bluuebunny/crossref_metadata_2025 huggingface dataset:
p53 β-hydroxybutyrylation attenuates p53 activity
Authors: Liu Kun , Li Fangzhou , Sun Qianqian , Lin Ning , Han Haichao , You Kaiqiang , Tian Feng , Mao Zebin , Li Tingting , Tong Tanjun , Geng Meiyu , Zhao Yingming , Gu Wei , Zhao Wenhui
Published: March 2019

p53 is an essential tumor suppressor, whose activity is finely tuned by the posttranslational modifications. Previous research has reported that β-hydroxybutyrate (BHB) induces β-hydroxybutyrylation (Kbhb), which is a novel histone posttranslational modification. Here we report that p53 is modified by kbhb and that this modification occurs at lysines 120, 319, and 370 of p53. We demonstrate that the level of p53 kbhb is dramatically increased in cultured cells treated with BHB and in thymus tissues of fasted mice, and that CBP catalyze p53 kbhb. We show that p53 kbhb results in lower levels of p53 acetylation and reduced expression of the p53 downstream genes p21 and PUMA, as well as reduced cell growth arrest and apoptosis in cultured cells under p53-activating conditions. Similar results were observed in mouse thymus tissue under starvation conditions, which result in increased concentrations of serum BHB, and in response to genotoxic stress caused by γ-irradiation to activate p53. Our findings thus show that BHB-mediated p53 kbhb is a novel mechanism of p53 activity regulation, which may explain the link between ketone bodies and tumor, and which may provide promising therapeutic target for cancer treatment.
SOX12 promotes colorectal cancer cell proliferation and metastasis by regulating asparagine synthesis
Authors: Du Feng , Chen Jie , Liu Hao , Cai Yanhui , Cao Tianyu , Han Weili , Yi Xiaofang , Qian Meirui , Tian Dean , Nie Yongzhan , Wu Kaichun , Fan Daiming , Xia Limin
Published: March 2019

The sex-determining region Y (SRY)-box (SOX) family has a crucial role in carcinogenesis and cancer progression. However, the role of SOX12 and the mechanism by which it is dysregulated in colorectal cancer (CRC) remain unclear. Here we analyzed SOX12 expression patterns in two independent CRC cohorts (cohort I, n = 390; cohort II, n = 363) and found that SOX12 was significantly upregulated in CRC, indicating a poor prognosis in CRC patients. Overexpression of SOX12 promoted CRC cell proliferation and metastasis, whereas downregulation of SOX12 hampered CRC aggressiveness. Mechanistically, SOX12 facilitated asparagine synthesis by transactivating glutaminase (GLS), glutamic oxaloacetic transaminase 2 (GOT2), and asparagine synthetase (ASNS). Downregulation of GLS, GOT2, and ASNS blocked SOX12-mediated CRC cell proliferation and metastasis, whereas ectopic expression of GLS, GOT2, and ASNS attenuated the SOX12 knockdown-induced suppression of CRC progression. In addition, serial deletion, site-directed mutagenesis, luciferase reporter, and chromatin immunoprecipitation (ChIP) assays indicated that hypoxia-inducible factor 1α (HIF-1α) directly binds to the SOX12 promoter and induces SOX12 expression. Administration of l-asparaginase decreased SOX12-mediated tumor growth and metastasis. In human CRC samples, SOX12 expression positively correlated with GLS, GOT2, ASNS, and HIF-1α expression. Based on these results, SOX12 may serve as a prognostic biomarker and l-asparaginase represents a potential novel therapeutic agent for CRC.
Sweat gland organoids contribute to cutaneous wound healing and sweat gland regeneration
Authors: Diao Jinmei , Liu Juan , Wang Shuyong , Chang Mingyang , Wang Xuan , Guo Baolin , Yu Qunfang , Yan Fang , Su Yuxin , Wang Yunfang
Published: March 2019

Sweat glands perform a vital thermoregulatory function in mammals. Like other skin components, they originate from epidermal progenitors. However, they have low regenerative potential in response to injury. We have established a sweat gland culture and expansion method using 3D organoids cultures. The epithelial cells derived from sweat glands in dermis of adult mouse paw pads were embedded into Matrigel and formed sweat gland organoids (SGOs). These organoids maintained remarkable stem cell features and demonstrated differentiation capacity to give rise to either sweat gland cells (SGCs) or epidermal cells. Moreover, the bipotent SGO-derived cells could be induced into stratified epidermis structures at the air−liquid interface culture in a medium tailored for skin epidermal cells in vitro. The SGCs embedded in Matrigel tailored for sweat glands formed epithelial organoids, which expressed sweat-gland-specific markers, such as cytokeratin (CK) 18 and CK19, aquaporin (AQP) 5 and αATP. More importantly, they had potential of regeneration of epidermis and sweat gland when they were transplanted into the mouse back wound and claw pad with sweat gland injury, respectively. In summary, we established and optimized culture conditions for effective generation of mouse SGOs. These cells are candidates to restore impaired sweat gland tissue as well as to improve cutaneous skin regeneration.
Low-dose 2-deoxyglucose and metformin synergically inhibit proliferation of human polycystic kidney cells by modulating glucose metabolism
Authors: Zhao Jing , Ma Yuxiang , Zhang Yingjie , Fu Bo , Wu Xiaoyuan , Li Qinggang , Cai Guangyan , Chen Xiangmei , Bai Xue-Yuan
Published: March 2019

