A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex degrades BNIP3 and NIX to restrain mitophagy and prevent mitochondrial disease.

Mitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here, via a mitochondria-targeted genetic screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4-KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer-membrane protein that forms an SCF-FBXL4 ubiquitin E3 ligase complex. SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF-FBXL4 assembly and impair substrate degradation. Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. Together, beyond identifying SCF-FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

Alterations in leukocyte telomere length and mitochondrial DNA copy number in benzene poisoning patients.

OBJECTIVE: The aim of this study is to examine and evaluate the impact of benzene poisoning on the relative content of the mitochondrial MT-ND1 gene and telomere length in individuals with occupational chronic benzene poisoning (CBP) compared to a control group. The study will analyze and gather data on the mitochondrial gene content and telomere length in cases of benzene poisoning, and investigate the relationship with blood routine parameters in order to contribute scientific experimental data for the prevention and treatment of CBP. METHOD: The case group comprised 30 individuals diagnosed with occupational chronic benzene poisoning, whereas the control group consisted of 60 healthy individuals who underwent physical examinations at our hospital concurrently. Blood routine indicators were detected and analyzed, and the PCR method was employed to measure changes in mitochondrial MT-ND1 content and telomere length. Subsequently, a comparison and analysis of the aforementioned indicators was conducted. RESULT: The case group exhibited a higher mitochondrial gene content (median 366.2, IQR 90.0 rate) compared to the control group (median 101.5, IQR 12.0 rate), with a statistically significant difference between the two groups (P < 0.05). Additionally, the case group demonstrated lower white blood cell levels (3.78 ± 1.387 × 109/L) compared to the control group (5.74 ± 1.41 × 109/L), with a significant difference between the two groups (P < 0.05). Furthermore, the case group displayed lower red blood cell levels (3.86 ± 0.65 × 1012/L) compared to the control group (4.89 ± 0.65 × 1012/L), with a significant difference between the two groups (P < 0.05). The hemoglobin level in the case group (113.33 ± 16.34 g/L) was lower than that in the control group (138.22 ± 13.22 g/L). There was a significant difference between the two groups (P < 0.05). Platelet levels in the case group (153.80 ± 58.31 × 109/L) is smaller than the control group (244.92 ± 51.99 × 109/L), there was a significant difference between the two groups (P < 0.05). The average telomere length of the normal control group was 1.451 ± 0.475 (rate); The mean telomere length of individuals in the case group diagnosed with benzene poisoning was determined to be 1.237 ± 0.457 (rate). No significant correlation was observed between telomere length and three blood routine parameters, namely white blood cells (WBC), hemoglobin (HB), and platelets (PLT). However, a significant correlation was found between telomere length and red blood cell count (RBC). Additionally, a negative correlation was observed between mitochondrial gene content and white blood cell count (r = - 0.314, P = 0.026), as well as between mitochondrial gene content and red blood cell count (r = - 0.226, P = 0.032). Furthermore, a negative correlation was identified between mitochondrial gene content and hemoglobin (r = - 0.314, P = 0.028), and platelets (r = - 0.445, P = 0.001). CONCLUSION: Individuals diagnosed with occupational chronic benzene poisoning exhibit a reduction in telomere length and an elevation in the relative content of the mitochondrial MT-ND1 gene. Moreover, a negative correlation is observed between the content of the mitochondrial MT-ND1 gene and four blood routine parameters, namely white blood cells (WBC), red blood cells (RBC), hemoglobin (HB), and platelets (PLT). Consequently, benzene exposure may potentially contribute to the onset of premature aging.

Association between BMI and osteoporotic fractures at different sites in Chinese women: a case-control retrospective study in Changsha.

