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1.
J Am Chem Soc ; 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39316456

RESUMO

Catalytic asymmetric multicomponent 1,2-boronate rearrangements provide a practical approach for synthesizing highly valuable enantioenriched boronic esters. When applied to alkenyl or heteroaryl boronates, these reactions have relied mainly on transition-metal catalysis. Herein, we present an organocatalytic, Lewis base-catalyzed asymmetric multicomponent 1,2-boronate rearrangement, involving indoles, boronic esters, and Morita-Baylis-Hillman carbonates, leading to enantioenriched, highly substituted indole and indoline derivatives. Using cinchona alkaloid-based catalysts, high selectivity has been achieved, enabling expansion of the chemical space around pharmaceutically relevant indole and indoline derivatives.

2.
Artigo em Inglês | MEDLINE | ID: mdl-39292199

RESUMO

Breastfeeding is the most complete nutritional method of feeding infants, but several impediments affect the decision to breastfeed, including questions of drug safety for medications needed during lactation. Despite recent FDA guidance, few labels provide clear dosing advice during lactation. Physiologically based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms to fill gaps in the absence of extensive clinical studies and complement existing real-world data. For lactation-focused PBPK (Lact-PBPK) models, information on system parameters (e.g., expression of drug transporters in mammary epithelial cells) is sparse. The breast cancer resistance protein (BCRP) is expressed on the apical side of mammary epithelial cells where it actively transports drugs/substrates into milk (reported milk: plasma ratios range from 2 to 20). A critical review of BCRP and its role in lactation was conducted. Longitudinal changes in BCRP mRNA expression have been identified in women with a maximum reached around 5 months postpartum. Limited data are available on the ontogeny of BCRP in infant intestine; however, data indicate lower BCRP abundance in infants compared to adults. Current status of incorporation of drug transporter information in Lact-PBPK models to predict active secretion of drugs into breast milk and consequential exposure of breast-fed infants is discussed. In addition, this review highlights novel clinical tools for evaluation of BCRP activity, namely a potential non-invasive BCRP biomarker (riboflavin) and liquid biopsy that could be used to quantitatively elucidate the role of this transporter without the need for administration of drugs and to inform Lact-PBPK models.

3.
J Anim Ecol ; 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39268554

RESUMO

Clarifying the effects of biodiversity on ecosystem stability in the context of global environmental change is crucial for maintaining ecosystem functions and services. Asynchronous changes between trophic levels over time (i.e. trophic community asynchrony) are expected to increase trophic mismatch and alter trophic interactions, which may consequently alter ecosystem stability. However, previous studies have often highlighted the stabilising mechanism of population asynchrony within a single trophic level, while rarely examining the mechanism of trophic community asynchrony between consumers and their food resources. In this study, we analysed the effects of population asynchrony within and between trophic levels on community stability under the disturbances of climate warming, fishery decline and de-eutrophication, based on an 18-year monthly monitoring dataset of 137 phytoplankton and 91 zooplankton in a subtropical lake. Our results showed that species diversity promoted community stability mainly by increasing population asynchrony both for phytoplankton and zooplankton. Trophic community asynchrony had a significant negative effect on zooplankton community stability rather than that of phytoplankton, which supports the match-mismatch hypothesis that trophic mismatch has negative effects on consumers. Furthermore, the results of the structural equation models showed that warming and top-down effects may simultaneously alter community stability through population dynamics processes within and between trophic levels, whereas nutrients act on community stability mainly through the processes within trophic levels. Moreover, we found that rising water temperature decreased trophic community asynchrony, which may challenge the prevailing idea that climate warming increases the trophic mismatch between primary producers and consumers. Overall, our study provides the first evidence that population and trophic community asynchrony have contrasting effects on consumer community stability, which offers a valuable insight for addressing global environmental change.

