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Glucocorticoids are key components of the current standard-of-care regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for treatment of B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. CD19 displays restricted expression in normal B-cells and is up-regulated in B-cell malignancies. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicities while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced Fc-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven anti-tumor activity against multiple malignant B-cell lines in vitro as well as in cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic prednisolone at the maximum tolerated dose (MTD) in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed anti-proliferative activity on a subset of B-cell lymphoma cell lines through the inhibition of PI3K signaling. Moreover, afucosylation of the CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payloads. Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ PBMC-engrafted NSG-tg(Hu-IL15) transgenic mice, demonstrating enhanced anti-tumor activity when multiple MOAs are enabled. ABBV-319 also showed durable anti-tumor activity across multiple B-cell lymphoma PDX models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma post R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in Phase I clinical trial (NCT05512390).
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The placenta plays a crucial role in pregnancy success. ΔNp63α (p63), a transcription factor from the TP53 family, is highly expressed in villous cytotrophoblasts (CTBs), the epithelial stem cells of the human placenta, and is involved in CTB maintenance and differentiation. We examined the mechanisms of action of p63 by identifying its downstream targets. Gene expression changes were evaluated following overexpression and knockdown of p63 in the JEG3 choriocarcinoma cell line, using microarray-based RNA profiling. High-temperature requirement A4 (HTRA4), a placenta-specific serine protease involved in trophoblast differentiation and altered in preeclampsia, was identified as a gene reciprocally regulated by p63, and its expression was characterized in primary human placental tissues by RNA-sequencing and in situ hybridization. Potential p63 DNA-binding motifs were identified in the HTRA4 promoter, and p63 occupancy at some of these sites was confirmed using chromatin immunoprecipitation, followed by quantitative PCR in both JEG3 and trophoblast stem cells. These data begin to identify members of the transcriptional network downstream of p63, thus laying the groundwork for probing mechanisms by which this important transcription factor regulates trophoblast stemness and differentiation.
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Fatores de Transcrição , Trofoblastos , Humanos , Trofoblastos/metabolismo , Feminino , Gravidez , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Serina Endopeptidases/metabolismo , Serina Endopeptidases/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Placenta/metabolismo , Serina Proteases/metabolismo , Serina Proteases/genética , Regiões Promotoras Genéticas/genética , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Transcrição GênicaRESUMO
BACKGROUND AND AIM: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining "high-risk" have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. APPROACH AND RESULTS: The derivation cohort included 1554 patients with cirrhosis and AVB who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in patients treated with endoscopy plus drugs, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y concordance-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c -for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 patients with cirrhosis with AVB from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). CONCLUSIONS: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.
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Varizes Esofágicas e Gástricas , Derivação Portossistêmica Transjugular Intra-Hepática , Humanos , Varizes Esofágicas e Gástricas/etiologia , Prognóstico , Modelos Estatísticos , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/prevenção & controle , Cirrose Hepática/etiologia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversosRESUMO
In traditional luminol electrochemiluminescence (ECL) systems, hydrogen peroxide (H2O2) and dissolved oxygen (DO) are the commonly used coreactants to generate reactive oxygen species (ROS) for ECL emission. However, the self-decomposition of hydrogen peroxide and the limited solubility and content of oxygen in solution undoubtedly restrict the luminescence efficiency and stability of the luminol ECL system. Inspired by the ROS-mediated ECL mechanism, we pioneered hydroxide ion as an advanced luminol ECL coreactant using nickel-doped and carbon nanotube-modified tungsten oxide (Ni-WOx-CNT) as the coreactant accelerator. Owing to the excellent catalytic activity of Ni-WOx-CNT, amounts of ROS were generated from OH- at a low excitation voltage, which subsequently reacted with luminol anion radicals and triggered intense ECL signals. Experiments confirmed an impressive ECL behavior in terms of high luminescent intensity (85,563 a.u.) and super stability over 1300 consecutive tests; both are superior to those recently reported luminol-H2O2 and luminol-DO systems with smaller ECL intensities and consecutive tests less than 25 times. To validate the feasibility and versatility of the developed system in sensor, traditional three-electrodes system and closed bipolar electrodes system with various sensing strategies of direct oxidation, "gate-effect" of molecularly imprinted polymer, immune reaction, and enzyme-catalyzed reaction were proposed to monitor uric acid (UA), C-reactive protein (CRP), immunoglobulin G (IgG), and glucose (Glu). The superior sensing performances confirmed the great application potential of the developed ROS-mediated ECL system.
