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Dravet syndrome is an intractable developmental and epileptic encephalopathy caused by de novo variants in SCN1A resulting in haploinsufficiency of the voltage-gated sodium channel Nav1.1. We showed previously that administration of the antisense oligonucleotide STK-001, also called ASO-22, generated using targeted augmentation of nuclear gene output technology to prevent inclusion of the nonsense-mediated decay, or poison, exon 20N in human SCN1A, increased productive Scn1a transcript and Nav1.1 expression and reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy in a mouse model of Dravet syndrome. Here, we investigated the mechanism of action of ASO-84, a surrogate for ASO-22 that also targets splicing of SCN1A exon 20N, in Scn1a+/- Dravet syndrome mouse brain. Scn1a +/- Dravet syndrome and wild-type mice received a single intracerebroventricular injection of antisense oligonucleotide or vehicle at postnatal Day 2. We examined the electrophysiological properties of cortical pyramidal neurons and parvalbumin-positive fast-spiking interneurons in brain slices at postnatal Days 21-25 and measured sodium currents in parvalbumin-positive interneurons acutely dissociated from postnatal Day 21-25 brain slices. We show that, in untreated Dravet syndrome mice, intrinsic cortical pyramidal neuron excitability was unchanged while cortical parvalbumin-positive interneurons showed biphasic excitability with initial hyperexcitability followed by hypoexcitability and depolarization block. Dravet syndrome parvalbumin-positive interneuron sodium current density was decreased compared to wild-type. GABAergic signalling to cortical pyramidal neurons was reduced in Dravet syndrome mice, suggesting decreased GABA release from interneurons. ASO-84 treatment restored action potential firing, sodium current density and GABAergic signalling in Dravet syndrome parvalbumin-positive interneurons. Our work suggests that interneuron excitability is selectively affected by ASO-84. This new work provides critical insights into the mechanism of action of this antisense oligonucleotide and supports the potential of antisense oligonucleotide-mediated upregulation of Nav1.1 as a successful strategy to treat Dravet syndrome.
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Epilepsias Mioclônicas , Oligonucleotídeos Antissenso , Camundongos , Animais , Humanos , Oligonucleotídeos Antissenso/farmacologia , Parvalbuminas/metabolismo , Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Interneurônios/metabolismo , Ácido gama-Aminobutírico , Modelos Animais de DoençasRESUMO
Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bß2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bß2 KO) nor fission (Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.
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OBJECTIVE: Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) are considered gold standards for measuring visceral fat area (VFA). However, their relatively high prices and potential radiation exposure limit their widespread use in clinical practice and everyday life. Therefore, our study aims to develop a VFA estimated equation based on sagittal abdominal diameter (SAD) and transverse abdominal diameter (TAD) using anthropometric indexes. To the best of our knowledge, there have been limited studies investigating this aspect thus far. METHODS: This study was designed as a cross-sectional, retrospective cohort survey. A total of 288 patients (167 males and 121 females) aged 18-80 with type 2 diabetes (T2D) were consecutively collected from a multicenter hospital, and VFA was measured by CT. Subsequently, variables highly correlated with VFA were screened through general linear correlation analysis. A stepwise regression analysis was then conducted to develop a VFA estimated equation. Discrepancies between the estimated and actual VFA values were assessed using the Bland-Altman method to validate the accuracy of the equation. RESULTS: In the female T2D population, triglyceride (TG), SAD, TAD were found to be independently correlated with VFA; in the male T2D population, BMI, TG, SAD and TAD showed independent correlations with VFA. Among these variables, SAD exhibited the strongest correlation with VFA (r = 0.83 for females, r = 0.88 for males), followed by TAD (r = 0.69 for females, r = 0.79 for males). Based on these findings, a VFA estimated equation was developed for the T2D population: VFA (male) =-364.16 + 15.36*SAD + 0.77*TG + 9.41*TAD - 5.00*BMI (R2 = 0.75, adjusted R2 = 0.74); VFA(female)=-170.87 + 9.72*SAD-24.29*(TG^-1) + 3.93*TAD (R2 = 0.69, adjusted R2 = 0.68). Both models demonstrated a good fit. The Bland-Altman plot indicated a strong agreement between the actual VFA values and the estimated values, the mean differences were close to 0, and the majority of differences fell within the 95% confidence interval. CONCLUSIONS: In the T2D population, a VFA estimated equation is developed by incorporating SAD and TAD along with other measurement indices. This equation demonstrates a favorable estimated performance, suggesting to the development of novel and practical VFA estimation models in the future study.
