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BACKGROUND: Breast cancer (BC) remains the most commonly malignancy among women worldwide. Although early-stage BC typically presents with curative possibilities, advanced-stage disease, especially with metastasis, is significantly limited in terms of effective therapeutic interventions, thereby establishing it as the second leading cause of cancer-related deaths in women. Antibody-Drug Conjugates (ADCs) establish a groundbreaking class of anti-neoplastic agents characterized by high specificity and targeting precision. These agents have been significant in reshaping the therapeutic approach to breast cancer, especially those subtypes with overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2). Comprising monoclonal antibodies, cytotoxic payloads, and conjugative linkers, ADCs function by specifically targeting antigens on cancer cells, thereby facilitating the intracellular delivery of the toxic payload. The present investigation endeavors to synthesize existing primary research outcomes through rigorous bibliometric and data analytical approaches, thereby elucidating the current research landscape, delineating research foci, and identifying potential avenues for future innovation. METHODS: For bibliometric analysis, a comprehensive data set comprising 2181 entries related to ADCs in breast cancer was retrieved from the Web of Science Core Collection (WoSCC) spanning the years 1999 to 2023. This data was further filtered from the Science Citation Index Expanded (SCI-Expanded). Analysis software tools such as CiteSpace and VOSviewer were employed for multifaceted analyses such as trends of publications, contributions of countries, and burst analytics. In the dimension of clinical trials, we interrogated databases including ClinicalTrials.gov ( https://www. CLINICALTRIALS: gov ) and the WHO International Clinical Trials Registry Platform (ICTRP) ( https://trialsearch.who.int ). A total of 239 clinical trials were initially sourced, among which, 175 were from ClinicalTrials.gov and 64 from ICTRP. After repetitive and correlation-based screening, 119 trials specifically addressing ADC therapeutic strategies in breast cancer were included. Analytical algorithms were executed using Microsoft-based software to evaluate treatment paradigms, emergent research themes, and progress. RESULTS: Our investigations signify a growing trend of research on ADCs, with consistent advancements in scientific achievements. The analysis revealed that variables such as economic stratification of nations, healthcare investment paradigms, and disease incidence rates serve as significant determinants in shaping research output. Geographically, the United States emerged as the predominant contributor to the research corpus (36.56%), closely followed by China (21.33%). The underpinning of research accomplishments was found to be significantly bolstered by advancements in molecular biology, immunology, and genetic research. Moreover, the advent of nuclear magnetic resonance diagnostic modalities has contributed saliently to the diagnostic and therapeutic management of breast cancer. CONCLUSION: Our study provides a comprehensive overview of the ADC research landscape through rigorous bibliometric and clinical trial evaluations. At present, the ADC arena has witnessed the successful development and FDA approval of 14 distinct agents, substantially improving the clinical outcomes for a broad spectrum of oncological patients. Future research imperatives may include the exploration of ADCs targeting mutated oncoproteins, dual-specificity ADCs, combination payload strategies, peptide-drug conjugates (PDCs), and non-internalizing ADC modalities. With sustained academic and clinical focus, the ADC domain is poised for transformative advancements in targeted therapeutics across a variety of malignancies.
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This study investigated the antibacterial effects of S-nitroso-N-acetylcysteine (SNAC) and sodium nitrite (NaNO2) against Escherichia coli and their application in beef sausages. Both SNAC and NaNO2 demonstrated pH-responsive antibacterial activity, with SNAC showing greater efficacy than NaNO2 (p < 0.05) at the same pH (3, 5, and 7). The reactive oxygen species (ROS) and reactive nitrogen species (RNS) induced in E. coli by SNAC were significantly higher than those induced by NaNO2 (p < 0.05), and both ROS and RNS values increased as the pH decreased. In addition, a lower pH led to more pores on the E. coli cell surface and increased membrane permeability, resulting in a more pronounced inhibitory effect. When applied to a beef sausage, SNAC-treated sausages had significantly lower total colony counts and carbonyl content compared to NaNO2-treated ones (p < 0.05). Consequently, SNAC shows great potential as a replacement for NaNO2 in meat products.