BACKGROUND: Osteoporotic fractures are a growing problem in an aging society. The association between body mass index (BMI) and osteoporotic fractures varies by fracture site and ethnicity. Limited knowledge exists regarding this association in native Chinese, particularly utilizing local databases as reference sources. OBJECTIVE: To investigate the association between BMI and osteoporotic fractures at different sites in Chinese women. METHODS: Three thousand ninety-eight female patients with radiographic fractures and 3098 age- and sex-matched healthy controls without fractures were included in the study. Both of them underwent assessment using dual-energy X-ray absorptiometry (DXA), with BMD measurements calculated using our own BMD reference database. Participants were classified into underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 24.0 kg/m2), overweight (24 ≤ BMI < 28 kg/m2) and obese (BMI ≥ 28 kg/m2) according to the Chinese BMI classification standard. RESULTS: There were 2296 (74.1%) vertebral fractures, 374 (12.1%) femoral neck fractures, and 428 (13.8%) other types of fractures in the case group. Bone mineral density (BMD) was almost lower in the fracture groups compared to the control groups (p = 0.048 to < 0.001). Compared with normal weight, underweight had a protective effect on total [odds ratio (OR) = 0.61; 95% confidence interval (CI), 0.49 -0.75; P< 0.001], and lumbar fractures (OR = 0.52; 95% CI, 0.41 - 0.67; P < 0.001), while obesity was associated with an increased risk for total (OR = 2.26; 95% CI, 1.85 - 2.76; P < 0.001), lumbar (OR = 2.17; 95% CI, 1.72 - 2.73; P < 0.001), and femoral neck fractures (OR = 4.08; 95% CI, 2.18 - 7.63; P < 0.001). Non-linear associations were observed between BMI and fractures: A J-curve for total, lumbar, and femoral neck fractures, and no statistical change for other types of fractures. Underweight was found to be a risk factor for other types of fracturess after adjusting for BMD (OR = 2.29; 95% CI, 1.09 - 4.80; P < 0.001). Osteoporosis and osteopenia were identified as risk factors for almost all sites of fracture when compared to normal bone mass. CONCLUSIONS: Underweight has a protective effect on total and lumbar spine fractures in Chinese women, while obesity poses a risk factor for total, lumbar, and femoral neck fractures. The effect of BMI on fractures may be mainly mediated by BMD.

A Self-Attention Integrated Learning Model for Landing Gear Performance Prediction.

The landing gear structure suffers from large loads during aircraft takeoff and landing, and an accurate prediction of landing gear performance is beneficial to ensure flight safety. Nevertheless, the landing gear performance prediction method based on machine learning has a strong reliance on the dataset, in which the feature dimension and data distribution will have a great impact on the prediction accuracy. To address these issues, a novel MCA-MLPSA is developed. First, an MCA (multiple correlation analysis) method is proposed to select key features. Second, a heterogeneous multilearner integration framework is proposed, which makes use of different base learners. Third, an MLPSA (multilayer perceptron with self-attention) model is proposed to adaptively capture the data distribution and adjust the weights of each base learner. Finally, the excellent prediction performance of the proposed MCA-MLPSA is validated by a series of experiments on the landing gear data.

Cardiovascular disease in type 2 diabetes mellitus: progress toward personalized management.

Cardiovascular diseases (CVDs) are the main cause of death among patients with type 2 diabetes mellitus (T2DM), particularly in low- and middle-income countries. To effectively prevent the development of CVDs in T2DM, considerable effort has been made to explore novel preventive approaches, individualized glycemic control and cardiovascular risk management (strict blood pressure and lipid control), together with recently developed glucose-lowering agents and lipid-lowering drugs. This review mainly addresses the important issues affecting the choice of antidiabetic agents and lipid, blood pressure and antiplatelet treatments considering the cardiovascular status of the patient. Finally, we also discuss the changes in therapy principles underlying CVDs in T2DM.

Identification and characterization of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency.

