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INTRODUCTION: More robust non-human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD. METHODS: We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3' and 5' intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non-human primate model. RESULTS: We observed early changes of AD-related pathological proteins (cerebrospinal fluid Aß42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1-ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1-ΔE9 cynomolgus monkeys. DISCUSSION: PSEN1 mutant cynomolgus monkeys recapitulate AD-related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD-associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions. HIGHLIGHTS: A dual-guide CRISPR/Cas9 system successfully mimics AD PSEN1-ΔE9 mutation by genomic excision of exon 9. PSEN1 mutant cynomolgus monkey-derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aß secretion. Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys. Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD-related pathological proteins (increased Aß42 and phosphorylated tau).
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Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Macaca fascicularis , Mutación , Presenilina-1 , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/sangre , Presenilina-1/genética , Mutación/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/genética , Sistemas CRISPR-Cas , Exones/genética , Masculino , Transcriptoma , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeoRESUMEN
Being a major obstacle, Ag2Te has always been restricted in p-type AgSbTe2-based materials to improve their thermoelectric performance. This work reveals a stabilized AgSbTe2 through Sn/Ge alloying as synthesized by melting, annealing, and hot press. Interestingly, addition of Sn/Ge in AgSbTe2 extended the solubility limit up to â¼30% and hence suppressed Ag2Te in Ag(1-x)SnxSb(1-y)GeyTe2 compounds and led to enhanced electrical transport. Moreover, electrical and thermal transport properties of AgSbTe2 have been greatly affected by the phase transition of Ag2Te near 425 K. However, high-entropy Ag0.85Sn0.15Sb0.85Ge0.15Te2 compound results in a stabilized rock-salt structure and presents a high power factor of â¼10.8 µW cm-1 K-2 at 757 K. Besides, density functional theory reveals that available multivalence bands in Sn/Ge-doped AgSbTe2 lead to reduction in energy offsets. Meanwhile, a variety of defects appear in the Ag0.85Sn0.15Sb0.85Ge0.15Te2 sample due to entropy change, and thus lattice thermal conductivity decreases. Ultimately, a high figure of merit of â¼1.5 is attained at 757 K. This work demonstrates a roadmap for other group IV-VI materials so that the high-entropy approach may inhibit the impurity phases with extended solubility limit and result in high thermoelectric performance.
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OBJECTIVE: The genomic and molecular ecology involved in the stepwise continuum progression of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) remains unclear and requires further elucidation. We aimed to characterize gene mutations and expression landscapes, and explore the association between differentially expressed genes (DEGs) and significantly mutated genes (SMGs) during the dynamic evolution from AIS to IAC. METHODS: Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed. RESULTS: The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD. CONCLUSIONS: Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.
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Adenocarcinoma del Pulmón , Secuenciación del Exoma , Neoplasias Pulmonares , Mutación , Invasividad Neoplásica , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Transcriptoma , Perfilación de la Expresión Génica , Adenocarcinoma in Situ/genética , Adenocarcinoma in Situ/patología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Biomarcadores de Tumor/genéticaRESUMEN
Magnetism in two dimensions is traditionally considered an exotic phase mediated by spin fluctuations, but far from collinearly ordered in the ground state. Recently, 2D magnetic states have been discovered in layered van der Waals compounds. Their robust and tunable magnetic state by material composition, combined with reduced dimensionality, foresee a strong potential as a key element in magnetic devices. Here, a class of 2D magnets based on metallic chlorides is presented. The magnetic order survives on top of a metallic substrate, even down to the monolayer limit, and can be switched from perpendicular to in-plane by substituting the metal ion from iron to nickel. Using functionalized STM tips as magnetic sensors, local exchange fields are identified, even in the absence of an external magnetic field. Since the compounds are processable by molecular beam epitaxy techniques, they provide a platform with large potential for incorporation into current device technologies.
