bluuebunny/crossref_metadata_2025 huggingface dataset:
Spin‐up of UK Earth System Model 1 (UKESM1) for CMIP6
Authors: Yool A. , Palmiéri J. , Jones C. G. , Sellar A. A. , de Mora L. , Kuhlbrodt T. , Popova E. E. , Mulcahy J. P. , Wiltshire A. , Rumbold S. T. , Stringer M. , Hill R. S. R. , Tang Y. , Walton J. , Blaker A. , Nurser A. J. G. , Coward A. C. , Hirschi J. , Woodward S. , Kelley D. I. , Ellis R. , Rumbold‐Jones S.
Published: April 2020

For simulations intended to study the influence of anthropogenic forcing on climate, temporal stability of the Earth's natural heat, freshwater, and biogeochemical budgets is critical. Achieving such coupled model equilibration is scientifically and computationally challenging. We describe the protocol used to spin‐up the UK Earth system model (UKESM1) with respect to preindustrial forcing for use in the sixth Coupled Model Intercomparison Project (CMIP6). Due to the high computational cost of UKESM1's atmospheric model, especially when running with interactive full chemistry and aerosols, spin‐up primarily used parallel configurations using only ocean/land components. For the ocean, the resulting spin‐up permitted the carbon and heat contents of the ocean's full volume to approach equilibrium over 5,000 years. On land, a spin‐up of 1,000 years brought UKESM1's dynamic vegetation and soil carbon reservoirs toward near‐equilibrium. The end‐states of these parallel ocean‐ and land‐only phases then initialized a multicentennial period of spin‐up with the full Earth system model, prior to this simulation continuing as the UKESM1 CMIP6 preindustrial control (piControl). The realism of the fully coupled spin‐up was assessed for a range of ocean and land properties, as was the degree of equilibration for key variables. Lessons drawn include the importance of consistent interface physics across ocean‐ and land‐only models and the coupled (parent) model, the extreme simulation duration required to approach equilibration targets, and the occurrence of significant regional land carbon drifts despite global‐scale equilibration. Overall, the UKESM1 spin‐up underscores the expense involved and argues in favor of future development of more efficient spin‐up techniques.
AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis
Authors: Zhou Yuhang , Zhang Jinglin , Li Hui , Huang Tingting , Wong Chi Chun , Wu Feng , Wu Man , Weng Nuoqing , Liu Liping , Cheng Alfred S. L. , Yu Jun , Wong Nathalie , Lo Kwok Wai , Tang Patrick M. K. , Kang Wei , To Ka Fai
Published: April 2020

Hippo signaling functions to limit cellular growth, but the aberrant nuclear accumulation of its downstream YAP1 leads to carcinogenesis. YAP1/TEAD complex activates the oncogenic downstream transcription, such as CTGF and c-Myc. How YAP1 is protected in the cytoplasm from ubiquitin-mediated degradation remains elusive. In this study, a member of Angiomotin (Motin) family, AMOTL1 (Angiomotin Like 1), was screened out as the only one to promote YAP1 nuclear accumulation by several clinical cohorts, which was further confirmed by the cellular functional assays. The interaction between YAP1 and AMOTL1 was suggested by co-immunoprecipitation and immunofluorescent staining. The clinical significance of the AMOTL1–YAP1–CTGF axis in gastric cancer (GC) was analyzed by multiple clinical cohorts. Moreover, the therapeutic effect of targeting the oncogenic axis was appraised by drug-sensitivity tests and xenograft-formation assays. The upregulation of AMOTL1 is associated with unfavorable clinical outcomes of GC, and knocking down AMOTL1 impairs its oncogenic properties. The cytoplasmic interaction between AMOTL1 and YAP1 protects each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nuclei to activate the downstream expression, such as CTGF. Knocking down AMOTL1, YAP1, and CTGF enhances the therapeutic efficacies of the first-line anticancer drugs. Taken together, AMOTL1 plays an oncogenic role in gastric carcinogenesis through interacting with YAP1 and promoting its nuclear accumulation. A combination of AMOTL1, YAP1, and CTGF expression might serve as a surrogate of Hippo activation status. The co-activation of the AMOTL1/YAP1–CTGF axis is associated with poor clinical outcomes of GC patients, and targeting this oncogenic axis may enhance the chemotherapeutic effects.
Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression
Authors: Nowacki Jan , Wingenfeld Katja , Kaczmarczyk Michael , Chae Woo Ri , Salchow Paula , Abu-Tir Ikram , Piber Dominique , Hellmann-Regen Julian , Otte Christian
Published: April 2020

