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Due to their exceptional adaptability, inherent compliance, and high flexibility, soft actuators have significant advantages over traditional rigid actuators in human-machine interaction and in grasping irregular or fragile objects. Most existing soft actuators are designed using preprogramming methods, which schedule complex motions into flexible structures by correctly designing deformation constraints. These constraints restrict undesired deformation, allowing the actuator to achieve the preprogrammed motion when stimulated. Therefore, these actuators can only achieve a certain type of motion, such as extension, bending, or twisting, since it is impossible to adjust the deformation constraints once they are embedded into the structures. In this study, we propose the use of variable stiffness materials, such as shape memory polymer (SMP), in the structural design of soft actuators to achieve variable stiffness constraints. A reconfigurable soft helical actuator with a variable stiffness skeleton is developed based on this concept. The skeleton, made of SMP, is encased at the bottom of a fiber-reinforced chamber. In its high-stiffness state, the SMP constrains the deformation toward the skeleton when the actuator is pressurized. This constraint is removed once the SMP skeleton is heated, endowing the actuator with the ability to switch between bending and helical motion in real-time. A theoretical model is proposed to predict the behavior of the actuator when driven by pressure, and experiments are conducted to verify the model's accuracy. In addition, the influence of different design parameters is investigated based on experimental results, providing reference guidelines for the design of the actuator.
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Regarding a recent dispute about the symmetry of the stress tensor of fluids, more considerations are presented. The usual proofs of this symmetry are reviewed, and contradictions between this symmetry and the mechanism of gas viscosity are analyzed for simple gas flows. It is emphasized that these proofs depend on the theorem of angular momentum that assumes that internal forces between any two fluid particles are always along the line connecting them. Without this assumption, from Newton's laws of motion one can only obtain the theorem of angular momentum with an additional term. It is proved within classical continuum mechanics that this additional term represents the total moment of internal forces, and its volume density is similar to the body couple introduced in generalized continuum mechanics. When discrete structure of matter is considered, this term corresponds to the total moment of the forces exerted on the nuclei by the internal electrons. This moment of internal forces may lead to nonsymmetry of the stress tensor and is, in general, nonzero as long as shear stress exists. A nonsymmetrical stress tensor suggested in the literature is discussed in terms of its effects in eliminating the contradictions and simplifying the Navier-Stokes equation. The derivation of this stress tensor for ideal gases based on the kinetic theory of gas molecules is presented, and its form in a general orthogonal curvilinear coordinate system is given. Finally, a possible experimental verification of this nonsymmetrical stress tensor is discussed.
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Low response rate, treatment relapse, and resistance remain key challenges for cancer treatment with immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TS) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Here we identify, by using in vivo CRISPR/Cas9 based loss-of-function screening, that NF1, TSC1, and TGF-ß RII as TSs regulating immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape, characterized by increased numbers of LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 and PD-L1 simultaneously inhibits metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-ß RII- deficient tumors. Our study thus reveals a role of TSs in regulating metastasis via non-cell-autonomous modulation of the immune compartment and provides proof-of-principle for ICB targeting LAG3 for patients with NF1-, TSC1- or TGF-ß RII-inactivated cancers.
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Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico , Proteína del Gen 3 de Activación de Linfocitos , Neoplasias de la Mama Triple Negativas , Proteína 1 del Complejo de la Esclerosis Tuberosa , Microambiente Tumoral , Microambiente Tumoral/inmunología , Animales , Ratones , Femenino , Humanos , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/genética , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , Inflamación/inmunología , Linfocitos T CD4-Positivos/inmunología , Regulación Neoplásica de la Expresión Génica , Sistemas CRISPR-CasRESUMEN
Objective: To achieve high throughput and high detection rate of circulating tumor cells (CTCs) in human peripheral blood, and to provide efficient and accurate early screening for cancer patients. Methods: A microfluidic chip with the integration of sorting, enrichment and detection was designed, and CTCs at the single cell level were detected by fluorescence detection system to obtain the number of CTCs in samples. Results: The peripheral blood samples after lysed red blood cells were used for 6 experiments. When the injection rate reached 0.2 mL/h, CTCs could reach the best detection rate of 78.6%, and the correlation coefficient within the group was above 0.8. Conclusion: CTCs detection system can achieve high detection rate and has good reliability, which can provide a reliable reference for clinical research in related fields.
