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1.
Molecules ; 29(18)2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39339329

RESUMEN

A tetraphenylethylene (TPE) derivative, TPEPhDAT, modified by diaminotriazine (DAT), was prepared by successive Suzuki-Miyaura coupling and ring-closing reactions. This compound exhibits aggregation-induced emission enhancement (AIEE) properties in the DMSO/MeOH system, with a fluorescence emission intensity in the aggregated state that is 5-fold higher than that of its counterpart in a dilute solution. Moreover, the DAT structure of the molecule is a good acceptor of protons; thus, the TPEPhDAT molecule exhibits acid-responsive fluorescence. TPEPhDAT was protonated by trifluoroacetic acid (TFA), leading to fluorescence quenching, which was reversibly restored by treatment with ammonia (on-off switch). Time-dependent density functional theory (TDDFT) computational studies have shown that protonation enhances the electron-withdrawing capacity of the triazine nucleus and reduces the bandgap. The protonated TPEPhDAT conformation became more distorted, and the fluorescence lifetime was attenuated, which may have produced a twisted intramolecular charge transfer (TICT) effect, leading to fluorescence redshift and quenching. MeOH can easily remove the protonated TPEPhDAT, and this acid-induced discoloration and erasable property can be applied in anti-counterfeiting.

2.
Cancer Res ; 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39288075

RESUMEN

Colorectal cancer (CRC) continues to be a major health issue even though screening methods have facilitated early detection. Despite the high sensitivity of white-light colonoscopy, it frequently overlooks invasive flat or depressed lesions, which can lead to the development of larger, advanced tumors. Fluorescence molecular imaging (FMI) offers a promising approach for early tumor detection by targeting specific molecular characteristics of lesions. CD24 is upregulated during the adenoma-to-CRC transition, providing a potential target for FMI. Here, we developed a second near-infrared window (NIR-II) fluorescent probe with a high affinity for CD24 and evaluated its efficacy and targeting ability in cellular models, murine models, and clinical samples of CRC. CD24 expression was elevated in 76% of adenomas and 80% of CRCs. In a colitis-associated cancer mouse model, NIR-II imaging with the CD24-targeted probe achieved a significantly higher tumor-to-background ratio compared to conventional NIR-I imaging. The probe demonstrated exceptional sensitivity (92%) and specificity (92%) for detecting CRC, including small lesions less than 1 mm in size. This led to the identification of precancerous lesions missed by white-light detection and lesions missed by NIR-I imaging. Moreover, ex vivo human tissue incubation with the probe supported the potential for intraprocedural lesion identification via topical probe application during colonoscopy. In conclusion, this study successfully demonstrates the potential of CD24-targeted NIR-II imaging for identifying colorectal neoplasia, highlighting its significance for early CRC detection in the gastrointestinal tract.

3.
Angew Chem Int Ed Engl ; : e202411535, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39136168

RESUMEN

The conventional covalent organic framework (COF)-based electrolytes with tailored ionic conducting behaviors are typically fabricated in the powder morphology, requiring further compaction procedures to operate as solid electrolyte tablets, which hinders the large-scale manufacturing of COF materials. In this study, we present a feasible electrospinning strategy to prepare scalable, self-supporting COF membranes (COMs) that feature a rigid COF skeleton bonded with flexible, lithiophilic polyethylene glycol (PEG) chains, forming an ion conduction network for Li⁺ transport. The resulting PEG-COM electrolytes exhibit enhanced dendrite inhibition and high ionic conductivity of 0.153 mS cm⁻¹ at 30 °C. The improved Li⁺ conduction in PEG-COM electrolytes stems from the loose ion pairing in the structure and the production of higher free Li⁺ content, as confirmed by solid-state 7Li NMR experiments. These changes in the local microenvironment of Li⁺ facilitate its directional movement within the COM pores. Consequently, solid-state symmetrical Li|Li, Li|LFP, and pouch cells demonstrate excellent electrochemical performance at 60 °C. This strategy offers a universal approach for constructing scalable COM-based electrolytes, thereby broadening the practical applications of COFs in solid-state lithium metal batteries.