Major depressive disorder (MDD) is associated with altered mineralocorticoid receptor (MR) and glucocorticoid receptor function, and disturbed glutamatergic signaling. Both systems are closely intertwined and likely contribute not only to the pathophysiology of MDD, but also to the increased cardiovascular risk in MDD patients. Less is known about other steroid hormones, such as aldosterone and DHEA-S, and how they affect the glutamatergic system and cardiovascular disease risk in MDD. We examined salivary cortisol, aldosterone, and DHEA-S secretion after stimulation of MR and glutamatergic NMDA receptors in 116 unmedicated depressed patients, and 116 age- and sex-matched healthy controls. Patients (mean age = 34.7 years, SD = ±13.3; 78% women) and controls were randomized to four conditions: (a) control condition (placebo), (b) MR stimulation (0.4 mg fludrocortisone), (c) NMDA stimulation (250 mg D-cycloserine (DCS)), and (d) combined MR/NMDA stimulation (fludrocortisone + DCS). We additionally determined the cardiovascular risk profile in both groups. DCS had no effect on steroid hormone secretion, while cortisol secretion decreased in both fludrocortisone conditions across groups. Independent of condition, MDD patients showed (1) increased cortisol, increased aldosterone, and decreased DHEA-S concentrations, and (2) increased glucose levels and decreased high-density lipoprotein cholesterol levels compared with controls. Depressed patients show profound alterations in several steroid hormone systems that are associated both with MDD pathophysiology and increased cardiovascular risk. Prospective studies should examine whether modulating steroid hormone levels might reduce psychopathology and cardiovascular risk in depressed patients.
Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C
Authors: Steitz Anna Mary , Steffes Alina , Finkernagel Florian , Unger Annika , Sommerfeld Leah , Jansen Julia M. , Wagner Uwe , Graumann Johannes , Müller Rolf , Reinartz Silke
Published: April 2020

A central and unique aspect of high-grade serous ovarian carcinoma (HGSC) is the extensive transcoelomic spreading of tumor cell via the peritoneal fluid or malignant ascites. We and others identified tumor-associated macrophages (TAM) in the ascites as promoters of metastasis-associated processes like extracellular matrix (ECM) remodeling, tumor cell migration, adhesion, and invasion. The precise mechanisms and mediators involved in these functions of TAM are, however, largely unknown. We observed that HGSC migration is promoted by soluble mediators from ascites-derived TAM, which can be emulated by conditioned medium from monocyte-derived macrophages (MDM) differentiated in ascites to TAM-like asc-MDM. A similar effect was observed with IL-10-induced alternatively activated m2c-MDM but not with LPS/IFNγ-induced inflammatory m1-MDM. These observations provided the basis for deconvolution of the complex TAM secretome by performing comparative secretome analysis of matched triplets of different MDM phenotypes with different pro-migratory properties (asc-MDM, m2c-MDM, m1-MDM). Mass spectrometric analysis identified an overlapping set of nine proteins secreted by both asc-MDM and m2c-MDM, but not by m1-MDM. Of these, three proteins, i.e., transforming growth factor beta-induced (TGFBI) protein, tenascin C (TNC), and fibronectin (FN1), have been associated with migration-related functions. Intriguingly, increased ascites concentrations of TGFBI, TNC, and fibronectin were associated with short progression-free survival. Furthermore, transcriptome and secretome analyses point to TAM as major producers of these proteins, further supporting an essential role for TAM in promoting HGSC progression. Consistent with this hypothesis, we were able to demonstrate that the migration-inducing potential of asc-MDM and m2c-MDM secretomes is inhibited, at least partially, by neutralizing antibodies against TGFBI and TNC or siRNA-mediated silencing of TGFBI expression. In conclusion, the present study provides the first experimental evidence that TAM-derived TGFBI and TNC in ascites promote HGSC progression.
Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
Authors: Nallanthighal Sameera , Rada Miran , Heiserman James Patrick , Cha Jennifer , Sage Jessica , Zhou Bo , Yang Wei , Hu Ye , Korgaonkar Chaitali , Hanos Christina Terpsithea , Ashkavand Zahra , Norman Kenneth , Orsulic Sandra , Cheon Dong-Joo
Published: April 2020

Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.
Self-sustainable protonic ceramic electrochemical cells using a triple conducting electrode for hydrogen and power production
Authors: Ding Hanping , Wu Wei , Jiang Chao , Ding Yong , Bian Wenjuan , Hu Boxun , Singh Prabhakar , Orme Christopher J. , Wang Lucun , Zhang Yunya , Ding Dong
Published: April 2020

The protonic ceramic electrochemical cell (PCEC) is an emerging and attractive technology that converts energy between power and hydrogen using solid oxide proton conductors at intermediate temperatures. To achieve efficient electrochemical hydrogen and power production with stable operation, highly robust and durable electrodes are urgently desired to facilitate water oxidation and oxygen reduction reactions, which are the critical steps for both electrolysis and fuel cell operation, especially at reduced temperatures. In this study, a triple conducting oxide of PrNi0.5Co0.5O3-δ perovskite is developed as an oxygen electrode, presenting superior electrochemical performance at 400~600 °C. More importantly, the self-sustainable and reversible operation is successfully demonstrated by converting the generated hydrogen in electrolysis mode to electricity without any hydrogen addition. The excellent electrocatalytic activity is attributed to the considerable proton conduction, as confirmed by hydrogen permeation experiment, remarkable hydration behavior and computations.
Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis
Authors: Xu Jianquan , Ma Hongqiang , Ma Hongbin , Jiang Wei , Mela Christopher A. , Duan Meihan , Zhao Shimei , Gao Chenxi , Hahm Eun-Ryeong , Lardo Santana M. , Troy Kris , Sun Ming , Pai Reet , Stolz Donna B. , Zhang Lin , Singh Shivendra , Brand Randall E. , Hartman Douglas J. , Hu Jing , Hainer Sarah J. , Liu Yang
Published: April 2020