4.
Heliyon ; 10(16): e35479, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39229538

RESUMO

In this study, Ginkgo biloba leave polyprenols (GBP) and polypyridine metal complex were individually utilized as functional ligand and main ligand, four kinds of novel GBP-based polypyridine metal complexes were successfully synthesized and their cell absorption capacity, light-dark stability, photodissociation efficiency, ROS production capacity, light-controlled antibacterial and anti-tumor activities as well as mechanisms were systematically investigated by ultraviolet visible spectrophotometer (UV-vis), confocal laser scanning microscope (CLSM), gel electrophoresis (GE), scanning electron microscope (SEM), oxford cup method, MTT method etc. The lipid water distribution coefficients of complex 1, 2 and 4 were all within the range of 0∼3, demonstrating their better cell absorption capacity and more competitive bioavailability potentiality compared with GBP. All of the synthesized complexes possessed excellent stability in a dark environment, and could conduct ligand dissociation under the condition of visible light irradiation except complex 1. In which, complex 2 and complex 4 were able to achieve degradation rates of 37.9 % and 54.4 % within 5 min, separately. In addition, complex 2 and complex 4 exhibited superior inhibitory activities on the HN-3 tumor cells on account of their stronger ROS production capacity. Moreover, the constricted expression of BCL-2 and NF-kB p-p65, especially the promoted expression of BAX may be one of the root cause. The four synthesized complexes had preferable inhibition effects against S. aureus under the condition of visible light irradiation in contrast to darkness, in which complex 4 was the best and its MIC and MBC values were 6.25 and 12.5 µg/mL, respectively. The antibacterial mechanism of the complex 4 may be in relation to the synergistic effect of multiple factors, including leakage of bacterial inclusion, change of cell membrane permeability and disruption of cell wall etc. All of the above generalized researches will pave a way for the high-value development and application of GBP-based functional products.

5.
Harmful Algae ; 138: 102694, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39244230

RESUMO

Despite significant reductions in phosphorus (P) loads, lakes still experience cyanobacterial blooms. Little is known regarding cellular P regulation in response to P deficiency in widely distributed bloom causing species such as Microcystis. In this study, we investigated changes in P containing and non-P lipids contents and their ratios concomitantly with the determinations of expression levels of genes encoding these lipids in cultural and field Microcystis samples. In the culture, the content of phosphatidylglycerol (PG) decreased from 2.1 µg g-1 in P replete control to 1.2 µg g-1 in P-deficient treatment, while non-P lipids, like sulfoquinovosyldiacylglycerol (SQDG) and monogalactosyldiacylglycerol (MGDG), increased dramatically from 13.6 µg g-1 to 142.3 µg g-1, and from 0.9 µg g-1 to 16.74 µg g-1, respectively. The expression of the MGDG synthesis gene, mgdE, also increased under low P conditions. Significant positive relationships between soluble reactive phosphorus (SRP) and ratios of P-containing lipids (PG) to non-P lipids, including SQDG, MGDG and digalactosyldiacylglycerol (DGDG) (P < 0.05) were observed in the field investigations. Both cultural and field data indicated that Microcystis sp. might increase non-P lipids proportion to lower P demand when suffering from P deficiency. Furthermore, despite lipid remodeling, photosynthetic activity remained stable, as indicated by comparable chlorophyll fluorescence and Fv/Fm ratios among cultural treatments. These findings suggested that Microcystis sp. may dominate in P-limited environments by substituting glycolipids and sulfolipids for phospholipids to reduce P demand without compromising the photosynthetic activity. This effective strategy in response to P deficiency meant a stricter P reduction threshold is needed in terms of Microcystis bloom control.


