bluuebunny/crossref_metadata_2025 huggingface dataset:
ITERATING SYMMETRIC EXTENSIONS
Authors: KARAGILA ASAF
Published: March 2019

The notion of a symmetric extension extends the usual notion of forcing by identifying a particular class of names which forms an intermediate model of $ZF$ between the ground model and the generic extension, and often the axiom of choice fails in these models. Symmetric extensions are generally used to prove choiceless consistency results. We develop a framework for iterating symmetric extensions in order to construct new models of $ZF$. We show how to obtain some well-known and lesser-known results using this framework. Specifically, we discuss Kinna–Wagner principles and obtain some results related to their failure.
Pacific walrus diet across 4000 years of changing sea ice conditions
Authors: Clark Casey T. , Horstmann Lara , de Vernal Anne , Jensen Anne M. , Misarti Nicole
Published: March 2019

Declining sea ice is expected to change the Arctic's physical and biological systems in ways that are difficult to predict. This study used stable isotope compositions (δ13C and δ15N) of archaeological, historic, and modern Pacific walrus (Odobenus rosmarus divergens) bone collagen to investigate the impacts of changing sea ice conditions on walrus diet during the last ~4000 yr. An index of past sea ice conditions was generated using dinocyst-based reconstructions from three locations in the northeastern Chukchi Sea. Archaeological walrus samples were assigned to intervals of high and low sea ice, and δ13C and δ15N were compared across ice states. Mean δ13C and δ15N values were similar for archaeological walruses from intervals of high and low sea ice; however, variability among walruses was greater during low-ice intervals, possibly indicating decreased availability of preferred prey. Overall, sea ice conditions were not a primary driver of changes in walrus diet. The diet of modern walruses was not consistent with archaeological low sea ice intervals. Rather, the low average trophic position of modern walruses (primarily driven by males), with little variability among individuals, suggests that trophic changes to this Arctic ecosystem are still underway or are unprecedented in the last ~4000 yr.
Stuck in a negative me: fMRI study on the role of disturbed self-views in social feedback processing in borderline personality disorder
Authors: van Schie Charlotte C. , Chiu Chui-De , Rombouts Serge A. R. B. , Heiser Willem J. , Elzinga Bernet M.
Published: March 2019

Background

Interpersonal difficulties in borderline personality disorder (BPD) could be related to the disturbed self-views of BPD patients. This study investigates affective and neural responses to positive and negative social feedback (SF) of BPD patients compared with healthy (HC) and low self-esteem (LSE) controls and how this relates to individual self-views.

Methods

BPD (N = 26), HC (N = 32), and LSE (N = 22) performed a SF task in a magnetic resonance imaging scanner. Participants received 15 negative, intermediate and positive evaluative feedback words putatively given by another participant and rated their mood and applicability of the words to the self.

Results

BPD had more negative self-views than HC and felt worse after negative feedback. Applicability of feedback was a less strong determinant of mood in BPD than HC. Increased precuneus activation was observed in HC to negative compared with positive feedback, whereas in BPD, this was similarly low for both valences. HC showed increased temporoparietal junction (TPJ) activation to positive v. negative feedback, while BPD showed more TPJ activation to negative feedback. The LSE group showed a different pattern of results suggesting that LSE cannot explain these findings in BPD.

Conclusions

The negative self-views that BPD have, may obstruct critically examining negative feedback, resulting in lower mood. Moreover, where HC focus on the positive feedback (based on TPJ activation), BPD seem to focus more on negative feedback, potentially maintaining negative self-views. Better balanced self-views may make BPD better equipped to deal with potential negative feedback and more open to positive interactions.
Chronic hepatitis B and C infections in the Netherlands: estimated prevalence in risk groups and the general population
Authors: Koopsen J. , van Steenbergen J. E. , Richardus J. H. , Prins M. , Op de Coul E. L. M. , Croes E. A. , Heil J. , Zuure F. R. , Veldhuijzen I. K.
Published: March 2019

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are usually asymptomatic for decades, thus targeted screening can prevent liver disease by timely diagnosis and linkage to care. More robust estimates of chronic HBV and HCV infections in the general population and risk groups are needed. Using a modified workbook method, the total number of ever chronically infected individuals in the Netherlands in 2016 was determined using population size and prevalence estimates from studies in the general and high-risk population. The estimated 2016 chronic HBV infection prevalence is 0.34% (low 0.22%, high 0.47%), corresponding to approximately 49 000 (low 31 000, high 66 000) HBV-infected individuals aged 15 years and older. The estimated ever-chronic HCV infection prevalence is 0.16% (low 0.06%, high 0.27%), corresponding to approximately 23 000 (low 8000, high 38 000) ever-chronic HCV-infected individuals. The prevalence of chronic HBV and HCV infections in the Netherlands is low. First-generation migrants account for most infections with 81% and 60% of chronic HBV and HCV infections, respectively. However, about one-fifth of HCV infections is found in the general population at low risk. This method can serve as an example for countries in need of more accurate prevalence estimates, to help the design and evaluation of prevention and control policies.
Secondary Fluorescence Correction for Characteristic and Bremsstrahlung X-Rays Using Monte Carlo X-ray Depth Distributions Applied to Bulk and Multilayer Materials
Authors: Yuan Yu , Demers Hendrix , Rudinsky Samantha , Gauvin Raynald
Published: March 2019

