model includes the representation of three iron sources including dust deposition, continental shelves, and hydrothermal vents. Two classes of organic ligands are parameterized based on the dissolved organic matter and apparent oxygen utilization. Parameterizations of particle‐dependent scavenging and desorption are included. Although the model still struggles in fully capturing the observed dissolved iron distribution, it starts reproducing some major features, especially in the main thermocline. A suite of numerical sensitivity experiments suggests that the release of scavenged iron associated with sinking organic particles forms the subsurface‐dissolved iron maxima in high‐dust regions of the Indian and Atlantic Oceans. In low‐dust regions of the Pacific basin, the subsurface‐dissolved iron extrema are sustained by inputs from the continental shelves or hydrothermal vents. In all cases, subsurface ligands produced by the remineralization of organic particles retain the dissolved iron and play a central role in the maintenance of the subsurface maxima in our model. Thus, the parameterization of subsurface ligands has a far‐reaching impact on the representation of global iron cycling and biological productivity in ocean biogeochemistry models.
Nonlinear Dynamics of Radiation Belt Electrons Interacting With Chorus Emissions Localized in Longitude
Authors: Kubota Yuko , Omura Yoshiharu
Published: May 2018

Using results of test particle simulations of electrons interacting with whistler mode chorus emissions, we numerically obtain Green's functions to model evolution of the electron distribution function after all of the possible interactions with the waves. In both wave models with and without subpackets, electrons undergoing the cyclotron resonance with the waves are efficiently accelerated by nonlinear wave trapping. Since the strong modulation of the wave amplitude (in the case of the waves with subpackets) affects dynamics of resonant electrons, the electrons are detrapped from the wave potential or entrapped into it more frequently than those interacting with the waves without subpackets. As a result of interaction with the waves with subpackets, the number of electrons undergoing the acceleration is increased, while the acceleration efficiency in energy is decreased because of shorter interaction time. Modifying the numerical Green's function method with the simplified model of chorus waves uniform in longitude (Omura et al., 2015, https://doi.org/10.1002/2015JA021563), we compute the formation process of the outer radiation belt electron fluxes induced by the interaction with the chorus waves localized in longitude occurring for a time scale of 1 hr. The formation of MeV electron fluxes is characterized by large acceleration rates and butterfly pitch angle distributions, which are found in satellite observation results.
Global Model of Plasmaspheric Hiss From Multiple Satellite Observations
Authors: Meredith Nigel P. , Horne Richard B. , Kersten Tobias , Li Wen , Bortnik Jacob , Sicard Angélica , Yearby Keith H.
Published: May 2018

We present a global model of plasmaspheric hiss, using data from eight satellites, extending the coverage and improving the statistics of existing models. We use geomagnetic activity dependent templates to separate plasmaspheric hiss from chorus. In the region 22–14 magnetic local time (MLT) the boundary between plasmaspheric hiss and chorus moves to lower values with increasing geomagnetic activity. The average wave intensity of plasmaspheric hiss is largest on the dayside and increases with increasing geomagnetic activity from midnight through dawn to dusk. Plasmaspheric hiss is most intense and spatially extended in the 200 to 500 Hz frequency band during active conditions, 400  750 nT, with an average intensity of 1,128 pT in the region 05–17 MLT from 1.5 . In the prenoon sector, waves in the 100 to 200 Hz frequency band peak near the magnetic equator and decrease in intensity with increasing magnetic latitude, inconsistent with a source from chorus outside the plasmapause, but more consistent with local amplification by substorm‐injected electrons. At higher frequencies the average wave intensities in this sector exhibit two peaks, one near the magnetic equator and one at high latitudes, 45° °, with a minimum at intermediate latitudes, 30° °, consistent with a source from chorus outside the plasmapause. In the premidnight sector, the intensity of plasmaspheric hiss in the frequency range 50 < f < 1,000 Hz decreases with increasing geomagnetic activity. The source of this weak premidnight plasmaspheric hiss is likely to be chorus at larger in the postnoon sector that enters that plasmasphere in the postnoon sector and subsequently propagates eastward in MLT.
Historical Traces of a General Measurement Theory in Psychology
Authors: Aftanas Marion S. , Solomon Joanna
Published: May 2018

