bluuebunny/crossref_metadata_2025 huggingface dataset:
Combinatory use of distinct single-cell RNA-seq analytical platforms reveals the heterogeneous transcriptome response
Authors: Kashima Yukie , Suzuki Ayako , Liu Ying , Hosokawa Masahito , Matsunaga Hiroko , Shirai Masataka , Arikawa Kohji , Sugano Sumio , Kohno Takashi , Takeyama Haruko , Tsuchihara Katsuya , Suzuki Yutaka
Published: February 2018

Single-cell RNA-seq is a powerful tool for revealing heterogeneity in cancer cells. However, each of the current single-cell RNA-seq platforms has inherent advantages and disadvantages. Here, we show that combining the different single-cell RNA-seq platforms can be an effective approach to obtaining complete information about expression differences and a sufficient cellular population to understand transcriptional heterogeneity in cancers. We demonstrate that it is possible to estimate missing expression information. We further demonstrate that even in the cases where precise information for an individual gene cannot be inferred, the activity of given transcriptional modules can be analyzed. Interestingly, we found that two distinct transcriptional modules, one associated with the Aurora kinase gene and the other with the DUSP gene, are aberrantly regulated in a minor population of cells and may thus contribute to the possible emergence of dormancy or eventual drug resistance within the population.
Enhanced efficiency of crystalline Si solar cells based on kerfless-thin wafers with nanohole arrays
Authors: Lee Hyeon-Seung , Suk Jaekwon , Kim Hyeyeon , Kim Joonkon , Song Jonghan , Jeong Doo Seok , Park Jong-Keuk , Kim Won Mok , Lee Doh-Kwon , Choi Kyoung Jin , Ju Byeong-Kwon , Lee Taek Sung , Kim Inho
Published: February 2018

Several techniques have been proposed for kerfless wafering of thin Si wafers, which is one of the most essential techniques for reducing Si material loss in conventional wafering methods to lower cell cost. Proton induced exfoliation is one of promising kerfless techniques due to the simplicity of the process of implantation and cleaving. However, for application to high efficiency solar cells, it is necessary to cope with some problems such as implantation damage removal and texturing of (111) oriented wafers. This study analyzes the end-of-range defects at both kerfless and donor wafers and ion cutting sites. Thermal treatment and isotropic etching processes allow nearly complete removal of implantation damages in the cleaved-thin wafers. Combining laser interference lithography and a reactive ion etch process, a facile nanoscale texturing process for the kerfless thin wafers of a (111) crystal orientation has been developed. We demonstrate that the introduction of nanohole array textures with an optimal design and complete damage removal lead to an improved efficiency of 15.2% based on the kerfless wafer of a 48 μm thickness using the standard architecture of the Al back surface field.
Plasma ceramide levels are altered in low and normal birth weight men in response to short-term high-fat overfeeding
Authors: Ribel-Madsen Amalie , Ribel-Madsen Rasmus , Nielsen Kristian Fog , Brix Susanne , Vaag Allan A. , Brøns Charlotte
Published: February 2018

Low birth weight (LBW) individuals have an increased risk of developing insulin resistance and type 2 diabetes compared with normal birth weight (NBW) individuals. We hypothesised that LBW individuals exhibit an increased fatty acid flux into lipogenesis in non-adipose tissue with a resulting accumulation of lipotoxic lipids, including ceramides, in the blood. Therefore, we measured fasting plasma levels of 27 ceramides in 18 young, healthy, LBW men and 25 NBW controls after an isocaloric control diet and a 5-day high-fat, high-calorie diet by HPLC-HRMS. LBW men did not show elevated plasma ceramide levels after the control or high-fat, high-calorie diet. An increased fatty acid oxidation rate in these individuals during both diets may limit ceramide synthesis and thereby compensate for a likely increased fatty acid load to non-adipose tissue. Interestingly, LBW and NBW men decreased d18:0–18:1/d18:1–18:0 and d18:1–24:2/d18:2–24:1 levels and increased the d18:0–24:1a level in response to overfeeding. Plasma d18:0–24:1a and total ceramide levels were positively associated with the fasting blood glucose level and endogenous glucose production after the control diet, and the total ceramide level was in addition positively associated with hepatic insulin resistance. Further studies are needed to determine if lipotoxicity contributes to insulin resistance in LBW individuals.
Nonlinear internal wave spirals in the northern East China Sea
Authors: Nam SungHyun , Kim Duk-jin , Lee Seung-Woo , Kim Bong Guk , Kang Ki-mook , Cho Yang-Ki
Published: February 2018

Oceanic internal waves are known to be important to the understanding of underwater acoustics, marine biogeochemistry, submarine navigation and engineering, and the Earth’s climate. In spite of the importance and increased knowledge of their ubiquity, the wave generation is still poorly understood in most parts of the world’s oceans. Here, we use satellite synthetic aperture radar images, in-situ observations, and numerical models to (1) show that wave energy (having relatively high amplitude) radiates from a shallow sill in the East China Sea in all directions, but with a significant time lag dependent on background conditions, (2) reveal that wave fronts are locally formed with often favorable conditions for re-initiation, and (3) demonstrate the resulting variety of wave patterns. These findings would be the case for any broad shelf having shallow sills with time-varying conditions, and therefore have significant implications on the redistribution of energy and materials in the global as well as regional ocean.
CXCL12/CXCR4-Mediated Procollagen Secretion Is Coupled To Cullin-RING Ubiquitin Ligase Activation
Authors: Patalano Susan , Rodríguez-Nieves José , Colaneri Cory , Cotellessa Justin , Almanza Diego , Zhilin-Roth Alisa , Riley Todd , Macoska Jill
Published: February 2018

