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1.
Br J Cancer ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600327

RESUMO

BACKGROUND: Tumour-associated macrophages (TAMs) are an important component of the tumour microenvironment (TME). However, the crosstalk between oesophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored. METHODS: Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism. RESULTS: Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumours. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays an essential role in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarisation via CD44/PI3K/AKT signalling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumour growth and M2 TAM infiltration in xenograft mouse models. CONCLUSIONS: This study highlights SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.

2.
Patterns (N Y) ; 5(4): 100950, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38645767

RESUMO

Standard energy-consumption testing, providing the only publicly available quantifiable measure of battery electric vehicle (BEV) energy consumption, is crucial for promoting transparency and accountability in the electrified automotive industry; however, significant discrepancies between standard testing and real-world driving have hindered energy and environmental assessments of BEVs and their broader adoption. In this study, we propose a data-driven evaluation method for standard testing to characterize BEV energy consumption. By decoupling the impact of the driving profile, our evaluation approach is generalizable to various driving conditions. In experiments with our approach for estimating energy consumption, we achieve a 3.84% estimation error for 13 different multiregional standardized test cycles and a 7.12% estimation error for 106 diverse real-world trips. Our results highlight the great potential of the proposed approach for promoting public awareness of BEV energy consumption through standard testing while also providing a reliable fundamental model of BEVs.

3.
Phys Rev E ; 109(3-2): 035205, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38632769

RESUMO

The double-cone ignition (DCI) scheme has been proposed as one of the alternative approaches to inertial confinement fusion, based on direct-drive and fast-ignition, in order to reduce the requirement for the driver energy. To evaluate the conical implosion energetics from the laser beams to the plasma flows, a series of experiments have been systematically conducted. The results indicate that 89%-96% of the laser energy was absorbed by the target, with moderate stimulated Raman scatterings. Here 2%-6% of the laser energy was coupled into the plasma jets ejected from the cone tips, which was mainly restricted by the mass reductions during the implosions inside the cones. The supersonic dense jets with a Mach number of 4 were obtained, which is favorable for forming a high-density, nondegenerated plasma core after the head-on collisions. These findings show encouraging results in terms of energy transport of the conical implosions in the DCI scheme.

4.
Heliyon ; 10(6): e27861, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38533073

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which immune cells and inflammatory cytokines are abnormally activated, leading to immunoregulatory dysfunction in the body and triggering systemic inflammatory responses. The interaction between CXC chemokine receptor 4 (CXCR4) and heterotrimeric G-protein α-subunit Gαq (Gnαq) activates phospholipase Cß (PLCß), which influences the expression of downstream effectors and participates widely in the onset and development of various diseases, thus suggesting the potential involvement of these molecules in RA pathogenesis. Therefore, the present study aimed to determine whether the CXCR4-Gnαq-PLCß signaling pathway participates in the onset and development of RA. Using a collagen-induced arthritis (CIA) rat model, we found that compared with the control (healthy) rat group, CIA rats exhibited highly time-dependent arthritis, with the maximum arthritis score occurring in week 3. In contrast to the splenic and joint tissue of control rats, CIA rats showed obvious hyperplasia in the lymphoid white pulp and main germination centers of the spleen, narrowing of joint cavities, and inflammatory cellular infiltration on articular surfaces. The serum levels of expression of IL-1ß, IL-4, IL-6, and TNF-α were significantly elevated (P < 0.05, P < 0.01). Core genes of the CXCR4-Gnαq-PLCß pathway, namely CXCR4, Gnαq, PLCß1, MMP1, and MMP3, also showed a significant increase in mRNA and protein expression levels (P < 0.05, P < 0.01). Proteins related to the CXCR4-Gnαq-PLCß pathway were mainly localized to the red and white pulp regions in the spleen as well as in stromal, endothelial, and subdifferentiated synovial cells in the joints. These results indicated that CXCR4 is dependent on Gnαq for inducing the expression of PLCß1 and stimulation of secretion of inflammatory cytokines by inflammatory cells. This consequently affects the expression of matrix metalloproteinases (MMPs), which serve as downstream effectors, thereby promoting RA pathogenesis. Our findings play an important role in elucidating the mechanisms of the onset and development of RA.