Genomic DNA is folded into a higher-order structure that regulates transcription and maintains genomic stability. Although progress has been made on understanding biochemical characteristics of epigenetic modifications in cancer, the in-situ higher-order folding of chromatin structure during malignant transformation remains largely unknown. Here, using optimized stochastic optical reconstruction microscopy (STORM) for pathological tissue (PathSTORM), we uncover a gradual decompaction and fragmentation of higher-order chromatin folding throughout all stages of carcinogenesis in multiple tumor types, and prior to tumor formation. Our integrated imaging, genomic, and transcriptomic analyses reveal functional consequences in enhanced transcription activities and impaired genomic stability. We also demonstrate the potential of imaging higher-order chromatin disruption to detect high-risk precursors that cannot be distinguished by conventional pathology. Taken together, our findings reveal gradual decompaction and fragmentation of higher-order chromatin structure as an enabling characteristic in early carcinogenesis to facilitate malignant transformation, which may improve cancer diagnosis, risk stratification, and prevention.
High density mechanical energy storage with carbon nanothread bundle
Authors: Zhan Haifei , Zhang Gang , Bell John M. , Tan Vincent B. C. , Gu Yuantong
Published: April 2020

The excellent mechanical properties of carbon nanofibers bring promise for energy-related applications. Through in silico studies and continuum elasticity theory, here we show that the ultra-thin carbon nanothreads-based bundles exhibit a high mechanical energy storage density. Specifically, the gravimetric energy density is found to decrease with the number of filaments, with torsion and tension as the two dominant contributors. Due to the coupled stresses, the nanothread bundle experiences fracture before reaching the elastic limit of any individual deformation mode. Our results show that nanothread bundles have similar mechanical energy storage capacity compared to (10,10) carbon nanotube bundles, but possess their own advantages. For instance, the structure of the nanothread allows us to realize the full mechanical energy storage potential of its bundle structure through pure tension, with a gravimetric energy density of up to 1.76 MJ kg−1, which makes them appealing alternative building blocks for energy storage devices.
TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism
Authors: Cheng Jie , Huang Yan , Zhang Xiaohui , Yu Yue , Wu Shumin , Jiao Jing , Tran Linh , Zhang Wanru , Liu Ran , Zhang Liuzhen , Wang Mei , Wang Mengyao , Yan Wenyu , Wu Yilin , Chi Fangtao , Jiang Peng , Zhang Xinxiang , Wu Hong
Published: April 2020

PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.
Multiplex secretome engineering enhances recombinant protein production and purity
Authors: Kol Stefan , Ley Daniel , Wulff Tune , Decker Marianne , Arnsdorf Johnny , Schoffelen Sanne , Hansen Anders Holmgaard , Jensen Tanja Lyholm , Gutierrez Jahir M. , Chiang Austin W. T. , Masson Helen O. , Palsson Bernhard O. , Voldborg Bjørn G. , Pedersen Lasse Ebdrup , Kildegaard Helene Faustrup , Lee Gyun Min , Lewis Nathan E.
Published: April 2020

Host cell proteins (HCPs) are process-related impurities generated during biotherapeutic protein production. HCPs can be problematic if they pose a significant metabolic demand, degrade product quality, or contaminate the final product. Here, we present an effort to create a “clean” Chinese hamster ovary (CHO) cell by disrupting multiple genes to eliminate HCPs. Using a model of CHO cell protein secretion, we predict that the elimination of unnecessary HCPs could have a non-negligible impact on protein production. We analyze the HCP content of 6-protein, 11-protein, and 14-protein knockout clones. These cell lines exhibit a substantial reduction in total HCP content (40%-70%). We also observe higher productivity and improved growth characteristics in specific clones. The reduced HCP content facilitates purification of a monoclonal antibody. Thus, substantial improvements can be made in protein titer and purity through large-scale HCP deletion, providing an avenue to increased quality and affordability of high-value biopharmaceuticals.
Novel allelic variation in the Phospholipase D alpha1 gene (OsPLDα1) of wild Oryza species implies to its low expression in rice bran
Authors: Kaur Amandeep , Neelam Kumari , Kaur Karminderbir , Kitazumi Ai , de los Reyes Benildo G. , Singh Kuldeep
Published: April 2020

Rice bran, a by-product after milling, is a rich source of phytonutrients like oryzanols, tocopherols, tocotrienols, phytosterols, and dietary fibers. Moreover, exceptional properties of the rice bran oil make it unparalleled to other vegetable oils. However, a lipolytic enzyme Phospholipase D alpha1 (OsPLDα1) causes rancidity and ‘stale flavor’ in the oil, and thus limits the rice bran usage for human consumption. To improve the rice bran quality, sequence based allele mining atOsPLDα1locus (3.6 Kb) was performed across 48 accessions representing 11 wildOryzaspecies, 8 accessions of African cultivated rice, and 7Oryza sativacultivars. From comparative sequence analysis, 216 SNPs and 30 InDels were detected at theOsPLDα1 locus. Phylogenetic analysis revealed 20OsPLDα1 cDNA variants which further translated into 12 protein variants. TheO. officinalisprotein variant, when compared to Nipponbare, showed maximum variability comprising 22 amino acid substitutions and absence of two peptides and two β-sheets. Further, expression profiling indicated significant differences in transcript abundance within as well as between theOsPLDα1 variants. Also, a newOsPLDα1transcript variant having third exon missing in it,Os01t0172400-06, has been revealed. AnO. officinalisaccession (IRGC101152) had lowest gene expression which suggests the presence of novel allele, named asOsPLDα1-1a(GenBank accession no. MF966931). The identified novel allele could be further deployed in the breeding programs to overcome rice bran rancidity in elite cultivars.
Preparation of TiO2-modified Biochar and its Characteristics of Photo-catalysis Degradation for Enrofloxacin
Authors: Wang Wen , Zhang Jing , Chen Tianya , Sun Jing , Ma Xiulan , Wang Yujun , Wang Jihong , Xie Zhonglei
Published: April 2020

