Evaluating the ability of the Wind Erosion Prediction System (WEPS) to simulate near-surface wind speeds in the Inland Pacific Northwest, USA.

Wind speed is one of the main control factors of wind erosion and dust emissions, which are major problems in arid and semiarid regions of the world. Accurately simulating highly precise hourly wind speeds is critical and cost-efficient for land management decisions with the goal of mitigating wind erosion and land degradation. The Wind Erosion Prediction System (WEPS) is a process-based, daily time-step model that simulates changes in the soil-vegetation-atmosphere. However, to date, relatively few studies have been conducted to test the ability of the WEPS in simulating hourly wind speeds. In this study, the performance of the WEPS model was tested in the Inland Pacific Northwest (iPNW), where wind erosion is a serious problem. Hourly wind speeds were observed and simulated by the WEPS at 13 meteorological stations from 2009 to 2018 using the WEPS hourly wind speed probability histogram. Owing to increasing wind shear, the model is not as precise in reproducing high wind speeds. The WEPS inadequately simulated the hourly wind speeds at six of the 13 stations, with a low index of agreement (d < 0.5). The complex regional topography may be one of the reasons for this lack of agreement, because the WEPS's performance of interpolation relies on spatial distances and surface complexity. Therefore, we validated the model using another wind-speed database to eliminate the impact of spatial interpolation. The performance of the WEPS was improved after removing the impact of spatial interpolation, producing d values > 0.5 at nine of the 13 stations. Our results suggest that the WEPS can accurately simulate hourly wind speeds and assess wind erosion in the absence of interpolation, whereas the model may be uncertain when invoking spatial interpolation. Some evidence also suggests that the model may have a tendency to underestimate observed hourly wind speeds. Pragmatically, this suggests that model users should consider the possibility that WEPS may underestimate wind erosion risk in the iPNW and plan implementation of conservation practices accordingly.

Genetic effect of basal metabolic rate on the benign neoplasm of bone and articular cartilage: a Mendelian randomization study.

Background: Previous studies have found an association between basal metabolic rate (BMR) and various malignant neoplasms, including bone tumors. BMR is also associated with bone mineral density, but the causality between BMR and benign neoplasms of bone and articular cartilage remains uncertain. Design: Single nucleotide polymorphisms (SNPs) associated with BMR (p < 5 × 10-8) were used as instrumental variables for Mendelian randomization analysis of neoplasm risk. The inverse variance weighted (IVW) method was the primary approach, with the weighted median and MR-Egger regression serving as supplements. Results: In this MR analysis, the IVW method supported a causal relationship between BMR and benign neoplasms of bone and articular cartilage (OR = 1.417; 95% CI, 1.039 to 1.930; p = 0.027). No evidence of heterogeneity or pleiotropy in the selected SNPs was found in our study. Thus, based on these results, we discovered a possible causal relationship between BMR and benign neoplasms of bone and articular cartilage. Conclusions: In this MR study, evidence suggested a genetic correlation between genetically predicted BMR and the risk of neoplasms in bone and articular cartilage.

ATF3 as a response factor to regulate Cd-induced reproductive damage by activating the NRF2/HO-1 ferroptosis pathway.

Cadmium (Cd) has garnered significant attention due to reproductive toxicity in inducing ferroptosis. However, the specific mechanisms underlying Cd-induced germ cell ferroptosis remain poorly understood. This study aimed to systematically explore the molecular mechanisms of germ cell ferroptosis by investigating differential changes in transcription factors and proteins in male mice treated orally with CdCl2 (0.5 g/L) reaching postnatal day 60, alongside Leydig cell (TM3) and Sertoli cell (TM4) lines. Results demonstrated that Cd exposure led to increased iron overload and oxidative stress in mouse testes, disrupted intracellular mitochondrial morphology characteristic of ferroptosis. RNA sequencing revealed significant upregulation of Atf3 and Hmox1 in Cd-exposed germ cells, along with increased expression of ATF3 and HO-1. Intervention in ferroptosis or HO-1 effectively rescued cells from Cd-induced mortality by breaking the detrimental cycle between lipid peroxidation and HO-1 activation. Further findings showed that NRF2 and HO-1 expression was notably elevated upon ATF3 overexpression in TM3 and TM4 cells, activating the Keap1-Nrf2 pathway and triggering ferroptosis in testes, whereas NRF2 and HO-1 expression levels were reversed when ATF3 was silenced. This study provides novel insights into ATF3-mediated NRF2/HO-1 signaling in Cd-induced mitochondrial ferroptosis in testes, shedding light on the mechanisms underlying Cd-induced ferroptosis and testicular injury.