Pyruvate, the end product of glycolysis, is a key metabolic molecule enabling mitochondrial adenosine triphosphate synthesis and takes part in multiple biosynthetic pathways within mitochondria. The mitochondrial pyruvate carrier (MPC) plays a vital role in transporting pyruvate from the cytosol into the organelle. In humans, MPC is a hetero-oligomeric complex formed by the MPC1 and MPC2 paralogs that are both necessary to stabilize each other and form a functional MPC. MPC deficiency (OMIM#614741) due to pathogenic MPC1 variants is a rare autosomal recessive disease involving developmental delay, microcephaly, growth failure, and increased serum lactate and pyruvate. To date, two MPC1 variants in four cases have been reported, though only one with a detailed clinical description. Herein, we report three novel pathogenic MPC1 variants in six patients from three unrelated families, identified within European, Kuwaiti, and Chinese mitochondrial disease patient cohorts, one of whom presented as a Leigh-like syndrome. Functional analysis in primary fibroblasts from the patients revealed decreased expression of MPC1 and MPC2. We rescued pyruvate-driven oxygen consumption rate in patient's fibroblasts by reconstituting with wild-type MPC1. Complementing homozygous MPC1 mutant cDNA with CRISPR-deleted MPC1 C2C12 cells verified the mechanism of variants: unstable MPC complex or ablated pyruvate uptake activity. Furthermore, we showed that glutamine and beta-hydroxybutyrate were alternative substrates to maintain mitochondrial respiration when cells lack pyruvate. In conclusion, we expand the clinical phenotypes and genotypes associated with MPC deficiency, with our studies revealing glutamine as a potential therapy for MPC deficiency.

Relationship between bone mineral density and fragility fracture risk: a case-control study in Changsha, China.

BACKGROUND: Fragility fracture is associated with bone mineral density (BMD), and most databases used in related researches are instrument-matched. Little is known about the relationship between BMD and fragility fracture risk of native Chinese, especially using local databases as reference databases. OBJECTIVE: To investigate relationship between BMD and risk of fragility fracture in native China. METHODS: 3,324 cases, including 2,423 women (67.7 ± 8.9 years) and 901 men (68.4 ± 11.6 years) having radiological fragility fractures and 3,324 age- and gender-matched controls participated in the study. We measured BMD at posteroanterior spine and hip using dual-energy X-ray absorptiometry (DXA), calculated BMD measurement parameters based on our own BMD reference database. RESULTS: BMDs and mean T-scores were lower in case group (with clinical fragility) than in control group (without clinical fragility). In patients with fragility fractures, prevalence of lumbar osteoporosis, low bone mass, and normal BMD were 78.9 %, 19.3 %, and 1.8 %, respectively, in women, and 49.5, 44.8 %, and 5.7 %, respectively, in men. In hip, these prevalence rates were 67.2 %, 28.4 %, and 4.4 % in females, and 43.2 %, 45.9 %, and 10.9 % in males, respectively, showing differences between females and males. Multivariate Cox regression analysis showed that after adjusting age, height, weight, and body mass index, fracture hazard ratio (HR) increased by 2.7-2.8 times (95 % CI 2.5-3.1) and 3.6-4.1 times (95 %CI 3.0-5.1) for women and men respectively with decreasing BMD parameters. In both sexes, risk of fragility fracture increased approximately 1.6-1.7 times (95 % CI 1.5-1.8) for every 1 T-score reduction in BMD. CONCLUSIONS: Risk of clinical fragility fracture increases with decreasing BMD measurement parameters and anthropometric indicators in native China, and fracture HR varies from gender and site.

A recursive approach for aeroacoustic phased array measurements in wind tunnels.

Noise-interference suppression and data-processing acceleration are crucial to aeroacoustic measurements with phased array in wind tunnels. In this paper, we develop a "multi-window" beamforming algorithm that recursively processes data based on an array-acquisition model. This spatial filtering algorithm is derived from the Kalman filter theory for signal processing. The simulated results show that by using recursive operations, accurate signal estimation is acquired with incoherent and coherent background noise removed in the presence of both channel noise and phase noise. The convergence rate of this recursive algorithm is faster than the existing algorithms. As a result, considerable storage space and computational resources are saved, while testing defects in wind tunnel measurement are revealed and corrected immediately on-site. It has a great potential for real-time localization of sound sources in a noisy environment.