5.
Arch Virol ; 169(4): 81, 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38519716

RESUMO

Bacillus subtilis is a Gram-positive bacterium that is widely used in fermentation and in the pharmaceutical industry. Phage contamination occasionally occurs in various fermentation processes and causes significant economic loss. Here, we report the isolation and characterization of a temperate B. subtilis phage, termed phi18-2, from spore powder manufactured in a fermentation plant. Transmission electron microscopy showed that phi18-2 has a symmetrical polyhedral head and a long noncontractile tail. Receptor analysis showed that phi18-2 recognizes wall teichoic acid (WTA) for infection. The phage virions have a linear double-stranded DNA genome of 64,467 bp with identical direct repeat sequences of 309 bp at each end of the genome. In lysogenic cells, the phage genome was found to be present in the cytoplasm without integration into the host cell chromosome, and possibly as a linear phage-plasmid with unmodified ends. Our data may provide some insight into the molecular basis of the unique lysogenic cycle of phage phi18-2.


Assuntos
Fagos Bacilares , Bacteriófagos , Bacteriófagos/genética , Fagos Bacilares/genética , DNA Viral/genética , Lisogenia , Genoma Viral , Plasmídeos/genética , Citoplasma
6.
Environ Sci Pollut Res Int ; 31(16): 24113-24128, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38436853

RESUMO

The presence of organic dyes in aquatic systems poses a significant threat to ecosystems and human well-being. Due to recycling challenges, traditional commercial activated carbon is not cost-effective. To address this, an imidazolate acid zeolite framework-8 (ZIF-8)-modified magnetic adsorbent (ZMPLB-800) was synthesized through the in-situ formation of ZIF-8 and subsequent carbonization at 800 °C, using magnetic pineapple leaf biochar (MPLB) as a carrier. The porous structure of ZMPLB-800 facilitates the rapid passage of dye molecules, enhancing adsorption performance. ZMPLB-800 exhibited remarkable adsorption capacity for methylene blue (MB) across a pH range of 3-13, with a maximum adsorption capacity of 455.98 mg g-1. Adsorption kinetics and thermodynamics followed the pseudo-second-order kinetic model and Langmuir isotherm model. Mechanisms of MB adsorption included pore filling, hydrogen bonding, electrostatic interactions, π-π interactions, and complexation through surface functional groups. Additionally, ZMPLB-800 demonstrated excellent regeneration performance, recording a removal efficiency exceeding 87% even after five adsorption/desorption cycles. This study provides a novel strategy for treating dye wastewater with MOF composites, laying the foundation for waste biomass utilization.


Assuntos
Ananas , Poluentes Químicos da Água , Zeolitas , Adsorção , Carvão Vegetal/química , Ecossistema , Concentração de Íons de Hidrogênio , Cinética , Fenômenos Magnéticos , Azul de Metileno/química , Folhas de Planta , Águas Residuárias , Poluentes Químicos da Água/química
7.
Chem Biol Interact ; 393: 110955, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38492842

RESUMO

Aucubin (AU), an iridoid glycoside extracted from Eucommia ulmoides, exerts anti-osteoporotic effects by promoting osteogenesis, as reported in previous studies. Here, we investigated the effects of AU under mechanical stretch stress. MC3T3-E1 cells were treated with dexamethasone (DEX) in vitro and subjected to mechanical stretch stress to establish an osteoporotic orthodontic force cell model. AU treatment increased the mRNA and protein expressions of BMP2, OPN, RUNX2, COL-1 and other osteogenic differentiation factors in MC3T3-E1 cells. Furthermore, we established an in vivo orthodontic tooth movement (OTM) model of osteoporosis. Serum parameter detection of ALP concentration, radiography of the femur, hematoxylin-eosin (HE) staining, and micro-CT of the maxilla confirmed that AU could partially reverse the damage induced by DEX. Immunohistochemical (IHC) analysis showed that AU increased the expression of COL-1, OCN, and OPN on the tension side of the periodontium. In conclusion, AU treatment promotes osteogenic differentiation under mechanical stretch stress and positively affects bone remodeling during OTM in DEX-induced osteoporosis.


Assuntos
Glucosídeos Iridoides , Osteogênese , Osteoporose , Humanos , Técnicas de Movimentação Dentária , Ligamento Periodontal , Diferenciação Celular , Osteoporose/tratamento farmacológico
8.
Mol Cancer ; 23(1): 62, 2024 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-38519953

RESUMO

While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are a new class of anticancer drugs comprising the coupling of antitumor mAbs with cytotoxic drugs. Compared with chemotherapeutic drugs, ADCs have the advantages of good tolerance, accurate target recognition, and small effects on noncancerous cells. ADCs occupy an increasingly important position in the therapeutic field. Currently, there are 13 Food and Drug Administration (FDA)‒approved ADCs and more than 100 ADC drugs at different stages of clinical trials. This review briefly describes the efficacy and safety of FDA-approved ADCs, and discusses the related problems and challenges to provide a reference for clinical work.