Tissue fibrosis is mediated by the actions of multiple pro-fibrotic proteins that can induce myofibroblast phenoconversion through diverse signaling pathways coupled predominantly to Smads or MEK/Erk proteins. The TGFβ/TGFβR and CXCL12/CXCR4 axes induce myofibroblast phenoconversion independently through Smads and MEK/Erk proteins, respectively. To investigate these mechanisms at the genetic level, we have now elucidated the TGFβ/TGFβR and CXCL12/CXCR4 transcriptomes in human fibroblasts. These transcriptomes are largely convergent, and up-regulate transcripts encoding proteins known to promote myofibroblast phenoconversion. These studies also revealed a molecular signature unique to CXCL12/CXCR4 axis activation for COPII vesicle formation, ubiquitination, and Golgi/ER localization/targeting. In particular, both CUL3 and KLHL12, key members of the Cullin-RING (CRL) ubiquitin ligase family of proteins involved in procollagen transport from the ER to the Golgi, were highly up-regulated in CXCL12-, but repressed in TGFβ-, treated cells. Up-regulation of CUL3 and KLHL12 was correlated with higher procollagen secretion by CXCL12-treated cells, and this affect was ablated upon treatment with inhibitors specific for CXCR4 or CUL3 and repressed by TGFβ/TGFβR axis activation. The results of these studies show that activation of the CXCL12/CXCR4 axis uniquely facilitates procollagen I secretion through a COPII-vesicle mediated mechanism to promote production of the ECM characteristic of fibrosis.
Author Correction: Additive manufacture of complex 3D Au-containing nanocomposites by simultaneous two-photon polymerisation and photoreduction
Authors: Hu Qin , Sun Xue-Zhong , Parmenter Christopher D. J. , Fay Michael W. , Smith Emily F. , Rance Graham A. , He Yinfeng , Zhang Fan , Liu Yaan , Irvine Derek , Tuck Christopher , Hague Richard , Wildman Ricky
Published: February 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.
P2X7 receptor regulates osteoclast function and bone loss in a mouse model of osteoporosis
Authors: Wang Ning , Agrawal Ankita , Jørgensen Niklas Rye , Gartland Alison
Published: February 2018

Post-menopausal osteoporosis is a condition that affects millions worldwide and places a huge socio-economic burden on society. Previous research has shown an association of loss of function SNPs in the gene for the purinergic receptor P2X7R with low bone mineral density, increased rates of bone loss and vertebral fractures in post-menopausal women. In this study we use a mouse model of oestrogen deficiency-induced bone loss and the BALB/cJ P2X7R−/− to show that absence of the P2X7R resulted in increased bone loss. Osteoclast precursors were isolated from both BALB/cJ P2X7R−/− and BALB/cJ P2X7R+/+ mice and then cultured in vitro to form mature resorbing osteoclasts. The BALB/cJ P2X7R−/− derived precursors generated slightly more osteoclasts but with a significant reduction in the amount of resorption per osteoclast. Furthermore, when using modified culture conditions osteoclast activity was additionally increased in the absence of the P2X7R suggest that P2X7R may regulate the lifespan and activity of osteoclasts. Finally using mechanical loading as an anabolic stimulus for bone formation, we demonstrated that the increased oestrogen-deficient bone loss could be rescued, even in the absence of P2X7R. This study paves the way for clinical intervention for women with post-menopausal osteoporosis and P2XR7 loss of function polymorphisms.
Endogenous insensitivity to the Orco agonist VUAA1 reveals novel olfactory receptor complex properties in the specialist fly Mayetiola destructor
Authors: Corcoran Jacob A. , Sonntag Yonathan , Andersson Martin N. , Johanson Urban , Löfstedt Christer
Published: February 2018

Insect olfactory receptors are routinely expressed in heterologous systems for functional characterisation. It was recently discovered that the essential olfactory receptor co-receptor (Orco) of the Hessian fly, Mayetiola destructor (Mdes), does not respond to the agonist VUAA1, which activates Orco in all other insects analysed to date. Here, using a mutagenesis-based approach we identified three residues in MdesOrco, located in different transmembrane helices as supported by 3D modelling, that confer sensitivity to VUAA1. Reciprocal mutations in Drosophila melanogaster (Dmel) and the noctuid moth Agrotis segetum (Aseg) Orcos diminish sensitivity of these proteins to VUAA1. Additionally, mutating these residues in DmelOrco and AsegOrco compromised odourant receptor (OR) dependent ligand-induced Orco activation. In contrast, both wild-type and VUAA1-sensitive MdesOrco were capable of forming functional receptor complexes when coupled to ORs from all three species, suggesting unique complex properties in M. destructor, and that not all olfactory receptor complexes are “created” equal.
Whole genome diversity of inherited chromosomally integrated HHV-6 derived from healthy individuals of diverse geographic origin
Authors: Telford Marco , Navarro Arcadi , Santpere Gabriel
Published: February 2018

