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OBJECTIVE: Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients. METHODS: Whole-exome sequencing was performed for 106 PRRT2-negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila. RESULTS: Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2-negative probands. Both co-segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation-carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes. INTERPRETATION: Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024.
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BACKGROUND: For several decades, it has been recognized that overactivation of the glutamate-gated N-methyl-D-aspartate receptors (NMDARs) and subsequent Ca2+ toxicity play a critical role in ischemic brain injury. 24S-hydroxycholesterol (24S-HC) is a major cholesterol metabolite in the brain, which has been identified as a potent positive allosteric modulator of NMDAR in rat hippocampal neurons. We hypothesize that 24S-HC worsens ischemic brain injury via its potentiation of the NMDAR, and reducing the production of 24S-HC by targeting its synthetic enzyme CYP46A1 provides neuroprotection. METHODS: We tested this hypothesis using electrophysiological, pharmacological, and transgenic approaches and in vitro and in vivo cerebral ischemia models. RESULTS: Our data show that 24S-HC potentiates NMDAR activation in primary cultured mouse cortical neurons in a concentration-dependent manner. At 10 µmol/L, it dramatically increases the steady-state currents by 51% and slightly increases the peak currents by 20%. Furthermore, 24S-HC increases NMDA and oxygen-glucose deprivation-induced cortical neuronal injury. The increased neuronal injury is largely abolished by NMDAR channel blocker MK-801, suggesting an NMDAR-dependent mechanism. Pharmacological inhibition of CYP46A1 by voriconazole or gene knockout of Cyp46a1 dramatically reduces ischemic brain injury. CONCLUSIONS: These results identify a new mechanism and signaling cascade that critically impacts stroke outcome: CYP46A1 â 24S-HC â NMDAR â ischemic brain injury. They offer proof of principle for further development of new strategies for stroke intervention by targeting CYP46A1 or its metabolite 24S-HC.
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BACKGROUND: Activation of the acid-sensing ion channels (ASICs) by tissue acidosis, a common feature of brain ischemia, contributes to ischemic brain injury, while blockade of ASICs results in protection. Cholestane-3ß,5α,6ß-triol (Triol), a major cholesterol metabolite, has been demonstrated as an endogenous neuroprotectant; however, the mechanism underlying its neuroprotective activity remains elusive. In this study, we tested the hypothesis that inhibition of ASICs is a potential mechanism. METHODS: The whole-cell patch-clamp technique was used to examine the effect of Triol on ASICs heterogeneously expressed in Chinese hamster ovary cells and ASICs endogenously expressed in primary cultured mouse cortical neurons. Acid-induced injury of cultured mouse cortical neurons and middle cerebral artery occlusion-induced ischemic brain injury in wild-type and ASIC1 and ASIC2 knockout mice were studied to examine the protective effect of Triol. RESULTS: Triol inhibits ASICs in a subunit-dependent manner. In Chinese hamster ovary cells, it inhibits homomeric ASIC1a and ASIC3 without affecting ASIC1ß and ASIC2a. In cultured mouse cortical neurons, it inhibits homomeric ASIC1a and heteromeric ASIC1a-containing channels. The inhibition is use-dependent but voltage- and pH-independent. Structure-activity relationship analysis suggests that hydroxyls at the 5 and 6 positions of the A/B ring are critical functional groups. Triol alleviates acidosis-mediated injury of cultured mouse cortical neurons and protects against middle cerebral artery occlusion-induced brain injury in an ASIC1a-dependent manner. CONCLUSIONS: Our study identifies Triol as a novel ASIC inhibitor, which may serve as a new pharmacological tool for studying ASICs and may also be developed as a potential drug for treating stroke.