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Diabetes Mellitus Tipo 2 , Gordura Intra-Abdominal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Estudos Transversais , Gordura Intra-Abdominal/diagnóstico por imagem , Estudos Retrospectivos , Diâmetro Abdominal Sagital , Tomografia Computadorizada por Raios XRESUMO
Semantic segmentation of target objects in power transmission line corridor point cloud scenes is a crucial step in powerline tree barrier detection. The massive quantity, disordered distribution, and non-uniformity of point clouds in power transmission line corridor scenes pose significant challenges for feature extraction. Previous studies have often overlooked the core utilization of spatial information, limiting the network's ability to understand complex geometric shapes. To overcome this limitation, this paper focuses on enhancing the deep expression of spatial geometric information in segmentation networks and proposes a method called BDF-Net to improve RandLA-Net. For each input 3D point cloud data, BDF-Net first encodes the relative coordinates and relative distance information into spatial geometric feature representations through the Spatial Information Encoding block to capture the local spatial structure of the point cloud data. Subsequently, the Bilinear Pooling block effectively combines the feature information of the point cloud with the spatial geometric representation by leveraging its bilinear interaction capability thus learning more discriminative local feature descriptors. The Global Feature Extraction block captures the global structure information in the point cloud data by using the ratio between the point position and the relative position, so as to enhance the semantic understanding ability of the network. In order to verify the performance of BDF-Net, this paper constructs a dataset, PPCD, for the point cloud scenario of transmission line corridors and conducts detailed experiments on it. The experimental results show that BDF-Net achieves significant performance improvements in various evaluation metrics, specifically achieving an OA of 97.16%, a mIoU of 77.48%, and a mAcc of 87.6%, which are 3.03%, 16.23%, and 18.44% higher than RandLA-Net, respectively. Moreover, comparisons with other state-of-the-art methods also verify the superiority of BDF-Net in point cloud semantic segmentation tasks.
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A compact efficient continuous wave (CW) laser with selectable two wavelengths at 671 and 714â nm is developed. The laser cavity comprises an Nd-doped and an undoped YVO4 crystal to generate the fundamental wave at 1342â nm and the first-Stokes Raman wave at 1525â nm, respectively. A single LBO crystal with the cut angle in the XZ plane is designed to achieve the selectable phase-matching via the thermal tuning for the second harmonic generation (SHG) of 1342â nm and the sum frequency generation (SFG) of 1342 and 1525â nm. At a pump power of 40 W, the optimal output powers at 671 and 714â nm can reach 4.5 and 1.8 W, respectively. The present compact CW laser source at 671 and 714â nm has practical usefulness for laser spectroscopy and numerous applications.
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Two compact laser sources at 707 and 714â nm are realized efficiently by using a diode-pumped a-cut Nd:YVO4 laser with intracavity stimulated Raman scattering and sum-frequency generation (SFG). The fundamental wave at 1342â nm is generated by the 4F3/2 â 4I13/2 transition in Nd:YVO4 crystal. The Raman Stokes waves at 1496 and 1526â nm were obtained by placing the c-axis of the Nd:YVO4 crystal along the Ng and Nm axes of an Np-cut KGW crystal, respectively. LBO crystals with critical phase matching are used to perform the intracavity SFG of fundamental and Stokes waves. At a pump power of 36 W, the maximum output powers at 707 and 714â nm can reach 2.72 and 3.14 W, corresponding to light-to-light conversion efficiencies of 7.5% and 8.7%, respectively. The developed 707 and 714â nm laser sources are practically useful in laser trapping and cooling related to atomic strontium and radium.
