Heterogeneous Cardiac- and Neural Crest-Derived Aortic Smooth Muscle Cells have Similar Transcriptional Changes after TGFß Signaling Disruption.

Smooth muscle cells (SMCs) of cardiac and neural crest origin contribute to the developing proximal aorta and are linked to disease propensity in adults. We analyzed single-cell transcriptomes of SMCs from mature thoracic aortas in mice to determine basal states and changes after disrupting transforming growth factor-ß (TGFß) signaling necessary for aortic homeostasis. A minority of Myh11 lineage-marked SMCs differentially expressed genes suggestive of embryological origin. Additional analyses in Nkx2-5 and Wnt1 lineage-marked SMCs derived from cardiac and neural crest progenitors, respectively, showed both lineages contributed to a major common cluster and each lineage to a minor distinct cluster. Common cluster SMCs extended from root to arch, cardiac subset cluster SMCs from root to mid-ascending, while neural crest subset cluster SMCs were restricted to the arch. The neural crest subset cluster had greater expression of a subgroup of TGFß-dependent genes suggesting specific responsiveness or skewed extracellular matrix synthesis. Nonetheless, deletion of TGFß receptors in SMCs resulted in similar transcriptional changes among all clusters, primarily decreased extracellular matrix molecules and modulators of TGFß signaling. Many embryological markers of murine aortic SMCs were not confirmed in adult human aortas. We conclude: (i) there are multiple subtypes of cardiac- and neural crest-derived SMCs with shared or distinctive transcriptional profiles, (ii) neural crest subset SMCs with increased expression of certain TGFß-inducible genes are not spatially linked to the aortic root predisposed to aneurysms from aberrant TGFß signaling, and (iii) loss of TGFß responses after receptor deletion is uniform among SMCs of different embryological origins.

Short-Term Disruption of TGFß Signaling in Adult Mice Renders the Aorta Vulnerable to Hypertension-Induced Dissection.

Hypertension and transient increases in blood pressure from extreme exertion are risk factors for aortic dissection in patients with age-related vascular degeneration or inherited connective tissue disorders. Yet, the common experimental model of angiotensin II-induced aortopathy in mice appears independent of high blood pressure as lesions do not occur in response to an alternative vasoconstrictor, norepinephrine, and are not prevented by co-treatment with a vasodilator, hydralazine. We investigated vasoconstrictor administration to adult mice 1 week after disruption of TGFß signaling in smooth muscle cells. Norepinephrine increased blood pressure and induced aortic dissection by 7 days and even within 30 minutes that was rescued by hydralazine; results were similar with angiotensin II. Changes in regulatory contractile molecule expression were not of pathological significance. Rather, reduced synthesis of extracellular matrix yielded a vulnerable aortic phenotype by decreasing medial collagen, most dynamically type XVIII, and impairing cell-matrix adhesion. We conclude that transient and sustained increases in blood pressure cause dissection in aortas rendered vulnerable by inhibition of TGFß-driven extracellular matrix production by smooth muscle cells. A corollary is that medial fibrosis, a frequent feature of medial degeneration, may afford some protection against aortic dissection.

Hierarchically porous magnetic biochar as an amendment for wheat (Triticum aestivum L.) cultivation in alkaline Cd-contaminated soils: Impacts on plant growth, soil properties and microbiota.

Hierarchically porous magnetic biochar (HMB) had been found to act as an effective amendment to remediate cadmium (Cd) in water and soil in a previous study, but the effects on wheat growth, Cd uptake and translocation mechanisms, and soil microorganisms were unknown. Therefore, soil Cd form transformation, soil enzyme activity, soil microbial diversity, wheat Cd uptake and migration, and wheat growth were explored by adding different amounts of HMB to alkaline Cd-contaminated soil under pot experiments. The results showed that application of HMB (0.5 %-2.0 %) raised soil pH, electrical conductivity (EC) and available Fe concentration, decreased soil available Cd concentration (35.11 %-50.91 %), and promoted Cd conversion to less bioavailable Cd forms. HMB treatments could reduce Cd enrichment in wheat, inhibit Cd migration from root to stem, rachis to glume, glume to grain, and promote Cd migration from stem to leaf and stem to rachis. HMB (0.5 %-1.0 %) boosted antioxidant enzyme activity, reduced oxidative stress, and enhanced photosynthesis in wheat seedlings. Application of 1.0 % HMB increased wheat grain biomass by 40.32 %. Besides, the addition of HMB (0.5 %-1.0 %) could reduce soil Cd bioavailability, increase soil enzyme activity, and increase the abundance and diversity of soil bacteria. Higher soil EC brought forth by HMB (2.0 %) made the wheat plants and soil bacteria poisonous. This study suggests that applying the right amount of HMB to alkaline Cd-contaminated soil could be a potential remediation strategy to decrease Cd in plants' edible parts and enhance soil quality.

