Computational Insights into SARS-CoV-2 Main Protease Mutations and Nirmatrelvir Efficacy: The Effects of P132H and P132H-A173V.

Nirmatrelvir, a pivotal component of the oral antiviral Paxlovid for COVID-19, targets the SARS-CoV-2 main protease (Mpro) as a covalent inhibitor. Here, we employed combined computational methods to explore how the prevalent Omicron variant mutation P132H, alone and in combination with A173V (P132H-A173V), affects nirmatrelvir's efficacy. Our findings suggest that P132H enhances the noncovalent binding affinity of Mpro for nirmatrelvir, whereas P132H-A173V diminishes it. Although both mutants catalyze the rate-limiting step more efficiently than the wild-type (WT) Mpro, P132H slows the overall rate of covalent bond formation, whereas P132H-A173V accelerates it. Comprehensive analysis of noncovalent and covalent contributions to the overall binding free energy of the covalent complex suggests that P132H likely enhances Mpro sensitivity to nirmatrelvir, while P132H-A173V may confer resistance. Per-residue decompositions of the binding and activation free energies pinpoint key residues that significantly affect the binding affinity and reaction rates, revealing how the mutations modulate these effects. The mutation-induced conformational perturbations alter drug-protein local contact intensities and the electrostatic preorganization of the protein, affecting noncovalent binding affinity and the stability of key reaction states, respectively. Our findings inform the mechanisms of nirmatrelvir resistance and sensitivity, facilitating improved drug design and the detection of resistant strains.

[Application of micro-computed tomography (µCT)in quantifying xylem vessels of broadleaved trees]. / 计算机显微断层扫描技术(µCT)åœ¨é‡åŒ–é˜”å¶æ ‘ç§å¯¼ç®¡ä¸­çš„åº”ç”¨.

Quantitative analysis of vessel characteristics at the cellular scale is of great significance for understan-ding plant adaptation strategies to environment. The direct grinding combined with stereo-microscope imaging is one of the main approaches to examine the anatomical structure of xylem (conifer tracheid and hardwood vessel) wood structure, which inevitably damages xylem cells, hindering the accurate understanding of anatomical structures. In this study, we applied X-ray micro-computed tomography (µCT) and stereo-microscope technology to quantitatively measure the diameter and area of vessels of seven Canadian broadleaved tree species (Acer saccharum, Betula papyrifera, Fraxinus americana, Ostrya virginiana, Populus grandidentata, Quercus rubra, and Carya cordiformis). We fitted the results by linear model and tested the feasibility of µCT technology in quantifying the vessel size of broadleaved species. We found that the results of the two methods for measuring vessel size were highly similar (R2=0.98). The goodness of fit of the vessel diameter results measured by the two methods for the ring-porous wood species (C. cordiformis, R2=0.98; F. americana, R2=0.96; Q. rubra, R2=0.99) was higher than that of the diffuse-porous wood species (B. papyrifera, R2=0.88; O. virginiana, R2=0.73; A. saccharum, R2=0.68; P. grandiden-tata, R2=0.88). The goodness of fit of small vessels (diameter≤200 µm, R2=0.94) measured by the two methods was higher than that of large vessels (diameter>200 µm, R2=0.92). Thus, the µCT technique provided a new non-destructive detection method for quantifying xylem vessels of broadleaved tree species.

Trends in temporal and spatial changes of Japanese encephalitis in Chinese mainland, 2004-2019: A population-based surveillance study.

BACKGROUND: Japanese encephalitis (JE) is a serious health concern in China, with approximately 80 % of global infections occurring in China. To develop effective prevention and control strategies, this study explored the epidemiological characteristics of JE in China based on spatiotemporal data, to understand the patterns and trends of JE incidence in different regions and time periods. METHOD: The incidence and mortality rates of JE were extracted from the Public Health Data Center, the official website of the National Health Commission of the People's Republic of China, and the National Notifiable Infectious Disease Surveillance System from 2004 to 2019. Joinpoint regression was applied to examine the spatiotemporal patterns and annual percentage change in incidence and mortality of the JE. RESULTS: From 2004 to 2019, a total of 43,569 cases of JE were diagnosed, including 2081 deaths. The annual incidence rate of JE decreased from 0.4171/100,000 in 2004 to 0.0298/100,000 in 2019, with an annual percentage change (APC) of -13.5 % (P < 0.001). The annual mortality rate of JE showed three stages of change, with inflection points in 2006 and 2014. The incidence and mortality rates of JE have declined in all provinces of China, and more cases were reported in 0-14 years of age, accounting for nearly 80 % of all patients. CONCLUSIONS: The morbidity and mortality rates of JE in China are generally on a downward trend, and emphasis should be placed on strengthening disease surveillance in special areas and populations, popularizing vaccination, and increasing publicity.