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Células Neoplásicas Circulantes , Humanos , Reproducibilidad de los Resultados , Separación Celular/instrumentación , Microfluídica , Técnicas Analíticas MicrofluídicasRESUMEN
Coastal bays serve as undeniable dissolved organic matter (DOM) reactors and the role of prevalent mariculture in DOM cycling deserves investigation. This study, based on four seasonal field samplings and a laboratory incubation experiment, examined the source and seasonal dynamics of DOM and fluorescent dissolved organic matter (FDOM) in the seawater of fish (Larimichthys crocea, LC), seaweed (Gracilaria lemaneiformis, GL) and abalone (Haliotis sp., HA) culturing zones in Sansha Bay, China. Using three-dimensional fluorescence spectroscopy coupled with parallel factor analysis (EEMs-PARAFAC), three fluorescent components were identified, i.e. protein-like C1, protein-like C2, and humic-like C3. Our results showed that mariculture activities dominated the DOM pool by seasonal generating abundant DOM with lower aromaticity and humification degrees. Accounting for 40-95 % of total fluorescent components, C1 (Ex/Em = 300/340 nm) was regarded the same as D1 (Ex/Em = 300/335 nm) identified in a 180-day degradation experiments of G. lemaneiformis detritus, indicating that the cultured seaweed modulated DOM through the seasonal production of C1. In addition, the incubation experiment revealed that 0.7 % of the total carbon content of seaweed detritus could be preserved as recalcitrant dissolved organic carbon (RDOC). However, fish culture appeared to contribute to liable DOC and protein-like C2, exerting a substantial impact on DOM during winter but making a negligible contribution to carbon sequestration, while abalone culture might promote the potential export and sequestration of seaweed-derived carbon to the ocean. Our results highlight the influences of mariculture activities, especially seaweed culture, in shaping DOM pool in coastal bays. These findings can provide reference for future studies on the carbon accounting of mariculture.
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Bahías , Secuestro de Carbono , Monitoreo del Ambiente , Gastrópodos , Estaciones del Año , Algas Marinas , China , Animales , Agua de Mar/química , Peces , Acuicultura , CarbonoRESUMEN
Symbol-level fiber-longitudinal power profile estimation (PPE) greatly reduces the implementation complexity compared with the waveform-level PPE using oversampled data. However, symbol-rate data cannot account for the inter-sample interaction, which leads to inaccuracy of the absolute power estimation. To realize an accurate symbol-level PPE, we provide an in-depth analysis of the differences between symbol-level and waveform-level perturbation matrices and propose a power calibration method based on the trace of the inverse matrix. Evaluated in the probabilistic constellation shaping (PCS) 64QAM 130 Gbaud 5 × 50 km optical links, the root mean squared error (RMSE) of the symbol-level PPE decreases by 0.98 and 0.62 dB at erbium-doped fiber amplifier (EDFA) positions and all estimated positions with the aid of matrix calibration.
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Recombinant human erythropoietin (rhEPO) is a glycoprotein that acts as the main hormone involved in regulating red blood cell production to treat anemia caused by chronic kidney disease or chemotherapy, which has three N-glycosylation sites and one O-glycosylation site. It contains a variety of different glycosylation modifications, such as sialyation, O-acetylation on sialic acids, etc., which causes a big challenge for the glycosylation analysis of rhEPO. In this study, a liquid chromatography-mass spectrometry (LC-MS) method combined with electron-activated dissociation (EAD) technology was used in qualitative and quantitative characterization of rhEPO N-glycosylation and O-glycosylation in just one injection. The usage of EAD not only generated abundant MS/MS fragment ions of glycopeptides and improved the MS/MS sequence coverage but also preserved the glycan structures in the MS/MS fragment ions and the integrity of the glycosidic bond between the glycans and peptides. Three N-glycosylation sites (N24, N38, and N83) and one O-glycosylation site (S126) of rhEPO samples were successfully identified. Among them, the glycosylation ratios of N24, N38, and N83 sites were 82.7%, 100%, and 100% respectively, and 15, 10, and 12 different N-glycans could be identified at the glycopeptide level. The total average number of sialic acids, N-hydroxyacetylneuraminoic acid, and O-acetylation on sialic acid were 7.28, 4.21, and 0.66 at the intact protein level, respectively. For O-glycosylation site S126, O-glycosylation ratios analyzed at the intact protein level and the glycopeptide level were 80.2% and 80.3%, respectively, and two O-glycans were identified, including Core1_S1 and Core1_S2. This study also compared the difference of the glycans and their relative contents in batch-to-batch rhEPO samples. The results proved that the workflow using EAD fragmentation in LC-MS method could be effectively applied for characterizing the glycosylation analysis of rhEPO samples and batch-to-batch consistency analysis, which would help to reasonably guide the optimization of rhEPO production process.