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias , Estados Unidos , Humanos , Imunoconjugados/uso terapêutico , United States Food and Drug Administration , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Resultado do Tratamento
9.
Environ Sci Pollut Res Int ; 31(16): 23979-23994, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38436846

RESUMO

The sulfate radical-based advanced oxidation processes (SR-AOPs) is a promising method for the degradation of pollutants, with the development of highly efficient catalysts for persulfate activation has been widely concerned. The novel BiCoFe-LDH (BCF-x) was synthesized successfully by coprecipitation method, which can activate peroxydisulfate (PDS) efficiently to degrade aniline. Comparative analysis with pure CoFe-LDH revealed a remarkable increase in reaction rate constant by approximately 14.66 times; the degradation rate of aniline (10 mg/L) was 100% in 60 min with the condition of 0.5 g/L BCF-1.5 and 0.5 g/L PDS, due to BCF-1.5 which was characterized as a complex of CoFe-LDH and Bi2O2CO3, promoting electron transport to improve the efficiency of activated PDS. In the reaction system, SO4•-, ·OH, and 1O2 were responsible for the aniline degradation and ·OH was the primary one. Furthermore, this work proposes a reaction electron transfer catalytic mechanism, which provided a new insight and good application prospect for efficient activation of PDS for pollutant degradation.


Assuntos
Compostos de Anilina , Poluentes Ambientais , Catálise , Transporte de Elétrons , Elétrons , Oxirredução
10.
J Colloid Interface Sci ; 664: 13-24, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38458051

RESUMO

At present, there are few reports on the micron-sized catalysts for overall water splitting. In this study, phosphating method were used to construct the self-supporting catalyst (V doped Ni microspheres coated by NiMoO4/Ni12P5) with microspherical structure, providing a short path and a stable structure to guarantee quick electron transfer and excellent catalytic performance. Hence, oxygen evolution reaction (OER) only needs 254 mV to reach a current density of 50 mA cm-2 in 1.0 mol/L KOH, after 114 h without attenuation. The catalyst can achieve a current densitiy of 10 mA cm-2 with a voltage of only 158 mV for hydrogen evolution reaction (HER). When micron scale V-Ni@NiMoO4/Ni12P5 is used as both anode and cathode for overall water splitting, the device can operate at a current density of 10 mA cm-2 for more than 200 h of good stability. Its superior catalytic performance can be attributed to the construction of micron size and phosphating. DFT calculations indicate that the introduction of P better activates the adsorbed *OH and H2O*, reduces reaction the energy barrier, and improves the catalytic activity.

11.
Huan Jing Ke Xue ; 45(3): 1830-1839, 2024 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-38471894

RESUMO

The removal mechanisms of phthalic acid esters (PAEs) have attracted much attention because of their endocrine-disrupting properties and persistence in environmental media. In order to reveal the removal mechanism of PAEs and involved keystone taxa and functional genes, purple soils were polluted by di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP), respectively, along a gradient of 0, 5, 10, and 20 mg·kg-1 and cultured for 90 days in the dark. The results showed that the degradation dynamics of DBP and DEHP were well-fitted by the first-order kinetic model, and the half-life of DBP and DEHP ranged from 17.0 to 38.2 days. The degradation rate of DBP (5 mg·kg-1) was the fastest, and that of DEHP (20 mg·kg-1) was the slowest. The soil samples of the seventh day and the fifteenth day were analyzed using metagenomic sequencing. NMDS and cluster analysis showed that there was a significant difference between the bacterial community structure of soil samples from the seventh day and the fifteenth day. The relative abundance of Actinobacteria increased from the seventh day to the fifteenth day. The smaller the half-life of DBP or DEHP, the higher the relative abundance of Actinobacteria in the different treatments. In addition, Streptomyces was the dominant genus in all polluted soils. Co-occurrence network analysis elucidated that Pandoraea was a keystone genus of the soil bacterial communities, which could be used to indicate the pollution levels of DBP and DEHP. The results of KEGG annotation demonstrated that Pandoraea was responsible for benzoate degradation, quorum sensing, ABC transporters, and the two-component system and could promote the intercellular communications and the microbial growth and proliferation and maintain the stability of the community structure. Therefore, the degradation rate of DBP and DEHP in purple soils depended on their initial content and their own properties. Actinobacteria played an important role in the PAEs degradation, and Pandoraea played a major part in promoting PAEs degradation and regulating the stability of the structure and function of degrading bacterial communities.


