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1.
Nucleic Acids Res ; 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33939832

RESUMO

The transition from meiotic spermatocytes to postmeiotic haploid germ cells constitutes an essential step in spermatogenesis. The epigenomic regulatory mechanisms underlying this transition remain unclear. Here, we find a prominent transcriptomic switch from the late spermatocytes to the early round spermatids during the meiotic-to-postmeiotic transition, which is associated with robust histone acetylation changes across the genome. Among histone deacetylases (HDACs) and acetyltransferases, we find that HDAC3 is selectively expressed in the late meiotic and early haploid stages. Three independent mouse lines with the testis-specific knockout of HDAC3 show infertility and defects in meiotic exit with an arrest at the late stage of meiosis or early stage of round spermatids. Stage-specific RNA-seq and histone acetylation ChIP-seq analyses reveal that HDAC3 represses meiotic/spermatogonial genes and activates postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations. Unexpectedly, abolishing HDAC3 catalytic activity by missense mutations in the nuclear receptor corepressor (NCOR or SMRT) does not cause infertility, despite causing histone hyperacetylation as HDAC3 knockout, demonstrating that HDAC3 enzyme activity is not required for spermatogenesis. Motif analysis of the HDAC3 cistrome in the testes identified SOX30, which has a similar spatiotemporal expression pattern as HDAC3 during spermatogenesis. Depletion of SOX30 in the testes abolishes the genomic recruitment of the HDAC3 to the binding sites. Collectively, these results establish the SOX30/HDAC3 signaling as a key regulator of the transcriptional program in a deacetylase-independent manner during the meiotic-to-postmeiotic transition in spermatogenesis.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33949212

RESUMO

The outcomes of coronavirus disease 2019 (COVID-19) vary between men and women. Some statistical reports have shown that men have a higher risk of developing COVID-19 and suffer from worse outcomes than females. While there are many factors that can explain the high prevalence of COVID-19 in men, such as lifestyle habits and the different profile of comorbidities among sexes, the distinctions between male and female immune systems cannot be ignored. It has been sufficiently shown that sex differences have a critical influence on the shaping of immune response, which then leads to different pathogenesis in infectious diseases. Compared with males, females typically have a more effective innate and adaptive immune response to viral infections in COVID-19. What's more, there is a growing body of evidence showing that estrogen exerts an effect on the regulation of immune response. This article examines the effect and mechanism of estrogen on COVID-19.

3.
Nucleic Acid Ther ; 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33891483

RESUMO

It is well documented and generally accepted that human clearance (CL) of unconjugated single-strand antisense oligonucleotides (ASOs) can be directly predicted from monkeys by body weight (BW) on a mg/kg dose basis. However, the scaling for triantennary N-acetyl galactosamine (GalNAc3)-conjugated ASOs has not been fully established. In this study, we retrospectively analyzed pharmacokinetic data from 9 GalNAc3-conjugated and 12 unconjugated single-stranded ASOs (ten 2'-methoxyethyl and two 2', 4'-constrained ethyl ASOs) to identify an appropriate allometric scaling factor between the two species. In addition, we compared the trough plasma concentrations (Ctrough, a surrogate for tissue exposure) between monkeys and humans at comparable dose levels, aiming at predicting tissue distribution in humans from monkeys. Overall, the median plasma CL ratios (monkey CL/human CL) were 1.05 and 0.94 when CL was normalized by BW, as compared with 0.33 and 0.29 when CL was normalized by body surface area (BSA) for the 12 unconjugated and 9 GalNAc3-conjugated ASOs, respectively. Similarly, the median Ctrough ratios (Ctrough in monkeys/Ctrough in humans) were 0.96 and 1.71, respectively, when Ctrough was normalized by mg/kg dose as compared with 3.10 and 5.50 when Ctrough was normalized by mg/m2 dose for the same unconjugated and conjugated ASOs, respectively. Equivalent CL and dose-normalized plasma Ctrough between monkeys and humans suggest similar pharmacokinetic profiles and tissue distribution between the two species on a per kilogram BW basis. In conclusion, human CL and plasma Ctrough (a surrogate of tissue distribution) can be directly predicted (1:1 or within twofold) from monkeys by BW on a mg/kg dose basis but these parameters can be under- or over-predicted by BSA on a mg/m2 dose basis. These results provide evidence for single species scaling from monkeys to humans directly and, thus, they can facilitate early human dose prediction in ASO drug development.

