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1.
Nature ; 607(7917): 142-148, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35732734

RESUMEN

The divergence of the common dendritic cell progenitor1-3 (CDP) into the conventional type 1 and type 2 dendritic cell (cDC1 and cDC2, respectively) lineages4,5 is poorly understood. Some transcription factors act in the commitment of already specified progenitors-such as BATF3, which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer4,6-but the mechanisms controlling the initial divergence of CDPs remain unknown. Here we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis7 suggested that Nfil3 acts upstream of Id2, Batf3 and Zeb2 in cDC1 development but did not reveal its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and chromatin immunoprecipitation followed by sequencing identified endogenous NFIL3 binding in the -165 kb Zeb2 enhancer8 at three sites that also bind the CCAAT-enhancer-binding proteins C/EBPα and C/EBPß. In vivo mutational analysis using CRISPR-Cas9 targeting showed that these NFIL3-C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites. A triple mutation of all three NFIL3-C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing the complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice did not generate T helper 2 (TH2) cell responses against Heligmosomoides polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths9-11. Thus, CDP divergence into cDC1 or cDC2 is controlled by competition between NFIL3 and C/EBPs at the -165 kb Zeb2 enhancer.


Asunto(s)
Diferenciación Celular , Células Dendríticas , Elementos de Facilitación Genéticos , Mutación , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Diferenciación Celular/genética , Células Dendríticas/clasificación , Células Dendríticas/citología , Células Dendríticas/patología , Elementos de Facilitación Genéticos/genética , Epistasis Genética , Proteína 2 Inhibidora de la Diferenciación , Linfocitos/citología , Ratones , Células Mieloides/citología , Nematospiroides dubius/inmunología , Proteínas Represoras , Células Th2/citología , Células Th2/inmunología , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética
2.
Nat Mater ; 23(10): 1402-1410, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39198713

RESUMEN

Novel two-dimensional semiconductor crystals can exhibit diverse physical properties beyond their inherent semiconducting attributes, making their pursuit paramount. Memristive properties, as exemplars of these attributes, are predominantly manifested in wide-bandgap materials. However, simultaneously harnessing semiconductor properties alongside memristive characteristics to produce memtransistors is challenging. Herein we prepared a class of semiconducting III-V-derived van der Waals crystals, specifically the HxA1-xBX form, exhibiting memristive characteristics. To identify candidates for the material synthesis, we conducted a systematic high-throughput screening, leading us to 44 prospective III-V candidates; of these, we successfully synthesized ten, including nitrides, phosphides, arsenides and antimonides. These materials exhibited intriguing characteristics such as electrochemical polarization and memristive phenomena while retaining their semiconductive attributes. We demonstrated the gate-tunable synaptic and logic functions within single-gate memtransistors, capitalizing on the synergistic interplay between the semiconducting and memristive properties of our two-dimensional crystals. Our approach guides the discovery of van der Waals materials with unique properties from unconventional crystal symmetries.

3.
Chem Rev ; 123(19): 11230-11268, 2023 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-37589590

RESUMEN

Polymorphic 2D materials allow structural and electronic phase engineering, which can be used to realize energy-efficient, cost-effective, and scalable device applications. The phase engineering covers not only conventional structural and metal-insulator transitions but also magnetic states, strongly correlated band structures, and topological phases in rich 2D materials. The methods used for the local phase engineering of 2D materials include various optical, geometrical, and chemical processes as well as traditional thermodynamic approaches. In this Review, we survey the precise manipulation of local phases and phase patterning of 2D materials, particularly with ideal and versatile phase interfaces for electronic and energy device applications. Polymorphic 2D materials and diverse quantum materials with their layered, vertical, and lateral geometries are discussed with an emphasis on the role and use of their phase interfaces. Various phase interfaces have demonstrated superior and unique performance in electronic and energy devices. The phase patterning leads to novel homo- and heterojunction structures of 2D materials with low-dimensional phase boundaries, which highlights their potential for technological breakthroughs in future electronic, quantum, and energy devices. Accordingly, we encourage researchers to investigate and exploit phase patterning in emerging 2D materials.

