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1.
Phys Rev Lett ; 124(12): 126601, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32281842

RESUMO

Despite extensive experimental and theoretical efforts, the important issue of the effects of surface magnetic impurities on the topological surface state of a topological insulator (TI) remains unresolved. We elucidate the effects of Cr impurities on epitaxial thin films of (Bi_{0.5}Sb_{0.5})_{2}Te_{3}: Cr adatoms are incrementally deposited onto the TI held in ultrahigh vacuum at low temperatures, and in situ magnetoconductivity and Hall effect measurements are performed at each increment with electrostatic gating. In the experimentally identified surface transport regime, the measured minimum electron density shows a nonmonotonic evolution with the Cr density (n_{Cr}): it first increases and then decreases with n_{Cr}. This unusual behavior is ascribed to the dual roles of the Cr as ionized impurities and electron donors, having competing effects of enhancing and decreasing the electronic inhomogeneities in the surface state at low and high n_{Cr}, respectively. The magnetoconductivity is obtained for different n_{Cr} on one and the same sample, which yields clear evidence that the weak antilocalization effect persists and the surface state remains gapless up to the highest n_{Cr}, contrary to the expectation that the deposited Cr should break the time-reversal symmetry and induce a gap opening at the Dirac point.

2.
J Colloid Interface Sci ; 573: 150-157, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278946

RESUMO

Oxygen evolution reaction (OER) is the key to achieve highly efficient hydrogen production during water splitting. Herein, flexible nanorods-integrated succulent-like Bi2S3/Ni3S2/NF heterostructure has been prepared by a facile solvothermal method and applied for OER. We highlight the unique nonequivalent sp3 hybridization of P-region metal based sulfides, which makes a possibility of electronic inductive effect and enhanced electrocatalytic performance. The Bi2S3/Ni3S2/NF catalyst shows low overpotential 268 mV at 10 mA cm-2 and low Tafel slope of 82 mV dec-1. Long-term stability evaluated at high current density suggests that succulent-like Bi2S3/Ni3S2 could be a promising alternative to noble-metal based electrocatalysts for water oxidation reaction in alkaline medium.

3.
Inflammation ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32239392

RESUMO

Endotoxemia induced by lipopolysaccharide (LPS) is an extremely severe syndrome identified by global activation of inflammatory responses. Neutrophil extracellular traps (NETs) play an important role in the development of endotoxemia. Histone hypercitrullination catalyzed by peptidylarginine deiminases (PADs) is a key step of NET formation. We have previously demonstrated that simultaneous inhibition of PAD2 and PAD4 with pan-PAD inhibitors can decrease NETosis and improve survival in a mouse model of LPS-induced endotoxic shock. However, the effects of PAD2 specific inhibition during NETosis and endotoxic shock are poorly understood. Therefore, in the present study, we aimed to investigate the effect of the specific PAD2 or PAD4 inhibitor on LPS-induced endotoxic shock in mice. We found that PAD2 inhibition but not PAD4 inhibition improves survival. Also, the levels of proinflammatory cytokines and NETosis were significantly reduced by PAD2 inhibitor. To our knowledge, this study demonstrates for the first time that PAD2 inhibition can reduce NETosis, decrease inflammatory cytokine production, and protect against endotoxin-induced lethality. Our findings provided a novel therapeutic strategy for the treatment of endotoxic shock.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32195993

RESUMO

BACKGROUND: Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase (HDAC) inhibitors, such as valproic acid (VPA), have been shown to improve survival in preclinical models of lethal trauma, hemorrhage and sepsis. The doses needed to achieve a survival benefit are higher than FDA-approved doses, and the nonspecificity raises concerns about unintended adverse effects. The isoform specific HDAC-6 inhibitor, ACY-1083, has been found to be as efficacious as VPA in a rodent model of hemorrhagic shock. We hypothesized that ACY-1083 treatment would improve survival in a swine model of lethal hemorrhage, polytrauma and bacteremia. METHODS: Swine were subjected to 45% blood volume hemorrhage, brain injury, femur fracture, rectus crush, splenic and liver lacerations, and colon injury. After 1 hour of shock (mean arterial pressure 30-35 mmHg), animals were randomized to normal saline resuscitation (control) or normal saline+ACY-1083 30mg/kg treatment (n=5/group). After 3 hours (simulating delayed evacuation), packed red blood cells and antibiotics were administered, the colon injury was repaired, and the abdomen was closed. Animals were then monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. RESULTS: This combination of injuries was lethal. All animals became bacteremic, in addition to the severe hemorrhagic shock. Survival in the control group was 0% and ACY-1083 treatment increased survival to 80% (p=0.019). There was no difference in the brain lesion size between the groups. CONCLUSION: A single dose of ACY-1083 markedly improves survival in an otherwise lethal model of polytrauma, hemorrhagic shock and bacteremia. LEVEL OF EVIDENCE: Basic science.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32218019