4.
Artif Organs ; 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33908066

RESUMO

BACKGROUND: In this study, we evaluated the restoring and defatting effect of hypothermic oxygenated perfusion (HOPE) on severe steatotic liver grafts with a defatting cocktail (DF) in a rat model. METHODS: Severe (≥60%) hepatic macrosteatosis was induced by a high-fat diet (HFD) for six weeks, after which the rats were randomly divided into four following groups: Control group, with lean livers being preserved in static cold storage (SCS) at 0-4℃ for 45 min; SCS group, with a steatotic liver graft (SLG) being preserved in SCS at 0-4℃ for 4 hours; HOPE group, where SLG was perfused with 3-h HOPE followed by 1-h SCS; HOPE+DF group, HOPE with the addition of DF. Graft function after orthotopic liver transplantation was assessed in terms of mitochondrial function (ATP, Glycogen), endoplasmic reticulum stress (PPY, GRP78, CHOP, and ATF-6), cell apoptosis (Tunel assay, Caspase-3), inflammatory level (HMGB1, TLR4, IL-1ß, IL-6. TNF-α, Factor V), and post-transplantation survival. RESULTS: HOPE protected steatotic liver grafts from microcirculation disturbance and endoplasmic reticulum stress and then promoted ATP and glycogen synthesis that improved mitochondrial function. Meanwhile, under conditions of ischemia-reperfusion injury, it prevented nuclear injury and endothelial damage by suppressing the release of an inflammatory mediator. The high efficacy of HOPE was enhanced after the addition of the defatting cocktail. CONCLUSION: Defatting cocktail agents cannot promote the lipid decomposition of the steatotic liver graft at 0-4℃, but they can further improve steatotic liver and postoperative survival compared to the HOPE. The defatted steatotic liver grafts can be safely used in rat orthotopic liver transplantation.

5.
Environ Pollut ; 283: 117103, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33894628

RESUMO

Nitrate (NO3-) is one of the common inorganic nitrogen compound pollutants in natural ecosystems, which may have serious risks for aquatic organisms. However, its toxicological mechanism remains unclear. In the current study, juvenile turbot (Scophthalmus maximus) were exposed to different concentrations of NO3- (CK- 3.57 ± 0.16, LN - 60.80 ± 1.21, MN - 203.13 ± 10.97 and HN - 414.16 ± 15.22 mg/L NO3-N) for 60 d. The blood biochemical assays results revealed that elevated NO3- exposure significantly increased the concentrations of plasma NO3-, NO2-, MetHb, K+, cortisol, glucose, triglyceride, lactate, while significantly decreased the concentrations of plasma Hb, Na+ and Cl-, which meant that NO3- caused hypoxic stress and further affected the osmoregulation and metabolism in fish. Besides, exposure to MN and HN induced a significant decrease in the level of antioxidants, including SOD (Point: 60th day, MN, HN v.s. CK: 258.36, 203.73 v.s. 326.95 U/mL), CAT (1.97, 1.17 v.s. 2.37 U/mL), GSH (25.38, 20.74 v.s. 37.00 µmol/L), and GPx (85.32, 71.46 v.s. 129.36 U/mL), and a significant increase of MDA (7.54, 9.73 v.s. 5.27 nmol/L), suggesting that NO3- exposure leading to a disruption of the redox status in fish. Also, further research revealed that NO3- exposure altered the mRNA levels of p53 (HN: up to 4.28 folds) and p53-regulated downstream genes such as Bcl-2 (inferior to 0.44 folds), caspase-3 (up to 2.90 folds) and caspase-7 (up to 3.49 folds), indicating that NO3- exposure induced abnormal apoptosis in the fish gills. Moreover, IBRv2 analysis showed that the toxicity of NO3- exposure to turbot was dose-dependent, and the toxicity peaked on the 15th day. In short, NO3- is an environmental toxicological factor that cannot be ignored, because its toxic effects are long-term and could cause irreversible damage to fish. These results would be beneficial to improve our understanding of the toxicity mechanism of NO3- to fish, which provides baseline evidence for the risk assessment of environmental NO3- in aquatic ecosystems.