Assuntos
Microcystis , Fósforo , Microcystis/metabolismo , Microcystis/genética , Fósforo/deficiência , Fósforo/metabolismo , Fosfolipídeos/metabolismo , Fosfolipídeos/análise , Lagos/microbiologia , Lagos/química , Proliferação Nociva de Algas , Lipídeos/análise
6.
Cell Immunol ; 403-404: 104864, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39190985

RESUMO

Mitochondria are highly dynamic organelles that maintain their homeostasis through mitochondrial dynamics. Mitochondrial fusion and fission are two important processes of mitochondrial dynamics. There is accumulating evidence that mitochondrial fusion and fission play an important role in the development of immune-mediated inflammatory diseases. This article provides a brief review of the essential role of mitochondrial fusion and fission in immune-mediated inflammatory diseases. It will provide a novel perspective and direction for the elucidation of the pathogenesis and treatment of immune-mediated inflammatory diseases.


Assuntos
Inflamação , Mitocôndrias , Dinâmica Mitocondrial , Dinâmica Mitocondrial/imunologia , Humanos , Inflamação/imunologia , Animais , Mitocôndrias/imunologia , Mitocôndrias/metabolismo
7.
Am J Obstet Gynecol MFM ; 6(9): 101436, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39096968

RESUMO

BACKGROUND: Induction of labor (IOL) with mechanical methods or pharmacological agents is used in about 20% to 30% of all pregnant women. We specialized in comparing the effectiveness and safety of dinoprostone vs transcervical Foley catheter for IOL in term pregnant women with an unfavorable cervix with adequate samples. OBJECTIVE: To compare the effectiveness and safety of dinoprostone vs transcervical Foley catheter for IOL in term pregnant women with an unfavorable cervix. STUDY DESIGN: This is a parallel, open-label randomized controlled trial in two maternal centers in Shanghai, China between October 2019 and July 2022. Women with a singleton pregnancy in cephalic presentation at term and an unfavorable cervix (Bishop score <6) scheduled for IOL were eligible. A total of 1860 women were randomly allocated to cervical ripening with either a dinoprostone vaginal insert (10 mg) or a 60 cc Foley catheter for up to 24 hours. The primary outcomes were vaginal delivery rate and time to vaginal delivery. Secondary outcomes included time to delivery and maternal and neonatal morbidity. Analysis was done from an intention-to-treat perspective. The trial was registered with the China trial registry (CTR2000038435). RESULTS: The vaginal birth rates were 72.8% (677/930) vs 69.9% (650/930) in vaginal dinoprostone and Foley catheter, respectively (aRR 1.04, 95% confidence interval [CI] 0.98-1.10, risk difference: 0.03). Time to vaginal delivery was not significantly different between the two groups (sub-distribution hazard ratio 1.11, 95% CI 0.99-1.24). Vaginal dinoprostone was more likely complicated with hyperstimulation with fetal heart rate changes (5.8% vs 2.8%, aRR 2.09, 95% CI 1.32-3.31) and placenta abruption (0.9% vs 0.1%, aRR: 8.04, 95% CI 1.01-64.15), while Foley catheter was more likely complicated with suspected intrapartum infection (5.1% vs 8.2%, aRR: 0.62, 95% CI 0.44-0.88) and postpartum infection (1.4% vs 3.7%, aRR: 0.38, 95% CI 0.20-0.72). The composite of poor neonatal outcomes was not significantly different between the two groups (4.5% vs 3.8%, aRR 1.21, 95% CI 0.78-1.88), while more neonatal asphyxia occurred in the dinoprostone group (1.2% vs 0.2%, aRR 5.39, 95% CI 1.22-23.92). In a subgroup analysis, vaginal dinoprostone decreased vaginal birth rate slightly in multiparous women (90.6% vs 97.0%, aRR 0.93, 95% CI 0.88-0.99). CONCLUSIONS: In term pregnant women with an unfavorable cervix, IOL with vaginal dinoprostone or Foley catheter has similar effectiveness. Foley catheter leads to better safety for neonates, while it may result in a higher risk of maternal infection. Furthermore, Foley catheter should be preferred in multiparous women.