RESUMO

BACKGROUND: Early single-dose treatment with human mesenchymal stem cell (MSC)-derived exosomes promotes neuroprotection and promotes blood-brain barrier (BBB) integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7-day), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model. METHODS: Yorkshire swine were subjected to a severe TBI (8-mm cortical impact) and HS (40% estimated total blood volume). After one hour of shock, animals were randomized (n=4/cohort) to receive either lactated Ringer's (LR; 5mL) or LR + exosomes (LR+EXO; 1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores (NSS) were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (BDNF) in brain tissue were compared between groups. RESULTS: Exosome-treated animals had significantly lower NSS (first 4 days; p < 0.05) and faster neurologic recovery. At 7-days, exosome-treated animals had significantly smaller (p < 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (IL-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony stimulating factor (GM-CSF) levels compared to the control animals, indicating specific impacts on various cytokines. BAX and NF-κB levels were significantly lower (p < 0.05) in exosome-treated animals, while BDNF levels were significantly higher (p < 0.05) in the exosome-treated animals. CONCLUSIONS: In a large animal model of TBI and HS, early single-dose exosome treatment attenuates neurologic injury, decreases brain lesion size, inhibits inflammation and apoptosis, and promotes neural plasticity over a seven-day period. LEVEL OF EVIDENCE: Not applicable (pre-clinical study).

6.
Viruses ; 12(3)2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32210095

RESUMO

Marek's disease virus (MDV), an alpha herpes virus, causes a lymphoproliferative state in chickens known as Marek's disease (MD), resulting in severe monetary losses to the poultry industry. Because lymphocytes of bursa of Fabricius and spleen are prime targets of MDV replication during the early cytolytic phase of infection, the immune response in bursa and spleen should be the foundation of late immunity induced by MDV. However, the mechanism of the MDV-mediated host immune response in lymphocytes in the early stage is poorly understood. The present study is primarily aimed at identifying the crucial genes and significant pathways involved in the immune response of chickens infected with MDV CVI988 and the very virulent RB1B (vvRB1B) strains. Using the RNA sequencing approach, we analyzed the generated transcriptomes from lymphocytes isolated from chicken bursa and spleen. Our findings validated the expression of previously characterized genes; however, they also revealed the expression of novel genes during the MDV-mediated immune response. The results showed that after challenge with CVI988 or vvRB1B strains, 634 and 313 differentially expressed genes (DEGs) were identified in splenic lymphocytes, respectively. However, 58 and 47 DEGs were observed in bursal lymphocytes infected with CVI988 and vvRB1B strains, respectively. Following MDV CVI988 or vvRB1B challenge, the bursal lymphocytes displayed changes in IL-6 and IL-4 gene expression. Surprisingly, splenic lymphocytes exhibited an overwhelming alteration in the expression of cytokines and cytokine receptors involved in immune response signaling. On the other hand, there was no distinct trend between infection with CVI988 and vvRB1B and the expression of cytokines and chemokines, such as IL-10, IFN-γ, STAT1, IRF1, CCL19, and CCL26. However, the expression profiles of IL-1ß, IL-6, IL8L1, CCL4 (GGCL1), and CCL5 were significantly upregulated in splenic lymphocytes from chickens infected with CVI988 compared with those of chickens infected with vvRB1B. Because these cytokines and chemokines are considered to be associated with B cell activation and antigenic signal transduction to T cells, they may indicate differences of immune responses initiated by vaccinal and virulent strains during the early phase of infection. Collectively, our study provides valuable data on the transcriptional landscape using high-throughput sequencing to understand the different mechanism between vaccine-mediated protection and pathogenesis of virulent MDV in vivo.