Human herpesviruses 6-A and -B (HHV-6A, HHV-6B) are ubiquitous in human populations worldwide. These viruses have been associated with several diseases such as multiple sclerosis, Hodgkin’s lymphoma or encephalitis. Despite of the need to understand the genetic diversity and geographic stratification of these viruses, the availability of complete viral sequences from different populations is still limited. Here, we present nine new inherited chromosomally integrated HHV-6 sequences from diverse geographical origin which were generated through target DNA enrichment on lymphoblastoid cell lines derived from healthy individuals. Integration with available HHV-6 sequences allowed the assessment of HHV-6A and -6B phylogeny, patterns of recombination and signatures of natural selection. Analysis of the intra-species variability showed differences between A and B diversity levels and revealed that the HHV-6B reference (Z29) is an uncommon sequence, suggesting the need for an alternative reference sequence. Signs of geographical variation are present and more defined in HHV-6A, while they appear partly masked by recombination in HHV-6B. Finally, we conducted a scan for signatures of selection in protein coding genes that yielded at least 6 genes (4 and 2 respectively for the A and B species) showing significant evidence for accelerated evolution, and 1 gene showing evidence of positive selection in HHV-6A.
Synthesis of armchair graphene nanoribbons from the 10,10′-dibromo-9,9′-bianthracene molecules on Ag(111): the role of organometallic intermediates
Authors: Simonov K. A. , Generalov A. V. , Vinogradov A. S. , Svirskiy G. I. , Cafolla A. A. , McGuinness C. , Taketsugu T. , Lyalin A. , Mårtensson N. , Preobrajenski A. B.
Published: February 2018

We investigate the bottom-up growth of N = 7 armchair graphene nanoribbons (7-AGNRs) from the 10,10′-dibromo-9,9′-bianthracene (DBBA) molecules on Ag(111) with the focus on the role of the organometallic (OM) intermediates. It is demonstrated that DBBA molecules on Ag(111) are partially debrominated at room temperature and lose all bromine atoms at elevated temperatures. Similar to DBBA on Cu(111), debrominated molecules form OM chains on Ag(111). Nevertheless, in contrast with the Cu(111) substrate, formation of polyanthracene chains from OM intermediates via an Ullmann-type reaction is feasible on Ag(111). Cleavage of C–Ag bonds occurs before the thermal threshold for the surface-catalyzed activation of C–H bonds on Ag(111) is reached, while on Cu(111) activation of C–H bonds occurs in parallel with the cleavage of the stronger C–Cu bonds. Consequently, while OM intermediates obstruct the Ullmann reaction between DBBA molecules on the Cu(111) substrate, they are required for the formation of polyanthracene chains on Ag(111). If the Ullmann-type reaction on Ag(111) is inhibited, heating of the OM chains produces nanographenes instead. Heating of the polyanthracene chains produces 7-AGNRs, while heating of nanographenes causes the formation of the disordered structures with the possible admixture of short GNRs.
Broad blocking of MDR efflux pumps by acetylshikonin and acetoxyisovalerylshikonin to generate hypersensitive phenotype of malignant carcinoma cells
Authors: Mirzaei Seyed Abbas , Reiisi Somayeh , Ghiasi Tabari Parmida , Shekari Abolfazl , Aliakbari Fatemeh , Azadfallah Elaheh , Elahian Fatemeh
Published: February 2018

Cytotoxic activities of acetylshikonin and acetoxyisovalerylshikonin alone and in combination with chemotherapeutic agents against parental and drug resistant cell lines were determined using the MTT assay. Effects of Shikonin derivatives on BCRP, MDR1 and MRP transcript and protein levels were relatively measured. Finally, accumulation and efflux kinetics were conducted. The results revealed cell- and concentration-dependency of the cell cytotoxicity. Acetylshikonin and acetoxyisovalerylshikonin transiently made the mRNA ocean turbulent, but FACS analyses using fluorescent-labeled antibodies showed no significant change in the MDR-protein levels. Functional kinetics revealed significant block of MDR1, BCRP and MRP transporter in the presence of shikonin derivatives. Maximum accumulation fold changes was quantified to be 4.4 and consequently, acetoxyisovalerylshikonin pretreated EPG85.257RDB cells was chemosensitized to daunorubicin tension 3.1-fold. Although, the MDR blockage was reported to follow time- and cell-dependent patterns, MDR1, BCRP and MRP2 responses to the shikonins are concentration-independent. These data suggest uncompetitive transporter blockage behavior of these agents. The results indicated that shikonin derivatives stimulate uptake and reduce efflux of chemotherapeutic agents in the malignant cancer cells, suggesting that chemotherapy in combination with shikonin compounds may be beneficial to cancer cells that overexpress multidrug resistance transporters.
Non-Invasive Radiofrequency Field Treatment of 4T1 Breast Tumors Induces T-cell Dependent Inflammatory Response
Authors: Newton Jared M. , Flores-Arredondo Jose H. , Suki Sarah , Ware Matthew J. , Krzykawska-Serda Martyna , Agha Mahdi , Law Justin J. , Sikora Andrew G. , Curley Steven A. , Corr Stuart J.
Published: February 2018