Assuntos
Maturidade Cervical , Dinoprostona , Trabalho de Parto Induzido , Ocitócicos , Humanos , Feminino , Trabalho de Parto Induzido/métodos , Gravidez , Dinoprostona/administração & dosagem , Dinoprostona/efeitos adversos , Adulto , Ocitócicos/administração & dosagem , Ocitócicos/efeitos adversos , Administração Intravaginal , Maturidade Cervical/efeitos dos fármacos , China/epidemiologia , Colo do Útero/efeitos dos fármacos , Cateterismo Urinário/métodos , Cateterismo Urinário/efeitos adversos , Parto Obstétrico/métodos , Parto Obstétrico/estatística & dados numéricos
8.
Zhonghua Nan Ke Xue ; 30(3): 241-248, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-39177391

RESUMO

OBJECTIVE: To explore the potential action mechanism of Huotu Jiji Pellets (HJP) in the treatment of erectile dysfunction (ED) based on network pharmacology and molecular docking. METHODS: We identified the main effective compounds and active molecular targets of HJP from the database of Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Integrative Pharmacology-Based Research Platform of Traditional Chinese Medicine (TCMIP) and the therapeutic target genes of ED from the databases of Genecards. Then we obtained the common targets of HJP and ED using the Venny software, constructed a protein-protein interaction (PPI) network of HJP acting on ED, and screened out the core targets with the Cytoscape software. Lastly we performed GO functional enrichment and KEGG pathway enrichment analyses of the core targets followed by molecular docking of HJP and the core targets using Chem3D and AutoDock Tools and QuickVina-W software. RESULTS: A total of 64 effective compounds, 822 drug-related targets, 1 783 disease-related targets and 320 common targets were obtained in this study. PPI network analysis showed that the core targets of HJP for ED included ESR1, HSP90AA1, SRC, and STAT3. GO functional enrichment analysis indicated the involvement of the core targets in such biological processes as response to xenobiotic stimulus, positive regulation of kinase activity, and positive regulation of MAPK cascade. KEGG pathway enrichment analysis suggested that PI3K-Akt, apoptosis, MAPK, HIF-1, VEGF, autophagy and other signaling pathways may be related to the mechanism of HJP acting on ED. Molecular docking prediction exhibited a good docking activity of the key active molecules of HJP with the core targets. CONCLUSION: This study showed that HJP acted on ED through multi-components, multi-targets and multi-pathways, which has provided some evidence and reference for the clinical treatment and subsequent studies of the disease.


Assuntos
Medicamentos de Ervas Chinesas , Disfunção Erétil , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Farmacologia em Rede , Mapas de Interação de Proteínas , Masculino , Disfunção Erétil/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Transdução de Sinais
9.
Sensors (Basel) ; 24(16)2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39204838

RESUMO

Device-to-device (D2D) is a pivotal technology in the next generation of communication, allowing for direct task offloading between mobile devices (MDs) to improve the efficient utilization of idle resources. This paper proposes a novel algorithm for dynamic task offloading between the active MDs and the idle MDs in a D2D-MEC (mobile edge computing) system by deploying multi-agent deep reinforcement learning (DRL) to minimize the long-term average delay of delay-sensitive tasks under deadline constraints. Our core innovation is a dynamic partitioning scheme for idle and active devices in the D2D-MEC system, accounting for stochastic task arrivals and multi-time-slot task execution, which has been insufficiently explored in the existing literature. We adopt a queue-based system to formulate a dynamic task offloading optimization problem. To address the challenges of large action space and the coupling of actions across time slots, we model the problem as a Markov decision process (MDP) and perform multi-agent DRL through multi-agent proximal policy optimization (MAPPO). We employ a centralized training with decentralized execution (CTDE) framework to enable each MD to make offloading decisions solely based on its local system state. Extensive simulations demonstrate the efficiency and fast convergence of our algorithm. In comparison to the existing sub-optimal results deploying single-agent DRL, our algorithm reduces the average task completion delay by 11.0% and the ratio of dropped tasks by 17.0%. Our proposed algorithm is particularly pertinent to sensor networks, where mobile devices equipped with sensors generate a substantial volume of data that requires timely processing to ensure quality of experience (QoE) and meet the service-level agreements (SLAs) of delay-sensitive applications.

