Histone methyltransferase KMT5C drives liver cancer progression and directs therapeutic response to PARP inhibitors.

BACKGROUND AND AIMS: Epigenetic plasticity is a major challenge in cancer-targeted therapy. However, the molecular basis governing this process has not yet been clearly defined. Despite the considerable success of poly(ADP-ribose) polymerase inhibitors (PARPi) in cancer therapy, the limited response to PARPi, especially in HCC, has been a bottleneck in its clinical implications. Herein, we investigated the molecular basis of the histone methyltransferase KMT5C (lysine methyltransferase 5C) that governs PARPi sensitivity and explored a potential therapeutic strategy for enhancing PARPi efficacy. APPROACH AND RESULTS: We identified KMT5C, a trimethyltransferase of H4K20, as a targetable epigenetic factor that promoted liver tumor growth in mouse de novo MYC/Trp53-/- and xenograft liver tumor models. Notably, induction of KMT5C by environmental stress was crucial for DNA repair and HCC cell survival. Mechanistically, KMT5C interacted with the pivotal component of homologous recombination repair, RAD51, and promoted RAD51/RAD54 complex formation, which was essential for the activation of dsDNA breaks repair. This effect depended on the methyltransferase activity of KMT5C. We further demonstrated that the function of KMT5C in promoting HCC progression was dependent on RAD51. Importantly, either a pharmacological inhibitor (A196) or genetic inhibition of KMT5C sensitized liver cancer cells to PARPi. CONCLUSIONS: KMT5C played a vital role in promoting liver cancer progression by activating the DNA repair response. Our results revealed a novel therapeutic approach using the KMT5C inhibitor A196, concurrent with olaparib, as a potential HCC therapy.

History of organic pollution in montane lake Issyk-Kul, Kyrgyzstan, Central Asia, inferred from a sediment core.

In arid regions, montane lakes are valuable water sources and play important ecological roles. However, recent human-induced inputs of organic pollutants are threatening lake ecology in such regions and becoming a matter of great concern. To investigate pollutant histories and sources, we measured polycyclic aromatic hydrocarbons (PAHs) and n-alkanes in a dated sediment core that spans the last ∼350 years, from montane Lake Issyk-Kul (Kyrgyzstan, Central Asia). Results showed that organic pollutants were delivered to Lake Issyk-Kul in four stages and that their concentrations increased from Stage I (∼1670-1800 CE) to Stage IV (∼2000-2010 CE). Furthermore, we tracked the sources of sedimented PAHs using their ratios combined with n-alkanes data. Ratios of PAHs Ant/(Ant + Phe), Flt/(Flt + Pyr) and Bap/BghiP indicated that inputs during Stage II (∼1800-1970 CE) and Stage III (∼1970-2000 CE) came mainly from high-temperature combustion of coal and vehicle emissions. PAHs in Stage I and Stage IV, however, were mainly derived from low-temperature combustion and petrogenic sources. Diagnostic PAH ratios, combined with the natural n-alkane ratio (NAR＜0) and unresolved complex mixtures (UCM), showed that the sources of PAHs in Stage I were mainly from erosion of bedrock and partly influenced by forest wildfires, different from the source during Stage IV, which was mainly from refined petroleum caused by accidental spills. Our assessment of the contamination history of the lake indicates that toxicity risk to the waterbody from sediment PAHs is low, but recent discharges arising from traffic deserve attention.

Paternal p,p'-DDE exposure and pre-pubertal high-fat diet increases the susceptibility to fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring.

