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Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.
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Canais Iônicos Sensíveis a Ácido , Isquemia Encefálica , Ácido Glutâmico , Animais , Feminino , Humanos , Masculino , Camundongos , 2-Amino-5-fosfonovalerato/efeitos adversos , 2-Amino-5-fosfonovalerato/metabolismo , 2-Amino-5-fosfonovalerato/farmacologia , Canais Iônicos Sensíveis a Ácido/química , Canais Iônicos Sensíveis a Ácido/deficiência , Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos , Canais Iônicos Sensíveis a Ácido/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sítios de Ligação/genética , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ácido Glutâmico/análogos & derivados , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Ácido Glutâmico/toxicidade , Camundongos Knockout , Mutagênese Sítio-Dirigida , Prótons , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Social behavior starts with dynamic approach prior to the final consummation. The flexible processes ensure mutual feedback across social brains to transmit signals. However, how the brain responds to the initial social stimuli precisely to elicit timed behaviors remains elusive. Here, by using real-time calcium recording, we identify the abnormalities of EphB2 mutant with autism-associated Q858X mutation in processing long-range approach and accurate activity of prefrontal cortex (dmPFC). The EphB2-dependent dmPFC activation precedes the behavioral onset and is actively associated with subsequent social action with the partner. Furthermore, we find that partner dmPFC activity is responsive coordinately to the approaching WT mouse rather than Q858X mutant mouse, and the social defects caused by the mutation are rescued by synchro-optogenetic activation in dmPFC of paired social partners. These results thus reveal that EphB2 sustains neuronal activation in the dmPFC that is essential for the proactive modulation of social approach to initial social interaction.
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Córtex Pré-Frontal , Receptor EphB2 , Comportamento Social , Animais , Camundongos , Encéfalo , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Receptor EphB2/genética , Receptor EphB2/fisiologiaRESUMO
Poplar (Populus) is a well-established model system for tree genomics and molecular breeding, and hybrid poplar is widely used in forest plantations. However, distinguishing its diploid homologous chromosomes is difficult, complicating advanced functional studies on specific alleles. In this study, we applied a trio-binning design and PacBio high-fidelity long-read sequencing to obtain haplotype-phased telomere-to-telomere genome assemblies for the 2 parents of the well-studied F1 hybrid "84K" (Populus alba × Populus tremula var. glandulosa). Almost all chromosomes, including the telomeres and centromeres, were completely assembled for each haplotype subgenome apart from 2 small gaps on one chromosome. By incorporating information from these haplotype assemblies and extensive RNA-seq data, we analyzed gene expression patterns between the 2 subgenomes and alleles. Transcription bias at the subgenome level was not uncovered, but extensive-expression differences were detected between alleles. We developed machine-learning (ML) models to predict allele-specific expression (ASE) with high accuracy and identified underlying genome features most highly influencing ASE. One of our models with 15 predictor variables achieved 77% accuracy on the training set and 74% accuracy on the testing set. ML models identified gene body CHG methylation, sequence divergence, and transposon occupancy both upstream and downstream of alleles as important factors for ASE. Our haplotype-phased genome assemblies and ML strategy highlight an avenue for functional studies in Populus and provide additional tools for studying ASE and heterosis in hybrids.
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Alelos , Genoma de Planta , Populus , Populus/genética , Genoma de Planta/genética , Regulação da Expressão Gênica de Plantas , Haplótipos/genética , Hibridização Genética , Aprendizado de MáquinaRESUMO
We propose a scheme for realizing nonreciprocal microwave photon routing with two cascaded magnon-cavity coupled systems, which work around the exceptional points of a parity-time (PT)-symmetric Hamiltonian. An almost perfect nonreciprocal transmission can be achieved with a broad bandwidth, where the transmission for a forward-propagating photon can be flexibly controlled with the backpropagating photon being isolated. The transmission or isolated direction can be reversed via simply controlling the magnetic field direction applied to the magnons. The isolation bandwidth is improved by almost three times in comparison with the device based on a single PT-symmetric system. Moreover, the effect of intrinsic cavity loss and added thermal noises is considered, confirming the experimental feasibility of the nonreciprocal device and potential applications in quantum information processing.