7.
Bull Environ Contam Toxicol ; 104(4): 484-488, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32100059

RESUMO

Biochar is an important material for remediation of contaminated soils, however, different biochars have variable effects on bioavailability of heavy metals. This experiment revealed that peanut shell biochar (PSB) has highest reduction of 78% concentration of Pb in plant roots. The maize straw biochar (MSB) has significantly decreased Zn and Cd concentration (mg/kg dry weight) in Chinese cabbage than other treatments of biochars. The plants of Chinese cabbage have exhibited an efficient transport capability for Zn and Cd. The biochars have reduced exchangeable form of Cd/Zn, enhanced residual heavy metals, and consequently diminished accumulation of heavy metals in plants. The straw block biochar (SBB), PSB and MSB have efficiently relieved the stresses of heavy metals in plants.

8.
Small ; 16(1): e1905611, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31793755

RESUMO

Bacterial infections leading to sepsis are a major cause of deaths in the intensive care unit. Unfortunately, no effective methods are available to capture the early onset of infectious sepsis near the patient with both speed and sensitivity required for timely clinical treatment. To fill the gap, the authors develop a highly miniaturized (2.5 × 2.5 µm2 ) plasmo-photoelectronic nanostructure device that detected citrullinated histone H3 (CitH3), a biomarker released to the blood circulatory system by neutrophils. Rapidly detecting CitH3 with high sensitivity has the great potential to prevent infections from developing life-threatening septic shock. To this end, the author's device incorporates structurally engineered arrayed hemispherical gold nanoparticles that are functionalized with high-affinity antibodies. A nanoplasmonic resonance shift induces a photoconduction increase in a few-layer molybdenum disulfide (MoS2 ) channel, and it provides the sensor signal. The device achieves label-free detection of serum CitH3 with a 5-log dynamic range from 10-4 to 101 ng mL and a sample-to-answer time <20 min. Using this biosensor, the authors longitudinally measure the dynamic CitH3 profiles of individual living mice in a sepsis model at high resolution over 12 hours. The developed biosensor may be poised for future translation to personalized management of systemic bacterial infections.

9.
Anal Chem ; 92(1): 1326-1332, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31793766

RESUMO

Confocal Raman microscopy is a powerful method for nondestructive and noninvasive detection of chemicals with high spatial resolution, but its long acquisition time hinders its applications in large-scale monitoring of fast dynamics. Here, we report the development of a compressive sensing technique for single-acquisition multifocal Raman spectroscopy, which is capable of improving the speed of conventional confocal Raman spectroscopy by 2-3 orders of magnitude. A sample is excited with a 2-D multifocus pattern, and the Raman scatterings from the multiple foci were projected onto the spectrometer's entrance in a 2-D array. The superimposed spectra within each row of the array were processed with an algorithm such that the spectra from the individual foci were retrieved in a single acquisition and with reduced noise. The performances of the developed technique were demonstrated by parallel Raman spectroscopy of multiple individual particles as well as by single-acquisition confocal Raman imaging of a large scale with high spatial resolution when combined with spatially sparse sampling. The technique is expected to find wide applications in investigating fast dynamics in large-scale biological systems.

