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1.
Ultrason Sonochem ; 110: 107021, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39153418

RESUMEN

The challenge of cavitation erosion (CE) in flow-handling components of marine engineering has promoted the development of advanced materials due to safety incidents and economic costs. High entropy alloys (HEAs), known for high hardness and corrosion resistance, emerge as promising candidates. This paper delved into the CE characteristics of CoCrFeNiMoCu0.1 HEA when subjected to the 3.5 wt% NaCl solution, elucidating the synergistic effect of CE-corrosion. The quantitative analysis revealed that CE-corrosion synergy contributed 48.02% to total CE mass loss, primarily attributed to corrosion-induced CE damage. Meanwhile, electrochemical noise (EN) was utilized to reveal the corrosion behavior of CoCrFeNiMoCu0.1 HEA in 3.5 wt% NaCl solution combined with the morphologies observation and surface roughness. Extended CE time compromised the corrosion resistance of CoCrFeNiMoCu0.1 HEA and diminished the impact of selective phase corrosion on the surface. Eventually, the CE damage mechanism of CoCrFeNiMoCu0.1 HEA was revealed based on pertinent experimental findings. The results showed that with increased CE time, the CoCrFeNiMoCu0.1 HEA transitioned from predominantly extensive exfoliation of the initial FCC phase to further damage of the intermetallic σ and µ phases.

2.
J Pineal Res ; 76(5): e12998, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39087379

RESUMEN

It is very crucial to investigate key molecules that are involved in myelination to gain an understanding of brain development and injury. We have reported for the first time that pathogenic variants p.R477H and p.P505S in KARS, which encodes lysyl-tRNA synthetase (LysRS), cause leukoencephalopathy with progressive cognitive impairment in humans. The role and action mechanisms of KARS in brain myelination during development are unknown. Here, we first generated Kars knock-in mouse models through the CRISPR-Cas9 system. Kars knock-in mice displayed significant cognitive deficits. These mice also showed significantly reduced myelin density and content, as well as significantly decreased myelin thickness during development. In addition, Kars mutations significantly induced oligodendrocyte differentiation arrest and reduction in the brain white matter of mice. Mechanically, oligodendrocytes' significantly imbalanced expression of differentiation regulators and increased capase-3-mediated apoptosis were observed in the brain white matter of Kars knock-in mice. Furthermore, Kars mutations significantly reduced the aminoacylation and steady-state level of mitochondrial tRNALys and decreased the protein expression of subunits of oxidative phosphorylation complexes in the brain white matter. Kars knock-in mice showed decreased activity of complex IV and significantly reduced ATP production and increased reactive oxygen species in the brain white matter. Significantly increased percentages of abnormal mitochondria and mitochondrion area were observed in the oligodendrocytes of Kars knock-in mouse brain. Finally, melatonin (a mitochondrion protectant) significantly attenuated mitochondrion and oligodendrocyte deficiency in the brain white matter of KarsR504H/P532S mice. The mice treated with melatonin also showed significantly restored myelination and cognitive function. Our study first establishes Kars knock-in mammal models of leukoencephalopathy and cognitive impairment and indicates important roles of KARS in the regulation of mitochondria, oligodendrocyte differentiation and survival, and myelination during brain development and application prospects of melatonin in KARS (or even aaRS)-related diseases.


Asunto(s)
Lisina-ARNt Ligasa , Melatonina , Vaina de Mielina , Oligodendroglía , Animales , Ratones , Aminoacil-ARNt Sintetasas/genética , Aminoacil-ARNt Sintetasas/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Técnicas de Sustitución del Gen , Leucoencefalopatías/genética , Leucoencefalopatías/metabolismo , Leucoencefalopatías/patología , Melatonina/metabolismo , Mutación , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Lisina-ARNt Ligasa/genética
3.
Ann Transl Med ; 12(4): 77, 2024 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-39118942

