Decoding Wilson disease: a machine learning approach to predict neurological symptoms.

Objectives: Wilson disease (WD) is a rare autosomal recessive disorder caused by a mutation in the ATP7B gene. Neurological symptoms are one of the most common symptoms of WD. This study aims to construct a model that can predict the occurrence of neurological symptoms by combining clinical multidimensional indicators with machine learning methods. Methods: The study population consisted of WD patients who received treatment at the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from July 2021 to September 2023 and had a Leipzig score ≥ 4 points. Indicators such as general clinical information, imaging, blood and urine tests, and clinical scale measurements were collected from patients, and machine learning methods were employed to construct a prediction model for neurological symptoms. Additionally, the SHAP method was utilized to analyze clinical information to determine which indicators are associated with neurological symptoms. Results: In this study, 185 patients with WD (of whom 163 had neurological symptoms) were analyzed. It was found that using the eXtreme Gradient Boosting (XGB) to predict achieved good performance, with an MCC value of 0.556, ACC value of 0.929, AUROC value of 0.835, and AUPRC value of 0.975. Brainstem damage, blood creatinine (Cr), age, indirect bilirubin (IBIL), and ceruloplasmin (CP) were the top five important predictors. Meanwhile, the presence of brainstem damage and the higher the values of Cr, Age, and IBIL, the more likely neurological symptoms were to occur, while the lower the CP value, the more likely neurological symptoms were to occur. Conclusions: To sum up, the prediction model constructed using machine learning methods to predict WD cirrhosis has high accuracy. The most important indicators in the prediction model were brainstem damage, Cr, age, IBIL, and CP. It provides assistance for clinical decision-making.

Connectome gradient dysfunction contributes to white matter hyperintensity-related cognitive decline.

BACKGROUND: Although white matter hyperintensity (WMH) is closely associated with cognitive decline, the precise neurobiological mechanisms underlying this relationship are not fully elucidated. Connectome studies have identified a primary-to-transmodal gradient in functional brain networks that support the spectrum from sensation to cognition. However, whether connectome gradient structure is altered as WMH progresses and how this alteration is associated with WMH-related cognitive decline remain unknown. METHODS: A total of 758 WMH individuals completed cognitive assessment and resting-state functional MRI (rs-fMRI). The functional connectome gradient was reconstructed based on rs-fMRI by using a gradient decomposition framework. Interrelations among the spatial distribution of WMH, functional gradient measures, and specific cognitive domains were explored. RESULTS: As the WMH volume increased, the executive function (r = -0.135, p = 0.001) and information-processing speed (r = -0.224, p = 0.001) became poorer, the gradient range (r = -0.099, p = 0.006), and variance (r = -0.121, p < 0.001) of the primary-to-transmodal gradient reduced. A narrower gradient range (r = 0.131, p = 0.001) and a smaller gradient variance (r = 0.136, p = 0.001) corresponded to a poorer executive function. In particular, the relationship between the frontal/occipital WMH and executive function was partly mediated by gradient range/variance of the primary-to-transmodal gradient. CONCLUSIONS: These findings indicated that WMH volume, the primary-to-transmodal gradient, and cognition were interrelated. The detrimental effect of the frontal/occipital WMH on executive function was partly mediated by the decreased differentiation of the connectivity pattern between the primary and transmodal areas.