A Deep Learning Approach to Classify Fabry Cardiomyopathy from Hypertrophic Cardiomyopathy Using Cine Imaging on Cardiac Magnetic Resonance.

A challenge in accurately identifying and classifying left ventricular hypertrophy (LVH) is distinguishing it from hypertrophic cardiomyopathy (HCM) and Fabry disease. The reliance on imaging techniques often requires the expertise of multiple specialists, including cardiologists, radiologists, and geneticists. This variability in the interpretation and classification of LVH leads to inconsistent diagnoses. LVH, HCM, and Fabry cardiomyopathy can be differentiated using T1 mapping on cardiac magnetic resonance imaging (MRI). However, differentiation between HCM and Fabry cardiomyopathy using echocardiography or MRI cine images is challenging for cardiologists. Our proposed system named the MRI short-axis view left ventricular hypertrophy classifier (MSLVHC) is a high-accuracy standardized imaging classification model developed using AI and trained on MRI short-axis (SAX) view cine images to distinguish between HCM and Fabry disease. The model achieved impressive performance, with an F1-score of 0.846, an accuracy of 0.909, and an AUC of 0.914 when tested on the Taipei Veterans General Hospital (TVGH) dataset. Additionally, a single-blinding study and external testing using data from the Taichung Veterans General Hospital (TCVGH) demonstrated the reliability and effectiveness of the model, achieving an F1-score of 0.727, an accuracy of 0.806, and an AUC of 0.918, demonstrating the model's reliability and usefulness. This AI model holds promise as a valuable tool for assisting specialists in diagnosing LVH diseases.

Construction and validation of a risk-prediction model for chemotherapy-related cognitive impairment in patients with breast cancer.

PURPOSE: To identify risk factors of chemotherapy-related cognitive impairment (CRCI) and construct and validate a visual prediction model of such for patients with breast cancer. METHODS: A multicenter, descriptive, and cross-sectional design was adopted. Data were collected from ten public tertiary hospitals in China. Cognitive function was assessed by using Functional Assessment of Cancer Therapy-cognitive function. Socio-demographic, clinical, psychological, and physical indicators were also assessed. The logistic prediction model was constructed by fivefold cross-validation. Then, a nomogram was utilized to visualize the prediction model, which was also evaluated via discrimination, calibration, and decision curve analysis. RESULTS: A total of 71 breast cancer patients had CRCI with a prevalence of 9.58%. This visual prediction model was constructed based on education background, exercise frequency, chemotherapy times, and fatigue and demonstrated good discrimination, with an area under the receiver operating characteristic curve of 0.882. The calibration curve indicated good agreement between experimental and projected values, and the decision curve proved good clinical applicability. CONCLUSION: Education background, exercise frequency, chemotherapy times, and fatigue were associated with high incidence of CRCI. The prediction model exhibits superior performance and has promise as a useful instrument for assessing the likelihood of CRCI in breast cancer patients. IMPLICATIONS FOR CANCER SURVIVORS: Our findings could provide breast cancer survivors with risk screening based on CRCI predictors to implement prevention and early intervention, and help patients integrate into society and achieve comprehensive recovery.

A proximity labeling-based orthogonal trap strategy identifies HDAC8 promotes cell motility by modulating cortactin acetylation.

It is a challenge for the traditional affinity methods to capture transient interactions of enzyme-post-translational modification (PTM) substrates in vivo. Herein we presented a strategy termed proximity labeling-based orthogonal trap approach (ProLORT), relying upon APEX2-catalysed proximity labeling and an orthogonal trap pipeline as well as quantitative proteomics to directly investigate the transient interactome of enzyme-PTM substrates in living cells. As a proof of concept, ProLORT allows for robust evaluation of a known HDAC8 substrate, histone H3K9ac. By leveraging this approach, we identified numerous of putative acetylated proteins targeted by HDAC8, and further confirmed CTTN as a bona fide substrate in vivo. Next, we demonstrated that HDAC8 facilitates cell motility via deacetylation of CTTN at lysine 144 that attenuates its interaction with F-actin, expanding the underlying regulatory mechanisms of HDAC8. We developed a general strategy to profile the transient enzyme-substrate interactions mediated by PTMs, providing a powerful tool for identifying the spatiotemporal PTM-network regulated by enzymes in living cells.