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OBJECTIVE: To investigate the association between sarcopenia, short-term efficacy, and long-term survival in patients with extensive small-cell lung cancer (SCLC) treated with standard first-line immunochemotherapy. METHODS: A total of 63 patients initially diagnosed with extensive-stage small cell lung cancer were enrolled in the prospective study from December 1, 2020 to December 31, 2022. The clinical characteristics, body composition, blood test results, and image data were obtained before treatment. Patients were divided into sarcopenia and non-sarcopenia groups according to the diagnostic criteria of the Asian Sarcopenia Working Group 2019. The primary outcome was overall survival (OS) and comprehensive survival analyses were performed. Secondary outcomes included short-term efficacy and adverse events associated with first-line immunochemotherapy. RESULTS: The median age of the 63 patients enrolled in our study was 63.0 years (40-80 years). The incidence of sarcopenia was 19.0% (12/63) in patients with extensive SCLC. Compared with non-sarcopenia patients, extensive-stage SCLC patients with sarcopenia were significantly older (69.0 vs. 62.0, P = 0.017), and had lower body mass index (BMI) (20.29 vs. 24.27, P < 0.001), hand grip strength (HGS) (20.42 vs. 30.75, P < 0.001), and albumin (35.9 vs. 41.40, P < 0.001). The objective response rate after two cycles of standard first-line immunochemotherapy in the sarcopenia group was lower than in the non-sarcopenia group (30.0 vs. 78.9%, P = 0.012). There was no significant difference in chemotherapy-related hematological toxicity between the two groups. During a median follow-up of 15 months (3-33 months), patients with extensive SCLC had a median OS of 24 months, with 1-year survival of 75% and 2-year survival of 52%, respectively. Compared to non-sarcopenia patients, the median OS in the sarcopenia group was significantly shorter (9 vs. 24 months, P = 0.0014). Multivariate Cox analysis showed that sarcopenia was an independent risk factor for OS in patients with extensive SCLC (HR = 4.993, 95%CI = 1.106-22.538, P = 0.037). CONCLUSIONS: Patients with Extensive SCLC and sarcopenia had worse clinical outcomes and shorter OS. Sarcopenia is a prognostic factor affecting first-line treatment efficacy and long-term survival of patients with SCLC in the era of immunotherapy.
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Carbonaceous materials are promising candidates as anode materials for non-lithium-ion batteries (NLIBs) due to their appealing properties such as good electrical conductivity, low cost, and high safety. However, graphene, a classic two-dimensional (2D) carbon material, is chemically inert to most metal atoms, hindering its application as an electrode material for metal-ion batteries. Inspired by the unique geometry of a four-penta unit, we explore a metallic 2D carbon allotrope C5-10-16 composed of 5-10-16 carbon rings. The C5-10-16 monolayer is free from any imaginary frequencies in the whole Brillouin zone. Due to the introduction of a non-sp2 hybridization state into C5-10-16, the extended conjugation of π-electrons is disrupted, leading to the enhanced surface activity toward metal ions. We investigate the performance of C5-10-16 as the anode for sodium/potassium-ion batteries by using first-principles calculations. The C5-10-16 sheet has high theoretical specific capacities of Na (850.84 mA h g-1) and K (743.87 mA h g-1). Besides, C5-10-16 exhibits a moderate migration barrier of 0.63 (0.32) eV for Na (K), ensuring rapid charging/discharging processes. The average open-circuit voltages of Na and K are 0.33 and 0.62 V, respectively, which are within the voltage acceptance range of anode materials. The fully sodiated (potassiated) C5-10-16 shows tiny lattice expansions of 1.4% (1.3%), suggesting the good reversibility. Moreover, bilayer C5-10-16 significantly affects both the adsorption strength and the mobility of Na or K. All these results show that C5-10-16 could be used as a promising anode material for NLIBs.