Efficacy of radiotherapy in combined treatment of hepatocellular carcinoma patients with portal vein tumor thrombus: a real-world study.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) has an extremely poor prognosis. A previous study proved that low-dose radiotherapy (RT) could prolong the prognosis of HCC patients with PVTT. This study aims to explore the sensitivity of PVTT to RT treatment. METHODS: Patients were selected based on imaging diagnosis of HCC accompanied by PVTT and received combined treatment of radiotherapy, antiangiogenic drugs and immune checkpoint inhibitors, followed by hepatectomy or liver transplantation from January 2019 to August 2022. The efficacy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and pathological assessment. The sensitivity of tumor cells to the treatment was compared between the primary tumor (PT)and PVTT by analyzing their residual tumor and pathologic complete remission (PCR) incidence. RESULTS: Data from 14 patients were collected in the study. After combined treatment, the size of PVTT decreased more significantly than that of the primary tumor in the imaging study (p < 0.05). The residual cancer was significantly more restrictive than that of primary tumor in paired patients based on pathological measurement (p = 0.008). The PCR incidence of the primary tumor (21.42%) was significantly lower (p = 0.008) than that of PVTT in the pathologic study (78.57%). CONCLUSION: PVTT is more sensitive to radiotherapy treatment than the primary tumor in patients with HCC. This combination therapy might be an effective option as a downstaging therapy for patients with HCC with PVTT.

Multiscale insights into postnatal aortic development.

Despite its vital importance for establishing proper cardiovascular function, the process through which the vasculature develops and matures postnatally remains poorly understood. From a clinical perspective, an ability to mechanistically model the developmental time course in arteries and veins, as well as to predict how various pathologies and therapeutic interventions alter the affected vessels, promises to improve treatment strategies and long-term clinical outcomes, particularly in pediatric patients suffering from congenital heart defects. In the present study, we conducted a multiscale investigation into the postnatal development of the murine thoracic aorta, examining key allometric relations as well as relationships between in vivo mechanical stresses, collagen and elastin expression, and the gradual accumulation of load-bearing constituents within the aortic wall. Our findings suggest that the production of fibrillar collagens in the developing aorta associates strongly with the ratio of circumferential stresses between systole and diastole, hence emphasizing the importance of a pulsatile mechanobiological stimulus. Moreover, rates of collagen turnover and elastic fiber compaction can be inferred directly by synthesizing transcriptional data and quantitative histological measurements of evolving collagen and elastin content. Consistent with previous studies, we also observed that wall shear stresses acting on the aorta are similar at birth and in maturity, supporting the hypothesis that at least some stress targets are established early in development and maintained thereafter, thus providing a possible homeostatic basis to guide future experiments and inform future predictive modeling.

Supplementing two wheat genotypes with ZnSO4 and ZnO nanoparticles showed differential mitigation of Cd phytotoxicity by reducing Cd absorption, preserving root cellular ultrastructure, and regulating metal-transporter gene expression.

Cadmium (Cd) contamination is a serious challenge in agricultural soils worldwide, resulting in Cd entering the food chain mainly through plant-based food and threatening human health. Minimizing Cd bioaccumulation in wheat is an important way to prevent Cd hazards to humans. Hydroponic and pot experiments were conducted to comprehensively evaluate the effects of zinc sulfate (ZnSO4) and zinc oxide nanoparticles (nZnO) on Cd uptake, translocation, subcellular distribution, cellular ultrastructure, and gene expression in two wheat genotypes that differ in grain Zn accumulation. Results showed that high-dose nZnO significantly reduced root Cd concentration (52.44%∼56.85%) in two wheats, in contrast to ZnSO4. The S216 exhibited higher tolerance to Cd compared to Z797. Importantly, Zn supplementation enhanced Cd sequestration into vacuoles and binding to cell walls, which conferred stability to ultracellular structures and photosynthetic apparatus. Down-regulation of influx transporter (TaHMA2 and TaLCT1) and up-regulation of efflux transporters (TaTM20 and TaHMA3) in Z797 might contribute to Zn-dependent alleviation of Cd toxicity and enhance its Cd tolerance. Down-regulation of ZIP transporters (TaZIP3, -5, and -7) might contribute to an increase in root Zn concentration and inhibit Cd absorption. Additionally, soil Zn provided an effective strategy for the reduction of grain Cd concentrations in both wheats, with a reduction of 26%∼32% (high ZnSO4) and 11%∼67% (high nZnO), respectively. Collectively, these findings provide new insights and perspectives on the mechanisms of Cd mitigation in wheats with different Zn fertilizers and demonstrate that the effect of nZnO in mitigating Cd stress is greater than that of ZnSO4 fertilizers.