A review of the historical measurement theory literature in psychology reveals a recurring focus on a physical rather than a psychological model of the measurement process, whereas the active measurement research literature points to an emphasis on elements of a psychological measurement process. On the basis of the relevant portions of these anomalous findings the authors outline parts of a general measurement structure for psychology that begins with an essential theoretical base. The review first explores a century-old statement that developed a promising starting point within test development. This is followed by a diversionary statement based on physical measurement that mandated discussions of measurement in psychology to a physical model. The statement appeared to be countered by the theory of scale types ( Stevens, 1946 ), which provided a promising element of the psychological measurement process. The legacy of the theory of scales, however, resulted in confusion and inconsistency about the specifics of psychological measurement. After reviewing some of the contributions in the research literature, a conciliation of the positive theory efforts of the past and the protocols for a measurement process are presented that is based upon the standard system of measurement ( Aftanas, 1988 , 2006 ) as the basic theoretically necessary element of measurement. The theoretical framework based on the standard system promises not only to integrate the components of measurement, and categories of psychological measurement that have been referenced in the past, but also to provide an easily assimilated protocol that can serve as a basis for future research and pedagogical exposition.
PTBP1 enhances miR-101-guided AGO2 targeting to MCL1 and promotes miR-101-induced apoptosis
Authors: Cui Jia , Placzek William J.
Published: May 2018

Myeloid cell leukemia 1 (MCL1) is a key anti-apoptotic protein belonging to the BCL-2 protein family. To preserve normal cellular homeostasis, cells must maintain strict control over MCL1 expression. Overexpression of MCL1 has been identified as a key contributor to tumorigenesis, and further enables resistance to a number of anti-cancer chemotherapies. Thus, there is an ongoing interest to develop selective MCL1 inhibitors. In order to better target MCL1, it is essential to understand the molecular mechanisms that regulate MCL1 expression in cells. While MCL1 expression is tightly controlled by multiple mechanisms, the post-transcriptional regulation of MCL1 mRNA is poorly studied. Our previous work identified that polypyrimidine tract binding protein 1 (PTBP1) binds to MCL1 mRNA and represses MCL1 expression by destabilizing MCL1 mRNA. In this report, we show that PTBP1 modulates MCL1 expression by regulating the microRNA (miRNA) direction of the miRNA-induced silencing complex (miRISC) to MCL1. We demonstrate that PTBP1 enhances miR-101-guided AGO2 interaction with MCL1, thereby regulating miR-101-induced apoptosis and clonogenic cell survival inhibition in cells. Taken together, not only do these studies expand our understanding on the regulation of MCL1, they also demonstrate that PTBP1 and miRNAs can function cooperatively on a shared target mRNA.
Prion protein is essential for the RE1 silencing transcription factor (REST)-dependent developmental switch in synaptic NMDA receptors
Authors: Song Zhiqi , Yang Wei , Cheng Guangyu , Zhou Xiangmei , Yang Lifeng , Zhao Deming
Published: May 2018

It is important that the correct amounts of GluN2 subunits are maintained, as they determine NMDAR functional properties, which are crucial to neuronal communication, synaptogenesis and cognitive function. The transcriptional repressor RE1 silencing transcription factor (REST) is critical for the postnatal developmental switch in NMDARs. However, the mechanisms triggering REST and the link between NMDARs and REST are unclear. Here we show a new physiological essential role for cellular prion protein (PrPC) in REST-dependent homeostasis and the developmental switch of NMDARs. REST and REST-associated proteins were overactivated in the hippocampi of Prnp knockout mice (Prnp
0/0
) compared with wild-type Prnp (Prnp
+/+
) mice. This coincided with the disruption of the normal developmental switch from GluN2B-to-GluN2A in vivo. PrPC co-located with REST under physiological environments and mediated the translocation of REST in conditioners of NMDARs in vitro in Prnp
+/+
hippocampal neurons. Regardless of whether REST was knocked down or overexpressed, deletion of PrPC not only disrupted REST-mediated distribution of mitochondria, but also prevented REST-regulated expression of GluN2B and GluN2A in Prnp
0/0
. Importantly, these effects were rescued after overexpression of full-length PrPC through restoration of NMDAR2 subunits and their distributions in dendritic processes in Prnp
0/0
. Consistently, knockdown of PrPC in Prnp
+/+
had a similar effect on Prnp
0/0
. Furthermore, PrPC colocalized with both GluN2B and GluN2A in Prnp
+/+
. For the first time, we demonstrate that PrPC is essential for REST-regulated NMDARs. Confirming the regulation of NMDAR-modulating mechanisms could provide novel therapeutic targets against dysfunctions of glutamatergic transmission in the nervous system.
TSPY1 suppresses USP7-mediated p53 function and promotes spermatogonial proliferation
Authors: Shen Ying , Tu Wenling , Liu Yunqiang , Yang Xiling , Dong Qiang , Yang Bo , Xu Jinyan , Yan Yuanlong , Pei Xue , Liu Mohan , Xu Wenming , Yang Yuan
Published: May 2018