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Canais Iônicos Sensíveis a Ácido , Acidose , Cricetulus , Camundongos Knockout , Animais , Canais Iônicos Sensíveis a Ácido/metabolismo , Canais Iônicos Sensíveis a Ácido/genética , Camundongos , Células CHO , Acidose/metabolismo , Acidose/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Cricetinae , Fármacos Neuroprotetores/farmacologia , Colestanóis/farmacologia , Camundongos Endogâmicos C57BL , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Masculino , Células CultivadasRESUMO
Skin wounds accompanied by bacterial infections threaten human health, and conventional antibiotic treatments are ineffective for drug-resistant bacterial infections and chronically infected wounds. The development of non-antibiotic-dependent therapeutics is highly desired but remains a challenging issue. Recently, 2D silicene nanosheets with considerable biocompatibility, biodegradability, and photothermal-conversion performance have received increasing attention in biomedical fields. Herein, copper-containing nanoparticles-loaded silicene (Cu2.8O@silicene-BSA) nanosheets with triple enzyme mimicry catalytic (peroxidase, catalase, and oxidase-like) activities and photothermal function are rationally designed and fabricated for efficient bacterial elimination, angiogenesis promotion, and accelerated wound healing. Cu2.8O@silicene-BSA nanosheets display excellent antibacterial activity through synergistic effects of reactive oxygen species generated from multiple catalytic reactions, intrinsic bactericidal activity of released Cu2+ ions, and photothermal effects, achieving high antibacterial efficiencies on methicillin-resistant Staphylococcus aureus (MRSA) of 99.1 ± 0.7% in vitro and 97.2 ± 1.6% in vivo. In addition, Cu2.8O@silicene-BSA nanosheets exhibit high biocompatibility for promoting human umbilical vein endothelial cell (HUVEC) proliferation and angiogenic differentiation. In vivo experiments reveal that Cu2.8O@silicene-BSA nanosheets with synergistic photothermal/chemodynamic therapeutics effectively accelerate MRSA-infected wound healing by eliminating bacteria, alleviating inflammation, boosting collagen deposition, and promoting angiogenesis. This research presents a promising strategy to engineer photothermal-assisted nanozyme catalysis for bacteria-invaded wound healing.
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Infecções Bacterianas , Staphylococcus aureus Resistente à Meticilina , Humanos , Cobre , Bactérias , Cicatrização , Antibacterianos/farmacologia , Antibacterianos/uso terapêuticoRESUMO
BACKGROUND: The relationship between whole grain intake and chronic kidney disease (CKD) remains uncertain. OBJECTIVE: This study aimed to evaluate the association between whole grain intake and risk of CKD in Chinese adults. METHODS: The present cross-sectional study used data from the China Health and Nutrition Survey conducted in 2009. Whole grain intake was measured using 3 consecutive 24-h dietary recalls and a household food inventory. A multivariable logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of CKD. In addition, a restricted cubic spline was used to investigate the doseâresponse relationship between whole grain and risk of CKD. RESULTS: A total of 6747 participants were included, 728 of whom had CKD. Compared with those in the lowest whole grain intake group, those in the higher grain intake group had an inverse association with risk of CKD (Q2: adjusted OR 0.70, 95% CI: 0.54, 0.89; Q3: adjusted OR 0.54, 95% CI: 0.42, 0.69; and Q4: adjusted OR 0.29, 95% CI: 0.21, 0.41). The association between whole grain intake and CKD seems to be stronger for individuals who were male (P for interaction = 0.008) or smokers (P for interaction = 0.013). In addition, the restricted cubic spline suggested an obvious L-shaped correlation. CONCLUSIONS: Increased whole grain intake was associated with a decreased risk of CKD in Chinese adults.
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Insuficiência Renal Crônica , Grãos Integrais , Adulto , Humanos , Masculino , Feminino , Estudos Transversais , Insuficiência Renal Crônica/epidemiologia , Dieta , Inquéritos NutricionaisRESUMO
Because of their various reactivities, propargyl acetates are refined chemical intermediates that are extensively applied in pharmaceutical synthesis. Currently, reactions between propargyl acetates and chlorosilanes may be the most effective method for synthesizing silylallenes. Nevertheless, owing to the adaptability and selectivity of substrates, transition metal catalysis is difficult to achieve. Herein, nickel-catalyzed reductive cross-coupling reactions between propargyl acetates and substituted vinyl chlorosilanes for the synthesis of tetrasubstituted silylallenes are described. Therein, metallic zinc is a crucial reductant that effectively enables two electrophilic reagents to selectively construct C(sp2)-Si bonds. Additionally, a Ni-catalyzed reductive mechanism involving a radical process is proposed on the basis of deuteration-labeled experiments.
