Publications by authors named "Yongqing Li"

259 Publications

Accurate High-Level -Based Global Potential Energy Surface and Quantum Dynamics Calculation for the First Excited State of CH.

J Phys Chem A 2021 Jun 17. Epub 2021 Jun 17.

Department of Physics, Liaoning University, Shenyang 110036, China.

A full three-dimensional global potential energy surface (PES), covering the whole configuration space, is reported first for the title system by fitting high-level energies at the multireference configuration interaction level with the aug-cc-pV6Z basis set. In this work, the many-body expansion method is invoked to fit the innate character of the CH(1″) PES. The topographical features are examined in detail based on the new global PES and in accordance with the other calculations from the energies, which show the correct behavior at the C(P) + H(Σ) and CH(Π) + H(S) dissociation limits. Using a time-dependent wave packet method, we provide insights into the dynamics behavior for reaction of C(P) + H(Σ) → CH(Π) + H(S). The integral cross sections and reaction probabilities increase monotonically in terms of the collision energy.
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http://dx.doi.org/10.1021/acs.jpca.1c02413DOI Listing
June 2021

miR-590-5p targets RMND5A and promotes migration in pancreatic adenocarcinoma cell lines.

Oncol Lett 2021 Jul 17;22(1):532. Epub 2021 May 17.

The Center for Heart Development, State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China.

Required for meiotic nuclear division 5 homolog A (RMND5A) functions as an E3 ubiquitin ligase. To date, few studies have investigated the role of RMND5A in cancer. In the present study, the expression levels of RMND5A in multiple types of cancer were analyzed using the Gene Expression Profiling Interactive Analysis platform. The results revealed that RMND5A was highly expressed and associated with overall survival in patients with pancreatic adenocarcinoma (PAAD). A wound-healing assay revealed that RMND5A overexpression significantly increased cell migration in the PAAD cell lines AsPC-1 and PANC-1. analysis predicted that RMND5A was a potential target of microRNA(miR)-590-5p. Further experiments demonstrated that overexpression of miR-590-5p downregulated the expression levels of RMND5A and decreased the migratory ability of the AsPC-1 and PANC-1 cell lines. In addition, overexpression of miR-590-5p attenuated the promoting effects of RMND5A on the migration of AsPC-1 and PANC-1 cells. The results of the present study may further elucidate the mechanisms underlying PAAD progression and provide novel targets for the treatment of PAAD.
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http://dx.doi.org/10.3892/ol.2021.12793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156640PMC
July 2021

Assessment of the Cytoprotective Effects of High-Dose Valproic Acid Compared to a Clinically Used Lower Dose.

J Surg Res 2021 May 11;266:125-141. Epub 2021 May 11.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan; Department of Surgery, Feinberg School of Medicine/Northwestern University, Chicago, Illinois. Electronic address:

Objective: Valproic acid (VPA) treatment improves survival in animal models of injuries on doses higher than those allowed by Food and Drug Administration (FDA). We investigated the proteomic alterations induced by a single high-dose (140mg/kg) of VPA (VPA140) compared to the FDA-approved dose of 30mg/kg (VPA30) in healthy humans. We also describe the proteomic and transcriptomic changes induced by VPA140 in an injured patient. We hypothesized that VPA140 would induce cytoprotective changes in the study participants.

Methods: Serum samples were obtained from healthy subjects randomized to two groups; VPA140 and VPA30 at 3 timepoints: 0h(baseline), 2h, and 24h following infusion(n = 3/group). Samples were also obtained from an injured patient that received VPA140 at 0h, 6h and 24h following infusion. Proteomic analyses were performed using liquid chromatography-mass spectrometry (LC-MS/MS), and transcriptomic analysis was performed using RNA-sequencing. Differentially expressed (DE) proteins and genes were identified for functional annotation and pathway analysis using iPathwayGuide and gene set enrichment analysis (GSEA), respectively.

Results: For healthy individuals, a dose comparison was performed between VPA140 and VPA30 groups at 2 and 24 h. Functional annotation showed that top biological processes in VPA140 versus VPA30 analysis at 2 h included regulation of fatty acid (P = 0.002) and ATP biosynthesis (P = 0.007), response to hypoxia (P = 0.017), cell polarity regulation (P = 0.031), and sequestration of calcium ions (P = 0.031). Top processes at 24 h in VPA140 versus VPA30 analysis included amino acid metabolism (P = 0.023), collagen catabolism (P = 0.023), and regulation of protein breakdown (P = 0.023). In the injured patient, annotation of the DE proteins in the serum showed that top biological processes at 2 h included neutrophil chemotaxis (P = 0.002), regulation of cellular response to heat (P = 0.008), regulation of oxidative stress (P = 0.008) and regulation of apoptotic signaling pathway (P = 0.008). Top biological processes in the injured patient at 24 h included autophagy (P = 0.01), glycolysis (P = 0.01), regulation of apoptosis (P = 0.01) and neuron apoptotic processes (P = 0.02).

Conclusions: VPA140 induces cytoprotective changes in human proteome not observed in VPA30. These changes may be responsible for its protective effects in response to injuries.
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http://dx.doi.org/10.1016/j.jss.2021.03.025DOI Listing
May 2021

Systematic theoretical investigation of two novel molecules BtyC-1 and BtyC-2 based on ESIPT mechanism.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Sep 27;258:119810. Epub 2021 Apr 27.

School of Physics, Liaoning University, Shenyang 110036, PR China; Collaborative Innovation Center of Light Manipulations and Applications, Shandong Normal University, Jinan 250358, PR China. Electronic address:

Inexperiment, Song et al. have successfully synthesizedtwo novel molecules BtyC-1 and BtyC-2 and observedasingle and dual fluorescence peaks in these two molecules respectively. (Song et al. Tetrahedron Lett. 2019, 60, 1696-1701) However, they still lack a detailed and reasonable theoretical explanation. Then we wonder why these two similar structures behave so much differently? In this work, we focus on explaining the photochemical and photophysical properties of BtyC-1 and BtyC-2 by studying the excited state intramolecular proton transfer (ESIPT) mechanisms. Based on the optimized geometric configurations, the calculated infrared spectra indicate the intramolecular hydrogen bonding interactions are heightened in their excited states. The frontier molecular orbitals reflect the charge redistribution in photoinduced process, which explains that the driving force of ESIPT process is provided by enhanced hydrogen bonding interactions. In the meantime, the calculations of potential energy curves vividly explain the principle of the experimental dual fluorescence phenomenon. The analysis of Mulliken charges deepens the discussion of molecular structures on the potential energy barriers. Calculated absorption spectra via using density functional theory and emission spectra via using time-dependent density functional theory are consistent with the experimental data, which confirms the correctness of our calculation methods. The reduced density gradient isosurfaces help us distinguish the complex non-covalent bonds. Base on the above analyses, we conclude that there is no stable structure for BtyC-1 in excited state, which make it occur the ESIPT reaction spontaneously. BtyC-2 exists a stable normal structure in excited state. Its dual fluorescence signals are emitted by its normal and isomer structures, respectively.
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http://dx.doi.org/10.1016/j.saa.2021.119810DOI Listing
September 2021

The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity.