Polycystic kidney disease (PKD) is a common hereditary kidney disease with abnormal proliferation and apoptosis of kidney cystic epithelial cells, eventually leading to chronic renal failure. Currently, there are no effective treatment methods. Similar to tumor cells, cystic epithelial cells have abnormal glycolysis and over-activation of proliferation signaling pathways. In the present study, for the first time, we investigated the effects of low-dose combinational use of 2-deoxyglucose (2-DG) and metformin (MET) on the proliferation and apoptosis in the human cystic kidney epithelial cells. Cystic epithelia cells were divided into control group, 2-DG group, MET group and 2-DG+MET group. Cell Proliferation, apoptosis and glucose metabolism were measured in each group. The results showed that low-dose combinational treatment of 2-DG and MET significantly inhibited the proliferation of renal cystic epithelial cells by suppressing the activities of PKA, mTOR and ERK signaling pathways and upregulating PI3K/Akt pathway. Combination of both drugs increased the apoptosis rates of cystic epithelial cells. Two drugs inhibited glucose metabolic phenotypes, glycolysis and oxidative phosphorylation, and significantly lowered the intracellular ATP level in cystic epithelial cells. 2-DG could also neutralize excessive production of lactate (lactic acidosis) caused by MET and both drugs had complementary effect for cystic epithelial cells. These results reveal that combinational use of low-dose 2-DG and MET can markedly inhibit proliferation via modulating glucose metabolic phenotypes in human polycystic kidney epithelial cells, low-dose combinational use of both drugs can also lower the toxic effects of each drug, and is a novel strategy for future treatment of human polycystic kidney disease.
Observation of dressed states of distant atoms with delocalized photons in coupled-cavities quantum electrodynamics
Authors: Kato Shinya , Német Nikolett , Senga Kohei , Mizukami Shota , Huang Xinhe , Parkins Scott , Aoki Takao
Published: March 2019

In a cavity quantum electrodynamics (QED) system, where atoms coherently interact with photons in a cavity, the eigenstates of the system are the superposition states of atoms and cavity photons, the so-called dressed states of atoms. When two cavities are connected by an optical fiber with negligible loss, the coherent coupling between the cavities gives rise to photonic normal modes. One of these normal modes is the fiber-dark mode, in which photons are delocalized in the two distant cavities. Here we demonstrate the setting of coupled-cavities QED, where two nanofiber cavity-QED systems are coherently connected by a meter-long low-loss channel in an all-fiber fashion. Specifically, we observe dressed states of distant atoms with delocalized photons of the fiber-dark normal mode. Our system will provide a platform for the study of delocalized atomic and photonic states, photonic many-body physics, and distributed quantum computation.
Unmasking Clever Hans predictors and assessing what machines really learn
Authors: Lapuschkin Sebastian , Wäldchen Stephan , Binder Alexander , Montavon Grégoire , Samek Wojciech , Müller Klaus-Robert
Published: March 2019

Current learning machines have successfully solved hard application problems, reaching high accuracy and displaying seemingly intelligent behavior. Here we apply recent techniques for explaining decisions of state-of-the-art learning machines and analyze various tasks from computer vision and arcade games. This showcases a spectrum of problem-solving behaviors ranging from naive and short-sighted, to well-informed and strategic. We observe that standard performance evaluation metrics can be oblivious to distinguishing these diverse problem solving behaviors. Furthermore, we propose our semi-automated Spectral Relevance Analysis that provides a practically effective way of characterizing and validating the behavior of nonlinear learning machines. This helps to assess whether a learned model indeed delivers reliably for the problem that it was conceived for. Furthermore, our work intends to add a voice of caution to the ongoing excitement about machine intelligence and pledges to evaluate and judge some of these recent successes in a more nuanced manner.
Exploring the ternary interactions in Cu–ZnO–ZrO2 catalysts for efficient CO2 hydrogenation to methanol
Authors: Wang Yuhao , Kattel Shyam , Gao Wengui , Li Kongzhai , Liu Ping , Chen Jingguang G. , Wang Hua
Published: March 2019

The synergistic interaction among different components in complex catalysts is one of the crucial factors in determining catalytic performance. Here we report the interactions among the three components in controlling the catalytic performance of Cu–ZnO–ZrO2 (CZZ) catalyst for CO2 hydrogenation to methanol. The in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) measurements under the activity test pressure (3 MPa) reveal that the CO2 hydrogenation to methanol on the CZZ catalysts follows the formate pathway. Density functional theory (DFT) calculations agree with the in situ DRIFTS measurements, showing that the ZnO–ZrO2 interfaces are the active sites for CO2 adsorption and conversion, while the presence of metallic Cu is also necessary to facilitate H2 dissociation and to provide hydrogen resource. The combined experiment and DFT results reveal that tuning the interaction between ZnO and ZrO2 can be considered as another important factor for designing high performance catalysts for methanol generation from CO2.
Ultrafast photonic micro-systems to manipulate hard X-rays at 300 picoseconds
Authors: Chen Pice , Jung Il Woong , Walko Donald A. , Li Zhilong , Gao Ya , Shenoy Gopal K. , López Daniel , Wang Jin
Published: March 2019