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Three new polyhydroxylated spirostanol steroidal saponins, dulongenosides B-D (2-4), along with 14 known compounds, dulongenoside A (1), padelaoside B (5), parisyunnanoside G (6), polyphyllin D (7), ophiopogonin C' (8), formosanin C (9), dioscin (10), paris saponin VII (11), paris H (12), parisyunnanoside I (13), protodioscin (14), proprotogracillin (15), crustecdysone (16), and stigmasterol-3-O-ß-d-glucopyranoside (17), were isolated from the rhizomes of Paris dulongensis (Melanthiaceae). Their chemical structures were elucidated based on extensive analyses of NMR and MS data and acidic hydrolyses. The isolates were evaluated for their cytotoxicity to five human cancer cell lines (HL-60, SW480, MDA-MB-231, A549, and A549/Taxol) and the normal human bronchial epithelial cell line BEAS-2B by the MTS test. Compounds 7-12 and 14 showed cytotoxic activity, with IC50 values ranging from 0.20 to 4.35â µM. Proprotogracillin selectively inhibited A549 (IC50=0.58â µM) and A549/Taxol (IC50=0.74â µM) cells, with no significant cytotoxic activity against HL-60, SW480, MDA-MB-231, or BEAS-2B cells, with IC50 values greater than 40â µM.
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Antineoplásicos Fitogénicos , Ensayos de Selección de Medicamentos Antitumorales , Melanthiaceae , Rizoma , Saponinas , Espirostanos , Humanos , Saponinas/aislamiento & purificación , Saponinas/farmacología , Saponinas/química , Rizoma/química , Melanthiaceae/química , Espirostanos/química , Espirostanos/aislamiento & purificación , Espirostanos/farmacología , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Conformación Molecular , Relación Dosis-Respuesta a DrogaRESUMEN
The Ras-mitogen-activated protein kinase (MAPK) pathway is a major target for cancer treatment. To better understand the genetic pathways that modulate cancer cell sensitivity to MAPK pathway inhibitors, we performed a CRISPR knockout screen with MAPK pathway inhibitors on a colorectal cancer (CRC) cell line carrying mutant KRAS. Genetic deletion of the catalytic subunit of protein phosphatase 6 (PP6), encoded by PPP6C, rendered KRAS- and BRAF-mutant CRC and BRAF-mutant melanoma cells more resistant to these inhibitors. In the absence of MAPK pathway inhibition, PPP6C deletion in CRC cells decreased cell proliferation in two-dimensional (2D) adherent cultures but accelerated the growth of tumor spheroids in 3D culture and tumor xenografts in vivo. PPP6C deletion enhanced the activation of nuclear factor κB (NF-κB) signaling in CRC and melanoma cells and circumvented the cell cycle arrest and decreased cyclin D1 abundance induced by MAPK pathway blockade in CRC cells. Inhibiting NF-κB activity by genetic and pharmacological means restored the sensitivity of PPP6C-deficient cells to MAPK pathway inhibition in CRC and melanoma cells in vitro and in CRC cells in vivo. Furthermore, a R264 point mutation in PPP6C conferred loss of function in CRC cells, phenocopying the enhanced NF-κB activation and resistance to MAPK pathway inhibition observed for PPP6C deletion. These findings demonstrate that PP6 constrains the growth of KRAS- and BRAF-mutant cancer cells, implicates the PP6-NF-κB axis as a modulator of MAPK pathway output, and presents a rationale for cotargeting the NF-κB pathway in PPP6C-mutant cancer cells.