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Object of our study was to analyze the carriage of resistance genes in carbapenem-resistant Raoultella planticola (CRRP) by whole genome sequencing (WGS). Three strains of CRRP (named WF0027, WF3597 and WF3648) were collected for clinical analysis and susceptibility of antimicrobial agents was determined. The WGS of three strains was done by Illumina platform and strain identification was performed by average nucleotide identity, and the antibiotic resistance genes carried by the three strains were detected by ABRicate software. Whole genome data of 46 CRRP strains were downloaded from the National Center for Biotechnology Information (NCBI) database, and the evolutionary tree was constructed by genomic single nucleotide polymorphism together with this study strains. Antimicrobial susceptibility testing revealed that WF3597 and WF3648 were susceptible to tigecycline and colistin, while exhibited resistance to 24 antimicrobial agents. WF0027 was resistant to 18 antimicrobial agents. A total of 25 resistance genes were identified using ABRicate software. WF0027 carried blaIMP-8, whereas WF3597 and WF3648 carried blaNDM-1 carbapenem resistance gene. As predicted by the PlasmidFinder, WF3597 and WF3648 carried one plasmid IncFII(p14)_1_p14, whereas WF0027 carried five plasmids. Evolutionary tree results show all strains are clustered into six groups, the strains WF3597 and WF3648 belonged to the same evolutionary group (E clade) and WF0027 belonged to the F clade. Three CRRP strains in our study carried carbapenem resistance genes (blaNDM-1 or blaIMP-8) and were resistant to multiple antimicrobial agents, posing a significant challenge for clinical treatment.
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Enterobacteriáceas Resistentes a Carbapenêmicos , beta-Lactamases , beta-Lactamases/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Plasmídeos , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Testes de Sensibilidade MicrobianaRESUMO
Cyclocodon lancifolius Bunge in the family Campanulaceae, and commonly known as Hong Guo Ginseng, is found in the Indonesia, Philippines, Vietnam, Japan, and China. The leaves and roots of C. lancifolius are widely used as tonics by ethnic minorities in Guizhou and Hunan Provinces in China. In addition, the fruit is edible, and it is a new resource for both medicine and food. In June 2022, symptoms of leaf spot (Fig 1 A and B.) were observed on C. lancifolius plants in the medicinal plant greenhouse of Guizhou University of Traditional Chinese Medicine (106°61'E, 26°39'N), Guizhou Province. The incidence of leaf spot on C. lancifolius was approximately 40 to 70% of all leaves in canopy. Early symptoms on leaves were small circular or irregular brown spots. As the disease progressed the lesions gradually expanded, and multiple lesions coalesced to form large irregular brown spots. Eventually the seedlings died and leaves of mature plants wilted. In order to isolate the pathogen, ten leaf pieces (5×5 mm) were cut from the junction of the diseased and the healthy tissues, surface sterilized with 75% ethanol for 30 s, 0.1% mercuric chloride (HgCl2) solution for 60 s, rinsed in sterile water three times, finally dried and placed on potato dextrose agar (PDA) and cultured in the dark at 27°C for 4 days. Five purified fungal isolates were obtained by single spore isolation. The colonies were olivaceous to dark olive with white margins and abundant aerial mycelia. On potato carrot agar (PCA) medium, these fungi produced septate conidiophores. Conidia were obclavate or ellipsoid, brown, with one to four transverse septa and one to two longitudinal septa. Spores measured 7.64 to 14.20 × 3.32 to 6.38 µm (n=50). These morphological characteristics are consistent with Alternaria alternata (S. P. Wiltshire. 1933). To further confirm the identification, four genomic DNA regions including the ribosomal DNA internal transcribed spacer (ITS), translation elongation factor 1-a gene (TEF), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), RNA polymerase II second largest subunit (RPB2), and Alternaria major allergen gene (Alt a1) were amplified and sequenced with primers ITS1/ITS4 (White et al. 1990), TEF1-728F/TEF1-986R (Carbone and Kohn 1999), gpd1/gpd2 (Berbee et al. 1999), RPB2-5F/RPB2-7cR (Liu et al. 1999), and Alt-for/Alt-rev (Hong et al. 2005), respectively. Sequences were deposited in GenBank with accession Nos. ITS: OQ128111, OQ690707, and OQ690708; TEF: OQ200380, OQ700996, and OQ700998; GAPDH: OQ200378, OQ700993, and OQ700995; RPB2:OQ200379, OQ701002, and OQ701004; Alt: OQ675614, OQ700999, and