Testis-specific protein Y-linked 1 (TSPY1) is expressed predominantly in adult human spermatogonia and functions in the process of spermatogenesis; however, our understanding of the underlying mechanism is limited. Here we observed that TSPY1, as an interacting partner of TSPY-like 5 (TSPYL5), enhanced the competitive binding of TSPYL5 to ubiquitin-specific peptidase 7 (USP7) in conjunction with p53. This activity, together with its promotion of TSPYL5 expression by acting as a transcription factor, resulted in increased p53 ubiquitylation. Moreover, TSPY1 could decrease the p53 level by inducing the degradation of ubiquitinated USP7. We demonstrated that the promotion of p53 degradation by TSPY1 influenced the activity of p53 target molecules (CDK1, p21, and BAX) to expedite the G2/M phase transition and decrease cell apoptosis, accelerating cell proliferation. Taken together, the observations reveal the significance of TSPY1 as a suppressor of USP7-mediated p53 function in inhibiting p53-dependent cell proliferation arrest. By simulating TSPY1 function in Tspy1-deficient spermatogonia derived from mouse testes, we found that TSPY1 could promote spermatogonial proliferation by decreasing the Usp7-modulated p53 level. The findings suggest an additional mechanism underlying the regulation of spermatogonial p53 function, indicating the significance of TSPY1 in germline homeostasis maintenance and the potential of TSPY1 in regulating human spermatogonial proliferation via the USP7-mediated p53 signaling pathway.
MicroRNA-125b reverses oxaliplatin resistance in hepatocellular carcinoma by negatively regulating EVA1A mediated autophagy
Authors: Ren Wei-Wei , Li Dan-Dan , Chen Xiaolan , Li Xiao-Long , He Ya-Ping , Guo Le-Hang , Liu Lin-Na , Sun Li-Ping , Zhang Xiao-Ping
Published: May 2018

EVA1A (also known as transmembrane protein 166) is a transmembrane protein involved in the regulation of autophagy that acts as an adaptor protein to recruit or bind proteins in the lysosome or endoplasmic reticulum. In the present study, we identified EVA1A as a target of microRNA-125b (miR-125b), a member of a highly conserved family of miRNAs that has been proposed as a biomarker for hepatocellular carcinoma (HCC). Analysis of oxaliplatin-sensitive and oxaliplatin-resistant HCC cell lines showed that miR-125b is downregulated in resistant cells and its overexpression in sensitive cells decreased resistance to oxaliplatin by inhibiting cell proliferation, migration and epithelial–mesenchymal transition (EMT). EVA1A expression was shown to be upregulated in tissue samples from oxaliplatin-resistant HCC patients, and its ectopic expression partially induced autophagy and reversed the effect of miR-125b on inhibiting the growth of oxaliplatin-resistant cell lines and xenograft tumors. Taken together, our results suggest that miR-125b plays a role in the resistance of HCC cells to chemotherapy via a mechanism involving the downregulation of EVA1A-mediated autophagy.
CD47-ligation induced cell death in T-acute lymphoblastic leukemia
Authors: Leclair Pascal , Liu Chi-Chao , Monajemi Mahdis , Reid Gregor S. , Sly Laura M. , Lim Chinten James
Published: May 2018

CD47 is a cell-surface marker well recognized for its anti-phagocytic functions. As such, an emerging avenue for targeted cancer therapies involves neutralizing the anti-phagocytic function using monoclonal antibodies (mAbs) to enhance tumour cell immunogenicity. A lesser known consequence of CD47 receptor ligation is the direct induction of tumour cell death. While several mAbs and their derivatives with this property have been studied, the best characterized is the commercially available mAb B6H12, which requires immobilization for induction of cell death. Here, we describe a commercially available mAb, CC2C6, which induces T-cell acute lymphoblastic leukemia (ALL) cell death in soluble form. Soluble CC2C6 induces CD47-dependent cell death in a manner consistent with immobilized B6H12, which is characterized by mitochondrial deficiencies but is independent of caspase activation. Titration studies indicated that CC2C6 shares a common CD47-epitope with B6H12. Importantly, CC2C6 retains the anti-phagocytic neutralizing function, thus possessing dual anti-tumour properties. Although CD47-ligation induced cell death occurs in a caspase-independent manner, CC2C6 was found to stimulate increases in Mcl-1 and NOXA levels, two Bcl-2 family proteins that govern the intrinsic apoptosis pathway. Further analysis revealed that the ratio of Mcl-1:NOXA were minimally altered for cells treated with CC2C6, in comparison to cells treated with agents that induced caspase-dependent apoptosis which alter this ratio in favour of NOXA. Finally, we found that CC2C6 can synergize with low dose chemotherapeutic agents that induce classical apoptosis, giving rise to the possibility of an effective combination treatment with reduced long-term sequelae associated with high-dose chemotherapies in childhood ALL.
MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1α-mediated Warburg effect
Authors: Chen Zhiqiang , Zuo Xueliang , Zhang Yao , Han Guoyong , Zhang Long , Wu Jindao , Wang Xuehao
Published: May 2018