Chemotherapy-induced ovarian damage and protective strategies.

More than 9.2 million women worldwide suffer from cancer, and about 5% of them are at reproductive age. Chemotherapy-induced impairment of fertility affects the quality of life of these women. Several chemotherapeutic agents have been proven to cause apoptosis and autophagy by inducing DNA damage and cellular stress. Injuries to the ovarian stroma and micro-vessel network are also considered as pivotal factors resulting in ovarian dysfunction induced by chemotherapeutic agents. Primordial follicle pool over-activation may also be the mechanism inducing damage to the ovarian reserve. Although many studies have explored the mechanisms involved in chemotherapy-induced reproductive toxicity, the exact molecular mechanisms have not been elucidated. It is essential to understand the mechanisms involved in ovarian damage, in order to develop potential protective treatments to preserve fertility. In this article, we reviewed the current knowledge on the mechanism of chemotherapy-induced ovarian damage and possible protective strategies that prevent the ovary from such damages.

Effectiveness and Safety of the PD-1 Inhibitor Lenvatinib Plus Radiotherapy in Patients with HCC with Main PVTT: Real-World Data from a Tertiary Centre.

Background: Patients with hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT), especially type Vp-4, usually have a poor prognosis. However, the vast majority of Phase III clinical trials exclude this population based on the inclusion criteria. Lenvatinib plus a PD-1 inhibitor has shown promising antitumour activity and tolerable safety in patients with unresectable HCC in Asian populations. Radiotherapy has also demonstrated high response rates and favourable survival for HCC patients with PVTT. This study aimed to explore the preliminary clinical efficacy and safety of lenvatinib plus the PD-1 inhibitor combined with radiotherapy for HCC patients with main portal vein tumour thrombus. Methods: Between 1 March 2018 and 31 October 2020, HCC patients with main PVTT who received lenvatinib plus a PD-1 inhibitor (pembrolizumab, nivolumab or sintilimab) combined with radiotherapy from Beijing Tsinghua Changgung Hospital in China were reviewed for eligibility. The efficacy was evaluated by the survival and PVTT response rate, and the safety was evaluated by the frequency of key adverse events (AEs). Results: In total, 39 eligible HCC patients with type Vp-4 PVTT who received triple therapy were included in this study. The 2-year OS rate was 15.4%, which was the primary end-point of our study. The median overall survival (OS) and progression-free survival (PFS) were 9.4 months (range 2.3 to 57.1) and 4.9 months (range 1.4 to 36.1), respectively. The objective response rate (ORR) of PVTT based on mRECIST was 61.5%. AFP dropped to normal 3 months after radiotherapy and was an independent risk factor associated with OS. All AEs were controlled, and no treatment-related deaths occurred. Conclusion: Lenvatinib plus PD-1 inhibitor combined with radiotherapy had a significant therapeutic effect and manageable AEs in HCC patients with type Vp-4 PVTT and may be a potential treatment option for advanced HCC.

A novel chaotic and neighborhood search-based artificial bee colony algorithm for solving optimization problems.