Previous work using non-invasive radiofrequency field treatment (RFT) in cancer has demonstrated its therapeutic potential as it can increase intratumoral blood perfusion, localization of intravenously delivered drugs, and promote a hyperthermic intratumoral state. Despite the well-known immunologic benefits that febrile hyperthermia can induce, an investigation of how RFT could modulate the intra-tumoral immune microenvironment had not been studied. Thus, using an established 4T1 breast cancer model in immune competent mice, we demonstrate that RFT induces a transient, localized, and T-cell dependent intratumoral inflammatory response. More specifically we show that multi- and singlet-dose RFT promote an increase in tumor volume in immune competent Balb/c mice, which does not occur in athymic nude models. Further leukocyte subset analysis at 24, 48, and 120 hours after a single RFT show a rapid increase in tumoral trafficking of CD4+ and CD8+ T-cells 24 hours post-treatment. Additional serum cytokine analysis reveals an increase in numerous pro-inflammatory cytokines and chemokines associated with enhanced T-cell trafficking. Overall, these data demonstrate that non-invasive RFT could be an effective immunomodulatory strategy in solid tumors, especially for enhancing the tumoral trafficking of lymphocytes, which is currently a major hindrance of numerous cancer immunotherapeutic strategies.
Temperature dependence of long coherence times of oxide charge qubits
Authors: Dey A. , Yarlagadda S.
Published: February 2018

The ability to maintain coherence and control in a qubit is a major requirement for quantum computation. We show theoretically that long coherence times can be achieved at easily accessible temperatures (such as boiling point of liquid helium) in small (i.e., ~10 nanometers) charge qubits of oxide double quantum dots when only optical phonons are the source of decoherence. In the regime of strong electron-phonon coupling and in the non-adiabatic region, we employ a duality transformation to make the problem tractable and analyze the dynamics through a non-Markovian quantum master equation. We find that the system decoheres after a long time, despite the fact that no energy is exchanged with the bath. Detuning the dots to a fraction of the optical phonon energy, increasing the electron-phonon coupling, reducing the adiabaticity, or decreasing the temperature enhances the coherence time.
Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropatic pain
Authors: Király Kornél , Kozsurek Márk , Lukácsi Erika , Barta Benjamin , Alpár Alán , Balázsa Tamás , Fekete Csaba , Szabon Judit , Helyes Zsuzsanna , Bölcskei Kata , Tékus Valéria , Tóth Zsuzsanna E. , Pap Károly , Gerber Gábor , Puskár Zita
Published: February 2018

Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naïve animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems.
Spin-helix Larmor mode
Authors: Karimi Shahrzad , Ullrich Carsten A. , D’Amico Irene , Perez Florent
Published: February 2018

A two-dimensional electron gas (2DEG) with equal-strength Rashba and Dresselhaus spin-orbit coupling sustains persistent helical spin-wave states, which have remarkably long lifetimes. In the presence of an in-plane magnetic field, there exist single-particle excitations that have the character of propagating helical spin waves. For magnon-like collective excitations, the spin-helix texture reemerges as a robust feature, giving rise to a decoupling of spin-orbit and electronic many-body effects. We prove that the resulting spin-flip wave dispersion is the same as in a magnetized 2DEG without spin-orbit coupling, apart from a shift by the spin-helix wave vector. The precessional mode about the persistent spin-helix state is shown to have an energy given by the bare Zeeman splitting, in analogy with Larmor’s theorem. We also discuss ways to observe the spin-helix Larmor mode experimentally.
Unbiased Spontaneous Solar Fuel Production using Stable LaFeO3 Photoelectrode
Authors: Pawar Govinder S. , Tahir Asif A.
Published: February 2018

Photoelectrochemical (PEC) water splitting to produce solar fuel (hydrogen) has long been considered as the Holy Grail to a carbon-free hydrogen economy. The PEC concept to produce solar fuel is to emulate the natural photosynthesis using man made materials. The bottle-neck in realising the concept practically has been the difficulty in identifying stable low-cost semiconductors that meet the thermodynamic and kinetic criteria for photoelectrolysis. We have fabricated a novel p-type LaFeO3 photoelectrode using an inexpensive and scalable spray pyrolysis method. Our nanostructured LaFeO3 photoelectrode results in spontaneous hydrogen evolution from water without any external bias applied. Moreover, the photoelectrode has a faradaic efficiency of 30% and showed excellent stability over 21 hours. From optical and impedance data, the constructed band diagram showed that LaFeO3 can straddle the water redox potential with the conduction band at −1.11 V above the reduction potential of hydrogen. We have fabricated a low cost LaFeO3 photoelectrode that can spontaneously produce hydrogen from water using sunlight, making it a strong future candidate for renewable hydrogen generation.
Computationally Efficient Modelling of Stochastic Spatio-Temporal Dynamics in Biomolecular Networks
Authors: Kim Jongrae , Foo Mathias , Bates Declan G.
Published: February 2018

Measurement techniques in biology are now able to provide data on the trajectories of multiple individual molecules simultaneously, motivating the development of techniques for the stochastic spatio-temporal modelling of biomolecular networks. However, standard approaches based on solving stochastic reaction-diffusion equations are computationally intractable for large-scale networks. We present a novel method for modeling stochastic and spatial dynamics in biomolecular networks using a simple form of the Langevin equation with noisy kinetic constants. Spatial heterogeneity in molecular interactions is decoupled into a set of compartments, where the distribution of molecules in each compartment is idealised as being uniform. The reactions in the network are then modelled by Langevin equations with correcting terms, that account for differences between spatially uniform and spatially non-uniform distributions, and that can be readily estimated from available experimental data. The accuracy and extreme computational efficiency of the approach is demonstrated on a model of the epidermal growth factor receptor network in the human mammary epithelial cell.
Cysteine residues are essential for dimerization of Hippo pathway components YAP2L and TAZ
Authors: Khanal Prem , Jia Zongchao , Yang Xiaolong
Published: February 2018