RESUMEN

Background and Objective: Pancreatic ductal adenocarcinoma (PDAC) is 3rd most lethal cancer in the USA leading to a median survival of six months and less than 5% 5-year overall survival (OS). As the only potentially curative treatment, surgical resection is not suitable for up to 90% of the patients with PDAC due to late diagnosis. Highly fibrotic PDAC with an immunosuppressive tumor microenvironment restricts cytotoxic T lymphocyte (CTL) infiltration and functions causing limited success with systemic therapies like dendritic cell (DC)-based immunotherapy. In this study, we investigated the potential benefits of irreversible electroporation (IRE) ablation therapy in combination with DC vaccine therapy against PDAC. Methods: We performed a literature search to identify studies focused on DC vaccine therapy and IRE ablation to boost therapeutic response against PDAC indexed in PubMed, Web of Science, and Scopus until February 20th, 2023. Key Content and Findings: IRE ablation destructs tumor structure while preserving extracellular matrix and blood vessels facilitating local inflammation. The studies demonstrated IRE ablation reduces tumor fibrosis and promotes CTL tumor infiltration to PDAC tumors in addition to boosting immune response in rodent models. The administration of the DC vaccine following IRE ablation synergistically enhances therapeutic response and extends OS rates compared to the use of DC vaccination or IRE alone. Moreover, the implementation of data-driven approaches further allows dynamic and longitudinal monitoring of therapeutic response and OS following IRE plus DC vaccine immunoablation. Conclusions: The combination of IRE ablation and DC vaccine immunotherapy is a potent strategy to enhance the therapeutic outcomes in patients with PDAC.

4.
Medicine (Baltimore) ; 103(30): e38747, 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39058887

RESUMEN

This study aims to develop and validate a machine learning (ML) predictive model for assessing mortality in patients with malignant tumors and hyperkalemia (MTH). We extracted data on patients with MTH from the Medical Information Mart for Intensive Care-IV, version 2.2 (MIMIC-IV v2.2) database. The dataset was split into a training set (75%) and a validation set (25%). We used the Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify potential predictors, which included clinical laboratory indicators and vital signs. Pearson correlation analysis tested the correlation between predictors. In-hospital death was the prediction target. The Area Under the Curve (AUC) and accuracy of the training and validation sets of 7 ML algorithms were compared, and the optimal 1 was selected to develop the model. The calibration curve was used to evaluate the prediction accuracy of the model further. SHapley Additive exPlanations (SHAP) and Local Interpretable Model-agnostic Explanations (LIME) enhanced model interpretability. 496 patients with MTH in the Intensive Care Unit (ICU) were included. After screening, 17 clinical features were included in the construction of the ML model, and the Pearson correlation coefficient was <0.8, indicating that the correlation between the clinical features was small. eXtreme Gradient Boosting (XGBoost) outperformed other algorithms, achieving perfect scores in the training set (accuracy: 1.000, AUC: 1.000) and high scores in the validation set (accuracy: 0.734, AUC: 0.733). The calibration curves indicated good predictive calibration of the model. SHAP analysis identified the top 8 predictive factors: urine output, mean heart rate, maximum urea nitrogen, minimum oxygen saturation, minimum mean blood pressure, maximum total bilirubin, mean respiratory rate, and minimum pH. In addition, SHAP and LIME performed in-depth individual case analyses. This study demonstrates the effectiveness of ML methods in predicting mortality risk in ICU patients with MTH. It highlights the importance of predictors like urine output and mean heart rate. SHAP and LIME significantly enhanced the model's interpretability.


Asunto(s)
Hiperpotasemia , Unidades de Cuidados Intensivos , Aprendizaje Automático , Neoplasias , Humanos , Hiperpotasemia/diagnóstico , Hiperpotasemia/mortalidad , Femenino , Masculino , Unidades de Cuidados Intensivos/estadística & datos numéricos , Persona de Mediana Edad , Pronóstico , Neoplasias/mortalidad , Neoplasias/complicaciones , Anciano , Mortalidad Hospitalaria , Algoritmos
5.
Molecules ; 29(13)2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38999159