With the development of artificial intelligence, numerous researchers are attracted to study new heuristic algorithms and improve traditional algorithms. Artificial bee colony (ABC) algorithm is a swarm intelligence optimization algorithm inspired by the foraging behavior of honeybees, which is one of the most widely applied methods to solve optimization problems. However, the traditional ABC has some shortcomings such as under-exploitation and slow convergence, etc. In this study, a novel variant of ABC named chaotic and neighborhood search-based ABC algorithm (CNSABC) is proposed. The CNSABC contains three improved mechanisms, including Bernoulli chaotic mapping with mutual exclusion mechanism, neighborhood search mechanism with compression factor, and sustained bees. In detail, Bernoulli chaotic mapping with mutual exclusion mechanism is introduced to enhance the diversity and the exploration ability. To enhance the convergence efficiency and exploitation capability of the algorithm, the neighborhood search mechanism with compression factor and sustained bees are presented. Subsequently, a series of experiments are conducted to verify the effectiveness of the three presented mechanisms and the superiority of the proposed CNSABC, the results demonstrate that the proposed CNSABC has better convergence efficiency and search ability. Finally, the CNSABC is applied to solve two engineering optimization problems, experimental results show that CNSABC can produce satisfactory solutions.

Temporal dynamics of soil dissolved organic carbon in temperate forest managed by prescribed burning in Northeast China.

Dissolved organic carbon (DOC) is an important function of soil organic carbon and sensitive to environmental disturbance. Few studies have explored the variations in soil DOC dynamics and effects on soil physicochemical properties following prescribed burnings. In this study, Pinus koraiensis plantation forests in Northeast China were selected and subjected to prescribed burning in early November 2018. Soil DOC and different soil physicochemical and biological properties in the 0-10 cm and 10-20 cm soil layers were sampled six times within two years after a prescribed burning. In this study, some soil physicochemical (SOC, TN, and ST) and microbial biomass properties (MBC) recovered within two years after a prescribed burning. Compared to the unburned control stands, the post-fire soil DOC concentrations in the upper and lower soil layers increased by 16% and 12%, respectively. Soil DOC concentrations varied with sampling time, and peaked one year after the prescribed burning. Our results showed that soil chemical properties (NH4+-N and pH) rather than biological properties (microbial biomass) were the main driving factors for changes in post-fire soil DOC concentrations. Current study provides an important reference for post-fire and seasonal soil C cycling in plantation forests of Northeast China.

The effect of working memory updating training on the Chinese writing ability of primary school students.

Objective: This study aimed to explore the effects of working memory updating training on primary school students' writing ability and performance. Methods: A total of 46 fourth-grade Chinese primary school students were recruited; their performance in the Chinese character N-back training task, the Writing Ability Questionnaire, and a time-limited writing task was assessed. Results: The paired-sample t-test revealed that working memory updating training significantly improved the experimental group's working memory level. After training, a repeated measures ANOVA revealed that the experimental group's performance on the Writing Ability Questionnaire improved and was higher than that of the control group. In the time-limited writing task, independent-sample t-tests revealed that the experimental group's writing fluency increased and was higher than that of the control group, while the latter's grammatical accuracy and complexity decreased and were lower than those of the former. Conclusion: Working memory updating training can be used as auxiliary cognitive training to improve primary school students' working memory level, thereby promoting their writing development.

Mitochondrial damage-induced abnormal glucose metabolism with ageing in the hippocampus of APP/PS1 mice.

INTRODUCTION: Accumulation of ß-amyloid (Aß) in neurons of patients with Alzheimer's disease (AD) inhibits the activity of key enzymes in mitochondrial metabolic pathways, triggering mitochondrial dysfunction, which plays an important role in the onset and development of AD. Mitophagy is a process whereby dysfunctional or damaged mitochondria are removed from the cell. Aberrant mitochondrial metabolism may hinder mitophagy, promote autophagosome accumulation, and lead to neuronal death. OBJECTIVES: The aim of this experiment is to explore the mechanism of neuronal mitochondria damage in the hippocampus of different age APP/PS1 double transgenic AD mice, and to explore the related metabolites and metabolic pathways for further understanding of the pathogenesis, so as to provide new ideas and strategies for the treatment of AD. METHODS: In this study, 24 APP/PS1(APPswe/PSEN1dE9) mice were divided into 3, 6, 9, and 12-month-old groups, and 6-month-old wild-type C57BL/6 mice were as controls. The Morris water maze test was used to evaluate learning and memory. Levels of Aß were detected by immunohistochemistry. Electron microscopy was used to observe mitochondrial damage and autophagosome accumulation. Western blot was for measuring LC3, P62, PINK1, Parkin, Miro1, and Tom 20 protein expression levels. Gas chromatography coupled with mass spectrometry was used to screen differentially abundant metabolites. RESULTS: The results showed that with the increase of age in APP/PS1 mice, cognitive impairment, hippocampal neuron mitochondrial damage, and autophagosome accumulation all increased. Furthermore, enhanced mitophagy and impaired mitochondrial clearance leading to metabolic abnormalities were observed with ageing in APP/PS1 mouse hippocampus. Especially, abnormal accumulation of succinic acid and citric acid in the Krebs cycle was observed. CONCLUSION: This study investigated the abnormal glucose metabolism associated with age-related damage to mitochondria in the hippocampus of APP/PS1 mice. These findings provide new insights into the pathogenesis of AD.