6.
Sci Rep ; 11(1): 9018, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33907245

RESUMO

Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33835920

RESUMO

The classical proportional integral (PI) controller of SISO linear system is realized by DNA chemical reaction networks (CRNs) in the previous work. Up to now, few works have been done to realize PI controller of chaotic system through DNA CRNs. In this paper, a three-dimensional chaotic oscillatory system and a PI controller of three-dimensional chaotic oscillatory system are proposed by DNA CRNs. The CRNs of chaotic oscillatory system are made up of catalysis modules, degradation module and annihilation module then chemical reaction equations can be compiled into three-dimensional chaotic oscillatory system by the law of mass action to generate chaotic oscillatory signals. The CRNs of PI controller are designed by an integral module, a proportion module and an addition module, which can be compiled into PI controller for stabilizing chaotic oscillatory signals. The simulations of Matlab and Visual DSD are given to show our design achieving the PI control of a three-variable chaotic oscillatory system.

8.
Clin Lab ; 67(3)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739051

RESUMO

BACKGROUND: To explore the comprehensive treatment of group A streptococcus haemolyticus complicated with streptococcal toxic shock syndrome (STSS) in surgery. METHODS: Six patients with Type II necrotizing fasciitis complicated with STSS were enrolled from September 2018 to October 2019 in the Burn Department at Quanzhou First Hospital. The patients were treated with early incision and reduction of tension, anti-shock, anti-infection, primary debridement and vacuum suction, maintenance of organ function, and adjustment of internal environment, secondary autologous skin graft, and early rehabilitation. RESULTS: Five patients were healed, while one elderly patient refused treatment. CONCLUSIONS: We should be alert to necrotizing fasciitis caused by group A hemolytic streptococcus (GAS) infection and effectively avoid the occurrence of STSS. By making an incision to reduce tension, adopting the principle of anti-infection, and actively anti-shock, maintaining the function of internal organs and the stability of internal environment, debridement and vacuum suction in early and effective stage, followed by selfskin graft to seal the wound and early rehabilitation the treatment of Type II NF and STSS can be effectively improved.

9.
Theriogenology ; 166: 83-89, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33711650

RESUMO

Sebastes schlegelii is a typical viviparous teleost with six months sperm storage duration from November to April. In this study, spermatozoa morphological and physiological characteristics and sperm location in the female ovary were investigated by electron microscopy, computer-assisted sperm analyzer and histologic analysis, respectively. During copulation, we observed that spermatozoa in the testis had mature structure with rod-shaped head, a short midpiece, and a long flagellum. And further verified sperm swam freely at a high speed in the ovary fluid. After copulation, we only found swimming sperm in the ovary fluid at the early storage stage (November to December) and the majority of sperm were scattered randomly in the ovary cavity and partially concentrated in the crypt between the oocyte and stalk of follicle. Thereafter, the ovarian epithelium around the oocytes proliferated rapidly and wrapping spermatozoa outside of the follicular layer and formed a lot of crypts outside of the follicular layer which served as the sperm storage site until fertilization. The present findings would be useful for further understanding the mechanism of long-term sperm storage in viviparous teleost.

10.
Med Sci Monit ; 27: e930591, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33723203

RESUMO

BACKGROUND Cytochrome P450 (CYP) genes are necessary for the production or metabolism of fetal sex hormones during pregnancy. The second-to-fourth digit ratio (2D: 4D) is formed in the early stage of human fetal development and considered an indicator reflecting prenatal sex steroids levels. We explored the association between 2D: 4D and single-nucleotide polymorphisms (SNPs) of CYP. MATERIAL AND METHODS Correlation analysis between 2D: 4D and 8 SNPs, rs2687133 (CPY3A7), rs7173655 (CYP11A1), rs1004467, rs17115149, and rs2486758 (CYP17A1), and rs4646, rs2255192, rs4275794 (CYP19A1), was performed using data from 426 female and 412 male Chinese university students. SNP genotyping was conducted using PCR. Digit lengths were photographed and measured by image processing software. RESULTS rs2486758 (CYP17A1) correlated with left hand 2D: 4D in men (P=0.026), and rs1004467 (CYP17A1) correlated with right hand 2D: 4D in men (P=0.008) and the whole population (P=0.032). In men, allele G rs1004467 decreased right hand 2D: 4D, while allele C of rs2486758 increased left hand 2D: 4D. In women, left hand 2D: 4D was higher in genotypes with allele A of SNP rs4646 (CYP19A1) under the dominant genetic model; female DR-L was higher in genotypes with allele T of rs17115149 (CYP11A1). SNPs rs2687133 (CYP3A7) and rs1004467 (CYP17A1) were significantly correlated with right hand 2D: 4D (P=0.0107). CONCLUSIONS SNPs rs1004467 and rs2486758 of CYP17A1 are significant in the relationship between 2D: 4D and CYP gene polymorphisms under different conditions. SNP interactions between CYP genes probably impact 2D: 4D. The correlation between 2D: 4D and some sex hormone-related diseases may be due to the effect of CYP variants on the 2 phenotypes.