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Conjugated polymers promise inherently flexible and low-cost thermoelectrics for powering the Internet of Things from waste heat1,2. Their valuable applications, however, have been hitherto hindered by the low dimensionless figure of merit (ZT)3-6. Here we report high-ZT thermoelectric plastics, which were achieved by creating a polymeric multi-heterojunction with periodic dual-heterojunction features, where each period is composed of two polymers with a sub-ten-nanometre layered heterojunction structure and an interpenetrating bulk-heterojunction interface. This geometry produces significantly enhanced interfacial phonon-like scattering while maintaining efficient charge transport. We observed a significant suppression of thermal conductivity by over 60 per cent and an enhanced power factor when compared with individual polymers, resulting in a ZT of up to 1.28 at 368 kelvin. This polymeric thermoelectric performance surpasses that of commercial thermoelectric materials and existing flexible thermoelectric candidates. Importantly, we demonstrated the compatibility of the polymeric multi-heterojunction structure with solution coating techniques for satisfying the demand for large-area plastic thermoelectrics, which paves the way for polymeric multi-heterojunctions towards cost-effective wearable thermoelectric technologies.
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The precise control of pore structures in porous organic polymer (POP) materials is of paramount importance in addressing a wide range of challenges associated with gas separation processes. In this study, we present a novel approach to optimize the gas separation performance of POPs through the introduction of fluorine groups and figure out an important factor of reaction decision that whether the AlCl3-catalyzed polymerization is Scholl reaction or Friedel-Crafts alkylation. In the chloroform system, the steric hindrance of function groups could make direct coupling between the benzene rings difficult, which would lead to part solvent knitting (Friedel-Crafts alkylation) instead. The fluorinated polymers show enhanced surface area and pore size characteristics. Notably, the fluorinated polymers exhibited significantly improved adsorption and separation performance for SF6, as evidenced by an ideal adsorbed solution theory selectivity (SF6/N2, v: v = 50:50, 273 K) increase of 75.0, 668.8, and 502.8% compared to the nonfluorinated POPs. These findings highlight the potential of fluorination as a strategy for tailoring the properties of POP materials for advanced gas separation applications.
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BACKGROUND: Lenvatinib is a tyrosine kinase inhibitor that can improve progression-free survival in patients with thyroid cancer and hepatocellular carcinoma. However, it is limited by adverse cardiovascular events, including hypertension and cardiac dysfunction. Activation of endoplasmic reticulum stress is involved in cardiomyocyte apoptosis. OBJECTIVE: This study aimed to confirm whether the cardiotoxicity of lenvatinib is associated with endoplasmic reticulum stress by targeting the activating transcription factor 6 (ATF6), inositol- requiring enzyme 1α (IRE1α) and protein kinase RNA-like ER kinase (PERK) signaling pathways. METHODS: Male C57/BL6 mice were intragastric administration with 30 mg/kg/day lenvatinib. Electrocardiography (ECG) and echocardiography were used to detect arrhythmias and cardiac function. Neonatal rat cardiomyocytes were treated with lenvatinib for 48h. Cell counting kit (CCK8), 2´,7´-dichlorodihydrofluoresceine diacetate (H2DCFHDA), Hoechst 33258 and dihydrorhodamine 123 were respectively used for evaluating cell viability, the level of reactive oxygen species (ROS), nuclear morphological changes and mitochondrial membrane potential (MMP) level. RESULTS: Lenvatinib remarkably decreased the posterior wall thickness of left ventricle during diastole and systole but caused little decrease to the left ventricular ejection fraction (LVEF, %). Furthermore, lenvatinib greatly prolonged the corrected QT interval (QTc) and altered the morphology of cardiomyocytes. No dramatic difference in fibrosis was found in mouse cardiac slices. Lenvatinib upregulates apoptosis-related protein expression. In addition, lenvatinib increased ERS-related protein expression (GRP78, CHOP, and ATF6) and enhanced PERK phosphorylation. In neonatal rat cardiac myocytes, lenvatinib markedly decreased the viability of cardiomyocytes and induced apoptosis. Furthermore, ROS production increased and MMP decreased. Similar to the mice experiment, lenvatinib caused upregulation of apoptosis-related and ERS-related proteins and increased the phosphorylation levels of PERK and IRE1α. CONCLUSION: Lenvatinib-induced cardiotoxicity is associated with ERS-induced apoptosis by targeting the ATF6, IRE1α, and PERK signaling pathways.