Time-resolved and ultrafast hard X-ray imaging, scattering and spectroscopy are powerful tools for elucidating the temporal and spatial evolution of complexity in materials. However, their temporal resolution has been limited by the storage-ring timing patterns and X-ray pulse width at synchrotron sources. Here we demonstrate that dynamic X-ray optics based on micro-electro-mechanical-system resonators can manipulate hard X-ray pulses on time scales down to 300 ps, comparable to the X-ray pulse width from typical synchrotron sources. This is achieved by timing the resonators with the storage ring to diffract X-ray pulses through the narrow Bragg peak of the single-crystalline material. Angular velocities exceeding 107degrees s−1are reached while maintaining the maximum linear velocity well below the sonic speed and material breakdown limit. As the time scale of the devices shortens, the devices promise to spatially disperse the temporal width of X-rays, thus generating a temporal resolution below the pulse-width limit.
A late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation
Authors: Cippà Pietro E. , Liu Jing , Sun Bo , Kumar Sanjeev , Naesens Maarten , McMahon Andrew P.
Published: March 2019

The mechanisms initiating late immune responses to an allograft are poorly understood. Here we show, via transcriptome analysis of serial protocol biopsies from kidney transplants, that the initial responses to kidney injury correlate with a late B lymphocyte signature relating to renal dysfunction and fibrosis. With a potential link between dysfunctional repair and immunoreactivity, we investigate the immunological consequences of dysfunctional repair examining chronic disease in mouse kidneys 18 months after a bilateral ischemia/reperfusion injury event. In the absence of foreign antigens, a sustained immune response involving both innate and adaptive immune systems accompanies a transition to chronic kidney damage. At late stages, B lymphocytes exhibite an antigen-driven proliferation, selection and maturation into broadly-reacting antibody-secreting cells. These findings reveal a previously unappreciated role for dysfunctional tissue repair in local immunomodulation that may have particular relevance to transplant-associated immunobiology.
Structural basis for transcription initiation by bacterial ECF σ factors
Authors: Li Lingting , Fang Chengli , Zhuang Ningning , Wang Tiantian , Zhang Yu
Published: March 2019

Bacterial RNA polymerase employs extra-cytoplasmic function (ECF) σ factors to regulate context-specific gene expression programs. Despite being the most abundant and divergent σ factor class, the structural basis of ECF σ factor-mediated transcription initiation remains unknown. Here, we determine a crystal structure of Mycobacterium tuberculosis (Mtb) RNAP holoenzyme comprising an RNAP core enzyme and the ECF σ factor σH (σH-RNAP) at 2.7 Å, and solve another crystal structure of a transcription initiation complex of Mtb σH-RNAP (σH-RPo) comprising promoter DNA and an RNA primer at 2.8 Å. The two structures together reveal the interactions between σH and RNAP that are essential for σH-RNAP holoenzyme assembly as well as the interactions between σH-RNAP and promoter DNA responsible for stringent promoter recognition and for promoter unwinding. Our study establishes that ECF σ factors and primary σ factors employ distinct mechanisms for promoter recognition and for promoter unwinding.
A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma
Authors: Syafruddin Saiful E. , Rodrigues Paulo , Vojtasova Erika , Patel Saroor A. , Zaini M. Nazhif , Burge Johanna , Warren Anne Y. , Stewart Grant D. , Eisen Tim , Bihary Dóra , Samarajiwa Shamith A. , Vanharanta Sakari
Published: March 2019

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.
Whole-genome resequencing reveals Brassica napus origin and genetic loci involved in its improvement
Authors: Lu Kun , Wei Lijuan , Li Xiaolong , Wang Yuntong , Wu Jian , Liu Miao , Zhang Chao , Chen Zhiyou , Xiao Zhongchun , Jian Hongju , Cheng Feng , Zhang Kai , Du Hai , Cheng Xinchao , Qu Cunming , Qian Wei , Liu Liezhao , Wang Rui , Zou Qingyuan , Ying Jiamin , Xu Xingfu , Mei Jiaqing , Liang Ying , Chai You-Rong , Tang Zhanglin , Wan Huafang , Ni Yu , He Yajun , Lin Na , Fan Yonghai , Sun Wei , Li Nan-Nan , Zhou Gang , Zheng Hongkun , Wang Xiaowu , Paterson Andrew H. , Li Jiana
Published: March 2019

Brassica napus (2n = 4x = 38, AACC) is an important allopolyploid crop derived from interspecific crosses between Brassica rapa (2n = 2x = 20, AA) and Brassica oleracea (2n = 2x = 18, CC). However, no truly wild B. napus populations are known; its origin and improvement processes remain unclear. Here, we resequence 588 B. napus accessions. We uncover that the A subgenome may evolve from the ancestor of European turnip and the C subgenome may evolve from the common ancestor of kohlrabi, cauliflower, broccoli, and Chinese kale. Additionally, winter oilseed may be the original form of B. napus. Subgenome-specific selection of defense-response genes has contributed to environmental adaptation after formation of the species, whereas asymmetrical subgenomic selection has led to ecotype change. By integrating genome-wide association studies, selection signals, and transcriptome analyses, we identify genes associated with improved stress tolerance, oil content, seed quality, and ecotype improvement. They are candidates for further functional characterization and genetic improvement of B. napus.
A chemically inert bismuth interlayer enhances long-term stability of inverted perovskite solar cells
Authors: Wu Shaohang , Chen Rui , Zhang Shasha , Babu B. Hari , Yue Youfeng , Zhu Hongmei , Yang Zhichun , Chen Chuanliang , Chen Weitao , Huang Yuqian , Fang Shaoying , Liu Tianlun , Han Liyuan , Chen Wei
Published: March 2019

