bluuebunny/crossref_metadata_2025_split huggingface dataset:
DPP8/9 inhibitors are universal activators of functional NLRP1 alleles
Authors: Gai Kuo , Okondo Marian C. , Rao Sahana D. , Chui Ashley J. , Ball Daniel P. , Johnson Darren C. , Bachovchin Daniel A. 
Published: August 2019

AbstractIntracellular pathogenic structures or activities stimulate the formation of inflammasomes, which recruit and activate caspase-1 and trigger an inflammatory form of cell death called pyroptosis. The well-characterized mammalian inflammasome sensor proteins all detect one specific type of signal, for example double-stranded DNA or bacterial flagellin. Remarkably, NLRP1 was the first protein discovered to form an inflammasome, but the pathogenic signal that NLRP1 detects has not yet been identified. NLRP1 is highly polymorphic, even among inbred rodent strains, and it has been suggested that these diverse NLRP1 alleles may have evolved to detect entirely different stimuli. Intriguingly, inhibitors of the serine proteases DPP8 and DPP9 (DPP8/9) were recently shown to activate human NLRP1, its homolog CARD8, and several mouse NLRP1 alleles. Here, we show now that DPP8/9 inhibitors activate all functional rodent NLRP1 alleles, indicating that DPP8/9 inhibition induces a signal detected by all NLRP1 proteins. Moreover, we discovered that the NLRP1 allele sensitivities to DPP8/9 inhibitor-induced and Toxoplasma gondii-induced pyroptosis are strikingly similar, suggesting that DPP8/9 inhibition phenocopies a key activity of T. gondii. Overall, this work indicates that the highly polymorphic NLRP1 inflammasome indeed senses a specific signal like the other mammalian inflammasomes.
The Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway
Authors: Rosenbaum Joel C. , Bonilla Braulio , Hengel Sarah R. , Mertz Tony M. , Herken Benjamin W. , Kazemier Hinke G. , Pressimone Catherine A. , Ratterman Timothy C. , MacNary Ellen , De Magis Alessio , Kwon Youngho , Godin Stephen K. , Van Houten Bennett , Normolle Daniel P. , Sung Patrick , Das Subha R. , Paeschke Katrin , Roberts Steven A. , VanDemark Andrew P. , Bernstein Kara A. 
Published: August 2019

AbstractAccurate DNA replication is essential for genomic stability and cancer prevention. Homologous recombination is important for high-fidelity DNA damage tolerance during replication. How the homologous recombination machinery is recruited to replication intermediates is unknown. Here, we provide evidence that a Rad51 paralog-containing complex, the budding yeast Shu complex, directly recognizes and enables tolerance of predominantly lagging strand abasic sites. We show that the Shu complex becomes chromatin associated when cells accumulate abasic sites during S phase. We also demonstrate that purified recombinant Shu complex recognizes an abasic analog on a double-flap substrate, which prevents AP endonuclease activity and endonuclease-induced double-strand break formation. Shu complex DNA binding mutants are sensitive to methyl methanesulfonate, are not chromatin enriched, and exhibit increased mutation rates. We propose a role for the Shu complex in recognizing abasic sites at replication intermediates, where it recruits the homologous recombination machinery to mediate strand specific damage tolerance.
Stoichiogenomics reveal oxygen usage bias, key proteins and pathways associated with stomach cancer
Authors: Zuo Xiaoyan , Li Bo , Zhu Chengxu , Yan Zheng-Wen , Li Miao , Wang Xinyi , Zhang Yu-Juan 
Published: August 2019