Hippo signalling pathway is an emerging signalling pathway that plays important roles in organ size control, tumorigenesis, metastasis, stress response, apoptosis, stem cell differentiation and renewal during development and tissue homeostasis. Recent studies reported that human serine/threonine protein kinase, Mst1, a core component of the Hippo pathway can be activated through formation of homodimer. However, it is still unclear whether or not other components of the Hippo pathway are also regulated through dimerization. Here we provide the first evidence that Hippo components and oncoprotein YAP2L and TAZ can form homodimer in vitro and in vivo by forming disulphide bond through cysteine residue(s). We have also shown that the homodimers of YAP2L/TAZ are more stable and showed more oncogenic behaviour than their corresponding monomers as revealed by colony formation and cell transformation assay. Since cysteine post-translational regulation plays important roles in redox signalling, tumorigenesis and drug resistance, further studies on the functional effect of this dimerization through post-translational modulation of cysteine residues in YAP2L/TAZ will provide a significant contribution to our understanding of the roles of YAP2L/TAZ in cancer development and therapy.
Onset and Evolution of Southern Annular Mode-Like Changes at Centennial Timescale
Authors: Moreno P. I. , Vilanova I. , Villa-Martínez R. , Dunbar R. B. , Mucciarone D. A. , Kaplan M. R. , Garreaud R. D. , Rojas M. , Moy C. M. , De Pol-Holz R. , Lambert F.
Published: February 2018

The Southern Westerly Winds (SWW) are the surface expression of geostrophic winds that encircle the southern mid-latitudes. In conjunction with the Southern Ocean, they establish a coupled system that not only controls climate in the southern third of the world, but is also closely connected to the position of the Intertropical Convergence Zone and CO2 degassing from the deep ocean. Paradoxically, little is known about their behavior since the last ice age and relationships with mid-latitude glacier history and tropical climate variability. Here we present a lake sediment record from Chilean Patagonia (51°S) that reveals fluctuations of the low-level SWW at mid-latitudes, including strong westerlies during the Antarctic Cold Reversal, anomalously low intensity during the early Holocene, which was unfavorable for glacier growth, and strong SWW since ~7.5 ka. We detect nine positive Southern Annular Mode-like events at centennial timescale since ~5.8 ka that alternate with cold/wet intervals favorable for glacier expansions (Neoglaciations) in southern Patagonia. The correspondence of key features of mid-latitude atmospheric circulation with shifts in tropical climate since ~10 ka suggests that coherent climatic shifts in these regions have driven climate change in vast sectors of the Southern Hemisphere at centennial and millennial timescales.
Cisplatin Enhances Hepatitis B Virus Replication and PGC-1α Expression through Endoplasmic Reticulum Stress
Authors: Li Xiaosong , Pan E. , Zhu Junke , Xu Lei , Chen Xuemei , Li Jingjing , Liang Li , Hu Yuan , Xia Jie , Chen Juan , Chen Wannan , Hu Jieli , Wang Kai , Tang Ni , Huang Ailong
Published: February 2018

Chronic hepatitis B infection remains a serious public health issue worldwide. Hepatitis B virus (HBV) reactivation is commonly reported in patients receiving anticancer therapy, immunosuppressive therapy, or organ and tissue transplantation. However, the precise mechanisms underlying chemotherapeutic agent-related HBV reactivation remain unclear. Here, we report that peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) plays a central role in cisplatin-induced HBV transcription and replication. First, cisplatin treatment upregulated the expression levels of PGC-1α and hepatocyte nuclear factor 4 alpha (HNF-4α) in both HBV-replicating cells and an HBV-transgenic mouse model. PGC-1α coactivates with HNF-4α, which interacts with a core promoter and enhancer II region of HBV genome, thereby promoting HBV production. In contrast, knockdown of PGC-1α and HNF-4α by RNA interference in hepatoma cells reversed HBV activation in response to cisplatin. Additionally, PGC-1α upregulation depended on cisplatin-mediated endoplasmic reticulum (ER) stress. We further observed that the recruitment of cyclic AMP-responsive element-binding protein plays a crucial role for PGC-1α transcriptional activation in cisplatin-treated cells. Finally, pharmacologic inhibition of ER stress impaired PGC-1α upregulation and HBV production induced by cisplatin treatment. These findings demonstrate novel molecular mechanisms indicating that ER stress-PGC1α signaling pathway plays a critical role in cisplatin-evoked HBV reactivation.
Climate-Driven Crop Yield and Yield Variability and Climate Change Impacts on the U.S. Great Plains Agricultural Production
Authors: Kukal Meetpal S. , Irmak Suat
Published: February 2018