RESUMEN

Poly(p-phenylene ethynylene) (PPE) molecular wires are one-dimensional materials with distinctive properties and can be applied in electronic devices. Here, the approach called first-principles quantum transport is utilized to investigate the PPE molecular wire field-effect transistor (FET) efficiency limit through the geometry of the gate-all-around (GAA) instrument. It is observed that the n-type GAA PPE molecular wire FETs with a suitable gate length (Lg = 5 nm) and underlap (UL = 1, 2, 3 nm) can gratify the on-state current (Ion), power dissipation (PDP), and delay period (τ) concerning the conditions in 2028 to achieve the higher performance (HP) request of the International Roadmap for Device and Systems (IRDS, 2022 version). In contrast, the p-type GAA PPE molecular wire FETs with Lg = 5, 3 nm, and UL of 1, 2, 3 nm could gratify the Ion, PDP, and τ concerning the 2028 needs to achieve the HP request of the IRDS in 2022, while Lg = 5 and UL = 3 nm could meet the Ion and τ concerning the 2028 needs to achieve the LP request of the IRDS in 2022. More importantly, this is the first one-dimensional carbon-based ambipolar FET. Therefore, the GAA PPE molecular wire FETs could be a latent choice to downscale Moore's law to 3 nm.

6.
Plant Physiol Biochem ; 214: 108891, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38959568

RESUMEN

Dendrobium loddigesii, a member of the Orchidaceae family, is a valuable horticultural crop known for its aromatic qualities. However, the mechanisms responsible for the development of its aromatic characteristics remain poorly understood. To elucidate these underlying mechanisms, we assembled the first chromosome-level reference genome of D. loddigesii using PacBio HiFi-reads, Illumina short-reads, and Hi-C data. The assembly comprises 19 pseudochromosomes with N50 contig and N50 scaffold sizes of 55.15 and 89.94 Mb, respectively, estimating the genome size to be 1.68 Gb, larger than that of other sequenced Dendrobium species. During the flowering stages, we conducted a comprehensive analysis combining volatilomics and transcriptomics to understand the characteristics and biosynthetic mechanisms pathways of the floral scent. Our findings emphasize the significant contribution of aromatic terpenoids, especially monoterpenoids, in defining the floral aroma. Furthermore, we identified two crucial terpene synthase (TPS) genes that play a key role in maintaining the aroma during flowering. Through the integration volatilomics data with catalytic assays of DlTPSbs proteins, we identified specific compounds responsible for the aromatic characteristics of D. loddigesii. This integrated analysis of the genome, transcriptome, and volatilome, offers valuable insights into the development and preservation of D. loddigesii's aromatic characteristics, setting the stage for further exploration of the botanical perfumer hypothesis.


Asunto(s)
Dendrobium , Flores , Dendrobium/genética , Dendrobium/metabolismo , Flores/genética , Flores/metabolismo , Odorantes , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Transcriptoma/genética , Genoma de Planta , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Regulación de la Expresión Génica de las Plantas , Multiómica
7.
Biology (Basel) ; 13(6)2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38927298

RESUMEN

The effects of tritium at low doses and low dose rates have received increasing attention due to recent developments in fusion energy and the associated risks of tritium releases into the environment. Mitochondria have been identified as a potential candidate for studying the effects of low-dose/low-dose-rate radiation, with extensive experimental results obtained using X-ray irradiation. In this study, irradiation experiments were conducted on normal B-lymphoblastoid cells using HTO at varying doses. When compared to X-ray irradiation, no significant differences in cell viability induced by different doses were observed. However, the results of ATP levels showed a significant difference between the irradiated sample at a dose of 500 mGy by tritium beta-rays and the sham-irradiated sample, while the levels obtained with X-ray irradiation were almost identical to the sham-irradiated sample. In contrast, ATP levels for both tritium beta-rays and X-rays at a dose of 1.0 Gy showed minimal differences compared to the sham-irradiated sample. Furthermore, distinct effects at 500 mGy were also confirmed in both ROS levels and apoptosis results obtained through tritium beta-ray irradiation. This suggests that mitochondria might be a potential sensitive target for investigating the effects of tritium beta-ray irradiation.