4.
World J Diabetes ; 15(6): 1263-1271, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38983812

RESUMEN

BACKGROUND: Cognitive dysfunction is the main manifestation of central neuropathy. Although cognitive impairments tend to be overlooked in patients with diabetes mellitus (DM), there is a growing body of evidence linking DM to cognitive dysfunction. Hyperglycemia is closely related to neurological abnormalities, while often disregarded in clinical practice. Changes in cerebral neurotransmitter levels are associated with a variety of neurological abnormalities and may be closely related to blood glucose control in patients with type 2 DM (T2DM). AIM: To evaluate the concentrations of cerebral neurotransmitters in T2DM patients exhibiting different hemoglobin A1c (HbA1c) levels. METHODS: A total of 130 T2DM patients were enrolled at the Department of Endocrinology of Shanghai East Hospital. The participants were divided into four groups according to their HbA1c levels using the interquartile method, namely Q1 (< 7.875%), Q2 (7.875%-9.050%), Q3 (9.050%-11.200%) and Q4 (≥ 11.200%). Clinical data were collected and measured, including age, height, weight, neck/waist/hip circumferences, blood pressure, comorbidities, duration of DM, and biochemical indicators. Meanwhile, neurotransmitters in the left hippocampus and left brainstem area were detected by proton magnetic resonance spectroscopy. RESULTS: The HbA1c level was significantly associated with urinary microalbumin (mALB), triglyceride, low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell function (HOMA-ß), N-acetylaspartate/creatine (NAA/Cr), and NAA/choline (NAA/Cho). Spearman correlation analysis showed that mALB, LDL-C, HOMA-IR and NAA/Cr in the left brainstem area were positively correlated with the level of HbA1c (P < 0.05), whereas HOMA-ß was negatively correlated with the HbA1c level (P < 0.05). Ordered multiple logistic regression analysis showed that NAA/Cho [Odds ratio (OR): 1.608, 95% confidence interval (95%CI): 1.004-2.578, P < 0.05], LDL-C (OR: 1.627, 95%CI: 1.119-2.370, P < 0.05), and HOMA-IR (OR: 1.107, 95%CI: 1.031-1.188, P < 0.01) were independent predictors of poor glycemic control. CONCLUSION: The cerebral neurotransmitter concentrations in the left brainstem area in patients with T2DM are closely related to glycemic control, which may be the basis for the changes in cognitive function in diabetic patients.

6.
Gels ; 10(7)2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39057502

RESUMEN

Breast cancer is the most common malignancy among women and is the second leading cause of cancer-related death for women. Depending on the tumor grade and stage, breast cancer is primarily treated with surgery and antineoplastic therapy. Direct or indirect side effects, emotional trauma, and unpredictable outcomes accompany these traditional therapies, calling for therapies that could improve the overall treatment and recovery experiences of patients. Hydrogels, biomimetic materials with 3D network structures, have shown great promise for augmenting breast cancer therapy. Hydrogel implants can be made with adipogenic and angiogenic properties for tissue integration. 3D organoids of malignant breast tumors grown in hydrogels retain the physical and genetic characteristics of the native tumors, allowing for post-surgery recapitulation of the diseased tissues for precision medicine assessment of the responsiveness of patient-specific cancers to antineoplastic treatment. Hydrogels can also be used as carrier matrices for delivering chemotherapeutics and immunotherapeutics or as post-surgery prosthetic scaffolds. The hydrogel delivery systems could achieve localized and controlled medication release targeting the tumor site, enhancing efficacy and minimizing the adverse effects of therapeutic agents delivered by traditional procedures. This review aims to summarize the most recent advancements in hydrogel utilization for breast cancer post-surgery tissue reconstruction, tumor modeling, and therapy and discuss their limitations in clinical translation.