Everolimus combined with PD-1 blockade inhibits progression of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Due to rapid progression and a lack of targetable receptors, TNBC is exceptionally difficult to treat. Available treatment options are nonspecific cytotoxic agents, which have had modest success; thus, there is a need for novel therapies for TNBC. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is aberrantly activated in TNBC, and this pathway has been shown to promote cancer cell survival and chemoresistance. As such, mTOR inhibition has been considered a potential therapeutic strategy for TNBC. The mTOR inhibitor everolimus (EVE) has been approved for the treatment of estrogen positive breast cancer; however, its efficacy in TNBC is still undetermined. In this study, we evaluated the effects of EVE monotherapy and the mechanism of EVE resistance in the 4T1 model of TNBC. Whereas EVE monotherapy inhibited mTOR signaling activity, it did not attenuate tumor progression. Additionally, tumors from EVE-treated mice had abnormal vasculature characterized by disorganized architecture and hyperpermeability. We also found that treatment with EVE increased PD-L1 expression in intratumoral vascular endothelial cells, and this increase in endothelial cell-associated PD-L1 corresponded to reduced CD8 + T cell tumor infiltration. Importantly, combination treatment with anti-PD-1 antibody and EVE normalized the tumor vasculature, rescued CD8 + T cell tumor infiltration, and reduced tumor growth. Taken together, our findings improve our current understanding of mechanisms underlying mTOR inhibition resistance in TNBC and identify a novel combination treatment strategy in the treatment of mTOR resistant tumors.

[Effects of P on the Uptake and Transport of Cd and As in Wheat Seedlings].

The aim of this study was to explore the effect of P on the physiological mechanism of Cd and As uptake and transport of wheat seedlings. Taking Bainong 207 as the test material, we investigated the effects of exogenous P supply and P deficiency treatment on the growth, root morphology, photosynthetic parameters, antioxidant system, ion content, and rhizome transfer coefficient of wheat seedlings under Cd and As stress using hydroponic experiments. The results showed that compared with that in the P deficiency treatment, the supply of exogenous P significantly increased the chlorophyll content of wheat seedlings under As stress, promoted the growth and development of roots, and increased biomass, whereas there were no significant effects on the growth of wheat seedlings under Cd stress. The contents of P and Cd in the root system under the condition of Cd stress were significantly increased by the supply of exogenous P, and the contents of P and Cd in the aboveground part were reduced. At the same time, the P and As content in the shoot and the transfer coefficient of As from the root to the shoot under As stress were significantly improved. Therefore, the effects of P on the poisoning of wheat Cd and As in this study showed obvious differences. Under As stress, exogenous P supply mainly promoted the growth of wheat seedlings by improving the transport of As from the root to the shoot and the CAT activity in the root system, reducing the poisoning of As in wheat. Under Cd stress, P and Cd showed a certain synergistic effect, and the toxic effect of Cd on wheat was aggravated to a certain extent after the supply of P.

Trehalose attenuates abdominal aortic aneurysm formation by inducing autophagy in smooth muscle cells.

BACKGROUND: Trehalose is a naturally occurring disaccharide, which has been identified as an autophagy inducer and exhibits protective effect in cardiovascular diseases such as myocardial infraction and atherosclerosis. However, the functional role of trehalose in abdominal aortic aneurysm (AAA) remains undefined. METHODS: To study the effect of trehalose in AAA, trehalose (1 g/kg per day) were given for 14 continuous days in a mouse model of elastase-induced abdominal aortic aneurysm. On day 14, ultrasound was performed to measure aortic diameter before the abdominal aortas were harvested and processed for further analysis. Verhoeff-Van Gieson staining and TUNEL staining were performed on paraffin sections to evaluate vascular histology and apoptosis, immunofluorescence staining and Western-blot were performed to evaluate expression of autophagy markers. RESULTS: Echocardiography and in situ pictures demonstrated that trehalose attenuated infrarenal aorta dilation. Verhoeff-Van Gieson staining showed elastin degradation was improved in trehalose-treated group. Compared with vehicle-treated mice, trehalose treatment restored smooth muscle cell contractile phenotype with increased α-SMA, Calponin and Myh11 expression. Furthermore, trehalose also attenuated cell apoptosis and leukocytes infiltration. Importantly, trehalose induced autophagy with decrease SQSTM1/p62 accumulation, increased lamp2 expression and LC3B conversion. CONCLUSION: Trehalose attenuated AAA progression with decreased inflammation and restored SMC contractile phenotype by inducing autophagy. These results demonstrated the therapeutic potential of trehalose in AAA.