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Sistema de Señalización de MAP Quinasas , FN-kappa B , Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , FN-kappa B/metabolismo , FN-kappa B/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Animales , Línea Celular Tumoral , Mutación , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Melanoma/genética , Melanoma/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Ratones DesnudosRESUMEN
Background: Pulmonary alveolar microlithiasis (PAM) is a rare disease whose clinical and imaging manifestations are non-specific, characterized by the deposition of microliths, which primarily consist of calcium and phosphorus, within the alveoli. In the cases of PAM, patients combined with calcification of other organs such as gastric mucosal calcification are less common. Case presentation: A 59-year-old woman was admitted to our hospital due to cough producing white, foamy sputum, accompanied by dyspnea and fever for 20 days. The CT scan showed diffuse ground-glass opacities and calcification of the gastric mucosa. Lung tissue biopsy revealed the presence of calcification and granulomatous foreign bodies in the interstitium and alveolar cavity. In the later stages, she developed painful skin petechiae. For this patient, the diagnosis of PAM, gastric mucosal calcification, and purpura fulminans was made. However, the genetic test results hinted that the patient and her son had a heterozygous mutation in the FBN1 gene, but her daughter's genetic test results were normal. Although the patient received anti-infection treatment, steroids, and oxygen therapy, her condition did not improve. Conclusion: We reported a rare case of PAM combined with calcification of other organs and purpura fulminans. Treatment of steroids did not show any benefit. The causative mechanism and effective treatment of this disease remain unclear. More treatments need to be explored.
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Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.
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Quinasa de Linfoma Anaplásico , Dibenzocicloheptenos , Farnesiltransferasa , GTP Fosfohidrolasas , MicroARNs , Neuroblastoma , Piperidinas , Inhibidores de Proteínas Quinasas , Piridinas , Animales , Femenino , Humanos , Ratones , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Farnesiltransferasa/antagonistas & inhibidores , Farnesiltransferasa/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , MicroARNs/genética , MicroARNs/metabolismo , Mutación , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Neuroblastoma/patología , Neuroblastoma/metabolismo , Piperidinas/farmacología , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Matrix metalloproteinase 13 (MMP13) is an extracellular matrix protease that affects the progression of atherosclerotic plaques and arterial thrombi by degrading collagens, modifying protein structures and regulating inflammatory responses, but its role in deep vein thrombosis (DVT) has not been determined. The purpose of this study was to investigate the potential effects of MMP13 and MMP13-related genes on the formation of DVT. METHODS: We altered the expression level of MMP13 in vivo and conducted a transcriptome study to examine the expression and relationship between MMP13 and MMP13-related genes in a mouse model of DVT. After screening genes possibly related to MMP13 in DVT mice, the expression levels of candidate genes in human umbilical vein endothelial cells (HUVECs) and the venous wall were evaluated. The effect of MMP13 on platelet aggregation in HUVECs was investigated in vitro. RESULTS: Among the differentially expressed genes, interleukin 1 beta, podoplanin (Pdpn), and factor VIII von Willebrand factor (F8VWF) were selected for analysis in mice. When MMP13 was inhibited, the expression level of PDPN decreased significantly in vitro. In HUVECs, overexpression of MMP13 led to an increase in the expression level of PDPN and induced platelet aggregation, while transfection of PDPN-siRNA weakened the ability of MMP13 to increase platelet aggregation. CONCLUSIONS: Inhibiting the expression of MMP13 could reduce the burden of DVT in mice. The mechanism involves downregulating the expression of Pdpn through MMP13, which could provide a novel gene target for DVT diagnosis and treatment.
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Trombosis de la Vena , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Metaloproteinasa 13 de la Matriz/genética , Agregación Plaquetaria , Trombosis de la Vena/genéticaRESUMEN
Learning and memory require activity-induced changes in dendritic translation, but which mRNAs are involved and how they are regulated are unclear. In this study, to monitor how depolarization impacts local dendritic biology, we employed a dendritically targeted proximity labeling approach followed by crosslinking immunoprecipitation, ribosome profiling and mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG caused rapid reprogramming of dendritic protein expression, where changes in dendritic mRNAs and proteins are weakly correlated. For a subset of pre-localized messages, depolarization increased the translation of upstream open reading frames (uORFs) and their downstream coding sequences, enabling localized production of proteins involved in long-term potentiation, cell signaling and energy metabolism. This activity-dependent translation was accompanied by the phosphorylation and recruitment of the non-canonical translation initiation factor eIF4G2, and the translated uORFs were sufficient to confer depolarization-induced, eIF4G2-dependent translational control. These studies uncovered an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 couples activity to local dendritic remodeling.