PFDN5 plays a dual role in breast cancer and regulates tumor immune microenvironment: Insights from integrated bioinformatics analysis and experimental validation.

BACKGROUND: Although the prognosis for patients with breast cancer has improved, breast cancer remains the leading cause of death for women worldwide. Prefoldin 5 (PFDN5), as a subunit of the prefoldin complex, plays a vital role in aiding the correct folding of newly synthesized proteins. However, the exact impact of PFDN5 on breast cancer development and its prognostic implications remain unclear. METHODS: We conducted bioinformatics analysis to investigate the correlation between PFDN5 and patient survival, as well as various clinicopathological characteristics in breast cancer. Additionally, various assays were employed to validate the biological functions of PFDN5 in breast cancer. Finally, RNA sequencing (RNA-seq) was utilized to investigate the molecular mechanisms associated with PFDN5. RESULTS: Compared to normal tissues, PFDN5 exhibited lower expression levels in breast cancer tissues, and lower expression of PFDN5 is associated with poorer prognosis. PFDN5 led to G2/M phase arrest in the cell cycle and reduced proliferative potential in breast cancer cells. However, PFDN5 also promoted migration and invasion of breast cancer cells. Also, RNA-seq analysis revealed an involvement of PFDN5 in the cell cycle and TGF-ß signaling pathway. Furthermore, PFDN5 had a significant impact on tumor immune microenvironment by promoting macrophage polarization towards the M1 phenotype and exhibited a positive correlation with CD8+ T cell infiltration levels. CONCLUSIONS: PFDN5 plays a dual role in breast cancer and serves as a key factor in tumor immune microenvironment. Therefore, PFDN5 holds promise as a valuable biomarker for predicting both metastatic and prognosis in breast cancer.

Mo-doped α-MnO2 for Enhanced Electrocatalytic Water Oxidation.

Manganese is a key metal involved in the catalysis of natural photosynthesis. Thus, the investigation of Mn-based electrocatalysts for water oxidation is of high importance. This work reports the doping of Mo into α-MnO2 nanorods to improve the water oxidation performance. The doping of Mo can transform the microstructure of α-MnO2 from nanorods into nanosphere superstructures. As a dopant, Mo expands the α-MnO2 lattice to result in a decrease in the average oxidation state of Mn and the generation of oxygen vacancies, which are beneficial to water oxidation catalysis. Under optimized doping, the OER overpotential of Mo/α-MnO2 is reduced by 80 mV (at 10 mA/cm2) compared with pure α-MnO2.

Research hotspots and trends of epigenetic therapy in oncology: a bibliometric analysis from 2004 to 2023.