Assuntos
Dietilexilftalato , Ácidos Ftálicos , Solo/química , Ácidos Ftálicos/análise , Dibutilftalato , Ésteres/análise
12.
Cancer Lett ; 588: 216739, 2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38395379

RESUMO

Prostate cancer (PCa) is a prevalent malignancy among men worldwide, and biochemical recurrence (BCR) after radical prostatectomy (RP) is a critical turning point commonly used to guide the development of treatment strategies for primary PCa. However, the clinical parameters currently in use are inadequate for precise risk stratification and informing treatment choice. To address this issue, we conducted a study that collected transcriptomic data and clinical information from 1662 primary PCa patients across 12 multicenter cohorts globally. We leveraged 101 algorithm combinations that consisted of 10 machine learning methods to develop and validate a 9-gene signature, named BCR SCR, for predicting the risk of BCR after RP. Our results demonstrated that BCR SCR generally outperformed 102 published prognostic signatures. We further established the clinical significance of these nine genes in PCa progression at the protein level through immunohistochemistry on Tissue Microarray (TMA). Moreover, our data showed that patients with higher BCR SCR tended to have higher rates of BCR and distant metastasis after radical radiotherapy. Through drug target prediction analysis, we identified nine potential therapeutic agents for patients with high BCR SCR. In conclusion, the newly developed BCR SCR has significant translational potential in accurately stratifying the risk of patients who undergo RP, monitoring treatment courses, and developing new therapies for the disease.


Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Masculino , Humanos , Benchmarking , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Neoplasias da Próstata/metabolismo , Próstata/patologia
13.
Medicine (Baltimore) ; 103(5): e37198, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38306523

RESUMO

INTRODUCTION: X-linked recessive chronic granulomatous disease (XR-CGD) is a severe primary immunodeficiency principally caused by a CYBB (OMIM: 300481) gene variant. Recurrent fatal bacterial or fungal infections are the main clinical manifestations of XR-CGD. PATIENT CONCERNS: In the current case, in vitro fertilization (IVF) associated with preimplantation genetic testing for monogenic disorder (PGT-M) was applied for a Chinese couple who had given birth to a boy with XR-CGD. DIAGNOSIS: Next-generation sequencing-based SNP haplotyping and Sanger-sequencing were used to detect the CYBB gene variant (c.804 + 2T>C, splicing) in this family. INTERVENTIONS: The patient was treated with IVF and PGT-M successively. OUTCOMES: In this IVF cycle, 7 embryos were obtained, and 2 of them were euploid and lacked the CYBB gene variant (c.804 + 2T>C). The PGT results were verified by prenatal diagnosis after successful pregnancy, and a healthy girl was eventually born. CONCLUSION: PGT-M is an effective method for helping families with these fatal and rare inherited diseases to have healthy offspring. It can availably block the transmission of disease-causing loci to descendant.


Assuntos
Doença Granulomatosa Crônica , Diagnóstico Pré-Implantação , Masculino , Gravidez , Feminino , Humanos , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Diagnóstico Pré-Implantação/métodos , Testes Genéticos/métodos , Diagnóstico Pré-Natal , Fertilização In Vitro , Aneuploidia , NADPH Oxidase 2/genética
14.
Phys Rev E ; 109(1-2): 015208, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38366504

RESUMO

Quasimonoenergetic GeV-scale protons are predicted to be efficiently generated via radiation pressure acceleration (RPA) when the foil thickness is matched with the laser intensity, e.g., L_{mat} of several nm to 100 nm for 10^{19}-10^{22}Wcm^{-2} available in laboratory. However, nonmonoenergetic protons with much lower energies than predicted were usually observed in RPA experiments because of too small foil thickness which cannot support insufficient laser contrast and foil surface roughness. Besides the technical problems, we here find that there is an upper-limit thickness L_{up} derived from the requirement that the laser energy should dominate over the ion source energy in the effective laser-proton interaction zone, and L_{up} is lower than L_{mat} with the intensity below 10^{22}Wcm^{-2}, which causes inefficient or unsteady RPA. As the intensity is enhanced to ≥10^{23}Wcm^{-2} provided by 10-100 PW laser facilities, L_{up} can significantly exceed L_{mat}, and therefore RPA becomes efficient. In this regime, L_{mat} acts as a lower-limit thickness for efficient RPA, so the matching thickness can be extended to a continuous range from L_{mat} to L_{up}; the range can reach micrometers, within which foil thickness is adjustable. This makes RPA steady and meanwhile the above technical problems can be overcome. Particle-in-cell simulation shows that multi-GeV quasimonoenergetic proton beams can be steadily generated and the fluctuation of the energy peaks and the energy conversation efficiency remains stable although the thickness is taken in a larger range with increasing intensity. This work predicts that near future RPA experiments with 10-100 PW facilities will enter a new regime with a large range of usable foil thicknesses that can be adjusted to the interaction conditions for steady acceleration.