7.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(6): 619-624, 2024 Jun 15.
Artículo en Chino | MEDLINE | ID: mdl-38926379

RESUMEN

OBJECTIVES: To assess the effectiveness and safety of prone positioning in the treatment of neonatal respiratory distress syndrome (NRDS) using invasive respiratory support. METHODS: A prospective study was conducted from June 2020 to September 2023 at Suining County People's Hospital, involving 77 preterm infants with gestational ages less than 35 weeks requiring invasive respiratory support for NRDS. The infants were randomly divided into a supine group (37 infants) and a prone group (40 infants). Infants in the prone group were ventilated in the prone position for 6 hours followed by 2 hours in the supine position, continuing in this cycle until weaning from the ventilator. The effectiveness and safety of the two approaches were compared. RESULTS: At 6 hours after enrollment, the prone group showed lower arterial blood carbon dioxide levels, inspired oxygen concentration, oxygenation index, rates of tracheal intubation bacterial colonization, and Neonatal Pain, Agitation and Sedation Scale scores compared to the supine group (P<0.05). There were no significant differences between the groups in terms of pH, arterial oxygen pressure, positive end-expiratory pressure, duration of mechanical ventilation, accidental extubation, ventilator-associated pneumonia, air leak syndrome, skin pressure sores, feeding intolerance, and grades II-IV intraventricular hemorrhage (P>0.05). CONCLUSIONS: Compared to supine positioning, prone ventilation effectively improves oxygenation, increases comfort, and reduces tracheal intubation bacterial colonization in neonates requiring mechanical ventilation for NRDS, without significantly increasing adverse reactions.


Asunto(s)
Respiración Artificial , Síndrome de Dificultad Respiratoria del Recién Nacido , Humanos , Posición Prona , Recién Nacido , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Masculino , Femenino , Estudios Prospectivos , Respiración Artificial/métodos
8.
ACS Appl Mater Interfaces ; 16(23): 29793-29804, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38819663

RESUMEN

The effectiveness of photodynamic therapy (PDT) in treating brain gliomas is limited by the solubility of photosensitizers and the production of reactive oxygen species (ROS), both of which are influenced by the concentration of photosensitizers and catalyst active sites. In this study, we developed a controllable surface hydroxyl concentration for the photosensitizer CN11 to address its poor water solubility issue and enhance PDT efficacy in tumor treatment. Compared to pure g-C3N4 (CN), CN11 exhibited 4.6 times higher hydrogen peroxide production under visible light, increased incidence of the n → π* electron transition, and provided more available reaction sites for cytotoxic ROS generation. These findings resulted in a 2.43-fold increase in photodynamic treatment efficacy against brain glioma cells. Furthermore, in vivo experiments conducted on mice demonstrated that CN11 could be excreted through normal cell metabolism with low cytotoxicity and high biosafety, effectively achieving complete eradication of tumor cells.


Asunto(s)
Neoplasias Encefálicas , Glioma , Nitrilos , Fotoquimioterapia , Fármacos Fotosensibilizantes , Glioma/tratamiento farmacológico , Glioma/patología , Glioma/metabolismo , Animales , Ratones , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Nitrilos/química , Nitrilos/farmacología , Humanos , Especies Reactivas de Oxígeno/metabolismo
9.
Nat Med ; 30(7): 1943-1951, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38778212

RESUMEN

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.


Asunto(s)
Adenocarcinoma , Unión Esofagogástrica , Receptor ErbB-2 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Persona de Mediana Edad , Masculino , Femenino , Unión Esofagogástrica/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Anciano , Receptor ErbB-2/metabolismo , Adulto , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores
10.
J Inflamm Res ; 17: 2217-2231, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38623466