Qifu-yin activates the Keap1/Nrf2/ARE signaling and ameliorates synaptic injury and oxidative stress in APP/PS1 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms through which QFY mitigates AD pathology remain to be fully delineated. AIM OF THE STUDY: This study aimed to explore the therapeutic implications of QFY on the synaptic injury and oxidative stress in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice, with a concerted effort to elucidate the molecular mechanisms related to synaptic preservation and memory improvement. MATERIALS AND METHODS: The components of QFY were identified by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The neuroprotective effects of QFY was evaluated using six-month-old male APP/PS1 mice. Subsequent to a 15 days of QFY regimen, spatial memory was assessed utilizing the Morris water maze (MWM) test. Amyloid-beta (Aß) aggregation was detected via immunostaining, while the quantification of Aß1-40 and Aß1-42 was achieved through enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy (TEM) was used to investigate the synaptic structure and mitochondrial morphology. Golgi staining was applied to examine dendritic spine density. Reactive oxygen species (ROS), 3-nitrotyrosine (3-NT) and 4-hydroxy-nonenal (4-HNE) assays were employed to assess oxidative stress. The expression profiles of Aß metabolism-associated enzymes and the Keap1/Nrf2/ARE signaling pathway were determined by Western blot. RESULTS: A total of 20 principal compounds in QFY were identified. QFY mitigated memory deficits of APP/PS1 mice, including reducing escape latency and search distance and increasing the time and distance spent in the target quadrant. In addition, QFY increased platform crossings of APP/PS1 mice in the probe trial of MWM tests. TEM analysis showed that QFY increased synapse number in the CA1 region of APP/PS1 mice. Further studies indicated that QFY elevated the expression levels of Post synaptic density protein 95 (PSD95) and synaptophysin, and mitigated the loss of dendritic spine density in the hippocampus of APP/PS1 mice. QFY has been shown to ameliorated the structural abnormalities of mitochondria, including mitochondrial dissolution and degradation, up-regulate ATP synthesis and membrane potential in the hippocampus of APP/PS1 mice. Moreover, QFY activated the Keap1/Nrf2/ARE signaling pathway in the hippocampus of APP/PS1 mice, which might contribute to the neuroprotective effects of QFY. CONCLUSION: QFY activates the Keap1/Nrf2/ARE signaling, and protects against synaptic and mitochondrial dysfunction in APP/PS1 mice, proposing a potential alternative therapeutic strategy for AD management.

Association between atherogenic index of plasma and new-onset stroke in individuals with different glucose metabolism status: insights from CHARLS.

BACKGROUND: Circulating atherogenic index of plasma (AIP) levels has been proposed as a novel biomarker for dyslipidemia and as a predictor of insulin resistance (IR) risk. However, the association between AIP and the incidence of new-onset stroke, particularly in individuals with varying glucose metabolism status, remains ambiguous. METHODS: A total of 8727 participants aged 45 years or older without a history of stroke from the China Health and Retirement Longitudinal Study (CHARLS) were included in this study. The AIP was calculated using the formula log [Triglyceride (mg/dL) / High-density lipoprotein cholesterol (mg/dL)]. Participants were divided into four groups based on their baseline AIP levels: Q1 (AIP ≤ 0.122), Q2 (0.122 < AIP ≤ 0.329), Q3 (0.329 < AIP ≤ 0.562), and Q4 (AIP > 0.562). The primary endpoint was the occurrence of new-onset stroke events. The Kaplan-Meier curves, multivariate Cox proportional hazard models, and Restricted cubic spline analysis were applied to explore the association between baseline AIP levels and the risk of developing a stroke among individuals with varying glycemic metabolic states. RESULTS: During an average follow-up of 8.72 years, 734 participants (8.4%) had a first stroke event. The risk for stroke increased with each increasing quartile of baseline AIP levels. Kaplan-Meier curve analysis revealed a significant difference in stroke occurrence among the AIP groups in all participants, as well as in those with prediabetes mellitus (Pre-DM) and diabetes mellitus (DM) (all P values < 0.05). After adjusting for potential confounders, the risk of stroke was significantly higher in the Q2, Q3, and Q4 groups than in the Q1 group in all participants. The respective hazard ratios (95% confidence interval) for stroke in the Q2, Q3, and Q4 groups were 1.34 (1.05-1.71), 1.52 (1.19-1.93), and 1.84 (1.45-2.34). Furthermore, high levels of AIP were found to be linked to an increased risk of stroke in both pre-diabetic and diabetic participants across all three Cox models. However, this association was not observed in participants with normal glucose regulation (NGR) (p > 0.05). Restricted cubic spline analysis also demonstrated that higher baseline AIP levels were associated with higher hazard ratios for stroke in all participants and those with glucose metabolism disorders. CONCLUSIONS: An increase in baseline AIP levels was significantly associated with the risk of stroke in middle-aged and elderly individuals, and exhibited distinct characteristics depending on the individual's glucose metabolism status.

