Search

• FTO knockout increased the secretion of IL-6 in adipocytes. • Adipocyte-derived IL-6 promoted lipolysis genes expressions in the liver. • FTOAKO alleviated HFD-induced hepatic steatosis in mice. Adipose dysfunction affects the secretion of adipokines and mediates the hepatic physiological changes. Fat mass and obesity associated protein (FTO) plays a crucial part in fat deposition but the crosstalk between FTO-mediated secretion of adipokines and hepatic steatosis is not clear. Firstly, adipose-selective FTO knockout (FTOAKO) and control (FTOflox/flox) mice were induced by high fat diet (HFD). Then qRT-PCR assay was performed to analyze the expressions of hepatic lipid metabolism genes and adipocytokines gene of inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT). Afterwards, 3T3-L1 cells were knocked out IL-6 and co-cultured with AML12 cells (3T3-L1 siIL-6/AML12) and the expressions of hepatic lipid lipolysis genes were measured. Finally, we detected the hepatic lipid metabolism genes expressions in AML12 cells with the medium from 3T3-L1 cells or IL-6 treatment. FTOAKO effectively alleviated HFD-induced hepatic steatosis in mice and improved the transcription level of genes involved in hepatic lipolysis. Further investigation demonstrated that FTO knockout increased level of IL-6 in adipose tissues and 3T3-L1 cells. Compared to 3T3-L1/AML12, our results showed lipolysis-related genes expressions were dramatically inhibited in 3T3-L1 siIL-6/AML12. Finally, both depletion of FTO in adipocytes and IL-6 supplement led to increased lipolysis genes expressions in AML12 cells. FTO knockout in adipose tissue alleviated hepatic steatosis via targeting adipocyte-derived IL-6. [ABSTRACT FROM AUTHOR]

• MILD combustion technology applies to the heat flue of a coke oven. • A novel type of diffusion heat flue structure and combustion method is proposed. • Effects of gas composition on the thermal process of the heat flue were studied. • Low NOx combustion performance with different ratios of mixed gas was compared. • The influence of gas composition on NOx emission is also studied. Based on high-temperature and low-oxygen diffusion clean combustion technology, a novel-type of heat flue in a coke oven was designed in this paper. By changing the internal structure of the flue and the supply mode of the combustion-supporting gas, fuel zoning and diffusion combustion in the heat flue are achieved. The combustion temperature in the flue and the formation of thermal NOx are greatly reduced. The flow, temperature and NOx concentration fields inside the flue are studied though a three-dimensional finite element numerical model. The results show that when coke oven gas is used as the fuel, the NOx concentration at the outlet of the diffused heat flue can be reduced to 312.89 mg/m3, which reduces the emission of nitrogen oxides by nearly 35%, compared with the result using graded heat flue. In addition, the influence of gas composition on NOx emission is also studied, and the mathematical relationship involving the gas composition (α), the maximum temperature (T max), and the outlet NOx concentration (C NOx) of the flue is obtained. When the preheating temperature reaches 550 K, T ave reaches 1626.76 K, and the outlet NOx concentration reaches 144.07 mg/m3, which can meet the standards for emissions and the heating requirements. [ABSTRACT FROM AUTHOR]

Obesity has become a major health crisis in the past decades. Branched-chain amino acids (BCAA), a class of essential amino acids, exerted beneficial health effects with regard to obesity and its related metabolic dysfunction, although the underlying reason is unknown. Here, we show that BCAA supplementation alleviates high-fat diet (HFD)-induced obesity and insulin resistance in mice and inhibits adipogenesis in 3T3-L1 cells. Further, we find that BCAA prevent the mitotic clonal expansion (MCE) of preadipocytes by reducing cyclin A2 (CCNA2) and cyclin-dependent kinase 2 (CDK2) expression. Mechanistically, BCAA decrease the concentration of nicotinamide adenine dinucleotide phosphate (NADPH) in adipose tissue and 3T3-L1 cells by reducing glucose-6-phosphate dehydrogenase (G6PD) expression. The reduced NADPH attenuates the expression of fat mass and obesity-associated (FTO) protein, a well-known m6A demethylase, to increase the N 6-methyladenosine (m6A) levels of Ccna2 and Cdk2 mRNA. Meanwhile, the high m6A levels of Ccna2 and Cdk2 mRNA are recognized by YTH N 6-methyladenosine RNA binding protein 2 (YTHDF2), which results in mRNA decay and reduction of their protein expressions. Overall, our data demonstrate that BCAA inhibit obesity and adipogenesis by reducing CDK2 and CCNA2 expression via an NADPH-FTO-m6A coordinated manner in vivo and in vitro , which raises a new perspective on the role of m6A in the BCAA regulation of obesity and adipogenesis. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: The EAT-Lancet Commission has proposed an EAT-Lancet diet (ELD), also known as a planetary health diet (PHD), which is environmentally sustainable and promotes human health. However, the association between this diet and the risk of hypertension remains unclear. This study aimed to determine whether adherence to ELD was associated with a lower risk of hypertension., Methods: 11,402 adults without hypertension at baseline from the China Health and Nutrition Survey were included. The PHD score was used to evaluate ELD adherence, with higher scores reflecting better compliance. Cox proportional hazards regression analysis was utilized to estimate the hazard ratio (HR) with a 95% confidence interval (CI). Additionally, a subgroup analysis was performed to identify the possible effect modifiers, and a mediation analysis was conducted to explore the mediation effects of anthropometric measurements on the association between ELD and hypertension., Results: A total of 3993 participants (35%) developed hypertension during 93,058 person-years of follow-up. In the covariate-adjusted model, hypertension risk was reduced in the highest quartile participants compared to the lowest quartile of the PHD score (adjusted HR: 0.79, 95%CI: 0.71-0.87; P -trend < 0.001), which remained significant after sensitivity analysis. Notably, the association was also observed in isolated systolic hypertension, isolated diastolic hypertension, and systolic-diastolic hypertension. Subgroup analysis revealed that the inverse association between the PHD score and hypertension risk was more pronounced in nonsmokers and high-sodium intake consumers than in smokers and low-sodium consumers ( P -interaction < 0.05). Additionally, mediation analysis revealed that 23.3% of the association between the PHD score and hypertension risk was mediated by the waist-to-height ratio., Conclusion: Our findings suggest that a higher adherence to ELD is associated with a lower risk of hypertension. These results emphasize that ELD may serve as a potential strategy to prevent hypertension.