Glucose metabolic reprogramming from oxidative to aerobic glycolysis, referred as the Warburg effect, is a hallmark of tumor cells. Accumulating evidence suggests that a subset of microRNAs play pivotal roles in modulating such reprogramming of glucose metabolism in cancer cells. miR-3662 has been implicated previously in both pro-tumorigenic and anti-tumorigenic effects in several types of cancer. The expression level of miR-3662 is downregulated in acute myeloid leukemia, whereas increased miR-3662 expression is observed in lung adenocarcinoma. However, the roles and underlying mechanisms of miR-3662 in hepatocellular carcinoma (HCC) metabolic reprogramming remain unclear. Our present study revealed that miR-3662 was frequently downregulated in HCC tissues and cell lines. The low expression level of miR-3662 was associated with tumor size, tumor multiplicity, Edmondson grade, and tumor-node-metastasis stage. Gain-of-function and loss-of-function assays showed that miR-3662 dampened glycolysis by reducing lactate production, glucose consumption, cellular glucose-6-phosphate level, ATP generation, and extracellular acidification rate, and increasing oxygen consumption rate in HCC cells after treatment with the hypoxia mimetic CoCl2. Moreover, miR-3662 suppressed cell growth in vitro and in vivo, and induced G1/S cell cycle arrest. miR-3662 inhibited the activation of ERK and JNK signaling pathways in HCC. By combined computational and experimental approaches, hypoxia-inducible factor-1α (HIF-1α) was determined as a direct target of miR-3662. After treatment with the hypoxia mimetic CoCl2, miR-3662 regulated the Warburg effect and HCC progression via decreasing HIF-1α expression. Our findings uncover a mechanistic role for miR-3662/HIF-1α axis in HCC metabolic reprogramming, providing a potential therapeutic strategy in liver cancer.
BH4 domain peptides derived from Bcl-2/Bcl-XL as novel tools against acute pancreatitis
Authors: Vervliet Tim , Gerasimenko Julia V. , Ferdek Pawel E. , Jakubowska Monika A. , Petersen Ole H. , Gerasimenko Oleg V. , Bultynck Geert
Published: May 2018

Biliary acute pancreatitis (AP) is a serious condition, which currently has no specific treatment. Taurolithocholic acid 3-sulfate (TLC-S) is one of the most potent bile acids causing cytosolic Ca2+ overload in pancreatic acinar cells (PACs), which results in premature activation of digestive enzymes and necrosis, hallmarks of AP. The inositol 1,4,5-trisphosphate receptor (IP3R) and the ryanodine receptor (RyR) play major roles in intracellular Ca2+ signaling. Inhibition of these endoplasmic reticulum-located channels suppresses TLC-S-induced Ca2+ release and necrosis, decreasing the severity of AP. Anti-apoptotic B-cell lymphoma (Bcl)-2-family members, such as Bcl-2 and Bcl-XL, have emerged as important modulators of IP3Rs and RyRs. These proteins contain four Bcl-2 homology (BH) domains of which the N-terminal BH4 domain exerts critical roles in regulating intracellular Ca2+ release channels. The BH4 domain of Bcl-2, but not of Bcl-XL, binds to and inhibits IP3Rs, whereas both BH4 domains inhibit RyRs. Although clear cytoprotective effects have been reported for these BH4 domains, it remains unclear whether they are capable of inhibiting pathological Ca2+-overload, associated with AP. Here we demonstrate in PACs that the BH4 domains of Bcl-2 and Bcl-XL inhibit RyR activity in response to the physiological agonist cholecystokinin. In addition, these BH4 domains inhibit pathophysiological TLC-S-induced Ca2+ overload in PACs via RyR inhibition, which in turn protects these cells from TLC-S-induced necrosis. This study shows for the first time the therapeutic potential of BH4 domain function by inhibiting pathological RyR-mediated Ca2+ release and necrosis, events that trigger AP.
Hyperglycemia potentiates a shift from apoptosis to RIP1-dependent necroptosis
Authors: McCaig William D. , Patel Payal S. , Sosunov Sergey A. , Shakerley Nicole L. , Smiraglia Tori A. , Craft Miranda M. , Walker Katharine M. , Deragon Matthew A. , Ten Vadim S. , LaRocca Timothy J.
Published: May 2018