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With the rapid advancement of urbanization and industrialization, ecological patches within cities and towns are fragmented and ecological corridors are cut off, regional ecological security is threatened and sustainable development is hindered. Building an ecological network that conforms to regional realities can connect fragmented patches, protect biodiversity and regional characteristics, and provide scientific reference for regional ecological protection and ecological network planning. By taking Qilin District, the main urban area of Qujing City as an example, and using geospatial data as the main data source, based on morphological spatial pattern analysis (MSPA) and minimum cumulative resistance (MCR), this study identified ecological source areas, extracted ecological corridors, and build & optimize ecological networks. (1) All landscape types are identified based on MSPA, the proportion of core area was the highest among all landscape types, which was 80.69%, combined with the connectivity evaluation, 14 important ecological source areas were selected. (2) 91 potential ecological corridors were extracted through MCR and gravity models, there were 16 important ones. (3) The network connectivity analysis method is used to calculate the α, ß, and γ indexes of the ecological network before optimization, which were 2.36, 6.5, and 2.53, while after optimization, α, ß and γ indices were 3.8, 9.5 and 3.5, respectively. The combined application of MSPA-MCR model and ecological network connectivity analysis evaluation is conducive to improving the structure and functionality of ecological network.
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OBJECTIVE: To explore the effect of Kümmell's disease with kyphosis on the sagittal morphology of the spine-pelvis. METHODS: A retrospective analysis of 34 patients of Kümmell's disease with kyphosis ï¼Kümmell groupï¼ admitted from August 2015 to September 2022, including 10 males and 24 females with an average age of ï¼71.1±8.5ï¼ years old. A control group of 37 asymptomatic population aged ï¼69.3±6.7ï¼ years old was matched. Spinal-pelvic sagittal parameters were measured on the anterior-posterior and lateral X-rays of the whole spine in the standing position, including segmental kyphosisï¼SKï¼ or thoracolumbar kyphosisï¼TLKï¼, thoracic kyphosisï¼TKï¼, lumbar lordosisï¼LLï¼, pelvic incidenceï¼PIï¼, pelvic tiltï¼PTï¼, sacral slopeï¼SSï¼, sagittal vertical axisï¼SVAï¼, T1 pelvic angleï¼TPAï¼ and PI-LL. Vertebral wedge angleï¼WAï¼ in Kümmell was measured and differences in parameters among groups were analyzed and the relationship between spino-pelvic parameters and WA, SK were also investigated. RESULTS: TK, SK, PT, SVA, TPA and PI-LL in Kümmell group were significantly larger than those in control group ï¼P<0.05ï¼, LL and SS in Kümmell group were significantly decreased than those in control group ï¼P<0.05ï¼, and there was no significant difference in PI between two groups ï¼P>0.05ï¼. In Kümmell group, WAï¼30.8±5.9ï¼° showed a positive correlation with SK and TKï¼r=0.366, 0.597, P<0.05ï¼, and SK was significantly correlated with LL and SSï¼r=0.539, -0.591, P<0.05ï¼. Strong positive correlation between LL and PI, SS, SVA, TPA, PI-LL were also confirmed in patients with Kümmell with kyphosisï¼r=0.559, 0.741, -0.273, -0.356, -0.882, P<0.05ï¼. CONCLUSION: Patients with Kümmell with kyphosis not only have segmental kyphosis, but also changes the overall spinal-pelvic sagittal parameters, including loss of lumbar lordosis, pelvic retrorotation, trunk forward tilt. The surgical treatment of Kümmell disease should not only pay attention to the recovery of the height of the collapsed vertebra, but also focus on the overall balance of the spine-pelvic sagittal plane for patients with kyphosis.
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Cifosis , Lordosis , Espondilosis , Masculino , Femenino , Humanos , Persona de Mediana Edad , Anciano , Lordosis/diagnóstico por imagen , Estudios Retrospectivos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Cifosis/diagnóstico por imagen , Cifosis/cirugía , Pelvis/diagnóstico por imagenRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2023.1153573.].