Secondary fluorescence effects are important sources of characteristic X-ray emissions, especially for materials with complicated geometries. Currently, three approaches are used to calculate fluorescence X-ray intensities. One is using Monte Carlo simulations, which are accurate but have drawbacks such as long computation times. The second one is to use analytical models, which are computationally efficient, but limited to specific geometries. The last approach is a hybrid model, which combines Monte Carlo simulations and analytical calculations. In this article, a program is developed by combining Monte Carlo simulations for X-ray depth distributions and an analytical model to calculate the secondary fluorescence. The X-ray depth distribution curves of both the characteristic and bremsstrahlung X-rays obtained from Monte Carlo program MC X-ray allow us to quickly calculate the total fluorescence X-ray intensities. The fluorescence correction program can be applied to both bulk and multilayer materials. Examples for both cases are shown. Simulated results of our program are compared with both experimental data from the literature and simulation data from PENEPMA and DTSA-II. The practical application of the hybrid model is presented by comparing with the complete Monte Carlo program.
Origins and Pathways of the Pacific Equatorial Undercurrent Identified by a Simulated Adjoint Tracer
Authors: Nie Xunwei , Gao Shan , Wang Fan , Chi Jianwei , Qu Tangdong
Published: March 2019

The origins and pathways of the Pacific Equatorial Undercurrent (EUC) are investigated using a simulated adjoint tracer of the consortium Estimating the Circulation and Climate of the Ocean. The main source waters of the EUC, as well as their transit time and contributions, are identified. The zonal variability of the EUC water composition and the contributions from different pathways are also estimated. Results show that the ratio of the EUC water coming from the tropics to that from extratropics is relatively stable (1 vs. 4) along the equator, except in the western Pacific where extratropical water is more dominant. The main body of extratropical water within the EUC is transported through the western boundary pathways, while the percent transported via the interior pathways gradually increases toward the east. Tropical water merges into the EUC mainly through the tropical cells with a larger portion through the northern side of the equator.
Evaluation of Space Traffic Effects in SBUV Polar Mesospheric Cloud Data
Authors: DeLand Matthew T. , Thomas Gary E.
Published: March 2019

Water‐rich rocket exhaust plumes, in particular those emitted by the National Aeronautics and Space Administration Space Shuttle, have been suggested to make a significant contribution to long‐term trends in polar mesospheric cloud (PMC) ice water content. We investigate this claim using the combined Solar Backscatter Ultraviolet (SBUV) PMC data record from eight separate instruments, which includes 60 Shuttle launches during PMC seasons between 1985 and 2011. No statistically significant postlaunch signal in PMC total ice is observed based on superposed epoch analysis of the SBUV record. Only a few launches show individual peaks in total ice anomaly above the seasonal background that exceed an empirical threshold, and the maximum cumulative signature from these infrequent cases is typically less than 5% of the season total in ice mass. Other non‐Shuttle launches show circumstantial evidence of possible PMC effects, although supporting evidence for plume transport is not available. We conclude that space traffic effects have been a negligible component of long‐term PMC behavior.
Monitoring of the field application of Metarhizium anisopliae in Brazil revealed high molecular diversity of Metarhizium spp in insects, soil and sugarcane roots
Authors: Iwanicki Natasha Sant′Anna , Pereira Alessandro Alves , Botelho Ana Beatriz Riguetti Zanardo , Rezende Janayne Maria , Moral Rafael de Andrade , Zucchi Maria Imaculada , Delalibera Júnior Italo
Published: March 2019

The use of Metarhizium against sugarcane spittlebugs in Brazil is one of the most successful and long lasting biological control programs using entomopathogenic fungus in the world. However, studies to monitor the fate of this fungus on the sugarcane agroecosystem are rare, especially with respect to its persistence, efficacy in pest control and impact on the local populations of Metarhizium. The present study aimed at documenting the efficacy and persistence of M. anisopliae strain ESALQ1604 in a sugarcane field by using microsatellite molecular markers. The species diversity of Metarhizium was characterized in insects, soil and sugarcane roots in a sprayed and an unsprayed plot. Although the infection rates were not very high (≤ 50%), the applied strain was recovered from spittlebugs after 7, 30 and 60 days’ post-application, but accounted for only 50%, 50% and 70.5% of all insects killed by M. anisopliae, respectively. All haplotypes from spittlebug were associated with a single subclade of M. anisopliae. The highest haplotype diversity was found in soil (h = 0.989) and in the smallest in spittlebug (h = 0.779). Metarhizium robertsii, M. anisopliae, M. brunneum; one taxonomically unassigned lineage was found in soil and only M. brunneum and M. anisopliae were isolated from roots. This study revealed the great diversity of Metarhizium spp. in the sugarcane agroecosystem and the importance of the local population of M. anisopliae on spittlebugs management.
The pharmacological and functional characterization of the serotonergic system in Anopheles gambiae and Aedes aegypti: influences on flight and blood-feeding behavior
Authors: Ngai Michelle , Shoue Douglas A. , Loh Zoe , McDowell Mary Ann
Published: March 2019