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Macrophage pyroptosis mediates vascular inflammation and atherosclerosis (AS). Hydrogen sulfide (H2S) exerts a protective role in preventing inflammation and AS. However, its molecular mechanisms of regulating the pyroptosis signaling pathway and inhibiting macrophage pyroptosis remain unexplored. The present study aimed to determine whether H2S mitigates macrophage pyroptosis by downregulating the pyroptosis signaling pathway and Ssulfhydrating caspase1 under the stimulation of oxidized lowdensity lipoprotein (oxLDL), a proatherosclerotic factor. Macrophages derived from THP1 monocytes were pretreated using exogenous H2S donors sodium hydrosulfide (NaHS) and D,Lpropargylglycine (PAG), a pharmacological inhibitor of endogenous H2Sproducing enzymes, alone or in combination. Subsequently, cells were stimulated with oxLDL or the desulfhydration reagent dithiothreitol (DTT) in the presence or absence of NaHS and/or PAG. Following treatment, the levels of H2S in THP1 derived macrophages were measured by a methylene blue colorimetric assay. The pyroptotic phenotype of THP1 cells was observed and evaluated by light microscopy, Hoechst 33342/propidium iodide fluorescent staining and lactate dehydrogenase (LDH) release assay. Caspase1 activity in THP1 cells was assayed by caspase1 activity assay kit. Immunofluorescence staining was used to assess the accumulation of active caspase1. Western blotting and ELISA were performed to determine the expression of pyroptosisspecific markers (NLRP3, procaspase1, caspase1, GSDMD and GSDMDN) in cells and the secretion of pyroptosisrelated cytokines [interleukin (IL)1ß and IL18] in the cellfree media, respectively. The Ssulfhydration of procaspase1 in cells was assessed using a biotin switch assay. oxLDL significantly induced macrophage pyroptosis by activating the pyroptosis signaling pathway. Inhibition of endogenous H2S synthesis by PAG augmented the propyroptotic effects of oxLDL. Conversely, exogenous H2S (NaHS) ameliorated oxLDLand oxLDL + PAGinduced macrophage pyroptosis by suppressing the activation of the pyroptosis signaling pathway. Mechanistically, oxLDL and the DTT increased caspase1 activity and downstream events (IL1ß and IL18 secretion) of the caspase1dependent pyroptosis pathway by reducing Ssulfhydration of procaspase1. Conversely, NaHS increased Ssulfhydration of procaspase1, reducing caspase1 activity and caspase1dependent macrophage pyroptosis. The present study demonstrated the molecular mechanism by which H2S ameliorates macrophage pyroptosis by suppressing the pyroptosis signaling pathway and Ssulfhydration of procaspase1, thereby suppressing the generation of active caspase-1 and activity of caspase-1.
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Caspase 1 , Sulfeto de Hidrogênio , Lipoproteínas LDL , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas de Ligação a Fosfato , Piroptose , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Piroptose/efeitos dos fármacos , Humanos , Caspase 1/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , Proteínas de Ligação a Fosfato/metabolismo , Células THP-1 , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Gasderminas , Alcinos , Glicina/análogos & derivados , SulfetosRESUMO
CONTEXT: Tumor-induced osteomalacia (TIO) is an ultra-rare, paraneoplastic syndrome caused by tumors that secrete fibroblast growth factor 23 (FGF23). Initial signs and musculoskeletal symptoms can be non-specific and unrecognized, leading to long delays in diagnosis and treatment, which results in severe and progressive disability in patients with TIO. This review aimed to identify published evidence on healthcare resource use in TIO to better understand the burden of the disease. EVIDENCE ACQUISITION: A targeted literature review was conducted to identify publications reporting on disease characteristics and healthcare resource use associated with TIO. EVIDENCE SYNTHESIS: In total, 414 publications were included in the review, of which 376 were case reports. From the case reports, data on 621 patients were extracted. These patients had a mean (standard deviation) age of 46.3 (15.8) years; 57.6% were male. Mean time from first symptoms to diagnosis of TIO was 4.6 (4.7) years and, in cases where imaging tests were reported, patients underwent a mean of 4.1 (2.7) procedures. Tumor resection was attempted in 81.0% of patients and successful in 67.0%. Fracture was reported in 49.3% of patients. Results from association analyses demonstrated that longer time to diagnosis was associated with poorer tumor resection outcomes and a higher probability of tumor recurrence. Unfavorable tumor resection outcomes were associated with greater use of pharmacologic treatment and a greater likelihood of orthopedic surgery. CONCLUSION: TIO is associated with a substantial healthcare resource burden. Improvements in the diagnostic process could lead to better management of TIO, thereby benefiting patients and reducing that burden.
