Mammalian species differ dramatically in telomere biology. Species larger than 5–10 kg repress somatic telomerase activity and have shorter telomeres, leading to replicative senescence. It has been ...proposed that evolution of replicative senescence in large-bodied species is an anti-tumour mechanism counteracting increased risk of cancer due to increased cell numbers. By contrast, small-bodied species express high telomerase activity and have longer telomeres. To counteract cancer risk due to longer lifespan, long-lived small-bodied species evolved additional telomere-independent tumour suppressor mechanisms. Here, we tested the connection between telomere biology and tumorigenesis by analysing the propensity of fibroblasts from 18 rodent species to form tumours. We found a negative correlation between species lifespan and anchorage-independent growth. Small-bodied species required inactivation of Rb and/or p53 and expression of oncogenic H-Ras to form tumours. Large-bodied species displayed a continuum of phenotypes requiring additional genetic ‘hits’ for malignant transformation. Based on these data we refine the model of the evolution of tumour suppressor mechanisms and telomeres. We propose that two different strategies evolved in small and large species because small-bodied species cannot tolerate small tumours that form prior to activation of the telomere barrier, and must instead use telomere-independent strategies that act earlier, at the hyperplasia stage.
This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.
In recent years, immune checkpoint inhibitors (ICIs) have emerged as a transformative approach in treating advanced hepatocellular carcinoma (HCC). Despite their success, challenges persist, ...including concerns about their effectiveness, treatment costs, frequent occurrence of treatment-related adverse events, and tumor hyperprogression. Therefore, it is imperative to identify indicators capable of predicting the efficacy of ICIs treatment, enabling optimal patient selection to maximize clinical benefits while minimizing unnecessary toxic side effects and economic losses. This review paper categorizes prognostic biomarkers of ICIs treatment into the following categories: biochemical and cytological indicators, tumor-related markers, imaging and personal features, etiology, gut microbiome, and immune-related adverse events (irAEs). By organizing these indicators systematically, we aim to guide biomarker exploration and inform clinical treatment decisions.
NLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still ...not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3
) to cross with TNFα-transgenic mice (TNF
) to generate NLRP3
/TNF
mice, and compared their joint phenotypes with those of their TNF
and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNF
mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNF
mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3' UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNF
mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.
The composition of the culture medium has great influence on the metabolite production of the marine fungus
F44-1. By adding amino acids to GPY culture medium, two new bisindole alkaloids, ...pseudboindoles A and B (
and
), together with 11 known indole alkaloids were isolated from the culture broth. Their structures were elucidated by comprehensive analysis of the NMR, MS, IR, and UV spectra. The 3,3'-cyclohexylidenebis(1
-indole) (
) showed cytotoxic activity against various cancer cell lines.
PurposeThe goal was to develop a fully automated grading system for the evaluation of punctate epithelial erosions (PEEs) using deep neural networks.MethodsA fully automated system was developed to ...detect corneal position and grade staining severity given a corneal fluorescein staining image. The fully automated pipeline consists of the following three steps: a corneal segmentation model extracts corneal area; five image patches are cropped from the staining image based on the five subregions of extracted cornea; a staining grading model predicts a score for each image patch from 0 to 3, and automated grading score for the whole cornea is obtained from 0 to 15. Finally, the clinical grading scores annotated by three ophthalmologists were compared with automated grading scores.ResultsFor corneal segmentation, the segmentation model achieved an intersection over union of 0.937. For punctate staining grading, the grading model achieved a classification accuracy of 76.5% and an area under the receiver operating characteristic curve of 0.940 (95% CI 0.932 to 0.949). For the fully automated pipeline, Pearson’s correlation coefficient between the clinical and automated grading scores was 0.908 (p<0.01). Bland-Altman analysis revealed 95% limits of agreement between the clinical and automated grading scores of between −4.125 and 3.720 (concordance correlation coefficient=0.904). The average time required for processing a single stained image during pipeline was 0.58 s.ConclusionA fully automated grading system was developed to evaluate PEEs. The grading results may serve as a reference for ophthalmologists in clinical trials and residency training procedures.
Abstract
In the Hong Kong–Zhuhai–Macau Bridge mega project, several ground treatment methods were applied in the transition area between the artificial island and immersed tube tunnels to reduce the ...potential uneven foundation settlement underlying the tunnel, as the backfilled sand layer is more than 10 m around it. One of the foundation improvement methods involves the combination of preload and high-pressure jet grouting (HPJG) columns. Current field tests, such as core bowling, standard penetration test, and plate loading test, are not suitable for evaluating the strength of this reinforced foundation. This study presents a full-scale load test to examine the construction quality and effects of an HPJG-reinforced foundation. A novel method was designed based on the Boussinesq equation to simulate the additional stress distribution from the immersed tube tunnel. The tangent modulus method considering the impact of modulus nonlinearity was employed to calculate the nonlinear settlement of the treated foundation. Preferable settlement results were obtained using a set of pre-embedded high-precision hydrostatic leveling systems. Both the measured data and calculated settlement demonstrate the reasonableness of the present in situ test.