Long-term stability remains a key issue impeding the commercialization of halide perovskite solar cells (HPVKSCs). The diffusion of molecules and ions causes irreversible degradation to photovoltaic device performance. Here, we demonstrate a facile strategy for producing highly stable HPVKSCs by using a thin but compact semimetal Bismuth interlayer. The Bismuth film acts as a robust permeation barrier that both insulates the perovskite from intrusion by undesirable external moisture and protects the metal electrode from iodine corrosion. The Bismuth-interlayer-based devices exhibit greatly improved stability when subjected to humidity, thermal and light stresses. The unencapsulated device retains 88% of its initial efficiency in ambient air in the dark for over 6000 h; the devices maintain 95% and 97% of their initial efficiencies after 85 °C thermal aging and light soaking in nitrogen atmosphere for 500 h, respectively. These sound stability parameters are among the best for planar structured HPVKSCs reported to date.
Author Correction: Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis
Authors: Liu Shujing , Zhang Gao , Guo Jianping , Chen Xiang , Lei Jingce , Ze Kan , Dong Liyun , Dai Xiangpeng , Gao Yang , Song Daisheng , Ecker Brett L. , Yang Ruifeng , Feltcher Caitlin , Peng Kai , Feng Cheng , Chen Hui , Lee Rebecca X. , Kerestes Heddy , Niu Jingwen , Kumar Suresh , Xu Weiting , Zhang Jie , Wei Zhi , Martin James S. , Liu Xiaoming , Mills Gordon , Lu Yiling , Guo Wei , Sun Lunquan , Zhang Lin , Weeraratna Ashani , Herlyn Meenhard , Wei Wenyi , Lee Frank S. , Xu Xiaowei
Published: March 2019

The original version of this Article contained an error in the spelling of the author Brett L. Ecker, which was incorrectly given as Brett Ecker. This has now been corrected in both the PDF and HTML versions of the Article.
Essential biodiversity variables for mapping and monitoring species populations
Authors: Jetz Walter , McGeoch Melodie A. , Guralnick Robert , Ferrier Simon , Beck Jan , Costello Mark J. , Fernandez Miguel , Geller Gary N. , Keil Petr , Merow Cory , Meyer Carsten , Muller-Karger Frank E. , Pereira Henrique M. , Regan Eugenie C. , Schmeller Dirk S. , Turak Eren
Published: March 2019

Species distributions and abundances are undergoing rapid changes worldwide. This highlights the significance of reliable, integrated information for guiding and assessing actions and policies aimed at managing and sustaining the many functions and benefits of species. Here we synthesize the types of data and approaches that are required to achieve such an integration and conceptualize ‘essential biodiversity variables’ (EBVs) for a unified global capture of species populations in space and time. The inherent heterogeneity and sparseness of raw biodiversity data are overcome by the use of models and remotely sensed covariates to inform predictions that are contiguous in space and time and global in extent. We define the species population EBVs as a space–time–species–gram (cube) that simultaneously addresses the distribution or abundance of multiple species, with its resolution adjusted to represent available evidence and acceptable levels of uncertainty. This essential information enables the monitoring of single or aggregate spatial or taxonomic units at scales relevant to research and decision-making. When combined with ancillary environmental or species data, this fundamental species population information directly underpins a range of biodiversity and ecosystem function indicators. The unified concept we present links disparate data to downstream uses and informs a vision for species population monitoring in which data collection is closely integrated with models and infrastructure to support effective biodiversity assessment.
Mesoporous Platinum Prepared by Electrodeposition for Ultralow Loading Proton Exchange Membrane Fuel Cells
Authors: Paul Michael T. Y. , Gates Byron D.
Published: March 2019

The porosity and utilization of platinum catalysts have a direct impact on their performance within proton exchange membrane fuel cells. It is desirable to identify methods that can prepare these catalysts with the desired features, and that can be widely implemented using existing and industrially scalable techniques. Through the use of electrodeposition processes, fuel cell testing, and electron microscopy analyses before and after fuel cell testing, we report the preparation and performance of mesoporous platinum catalysts for proton exchange membrane fuel cells. We found that these mesoporous platinum catalysts can be prepared in sufficient quantities through techniques that also enable their direct incorporation into membrane electrode assemblies. We also determined that the mesoporous catalysts achieved a high porosity, which was retained after assembly and utilization within fuel cells. In addition, these mesoporous platinum catalysts exhibited an improved platinum mass specific power over catalysts prepared from commercially available platinum nanocatalysts.
USP18 and ISG15 coordinately impact on SKP2 and cell cycle progression
Authors: Vuillier Françoise , Li Zhi , Commere Pierre-Henri , Dynesen Lasse Toftdal , Pellegrini Sandra
Published: March 2019

USP18 is an isopeptidase that cleaves the ubiquitin-like ISG15 from conjugates and is also an essential negative feedback regulator of type I interferon signaling. We and others reported that USP18 protein is stabilized by ISG15 and targeted for degradation by SKP2 (S-phase kinase associated protein 2), the substrate-recognition subunit of the SCFSKP2 ubiquitin E3 ligase complex, which operates in cell cycle progression. Here, we have analyzed how, under non stimulated conditions, USP18, ISG15 and SKP2 communicate with each other, by enforcing or silencing their expression. We found that USP18 and SKP2 interact and that free ISG15 abrogates the complex, liberating USP18 from degradation and concomitantly driving SKP2 to degradation and/or ISGylation. These data reveal a dynamic interplay where the substrate USP18 stabilizes SKP2, both exogenous and endogenous. Consistent with this we show that silencing of baseline USP18 slows down progression of HeLa S3 cells towards S phase. Our findings point to USP18 and ISG15 as unexpected new SKP2 regulators, which aid in cell cycle progression at homeostasis.
The role of surgical resection before palliative chemotherapy in advanced gastric cancer
Authors: Choi Yong Won , Ahn Mi Sun , Jeong Geum Sook , Lee Hyun Woo , Jeong Seong Hyun , Kang Seok Yun , Park Joon Seong , Choi Jin-Hyuk , Son Sang-Yong , Hur Hoon , Han Sang-Uk , Sheen Seung Soo
Published: March 2019