Apoptosis and necroptosis are the primary modes of eukaryotic cell death, with apoptosis being non-inflammatory while necroptosis is highly inflammatory. We previously demonstrated that, once activated, necroptosis is enhanced by hyperglycemia in several cell types. Here, we determine if hyperglycemia affects apoptosis similarly. We show that hyperglycemia does not enhance extrinsic apoptosis but potentiates a shift to RIP1-dependent necroptosis. This is due to increased levels and activity of RIP1, RIP3, and MLKL, as well as decreased levels and activity of executioner caspases under hyperglycemic conditions following stimulation of apoptosis. Cell death under hyperglycemic conditions was classified as necroptosis via measurement of markers and involvement of RIP1, RIP3, and MLKL. The shift to necroptosis was driven by RIP1, as mutation of this gene using CRISPR–Cas9 caused cell death to revert to apoptosis under hyperglycemic conditions. The shift of apoptosis to necroptosis depended on glycolysis and production of mitochondrial ROS. Importantly, the shift in PCD was observed in primary human T cells. Levels of RIP1 and MLKL increased, while executioner caspases and PARP1 cleavage decreased, in cerebral tissue from hyperglycemic neonatal mice that underwent hypoxia-ischemia (HI) brain injury, suggesting that this cell death shift occurs in vivo. This is significant as it demonstrates a shift from non-inflammatory to inflammatory cell death which may explain the exacerbation of neonatal HI-brain injury during hyperglycemia. These results are distinct from our previous findings where hyperglycemia enhanced necroptosis under conditions where apoptosis was inhibited artificially. Here we demonstrate a shift from apoptosis to necroptosis under hyperglycemic conditions while both pathways are fully active. Therefore, while our previous work documented that intensity of necroptosis is responsive to glucose, this work sheds light on the molecular balance between apoptosis and necroptosis and identifies hyperglycemia as a condition that pushes cells to undergo necroptosis despite the initial activation of apoptosis.
Precise control of SCRaMbLE in synthetic haploid and diploid yeast
Authors: Jia Bin , Wu Yi , Li Bing-Zhi , Mitchell Leslie A. , Liu Hong , Pan Shuo , Wang Juan , Zhang Hao-Ran , Jia Nan , Li Bo , Shen Michael , Xie Ze-Xiong , Liu Duo , Cao Ying-Xiu , Li Xia , Zhou Xiao , Qi Hao , Boeke Jef D. , Yuan Ying-Jin
Published: May 2018

Compatibility between host cells and heterologous pathways is a challenge for constructing organisms with high productivity or gain of function. Designer yeast cells incorporating the Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution (SCRaMbLE) system provide a platform for generating genotype diversity. Here we construct a genetic AND gate to enable precise control of the SCRaMbLE method to generate synthetic haploid and diploid yeast with desired phenotypes. The yield of carotenoids is increased to 1.5-fold by SCRaMbLEing haploid strains and we determine that the deletion of YEL013W is responsible for the increase. Based on the SCRaMbLEing in diploid strains, we develop a strategy called Multiplex SCRaMbLE Iterative Cycling (MuSIC) to increase the production of carotenoids up to 38.8-fold through 5 iterative cycles of SCRaMbLE. This strategy is potentially a powerful tool for increasing the production of bio-based chemicals and for mining deep knowledge.
Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence
Authors: Vera-Ramirez Laura , Vodnala Suman K. , Nini Ryan , Hunter Kent W. , Green Jeffrey E.
Published: May 2018

Cancer recurrence after initial diagnosis and treatment is a major cause of breast cancer (BC) mortality, which results from the metastatic outbreak of dormant tumour cells. Alterations in the tumour microenvironment can trigger signalling pathways in dormant cells leading to their proliferation. However, processes involved in the initial and the long-term survival of disseminated dormant BC cells remain largely unknown. Here we show that autophagy is a critical mechanism for the survival of disseminated dormant BC cells. Pharmacologic or genetic inhibition of autophagy in dormant BC cells results in significantly decreased cell survival and metastatic burden in mouse and human 3D in vitro and in vivo preclinical models of dormancy. In vivo experiments identify autophagy gene autophagy-related 7 (ATG7) to be essential for autophagy activation. Mechanistically, inhibition of the autophagic flux in dormant BC cells leads to the accumulation of damaged mitochondria and reactive oxygen species (ROS), resulting in cell apoptosis.
Heterozygous diploid and interspecies SCRaMbLEing
Authors: Shen Michael J. , Wu Yi , Yang Kun , Li Yunxiang , Xu Hui , Zhang Haoran , Li Bing-Zhi , Li Xia , Xiao Wen-Hai , Zhou Xiao , Mitchell Leslie A. , Bader Joel S. , Yuan Yingjin , Boeke Jef D.
Published: May 2018