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Dendritas , Factor 4G Eucariótico de Iniciación , Sistemas de Lectura Abierta , Biosíntesis de Proteínas , Animales , Ratones , Células Cultivadas , Dendritas/metabolismo , Factor 4G Eucariótico de Iniciación/metabolismo , Neuronas/metabolismo , Sistemas de Lectura Abierta/genética , Cloruro de Potasio/farmacología , Biosíntesis de Proteínas/fisiologíaRESUMEN
Heat capacity is a fundamental thermodynamic property of a substance. Although heat capacity values and related thermodynamic functions are available for many materials, low-temperature heat capacity measurements, especially for novel materials, can still provide valuable insights for research in physics, chemistry, thermodynamics, and other fields. Reliable low-temperature heat capacity data are typically measured using classical adiabatic calorimeters, which use liquid helium as the refrigerant to provide a cryogenic environment for heat capacity measurements. However, liquid helium is not only expensive but also not easy to obtain, which greatly limits the application of adiabatic calorimetry. In this work, an accurate adiabatic calorimeter equipped with a Gifford-MacMahon refrigerator was designed and constructed for measuring the heat capacity of condensed matter in the temperature range from 4 to 100 K. The Gifford-MacMahon refrigerator was utilized to provide a stable liquid helium-free cryogenic environment. A simple mechanical thermal switch assembly was designed to facilitate switching between the refrigeration mode and the adiabatic measurement mode of the calorimeter. Based on the measurement results of standard reference materials, the optimized repeatability and accuracy of heat capacity measurements were determined to be within 0.8% and 1.5%, respectively. The heat capacity of α-Fe2O3 nanoparticles was also investigated with this device. Furthermore, this adiabatic calorimeter only requires electricity to operate in the liquid helium temperature range, which may significantly advance the research on low-temperature heat capacity based on adiabatic calorimetry.
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Background: Home beauty devices for facial rejuvenation utilizing technologies such as radiofrequency, microcurrent, and light emitting diode have gained widespread attention due to their claimed ability to improve skin tightness and elasticity, making them popular among consumers. However, there is controversy within the industry regarding the effectiveness and safety of these devices. Objective: This study aims to verify the safety and effectiveness of these home beauty devices in treating skin aging based on relevant efficacy evaluation indicators. Methods: A systematic search of PubMed and web of science was conducted to include original research literature on the efficacy of home beauty devices for facial rejuvenation over the past two decades. The selected literature was processed and analyzed based on efficacy evaluation indicators such as sample size, follow-up period, experimental results, adverse reactions, and others. Results: After screening, a total of 18 clinical studies were included. A comprehensive analysis of the experimental results and adverse reaction indicators from existing literature revealed that home beauty devices for facial rejuvenation can improve skin aging to a certain extent. Apart from transient redness and swelling, no other adverse reactions were observed. Conclusion: Despite the variety of home beauty devices for facial rejuvenation available in the market, corresponding research reports are limited. Existing studies suffer from issues such as small sample sizes and short follow-up periods, highlighting the need for a more comprehensive efficacy evaluation system. Furthermore, the physical stimulation of meridian acupoints by home beauty devices for facial rejuvenation may meet the multi-dimensional anti-aging needs of patients, suggesting a potential direction for future research.
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The properties of the cell types that are selectively vulnerable in Huntington's disease (HD) cortex, the nature of somatic CAG expansions of mHTT in these cells, and their importance in CNS circuitry have not been delineated. Here, we employed serial fluorescence-activated nuclear sorting (sFANS), deep molecular profiling, and single-nucleus RNA sequencing (snRNA-seq) of motor-cortex samples from thirteen predominantly early stage, clinically diagnosed HD donors and selected samples from cingulate, visual, insular, and prefrontal cortices to demonstrate loss of layer 5a pyramidal neurons in HD. Extensive mHTT CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layers 6a and 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somatic mHTT CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in HD cerebral cortex.
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Enfermedad de Huntington , Animales , Enfermedad de Huntington/metabolismo , Neuronas/metabolismo , Células Piramidales/metabolismo , Corteza Cerebral/metabolismo , Núcleo Solitario/metabolismo , Modelos Animales de Enfermedad , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismoRESUMEN
BACKGROUND: With the advancement of diagnostic technology, true acute undifferentiated leukemia (AUL) is becoming more rare, and AUL with extramedullary sarcoma has not been reported. CASE PRESENTATION: This article reports a case of AUL with extramedullary sarcoma. Flow cytometric analysis of the bone marrow and lymph nodes indicated that the tumor cells of both were of the same origin and mainly expressed stem cell markers and CD7, no myeloid-specific markers, T-lymphoblastic-related markers, and B-lymphoblastic-related markers. Although the priming regimen combined with azacitidine was ineffective, complete remission was achieved by switching to azacitidine combined with HIA (homoharringtonine, idarubicin plus Ara-C). CONCLUSION: To diagnosis de novo acute leukemia with extensive and comprehensive cellular immune maker detection is available and credible, the expression of a single relatively nonspecific myeloid antigen as a immune maker to detect AUL or AUL associated with sarcoma is precise and effective in our case, which patient was benefit from HIA regiment.