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Point of care testing (POCT) of nucleic acid (NA) contributes to the timely disease diagnosis, like bacteria and virus screening in households or resource-constrained areas, but its development has always been stagnant. Herein, we proposed an exonuclease III cascaded with CRISPR/Cas12a (Exo-III/Cas12a) amplification strategy and constructed a smartphone-based portable fluorescence detector (SPFD) to repurpose the commercial alpha-fetoprotein (AFP) strip for the ultrasensitive and hand-held detection of NA samples. In detail, the target-initiated-Exo-III/Cas12a strategy realizes the signal amplification and liberates AFP from magnetic beads through the trans-cleavages of activated Cas12a toward the AFP aptamer. After magnetic separation and migration, the fluorescence signals of the test (FT) and control (FC) lines on the AFP strip were digitally output by the SPFD, and the FT/FC was employed for the quantitative analysis to minimize external disturbances and improve accuracy. We experimentally assessed the universe applicability of the proposed NA-POCT platform toward miRNA-155, 16S rRNA of Staphylococcus aureus, and ORF1a/b RNA of Covid-19 pseudovirus, achieving favorable detection limits of 42 aM, 18 CFU/mL, and 87 copies/µL, respectively. Moreover, its simplicity, universality, and admirable detection performance demonstrate a great potential in the aspect of rapidly transforming the existing POCT devices for multiple new applications at the time of need.
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Exodesoxirribonucleases , Técnicas de Amplificação de Ácido Nucleico , Testes Imediatos , Smartphone , alfa-Fetoproteínas , alfa-Fetoproteínas/análise , Exodesoxirribonucleases/metabolismo , Exodesoxirribonucleases/química , Humanos , Sistemas CRISPR-Cas , Fluorescência , Proteínas Associadas a CRISPR/metabolismo , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/genética , Limite de Detecção , Técnicas Biossensoriais/métodos , RNA Viral/análise , Espectrometria de Fluorescência , Proteínas de Bactérias , EndodesoxirribonucleasesRESUMO
Molecular imprinting techniques have attracted a lot of attention as a potential biomimetic technology, but there are still challenges in protein imprinting. Herein, multifunctional nanosized molecularly imprinted polymers (nanoMIPs) for human angiotensin-converting enzyme 2 (ACE2) were prepared by epitope imprinting of magnetic nanoparticles-anchored peptide (magNP-P) templates, which were further applied to construct a competitive displacement fluorescence assay toward ACE2. A cysteine-flanked dodecapeptide sequence was elaborately selected as an epitope for ACE2, which was immobilized onto the surface of magnetic nanoparticles and served as a magNP-P template for imprinting. During polymerization, fluorescent monomers were introduced to endow fluorescence responsiveness to the prepared self-signaling nanoMIPs. A competitive displacement fluorescence assay based on the nanoMIPs was established and operated in a washing-free manner, yielding a wide range for ACE2 (0.1-6.0 pg/mL) and a low detection limit (0.081 pg/mL). This approach offers a promising avenue in the preparation of nanoMIPs for macromolecule recognition and expands potential application of an MIP in the detection of proteins as well as peptides.
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Enzima de Conversão de Angiotensina 2 , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/química , Impressão Molecular , Nanopartículas de Magnetita/química , Polímeros Molecularmente Impressos/química , Limite de Detecção , Peptídeos/química , Peptídeos/metabolismoRESUMO
Peptide-based supramolecules exhibit great potential in various fields due to their improved target recognition ability and versatile functions. However, they still suffer from numerous challenges for the biopharmaceutical analysis, including poor self-assembly ability, undesirable ligand-antibody binding rates, and formidable target binding barriers caused by ligand crowding. To tackle these issues, a "polyvalent recognition" strategy employing the CD20 mimotope peptide derivative NBD-FFVLR-GS-WPRWLEN (acting on the CDR domains of rituximab) was proposed to develop supramolecular nanofibers for target antibody recognition. These nanofibers exhibited rapid self-assembly within only 1 min and robust stability. Their binding affinity (179 nM) for rituximab surpassed that of the monomeric peptide (7 µM) by over 38-fold, highlighting that high ligand density and potential polyvalent recognition can efficiently overcome the target binding barriers of traditional supramolecules. Moreover, these nanofibers exhibited an amazing "instantaneous capture" rate (within 15 s), a high recovery (93 ± 3%), and good specificity for the target antibody. High-efficiency enrichment of rituximab was achieved from cell culture medium with good recovery and reproducibility. Intriguingly, these peptide nanofibers combined with bottom-up proteomics were successful in tracking the deamidation of asparagine 55 (from 10 to 16%) on the rituximab heavy chain after 21 day incubation in human serum. In summary, this study may open up an avenue for the development of versatile mimotope peptide supramolecules for biorecognition and bioanalysis of biopharmaceuticals.