4.
Proc Natl Acad Sci U S A ; 119(46): e2215528119, 2022 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-36343258

RESUMEN

Group 2 innate lymphoid cells (ILC2) are innate counterparts of T helper 2 (Th2) cells that maintain tissue homeostasis and respond to injuries through rapid interleukin (IL)-5 and IL-13 secretion. ILC2s depend on availability of arginine and branched-chain amino acids for sustaining cellular fitness, proliferation, and cytokine secretion in both steady state and upon activation. However, the contribution of amino acid transporters to ILC2 functions is not known. Here, we found that ILC2s selectively express Slc7a8, encoding a transporter for arginine and large amino acids. Slc7a8 was expressed in ILC2s in a tissue-specific manner in steady state and was further increased upon activation. Genetic ablation of Slc7a8 in lymphocytes reduced the frequency of ILC2s, suppressed IL-5 and IL-13 production upon stimulation, and impaired type 2 immune responses to helminth infection. Consistent with this, Slc7a8-deficient ILC2s also failed to induce cytokine production and recruit eosinophils in a model of allergic lung inflammation. Mechanistically, reduced amino acid availability due to Slc7a8 deficiency led to compromised mitochondrial oxidative phosphorylation, as well as impaired activation of mammalian target of rapamycin and c-Myc signaling pathways. These findings identify Slc7a8 as a key supplier of amino acids for the metabolic programs underpinning fitness and activation of ILC2s.


Asunto(s)
Inmunidad Innata , Linfocitos , Interleucina-13/genética , Aminoácidos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Homeostasis , Arginina , Citocinas/metabolismo , Interleucina-33 , Pulmón/metabolismo
5.
Proc Natl Acad Sci U S A ; 119(23): e2204557119, 2022 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-35653568

RESUMEN

C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α− conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4− eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.


Asunto(s)
Eosinófilos , Receptores de Hidrocarburo de Aril , Receptores de Superficie Celular , Eosinofilia/terapia , Hipersensibilidad a los Alimentos/terapia , Inmunomodulación , Intestino Delgado , Recuento de Leucocitos , Ligandos , Receptores de Hidrocarburo de Aril/genética
6.
J Neurosci ; 43(11): 1976-1986, 2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36788030

RESUMEN

Recent evidence suggests that, in the absence of any task, spontaneous brain activity patterns and connectivity in the visual and motor cortex code for natural stimuli and actions, respectively. These "resting-state" activity patterns may underlie the maintenance and consolidation (replay) of information states coding for ecological stimuli and behaviors. In this study, we examine whether replay patterns occur in resting-state activity in association cortex grouped into high-order cognitive networks not directly processing sensory inputs or motor outputs. Fifteen participants (7 females) performed four hand movements during an fMRI study. Three movements were ecological. The fourth movement as control was less ecological. Before and after the task scans, we acquired resting-state fMRI scans. The analysis examined whether multivertex task activation patterns for the four movements computed at the cortical surface in different brain networks resembled spontaneous activity patterns measured at rest. For each movement, we computed a vector of r values indicating the strength of the similarity between the mean task activation pattern and frame-by-frame resting-state patterns. We computed a cumulative distribution function of r 2 values and used the 90th percentile cutoff value for comparison. In the dorsal attention network, resting-state patterns were more likely to match task patterns for the ecological movements than the control movement. In contrast, rest-task pattern correlation was more likely for less ecological movement in the ventral attention network. These findings show that spontaneous activity patterns in human attention networks code for hand movements.SIGNIFICANCE STATEMENT fMRI indirectly measures neural activity noninvasively. Resting-state (spontaneous) fMRI signals measured in the absence of any task resemble signals evoked by task performance both in topography and inter-regional (functional) connectivity. However, the function of spontaneous brain activity is unknown. We recently showed that spatial activity patterns evoked by visual and motor tasks in visual and motor cortex, respectively, occur at rest in the absence of any stimulus or response. Here we show that activity patterns related to hand movements replay at rest in frontoparietal regions of the human attention system. These findings show that spontaneous activity in the human cortex may mediate the maintenance and consolidation of information states coding for ecological stimuli and behaviors.