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BACKGROUND: Excess aldosterone is implicated in vascular calcification (VC), but the mechanism by which aldosterone-MR (mineralocorticoid receptor) complex promotes VC is unclear. Emerging evidence indicates that long-noncoding RNA H19 (H19) plays a critical role in VC. We examined whether aldosterone-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) through H19 epigenetic modification of Runx2 (runt-related transcription factor-2) in a MR-dependent manner. METHODS: We induced in vivo rat model of chronic kidney disease using a high adenine and phosphate diet to explore the relationship among aldosterone, MR, H19, and VC. We also cultured human aortic VSMCs to explore the roles of H19 in aldosterone-MR complex-induced osteogenic differentiation and calcification of VSMCs. RESULTS: H19 and Runx2 were significantly increased in aldosterone-induced VSMC osteogenic differentiation and VC, both in vitro and in vivo, which were significantly blocked by the MR antagonist spironolactone. Mechanistically, our findings reveal that the aldosterone-activated MR bound to H19 promoter and increased its transcriptional activity, as determined by chromatin immunoprecipitation, electrophoretic mobility shift assay, and luciferase reporter assay. Silencing H19 increased microRNA-106a-5p (miR-106a-5p) expression, which subsequently inhibited aldosterone-induced Runx2 expression at the posttranscriptional level. Importantly, we observed a direct interaction between H19 and miR-106a-5p, and downregulation of miR-106a-5p efficiently reversed the suppression of Runx2 induced by H19 silencing. CONCLUSIONS: Our study clarifies a novel mechanism by which upregulation of H19 contributes to aldosterone-MR complex-promoted Runx2-dependent VSMC osteogenic differentiation and VC through sponging miR-106a-5p. These findings highlight a potential therapeutic target for aldosterone-induced VC.
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MicroRNAs , RNA Longo não Codificante , Calcificação Vascular , Humanos , Ratos , Animais , MicroRNAs/metabolismo , Aldosterona/toxicidade , RNA Longo não Codificante/metabolismo , Osteogênese , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismoRESUMO
OBJECTIVE: Acute mesenteric vein thrombosis (AMVT) is an acute abdominal disease with onset, rapid progression, and extensive intestinal necrosis that requires immediate surgical resection. The purpose of this study was to determine the risk factors for nosocomial intestinal resection in patients with AMVT. METHODS: We retrospectively analysed 64 patients with AMVT diagnosed by CTA at the Affiliated Hospital of Kunming University of Science and Technology from January 2013 to December 2021. We compared patients who underwent intestinal resection (42 patients) with those who did not undergo intestinal resection (22 patients). The area under the ROC curve was evaluated, and a forest map was drawn. RESULTS: Among the 64 patients, 6 (9.38%) had a fever, 60 (93.75%) had abdominal pain, 9 (14.06%) had a history of diabetes, 8 (12.5%) had a history of deep vein thrombosis (DVT), and 25 (39.06%) had ascites suggested by B ultrasound or CT after admission. The mean age of all patients was 49.86 ± 16.25 years. The mean age of the patients in the enterectomy group was 47.71 ± 16.20 years. The mean age of the patients in the conservative treatment group (without enterectomy) was 53.95 ± 15.90 years. In the univariate analysis, there were statistically significant differences in leukocyte count (P = 0.003), neutrophil count (P = 0.001), AST (P = 0.048), total bilirubin (P = 0.047), fibrinogen (P = 0.022) and DD2 (P = 0.024) between the two groups. The multivariate logistic regression analysis showed that admission white blood cell count (OR = 1.153, 95% CI: 1.039-1.280, P = 0.007) was an independent risk factor for intestinal resection in patients with AMVT. The ROC curve showed that the white blood cell count (AUC = 0.759 95% CI: 0.620-0.897; P = 0.001; optimal threshold: 7.815; sensitivity: 0.881; specificity: 0.636) had good predictive value for emergency enterectomy for AMVT. CONCLUSIONS: Among patients with AMVT, patients with a higher white blood cell count at admission were more likely to have intestinal necrosis and require emergency enterectomy. This study is helpful for clinicians to accurately determine whether emergency intestinal resection is needed in patients with AMVT after admission, prevent further intestinal necrosis, and improve the prognosis of patients.