The hypothesis of paternal origins of health and disease (POHaD) indicates that paternal exposure to adverse environment could alter the epigenetic modification in germ line, increasing the disease susceptibility in offspring or even in subsequent generations. p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is an anti-androgenic chemical and male reproductive toxicant. Gestational p,p'-DDE exposure could impair reproductive development and fertility in male offspring. However, the effect of paternal p,p'-DDE exposure on fertility in male offspring remains uncovered. From postnatal day (PND) 35 to 119, male rats (F0) were given 10 mg/body weight (b.w.) p,p'-DDE or corn oil by gavage. Male rats were then mated with the control females to generate male offspring. On PND35, the male offspring were divided into 4 groups according whether to be given the high-fat diet (HF): corn oil treatment with control diet (C-C), p,p'-DDE treatment with control diet (DDE-C), corn oil treatment with high-fat diet (C-HF) or p,p'-DDE treatment with high-fat diet (DDE-HF) for 35 days. Our results indicated that paternal p,p'-DDE exposure did not affect the male fertility of male offspring directly, but decreased sperm quality and induced testicular apoptosis after the high-fat diet treatment. Further analysis demonstrated that paternal exposure to p,p'-DDE and pre-pubertal high-fat diet decreased sperm Igf2 DMR2 methylation and gene expression in male offspring. Hence, paternal exposure to p,p'-DDE and pre-pubertal high-fat diet increases the susceptibility to male fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring, posing a significant implication in the disease etiology.

RIG-I contributes to keratinocyte proliferation and wound repair by inducing TIMP-1 expression through NF-κB signaling pathway.

Epithelial keratinocyte proliferation is an essential element of wound repair, and chronic wound conditions, such as diabetic foot, are characterized by aberrant re-epithelialization. In this study, we examined the functional role of retinoic acid inducible-gene I (RIG-I), a key regulator of epidermal keratinocyte proliferation, in promoting TIMP-1 expression. We found that RIG-I is overexpressed in keratinocytes of skin injury and underexpressed in skin wound sites of diabetic foot and streptozotocin-induced diabetic mice. Moreover, mice lacking RIG-I developed an aggravated phenotype when subjected to skin injury. Mechanistically, RIG-I promoted keratinocyte proliferation and wound repair by inducing TIMP-1 via the NF-κB signaling pathway. Indeed, recombinant TIMP-1 directly accelerated HaCaT cell proliferation in vitro and promoted wound healing in Ddx58-/- and diabetic mice in vivo. In summary, we demonstrated that RIG-I is a crucial factor that mediates epidermal keratinocyte proliferation and may be a potential biomarker for skin injury severity, thus making it an attractive locally therapeutic target for the treatment of chronic wounds such as diabetic foot.

Short-term variation in leaf-level water use efficiency in a tropical forest.

The representation of stomatal regulation of transpiration and CO2 assimilation is key to forecasting terrestrial ecosystem responses to global change. Given its importance in determining the relationship between forest productivity and climate, accurate and mechanistic model representation of the relationship between stomatal conductance (gs ) and assimilation is crucial. We assess possible physiological and mechanistic controls on the estimation of the g1 (stomatal slope, inversely proportional to water use efficiency) and g0 (stomatal intercept) parameters, using diurnal gas exchange surveys and leaf-level response curves of six tropical broadleaf evergreen tree species. g1 estimated from ex situ response curves averaged 50% less than g1 estimated from survey data. While g0 and g1 varied between leaves of different phenological stages, the trend was not consistent among species. We identified a diurnal trend associated with g1 and g0 that significantly improved model projections of diurnal trends in transpiration. The accuracy of modeled gs can be improved by accounting for variation in stomatal behavior across diurnal periods, and between measurement approaches, rather than focusing on phenological variation in stomatal behavior. Additional investigation into the primary mechanisms responsible for diurnal variation in g1 will be required to account for this phenomenon in land-surface models.

The effect of the vertical gradients of photosynthetic parameters on the CO2 assimilation and transpiration of a Panamanian tropical forest.