Asunto(s)
Mapeo Encefálico , Encéfalo , Femenino , Humanos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Mano , Movimiento , Análisis y Desempeño de Tareas , Imagen por Resonancia Magnética
7.
Small ; 20(15): e2308872, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37994300

RESUMEN

Chemotherapy using a nanoscaled drug delivery system is an effective cancer therapy, but its high drug concentration often causes drug resistance in cancer cells and normal cell damage. Combination therapy involving two or more different cell signaling pathways can be a powerful tool to overcome the limitations of chemotherapy. Herein, this article presents nanogel (NG)-mediated co-delivery of a chemodrug camptothecin (CPT) and mitochondria-targeting monomer (MT monomer) for efficient activation of two modes of the programmed cell death pathway (apoptosis and necroptosis) and synergistic enhancement of cancer therapy. CPT and the monomer are incorporated together into the redox-degradable polymeric NGs for release in response to the intracellular glutathione. The MT monomer is shown to undergo reactive oxygen species (ROS)-triggered disulfide polymerization inside the cancerous mitochondria in cooperation with the chemotherapeutic CPT elevating the intracellular ROS level. The CPT/monomer interconnection in cell death mechanisms for mitochondrial dysfunction and enhanced cell death is evidenced by a series of cell analyses showing ROS generation, mitochondria damage, impacts on (non)cancerous or drug-resistant cells, and cell death modes. The presented work provides beneficial insights for utilizing combination therapy to facilitate a desired cell death mechanism and developing a novel nanosystem for more efficacious cancer treatment.


Asunto(s)
Disulfuros , Neoplasias , Polietilenglicoles , Polietileneimina , Humanos , Nanogeles , Preparaciones Farmacéuticas , Disulfuros/farmacología , Especies Reactivas de Oxígeno/metabolismo , Polimerizacion , Muerte Celular , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Camptotecina/farmacología , Camptotecina/uso terapéutico
8.
Small ; 20(2): e2304592, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37688336

RESUMEN

An approach for synthesizing AgInZnS/CdS/ZnS core-shell-shell quantum dots (QDs) that demonstrate exceptional stability and electroluminescence (EL) performance is introduced. This approach involves incorporating a cadmium sulfide (CdS) interlayer between an AgInZnS (AIZS) core and a zinc sulfide (ZnS) shell to prevent the diffusion of Zn ions into the AIZS core and the cation exchange at the core-shell interface. Consequently, a uniform and thick ZnS shell, with a thickness of 2.9 nm, is formed, which significantly enhances the stability and increases the photoluminescence quantum yield (87.5%) of the QDs. The potential for AIZS/CdS/ZnS QDs in electroluminescent devices is evaluated, and an external quantum efficiency of 9.6% in the 645 nm is achieved. These findings highlight the importance of uniform and thick ZnS shells in improving the stability and EL performance of QDs.

9.
J Integr Neurosci ; 23(6): 122, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38940090

RESUMEN

BACKGROUND: Rheum tanguticum root, cataloged as "Daehwang" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations containing Daehwang are traditionally employed for treating neurological conditions. This study aimed to substantiate the antiepileptic and neuroprotective efficacy of R. tanguticum root extract (RTE) against trimethyltin (TMT)-induced epileptic seizures and hippocampal neurodegeneration. METHODS: The constituents of RTE were identified by ultra-performance liquid chromatography (UPLC). Experimental animals were grouped into the following five categories: control, TMT, and three TMT+RTE groups with dosages of 10, 30, and 100 mg/kg. Seizure severity was assessed daily for comparison between the groups. Brain tissue samples were examined to determine the extent of neurodegeneration and neuroinflammation using histological and molecular biology techniques. Network pharmacology analysis involved extracting herbal targets for Daehwang and disease targets for epilepsy from multiple databases. A protein-protein interaction network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and pivotal targets were determined by topological analysis. Enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool to elucidate the underlying mechanisms. RESULTS: The RTE formulation was found to contain sennoside A, sennoside B, chrysophanol, emodin, physcion, (+)-catechin, and quercetin-3-O-glucuronoid. RTE effectively inhibited TMT-induced seizures at 10, 30, and 100 mg/kg dosages and attenuated hippocampal neuronal decay and neuroinflammation at 30 and 100 mg/kg dosages. Furthermore, RTE significantly reduced mRNA levels of tumor necrosis factor (TNF-α), glial fibrillary acidic protein (GFAP), and c-fos in hippocampal tissues. Network analysis revealed TNF, Interleukin-1 beta (IL-1ß), Interleukin-6 (IL-6), Protein c-fos (FOS), RAC-alpha serine/threonine-protein kinase (AKT1), and Mammalian target of rapamycin (mTOR) as the core targets. Enrichment analysis demonstrated significant involvement of R. tanguticum components in neurodegeneration (p = 4.35 × 10-5) and TNF signaling pathway (p = 9.94 × 10-5). CONCLUSIONS: The in vivo and in silico analyses performed in this study suggests that RTE can potentially modulate TMT-induced epileptic seizures and neurodegeneration. Therefore, R. tanguticum root is a promising herbal treatment option for antiepileptic and neuroprotective applications.