Background: Epigenetics denotes heritable alterations in gene expression patterns independent of changes in DNA sequence. Epigenetic therapy seeks to reprogram malignant cells to a normal phenotype and has been extensively investigated in oncology. This study conducts a bibliometric analysis of epigenetic therapy in cancer, providing a comprehensive overview of current research, identifying trends, and highlighting key areas of investigation. Methods: Publications concerning epigenetic inhibitors in cancer spanning 2004 to 2023 were retrieved from the Web of Science Core Collection (WoSCC). Co-occurrence analysis using VOSviewer assessed current status and focal points. Evolutionary trends and bursts in the knowledge domain were analyzed using CiteSpace. Bibliometrix facilitated topic evolution and revealed trends in keywords. National, institutional, and author affiliations and collaborations were also examined. Results: A total of 2,153 articles and reviews on epigenetic therapy in oncology were identified, demonstrating a consistent upward trend over time. The United States (745 papers), University of Texas MD Anderson Cancer Center (57 papers), and Stephen B. Baylin (27 papers) emerged as the most productive country, institution, and author, respectively. Keyword co-occurrence analysis identified five primary clusters: tumor, DNA methylation, epigenetic therapy, expression, and immunotherapy. In the past 5 years, newly emerging themes with increased centrality and density include "drug resistance," "immunotherapy," and "combination therapy." The most cited publication reviewed current understanding of potential causes of epigenetic diseases and proposed future therapeutic strategies. Conclusion: In the past two decades, the importance of epigenetic therapy in cancer research has become increasingly prominent. The United States occupies a key position in this field, while China, despite having published a large number of related papers, still has relatively limited influence. Current research focuses on the "combination therapy" of epigenetic drugs. Future studies should further explore the sequencing and scheduling of combination therapies, optimize trial designs and dosing regimens to improve clinical efficacy.

Promotion or prevention: regulatory foci as moderators in the job demands-resources model.

BACKGROUND: Building on the job demands-resources (JD-R) model and regulatory focus theory, this study examined how regulatory foci shaped the effects of different job demands and resources on both negative and positive workplace outcomes among medical staff. METHODS: Two independent studies (NStudy 1 = 267; NStudy 2 = 350) were designed for cross-validation. Participants completed a battery of measures evaluating job demands (workload, emotional demands, interpersonal stress), job resources (psychological safety, perceived organizational support, servant leadership), and well-being (job burnout, affective commitment, job satisfaction). RESULTS: Multiple linear regression analyses showed employees' well-being was affected by job demands and resources through energetic and motivational processes, respectively. The deleterious effect of emotional demands on job burnout was pronounced in individuals with weak prevention focus (B = 0.392, standard error [SE] = 0.069, p < .001). Psychological safety (Study 1) and servant leadership (Study 2) had stronger positive associations with motivational outcomes among individuals with weak promotion focus than those with strong promotion focus (B = 0.394, SE = 0.069, p < .001; B = 0.679, SE = 0.121, p < .001; and B = 0.476, SE = 0.072, p < .001, respectively). CONCLUSION: We used two samples to examine and cross-validate the joint effects of job characteristics and personal traits on workplace well-being among Chinese medical staff. Although heterogenous, the results showed regulatory foci were especially important in determining the effects of job demands and resources on well-being when there was (autonomous) self-regulation in the workplace.

Effect of vascular compression and drug injection time on thrombolytic therapy: Numerical simulation and validation.

Venous thromboembolism (VTE) has been occurring frequently in human society. There is an urgent need to study the influence of several factors on thrombolytic therapy, such as the effects of vascular pressure levels (VPL) and the drug injection time (DIT). Considering blood as a non-Newtonian fluid, valve as a hyperelastic material, and thrombus as a porous medium, a new numerical simulation model of biofluid mechanics incorporating fluid-solid coupling phenomena and biochemical substance reactions is established based on the N-S equations and the convection-diffusion reaction equations. Then, a unique in vitro experimental platform is established to verify the correctness of the constructed mathematical model. The results showed that vascular compression resulted in significant differences in blood flow status localized within the vessel. Vascular compression causes the blood boosting index to fluctuate and the valve displacement values are 135% and 158% greater than the lower VPL, respectively. At the same time, vascular compression weakened vortex intensity, accelerated material transport and response, and improved the treatment. Compared with low VPL, the therapeutic efficacy increased by 7% and 15%, respectively. In addition, when the dose of the drug is high, different injection times can increase the therapeutic effect to different degrees, with a maximum difference of 12%. Our in vitro experiments are similar to the results obtained by numerical simulation, which can verify the reliability of numerical simulation. The computational model proposed and the experimental platform designed in this study have the potential to assist in clinical medication prediction in different venous thromboembolism patients.

Therapeutic potential of Shaoyao Gancao Decoction in mitigating anti-tuberculosis drug-induced liver injury through Nrf-2/HO-1/NF-κB signaling.