RESUMEN

Purpose: Neuroinflammation occurs in response to central nervous system (CNS) injury, infection, stimulation by toxins, or autoimmunity. We previously analyzed the downstream molecular changes in HT22 cells (mouse hippocampal neurons) upon lipopolysaccharide (LPS) stimulation. We detected elevated expression of Fibrillarin (FBL), a nucleolar methyltransferase, but the associated proinflammatory mechanism was not systematically elucidated. The aim of this study was to investigate the underlying mechanisms by which FBL affects neuroinflammation. Methods: RT-real-time PCR, Western blotting and immunofluorescence were used to assess the mRNA and protein expression of FBL in HT22 cells stimulated with LPS, as well as the cellular localization and fluorescence intensity of FBL. BAY-293 (a son of sevenless homolog 1 (SOS1) inhibitor), SR11302 (an activator protein-1 (AP-1) inhibitor) and KRA-533 (a KRAS agonist) were used to determine the molecular mechanisms underlying the effect of FBL. AP-1 was predicted to be the target protein of FBL by molecular docking analysis, and validation was performed with T-5224 (an AP-1 inhibitor). In addition, the downstream signaling pathways of FBL were identified by transcriptome sequencing and verified by RT-real-time PCR. Results: LPS induced FBL mRNA and protein expression in HT22 cells. In-depth mechanistic studies revealed that when we inhibited c-Fos, AP-1, and SOS1, FBL expression decreased, whereas FBL expression increased when KRAS agonists were used. In addition, the transcript levels of inflammatory genes in the NF-kB signaling pathway (including CD14, MYD88, TNF, TRADD, and NFKB1) were elevated after the overexpression of FBL. Conclusion: LPS induced the expression of FBL in HT22 cells through the RAS/MAPK signaling pathway, and FBL further activated the NF-kB signaling pathway, which promoted the expression of relevant inflammatory genes and the release of cytokines. The present study reveals the mechanism by which FBL promotes neuroinflammation and offers a potential target for the treatment of neuroinflammation.

11.
Biomed Pharmacother ; 175: 116669, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38677243

RESUMEN

BACKGROUND: The lack of an efficient way to screen patients who are responsive to immunotherapy challenges PD1/CTLA4-targeting cancer treatment. Immunotherapeutic efficacy cannot be clearly determined by peripheral blood analyses, tissue gene markers or CT/MR value. Here, we used a radionuclide and imaging techniques to investigate the novel dual targeted antibody cadonilimab (AK104) in PD1/CTLA4-positive cells in vivo. METHODS: First, humanized PD1/CTLA4 mice were purchased from Biocytogen Pharmaceuticals (Beijing) Co., Ltd. to express hPD1/CTLA4 in T-cells. Then, mouse colon cancer MC38-hPD-L1 cell xenografts were established in humanized mice. A bispecific antibody targeting PD1/CTLA4 (AK104) was labeled with radio-nuclide iodine isotopes. Immuno-PET/CT imaging was performed using a bispecific monoclonal antibody (mAb) probe 124I-AK104, developed in-house, to locate PD1+/CTLA4+ tumor-infiltrating T cells and monitor their distribution in mice to evaluate the therapeutic effect. RESULTS: The 124I-AK104 dual-antibody was successfully constructed with ideal radiochemical characteristics, in vitro stability and specificity. The results of immuno-PET showed that 124I-AK104 revealed strong hPD1/CTLA4-positive responses with high specificity in humanized mice. High uptake of 124I-AK104 was observed not only at the tumor site but also in the spleen. Compared with PD1- or CTLA4-targeting mAb imaging, 124I-AK104 imaging had excellent standard uptake values at the tumor site and higher tumor to nontumor (T/NT) ratios. CONCLUSIONS: The results demonstrated the potential of translating 124I-AK104 into a method for screening patients who benefit from immunotherapy and the efficacy, as well as the feasibility, of this method was verified by immuno-PET imaging of humanized mice.


Asunto(s)
Anticuerpos Biespecíficos , Antígeno CTLA-4 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Receptor de Muerte Celular Programada 1 , Animales , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/inmunología , Humanos , Ratones , Antígeno CTLA-4/inmunología , Línea Celular Tumoral , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/inmunología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Radioisótopos de Yodo , Ensayos Antitumor por Modelo de Xenoinjerto , Distribución Tisular , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Femenino
12.
Redox Biol ; 71: 103103, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38471282