11.
IEEE Trans Cybern ; PP2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33566789

RESUMO

The fault detection (FD) problem for systems with both model uncertainty and external disturbance is investigated in this article. First, the mathematical models of systems with model uncertainty and disturbance, systems with additive faults, and systems with multiplicative faults are established with both left and right coprime factorization. Then, an observer-based FD scheme is proposed and the FD thresholds are derived for both open-loop and closed-loop manners. The necessary conditions on multiplicative FD are obtained and the fault detectability analyses are carried out with the aid of the gap metric technique. Finally, the effectiveness of the proposed method is illustrated by a case study on a cart dynamic system.

12.
J Mater Chem B ; 9(7): 1781-1786, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33594402

RESUMO

Iron oxide nanoparticles (IO NPs) have become the focus of molecular imaging probes for contrast enhanced magnetic resonance (MR) imaging due to their intrinsic magnetic and biodegradable properties, as well as long blood half-lives and low toxicity. Massive efforts have been made to explore the IO NPs as T2-weighted MR contrast agents, which have high susceptibility to induce a long-range magnetic field that interferes with diagnosis. Thus, the development of IO NPs with potent T1 relaxivity might help in providing an alternative for clinically applied gadolinium chelates. Herein, biomineralized iron oxide-polydopamine hybrid nanodots (IO/PDA-NDs) have been constructed using albumin as the nanoreactors to induce nanoprecipitation and polymerization simultaneously, facilitating T1-weighted contrast-enhancement as well as photothermal therapeutic capability. The IO nanoclusters in IO/PDA-NDs have an r1 relaxivity of 5.79 mM-1 s-1 with a relatively low r2/r1 ratio of 1.71, demonstrating the preferable iron oxide based T1 contrast agents. The high photothermal conversion coefficient and tumor targeting effect of the hybrid nanodots could result in complete tumor ablation efficacy. The biomineralization method provides a promising approach for the integration of tumor diagnosis and treatment to achieve efficient cancer theranostics.

13.
Cell Death Dis ; 12(2): 211, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627626

RESUMO

Ischemia-reperfusion injury (IRI) is an inevitable and serious clinical problem in donations after heart death (DCD) liver transplantation. Excessive sterile inflammation plays a fateful role in liver IRI. Hypothermic oxygenated perfusion (HOPE), as an emerging organ preservation technology, has a better preservation effect than cold storage (CS) for reducing liver IRI, in which regulating inflammation is one of the main mechanisms. HECTD3, a new E3 ubiquitin ligase, and TRAF3 have an essential role in inflammation. However, little is known about HECTD3 and TRAF3 in HOPE-regulated liver IRI. Here, we aimed to investigate the effects of HOPE on liver IRI in a DCD rat model and explore the roles of HECTD3 and TRAF3 in its pathogenesis. We found that HOPE significantly improved liver damage, including hepatocyte and liver sinusoidal endothelial cell injury, and reduced DCD liver inflammation. Mechanistically, both the DOC and HECT domains of HECTD3 directly interacted with TRAF3, and the catalytic Cys (C832) in the HECT domain promoted the K63-linked polyubiquitination of TRAF3 at Lys138. Further, the ubiquitinated TRAF3 at Lys138 increased oxidative stress and activated the NF-κB inflammation pathway to induce liver IRI in BRL-3A cells under hypoxia/reoxygenation conditions. Finally, we confirmed that the expression of HECTD3 and TRAF3 was obviously increased in human DCD liver transplantation specimens. Overall, these findings demonstrated that HOPE can protect against DCD liver transplantation-induced-liver IRI by reducing inflammation via HECTD3-mediated TRAF3 K63-linked polyubiquitination. Therefore, HOPE regulating the HECTD3/TRAF3 pathway is a novel target for improving IRI in DCD liver transplantation.