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Isquemia Mesentérica , Trombose , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Veias Mesentéricas/cirurgia , Doença Aguda , Prognóstico , Isquemia Mesentérica/cirurgia , Contagem de Leucócitos , Trombose/complicações , Necrose , Curva ROCRESUMO
OBJECTIVES: Utilizing RBC or PLT-related parameters to establish rules for the PLT-O reflex test can assist laboratories in quickly identifying specimens with interfered PLT-I that require PLT-O retesting. METHODS: Prospective PLT-I and PLT-O testing was performed on 6857 EDTA-anticoagulated whole blood samples, split randomly into training and validation cohorts at a 2:3 ratio. Reflex and non-reflex groups were distinguished based on the differences between PLT-I and PLT-O results. By comparing RBC and PLT parameter differences and flags in the training set, we pinpointed factors linked to PLT-O reflex testing. Utilizing Lasso regression, then refining through univariate and multivariate logistic regression, candidate parameters were selected. A predictive nomogram was constructed from these parameters and subsequently validated using the validation set. ROC curves were also plotted. RESULTS: Significant differences were observed between the reflex and non-reflex groups for 19 parameters including RBC, MCV, MCH, MCHC, RDW-CV, RDW-SD, Micro-RBC#, Micro-RBC%, Macro-RBC#, Macro-RBC%, MPV, PCT, P-LCC, P-LCR, PLR,"PLT clumps?" flag, "PLT abnormal histogram" flag, "IDA Anemia?" flag, and "RBC abnormal histogram" flag. After further analysis, Micro-RBC#, Macro-RBC%,"PLT clumps?", and "PLT abnormal histogram" flag were identified as candidate parameters to develop a nomogram with an AUC of 0.636 (95â¯%CI: 0.622-0.650), sensitivity of 42.9â¯% (95â¯%CI: 37.8-48.1â¯%), and specificity of 90.5â¯% (95â¯%C1: 89.6-91.3â¯%). CONCLUSIONS: The established rules may help laboratories improve efficiency and increase accuracy in determining platelet counts as a supplement to ICSH41 guidelines.
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IMPORTANCE: Epidemiological evidences regarding the association between whole grain intake and the risk of new-onset hypertension are still controversial. OBJECTIVE: We aimed to investigate the relationship between whole grain intake and new-onset hypertension and examine possible effect modifiers in the general population. METHODS: A total of 10,973 participants without hypertension from the China Health and Nutrition Survey were enrolled, with follow-up beginning in 1997 and ending in 2015. Whole grain intake was assessed by 3 consecutive 24-h dietary recalls combined with a household food inventory. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression model after adjusting for potential risk factors. RESULTS: During a median follow-up of 7.0 years, 3,733 participants developed new-onset hypertension. The adjusted HRs (95% CIs) were as follows: for quartile 2 (HR: 0.52; 95% CI: 0.47-0.57), quartile 3 (HR: 0.46; 95% CI: 0.42-0.51), and quartile 4 (HR: 0.35; 95% CI: 0.31-0.38), compared with quartile 1. Different types of whole grain types, including wheat (adjusted HR, 0.35; 95% CI, 0.32-0.39), maize (adjusted HR, 0.50; 95% CI, 0.42-0.59), and millet (adjusted HR, 0.38; 95% CI, 0.30-0.48), showed significant associations with a reduced risk of hypertension. The association between whole grain intake and new-onset hypertension was stronger in individuals with older age (P for interaction < 0.001) and higher BMI (P for interaction < 0.001). CONCLUSION: Higher consumption of whole grains was significantly associated with a lower risk of new-onset hypertension. This study provides further evidence supporting the importance of increasing whole grain intake for hypertension prevention among Chinese adults.
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Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function mutations in maternally expressed UBE3A. No gene-specific treatment is available for patients so far. Although intact and transcriptionally active, paternally inherited UBE3A is silenced by elongation of antisense long noncoding RNA UBE3A-ATS in neurons. Here, we demonstrated that RNA targeting of paternal Ube3a-ATS with a high-fidelity CRISPR-Cas13 (hfCas13x.1) system could restore Ube3a expression to similar levels as that of maternal Ube3a in the cultured mouse neurons. Furthermore, injection into lateral ventricles with neuron-specific hSyn1 promoter-driven hfCas13x.1 packaged in adeno-associated virus (AAV-PHP.eb) could restore paternal Ube3a expression in cortex and hippocampus of neonatal AS mice for up to 4 months after treatment. Behavioral tests showed that expression of paternal Ube3a significantly alleviated AS-related symptoms, including obesity and motor function. Our results suggested that hfCas13x.1-mediated suppression of the Ube3a-ATS lncRNA potentially serves as a promising targeted intervention for AS.