Darwin3: a large-scale neuromorphic chip with a novel ISA and on-chip learning.

Spiking neural networks (SNNs) are gaining increasing attention for their biological plausibility and potential for improved computational efficiency. To match the high spatial-temporal dynamics in SNNs, neuromorphic chips are highly desired to execute SNNs in hardware-based neuron and synapse circuits directly. This paper presents a large-scale neuromorphic chip named Darwin3 with a novel instruction set architecture, which comprises 10 primary instructions and a few extended instructions. It supports flexible neuron model programming and local learning rule designs. The Darwin3 chip architecture is designed in a mesh of computing nodes with an innovative routing algorithm. We used a compression mechanism to represent synaptic connections, significantly reducing memory usage. The Darwin3 chip supports up to 2.35 million neurons, making it the largest of its kind on the neuron scale. The experimental results showed that the code density was improved by up to 28.3× in Darwin3, and that the neuron core fan-in and fan-out were improved by up to 4096× and 3072× by connection compression compared to the physical memory depth. Our Darwin3 chip also provided memory saving between 6.8× and 200.8× when mapping convolutional spiking neural networks onto the chip, demonstrating state-of-the-art performance in accuracy and latency compared to other neuromorphic chips.

Progressive reduction of nuclear receptor Nr4a1 mediates age-dependent cognitive decline.

INTRODUCTION: Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age-related Nr4a1 reduction and cognitive decline is undefined. METHODS: Nr4a1 expressions were evaluated by quantitative PCR and immunochemical approaches. The cognition of mice was examined by multiple behavioral tests. Patch-clamp experiments were conducted to investigate the synaptic function. RESULTS: NR4A1 in peripheral blood mononuclear cells decreased with age in humans. In the mouse brain, age-dependent Nr4a1 reduction occurred in the hippocampal CA1. Deleting Nr4a1 in CA1 pyramidal neurons (PyrNs) led to the impairment of cognition and excitatory synaptic function. Mechanistically, Nr4a1 enhanced TrkB expression via binding to its promoter. Blocking TrkB compromised the cognitive amelioration with Nr4a1-overexpression in CA1 PyrNs. DISCUSSION: Our results elucidate the mechanism of Nr4a1-dependent TrkB regulation in cognition and synaptic function, indicating that Nr4a1 is a target for the treatment of cognitive decline. HIGHLIGHTS: Nr4a1 is reduced in PBMCs and CA1 PyrNs with aging. Nr4a1 ablation in CA1 PyrNs impaired cognition and excitatory synaptic function. Nr4a1 overexpression in CA1 PyrNs ameliorated cognitive impairment of aged mice. Nr4a1 bound to TrkB promoter to enhance transcription. Blocking TrkB function compromised Nr4a1-induced cognitive improvement.

AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.

AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.

An integrated analysis of the anticarcinogenic role of forkhead box protein 1 in oesophageal squamous cell carcinoma.

Forkhead box protein 1 (FOXP1) serves as a tumour promoter or suppressor depending on different cancers, but its effect in oesophageal squamous cell carcinoma has not been fully elucidated. This study investigated the role of FOXP1 in oesophageal squamous cell carcinoma through bioinformatics analysis and experimental verification. We determined through public databases that FOXP1 expresses low in oesophageal squamous cell carcinoma compared with normal tissues, while high expression of FOXP1 indicates a better prognosis. We identified potential target genes regulated by FOXP1, and explored the potential biological processes and signalling pathways involved in FOXP1 in oesophageal squamous cell carcinoma through GO and KEGG enrichment, gene co-expression analysis, and protein interaction network construction. We also analysed the correlation between FOXP1 and tumour immune infiltration levels. We further validated the inhibitory effect of FOXP1 on the proliferation of oesophageal squamous cell carcinoma cells through CCK-8, colony formation and subcutaneous tumour formation assays. This study revealed the anticarcinogenic effect of FOXP1 in oesophageal squamous cell carcinoma, which may serve as a novel biological target for the treatment of tumour.