The study of motor muscle control mechanisms can improve rehabilitation therapy and human-computer interaction technology. The limitations of traditional electroencephalography (EEG) limit the comprehensive understanding of motor muscle control mechanisms. Therefore, this study aims to explore the mechanism of motor muscle control based on optical EEG images, in order to expand the understanding of the process of motor control. The study selected optical EEG imaging technology as the main data acquisition tool. Optical EEG images have higher spatiotemporal resolution and can provide more detailed neural activity information. This technology combines optical imaging with EEG images to obtain spatiotemporal information of brain activity in a short period of time. The device is composed of multiple optical sensors and can measure blood oxygen concentration and neuronal activity in the cerebral cortex. Preprocess EEG image data using image processing and signal processing techniques, then use computational methods and algorithms to detect activated regions, and evaluate their relationships using correlation analysis and statistical methods. By comparing EEG image data and motor muscle activity data under different motor tasks. The research results show that optical EEG imaging technology can provide more detailed information on brain neural activity and accurately capture the activity patterns of different motor muscles. These results provide new perspectives and methods for further studying the control mechanisms of motor muscles., Competing Interests: Declaration of interests The authors declare that there is no conflict of interests regarding the publication of this article., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) has emerged as a major public health crisis with significant health threats and economic burdens worldwide in the past decades. Betaine, a naturally occurring alkaloid compound present in various dietary sources including spinach and beets, has been shown to ameliorate hepatic lipid metabolism and attenuate (NAFLD), while the underlying mechanism remains elusive. Here, we propose a novel mechanism through which betaine exerts its protective effects against hepatic lipid accumulation and (NAFLD) from an epigenetics perspective. Specifically, we discover that betaine upregulates betaine homocysteine S-methyltransferase (BHMT) expression, leading to increased nicotinamide adenine dinucleotide phosphate (NADPH) production and subsequent upregulation of fat mass and obesity-associated protein (FTO) expression. Increased abundance of FTO targets peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) mRNA and reduces the N 6 -methyladenosine (m 6 A) level in the CDS of Ppargc1α transcript, which positively regulates PGC1α expression and subsequently inhibits hepatic lipid accumulation. Overall, our works demonstrate that betaine may be a promising therapeutic strategy for treating (NAFLD) and improving liver function through the regulation of (NADPH) and m 6 A-mediated pathways., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Accurate in vivo imaging of G-quadruplexes (G4) is critical for understanding the emergence and progression of G4-associated diseases like cancer. However, existing in vivo G4 fluorescent probes primarily operate within the near-infrared region (NIR-I), which limits their application accuracy due to the short emission wavelength. The transition to second near-infrared (NIR-II) fluorescent imaging has been of significant interest, as it offers reduced autofluorescence and deeper tissue penetration, thereby facilitating more accurate in vivo imaging. Nonetheless, the advancement of NIR-II G4 probes has been impeded by the absence of effective probe design strategies. Herein, through a "step-by-step" rational design approach, we have successfully developed NIRG-2, the first small-molecule fluorescent probe with NIR-II emission tailored for in vivo G4 detection. Molecular docking calculations reveal that NIRG-2 forms stable hydrogen bonds and strong π-π interactions with G4 structures, which effectively inhibit twisted intramolecular charge transfer (TICT) and, thereby, selectively illuminate G4 structures. Due to its NIR-II emission (940 nm), large Stokes shift (90 nm), and high selectivity, NIRG-2 offers up to 47-fold fluorescence enhancement and a tissue imaging depth of 5 mm for in vivo G4 detection, significantly outperforming existing G4 probes. Utilizing NIRG-2, we have, for the first time, achieved high-contrast visualization of tumor metastasis through lymph nodes and precise tumor resection. Furthermore, NIRG-2 proves to be highly effective and reliable in evaluating surgical and drug treatment efficacy in cancer lymphatic metastasis models. We are optimistic that this study not only provides a crucial molecular tool for an in-depth understanding of G4-related diseases in vivo but also marks a promising strategy for the development of clinical NIR-II G4-activated probes.