15.
Phys Rev Lett ; 132(6): 065105, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38394557

RESUMO

Stable transport of laser beams in highly overdense plasmas is of significance in the fast ignition of inertial confinement fusion, relativistic electron generation, and powerful electromagnetic emission, but hard to realize. Early in 1996, Harris proposed an electromagnetically induced transparency (EIT) mechanism, analogous to the concept in atomic physics, to transport a low-frequency (LF) laser in overdense plasmas aided by a high-frequency pump laser. However, subsequent investigations show that EIT cannot occur in real plasmas with boundaries. Here, our particle-in-cell simulations show that EIT can occur in the strongly relativistic regime and result in stable propagation of a LF laser in bounded plasmas with tens of its critical density. A relativistic three-wave coupling model is developed, and the criteria and frequency passband for EIT occurrence are presented. The passband is sufficiently wide in the strongly relativistic regime, allowing EIT to work sustainably. Nevertheless, it is narrowed to nearly an isolated point in the weakly relativistic regime, which can explain the quenching of EIT in bounded plasmas found in previous investigations.

16.
Front Psychiatry ; 15: 1328240, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38362032

RESUMO

Aims: Autism is a multifaceted developmental disorder of the nervous system, that necessitates novel therapeutic approaches beyond traditional medications and psychosomatic therapy, such as appropriate sensory integration training. This systematic mapping review aims to synthesize existing knowledge on enriching environmental interventions as an alternative avenue for improving autism, guiding future research and practice. Method: A comprehensive search using the terms ASD and Enriched Environment was conducted across PubMed, EMBASE, ISI, Cochrane, and OVID databases. Most of the literature included in this review was derived from animal model experiments, with a particular focus on assessing the effect of EE on autism-like behavior, along with related pathways and molecular mechanisms. Following extensive group discussion and screening, a total of 19 studies were included for analysis. Results: Enriched environmental interventions exhibited the potential to induce both behavioral and biochemical changes, ameliorating autism-like behaviors in animal models. These improvements were attributed to the targeting of BDNF-related pathways, enhanced neurogenesis, and the regulation of glial inflammation. Conclusion: This paper underscores the positive impact of enriched environmental interventions on autism through a review of existing literature. The findings contribute to a deeper understanding of the underlying brain mechanisms associated with this intervention.

17.
J Colloid Interface Sci ; 661: 690-699, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38320405

RESUMO

The discovery of earth-abundant electrocatalysts to replace platinum and iridium for overall water splitting is a crucial step in reducing the cost of green hydrogen production. Transition metal phosphides have drawn wide attention due to their non-toxicity, good chemical stability, low cost, and stable catalytic activity in alkaline electrolytes. We report a three-dimensional flower-like structure composed of core-shell nanoneedles as catalysts, in which CeO2 is introduced on the surface of nickel cobalt bimetallic phosphide through electrodeposition. And X-ray photoelectron spectroscopy testing and DFT calculations show electron coupling and transfer between CeO2 and CoP3, thereby modulating the electronic structure of the catalyst surface and reducing the adsorption energy of H atoms during the catalytic process, resulting in enhanced catalytic activity. In 1 M KOH, it exhibits a low overpotential of 109 and 296 mV to achieve the current density of 50 mA cm-2 for HER and OER, respectively. When used as both cathode and anode as a bifunctional catalyst, a voltage of only 1.77 V is required to achieve a current density of 50 mA cm-2, demonstrating great industrial potential.