[Jujing Gouju Granules promote reproductive function in rats with spermatozoa].

OBJECTIVE: To observe the intervention effect of Jujing Gouju Granules (JGG) on teratozoospermia (TZ) in rats and explore its action mechanism. METHODS: Thirty-two male SD rats were randomly divided into four groups of an equal number: normal control, TZ model control, high-dose JGG and low-dose JGG. The TZ model was established in the latter three groups of rats by intragastric administration of methyl methanesulfonate at 4 mg/100 g body weight/day for 7 consecutive days. After successful modeling, the animals in the high- and low-dose JGG groups were treated with JGG at 0.288 and 0.072g/100 g body weight/d, respectively, while the normal controls with the same dose of normal saline, all for 48 days. At two days after medication, all the rats were sacrificed and the right epididymides harvested for sperm counting, sperm motility analysis, observation the sperm morphology, and determination of contents of fructose, zinc, α-glucosidase and superoxide dismutase (SOD) in the epididymal suspension, the levels of IL-6, IL-8 and TNF-α in the seminal plasma, and that of reactive oxygen species (ROS) in the sperm. RESULTS: Both sperm concentration and motility were significantly increased and the percentage of morphologically abnormal sperm decreased in the JGG groups compared with the model controls, even more significantly in the high- than in the low-dose JGG group (P < 0.05). No statistically significant difference was found in the contents of fructose and zinc in the epididymal suspension among the four groups, but that of α-glucosidase was remarkably lower in the TZ model than in the normal controls (ï¼»50.31 ± 2.12ï¼½ vs ï¼»67.23 ± 3.54ï¼½ U/L, P < 0.05), but higher in the high- and low-dose JGG groups (ï¼»79.36 ± 2.35ï¼½ and ï¼»56.25 ± 3.44ï¼½ U/L) than in the model control group (P < 0.05). The level of ROS was markedly higher and that of SOD lower in the TZ model than in the normal controls, while the former was lower and the latter was higher in the JGG groups than in the TZ model controls (P < 0.05), even more significantly in the in the high- than in the low-dose JGG group (P < 0.05). Compared with the TZ model controls, the rats in the JGG groups showed dramatically decreased levels of IL-6, IL-8 and TNF-α in the seminal plasma, even more significantly in the high- than in the low-dose JGG group (P < 0.05). CONCLUSIONS: Jujing Gouju Granules can improve sperm morphology in teratozoospermia rats, possibly by regulating oxidative stress and inflammation-related factors.

[Essentials of the differentiation and standardization of syndromes for male impotence in Xu Fu-song's clinical experience].