In order to solve the problem that the traditional biochar(BC) has insufficient removal ability of enrofloxacin and TiO2 is difficult to recycle. In this study, TiO2-modified biochar composites were prepared by impregnation method. Through characterization analysis, The BET specific surface area results indicated that after loading TiO2, the specific surface area of TiO2-biochar(Ti-BC), TiO2-ironized biochar(Ti-FBC) and TiO2-alkaline biochar(Ti-KBC) increased by 4.34, 10.43 and 11.52 times, respectively. The analysis results of SEM, EDS, FT-IR, XRD and XPS showed that TiO2 was supported on biochar in the anatase state. The UV-vis DRS measurement showed that the band width of Ti-KBC was the smallest and the best catalytic activity. Under 15 W UV lamp (254 nm) irradiation, the photocatalytic degradation process of enrofloxacin by different biochar accords with the first-order kinetic equation. Ti-KBC showed best degradation effect under different initial concentrations of enrofloxacin. When the pH of the solution was 5.0 and the dosage of Ti-KBC was at 2.5 g·L−1, the enrofloxacin degradation rate of 100 mg·L−1 reached 85.25%. The quenching test confirmed that the active substance O2•— played a major role in the photocatalytic degradation process. After five cycles of the test, the degradation rate of Ti-KBC for enrofloxacin was 77.14%, which was still better than that of BC, Ti-BC and Ti-FBC.
Effects of Balneotherapy in Jeju Magma-Seawater on Knee Osteoarthritis Model
Authors: Kim Choong-Gon , Lee Dae-Geon , Oh Jina , Lee Youn-Ho , Lee Young Joon , Song Phil Hyun , Song Chang-Hyun , Ku Sae-Kwang
Published: April 2020

Balneotherapy is a common non-pharmacological treatment for osteoarthritis (OA), however, the efficacy is controversial in knee OA. Jeju magma-seawater (JMS) has high contents of various minerals, which has anti-inflammatory and antioxidant properties via an oral route. Thus, we examined the effects of JMS bathing on knee OA and the combination effects with diclofenac sodium as an anti-inflammatory drug. Knee OA was induced by transection of the anterior cruciate ligament and the partial meniscectomy in rat. The rats were administered subcutaneously saline or diclofenac sodium in saline, followed by bathing in thermal distilled water or JMS for 8 weeks. The model represented the characteristic changes of the cartilage degradation, osteophyte formation and synovial inflammation, and the relevant symptoms of the joint swelling and stiffness. However, the JMS bathing reduced the joint thickness and improved the mobility. It also contributed to a well-preserved tissue supported by increases in bone mineral density of the joint and decreases in Mankin scores in the cartilages. The effects involved anti-inflammation, chondroprotection, anti-apoptosis, and chondrogenesis. Overall, the JMS bathing in combination with diclofenac sodium showed a similar trend associated with synergic effects. It suggests that JMS bathing can be promising for a clinical use in knee OA.
Author Correction: Isogambogenic acid induces apoptosis-independent autophagic cell death in human non-small-cell lung carcinoma cells
Authors: Yang Jianhong , Zhou Yongzhao , Cheng Xia , Fan Yi , He Shichao , Li Shucai , Ye Haoyu , Xie Caifeng , Wu Wenshuang , Li Chunyan , Pei Heying , Li Luyuan , Wei Zhe , Peng Aihua , Wei Yuquan , Li Weimin , Chen Lijuan
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Diffraction-limited ultrabroadband terahertz spectroscopy
Authors: Baillergeau M. , Maussang K. , Nirrengarten T. , Palomo J. , Li L. H. , Linfield E. H. , Davies A. G. , Dhillon S. , Tignon J. , Mangeney J.
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease
Authors: Jaminon Armand M. G. , Dai Lu , Qureshi Abdul Rashid , Evenepoel Pieter , Ripsweden Jonaz , Söderberg Magnus , Witasp Anna , Olauson Hannes , Schurgers Leon J. , Stenvinkel Peter
Published: April 2020

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0–1312]) compared to patients carrying a T allele (median 0 [range 0–966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.
Author Correction: A transgenic embryonic sexing system for the Australian sheep blow fly Lucilia cuprina
Authors: Yan Ying , Scott Maxwell J.
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Molecular Mechanism of Switching of TrkA/p75NTR Signaling in Monocrotophos Induced Neurotoxicity
Authors: Kumar Vivek , Gupta Amit Kumar , Shukla Rajendra Kumar , Tripathi Vinay Kumar , Jahan Sadaf , Pandey Ankita , Srivastava Akriti , Agrawal Megha , Yadav Sanjay , Khanna Vinay Kumar , Pant Aditya Bhushan
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
HLA class II genotyping of admixed Brazilian patients with type 1 diabetes according to self-reported color/race in a nationwide study
Authors: Santos Deborah Conte , Porto Luís Cristóvão , Oliveira Romulo Vianna , Secco Danielle , Hanhoerderster Leonardo , Pizarro Marcela Haas , Barros Bianca S. V. , Mello Laura G. N. , Muniz Luiza Harcar , Silva Dayse A. , Gomes Marília Brito
Published: April 2020