Terrestrial biosphere models (TBMs) include the representation of vertical gradients in leaf traits associated with modeling photosynthesis, respiration, and stomatal conductance. However, model assumptions associated with these gradients have not been tested in complex tropical forest canopies. We compared TBM representation of the vertical gradients of key leaf traits with measurements made in a tropical forest in Panama and then quantified the impact of the observed gradients on simulated canopy-scale CO2 and water fluxes. Comparison between observed and TBM trait gradients showed divergence that impacted canopy-scale simulations of water vapor and CO2 exchange. Notably, the ratio between the dark respiration rate and the maximum carboxylation rate was lower near the ground than at the top-of-canopy, leaf-level water-use efficiency was markedly higher at the top-of-canopy, and the decrease in maximum carboxylation rate from the top-of-canopy to the ground was less than TBM assumptions. The representation of the gradients of leaf traits in TBMs is typically derived from measurements made within-individual plants, or, for some traits, assumed constant due to a lack of experimental data. Our work shows that these assumptions are not representative of the trait gradients observed in species-rich, complex tropical forests.

Photo-Induced C-H Methylation Reactions.

Direct C-H methylation is a highly valuable approach for introducing methyl groups into organic molecules, particularly in pharmaceutical chemistry. Among the various methodologies available, photo-induced methylation stands out as an exceptional choice due to its mild reaction conditions, energy efficiency, and compatibility with functional groups. This article offers a comprehensive review of photochemical strategies employed for the direct and selective methylation of C(sp3 )-H, C(sp2 )-H, and C(sp)-H bonds in various organic molecules. The discussed methodologies encompass transition-metal-based photocatalysis, organophotocatalysis, as well as other metal-free approaches, including electron donor-acceptor (EDA)-enabled transformations. Importantly, a wide range of easily accessible agents such as tert-butyl peroxide, methanol, DMSO, methyl tert-butyl ether, TsOMe, N-(acetoxy)phthalimide, acetic acid, methyl halides, and even methane can serve as effective methylating reagents for modifying diverse targets. These advancements in photochemical C-H methylation are anticipated to drive further progress in the fields of organic synthesis, photocatalysis, and pharmaceutical development, opening up exciting avenues for creating novel organic molecules and discovering new drug compounds.

Application of essential oils as slow-release antimicrobial agents in food preservation: Preparation strategies, release mechanisms and application cases.

Food spoilage caused by foodborne microorganisms will not only cause significant economic losses, but also the toxins produced by some microorganisms will also pose a serious threat to human health. Essential oil (EOs) has significant antimicrobial activity, but its application in the field of food preservation is limited because of its volatile, insoluble in water and sensitive to light and heat. Therefore, in order to solve these problems effectively, this paper first analyzed the antibacterial effect of EOs as an antimicrobial agent on foodborne bacteria and its mechanism. Then, the application strategies of EOs as a sustained-release antimicrobial agent in food preservation were reviewed. On this basis, the release mechanism and application cases of EOs in different antibacterial composites were analyzed. The purpose of this paper is to provide technical support and solutions for the preparation of new antibacterial packaging materials based on plant active components to ensure food safety and reduce food waste.

Unveiling the intrinsic role of water in the catalytic cycle of formaldehyde oxidation: a comprehensive study integrating density functional theory and microkinetic analysis.

Previous research is predominantly in consensus on the reaction mechanism between formaldehyde (HCHO) and oxygen (O2) over catalysts. However, water vapor (H2O) always remains present during the reaction, and the intrinsic role of H2O in the oxidation of HCHO still needs to be fully understood. In this study, a single-atom catalyst, Al-doped C2N substrate, Al1/C2N, can be adopted as an example to investigate the relationship and interaction among O2, H2O, and HCHO. Density functional theory (DFT) calculations and microkinetic simulations were carried out to interpret the enhancement mechanism of H2O on HCHO oxidation over Al1/C2N. The outcome demonstrates that H2O directly breaks down a surface hydroxyl group on Al1/C2N, considerably lowering the energy required to form crucial intermediates, thus promoting oxidation. Without H2O, Al1/C2N cannot effectively oxidize HCHO at ambient temperature. During oxidation, H2O takes the major catalytic responsibility, delaying the entrance of O2 into the reaction, which is not only the product but also the crucial reactant to initiate catalysis, thereby sustaining the catalytic cycle. Moreover, this study predicts the catalytic behavior at various temperatures and presents feasible recommendations for regulating the reaction rates. The oxidation mechanism of HCHO is explained at the molecular level in this study, emphasizing the intrinsic role of water on Al1/C2N, which fills in the relevant studies for HCHO oxidation on two-dimensional carbon materials.