The long-term outcome of chronic thromboembolic pulmonary hypertension: Pulmonary endarterectomy and balloon pulmonary angioplasty.

BACKGROUND: The long-term outcome on patients with chronic thromboembolic pulmonary hypertension (CTEPH) has not been ideal after standard medical treatment. However, good outcome for patients with CTEPH after interventions such as pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) has been reported recently. The aim of this study was to evaluate the impact of PEA or BPA on long-term outcomes for CTEPH patients in Han-Chinese population. METHODS: This was a multicenter, prospective case-control study. Patients with CTEPH were enrolled between January, 2018 and March, 2020. They were divided into two groups, including intervention (PEA or BPA) and conservative groups. The followed-up period was 26 months after treatment. The endpoints were all-cause mortality and CTEPH mortality. RESULTS: A total of 129 patients were enrolled and assigned to receive PEA/BPA (N = 73), or conservative therapy (N = 56). Overall, the 26-month survival rate of all-cause mortality was significantly higher in intervention group compared to that in conservative group (95.89% vs 80.36%; log-rank p = 0.0164). The similar trend was observed in the 26-month survival rate of CTEPH mortality (97.26% vs 85.71%; log-rank p = 0.0355). Regarding Cox proportional-hazard regression analysis, the hazard ratios (HRs) on patients with CTEPH receiving intervention in the outcome of all-cause mortality and CTEPH mortality were statistically significant (HR = 0.07 and p = 0.0141 in all-cause mortality; HR = 0.11 and p = 0.0461 in CTEPH mortality). CONCLUSION: This multicenter prospective case-control study demonstrated that intervention such as PEA and BPA increased the long-term survival rate for patient with CTEPH significantly. Intervention was an independent factor in long-term outcome for patients with CTEPH, including all-cause mortality and CTEPH mortality.

Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the APP/PS1 Alzheimer's disease mouse model by regulating the expression of APP secretases.

BACKGROUND: Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. METHODS: A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test. RESULTS: Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aß deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. CONCLUSIONS: In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD.

Effects of a 12-week exercise-based intervention on weight management in overweight or obese breast cancer survivors: a randomized controlled trial.

PURPOSE: Breast cancer survivors face dual challenges: long-term sequelae of treatment and the risk of recurrent disease. Furthermore, obesity and a sedentary lifestyle can complicate both challenges. We aimed to assess the effect of a 12-week exercise-based weight-management program in overweight/obese breast cancer survivors. METHODS: A two-arm, single-blinded, randomized controlled trial was conducted among 60 overweight/obese, stage 0-III breast cancer survivors. During the 12-week program, the intervention group received weekly information support, fortnightly exercise prescriptions, including aerobic and resistance exercises to perform at home, and one dietary instruction. The control group received information support about weight management and exercise. Weight, body composition, and physical fitness data were collected at baseline, postintervention, and the 3-month follow-up. RESULTS: The intervention group showed significant improvements in body weight and all adiposity indices, including body mass index, waist circumference, and %body fat, in comparison with baseline (P < 0.001) and the control group (P < 0.05). Both groups showed no significant changes in fat-free mass during the 6-month period (P > 0.05). International Physical Activity Questionnaire scores and left grip strength increased significantly in the intervention group in comparison with the baseline (P < 0.01) and the control group (P < 0.05). Right grip strength, lower-body strength, and aerobic endurance showed no significant intergroup differences (P > 0.05). CONCLUSIONS: A combination of exercise prescription and weight-loss interventions yielded clinically meaningful weight loss in overweight/obese breast cancer survivors. These findings may facilitate the incorporation of home-based exercise and weight management into breast cancer treatment and survivorship care.

Source term estimation for continuous plume dispersion in Fusion Field Trial-07: Bayesian inference probability adjoint inverse method.