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Produtos Biológicos , Nanofibras , Humanos , Rituximab , Nanofibras/química , Ligantes , Reprodutibilidade dos Testes , Peptídeos/químicaRESUMO
Viral infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are some of the most dangerous threats to humans. SARS-CoV-2 has caused a global pandemic, highlighting the unprecedented demand for rapid and portable diagnostic methods. To meet these requirements, we designed a label-free colorimetric platform that combines the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) 12a system for naked-eye detection (named LFP). This method utilizes reverse transcription loop-mediated isothermal amplification (RT-LAMP) and the trans-cleavage activity of the CRISPR/Cas12a system to increase the sensitivity and specificity of the reaction. This platform can detect as few as 4 copies/µL of RNA and produces no false positive results when tested against the influenza virus. To better meet the requirements of point-of-care (POC) detection, we developed a portable device that can be applied in resource-poor and densely populated regions. The LFP assay holds great potential for application in resource-limited settings, and the label-free gold nanoparticle (AuNPs) probe can reduce costs, making it suitable for large-scale screening. We expect that the LFP assay will be promising for the POC screening of COVID-19.
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Colorimetria , Ouro , Nanopartículas Metálicas , Técnicas de Amplificação de Ácido Nucleico , RNA Viral , SARS-CoV-2 , Ouro/química , Colorimetria/métodos , Colorimetria/instrumentação , Nanopartículas Metálicas/química , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , RNA Viral/análise , RNA Viral/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Técnicas de Amplificação de Ácido Nucleico/instrumentação , Humanos , COVID-19/diagnóstico , COVID-19/virologia , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas de Diagnóstico MolecularRESUMO
The current treatment for osteosarcoma (OS) is based on surgery combined with systemic chemotherapy, however, gene therapy has been hypothesized to improve patient survival rates. The density-enhanced protein domain 1 protein (DEPDC1) functions as a crucial determinant in the advancement of OS, which is highly expressed in OS cells. The current study was designed to delve into the effect and mechanism of DEPDC1 and phosphotyrosine-picked threonine tyrosine kinase (TTK) in OS. The expression of DEPDC1 and TTK in OS cells was detected by western blotting. Furthermore, the assessment of glycolysis encompassed the quantification of extracellular acidification rate, glucose uptake rate, lactate concentration, and the expression of glucose transporter 1, hexokinase 2, and pyruvate kinase M2. Finally, the functions of DEPDC1 and TTK in autophagy and ras-extracellular signal-regulated kinase signaling were determined by western blotting after interfering with DEPDC1 in SaOS-2 cells. The results revealed that DEPDC1 and TTK were upregulated in OS cell lines and interfering with DEPDC1 inhibited glycolysis and autophagy in OS cells. Furthermore, the STRING database suggested that DEPDC1 and TTK perform targeted binding. Notably, the results of the present study revealed that DEPDC1 upregulated RAS expression through TTK and enhanced ERK activity, thereby affecting glycolysis and autophagy in OS cells. Collectively, the present investigation demonstrated that DEPDC1 affected autophagy-dependent glycolysis levels of OS cells by regulating RAS/ERK signaling through TTK.
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LiDAR offers a wide range of uses in autonomous driving, remote sensing, urban planning, and other areas. The laser 3D point cloud acquired by LiDAR typically encounters issues during registration, including laser speckle noise, Gaussian noise, data loss, and data disorder. This work suggests a novel Student's t-distribution point cloud registration algorithm based on the local features of point clouds to address these issues. The approach uses Student's t-distribution mixture model (SMM) to generate the probability distribution of point cloud registration, which can accurately describe the data distribution, in order to tackle the problem of the missing laser 3D point cloud data and data disorder. Owing to the disparity in the point cloud registration task, a full-rank covariance matrix is built based on the local features of the point cloud during the objective function design process. The combined penalty of point-to-point and point-to-plane distance is then added to the objective function adaptively. Simultaneously, by analyzing the imaging characteristics of LiDAR, according to the influence of the laser waveform and detector on the LiDAR imaging, the composite weight coefficient is added to improve the pertinence of the algorithm. Based on the public dataset and the laser 3D point cloud dataset acquired in the laboratory, the experimental findings demonstrate that the proposed algorithm has high practicability and dependability and outperforms the five comparison algorithms in terms of accuracy and robustness.