PLoS Pathog 2021 Apr 28;17(4):e1009530. Epub 2021 Apr 28.

Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, P. R. China.

Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. However, its regulatory effect in antiviral innate immunity remains unclear. We found that DDX5 interacts with the N6-methyladenosine (m6A) writer METTL3 to regulate methylation of mRNA through affecting the m6A writer METTL3-METTL14 heterodimer complex. Meanwhile, DDX5 promoted the m6A modification and nuclear export of transcripts DHX58, p65, and IKKγ by binding conserved UGCUGCAG element in innate response after viral infection. Stable IKKγ and p65 transcripts underwent YTHDF2-dependent mRNA decay, whereas DHX58 translation was promoted, resulting in inhibited antiviral innate response by DDX5 via blocking the p65 pathway and activating the DHX58-TBK1 pathway after infection with RNA virus. Furthermore, we found that DDX5 suppresses antiviral innate immunity in vivo. Our findings reveal that DDX5 serves as a negative regulator of innate immunity by promoting RNA methylation of antiviral transcripts and consequently facilitating viral propagation.
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http://dx.doi.org/10.1371/journal.ppat.1009530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081163PMC
April 2021

TWIST2 and the PPAR signaling pathway are important in the progression of nonalcoholic steatohepatitis.

Lipids Health Dis 2021 Apr 20;20(1):39. Epub 2021 Apr 20.

Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250014, P. R. China.

Background: To investigate the roles of the transcription factors twist family bHLH transcription factor 1 (TWIST1), twist family bHLH transcription factor 2 (TWIST2), and peroxisome proliferator activated receptor gamma (PPARγ) in the progression of nonalcoholic steatohepatitis.

Methods: The protein levels of TWIST1, TWIST2 and PPARγ were determined in the serum of nonalcoholic fatty liver disease (NAFLD) patients and healthy controls by enzyme-linked immunosorbent assay (ELISA). An in vivo model for fatty liver was established by feeding C57BL/6 J mice a high-fat diet (HFD). An in vitro model of steatosis was established by treating LO-2 cells with oleic acid (OA). RNA sequencing was performed on untreated and OA-treated LO-2 cells followed by TWIST1, TWIST2 and PPARγ gene mRNA levels analysis, Gene Ontology (GO) enrichment and pathway analysis.

Results: The TWIST2 serum protein levels decreased significantly in all fatty liver groups (P < 0.05), while TWIST1 varied. TWIST2 tended to be lower in mice fed an HFD and was significantly lower at 3 months. Similarly, in the in vitro model, the TWIST2 protein level was downregulated significantly at 48 and 72 h after OA treatment. RNA sequencing of LO-2 cells showed an approximately 2.3-fold decrease in TWIST2, with no obvious change in TWIST1 and PPARγ. The PPAR signaling pathway was enriched, with 4 genes upregulated in OA-treated cells (P = 0.0018). The interleukin (IL)-17 and tumor necrosis factor (TNF) signaling pathways were enriched in OA-treated cells.

Conclusions: The results provide evidence that the TWIST2 and PPAR signaling pathways are important in NAFLD and shed light on a potential mechanism of steatosis.
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http://dx.doi.org/10.1186/s12944-021-01458-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059034PMC
April 2021

A C-terminal fragment of Arabidopsis OXIDATIVE STRESS 2 can play a positive role in salt tolerance.

Biochem Biophys Res Commun 2021 Jun 6;556:23-30. Epub 2021 Apr 6.

Plant Gene Engineering Center, Chinese Academy of Sciences Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, Guangdong Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, 510650, China. Electronic address:

The zinc finger transcription factor OXIDATIVE STRESS 2 (OXS2) was previously reported to be involved in oxidative stress tolerance and stress escape. Here we report that an Arabidopsis oxs2-1 mutant is also more sensitive to salt stress. Conversely, the overproduction of a C-terminal fragment of OXS2, the 'AT3' fragment, can enhance salt tolerance in Arabidopsis by upregulating the transcription of at least six salt-induced genes: COR15A, COR47, RD29B, KIN1, ACS2 and ACS6. Mutant analysis showed that the AT3-mediated salt tolerance requires MPK3, MPK6 and 14-3-3Ω. AT3 was shown to interact with MPK3 in planta, with 14-3-3Ω as a likely linker protein. AT3 can be phosphorylated by MPK3 during salt stress, upon which it relocates from the cytoplasm to the nucleus. It appears that the phosphorylation-induced nuclear localization of OXS2 contributes a positive role to the salt stress response.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.127DOI Listing
June 2021

Substituent Effects on Excited-State Intramolecular Proton Transfer Reaction of 2-Aryloxazoline Derivatives.

J Phys Chem A 2021 Apr 29;125(13):2743-2750. Epub 2021 Mar 29.

School of Physics, Liaoning University, Shenyang 110036, P. R. China.