Asunto(s)
Anticonvulsivantes , Modelos Animales de Enfermedad , Epilepsia , Hipocampo , Fármacos Neuroprotectores , Extractos Vegetales , Raíces de Plantas , Rheum , Compuestos de Trimetilestaño , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Rheum/química , Raíces de Plantas/química , Masculino , Anticonvulsivantes/farmacología , Epilepsia/tratamiento farmacológico , Epilepsia/inducido químicamente , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Simulación por Computador , Farmacología en Red , Mapas de Interacción de Proteínas , Ratas
10.
Sensors (Basel) ; 24(6)2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38544078

RESUMEN

This paper highlights the significance of safety and reliability in modern industries, particularly in sectors like petroleum and LNG, where safety valves play a critical role in ensuring system safety under extreme conditions. To enhance the reliability of these valves, this study aims to develop a deep learning-based prognostics and health management (PHM) model. Past empirical methods have limitations, driving the need for data-driven prediction models. The proposed model monitors safety valve performance, detects anomalies in real time, and prevents accidents caused by system failures. The research focuses on collecting sensor data, analyzing trends for lifespan prediction and normal operation, and integrating data for anomaly detection. This study compares related research and existing models, presents detailed results, and discusses future research directions. Ultimately, this research contributes to the safe operation and anomaly detection of pilot-operated cryogenic safety valves in industrial settings.


Asunto(s)
Aprendizaje Profundo , Pronóstico , Reproducibilidad de los Resultados , Industrias , Longevidad
11.
Sensors (Basel) ; 24(11)2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38894334

RESUMEN

Amnestic mild cognitive impairment (aMCI) is a transitional stage between normal aging and Alzheimer's disease, making early screening imperative for potential intervention and prevention of progression to Alzheimer's disease (AD). Therefore, there is a demand for research to identify effective and easy-to-use tools for aMCI screening. While behavioral tests in virtual reality environments have successfully captured behavioral features related to instrumental activities of daily living for aMCI screening, further investigations are necessary to establish connections between cognitive decline and neurological changes. Utilizing electroencephalography with steady-state visual evoked potentials, this study delved into the correlation between behavioral features recorded during virtual reality tests and neurological features obtained by measuring neural activity in the dorsal stream. As a result, this multimodal approach achieved an impressive screening accuracy of 98.38%.


Asunto(s)
Disfunción Cognitiva , Electroencefalografía , Potenciales Evocados Visuales , Realidad Virtual , Humanos , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/fisiopatología , Electroencefalografía/métodos , Anciano , Masculino , Femenino , Potenciales Evocados Visuales/fisiología , Enfermedad de Alzheimer/fisiopatología , Pruebas Neuropsicológicas , Actividades Cotidianas , Persona de Mediana Edad
12.
Odontology ; 112(4): 1307-1315, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38429393