10.
Curr Mol Med ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31749426

RESUMO

BACKGROUND: Our previous studies have shown that Pygo (Pygopus) in Drosophila plays a critical role in adult heart function that is likely conserved in mammals. However, its role in the differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into cardiomyocytes remains unknown. OBJECTIVE: To investigate the role of pygo2 in the differentiation of hUN-MSCs into cardiomyocytes. METHODS: Third passage hUC-MSCs were divided into two groups: a p+ group infected with the GV492-pygo2 virus and a p- group infected with the GV492 virus. After infection and 3 or 21 days of incubation, Quantitative real-time PCR (qRT-PCR) was performed to detect pluripotency markers, including OCT-4 and SOX2. Nkx2.5, Gata-4 and cTnT were detected by immunofluorescence at 7, 14 and 21 days post-infection, respectively. Expression of cardiac-related genes-including Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin-were analysed by qRT-PCR following transfection with the virus at one, two and three weeks. RESULTS: After three days of incubation, there were no significant changes in expression of the pluripotency stem cell markers OCT-4 and SOX2 in the p+ group hUC-MSCs relative to controls (OCT-4: 1.03 ± 0.096 VS 1,P > 0.05, SOX2: 1.071 ± 0.189 VS 1, P > 0.05); however, after 21 days, significant decreases were observed (OCT-4: 0.164 ± 0.098 VS 1, P <0.01, SOX2: 0.209 ± 0.109 VS 1, P <0.001). Seven days following incubation, expression of mesoderm specialisation markers, such as Nkx2.5, Gata-4, MEF2c and KDR, was increased; at 14 days following incubation, expression of cardiac genes, such as Nkx2.5, Gata-4, TNNT2, MEF2c, ISL-1, FOXH1, KDR, αMHC and α-Actin, were significantly upregulated in the p+ group relative to the p- group (P < 0.05). Taken together, these findings suggest that overexpression of pygo2 results in more hUC-MSCs gradually differentiating into cardiomyocyte-like cells. CONCLUSION: We are the first to show that overexpression of pygo2 significantly enhances the expression of cardiac-genic genes, including Nkx2.5 and Gata-4, and promotes the differentiation of hUC-MSCs into cardiomyocyte-like cells.

11.
Shock ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31764615

RESUMO

BACKGROUND: The peptidylarginine deiminase (PAD) family converts arginine into citrulline through protein citrullination. PAD2 and PAD4 inhibitors can improve survival in hemorrhagic shock (HS). However, the impact of isoform specific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2 knockout (KO) mice to elucidate loss of function of PAD2 leads to pro-survival effect in HS. METHODS: HS: Pad2 and wild type (WT) mice (n = 5/group) were subjected to lethal HS (55% volume hemorrhage). Survival was monitored over seven days. Myocardial infarction (MI): Pad2 and WT mice (n = 9/group) were subjected to MI by permanent LAD ligation to examine the effect of ischemia on the heart. After 24 hours cardiac function and infarct size were measured. RESULTS: HS: Pad2 mice demonstrated 100% survival compared to 0% for WT mice (p = 0.002). In a sub-lethal HS model, cardiac ß-catenin levels were higher in Pad2 compared to WT after 24 hours. MI: WT mice demonstrated larger MI (75%) compared to Pad2 (60%) (p < 0.05). Pad2 had significantly higher ejection fraction and fractional shortening compared to WT (p < 0.05). CONCLUSIONS: Pad2 improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improve survival include the activation of cell survival pathways, improved tolerance of cardiac ischemia and improved cardiac function during ischemia. PAD2 is promising as a future therapeutic target for the treatment of HS and cardiac ischemia.

12.
Vaccines (Basel) ; 7(4)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31766655

RESUMO

Avian influenza viruses (AIVs) are highly contagious and have caused huge economical loss to the poultry industry. AIV vaccines remain one of the most effective methods of controlling this disease. Turkey herpesvirus (HVT) is a commonly used live attenuated vaccine against Marek's disease; it has also been used as a viral vector for recombinant AIV vaccine development. The clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system is a gene editing tool which, in vaccinology, has facilitated the development of recombinant DNA viral-vectored vaccines. Here, we utilize homology-directed repair (HDR) for the generation of a HVT-H7N9 HA bivalent vaccine; a H7N9 HA expression cassette was inserted into the intergenic region between UL45 and UL46 of HVT. To optimize the selection efficiency of our bivalent vaccine, we combined CRISPR/Cas9 with erythrocyte binding to rapidly generate recombinant HVT-H7HA candidate vaccines.