18.
Artif Intell Med ; 147: 102700, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38184363

RESUMO

BACKGROUND: The search for new antimalarial treatments is urgent due to growing resistance to existing therapies. The Open Source Malaria (OSM) project offers a promising starting point, having extensively screened various compounds for their effectiveness. Further analysis of the chemical space surrounding these compounds could provide the means for innovative drugs. METHODS: We report an optimisation-based method for quantitative structure-activity relationship (QSAR) modelling that provides explainable modelling of ligand activity through a mathematical programming formulation. The methodology is based on piecewise regression principles and offers optimal detection of breakpoint features, efficient allocation of samples into distinct sub-groups based on breakpoint feature values, and insightful regression coefficients. Analysis of OSM antimalarial compounds yields interpretable results through rules generated by the model that reflect the contribution of individual fingerprint fragments in ligand activity prediction. Using knowledge of fragment prioritisation and screening of commercially available compound libraries, potential lead compounds for antimalarials are identified and evaluated experimentally via a Plasmodium falciparum asexual growth inhibition assay (PfGIA) and a human cell cytotoxicity assay. CONCLUSIONS: Three compounds are identified as potential leads for antimalarials using the methodology described above. This work illustrates how explainable predictive models based on mathematical optimisation can pave the way towards more efficient fragment-based lead discovery as applied in malaria.


Assuntos
Antimaláricos , Malária , Humanos , Antimaláricos/farmacologia , Ligantes , Malária/tratamento farmacológico
19.
Carbohydr Polym ; 328: 121709, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38220343

RESUMO

Chroogomphus rutilus (CR) possesses anti-inflammatory, antioxidant, and hypoglycemic properties. However, studies are yet to evaluate the anti-osteoporotic activity of the fungi and its polysaccharides. Therefore, this study is aimed at characterizing and evaluating the anti-osteoporotic effects of a novel polysaccharide from CR. The neutral polysaccharide CRP2 extracted and purified from the fruiting body of CR had a molecular weight of 20.41 kDa. Monosaccharide composition analysis revealed that CRP2 is composed of galactose, glucose, fucose, and mannose. The backbone of CRP2 primarily consisted of →6)-α-D-Galp-(1 â†’ residues, with specific site substitutions speculated at partial positions, such as O-CH3 substitution at H-3 position, or a branch site located at C-2, including α-L-Fucp-(1 â†’ 6)-ß-D-Glcp-(1 â†’ and α-D-Manp-(1→. CRP2 treatment increased trabecular bone density, restored a network-shaped structure, and upregulated the expression of osteoblast differentiation markers, including runt-related transcription factor 2, osterix, osteocalcin, and osteopontin in the femoral tissue of mice with osteoporosis (OP). Additionally, CRP2 treatment suppressed the expression of tumor necrosis factor-α and interleukin-1ß in the femoral tissue of mice with OP. Mechanistically, CRP2 exerted anti-OP effect by inhibiting inflammation and promoting osteogenesis through the transforming growth factor ß-1/Smad pathway. Conclusively, these findings augment our understanding of the potential role of CRP2 in OP treatment.


Assuntos
Basidiomycota , Osteogênese , Animais , Camundongos , Polissacarídeos/farmacologia , Polissacarídeos/química , Monossacarídeos/análise
20.
Front Bioeng Biotechnol ; 12: 1354241, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38288261

RESUMO

Objective: The present study aimed to assess the bond strength and durability of six bonding agents concerning their application to metal or ceramic brackets and zirconia. Materials and Methods: Six resin cement bonding agents (XT, XTS, RSBU, RGBU, SBPM, and GMP) were chosen for this investigation. Specimens were either stored in distilled water at 37°C for 24 h or subjected to 5,000 thermocycles before conducting a Shear Bond Strength (SBS) test. Statistical analysis of the SBS data was performed using three-way ANOVA and Games-Howell tests (α = 0.05). The Adhesive Remnant Index was examined, and the debonding surface details on brackets and zirconia were observed. Results: For metal brackets, all groups demonstrated clinically acceptable bond strength, irrespective of storage conditions, except for the XT group. Regarding ceramic brackets, all groups displayed acceptable bond strength after 24 h of water storage. However, following thermocycling, a significant decrease in SBS was noted across all groups (p < 0.05), with SBPM exhibiting a higher bond strength. Three-way ANOVA analysis indicated that SBS values were notably influenced by each factor, and an interaction among the three independent variables was observed (p = 0.000). Conclusion: The reliable bond strength between ceramic brackets and zirconia was significantly lower after thermocycling compared to that of metal brackets and zirconia. SBPM exhibited consistent and robust bond strength between ceramic/metal brackets and zirconia across various storage conditions. Furthermore, the HEMA-free adhesive demonstrated a potentially more consistent bonding performance compared to the HEMA-containing adhesive employed in this study.

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