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Retrograde adeno-associated viruses (AAVs) are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks. However, few retrograde AAV capsids have been shown to offer access to cortical projection neurons across different species and enable the manipulation of neural function in non-human primates (NHPs). Here, we report the development of a novel retrograde AAV capsid, AAV-DJ8R, which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques. In addition, intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations. Moreover, AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen. These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.
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Axones , Neuronas Motoras , Animales , Haplorrinos , Interneuronas , Macaca , Dependovirus/genética , Vectores GenéticosRESUMEN
INTRODUCTION: LUAD (Lung adenocarcinoma), the most common subtype of lung carcinoma and one of the highest incidences and mortality cancers in the world remains still a substantial treatment challenge. Ivermectin, an avermectin derivative, has been traditionally used as an antiparasitic agent in human and veterinary medicine practice during the last few decades. Though ivermectin has been shown to be effective against a variety of cancers, however, there is few available data reporting the antitumor effects of ivermectin in LUAD. METHODS: The effect of ivermectin on cell viability and proliferative ability of LUAD cells was evaluated using CCK-8 and colony formation assay. Apoptosis rate and autophagy flux were detected using flow cytometry based on PI/Annexin V staining and confocal laser scanning microscope based on LC3-GFP/RFP puncta, respectively. Western blotting experiment was conducted to verify the results of changes in apoptosis and autophagy. LUAD-TCGA and GEO databases were used to analyse the expression and predictive value of PAK1 in LUAD patients. Xenograft model and immumohistochemical staining were used for verification of the inhibitor effect of ivermectin in vivo. RESULTS: Ivermectin treatment strikingly impeded the colony formation, and the viability of the cell, along with cell proliferation, and caused the apoptosis and enhanced autophagy flux in LUAD cells. In addition, ivermectin-induced nonprotective autophagy was confirmed by treating LUAD cells with 3-MA, an autophagy inhibitor. Mechanistically, we found that ivermectin inhibited PAK1 protein expression in LUAD cells and we confirmed that overexpression of PAK1 substantially inhibited ivermectin-induced autophagy in LUAD cells. Based on TCGA and GEO databases, PAK1 was highly expressed in LUAD tissues as compared with normal tissues. Furthermore, LUAD patients with high PAK1 level have poor overall survival. Finally, in vivo experiments revealed that ivermectin efficiently suppressed the cellular growth of LUAD among nude mice. CONCLUSION: This study not only revealed the mechanism of ivermectin inhibited the growth of LUAD but also supported an important theoretical basis for the development of ivermectin during the therapy for LUAD.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Animales , Ratones , Humanos , Ivermectina/farmacología , Ratones Desnudos , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/patología , Autofagia , Proliferación Celular , Apoptosis , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismo , Quinasas p21 Activadas/farmacologíaRESUMEN
Effective delivery of viruses into required brain regions is critical to the success of optogenetic or chemogenetic experiments. However, in monkeys, due to the large size and heterogeneity of their brain, precise injections in deep brain regions have been challenging. Here, we present a protocol for virus injection in monkey deep brain regions under the guidance of MRI. We describe the steps for installing the guiding grid, MRI scanning, MRI-based localization, and virus injection. For complete details on the use and execution of this protocol, please refer to Chen et al. (2023).1.