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Skin hyperpigmentation is mainly caused by excessive synthesis of melanin; however, there is still no safe and effective therapy for its removal. Here, we found that the dermal freezer was able to improve UVB-induced hyperpigmentation of guinea pigs without causing obvious epidermal damage. We also mimic freezing stimulation at the cellular level by rapid freezing and observed that freezing treatments <2.5 min could not decrease cell viability or induce cell apoptosis in B16F10 and Melan-A cells. Critically, melanin content and tyrosinase activity in two cells were greatly reduced after freezing treatments. The dramatic decrease in tyrosinase activity was associated with the downregulation of MITF, TYR, TRP-1 and TRP-2 protein expression in response to freezing treatments for two cells. Furthermore, our results first demonstrated that freezing treatments significantly reduced the levels of p-GSK3ß and ß-catenin and the nuclear accumulation of ß-catenin in B16F10 and Melan-A cells. Together, these data suggest that fast freezing treatments can inhibit melanogenesis-related gene expression in melanocytes by regulating the Wnt/ß-catenin signalling pathway. The inhibition of melanin production eventually contributed to the improvement in skin hyperpigmentation induced by UVB. Therefore, fast freezing treatments may be a new alternative of skin whitening in the clinic in the future.
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Congelamento , Melaninas , Melanócitos , Via de Sinalização Wnt , beta Catenina , Animais , Cobaias , Camundongos , Apoptose , beta Catenina/metabolismo , Sobrevivência Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Hiperpigmentação/terapia , Interferon Tipo I , Oxirredutases Intramoleculares/metabolismo , Melaninas/biossíntese , Melanócitos/metabolismo , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/metabolismo , Raios UltravioletaRESUMO
BACKGROUND: Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH. METHODS: We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets. RESULTS: We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells. CONCLUSION: The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.
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Diterpenos do Tipo Caurano , Glutationa , Leucemia Mieloide Aguda , Lipossomos , Espécies Reativas de Oxigênio , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Glutationa/metabolismo , Glutationa/química , Lipossomos/química , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral , Receptor 2 Toll-Like/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacosRESUMO
The musculoskeletal system, constituting the largest human physiological system, plays a critical role in providing structural support to the body, facilitating intricate movements, and safeguarding internal organs. By virtue of advancements in revolutionized materials and devices, particularly in the realms of motion capture, health monitoring, and postoperative rehabilitation, "musculoskeletal electronics" has actually emerged as an infancy area, but has not yet been explicitly proposed. In this review, the concept of musculoskeletal electronics is elucidated, and the evolution history, representative progress, and key strategies of the involved materials and state-of-the-art devices are summarized. Therefore, the fundamentals of musculoskeletal electronics and key functionality categories are introduced. Subsequently, recent advances in musculoskeletal electronics are presented from the perspectives of "in vitro" to "in vivo" signal detection, interactive modulation, and therapeutic interventions for healing and recovery. Additionally, nine strategy avenues for the development of advanced musculoskeletal electronic materials and devices are proposed. Finally, concise summaries and perspectives are proposed to highlight the directions that deserve focused attention in this booming field.
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Dispositivos Eletrônicos Vestíveis , Humanos , Sistema Musculoesquelético , EletrônicaRESUMO
Nanoresolved doping of polymeric semiconductors can overcome scaling limitations to create highly integrated flexible electronics, but remains a fundamental challenge due to isotropic diffusion of the dopants. Here we report a general methodology for achieving nanoscale ion-implantation-like electrochemical doping of polymeric semiconductors. This approach involves confining counterion electromigration within a glassy electrolyte composed of room-temperature ionic liquids and high-glass-transition-temperature insulating polymers. By precisely adjusting the electrolyte glass transition temperature (Tg) and the operating temperature (T), we create a highly localized electric field distribution and achieve anisotropic ion migration that is nearly vertical to the nanotip electrodes. The confined doping produces an excellent resolution of 56 nm with a lateral-extended doping length down to as little as 9.3 nm. We reveal a universal exponential dependence of the doping resolution on the temperature difference (Tg - T) that can be used to depict the doping resolution for almost infinite polymeric semiconductors. Moreover, we demonstrate its implications in a range of polymer electronic devices, including a 200% performance-enhanced organic transistor and a lateral p-n diode with seamless junction widths of <100 nm. Combined with a further demonstration in the scalability of the nanoscale doping, this concept may open up new opportunities for polymer-based nanoelectronics.