Aedes aegypti and Anopheles gambiae harbor the causative agents of diseases such as dengue fever and malaria, afflicting human morbidity and mortality worldwide. Given the worldwide emergence of resistance to insecticides, the current mainstay for vector control, identification of alternative modes of action for future insecticides is paramount. The serotonergic (5-HT) system has been documented to impact physiological mechanisms involved in disease transmission, suggesting its potential as a new mode of action target for future insecticide development. Target 5-HT receptors were cloned and expressed in the HEK293 cell line for functional and pharmacological characterization. Manipulation of the 5-HT system through microinjection of compounds suggests its involvement in the modulation of flight performance and blood-feeding behavior. By attenuating these two determinants of vectorial capacity, transmission and burden of disease could effectively be reduced. Considering these positive global health implications, the 5-HT system is a compelling target for the novel insecticide pipeline.
Corneal remodelling and topography following biological inlay implantation with combined crosslinking in a rabbit model
Authors: Damgaard Iben Bach , Liu Yu-Chi , Riau Andri Kartasasmita , Teo Ericia Pei Wen , Tey Min Li , Nyein Chan Lwin , Mehta Jodhbir Singh
Published: March 2019

Implantation of biological corneal inlays, derived from small incision lenticule extraction, may be a feasible method for surgical management of refractive and corneal diseases. However, the refractive outcome is dependent on stromal remodelling of both the inlay and recipient stroma. This study aimed to investigate the refractive changes and tissue responses following implantation of 2.5-mm biological inlays with or without corneal collagen crosslinking (CXL) in a rabbit model. Prior to implantation, rotational rheometry demonstrated an almost two-fold increase in corneal stiffness after CXL. After implantation, haze gradually subsided in the CXL-treated inlays (p = 0.001), whereas the untreated inlays preserved their clarity (p = 0.75).In-vivoconfocal microscopy revealed reduced keratocyte cell count at the interface of the CXL inlays at week 8. Following initial steepening, regression was observed in anterior mean curvature from week 1 to 12, being most prominent for the non-CXL subgroups (non-CXL: −12.3 ± 2.6D vs CXL: −2.3 ± 4.4D at 90 μm depth, p = 0.03; non-CXL: −12.4 ± 8.0D vs CXL: −5.0 ± 4.0D at 120 μm depth, p = 0.22). Immunohistochemical analysis revealed comparable tissue responses in CXL and untreated subgroups. Our findings suggest that CXL of biological inlays may reduce the time before refractive stabilization, but longer postoperative steroid treatment is necessary in order to reduce postoperative haze.
Depiction of Oral Tumor-Induced Trigeminal Afferent Responses Using Single-Fiber Electrophysiology
Authors: Grayson Max , Furr Ashley , Ruparel Shivani
Published: March 2019

Considerable gap in knowledge exists about the mechanisms by which oral tumors regulate peripheral sensory fibers to produce pain and altered sensations. To address this gap, we used a murine model of oral squamous cell carcinoma (OSCC) of the tongue to investigate changes in response properties of trigeminal afferent neurons. Using this model, we developed an ex vivo method for single neuron recordings of the lingual nerve from isolated tongue tissue. Our data demonstrated that the tongue tumor produced increased spontaneous firing of lingual fibers compared to control as well as produced mechanical hypersensitivity and reduced von Frey thresholds of C- and A-slow-high-threshold mechanoreceptors (HTMR) fibers but had no effect on C-LTMR, A-slow-LTMR and A-fast lingual fibers. Mechanically-insensitive fibers were also detected in lingual afferents of the control group, that were significantly decreased in tumor-bearing preparations. Collectively, using single fiber electrophysiology of lingual sensory fibers, we show that human OSCC tumors sensitize peripheral trigeminal nerve terminals, providing a unique opportunity to study mechanisms of oral cancer pain.
A simple genotyping method to detect small CRISPR-Cas9 induced indels by agarose gel electrophoresis
Authors: Bhattacharya Debanjan , Van Meir Erwin G.
Published: March 2019

CRISPR gene editing creates indels in targeted genes that are detected by genotyping. Separating PCR products generated from wild-type versus mutant alleles with small indels based on size is beyond the resolution capacity of regular agarose gel electrophoresis. To overcome this limitation, we developed a simple genotyping method that exploits the differential electrophoretic mobility of homoduplex versus heteroduplex DNA hybrids in high concentration agarose gels. First, the CRISPR target region is PCR amplified and homo- and hetero-duplexed amplicons formed during the last annealing cycle are separated by 4–6% agarose gel electrophoresis. WT/mutant heteroduplexes migrate more slowly and are distinguished from WT or mutant homoduplexes. Heterozygous alleles are immediately identified as they produce two distinct bands, while homozygous wild-type or mutant alleles yield a single band. To discriminate the latter, equal amounts of PCR products of homozygous samples are mixed with wild-type control samples, subjected to one denaturation/renaturation cycle and products are electrophoresed again. Samples from homozygous mutant alleles now produce two bands, while those from wild-type alleles yield single bands. This method is simple, fast and inexpensive and can identify indels >2 bp. in size in founder pups and genotype offspring in established transgenic mice colonies.
Changes in the asymmetric distribution of cholesterol in the plasma membrane influence streptolysin O pore formation
Authors: Ogasawara Fumihiko , Kano Fumi , Murata Masayuki , Kimura Yasuhisa , Kioka Noriyuki , Ueda Kazumitsu
Published: March 2019