The HLA region is responsible for almost 50% of the genetic risk of type 1 diabetes (T1D). However, haplotypes and their effects on risk or protection vary among different ethnic groups, mainly in an admixed population. We aimed to evaluate the HLA class II genetic profile of Brazilian individuals with T1D and its relationship with self-reported color/race. This was a nationwide multicenter study conducted in 10 Brazilian cities. We included 1,019 T1D individuals and 5,116 controls matched for the region of birth and self-reported color/race. Control participants belonged to the bone marrow transplant donor registry of Brazil (REDOME). HLA-class II alleles (DRB1, DQA1, and DQB1) were genotyped using the SSO and NGS methods. The most frequent risk and protection haplotypes wereHLA~DRB1*03:01~DQA1*05:01 g~DQB1*02:01(OR 5.8, p < 0.00001) andHLA~DRB1*07:01~DQA1*02:01~DQB1*02:02(OR 0.54, p < 0.0001), respectively, regardless of self-reported color/race. HaplotypesHLA~DRB1*03:01~DQA1*05:01 g~DQB1*02:01andHLA~DRB1*04:02~DQA1*03:01 g~DQB1*03:02were more prevalent in the self-reported White group than in the Black group (p = 0.04 and p = 0.02, respectively). The frequency of haplotype HLA~DRB1*09:01~DQA1*03:01 g~DQB1*02:02was higher in individuals self-reported as Black than White (p = <0.00001). No difference between the Brazilian geographical regions was found. Individuals with T1D presented differences in frequencies of haplotypes within self-reported color/race, but the more prevalent haplotypes, regardless of self-reported color/race, were the ones described previously in Europeans. We hypothesize that, in the T1D population of Brazil, although highly admixed, the disease risk alleles come mostly from Europeans as a result of centuries of colonization and migration.
Enhancement of silicon modulating properties in the THz range by YAG-Ce coating
Authors: Li Jiu-sheng , Hu Mu-shu
Published: April 2020

Y3Al5-xGaxO12:Ce3+,V3+ (YAG:Ce) has excellent chemical stability and unprecedented luminous efficiency. Its strong photoresponsive property is thoroughly utilized in designing excellent optical information storage device. Here, the remarkable photoconductivity of YAG:Ce is exploited to demonstrate a hybrid YAG:Ce-silicon device that shows high speed terahertz wave spatial modulation. A wide terahertz spectra modulation is observed under different pump powers in frequency range from 0.2 to 1.8 THz. Furthermore, a dynamic control of the terahertz wave intensity is also observed in the transmission system. The modulation speed and depth of the device is measured to be 4 MHz (vs 0.2 kHz)and 83.8%(vs50%) for bare silicon, respectively. The terahertz transmission spectra exhibits highly efficiency terahertz modulation by optically pumping a YAG:Ce film on silicon with low optical pump fluence.
Bighorn sheep gut microbiomes associate with genetic and spatial structure across a metapopulation
Authors: Couch Claire E. , Arnold Holly K. , Crowhurst Rachel S. , Jolles Anna E. , Sharpton Thomas J. , Witczak Marci F. , Epps Clinton W. , Beechler Brianna R.
Published: April 2020

Studies in laboratory animals demonstrate important relationships between environment, host traits, and microbiome composition. However, host-microbiome relationships in natural systems are understudied. Here, we investigate metapopulation-scale microbiome variation in a wild mammalian host, the desert bighorn sheep (Ovis canadensis nelsoni). We sought to identify over-represented microbial clades and understand how landscape variables and host traits influence microbiome composition across the host metapopulation. To address these questions, we performed 16S sequencing on fecal DNA samples from thirty-nine bighorn sheep across seven loosely connected populations in the Mojave Desert and assessed relationships between microbiome composition, environmental variation, geographic distribution, and microsatellite-derived host population structure and heterozygosity. We first used a phylogenetically-informed algorithm to identify bacterial clades conserved across the metapopulation. Members of genusRuminococcaceae, genusLachnospiraceae, and familyChristensenellaceae R7 groupwere among the clades over-represented across the metapopulation, consistent with their known roles as rumen symbionts in domestic livestock. Additionally, compositional variation among hosts correlated with individual-level geographic and genetic structure, and with population-level differences in genetic heterozygosity. This study identifies microbiome community variation across a mammalian metapopulation, potentially associated with genetic and geographic population structure. Our results imply that microbiome composition may diverge in accordance with landscape-scale environmental and host population characteristics.
Determining organ weight toxicity with Bayesian causal models: Improving on the analysis of relative organ weights
Authors: Lazic Stanley E. , Semenova Elizaveta , Williams Dominic P.
Published: April 2020