10.
Front Nutr ; 11: 1435977, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39144284

RESUMO

In this study, it was compared the physicochemical properties and cooking taste quality between four different types of compound nutritional rice (rice flour with the addition of other coarse grains, legumes, potatoes, and other powders, extruded as artificial rice grains) and common rice. We found that the protein and apparent amylose contents of compound nutritional rice were higher than that of common rice, up to 9.775% and 19.45% respectively. The γ-aminobutyric acid (GABA) and resistant starch contents were much lower than in common rice, and the dietary fiber content did not differ from that in common rice. The results of Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis revealed that the starch properties and structure of the compound nutritional rice changed due to high temperature and high pressure processing. In particular, the crystalline structures of starch became V-shaped. In addition, the results of artificial tasting and tasting meter showed that the taste of compound nutritional rice was generally inferior to that of common rice. In summary, compound nutritional rice had problems such as nutritional imbalance and poor taste. There was still a lot of room for improving the taste quality of compound nutritional rice. Therefore, the future development of compound nutritional rice should focus on both nutritional balance and taste improvement. The results of this paper also provided a certain theoretical basis for this.

11.
Nat Commun ; 15(1): 7071, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39152117

RESUMO

Acquiring multi-dimensional optical information, such as intensity, spectrum, polarization, and phase, can significantly enhance the performance of photodetectors. Incorporating these dimensions allows for improved image contrast, enhanced recognition capabilities, reduced interference, and better adaptation to complex environments. However, the challenge lies in obtaining these dimensions on a single photodetector. Here we propose a misaligned unipolar barrier photodetector based on van der Waals heterojunction to address this issue. This structure enables spectral detection by switching between two absorbing layers with different cut-off wavelengths for dual-band detection. For polarization detection, anisotropic semiconductors like black phosphorus and black arsenic phosphorus inherently possess polarization-detection capabilities without additional complex elements. By manipulating the crystal direction of these materials during heterojunction fabrication, the device becomes sensitive to incident light at different polarization angles. This research showcases the potential of the misaligned unipolar barrier photodetector in capturing multi-dimensional optical information, paving the way for next-generation photodetectors.

12.
Opt Lett ; 49(16): 4497-4500, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39146087

RESUMO

Lap welding restricts the connection state of glasses by vertically incident ultrafast laser at the interface to be welded, which cannot meet the increasingly flexible welding needs. In this Letter, glass butt welding is achieved by oblique incidence of an ultrafast laser, expanding the applicability of ultrafast laser glass welding. Furthermore, the propagation path of the laser beam after oblique incidence into a glass is solved based on geometric optics, the dynamic development of the molten pool in a glass is observed through a high-speed camera, and the mechanism of glass butt welding is elucidated. Finally, the influence of laser pulse energy, glass tilt angle, and defocus amount on welding strength is investigated, achieving a maximum shear strength of 11.5 MPa.

13.
Front Oncol ; 14: 1388302, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39104718

RESUMO

Introduction: Desmoid tumor (DT) is a rare proliferative disease occurring in connective tissues, characterized by high infiltration and recurrence rates. While surgery remains the primary treatment, its recurrence risk is high, and some extra-abdominal desmoid tumors are inoperable due to their locations. Despite attempts with radiotherapy and systemic therapy, the efficacy remains limited. Methods: We used low-power cumulative high-intensity focused ultrasound (HIFU) therapy as an initial treatment for desmoid tumor patients either ineligible or unwilling for surgery. Low-power cumulative HIFU employs slower heat accumulation and diffusion, minimizing damage to surrounding tissues while enhancing efficacy. Results: Fifty-seven non-FAP desmoid tumor patients, previously untreated surgically, underwent low-power cumulative HIFU therapy. Among them, 35 had abdominal wall DT, 20 had extra-abdominal DT, and 2 had intra- abdominal DT, with an 85% median ablation ratio. Abdominal wall DT patients showed significantly better response rates (91.4% vs. 86%) and disease control rates (100% vs. 32%) than that of non-abdominal wall DT patients. Median event- free survival time was not reached after a median follow-up duration of 34 months. Discussion: With its high response rate, durable efficacy, and mild adverse effects, our findings suggest that low-power cumulative HIFU presents a promising novel treatment for desmoid tumors, particularly abdominal wall DT patients.