ATP-binding cassette A1 (ABCA1) plays a key role in generating high-density lipoprotein (HDL) and preventing atherosclerosis. ABCA1 exports cholesterol and phospholipid to apolipoprotein A-I (apoA-I) in serum to generate HDL. We found that streptolysin O (SLO), a cholesterol-dependent pore-forming toxin, barely formed pores in ABCA1-expressing cells, even in the absence of apoA-I. Neither cholesterol content in cell membranes nor the amount of SLO bound to cells was affected by ABCA1. On the other hand, binding of the D4 domain of perfringolysin O (PFO) to ABCA1-expressing cells increased, suggesting that the amount of cholesterol in the outer leaflet of the plasma membrane (PM) increased and that the cholesterol dependences of these two toxins differ. Addition of cholesterol to the PM by the MβCD–cholesterol complex dramatically restored SLO pore formation in ABCA1-expressing cells. Therefore, exogenous expression of ABCA1 causes reduction in the cholesterol level in the inner leaflet, thereby suppressing SLO pore formation.
Evolutionary history and palaeoecology of brown bear in North-East Siberia re-examined using ancient DNA and stable isotopes from skeletal remains
Authors: Rey-Iglesia Alba , García-Vázquez Ana , Treadaway Eve C. , van der Plicht Johannes , Baryshnikov Gennady F. , Szpak Paul , Bocherens Hervé , Boeskorov Gennady G. , Lorenzen Eline D.
Published: March 2019

Over 60% of the modern distribution range of brown bears falls within Russia, yet palaeoecological data from the region remain scarce. Complete modern Russian brown bear mitogenomes are abundant in the published literature, yet examples of their ancient counterparts are absent. Similarly, there is only limited stable isotopic data of prehistoric brown bears from the region. We used ancient DNA and stable carbon (δ13C) and nitrogen (δ15N) isotopes retrieved from five Pleistocene Yakutian brown bears (one Middle Pleistocene and four Late Pleistocene), to elucidate the evolutionary history and palaeoecology of the species in the region. We were able to reconstruct the complete mitogenome of one of the Late Pleistocene specimens, but we were unable to assign it to any of the previously published brown bear mitogenome clades. A subsequent analysis of published mtDNA control region sequences, which included sequences of extinct clades from other geographic regions, assigned the ancient Yakutian bear to the extinct clade 3c; a clade previously identified from Late Quaternary specimens from Eastern Beringia and Northern Spain. Our analyses of stable isotopes showed relatively high δ15N values in the Pleistocene Yakutian brown bears, suggesting a more carnivorous diet than contemporary brown bears from Eastern Beringia.
Effective high compression of ECG signals at low level distortion
Authors: Rebollo-Neira Laura
Published: March 2019

An effective method for compression of ECG signals, which falls within the transform lossy compression category, is proposed. The transformation is realized by a fast wavelet transform. The effectiveness of the approach, in relation to the simplicity and speed of its implementation, is a consequence of the efficient storage of the outputs of the algorithm which is realized in compressed Hierarchical Data Format. The compression performance is tested on the MIT-BIH Arrhythmia database producing compression results which largely improve upon recently reported benchmarks on the same database. For a distortion corresponding to a percentage root-mean-square difference (PRD) of 0.53, in mean value, the achieved average compression ratio is 23.17 with quality score of 43.93. For a mean value of PRD up to 1.71 the compression ratio increases up to 62.5. The compression of a 30 min record is realized in an average time of 0.14 s. The insignificant delay for the compression process, together with the high compression ratio achieved at low level distortion and the negligible time for the signal recovery, uphold the suitability of the technique for supporting distant clinical health care.
Primary neurons can enter M-phase
Authors: Walton Chaska C. , Zhang Wei , Patiño-Parrado Iris , Barrio-Alonso Estíbaliz , Garrido Juan-José , Frade José M.
Published: March 2019

Differentiated neurons can undergo cell cycle re-entry during pathological conditions, but it remains largely accepted that M-phase is prohibited in these cells. Here we show that primary neurons at post-synaptogenesis stages of development can enter M-phase. We induced cell cycle re-entry by overexpressing a truncated Cyclin E isoform fused to Cdk2. Cyclin E/Cdk2 expression elicits canonical cell cycle checkpoints, which arrest cell cycle progression and trigger apoptosis. As in mitotic cells, checkpoint abrogation enables cell cycle progression through S and G2-phases into M-phase. Although most neurons enter M-phase, only a small subset undergo cell division. Alternatively, neurons can exit M-phase without cell division and recover the axon initial segment, a structural determinant of neuronal viability. We conclude that neurons and mitotic cells share S, G2 and M-phase regulation.
Structure and evolutionary implications of the earliest (Sinemurian, Early Jurassic) dinosaur eggs and eggshells
Authors: Stein Koen , Prondvai Edina , Huang Timothy , Baele Jean-Marc , Sander P. Martin , Reisz Robert
Published: March 2019

One of the fossil record’s most puzzling features is the absence of preserved eggs or eggshell for the first third of the known 315 million year history of amniote evolution. Our meagre understanding of the origin and evolution of calcareous eggshell and amniotic eggs in general, is largely based on Middle Jurassic to Late Cretaceous fossils. For dinosaurs, the most parsimonious inference yields a thick, hard shelled egg, so richly represented in the Late Cretaceous fossil record. Here, we show that a thin calcareous layer (≤100 µm) with interlocking units of radiating crystals (mammillae) and a thick shell membrane already characterize the oldest known amniote eggs, belonging to three coeval, but widely distributed Early Jurassic basal sauropodomorph dinosaurs. This thin shell layer strongly contrasts with the considerably thicker calcareous shells of Late Jurassic dinosaurs. Phylogenetic analyses and their Sinemurian age indicate that the thin eggshell of basal sauropodomorphs represents a major evolutionary innovation at the base of Dinosauria and that the much thicker eggshell of sauropods, theropods, and ornithischian dinosaurs evolved independently. Advanced mineralization of amniote eggshell (≥150 µm in thickness) in general occurred not earlier than Middle Jurassic and may correspond with a global trend of increase in atmospheric oxygen.
Interindividual neural differences in moral decision-making are mediated by alpha power and delta/theta phase coherence
Authors: Wolff Annemarie , Gomez-Pilar Javier , Nakao Takashi , Northoff Georg
Published: March 2019