RESUMEN

Although some cohort studies have indicated a close association between diabetes and HCC, the underlying mechanism about the contribution of diabetes to HCC progression remains largely unknown. In the study, we applied a novel HCC model in SD rat with diabetes and a series of high glucose-stimulated cell experiments to explore the effect of a high glucose environment on HCC metastasis and its relevant mechanism. Our results uncovered a novel regulatory mechanism by which nuclear translocation of metabolic enzyme PKM2 mediated high glucose-promoted HCC metastasis. Specifically, high glucose-increased PKM2 nuclear translocation downregulates chemerin expression through the redox protein TRX1, and then strengthens immunosuppressive environment to promote HCC metastasis. To the best of our knowledge, this is the first report to elucidate the great contribution of a high glucose environment to HCC metastasis from a new perspective of enhancing the immunosuppressive microenvironment. Simultaneously, this work also highlights a previously unidentified non-metabolic role of PKM2 and opens a novel avenue for cross research and intervention for individuals with HCC and comorbid diabetes.


Asunto(s)
Carcinoma Hepatocelular , Diabetes Mellitus , Neoplasias Hepáticas , Animales , Humanos , Ratas , Carcinoma Hepatocelular/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Glucosa , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratas Sprague-Dawley , Proteínas de Unión a Hormona Tiroide , Microambiente Tumoral
13.
Biomolecules ; 14(3)2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38540796

RESUMEN

Ischemic stroke is a fatal and disabling disease worldwide and imposes a significant burden on society. At present, biological markers that can be conveniently measured in body fluids are lacking for the diagnosis of ischemic stroke, and there are no effective treatment methods to improve neurological function after ischemic stroke. Therefore, new ways of diagnosing and treating ischemic stroke are urgently needed. The neurovascular unit, composed of neurons, astrocytes, microglia, and other components, plays a crucial role in the onset and progression of ischemic stroke. Extracellular vesicles are nanoscale lipid bilayer vesicles secreted by various cells. The key role of extracellular vesicles, which can be released by cells in the neurovascular unit and serve as significant facilitators of cellular communication, in ischemic stroke has been extensively documented in recent literature. Here, we highlight the role of neurovascular unit-derived extracellular vesicles in the diagnosis and treatment of ischemic stroke, the current status of extracellular vesicle engineering for ischemic stroke treatment, and the problems encountered in the clinical translation of extracellular vesicle therapies. Extracellular vesicles derived from the neurovascular unit could provide an important contribution to diagnostic and therapeutic tools in the future, and more studies in this area should be carried out.


Asunto(s)
Vesículas Extracelulares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/terapia , Barrera Hematoencefálica , Astrocitos
14.
iScience ; 27(3): 109193, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38433916

RESUMEN

In some vertebrates and invertebrates, semen release factors affecting female physiology and behavior. Here, we report that semen delivered to females is potentially beneficial for promoting oocyte development in a viviparous teleost, Sebastes schlegelii. 88% of mated ovaries develop normally and give birth to larval fish, whereas 61% of non-mated ovaries are arrested in the previtellogenic stage. Semen's significant role (p < 0.0001) in promoting oocyte development may involve remodeling follicular cells and regulating the expression of the extracellular matrix, which facilitates cell communication. Furthermore, the ovarian response to semen may influence the brain, affecting hormone release, follicular cell development and steroid production, and crucial for oocyte growth. This mechanism, which could potentially delay maternal investment in offspring until male genetic input occurs to avoid energy wastage, has not been previously described in teleosts. These findings enhance our understanding of ovarian development in viviparous fish, with broader implications for reproductive biology.