8.
Cell Death Discov ; 10(1): 228, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740771

RESUMEN

Chemotherapy is an important therapuetic strategy for colorectal cancer (CRC), but chemoresistance severely affects its efficacy, and the underlying mechanism has not been fully elucidated. Increasing evidence suggests that lipid peroxidation imbalance-mediated ferroptosis is closely associated with chemoresistance. Hence, targeting ferroptosis pathways or modulating the tolerance to oxidative stress might be an effective strategy to reverse tumor chemoresistance. HtrA serine protease 1 (HTRA1) was screened out as a CRC progression- and chemoresistance-related gene. It is highly expressed in CRC cells and negatively correlated with the prognosis of CRC patients. Gain- and loss-of-function analyses demonstrated a stimulatory role of HTRA1 on the proliferation of CRC cells. The enrichment analysis of HTRA1-interacting proteins indicated the involvement of ferroptosis in the HTRA1-mediated chemoresistance. Moreover, electron microscope analysis, as well as the ROS and MDA levels in CRC cells also confirmed the effect of HTRA1 on ferroptosis. We also verified that HTRA1 could interact with SLC7A11 through its Kazal structural domain and up-regulate the expression of SLC7A11, which in turn inhibited the ferroptosis and leaded to the chemoresistance of CRC cells to 5-FU/L-OHP. Hence, we propose that HTRA1 may be a potential therapeutic target and a prognostic indicator in CRC.

9.
J Fungi (Basel) ; 10(4)2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38667925

RESUMEN

Flavonoids are a diverse family of natural compounds that are widely distributed in plants and play a critical role in plant growth, development, and stress adaptation. In recent years, the biosynthesis of flavonoids in plants has been well-researched, with the successive discovery of key genes driving this process. However, the regulation of flavonoid biosynthesis in fungi remains unclear. Stropharia rugosoannulata is an edible mushroom known for its high nutritional and pharmacological value, with flavonoids being one of its main active components. To investigate the flavonoid content of S. rugosoannulata, a study was conducted to extract and determine the total flavonoids at four stages: young mushroom (Ym), gill (Gi), maturation (Ma), and parachute-opening (Po). The findings revealed a gradual increase in total flavonoid concentration as the fruiting body developed, with significant variations observed between the Ym, Gi, and Ma stages. Subsequently, we used UPLC-MS/MS and transcriptome sequencing (RNA-seq) to quantify the flavonoids and identify regulatory genes of Ym, Gi, and Ma. In total, 53 flavonoid-related metabolites and 6726 differentially expressed genes (DEGs) were identified. Through KEGG pathway enrichment analysis, we identified 59 structural genes encoding flavonoid biosynthesis-related enzymes, most of which were up-regulated during the development of the fruiting body, consistent with the accumulation of flavonoids. This research led to the establishment of a comprehensive transcriptional metabolic regulatory network encompassing flavonoids, flavonoid synthases, and transcription factors (TFs). This represents the first systematic exploration of the molecular mechanism of flavonoids in the fruiting of fungi, offering a foundation for further research on flavonoid mechanisms and the breeding of high-quality S. rugosoannulata.

10.
ACS Nano ; 18(18): 11525-11559, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38655632

RESUMEN

The design and preparation of flexible aerogel materials with high deformability and versatility have become an emerging research topic in the aerogel fields, as the brittle nature of traditional aerogels severely affects their safety and reliability in use. Herein, we review the preparation methods and properties of flexible aerogels and summarize the various controlling and design methods of aerogels to overcome the fragility caused by high porosity and nanoporous network structure. The mechanical flexibility of aerogels can be revolutionarily improved by monomer regulation, nanofiber assembly, structural design and controlling, and constructing of aerogel composites, which can greatly broaden the multifunctionality and practical application prospects. The design and construction criterion of aerogel flexibility is summarized: constructing a flexible and deformable microstructure in an aerogel matrix. Besides, the derived multifunctional applications in the fields of flexible thermal insulation (flexible thermal protection at extreme temperatures), flexible wearable electronics (flexible sensors, flexible electrodes, electromagnetic shielding, and wave absorption), and environmental protection (oil/water separation and air filtration) are summarized. Furthermore, the future development prospects and challenges of flexible aerogel materials are also summarized. This review will provide a comprehensive research basis and guidance for the structural design, fabrication methods, and potential applications of flexible aerogels.