OBJECTIVE: To analyze the essentials of the differentiation and standardization of syndromes for male impotence in Xu Fu-song's clinical practice. METHODS: We conducted a randomized survey of 183 cases of male impotence diagnosed and treated at Professor Xu Fu-song's Clinic. We collected the data on the four diagnostic methods of traditional Chinese medicine (TCM), namely, observation, auscultation and olfaction, inquiry, and pulse feeling and palpation, and subjected them to principal component and factor analyses. RESULTS: Eleven common factors were extracted in the principal component and factor analyses, which were in accordance with Xu Fu-song's clinical practice. Based on the results of the analysis of the 11 factors, male impotence is differentiated as 11 syndrome types as follows: damp-heat syndrome, with the manifestations of bitter taste, scrotal moisture, reddish yellow urine, dribbling urination, frequent urination, urgent urination, sticky stool, red tongue, yellow greasy fur, rapid pulse, slippery pulse, and soggy pulse; kidney-yin deficiency syndrome, featured by polyhidrosis of hands and feet, night sweating, cold drink preference, dry mouth, red tongue, less fur, thready pulse, and rapid pulse; liver-qi stagnation syndrome, presented as depression, anxiety, introvert, dark tongue, and stringy pulse; phlegm turbidity syndrome, shown as sticky mouth, phlegmy mouth, throat discomfort, chest congestion, gastric fullness, low sexual desire, white greasy fur, and slippery pulse; kidney-yang deficiency syndrome, manifested as intolerance of cold, mental fatigue, lower abdominal cold, nocturnal enuresis, hot drink preference, pale tongue, and deep pulse; lung and spleen deficiency syndrome, with the presentations of cough, easy cold, spontaneous sweating, nasal stuffiness, pale tongue, and thready pulse; qi stagnation and blood stasis syndrome, characterized by lower abdominal pain, perineal or testicular prolapse, purple tongue, and deep pulse; heart-kidney disharmony syndrome, distinguished by insomnia, gonobolia, premature ejaculation, red tongue, and thready pulse; heart and spleen deficiency syndrome, featured by palpitation, amnesia, pale complexion, pale tongue, and deep pulse; spleen and kidney deficiency syndrome, manifested as dizziness, pale complexion, pale tongue, deep pulse, and thready pulse; lung and kidney deficiency syndrome, characterized by five-center dysphoria, tinnitus, general heaviness, pale tongue, less fur, and thready pulse. CONCLUSIONS: The syndromes of male impotence are regularly differentiated and standardized in Xu Fu-song's clinical practice, each with its core symptoms and typical tongue and pulse manifestations.

[Application of Tri-Jiao Theory in the treatment of male immune infertility].

Male immune infertility is a common disease with an incidence rate of about 10%. This article aimed to find some breakthrough clues to the etiology and pathogenesis of male immune infertility from years of relevant studies in traditional Chinese medicine (TCM). Some consensuses on the diagnosis, etiology and pathogenesis of the disease are based on limited and isolated understandings. With the Tri-Jiao Theory as the breakthrough point, we analyzed the three studies by the Xu Fu-song Group and discussed the causes, development and outcome of male immune infertility from the aspects of its positioning, transmission and syndrome differentiation. The Tri-Jiao Theory reflects the holistic thought of TCM and offers a comprehensive insight into the dynamic changes of the disease. As the basis for TCM understanding of male immune infertility, studies on the mucosal immune system have provided some new ideas for applying the Tri-Jiao Theory to TCM researches into the disease.

USP3 stabilizes p53 protein through its deubiquitinase activity.

p53 is the guardian of the genome integrity and the degradation of p53 protein is mediated by MDM2. Here we report that USP3 interacts with p53 and regulates p53 stability. Depletion of USP3 lead to accelerated degradation of p53 in normal cells thereby enhanced cell proliferation and transformation. Reconstitution of wildtype USP3, but not the USP3 C168S mutant, restored the stability of p53 protein and inhibited cell proliferation and transformation. These findings suggest that USP3 is an important regulator of p53 and regulates normal cell transformation.

Catalyst-Free Synthesis of Pyrrolo[1,2-a]quinolines via Dehydration/[3 + 2] Cycloaddition Directly from 2-Methylquinolines, Aldehydes, and Alkynoates.

A simple and efficient catalyst-free synthesis of pyrrolo[1,2-a]quinoline derivatives from 2-methylquinolines, aldehydes, and alkynoates via dehydration/[3 + 2] cycloaddition has been developed. The reaction conditions are tolerant to air, and H2O is the only byproduct of this transformation, thus offering an environmentally benign process with a wide range of potential applications in organic synthesis and medicinal chemistry.

[Chinese medicinal compound CFF-1 induces the apoptosis and cycle-arrest of prostate cancer cells via the PI3K/AKT/FOXO1 signaling pathway].