15.
Cell Death Discov ; 10(1): 153, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38531909

RESUMEN

Glutamate receptor (GluR)-mediated excitotoxicity is an important mechanism causing delayed neuronal injury after traumatic brain injury (TBI). Preso, as a core scaffolding protein of postsynaptic density (PSD), is considered an important regulator during excitotoxicity and TBI and combines with glutamate receptors to form functional units for excitatory glutamatergic neurotransmission, and elucidating the mechanisms of these functional units will provide new targets for the treatment of TBI. As a multidomain scaffolding protein, Preso directly interacts with metabotropic GluR (mGluR) and another scaffold protein, Homer. Because the mGluR-Homer complex plays a crucial role in TBI, modulation of this complex by Preso may be an important mechanism affecting the excitotoxic damage to neurons after TBI. Here, we demonstrate that Preso facilitates the interaction between metabotropic mGluR1 and Homer1 to activate mGluR1 signaling and cause excitotoxic neuronal injury and endoplasmic reticulum (ER) stress after TBI. The regulatory effect of Preso on the mGluR1-Homer1 complex is dependent on the direct association between Preso and this complex and also involves the phosphorylation of the interactive binding sites of mGluR1 and Homer1 by Preso. Further studies confirmed that Preso, as an adaptor of cyclin-dependent kinase 5 (CDK5), promotes the phosphorylation of the Homer1-binding site on mGluR1 by CDK5 and thereby enhances the interaction between mGluR1 and Homer1. Preso can also promote the formation of the mGluR1-Homer1 complex by inhibiting the phosphorylation of the Homer1 hinge region by Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα). Based on these molecular mechanisms, we designed several blocking peptides targeting the interaction between Preso and the mGluR1-Homer1 complex and found that directly disrupting the association between mGluR1 and scaffolding proteins significantly promotes the recovery of motor function after TBI.

16.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(2): 188-193, 2024 Feb 15.
Artículo en Chino | MEDLINE | ID: mdl-38436318

RESUMEN

OBJECTIVES: To study the in vitro expression of three phenylalanine hydroxylase (PAH) mutants (p.R243Q, p.R241C, and p.Y356X) and determine their pathogenicity. METHODS: Bioinformatics techniques were used to predict the impact of PAH mutants on the structure and function of PAH protein. Corresponding mutant plasmids of PAH were constructed and expressed in HEK293T cells. Quantitative reverse transcription polymerase chain reaction was used to measure the mRNA expression levels of the three PAH mutants, and their protein levels were assessed using Western blot and enzyme-linked immunosorbent assay. RESULTS: Bioinformatics analysis predicted that all three mutants were pathogenic. The mRNA expression levels of the p.R243Q and p.R241C mutants in HEK293T cells were similar to the mRNA expression level of the wild-type control (P>0.05), while the mRNA expression level of the p.Y356X mutant significantly decreased (P<0.05). The PAH protein expression levels of all three mutants were significantly reduced compared to the wild-type control (P<0.05). The extracellular concentration of PAH protein was reduced in the p.R241C and p.Y356X mutants compared to the wild-type control (P<0.05), while there was no significant difference between the p.R243Q mutant and the wild type control (P>0.05). CONCLUSIONS: p.R243Q, p.R241C and p.Y356X mutants lead to reduced expression levels of PAH protein in eukaryotic cells, with p.R241C and p.Y356X mutants also affecting the function of PAH protein. These three PAH mutants are to be pathogenic.


Asunto(s)
Fenilalanina Hidroxilasa , Humanos , Células HEK293 , Fenilalanina Hidroxilasa/genética , Western Blotting , Biología Computacional , ARN Mensajero
17.
Materials (Basel) ; 17(6)2024 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-38541524

RESUMEN

This study investigates how deviation angles close to the [001] orientation affect the tensile properties and deformation behavior of a nickel-based single-crystal superalloy at room temperature. The research focuses on samples with deviation angles of 3°, 8°, and 13° from the [001] orientation and examines their strength and ductility. We employed scanning electron microscopy (SEM), electron backscatter diffraction (EBSD), and transmission electron microscopy (TEM) to explore the deformation micro-mechanisms at varying angles. Findings reveal that strength decreases and ductility increases as the deviation angle widens within the [001] vicinity. The study emphasizes that <110> octahedral slip-driven crystal slip and rotation are crucial for understanding tensile deformation. The deformation differences in samples at varying angles are attributed to the differential engagement of mechanisms. Specifically, at lower angles, reduced ductility and increased strength are due to short lattice rotation paths and work hardening causing superlattice stacking faults (SSFs) to slip in two directions on the {111} plane within the γ' phase. As the angles increase, the lattice rotation paths extend, and Shockley partial dislocations (a/6<112>) accumulate in γ channels. This process, involving SSFs moving in a single direction within the γ' phase, results in higher ductility and reduced strength.