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Corneal dystrophies may develop gradually from early onset in childhood and persist for years to decades. Visual impairment or repeated ocular irritations caused by corneal dystrophies severely affect the quality of life. Although various surgical treatment options are indicated for adult patients, the treatment plan for pediatric patients remains unclear. Herein we describe clinical observations of phototherapeutic keratectomy for corneal epithelial-stromal dystrophies in three pediatric patients (five eyes). Corneal opacities were successfully removed, and visual acuity was greatly improved in all operated eyes. The procedure of phototherapeutic keratectomy seems to be feasible in the treatment of corneal epithelial-stromal dystrophies in c hildren, with advantages of minimal invasion and good visual outcomes.
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BACKGROUND: The prevalence of hypertensive heart disease (HHD) is high and there is currently no easy way to detect early HHD. Explore the application of radiomics using cardiac magnetic resonance (CMR) non-enhanced cine sequences in diagnosing HHD and latent cardiac changes caused by hypertension. METHODS: 132 patients who underwent CMR scanning were divided into groups: HHD (42), hypertension with normal cardiac structure and function (HWN) group (46), and normal control (NOR) group (44). Myocardial regions of the end-diastolic (ED) and end-systolic (ES) phases of the CMR short-axis cine sequence images were segmented into regions of interest (ROI). Three feature subsets (ED, ES, and ED combined with ES) were established after radiomic least absolute shrinkage and selection operator feature selection. Nine radiomic models were built using random forest (RF), support vector machine (SVM), and naive Bayes. Model performance was analyzed using receiver operating characteristic curves, and metrics like accuracy, area under the curve (AUC), precision, recall, and specificity. RESULTS: The feature subsets included first-order, shape, and texture features. SVM of ED combined with ES achieved the highest accuracy (0.833), with a macro-average AUC of 0.941. AUCs for HHD, HWN, and NOR identification were 0.967, 0.876, and 0.963, respectively. Precisions were 0.972, 0.740, and 0.826; recalls were 0.833, 0.804, and 0.863, respectively; and specificities were 0.989, 0.863, and 0.909, respectively. CONCLUSIONS: Radiomics technology using CMR non-enhanced cine sequences can detect early cardiac changes due to hypertension. It holds promise for future use in screening for latent cardiac damage in early HHD.
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Diagnóstico Precoce , Hipertensão , Imagem Cinética por Ressonância Magnética , Humanos , Feminino , Masculino , Imagem Cinética por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Hipertensão/diagnóstico por imagem , Hipertensão/complicações , Máquina de Vetores de Suporte , Cardiopatias/diagnóstico por imagem , Idoso , Adulto , Teorema de Bayes , Curva ROC , Interpretação de Imagem Assistida por Computador/métodos , RadiômicaRESUMO
Toxocara canis is a parasitic zoonose that is distributed worldwide and is one of the two pathogens causing toxocariasis. After infection, it causes serious public health and safety problems, which pose significant veterinary and medical challenges. To better understand the regulatory effects of T. canis infection on the host immune cells, murine macrophages (RAW264.7) were incubated with recombinant T. canis C-type lectin 4 (rTc-CTL-4) protein in vitro. The quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to analyze the nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2), receptor-interacting protein 2 (RIP2), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and mitogen-activated protein kinase (MAPK) on mRNA level and protein expression level in macrophages. Our results indicated that 10 µg/mL rTc-CTL-4 protein could modulate the expression of NOD1, NOD2, and RIP2 at both the transcriptional and translational levels. The protein translation levels of NF-κB, P-p65, p38, and P-p38 in macrophages were also modulated by rTc-CTL-4 protein. Macrophages were co-incubated with rTc-CTL-4 protein after siRNA silencing of NOD1, NOD2, and RIP2. The expression levels of NF-κB, P-p65, p38, and P-p38 were significantly changed compared with the negative control groups (Neg. Ctrl.). Taken together, rTc-CTL-4 protein seemed to act on NOD1/2-RIP2-NF-κB and MAPK signaling pathways in macrophages and might activate MAPK and NF-κB signaling pathways by regulating NOD1, NOD2, and RIP2. The insights from the above studies could contribute to our understanding of immune recognition and regulatory mechanisms of T. canis infection in the host animals.