Changes in Arsenic Speciation in Wild Edible Fungi after Different Cooking Processes and Gastrointestinal Digestion.

Arsenic (As) is enriched in wild edible fungi, which is one of the main important sources of As in humans' diet. In this study, two wild edible fungi were employed for investigation: (1) Pleurotus citrinopileatusone, which contains a high content of inorganic As (iAs) and (2) Agaricus blazei Murill, which contains a high content of organic As. This study investigated the changes in As content and its speciation after different daily cooking methods. We found that the content of As in Pleurotus citrinipileatus and Agaricus blazei Murill reduced by soaking plus stir-frying by 55.4% and 72.9%, respectively. The As content in Pleurotus citrinipileatus and Agaricus blazei Murill decreased by 79.4% and 93.4%, respectively, after soaking plus boiling. The content of As speciation in dried wild edible fungi reduced significantly after different treatments. Among them, iAs decreased by 31.9~88.3%, and organic As decreased by 33.3~95.3%. This study also investigated the bioaccessibility of As in edible fungi after different cooking processes via an in-vitro physiologically based extraction test (PBET). The results showed that the bioaccessibility of As was relatively high if the edible fungi were uncooked, boiled, or stir-fried. The gastric (G) bioaccessibility of As ranged from 51.7% to 93.0% and the gastrointestinal (GI) bioaccessibility of As ranged from 63.5% to 98.1%. Meanwhile, the bioaccessibility of inorganic As was found to be as high as 94.6% to 151%, which indicates that further evaluation of the potential health risks of wild edible fungi is necessary.

A Review of the Regulatory Mechanisms of N-Myc on Cell Cycle.

Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However, for its high-risk type, even with various intensive treatment options, the prognosis is still unsatisfactory. At the same time, a large number of research data show that the abnormal amplification and high-level expression of the MYCN gene are positively correlated with the malignant progression, poor prognosis, and mortality of neuroblastoma. In this context, this article explores the role of the N-Myc, MYCN gene expression product on its target genes related to the cell cycle and reveals its regulatory network in promoting tumor proliferation and malignant progression. We hope it can provide ideas and direction for the research and development of drugs targeting N-Myc and its downstream target genes.

Urinary exosomal hsa_circ_0001250 as a novel diagnostic biomarker of idiopathic membranous nephropathy.

AIMS: Idiopathic membranous nephropathy (IMN) is a common cause of adult nephrotic syndrome. Currently, the diagnosis of IMN mainly depends on renal biopsy, which is invasive. What's more, markers already known for the clinical diagnosis of IMN are not sensitive enough. The present study aims to investigate the profiling of urinary exosomal circular RNAs (circRNAs) of IMN, and to look for a potential biomarker for diagnosis of IMN. METHODS: Urine exosomes were collected from patients with IMN and idiopathic nephrotic syndrome (INS), as well as healthy controls (HCs) by ultracentrifuge. A pairwise comparison between 5 IMN and 5 HC was performed by high-throughput sequencing. Enrichment analysis were performed to explore the potential functions of differentially expressed circRNAs in IMN. Among three differentially expressed circRNAs which may be involved in signaling pathways of pathogenesis of IMN and matched conserved mouse circRNAs, hsa_circ_0001250 was selected as the target circRNA after quantitative polymerase chain reaction among 23 IMN, 19 INS and 23HC. Sanger sequencing and RNase R digestion assay were performed to validated the ring-structure and sequence of hsa_circ_0001250. ROC (Receiver Operating Characteristic) curve correlation analysis was used to further validate the potential utility of hsa_circ_0001250 as a diagnostic biomarker of IMN. A circRNA-miRNA-mRNA network was constructed to reflect the relationship between hsa_circ_0001250 and its target miRNAs and mRNAs. RESULTS: 766 up-regulated and 283 down-regulated circRNAs were identified in IMN patients. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed signaling pathways of pathogenesis of IMN which the different expressed circRNAs may participate in. The ring-structure and the sequence of hsa_circ_0001250 were confirmed, the expression of hsa_circ_0001250 was validated significantly increased in IMN, relevant with high level of proteinuria. A circRNA-miRNA-mRNA network reflected that hsa_circ_0001250 may play a role in the pathogenesis of IMN by target hsa-miR-639 and hsa-miR-4449. CONCLUSION: We revealed the expression and functional profile of differentially expressed urinary exosomal circRNAs of IMN patients. Urinary exosomal hsa_circ_0001250 was tested as a potential biomarker of IMN and a predicted circRNA-miRNA-mRNA network was constructed.