In scenarios involving sudden releases of unidentified gases or concealed pollution emergencies, source control emerges as a critical procedure to safeguard residential air quality. Appropriate inverse source tracking methodology depending on diverse measurement data could be utilized to promptly identify pollutant source parameters. In this study, source term estimation (STE) method, i.e., jointly combining probability adjoint method with the Bayesian inference method, has been proposed. General form of the pollutant inverse transport equation was firstly established. Subsequently, the pollution source information, assumed from single continuous point releases during Fusion Field Trials 2007 under an unsteady wind field, was identified using the Bayesian inference probability adjoint inverse method. Metropolis-Hastings Markov Chain Monte Carlo (MH-MCMC) and Differential Evolution Markov Chain Monte Carlo (DE-MCMC) were then compared as sampling methods for Bayesian inference. Results indicated that the DE-MCMC algorithm has superior convergence and could present higher accuracy of pollutant source information than that of MH-MCMC algorithm, particularly for highly nonlinear and multi-modal distribution systems. Furthermore, the integration of Union standard Adjoint Location Probability (UALP) as prior information into the Bayesian inference probability adjoint inverse method effectively narrowed the sampling range, enhancing both the accuracy and robustness of the proposed approach. Finally, the impact of the covariance matrix on the inverse identification accuracy was explored. Overall, this research has provided insights into the future applicability of this Bayesian inference inversion technique for point source identification.

Association of sugar sweetened beverage consumption with insomnia and depressive symptoms among first grade middle school students from Yunnan Province / 中国学校卫生

Objective@#To investigate the association of sugar sweetened beverage (SSB) consumption with insomnia and depressive symptoms among first grade middle school students from Yunnan Province, so as to provide evidence to guide interventions for the treatment of these symptoms in this population.@*Methods@#From October to December 2022, 8 500 firstgrade middle school students from 11 counties in Yunnan Province were selected by cluster random sampling. Depressive symptoms, SSB consumption, and insomnia symptoms among students were evaluated by the Child Depression Scale (CDI), dietary frequency questionnaire, and Insomnia Severity Index (ISI). A Logistic regression model was employed to analyze the relationship between SSB consumption, insomnia, depressive symptoms, and their interaction effects among students.@*Results@#The detection rate of depressive symptoms was 28.3%, and having insomnia symptoms ( OR=6.07, 95%CI =5.46-6.75), consuming carbonated beverages ( OR=1.20, 95%CI =1.08-1.34), tea ( OR=1.13, 95%CI =1.02-1.25), energy drinks ( OR=1.36, 95%CI =1.23-1.50), and other beverages ( OR=1.32, 95%CI =1.19-1.45) were positively correlated with depressive symptoms among first grade middle school students ( P < 0.05). Carbonated beverages (additive effect: OR=2.96, 95%CI =2.72-3.22, multiplicative effect: OR=4.75, 95%CI =4.25- 5.32 ), fruit drinks (additive effect: OR=2.61, 95%CI =2.40-2.82; multiplicative effect: OR=4.43, 95%CI =3.94-4.97), tea (additive effect: OR=2.70, 95%CI =2.47-2.89; multiplicative effect: OR=4.34, 95%CI =3.86-4.89), energy drinks (additive effect: OR=2.82, 95%CI =2.61-3.05; multiplicative effect: OR=4.48, 95%CI =3.92-5.12), sweetened milk (additive effect: OR= 2.73, 95%CI =2.06-2.96; multiplicative effect: OR=4.61, 95%CI =4.12-5.17) and other beverages (additive effect: OR= 2.73 , 95%CI =2.53-2.95; multiplicative effect: OR=4.56, 95%CI =4.00-5.20) had both additive and multiplicative effects with insomnia, and increased the risk of depressive symptoms in first grade middle school students ( P <0.01).@*Conclusions@#The interaction between the consumption of SSB and insomnia symptoms may increase the risk of depressive symptoms among first grade middle school students in Yunnan Province. It is necessary to advocate middle school students to reduce SSB intake, in order to decrease the occurrence of depressive symptoms among this population.