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Bioaerosol is one of the main ways to spread respiratory infectious diseases. In order to further improve the sterilization efficiency of copper-manganese-cerium oxide (CuMnCeOx), the post-treatment method based on acid etching was adopted. The results showed that sterilization efficiency of the treated CuMnCeOx could reach 99% in aerosol with space velocity of 1400 h-1. L(+)-ascorbic acid successfully promoted the formation of Cu+, oxygen vacancies and the generation of reactive oxygen species (ROS) on the surface of the treated CuMnCeOx. During sterilization in liquid system, the transcriptome identified 316 differentially expressed genes, including 270 up-regulated genes and 46 down-regulated genes. Differentially expressed genes were significantly enriched in cell wall (GO:0005618) and external encapsulating structure (GO:0030312). Up-regulated genes were shown in regulation of reactive oxygen species biosynthetic processes (GO:1903409, GO:1903426, GO:1903428) and positive regulation all of reactive oxygen species metabolic process (GO:2000379), indicating that ROS induced cell death by destroying cell wall.
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Aerossóis , Cobre , Manganês , Espécies Reativas de Oxigênio , Esterilização , Cobre/química , Espécies Reativas de Oxigênio/metabolismo , Esterilização/métodos , Manganês/química , Óxidos/química , Transcriptoma/efeitos dos fármacosRESUMO
The circadian clock regulates animal physiological activities. How temperature reorganizes circadian-dependent physiological activities remains elusive. Here, using in-vivo two-photon imaging with the temperature control device, we investigated the response of the Drosophila central circadian circuit to temperature variation and identified that DN1as serves as the most sensitive temperature-sensing neurons. The circadian clock gate DN1a's diurnal temperature response. Trans-synaptic tracing, connectome analysis, and functional imaging data reveal that DN1as bidirectionally targets two circadian neuronal subsets: activity-related E cells and sleep-promoting DN3s. Specifically, behavioral data demonstrate that the DN1a-E cell circuit modulates the evening locomotion peak in response to cold temperature, while the DN1a-DN3 circuit controls the warm temperature-induced nocturnal sleep reduction. Our findings systematically and comprehensively illustrate how the central circadian circuit dynamically integrates temperature and light signals to effectively coordinate wakefulness and sleep at different times of the day, shedding light on the conserved neural mechanisms underlying temperature-regulated circadian physiology in animals.
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Relógios Circadianos , Proteínas de Drosophila , Animais , Ritmo Circadiano/fisiologia , Temperatura , Sono/fisiologia , Drosophila , Relógios Circadianos/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologiaRESUMO
Taking a city in Guangdong Province as the research area, the concentration and spatial distribution characteristics of heavy metals in the surface soil were studied to clarify the situation of soil heavy metal pollution and priority control factors, providing basic data for the prevention and control of soil heavy metal pollution in the city. The content characteristics of heavy metals in 221 soil samples in the city were analyzed, and the potential health risk assessment and source analysis were carried out through the Monte Carlo model, the potential health risk assessment (HRA) model, and the PMF receptor model. It was found that heavy metals ω(As), ω(Hg), ω(Cd), ω(Pb), ω(Cr), ω(Cu), ω(Ni), and ω(Zn) in the soil of the city were 18.16, 0.43, 1.46, 68.57, 98.34, 64.19, 26.53, and 257.32 mg·kg-1, respectively, with a moderate to high degree of variation. Except for Ni concentration, the soil concentrations of other heavy metal elements exceeded the background values of soil in Guangdong Province to a certain extent, and the concentrations of Cd and Zn exceeded the national secondary standards, resulting in severe heavy metal pollution; the main sources of heavy metals were industrial sources, and natural parent materials, lead battery manufacturing, transportation, artificial cultivation, and pesticide and fertilizer inputs also had an undeniable impact on the accumulation of heavy metals in the soil. Heavy metals in the soil had a certain degree of tolerable carcinogenic health risk for both children and adults, whereas non-carcinogenic risks could be ignored. The potential health risk of children was greater than that of adults, and the main exposure route was through oral intake. The input sources of pesticides and fertilizers and As should be the main controlling factors for the health risks of heavy metals in the city's soil, followed by mixed sources and Cr. There were differences in the spatial distribution characteristics and relative pollution levels of heavy metals, and it is necessary to deepen zoning monitoring and control, strengthen soil pollution prevention and control, and reduce human input of heavy metals in soil.