An improved representation of the relationship between photosynthesis and stomatal conductance leads to more stable estimation of conductance parameters and improves the goodness-of-fit across diverse data sets.

Stomata play a central role in surface-atmosphere exchange by controlling the flux of water and CO2 between the leaf and the atmosphere. Representation of stomatal conductance (gsw ) is therefore an essential component of models that seek to simulate water and CO2 exchange in plants and ecosystems. For given environmental conditions at the leaf surface (CO2 concentration and vapor pressure deficit or relative humidity), models typically assume a linear relationship between gsw and photosynthetic CO2 assimilation (A). However, measurement of leaf-level gsw response curves to changes in A are rare, particularly in the tropics, resulting in only limited data to evaluate this key assumption. Here, we measured the response of gsw and A to irradiance in six tropical species at different leaf phenological stages. We showed that the relationship between gsw and A was not linear, challenging the key assumption upon which optimality theory is based-that the marginal cost of water gain is constant. Our data showed that increasing A resulted in a small increase in gsw at low irradiance, but a much larger increase at high irradiance. We reformulated the popular Unified Stomatal Optimization (USO) model to account for this phenomenon and to enable consistent estimation of the key conductance parameters g0 and g1 . Our modification of the USO model improved the goodness-of-fit and reduced bias, enabling robust estimation of conductance parameters at any irradiance. In addition, our modification revealed previously undetectable relationships between the stomatal slope parameter g1 and other leaf traits. We also observed nonlinear behavior between A and gsw in independent data sets that included data collected from attached and detached leaves, and from plants grown at elevated CO2 concentration. We propose that this empirical modification of the USO model can improve the measurement of gsw parameters and the estimation of plant and ecosystem-scale water and CO2  fluxes.

Changes of intestinal microbiota and microbiota-based treatments in IBD.

Inflammatory bowel disease (IBD) has gained increasing attention from researchers in terms of its pathophysiology as a global disease with a growing incidence. Although the exact etiology of IBD is still unknown currently, various studies have made us realize that it is related to the dysbiosis of intestinal microbiota and the link between the two may not just be a simple causal relationship, but also a dynamic and complicated one. The intestinal microbiota has been confirmed to be closely related to the occurrence, development, and treatment of IBD. Therefore, this review focuses on the changes in the structure, function, and metabolites of intestinal bacteria, fungi, and viruses in influencing IBD, as well as various approaches to IBD treatment by changing disordered intestinal microbiota. Ultimately, more clinical studies will be needed to focus on the efficacy of intestinal microbiota-based treatments in IBD, because of the existence of both advantages and disadvantages.

Antifungal mechanism of essential oil against foodborne fungi and its application in the preservation of baked food.

Baked food is one of the most important staple foods in people's life, but its shelf life is limited. In addition, the spoilage of baked food caused by microbial deterioration will not only cause huge economic losses, but also pose a serious threat to human health. At present, due to the improvement of consumers' health awareness, the use of chemical preservatives has been gradually restricted. Compared with other types of synthetic preservatives, essential oils are becoming more and more popular because they are in line with the current development trend of "green," "safety" and "health" of food additives. Therefore, in this paper, we first summarized the main factors affecting the fungal contamination of baked food. Then analyzed the antifungal activity and mechanism of essential oil. Finally, we comprehensively summarized the application strategy of essential oil in the preservation of baked food. This review is of great significance for fully understanding the antifungal mechanism of essential oils and promoting the application of essential oils in the preservation of baked food.