Association between latent classes of dietary patterns and depressive symptoms among firstgrade students from multi ethnic middle schools in Yunnan Province / 中国学校卫生

Objective@#To determine the latent class of dietary patterns and their association with depressive symptoms among first grade students from multi ethnic middle schools in Yunnan Province, so as to provide a reference basis for promoting mental health among border middle school students.@*Methods@#A cluster random sampling involving 8 500 first grade middle school students from 11 counties in Yunnan Province was conducted by a questionnaire survey between October to December 2022. The Children s Depression Inventory (CDI) was used to assess the depressive symptoms and the Food Frequency Questionnaire was used to collect eating behavior data. The latent profile analysis model was used to fit the latent class of dietary patterns among students. The association between the dietary pattern latent class and depressive symptoms was analyzed by Logistic regression.@*Results@#The depressive symptom detection rate among firstgrade middle school students was 28.3%. Prevalence of depressive symptom in girls (30.9%) was higher than boys (25.5%) with a statistically significant difference ( χ 2=29.83, P <0.01). The dietary patterns among first grade middle school students were classified into four latent classes, as follows:class 1 (low consumption of all dietary components), class 2 (high consumption of fruit, milk and dairy products), class 3 (high consumption of vegetables and meat, and low consumption of processed foods) and class 4 (low consumption of milk, dairy products and eggs, and high consumption of processed foods). After adjusting for confounding variables, the class 3 dietary pattern was negatively correlated with depressive symptoms ( OR=0.62, 95%CI =0.52-0.74) and the class 4 dietary pattern was positively correlated with depressive symptoms ( OR= 1.28 , 95%CI =1.05-1.57) ( P <0.05), compared with the class 1 dietary pattern.@*Conclusions@#Multi ethnic first grade middle school students in Yunnan Province follow various dietary patterns. Unhealthy dietary patterns increase the risk of depressive symptoms. The dietary patterns of multi ethnic middle school students in Yunnan Province should be adjusted to promote the establishment of healthy dietary patterns and reduce the risk of depression symptoms in middle school students.

Decision tree model of depressive symptoms among first grade students from multi ethnic middle schools in Yunnan Province / 中国学校卫生

Objective@#To understand the occurrence and predictive factors of depressive symptoms among multi ethnic middle school students in Yunnan Province, so as to provide a referential framework for schools to carry out targeted mental health education.@*Methods@#From October to December 2022, 8 500 first grade students from 23 middle schools were selected from 11 minority areas in Yunnan Province by cluster random sampling method. Demographic information and data relating to the students lifestyles were collected by questionnaire, and the Children s Depression Inventory (CDI) was used to evaluate depressive symptoms. Chi square test was performed to compare differences in the detection rate of depressive symptoms among first grade middle school students for univariate analysis. A decision tree model of depressive symptoms in middle school students was established by using the Chi squared automatic interaction detector (CHAID).@*Results@#The detection rate of depressive symptoms among first grade students from multi ethnic middle schools in Yunnan Province was 28.26%. The decision tree model of depressive symptoms was academic stress ( χ 2=469.08) at the first level, breakfast behaviors (low/moderate academic stress: χ 2=155.49; severe academic stress: χ 2=105.24) at the second level, and the number of close friends (low/moderate academic stress and consuming breakfast 0- 2 days weekly: χ 2=23.15; low/moderate academic stress and consuming breakfast 3-4 days weekly: χ 2=14.99; severe academic stress and consuming breakfast 0-2 days weekly: χ 2=29.26; severe academic stress and consuming breakfast 3-4 days weekly: χ 2=20.15), ethnicity ( χ 2=78.22) and drinking ( χ 2=50.36) at the third level ( P <0.01).@*Conclusions@#The study identifies academic stress, breakfast behaviors, number of close friends, drinking and ethnicity as predictive factors of depressive symptoms among multi ethnic middle school students in Yunnan Province. Schools should develop targeted strategies for preventing and managing depressive symptoms in middle school students, so as to reduce their occurrence.

Independent risk factors for depression in older adult patients receiving peritoneal dialysis for chronic kidney disease.