As technology in Artificial Intelligence has developed, the question of how to program driverless cars to respond to an emergency has arisen. It was recently shown that approval of the consequential behavior of driverless cars varied with the number of lives saved and showed interindividual differences, with approval increasing alongside the number of lives saved. In the present study, interindividual differences in individualized moral decision-making at both the behavioral and neural level were investigated using EEG. It was found that alpha event-related spectral perturbation (ERSP) and delta/theta phase-locking – intertrial coherence (ITC) and phase-locking value (PLV) – play a central role in mediating interindividual differences in Moral decision-making. In addition, very late alpha activity differences between individualized and shared stimuli, and delta/theta ITC, where shown to be closely related to reaction time and subjectively perceived emotional distress. This demonstrates that interindividual differences in Moral decision-making are mediated neuronally by various markers – late alpha ERSP, and delta/theta ITC - as well as psychologically by reaction time and perceived emotional distress. Our data show, for the first time, how and according to which neuronal and behavioral measures interindividual differences in Moral dilemmas can be measured.
Simvastatin reduces the carcinogenic effect of 3-methylcholanthrene in renal epithelial cells through histone deacetylase 1 inhibition and RhoA reactivation
Authors: Chang Chih-Cheng , Huang Kuo-How , Hsu Sung-Po , Lee Yuan-Chii G. , Sue Yuh-Mou , Juan Shu-Hui
Published: March 2019

The therapeutic effects of simvastatin for renal cell carcinoma (RCC) are controversial. In this study, the effects of simvastatin on the carcinogenic properties of 3-methylcholanthrene (3MC; an aryl-hydrocarbon receptor [AhR] agonist) in human renal epithelial cells (hRECs) were investigated. We exposed in vitro and in vivo models to 3MC to induce RCC onset. 3MC upregulated the epithelial–mesenchymal transition (EMT) and tumor biomarkers; the models exhibited the reciprocal expression of histone deacetylase 1 (HDAC1) and RhoA, namely increased HDAC1 and decreased RhoA expression, through hypoxia-inducible-factor (HIF)- and AhR-dependent mechanisms. In addition to inducing EMT biomarkers, 3MC decreased von Hippel–Lindau protein levels (a risk factor for RCC) and increased CD44 expression in hRECs, which were reversed by digoxin (a HIF inhibitor) and HDAC inhibitors (suberoylanilide hydroxamic acid and trichostatin A [TSA]). Simvastatin abolished the detrimental effects of 3MC by reducing HDAC1 expression, with resulting RhoA upregulation, and reactivating RhoA in vitro and in vivo. Notably, the protective effects of simvastatin were negated by an HDAC activator (ITSA) through TSA suppression. The crucial role of RhoA in RCC carcinogenesis was verified by the overexpression of constitutively active RhoA. Collectively, these results demonstrate that simvastatin restores RhoA function through HDAC1 inhibition; therefore, simvastatin might serve as adjunct therapy for RCC induced by 3MC.
Differential transactivation of the upstream aggrecan enhancer regulated by PAX1/9 depends on SOX9-driven transactivation
Authors: Takimoto Aki , Kokubu Chikara , Watanabe Hitomi , Sakuma Tetsushi , Yamamoto Takashi , Kondoh Gen , Hiraki Yuji , Shukunami Chisa
Published: March 2019

A previously identified enhancer 10 kb upstream of the Aggrecan (Acan) gene (UE) can drive cartilage specific reporter expression in vivo. Here, we report that the paralogous transcription factors PAX1 and PAX9 differentially drive UE, depending on the presence or absence of SOX9-driven transactivation. In the developing vertebral column, PAX1/9 expression was inversely correlated with Acan expression. Moreover, PAX1/9 was co-expressed with SOX9/5/6 in the intervertebral mesenchyme and the inner annulus fibrosus (AF), and with SOX9 in the outer AF. Significant Acan upregulation was observed during chondrification of Pax1-silenced AF cells, while, Acan was significantly downregulated by persistent expression of Pax1 in cartilage. Deletion of UE using CRISPR/Cas9 resulted in ~30% and ~40% reduction of Acan expression in cartilage and the AF, respectively. In the UE, PAX1/9 acts as weak transactivators through a PAX1/9-binding site partially overlapped with a SOX9-binding site. In the presence of SOX9, which otherwise drives robust Acan expression along with SOX5/6, PAX1/9 competes with SOX9 for occupancy of the binding site, resulting in reduced transactivation of Acan. Coimmunoprecipitation revealed the physical interaction of Pax1 with SOX9. Thus, transactivation of the UE is differentially regulated by concerted action of PAX1/9, SOX9, and SOX5/6 in a context-dependent manner.
The association analysis between HLA-A*26 and Behçet’s disease
Authors: Nakamura Jutaro , Meguro Akira , Ishii Genji , Mihara Takahiro , Takeuchi Masaki , Mizuki Yuki , Yuda Kentaro , Yamane Takahiro , Kawagoe Tatsukata , Ota Masao , Mizuki Nobuhisa
Published: March 2019