Tuberculosis (TB) is a persistent global health issue, evidenced by an increasing number of cases. Although anti-TB drugs have proven efficacy, they are often associated with severe liver injury (ATB-DILI). The objective of this research was to uncover the mechanisms through which Shaoyao Gancao Decoction (SGD) mitigates ATB-DILI, emphasizing the role of the Nrf-2/HO-1/NF-κB signaling pathway. We prepared SGD granules and subjected them to HPLC-MS/MS for analysis. An ATB-DILI rat model was then developed and administered SGD. We evaluated liver injury markers, the extent of oxidative stress, inflammation, and the principal proteins involved in the Nrf-2/HO-1/NF-κB pathway. Additionally, network pharmacology techniques were utilized to discern potential SGD targets and their associated pathways. Administering SGD had a notable effect in counteracting the elevation of liver injury markers and pathological alterations induced by ATB-DILI. Moreover, there was a marked reduction in oxidative stress and inflammation in the treated rats. We identified 12 active compounds in SGD, with 88 shared targets between SGD and ATB-DILI. Subsequent KEGG analysis brought attention to pathways like MAPK, NF-κB, and IL-17 signaling. Our findings pave the way for more in-depth studies into the application of SGD in treating drug-induced liver injuries.

Restriction-induced time-dependent transcytolemmal water exchange: Revisiting the Kӓrger exchange model.

The Kӓrger model and its derivatives have been widely used to incorporate transcytolemmal water exchange rate, an essential characteristic of living cells, into analyses of diffusion MRI (dMRI) signals from tissues. The Kӓrger model consists of two homogeneous exchanging components coupled by an exchange rate constant and assumes measurements are made with sufficiently long diffusion time and slow water exchange. Despite successful applications, it remains unclear whether these assumptions are generally valid for practical dMRI sequences and biological tissues. In particular, barrier-induced restrictions to diffusion produce inhomogeneous magnetization distributions in relatively large-sized compartments such as cancer cells, violating the above assumptions. The effects of this inhomogeneity are usually overlooked. We performed computer simulations to quantify how restriction effects, which in images produce edge enhancements at compartment boundaries, influence different variants of the Kӓrger-model. The results show that the edge enhancement effect will produce larger, time-dependent estimates of exchange rates in e.g., tumors with relatively large cell sizes (>10 µm), resulting in overestimations of water exchange as previously reported. Moreover, stronger diffusion gradients, longer diffusion gradient durations, and larger cell sizes, all cause more pronounced edge enhancement effects. This helps us to better understand the feasibility of the Kärger model in estimating water exchange in different tissue types and provides useful guidance on signal acquisition methods that may mitigate the edge enhancement effect. This work also indicates the need to correct the overestimated transcytolemmal water exchange rates obtained assuming the Kärger-model.

Comprehensive characterization of tumor therapeutic response with simultaneous mapping cell size, density, and transcytolemmal water exchange.

Early assessment of tumor therapeutic response is an important topic in precision medicine to optimize personalized treatment regimens and reduce unnecessary toxicity, cost, and delay. Although diffusion MRI (dMRI) has shown potential to address this need, its predictive accuracy is limited, likely due to its unspecific sensitivity to overall pathological changes. In this work, we propose a new quantitative dMRI-based method dubbed EXCHANGE (MRI of water Exchange, Confined and Hindered diffusion under Arbitrary Gradient waveform Encodings) for simultaneous mapping of cell size, cell density, and transcytolemmal water exchange. Such rich microstructural information comprehensively evaluates tumor pathologies at the cellular level. Validations using numerical simulations and in vitro cell experiments confirmed that the EXCHANGE method can accurately estimate mean cell size, density, and water exchange rate constants. The results from in vivo animal experiments show the potential of EXCHANGE for monitoring tumor treatment response. Finally, the EXCHANGE method was implemented in breast cancer patients with neoadjuvant chemotherapy, demonstrating its feasibility in assessing tumor therapeutic response in clinics. In summary, a new, quantitative dMRI-based EXCHANGE method was proposed to comprehensively characterize tumor microstructural properties at the cellular level, suggesting a unique means to monitor tumor treatment response in clinical practice.