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NF-kappa B , Toxocara canis , Animais , Camundongos , NF-kappa B/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Toxocara canis/metabolismo , Transdução de Sinais/fisiologia , MacrófagosRESUMO
The use of autologous costal cartilage in augmentation rhinoplasty is well-established. However, scenarios where costal cartilage is insufficient or patients are unwilling to undergo additional cartilage harvesting present a challenge. This study introduces a composite dorsal onlay implant, combining silicone and costal cartilage, as an effective solution. Twenty female patients were enrolled in this study. Of these patients, 8 underwent revision surgery who had previous rhinoplasty with costal cartilage graft, and 12 had never previously undergone surgery involving the harvesting of costal cartilage. The implant, created by suturing a silicone base with a costal cartilage overlay, demonstrated low rates of warping and translucency over a mean follow-up of 11.4 months. This method offers a refined nasal appearance, particularly a higher dorsum with reduced translucency for patients with limited costal cartilage availability.
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BACKGROUND: The application of the expanded forehead flap in nasal reconstruction has the advantage of being able to provide a sufficient amount of flap and can provide good aesthetic results. For an expanded forehead flap to survive, there must be adequate arterial supply and venous return. Despite this, limited studies have been conducted on preoperative vascular mapping and the design of the expanded forehead flap for nasal reconstruction. In this article, the authors present a technique of hand-held Doppler detection with light illumination for vascular mapping. PATIENTS AND METHODS: The study included patients who underwent total nasal reconstruction with expanded forehead flaps between May 2016 and April 2021. The design of the flap was based on the result of preoperative vascular detection by hand-held Doppler detection assisted by light illumination. RESULTS: A total of 32 patients underwent total nasal reconstruction with an expanded forehead flap. The distal part of the flap became necrotic 1 week after the surgery in 2 patients. Following dressing changes and the administration of antibiotics, the distal flap in these patients survived well. No complications were reported in the long term. CONCLUSIONS: Hand-held Doppler detection combined with light illumination is a convenient and effective preoperative design method for nasal reconstruction with an expanded forehead flap. All flaps survived well in the long term. LEVEL OF EVIDENCE: Level IV.
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Iluminação , Rinoplastia , Humanos , Estética Dentária , Retalhos Cirúrgicos/cirurgia , Nariz/cirurgia , Rinoplastia/métodos , Testa/diagnóstico por imagem , Testa/cirurgia , Testa/irrigação sanguíneaRESUMO
In addition to providing extra flap size, the tissue expansion process also brings changes in flap thickness. This study aims to identify the changes in the forehead flap thickness during the tissue expansion period. Patients undergoing forehead expander embedment from September 2021 to September 2022 were included. The thickness of the forehead skin and subcutaneous tissue were measured with ultrasound before and 1, 2, 3, and 4 months after expansion. Twelve patients were included. The average expansion period was 4.6 months, and the mean expansion volume was 657.1 mL. The thickness of skin and subcutaneous tissue in the central forehead changed from 1.09 ± 0.06 to 0.63 ± 0.05 mm and from 2.53 ± 0.25 to 0.71 ± 0.09 mm, respectively. In the left frontotemporal region, skin and subcutaneous tissue thickness changed from 1.03 ± 0.05 to 0.52 ± 0.05 mm and 2.02 ± 0.21 to 0.62 ± 0.08 mm. On the right side, skin and subcutaneous tissue thickness changed from 1.01 ± 0.05 to 0.50 ± 0.04 mm and 2.06 ± 0.21 to 0.50 ± 0.05 mm. This study measured the dynamic changes in the thickness of the forehead flap during expansion. The thickness of the forehead flap decreased the fastest in the first 2 months of expansion, and the changes in skin and subcutaneous thickness slowed down in the third and fourth months and tended to a minimum value. Additionally, the thickness of subcutaneous tissue decreased greater in magnitude than the dermal tissue.