Different substituents and benzene ring numbers had significant effects on the fluorescence phenomenon of 2-aryloxazoline derivatives as observed in an experiment. Here, we select five 2-aryloxazoline derivatives with different substituents and benzene ring numbers (2u, 2ad, 2af, 2ai, and 2ah) to analyze the effects on the fluorescence phenomena. For 2ad, 2ah, and 2ai, first, the geometric structures are optimized based on the density functional theory and time-dependent density functional theory methods. The analysis of the obtained bond parameters reveals the variation of hydrogen bond interactions from S to S states. Second, the calculated absorption and emission spectra are consistent with the experimental values, which proves that the theoretical method is feasible. Finally, through the analysis of the infrared vibrational spectrum, reduced density gradient isosurfaces, frontier molecular orbitals, and potential energy curves, the strengthening mechanism of the hydrogen bond interaction and the ability of the excited-state intramolecular proton transfer (ESIPT) reaction to occur are further explained. Since the proton transfer reactions of 2u and 2af occur spontaneously under photoexcitation, they have no stable structures in the S state. In conclusion, due to the different substituents, 2u is more prone to the proton transfer reaction than 2ad. For 2af, 2ai, and 2ah with different benzene ring numbers, the ESIPT reaction is more difficult to occur as the number of benzene rings increases. The ability of the ESIPT reaction to occur follows the order 2af → 2ah → 2ai. For 2-aryloxazoline derivatives with different substituents or different benzene ring numbers, the hydrogen bond strengthening mechanism has been authenticated, which promotes the occurrence of the ESIPT reactions.
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http://dx.doi.org/10.1021/acs.jpca.0c10799DOI Listing
April 2021

Spatio-temporal selection of reference genes in the two congeneric species of Glycyrrhiza.

Sci Rep 2021 Mar 2;11(1):1122. Epub 2021 Mar 2.

Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement and Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, 510650, China.

Glycyrrhiza, a genus of perennial medicinal herbs, has been traditionally used to treat human diseases, including respiratory disorders. Functional analysis of genes involved in the synthesis, accumulation, and degradation of bioactive compounds in these medicinal plants requires accurate measurement of their expression profiles. Reverse transcription quantitative real-time PCR (RT-qPCR) is a primary tool, which requires stably expressed reference genes to serve as the internal references to normalize the target gene expression. In this study, the stability of 14 candidate reference genes from the two congeneric species G. uralensis and G. inflata, including ACT, CAC, CYP, DNAJ, DREB, EF1, RAN, TIF1, TUB, UBC2, ABCC2, COPS3, CS, R3HDM2, were evaluated across different tissues and throughout various developmental stages. More importantly, we investigated the impact of interactions between tissue and developmental stage on the performance of candidate reference genes. Four algorithms, including geNorm, NormFinder, BestKeeper, and Delta Ct, were used to analyze the expression stability and RefFinder, a comprehensive software, provided the final recommendation. Based on previous research and our preliminary data, we hypothesized that internal references for spatio-temporal gene expression are different from the reference genes suited for individual factors. In G. uralensis, the top three most stable reference genes across different tissues were R3HDM2, CAC and TUB, while CAC, CYP and ABCC2 were most suited for different developmental stages. CAC is the only candidate recommended for both biotic factors, which is reflected in the stability ranking for the spatio (tissue)-temporal (developmental stage) interactions (CAC, R3HDM2 and DNAJ). Similarly, in G. inflata, COPS3, R3HDM2 and DREB were selected for tissues, while RAN, COPS3 and CS were recommended for developmental stages. For the tissue-developmental stage interactions, COPS3, DREB and ABCC2 were the most suited reference genes. In both species, only one of the top three candidates was shared between the individual factors and their interactions, specifically, CAC in G. uralensis and COPS3 in G. inflata, which supports our overarching hypothesis. In summary, spatio-temporal selection of reference genes not only lays the foundation for functional genomics research in Glycyrrhiza, but also facilitates these traditional medicinal herbs to reach/maximize their pharmaceutical potential.
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http://dx.doi.org/10.1038/s41598-020-79298-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925658PMC
March 2021

regulates pathological cardiac hypertrophy via a β-catenin-dependent mechanism.

Am J Physiol Heart Circ Physiol 2021 04 26;320(4):H1634-H1645. Epub 2021 Feb 26.

The Center for Heart Development, State Key Laboratory of Development Biology of Freshwater Fish, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development College of Life Sciences, Hunan Normal University, Changsha, China.

Wnt/β-catenin signaling plays a key role in pathological cardiac remodeling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may provide a tissue-specific clinical targeting strategy. encodes the core interaction factor of Wnt/β-catenin. Two homologs ( and ) have been identified in mammals. Different from the ubiquitous expression profile of , is enriched in cardiac tissue. However, the role of in mammalian cardiac disease is yet to be elucidated. In this study, we found that was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios, and increased cell size. The canonical β-catenin/T-cell transcription factor 4 (TCF4) complex was abundant in -overexpressing transgenic (-TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, , , and c-Myc, were upregulated. A tail vein injection of β-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodeling in -TG mice. Furthermore, in vivo downregulated during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for tissue-specific clinical treatment via targeting this pathway. In this study, we found that is associated with human pathological hypertrophy. Cardiac-specific overexpression of in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.
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http://dx.doi.org/10.1152/ajpheart.00538.2020DOI Listing
April 2021

DEAD/DEAH-box helicase 5 is hijacked by an avian oncogenic herpesvirus to inhibit interferon beta production and promote viral replication.

Dev Comp Immunol 2021 Jun 17;119:104048. Epub 2021 Feb 17.

Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, 100097, PR China. Electronic address:

DEAD-box helicase 5 (DDX5) plays a significant role in tumorigenesis and regulates viral replication of several viruses. An avian oncogenic herpesvirus, Marek's disease virus (MDV), is widely known to cause immunosuppression and lymphoma in chickens. However, the underlying mechanisms of how DDX5 plays a role in viral replication remain unclear. In this study, we show that MDV inhibits the production of interferon beta (IFN-β) in chicken embryo fibroblasts (CEFs) by increasing the expression level and promoting the nuclear aggregation of DDX5. We further reveal how DDX5 down-regulates melanoma differentiation-associated gene 5/toll-like receptor 3 signaling through the fundamental transcription factor, interferon regulatory factor 1. MDV replication is suppressed, and the production of IFN-β is promoted in the DDX5 absented CEFs. Taken together, our investigations demonstrate that MDV inhibits IFN-β production by targeting DDX5-mediated signaling to facilitate viral replication, which offers a novel insight into the mechanism by which an avian oncogenic herpesvirus replicates in chicken cells.
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http://dx.doi.org/10.1016/j.dci.2021.104048DOI Listing
June 2021

Development of a large animal model of lethal polytrauma and intra-abdominal sepsis with bacteremia.

Trauma Surg Acute Care Open 2021 1;6(1):e000636. Epub 2021 Feb 1.

Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Background: Trauma and sepsis are individually two of the leading causes of death worldwide. When combined, the mortality is greater than 50%. Thus, it is imperative to have a reproducible and reliable animal model to study the effects of polytrauma and sepsis and test novel treatment options. Porcine models are more translatable to humans than rodent models due to the similarities in anatomy and physiological response. We embarked on a study to develop a reproducible model of lethal polytrauma and intra-abdominal sepsis, which was lethal, though potentially salvageable with treatment.

Methods: Our laboratory has a well-established porcine model that was used as the foundation. Animals were subjected to a rectus crush injury, long bone fracture, liver and spleen laceration, traumatic brain injury and hemorrhage that was used as a foundation. We tested various colon injuries to create intra-abdominal sepsis. All animals underwent injuries followed by a period of shock, then subsequent resuscitation.

Results: All animals had blood culture-proven sepsis. Attempts at long-term survival of animals after injury were ceased because of poor appetite and energy. We shifted to an 8-hour endpoint. The polytrauma injury pattern remained constant and the colon injury pattern changed with the intention of creating a model that was ultimately lethal but potentially salvageable with a therapeutic drug. An uncontrolled cecal injury (n=4) group resulted in very early deaths. A controlled cecal injury (CCI; n=4) group had prolonged time prior to mortality with one surviving to the endpoint. The sigmoid injury (n=5) produced a similar survival curve to CCI but no animals surviving to the endpoint.

Conclusion: We have described a porcine model of polytrauma and sepsis that is reproducible and may be used to investigate novel treatments for trauma and sepsis.

Level Of Evidence: Not applicable. Animal study.
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http://dx.doi.org/10.1136/tsaco-2020-000636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852924PMC
February 2021

Substituent effect on ESIPT mechanisms and photophysical properties of HBT derivatives.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Apr 23;250:119375. Epub 2020 Dec 23.

School of Physics, Liaoning University, Shenyang 110036, PR China. Electronic address:

Substituent effects on excited-state intramolecular proton transfer (ESIPT) and photophysical properties of 2-(2-Hydroxyphenyl) benzothiazole (HBT) derivatives have been theoretically unveiled via the density functional theory (DFT) and time-dependent DFT (TDDFT). The optimized geometrical configurations and normal mode analyses confirm that the proton transfer processes are more reactive in excited state. Through calculating the activation energies and rate constants of ESIPT processes, finding that the processes are increasingly inactive when substituent group changes from -CN, -COMe, -Cl, -Me, -NMe to -NO. In addition, the photophysical properties analyses indicate the vertical transition energies are in good agreement with those observed in experiment. Note that all the absorption and emission maxima of enol and keto forms have the significant red-shift. In order to clarify the substituent effect on ESIPT and photophysical properties, we draw the frontier molecular orbitals (FMOs) isosurfaces and calculate the distances of electrons and holes and atomic charges. It follows that the intramolecular charge transfer (ICT) degrees are increasingly enlarged as substituting from -CN, -COMe, -Cl, -Me, -NMe to -NO groups, which not only causes the red-shift of absorption and emission of enol and keto forms, but also affects the charge distribution of proton donor and acceptor, inhibiting the occurrence of ESIPT processes.
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http://dx.doi.org/10.1016/j.saa.2020.119375DOI Listing
April 2021

Cloning and structural analysis of complement component 3d in wild birds provides insight into its functional evolution.

Dev Comp Immunol 2021 Apr 15;117:103979. Epub 2020 Dec 15.

Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agricultural and Forestry Sciences, Beijing, 100097, PR China. Electronic address:

Complement component 3 d (C3d) is the final cleavage product of the complement component C3 and serves as a crucial role in link innate and adaptive immunity, and increase B-cell sensitivity to an antigen by 1000-10000 fold. The crystal structure of human C3d revealed there are two distinct surfaces, a convex surface containing the thioester-constituting residues that mediate covalent binding to the target antigen, and a concave surface with an acidic pocket responsible for interaction with CR2. In this study, we cloned and sequenced cDNA fragment encoding C3d region from 15 wild bird species. Then, the C3d sequences from wild birds, chicken and mammals were aligned to construct phylogenetic trees. Phylogenetic tree displayed two main branches, indicating mammals and birds, but the bird C3d branch was divided into two main parts, with five wild birds (Ardeola bacchus, Zoothera, Bubo, Crossoptilon mantchuricum and Caprimulgus europaeus) clustering much closer to mammals. In addition, the C3d proteins of Ardeola bacchus, Bubo, Crossoptilon mantchuricum and Caprimulgus europaeus contained a Glu163 residue at the position at which Lys163 was found in other birds. However, Glu163 have the same charge polarity as Asp163, which is the key amino acid residue comprising the acidic pocket combined with CR2 found at this position in mammals, and Zoothera also possessed Asp163 at this position. Structure modeling analyses also verified that the C3ds of these five wild bird species exhibited the amino acid sequence and structure comprising the typical acidic pocket found in mammals that is required for combination with B cell surface receptors, which contribute electrostatic forces to interact with CR2. Our investigations indicate that some bird C3ds may already have the ability to bind with CR2 by electrostatic force, like mammals. As Ardeola bacchus, Zoothera, Bubo, Crossoptilon mantchuricum and Caprimulgus europaeus have more typical C3d concave acid pockets and thus a stronger ability to bind CR2, we speculate that these five wild birds may have a solider immunity against pathogens. Our phylogenetic and structural analyses of bird C3ds provide insights on the evolutionary divergence in the function of immune factors of avian and mammalian.
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http://dx.doi.org/10.1016/j.dci.2020.103979DOI Listing
April 2021

Prenatal exposure and transplacental transfer of perfluoroalkyl substance isomers in participants from the upper and lower reaches of the Yangtze River.

Environ Pollut 2021 Feb 6;270:116202. Epub 2020 Dec 6.