SCRaMbLE (Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution) is a genome restructuring technique that can be used in synthetic genomes such as that of Sc2.0, the synthetic yeast genome, which contains hundreds to thousands of strategically positioned loxPsym sites. SCRaMbLE has been used to induce rearrangements in yeast strains harboring one or more synthetic chromosomes, as well as plasmid DNA in vitro and in vivo. Here we describe a collection of heterozygous diploid strains produced by mating haploid semisynthetic Sc2.0 strains to haploid native parental strains. We subsequently demonstrate that such heterozygous diploid strains are more robust to the effects of SCRaMbLE than haploid semisynthetic strains, rapidly improve rationally selected phenotypes in SCRaMbLEd heterozygous diploids, and establish that multiple sets of independent genomic rearrangements are able to lead to similar phenotype enhancements. Finally, we show that heterozygous diploid SCRaMbLE can also be carried out in interspecies hybrid strains.
Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer
Authors: Sarkar Anita , Bale Shridhar , Behrens Anna-Janina , Kumar Sonu , Sharma Shailendra Kumar , de Val Natalia , Pallesen Jesper , Irimia Adriana , Diwanji Devan C. , Stanfield Robyn L. , Ward Andrew B. , Crispin Max , Wyatt Richard T. , Wilson Ian A.
Published: May 2018

Furin cleavage of the HIV envelope glycoprotein is an essential step for cell entry that enables formation of well-folded, native-like glycosylated trimers, releases constraints on the fusion peptide, and limits enzymatic processing of the N-glycan shield. Here, we show that a cleavage-independent, stabilized, soluble Env trimer mimic (BG505 NFL.664) exhibits a “closed-form”, native-like, prefusion conformation akin to furin-cleaved Env trimers. The crystal structure of BG505 NFL.664 at 3.39 Å resolution with two potent bNAbs also identifies the full epitopes of PGV19 and PGT122 that target the receptor binding site and N332 supersite, respectively. Quantitative site-specific analysis of the glycan shield reveals that native-like glycan processing is maintained despite furin-independent maturation in the secretory pathway. Thus, cleavage-independent NFL Env trimers exhibit quaternary protein and carbohydrate structures similar to the native viral spike that further validate their potential as vaccine immunogen candidates.
A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica
Authors: Estrada Karol , Whelan Christopher W. , Zhao Fengmei , Bronson Paola , Handsaker Robert E. , Sun Chao , Carulli John P. , Harris Tim , Ransohoff Richard M. , McCarroll Steven A. , Day-Williams Aaron G. , Greenberg Benjamin M. , MacArthur Daniel G.
Published: May 2018

Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.
Optical functionalization of human Class A orphan G-protein-coupled receptors
Authors: Morri Maurizio , Sanchez-Romero Inmaculada , Tichy Alexandra-Madelaine , Kainrath Stephanie , Gerrard Elliot J. , Hirschfeld Priscila P. , Schwarz Jan , Janovjak Harald
Published: May 2018

G-protein-coupled receptors (GPCRs) form the largest receptor family, relay environmental stimuli to changes in cell behavior and represent prime drug targets. Many GPCRs are classified as orphan receptors because of the limited knowledge on their ligands and coupling to cellular signaling machineries. Here, we engineer a library of 63 chimeric receptors that contain the signaling domains of human orphan and understudied GPCRs functionally linked to the light-sensing domain of rhodopsin. Upon stimulation with visible light, we identify activation of canonical cell signaling pathways, including cAMP-, Ca2+-, MAPK/ERK-, and Rho-dependent pathways, downstream of the engineered receptors. For the human pseudogene GPR33, we resurrect a signaling function that supports its hypothesized role as a pathogen entry site. These results demonstrate that substituting unknown chemical activators with a light switch can reveal information about protein function and provide an optically controlled protein library for exploring the physiology and therapeutic potential of understudied GPCRs.
Author Correction: Towards an arthritis flare-responsive drug delivery system
Authors: Joshi Nitin , Yan Jing , Levy Seth , Bhagchandani Sachin , Slaughter Kai V. , Sherman Nicholas E. , Amirault Julian , Wang Yufeng , Riegel Logan , He Xueyin , Rui Tan Shi , Valic Michael , Vemula Praveen K. , Miranda Oscar R. , Levy Oren , Gravallese Ellen M. , Aliprantis Antonios O. , Ermann Joerg , Karp Jeffrey M.
Published: May 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 National Football League Players Association.
Discretization of the total magnetic field by the nuclear spin bath in fluorine-doped ZnSe
Authors: Zhukov E. A. , Kirstein E. , Kopteva N. E. , Heisterkamp F. , Yugova I. A. , Korenev V. L. , Yakovlev D. R. , Pawlis A. , Bayer M. , Greilich A.
Published: May 2018