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AIM: To assess heart rate variability (HRV) as a measure to assess job stress and sleep quality among nurses in the post-COVID-19 period. BACKGROUND: The COVID-19 pandemic significantly affected nurses, with heightened job stress and impaired sleep quality impacting their well-being and effectiveness in patient care. HRV could offer insights for supporting strategies in the pandemic aftermath. DESIGN: A quantitative cross-sectional study. METHODS: This study involved 403 clinical nurses recruited from a teaching hospital in Taiwan. Data on job stress, work frustration, sleep quality and HRV were collected and analysed. RESULTS: Among the nurses surveyed during the COVID-19 pandemic, 72.7% reported poor sleep quality (PSQI = 9.369). Job stress emerged as a strong predictor of work frustration. High stress levels and poor sleep quality were correlated with significantly decreased HRV, indicating a potential physiological impact of stress on the nurses' health and well-being. CONCLUSIONS: HRV is a valuable and cost-effective measure for monitoring and managing nurses' well-being in the post-COVID-19 era. Targeted interventions can be implemented to support nurses' overall performance and promote their well-being by identifying those at high risk of job stress and poor sleep quality.
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We describe a new kudoid species, Kudoa tanakai n. sp., in the scalpel sawfish, Prionurus scalprum (Actinopterygii: Acanthuriformes: Acanthuridae), from the natural water around western Japan. The plasmodia were filamentous, localized in pseudocysts in the myofibers of the trunk muscles. The occurrence of plasmodia in the trunk muscle showed no site preference. Its myxospores were spheroid, measuring 6.6-7.6 (7.0) µm by 5.8-6.9 (6.3) µm in apical view (width) and 5.7-6.6 (6.2) in length (n = 30), with four shell valves and a corresponding number of spheroid polar capsules. Shell valves lacked apical protrusions, but scanning electron microscopy revealed that one of the four shell valves had two semi-lunar flaps at its apical terminus. Nucleotide sequencing of the small and large subunit ribosomal RNA genes of the present isolate showed phylogenetic affinities to kudoid species characterized by spheroid myxospores, such as K. musculoliquefaciens, K. hemiscylli, and K. carcharhini, but was molecularly and morphometrically distinct from these and other kudoid species. For direct comparison, Kudoa hemiscylli was collected from the Pacific spadenose shark, Scoliodon macrorhynchos (Elasmobranchii: Carcharhiniformes: Carcharhinidae), in the South China Sea off Guangdong Province, China, and the myxospore surface of the species was observed using scanning electron microscopy. Our study describes the new host and distribution record of this kudoid species originally described from a variety of elasmobranchs in the Australian Coral Sea.
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Myxozoa , Perciformes , Tubarões , Animais , Myxozoa/genética , Japão , Filogenia , Austrália , Especificidade da Espécie , PeixesRESUMO
Eight Eimeria spp. (Apicomplexa: Eimeriidae) have been isolated from the ring-necked pheasant (Phasianus colchicus Linnaeus), native to the temperate zone of Asia and eastern regions of Europe. Enteric coccidiosis has become a major issue associated with the breeding of farmed pheasants for game bird release or meat production. In this study, 35 fecal samples were collected from two-to-three-month-old ring-necked pheasants from four pheasant-rearing farms in Ehime Prefecture, Japan. Microscopic examination using a saturated sugar solution technique detected numerous subspherical oocysts from the samples of one farm and ellipsoidal Eimeria phasiani Tyzzer, 1929 oocysts from the three other farms. The subspherical oocysts were artificially sporulated and measured 18.6 µm by 15.7 µm with a 1.18 shape index (n = 150). Each oocyst contained four 10.7 µm × 5.8 µm sporocysts (n = 30) and one coarse refractile polar granule; no micropyle or residua were detected. Each sporocysts contained two sporozoites with one large and one small refractile body and sparsely distributed residua. The complete, 1,443-bp cytochrome c oxidase subunit I gene (cox1) of this isolate exhibited low sequence identity with published Eimeria spp. sequences including E. phasiani that was previously recorded in the same area. Meanwhile, the oocyst morphology most closely resembled that of Eimeria tetartooimia Wacha, 1973, but with distinct refractile polar granules and sporocyst residua. The available GenBank cox1 sequence of E. tetartooimia exhibited a sequence identity of < 94.5% with the study isolate. Here, the coccidian isolate identified in this study represents a new Eimeria iyoensis n. sp. capable of infecting ring-necked pheasant.