11.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124335, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38663130

RESUMEN

Pancytopenia is a common blood disorder defined as the decrease of red blood cells, white blood cells and platelets in the peripheral blood. Its genesis mechanism is typically complex and a variety of diseases have been found to be capable of causing pancytopenia, some of which are featured by their high mortality rates. Early judgement on the cause of pancytopenia can benefit timely and appropriate treatment to improve patient survival significantly. In this study, a serum surface-enhanced Raman spectroscopy (SERS) method was explored for the early differential diagnosis of three pancytopenia related diseases, i.e., aplastic anemia (AA), myelodysplastic syndrome (MDS) and spontaneous remission of pancytopenia (SRP), in which the patients with those pancytopenia related diseases at initial stage exhibited same pancytopenia symptom but cannot be conclusively diagnosed through conventional clinical examinations. The SERS spectral analysis results suggested that certain amino acids, protein substances and nucleic acids are expected to be potential biomarkers for their early differential diagnosis. In addition, a diagnostic model was established based on the joint use of partial least squares analysis and linear discriminant analysis (PLS-LDA), and an overall accuracy of 86.67 % was achieved to differentiate those pancytopenia related diseases, even at the time that confirmed diagnosis cannot be made by routine clinical examinations. Therefore, the proposed method has demonstrated great potential for the early differential diagnosis of pancytopenia related diseases, thus it has significant clinical importance for the timely and rational guidance on subsequent treatment to improve patient survival.


Asunto(s)
Pancitopenia , Espectrometría Raman , Humanos , Espectrometría Raman/métodos , Pancitopenia/diagnóstico , Pancitopenia/sangre , Diagnóstico Diferencial , Análisis Discriminante , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/sangre , Femenino , Análisis de los Mínimos Cuadrados , Persona de Mediana Edad , Masculino , Diagnóstico Precoz , Adulto , Anemia Aplásica/diagnóstico , Anemia Aplásica/sangre , Anciano
12.
Zookeys ; 1195: 199-217, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38525357

RESUMEN

Two new species of ponerine ants from Hainan Province, China, Leptogenyshainanensissp. nov. and L.zhouisp. nov., are delineated and depicted based on the worker caste. Leptogenyshainanensissp. nov. belongs to the L.leleji species group, with mandibles elongate, slender and curved, lacking a distinct masticatory margin. On the other hand, L.zhouisp. nov. belongs to the L.crassicornis species group, distinguished by its square head, smooth body, mandibles with a dentate masticatory margin, and short antennae. A key to workers for the known species of Leptogenys in China are provided and a map is provided for the newly described species.

13.
Appl Radiat Isot ; 206: 111200, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38324937

RESUMEN

Measurement of tritium surface contamination is important for tritium related facilities, especially for fusion devices. A novel detector has been designed for tritium surface contamination measurements based on CaF2(Eu) sheet and Microchannel plate photomultiplier tube (MCP-PMT). Self-coincidence technology has been introduced to obtain lower detection limit by diminishing the background noise caused by γ-rays and hot electrons. Performance of the detector was optimized by specifying the key parameters including the distance of the scintillator and sample, the thickness of light guide, the number of annular electrodes et al., using Monte Carlo method. Results indicate that detection efficiency of 49.4 % and the response deviations at different positions less than 0.5 % could be achieved. The detection limit of tritium under the simulation conditions is 0.09 Bq/cm2 and 0.03 Bq/cm2 when the counting time is 10 s and 60 s, respectively.