14.
Ther Adv Med Oncol ; 16: 17588359241264730, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39091606

RESUMO

Background: MET overexpression represents the most MET aberration in advanced non-small-cell lung cancer (NSCLC). However, except MET exon 14 (METex14) skipping mutation was recognized as a clinical biomarker, the role of MET overexpression as a predictive factor to MET inhibitor is not clear. Objectives: The purpose of the pooled analysis is to explore the safety and efficiency of gumarontinib, a highly selective oral MET inhibitor, in drive-gene negative NSCLC patients with MET overexpression. Design and methods: NSCLC patients with MET overexpression [immunohistochemistry (IHC) ⩾3+ as determined by central laboratory] not carrying epidermal growth factor receptor mutation, METex14 skipping mutation or other known drive gene alternations who received Gumarontinib 300 mg QD from two single arm studies were selected and pooled for the analysis. The efficacy [objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS)] and safety [treatment emergent adverse event (TEAE), treatment related AE (TRAE) and serious AE (SAE) were assessed. Results: A total of 32 patients with MET overexpression were included in the analysis, including 12 treatment naïve patients who refused or were unsuitable for chemotherapy, and 20 pre-treated patients who received ⩾1 lines of prior systemic anti-tumour therapies. Overall, the ORR was 37.5% [95% confidence interval (CI): 21.1-56.3%], the DCR was 81.3% (95% CI: 63.6-92.8%), median PFS (mPFS) and median OS (mOS) were 6.9 month (95% CI: 3.6-9.7) and 17.0 month (95% CI: 10.3-not evaluable), respectively. The most common AEs were oedema (59.4%), hypoalbuminaemia (40.6%), alanine aminotransferase increased (31.3%). Conclusion: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.

15.
World J Gastroenterol ; 30(28): 3386-3392, 2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-39091716

RESUMO

Acute appendicitis is a common surgical emergency. It is commonly caused by obstruction of the appendiceal lumen due to fecaliths, tumors, or lymphoid hyperplasia. For over a century, appendectomy has been the primary treatment for acute appendicitis. Abraham Groves performed the first open appendectomy in 1883. In 1983, Kurt Semm completed the first laparoscopic appendectomy, heralding a new era in appendectomy. However, appendectomy is associated with certain complications and a rate of negative appendectomies. Studies have suggested controversy over the impact of appendectomy on the development of inflammatory bowel disease and Parkinson's disease, but an increasing number of studies indicate a possible positive correlation between appendectomy and colorectal cancer, gallstones, and cardiovascular disease. With the recognition that the appendix is not a vestigial organ and the advancement of endoscopic te-chnology, Liu proposed the endoscopic retrograde appendicitis therapy. It is an effective minimally invasive alternative for treating uncomplicated acute appendicitis. Our team has developed an appendoscope with a disposable digital imaging system operated through the biopsy channel of a colonoscope and successfully applied it in the treatment of appendicitis. This article provides an overview of the progress in endoscopic treatment for acute appendicitis and offers a new perspective on the future direction of appendiceal disease treatment.