OBJECTIVE: To explore the apoptosis-inducing effect of the Chinese medicinal compound CFF-1 on prostate cancer cells and its related molecular mechanisms. METHODS: Normal prostate WPMY-1 cells and prostate cancer LNCaP, CWR22Rv1, PC3 and DU145 cells were treated in dehydrated alcohol with CFF-1 at 0, 2, 5, or 10 mg/ml for 24 hours. Then the viability of the prostate cells was detected by morphological observation, MTT and CCK-8 assay, nuclear condensation and disruption measured by DAPI staining, the cell cycle and apoptosis calculated by flow cytometry, the activity of the PI3K/AKT/FOXO1 signaling pathway and the expressions of its downstream apoptosis- and cycle-related proteins determined by Western blot. RESULTS: CFF-1 significantly arrested the cell cycle in the G1 phase, decreased the cell viability and increased the nuclear condensation and disruption in a dose-dependent manner, and elevated the apoptosis rate of prostate cancer cells. At the molecular level, CFF-1 dose-dependently reduced the activity of the PI3K/AKT signaling pathway and phosphorylation of the FOXO1 protein, increased the transcription activity of FOXO1, and eventually regulated the expressions of cell apoptosis- and cycle-related genes. CONCLUSIONS: The Chinese medicinal compound CFF-1 can significantly inhibit the growth, arrest the cycle, and induce the apoptosis of prostate cancer cells by decreasing the activity of the PI3K/AKT/FOXO1 signaling pathway, which suggests its potential clinical application value in the treatment of prostate cancer.

[Professor Xu Fu-song's traditional Chinese medicine protocols for male diseases: A descriptive analysis].

OBJECTIVE: To analyze the efficacy and medication principles of Professor Xu Fu-songs traditional Chinese medicine (TCM) protocols for male diseases. METHODS: We reviewed and descriptively analyzed the unpublished complete medical records of 100 male cases treated by Professor Xu Fu-song with his TCM protocols from 1978 to 1992. RESULTS: The 100 cases involved 32 male diseases, most of which were difficult and complicated cases. The drug compliance was 95%. Each prescription was made up of 14 traditional Chinese drugs on average. The cure rate was 32% , and the effective rate was 85%. Professor Xu Fu-song advanced and proved some new theories and therapeutic methods. CONCLUSION: Professor Xu Fu-song's TCM protocols can be applied to a wide range of male diseases, mostly complicated, and are characterized by accurate differentiation of symptoms and signs, high drug compliance, and excellent therapeutic efficacy.

Astrocyte elevated gene-1 mediates glycolysis and tumorigenesis in colorectal carcinoma cells via AMPK signaling.

To investigate the role of AEG-1 in glycolysis and tumorigenesis, we construct myc-AEG-1 expression vector and demonstrate a novel mechanism that AEG-1 may increase the activity of AMPK by Thr172 phosphorylation. The higher expression levels of AEG-1 in colorectal carcinoma cells were found but showed significant difference in different cell lines. To study the role of AEG-1 in colorectal cells, myc-AEG-1 vector was constructed and transfected into NCM460 colonic epithelial cells. We observed consistent increasing of glucose consumption and lactate production, typical features of anaerobic glycolysis, suggesting that AEG-1 may promote anaerobic glycolysis. Moreover, we noted that AMPK phosphorylation at Thr172 as well as pPFK2 (Ser466) was increased in NCM460 cells overexpressing AEG-1. Compound C may block AMPK and PFK2 phosphorylation in both control and AEG-1-overexpressed cells and decrease the glucose consumption and lactate production. The present findings indicated that reduced AEG-1 protein levels by RNAi may decrease the glucose consumption and lactate production in HCT116 colorectal carcinoma cells. The present identified AEG-1/AMPK/PFK2 glycolysis cascade may be essential to cell proliferation and tumor growth. The present results may provide us with a mechanistic insight into novel targets controlled by AEG-1, and the components in the AEG-1/AMPK/PFK2 glycolysis process may be targeted for the clinical treatment of cancer.