Lycoperoside H protects against diabetic nephropathy via alteration of gut microbiota and inflammation.

It is well known that hyperglycemia leads to the progression and expansion of various micro and macrovascular disease such as diabetic nephropathy (DN). Lycoperoside H (LH) alkaloidal saponin exhibited the antidiabetic effect, but its DN effect is unclear. In this experimental study, we scrutinized the renal protective effect of LH against the streptozotocin (STZ)-induced DN in rats and explore the underlying mechanism. Sprague-Dawley rats were used in this experimental study and an intraperitoneal injection of STZ (45 mg/kg) was used for the induction of diabetes, rats received the oral administration of LH (20 mg/kg). The blood glucose level, body weight, organ weight (renal and pancreas), and biochemical parameters were estimated. We also scrutinized the effect of LH to enhance intestinal barrier function and suppress inflammation and intestinal permeability. LH significantly (p < 0.001) decreased the glucose level and enhanced the body weight with a reduction of renal weight and boost the pancreas weight. LH significantly (p < 0.001) enhanced the creatinine level and decreased the albumin level, urine volume, urinary albumin excretion rate, and urinary albumin creatinine ratio in the urine. It also suppressed the renal parameters, such as creatinine, blood urea nitrogen, and urea. LH significantly (p < 0.001) altered the level of lipid and antioxidant parameters. LH treatment significantly (p < 0.001) suppressed the cytokines and inflammatory parameters. LH considerably enhanced the Ruminococcaceae, Blautia, and suppressed the abundance of Bifidobacterium, Clostridium, and Turicibacter. It reduced the F/B ratio along with alteration of community abundance of Firmicutes, Actinobacteria, Proteobacteria, Tenericutes, other bacteria, and Bacteroidetes. The current result suggests that LH suppressed the diabetic nephropathological condition via alteration of gut microbiota and inflammation.

Hepatocyte-derived VEGFA accelerates the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via activating hepatic stellate cells.

Non-alcoholic fatty liver disease (NAFLD) is emerging as an epidemic risk factor for hepatocellular carcinoma (HCC). The progression of NAFLD to HCC is closely associated with paracrine communication among hepatic cells. Vascular endothelial growth factor A (VEGFA) plays a key role in NAFLD and HCC; however, the cellular communication of VEGFA in the pathological transition from NAFLD to HCC remains unclear. Here, we found that VEGFA elevation was considerably distributed in hepatocytes of clinical and murine NAFLD-HCC specimens. Notably, progression from NAFLD to HCC was attenuated in hepatocyte-specific deletion of Vegfa (VegfaΔhep) mice. Mechanistically, VEGFA activated human hepatic stellate cell (HSC) LX2 into a fibrogenic phenotype via VEGF-VEGFR signaling in fatty acid medium, and HSC activation was largely attenuated in VegfaΔhep mice during NAFLD-HCC progression. Additionally, a positive correlation between VEGFA and hepatic fibrosis was observed in the NAFLD-HCC cohort, but not in the HBV-HCC cohort. Moreover, LX2 cells could be activated by conditioned medium from NAFLD-derived organoids, but not from HBV livers, whereas this activation was blocked by a VEGFA antibody. In summary, our findings reveal that hepatocyte-derived VEGFA contributes to NAFLD-HCC development by activating HSCs and highlight the potential of precisely targeting hepatocytic VEGFA as a promising therapeutic strategy for NAFLD-HCC.

Association between visceral adiposity index and incident stroke: Data from the China Health and Retirement Longitudinal Study.