OQ701001. In a BLAST search, the sequences were 99-100% identical with corresponding sequences of A. alternata. A maximum likelihood phylogenetic tree was constructed with the combined sequence data sets of ITS, TEF, GAPDH, RPB2, and Alt a1 using MEGA 11. The isolate DHY0, DHY1, and DHY3 clustered with A. alternata (J. H. C. Woudenberg et al. 2015) (Fig. 2). To fulfill Koch's postulates, leaves on three healthy 3-month-old potted C. lancifolius seedlings were wounded with sterile needles and inoculated with 5 mm diameter mycelium, which was covered moist by sterile cotton for 24 h. Sterile water was used as the control. After inoculation, the plants were incubated at 27°C, 85% relative humidity, and a 12 h photoperiod. The experiment was repeated three times. Fifteen days after inoculation, all the leaves showed leaf spot symptoms that were similar to those observed in the greenhouse, while control leaves were asymptomatic (Fig. 1). A. alternata was successfully re-isolated from the symptomatic leaves and identified by morphology and the molecular methods described above. This pathogen has been reported to cause a leaf disease in a wide range of vegetables (Zhang et al. 2021), flowers (Zhang et al. 2022), and medicinal plants (Xing et al. 2020). To the best of our knowledge, this is the first report of A. alternata causing leaf spot on C. lancifolius in China. The accurate identification of this pathogen will provide a basis for the prevention and control of C. lancifolius leaf spot disease in the future.
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Intolerance of uncertainty (IU) is widely considered a transdiagnostic risk and maintaining factor for psychiatric disorders. However, little is known about the overall nature and profile of IU among adolescents. This study aims to investigate the profiles of IU among Chinese adolescents and explore their associations with sociodemographic characteristics and mental health problems. A sample of 108,540 adolescents provided data on IU, sociodemographic characteristics, and mental health via an online platform. Latent profile analysis revealed three profiles: Low IU, Medium IU, and High IU. Girls, older adolescents, and those with specific sociodemographics were more likely to belong to the "High IU" profile. Furthermore, the "High IU" profile was associated with the highest risk of several mental health problems. These findings provided valuable information for early prevention and intervention strategies targeting IU and highlighted the importance of IU-based interventions for mental health among adolescents.
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Skin lesion segmentation is the first and indispensable step of malignant melanoma recognition and diagnosis. At present, most of the existing skin lesions segmentation techniques often used traditional methods like optimum thresholding, etc., and deep learning methods like U-net, etc. However, the edges of skin lesions in malignant melanoma images are gradually changed in color, and this change is nonlinear. The existing methods can not effectively distinguish banded edges between lesion areas and healthy skin areas well. Aiming at the uncertainty and fuzziness of banded edges, the neutrosophic set theory is used in this paper which is better than fuzzy theory to deal with banded edge segmentation. Therefore, we proposed a neutrosophy domain-based segmentation method that contains six steps. Firstly, an image is converted into three channels and the pixel matrix of each channel is obtained. Secondly, the pixel matrixes are converted into Neutrosophic Set domain by using the neutrosophic set conversion method to express the uncertainty and fuzziness of banded edges of malignant melanoma images. Thirdly, a new Neutrosophic Entropy model is proposed to combine the three memberships according to some rules by using the transformations in the neutrosophic space to comprehensively express three memberships and highlight the banded edges of the images. Fourthly, the feature augment method is established by the difference of three components. Fifthly, the dilation is used on the neutrosophic entropy matrixes to fill in the noise region. Finally, the image that is represented by transformed matrix is segmented by the Hierarchical Gaussian Mixture Model clustering method to obtain the banded edge of the image. Qualitative and quantitative experiments are performed on malignant melanoma image dataset to evaluate the performance of the NeDSeM method. Compared with some state-of-the-art methods, our method has achieved good results in terms of performance and accuracy.