RESUMEN

This randomized clinical trial compared postoperative pain between a minimally invasive (MP) and conventional root canal treatment protocol (CP). A total of 170 mature permanent teeth (either with vital or necrotic pulp), were randomly assigned into two groups. In the CP group, ProTaper Gold (Dentsply Sirona, Ballaigues, Switzerland) and a continuous wave of condensation technique were used, whereas, in the MP group, TruNatomy (Dentsply Sirona), ultrasonic-assisted irrigation (UI), calcium hydroxide, and a sealer-based obturation technique were used. Patients recorded preoperative and postoperative pain using a 0-10 numerical rating scale (NRS) at 4 h, 1, 2, 3, 4, 5, 6, and 7 days after instrumentation and 1 day after canal obturation, respectively. There were no significant differences in pain intensity at any time points assessed between the two groups (p > 0.05). The occurrence of moderate/intense pain after instrumentation was significantly associated with preoperative periapical index (PAI) (p = 0.017) and NRS scores (p < 0.001). Preoperative pulp status (p = 0.009) and NRS score (p = 0.006) were identified as significant factors in the occurrence of moderate/intense pain after obturation. Instrumentation unequivocally reduced pain severity for both groups. The post-endodontic pain associated with the use of MP, combined with UI, Ca(OH)2, and calcium-silicate cement, did not differ from that of CP. Preoperative pain score, PAI, and preoperative pulp status were determined to be prognostic factors for postoperative pain.


Asunto(s)
Hidróxido de Calcio , Dimensión del Dolor , Dolor Postoperatorio , Tratamiento del Conducto Radicular , Humanos , Femenino , Masculino , Adulto , Hidróxido de Calcio/uso terapéutico , Procedimientos Quirúrgicos Mínimamente Invasivos , Obturación del Conducto Radicular/métodos , Persona de Mediana Edad , Resultado del Tratamiento , Materiales de Obturación del Conducto Radicular/uso terapéutico
13.
BMC Oral Health ; 24(1): 865, 2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39080607

RESUMEN

BACKGROUND: Recent studies have reported the inhomogeneity in the light emitted by dental light-curing units (LCUs). It is essential to understand how this uneven light distribution affects the physical properties of resin-based composites (RBCs) at various points across their surfaces. This study aimed to evaluate the effect of LCU beam's inhomogeneity on the microhardness of RBCs with different shades and thicknesses. METHODS: Four body (A1B, A2B, A3B, and A4B), one dentin (A3D), and one enamel shade (A3E) of RBC (Filtek Z350 XT) were examined. The specimens were fabricated in four thicknesses (1, 2, 3, and 4 mm) and subjected to a 40-second light-curing. Vickers microhardness testing was performed at the center point, and 3 mm left and right from the center at the bottom surface of each sample. The LCU beam profile was characterized using a beam profiler, while irradiance after specimen passage was measured using a spectrometer. One-way analysis of variance (ANOVA) and Tukey's post-hoc tests were used to analyze the effects of shades and thicknesses on irradiance and microhardness, respectively. One-way repeated-measures ANOVA was used to compare the microhardness across different points. Pearson's correlation analysis examined the relationship between irradiance and microhardness. RESULTS: The beam profile of LCU revealed inhomogeneous light distribution. Light irradiance was decreased with both the increase in thickness and darker shade of the specimens (p < 0.05). Microhardness was found to decline with an increase in sample thickness (p < 0.05), and was consistently higher at the center point compared to the periphery, particularly in thicker (3 and 4 mm) and darker shades (A3B, A4B, and A3D). A positive correlation was found between the irradiance and microhardness across all evaluated points (p < 0.05). CONCLUSIONS: Inhomogeneous light emission from LCU significantly influences the microhardness of RBC samples, depending on the thicknesses and shades. The findings underline the importance of considering LCU beam inhomogeneity in clinical settings to ensure optimal polymerization of RBC.


Asunto(s)
Color , Resinas Compuestas , Luces de Curación Dental , Dureza , Ensayo de Materiales , Resinas Compuestas/efectos de la radiación , Resinas Compuestas/química , Humanos , Propiedades de Superficie , Curación por Luz de Adhesivos Dentales/métodos , Esmalte Dental/efectos de la radiación , Dentina/efectos de la radiación , Materiales Dentales/efectos de la radiación , Materiales Dentales/química , Polimerizacion , Luz
14.
J Am Chem Soc ; 145(33): 18414-18431, 2023 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-37525328

RESUMEN

Lysosomes remain powerful organelles and important targets for cancer therapy because cancer cell proliferation is greatly dependent on effective lysosomal function. Recent studies have shown that lysosomal membrane permeabilization induces cell death and is an effective way to treat cancer by bypassing the classical caspase-dependent apoptotic pathway. However, most lysosome-targeted anticancer drugs have very low selectivity for cancer cells. Here, we show intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. We designed a peptide amphiphile that localizes in the cancer lysosome and undergoes cathepsin B enzyme-instructed supramolecular assembly. This localized assembly induces lysosomal swelling, membrane permeabilization, and damage to the lysosome, which eventually causes caspase-independent apoptotic death of cancer cells without conventional chemotherapeutic drugs. It has specific anticancer effects and is effective against drug-resistant cancers. Moreover, this peptide amphiphile exhibits high tumor targeting when attached to a tumor-targeting ligand and causes significant inhibition of tumor growth both in cancer and drug-resistant cancer xenograft models.