Enhancing nitrate removal from small wetlands via regulating bacterial-algal symbiosis with macrophyte coverage.

With increasing land resource constraints, wetlands, as ecological hotspots, are expected to enhance biogeochemical processes to mitigate nitrogen (N) pollution, particularly nitrate-nitrogen (NO3--N). However, the interactions among bacteria, algae, and macrophytes in wetlands, which are crucial for N removal, remain largely unknown. This study explored how macrophyte coverage influences bacterial-algal interactions, shifting from mutualism to inhibition, thereby affecting N removal. Moderate coverage enhanced NO3--N and total nitrogen (TN) removal (P < 0.05), which was correlated with increased microbial abundance (P < 0.05). This may have resulted from moderate algal photosynthesis, reduced physiological stress, and the expansion of ecological niches for microbes. Insufficient coverage promoted algal growth (chlorophyll-a > 31.8 µg·L-1), leading to increased competition for substrates and elevated pH, which further inhibited bacterial activity. Excessive coverage also inhibited bacterial activity by reducing illumination and oxidation-reduction potential. Consequently, insufficient and excessive coverage decreased N removal efficiencies by 2.7-15.7 % (NO3--N) and 3.7-11.1 % (TN) while increasing methane emission potential by 1.4-6.9 times compared with moderate coverage. These findings offer insights into solving NO3--N contamination using near-natural methods and balancing the ecological and practical considerations for small wetlands.

Acute T-cell lymphoblastic leukemia: chimeric antigen receptor technology may offer a new hope.

Acute lymphoblastic leukemia (ALL) is a prevalent malignancy affecting the hematopoietic system, encompassing both B-cell ALL (B-ALL) and T-cell ALL (T-ALL). T-ALL, characterized by the proliferation of T-cell progenitors in the bone marrow, presents significant treatment challenges, with patients often experiencing high relapse rates and poor long-term survival despite advances in chemotherapy and hematopoietic stem cell transplantation (HSCT). This review explores the pathogenesis and traditional treatment strategies of T-ALL, emphasizing the promising potential of chimeric antigen receptor (CAR) technology in overcoming current therapeutic limitations. CAR therapy, leveraging genetically modified immune cells to target leukemia-specific antigens, offers a novel and precise approach to T-ALL treatment. The review critically analyzes recent developments in CAR-T and CAR-NK cell therapies, their common targets, optimization strategies, clinical outcomes, and the associated challenges, providing a comprehensive overview of their clinical prospects in T-ALL treatment.

Clinical and virological characteristics of coexistent hepatitis B surface antigen and antibody in treatment-naive children with chronic hepatitis B virus infection.

Serological pattern of simultaneous positivity for hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs) is considered a specific and atypical phenomenon among patients with chronic hepatitis B virus (HBV) infection, especially in pediatric patients. Unfortunately, there is limited understanding of the clinical and virological characteristics among children having chronic HBV infection and the coexistence of HBsAg and anti-HBs. Hence, our objective was to determine the prevalence of coexistent HBsAg and anti-HBs and to explore the associated clinical and virological features in this patient population. The researchers conducted a retrospective cohort study on the 413 pediatric patients with chronic HBV infection from December 2011 to June 2022. The patients were stratified into two groups based on their anti-HBs status. Demographic, serum biochemical and virological parameters of two group were compared. Of the total 413 enrolled subjects, 94 (22.8%) were tested positive for both HBsAg and anti-HBs. Patients with anti-HBs were younger and demonstrated significantly higher ratio of albumin to globulin (A/G), elevated serum levels of alanine transaminase (ALT), lower ratio of aspartate transaminase (AST)/ALT (AST/ALT) and reduced serum levels of globulin, HBsAg and HBV DNA, Additionally, these patients were more likely to show coexistent HBeAg and anti-HBe when compared to patients without anti-HBs. The results of multivariate logistical analysis revealed that AST/ALT, serum levels of globulin and HBsAg were negatively associated with coexistence of HBsAg and anti-HBs. Our data demonstrated a considerable prevalence of coexisting HBsAg and anti-HBs in pediatric patients. Children with this specific serological pattern were commonly of a younger age, seemly predisposing them to early liver impairment and lower HBV replication activity.