Regulatory authorities require animal toxicity tests for new chemical entities. Organ weight changes are accepted as a sensitive indicator of chemically induced organ damage, but can be difficult to interpret because changes in organ weight might reflect chemically-induced changes in overall body weight. A common solution is to calculate the relative organ weight (organ to body weight ratio), but this inadequately controls for the dependence on body weight – a point made by statisticians for decades, but which has not been widely adopted. The recommended solution is an analysis of covariance (ANCOVA), but it is rarely used, possibly because both the method of statistical correction and the interpretation of the output may be unclear to those with minimal statistical training. Using relative organ weights can easily lead to incorrect conclusions, resulting in poor decisions, wasted resources, and an ethically questionable use of animals. We propose to cast the problem into a causal modelling framework as it directly assesses questions of scientific interest, the results are easy to interpret, and the analysis is simple to perform with freely available software. Furthermore, by taking a Bayesian approach we can model unequal variances, control for multiple testing, and directly provide evidence of safety.
Polymorphism of nucleotide binding domain-like receptor protein 3 (NLRP3) increases susceptibility of total urinary arsenic to renal cell carcinoma
Authors: Chung Chi-Jung , Bao Bo-Ying , Lin Ying-Chin , Huang Ya-Li , Shiue Horng-Sheng , Ao Pui-Lam , Pu Yeong-Shiau , Huang Chao-Yuan , Hsueh Yu-Mei
Published: April 2020

Our study showed that total urinary arsenic concentrations were positively correlated with renal cell carcinoma (RCC). Chronic inflammation is a key player in the development of RCC. This study explored the association between nucleotide-binding domain-like receptor protein 3 (NLRP3) genotypes and the development of RCC. We also investigated whether any of the NLRP3 genotypes modified the risk between arsenic and RCC. We recruited 350 RCC patients and 700 age-sex matched controls. RCC was confirmed by pathological assessment following surgical resection or image-guided biopsy of a renal tumor. Fifteen sites of NLRP3 gene polymorphisms were identified using the Agena Bioscience MassARRAY platform. The concentrations of the urinary arsenic species were determined by HPLC-HG-AAS. There was a significant dose-dependent association between arsenic and RCC. In addition, six of thirteen NLRP3 alleles, including rs12239046 C, rs10925025 G, rs1539019 C, rs10925026 A, rs10157379 T, and rs12143966 A, had increased odds ratios (ORs) for RCC than other NLRP3 alleles. Among these sites, we found the novel haplotype of five tag-SNPs (C-A-A-A-A) was significantly related to RCC, the OR and 95% confidence interval was 1.44 (1.08–1.92). Furthermore, participants with high total urinary arsenic levels and the NLRP3 rs1539019 C allele had significantly multiplicative and additive interactions for the risk of RCC (p interaction = 0.012). This study is the first to identify the modified effects of NLRP3 risk alleles involved in the association between arsenic and RCC risk in a population with low arsenic exposure.
Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration
Authors: Wang Yanjie , Rhee Kun-Do , Pellegrini Matteo , Yang Xian-Jie
Published: April 2020

Ciliary neurotrophic factor (CNTF) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models. To decipher CNTF-triggered molecular events in the degenerating retina, we performed high-throughput RNA sequencing analyses using the Rds/Prph2 (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. In the absence of CNTF treatment, transcriptome alterations were detected at the onset of rod degeneration compared with wild type mice, including reduction of key photoreceptor transcription factors Crx, Nrl, and rod phototransduction genes. Short-term CNTF treatments caused further declines of photoreceptor transcription factors accompanied by marked decreases of both rod- and cone-specific gene expression. In addition, CNTF triggered acute elevation of transcripts in the innate immune system and growth factor signaling. These immune responses were sustained after long-term CNTF exposures that also affected neuronal transmission and metabolism. Comparisons of transcriptomes also uncovered common pathways shared with other retinal degeneration models. Cross referencing bulk RNA-seq with single-cell RNA-seq data revealed the CNTF responsive cell types, including Müller glia, rod and cone photoreceptors, and bipolar cells. Together, these results demonstrate the influence of exogenous CNTF on the retinal transcriptome landscape and illuminate likely CNTF impacts in degenerating human retinas.
Phenology of reproductive condition varies with age and spring weather conditions in male Myotis daubentonii and M. nattereri (Chiroptera: Vespertilionidae)
Authors: Linton Danielle M. , Macdonald David W.
Published: April 2020

We examine the extent to which intrinsic and extrinsic factors influence reproductive phenology in male bats at the population level. Using data from thirteen breeding seasons (2006–2018), encompassing the reproductive histories of 1546 Myotis daubentonii and 530 M. nattereri males, we compare rates of sexual maturation and the temporal distribution of phases of spermatogenesis between juvenile (born that season) and adult (born in previous seasons) males. We found that (i) higher proportions of M. daubentonii (50.81%) than M. nattereri (12.85%) became sexually mature as juveniles, (ii) the proportion of juveniles in reproductive condition per annum was influenced by spring weather conditions, (iii) in both species males that reached puberty as juveniles had higher body mass, on average, than immature juveniles, (iv) older males (aged ≥4 years old) commenced spermatogenesis earlier than young adult males (aged 1–3 years old), whilst juveniles that commenced spermatogenesis did so later in the year than adults, in both species, and (v) M. daubentonii commenced and completed spermatogenesis earlier than M. nattereri in the equivalent age class. Our findings suggest that selection pressure exists for early mating readiness and synchronisation with female receptivity.
Virtual monoenergetic images and post-processing algorithms effectively reduce CT artifacts from intracranial aneurysm treatment
Authors: Zopfs David , Lennartz Simon , Pennig Lenhard , Glauner Andreas , Abdullayev Nuran , Bremm Johannes , Große Hokamp Nils , Persigehl Thorsten , Kabbasch Christoph , Borggrefe Jan , Laukamp Kai Roman
Published: April 2020