Asunto(s)
Apoptosis , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Lisosomas/metabolismo , Caspasas/metabolismo , Péptidos/farmacología , Péptidos/metabolismo , Línea Celular Tumoral
15.
J Am Chem Soc ; 145(40): 21991-22008, 2023 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-37664981

RESUMEN

Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvß3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvß3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.


Asunto(s)
Senescencia Celular , Senoterapéuticos , Ratones , Animales , Especies Reactivas de Oxígeno , Péptidos/farmacología , Integrinas
16.
Trends Immunol ; 41(1): 7-16, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31787504

RESUMEN

Group 2 innate lymphoid cells (ILC2s) mediate allergic immunity but have also recently come into focus as key sentinels of tissue health and homeostasis. Clues as to how these rare immune cells coordinate tissue-wide responses to perturbation have emerged from deciphering the communication between ILC2s and an ever-expanding list of diverse nonhematopoietic cells. High-resolution tracking and profiling approaches have accelerated these efforts, revealing ILC2 transcriptional programs that are coordinated with tissue and organism development. We propose that the engagement of these homeostatic feedback circuits by internal and external cues forms the basis for how tissues instruct type 2 immunity. Understanding how these normally restorative networks become unbalanced may be crucial in devising appropriately targeted therapies for allergic diseases.


Asunto(s)
Inmunidad Innata , Linfocitos , Homeostasis/inmunología , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/terapia , Inmunidad Innata/inmunología , Linfocitos/inmunología
17.
Oral Dis ; 2023 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-37927178

RESUMEN

INTRODUCTION: Medication-related osteonecrosis of the jaw (MRONJ) is uncommon but can result in severe destruction of the jaw. This case-control study investigated the therapeutic effects of daily or weekly administration of teriparatide in the management of MRONJ using a cohort for osteonecrosis of the jaw. METHODS: Patients who were diagnosed with MRONJ and consented to teriparatide administration were assigned either to a group of daily injection or of weekly injection and completed a 4-week course of injection preoperatively and at least an 8-week course postoperatively. The control group received either the intraoperative rhBMP treatment (CG_BMP) or no additional perioperative treatment (CG_noBMP). The state of MRONJ was evaluated 2 months (T1) and 6 months (T2) postoperatively for all participants. RESULTS: Either group of daily injection (8.35 weeks ± 1.58; n = 17) or weekly injection (9.17 ± 3.79; n = 12) showed significantly faster healing than those of CG_BMP (14.40 ± 6.08; n = 25) or CG_noBMP (15.79 ± 9.79; n = 39). MRONJ was resolved completely in 24 out of 29 participants who completed the course of teriparatide injections, whereas 46.9% of CG showed delayed resolution. Multiple regression analysis indicated 7.50 times (95% CI, 1.77-31.82) more likelihood of complete resolution of MRONJ for participants with teriparatide injections. CONCLUSION: A course of daily or weekly administration of teriparatide injections may improve treatment outcomes for patients with MRONJ.

18.
J Korean Med Sci ; 38(1): e15, 2023 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-36593691

RESUMEN

BACKGROUND: The purpose of this study was to identify the prevalence of posttraumatic embitterment disorder (PTED) among soldiers, and examine its relation to stress, depression, self-esteem, impulsiveness, and suicidal ideation. METHODS: The subjects of this study were 200 soldiers and 197 control subjects, a total of 397 persons. Measurement tools used included the PTED self-rating scale, Stress Response Inventory, Beck Depression Inventory, Rosenberg Self-Esteem Inventory, Barratt Impulsiveness Scale, and Beck Scale of Suicide Ideation. RESULT: The major findings of the analysis are as follows: first, 11.5% of the soldiers were in the risk group for PTED, and 4% of them had PTED. Second, PTED in the soldiers was significantly associated with a number of variables such as their educational background, stress, depression, self-esteem, impulsiveness, and suicidal ideation, while it was not significantly associated with age. Third, through the hierarchical multiple regression analysis, it was found that academic background, stress, and depression had a statistically significant positive effect on the incidence of PTED in the soldiers. CONCLUSION: In order to prevent and effectively intervene in PTED in soldiers, there is a need for interventional efforts focused on depression and stress related to negative life events.