AbstractStomach cancer involves hypoxia-specific microenvironments. Stoichiogenomics explores environmental resource limitation on biological macromolecules in terms of element usages. However, the patterns of oxygen usage by proteins and the ways that proteins adapt to a cancer hypoxia microenvironment are still unknown. Here we compared the oxygen and carbon contents ([C]) between proteomes of stomach cancer (hypoxia) and two stomach glandular cells (normal). Key proteins, genome locations, pathways, and functional dissection associated with stomach cancer were also studied. An association of oxygen content ([O]) and protein expression level was revealed in stomach cancer and stomach glandular cells. For differentially expressed proteins (DEPs), oxygen contents in the up regulated proteins were3.2%higherthan that in the down regulated proteins in stomach cancer. A total of 1,062 DEPs were identified; interestingly none of these proteins were coded on Y chromosome. The up regulated proteins were significantly enriched in pathways including regulation of actin cytoskeleton, cardiac muscle contraction, pathway of progesterone-mediated oocyte maturation, etc. Functional dissection of the up regulated proteins with high oxygen contents showed that most of them were cytoskeleton, cytoskeleton associated proteins, cyclins and signaling proteins in cell cycle progression. Element signature of resource limitation could not be detected in stomach cancer for oxygen, just as what happened in plants and microbes. Unsaved use of oxygen by the highly expressed proteins was adapted to the rapid growth and fast division of the stomach cancer cells. In addition, oxygen usage bias, key proteins and pathways identified in this paper laid a foundation for application of stoichiogenomics in precision medicine.
Enrichment technique to allow early detection and monitor emergence of KRAS mutation in response to treatment
Authors: Kitagawa Yoshiyasu , Okumura Kazuhiro , Watanabe Takayoshi , Tsukamoto Kei , Kitano Shiro , Nankinzan Rino , Suzuki Takuto , Hara Taro , Soda Hiroaki , Denda Tadamichi , Yamaguchi Taketo , Nagase Hiroki 
Published: August 2019

AbstractSensitivity of cell-free circulating tumour DNA (ctDNA) assays is often hampered by the limited quantity of intact mutant nucleotide fragments. To overcome the issue of substrate limitation in clinical applications, we developed an enrichment method utilizing pyrrole-imidazole (PI) polyamides and their ability to bind the minor groove of B-DNA. We present here a proof-of-concept experiment to enrich specific mutant KRAS alleles with biotinylated PI polyamides. We investigated the clinical feasibility of incorporating PI polyamides to detect KRAS mutations in ctDNA from 40 colorectal cancer (CRC) patients, of whom 17 carried mutations in KRAS. After enriching ctDNA with those polyamides, we used digital PCR to detect several common KRAS codon 12 mutations. Enrichment by biotinylated PI polyamides improved the sensitivity of ctDNA analysis (88.9% vs. 11.1%, P < 0.01) in 9 non-metastatic mutation-positive patients. We observed no differences in performance for the 8 metastatic subjects (100% vs. 75%, P = 0.47). In the remaining 23/40 patients with wild type KRAS codon 12, no mutant alleles were detected with or without polyamide-facilitated enrichment. Enriching B-form of ctDNA with PI polyamides significantly improved the assay sensitivity in detecting KRAS mutations in non-metastatic CRC patient samples.
Breakdown of the strong multiplet description of the Sm2+ ion in the topological Kondo insulator SmB6: specific heat studies
Authors: Radwanski Ryszard J. , Nalecz Dawid M. , Ropka Zofia 
Published: August 2019

AbstractWe have theoretically confirmed the existence of in-gap real quantum-mechanical states in SmB6, which have been suggested by experiments. These in-gap states, below the hybridization gap of 20 meV, are related to the Sm2+ ion states and can be revealed by calculations within the spin-orbital |LSLzSz〉 space, with L = 3 and S = 3. Our approach overcomes difficulties related to the singlet J = 0 multiplet ground state. The in-gap states originate from the 49-fold degenerated term 7F (4f 6), which is split by cubic crystal-field (CEF) and spin-orbit (s − o) interactions. There is competition between these interactions: the six-order CEF interactions produce a 7-fold degenerated ground state, whereas the s − o interactions, even the weakest one, produce a singlet (J = 0) ground state. We have found preliminary CEF and s − o parameters that produce the lowest states at 0 K (singlet) and 91 K (triplet) and the next triplet at 221 K, i.e., within the hybridization gap. The derived states well explain the large extra specific heat of SmB6, confirming the consistency and adequateness of our theoretical approach with the breakdown of the strong multiplet description of the Sm2+ ion in SmB6.
Biliary stenting alone versus biliary stenting combined with 125I particles intracavitary irradiation for the treatment of advanced cholangiocarcinoma
Authors: Pang Qing , Zhou Lei , Hu Xiao-Si , Wang Yong , Man Zhong-Ran , Yang Song , Wang Wei , Qian Zhen , Jin Hao , Liu Hui-Chun 
Published: August 2019