13.
Polymers (Basel) ; 11(11)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731723

RESUMO

Polyurea has attracted considerable attention owing to its potential applications in protective fields to improve the resistant performance of structures subjected to damage loads resulting from intentional or accidental explosions. However, different spraying strategies of polyurea may lead to significant differences in overall resistance performance of polyurea-coated structures, and the underlying mechanisms have not been clear until now. This study aims to elucidate the influence of spraying strategy, i.e., spraying area, spraying thickness, and spraying interface condition, on the dynamic response of polyurea-coated steel plates under localized air blast loading. Three types of plates manufactured using different spraying strategies were adopted to evaluate their blast-resistant performance. The spraying strategies used were (i) whole-area spraying, (ii) partial-area spraying, and (iii) in-contact backing of polyurea on the rear surfaces of steel plates. In addition, the influence of spraying thickness of polyurea for whole-area sprayed plates was evaluated. The energy absorbing mechanisms of polyurea backing layers were highlighted. The energy absorption of plates was quantitatively analyzed. The results show that the air blast resistances of whole-area sprayed and in-contact backed plates are both superior to, whereas that of partial-area sprayed plates is inferior to, bare steel counterparts. A suitable spraying thickness of polyurea can significantly reduce the damage of the front steel layer, whereas excessive spraying thickness decreases the overall air blast resistance of plates. The polyurea backing layer exhibits favorable performance in absorbing energy under a whole-area spraying condition. This study provides useful guidance for the design of polyurea-coated metal plates in engineering applications.

14.
Trauma Surg Acute Care Open ; 4(1): e000321, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692634

RESUMO

Background: Isoform-specific histone deacetylase inhibitors (HDACIs) MC1568 and ACY1083 are comparable to the non-selective HDACI valproic acid (VPA) in improving survival in rodents undergoing lethal hemorrhage. However, the organ-specific properties of isoform-specific HDACIs have not been fully evaluated. Also, whether they can act synergistically is not known. We hypothesized that isoform-specific HDACIs are superior to VPA in attenuating intestinal injury and act synergistically when coadministered. Methods: Sprague Dawley rats were hemorrhaged (40% of total blood volume) and randomized to receive (n=4 per group) (1) MC1568 (5 mg/kg), (2) ACY1083 (30 mg/kg), (3) MC1568+ACY1083 (combination: 5 mg/kg + 30 mg/kg, respectively), (4) VPA (250 mg/kg), or (5) normal saline (NS; vehicle; 250 µL). Animals were observed for 3 hours, after which blood samples were collected and samples of the ileum were harvested. Expression of interleukin 1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and cytokine-induced neutrophil chemoattractant 1 (CINC-1) was assessed in the tissues using enzyme-linked immunosorbent assay. Intestinal cleaved caspase 3 (c-caspase 3) levels were assessed as a marker of apoptosis, and histologic sections of the ileum were examined for signs of bowel injury. Levels of IL-1ß and TNF-α were also measured in the serum as global markers of inflammation. Results: Treatments with MC1568, ACY1083, MC1568+ACY1083, and VPA were associated with decreased IL-1ß levels in the intestine and serum compared with NS. IL-1ß and TNF-α levels were significantly lower in the ACY1083 group compared with the VPA group. CINC-1 levels were significantly lower in the isoform-specific HDACI groups compared with the NS; however, no significant differences were seen with VPA. All treatment groups had a lower expression of intestinal c-caspase 3 compared with NS. Furthermore, MC1568 and ACY1083 groups had lower apoptosis compared with the VPA group. Bowel injury scores were significantly lower in the isoform-specific HDACI groups compared with the NS group; however, the attenuation in the VPA-treated animals did not reach statistical significance. Discussion: Isoform-specific HDACIs provide superior intestinal protection compared with VPA in a rodent model of hemorrhagic shock. Level of evidence: Preclinical study.

15.
Curr Mol Med ; 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31663468

RESUMO

Background: Previously, we first identified the human tri-partite motif-containing protein 45 (TRIM45) acts as a novel transcriptional repressor in mitogen-activated protein kinase (MAPK) signaling pathway. After that, the inhibitory role of TRIM45 in the development of tumor was gradually unveiled. However, the function of TRIM45 in the tumorigenesis of lung cancer has not been characterized. Results: In this study, we found that TRIM45 was up-regulated in early-stage human non-small-cell lung cancer (NSCLC) tissues. Overexpression of TRIM45 in lung cancer cells induces G1 arrest and promotes apoptosis, which accompanied with up-regulated expression of RB, p16, p53, p27Kip1 and Caspase3 and down-regulated expression of CyclinE1 and CyclinE2. Further detection of the expression of the molecules in the MAPK signaling pathway revealed that overexpression of TRIM45 in lung cancer cells promotes phosphorylated p38 (p-p38) activation and inhibits phosphorylated ERK (p-ERK) activation. In accordance with this, p-p38 is increased while p-ERK is decreased in lung cancer tissues. Conclusion: These findings indicate that TRIM45 plays an inhibitory role in the tumorigenesis of lung cancer. High-level expression of TRIM45 in lung cancer tissue may promote cell apoptosis by activating p38 signal and inhibit proliferation by down-regulating p-ERK, which provides a new clue for understanding the tumorigenesis of lung cancer.