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Síndrome de Angelman , Animais , Camundongos , Síndrome de Angelman/genética , Síndrome de Angelman/terapia , RNA Antissenso/genética , Obesidade , Ubiquitina-Proteína Ligases/genéticaRESUMO
Cooperative localization (CL) for air-to-ground robots in a satellite-denial environment has become a current research hotspot. The traditional distance-based heterogeneous multiple-robot CL method requires at least four unmanned aerial vehicles (UAVs) with known positions. When the number of known-position UAVs in a cluster collaborative network is insufficient, the traditional distance-based CL method has a certain inapplicability. A novel adaptive CL method for air-to-ground robots based on relative distance constraints is proposed in this paper. Based on a dynamically changing number of known-position UAVs in the cluster collaborative network, the adaptive fusion estimation threshold is set. When the number of known-position UAVs in the cluster cooperative network is large, the real-time dynamic topology characteristics of multiple robots' spatial geometric configurations are considered. The optimal spatial geometric configuration between UAVs and unmanned ground vehicles (UGVs) is utilized to achieve a high-precision CL solution for UGVs. Otherwise, in the event that the number of known-position UAVs in a cluster collaborative network is insufficient, distance observation constraint information between UAVs and UGVs is retained in real time. Position observation equations for UGVs' inertial navigation system (INS) have been constructed using inertial-based high-precision relative position constraints and relative distance constraints from historical to current times. The experimental results show that the proposed method achieves adaptive fusion estimation with a dynamically changing number of known-position UAVs in the cluster collaborative network, effectively verifying the effectiveness of the proposed method.
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A typical magnetometer-based measurement-while-drilling (MWD) system determines the azimuth of the bottom hole assembly during the drilling process by employing triaxial accelerometers and magnetometers. The geomagnetic azimuth solution is susceptible to magnetic interference, especially strong magnetic interference and so a rotary norm constraint filtering (RNCF) method for azimuth estimation, designed to support a gyroscope-aided magnetometer-based MWD system, is proposed. First, a new magnetic dynamical system, one whose output is observed by the magnetometers triad, is designed based on the Coriolis equation of the desired geomagnetic vector. Second, given that the norm of the non-interfered geomagnetic vector can be approximated as a constant during a short-term drilling process, a norm constraint procedure is introduced to the Kalman filter. This is achieved by the normalization of the geomagnetic part of the state vector of the dynamical system and is undertaken in order to obtain a precise geomagnetic component. Simulation and actual drilling experiments show that the proposed RNCF method can effectively improve the azimuth measurement precision with 98.5% over the typical geomagnetic solution and 37.1% over the KF in a RMSE sense when being strong magnetic interference environment.
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Ultralong nanowires with ultrahigh aspect ratios exhibit high flexibility, and they are promising for applications in various fields. Herein, a cadmium oleate precursor hydrothermal method is developed for the synthesis of ultralong nanowires of cadmium phosphate hydroxide. In this method, water-soluble cadmium salt is used as the cadmium source, water-soluble phosphate is used as the phosphorus source, and sodium oleate is adopted as a reactant to form cadmium oleate precursor and as a structure-directing agent. By using this method, ultralong nanowires of cadmium phosphate hydroxide are successfully synthesized using CdCl2, sodium oleate, and NaH2PO4 as reactants in an aqueous solution by hydrothermal treatment at 180 °C for 24 h. In addition, a new type of flexible fire-resistant inorganic paper with good electrical insulation performance is fabricated using ultralong nanowires of cadmium phosphate hydroxide. As an example of the extended application of this synthetic method, ultralong nanowires of cadmium phosphate hydroxide can be converted to ultralong CdS nanowires through a convenient sulfidation reaction. In this way, ultralong CdS nanowires are successfully synthesized by simple sulfidation of ultralong nanowires of cadmium phosphate hydroxide under mild conditions. The as-prepared ultralong nanowires of cadmium phosphate hydroxide are promising for applications as the precursors and templates for synthesizing other inorganic ultralong nanowires and have wide applications in various fields.