Necroptosis is a form of regulated cell death that depends on the receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL). The molecular mechanisms underlying distinct instances of necroptosis have only recently begun to emerge. In the present study, we characterized RABGEF1 as a positive regulator of RIPK1/RIPK3 activation in vitro. Based on the overexpression and knockdown experiments, we determined that RABGEF1 accelerated the phosphorylation of RIPK1 and promoted necrosome formation in L929 cells. The pro-necrotic effect of RABGEF1 is associated with its E3 ubiquitin ligase activity and guanine nucleotide exchange factor (GEF) activity. We further confirmed that RABGEF1 interacts with cIAP1 protein by inhibiting its function and plays a regulatory role in necroptosis, which can be abolished by treatment with the antagonist Smac mimetic (SM)-164. In conclusion, our study highlights a potential and novel role of RABGEF1 in promoting TNF-induced cell necrosis., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript. All authors listed have approved the manuscript that is enclosed and declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Previous experimental studies have suggested that the consumption of soy isoflavones may have a potential impact on lowering blood pressure. Nevertheless, epidemiological studies have presented conflicting outcomes concerning the correlation between soy isoflavone consumption and blood pressure levels. Consequently, a comprehensive meta-analysis of all eligible randomized controlled trials (RCTs) was conducted to explore the influence of soy isoflavones on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults., Methods: A thorough search of PubMed, Embase, and the Cochrane Library for relevant literature up to April 30, 2023 was conducted. RCTs involving adults that compared soy isoflavone supplementation with a placebo (the same matrix devoid of soy isoflavone) were included. The combined effect size was presented as the weighted mean difference (WMD) along with 95% confidence interval (CI), employing a fixed-effects model., Results: Our meta-analysis included a total of 24 studies involving 1945 participants. The results revealed a significant reduction in both SBP and DBP with soy isoflavone supplementation. Subgroup analyses suggested more pronounced reductions in SBP and DBP for interventions lasting ≥6 months, in individuals receiving mixed-type soy isoflavone, and among patients with metabolic syndrome or prehypertension. However, we did not detect significant nonlinear associations between supplementation dosage and intervention duration concerning both SBP and DBP. The overall quality of evidence was deemed moderate., Conclusions: The current meta-analysis revealed that supplementation with soy isoflavones alone effectively reduces blood pressure. Additional high-quality studies are required to investigate the efficacy of blood pressure reduction through supplementation with an optimal quantity and proportion of soy isoflavone., (© 2024. The Author(s).)

Background: Syndrome of inappropriate antidiuretic(SIAD) occurs secondary to various diseases, which is characterised by hypotonic hyponatremia and impaired urinary diluting capacity. Research on SIAD in both domestic and international contexts has a long history. This study objectively and comprehensively analyses the research trends, hotspots and development of SIAD research of the past 20 years using the method of bibliometric analysis., Methods: The 2003-2022 data in the Web of Science Core Collection database were searched. The Bibliometrix software package, VOSviewer and CiteSpace were used to mine, extract and visualise the retrieved literature, and the generated maps were used in analysing the main topics and trends in the field of SIAD research., Results: A total of 1215 articles published in 623 journals were included in the analysis, with a total of 18,886 citations. Results showed that the research output on SIAD has continuously increased in the past 20 years, and the United States had the highest number of publications and citations. Keywords with the highest burst strength in recent years were the most mentioned keywords, in addition to the search terms 'hyponatremia', 'covid-19', and 'mortality'. Thus, the relationship among SIAD, covid-19 and mortality may become research frontiers and trends. Fifteen milestone articles were identified through co-citation analysis, which mainly focused on the pathophysiology and treatment of SIAD., Conclusion: Based on bibliometric analysis and knowledge mapping, this study summarises development trends in the field of SIAD research, providing references for current and future research into SIAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wei, Pan, Lun, Wu, Chen, Feng, Liu and Chen.)

Necroptosis is a kind of programmed cell death that causes the release of damage-associated molecular patterns and inflammatory disease including skin inflammation. Activation of receptor-interacting serine/threonine kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) is the hallmark of tumour necrosis factor α (TNF)-induced necroptosis. Here, we screened a small-molecule compound library and found that saracatinib inhibited TNF-induced necroptosis. By targeting MLKL, Saracatinib interfered with the phosphorylation, translocation, and oligomerization of MLKL induced by TNF. Consistently, mutation of the saracatinib-binding site of MLKL reduced the inhibitory effect of saracatinib on TNF-induced necroptosis. In an imiquimod (IMQ)-induced psoriasis mouse model, saracatinib effectively blocked MLKL phosphorylation and inflammatory responses in vivo. Taken together, these findings indicate that saracatinib inhibits necroptosis by targeting MLKL, providing a potential therapeutic approach for skin inflammation-related diseases such as psoriasis., (© 2024. The Author(s).)