16.
Phys Rev Lett ; 123(9): 096601, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31524447

RESUMO

At sufficiently low temperatures, many quantum effects, such as weak localization, electron-electron interaction (EEI), and Kondo screening, can lead to pronounced corrections to the semiclassical electron transport. Although low temperature corrections to longitudinal resistivity, ordinary Hall resistivity, or anomalous Hall (AH) resistivity are often observed, the corrections to three of them have never been simultaneously detected in a single sample. Here, we report on the observation of sqrt[T]-type temperature dependences of the longitudinal, ordinary Hall and AH resistivities at temperatures down to at least 20 mK in n-type HgCr_{2}Se_{4}, a half-metallic ferromagnetic semiconductor that can reach extremely low carrier densities. For the samples with moderate disorder, the longitudinal and ordinary Hall conductivities can be satisfactorily described by the EEI theory developed by Altshuler et al., whereas the large corrections to AH conductivity are inconsistent with the existing theory, which predicts vanishing and finite corrections to AH conductivity for EEI and weak localization, respectively.

17.
J Trauma Acute Care Surg ; 87(5): 1133-1139, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31389922

RESUMO

BACKGROUND: Trauma is a leading cause of death, and traumatic brain injury is one of the hallmark injuries of current military conflicts. Valproic acid (VPA) administration in high doses (300-400 mg/kg) improves survival in lethal trauma models, but effectiveness of lower doses on survival is unknown. This information is essential for properly designing the upcoming clinical trials. We, therefore, performed the current study to determine the lowest dose at which VPA administration improves survival in a model of lethal injuries. METHODS: Swine were subjected to traumatic brain injury (10-mm cortical impact), 40% blood volume hemorrhage, and multiple trauma (femur fracture, rectus crush, and Grade V liver laceration). After 1 hour of shock, animals were randomized (n = 6/group) to four groups: normal saline (NS) resuscitation; or NS with VPA doses of 150 mg/kg (VPA 150) or 100 mg/kg (VPA 100) administered over 3 hours or 100 mg/kg over 2 hours (VPA 100 over 2 hours). Three hours after shock, packed red blood cells were given, and animals were monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. RESULTS: Without resuscitation, all of the injured animals died within 5 hours. Similar survival rates were observed in the NS (17%) and VPA 100 (0%) resuscitation groups. Survival rates in the 100-mg/kg VPA groups were significantly (p < 0.05) better when it was given over 2 hours (67%) compared to 3 hours (0%). 83% of the animals in the VPA 150 group survived, which was significantly higher than the NS and VPA 100 over 3 hours groups (p < 0.05). CONCLUSION: A single dose of VPA (150 mg/kg) significantly improves survival in an otherwise lethal model of multiple injuries. This is a much lower dose than previously shown to have a survival benefit and matches the dose that is tolerated by healthy human subjects with minimal adverse effects. LEVEL OF EVIDENCE: Therapeutic, level V.

18.
Phys Chem Chem Phys ; 21(32): 17711-17719, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31367718

RESUMO

The new ratiometric fluorescent probe 2-(4-(dimethylamino)phenyl)-3-hydroxy-6,7-dimethoxy-4h-chromen-4-one (HOF) monitoring of methanol in biodiesel was discovered experimentally (T. Y. Qin et al., Sens. Actuators, B, 2018, 277, 484-491). But the experimental study did not report the reaction mechanism in detail. In this study, density functional theory (DFT) and time-density functional theory (TDDFT) methods were used to theoretically study the excited-state intramolecular proton transfer (ESIPT) process of the HOF molecule. The molecular structure in the ground state and the excited state was optimized, and the infrared vibrational spectra, the frontier molecular orbitals, the charge transfer, the potential energy curves and the transition-state structures were calculated. The calculated results prove that the solvent polarity has a great influence on the ESIPT reaction of the HOF molecule. As the solvent polarity increased, the intensity of the intramolecular hydrogen bond decreased, and ESIPT was more difficult to occur. This work has studied the mechanism of the ESIPT reaction in more detail, and paved the way for future research on HOF molecules.