The coherent spin dynamics of fluorine donor-bound electrons in ZnSe induced by pulsed optical excitation is studied in a perpendicular applied magnetic field. The Larmor precession frequency serves as a measure for the total magnetic field exerted onto the electron spins and, surprisingly, does not increase linearly with the applied field, but shows a step-like behavior with pronounced plateaus, given by multiples of the laser repetition rate. This discretization occurs by a feedback mechanism in which the electron spins polarize the nuclear spins, which in turn generate a local Overhauser field adjusting the total magnetic field accordingly. Varying the optical excitation power, we can control the plateaus, in agreement with our theoretical model. From this model, we trace the observed discretization to the optically induced Stark field, which causes the dynamic nuclear polarization.
Methionine metabolism influences genomic architecture and gene expression through H3K4me3 peak width
Authors: Dai Ziwei , Mentch Samantha J. , Gao Xia , Nichenametla Sailendra N. , Locasale Jason W.
Published: May 2018

Nutrition and metabolism are known to influence chromatin biology and epigenetics through post-translational modifications, yet how this interaction influences genomic architecture and connects to gene expression is unknown. Here we consider, as a model, the metabolically-driven dynamics of H3K4me3, a histone methylation mark that is known to encode information about active transcription, cell identity, and tumor suppression. We analyze the genome-wide changes in H3K4me3 and gene expression in response to alterations in methionine availability in both normal mouse physiology and human cancer cells. Surprisingly, we find that the location of H3K4me3 peaks is largely preserved under methionine restriction, while the response of H3K4me3 peak width encodes almost all aspects of H3K4me3 biology including changes in expression levels, and the presence of cell identity and cancer-associated genes. These findings may reveal general principles for how nutrient availability modulates specific aspects of chromatin dynamics to mediate biological function.
Vestigial nematic order and superconductivity in the doped topological insulator Cu
x
Bi2Se3
Authors: Hecker Matthias , Schmalian Jörg
Published: May 2018

If the topological insulator Bi2Se3 is doped with electrons, superconductivity with Tc = 3–4 K emerges for a low density of carriers (n = 1020 cm−3) and with a small ratio of the superconducting coherence length and Fermi wave length: ξ/λ
F
 = 2…4. These values make fluctuations of the superconducting order parameter increasingly important, to the extend that the Tc-value is surprisingly large. Strong spin–orbit interaction led to the proposal of an odd-parity pairing state. This begs the question of the nature of the transition in an unconventional superconductor with strong pairing fluctuations. We show that for a multi-component order parameter, these fluctuations give rise to a nematic phase at Tnem > Tc. Below Tc several experiments demonstrated a rotational symmetry breaking where the Cooper pair wave function is locked to the lattice. Our theory shows that this rotational symmetry breaking, as vestige of the superconducting state, already occurs above Tc. The nematic phase is characterized by vanishing off-diagonal long range order, yet with anisotropic superconducting fluctuations. It can be identified through direction-dependent para-conductivity, lattice softening, and an enhanced Raman response in the Eg symmetry channel. In addition, nematic order partially avoids the usual fluctuation suppression of Tc.
Author Correction: Sodium fluoride induces nephrotoxicity via oxidative stress-regulated mitochondrial SIRT3 signaling pathway
Authors: Song Chao , Fu Beibei , Zhang Jingcheng , Zhao Jiamin , Yuan Mengke , Peng Wei , Zhang Yong , Wu Haibo
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Systematic pan-cancer analysis of somatic allele frequency
Authors: Spurr Liam , Li Muzi , Alomran Nawaf , Zhang Qianqian , Restrepo Paula , Movassagh Mercedeh , Trenkov Chris , Tunnessen Nerissa , Apanasovich Tatiyana , Crandall Keith A. , Edwards Nathan , Horvath Anelia
Published: May 2018