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Leucemia Mieloide Aguda , Leucemia , Sarcoma Mieloide , Humanos , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/tratamiento farmacológico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia/diagnóstico , Médula Ósea/patología , Enfermedad Aguda , AzacitidinaRESUMEN
INTRODUCTION: Machine learning (ML) can optimize amyloid (Aß) comparability among positron emission tomography (PET) radiotracers. Using multi-regional florbetapir (FBP) measures and ML, we report better Pittsburgh compound-B (PiB)/FBP harmonization of mean-cortical Aß (mcAß) than Centiloid. METHODS: PiB-FBP pairs from 92 subjects in www.oasis-brains.org and 46 in www.gaain.org/centiloid-project were used as the training/testing sets. FreeSurfer-extracted FBP multi-regional Aß and actual PiB mcAß in the training set were used to train ML models generating synthetic PiB mcAß. The correlation coefficient (R) between the synthetic/actual PiB mcAß in the testing set was assessed. RESULTS: In the testing set, the synthetic/actual PiB mcAß correlation R = 0.985 (R2 = 0.970) using artificial neural network was significantly higher (p ≤ 6.6e-4) than the FBP/PiB correlation R = 0.927 (R2 = 0.860), improving total variance percentage (R2 ) from 86% to 97%. Other ML models such as partial least square, ensemble, and relevance vector regressions also improved R (p = 9.677e-05 /0.045/0.0017). DISCUSSION: ML improved mcAß comparability. Additional studies are needed for the generalizability to other amyloid tracers, and to tau PET. Highlights Centiloid is a calibration of the amyloid scale, not harmonization. Centiloid unifies the amyloid scale without improving inter-tracer association (R2 ). Machine learning (ML) can harmonize the amyloid scale by improving R2 . ML harmonization maps multi-regional florbetapir SUVRs to PiB mean-cortical SUVR. Artificial neural network ML increases Centiloid R2 from 86% to 97%.
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Enfermedad de Alzheimer , Tomografía de Emisión de Positrones , Humanos , Tomografía de Emisión de Positrones/métodos , Compuestos de Anilina , Glicoles de Etileno , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Amiloide/metabolismo , Proteínas Amiloidogénicas , Placa Amiloide , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagenRESUMEN
Touch induces marked morphological changes in plants, including reduced rosette diameters and delayed flowering, a process called thigmomorphogenesis. Previous studies have revealed that thigmomorphogenesis in Arabidopsis (Arabidopsis thaliana) results from touch-induced accumulation of jasmonic acid (JA) and GIBBERELLIN 2-OXIDASE7 (GA2ox7) transcripts, which encode a gibberellin (GA) catabolism enzyme, leading to reduced levels of active GAs. However, the mechanisms underlying thigmomorphogenesis remain uncharacterized. Here, we showed that touch induces ethylene (ET) production in Arabidopsis. After touch treatment, ET biosynthesis and signaling mutants exhibited even greater thigmomorphogenic changes and more decreased GA4 contents than did wild-type (WT) plants. Biochemical analysis indicated that the transcription factor ETHYLENE INSENSITIVE3 (EIN3) of the ET pathway binds to the promoter of GA2ox8 (encoding another GA 2-oxidase performing the same GA modification as GA2ox7) and represses GA2ox8 transcription. Moreover, MYC2, the master regulator of JA signaling, directly promoted GA2ox7 expression by binding the G-box motif on GA2ox7 promoter. Further genetic analysis suggested that the ET and JA pathways independently control the expression of GA2ox8 and GA2ox7, respectively. This study reveals that the ET pathway is a novel repressor of touch-induced thigmomorphogenesis and highlights that the ET and JA pathways converge on GA catabolism but play opposite roles to fine-tune GA4 content during thigmomorphogenesis.