19.
Genet Test Mol Biomarkers ; 23(9): 601-609, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31386585

RESUMO

Background: Tetralogy of Fallot (TOF) accounts for ∼10% of congenital heart disease cases. The blood vessel epicardial substance (BVES) gene has been reported to play a role in the function of adult hearts. However, whether allelic variants in BVES contribute to the risk of TOF and its possible mechanism remains unknown. Methods: The open reading frame of the BVES gene was sequenced using samples from 146 TOF patients and 100 unrelated healthy controls. qRT-PCR and western blot assays were used to confirm the expression of mutated BVES variants in the TOF samples. The online software Polyphen2 and SIFT were used to predict the deleterious effects of the observed allelic variants. The effects of these allelic variants on the transcriptional activities of genes were examined using dual-fluorescence reporter assays. Results: We genotyped four single nucleotide polymorphisms (SNPs) in the BVES gene from each of the 146 TOF patients. Among them, the minor allelic frequencies of c.385C>T (p.R129W) were 0.035% in TOF, but ∼0.025% in 100 controls and the Chinese Millionome Database. This allelic variant was predicted to be a potentially harmful alteration by the Polyphen2 and SIFT softwares. qRT-PCR and western blot analyses indicated that the expression of BVES in the six right ventricular outflow tract samples with the c.385C>T allelic variant was significantly downregulated. A dual-fluorescence reporter system showed that the c.385C>T allelic variant significantly decreased the transcriptional activity of the BVES gene and also decreased transcription from the GATA4 and NKX2.5 promoters. Conclusions: c.385C>T (p.R129W) is a functional SNP of the BVES gene that reduces the transcriptional activity of BVES in vitro and in vivo in TOF tissues. This subsequently affects the transcriptional activities of GATA4 and NKX2.5 related to TOF. These findings suggest that c.385C>T may be associated with the risk of TOF in the Han Chinese population.


Assuntos
Moléculas de Adesão Celular/genética , Proteínas Musculares/genética , Tetralogia de Fallot/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Moléculas de Adesão Celular/metabolismo , China/etnologia , Fator de Transcrição GATA4/metabolismo , Genótipo , Proteína Homeobox Nkx-2.5/metabolismo , Humanos , Proteínas Musculares/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sequência de DNA/métodos
20.
Int J Biol Macromol ; 140: 1226-1238, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445153

RESUMO

Bovine herpesvirus 1 (BoHV-1) is a major pathogen of infectious bovine rhinotracheitis in bovine. Previously, we generated the aptamer IBRV A4 using systemic evolution of ligands by exponential enrichment. This aptamer inhibited infectivity of BoHV-1 by blocking viral particle absorption onto cell membranes. In this study, we found that the major tegument protein VP8 of BoHV-1 was involved in inhibition of infectious virus production by IBRV A4. We improved the affinity of IBRV A4 for VP8 by optimizing aptamer's structure and repeat conformation. An optimized aptamer, IBRV A4.7, was constructed with quadruple binding sites and a new stem-loop structure, which had a stronger binding affinity for VP8 or BoHV-1 than raw aptamer IBRV A4. IBRV A4.7 bound to VP8 with a dissociation constant (Kd) value of 0.2054 ±â€¯0.03948 nM and bound to BoHV-1 with a Kd value of 0.3637 ±â€¯0.05452 nM. Crucially, IBRV A4.7 had improved antiviral activity compared to IBRV A4, with a half-maximal inhibitory concentration of 1.16 ±â€¯0.042 µM. Our results also revealed IBRV A4.7 inhibited BoHV-1 production in MDBK cells through blocking nucleocytoplasmic shuttling of viral VP8 in BoHV-1-infected MDBK cells. In conclusion, the aptamer IBRV A4.7 may have potency in preventing outbreaks in herds due to reactivation of latency.

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