Selenium uptake, translocation, subcellular distribution and speciation in winter wheat in response to phosphorus application combined with three types of selenium fertilizer.

BACKGROUND: Selenium (Se) deficiency causes a series of health disorders in humans, and Se concentrations in the edible parts of crops can be improved by altering exogenous Se species. However, the uptake, transport, subcellular distribution and metabolism of selenite, selenate and SeMet (selenomethionine) under the influence of phosphorus (P) has not been well characterized. RESULTS: The results showed that increasing the P application rate enhanced photosynthesis and then increased the dry matter weight of shoots with selenite and SeMet treatment, and an appropriate amount of P combined with selenite treatment increased the dry matter weight of roots by enhancing root growth. With selenite treatment, increasing the P application rate significantly decreased the concentration and accumulation of Se in roots and shoots. P1 decreased the Se migration coefficient, which could be attributed to the inhibited distribution of Se in the root cell wall, but increased distribution of Se in the root soluble fraction, as well as the promoted proportion of SeMet and MeSeCys (Se-methyl-selenocysteine) in roots. With selenate treatment, P0.1 and P1 significantly increased the Se concentration and distribution in shoots and the Se migration coefficient, which could be attributed to the enhanced proportion of Se (IV) in roots but decreased proportion of SeMet in roots. With SeMet treatment, increasing the P application rate significantly decreased the Se concentration in shoots and roots but increased the proportion of SeCys2 (selenocystine) in roots. CONCLUSION: Compared with selenate or SeMet treatment, treatment with an appropriate amount of P combined with selenite could promote plant growth, reduce Se uptake, alter Se subcellular distribution and speciation, and affect Se bioavailability in wheat.

Mitochondrial stress response gene Clpp deficiency impairs oocyte competence and deteriorate cyclophosphamide-induced ovarian damage in young mice.

Chemotherapy is extensively used to treat cancers and is often associated with ovarian damage and leads to premature ovarian insufficiency and infertility, while the role of mitochondria during ovarian damage with chemotherapy remains unknown. This study used a mouse model with oocyte-specific deletion of mitochondrial stress response gene Caseinolytic peptidase P (Clpp) to investigate mitochondrial homeostasis in oocytes from mice receiving a chemotherapeutic drug cyclophosphamide (CTX). We found that oocyte-specific deletion of Clpp reduced fecundity of the mice at advanced age. The deletion led to meiotic defects with elevated abnormal spindle rate and aneuploidy rate with impaired mitochondrial function in the MII oocytes from 8-week-old mice. Upon CTX treatment at 8-week-old, the oocyte competence and folliculogenesis from the oocyte-specific Clpp knockout mice was further deteriorated with dramatic impairment of mitochondrial distribution and function including elevated ROS level, decreased mitochondrial membrane potential, respiratory chain activity and ATP production. Taken together, the results indicate that that ClpP was required for oocyte competence during maturation and early folliculogenesis, and its deficiency deteriorate cyclophosphamide-induced ovarian damage.

Raltitrexed enhanced antitumor effect of anlotinib in human esophageal squamous carcinoma cells on proliferation, invasiveness, and apoptosis.