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Testa , Expansão de Tecido , Humanos , Testa/cirurgia , Retalhos Cirúrgicos , Transplante de Pele , Dispositivos para Expansão de TecidosRESUMO
Due to the prevalence of anterior maxilla dysplasia in Asian population, paranasal concavity is a common accompaniment to low nose, but its impact on facial harmonization is often underestimated. A retrospective comparative study was conducted on patients diagnosed as low nose with paranasal concavity between June 2017 and June 2021, with a total of 56 patients followed up successfully. The control and observation groups were established according to whether the paranasal augmentation was performed. Demographic data were collected. Cosmetic enhancement was quantitatively evaluated by sagittal planimetry, establishing related anatomical landmarks and measuring columella base prominence (CBP) and alar base prominence (ABP). Subjective evaluation concluded the patient-reported satisfaction (FACE-Q-Rhinoplasty Module and Facial Appearance Module) and the third-party physician assessment (Global Aesthetic Improvement Scale, GAIS).Significant improvements in CBP and ABP were reported both in the control and the observation group (p < 0.01). In postoperative intergroup comparisons, the observation group was superior to the control group regarding ABP values (2.5 ± 0.75 degrees, p < 0.01), FACE-Q-Facial scores (7.49 ± 3.70, p < 0.05), and GAIS scores (p < 0.05). However, no statistical difference was found in CBP values and FACE-Q-Rhinoplasty scores. Paranasal augmentation-related complications included asymmetry of alar bases (6.9%) and facial or intraoral foreign body sensation (34.5%). This study affirmed that paranasal augmentation using diced costal cartilage in rhinoplasty is a safe procedure effective in remedying paranasal concavity and improving facial satisfaction. LEVEL OF EVIDENCE:: IV.
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BACKGROUND: There has been no previous study on the availability of different glucocorticoid varieties used in the multimodal cocktail for harvesting autologous costal cartilage. This randomized controlled trial (RCT) was to compare the significance and complications of betamethasone and triamcinolone acetonide as a component of the cocktail for harvesting costal cartilage in patients. MATERIALS AND METHODS: The patients were randomized to two groups. The group A used multimodal cocktail: ropivacaine, parecoxib sodium, epinephrine, and triamcinolone acetonide; group B used multimodal cocktail: ropivacaine, parecoxib sodium, epinephrine, and betamethasone. The primary outcomes were chest pain after surgery evaluated with a visual analog scale (VAS). The secondary outcomes evaluated the quality of recovery. The tertiary outcomes included rescue analgesic consumption, the first feeding time and the time to the first ambulation, and duration of hospital stay. RESULTS: The VAS scores between the two groups was not considered clinically significant, but the groups achieved a VAS score of 3 or less. However, the time until the first rescue analgesia and the number were significantly longer and smaller for group A. Additionally, there were no significant differences between the two groups in the duration of hospital stay, first feeding time, the quality of recovery, and the first ambulation time. CONCLUSION: Adding corticosteroids into the multimodal cocktails could improve pain relief after costal cartilage harvest. And the efficacy of Triamcinolone acetonide was better than betamethasone. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Cartilagem Costal , Triancinolona Acetonida , Humanos , Betametasona , Ropivacaina , Epinefrina , Dor no Peito , Dor Pós-Operatória , Método Duplo-CegoRESUMO
PURPOSE: To compare image quality, iodine intake, and radiation dose in overweight and obese patients undergoing abdominal computed tomography (CT) enhancement using different scanning modes and contrast medium. METHODS: Ninety overweight and obese patients (25âkg/m2≤body mass index (BMI)<â30âkg/m2 and BMI≥30âkg/m2) who underwent abdominal CT-enhanced examinations were randomized into three groups (A, B, and C) of 30 each and scanned using gemstone spectral imaging (GSI) +320âmgI/ml, 100âkVp + 370âmgI/ml, and 120âkVp + 370âmgI/ml, respectively. Reconstruct monochromatic energy images of group A at 50-70âkeV (5âkeV interval). The iodine intake and radiation dose of each group were recorded and calculated. The CT values, contrast-to-noise ratios (CNRs), and subjective scores of each subgroup image in group A versus images in groups B and C were by using one-way analysis of variance or Kruskal-Wallis H test, and the optimal keV of group A was selected. RESULTS: The dual-phase CT values and CNRs of each part in group A were higher than or similar to those in groups B and C at 50-60âkeV, and similar to or lower than those in groups B and C at 65âkeV and 70âkeV. The subjective scores of the dual-phase images in group A were lower than those of groups B and C at 50âkeV and 55âkeV, whereas no significant difference was seen at 60-70âkeV. Compared to groups B and C, the iodine intake in group A decreased by 12.5% and 13.3%, respectively. The effective doses in groups A and B were 24.7% and 25.8% lower than those in group C, respectively. CONCLUSION: GSI +320âmgI/ml for abdominal CT-enhanced in overweight patients satisfies image quality while reducing iodine intake and radiation dose, and the optimal keV was 60âkeV.