Prepuberty is a window period for curcumin to prevent obesity in postnatal overfed rats.

BACKGROUND: Overnutrition in early life increases the risk of obesity and metabolic diseases. We investigated the effects and the window period of a curcumin (CUR) diet on postnatal overfed rats. METHODS: Male rats aged 3 days were randomly divided into normal litters (NL, 10 pups/litter) and small litters (SL, 3 pups/litter). After weaning (Week 3, W3), NL rats were fed a normal diet (NL) and SL rats were fed a normal diet (SL) or 2% CUR diet from weaning (W3) (SL-CURW13), beginning of puberty (W6) (SL-CURW16), or end of puberty (W8) (SL-CURW18) for 10 weeks. RESULTS: Body weight, glucose intolerance and hyperlipidemia in the SL rats were higher than in the NL rats, especially after puberty. After the CUR intervention, SL-CURW13 and SL-CURW16 rats showed lower body weight gain, adipose tissue weight and mRNA level of C/EBPα in SAT, along with higher mRNA levels of ß-catenin. There was no difference between SL and SL-CURW18 rats. Glucose tolerance, serum lipids and hepatic lipids recovered to normal in the SL-CURW13 rats, but only partially in the SL-CURW16 and SL-CURW18 rats. CONCLUSION: Prepuberty is a window period for CUR intervention to improve programmed outcomes in postnatal overfed rats. IMPACT: Overnutrition during the first 1000 days of life has persistent negative effects on metabolism. Strategies should be taken to prevent overnutrition in early life to reduce the risk of obesity and metabolic disease in later life. A small-litter rat model was utilized to simulate early-life overnutrition in humans. We investigated the different effects and critical period for curcumin intervention on postnatal overfed rats. Dietary curcumin intervention before puberty could effectively transform nutritional programming to reduce obesity and metabolic disorders caused by early-life overnutrition, and an earlier intervention might predict a better outcome.

Propofol modulates Nrf2/NLRP3 signaling to ameliorate cigarette smoke-induced damage in human bronchial epithelial cells.

Cigarette smoke extract (CSE) is known as a significant contributor to chronic obstructive pulmonary disease (COPD). Propofol, an anesthetic agent, has been studied for its potential protective effects against lung damage. This study aimed to elucidate the protective mechanisms of propofol against CSE-induced damage in human bronchial epithelial 16HBE cells. In CSE-induced 16HBE cells treated by propofol with or without transfection of nuclear factor erythroid 2-related factor 2 (Nrf2) interference plasmids, CCK-8 assay and lactate dehydrogenase (LDH) assay evaluated cytotoxicity. TUNEL assay and Western blot appraised cell apoptosis. ELISA and relevant assay kits severally measured inflammatory and oxidative stress levels. DCFH-DA fluorescent probe detected intracellular reactive oxygen species (ROS) activity. Immunofluorescence staining and Western blot estimated pyroptosis. Also, Western blot analyzed the expression of Nrf2/NLR family pyrin domain containing 3 (NLRP3) signaling-related proteins. Propofol was found to enhance the viability, reduce LDH release, and alleviate the apoptosis, inflammatory response, oxidative stress and pyroptosis in CSE-induced 16HBE cells in a concentration-dependent manner. Meanwhile, propofol decreased NLRP3 expression while raised Nrf2 expression. Further, after Nrf2 was silenced, the impacts of propofol on Nrf2/NLRP3 signaling, LDH release, apoptosis, inflammatory response, oxidative stress and pyroptosis in CSE-exposed 16HBE cells were eliminated. Conclusively, propofol may exert protective effects against CSE-induced damage in 16HBE cells, partly through the modulation of the Nrf2/NLRP3 signaling pathway, suggesting a potential therapeutic role for propofol in CSE-induced bronchial epithelial cell damage.