Asunto(s)
Personal Militar , Ideación Suicida , Humanos , Depresión/complicaciones , Factores de Riesgo , República de Corea/epidemiología
19.
Sensors (Basel) ; 23(21)2023 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-37960630

RESUMEN

Drones, also known as unmanned aerial vehicles (UAVs) and sometimes referred to as 'Mobile IoT' or 'Flying IoT', are widely adopted worldwide, with their market share continuously increasing. While drones are generally harnessed for a wide range of positive applications, recent instances of drones being employed as lethal weapons in conflicts between countries like Russia, Ukraine, Israel, Palestine, and Hamas have demonstrated the potential consequences of their misuse. Such misuse poses a significant threat to cybersecurity and human lives, thereby highlighting the need for research to swiftly and accurately analyze drone-related crimes, identify the responsible pilot, and establish when and what illegal actions were carried out. In contrast to existing research, involving limited data collection and analysis of the drone, our study focused on collecting and rigorously analyzing data without restrictions from the remote controller used to operate the drone. This comprehensive approach allowed us to unveil essential details, including the pilot's account information, the specific drone used, pairing timestamps, the pilot's operational location, the drone's flight path, and the content captured during flights. We developed methodologies and proposed artifacts to reveal these specifics, which were supported by real-world data. Significantly, this study is the pioneering digital forensic investigation of remote controller devices. We meticulously collected and analyzed all internal data, and we even employed reverse engineering to decrypt critical information files. These achievements hold substantial significance. The outcomes of this research are expected to serve as a digital forensic methodology for drone systems, thereby making valuable contributions to numerous investigations.

20.
J Prosthet Dent ; 129(3): 478-485, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36621357

RESUMEN

STATEMENT OF PROBLEM: Support structures are essential for the quality of resin-based prostheses made by the digital light processing (DLP), but few studies have evaluated the effect of support structure on the accuracy of zirconia-based anatomic contour prostheses. PURPOSE: The purpose of this in vitro study was to evaluate the effect of maximum support attachment angle (MSA) on the intaglio surface trueness of anatomic contour prostheses made by DLP and compare the trueness of 2-unit anatomic contour prostheses with that of those produced by milling. MATERIAL AND METHODS: Anatomic contour single-unit prostheses were manufactured using DLP and a suspension with 3-mol% yttria-stabilized zirconia. Four different conditions of MSA values to the vertical axis of the object (50, 55, 60, and 65 degrees) were applied (n=10). After printing, postprocessing, and sintering, all successfully produced prostheses were evaluated for intaglio surface trueness by considering the root mean square (RMS). Using the MSA showing the highest trueness, the 2-unit prostheses made by DLP (DLP group) were compared with milled (MIL group) prostheses in terms of intaglio accuracy (n=10). One-way analysis of variance and a post hoc pairwise comparison or independent t test were used for trueness analysis (α=.05). RESULTS: Three MSA groups (50, 55, and 60 degrees) were successfully produced with significant differences between the trueness of the single-unit prostheses for the groups with different MSA values (P<.05). The highest trueness was in the 50-degree MSA group. The 2-unit prostheses of the DLP group with 50-degree MSA showed significantly lower trueness than those of the MIL group (P<.05); however, the RMS values of both groups were lower than 50 µm. CONCLUSIONS: The intaglio surface trueness of anatomic contour DLP-generated prostheses can be improved by changing the MSA. The 50-degree MSA was beneficial for the accuracy of both single-unit and 2-unit DLP-generated prostheses, produced within clinically acceptable limits.


Asunto(s)
Diseño Asistido por Computadora , Implantes Dentales , Circonio , Dentadura Completa
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