Ministry of Education Key Laboratory of Environmental Remediation and Ecosystem Health, Institution of Environmental Health, Zhejiang University, Hangzhou, 310058, China. Electronic address:

Data on gestational exposure characteristics and transplacental transfer are quite limited for perfluoroalkyl substance (PFAS) isomers, especially those from large-scale comparative studies. To fill this gap, we examined isomers of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS) in matched maternal and cord serum from Mianyang and Hangzhou, which are located in the upper and lower reaches of the Yangtze River, China, respectively. These data were compared with those from our previous study on Wuhan in the middle reach. The average ΣPFAS concentration increased from upstream to downstream (Mianyang (4.44 ng/mL) < Wuhan (9.88 ng/mL) < Hangzhou (19.72 ng/mL)) and may be related to the per capita consumption expenditure of each city. The ln-transformed PFAS concentrations showed significant differences between Mianyang and Hangzhou after adjusting confounding factors (p < 0.05). The percentages of linear PFOS and PFOA in maternal and cord serum from these cities all exceeded those in electrochemical fluorination products. The isomer profiles of PFASs in maternal and cord serum might be greatly influenced by local production processes of PFASs and residents' dietary habits. The transplacental transfer efficiencies decreased significantly with increasing concentrations in maternal serum for ΣPFAS, ΣPFOS, ΣPFOA, ΣPFHxS, n-PFOS, iso-PFOS, 4m-PFOS, 1m-PFOS, n-PFOA, n-PFHxS, and br-PFHxS (Spearman rank correlation coefficients (r) = 0.373-0.687, p < 0.01). These findings support an understanding of the regional characteristics in maternal exposure to PFASs along the Yangtze River, isomeric profiles of PFASs in these regions, and the transplacental transfer processes of PFAS isomers.
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http://dx.doi.org/10.1016/j.envpol.2020.116202DOI Listing
February 2021

Incidental squamous cell carcinoma of renal pelvis presenting as skin invasion: a case report.

J Med Case Rep 2020 Dec 15;14(1):244. Epub 2020 Dec 15.

Department of Oncology Radiotherapy, Affiliated the 900th Hospital of PLA, Fujian Medical University, 156 Xi Er Huan Road, Fuzhou City, Fujian Province, 350025, People's Republic of China.

Introduction: Squamous cell carcinoma of the renal pelvis is a rare neoplasm, accounting for less than 0.8% of malignant renal tumors. Chronic irritation is believed to be the primary pathogenic cause for squamous cell carcinoma of the renal pelvis. The most frequently reported cases of squamous cell carcinoma of the renal pelvis generally present with hydronephrosis, pyelonephritis, or nephrolithiasis. The skin of the flank is a very uncommon site of clinical presentation. Here, we report an exceedingly rare case of squamous cell carcinoma of the renal pelvis presenting as skin invasion of the flank.

Case Presentation: A 66-year-old Han Chinese man consulted our hospital because of a right lumbar skin lesion lasting more than 3 months. His physical examination revealed that he had a palpable mass about 6.0 cm × 5.0 cm in size at the posterior axillary line in the right low back with skin ulceration 3 mm in diameter and exudation on it. Magnetic resonance imaging showed hydronephrosis of the right kidney and plaque-like abnormal signal in the middle portion of the kidney. The patient underwent a right nephrectomy. The sinus tract formation between the ulcerative skin in the right low back and the middle portion of the right kidney could be found. The distended kidney could not be excised entirely for tight adhesion. Pathological examination showed moderately differentiated renal squamous cell carcinoma with invasion of the renal parenchyma and perirenal adipose tissue.

Conclusion: It is extremely rare for renal squamous cell carcinoma to present as skin invasion. Recurrent percutaneous nephrolithotomy may be a risk factor for squamous cell carcinoma of the renal pelvis. The possibility of renal squamous cell carcinoma should be kept in mind in patients who have hydronephrosis, nephrolithiasis, or chronic pyelonephritis for a long time or with renal anomalies. More radiological examinations are suggested for such patients.
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http://dx.doi.org/10.1186/s13256-020-02530-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737292PMC
December 2020

Rapid single-molecule digital detection of protein biomarkers for continuous monitoring of systemic immune disorders.

Blood 2021 Mar;137(12):1591-1602

Department of Mechanical Engineering.

Digital protein assays have great potential to advance immunodiagnostics because of their single-molecule sensitivity, high precision, and robust measurements. However, translating digital protein assays to acute clinical care has been challenging because it requires deployment of these assays with a rapid turnaround. Herein, we present a technology platform for ultrafast digital protein biomarker detection by using single-molecule counting of immune-complex formation events at an early, pre-equilibrium state. This method, which we term "pre-equilibrium digital enzyme-linked immunosorbent assay" (PEdELISA), can quantify a multiplexed panel of protein biomarkers in 10 µL of serum within an unprecedented assay incubation time of 15 to 300 seconds over a 104 dynamic range. PEdELISA allowed us to perform rapid monitoring of protein biomarkers in patients manifesting post-chimeric antigen receptor T-cell therapy cytokine release syndrome, with ∼30-minute sample-to-answer time and a sub-picograms per mL limit of detection. The rapid, sensitive, and low-input volume biomarker quantification enabled by PEdELISA is broadly applicable to timely monitoring of acute disease, potentially enabling more personalized treatment.
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http://dx.doi.org/10.1182/blood.2019004399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065241PMC
March 2021

Accurate global adiabatic potential energy surfaces for three low-lying electronic states of AlH free radicals.

Phys Chem Chem Phys 2020 Nov;22(45):26544-26551

Department of Physics, Liaoning University, Shenyang 110036, China.

In order to obtain the all-round molecular properties of the AlH2 system and the corresponding dynamical characteristics of the Al + H2 (v = 0, j = 0) → H + AlH reaction, three significant global adiabatic potential energy surfaces of AlH2 (X2A1, 2B1, and 2B2) free radicals were constructed for the first time. Ab initio energies were calculated under the multi-reference configuration interaction method and the aug-cc-pV(T,Q)Z basis sets; then the ab initio energies were extrapolated to the complete basis sets limit. The three adiabatic potential energy surfaces were constructed by the many-body expansion theory. The maximum root-mean square error was just 50 cm-1, which was small enough to ensure that the potential energy surfaces were accurate. The concerned T-type insertion topographical features, dissociation schemes, C2v geometry reaction mechanisms, and minimum energy curve paths were investigated and are discussed in detail. Several differences from previous studies are also pointed out. Eventually, the integral cross-sections of Al + H2 (v = 0, j = 0) → H + AlH reaction as calculated by quasi-classical trajectory method were employed to predict the dynamical properties of AlH2, providing the most reliable theoretical reference of the dynamical characteristics known thus far for such a reaction. These new potential energy surfaces can be treated as a reliable basis for investigation of the dynamics and as a component for constructing larger aluminum-/hydrogen-containing systems.
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http://dx.doi.org/10.1039/d0cp02939dDOI Listing
November 2020

Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment.