AbstractWe aimed to compare the efficacy of percutaneous transhepatic biliary stenting (PTBS) and PTBS combined with 125I particles implantation in the treatment of advanced extrahepatic cholangiocarcinoma (EHC). A total of 184 advanced EHC patients, who received PTBS (PTBS group) or PTBS combined with 125I particles implantation (PTBS + 125I group) from January 2012 to April 2017 in our department, were retrospectively reviewed. The improvement of jaundice and liver function was observed in both groups. The postoperative complications, risk of biliary re-obstruction, and overall survival (OS) were compared between the two groups. Amongst, 71 cases received PTBS and 113 had the additional implantation of 125I particles. The jaundice and liver function were significantly improved in all patients, especially in PTBS + 125I group. There was no significant difference in the risk of postoperative complications between the two groups. However, the risk of biliary re-obstruction significantly reduced in PTBS + 125I group (19.5% vs. 35.2%, p = 0.017). Kaplan Meier analysis showed that patients in PTBS + 125I group had a significantly better OS, both for hilar and distal cholangiocarcinoma. Univariate analysis demonstrated that preoperative levels of carbohydrate antigen 19-9 (CA19-9), total bilirubin, neutrophil count, lymphocyte count, and different therapeutic method were significant factors affecting OS. Multivariate analysis further identified the treatment of PTBS combined with 125I particles implantation as an independent protective prognostic factor (HR = 0.26, 95% CI: 0.17–0.39, p < 0.001). In conclusion, for patients with advanced EHC, PTBS combined with 125I particles implantation is superior to PTBS alone in improving liver function, inhibiting biliary re-obstruction, and prolonging survival time.
Genomic regions on chromosome 5H containing a novel QTL conferring barley yellow dwarf virus-PAV (BYDV-PAV) tolerance in barley
Authors: Hu Hongliang , Choudhury Shormin , Shabala Sergey , Gupta Sanjiv , Zhou Meixue 
Published: August 2019

AbstractBarley yellow dwarf virus is a widespread disease affecting plant growth and yield in cereal crops including barley. Complete resistance to BYDV encoded by a single gene is lacking in barley. To identify novel resistance genes that can be further utilised in breeding for plant disease resistance, a doubled haploid population originated from a cultivated barley with a known resistance gene and a wild barley was constructed and assessed for barley yellow dwarf tolerance in three trials with two in Tasmania (TAS) and one in Western Australia (WA). We identified two Quantitative trait loci (QTL) in both Tasmanian trials, and four QTL in Western Australian trial. Two QTL from TAS trials were also detected from WA. The QTL on chromosome 3H corresponds to the known major resistance gene Ryd2. The other QTL, Qbyd-5H, represents a potential new resistance locus and contributed 7.0~10.4% of total phenotypic variation in the three trials. It was mapped within the interval of 125.76~139.24 cM of chromosome 5H. Two additional minor effect QTL were identified on chromosome 7H from WA trial, contributing slightly less effect on BYD tolerance. The consistently detected new gene on chromosome 5H will potentially serve as a novel source of tolerance to achieve more sustainable resistance to BYDV in barley.
The lipid-dependent structure and function of LacY can be recapitulated and analyzed in phospholipid-containing detergent micelles
Authors: Vitrac Heidi , Mallampalli Venkata K P S , Bogdanov Mikhail , Dowhan William 
Published: August 2019

AbstractMembrane proteins play key roles in cellular functions, their activity mainly depending on their topological arrangement in membranes. Structural studies of membrane proteins have long adopted a protein-centric view regarding the determinants of membrane protein topology and function. Several studies have shown that the orientation of transmembrane domains of polytopic membrane proteins with respect to the plane of the lipid bilayer can be largely determined by membrane lipid composition. However, the mechanism by which membrane proteins exhibit structural and functional duality in the same membrane or different membranes is still unknown. Here we show that lipid-dependent structural and functional assessment of a membrane protein can be conducted in detergent micelles, opening the possibility for the determination of lipid-dependent high-resolution crystal structures. We found that the lactose permease purified from Escherichia coli cells exhibiting varied phospholipid compositions exhibits the same topology and similar function as in its membrane of origin. Furthermore, we found several conditions, including protein mutations and micelle lipid composition, that lead to increased protein stability, correlating with a higher yield of two-dimensional crystal formation. Altogether, our results demonstrate how the membrane lipid environment influences membrane protein topology and arrangement, both in native membranes and in mixed detergent micelles.
Visualizing the trigeminovagal complex in the human medulla by combining ex-vivo ultra-high resolution structural MRI and polarized light imaging microscopy
Authors: Henssen D. J. H. A. , Derks B. , van Doorn M. , Verhoogt N. C. , Staats P. , Vissers K. , Van Cappellen van Walsum A. M. 
Published: August 2019