A Chinese family was identified to have two patients with rickets, an adult female and a male child (proband), both exhibiting signs related to X-linked hypophosphatemic rickets (XLH). Gene sequencing analysis revealed a deletion of adenine at position 1985 (c.1985delA) in the PHEX -encoding gene. To investigate the relationship between this mutation and the pathogenicity of XLH, as well as analyze the effects of different dosages of PHEX gene mutations on clinical phenotypes, we developed a rat model carrying the PHEX deletion mutation. The CRISPR/Cas9 gene editing technology was employed to construct the rat model with the PHEX gene mutation (c.1985delA). Through reproductive procedures, five genotypes of rats were obtained: female wild type (X/X), female heterozygous (-/X), female homozygous wild type (-/-), male wild type (X/Y), and male hemizygous (-/Y). The rats with different genotypes underwent analysis of growth, serum biochemical parameters, and bone microstructure. The results demonstrated the successful generation of a stable rat model inheriting the PHEX gene mutation. Compared to the wild-type rats, the mutant rats displayed delayed growth, shorter femurs, and significantly reduced bone mass. Among the female rats, the homozygous individuals exhibited the smallest body size, decreased bone mass, shortest femur length, and severe deformities. Moreover, the mutant rats showed significantly lower blood phosphorus concentration, elevated levels of FGF23 and alkaline phosphatase, and increased expression of phosphorus regulators. In conclusion, the XLH rat model with the PHEX gene mutation dosage demonstrated its impact on growth and development, serum biochemical parameters, and femoral morphology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Cai, Lun, Ye, Pan, Chen, Wu, Feng, Su, Ma, Luo, Liu and Ma.)

Neoadjuvant chemotherapy (NAC) for breast cancer is widely used in the clinical setting to improve the chance of surgery, breast conservation and quality of life for patients with advanced breast cancer. A more accurate efficacy evaluation system is important for the decision of surgery timing and chemotherapy regimen implementation. However, current methods, encompassing imaging techniques such as ultrasound and MRI, along with non-imaging approaches like pathological evaluations, often fall short in accurately depicting the therapeutic effects of NAC. Imaging techniques are subjective and only reflect macroscopic morphological changes, while pathological evaluation is the gold standard for efficacy assessment but has the disadvantage of delayed results. In an effort to identify assessment methods that align more closely with real-world clinical demands, this paper provides an in-depth exploration of the principles and clinical applications of various assessment approaches in the neoadjuvant chemotherapy process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Qi and Wang.)

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a global health problem, and dietary intervention is still considered one of the primary interventions. This study aimed to examine cross-sectional associations between dietary and serum levels of folate and NAFLD. Methods: We conducted a study of 7543 adults who participated in the National Health and Nutrition Examination Survey, 2009-2018. NAFLD status was determined by a fatty liver index (FLI) value ≥60. Multivariable logistic regression models were used to estimate associations between folate and NAFLD. Results: Almost half (45%) of the patients were classified as having NAFLD based on the FLI. In the fully adjusted model, participants in the highest quartile of dietary total folate and food folate were found to have a lower prevalence of NAFLD than those in the lowest quartile [odds ratio (OR) quartile 4 versus 1  = 0.582; 95% confidence interval (CI) = 0.350-0.968; and OR quartile 4 versus 1  = 0.737; 95% CI = 0.611-0.888, respectively], and the fourth quartile values of serum total folate and 5-methyl-tetrahydrofolate were significantly negatively associated with NAFLD prevalence (OR quartile 4 versus 1  = 0.664; 95% CI = 0.495-0.891; and OR quartile 4 versus 1  = 0.712; 95% CI = 0.532-0.954, respectively). Subgroup analyses revealed that this beneficial association was more significant in women (OR quartile 4 versus 1  = 0.526; 95% CI = 0.329-0.843; p interaction < 0.001) than in men (OR quartile 4 versus 1  = 0.805; 95% CI = 0.546-1.186). Conclusions: Higher dietary folate intake and serum folate levels are associated with a lower NAFLD prevalence among U.S. adults and the trend is more pronounced among women, indicating opportunities for dietary NAFLD interventions.