14.
BMC Oral Health ; 21(1): 79, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602197

RESUMO

BACKGROUND: (-)-Epigallocatechin Gallate (EGCG) as green tea catechins possessed antibacterial and anti-inflammatory effects on periodontal disease. This study was designed to evaluate the clinical and microbiological efficacy of scaling and root planing (SRP) using EGCG aqueous solution as coolants through a new-type ultrasonic scaler tip on chronic periodontitis. METHODS: This split-mouth, randomized clinical trial included 20 patients (2 drop-outs) with chronic periodontitis and the maxillary contra-lateral sides were allocated into test and control groups randomly. Through the new-type scaler tip, 762 sites with probing depth (PD) ≥ 4 mm were treated by SRP using EGCG solution or distilled water as coolants respectively. Clinical parameters and red complex pathogens in subgingival microbiome were evaluated at baseline, 3 and 6 months after treatments. RESULTS: During 6 months, the SRP plus EGCG medication contributed to additional PD reduction as 0.33 mm and gain of clinical attachment level as 0.3 mm compared with SRP alone, and approximate 8% more sites obtained PD reduction ≥ 2 mm (p < 0.05). Meanwhile, the mean relative abundance of Tannerella forsythia was significantly lower in the combined treatment group (p < 0.05). CONCLUSION: The purified EGCG showed the potential to improve the outcome of periodontal non-surgical treatment and the new-type scaler tip provided an alternative vehicle for subgingival medication. Trial registration The trial was registered in Chinese Clinical Trial Registry on 15 February 2020 (No.: ChiCTR2000029831, retrospectively registered). http://www.chictr.org.cn/showprojen.aspx?proj=49441 .


Assuntos
Periodontite Crônica , Catequina/análogos & derivados , Periodontite Crônica/tratamento farmacológico , Raspagem Dentária , Humanos , Perda da Inserção Periodontal/terapia , Aplainamento Radicular , Resultado do Tratamento
15.
Biomed Res Int ; 2021: 8621464, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33542926

RESUMO

In addition to serving as the building blocks for protein synthesis, amino acids can be used as an energy source, through catabolism. The transamination, oxidative deamination, and decarboxylation processes that occur during amino acid catabolism are catalyzed by specific enzymes, including aspartate aminotransferase (AST), glutamate dehydrogenase (GDH), glutamic acid decarboxylase (GAD), and ornithine decarboxylase (ODC); however, the overall molecular mechanisms through which amino acid catabolism occurs remain largely unknown. To examine the role of mechanistic target of rapamycin complex 1 (mTORC1) on amino acid catabolism, mTORC1 was inactivated by rapamycin or shRNA targeting Raptor, versus activated by overexpressing Rheb or amino acids in human hepatocytes. The expression of amino acid catabolic genes and related transcription factor was investigated by RT/real-time PCR and western blot analysis. A few types of amino acid metabolite were examined by ELISA and HPLC analysis. The data showed that inactivated mTORC1 resulted in inhibition of NF-κB and the expression of AST, GDH, GAD, and ODC, whereas activated mTORC1 enhanced NF-κB activation and the expression levels of the catabolism-associated genes. Further, inhibition of NF-κB reduced the expression levels of AST, GDH, GAD, and ODC. mTORC1 upregulated NF-κB activation and the expression of AST and ODC in response to glutamate and ornithine treatments, whereas rapamycin inhibited the utilization of glutamate and ornithine in hepatocytes. Taken together, these results indicated that the mTORC1/NF-κB axis modulates the rate of amino acid catabolism by regulating the expression of key catabolic enzymes in hepatocytes.