BACKGROUND AND AIMS: Visceral adiposity index (VAI), an indicator of visceral fat, is associated with metabolic health and arterial stiffness. However, studies correlating VAI and stroke are limited. This study aimed to explore the association between VAI and incident stroke in the Chinese population. METHODS AND RESULTS: We retrospectively analysed the data of 9127 individuals enrolled in the China Health and Retirement Longitudinal Study. The first survey of the study was conducted during 2011-2012 and the individuals were followed up until Survey 4 (2017-2018). Multivariable-adjusted Cox regression models were used to evaluate the association between VAI and stroke. The mean age of the study population was 59.3 ± 9.5 years and 4938 (54.1%) participants were women. During the median follow-up of 5.2 [1.0-7.0] years, 833 (9.1%) participants developed stroke, and the cumulative incidence of stroke increased with increasing quartiles of VAI (8.6%, 8.7%, 9.2%, and 10.0%). Compared to those in the first quartile of VAI, individuals in the fourth quartile had an increased risk of stroke (adjusted hazard ratio, 1.45; 95% CI, 1.15-1.75). The results were stable in several sensitivity analyses. CONCLUSION: Our findings suggest a positive association between VAI and incident stroke in the Chinese population.

A potential model of systemic sclerosis with pulmonary hypertension induced by monocrotaline plus bleomycin.

OBJECTIVE: The lack of a well-established animal model limits the clarification of the detailed mechanisms of the pathogenesis of systemic sclerosis with pulmonary hypertension (SSc-PH) and the development of effective treatments for it. METHODS: In this study, New Zealand rabbits were injected with monocrotaline (MCT), bleomycin (BLM), and MCT plus BLM, respectively. Three and six weeks after the first injection, the mean pulmonary artery pressure (mPAP) was measured. Skin and lung samples were isolated and the histological changes were analyzed by hematoxylin and eosin staining or Masson's trichrome staining. RESULTS: All groups of rabbits showed an increased mean mPAP compared with the saline-injected rabbits. The high mPAP persisted until week six only in the MCT and MCT + BLM groups. Furthermore, persistent high Fulton's indices were found in the MCT and MCT + BLM groups, indicating that these treatments successfully induced right ventricular hypertrophy. The rabbits in the MCT + BLM group developed severe lung inflammation, as evidenced by a high level of neutrophil infiltration in the pulmonary interstitium. Importantly, pathological changes of the skin in the MCT + BLM group were observed, and further damage to the skin was caused by additional exposure to MCT plus BLM. Meanwhile, an excessive production of cytokines, including tumor necrosis factor alpha (TNF-α), and transforming growth factor beta 1 (TGF-ß1), were detected in the MCT + BLM group. CONCLUSION: These data indicate that SSc-PH induced by co-injection with MCT plus BLM shows persistent fibrosis and progressive PH, constituting a potential study model for SSc-PH.

Assessing the ecological risk induced by PM2.5 pollution in a fast developing urban agglomeration of southeastern China.

High PM2.5 concentration threats ecosystem functions but limited quantitative studies have recognized PM2.5 pollution as an individual stressor in evaluating ecological risk. In this study, we applied a machine-learning-based simulation model incorporating full-coverage satellite-driven PM2.5 dataset to estimate high-resolution ground PM2.5 concentration for the Golden Triangle of Southern Fujian Province, China (GTSF) in 2030 under two Representative Concentration Pathways (RCPs). Based on the simulation output, the ecological risk's spatiotemporal change and the risk for different land cover types, which were caused by PM2.5 pollution, were assessed. We found that the PM2.5 levels and ecological risk in the GTSF under RCP 4.5 would be reduced while those under RCP 8.5 would continue to increase. The regions with the highest ecological risk under RCP 4.5 are the most urbanized and industrialized districts, while those with the highest ecological risk under RCP 8.5 are of the highest rate in urbanization and the greatest decrease in planetary potential layer height. For both base years and 2030 under two RCPs, the ecological risk on developed land is the highest, while that on the forest is the lowest. Our study can provide useful information for environmental policy risk assessment.