The strongest genetic risk factor of Behçet’s disease (BD) is HLA-B*51. Our group previously reported that HLA-A*26 is independently associated with the risk of the onset of BD apart from HLA-B*51. Here, we re-evaluated the association between HLA-A*26 and BD in the Japanese population. We also performed a comprehensive literature search and meta-analyzed the extracted published data concerning the relationship between HLA-A*26 and BD to estimate the odds ratio (OR) of HLA-A*26 to BD. In this study, we genotyped 611 Japanese BD patients and 2,955 unrelated ethnically matched healthy controls. Genotyping results showed that the phenotype frequency of HLA-A*26 was higher in BD patients than in controls (OR = 2.12, 95% CI: 1.75–2.56). Furthermore, within the HLA-B*51-negative populations, the phenotype frequency of HLA-A*26 was significantly higher in BD patients than in controls (OR = 3.10, 95% CI: 2.43–3.95). Results obtained from meta-analysis combined with our data showed that the modified OR of HLA-A*26 became 1.80 (95% CI:1.58–2.06), whereas within the HLA-B*51-negative population, the modified OR became 4.02 (95% CI: 2.29–7.05). A subgroup analysis arranged by the geographical regions showed HLA-A*26 is in fact associated with the onset of BD in Northeast Asia (OR = 2.11, 95% CI: 1.75–2.56), but not in the Middle East or in Europe.
Clathrin Adaptor Complex-interacting Protein Irc6 Functions through the Conserved C-Terminal Domain
Authors: Zhou Huajun , Costaguta Giancarlo , Payne Gregory S.
Published: March 2019

Clathrin coats drive transport vesicle formation from the plasma membrane and in pathways between the trans-Golgi network (TGN) and endosomes. Clathrin adaptors play central roles orchestrating assembly of clathrin coats. The yeast clathrin adaptor-interacting protein Irc6 is an orthologue of human p34, which is mutated in the inherited skin disorder punctate palmoplantar keratoderma type I. Irc6 and p34 bind to clathrin adaptor complexes AP-1 and AP-2 and are members of a conserved family characterized by a two-domain architecture. Irc6 is required for AP-1-dependent transport between the TGN and endosomes in yeast. Here we present evidence that the C-terminal two amino acids of Irc6 are required for AP-1 binding and transport function. Additionally, like the C-terminal domain, the N-terminal domain when overexpressed partially restores AP-1-mediated transport in cells lacking full-length Irc6. These findings support a functional role for Irc6 binding to AP-1. Negative genetic interactions with irc6∆ are enriched for genes related to membrane traffic and nuclear processes, consistent with diverse cellular roles for Irc6.
Sensitization and synergistic anti-cancer effects of Furanodiene identified in zebrafish models
Authors: Zhu Xiao-Yu , Guo Dian-Wu , Lao Qiao-Cong , Xu Yi-Qiao , Meng Zhao-Ke , Xia Bo , Yang Hua , Li Chun-Qi , Li Ping
Published: March 2019

Furanodiene is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anticancer effects in various types of cancer cell lines. In this study, we have successfully established zebrafish xenografts with 5 various human cancer cell lines; and validated these models with anti-cancer drugs used clinically for treating human cancer patients. We found that Furanodiene was therapeutically effective for human JF 305 pancreatic cancer cells and MCF-7 breast cancer cells xenotranplanted into zebrafish. Furanodiene showed a markedly synergistic anti-cancer effect when used in combination with 5-FU (5-Fluorouracil) for both human breast cancer MDA-MB-231 cells and human liver cancer BEL-7402 cells xenotransplanted into zebrafish. Unexpectedly, Furanodiene reversed multiple drug resistance in the zebrafish xenotransplanted with cis-Platinum-resistant human non-small cell lung cancer cells and Adriamycin-resistant human breast cancer cells. Furanodiene played its anti-cancer effects through anti-angiogenesis and inducing ROS production, DNA strand breaks and apoptosis. Furanodiene suppresseed efflux transporter Pgp (P-glycoprotein) function and reduced Pgp protein level, but no effect on Pgp related gene (MDR1) expression. These results suggest sensitizition and synergistic anti-cancer effects of Furanodiene that is worthy of a further investigation.
Simulating Anisotropic quantum Rabi model via frequency modulation
Authors: Wang Gangcheng , Xiao Ruoqi , Shen H. Z. , Sun Chunfang , Xue Kang
Published: March 2019

Anisotropic quantum Rabi model is a generalization of quantum Rabi model, which allows its rotating and counter-rotating terms to have two different coupling constants. It provides us with a fundamental model to understand various physical features concerning quantum optics, solid-state physics, and mesoscopic physics. In this paper, we propose an experimental feasible scheme to implement anisotropic quantum Rabi model in a circuit quantum electrodynamics system via periodic frequency modulation. An effective Hamiltonian describing the tunable anisotropic quantum Rabi model can be derived from a qubit-resonator coupling system modulated by two periodic driving fields. All effective parameters of the simulated system can be adjusted by tuning the initial phases, the frequencies and the amplitudes of the driving fields. We show that the periodic driving is able to drive a coupled system in dispersive regime to ultrastrong coupling regime, and even deep-strong coupling regime. The derived effective Hamiltonian allows us to obtain pure rotating term and counter-rotating term. Numerical simulation shows that such effective Hamiltonian is valid in ultrastrong coupling regime, and stronger coupling regime. Moreover, our scheme can be generalized to the multi-qubit case. We also give some applications of the simulated system to the Schrödinger cat states and quantum gate generalization. The presented proposal will pave a way to further study the stronger anisotropic Rabi model whose coupling strength is far away from ultrastrong coupling and deep-strong coupling regimes in quantum optics.
Molecular dynamic simulations of oxidized skin lipid bilayer and permeability of reactive oxygen species
Authors: Yadav Dharmendra Kumar , Kumar Surendra , Choi Eun-Ha , Chaudhary Sandeep , Kim Mi-Hyun
Published: March 2019