Climate variability and trends affect global crop yields and are characterized as highly dependent on location, crop type, and irrigation. U.S. Great Plains, due to its significance in national food production, evident climate variability, and extensive irrigation is an ideal region of investigation for climate impacts on food production. This paper evaluates climate impacts on maize, sorghum, and soybean yields and effect of irrigation for individual counties in this region by employing extensive crop yield and climate datasets from 1968–2013. Variability in crop yields was a quarter of the regional average yields, with a quarter of this variability explained by climate variability, and temperature and precipitation explained these in singularity or combination at different locations. Observed temperature trend was beneficial for maize yields, but detrimental for sorghum and soybean yields, whereas observed precipitation trend was beneficial for all three crops. Irrigated yields demonstrated increased robustness and an effective mitigation strategy against climate impacts than their non-irrigated counterparts by a considerable fraction. The information, data, and maps provided can serve as an assessment guide for planners, managers, and policy- and decision makers to prioritize agricultural resilience efforts and resource allocation or re-allocation in the regions that exhibit risk from climate variability.
PANDA: Protein function prediction using domain architecture and affinity propagation
Authors: Wang Zheng , Zhao Chenguang , Wang Yiheng , Sun Zheng , Wang Nan
Published: February 2018

We developed PANDA (Propagation of Affinity and Domain Architecture) to predict protein functions in the format of Gene Ontology (GO) terms. PANDA at first executes profile-profile alignment algorithm to search against PfamA, KOG, COG, and SwissProt databases, and then launches PSI-BLAST against UniProt for homologue search. PANDA integrates a domain architecture inference algorithm based on the Bayesian statistics that calculates the probability of having a GO term. All the candidate GO terms are pooled and filtered based on Z-score. After that, the remaining GO terms are clustered using an affinity propagation algorithm based on the GO directed acyclic graph, followed by a second round of filtering on the clusters of GO terms. We benchmarked the performance of all the baseline predictors PANDA integrates and also for every pooling and filtering step of PANDA. It can be found that PANDA achieves better performances in terms of area under the curve for precision and recall compared to the baseline predictors. PANDA can be accessed from http://dna.cs.miami.edu/PANDA/.
Inhibitory modulation of cytochrome c oxidase activity with specific near-infrared light wavelengths attenuates brain ischemia/reperfusion injury
Authors: Sanderson Thomas H. , Wider Joseph M. , Lee Icksoo , Reynolds Christian A. , Liu Jenney , Lepore Bradley , Tousignant Reneé , Bukowski Melissa J. , Johnston Hollie , Fite Alemu , Raghunayakula Sarita , Kamholz John , Grossman Lawrence I. , Przyklenk Karin , Hüttemann Maik
Published: February 2018

The interaction of light with biological tissue has been successfully utilized for multiple therapeutic purposes. Previous studies have suggested that near infrared light (NIR) enhances the activity of mitochondria by increasing cytochrome c oxidase (COX) activity, which we confirmed for 810 nm NIR. In contrast, scanning the NIR spectrum between 700 nm and 1000 nm revealed two NIR wavelengths (750 nm and 950 nm) that reduced the activity of isolated COX. COX-inhibitory wavelengths reduced mitochondrial respiration, reduced the mitochondrial membrane potential (ΔΨm), attenuated mitochondrial superoxide production, and attenuated neuronal death following oxygen glucose deprivation, whereas NIR that activates COX provided no benefit. We evaluated COX-inhibitory NIR as a potential therapy for cerebral reperfusion injury using a rat model of global brain ischemia. Untreated animals demonstrated an 86% loss of neurons in the CA1 hippocampus post-reperfusion whereas inhibitory NIR groups were robustly protected, with neuronal loss ranging from 11% to 35%. Moreover, neurologic function, assessed by radial arm maze performance, was preserved at control levels in rats treated with a combination of both COX-inhibitory NIR wavelengths. Taken together, our data suggest that COX-inhibitory NIR may be a viable non-pharmacologic and noninvasive therapy for the treatment of cerebral reperfusion injury.
African swine fever virus encodes for an E2-ubiquitin conjugating enzyme that is mono- and di-ubiquitinated and required for viral replication cycle
Authors: Freitas Ferdinando B. , Frouco Gonçalo , Martins Carlos , Ferreira Fernando
Published: February 2018

African swine fever virus is the etiological agent of a contagious and fatal acute haemorrhagic viral disease for which there are no vaccines or therapeutic options. The ASFV encodes for a putative E2 ubiquitin conjugating enzyme (ORF I215L) that shows sequence homology with eukaryotic counterparts. In the present study, we showed that pI215L acts as an E2-ubiquitin like enzyme in a large range of pH values and temperatures, after short incubation times. Further experiments revealed that pI215L is polyubiquitinated instead of multi-mono-ubiquitinated and Cys85 residue plays an essential role in the transthioesterification reaction. In infected cells, I215L gene is transcribed from 2 hours post infection and immunoblot analysis confirmed that pI215L is expressed from 4 hpi. Immunofluorescence studies revealed that pI215L is recruited to viral factories from 8 hpi and a diffuse distribution pattern throughout the nucleus and cytoplasm. siRNA studies suggested that pI215L plays a critical role in the transcription of late viral genes and viral DNA replication. Altogether, our results emphasize the potential use of this enzyme as target for drug and vaccine development against ASF.
Effectiveness and Safety of Different Rivaroxaban Dosage Regimens in Patients with Non-Valvular Atrial Fibrillation: A Nationwide, Population-Based Cohort Study
Authors: Huang Hsin-Yi , Lin Shin-Yi , Cheng Shou-Hsia , Wang Chi-Chuan
Published: February 2018