Microbial imbalance in Chinese children with diarrhea or constipation.

Diarrhea and constipation are common health concerns in children. Numerous studies have identified strong association between gut microbiota and digestive-related diseases. But little is known about the gut microbiota that simultaneously affects both diarrhea and constipation or their potential regulatory mechanisms. Stool samples from 618 children (66 diarrhea, 138 constipation, 414 healthy controls) aged 0-3 years were collected to investigate gut microbiota changes using 16S rRNA sequencing. Compared with healthy, children with diarrhea exhibited a significant decrease in microbial diversity, while those with constipation showed a marked increase (p < 0.05). Significantly, our results firstly Ruminococcus increased in constipation (p = 0.03) and decreased in diarrhea (p < 0.01) compared to healthy controls. Pathway analysis revealed that Ruminococcus highly involved in the regulation of five common pathways (membrane transport, nervous system, energy metabolism, signal transduction and endocrine system pathways) between diarrhea and constipation, suggesting a potential shared regulatory mechanism. Our finding firstly reveals one core microorganisms that may affect the steady balance of the gut in children with diarrhea or constipation, providing an important reference for potential diagnosis and treatment of constipation and diarrhea.

Association between obesity and the prevalence of dyslipidemia in middle-aged and older people: an observational study.

This study aimed to explore the link between various forms of obesity, including body mass index (BMI) and waist circumference (WC), and the risk of dyslipidemia among Chinese residents. We selected the study population through a multi-stage random sampling method from permanent residents aged 35 and older in Ganzhou. Obesity was categorized as non-obesity, general obesity, central obesity, or compound obesity according to established diagnostic criteria. We employed a logistic regression model to assess the relationship between different types of obesity and the risk of dyslipidemia. Additionally, we used the restricted cubic spline model to analyze the association between BMI, WC, and the risk of dyslipidemia. The study included 2030 residents aged 35 or older from Ganzhou, China. The prevalence of dyslipidemia was found to be 39.31%, with an age-standardized prevalence of 36.51%. The highest prevalence of dyslipidemia, 58.79%, was observed among those with compound obesity. After adjusting for confounding factors, we found that the risk of dyslipidemia in those with central and compound obesity was respectively 2.00 (95% CI 1.62-2.46) and 2.86 (95% CI 2.03-4.03) times higher than in the non-obese population. Moreover, the analysis using the restricted cubic spline model indicated a nearly linear association between BMI, WC, and the risk of dyslipidemia. The findings emphasize the significant prevalence of both dyslipidemia and obesity among adults aged 35 and above in Ganzhou, China. Notably, individuals with compound obesity are at a substantially increased risk of dyslipidemia. Therefore, it is crucial to prioritize the use of BMI and WC as screening and preventive measures for related health conditions.

Electroacupuncture modulates abnormal brain connectivity after ischemia reperfusion injury in rats: A graph theory-based approach.

BACKGROUND: Electroacupuncture (EA) has been shown to facilitate brain plasticity-related functional recovery following ischemic stroke. The functional magnetic resonance imaging technique can be used to determine the range and mode of brain activation. After stroke, EA has been shown to alter brain connectivity, whereas EA's effect on brain network topology properties remains unclear. An evaluation of EA's effects on global and nodal topological properties in rats with ischemia reperfusion was conducted in this study. METHODS AND RESULTS: There were three groups of adult male Sprague-Dawley rats: sham-operated group (sham group), middle cerebral artery occlusion/reperfusion (MCAO/R) group, and MCAO/R plus EA (MCAO/R + EA) group. The differences in global and nodal topological properties, including shortest path length, global efficiency, local efficiency, small-worldness index, betweenness centrality (BC), and degree centrality (DC) were estimated. Graphical network analyses revealed that, as compared with the sham group, the MCAO/R group demonstrated a decrease in BC value in the right ventral hippocampus and increased BC in the right substantia nigra, accompanied by increased DC in the left nucleus accumbens shell (AcbSh). The BC was increased in the right hippocampus ventral and decreased in the right substantia nigra after EA intervention, and MCAO/R + EA resulted in a decreased DC in left AcbSh compared to MCAO/R. CONCLUSION: The results of this study provide a potential basis for EA to promote cognitive and motor function recovery after ischemic stroke.