Lipid peroxidation by reactive oxygen species (ROS) during oxidative stress is non-enzymatic damage that affects the integrity of biological membrane, and alters the fluidity and permeability. We conducted molecular dynamic simulation studies to evaluate the structural properties of the bilayer after lipid peroxidation and to measure the permeability of distinct ROS. The oxidized membrane contains free fatty acid, ceramide, cholesterol, and 5α-hydroperoxycholesterol (5α-CH). The result of unconstrained molecular dynamic simulations revealed that lipid peroxidation causes area-per-lipid of the bilayer to increase and bilayer thickness to decrease. The simulations also revealed that the oxidized group of 5α-CH (-OOH) moves towards the aqueous layer and its backbone tilts causing lateral expansion of the bilayer membrane. These changes are detrimental to structural and functional properties of the membrane. The measured free energy profile for different ROS (H2O2, HO2, HO, and O2) across the peroxidized lipid bilayer showed that the increase in lipid peroxidation resulted in breaching barrier decrease for all species, allowing easy traversal of the membrane. Thus, lipid peroxidation perturbs the membrane barrier and imposes oxidative stress resulting into apoptosis. The collective insights increase the understanding of oxidation stress at the atomic level.
Transgenerational response to early spring warming in Daphnia
Authors: Toyota Kenji , Cambronero Cuenca Maria , Dhandapani Vignesh , Suppa Antonio , Rossi Valeria , Colbourne John K. , Orsini Luisa
Published: March 2019

Temperature and photoperiod regulate key fitness traits in plants and animals. However, with temperature increase due to global warming, temperature cue thresholds are experienced at shorter photoperiods, disrupting the optimal seasonal timing of physiological, developmental and reproductive events in many species. Understanding the mechanisms of adaptation to the asynchrony between temperature and photoperiod is key to inform our understanding of how species will respond to global warming. Here, we studied the transgenerational mechanisms of responses of the cyclical parthenogenDaphnia magnato different photoperiod lengths co-occurring with warm temperature thereby assessing the impact of earlier spring warming on its fitness.Daphniauses temperature and photoperiod cues to time dormancy, and to switch between sexual and asexual reproduction.Daphnialife cycle offers the opportunity to measure the relative contribution of plastic and genetic responses to environmental change across generations and over evolutionary time. We use transgenerational common garden experiments on three populations ‘resurrected’ from a biological archive experiencing temperature increase over five decades. Our results suggest that response to early spring warming evolved underpinned by a complex interaction between plastic and genetic mechanisms while a positive maternal contribution at matching environments between parental and offspring generation was also observed.
Electrically tunable valley polarization in Weyl semimetals with tilted energy dispersion
Authors: Yesilyurt Can , Siu Zhuo Bin , Tan Seng Ghee , Liang Gengchiau , Yang Shengyuan A. , Jalil Mansoor B. A.
Published: March 2019

Tunneling transport across electrical potential barriers in Weyl semimetals with tilted energy dispersion is investigated. We report that the electrons around different valleys experience opposite direction refractions at the barrier interface when the energy dispersion is tilted along one of the transverse directions. Chirality dependent refractions at the barrier interface polarize the Weyl fermions in angle-space according to their valley index. A real magnetic barrier configuration is used to select allowed transmission angles, which results in electrically controllable and switchable valley polarization. Our findings may pave the way for experimental investigation of valley polarization, as well as valleytronic and electron optic applications in Weyl semimetals.
The rsmS (ybaM) mutation causes bypass suppression of the RsmAB post-transcriptional virulence regulation system in enterobacterial phytopathogens
Authors: Monson Rita E. , Apagyi Katinka , Bowden Steven D. , Simpson Natalie , Williamson Neil R , Cubitt Marion F. , Harris Steve , Toth Ian K. , Salmond George P. C.
Published: March 2019

Plant cell wall degrading enzymes (PCWDEs) are the primary virulence determinants of soft rotting bacteria such as the potato pathogen, Pectobacterium atrosepticum. The regulation of secondary metabolite (Rsm) system controls production of PCWDEs in response to changing nutrient conditions. This work identified a new suppressor of an rsmB mutation – ECA1172 or rsmS (rsmBsuppressor). Mutants defective in rsmB (encoding a small regulatory RNA), show reduced elaboration of the quorum sensing molecule (N-3-oxohexanoyl-homoserine lactone; OHHL) and PCWDEs. However, OHHL and PCWDE production were partially restored in an rsmB, rsmS double mutant. Single rsmS mutants, overproduced PCWDEs and OHHL relative to wild type P. atrosepticum and exhibited hypervirulence in potato. RsmS overproduction also resulted in increased PCWDEs and OHHL. Homology searches revealed rsmS conservation across pathogens such as Escherichia coli (ybaM), Dickeya solani, Klebsiella pneumoniae and Shigella flexneri. An rsmS mutant of Pectobacterium carotovorum ATCC39048 showed bypass of rsmB-dependent repression of PCWDEs and OHHL production. P. carotovorum ATCC39048 produces the β-lactam antibiotic, 1-carbapen-2-em-3-carboxylic acid (a carbapenem). Production of the antibiotic was repressed in an rsmB mutant but partially restored in an rsmB, rsmS double mutant. This work highlights the importance of RsmS, as a conserved pleiotropic regulator of virulence and antibiotic biosynthesis.
High-throughput epitope profiling of antibodies in the plasma of Alzheimer’s disease patients using random peptide microarrays
Authors: Sim Kyu-Young , Park Sang-Heon , Choi Kyu Yeong , Park Jung Eun , Lee Jung Sup , Kim Byeong C. , Gwak Jeonghwan , Song Woo Keun , Lee Kun Ho , Park Sung-Gyoo
Published: March 2019