Imbalanced expression of somatic alleles in cancer can suggest functional and selective features, and can therefore indicate possible driving potential of the underlying genetic variants. To explore the correlation between allele frequency of somatic variants and total gene expression of their harboring gene, we used the unique data set of matched tumor and normal RNA and DNA sequencing data of 5523 distinct single nucleotide variants in 381 individuals across 10 cancer types obtained from The Cancer Genome Atlas (TCGA). We analyzed the allele frequency in the context of the variant and gene functional features and linked it with changes in the total gene expression. We documented higher allele frequency of somatic variants in cancer-implicated genes (Cancer Gene Census, CGC). Furthermore, somatic alleles bearing premature terminating variants (PTVs), when positioned in CGC genes, appeared to be less frequently degraded via nonsense-mediated mRNA decay, indicating possible favoring of truncated proteins by the tumor transcriptome. Among the genes with multiple PTVs with high allele frequency, ARID1, TP53 and NSD1 were known key cancer genes. All together, our analyses suggest that high allele frequency of tumor somatic variants can indicate driving functionality and can serve to identify potential cancer-implicated genes.
Clinical, retrospective case-control study on the mechanics of obstacle in mouth opening and malocclusion in patients with maxillofacial fractures
Authors: Zhou Hai-Hua , Lv Kun , Yang Rong-Tao , Li Zhi , Yang Xue-Wen , Li Zu-Bing
Published: May 2018

This study aims to identify and distinguish various factors that may influence the clinical symptoms (limited mouth opening and malocclusion) in patients with maxillofacial fractures. From January 2000 to December 2009, 963 patients with maxillofacial fractures were enrolled in this statistical study to aid in evaluating the association between various risk factors and clinical symptoms. Patients with fractured posterior mandibles tended to experience serious limitation in mouth opening. Patients who sustained coronoid fractures have the highest risk of serious limitation in mouth opening (OR = 9.849), followed by arch fractures, maxilla fractures, condylar fractures, zygomatic complex fractures and symphysis fractures. Meanwhile, the combined fracture of zygomatic arch and condylar process results in normal or mild mouth opening. High risks of sustaining malocclusion are preceded by the fracture of nasal bone (OR = 3.067), mandible, condylar neck/base, combined fracture of zygomatic arch and condylar process, mandibular body, bilateral condylar, dental trauma, mandibular ramus, symphysis, mandibular angle and mid-facial. Patients who experienced serious limitation in mouth opening are treated with surgery more frequently (OR = 2.118). No relationship exists between the treatment options and the patients with malocclusion.
Author Correction: Genetic homogeneity of goat malaria parasites in Asia and Africa suggests their expansion with domestic goat host
Authors: Kaewthamasorn Morakot , Takeda Mika , Saiwichai Tawee , Gitaka Jesse N. , Tiawsirisup Sonthaya , Imasato Yuhei , Mossaad Ehab , Sarani Ali , Kaewlamun Winai , Channumsin Manun , Chaiworakul Suchart , Katepongpun Wichit , Teeveerapunya Surapong , Panthong Jarus , Mureithi Dominic K. , Bawm Saw , Htun Lat Lat , Win Mar Mar , Ismail Ahmed Ali , Ibrahim Abdalla Mohamed , Suganuma Keisuke , Hakimi Hassan , Nakao Ryo , Katakura Ken , Asada Masahito , Kaneko Osamu
Published: May 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 comprehensive bioinformatics analysis on multiple Gene Expression Omnibus datasets of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Authors: Huang Shanzhou , Sun Chengjun , Hou Yuchen , Tang Yunhua , Zhu Zebin , Zhang Zhiheng , Zhang Yixi , Wang Linhe , Zhao Qiang , Chen Mao-Gen , Guo Zhiyong , Wang Dongping , Ju Weiqiang , Zhou Qi , Wu Linwei , He Xiaoshun
Published: May 2018

Fatty liver disease is one of the leading causes of chronic damage in western countries. Approximately 25% of adults in the United States have fatty livers in the absence of excessive alcohol consumption, a condition termed nonalcoholic fatty liver disease (NAFLD). Little is known about the prevalence and genetic background of NAFLD or the factors that determine its development. In this study, we used the Gene-Cloud of Biotechnology Information bioinformatics platform to carry out a comprehensive bioinformatics analysis identifying differentially expressed genes (DEGs), key biological processes and intersecting pathways. We imported 3 Gene Expression Omnibus datasets (GSE66676, GSE49541, and GSE83452). Then, we assessed the expression of the DEGs in clinical samples. We found that CD24 was the only gene co-expressed in all 3 datasets. “Glycolysis/gluconeogenesis”, “p53 signaling pathway” and “glycine, serine and threonine metabolism” were 3 common pathways related to the fatty liver process. In NAFLD tissues, CD24, COL1A1, LUM, THBS2 and EPHA3 were upregulated, and PZP was downregulated. CD24 is a core gene among these DEGs and have not yet been studied of its impact on NAFLD. Co-expressed genes, common biological processes and intersecting pathways identified in the study might play an important role in NAFLD progression. Further studies are needed to elucidate the mechanism of these potential genes and pathways in NAFLD.