Functional study of a rare L1CAM gene c.1759G>C variant prove its pathogenicity.

L1 syndrome, a neurological disorder with an X-linked inheritance pattern, mainly results from mutations occurring in the L1 cell adhesion molecule (L1CAM) gene. The L1CAM molecule, belonging to the immunoglobulin (Ig) superfamily of neurocyte adhesion molecules, plays a pivotal role in facilitating intercellular signal transmission across membranes and is indispensable for proper neuronal development and function. This study identified a rare missense variant (c.1759G>C; p.G587R) in the L1CAM gene within a male fetus presenting with hydrocephalus. Due to a lack of functional analysis, the significance of the L1CAM mutation c.1759G>C (p.G587R) remains unknown. We aimed to perform further verification for its pathogenicity. Blood samples were obtained from the proband and his parents for trio clinical exome sequencing and mutation analysis. Expression level analysis was conducted using western blot techniques. Immunofluorescence was employed to investigate L1CAM subcellular localization, while cell aggregation and cell scratch assays were utilized to assess protein function. The study showed that the mutation (c.1759G>C; p.G587R) affected posttranslational glycosylation modification and induced alterations in the subcellular localization of L1-G587R in the cells. It resulted in the diminished expression of L1CAM on the cell surface and accumulation in the endoplasmic reticulum. The p.G587R altered the function of L1CAM protein and reduced homophilic adhesion capacity of proteins, leading to impaired adhesion and migration of proteins between cells. Our findings provide first biological evidence for the association between the missense mutation (c.1759G>c; p.G587R) in the L1CAM gene and L1 syndrome, confirming the pathogenicity of this missense mutation.

Pre-eclamptic foetal programming predisposes offspring to hepatic steatosis via DNA methylation.

OBJECTIVES: Gamete and embryo-foetal origins of adult diseases hypothesis proposes that adulthood chronic disorders are associated with adverse foetal and early life traits. Our study aimed to characterise developmental changes and underlying mechanisms of metabolic disorders in offspring of pre-eclampsia (PE) programmed pregnancy. METHODS: Nω-Nitro-l-arginine methyl ester hydrochloride (L-NAME) induced pre-eclampsia-like C57BL/6J mouse model was used. Lipid profiling, histological morphology, indirect calorimetry, mRNA sequencing, and pyrosequencing were performed on PE offspring of both young and elderly ages. RESULTS: PE offspring exhibited increased postnatal weight gain, hepatic lipid accumulation, enlarged adipocytes, and impaired energy balance that continued to adulthood. Integrated RNA sequencing of foetal and 52-week-old livers revealed that the differentially expressed genes were mainly enriched in lipid metabolism, including glycerol-3-phosphate acyl-transferase 3 (Gpat3), a key enzyme for de novo synthesis of triglycerides (TG), and carnitine palmitoyltransferase-1a (Cpt1a), a key transmembrane enzyme that mediates fatty acid degradation. Pyrosequencing of livers from PE offspring identified hypomethylated and hypermethylated regions in Gpat3 and Cpt1a promoters, which were associated with upregulated and downregulated expressions of Gpat3 and Cpt1a, respectively. These epigenetic alterations are persistent and consistent from the foetal stage to adulthood in PE offspring. CONCLUSION: These findings suggest a methylation-mediated epigenetic mechanism for PE-induced intergenerational lipid accumulation, impaired energy balance and obesity in offspring, and indicate the potential benefits of early interventions in offspring exposed to maternal PE to reduce their susceptibility to metabolic disorder in their later life.