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Solar energy-driven water evaporation is a promising sustainable strategy to purify seawater and contaminated water. However, developing solar evaporators with high water evaporation rates and excellent salt resistance still faces a great challenge. Herein, inspired by the long-range ordered structure and water transportation capability of lotus stem, a biomimetic aerogel with vertically ordered channels and low water evaporation enthalpy for high-efficiency solar energy-driven salt-resistant seawater desalination and wastewater purification is developed. The biomimetic aerogel consists of ultralong hydroxyapatite nanowires as heat-insulating skeletons, polydopamine-modified MXene as a photothermal material with broadband sunlight absorption and high photothermal conversion efficiency, polyacrylamide, and polyvinyl alcohol as reagents to lower the water evaporation enthalpy and as glues to enhance the mechanical performance. The honeycomb porous structure, unidirectionally aligned microchannels, and nanowire/nanosheet/polymer pore wall endow the biomimetic aerogel with excellent mechanical properties, rapid water transportation, and excellent solar water evaporation performance. The biomimetic aerogel exhibits a high water evaporation rate (2.62 kg m-2 h-1 ) and energy efficiency (93.6%) under one sun irradiation. The superior salt-rejecting ability of the designed water evaporator enables stable and continuous seawater desalination, which is promising for application in water purification to mitigate the global water crisis.
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This paper proposes a novel three-dimensional hologram calculation method based on the angular spectrum approach, with the aim of reducing the noise generated during the hologram reconstruction process. The proposed algorithm divides the spatial domain into multiple layers and employs the angular spectrum method to propagate the image between these layers, thus avoiding the paraxial approximation. To enhance the quality of the hologram, an error iteration algorithm is utilized to alleviate the occurrence of aliasing errors when directly superimposing holograms. Moreover, constraint factors are introduced between different layers within the same region to effectively utilize spatial resources for multi-image reconstruction, thereby mitigating the noise caused by inter-layer crosstalk. The feasibility of the proposed method is demonstrated through numerical simulations and optical experiments, highlighting its potential applicability to a wide range of three-dimensional reconstruction algorithms.
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In this study, an on-site attitude accuracy evaluation method based on parallel mechanism model and indirect traceability from length to angle is proposed. Firstly, the mathematical model is established. Through orthogonal experimental design, quantitative analysis shows that the ranging accuracy and control layout have a significant impact on the accuracy of the evaluation system. On this basis, the layout of control field is optimized by genetic algorithm. Finally, the practicability of the evaluation method is verified by experiments. The results show that the yaw and pitch accuracy of the method are 0.008°and 0.007°respectively in the range of -25°to 25°within the working distance of 8 m. This method can accurately and effectively evaluate the attitude angle information of the measurement system and is adapted to various on-site environments. The research provides an innovative idea which can be used to ensure the strict requirements of attitude angle measurement in fields such as intelligent manufacturing and in situ processing.
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BACKGROUND: Recurrences are the main reasons for unfavorable outcomes for patients with stage II colorectal cancer (CRC). To obtain a clear understanding of the high-risk factors, further investigation is warranted. The present study aimed to analyze the risk factors associated with postoperative recurrence in patients with stage II CRC. METHODS: Eligible patients with pathologically confirmed stage II CRC were enrolled in the study retrospectively based on a prospectively maintained database from April 2008 to March 2019. The Kaplan-Meier method were used to calculate the overall survival (OS) rate and the cumulative recurrence rate. Univariate and multivariable Cox regression analyses were performed to identify risk factors for recurrence. RESULTS: There were 2515 patients included, of whom 233 (9.3%) developed local or distant recurrence. Recurrence was associated with a significantly worse 5-year OS (45.4% vs. 95.5%, p < 0.0001). The 5-year cumulative recurrence rate was 13.0% in patients with stage II CRC. On multivariable Cox analysis, tumor size (Hazard Ratio (HR) [95% confidence interval (CI)] = 1.79[1.38, 2.33]), preoperative carbohydrate antigen (CA) 125 level (HR [95% CI] = 1.78[1.17, 2.70]), preoperative CA 199 level (HR [95% CI] = 1.56[1.09, 2.22]), and ulcerating tumor (HR [95% CI] = 1.61[1.19, 2.17]) were found to be associated with postoperative recurrence. Adjuvant chemotherapy was associated with a lower cumulative recurrence rate in patients with these risk factors (p = 0.00096). CONCLUSION: The tumor diameter, preoperative CA125 level, preoperative CA199 level, and an ulcerative tumor can predict postoperative recurrence in patients with stage II CRC, and postoperative chemotherapy could reduce the cumulative recurrence rate in patients with these high-risk factors.