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Metais Pesados , Poluentes do Solo , Criança , Adulto , Humanos , Monitoramento Ambiental , Solo , Cádmio/análise , Poluentes do Solo/análise , Metais Pesados/análise , Medição de Risco , ChinaRESUMO
Besides its original spin representation, the Ising model is known to have the Fortuin-Kasteleyn (FK) bond and loop representations, of which the former was recently shown to exhibit two upper critical dimensions (d_{c}=4,d_{p}=6). Using a lifted worm algorithm, we determine the critical coupling as K_{c}=0.07770891(4) for d=7, which significantly improves over the previous results, and then study critical geometric properties of the loop Ising clusters on tori for spatial dimensions d=5 to 7. We show that as the spin representation, the loop Ising model has only one upper critical dimension at d_{c}=4. However, sophisticated finite-size scaling (FSS) behaviors, such as two length scales, two configuration sectors, and two scaling windows, still exist as the interplay effect of the Gaussian fixed point and complete-graph asymptotics. Moreover, using the loop-cluster algorithm, we provide an intuitive understanding of the emergence of the percolation-like upper critical dimension d_{p}=6 in the FK-Ising model. As a consequence, a unified physical picture is established for the FSS behaviors in all three representations of the Ising model above d_{c}=4.
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PURPOSE: The purpose of the study was to describe a novel growth guidance system, which can avoid metal debris and reduce the sliding friction forces, and test the durability and glidability of the system by in vitro test. METHOD: Two major modifications were made to the traditional Shilla system, including the use of ultra-high molecular weight polyethylene (UHMWPE) gaskets to avoid direct contact between the screw and rod, and polishing the surface of the sliding part of the rod. We tested the durability of the system by a fatigue test, which the samples were test on the MTS system for a 10 million cycle of a constant displacement. Pre and post-testing involved weighing the UHMWPE gaskets and observing the wear conditions. The sliding ability were measured by a sliding displacement test. The maximum sliding displacement of the system was measured after a 300 cycles of dynamic compressive loads in a sinusoidal waveform. RESULTS: After the fatigue test, all the UHMWPE gaskets samples showed some of the fretting on the edge of the inner sides, but its still isolated and avoided the friction between the screws and rods. There was no production of metallic fretting around the sliding screws and rods. The average wear mass of the UHMWPE gaskets was 0.002 ± 0.001 g, less than 1.7% of the original mass. In the sliding test, the novel growth guidance system demonstrated the best sliding ability, with an average maximum sliding distance(AMSD) of 35.75 ± 5.73 mm, significantly better than the group of the traditional Shilla technique(AMSD 3.65 ± 0.46 mm, P < 0.0001). CONCLUSION: In conclusion, we modified the Shilla technique and designed a novel growth guidance system by changing the friction interface of sliding screw and rod, which may significantly reduce the metallic debris and promote spine growth. The fatigue test and sliding dislocation test demonstrated the better durability and glidability of the system. An in vivo animal experiment should be performed to further verify the system.
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Teste de Materiais , Polietilenos , Escoliose , Humanos , Teste de Materiais/métodos , Fricção , Parafusos Ósseos , Técnicas In VitroRESUMO
Rheb is a small G protein that functions as the direct activator of the mechanistic target of rapamycin complex 1 (mTORC1) to coordinate signaling cascades in response to nutrients and growth factors. Despite extensive studies, the guanine nucleotide exchange factor (GEF) that directly activates Rheb remains unclear, at least in part due to the dynamic and transient nature of protein-protein interactions (PPIs) that are the hallmarks of signal transduction. Here, we report the development of a rapid and robust proximity labeling system named Pyrococcus horikoshii biotin protein ligase (PhBPL)-assisted biotin identification (PhastID) and detail the insulin-stimulated changes in Rheb-proximity protein networks that were identified using PhastID. In particular, we found that the lysosomal V-ATPase subunit ATP6AP1 could dynamically interact with Rheb. ATP6AP1 could directly bind to Rheb through its last 12 amino acids and utilizes a tri-aspartate motif in its highly conserved C-tail to enhance Rheb GTP loading. In fact, targeting the ATP6AP1 C-tail could block Rheb activation and inhibit cancer cell proliferation and migration. Our findings highlight the versatility of PhastID in mapping transient PPIs in live cells, reveal ATP6AP1's role as an unconventional GEF for Rheb, and underscore the importance of ATP6AP1 in integrating mTORC1 activation signals through Rheb, filling in the missing link in Rheb/mTORC1 activation.