J Trauma Acute Care Surg 2021 03;90(3):507-514

From the Department of Surgery (U.F.B., I.S.D., A.M.W., V.C.N., B.E.B., A.S., R.L.O., B.L., Y.L., H.B.A.), University of Michigan, Ann Arbor, Michigan; Department of Surgery (U.F.B.), Washington University, St. Louis, Missouri; Department of Surgery (H.B.A.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Computational Medicine and Bioinformatics (A.K.), and Michigan Regional Comprehensive Metabolomics Resource Core (M.K.), University of Michigan Health System, Ann Arbor, Michigan.

Objective: Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment.

Methods: We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss and 2 hours of hypotension) and randomized them to two groups (n = 5/group): (1) normal saline (NS; 3× hemorrhage volume) and (2) NS-VPA (NS, 3× hemorrhage volume; VPA, 150 mg/kg). After 6 hours, brains were harvested, and 100 mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using reversed-phase liquid chromatography-mass spectrometry in positive and negative ion modes, and data were analyzed using MetaboAnalyst software (McGill University, Quebec, Canada).

Results: In untargeted reversed-phase liquid chromatography-mass spectrometry analysis, we detected 3,750 and 1,955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on glycolysis/tricarboxylic acid (TCA) cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p = 0.001).

Conclusion: Valproic acid can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment.
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http://dx.doi.org/10.1097/TA.0000000000003026DOI Listing
March 2021

Linear and Nonlinear Two-Terminal Spin-Valve Effect from Chirality-Induced Spin Selectivity.

ACS Nano 2020 Nov 2;14(11):15983-15991. Epub 2020 Nov 2.

Department of Physics, Florida State University, Tallahassee, Florida 32306, United States.

Various mechanisms of electrical generation of spin polarization in materials have been a subject of broad interest for their underlying physics and device potential in spintronics. One such scheme is chirality-induced spin selectivity (CISS), with which structural chirality leads to different electric conductivities for electrons of opposite spins. The resulting effect of spin filtering has been reported for a number of chiral molecules assembled on different surfaces. However, the microscopic origin and transport mechanisms remain controversial. In particular, the fundamental Onsager relation was argued to preclude linear-response detection of CISS by a ferromagnet. Here, we report definitive observation of CISS-induced magnetoconductance in vertical heterojunctions of (Ga,Mn)As/AHPA-L molecules/Au, directly verifying spin filtering by the AHPA-L molecules spin detection by the (Ga,Mn)As. The pronounced and robust magnetoconductance signals resulting from the use of a magnetic semiconductor enable a rigorous examination of its bias dependence, which shows both linear- and nonlinear-response components. The definitive identification of the linear-response CISS-induced two-terminal spin-valve effect places an important constraint for a viable theory of CISS and its device manifestations. The results present a promising route to spin injection and detection in semiconductors without using any magnetic material.
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http://dx.doi.org/10.1021/acsnano.0c07438DOI Listing
November 2020

Selection of Reference Genes for qRT-PCR Analysis in Medicinal Plant under Abiotic Stresses and Hormonal Treatments.

Plants (Basel) 2020 Oct 26;9(11). Epub 2020 Oct 26.

Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement & Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China.

Best known as licorice, Linn., a genus of herbaceous perennial legume, has been used as a traditional herbal medicine in Asia and a flavoring agent for tobacco and food industry in Europe and America. Abiotic stresses and hormonal treatments can significantly impact the development and metabolism of secondary metabolites in . To better understand the biosynthesis of the trace-amount bioactive compounds, we first screened for the suitable reference genes for quantitative real-time reverse transcription PCR (qRT-PCR) analysis in The expression profiles of 14 candidate reference genes, including () (), (), (), (), (), (), (), (), (), (), (), (), and () from two congeneric species, F. and B., were examined under abiotic stresses (osmotic and salinity) and hormonal treatments (Abscisic acid (ABA) and methyl jasmonic acid (MeJA)) using a panel of software, including geNorm, NormFinder, BestKeeper, and Delta CT. The overall stability, however, was provided by RefFinder, a comprehensive ranking system integrating inputs from all four algorithms. In , the most stable reference genes under osmotic stress, salt stress, ABA treatment, and MeJA treatment were , , , and for leaves and , , , and for roots, respectively. In comparison, the top ranked genes were , , , and for leaves and , , , and for roots, respectively, under stress and hormonal treatments in . and , on the other hand, were the least stable genes under the most experimental conditions in the two congeneric species. Finally, our survey of the reference genes in legume shows that , , , and were the top choices for the abiotic stresses while , , , and were recommended for the hormonal treatments in Leguminosae. Our combined results provide reliable normalizers for accurate gene quantifications in species, which will allow us to exploit its medicinal potential in general and antiviral activities in particular.
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http://dx.doi.org/10.3390/plants9111441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692165PMC
October 2020

Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells.

iScience 2020 Oct 23;23(10):101600. Epub 2020 Sep 23.

Department of Internal Medicine, National Taiwan University Hospital, Taipei 10048, Taiwan.

The enlarged distinct bulky-ball-like nucleolus matrix assembly is observed in most cancer stem cells (CSCs); however, the underlying mechanism is largely unknown. We show that matrix metalloproteinase-7 (MMP-7) shedding MUC-1 SEA domain releases MUC-1 C-ter, facilitating the nucleolus trafficking of p53 in gefitinib-resistant lung CSCs. The nucleolus colocalizations of p53, MUC-1 C-ter, MMP-7 and nucleolin were observed in the CD34 CXADR CD44v gefitinib-resistant EGFR CSC colonies. MUC-1 C-ter induced a unique porous bulky-ball-shaped, cagelike nucleolus that functions as a nucleus molecular "garage" for potent tumor suppressor, p53. Nucleolus could also facilitate the novel sub-nucleus compartment for proteolytic processing p53 by MMP-7 to generate a 35 kDa fragment. Moreover, we show that salinomycin, an anti-CSC agent, disrupts nucleolus by inducing nucleoplasm translocation of p53 and sensitizing CSC to chemotherapy drugs. Thus, this study highlights the MMP-7-MUC-1-p53 axis in nucleolus as a potential therapeutic target for anti-CSCs to resolve the chemotherapy-resistance dilemma.
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http://dx.doi.org/10.1016/j.isci.2020.101600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559243PMC
October 2020

Peptidylarginine deiminase 2 has potential as both a biomarker and therapeutic target of sepsis.