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BACKGROUND: A simple and accurate scoring system to guide perioperative blood transfusion in patients with coronary artery disease (CAD) undergoing cardiac surgery is lacking. The trigger point for blood transfusions for these patients may be different from existing transfusion guidelines. This study aimed to evaluate the safety and efficacy of a new scoring strategy for use in guiding transfusion decisions in patients with CAD. METHODS: A multicenter randomized controlled trial was conducted at three third-level grade-A hospitals from January 2015 to May 2018. Data of 254 patients in a Cardiac Peri-Operative Transfusion Trigger Score (cPOTTS) group and 246 patients in a group receiving conventional evaluation of the need for transfusion (conventional group) were analysed. The requirements for transfusion and the per capita consumption of red blood cells (RBCs) were compared between groups. RESULTS: Baseline characteristics of the two groups were comparable. Logistic regression analyses revealed no significant differences between the two groups in primary outcomes (1-year mortality and perioperative ischemic cardiac events), secondary outcomes (shock, infections, and renal impairment), ICU admission, and ICU stay duration. However, patients in the cPOTTS group had significantly shorter hospital stays, lower hospital costs, lower utilization rate and lower per capita consumption of transfused RBCs than controls. Stratified analyses revealed no significant differences between groups in associations between baseline characteristics and perioperative ischemic cardiac events, except for hemofiltration or dialysis and NYHA class in I. CONCLUSIONS: This novel scoring system offered a practical and straightforward guideline of perioperative blood transfusion in patients with CAD. Trial registration chiCTR1800016561(2017/7/19).
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Anemia/terapia , Perda Sanguínea Cirúrgica/prevenção & controle , Regras de Decisão Clínica , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Transfusão de Eritrócitos , Hemorragia Pós-Operatória/terapia , Adolescente , Adulto , Idoso , Anemia/etiologia , Anemia/mortalidade , Perda Sanguínea Cirúrgica/mortalidade , China , Tomada de Decisão Clínica , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/mortalidade , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Transfusão de Eritrócitos/efeitos adversos , Transfusão de Eritrócitos/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/mortalidade , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: ß2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral ß2-adrenoceptor, induced Cl- secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the ß2-adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood. METHODS: We investigated ß2-adrenoceptor-mediated signaling pathways involved in the production of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, in 16HBE14o- human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. The involvement of ß-arrestin2 was examined using siRNA knockdown. RESULTS: Isoprenaline and formoterol (both ß2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118,551 (ß2 antagonist). The PKA-specific inhibitor, H89, partially inhibited IL-6 release. Another intracellular cAMP receptor, EPAC, was not involved in IL-6 release. Isoprenaline-mediated IL-6 secretion was attenuated by dasatinib, a Src inhibitor, and PD98059, an ERK1/2 inhibitor. Isoprenaline treatment also led to ERK1/2 phosphorylation. In addition, knockdown of ß-arrestin2 by siRNA specifically suppressed cytokine release when a high concentration of isoprenaline (1 mM) was used. CONCLUSION: Our results suggest that activation of the ß2-adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or ß-arrestin2 signaling pathways, leading to IL-6 release. Therefore, our data reveal that ß2-adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.