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Neoplasias Colorretais , Humanos , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Colorretais/patologia , Fatores de Risco , Recidiva Local de Neoplasia/patologiaRESUMO
CRISPR-Cas9 systems are bacterial adaptive immune systems that defend against infection by phages. Through the RNA-guided endonuclease activity of Cas9 they degrade double-stranded DNA with a protospacer adjacent motif (PAM) and sequences complementary to the guide RNA. Recently, two anti-CRISPR proteins (AcrIIA2 and AcrIIA4 from Listeria monocytogenes prophages) were identified, both of which inhibit Streptococcus pyogenes Cas9 (SpyCas9) and L. monocytogenes Cas9 activity in bacteria and human cells. However, the mechanism of AcrIIA2- or AcrIIA4-mediated Cas9 inhibition remains unknown. Here we report a crystal structure of SpyCas9 in complex with a single-guide RNA (sgRNA) and AcrIIA4. Our data show that AcrIIA2 and AcrIIA4 interact with SpyCas9 in a sgRNA-dependent manner. The structure reveals that AcrIIA4 inhibits SpyCas9 activity by structurally mimicking the PAM to occupy the PAM-interacting site in the PAM-interacting domain, thereby blocking recognition of double-stranded DNA substrates by SpyCas9. AcrIIA4 further inhibits the endonuclease activity of SpyCas9 by shielding its RuvC active site. Structural comparison reveals that formation of the AcrIIA4-binding site of SpyCas9 is induced by sgRNA binding. Our study reveals the mechanism of SpyCas9 inhibition by AcrIIA4, providing a structural basis for developing 'off-switch' tools for SpyCas9 to avoid unwanted genome edits within cells and tissues.
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Proteínas de Bactérias/antagonistas & inibidores , Proteínas Associadas a CRISPR/antagonistas & inibidores , Listeria monocytogenes/enzimologia , Listeria monocytogenes/virologia , Prófagos/genética , Streptococcus pyogenes/enzimologia , Proteínas Virais/metabolismo , Sítios de Ligação , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/fisiologia , Cristalografia por Raios X , DNA/genética , DNA/metabolismo , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Edição de Genes , Listeria monocytogenes/genética , Modelos Moleculares , Ligação Proteica , Conformação Proteica , RNA Guia de Cinetoplastídeos/genética , RNA Guia de Cinetoplastídeos/metabolismo , Especificidade por Substrato , Proteínas Virais/genéticaRESUMO
Accurate localization between cameras is a prerequisite for a vision-based heterogeneous robot systems task. The core issue is how to accurately perform place recognition from different view-points. Traditional appearance-based methods have a high probability of failure in place recognition and localization under large view-point changes. In recent years, semantic graph matching-based place recognition methods have been proposed to solve the above problem. However, these methods rely on high-precision semantic segmentation results and have a high time complexity in node extraction or graph matching. In addition, methods only utilize the semantic labels of the landmarks themselves to construct graphs and descriptors, making such approaches fail in some challenging scenarios (e.g., scene repetition). In this paper, we propose a graph-matching method based on a novel landmark topology descriptor, which is robust to view-point changes. According to the experiment on real-world data, our algorithm can run in real-time and is approximately four times and three times faster than state-of-the-art algorithms in the graph extraction and matching phases, respectively. In terms of place recognition performance, our algorithm achieves the best place recognition precision at a recall of 0-70% compared with classic appearance-based algorithms and an advanced graph-based algorithm in the scene of significant view-point changes. In terms of positioning accuracy, compared to the traditional appearance-based DBoW2 and NetVLAD algorithms, our method outperforms by 95%, on average, in terms of the mean translation error and 95% in terms of the mean RMSE. Compared to the state-of-the-art SHM algorithm, our method outperforms by 30%, on average, in terms of the mean translation error and 29% in terms of the mean RMSE. In addition, our method outperforms the current state-of-the-art algorithm, even in challenging scenarios where the benchmark algorithms fail.