The role of palliative surgical resection in recurrent or metastatic gastric cancer is still controversial. A retrospective review was conducted on 689 patients who received palliative chemotherapy for recurrent (n = 307) or primary metastatic (n = 382) gastric cancer. Among 131 patients (89 primary metastatic and 42 recurrent) with surgical resection before chemotherpay, 75 underwent gastrectomy, 42 metastasectomy, and 14 gastrectomy with metastasectomy. The median overall survival (OS) of patients who underwent surgical resection was significantly longer than that of patients who received chemotherapy alone (18 vs. 9 months, p < 0.0001). The OS benefit of surgical resection was consistent across subgroups. In multivariate analysis, surgical resection was independently associated with favorable OS (hazard ratio = 0.42, p < 0.0001). Moreover, patients with surgical resection showed favorable OS both in univariate (p < 0.0001) and multivariate (p < 0.0001) analysis even after propensity score matching. In addition, the median OS of patients who underwent gross complete resection (n = 54) was significantly longer than that of patients who underwent incomplete resection (n = 77) (30 vs. 15 months, p = 0.002). The present study suggests that judicious use of surgical resection before chemotherapy in recurrent or metastatic gastric cancer patients may result in a favorable outcome, especially when complete resection is achievable.
Conversion of tectonic and climatic forcings into records of sediment supply and provenance
Authors: Sharman Glenn R. , Sylvester Zoltan , Covault Jacob A.
Published: March 2019

Understanding how environmental forcings (e.g., tectonics, climate) are transformed by erosional landscapes into sedimentary signals is a critical component of inverting the stratigraphic record. Previous research has largely focused on sediment supply (Qs) and grain size as the de facto sedimentary signals of changing forcing mechanisms. We use a numerical model to consider the paired response of sediment provenance (Pv), expressed as fractional sediment load, andQsto demonstrate that the same change in environmental forcing may have a different expression in the sedimentary record. WhileQsreflects integrated denudation across an erosional catchment,Pvis controlled by spatially variable erosion that occurs in transient landscapes.Pvfrom proximal sediment sources increases during upstream knickpoint migration, whereasPvfrom distal sediment sources increases when bedrock channels incise to produce lower gradient profiles. Differences between theQsandPvsignals relate to distinct geomorphic processes that operate on different time scales and allow for a refined differentiation of the timing and mechanism of forcings than possible via analysis of either signal alone. Future efforts to integrate multiple sedimentary signals may thus yield a richer picture of underlying forcing mechanisms, facilitating efforts to invert the stratigraphic record.
Toxic aldehyde generation in and food uptake from culinary oils during frying practices: peroxidative resistance of a monounsaturate-rich algae oil
Authors: Moumtaz Sarah , Percival Benita C. , Parmar Devki , Grootveld Kerry L. , Jansson Pim , Grootveld Martin
Published: March 2019

Human ingestion of cytotoxic and genotoxic aldehydes potentially induces deleterious health effects, and high concentrations of these secondary lipid oxidation products (LOPs) are generated in polyunsaturated fatty acid (PUFA)-rich culinary oils during high temperature frying practices. Here, we explored the peroxidative resistance of a novel monounsaturate-rich algae frying oil (MRAFO) during laboratory-simulated shallow- and domestically-based repetitive deep-frying episodes (LSSFEs and DBRDFEs respectively), the latter featuring potato chip fryings. Culinary frying oils underwent LSSFEs at 180 °C, and DBRDFEs at 170 °C: aldehydes were determined by1H NMR analysis in samples collected at increasing heating/frying time-points. Fast food restaurant-fried potato chip serving (FFRPCS) aldehyde contents were also monitored. Substantially lower levels of aldehydes were generated in the MRAFO product than those observed in PUFA-richer oils during LSSFEs. Toxicologically-significant concentrations of aldehydes were detected in FFRPCSs, and potato chips exposed to DBRDFEs when using a PUFA-laden sunflower oil frying medium: these contents increased with augmented deep-frying episode repetition. FFRPCS aldehyde contents were 10–25 ppm for each class monitored. In conclusion, the MRAFO product generated markedly lower levels of food-penetrative, toxic aldehydes than PUFA-rich ones during LSSFEs. Since FFRPCS and DBRDFE potato chip aldehydes are predominantly frying oil-derived, PUFA-deplete MRAFOs potentially offer health-friendly advantages.
Relevance of Titin Missense and Non-Frameshifting Insertions/Deletions Variants in Dilated Cardiomyopathy
Authors: Akinrinade Oyediran , Heliö Tiina , Lekanne Deprez Ronald H. , Jongbloed Jan D. H. , Boven Ludolf G. , van den Berg Maarten P. , Pinto Yigal M. , Alastalo Tero-Pekka , Myllykangas Samuel , Spaendonck-Zwarts Karin van , van Tintelen J. Peter , van der Zwaag Paul A. , Koskenvuo Juha
Published: March 2019