Background: Various neurologic manifestations have been reported in patients with COVID-19, mostly in retrospective studies of patients admitted to hospital, but there are few data on patients with mild COVID-19. We examined the frequency and persistence of neurologic/neuropsychiatric symptoms in patients with mild COVID-19 in a 1-year prospective cohort study, as well as assessment of use of health care services and patient-reported outcomes., Methods: Participants in the Alberta HOPE COVID-19 trial (hydroxychloroquine v. placebo for 5 d), managed as outpatients, were prospectively assessed 3 months and 1 year after their positive test result. They completed detailed neurologic/neuropsychiatric symptom questionnaires, the telephone version of the Montreal Cognitive Assessment (T-MoCA), the Kessler Psychological Distress Scale (K10) and the EuroQol EQ-5D-3L (measure of quality of life). Close informants completed the Mild Behavioural Impairment Checklist (MBI-C) and the Informant Questionnaire on Cognitive Decline in the Elderly. We also tracked use of health care services and neurologic investigations., Results: The cohort consisted of 198 participants (87 female [43.9%] median age 45 yr, interquartile range 37-54 yr). Of the 179 participants with symptom assessments, 139 (77.6%) reported at least 1 neurologic symptom, the most common being anosmia/dysgeusia (99 [55.3%]), myalgia (76 [42.5%]) and headache (75 [41.9%]). Forty patients (22.3%) reported persistent symptoms at 1 year, including confusion (20 [50.0%]), headache (21 [52.5%]), insomnia (16 [40.0%]) and depression (14 [35.0%]); 27/179 (15.1%) reported no improvement. Body mass index (BMI), a history of asthma and lack of full-time employment were associated with the presence and persistence of neurologic/neuropsychiatric symptoms; female sex was independently associated with both (presence: odds ratio [OR] adjusted for age, race, BMI, history of asthma and neuropsychiatric history 5.04, 95% confidence interval [CI] 1.58 to 16.10). Compared to participants without persistent symptoms, those with persistent symptoms had more hospital admissions and family physician visits, and worse MBI-C scores and less frequent independence for instrumental activities at 1 year (83.8% v. 97.8%, p = 0.005). Patients with any or persistent neurologic symptoms had worse psychologic distress (K10 score ≥ 20: adjusted OR 12.1, 95% CI 1.4 to 97.2) and quality of life (median EQ-5D-3L visual analogue scale rating 75 v. 90, p < 0.001); 42/84 (50.0%) had a T-MoCA score less than 18 at 3 months, as did 36 (42.9%) at 1 year. Participants who reported memory loss were more likely than those who did not report such symptoms to have informant-reported cognitive-behavioural decline (1-yr MBI-C score ≥ 6.5: adjusted OR 15.0, 95% CI 2.42 to 92.60)., Interpretation: Neurologic/neuropsychiatric symptoms were commonly reported in survivors of mild COVID-19, and they persisted in 1 in 5 patients 1 year later. Symptoms were associated with worse participant- and informant-reported outcomes. Trial registration: ClinicalTrials.gov, no. NCT04329611., Competing Interests: Competing interests: Aravind Ganesh reports membership on the editorial boards of Neurology, Stroke and Neurology Clinical Practice; consulting fees and honoraria from Atheneum, MD Analytics, Figure 1, MyMedicalPanel, Creative Research Designs, CTC Communications Corp, Alexion and Biogen; research support from Alberta Innovates, Campus Alberta Neuroscience, the Canadian Cardiovascular Society, the University of Calgary (Hotchkiss Brain Institute), the Sunnybrook Research Institute INOVAIT program and the Canadian Institutes of Health Research (CIHR), outside the submitted work; and stock/stock options from SnapDx and Let’s Get Proof. He has a patent application (US 17/317,771) for a system for prehospital patient monitoring/assessment and delivery of remote ischemic conditioning or other cuff-based therapies. Ryan Rosentreter reports the same patent application (US 17/317,771). Luanne Metz reports grant funding from the MS Society of Canada, outside the submitted work. Eric Smith reports grant funding from the CIHR, Brain Canada and the Weston Brain Institute, outside the submitted work; consulting fees from Bayer, Biogen and Javelin Technologies; royalties from UpToDate; and payment from the American Heart Association for work as associate editor of Stroke. Michael Hill is a director of the Canadian Neurological Sciences Federation and the Canadian Stroke Consortium. He reports consulting fees from BrainsGate; industry grant support to the University of Calgary from NoNO, Biogen, Medtronic and Boehringer-Ingelheim Canada; and public grant support to the University of Calgary from Alberta Innovates, CIHR, the Heart & Stroke Foundation of Canada, and the National Institute of Neurological Disorders and Stroke. He reports a patent to US Patent office (US 62/086,077) issued and licensed. He owns stock in PureWeb. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Background: Current artificial intelligence (AI) in histopathology typically specializes on a single task, resulting in a heavy workload of collecting and labeling a sufficient number of images for each type of cancer. Heterogeneous transfer learning (HTL) is expected to alleviate the data bottlenecks and establish models with performance comparable to supervised learning (SL)., Methods: An accurate source domain model was trained using 28,634 colorectal patches. Additionally, 1000 sentinel lymph node patches and 1008 breast patches were used to train two target domain models. The feature distribution difference between sentinel lymph node metastasis or breast cancer and CRC was reduced by heterogeneous domain adaptation, and the maximum mean difference between subdomains was used for knowledge transfer to achieve accurate classification across multiple cancers., Result: HTL on 1000 sentinel lymph node patches (L-HTL-1000) outperforms SL on 1000 sentinel lymph node patches (L-SL-1-1000) (average area under the curve (AUC) and standard deviation of L-HTL-1000 vs. L-SL-1-1000: 0.949 ± 0.004 vs. 0.931 ± 0.008, p value = 0.008). There is no significant difference between L-HTL-1000 and SL on 7104 patches (L-SL-2-7104) (0.949 ± 0.004 vs. 0.948 ± 0.008, p value = 0.742). Similar results are observed for breast cancer. B-HTL-1008 vs. B-SL-1-1008: 0.962 ± 0.017 vs. 0.943 ± 0.018, p value = 0.008; B-HTL-1008 vs. B-SL-2-5232: 0.962 ± 0.017 vs. 0.951 ± 0.023, p value = 0.148., Conclusions: HTL is capable of building accurate AI models for similar cancers using a small amount of data based on a large dataset for a certain type of cancer. HTL holds great promise for accelerating the development of AI in histopathology.