AbstractA trigeminovagal complex, as described in some animals, could help to explain the effect of vagus nerve stimulation as a treatment for headache disorders. However, the existence of a trigeminovagal complex in humans remains unclear. This study, therefore investigated the existence of the trigeminovagal complex in humans. One post-mortem human brainstem was scanned at 11.7T to obtain structural (T1-weighted) and diffusion magnetic resonance images ((d)MR images). Post-processing of dMRI data provided track density imaging (TDI) maps to investigate white matter at a smaller resolution than the imaging resolution. To evaluate the reconstructed tracts, the MR-scanned brainstem and three additional brainstems were sectioned for polarized light imaging (PLI) microscopy. T1-weighted images showed hyperintense vagus medullar striae, coursing towards the dorsomedial aspect of the medulla. dMRI-, TDI- and PLI-images showed these striae to intersect the trigeminal spinal tract (sp5) in the lateral medulla. In addition, PLI images showed that a minority of vagus fibers separated from the vagus trajectory and joined the trigeminal spinal nucleus (Sp5) and the sp5. The course of the vagus tract in the rostral medulla was demonstrated in this study. This study shows that the trigeminal- and vagus systems interconnect anatomically at the level of the rostral medulla where the vagus fibers intersect with the Sp5 and sp5. Physiological and clinical utility of this newly identified interconnection is a topic for further research.
Lipid profile of cerebrospinal fluid in multiple sclerosis patients: a potential tool for diagnosis
Authors: Nogueras L. , Gonzalo H. , Jové M. , Sol J. , Gil-Sanchez A. , Hervás J. V. , Valcheva P. , Gonzalez-Mingot C. , Solana M. J. , Peralta S. , Pamplona R. , Brieva L. 
Published: August 2019

AbstractMultiple sclerosis (MS) is a complex multifactorial neuropathology. Although its etiology remains unclear, it has been demonstrated that the immune system attacks myelin, leading to demyelination and axonal damage. The involvement of lipids as one of the main components of myelin sheaths in MS and other demyelinating diseases has been postulated. However, it is still a matter of debate whether specific alteration patterns exist over the disease course. Here, using a lipidomic approach, we demonstrated that, at the time of diagnosis, the cerebrospinal fluid of MS patients presented differences in 155 lipid species, 47 of which were identified. An initial hierarchical clusterization was used to classify MS patients based on the presence of 25 lipids. When a supervised method was applied in order to refine this classification, a lipidomic signature was obtained. This signature was composed of 15 molecules belonging to five different lipid families including fatty acids (FAs). An FA-targeted approach revealed differences in two members of this family: 18:3n3 and 20:0 (arachidic acid). These results reveal a CSF lipidomic signature in MS patients at the time of diagnosis that might be considered as a potential diagnostic tool.
Voids healing and carbide refinement of cold rolled M50 bearing steel by electropulsing treatment
Authors: Wang Feng , Qian Dongsheng , Hua Lin , Mao Huajie , Xie Lechun 
Published: August 2019

AbstractThe voids caused by the cold rolling (CR) quite deteriorates the final performance of M50 bearing steel. In this work, the effect of electropulsing treatment (EPT) on the voids has been investigated, finding that the nano-size voids around carbides have been extensively healed. Moreover, it is interesting to find that the Cr-rich carbides are partially dissolved and consequently refined by EPT, which could be attributed to the decreased thermodynamic dissolution barriers and accelerated kinetic diffusion of carbon atoms towards dislocation. These results inspire people to develop a novel strategy (CR + EPT) to fully take advantage of CR and tailor the carbides size in bearing steels.
Evaluation of liver regeneration and post-hepatectomy liver failure after hemihepatectomy in patients with hepatocellular carcinoma
Authors: Gong Wen-Feng , Zhong Jian-Hong , Lu Zhan , Zhang Qiu-Ming , Zhang Zhi-Yuan , Chen Chang-Zhi , Liu Xu , Ma Liang , Zhang Zhi-Ming , Xiang Bang-De , Li Le-Qun 
Published: August 2019