PI3Kα inhibitor GNE-493 triggers antitumor immunity in murine lung cancer by inducing immunogenic cell death and activating T cells.

Phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer, playing pivotal roles in the pathophysiology of both malignant and immune cells. The impact of PI3K inhibitors on the tumor microenvironment (TME) within lung cancer remains largely unknown. In this study, we explored the regulatory effects of GNE-493, an innovative dual inhibitor of PI3K and mammalian target of rapamycin (mTOR), on the TME of lung cancer. First, through the analysis of The Cancer Genome Atlas-lung squamous cell carcinoma (LUSC) cohort, we found PIK3CA to be related to CD8 T cells, which may affect the overall survival rate of patients by affecting CD8 function. We herein demonstrated that GNE-493 can significantly inhibit tumor cell proliferation and promote cell apoptosis while increasing the expression of the immunogenic death-related molecules CRT and HSP70 using in vitro cell proliferation and apoptosis experiments on the murine KP lung cancer cell line and human A549 lung cancer cell line. Next, through the establishment of an orthotopic tumor model in vivo, it was found that after GNE-493 intervention, the infiltration of CD4+ and CD8+ T cells in mouse lung tumor was significantly increased, and the expression of CRT in tumors could be induced to increase. To explore the mechanisms underlying PI3K inhibition-induced changes in the TME, the gene expression differences of T cells in the control group versus GNE-493-treated KP tumors were analyzed by RNA-seq, and the main effector pathway of anti-tumor immunity was identified. The IFN/TNF family molecules were significantly upregulated after GNE-493 treatment. In summary, our findings indicate that GNE-493 promotes immunogenic cell death in lung cancer cells, and elucidates its regulatory impact on molecules associated with the adaptive immune response. Our study provides novel insights into how PI3K/mTOR inhibitors exert their activity by modulating the tumor-immune interaction.

Neuroprotective effects of Aucubin against cerebral ischemia-reperfusion injury.

AIMS: To study the role of Aucubin (AU) in cerebral ischemia-reperfusion injury and investigate the potential mechanisms. METHODS: For the in vitro experiment, primary microglia were cultured and stimulated by Lipopolysaccharides (LPS) and treated with AU. Male C57/BL6J mice were used and middle cerebral artery occlusion (MCAO) model was performed to induce cerebral ischemia-reperfusion injury. For the short-term effects, mice administrated with AU (40 mg/kg) for 3 days after MCAO were evaluated for the infarct volume and neurological deficits. The neuroinflammatory factors and microglia activation were determined by Real-time PCR, western blot and immunofluorescence staining. For the long-term effects, MCAO mice were injected daily with AU (5 mg/kg or 10 mg/kg) for 28 days. Behavior tests were used to assess the neurological deficits of MCAO mice, and white matter integrity was determined by myelin basic protein (MBP) staining and black-gold staining. RESULTS: AU suppressed LPS-induced activation of microglia and pro-inflammatory cytokines release, and downregulated the NF-κB and MAPK pathways in primary microglia. In addition, AU attenuated ischemic injury and inhibited the neuro-inflammatory response in MCAO mice. Moreover, AU induced prolonged improvements in sensorimotor function and memory function following MCAO, and preserved white matter integrity in the long-term experiments. CONCLUSIONS: AU protected against ischemic injury, which might be correlated with the downregulation of NF-κB and MAPK signaling pathways. Furthermore, AU alleviated cognitive impairment after stroke and restored white matter integrity. Our data indicated that AU might be a potential compound for the treatment of stroke and post-stroke cognitive impairment.

The Interaction Mechanism of Picolinamide Fungicide Targeting on the Cytochrome bc1 Complex and Its Structural Modification.