Assuntos
Apendicectomia , Apendicite , Humanos , Apendicite/cirurgia , Apendicectomia/efeitos adversos , Apendicectomia/métodos , Apendicectomia/história , Resultado do Tratamento , Apêndice/cirurgia , Apêndice/patologia , Apêndice/diagnóstico por imagem , Colonoscópios , Doença Aguda , Desenho de Equipamento
16.
Immunology ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39095968

RESUMO

OBJECTIVES: We aimed to characterize and investigate the safety and efficacy of Plonmarlimab, a novel anti-granulocyte-macrophage colony-stimulating factor (anti-GM-CSF) neutralizing antibody, on the treatment of macrophage activation syndrome (MAS), a life-threatening systemic inflammatory disease, in pre-clinical models. METHODS: The binding affinity was evaluated using Biacore. The neutralizing activity was measured through the blockade of ligand-receptor interaction, inhibition of STAT5 phosphorylation and suppression of TF-1 cell proliferation. The efficacy of Plonmarlimab was evaluated in a humanized MAS model, which was established by engrafting human umbilical cord blood (UCB) cells into NOG-EXL mice. Additionally, the safety profile of Plonmarlimab was investigated in cynomolgus monkeys. RESULTS: At the molecular level, Plonmarlimab showed sub-nanomolar binding affinity with human GM-CSF and effectively blocked the binding of GM-CSF to its receptor. At the cellular level, Plonmarlimab dose-dependently inhibited intracellular STAT5 phosphorylation and suppressed GM-CSF-induced TF-1 proliferation. In the UCB-engrafted NOG-EXL MAS mouse model, Plonmarlimab treatment significantly ameliorated disease progression, demonstrated by the improvements in body weight loss, anaemia and some histopathological features. Furthermore, Plonmarlimab was well tolerated up to 150 mg/kg weekly in monkeys with no reported adverse effects. CONCLUSIONS: Plonmarlimab is a highly potent GM-CSF blocking antibody and has demonstrated promising efficacy in a pre-clinical MAS model with a favourable safety profile, supporting its clinical development.

18.
J Fungi (Basel) ; 10(8)2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39194842

RESUMO

Pleurotheciaceae is a genera-rich and highly diverse family of fungi with a worldwide distribution in aquatic and terrestrial habitats. During the investigation of lignicolous freshwater fungi from karst landscapes in Yunnan Province, China, 15 fresh strains were obtained from submerged decaying wood. Based on the morphology and phylogenetic analysis of a combined LSU, ITS, SSU, and rpb2 sequence dataset, Obliquifusoideum triseptatum, Phaeoisaria obovata, Pleurotheciella brachyspora, Pl. longidenticulata, and Pl. obliqua were introduced as new species, P. synnematica and Rhexoacrodictys melanospora were reported as new habitat records, and P. sedimenticola and Pl. hyalospora were reported as new collections. In addition, based on morphological comparisons and phylogenetic analysis, we accepted Obliquifusoideum into in the family Pleurotheciaceae (Pleurotheciales, Savoryellomycetidae). Freshwater habitats are the primary habitats of Pleurotheciaceae species, and Yunnan Province has the highest concentration and species diversity of Pleurotheciaceae in China.

19.
IEEE Trans Med Imaging ; PP2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39178085

RESUMO

CT-based bronchial tree analysis is a key step for the diagnosis of lung and airway diseases. However, the topology of bronchial trees varies across individuals, which presents a challenge to the automatic bronchus classification. To solve this issue, we propose the Bronchus Classification Network (BCNet), a structure-guided framework that exploits the segment-level topological information using point clouds to learn the voxel-level features. BCNet has two branches, a Point-Voxel Graph Neural Network (PV-GNN) for segment classification, and a Convolutional Neural Network (CNN) for voxel labeling. The two branches are simultaneously trained to learn topology-aware features for their shared backbone while it is feasible to run only the CNN branch for the inference. Therefore, BCNet maintains the same inference efficiency as its CNN baseline. Experimental results show that BCNet significantly exceeds the state-of-the-art methods by over 8.0% both on F1-score for classifying bronchus. Furthermore, we contribute BronAtlas: an open-access benchmark of bronchus imaging analysis with high-quality voxel-wise annotations of both anatomical and abnormal bronchial segments. The benchmark is available at link1.

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