14.
Am J Cancer Res ; 14(1): 344-354, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38323279

RESUMEN

Sorafenib, FDA-approved therapy for patients with advanced hepatocellular carcinoma (HCC), leads to limited improvement in overall survival. However, it may indirectly impact the expansion and activity of natural killer (NK) cells. While NK cell-based immunotherapies generally exhibit favorable safety profiles, their effectiveness in controlling solid tumor growth is constrained, primarily due to the absence of antigen specificity and suboptimal expansion and persistence within the tumor microenvironment. In this study, we postulated that enhancing NK cell functionality via cytokine activation could bolster their viability and cytotoxic capabilities, leading to an improved therapeutic response when combined with sorafenib. Memory-like (ML)-NK cells were generated through the supplementation of optimal concentrations of interleukin (IL)-12 and IL-18 cytokines. Following a single day of treatment, cytotoxicity against rat and human HCC cells was evaluated via flow cytometry analysis. A rat HCC model was developed in 30 animals via subcapsular implantation and assigned to control, NK, sorafenib, ML-NK, and combination groups. Sorafenib was administered orally, and NK cells were delivered via the intrahepatic artery. Tumor growth was measured one week after treatment evaluation. Therapeutic efficacy during in-vitro and in-vivo analysis was investigated through a one-way ANOVA test, followed by pairwise two-tailed Student t-tests, considering P < 0.05 statistically significant. The in-vitro experiment results demonstrated that sorafenib and conventional NK cell therapies induced more substantial cell death than the control group (P < 0.01). ML NK cells significantly improved cell death compared to conventional NK cell immunotherapy. Furthermore, sorafenib in combination with ML-NK cells significantly decreased the viability of HCC cells (P < 0.05) compared to sorafenib plus conventional NK cell combination therapy. In vivo experiments have shown that sorafenib and ML-NK cell immunotherapy reduced the growth rate of HCC tumors compared to conventional NK immunotherapy and control groups. Notably, a combination of sorafenib and ML-NK cell immunochemotherapy resulted in the most significant suppression of tumor growth when compared to other therapies. In conclusion, our experimental findings demonstrate that the concurrent administration of sorafenib and ML-NK immunotherapy enhances cytotoxicity against HCC by optimizing the therapeutic response through cytokine activation, resulting in a significant decrease in tumor growth.

15.
Small ; 20(25): e2307986, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38189535

RESUMEN

The volume collapse and slow kinetics reaction of anode materials are two key issues for sodium ion batteries (SIBs). Herein, an "embryo" strategy is proposed for synthesis of nanorod-embedded MoO2/MoS2/C network nanoarchitecture as anode for SIBs with high-rate performance. Interestingly, L-cysteine which plays triple roles including sulfur source, reductant, and carbon source can be utilized to produce the sulfur vacancy-enriched heterostructure. Specifically, L-cysteine can combine with metastable monoclinic MoO3 nanorods at room temperature to encapsulate the "nutrient" of MoOx analogues (MoO2.5(OH)0.5 and MoO3·0.5H2O) and hydrogen-deficient L-cysteine in the "embryo" precursor affording for subsequent in situ multistep heating treatment. The resultant MoO2/MoS2/C presents a high-rate capability of 875 and 420 mAh g-1 at 0.5 and 10 A g-1, respectively, which are much better than the MoS2-based anode materials reported by far. Finite element simulation and analysis results verify that the volume expansion can be reduced to 42.8% from 88.8% when building nanorod-embedded porous network structure. Theoretical calculations reveal that the sulfur vacancies and heterointerface engineering can promote the adsorption and migration of Na+ leading to highly enhanced thermodynamic and kinetic reaction. The work provides an efficient approach to develop advanced electrode materials for energy storage.

16.
Mol Ther Methods Clin Dev ; 32(1): 101168, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38205442

RESUMEN

The pathological accumulation of GM2 ganglioside associated with Tay-Sachs disease (TSD) and Sandhoff disease (SD) occurs in individuals who possess mutant forms of the heterodimer ß-hexosaminidase A (Hex A) because of mutation of the HEXA and HEXB genes, respectively. With a lack of approved therapies, patients experience rapid neurological decline resulting in early death. A novel bicistronic vector carrying both HEXA and HEXB previously demonstrated promising results in mouse models of SD following neonatal intravenous administration, including significant reduction in GM2 accumulation, increased levels of Hex A, and a 2-fold extension of survival. The aim of the present study was to identify an optimal dose of the bicistronic vector in 6-week-old SD mice by an intrathecal route of administration along with transient immunosuppression, to inform possible clinical translation. Three doses of the bicistronic vector were tested: 2.5e11, 1.25e11, and 0.625e11 vector genomes per mouse. The highest dose provided the greatest increase in biochemical and behavioral parameters, such that treated mice lived to a median age of 56 weeks (>3 times the lifespan of the SD controls). These results have direct implications in deciding a human equivalent dose for TSD/SD and have informed the approval of a clinical trial application (NCT04798235).