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Encéfalo , Sistemas de Computación , Animales , Encéfalo/diagnóstico por imagen , Inyecciones , Macaca , Imagen por Resonancia MagnéticaRESUMEN
Background: Volumetric Muscle Loss (VML) denotes the traumatic loss of skeletal muscle, a condition that can result in chronic functional impairment and even disability. While the body can naturally repair injured skeletal muscle within a limited scope, patients experiencing local and severe muscle loss due to VML surpass the compensatory capacity of the muscle itself. Currently, clinical treatments for VML are constrained and demonstrate minimal efficacy. Selenium, a recognized antioxidant, plays a crucial role in regulating cell differentiation, anti-inflammatory responses, and various other physiological functions. Methods: We engineered a porous Se@SiO2 nanocomposite (SeNPs) with the purpose of releasing selenium continuously and gradually. This nanocomposite was subsequently combined with a decellularized extracellular matrix (dECM) to explore their collaborative protective and stimulatory effects on the myogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs). The influence of dECM and NPs on the myogenic level, reactive oxygen species (ROS) production, and mitochondrial respiratory chain (MRC) activity of ADSCs was evaluated using Western Blot, ELISA, and Immunofluorescence assay. Results: Our findings demonstrate that the concurrent application of SeNPs and dECM effectively mitigates the apoptosis and intracellular ROS levels in ADSCs. Furthermore, the combination of dECM with SeNPs significantly upregulated the expression of key myogenic markers, including MYOD, MYOG, Desmin, and myosin heavy chain in ADSCs. Notably, this combination also led to an increase in both the number of mitochondria and the respiratory chain activity in ADSCs. Conclusion: The concurrent application of SeNPs and dECM effectively diminishes ROS production, boosts mitochondrial function, and stimulates the myogenic differentiation of ADSCs. This study lays the groundwork for future treatments of VML utilizing the combination of SeNPs and dECM.
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Células Madre Mesenquimatosas , Nanocompuestos , Selenio , Humanos , Dióxido de Silicio , Especies Reactivas de Oxígeno/metabolismo , Selenio/farmacología , Porosidad , Músculo Esquelético , Diferenciación CelularRESUMEN
Promoters are essential tools for basic and translational neuroscience research. An ideal promoter should possess the shortest possible DNA sequence with cell-type selectivity. However, whether ultra-compact promoters can offer neuron-specific expression is unclear. Here, we report the development of an extremely short promoter that enables selective gene expression in neurons, but not glial cells, in the brain. The promoter sequence originates from the human CALM1 gene and is only 120 bp in size. The CALM1 promoter (pCALM1) embedded in an adeno-associated virus (AAV) genome directed broad reporter expression in excitatory and inhibitory neurons in mouse and monkey brains. Moreover, pCALM1, when inserted into an all-in-one AAV vector expressing SpCas9 and sgRNA, drives constitutive and conditional in vivo gene editing in neurons and elicits functional alterations. These data demonstrate the ability of pCALM1 to conduct restricted neuronal gene expression, illustrating the feasibility of ultra-miniature promoters for targeting brain-cell subtypes.
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Neuronas , ARN Guía de Sistemas CRISPR-Cas , Ratones , Animales , Humanos , Neuronas/metabolismo , Encéfalo/metabolismo , Neuroglía/metabolismo , Terapia Genética , Vectores Genéticos/genética , Dependovirus/genética , Dependovirus/metabolismoRESUMEN
Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.
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Terapia Genética , Enfermedad de Parkinson , Animales , Humanos , Ratones , Cuerpo Estriado/metabolismo , Levodopa/uso terapéutico , Levodopa/genética , Neuronas/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Primates , Receptores de Dopamina D1/metabolismo , Modelos Animales de EnfermedadRESUMEN
Urban forest is an integral part of the complex urban ecosystem, and tree canopy plays a key role in improving urban climatic environment. Urban Tree Canopy (UTC) is strongly linked to urban thermal environment and living quality of residents. In this study, Luoping County, a mountainous county in southwest China, was selected as the study area to uncover the inner connections between tree canopy and thermal environment, and provide relevant scientific references for the construction of livable forest cities in similar areas. Through eCongnition Developer, ENVI and ArcGIS software, the distribution of Land Surface Temperature (LST) and land cover types in the study area was extracted, 63 patches with super-large and extra-large tree canopy coverage selected, to explore the regulatory effect of UTC patches on urban thermal environment based on SPSS software. Results showed that the highest LST in the research area was 37.63 â, the lowest 24.73 â, and the average 30.83 â. Among the land cover types, the area of buildings and impervious surfaces was 1615.71 hm2, accounting for 55.76% of the total study area, which was the largest proportion and with widespread distribution; the area of grassland and water body was 57.48 hm2 and 12.35 hm2, respectively, taking up 1.98% and 0.43%, with a smaller proportion. Mean LST: impervious surface > bare land > grassland > tree canopy > water body. By increasing the area and perimeter of the patch covered by tree canopy, the cooling rate of the patch can be increased while the temperature inside the patch can be reduced. The relationship between the area and cooling rate is closer than that between perimeter and cooling rate. The increase of perimeter has a stronger alleviation effect on the internal temperature of the patch, whereas, the increase of area has a weaker effect in this respect.