Picolinamide fungicides, structurally related to UK-2A and antimycin-A, bind into the Qi-site in the bc1 complex. However, the detailed binding mode of picolinamide fungicides remains unknown. In the present study, antimycin-A and UK-2A were selected to study the binding mode of picolinamide inhibitors with four protonation states in the Qi-site by integrating molecular dynamics simulation, molecular docking, and molecular mechanics Generalized Born surface area (MM/GBSA) calculations. Subsequently, a series of new picolinamide derivatives were designed and synthesized to further understand the effects of substituents on the tail phenyl ring. The computational results indicated that the substituted aromatic rings in antimycin-A and UK-2A were the pharmacophore fragments and made the primary contribution when bound to a protein. Compound 9g-hydrolysis formed H-bonds with Hie201 and Ash228 and showed an IC50 value of 6.05 ± 0.24 µM against the porcine bc1 complex. Compound 9c, with a simpler chemical structure, showed higher control effects than florylpicoxamid against cucumber downy mildew and expanded the fungicidal spectrum of picolinamide fungicides. The structural and mechanistic insights obtained from the present study will provide a valuable clue for the future designing of new promising Qi-site inhibitors.

Conditional knockout of AIM2 in microglia ameliorates synaptic plasticity and spatial memory deficits in a mouse model of Alzheimer's disease.

AIMS: Synaptic dysfunction is a hallmark pathology of Alzheimer's disease (AD) and is strongly associated with cognitive impairment. Abnormal phagocytosis by the microglia is one of the main causes of synapse loss in AD. Previous studies have shown that the absence of melanoma 2 (AIM2) inflammasome activity is increased in the hippocampus of APP/PS1 mice, but the role of AIM2 in AD remains unclear. METHODS: Injection of Aß1-42 into the bilateral hippocampal CA1 was used to mimic an AD mouse model (AD mice). C57BL/6 mice injected with AIM2 overexpression lentivirus and conditional knockout of microglial AIM2 mice were used to confirm the function of AIM2 in AD. Cognitive functions were assessed with novel object recognition and Morris water maze tests. The protein and mRNA expression levels were evaluated by western blotting, immunofluorescence staining, and qRT-PCR. Synaptic structure and function were detected by Golgi staining and electrophysiology. RESULTS: The expression level of AIM2 was increased in AD mice, and overexpression of AIM2 induced synaptic and cognitive impairments in C57BL/6 mice, similar to AD mice. Elevated expression levels of AIM2 occurred in microglia in AD mice. Conditional knockout of microglial AIM2 rescued cognitive and synaptic dysfunction in AD mice. Excessive microglial phagocytosis activity of synapses was decreased after knockout of microglial AIM2, which was associated with inhibiting complement activation. CONCLUSION: Our results demonstrated that microglial AIM2 plays a critical role in regulating synaptic plasticity and memory deficits associated with AD, providing a new direction for developing novel preventative and therapeutic interventions for this disease.

Calculation of carbon emissions in wastewater treatment and its neutralization measures: A review.

As the pursuit of "carbon neutrality" gains momentum, the emphasis on low-carbon solutions, emphasizing energy conservation and resource reuse, has introduced fresh challenges to conventional wastewater treatment approaches. Precisely evaluating carbon emissions in urban water supply and drainage systems, wastewater treatment plants, and establishing carbon-neutral operating models has become a pivotal concern in the future of wastewater treatment. Regrettably, limited research has been devoted to carbon accounting and the development of carbon-neutral strategies for wastewater treatment. In this review, to facilitate comprehensive carbon accounting, we initially recognizes direct and indirect carbon emission sources in the wastewater treatment process. We then provide an overview of several major carbon accounting methods and propose a carbon accounting framework. Furthermore, we advocate for a systemic perspective, highlighting that achieving carbon neutrality in wastewater treatment extends beyond the boundaries of wastewater treatment plants. We assess current technical measures both within and outside the plants that contribute to achieving carbon-neutral operations. Encouraging the application of intelligent algorithms for the multifaceted monitoring and control of wastewater treatment processes is paramount. Supporting resource and energy recycling is also essential, as is recognizing the benefits of synergistic wastewater treatment technologies. We advocate a systematic, multi-level planning approach that takes into account a wide range of factors. Our goal is to offer valuable insights and support for the practical implementation of water environment management within the framework of carbon neutrality, and to advance sustainable socio-economic development and contribute to a more environmentally responsible future.