Abstract
Aim: To explore clinical factors associated with extent of liver regeneration after hemihepatectomy to treat hepatocellular carcinoma (HCC).
Methods: Future liver remnant volume (as a percentage of functional liver volume, %FLRV) and remnant liver volume were measured preoperatively and at 1, 5, 9, and 13 weeks postoperatively.
Results: After hepatectomy, 1 of 125 patients (0.8%) died within 3 months, 13 (10.4%) experienced liver failure, and 99 (79.2%) experienced complications. %FLRV was able to predict liver failure with an area under the receiver operating characteristic curve of 0.900, and a cut-off value of 42.7% showed sensitivity of 85.7% and specificity of 88.6%. Postoperative median growth ratio was 21.3% at 1 week, 30.9% at 5 weeks, 34.6% at 9 weeks, and 37.1% at 13 weeks. Multivariate analysis identified three predictors associated with liver regeneration: FLRV &lt; 601 cm3, %FLRV, and liver cirrhosis. At postoperative weeks (POWs) 1 and 5, liver function indicators were significantly better among patients showing high extent of regeneration than among those showing low extent, but these differences disappeared by POW 9.
Conclusions: FLRV, %FLRV, and liver cirrhosis strongly influence extent of liver regeneration after hepatectomy. %FLRV values below 42.7% are associated with greater risk of post-hepatectomy liver failure.
Liraglutide inhibits the apoptosis of human nucleus pulposus cells induced by high glucose through PI3K/Akt/caspase-3 signaling pathway
Authors: Ming-yan Yao , Jing Zhang , Shu-qin Guo , Xiao-liang Bai , Zhi-hong Li , Xue Zhou 
Published: August 2019

Abstract
Diabetes mellitus (DM) is a potential etiology of disc degeneration. Glucagon-like peptide-1 (GLP-1) is currently regarded as a powerful treatment option for type 2 diabetes. Apart from the beneficial effects on glycaemic control, GLP-1 has been reported to exert functions in a variety of tissues on modulation of cell proliferation, differentiation, and apoptosis. However, little is known regarding the effects of GLP-1 on nucleus pulposus cells (NPCs). In the present study, we investigated the effects of liraglutide (LIR), a long-lasting GLP-1 analogue, on apoptosis of human NPCs and the underlying mechanisms involved. We confirmed the presence of GLP-1 receptor (GLP-1R) in NPCs. Our data demonstrated that liraglutide inhibited the apoptosis of NPCs induced by high glucose (HG), as detected by Annexin V/Propidium Iodide (PI) and ELISA assays. Moreover, liraglutide down-regulated caspase-3 activity at intermediate concentration (100 nM) for maximum effect. Further analysis suggested that liraglutide suppressed reactive oxygen species (ROS) generation and stimulated the phosphorylation of Akt under HG condition. Pretreatment of cells with the Phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (LY) and small interfering RNAs (siRNAs) GLP-1R abrogated the liraglutide-induced activation of Akt and the protective effects on NPCs’ apoptosis. In conclusion, liraglutide could directly protect NPCs against HG-induced apoptosis by inhibiting oxidative stress and activate the PI3K/Akt/caspase-3 signaling pathway via GLP-1R.
Dexmedetomidine exerts dual effects on human annulus fibrosus chondrocytes depending on the oxidative stress status
Authors: Zhou Lin , Zhou Jinhua , Sheng Bin , Li Xin , Yuan Youchao 
Published: August 2019

Abstract
Dexmedetomidine (Dex) is an anesthetic widely used in lumbar discectomy, but its effect on chondrocytes remains unclear. Dex is speculated to promote cartilage degeneration by activating α-2 adrenergic receptor. However, the antioxidative and anti-inflammatory effects of Dex implied the potential chondrocyte protective effect under stress conditions. The present study aimed to determine the effect of Dex on chondrocytes under non-stress and stress conditions. Chondrocytes were isolated from human annulus fibrosus (AF) tissues and oxidative stress was induced by treatment with 1 mM hydrogen peroxide (H2O2). Chondrocytes were treated with Dex alone or in combination with H2O2. Treatment with Dex alone decreased mRNA expression of COL2A1 and increased that of MMP-3 and MMP-13, thus contributing to cartilage degeneration. However, Dex prevented H2O2-induced death and degeneration of chondrocytes partly by enhancing antioxidant capacity. Mechanistically, Dex attenuated H2O2-mediated activation of NF-κB and NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), both of which play key roles in inflammation and inflammatory damage. Dex inactivated NLRP3 through the suppression of NF-κB and JNK signals. Co-treatment with Dex and H2O2 increased protein level of XIAP (X-linked inhibitor-of-apoptosis, an anti-apoptosis protein), compared with H2O2 treatment alone. H2O2 treatment increased the expression of neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) that is a ubiquitin ligase targeting XIAP. However, Dex decreased the amount of NEDD4 adhering to XIAP, thus protecting XIAP protein from NEDD4-mediated ubiquitination and degradation. Given that surgery inevitably causes oxidative stress and inflammation, the protective effect of Dex on chondrocytes during oxidative stress is noteworthy and warrants further study.