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Eimeria , Galliformes , Animais , Eimeria/classificação , Eimeria/genética , Eimeria/citologia , Galliformes/parasitologia , Japão , Filogenia , Oocistos/citologia , Especificidade da Espécie , Fezes/parasitologia , Coccidiose/parasitologia , Coccidiose/veterináriaRESUMO
Accurate and in-time detection of bacteria conduces to preventing their rapid spread around the environment, while a nucleic acid test (NAT) is a powerful tool for early diagnosis of pathogens. Herein, we propose a hybridization chain reaction (HCR)-mediated multisite exonuclease III (Exo-III) amplification strategy (HCR/Exo-III amplifier) to achieve the one-pot and ultrasensitive isothermal amplification of bacterial 16S rRNA and a portable fluorescence detection device (PFD) to directly read signals in a lateral flow assay (LFA). In detail, the target-initiated HCR products present multiple binding sites for triggering the Exo-III amplifier that produces numerous target amplicons. Following that, the target amplicons travel up on the strip and bridge between the DNA-CdTe/CdS probes and the capture DNA to form a positive fluorescence line. After that, the strip is inserted into the PFD to accomplish the fluorescence signal reading. The constructed HCR/Exo-III amplifier-based PFD-LFA implemented the simultaneous and specific detection of three bacteria with a detection limit of a few tenths of fM for synthetic 16S rRNA fragments and dozens of CFU/mL for Staphylococcus aureus, Listeria monocytogenes, and Salmonella typhimurium in pure cultures. The sensing platform features isothermal amplification, convenient operation, and good economy, displaying great potential for on-site testing toward multiple nucleic acid analytes.
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Técnicas Biossensoriais , Compostos de Cádmio , Pontos Quânticos , RNA Ribossômico 16S/genética , Telúrio , Hibridização de Ácido Nucleico , DNA/química , Exodesoxirribonucleases/metabolismo , Sondas de DNA , Técnicas de Amplificação de Ácido Nucleico/métodos , Limite de Detecção , Técnicas Biossensoriais/métodosRESUMO
The mechanisms by which neonatal inflammation leads to cognitive deficits in adulthood remain poorly understood. Inhibitory GABAergic synaptic transmission plays a vital role in controlling learning, memory and synaptic plasticity. Since early-life inflammation has been reported to adversely affect the GABAergic synaptic transmission, the aim of this study was to investigate whether and how neonatal inflammation affects GABAergic synaptic transmission resulting in cognitive impairment. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 µg/kg) or saline on postnatal days 3-5. It was found that blocking GABAergic synaptic transmission reversed the deficit in hippocampus-dependent memory or the induction failure of long-term potentiation in the dorsal CA1 in adult LPS mice. An increase of mIPSCs amplitude was further detected in adult LPS mice indicative of postsynaptic potentiation of GABAergic transmission. Additionally, neonatal LPS resulted in the increased expression and function of K+-Cl--cotransporter 2 (KCC2) and the decreased expression of transforming growth factor-beta 1 (TGF-ß1) in the dorsal CA1 during adulthood. The local TGF-ß1 overexpression improved KCC2 expression and function, synaptic plasticity and memory of adult LPS mice. Adult LPS mice show hypermethylation of TGFb1 promoter and negatively correlate with reduced TGF-ß1 transcripts. 5-Aza-deoxycytidine restored the changes in TGFb1 promoter methylation and TGF-ß1 expression. Altogether, the results suggest that hypermethylation-induced reduction of TGF-ß1 leads to enhanced GABAergic synaptic inhibition through increased KCC2 expression, which is a underlying mechanism of neonatal inflammation-induced hippocampus-dependent memory impairment in adult mice.