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Accurately recognizing facial expressions is essential for effective social interactions. Non-human primates (NHPs) are widely used in the study of the neural mechanisms underpinning facial expression processing, yet it remains unclear how well monkeys can recognize the facial expressions of other species such as humans. In this study, we systematically investigated how monkeys process the facial expressions of conspecifics and humans using eye-tracking technology and sophisticated behavioral tasks, namely the temporal discrimination task (TDT) and face scan task (FST). We found that monkeys showed prolonged subjective time perception in response to Negative facial expressions in monkeys while showing longer reaction time to Negative facial expressions in humans. Monkey faces also reliably induced divergent pupil contraction in response to different expressions, while human faces and scrambled monkey faces did not. Furthermore, viewing patterns in the FST indicated that monkeys only showed bias toward emotional expressions upon observing monkey faces. Finally, masking the eye region marginally decreased the viewing duration for monkey faces but not for human faces. By probing facial expression processing in monkeys, our study demonstrates that monkeys are more sensitive to the facial expressions of conspecifics than those of humans, thus shedding new light on inter-species communication through facial expressions between NHPs and humans.
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Expresión Facial , Percepción del Tiempo , Animales , Tecnología de Seguimiento Ocular , HaplorrinosRESUMEN
OBJECTIVE: To explore the effects of morphological changes such as vertebral wedge deformation and disc degeneration (collapse) on adult thoracolumbar/lumbar degenerative kyphosis(TL/LDK) deformity. METHODS: A retrospective analysis of 32 patients with spinal TL/LDK deformity admitted from August 2015 to December 2020, including 8 males and 24 females, aged 48 to 75(60.3±12.4) years old. On the long-cassette standing upright lateral radiographs, the coronal Cobb angle, sagittal thoracic lumbar/lumbar kyphosis angle(KA) of spine were measured, and the height and wedge parameters of apex vertebral(AV) and two vertebrae(AV-1, AV-2, AV+1, AV+2) above and below AV and the intervertebrae and the intervertebral disc(AV-1D, AV-2D, AV+1D, AV+2D) were evaluated, involving anterior vertebral body height(AVH), posterior vertebral body height(PVH), vertebral wedge angle(VWA), ratio of vertebral wedging(RVW), anterior disc height(ADH), posterior disc height(PDH), disc wedge angle(DWA), ratio of disc wedging(RDW), and DWA/KA. RESULTS: The average angle of kyphosis was (44.2±19.1)°. A significant decrease in anterior height of vertebral was observed compared to the posterior height of vertebral(P<0.005). There was no significant difference in anterior and posterior height of discs. The vertebral wedging ratio/contribution ratio:AV-2(14.98±10.95)%/(14.21±8.08)%, AV-1(21.08±12.39)%/(18.09±7.38)%, AV(26.94±11.94)%/(25.52±8.64)%, AV+1(24.19±8.42)%/(20.82±8.69)%, AV+2(20.56±7.80)%/(15.60±9.71)%, total contribution(94.23±22.25)%, the disc wedging ratio/contribution ratio:AV-2D(2.88±2.57)%/(5.27±4.11)%, AV-1D(1.98±1.41)%/(2.29±2.16)%, AV+1D(-5.54±3.75)%/(-0.57±0.46)%, AV+2D(-8.27±4.62)%/(-1.22±1.11)%, total contribution (5.77±4.79)%. And the contribution rate of AV was significantly higher than that of adjacent vertebral(P<0.05). CONCLUSION: The vertebral body and intervertebral disc shape both have influence on thoracolumbar kyphosis. However, the contribution of vertebral morphometry to the angle of TL/LDK deformity is relatively more important than the disc. The contribution of the wedge change of the AV to the TL/LDK deformity is particularly significant.