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Proteínas Quinases Dependentes de AMP Cíclico , Interleucina-6 , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases , Transdução de Sinais , beta-Arrestina 2RESUMO
OBJECTIVES: To evaluate the prevalence and associated prognostic indicators in patients with vulvar carcinoma with and without evidence of perineural invasion (PNI). METHODS: A retrospective review identified 421 patients with invasive vulvar carcinoma evaluated at a single institution between 1993 and 2011. Medical records were reviewed for demographic data, pathologic information and presence or absence of PNI, treatment type, and recurrence/outcome information. Variables were compared between patients with PNI to those without PNI. RESULTS: Of the 421 patients included in the study, 32 (7.6%) had tumors with PNI. There were no significant differences in age, race/ethnicity, smoking history, histologic subtype, or grade between the group of patients with PNI and the group without PNI. The group with PNI was more likely to have lichen sclerosus (25.0% vs. 15.4%, pâ¯=â¯0.024), stage III/IV disease (59.4% vs. 36.0%, pâ¯=â¯0.007), lymph node involvement (50.0% vs. 21.6%, pâ¯=â¯0.002), and lymphovascular space invasion (LVSI) (53.1% vs. 15.9%, pâ¯<â¯0.001). A higher proportion of patients in the PNI group underwent primary or adjuvant radiation therapy (68.8% vs. 45.0%, pâ¯=â¯0.016). The median follow-up was 67.1â¯months (rangeâ¯<â¯1.0 to 284.3). Patients with PNI had significantly shorter overall survival (OS), median 25.5 vs. 94.3â¯months (pâ¯<â¯0.001), and progression-free survival (PFS), median 17.5 vs. 29.0â¯months (pâ¯=â¯0.004). After adjusting for stage, patients with PNI had a greater risk for death and progression (OS: hazard ratio, 2.71; pâ¯<â¯0.001; PFS: hazard ratio, 1.64; p-valueâ¯=â¯0.020). CONCLUSION: PNI should be considered an independent poor prognostic factor for patients with vulvar carcinoma, and should be included as part of the pathologic analysis.
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Períneo/patologia , Neoplasias Vulvares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos , Neoplasias Vulvares/mortalidadeRESUMO
Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy is a label-free, non-destructive analytical technique for biochemical analysis of macromolecular components within tissue samples. Cadmium (Cd) and mono-(2-ethylhexyl) phthalate (MEHP), a primary metabolite of di-(2-ethylhexyl) phthalate, are present ubiquitously in the environment and in organisms, and have adverse impacts on ecosystems and human health. Herein we employed ATR-FTIR analysis to identify biomolecular changes in rat liver, spleen, lung and kidney after prepubertal exposure to Cd and MEHP. Our results showed clear segregations between the 3 mg/kg Cd-, 10 mg/kg, 50 mg/kg, 250 mg/kg MEHP- and binary mixture-treated groups vs. the solvent control group. Following principal components analysis coupled with linear discriminant analysis, biochemical alterations associated with different doses of Cd and MEHP were attributed mainly to lipids, proteins, phosphates and carbohydrates. In addition, the ratios of lipid/protein, C=O stretching/CH2 methylene (lipid oxidation level), amide I/amide II, α-helix/ß-sheet and CH3 methyl/CH2 methylene (acetylation level) in target organs were affected by these toxicants. There seems to be no dose-response effect of Cd and MEHP on target organs. We observed hardly any joint toxic action of these toxicants. This is the first study showing the application of ATR-FTIR spectroscopy to the assessment of toxicity of Cd and MEHP. Possibly, destruction of cell membrane structure and integrity could be the common mechanism of Cd and MEHP toxicity in liver, spleen, lung and kidney.
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Cádmio/toxicidade , Dietilexilftalato/análogos & derivados , Poluentes Ambientais/toxicidade , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Baço/efeitos dos fármacos , Animais , Cádmio/administração & dosagem , Dietilexilftalato/administração & dosagem , Dietilexilftalato/toxicidade , Poluentes Ambientais/administração & dosagem , Rim/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Oxirredução , Análise de Componente Principal , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Baço/metabolismoRESUMO
OBJECTIVE: Primary carcinoma of the Bartholin gland is a rare malignancy that accounts for approximately 5% of vulvar carcinomas. The aim of the study was to compare the outcomes of women with primary Bartholin gland carcinoma (BGC) with those with non-Bartholin gland-related vulvar carcinoma. MATERIALS AND METHODS: A retrospective chart review of 429 patients with invasive vulvar carcinoma evaluated at a single institution between 1993 and 2011 was performed. Medical records were reviewed for demographic data, pathologic information, treatment type, and recurrence/outcome information. These variables were compared between patients with primary BGC and patients with non-Bartholin gland-related vulvar carcinoma. RESULTS: Thirty-three (7.7%) of the 429 patients with invasive vulvar carcinoma had primary carcinoma of the Bartholin gland. Twenty-nine patients (87.9%) had squamous cell histology and 4 patients (12.1%) had adenocarcinoma. When compared with non-Bartholin gland-related vulvar carcinoma, patients with primary BGC had a younger age at diagnosis (median, 57 vs 63 years; P = 0.045), had a higher rate of stage III/IV disease (60.6% vs 35.8%; P = 0.008), and were more likely to receive radiation therapy (78.8% vs 43.9%; P < 0.001). However, there were no significant differences between the 2 groups with regard to histologic subtype, lymphovascular space involvement, perineural invasion, positive margins, recurrence-free survival, or overall survival. CONCLUSIONS: Despite being diagnosed at a more advanced stage, patients with primary carcinoma of the Bartholin gland seem to have similar oncologic outcomes and survival rates to patients with non-Bartholin gland-related vulvar carcinoma.