To evaluate artifact reduction by virtual monoenergetic images (VMI) and metal artifact reduction algorithms (MAR) as well as the combination of both approaches (VMIMAR) compared to conventional CT images (CI) as standard of reference. In this retrospective study, 35 patients were included who underwent spectral-detector CT (SDCT) with additional MAR-reconstructions due to artifacts from coils or clips. CI, VMI, MAR and VMIMAR (range: 100–200 keV, 10 keV-increment) were reconstructed. Region-of-interest based objective analysis was performed by assessing mean and standard deviation of attenuation (HU) in hypo- and hyperdense artifacts from coils and clips. Visually, extent of artifact reduction and diagnostic assessment were rated. Compared to CI, VMI ≥ 100 keV, MAR and VMIMAR between 100–200 keV increased attenuation in hypoattenuating artifacts (CI/VMI200keV/MAR/VMIMAR200keV, HU: −77.6 ± 81.1/−65.1 ± 103.2/−36.9 ± 27.7/−21.1 ± 26.7) and decreased attenuation in hyperattenuating artifacts (HU: 47.4 ± 32.3/42.1 ± 50.2/29.5 ± 18.9/20.8 ± 25.8). However, differences were only significant for MAR in hypodense and VMIMAR in hypo- and hyperdense artifacts (p < 0.05). Visually, hypo- and hyperdense artifacts were significantly reduced compared to CI by VMI≥140/100keV, MAR and VMIMAR≥100keV. Diagnostic assessment of surrounding brain tissue was significantly improved in VMI≥100keV, MAR and VMIMAR≥100keV. The combination of VMI and MAR facilitates a significant reduction of artifacts adjacent to intracranial coils and clips. Hence, if available, these techniques should be combined for optimal reduction of artifacts following intracranial aneurysm treatment.
Oligocene incursion of the Paratethys seawater to the Junggar Basin, NW China: insight from multiple isotopic analysis of carbonate
Authors: Li Qian , Li Long , Zhang Yuanyuan , Guo Zhaojie
Published: April 2020

The Cenozoic retreat of the Paratethys Sea, as well as uplift of the Tibet plateau and global cooling, have been considered as the main mechanisms for the onset of the Asian monsoon. However, due to the weak constraints on the time and path of the Paratethys Sea, the relative contribution of each of the three factors to the onset of the Asian monsoon remains debatable. Previous studies on the retreat process of the Paratethys suggested that its east coastline had already withdrawn from the Chinese Tianshan area to the west by the Oligocene. Here, we provide a new perspective on this discussion through the study of the Oligocene Anjihaihe dolomite from the northern Chinese Tianshan. Through the comparisons of carbon, oxygen, magnesium, and strontium isotope compositions between the dolomite beds and their interlayered precursor lacustrine limestone beds, we show that the Anjihaihe dolomites were formed at the end of the Oligocene from dolomitization by a fluid characterized by high δ18O, low δ26Mg, low temperature, relatively poor in carbon and Sr. This fluid was likely derived from seawater from the close-by Paratethys Sea at the time. This discovery suggests a larger Paratethys Sea during the Oligocene than previously thought and may have important implications to understand the evolution of the palaeogeography in the Chinese Tianshan region and the onset of the Asian monsoon.
Deep Equatorial Pacific Ocean Oxygenation and Atmospheric CO2 Over The Last Ice Age
Authors: Marcantonio Franco , Hostak Ryan , Hertzberg Jennifer E. , Schmidt Matthew W.
Published: April 2020

Ventilation of carbon stored in the deep ocean is thought to play an important role in atmospheric CO2 increases associated with Pleistocene deglaciations. The presence of this respired carbon has been recorded by an array of paleoceanographic proxies from various locations across the global ocean. Here we present a new sediment core from the Eastern Equatorial Pacific (EEP) Ocean spanning the last 180,000 years and reconstruct high-resolution 230Th-derived fluxes of 232Th and excess barium, along with redox-sensitive uranium concentrations to examine past variations in dust delivery, export productivity, and bottom-water oxygenation, respectively. Our bottom-water oxygenation record is compared to other similar high-resolution records from across the Pacific and in the Southern Ocean. We suggest that the deep Pacific is a site of respired carbon storage associated with periods of decreased global atmospheric CO2 concentration during the LGM, confirming the conclusions from a wealth of previous studies. However, our study is the first to show a similar relationship beyond the last glacial, extending to at least 70,000 years.
UTMD inhibit EMT of breast cancer through the ROS/miR-200c/ZEB1 axis
Authors: Shi Dandan , Guo Lu , Sun Xiao , Shang Mengmeng , Meng Dong , Zhou Xiaoying , Liu Xinxin , Zhao Yading , Li Jie
Published: April 2020