The symptoms of Alzheimer’s disease (AD), a major cause of dementia in older adults, are linked directly with neuronal cell death, which is thought to be due to aberrant neuronal inflammation. Autoantibodies formed during neuronal inflammation show excellent stability in blood; therefore, they may be convenient blood-based diagnostic markers of AD. Here, we performed microarray analysis of 29,240 unbiased random peptides to be used for comprehensive screening of AD-specific IgG and IgM antibodies in the blood. The results showed that (1) sequence-specific and isotype-specific antibodies are regulated differentially in AD, and combinations of these antibodies showing high area under the receiver operating characteristic curve values (0.862–0.961) can be used to classify AD, (2) AD-specific IgG antibodies arise from IgM antibody-secreting cells that existed before disease onset and (3) target protein profiling of the antibodies identified some AD-related proteins, some of which are involved in AD-related signalling pathways. Therefore, we propose that these epitopes may facilitate the development of biomarkers for AD diagnosis and form the basis for a mechanistic study related to AD progression.
Extreme temperature impairs growth and productivity in a common tropical marine copepod
Authors: Doan Nam X. , Vu Minh T. T. , Pham Hung Q. , Wisz Mary S. , Nielsen Torkel Gissel , Dinh Khuong V.
Published: March 2019

Shallow, tropical marine ecosystems provide essential ecosystem goods and services, but it is unknown how these ecosystems will respond to the increased exposure to the temperature extremes that are likely to become more common as climate change progresses. To address this issue, we tracked the fitness and productivity of a key zooplankton species, the copepodPseudodiaptomus annandalei, acclimated at two temperatures (30 and 34 °C) over three generations. 30 °C is the mean temperature in the shallow water of the coastal regions in Southeast Asia, while 34 °C simulated a temperature extreme that occurs frequently during the summer period. For each generation, we measured the size at maturity and reproductive success of individuals. In all three generations, we found strong negative effects of warming on all measured fitness-related parameters, including prolonged development time, reduced size at maturity, smaller clutch sizes, lower hatching success, and reduced naupliar production. Our results suggest thatP.annandaleiare already exposed to temperatures that exceed their upper thermal optimum. Increased exposure to extreme temperatures may reduce the abundance of these tropical marine copepods, and thus reduce the availability of resources to higher trophic levels.
Scattering Assisted Imaging
Authors: Leonetti Marco , Grimaldi Alfonso , Ghirga Silvia , Ruocco Giancarlo , Antonacci Giuseppe
Published: March 2019

Standard imaging systems provide a spatial resolution that is ultimately dictated by the numerical aperture (NA) of the illumination and collection optics. In biological tissues, the resolution is strongly affected by scattering, which limits the penetration depth to a few tenths of microns. Here, we exploit the properties of speckle patterns embedded into a strongly scattering matrix to illuminate the sample at high spatial frequency content. Combining adaptive optics with a custom deconvolution algorithm, we obtain an increase in the transverse spatial resolution by a factor of 2.5 with respect to the natural diffraction limit. Our Scattering Assisted Imaging (SAI) provides an effective solution to increase the resolution when long working distance optics are needed, potentially paving the way to bulk imaging in turbid tissues.
Systematic evaluation of gene variants linked to hearing loss based on allele frequency threshold and filtering allele frequency
Authors: Rim John Hoon , Lee Joon Suk , Jung Jinsei , Lee Ji Hyun , Lee Seung-Tae , Choi Jong Rak , Choi Jae Young , Lee Min Goo , Gee Heon Yung
Published: March 2019

As the number of genes identified for linkage to hearing loss has been increasing and more public databases have become available, we aimed to systematically evaluate all variants reported for nonsyndromic hearing loss (NSHL) based on their allele frequencies (AFs) in the general population. Among the 3,549 variants in 97 NSHL genes reported as pathogenic/likely pathogenic in ClinVar and HGMD, 1,618 were found in public databases (gnomAD, ExAC, EVS, and 1000G). To evaluate the pathogenicity of these variants, we employed AF thresholds and NSHL-optimized ACMG guidelines. AF thresholds were determined using a high-resolution variant frequency framework and Hardy-Weinberg equilibrium calculation: 0.6% and 0.1% for recessive and dominant genes, respectively. Filtering AFs of variants linked to NSHL were obtained based on AFs reported in gnomAD and ExAC. We found that 48 variants in 23 genes had filtering AFs above the suggested thresholds and assumed that these variants might be benign based on their filtering AFs. 47 variants, except for one notorious high-frequency GJB2 mutation (c.109G > A; p.Val37Ile), were confirmed to be benign/likely benign by the NSHL-optimized ACMG guidelines. The proposed systematic approach will aid in precise evaluation of NSHL variant pathogenicity in the context of filtering AFs, AF thresholds, and NSHL-specific ACMG guidelines, thus improving NSHL diagnostics.