In order to alleviate the current domestic oil shortage, China has studied the technology of using coal as the source to produce low carbon olefins, among which methanol to olefin (MTO) is an important process. Since the coke deposition of MTO catalyst is inevitable, the deactivated MTO catalysts need to be regenerated by continuous coke combustion to recover the activity. This paper used the actual industrial data to study the gas-solid two-phase fluidized bed of a SMTO regenerator and the coke combustion kinetics of the deactivated SAPO-34 catalyst, and established the mathematical model of the SMTO industrial regenerator. The kinetic parameters in the model were obtained and validated with different data, which showed that the model is reliable and can accurately predict the industrial reaction results and provide guidance for the SMTO production operation., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The methanol-to-olefins (MTO) technology creates a new non-oil route to produce light olefins. This paper reports a 14-lump MTO kinetic model for SAPO-34 catalyst, combined with the hydrodynamic model for the fast fluidized bed reactor of the industrial SMTO process. Selective deactivation is considered to quantify the product selectivity and abrupt catalytic activity change. Moreover, referring to the parallel compartment (PC) model, the activity difference between the circulating spent catalyst and the regenerated catalyst is considered. The validation results with the optimized kinetic parameters showed good agreement between the calculated value and the actual value. Sensitivity analysis of the industrial SMTO process was performed. According to the results, the established mathematical model can provide guidance for industrial production operations., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Recurrent events after a first symptomatic deep venous thrombosis (DVT) are relatively frequent, but little is known about contralateral recurrent DVT (RDVT)., Methods: We retrospectively reviewed the medical records of patients with a first symptomatic lower extremity DVT between January 2017 and April 2021. The incidence, demographics, risk factors, and prognosis of RDVT were analyzed, with differences compared between patients with contralateral RDVT and those with ipsilateral RDVT., Results: In 570 consecutive patients with DVT, 28 patients (4.91%) developed contralateral RDVT, and 49 patients (8.60%) developed ipsilateral RDVT during a mean follow-up of 27.62 ± 14.84 months. Contralateral RDVT was more frequently found in the right lower extremity, whereas ipsilateral RDVT had more left lower extremity involvement. The median follow-up was 12 months until ipsilateral RDVT and 26.5 months until contralateral RDVT. In multivariate Cox analysis, inherited thrombophilia, stent extension with 50% to 100% coverage, autoimmune disease and anticoagulation noncompliance were identified as risk factors for contralateral RDVT. During follow-up, 5 patients (17.86%) with contralateral RDVT and 10 patients (20.41%) with ipsilateral RDVT died (P > .05), with 12 of 15 dying of an underlying malignancy., Conclusions: The incidence of contralateral RDVT after a first symptomatic DVT is relatively low, and contralateral DVT is strongly associated with stent extension with 50% to 100% coverage, autoimmune disease, anticoagulation noncompliance, and inherited thrombophilia. Compared with ipsilateral RDVT, contralateral RDVT occurs later and is more often in the right lower extremity. Survival following contralateral RDVT is similar to survival following ipsilateral RDVT, with underlying malignancy being the leading cause of death., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Obesity has become a health threat and hard enough to deal with. Evidences show that metformin could inhibit adipogenesis and combat obesity, while its mechanisms remain to be elucidated more comprehensively. In this study, we found that administration of metformin could combat obesity of mice induced by high-fat diet (HFD), indicated by strikingly decreased body weight and weight of inguinal white adipose tissue (iWAT) and epidydimal white adipose tissue (eWAT) compared with the control group. Mechanically, we revealed that metformin could inhibit protein expression of FTO, leading to increased m 6 A methylation levels of cyclin D1 ( Ccnd1 ) and cyclin dependent kinase 2 ( Cdk2 ), two crucial regulators in cell cycle. Ccnd1 and Cdk2 with increased m 6 A levels were recognised by YTH m 6 A RNA binding protein 2 (YTHDF2), causing an YTHDF2-dependent decay and decreased protein expressions. In consequence, mitotic clonal expansion (MCE) process was blocked and adipogenesis was inhibited.