JCI Insight 2020 10 15;5(20). Epub 2020 Oct 15.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that are involved in a variety of human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit in sepsis, the role of PAD2 remains unknown. Here, we report that PAD2 is engaged in sepsis and sepsis-induced acute lung injury in both human patients and mice. Pad2-/- or selective inhibition of PAD2 by a small molecule inhibitor increased survival and improved overall outcomes in mouse models of sepsis. Pad2 deficiency decreased neutrophil extracellular trap (NET) formation. Importantly, Pad2 deficiency inhibited Caspase-11-dependent pyroptosis in vivo and in vitro. Suppression of PAD2 expression reduced inflammation and increased macrophage bactericidal activity. In contrast to Pad2-/-, Pad4 deficiency enhanced activation of Caspase-11-dependent pyroptosis in BM-derived macrophages and displayed no survival improvement in a mouse sepsis model. Collectively, our findings highlight the potential of PAD2 as an indicative marker and therapeutic target for sepsis.
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http://dx.doi.org/10.1172/jci.insight.138873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605547PMC
October 2020

Serum citrullinated histone H3 concentrations differentiate patients with septic verses non-septic shock and correlate with disease severity.

Infection 2021 Feb 30;49(1):83-93. Epub 2020 Sep 30.

Department of Surgery, University of Michigan Health System, University of Michigan Medical School, 1500 E Medical Center Dr. SPC 5331, Ann Arbor, MI, 48109-5331, USA.

Purpose: Microbial infection stimulates neutrophil/macrophage/monocyte extracellular trap formation, which leads to the release of citrullinated histone H3 (CitH3) catalyzed by peptidylarginine deiminase (PAD) 2 and 4. Understanding these molecular mechanisms in the pathogenesis of septic shock will be an important next step for developing novel diagnostic and treatment modalities. We sought to determine the expression of CitH3 in patients with septic shock, and to correlate CitH3 levels with PAD2/PAD4 and clinically relevant outcomes.

Methods: Levels of CitH3 were measured in serum samples of 160 critically ill patients with septic and non-septic shock, and healthy volunteers. Analyses of clinical and laboratory characteristics of patients were conducted.

Results: Levels of circulating CitH3 at enrollment were significantly increased in septic shock patients (n = 102) compared to patients hospitalized with non-infectious shock (NIC) (n = 32, p < 0.0001). The area under the curve (95% CI) for distinguishing septic shock from NIC using CitH3 was 0.76 (0.65-0.86). CitH3 was positively correlated with PAD2 and PAD4 concentrations and Sequential Organ Failure Assessment Scores [total score (r = 0.36, p < 0.0001)]. The serum levels of CitH3 at 24 h (p < 0.01) and 48 h (p < 0.05) were significantly higher in the septic patients that did not survive.

Conclusion: CitH3 is increased in patients with septic shock. Its serum concentrations correlate with disease severity and prognosis, which may yield vital insights into the pathophysiology of sepsis.
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http://dx.doi.org/10.1007/s15010-020-01528-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527151PMC
February 2021

HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation.

Science 2020 09;369(6510)

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.

Inflammasomes are supramolecular complexes that play key roles in immune surveillance. This is accomplished by the activation of inflammatory caspases, which leads to the proteolytic maturation of interleukin 1β (IL-1β) and pyroptosis. Here, we show that nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3)- and pyrin-mediated inflammasome assembly, caspase activation, and IL-1β conversion occur at the microtubule-organizing center (MTOC). Furthermore, the dynein adapter histone deacetylase 6 (HDAC6) is indispensable for the microtubule transport and assembly of these inflammasomes both in vitro and in mice. Because HDAC6 can transport ubiquitinated pathological aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for the down-regulation of these inflammasomes by autophagy. This work suggests an unexpected parallel between the formation of physiological and pathological aggregates.
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http://dx.doi.org/10.1126/science.aas8995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814939PMC
September 2020

Modulation of Brain Transcriptome by Combined Histone Deacetylase Inhibition and Plasma Treatment Following Traumatic Brain Injury and Hemorrhagic Shock.

Shock 2021 01;55(1):110-120

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Introduction: We previously showed that the addition of valproic acid (VPA), a histone deacetylase inhibitor, to fresh frozen plasma (FFP) resuscitation attenuates brain lesion size and swelling following traumatic brain injury (TBI) and hemorrhagic shock (HS). The goal of this study was to use computational biology tools to investigate the effects of FFP+VPA on the brain transcriptome following TBI+HS.

Methods: Swine underwent TBI+HS, kept in shock for 2 h, and resuscitated with FFP or FFP + VPA (n = 5/group). After 6 h of observation, brain RNA was isolated and gene expression was analyzed using a microarray. iPathwayGuide, Gene Ontology (GO), Gene-Set Enrichment Analysis, and Enrichment Mapping were used to identify significantly impacted genes and transcriptomic networks.

Results: Eight hundred differentially expressed (DE) genes were identified out of a total of 9,118 genes. Upregulated genes were involved in promotion of cell division, proliferation, and survival, while downregulated genes were involved in autophagy, cell motility, neurodegenerative diseases, tumor suppression, and cell cycle arrest. Seven hundred ninety-one GO terms were significantly enriched. A few major transcription factors, such as TP53, NFKB3, and NEUROD1, were responsible for modulating hundreds of other DE genes. Network analysis revealed attenuation of interconnected genes involved in inflammation and tumor suppression, and an upregulation of those involved in cell proliferation and differentiation.

Conclusion: Overall, these results suggest that VPA treatment creates an environment that favors production of new neurons, removal of damaged cells, and attenuation of inflammation, which could explain its previously observed neuroprotective effects.
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http://dx.doi.org/10.1097/SHK.0000000000001605DOI Listing
January 2021

BVES downregulation in non-syndromic tetralogy of fallot is associated with ventricular outflow tract stenosis.

Sci Rep 2020 08 25;10(1):14167. Epub 2020 Aug 25.

The Center for Heart Development, State Key Lab of Development Biology of Freshwater Fish, Key Lab of MOE for Development Biology and Protein Chemistry, College of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.

BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription. However, the relationship between BVES and the pathogenesis of TOF has not been determined. Here we reported our research results about the relationship between BVES and the right ventricular outflow tract (RVOT) stenosis. BVES expression was significantly downregulated in most TOF samples compared with controls. The expression of the second heart field (SHF) regulatory network genes, including NKX2.5, GATA4 and HAND2, was also decreased in the TOF samples. In zebrafish, bves knockdown resulted in looping defects and ventricular outflow tract (VOT) stenosis, which was mostly rescued by injecting bves mRNA. bves knockdown in zebrafish also decreased the expression of SHF genes, such as nkx2.5, gata4 and hand2, consistent with the TOF samples` results. The dual-fluorescence reporter system analysis showed that BVES positively regulated the transcriptional activity of GATA4, NKX2.5 and HAND2 promoters. In zebrafish, nkx2.5 mRNA partially rescued VOT stenosis caused by bves knockdown. These results indicate that BVES downregulation may be associated with RVOT stenosis of non-syndromic TOF, and bves is probably involved in the development of VOT in zebrafish.
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http://dx.doi.org/10.1038/s41598-020-70806-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447802PMC
August 2020

Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Rabbit Model of Endotoxic Shock.

Surg Infect (Larchmt) 2021 May 20;22(4):421-426. Epub 2020 Aug 20.

Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.

Sepsis causes millions of deaths on a global scale annually. Activation of peptidylarginine deiminase (PAD) enzymes in sepsis causes citrullination of histones, which results in neutrophil extracellular trap formation and sepsis progression. This study evaluates pan-PAD inhibitor, Cl-amidine, in a model of lipopolysaccharide (LPS)-induced endotoxic shock in rabbits. We hypothesized that Cl-amidine would improve survival and attenuate kidney injury. In the survival model, rabbits were injected injected intravenously with 1 mg/kg of LPS, and then randomly assigned either to receive dimethyl sulfoxide (DMSO; 1 mcL/g) or Cl-amidine (10 mg/kg diluted in 1 mcL/g DMSO). They were then monitored for 14 days to evaluate survival. In the non-survival experiment, the same insult and treatment were administered, however; the animals were euthanized 12 hours after LPS injection for kidney harvest. Acute kidney injury (AKI) scoring was performed by a histopathologist who was blinded to the group assignment. Serial blood samples were also collected and compared. Rabbits that received Cl-amidine had a higher survival (72%) compared with the rabbits that received DMSO (14%; p < 0.05). Cl-amidine-treated rabbits had lower (p < 0.05) histopathologic AKI scores, as well as plasma creatinine and blood urea nitrogen (BUN) levels 12 hours after insult. Pan-PAD inhibitor Cl-amidine improves survival and attenuates kidney injury in LPS-induced endotoxic shock in rabbits.
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http://dx.doi.org/10.1089/sur.2020.189DOI Listing
May 2021

Overproduction of plant nuclear export signals enhances diamide tolerance in Schizosaccharomyces pombe.

Biochem Biophys Res Commun 2020 10 13;531(3):335-340. Epub 2020 Aug 13.

Plant Gene Engineering Center, Chinese Academy of Sciences Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, Guangdong Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China. Electronic address:

The nuclear export signal (NES) endows a protein nuclear export ability. Surprisingly, our previous study shows that just the NES peptide of Schizosaccharomyces pombe Oxs1 (SpOxs1) can confer diamide tolerance by competing with transcription factor Pap1 for nuclear transport. This finding intrigued us to test the function of NESs from heterologous organisms. The Arabidopsis thaliana zinc finger transcription factor OXIDATIVE STRESS 2 (AtOXS2) is a nucleocytoplasmic shuttling protein and nearly all OXS2 members from maize and rice contain an NES. In this study, we find that the plant OXS2 members and their C-terminus (AT3 peptide) can confer diamide tolerance due to their NESs, and amino acids in non-conserved as well as conserved positions are necessary for the diamide tolerance. As in SpOxs1, the enhanced tolerance to diamide in fission yeast depends on Pap1. Like SpOxs1, OXS2 family NESs appear to compete for nuclear transport of the Pap1-like Arabidopsis protein bZIP10, as when overproduced in Arabidopsis protoplasts, bZIP10 is retained in the nucleus.
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http://dx.doi.org/10.1016/j.bbrc.2020.07.054DOI Listing
October 2020

Comparison of postoperative CT- and preoperative MRI-based breast tumor bed contours in prone position for radiotherapy after breast-conserving surgery.

Eur Radiol 2021 Jan 1;31(1):345-355. Epub 2020 Aug 1.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, 440 Jiyan Road, Jinan, 250117, Shandong, China.

Objectives: To compare the target volume of tumor bed defined by postoperative computed tomography (post-CT) in prone position registered with or without preoperative magnetic resonance imaging (pre-MRI).

Methods: A total of 22 patients were included with early-stage breast invasive ductal cancer, who have undergone breast-conservative surgery and received the pre-MRI and post-CT in prone position. The MRI sequences (T1W, T2W, T2W-SPAIR, DWI, dyn-eTHRIVE, sdyn-eTHRIVE) were delineated and manually registered to CT, respectively. The clinical target volumes (CTVs) and planning target volumes (PTVs) were contoured on CT and different MRI sequences, respectively. Differences were measured in terms of consistence index (CI), dice coefficient (DC), geographical miss index (GMI), and normal tissue index (NTI).

Results: The differences of delineation volumes among CT and MRIs were significant, both in the CTVs (p = 0.035) and PTVs (p < 0.001). The values of CI and DC for sdyn-eTHRIVE registration to CT were the largest among all MRI sequences, but GMI and NTI were the smallest. No obvious linear correlation (p > 0.05) between the CI derived from the registration of CT and sdyn-eTHRIVE of CTV with the breast volume, the cavity visualization score (CVS) of CT, time interval from surgery to CT simulation, the maximum diameter of the intraoperative mass, and the number of titanium clips, respectively.

Conclusions: The CTVs and PTVs in MRI sequences were all smaller than those in CT. The pre-MRI, especially the sdyn-eTHRIVE, could be used to optimize the post-CT-based target delineation of breast cancer.

Key Points: • Registered pre-MRI to post-CT in order to improve the accuracy of target volume delineation of breast cancer. • The CTVs and PTVs in MRI sequences were all smaller than those in CT. • The sdyn-eTHRIVE of pre-MRIs may be a better choice to improve the delineation of CT-based CTV and PTV.
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http://dx.doi.org/10.1007/s00330-020-07085-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755637PMC
January 2021