The objective of this study is to evaluate the effectiveness of different rivaroxaban dosage regimens in preventing ischemic stroke and systemic thromboembolism among Asians. A retrospective cohort study was conducted on data from nationwide insurance claims in Taiwan. Patients with non-valvular atrial fibrillation under warfarin or rivaroxaban therapy were included. Propensity score matching was used to balance the covariates, and Cox-proportional hazard models were applied to compare the effectiveness and safety of each treatment group. Rivaroxaban was associated with a significantly lower risk of venous thromboembolism (hazard ratio [HR]: 0.51; 95% confidence interval [CI]: 0.29–0.92, P = 0.02) and intracranial hemorrhage (HR: 0.48; 95% CI: 0.32–0.72, P < 0.001) than warfarin. Rivaroxaban 20 mg and 15 mg were associated with a significantly lower risk of ischemic stroke (20 mg, HR: 0.48; CI: 0.29–0.80, P = 0.005; 15 mg, HR: 0.69; CI: 0.53–0.90, P = 0.005), but rivaroxaban 10 mg was not. In the subgroup analysis of patients older than 65 years, the results were generally the same, except that rivaroxaban had a significantly lower risk of ischemic stroke than warfarin.
Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model
Authors: Courbon Guillaume , Lamarque Raphaëlle , Gerbaix Maude , Caire Robin , Linossier Marie-Thérèse , Laroche Norbert , Thomas Mireille , Thomas Thierry , Vico Laurence , Marotte Hubert
Published: February 2018

Periarticular bone loss in rheumatoid arthritis (RA) is considered to be mainly related to synovial inflammation. However, strong bone loss has also described at the time of arthritis onset. Recently, a paradoxical exacerbation of joint damage was described when blocking sclerostin in various arthritis models. Thus, we aimed to determine kinetics of bone loss and its mechanisms in the adjuvant induced arthritis (AIA) rat model of RA. AIA was induced (n = 35) or not (n = 35) at day 0. In addition to well-known arthritis at day 12, we showed with 3D-imaging and histomorphometry that bone microstructural alterations occurred early from day 8 post-induction, characterized by cortical porosity and trabecular bone loss. Active osteoclastic surfaces were increased from day 8 with RANKL upregulation. More surprisingly SOST and DKK1 were overexpressed from day 6 and followed by a dramatic decrease in bone formation from day 8. At the time of arthritis onset, SOST and DKK1 returned to control values, but frizzled related protein 1 (SFRP1), proinflammatory cytokines, and MMPs started to increase. Bone alterations before arthritis onset reinforce the hypothesis of an early bone involvement in arthritis. Kinetics of osteocyte markers expression should be considered to refine Wnt inhibitor treatment strategies.
Association between autonomic control indexes and mortality in subjects admitted to intensive care unit
Authors: Porta Alberto , Colombo Riccardo , Marchi Andrea , Bari Vlasta , De Maria Beatrice , Ranuzzi Giovanni , Guzzetti Stefano , Fossali Tommaso , Raimondi Ferdinando
Published: February 2018

This study checks whether autonomic markers derived from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and from their interactions with spontaneous or mechanical respiration (R) are associated with mortality in patients admitted to intensive care unit (ICU). Three-hundred consecutive HP, SAP and R values were recorded during the first day in ICU in 123 patients. Population was divided into survivors (SURVs, n = 83) and non-survivors (NonSURVs, n = 40) according to the outcome. SURVs and NonSURVs were aged- and gender-matched. All subjects underwent modified head-up tilt (MHUT) by tilting the bed back rest segment to 60°. Autonomic control indexes were computed using time-domain, spectral, cross-spectral, complexity, symbolic and causality techniques via univariate, bivariate and conditional approaches. SAP indexes derived from time-domain, model-free complexity and symbolic approaches were associated with the endpoint, while none of HP variability markers was. The association was more powerful during MHUT. Linear cross-spectral and causality indexes were useless to separate SURVs from NonSURVs, while nonlinear bivariate symbolic markers were successful. When indexes were combined with clinical scores, only SAP variance provided complementary information. Cardiovascular control variability indexes, especially when derived after an autonomic challenge such as MHUT, can improve mortality risk stratification in ICU.
The relationship between self-enhancing humor and precuneus volume in young healthy individuals with high and low cognitive empathy
Authors: Li Bingbing , Li Xu , Pan Yangu , Qiu Jiang , Zhang Dajun
Published: February 2018

A self-enhancing humor style (SEHS) plays an important role in the regulation of negative emotion through humorous perspective-taking. Following the mind-reading theories of humor, we investigated the relationship between gray-matter volume (GMV) of brain areas related to theory of mind and SEHS in young college students, using voxel-based morphometry analysis. We then performed a voxel-wise analysis of covariance to assess any moderation effect of cognitive empathy on the relationship. Results demonstrated that higher SEHS scores were associated with larger GMV of the precuneus in the group with high cognitive empathy, but there was no association in the group with low cognitive empathy. These results suggest that high cognitive empathy and increased precuneus volume can predict greater use of self-enhancing humor in young healthy individuals.
HIF-1α hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis
Authors: Hammami Akil , Abidin Belma Melda , Heinonen Krista M. , Stäger Simona
Published: February 2018