17.
PLoS Pathog ; 19(12): e1011853, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38100526

RESUMEN

Engineered T cells hold great promise to become part of an effective HIV cure strategy, but it is currently unclear how best to redirect T cells to target HIV. To gain insight, we generated engineered T cells using lentiviral vectors encoding one of three distinct HIV-specific T cell receptors (TCRs) or a previously optimized HIV-targeting chimeric antigen receptor (CAR) and compared their functional capabilities. All engineered T cells had robust, antigen-specific polyfunctional cytokine profiles when mixed with artificial antigen-presenting cells. However, only the CAR T cells could potently control HIV replication. TCR affinity enhancement did not augment HIV control but did allow TCR T cells to recognize common HIV escape variants. Interestingly, either altering Nef activity or adding additional target epitopes into the HIV genome bolstered TCR T cell anti-HIV activity, but CAR T cells remained superior in their ability to control HIV replication. To better understand why CAR T cells control HIV replication better than TCR T cells, we performed a time course to determine when HIV-specific T cells were first able to activate Caspase 3 in HIV-infected targets. We demonstrated that CAR T cells recognized and killed HIV-infected targets more rapidly than TCR T cells, which correlates with their ability to control HIV replication. These studies suggest that the speed of target recognition and killing is a key determinant of whether engineered T cell therapies will be effective against infectious diseases.


Asunto(s)
Infecciones por VIH , VIH-1 , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Receptores de Antígenos de Linfocitos T/genética , Infecciones por VIH/terapia , Replicación Viral
18.
Polymers (Basel) ; 15(23)2023 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-38231928

RESUMEN

Particle boards are manufactured through a hot pressing process using wood materials (natural polymer materials) and adhesive, which find common usage in indoor decorative finishing materials. Flame-retardant particleboard, crucial for fire safety in such applications, undergoes performance analysis that includes assessing temperature distribution across its facing surface and temperature increase on the backside surface during facade combustion, yielding critical insights into fire scenario development. In this study, a compact flame spread apparatus is utilized to examine the flame retardancy and combustion behavior of particle boards, with a specific emphasis on the application of cost-effective flame retardants, encompassing aluminum hypophosphite (ALHP), an intumescent flame retardant (IFR) comprising ammonium polyphosphate (APP), melamine (MEL), and Dipentaerythritol (DPE), alongside magnesium hydroxide (MDH), and their associated combustion characteristics. The D300°C values, representing the vertical distance from the ignition point (IP) to P300°C (the temperature point at 300 °C farthest from IP), are measured using a compact temperature distribution measurement platform. For MDH/PB, APP + MEL + DPE/PB, and ALHP/PB samples, the respective D300°C values of 145.79 mm, 117.81 mm, and 118.57 mm indicate reductions of 11.11%, 28.17%, and 27.71%, compared to the untreated sample's value of 164.02 mm. The particle boards treated with ALHP, IFR, and MDH demonstrated distinct flame-retardant mechanisms. MDH/PB relied on the thermal decomposition of MDH to produce MgO and H2O for flame retardancy, while APP + MEL + DPE/PB achieved flame retardancy through a cross-linked structure with char expansion, polyphosphate, and pyrophosphate during combustion. On the other hand, ALHP/PB attained flame retardancy by reacting with wood materials and adhesives, forming a stable condensed P-N-C structure. This study serves as a performance reference for the production of cost-effective flame-resistant particleboards and offers a practical method for assessing its fire-resistant properties when used as a decorative finishing material on facades in real fire situations.

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