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Meios de Contraste , Obesidade , Sobrepeso , Radiografia Abdominal , Tomografia Computadorizada por Raios X , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Sobrepeso/diagnóstico por imagem , Doses de Radiação , Intensificação de Imagem Radiográfica/métodos , Radiografia Abdominal/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso de 80 Anos ou maisRESUMO
PURPOSE: Colorectal cancer (CRC) is the third most common cancer in the world. The purpose of this study was to investigate the role of TNNT2 in the proliferation, migration and invasion of CRC cells and its expression in CRC tissues to better understand the regulatory role of TNNT2 in CRC. METHODS: Western blotting (WB) and qPCR were used to detect the expression of TNNT2 in colorectal cancer tissues and paracancerous tissues. CCK-8, colony formation, Transwell and other experiments were used to clarify the role of TNNT2 in the proliferation, migration and invasion of colorectal cancer cells. Changes in TNNT2, EGFR and HER2 mRNA transcription levels were detected by SYBR Real-Time PCR assay, and the effects of TNNT2 overexpression or knockdown on the expression of EGFR, HER2 and EMT-related proteins in CRC cells were determined by WB. TNNT2 and EGFR intreaction was carried out in HCT116 cells by coimmunoprecipitation experiments. RESULTS: The protein and mRNA expression level of TNNT2 in CRC tissues were higher than those in paracancerous tissues. The CCK-8 results suggested that overexpression of TNNT2 significantly promoted the proliferation of HCT116 and RKO cells, and TNNT2 konckdown gets the opposite result; and the colony formation results were the same as tthose of CCK-8 assay. Transwell invasion and migration experiments showed that overexpression of TNNT2 promoted the migration and invasion of HCT116 and PKO cells, and TNNT2 konckdown suppressed the migration and invasion of the these cells. The SYBR Green I real-time PCR method revealed that them RNA levels of TNNT2, EGFR and HER2 in the TNNT2 overexpression group were higher than those in RKO cells. WB showed that overexpressing TNNT2 increased the expression of EGFR and HER2 in HCT16 and RKO cells,decreased the expression of EMT marker E-cadherin, and increased the expression of Vimentin and N-cadherin. Konckdown of TNNT2 decreased the expression of EGFR and HER2, increased the expression of E-cadherin, and decreased the expression of Vimentin and N-cadherin in HCT16 and RKO cells. The immunocoprecipitation experiment showed that there was an interaction between EGFR and TNNT2. CONCLUSION: TNNT2 can promote the proliferation, invasion and metastasis of colorectal cancer cells. There is an interaction between TNNT2 and EGFR protein. TNNT2 can upregulate EGFR and HER2-related proteins in colorectal cancer cells and promote the occurrence of EMT. Therefore, TNNT2 can promote the invasion and metastasis of CRC cells through the EGFR/HER2/EMT signal axis, suggesting that TNNT2 is a potential target of CRC treatment.
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BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors, influenced by several genetic loci in its clinical phenotypes. The aim of this study was to determine the relationship between the MMP8 gene polymorphism and CRC risk in the Chinese Han population. METHOD: This study recruited 688 CRC patients and 690 healthy controls. The relationship between MMP8 polymorphism and CRC susceptibility was assessed by calculating the odds ratio (OR) and 95% confidence interval (CI) after stratifying by age, gender, body mass index (BMI), smoking, and alcohol consumption under a multi-genetic model. RESULTS: MMP8 rs3740938 was associated with increased CRC predisposition (p = 0.016, OR = 1.24, 95% CI: 1.04-1.48), and this association was detected particularly in subjects aged > 60 years, females, people with BMI > 24 kg/m2, smokers, and drinkers. Moreover, rs3740938 was found to be associated with the pathological type of rectal cancer. CONCLUSIONS: Our results first displayed that rs3740938 in MMP8 was a risk factor for CRC predisposition. This finding may provide a new biological perspective for understanding the role of the MMP8 gene in CRC pathogenesis.