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Adenocarcinoma/patologia , Glândulas Vestibulares Maiores/patologia , Carcinoma de Células Escamosas/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Vulvares/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Prognóstico , Radioterapia , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Vulvares/terapiaRESUMO
KEY POINTS: Na(+) current (INa) results from the integrated function of a molecular aggregate (the voltage-gated Na(+) channel complex) that includes the ß subunit family. Mutations or rare variants in Scn1b (encoding the ß1 and ß1B subunits) have been associated with various inherited arrhythmogenic syndromes, including Brugada syndrome and sudden unexpected death in patients with epilepsy. We used Scn1b null mice to understand better the relation between Scn1b expression, and cardiac electrical function. Loss of Scn1b caused, among other effects, increased amplitude of tetrodotoxin-sensitive INa, delayed after-depolarizations, triggered beats, delayed Ca(2+) transients, frequent spontaneous calcium release events and increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nM tetrodotoxin. We propose that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel α subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis. ABSTRACT: Na(+) current (INa) is determined not only by the properties of the pore-forming voltage-gated Na(+) channel (VGSC) α subunit, but also by the integrated function of a molecular aggregate (the VGSC complex) that includes the VGSC ß subunit family. Mutations or rare variants in Scn1b (encoding the ß1 and ß1B subunits) have been associated with various inherited arrhythmogenic syndromes, including cases of Brugada syndrome and sudden unexpected death in patients with epilepsy. Here, we have used Scn1b null mouse models to understand better the relation between Scn1b expression, and cardiac electrical function. Using a combination of macropatch and scanning ion conductance microscopy we show that loss of Scn1b in juvenile null animals resulted in increased tetrodotoxin-sensitive INa but only in the cell midsection, even before full T-tubule formation; the latter occurred concurrent with increased message abundance for the neuronal Scn3a mRNA, suggesting increased abundance of tetrodotoxin-sensitive NaV 1.3 protein and yet its exclusion from the region of the intercalated disc. Ventricular myocytes from cardiac-specific adult Scn1b null animals showed increased Scn3a message, prolonged action potential repolarization, presence of delayed after-depolarizations and triggered beats, delayed Ca(2+) transients and frequent spontaneous Ca(2+) release events and at the whole heart level, increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nM tetrodotoxin. Our results suggest that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel α subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis in ventricular myocytes.
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Potenciais de Ação , Arritmias Cardíacas/genética , Sinalização do Cálcio , Miócitos Cardíacos/fisiologia , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética , Animais , Arritmias Cardíacas/metabolismo , Células Cultivadas , Deleção de Genes , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismoRESUMO
The prognostic significance of CXC chemokine receptor type 4 (CXCR4) for survival of patients with esophageal cancer remains controversial. To investigate its expression impact on clinicopathological features and survival outcome, a meta-analysis was performed. A comprehensive search in the PubMed, Embase, and Web of Science (up to October 8, 2013) was performed for relevant studies using multiple search strategies. Correlation between CXCR4 expression and clinicopathological features and overall survival (OS) was analyzed. A total of 1,055 patients with esophageal cancer from seven studies were included. The pooled odds ratios (ORs) which indicated CXCR4 expression was associated with tumor depth (OR = 0.35, confidence interval (CI) = 0.27-0.47, P < 0.00001), status of lymph node (OR = 0.36, CI = 0.21-0.61, P < 0.0002), TNM (tumor, node, metastasis) stage (OR = 0.38, CI = 0.25-0.56, P < 0.00001), and histological type (OR = 1.81, CI = 1.07-3.05, P = 0.03). Poor overall survival of esophageal cancer was found to be significantly related to CXCR4 overexpression (hazard ratio (HR) 1.49, 95% CI = 1.24-1.80, P < 0.0001), whereas combined ORs exhibited that CXCR4 expression has no correlation with gender or tumor differentiation. Based on the published studies, CXCR4 overexpression in patients with esophageal cancer indicated worse survival outcome and was associated with common clinicopathological poor prognostic factors.