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Proteína Enriquecida em Homólogo de Ras do Encéfalo , Humanos , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Células HEK293 , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Ligação Proteica , Transdução de Sinais , Linhagem Celular TumoralRESUMO
BACKGROUND: Peracetic acid and irradiation are common sterilization methods for allograft tendons; however, under some conditions, both methods adversely affect the fiber arrangement and ultimate load of the tendon. An in vitro study showed that low-dose peracetic acid combined with irradiation may be less detrimental to allograft tendon structure and properties, possibly because the breakdown of peracetic acid can lead to an enlargement of the interstitial spaces and an increase in porosity. QUESTIONS/PURPOSES: Using a rabbit Achilles tendon model, we asked: What is the effect of peracetic acid-ethanol combined irradiation on (1) the histopathology and fiber diameter of the allograft tendon, (2) tensile creep and load-to-failure biomechanical properties of allograft tendons, and (3) healing of the treated tendon in vivo compared with fresh-frozen allograft and peracetic acid-ethanol sterilization at 4 and 8 weeks? METHODS: The Achilles tendons used in this study were sourced from euthanized 10-week-old male New Zealand White rabbits previously used for ophthalmic experiments. All allografts were divided into three groups: fresh-frozen group (control group, n = 20), peracetic acid-ethanol sterilization group (n =20), and peracetic acid-ethanol combined irradiation group (n = 20). The sterilization protocols were performed per a predetermined plan. In the peracetic acid-ethanol sterilization group, the tendon tissues were covered with the peracetic acid-ethanol sterilization solution (1% peracetic acid for 30 minutes). In the peracetic acid-ethanol combined irradiation group, the tendon tissues were covered with the peracetic acid-ethanol sterilization solution (0.2% peracetic acid for 30 minutes) and were subjected to 15 kGy gamma irradiation. Thirty 10-week-old male New Zealand White rabbits received bilateral Achilles tendon allografts surgically. Tendon samples from each group were harvested at 4 weeks (n = 30) and 8 weeks (n = 30) postoperatively. For each timepoint, eight tissues were used for histologic staining and electron microscopy, 15 tissues were used for biomechanical testing, and seven tissues were used for hydroxyproline assay and quantitative polymerase chain reaction. Histopathology was determined qualitatively by hematoxylin and eosin and Masson staining, while fiber diameter was measured quantitatively by transmission electron microscopy. Biomechanical properties were measured using cyclic loading tests and load-to-failure tests. The healing outcome was quantitatively judged through healing-related genes and proteins. RESULTS: At 4 weeks and 8 weeks postoperatively, the peracetic acid-ethanol combined irradiation group visually demonstrated the best continuity and minimal peripheral adhesions. Histologic staining showed that tendon fibers in the peracetic acid-ethanol combined irradiation group maintained consistent alignment without notable disruptions or discontinuities, and there was a qualitatively observed increase in the number of infiltrating cells compared with the control group at the 4-week timepoint (444 ± 49 /mm 2 versus 256 ± 43 /mm 2 , mean difference 188 /mm 2 [95% confidence interval 96 to 281]; p < 0.001). At 8 weeks postoperatively, the tendon fiber diameter in the peracetic acid-ethanol combined irradiation groups was similar to that of the control group (0.23 ± 0.04 µm versus 0.21 ± 0.03 µm, mean difference 0.02 µm [95% CI -0.04 to 0.08]; p = 0.56). At 8 weeks postoperatively, the peracetic acid-ethanol combined irradiation group exhibited better properties in terms of both ultimate load (129 ± 15 N versus 89 ± 20 N, mean difference 40 N [95% CI 7 to 73]; p = 0.02) and energy absorption density (17 ± 6 kJ/m 2 versus 8 ± 4 kJ/m 2 , mean difference 8 kJ/m 2 [95% CI 0.7 to 16]; p = 0.004) compared with the control group. Gene expression analysis revealed higher expression levels of COL1A1 (2.1 ± 0.8 versus 1.0 ± 0, mean difference 1.1 [95% CI 0.1 to 2.1]; p = 0.003) and MMP13 (2.0 ± 0.8 versus 1.0 ± 0, mean difference 1.0 [95% CI 0.4 to 1.6]; p = 0.03) in the peracetic acid-ethanol combined irradiation group than in the control group. There was a higher amount of collagen Type I in tendons treated with peracetic acid-ethanol combined irradiation than in the control group (0.36 ± 0.03 versus 0.31 ± 0.04, mean difference 0.05 [95% CI 0.01 to 0.09]; p = 0.02). CONCLUSION: Treatment with peracetic acid-ethanol combined irradiation did not have any discernible adverse effect on the histology, fiber diameter, enzymatic resistance, collagen content, or biomechanical strength of the allograft tendons compared with the control group. Peracetic acid-ethanol combined irradiation treatment had a positive impact on remodeling of the extracellular matrix and realignment of collagen fibers. CLINICAL RELEVANCE: This sterilization method could be helpful to expand the scope and frequency with which allogeneic materials are applied. The long-term healing effect and strength of allograft tendons must be tested before clinical use, and it is necessary to conduct comparative studies on autografts and synthetic materials that are currently widely used clinically.