Low Selenium and Low Protein Exacerbate Myocardial Damage in Keshan Disease by Affecting the PINK1/Parkin-mediated Mitochondrial Autophagy Pathway.

OBJECTIVE: Keshan disease (KD) is a myocardial mitochondrial disease closely related to insufficient selenium (Se) and protein intake. PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitochondrial autophagy regulates various physiological and pathological processes in the body. This study aimed to elucidate the relationship between PINK1/Parkin-regulated mitochondrial autophagy and KD-related myocardial injury. METHODS: A low Se and low protein animal model was established. One hundred Wistar rats were randomly divided into 5 groups (control group, low Se group, low protein group, low Se + low protein group, and corn from KD area group). The JC-1 method was used to detect the mitochondrial membrane potential (MMP). ELISA was used to detect serum creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and mitochondrial-glutamicoxalacetic transaminase (M-GOT) levels. RT-PCR and Western blot analysis were used to detect the expression of PINK1, Parkin, sequestome 1 (P62), and microtubule-associated proteins1A/1B light chain 3B (MAP1LC3B). RESULTS: The MMP was significantly decreased and the activity of CK-MB, cTnI, and M-GOT significantly increased in each experimental group (low Se group, low protein group, low Se + low protein group and corn from KD area group) compared with the control group (P<0.05 for all). The mRNA and protein expression levels of PINK1, Parkin and MAP1LC3B were profoundly increased, and those of P62 markedly decreased in the experimental groups compared with the control group (P<0.05 for all). CONCLUSION: Low Se and low protein levels exacerbate myocardial damage in KD by affecting the PINK1/Parkin-mediated mitochondrial autophagy pathway.

The BRAFV600E mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia.

Although disorders of primary cilia (PCs) were first reported in human papillary thyroid cancer (PTC) tissues in 1987, their precise role in PTC remains unclear. PCs sense the thyroid follicle colloid environment and act as a cell signaling hub. The present study investigated whether PCs are needed for BRAFV600E-driven PTC. We assessed whether BRAFV600E protein expression correlates with papillary histological architecture and clinicopathological features of PTC. We found that expression of ciliary intraflagellar transport 88 (IFT88) and PC formation were reduced in BRAFV600E-driven PTCs and that loss of cilia may be associated with lymph node metastasis. In PTC cells, the BRAFV600E mutation maintained the aggressiveness of PTC, which was partially related to loss of PCs. Our work confirms that BRAFV600E mutation-driven PC downregulation contributes to maintaining the aggressiveness of PTCs and that manipulating PC can potentially reduce the adverse incidence of PTC in a range of conditions.

Improving prediction of N2O emissions during composting using model-agnostic meta-learning.

Nitrous oxide (N2O) represents a significant environmental challenge as a harmful, long-lived greenhouse gas that contributes to the depletion of stratospheric ozone and exacerbates global anthropogenic greenhouse warming. Composting is considered a promising and economically feasible strategy for the treatment of organic waste. However, recent research indicates that composting is a source of N2O, contributing to atmospheric pollution and greenhouse effect. Consequently, there is a need for the development of effective, cost-efficient methodologies to quantify N2O emissions accurately. In this study, we employed the model-agnostic meta-learning (MAML) method to improve the performance of N2O emissions prediction during manure composting. The highest R2 and lowest root mean squared error (RMSE) values achieved were 0.939 and 18.42 mg d-1, respectively. Five machine learning methods including the backpropagation neural network, extreme learning machine, integrated machine learning method based on ELM and random forest, gradient boosting decision tree, and extreme gradient boosting were adopted for comparison to further demonstrate the effectiveness of the MAML prediction model. Feature analysis showed that moisture content of structure material and ammonium concentration during composting process were the two most significant features affecting N2O emissions. This study serves as proof of the application of MAML during N2O emissions prediction, further giving new insights into the effects of manure material properties and composting process data on N2O emissions. This approach helps determining the strategies for mitigating N2O emissions.