Inflammation, although responsible for controlling infection, is often associated with the pathogenesis of chronic diseases. Leishmania donovani, the causative agent of visceral leishmaniasis, induces a strong inflammatory response that leads to splenomegaly and ultimately immune suppression. Inflamed tissues are typically characterized by low levels of oxygen, a microenvironment that triggers the hypoxia-inducible transcription factor 1α (HIF-1α). Although HIF-1α plays an integral role in dendritic cell function, its involvement in the generation of protective Th1 responses against Leishmania has not yet been studied. Here we demonstrate that HIF-1α inhibits IL-12 production in dendritic cells, limiting therefore Th1 cell development. Indeed, depletion of HIF-1α in CD11c+ cells resulted in higher and sustained expression of IL-12 and complete abrogation of IL-10. Moreover, CD11c-specific HIF-1α-deficient mice showed higher frequencies of IFN-γ-producing CD4 T cells in the spleen and bone marrow and, consequently, a significantly reduced parasite burden in both organs. Taken together, our results suggest that HIF-1α expression in dendritic cells largely contributes to the establishment of persistent Leishmania infection and may therefore represent a possible therapeutic target.
Reactive Oxygen Species Mediate the Suppression of Arterial Smooth Muscle T-type Ca2+ Channels by Angiotensin II
Authors: Hashad Ahmed M. , Sancho Maria , Brett Suzanne E. , Welsh Donald G.
Published: February 2018

Vascular T-type Ca2+ channels (CaV3.1 and CaV3.2) play a key role in arterial tone development. This study investigated whether this conductance is a regulatory target of angiotensin II (Ang II), a vasoactive peptide that circulates and which is locally produced within the arterial wall. Patch clamp electrophysiology performed on rat cerebral arterial smooth muscle cells reveals that Ang II (100 nM) inhibited T-type currents through AT1 receptor activation. Blocking protein kinase C failed to eliminate channel suppression, a finding consistent with unique signaling proteins enabling this response. In this regard, inhibiting NADPH oxidase (Nox) with apocynin or ML171 (Nox1 selective) abolished channel suppression highlighting a role for reactive oxygen species (ROS). In the presence of Ni2+ (50 µM), Ang II failed to modulate the residual T-type current, an observation consistent with this peptide targeting CaV3.2. Selective channel suppression by Ang II impaired the ability of CaV3.2 to alter spontaneous transient outward currents or vessel diameter. Proximity ligation assay confirmed Nox1 colocalization with CaV3.2. In closing, Ang II targets CaV3.2 channels via a signaling pathway involving Nox1 and the generation of ROS. This unique regulatory mechanism alters BKCa mediated feedback giving rise to a “constrictive” phenotype often observed with cerebrovascular disease.
A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway
Authors: Antoniou Nasia , Vlachakis Dimitrios , Memou Anna , Leandrou Emmanouela , Valkimadi Polytimi-Eleni , Melachroinou Katerina , Re Diane B. , Przedborski Serge , Dauer William T. , Stefanis Leonidas , Rideout Hardy J.
Published: February 2018

In experimental models, both in vivo and cellular, over-expression of Parkinson’s linked mutant leucine-rich repeat kinase 2 (LRRK2) is sufficient to induce neuronal death. While several cell death associated proteins have been linked to LRRK2, either as protein interactors or as putative substrates, characterization of the neuronal death cascade remains elusive. In this study, we have mapped for the first time the domain within LRRK2 that mediates the interaction with FADD, thereby activating the molecular machinery of the extrinsic death pathway. Using homology modeling and molecular docking approaches, we have identified a critical motif within the N-terminal armadillo repeat region of LRRK2. Moreover, we show that co-expression of fragments of LRRK2 that contain the FADD binding motif, or deletion of this motif itself, blocks the interaction with FADD, and is neuroprotective. We further demonstrate that downstream of FADD, the mitochondrial proteins Bid and Bax are recruited to the death cascade and are necessary for neuronal death. Our work identifies multiple novel points within neuronal death signaling pathways that could potentially be targeted by candidate therapeutic strategies and highlight how the extrinsic pathway can be activated intracellularly in a pathogenic context.
Aberrant methylated key genes of methyl group metabolism within the molecular etiology of urothelial carcinogenesis
Authors: Erichsen Lars , Ghanjati Foued , Beermann Agnes , Poyet Cedric , Hermanns Thomas , Schulz Wolfgang A. , Seifert Hans-Helge , Wild Peter J. , Buser Lorenz , Kröning Alexander , Braunstein Stefan , Anlauf Martin , Jankowiak Silvia , Hassan Mohamed , Bendhack Marcelo L. , Araúzo-Bravo Marcos J. , Santourlidis Simeon
Published: February 2018

Urothelial carcinoma (UC), the most common cancer of the urinary bladder causes severe morbidity and mortality, e.g. about 40.000 deaths in the EU annually, and incurs considerable costs for the health system due to the need for prolonged treatments and long-term monitoring. Extensive aberrant  DNA methylation is described to prevail in urothelial carcinoma and is thought to contribute to genetic instability, altered gene expression and tumor progression. However, it is unknown how this epigenetic alteration arises during carcinogenesis. Intact methyl group metabolism is required to ensure maintenance of cell-type specific methylomes and thereby genetic integrity and proper cellular function. Here, using two independent techniques for detecting DNA methylation, we observed DNA hypermethylation of the 5′-regulatory regions of the key methyl group metabolism genes ODC1, AHCY and MTHFR in early urothelial carcinoma. These hypermethylation events are associated with genome-wide DNA hypomethylation which is commonly associated with genetic instability. We therefore infer that hypermethylation of methyl group metabolism genes acts in a feed-forward cycle to promote additional DNA methylation changes and suggest a new hypothesis on the molecular etiology of urothelial carcinoma.