Assuntos
Tendão do Calcâneo , Aloenxertos , Etanol , Ácido Peracético , Esterilização , Cicatrização , Animais , Coelhos , Masculino , Cicatrização/efeitos da radiação , Cicatrização/efeitos dos fármacos , Ácido Peracético/farmacologia , Etanol/farmacologia , Esterilização/métodos , Tendão do Calcâneo/cirurgia , Tendão do Calcâneo/efeitos da radiação , Tendão do Calcâneo/patologia , Resistência à Tração , Fenômenos Biomecânicos , Fatores de Tempo , Traumatismos dos Tendões/cirurgiaRESUMO
In order to comprehensively study the pollution characteristics of polycyclic aromatic hydrocarbons ï¼PAHsï¼ in soils of Guangzhouï¼ 222 topsoil samples were collected and analyzed. The ecological risk of soil PAHs pollution was evaluated using the effect interval low/median method ï¼ERL/ERMï¼ and the ï¼BaPï¼ toxicity equivalent methodï¼ and the health risk of soil PAHs pollution was evaluated using the lifelong cancer risk increment model. The source of PAHs was analyzed using the characteristic compound ratio method and PMF model. The results indicated thatï¼ the content of surface soil ï¼∑16PAHsï¼ in Guangzhou was 38-11 115 µg·kg-1ï¼ with an average of 526 µg·kg-1ï¼ and 16 types of polycyclic aromatic hydrocarbon monomers showed strong variation. There was a certain degree of ecological risk of PAHs in Guangzhouï¼ and there was already a significant ecological risk of PAHs pollution in individual sampling pointsï¼ which were generally in a state of mild pollution. Based on the results of the health risk assessmentï¼ the contribution rates of total cancer risk in both adults and children were presented as followsï¼ skin contact > ingestion of soil > respiratory intake. The health risk of children was greater than that of adultsï¼ and the overall health risk was within an acceptable range. Source analysis showed that the main sources of soil PAHs in Guangzhou were coal ï¼37.1%ï¼ï¼ diesel ï¼32%ï¼ï¼ coking ï¼17.3%ï¼ï¼ and mixed sources of traffic emissionsï¼ biomass combustionï¼ and petrochemical product volatilization ï¼13.6%ï¼. The overall source of soil PAHs belonged to mixed sources. The research results have enriched our understanding of the pollution status of PAHs in the surface soil of Guangzhou and are helpful in promoting soil pollution prevention and control actions.
Assuntos
Neoplasias , Hidrocarbonetos Policíclicos Aromáticos , Poluentes do Solo , Criança , Adulto , Humanos , Solo/química , Monitoramento Ambiental/métodos , Hidrocarbonetos Policíclicos Aromáticos/análise , Poluentes do Solo/análise , Poluição Ambiental/análise , Medição de Risco , ChinaRESUMO
Bone tissue engineering using osteoconductive scaffolds holds promise for regeneration, with pearl powder gaining interest for its bioactive qualities. This study used freeze drying to create chitosan (CS) scaffolds with pearl/calcium phosphate (p/CaP) powders, mimicking bone tissue structurally and compositionally. Characterization included scanning electron microscopy (SEM) and mechanical testing. X-ray diffraction (XRD) Fourier-transform infrared-photoacoustic photo-acoustic sampling (FTIR-PAS), and FTIR- attenuated total reflectance (FTIR-ATR) were used to characterize p/CaP. In vitro tests covered degradation, cell activity, and SEM analysis. The scaffolds showed notable compressive strength and modulus enhancements with increasing p/CaP content. Porosity, ranging from 60% to 90%, decreased significantly at higher pearl/CaP ratios. Optimal cell proliferation and differentiation were observed with scaffolds containing up to 30 wt.% p/CaP, with 30 wt.% pearl powder and 30 wt.% p/CaP yielding the best results. In conclusion, pearl/calcium phosphate chitosan (p/CaP_CS) composite scaffolds emerged as promising biomaterials for bone tissue engineering, combining structural mimicry and favourable biological responses.