Assuntos
Neoplasias Esofágicas/patologia , Receptores CXCR4/fisiologia , Neoplasias Esofágicas/mortalidade , Humanos , Estadiamento de Neoplasias , Prognóstico , Viés de PublicaçãoRESUMO
The spike protein of SARS-CoV-2 as well as its receptor binding domain (RBD) has been demonstrated to be capable of activating the release of pro-inflammatory mediators in endothelial cells and immune cells such as monocytes. However, the effects of spike protein or its RBD on airway epithelial cells and mechanisms underlying these effects have not been adequately characterized. Here, we show that the RBD of spike protein alone can induce bronchial epithelial inflammation in a manner of ATP/P2Y2 dependence. Incubation of human bronchial epithelia with RBD induced IL-6 and IL-8 release, which could be inhibited by antibody. The incubation of RBD also up-regulated the expression of inflammatory indicators such as ho-1 and mkp-1. Furthermore, ATP secretion was observed after RBD treatment, P2Y2 receptor knock down by siRNA significantly suppressed the IL-6 and IL-8 release evoked by RBD. Additionally, S-RBD elevated the phosphorylation level of ERK1/2, and the effect that PD98059 can inhibit the pro-inflammatory cytokine release suggested the participation of ERK1/2. These novel findings provide new evidence of SARS-CoV-2 on airway inflammation and introduce purinergic signaling as promising treatment target.
Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Humanos , Glicoproteína da Espícula de Coronavírus/metabolismo , Sistema de Sinalização das MAP Quinases , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Células Endoteliais/metabolismo , SARS-CoV-2/metabolismo , COVID-19/metabolismo , Transdução de Sinais , Mucosa Respiratória/metabolismo , Inflamação/metabolismo , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Ligação ProteicaRESUMO
BACKGROUND: Nanguo pear is a distinctive pear variety in northeast China, grown mainly in mountainous areas. Due to terrain limitations, ground-based pesticide application equipment is difficult to use. This limitation could be overcome by using unmanned aerial vehicles (UAVs) for pesticide application in Nanguo pear orchards. This study evaluated the spraying performance of two UAVs in the Nanguo pear orchards and compared them with a manually used backpack electric sprayer (BES). The study also analyzed the effect of canopy size on droplet deposition and ground loss, and evaluated two sampling methods, leaf sampling and telescopic rod sampling. RESULTS: Compared to BESs, droplet deposition is lower for UAVs, but the actual pesticide active ingredient deposition is not necessarily lower given the solution concentration. The droplet deposition varies among different UAVs due to structural differences. Under the same UAV operating parameters, droplet deposition on trees with smaller canopy sizes is typically greater than that on trees with larger canopy sizes, and the ground loss was also more severe. Although telescopic rod sampling is a quick and convenient method, it can only reflect the trend of droplet deposition, and the data error is greater compared with leaf sampling. CONCLUSION: UAVs can achieve better droplet deposition in mountainous Nanguo pear orchards and does almost no harm to the operators compared with the BES. However, canopy size needs to be considered to adjust the application volume rate. Telescopic rods can be used for qualitative analyses, but are not recommended for quantitative analyses. © 2024 Society of Chemical Industry.
Assuntos
Pyrus , Pyrus/química , Dispositivos Aéreos não Tripulados , China , Folhas de Planta/químicaRESUMO
Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bß2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bß2 KO) nor fission (Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.