Recent advancements in next generation sequencing (NGS) technology have led to the identification of the giant sarcomere gene, titin (TTN), as a major human disease gene. Truncating variants of TTN (TTNtv) especially in the A-band region account for 20% of dilated cardiomyopathy (DCM) cases. Much attention has been focused on assessment and interpretation of TTNtv in human disease; however, missense and non-frameshifting insertions/deletions (NFS-INDELs) are difficult to assess and interpret in clinical diagnostic workflow. Targeted sequencing covering all exons of TTN was performed on a cohort of 530 primary DCM patients from three cardiogenetic centres across Europe. Using stringent bioinformatic filtering, twenty-nine and two rare TTN missense and NFS-INDELs variants predicted deleterious were identified in 6.98% and 0.38% of DCM patients, respectively. However, when compared with those identified in the largest available reference population database, no significant enrichment of such variants was identified in DCM patients. Moreover, DCM patients and reference individuals had comparable frequencies of splice-region missense variants with predicted splicing alteration. DCM patients and reference populations had comparable frequencies of rare predicted deleterious TTN missense variants including splice-region missense variants suggesting that these variants are not independently causative for DCM. Hence, these variants should be classified as likely benign in the clinical diagnostic workflow, although a modifier effect cannot be excluded at this stage.
The metabolic fingerprints of HCV and HBV infections studied by Nuclear Magnetic Resonance Spectroscopy
Authors: Meoni Gaia , Lorini Serena , Monti Monica , Madia Francesco , Corti Giampaolo , Luchinat Claudio , Zignego Anna Linda , Tenori Leonardo , Gragnani Laura
Published: March 2019

Few studies are available on metabolic changes in liver injuries and this is the first metabolomic study evaluating a group of HCV-positive patients, before and after viral eradication via DAA IFN-free regimens, using1H-NMR to characterize and compare their serum fingerprints to naïve HBV-patients and healthy donors. The investigation clearly shows differences in the metabolomic profile of HCV patients before and after effective DAA treatment. Significant changes in metabolites levels in patients undergoing therapy suggest alterations in several metabolic pathways. It has been shown that1H-NMR fingerprinting approach is an optimal technique in predicting the specific infection and the healthy status of studied subjects (Monte-Carlo cross validated accuracies: 86% in the HCV vs HBV model, 98.7% in the HCV vs HC model). Metabolite data collected support the hypothesis that the HCV virus induces glycolysis over oxidative phosphorylation in a similar manner to the Warburg effect in cancer, moreover our results have demonstrated a different action of the two viruses on cellular metabolism, corroborating the hypothesis that the metabolic perturbation on patients could be attributed to a direct role in viral infection. This metabolomic study has revealed some alteration in metabolites for the first time (2-oxoglutarate and 3-hydroxybutrate) concerning the HCV-infection model that could explain several extrahepatic manifestations associated with such an infection.
Glycosylated nanostructures in sublingual immunotherapy induce long-lasting tolerance in LTP allergy mouse model
Authors: Rodriguez Maria J. , Ramos-Soriano Javier , Perkins James R. , Mascaraque Ainhoa , Torres Maria J. , Gomez Francisca , Diaz-Perales Araceli , Rojo Javier , Mayorga Cristobalina
Published: March 2019

An effective specific immunotherapy should contain elements to generate specific recognition (T-cell peptides) and to modulate the immunological response towards a Th1/Treg pattern by enhancing dendritic cells (DCs). We propose a novel sublingual immunotherapy for peach allergy, using systems, that combine Prup3-T-cell peptides with mannose dendrons (D1ManPrup3 and D4ManPrup3). Peach anaphylactic mice were treated 1, 2 and 5 nM concentrations. Tolerance was assessed one/five weeks after finishing treatment by determining in vivo/in vitro parameters after challenge with Prup3. Only mice receiving D1ManPrup3 at 2 nM were protected from anaphylaxis (no temperature changes, decrease in Prup3-sIgE and -sIgG1 antibody levels, and secreting cells) compared to PBS-treated mice. Moreover, an increase of Treg-cells and regulatory cytokines (IL-10+/IFN-γ+) in CD4+-T-cells and DCs were found. These changes were maintained at least five weeks after stopping treatment. D1ManPrup3 is an effective new approach of immunotherapy inducing protection from anaphylaxis which persists after finishing treatment.
Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington’s disease subjects
Authors: Herman Stephanie , Niemelä Valter , Emami Khoonsari Payam , Sundblom Jimmy , Burman Joachim , Landtblom Anne-Marie , Spjuth Ola , Nyholm Dag , Kultima Kim
Published: March 2019

Huntington’s disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.
Epigenetically dysregulated genes and pathways implicated in the pathogenesis of non-syndromic high myopia
Authors: Vishweswaraiah Sangeetha , Swierkowska Joanna , Ratnamala Uppala , Mishra Nitish K. , Guda Chittibabu , Chettiar Shiva S. , Johar Kaid R. , Mrugacz Malgorzata , Karolak Justyna A. , Gajecka Marzena , Radhakrishna Uppala
Published: March 2019