Herein, two new electron acceptors, BTTPC and BTTPC-Br, are developed through extending the conjugation of terminal electron accepting moieties with thiophene and bromine units. Such a structural ...design effectively improves the hole transfer of exciton dynamics in blends, revealing that BTTPC-Br and BTTPC based blends, in the presence of a smaller energetic offset as a driving force, exhibit faster hole transfer from acceptors to the polymeric donor interface, 4 times (BTTPC-Br) and 1.5 times (BTTPC) faster than 0.44 picoseconds of unmodified Y5. As a result, organic solar cells (OSCs) based on the BTTPC-Br acceptor, outperforming those of BTTPC:PBDB-T and Y5:PBDB-T, reach a power conversion efficiency of 15.22%, which is so far one of the highest among the single junction OSCs made with PBDB-T polymer donor.
The structural tuning of non-fullerene acceptors with extended terminal aromatics enables faster hole transfer from the acceptor to the donor at smaller energy offsets, thereby achieving high efficiency in organic solar cells.
Particulate matter of 2.5 µm or less in diameter (PM2.5) is one of the most complex pollutants in the atmospheric environment and harmful to human health. Epidemiologic evidence suggests that asthma ...exacerbation is associated with PM2.5 exposure. However, the molecular mechanism of PM2.5 in the development of asthma is not fully addressed.
PM2.5 was collected from Chengdu, China, and the components were analyzed. The relationship between PM2.5 exposure and asthma severity was investigated in an Ovalbumin (OVA)-induced murine model of asthma. U-BIOPRED data from public database and our own RNA-seq data were analyzed to identify the hub genes. Real-time qPCR, immunofluorescence, immunohistochemistry and pathological staining were applied for mechanism dissection in both in vitro and in vivo studies.
In PM2.5 samples, a total of 11 elements including major elements and trace elements were identified, 14 of the 16 Polycyclic aromatic hydrocarbons (PAHs) were detected except Acenaphthene and Fluorene. PM2.5 exposure aggravated pulmonary inflammation, mucus secretion, and neutrophils infiltration in asthma model. Based on transcriptome analysis of mild-to-severe asthma dataset, it showed that mucus secretion and neutrophil degranulation correlated with asthma severity. Moreover, NAD(P)H:quinone oxidoreductase 1 (NQO1) was screened out as a hub gene whose expression positively correlated with MUC5AC expression in patient with asthma by performing joint analysis. Furthermore, in OVA-induced asthma model and in vitro assay, it also revealed that PM2.5-induced MU5AC expression was regulated by NQO1 through neutrophil extracellular traps (NETs) caused by oxidative stress.
Taken together, we discovered a potential relationship between asthma severity and PM2.5 exposure. In addition, neutrophil depletion, NETs inhibition or anti-NQO1 might be novel potential therapeutic options for treatment of PM2.5-induced mucus hyper-secretion.
•Explore a potential relationship between asthma severity and PM2.5 exposure.•PM2.5 aggravated asthma through mucus secretion and neutrophils infiltration.•PM2.5 up-regulated NQO1 through NETs release.•Neutrophil depletion or anti-NQO1 might be novel potential therapeutic options.
Firsocostat (FIR: previously GS‐0976), a highly sensitive OATP substrate, reduces hepatic de novo lipogenesis (DNL) by inhibiting acetyl‐CoA carboxylases (ACC). Measuring the pharmacodynamic (PD) ...efficacy of FIR on DNL provides a unique opportunity to determine optimal dosing strategies for liver‐targeted OATP substrates in settings of altered OATP function. A randomized, four‐way crossover drug‐drug interaction study was conducted. Hepatic DNL, a marker for ACC activity, was measured in 28 healthy volunteers after reference, single dose FIR 10 mg, FIR 10 mg plus the OATP inhibitor rifampin (RIF) 300 mg i.v., or RIF 300 mg i.v. (control for DNL effect of RIF), each separated by a 7‐day washout. Samples were collected for pharmacokinetic (PK) and PD assessments through 24 hours after each treatment. Hepatic DNL and its inhibition by FIR were assessed. Twenty‐four subjects completed the study. All adverse events were mild. RIF alone increased hepatic DNL area under the effect curve from time of administration up to the time of the last quantifiable concentration (AUEClast; 35.7%). Despite a 5.2‐fold increase in FIR plasma exposure (area under the concentration‐time curve from zero to infinity (AUCinf)) when administered with RIF, FIR alone, and FIR + RIF had the same hepatic PD effect, 37.1% and 34.9% reduction in DNL AUEClast, respectively, compared with their respective controls. These findings indicate that large decreases in OATP activity do not alter hepatic intracellular exposure (as inferred by no change in PD) for drugs that are primarily eliminated hepatically and permeability rate‐limited, such as FIR. These results support PK theory that has been difficult to test and provide practical guidance on administration of liver‐targeted drugs in settings of reduced OATP function.
To address the critical issue of slope stability in jointed rock masses with complex and rough structural planes, a rough joint network model using the Fourier transform was proposed and applied to ...the Shilu open pit mine. The on-site structural plane survey results were combined with MATLAB and PFC2D to establish numerical models for slope stability analysis considering both linear-jointed and rough-jointed rock slopes. By comparing the slip body and fracture distribution, it was found that the rough-jointed slope was stabler than the linear-jointed slope. In addition, the fracture patterns and slip displacement were significantly influenced by the inclination and undulation of the bedding planes. Slip failure patterns occurred when the angle of inclination was set at 60°. The joints played a crucial role in inducing the shear strength of slope rock masses, and the slide area was mainly observed in the shallow slope surface for inclination angles of 0° and 45°, and in the middle deep area for 60° and 90°. These results demonstrated the importance of considering rough non-persistent fractures when developing a new numerical model for slope failure modes.
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