16.
Cancer Cell Int ; 21(1): 71, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482821

RESUMO

BACKGROUND: Recent studies have established the roles of microRNAs (miRNAs) in cancer progression. The aberrant expression of miR-335-5p has been reported in many cancers, including gastric cancer (GC). In this study, the precise roles of miR-335-5p in GC as well as the molecular mechanisms underlying its effects, including the role of its target MAPK10, were evaluated. METHODS: Quantitative real-time PCR was used to evaluate miR-335-5p levels in GC cell lines and tissues. MTT and colony formation assays were used to detect cell proliferation, and Transwell and wound-healing assays were used to evaluate the invasion and migration of GC cells. The correlation between levels of miR-335-5p and the cell cycle-related target gene mitogen-activated protein kinase 10 (MAPK10) in GC was analyzed. In addition, the candidate target was evaluated by a luciferase reporter assay, qRT-PCR, and western blotting. RESULTS: The levels of miR-335-5p were downregulated in GC tissues and cell lines. Furthermore, miR-335-5p inhibited the proliferation and migration of GC cells and induced apoptosis. Additionally, miR-335-5p arrested the cell cycle at the G1/S phase in GC cells in vitro. Levels of miR-335-5p and the cell cycle-related target gene MAPK10 in GC were correlated, and MAPK10 was directly targeted by miR-335-5p. CONCLUSIONS: These data suggest that miR-335-5p is a tumor suppressor and acts via MAPK10 to inhibit GC progression.

17.
Ecotoxicol Environ Saf ; 208: 111617, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396137

RESUMO

Nitrate (NO3-), a potential toxic nitrogenous compound to aquatic animals, is distributed in aquatic ecosystems worldwide. The aim of this study was to investigate the effects of different NO3- levels on growth performance, health status, and endocrine function of juvenile turbot (Scophthalmus maximus) in recirculating aquaculture systems (RAS). Fish were exposed to 0 mg/L (control, CK), 50 mg/L (low nitrate, LN), 200 mg/L (medium nitrate, MN), and 400 mg/L (high nitrate, HN) NO3-N for 60 d in experimental RAS. Cumulative survival (CS) was significantly decreased with increasing NO3- levels in LN, MN, and HN. The lowest CS was 35% in the HN group. Growth parameters, including absolute growth rate, specific growth rate, and feed conversion rate, were significantly different in HN compared with that in the CK. Histological survey of gills and liver revealed dose-dependent histopathological damage induced by NO3- exposure and significant differences in glutamate pyruvate transaminase and glutamate oxalate transaminase in MN and HN compared with that in the CK. The hepatosomatic index in HN was significantly higher than that in the CK. Additionally, NO3- significantly increased bioaccumulation in plasma in LN, MN, and HN compared to that in the CK. Significant decreases in hemoglobin and increases in methemoglobin levels indicated reduced oxygen-carrying capacity in HN. Additionally, qRT-PCR and enzyme-linked immunosorbent assay (ELISA) were developed to investigate key biomarkers involved in the GH/IGF-1, HPT, and HPI axes. Compared with that in the CK, the abundance of GH, GHRb, and IGF-1 was significantly lower in HN, whereas GHRa did not differ between treatments. The plasma T3 level significantly decreased in LN, MN, and HN and T4 significantly decreased in HN. The CRH, ACTH, and plasma cortisol levels were significantly upregulated in HN compared with that in the CK. We conclude that elevated NO3- exposure leads to growth retardation, impaired health status, and endocrine disorders in turbot and the NO3- level for juvenile turbot culture should not exceed 50 mg/L NO3-N in RAS. Our findings indicate that endocrine dysfunction of the GH/IGF-1, HPT, and HPI axes might be responsible for growth inhibition induced by NO3- exposure.


Assuntos
Aquicultura/métodos , Sistema Endócrino/efeitos dos fármacos , Linguados/crescimento & desenvolvimento , Nitratos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Ecossistema , Sistema Endócrino/metabolismo , Brânquias/efeitos dos fármacos , Brânquias/patologia , Nível de Saúde , Fígado/efeitos dos fármacos , Fígado/patologia , Alimentos Marinhos , Hormônios Tireóideos/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-33481706