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Simportadores , Fator de Crescimento Transformador beta1 , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Metilação , Regulação para Baixo , Lipopolissacarídeos/metabolismo , Hipocampo/metabolismo , Plasticidade Neuronal , Transmissão Sináptica/fisiologia , Inflamação/metabolismo , Cognição , Simportadores/metabolismoRESUMO
Preeclampsia (PE) is a heterogeneous disease for which the current clinical classification system is based on the presence or absence of specific clinical features. PE-associated placentas also show heterogeneous findings on pathologic examination, suggesting that further subclassification is possible. We combined clinical, pathologic, immunohistochemical, and transcriptomic profiling of placentas to develop integrated signatures for multiple subclasses of PE. In total, 303 PE and 1388 nonhypertensive control placentas were included. We found that maternal vascular malperfusion (MVM) in the placenta was associated with preterm PE with severe features and with small-for-gestational-age neonates. Interestingly, PE placentas with either MVM or no histologic pattern of injury showed a linear decrease in proliferative (p63+) cytotrophoblast per villous area with increasing gestational age, similar to placentas obtained from the nonhypertensive patient cohort; however, PE placentas with fetal vascular malperfusion or villitis of unknown etiology lost this phenotype. This is mainly because of cases of fetal vascular malperfusion in placentas of patients with preterm PE and villitis of unknown etiology in placentas of patients with term PE, which are associated with a decrease or increase, respectively, in the cytotrophoblast per villous area. Finally, a transcriptomic analysis identified pathways associated with hypoxia, inflammation, and reduced cell proliferation in PE-MVM placentas and further subclassified this group into extravillous trophoblast-high and extravillous trophoblast-low PE, confirmed using an immunohistochemical analysis of trophoblast lineage-specific markers. Our findings suggest that within specific histopathologic patterns of placental injury, PE can be subclassified based on specific cellular and molecular defects, allowing the identification of pathways that may be targeted for diagnostic and therapeutic purposes.
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Patologia Clínica , Pré-Eclâmpsia , Feminino , Gravidez , Humanos , Trofoblastos , Placenta , Pré-Eclâmpsia/genética , TranscriptomaRESUMO
In recent years, hydrogels have attracted extensive attention in smart sensing owing to their biocompatibility and high elasticity. However, it is still a challenge to develop hydrogels with excellent multiple responsiveness for smart wearable sensors. In this paper, a facile synthesis of carbon quantum dots (CQDs)-doped cross-linked chitosan quaternary/carboxymethylcellulose hydrogels (CCCDs) is presented. Designing of dual network hydrogels decorated with CQDs provides abundant crosslinking and improves the mechanical properties of the hydrogels. The hydrogel-based strain sensor exhibits excellent sensitivity (gauge factor: 9.88), linearity (R2 : 0.97), stretchable ability (stress: 0.67 MPa; strain: 404%), good cyclicity, and durability. The luminescent properties are endowed by the CQDs further broaden the application of hydrogels for realizing flexible electronics. More interestingly, the strain sensor based on CCCDs hydrogel demonstrates photo responsiveness (ΔR/R0 ≈20%) and pH responsiveness (pH range ≈4-7) performance. CCCDs hydrogels can be used for gesture recognition and light sensing switch. As a proof-of-concept, a smart wearable sensor is designed for monitoring human activities and detecting pH variation in human sweat during exercise. This study reveals new possibilities for further applications in wearable health monitoring.
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Quitosana , Pontos Quânticos , Dispositivos Eletrônicos Vestíveis , Humanos , Carbono , Hidrogéis , Concentração de Íons de Hidrogênio , Condutividade ElétricaRESUMO
Pancreatic cancer is one of the most lethal tumors due to its rapid proliferation and aggressiveness. RAD51AP1 is a protein-coding gene with critical functions in many cancers but few studies have assessed RAD51AP1 in pancreatic cancer. Bioinformatics methods and cell function experiments were performed to reveal the functions of RAD51AP1 in vitro. Gene Expression Profiling Interactive Analysis (GEPIA) was used to explore key proteins and their relationships with RAD51AP1 in the PI3K/AKT/NF-κB signaling pathways. Western blotting (WB) was conducted to detect the expression of key proteins after the downregulation of RAD51AP1. Co-Immunoprecipitation (Co-IP) was applied to confirm the binding of RAD51AP1 and PI3K. In addition, the lentivirus was used to construct subcutaneous tumors in nude mice to verify the function of RAD51AP1 in vivo. The Kaplan-Meier curves illustrated that elevated expression levels of RAD51AP1 were significantly correlated with reduced overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in pancreatic cancer patients. The results of WB showed that several key proteins in the PI3K/AKT/NF-κB signaling pathway (including PI3K, AKT, IKK1, IKK2, P65, P50, C-FLIP, and XIAP) exhibited a significant knockdown upon reducing the expression of RAD51AP1. Co-IP suggested that RAD51AP1 could directly bind to PI3K. In vitro, CCK-8, wound healing, and Transwell assays revealed that high RAD51AP1 expression was significantly correlated with increased cell proliferation, migration, and invasion. In vivo, mouse tumor formation experiments showed that RAD51AP1 inhibition significantly inhibited tumor growth. RAD51AP1 plays an important role in fostering cellular proliferation, invasion, metastasis, and tumor enlargement via the PI3K/AKT/NF-κB signaling pathway.