Gelidium amansii (GA) is a kind of red alga homologous to medicine and food and is distributed all over the world. Studies on GA are mainly focused on its polysaccharides, with little research on the ethanol extract. The ethanol extract of Gelidium amansii (GAE) was subjected to a reverse-phase column to obtain 7 components. Among them, 100% methanol solution (GAM), enriched with phytene-1,2-diol, exhibited the strongest DPPH free radical scavenging activity (IC 50 = 0.17 mg mL -1 ). Subsequently, high-fat male flies (HMFs) were used as a model to explore the antioxidant and anti-aging effects of GAM in vivo . Studies showed that GAM can effectively prolong the lifespan of HMFs. When GAM concentrations were 0.2 and 1.0 mg mL -1 , the average lifespan of HMFs was increased by 28.7 and 40.7%, respectively, while the longest lifespan of HMFs was increased by 20.55% and 32.88%, respectively. Further research revealed that GAM can significantly downregulate the levels of malondialdehyde (MDA) and protein carbonyl (PCO), and can significantly upregulate the levels of catalase (CAT) and total superoxide dismutase (T-SOD). In addition, by analyzing differential metabolites, we found that GAM relieves aging caused by oxidative stress by regulating amino acid, lipid, sugar, and energy metabolism. The GAM group significantly regulated the levels of adenine, cholic acid, glutamate, L-proline, niacin, and stachyose which tend to recover to the levels of the normal diet male fly (NMF) group. In general, our research provides ideas for the high-value utilization of GA and provides a lead compound for the research and development of anti-aging food or medicine.

Although 5-methylcytosine (m 5 C) has been identified as a novel and abundant mRNA modification and associated with energy metabolism, its regulation function in adipose tissue and skeletal muscle is still limited. This study aimed at investigating the effect of mRNA m 5 C on adipogenesis and myogenesis using Jinhua pigs (J), Yorkshire pigs (Y) and their hybrids Yorkshire-Jinhua pigs (YJ). We found that Y grow faster than J and YJ, while fatness-related characteristics observed in Y were lower than those of J and YJ. Besides, total mRNA m 5 C levels and expression rates of NSUN2 were higher both in backfat layer (BL) and longissimus dorsi muscle (LDM) of Y compared to J and YJ, suggesting that higher mRNA m 5 C levels positively correlate with lower fat and higher muscle mass. RNA bisulfite sequencing profiling of m 5 C revealed tissue-specific and dynamic features in pigs. Functionally, hyper-methylated m 5 C-containing genes were enriched in pathways linked to impaired adipogenesis and enhanced myogenesis. In in vitro, m 5 C inhibited lipid accumulation and promoted myogenic differentiation. Furthermore, YBX2 and SMO were identified as m 5 C targets. Mechanistically, YBX2 and SMO mRNAs with m 5 C modification were recognized and exported into the cytoplasm from the nucleus by ALYREF, thus leading to increased YBX2 and SMO protein expression and thereby inhibiting adipogenesis and promoting myogenesis, respectively. Our work uncovered the critical role of mRNA m 5 C in regulating adipogenesis and myogenesis via ALYREF-m 5 C-YBX2 and ALYREF-m 5 C-SMO manners, providing a potential therapeutic target in the prevention and treatment of obesity, skeletal muscle dysfunction and metabolic disorder diseases., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Autophagy classically functions as a physiological process to degrade cytoplasmic components, protein aggregates, and/or organelles, as a mechanism for nutrient breakdown, and as a regulator of cellular architecture. Its biological functions include metabolic stress adaptation, stem cell differentiation, immunomodulation and diseases regulation, and so on. Current researches have proved that autophagy dysfunction may contribute to the pathogenesis of some myopathies through impairment of myofibres regeneration. Studies of autophagy inhibition also indicate the importance of autophagy in muscle regeneration, while activation of autophagy can restore muscle function in some myopathies. In this review, we aim to report the mechanisms of action of autophagy on muscle regeneration to provide relevant references for the treatment of regenerating defective myopathies by regulating autophagy. Results have shown that one key mechanism of autophagy regulating the muscle regeneration is to affect the differentiation fate of muscle stem cells (MuSCs), including quiescence maintenance, activation and differentiation. The roles of autophagy (organelle/protein degradation, energy facilitation, and/or other) vary at different myogenic stages of the repair process. When the muscle is in homeostasis, basal autophagy can maintain the quiescence state and stemness of MuSCs by renewing organelle and protein. After injury, the increased autophagy flux contributes to meet biological energy demand of MuSCs during activation and proliferation. By mitochondrial remodelling, autophagy during differentiation can promote the metabolic transformation and balance mitochondrial-mediated apoptosis signals in myoblasts. Autophagy in mature myofibres is also essential for the degradation of necrotic myofibres, and may affect the dynamics of MuSCs by affecting the secretion spectrum of myofibres or the recruitment of supporting cells. Except for myogenic cells, autophagy also plays an important role in regulating the function of non-myogenic cells in the muscle microenvironment, which is also essential for successful muscle recovery. Autophagy can regulate the immune microenvironment during muscle regeneration through the recruitment and polarization of macrophages, while autophagy in endothelial cells can regulate muscle regeneration in an angiogenic or angiogenesis-independent manner. Drug or nutrition targeted autophagy has been preliminarily proved to restore muscle function in myopathies by promoting muscle regeneration, and further understanding the role and mechanism of autophagy in various cell types during muscle regeneration will enable more effective combinatorial therapeutic strategies., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