As a potential drug/gene delivery system, the ultrasound-targeted microbubble destruction (UTMD) system can be used as a vehicle as well as increasing the permeability of biological barriers to enhance the effect of tumor treatment. However, the effect of UTMD in the tumor EMT process is unknown. In this study, we aimed to investigate the potential and mechanism of UTMD induced oxidative stress in inhibiting EMT of breast cancer. Human breast MDA231 cells were treated with microbubble (MB), ultrasound (US) and UTMD, respectively. The generation of oxidative stress, the levels of miR-200c, ZEB1 and vimentin, and the numbers of migratory cells were evaluated quantitatively and qualitatively by the measurement of intracellular reactive oxygen species (ROS), qRT-PCR, western blot assay, and transwell assay. Then, to evaluate the role of UTMD-induced oxidative stress and miR-200c in the epithelial-mesenchymal transition (EMT) inhibition, the ROS scavenger N-acetyl-L-cysteine (NAC) and miR-200c inhibitor were used before UTMD treatment. We found that UTMD induced oxidative stress, upregulated the expression of miR-200c, downregulated the expression of ZEB1 and vimentin and suppressed the MDA231 cell migration. The addition of NAC and miR-200c inhibitor had an opposite impact on the expression of miR-200c and ZEB1, thus hindered the effects of UTMD on MDA231 cells EMT. In conclusion, UTMD can inhibit the EMT characteristics of MDA231 cells. The mechanism may be related to the regulation of the miR-200c/ZEB1 axis through the generation of ROS induced by UTMD, which may provide a new strategy to prevent the tumor cells EMT under UTMD treatment.
Accuracy and stability of an arterial sensor for glucose monitoring in a porcine model using glucose clamp technique
Authors: Aberer Felix , Theiler-Schwetz Verena , Ziko Haris , Hausegger Bettina , Wiederstein-Grasser Iris , Hochfellner Daniel A. , Eller Philipp , Tomberger Georg , Ellmerer Martin , Mader Julia K , Bubalo Vladimir
Published: April 2020

Intravascular glucose sensors have the potential to improve and facilitate glycemic control in critically ill patients and might overcome measurement delay and accuracy issues. This study investigated the accuracy and stability of a biosensor for arterial glucose monitoring tested in a hypo- and hyperglycemic clamp experiment in pigs. 12 sensors were tested over 5 consecutive days in 6 different pigs. Samples of sensor and reference measurement pairs were obtained every 15 minutes. 1337 pairs of glucose values (range 37–458 mg/dl) were available for analysis. The systems met ISO 15197:2013 criteria in 99.2% in total, 100% for glucose <100 mg/dl (n = 414) and 98.8% for glucose ≥100 mg/dl (n = 923). The mean absolute relative difference (MARD) during the entire glycemic range of all sensors was 4.3%. The MARDs within the hypoglycemic (<70 mg/dl), euglycemic (≥70–180 mg/dl) and hyperglycemic glucose ranges (≥180 mg/dl) were 6.1%, 3.6% and 4.7%, respectively. Sensors indicated comparable performance on all days investigated (day 1, 3 and 5). None of the systems showed premature failures. In a porcine model, the performance of the biosensor revealed a promising performance. The transfer of these results into a human setting is the logical next step.
Influence of different knee and ankle ranges of motion on the elasticity of triceps surae muscles, Achilles tendon, and plantar fascia
Authors: Liu Chun-Long , Zhou Ji-Ping , Sun Peng-Tao , Chen Bai-Zhen , Zhang Jun , Tang Chun-Zhi , Zhang Zhi-Jie
Published: April 2020

Stiffness is a valuable indicator of the functional capabilities of muscle-tendon-fascia. Twenty healthy subjects participated in this study in which the passive elastic properties of the medial gastrocnemius (MG), lateral gastrocnemius (LG), soleus muscles (SOL), Achilles tendon (AT, at 0 cm, 3 cm and 6 cm proximal to the calcaneus tubercle, corresponding to AT0cm, AT3cm and AT6cm, respectively) and plantar fascia (PF) were quantified when their knee was fully extended or flexed to 90° using shear wave elastography at 25° of dorsiflexion (DF25°), 0° (neutral position) of flexion, and 50° of plantar flexion (PF50°) of the ankle joint. The stiffnesses of the AT, MG, LG, SOL and the fascia with the knee fully extended were significantly higher than those with the knee flexed to 90° (p < 0.05), while the stiffness of the PF showed the opposite relationship (p < 0.05). When the knee was fully extended, the stiffness was higher in the LG than in the MG at PF50° and 0° (p < 0.01), and it was higher in the MG than in the LG at DF25° (p = 0.009). Nevertheless, regardless of the knee angle, the stiffness decreased from AT3cm > AT0cm > AT6cm at PF50° and 0° (p < 0.001), while the stiffness decreased from AT0cm > AT3cm > AT6cm at DF25°. Regardless of the knee and ankle angles, the stiffness of the PF increased in a proximal-to-distal direction (p < 0.001). These insights can be used to gain a more intuitive understanding of the relationships between the elastic properties of the muscle-tendon unit and its function.
Author Correction: Neglecting diurnal variations leads to uncertainties in terrestrial nitrous oxide emissions
Authors: Shurpali Narasinha J. , Rannik Üllar , Jokinen Simo , Lind Saara , Biasi Christina , Mammarella Ivan , Peltola Olli , Pihlatie Mari , Hyvönen Niina , Räty Mari , Haapanala Sami , Zahniser Mark , Virkajärvi Perttu , Vesala Timo , Martikainen Pertti J.
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.