BERT-5mC: an interpretable model for predicting 5-methylcytosine sites of DNA based on BERT.

DNA 5-methylcytosine (5mC) is widely present in multicellular eukaryotes, which plays important roles in various developmental and physiological processes and a wide range of human diseases. Thus, it is essential to accurately detect the 5mC sites. Although current sequencing technologies can map genome-wide 5mC sites, these experimental methods are both costly and time-consuming. To achieve a fast and accurate prediction of 5mC sites, we propose a new computational approach, BERT-5mC. First, we pre-trained a domain-specific BERT (bidirectional encoder representations from transformers) model by using human promoter sequences as language corpus. BERT is a deep two-way language representation model based on Transformer. Second, we fine-tuned the domain-specific BERT model based on the 5mC training dataset to build the model. The cross-validation results show that our model achieves an AUROC of 0.966 which is higher than other state-of-the-art methods such as iPromoter-5mC, 5mC_Pred, and BiLSTM-5mC. Furthermore, our model was evaluated on the independent test set, which shows that our model achieves an AUROC of 0.966 that is also higher than other state-of-the-art methods. Moreover, we analyzed the attention weights generated by BERT to identify a number of nucleotide distributions that are closely associated with 5mC modifications. To facilitate the use of our model, we built a webserver which can be freely accessed at: http://5mc-pred.zhulab.org.cn.

MSTL-Kace: Prediction of Prokaryotic Lysine Acetylation Sites Based on Multistage Transfer Learning Strategy.

As one of the most important post-translational modifications (PTM), lysine acetylation (Kace) plays an important role in various biological activities. Traditional experimental methods for identifying Kace sites are inefficient and expensive. Instead, several machine learning methods have been developed for Kace site prediction, and hand-crafted features have been used to encode the protein sequences. However, there are still two challenges: the complex biological information may be under-represented by these manmade features and the small sample issue of some species needs to be addressed. We propose a novel model, MSTL-Kace, which was developed based on transfer learning strategy with pretrained bidirectional encoder representations from transformers (BERT) model. In this model, the high-level embeddings were extracted from species-specific BERT models, and a two-stage fine-tuning strategy was used to deal with small sample issue. Specifically, a domain-specific BERT model was pretrained using all of the sequences in our data sets, which was then fine-tuned, or two-stage fine-tuned based on the training data set of each species to obtain the species-specific BERT models. Afterward, the embeddings of residues were extracted from the fine-tuned model and fed to the different downstream learning algorithms. After comparison, the best model for the six prokaryotic species was built by using a random forest. The results for the independent test sets show that our model outperforms the state-of-the-art methods on all six species. The source codes and data for MSTL-Kace are available at https://github.com/leo97king/MSTL-Kace.

Magnetic Resonance Imaging Biomarkers of Punding in Parkinson's Disease.

Punding is a rare condition triggered by dopaminergic therapy in Parkinson's disease (PD), characterized by a complex, excessive, repetitive, and purposeless abnormal movement, and its pathogenesis remains unclear. We aimed to assess the brain structure alterations related to punding by using multipametric magnetic resonance imaging (MRI). Thirty-eight PD patients (19 with punding and 19 without punding) from the Parkinson's Progression Marker Initiative (PPMI) were included in this study. Cortical thickness was assessed with FreeSurfer, and the integrity of white matter fiber tracts and network topologies were analyzed by using FMRIB Software Library (FSL) and Pipeline for Analyzing braiN Diffusion imAges (PANDA). PD patients with punding showed a higher apathy score and more severe cortical atrophy in the left superior parietal, right inferior parietal, and right superior frontal gyrus, and worse integrity of the right cingulum cingulate tract compared to those without punding. On the other hand, no significant difference in structural network topologies was detected between the two groups. These data suggest that the specific area of destruction may be an MRI biomarker of punding risk, and these findings may have important implications for understanding the neural mechanisms of punding in PD.