The application of organic fertilizer is an important measure for improving the quality of agricultural products and realizing the sustainable development of agriculture. The original small-scale family business model in China is no longer suitable for the development of modern agriculture. Large-scale agricultural business has become the mainstream trend, accompanied by the increasingly active land-transfer market. It is, therefore, necessary to determine whether farmland scale influences farmers' organic fertilizer applications in China. Based on the analysis of the influence mechanism of farmland scale on farmers' organic fertilizer application behaviors, empirical tests were conducted using survey data from 812 citrus farmers in Sichuan Province, China. The results show that the large-scale farmers are more likely to apply organic fertilizer and increase the application intensity than small-scale farmers and that the heterogeneity of farmers also affect their organic fertilizer application behavior. The results suggest that the government should encourage farmers to conduct moderate-scale management and promote their application behavior with organic fertilizer by improving awareness, strengthening education and training, and providing financial support.

The alkylation of isobutane and low molecular olefins using strong acid as catalysts is an important process in the petrochemical field, and its product, alkylate, is an ideal gasoline blending component due to high octane number, low vapor pressure, low sulfur, and lack of aromatics. To better meet the optimization process of the simulation of the alkylation unit, a reaction kinetic model with 20 reactions based on industrial data was developed, in which the alkylation products were divided into lumped components in detail. The reactor model was established based on the flow state and structural pattern of the industrial reactor, considering the internal circulation flow, and is suitable for the simulation of the DuPont alkylation process. Also, eventually, the model parameters were solved by the nonlinear least-squares fitting method. The results of the validation calculations showed that the kinetic model fitted the experimental data with good agreement. In addition, the reaction kinetic model was used to predict the influence of operating conditions, which is consistent with the trend in actual industrial production., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Obesity leads to a decline in the exercise capacity of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. Dietary intervention has been shown to be an important measure to regulate skeletal muscle function, and previous studies have demonstrated the beneficial effects of docosahexaenoic acid (DHA; 22:6 ω-3) on skeletal muscle function. At the molecular level, DHA and its metabolites were shown to be extensively involved in regulating epigenetic modifications, including DNA methylation, histone modifications, and small non-coding microRNAs. However, whether and how epigenetic modification of mRNA such as N6-methyladenosine (m6A) mediates DHA regulation of skeletal muscle function remains unknown. Here, we analyze the regulatory effect of DHA on skeletal muscle function and explore the involvement of m 6 A mRNA modifications in mediating such regulation., Results: DHA supplement prevented HFD-induced decline in exercise capacity and conversion of muscle fiber types from slow to fast in mice. DHA-treated myoblasts display increased mitochondrial biogenesis, while slow muscle fiber formation was promoted through DHA-induced expression of PGC1α. Further analysis of the associated molecular mechanism revealed that DHA enhanced expression of the fat mass and obesity-associated gene (FTO), leading to reduced m6A levels of DNA damage-induced transcript 4 (Ddit4). Ddit4 mRNA with lower m6A marks could not be recognized and bound by the cytoplasmic m6A reader YTH domain family 2 (YTHDF2), thereby blocking the decay of Ddit4 mRNA. Accumulated Ddit4 mRNA levels accelerated its protein translation, and the consequential increased DDIT4 protein abundance promoted the expression of PGC1α, which finally elevated mitochondria biogenesis and slow muscle fiber formation., Conclusions: DHA promotes mitochondrial biogenesis and skeletal muscle fiber remodeling via FTO/m 6 A/DDIT4/PGC1α signaling, protecting against obesity-induced decline in skeletal muscle function., (© 2022. The Author(s).)

Genistein is an abundant phytoestrogen in soybean. This study aimed to determine the effects of genistein on cholesterol distribution and metabolism in female yellow catfish. Three hundred fish (49.2 ± 1.4 g) were randomly divided into five treatments and received intraperitoneal injections as follows: (1) blank, no injection; (2) control, vehicle only; (3) E2, 17β-estradiol at 10 μg·g -1 body weight; (4) low genistein doses, genistein at 10 μg·g -1 body weight; (5) high genistein doses, genistein at 100 μg·g -1 body weight. Both high and low genistein doses significantly reduced (p < 0.05) serum TC and LDL-C 24 h after injection. Moreover, the high genistein doses significantly reduced (p < 0.05) serum HDL-C. Both high and low doses of genistein significantly increased (p < 0.05) hepatic TC. Only high genistein doses significantly increased (p < 0.05) ovary TC. In the liver, both high and low genistein doses significantly increased (p < 0.05) protein and mRNA expression of ldlr. Meanwhile, high genistein doses significantly decreased (p < 0.05) mRNA expression of hmgcr. In ovary tissue, high genistein doses significantly decreased (p < 0.05) mRNA expression of cyp11a1. These results suggested that genistein affected the cholesterol distribution in female yellow catfish. Both high and low doses of genistein reduced cholesterol content in blood and increased its content in the liver by increasing the uptake of blood cholesterol. Meanwhile, high genistein doses may inhibit hepatic cholesterol synthesis. Additionally, high genistein doses could increase cholesterol transfer from serum into the ovary and disturb cholesterol conversion to pregnenolone., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)