Myopia, commonly referred to as nearsightedness, is one of the most common causes of visual disability throughout the world. It affects more people worldwide than any other chronic visual impairment condition. Although the prevalence varies among various ethnic groups, the incidence of myopia is increasing in all populations across globe. Thus, it is considered a pressing public health problem. Both genetics and environment play a role in development of myopia. To elucidate the epigenetic mechanism(s) underlying the pathophysiology of high-myopia, we conducted methylation profiling in 18 cases and 18 matched controls (aged 4–12 years), using Illumina MethylationEPIC BeadChips array. The degree of myopia was variable among subjects, ranging from −6 to −15D. We identified 1541 hypermethylated CpGs, representing 1745 genes (2.0-fold or higher) (false discovery rate (FDR) p ≤ 0.05), multiple CpGs were p < 5 × 10−8 with a receiver operating characteristic area under the curve (ROC-AUC) ≥ 0.75 in high-myopia subjects compared to controls. Among these, 48 CpGs had excellent correlation (AUC ≥ 0.90). Herein, we present the first genome-wide DNA methylation analysis in a unique high-myopia cohort, showing extensive and discrete methylation changes relative to controls. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination.
Altering brain dynamics with transcranial random noise stimulation
Authors: van der Groen Onno , Mattingley Jason B. , Wenderoth Nicole
Published: March 2019

Random noise can enhance the detectability of weak signals in nonlinear systems, a phenomenon known as stochastic resonance (SR). This concept is not only applicable to single threshold systems but can also be applied to dynamical systems with multiple attractor states, such as observed during the phenomenon of binocular rivalry. Binocular rivalry can be characterized by marginally stable attractor states between which the brain switches in a spontaneous, stochastic manner. Here we used a computational model to predict the effect of noise on perceptual dominance durations. Subsequently we compared the model prediction to a series of experiments where we measured binocular rivalry dynamics when noise (zero-mean Gaussian random noise) was added either to the visual stimulus (Exp. 1) or directly to the visual cortex (Exp. 2) by applying transcranial Random Noise Stimulation (tRNS 1 mA, 100–640 Hz zero -mean Gaussian random noise). We found that adding noise significantly reduced the mixed percept duration (Exp. 1 and Exp. 2). Our results are the first to demonstrate that both central and peripheral noise can influence state-switching dynamics of binocular rivalry under specific conditions (e.g. low visual contrast stimuli), in line with a SR-mechanism.
Quantitative evaluation of ontology design patterns for combining pathology and anatomy ontologies
Authors: Alghamdi Sarah M. , Sundberg Beth A. , Sundberg John P. , Schofield Paul N. , Hoehndorf Robert
Published: March 2019

Data are increasingly annotated with multiple ontologies to capture rich information about the features of the subject under investigation. Analysis may be performed over each ontology separately, but recently there has been a move to combine multiple ontologies to provide more powerful analytical possibilities. However, it is often not clear how to combine ontologies or how to assess or evaluate the potential design patterns available. Here we use a large and well-characterized dataset of anatomic pathology descriptions from a major study of aging mice. We show how different design patterns based on the MPATH and MA ontologies provide orthogonal axes of analysis, and perform differently in over-representation and semantic similarity applications. We discuss how such a data-driven approach might be used generally to generate and evaluate ontology design patterns.
Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea
Authors: Bhatta Puspanjali , Dhukhwa Asmita , Sheehan Kelly , Al Aameri Raheem F.H , Borse Vikrant , Ghosh Sumana , Sheth Sandeep , Mamillapalli Chaitanya , Rybak Leonard , Ramkumar Vickram , Mukherjea Debashree
Published: March 2019

Capsaicin, the spicy component of hot chili peppers activates the TRPV1 pain receptors, and causes rapid desensitization. Capsaicin also ameliorates cisplatin-induced nephrotoxicity. Cisplatin, a commonly used anti-neoplastic agent for solid tumors causes significant hearing loss, nephrotoxicity and peripheral neuropathy. Upregulation of cochlear TRPV1 expression is related to cisplatin-mediated ototoxicity. Here we report that direct TRPV1 activation by localized trans-tympanic (TT) or oral administration of capsaicin (TRPV1 agonist) prevents cisplatin ototoxicity by sustained increased activation of pro-survival transcription factor signal transducer and activator of transcription (STAT3) in the Wistar rat. Cisplatin treatment produced prolonged activation of pro-apoptotic Ser727 p-STAT1 and suppressed Tyr705-p-STAT3 for up to 72 h in the rat cochlea. Our data indicate that capsaicin causes a transient STAT1 activation via TRPV1 activation, responsible for the previously reported temporary threshold shift. Additionally, we found that capsaicin increased cannabinoid receptor (CB2) in the cochlea, which leads to pro-survival Tyr705-p-STAT3 activation. This tilts the delicate balance of p-STAT3/p-STAT1 towards survival. Furthermore, capsaicin mediated protection is lost when CB2 antagonist AM630 is administered prior to capsaicin treatment. In conclusion, capsaicin otoprotection appears to be mediated by activation of CB2 receptors in the cochlea which are coupled to both STAT1 and STAT3 activation.
Hyaluronic acid inhibition by 4-methylumbelliferone reduces the expression of cancer stem cells markers during hepatocarcinogenesis
Authors: Sukowati Caecilia H. C. , Anfuso Beatrice , Fiore Esteban , Ie Susan I. , Raseni Alan , Vascotto Fulvia , Avellini Claudio , Mazzolini Guillermo , Tiribelli Claudio
Published: March 2019