18.
Environ Res ; 251(Pt 1): 118578, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38423498

RESUMEN

Biochar produced from bio-wastes has been widely used to promote the performance of anaerobic digestion. Waste activated sludge (WAS) is considered as a kind of popular precursor for biochar preparation, but the abundant resources in WAS were neglected previously. In this study, the roles of biochar prepared from raw, pretreated, and fermented sludge on anaerobic digestion were investigated. That is, parts of carbon sources and nutrients like polysaccharides, proteins, and phosphorus were firstly recovered after sludge pretreatment or fermentation, and then the sludge residuals were used as raw material to prepare biochar. The methane yield improved by 22.1% with adding the biochar (AK-BC) prepared by sludge residual obtained from alkaline pretreatment. Mechanism study suggested that the characteristics of AK-BC like specific surface area and defect levels were updated. Then, the conversion performance of intermediate metabolites and electro-activities of extracellular polymeric substances were up-regulated. As a result, the activity of electron transfer was increased with the presence of AK-BC, with increase ratio of 21.4%. In addition, the electroactive microorganisms like Anaerolineaceae and Methanosaeta were enriched with the presence of AK-BC, and the potential direct interspecies electron transfer was possibly established. Moreover, both aceticlastic and CO2-reducing methanogenesis pathways were improved by up-regulating related enzymes. Therefore, the proposed strategy can not only obtain preferred biochar but also recover abundant resources like carbon source, nutrients, and bioenergy.


Asunto(s)
Carbón Orgánico , Metano , Aguas del Alcantarillado , Carbón Orgánico/química , Aguas del Alcantarillado/química , Aguas del Alcantarillado/microbiología , Anaerobiosis , Metano/metabolismo , Eliminación de Residuos Líquidos/métodos , Álcalis/química , Reactores Biológicos
19.
Nat Commun ; 15(1): 805, 2024 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-38280898

RESUMEN

Simultaneously generating various motion modes with high strains in piezoelectric devices is highly desired for high-technology fields to achieve multi-functionalities. However, traditional approach for designing multi-degrees-of-freedom systems is to bond together several multilayer piezoelectric stacks, which generally leads to cumbersome and complicated structures. Here, we proposed a transparent piezo metasurface to achieve various types of strains in a wide frequency range. As an example, we designed a ten-unit piezo metasurface, which can produce high strains (ε3 = 0.76%), and generate linear motions along X-, Y- and Z-axis, rotary motions around X-, Y- and Z-axis as well as coupled modes. An adaptive lens based on the proposed piezo metasurface was demonstrated. It can realize a wide range of focal length (35.82 cm ~ ∞) and effective image stabilization with relatively large displacements (5.05 µm along Y-axis) and tilt angles (44.02' around Y-axis). This research may benefit the miniaturization and integration of multi-degrees-of-freedom systems.

20.
J Am Chem Soc ; 146(1): 627-634, 2024 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-38133431

RESUMEN

The self-healing behavior has been extensively used in intelligent sensing systems capable of molecular recognition. However, most rigid crystalline frameworks, once collapsed under external stimuli like pressure, heat, or vacuum, could hardly recover to their crystalline phases under ambient conditions. Here, we report the self-healing of a new microporous hydrogen-bonded organic framework, FDU-HOF-3 (FDU = Fudan University), for ammonia (NH3) capture and compared it with the established mesoporous HOF-101. With the introduction of low-concentration NH3 into the pores, the HOFs became disordered but were then simply heated under a vacuum to return to their original crystalline states after NH3 removal. Close characterizations revealed that the repeatable self-healing behavior of these HOFs was achieved due to the COOH-NH3 acid-base interactions accompanied by the breaking and regeneration of complementary COOH-COOH hydrogen bonds. FDU-HOF-3 showed a record-capturing capability for low-concentration NH3 (8.13 mmol/g at 25 mbar) among all HOFs and displayed a quick photocurrent decrease after exposure to 250 ppm NH3 for less than 10 s. These self-healing HOFs were used to capture and release NH3 for over 10 cycles without any decrease in the adsorption capacities.

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