BACKGROUND: Anlotinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) which has exhibited encouraging clinical activity in advanced non-small cell lung cancer (NSCLC) and soft tissue sarcoma. Raltitrexed is well known to be effective in the treatment of colorectal cancer in China. The present study aims to investigate the combinatory antitumor effect of anlotinib and raltitrexed on human esophageal squamous carcinoma cells and further explore the molecular mechanisms in vitro. METHODS: Human esophageal squamous cell lines KYSE-30 and TE-1 were treated with anlotinib or raltitrexed, or both, then cell proliferation was measured by MTS and colony formation assay; cell migration and invasion were detected by wound-healing and transwell assays; cell apoptosis rate was studied by flow cytometry and the transcription of apoptosis-associated proteins were monitored by quantitative polymerase chain reaction (qPCR) analysis. Finally, western blot was performed to check phosphorylation of apoptotic proteins after treatment. RESULTS: Treatment with raltitrexed and anlotinib showed enhanced inhibitory effects on cell proliferation, migration and invasiveness compared with raltitrexed or anlotinib monotherapy. Meanwhile, raltitrexed combined with anlotinib strongly increased cell apoptosis percentage. Moreover, the combined treatment down-regulated mRNA level of the anti-apoptotic protein Bcl-2 and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9), while up-regulated pro-apoptotic Bax and caspase-3 transcription. Western blotting showed that the combination of raltitrexed and anlotinib could inhibit the expression of phosphorylated Akt (p-Akt), Erk (p-Erk) and MMP-9. CONCLUSIONS: This study indicated that raltitrexed enhanced the antitumor effects of anlotinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, providing a novel treatment option for patients with esophageal squamous cell carcinoma (ESCC).

Association between the uric acid to high density lipoprotein cholesterol ratio and alanine transaminase in Chinese short stature children and adolescents: A cross-sectional study.

Objective: Uric acid to high-density lipoprotein cholesterol ratio (UHR), the ratio of uric acid to high-density lipoprotein cholesterol, is a newly proposed marker of metabolic abnormalities. There are few previous studies directly investigating the relationship between UHR and alanine aminotransferase (ALT), especially in short stature populations, however, short stature children and adolescents are more likely to have metabolic disorders. This research aimed to investigate the relationship between the UHR and ALT in children and adolescents with short stature. Methods: In this cross-sectional analysis, the clinical data of 1,510 children with height below -2 SD who were evaluated at the Department of Endocrinology, Affiliated Hospital of Jining Medical University from 1 March 2013 to 31 December 2021, were selected. Anthropometric and biochemical indicators were measured. The relationship between UHR and ALT was analysed. Results: The univariate analysis results showed that UHR was positively associated with ALT (ß = 0.43, P < 0.0001). Furthermore, after adjusting for possible confounding factors, a non-linear relationship was detected between UHR and ALT through smooth curve fitting, and the inflection point of UHR was 10.93% after multivariate piecewise linear regression analysis. ALT increased with UHR elevation when the UHR was greater than 10.93% (ß = 0.69, 95% CI 0.39, 0.98; P < 0.0001). However, we did not observe a significant relationship when the UHR was less than 10.93% (P = 0.9229). Conclusion: Our study demonstrated that in Chinese children and adolescents with short stature, UHR may be associated with the regulation of ALT levels, and this relationship merits further investigation.

Effects of pyrogenic carbon addition after fire on soil carbon mineralization in the Great Khingan Mountains peatlands (Northeast China).

Wildfires play a critical role in regulating soil carbon (C) budgets in peatland ecosystems, and their frequency and intensity are increasing owing to climate change and human activities. Wildfires not only emit CO2 during the combustion process but also produce pyrogenic carbon (PyC), which accumulates in the soil C pool and influences soil C decomposition. However, the role of PyC after a fire in peatland soil C mineralization has rarely been examined. This study investigated the effects of PyC addition on peatland soil C mineralization and its potential driving mechanisms using an anaerobic/aerobic incubation experiment with peat soils collected from typical peatlands in the Great Khingan Mountains, Northeast China. The effect of PyC was more pronounced under aerobic conditions than under anaerobic conditions. The mean C- mineralization rates of soil were significantly increased by 45.2 ± 15.5 % and 87.6 ± 14.3 % with 10 % PyC250°C addition after the initial stage (D7) of aerobic and anaerobic incubation, but PyC600°C addition caused a to decrease. Compared with PyC600°C, PyC250°C addition significantly increased the available N content and altered the soil microbial activities, which may be the primary reason for the increase in C mineralization rates. Furthermore, adding a high concentration of PyC (10 %) reduced the concentration of phenolics but increased phenol oxidase activity, which promoted C mineralization rates. Thus, PyC250°C addition to peat soils mainly influences the microbial biomass C content through the accumulation of available N and phenolics, which ultimately positively affects C mineralization rates.