Hyaluronic acid (HA) is a glycosaminoglycan of extracellular matrix related to cell surface which interacts with various cell types. To understand the role of HA during hepatocarcinogenesis, we assessed the effect of the inhibition of HA deposition and its association with heterogeneous hepatocellular carcinoma (HCC) cells. In this study, we used transgenic mice C57BL/6J-Tg(Alb1HBV)44Bri/J (HBV-TG) and normal C57BL/6 J (WT) for in vivo study, while HCC cells Huh7 and JHH6 as in vitro models. Both models were treated with an HA inhibitor 4-methylumbelliferone (4MU). We observed that 4MU treatments in animal model down-regulated the mRNA expressions of HA-related genes Has3 and Hyal2 only in HBV-TG but not in normal WT. As observed in vivo, in HCC cell lines, the HAS2 mRNA expression was down-regulated in Huh7 while HAS3 in JHH6, both with or without the presence of extrinsic HA. Interestingly, in both models, the expressions of various cancer stem cells (CD44, CD90, CD133, and EpCAM) were also decreased. Further, histological analysis showed that 4MU treatment with dose 25 mg/kg/day reduced fibrosis, inflammation, and steatosis in vivo, in addition to be pro-apoptotic. We concluded that the inhibition of HA reduced the expressions of HA-related genes and stem cells markers in both models, indicating a possible modulation of cells-to-cells and cells-to-matrix interaction.
The kinetics of folding of the NSH2 domain from p85
Authors: Visconti Lorenzo , Malagrinò Francesca , Toto Angelo , Gianni Stefano
Published: March 2019

SH2 domains are protein domains that mediate protein-protein interaction through the recognition and binding of specific sequences containing phosphorylated tyrosines. The p85 protein is the regulatory subunit of the heterodimeric enzyme PI3K, an important enzyme involved in several molecular pathways. In this work we characterize the folding kinetics of the NSH2 domain of p85. Our data clearly reveal peculiar folding kinetics, characterized by an apparent mismatch between the observed folding and unfolding kinetics. Taking advantage of double mixing stopped flow experiments and site directed mutagenesis we demonstrate that such behavior is due to the cis/trans isomerization of the peptide bond between D73 and P74, being in a cis conformation in the native protein. Our data are discussed in comparison with previous works on the folding of other SH2 domains.
Adult human pancreatic acinar cells dedifferentiate into an embryonic progenitor-like state in 3D suspension culture
Authors: Baldan Jonathan , Houbracken Isabelle , Rooman Ilse , Bouwens Luc
Published: March 2019

Human pancreatic exocrine cells were cultured in 3D suspension and formed pancreatospheres composed of acinar-derived and duct-like cells. We investigated, up to 6 days, the fate of human pancreatic acinar cells using fluorescein-conjugated Ulex Europaeus Agglutinin 1 lectin, a previously published acinar-specific non-genetic lineage tracing strategy. At day 4, fluorescence-activated cell sort for the intracellularly incorporated FITC-conjugated UEA1 lectin and the duct-specific CA19.9 surface marker, distinguished acinar-derived cells (UEA1+CA19.9−) from duct-like cells (UEA1−CA19.9+) and acinar-to-duct-like transdifferentiated cells (UEA1+CA19.9+). mRNA expression analysis of the acinar-derived (UEA1+CA19.9−) and duct-like (UEA1-CA19.9+) cell fractions with concomitant immunocytochemical analysis of the pancreatospheres revealed acquisition of an embryonic signature in the UEA1+CA19.9− acinar-derived cells characterized by de novo expression of SOX9 and CD142, robust expression of PDX1 and surface expression of GP2. The colocalisation of CD142, a multipotent pancreatic progenitor surface marker, PDX1, SOX9 and GP2 is reminiscent of a cellular state present during human embryonic development. Addition of TGF-beta signalling inhibitor Alk5iII, induced a 28-fold increased KI67-labeling in pancreatospheres, more pronounced in the CD142+GP2+ acinar-derived cells. These findings with human cells underscore the remarkable plasticity of pancreatic exocrine acinar cells, previously described in rodents, and could find applications in the field of regenerative medicine.
Long Range Correlation in Redox Potential Fluctuations Signals Energetic Efficiency of Bacterial Fe(II) Oxidation
Authors: Enright Allison M. L. , Edwards Brock A. , Ferris F. Grant
Published: March 2019

Differentiating biotic and abiotic processes in nature remains a persistent challenge, specifically in evaluating microbial contributions to geochemical processes through time. Building on previous work reporting that biologically-influenced systems exhibit stronger long-range correlation than abiotic systems, this study evaluated the relationship between long-range correlation of redox potential and oxidation rates of circumneutral microaerophilic bacterial Fe(II) oxidation using a series of batch microcosms with bacteriogenic iron oxides (BIOS). Initial detrended fluctuation analysis (DFA) scaling exponents of the abiotic microcosms were lower (ca. 1.20) than those of the biotic microcosms (ca. 1.80). As Fe(II) oxidation proceeded, correlation strength decayed as a logistic function of elapsed reaction time, exhibiting direct dependence on the free energy of reaction. Correlation strength for all microcosms decayed sharply from strong correlation to uncorrelated fluctuations. The decay rates are greater for abiotic microcosms than biotic microcosms. The ΔGm relaxation edges for biotic microcosms were lower, indicating less remaining free energy for Fe(II) oxidation than abiotic systems, with the implication that biologically-catalyzed reactions are likely more energetically efficient than abiotic reactions. These results strengthen the case for employing novel DFA techniques to distinguish in situ microbial metabolic activity from abiotic processes, as well as to potentially differentiate metabolisms among different chemoautotrophs.