Assuntos
NF-kappa B , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Camundongos Nus , NF-kappa B/metabolismo , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Food availability and climate represent environmental factors that affect species' social behavior, ranging patterns, diet, and activity budget. From August 2012 to September 2013, we examined the effects of seasonal changes in food availability, temperature, and rainfall on the diet and behavioral ecology of Shortridge's langur (Trachypithecus shortridgei) an Endangered primate species inhabiting moist evergreen broadleaf forests in the Eastern Himalayas. Our field site represents the northernmost latitudinal distribution of this species. Data were collected using scan sampling at 10 min intervals, and analyzed based on generalized linear models. The results indicate that the langurs experienced two feeding peaks (9:00 and 17:00) and two traveling peaks (10:00 and 19:00) during each day. Periods of rest, mainly occurred between 10:00 and 13:00, and overnight. Feeding accounted for 38.5% of the daily activity budget, followed by resting (35%), traveling (24.5%), and socializing (2%). During periods when young leaves were most available, the langurs increased feeding time on young leaves (35% vs. 4%). During periods of maximum fruit availability, the langurs decreased total time spent feeding (36.6% vs. 40.4%), devoted more time to traveling (28.1% vs. 21%), and increased time spent consuming fruit (49.1% vs. 11.8%). During the winter, the langurs increased their consumption of mature leaves (44.5%) and reduced time spent traveling (20.2% vs. 25.4%). Overall, time spent resting was greatest in the spring (47.5%), time spent feeding was greatest during the summer (51.1%), and time spent in traveling was greatest in the autumn (33.2%). The frequency of social interactions remained relatively constant throughout the year. Foraging effort was greatest in the summer, when fruits dominated the diet. Like other species of temperate langurs, T. shortridgei devoted less time to resting, more time to feeding, and was characterized by a greater year-round foraging effort than tropical/subtropical langurs.
Assuntos
Presbytini , Animais , Florestas , Dieta/veterinária , Frutas , Comportamento Social , China , Comportamento AlimentarRESUMO
Neonatal inflammation can increase the risk of anxiety disorder in adulthood. The balance between glutamatergic excitatory and GABAergic inhibitory transmissions in the basolateral amygdala (BLA) plays a vital role in controlling anxiety state. Based on the reports that early-life inflammation had adverse effects on GABAergic system, the aim of this study was to investigate whether and how neonatal inflammation affects excitatory-inhibitory circuits in the BLA resulting in anxiety disorder. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 µg/kg) or saline on postnatal days 3-5. LPS-treated mice developed anxiety behaviors accompanied by the hyperactivity of adrenal axis in adulthood. Electrophysiological study revealed the increase of postsynaptic neuronal excitability in the cortical-BLA excitatory synapses of LPS mice which could be recovered by bath-application of GABAAR agonist suggesting the impairment of GABAergic system in LPS mice. Compared with controls, GABAARα2 subunit expression and density of GABA-evoked current in BLA principal neurons were reduced in LPS mice. Additionally, neonatal LPS treatment resulted in the down-regulation of transforming growth factor-beta 1 (TGF-ß1) expression and PKC signaling pathway in the adult BLA. The local TGF-ß1 overexpression in the BLA improved GABAARα2 expression via up-regulating the activity of PKC signaling, which corrected GABAAR-mediated inhibition leading to the abolishment of anxiety-like change in adrenal axis regulation and behaviors in LPS mice. These data suggest the persistent TGF-ß1deficit induces the down-regulation of GABAARα2 expression and subsequent disruption of the excitation-inhibition balance in the BLA circuits, which is the important mechanisms of neonatal inflammation-induced anxiety disorder.