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Neoplasias Colorretais , Predisposição Genética para Doença , Feminino , Humanos , Genótipo , Metaloproteinase 8 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Neoplasias Colorretais/genética , Estudos de Casos e ControlesRESUMO
Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.
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Complexo Nuclear Basolateral da Amígdala , Extinção Psicológica , Extinção Psicológica/fisiologia , Medo/fisiologia , Córtex Pré-Frontal/fisiologia , Condicionamento Psicológico/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologiaRESUMO
BACKGROUND: Outbreaks of monkeypox have been ongoing in non-endemic countries since May 2022. A thorough assessment of its global zoonotic niche and potential transmission risk is lacking. METHODS: We established an integrated database on global monkeypox virus (MPXV) occurrence during 1958 - 2022. Phylogenetic analysis was performed to examine the evolution of MPXV and effective reproductive number (Rt) was estimated over time to examine the dynamic of MPXV transmissibility. The potential ecological drivers of zoonotic transmission and inter-regional transmission risks of MPXV were examined. RESULTS: As of 24 July 2022, a total of 49 432 human patients with MPXV infections have been reported in 78 countries. Based on 525 whole genome sequences, two main clades of MPXV were formed, of which Congo Basin clade has a higher transmissibility than West African clade before the 2022-monkeypox, estimated by the overall Rt (0.81 vs. 0.56), and the latter significantly increased in the recent decade. Rt of 2022-monkeypox varied from 1.14 to 4.24 among the 15 continuously epidemic countries outside Africa, with the top three as Peru (4.24, 95% CI: 2.89-6.71), Brazil (3.45, 95% CI: 1.62-7.00) and the United States (2.44, 95% CI: 1.62-3.60). The zoonotic niche of MPXV was associated with the distributions of Graphiurus lorraineus and Graphiurus crassicaudatus, the richness of Rodentia, and four ecoclimatic indicators. Besides endemic areas in Africa, more areas of South America, the Caribbean States, and Southeast and South Asia are ecologically suitable for the occurrence of MPXV once the virus has invaded. Most of Western Europe has a high-imported risk of monkeypox from Western Africa, whereas France and the United Kingdom have a potential imported risk of Congo Basin clade MPXV from Central Africa. Eleven of the top 15 countries with a high risk of MPXV importation from the main countries of 2022-monkeypox outbreaks are located at Europe with the highest risk in Italy, Ireland and Poland. CONCLUSIONS: The suitable ecological niche for MPXV is not limited to Africa, and the transmissibility of MPXV was significantly increased during the 2022-monkeypox outbreaks. The imported risk is higher in Europe, both from endemic areas and currently epidemic countries. Future surveillance and targeted intervention programs are needed in its high-risk areas informed by updated prediction.
Assuntos
Mpox , Humanos , Mpox/epidemiologia , Filogenia , Surtos de Doenças , Estudos Retrospectivos , BrasilRESUMO
Lung cancer is the leading cause of deaths from malignant neoplasms worldwide, and a satisfactory biopsy that allows for histological and other analyses is critical for its diagnosis. Guidelines have recommended endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as the reference standard for the staging of lung cancer. However, the relatively limited sample volume retrieved by needle aspiration might restrict the diagnostic capacity of EBUS-TBNA in other uncommon thoracic tumors. Transbronchial mediastinal cryobiopsy is a recently developed sampling strategy for mediastinal lesions, which demonstrates added diagnostic value to conventional needle aspiration. Here, we present a case of thoracic SMARCA4-deficient undifferentiated tumor successfully diagnosed by mediastinal cryobiopsy additional to EBUS-TBNA.