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Disco Intervertebral , Cifosis , Escoliosis , Masculino , Adulto , Femenino , Humanos , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Vértebras Torácicas/diagnóstico por imagen , Vértebras Lumbares/diagnóstico por imagenRESUMEN
Objective: Inflammation is recognized as a contributor in the development of pulmonary arterial hypertension (PAH), and the recruitment and functional capacity of immune cells are well-orchestrated by chemokines and their receptors. This study is aimed at identification of critical chemokines in the progression of PAH via transcriptomic analysis. Methods: Differentially expressed genes (DEGs) from lungs of PAH patients were achieved compared to controls based on Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) was applied for functional annotation and pathway enrichement. The abundance of immune cells was estimated by the xCell algorithm. Weighted correlation network analysis (WGCNA) was used to construct a gene expression network, based on which a diagnostic model was generated to determine its accuracy to distinguish PAH from control subjects. Target genes were then validated in lung of hypoxia-induce pulmonary hypertension (PH) mouse model. Results: ACKR4 (atypical chemokine receptor 4) was downregulated in PAH lung tissues in multiple datasets. PAH relevant biological functions and pathways were enriched in patients with low-ACKR4 level according to GSEA enrichment analysis. Immuno-infiltration analysis revealed a negative correlation of activated dendritic cells, Th1 and macrophage infiltration with ACKR4 expression. Three gene modules were associated with PAH via WGCNA analysis, and a model for PAH diagnosis was generated using CXCL12, COL18A1 and TSHZ2, all of which correlated with ACKR4. The ACKR4 expression was also downregulated in lung tissues of our experimental PH mice compared to that of controls. Conclusions: The reduction of ACKR4 in lung tissues of human PAH based on transcriptomic data is consistent with the alteration observed in our rodent PH. The correlation with immune cell infiltration and functional annotation indicated that ACKR4 might serve as a protective immune checkpoint for PAH.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Humanos , Ratones , Animales , Hipertensión Arterial Pulmonar/genética , Hipertensión Pulmonar Primaria Familiar , Hipertensión Pulmonar/genética , Perfilación de la Expresión Génica , PulmónRESUMEN
INTRODUCTION: The current study aims to investigate the etiology spectrum and the clinical characteristics of bronchiectasis in Chinese children. METHODS: The study is designed as a multicenter retrospective study. 193 cases were enrolled in 13 centers in China between 2008 and 2017. The inclusive cases must meet the clinical as well as the HRCT criteria. Only if both two radiologists confirmed the diagnosis, the case could be enrolled. The cases that could not provide clinical and imageology data were excluded. The data were entered into the specialized system and then analyzed. RESULTS: One hundred sixty-nine cases (87%) were found to have the underlying etiology. Post-infective (46%), primary immunodeficiency (14%), and PCD (13%) were the common causes. All cases came from 28 provinces in Mainland China. The median age of symptom onset was 5.8 (2.0, 8.9) years. The median age of diagnosis was 8.4 (4.5, 11.6) years. The main symptoms were cough, sputum expectoration, and fever during the exacerbation. Nineteen percent of patients suffered from limited exercise tolerance. Clubbing was found in 17% of cases. Nearly 30% of patients presented growth limitations. On the HRCT findings, 126 cases had diffused bronchiectasis, and bilateral involvement was found in 94 cases. The lower lobes and right middle lobes were most commonly involved. Approximately 30% of cultures of sputum and bronchoalveolar lavage were positive. CONCLUSION: A majority of cases could be found the underlying etiology. Post-infective, primary immunodeficiency, and PCD were the most common causes. Some clinical figures might indicate a specific etiology.