RESUMO

3D skeleton-based action recognition and motion prediction are two essential problems of human activity understanding. In many previous works: 1) they studied two tasks separately, neglecting internal correlations; 2) they did not capture sufficient relations inside the body. To address these issues, we propose a symbiotic model to handle two tasks jointly; and we propose two scales of graphs to explicitly capture relations among body-joints and body-parts. Together, we propose symbiotic graph neural networks, which contain a backbone, an action-recognition head, and a motion-prediction head. Two heads are trained jointly and enhance each other. For the backbone, we propose multi-branch multiscale graph convolution networks to extract spatial and temporal features. The multiscale graph convolution networks are based on joint-scale and part-scale graphs. The joint-scale graphs contain actional graphs, capturing action-based relations, and structural graphs, capturing physical constraints. The part-scale graphs integrate body-joints to form specific parts, representing high-level relations. Moreover, dual bone-based graphs and networks are proposed to learn complementary features. We conduct extensive experiments for skeleton-based action recognition and motion prediction with four datasets, NTU-RGB+D, Kinetics, Human3.6M, and CMU Mocap. Experiments show that our symbiotic graph neural networks achieve better performances on both tasks compared to the state-of-the-art methods.

19.
Environ Sci Technol ; 55(3): 2110-2120, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33427455

RESUMO

Oxygen vacancies (OVs) play a crucial role in the catalytic activity of metal-based catalysts; however, their activation mechanism toward peroxydisulfate (PDS) still lacks reasonable explanation. In this study, by taking bismuth bromide (BiOBr) as an example, we report an OV-mediated PDS activation process for degradation of bisphenol A (BPA) employing singlet oxygen (1O2) as the main reactive species under alkaline conditions. The experimental results show that the removal efficiency of BPA is proportional to the number of OVs and is highly related to the dosage of PDS and the catalyst. The surface OVs of BiOBr provide ideal sites for the inclusion of hydroxyl ions (HO-) to form BiIII-OH species, which are regarded as the major active sites for the adsorption and activation of PDS. Unexpectedly, the activation of PDS occurs through a nonradical mechanism mediated by 1O2, which is generated via multistep reactions, involving the formation of an intermediate superoxide radical (O2•-) and the redox cycle of Bi(III)/Bi(IV). This work is dedicated to the in-depth mechanism study into PDS activation over OV-rich BiOBr samples and provides a novel perspective for the activation of peroxides by defective materials in the absence of additional energy supply or aqueous transition metal ions.


Assuntos
Oxigênio , Oxigênio Singlete , Catálise , Oxirredução , Peróxidos
20.
J Pharmacol Exp Ther ; 377(1): 51-63, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33431610

RESUMO

Cellular uptake of antisense oligonucleotides (ASOs) is one of the main determinants of in vivo activity and potency. A significant advancement in improving uptake into cells has come through the conjugation of ASOs to triantenarry N-acetyl-galactosamine (GalNAc3), a ligand for the asialoglycoprotein receptor on hepatocytes. The impact for antisense oligonucleotides, which are already taken up into hepatocytes, is a 10-fold improvement in potency in mice and up to a 30-fold potency improvement in humans, resulting in overall lower effective dose and exposure levels. 2'-Methoxyethyl-modified antisense oligonucleotide conjugated to GalNAc3 (ISIS 702843) is specific for human transmembrane protease serine 6 and is currently in clinical trials for the treatment of ß-thalassemia. This report summarizes a chronic toxicity study of ISIS 702843 in nonhuman primates (NHPs), including pharmacokinetic and pharmacology assessments. Suprapharmacologic doses of ISIS 702843 were well tolerated in NHPs after chronic dosing, and the data indicate that the overall safety profile is very similar to that of the unconjugated 2'-(2-methoxyethyl)-D-ribose (2'-MOE) ASOs. Notably, the GalNAc3 moiety did not cause any new toxicities nor exacerbate the known nonspecific class effects of the 2'-MOE ASOs. This observation was confirmed with multiple GalNAc3-MOE conjugates by querying a data base of monkey studies containing both GalNAc3-conjugated and unconjugated 2'-MOE ASOs. SIGNIFICANCE STATEMENT: This report documents the potency, pharmacology, and overall tolerability profile of a triantenarry N-acetyl-galactosamine (GalNAc3)-conjugated 2'-(2-methoxyethyl)-D-ribose (2'-MOE) antisense oligonucleotide (ASO) specific to transmembrane protease serine 6 after chronic treatment in the cynomolgus monkey. Collective analysis of 15 independent GalNAc3-conjugated and unconjugated 2'-MOE ASOs shows the consistency in the dose response and character of hepatic and platelet tolerability across sequences that will result in much larger safety margins for the GalNAc3-conjugated 2'-MOE ASOs when compared with the unconjugated 2'-MOE ASOs given the increased potency.

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