BACKGROUND: According to the trend of global population aging, the proportion of elderly patients with chronic kidney disease (CKD) is expected to increase. However, there are more than 20 million people in China with decompensated kidney function, of which 19.25% are elderly people. Therefore, special attention should be paid to the education years, sleep quality, anxiety status, comorbidities with diabetes, cardiovascular disease (CVD), and anemia as independent risk factors for depression in elderly CKD patients. This study explores the clinical mana-gement of elderly CKD patients that should address these risk factors to prevent depression and improve their prognosis. AIM: To investigate depression risk factors in older patients receiving peritoneal dialysis, aiding future prevention of depression in these patients. METHODS: This retrospective study included a primary study population of 170 patients with CKD who received peritoneal dialysis from January 2020 to December 2022. We assessed the patients' mental status using the Beck Depression Inventory Score-II (BDI-II), Self-Rating Anxiety Scale (SAS), Anxiety Inventory Score, and the Pittsburgh Sleep Quality Index (PSQI). Logistic regression was employed to identify depression independent risk factors among these patients. RESULTS: The non-depressed group had a significantly longer education period than the depressed group (P < 0.05). The depressed group exhibited significantly higher mental status scores than the non-depressed group (P < 0.001). Patients with diabetes mellitus (DM) or CVD had a higher probability of developing dep-ression. Patients with depression had significantly lower hemoglobin and albumin levels than patients without depression (P < 0.05). Spearman correlation analysis of BDI-II scale scores, measuring depression, indicated positive correlations with BDI-II and SAS scores as risk factors for depression in patients with CKD. In contrast, years of education, hemoglobin levels, and peritoneal Kt/V were negatively correlated, serving as protective factors against depression. An analysis of variance for influences with significant differences in the univariate analysis revealed that years of schooling, BDI-II, SAS, PSQI, DM, CVD, and hemoglobin levels independently influenced depression in older patients with CKD. CONCLUSION: Education, BDI-II, SAS, PSQI, DM, and CVD are independent risk factors for depression in older patients with CKD; therefore, post-treatment psychological monitoring of high-risk patients is crucial to prevent depression.

A nigroincertal projection mediates aversion and enhances coping responses to potential threat.

Recent studies have shown that the non-DA neurons in the ventral tegmental area (VTA) and substantia nigra (SN) not only modulate motivational behaviors but also regulate defensive behaviors. While zona incerta (ZI) is a threat-responsive substrate and receives innervations from the ventral midbrain, the function of the ventral midbrain-to-ZI connection remains poorly defined. Here, we demonstrate that the ZI receives heterogenous innervations from the ventral midbrain. By utilizing a retrograde AAV preferentially labeling non-DA neurons in the ventral midbrain, we found that ZI-projecting non-DA cells in the ventral midbrain are activated by restraint stress. We focused on the SN and found that SN-to-ZI GABAergic input is engaged by a predatory odor. Sustained pan-neuronal SN-to-ZI activation results in aversion and enhances defensive behaviors, likely through a disinhibition mechanism to recruit downstream brain regions that regulate defensive behaviors. Collectively, our results reveal a novel role of nigroincertal projection in mediating negative valence and regulating defensive behaviors.

Ferritinophagy-mediated apoptosis and paraptosis induction involved MAPK and PI3K/AKT pathway in mechanism of an iron chelator.

Melanoma cells were more resistant to ferroptosis with still poor therapy outcomes. Sensitizing melanoma cell to the ferroptosis inducer was a crucial strategy for treatment of melanoma. In the present study, 2,2'-di-pyridylketone hydrazone dithiocarbamate s-butyric acid (DpdtbA) displayed superior inhibitory activity than ferroptosis inducer Erastin in melanoma cells, which prompt us to explore the underlying mechanism. The analyses from flow cytometry and Western blot showed that the growth inhibition of DpdtbA against SK-MEL-28 and A375 cells involved apoptosis induction and G1 phase arrest. Surprisingly, the cytoplasmic vacuoles were found upon the treatment; transmission electron microscopy and endoplasmic reticulum (ER) staining revealed that the cytoplasmic vacuoles were in ER; while down-regulation of alix and requirement of protein synthesis suggested there was an occurrence of paraptosis. However, both NAC and 3-MA could significantly attenuate the cytoplasmic vacuolization and growth inhibition, hinting that both ROS and autophagy involved the paraptosis induction. The additional evidence revealed that there was an occurrence of continuous ferritinophagy, which was responsible for the ROS production. Downregulation of NCOA4 clearly attenuated the apoptosis and paraptosis induction. In addition, activation of MAPK involved regulation of paraptosis, but only ERK and JNK had role in the formation of cytoplasmic vacuoles and growth inhibition. Furthermore, a ROS dependent regulation of PI3K/AKT pathway was also involved. Taken together, our result firstly demonstrated that a continuous ferritinophagy contributed to the apoptosis and paraptosis induction, highlighting that the lysosomal labile iron pool had a crucial role in control of melanoma cell fate.

Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell RNA sequencing of rat dorsal root ganglion neurons.

BACKGROUND: Severe peripheral nerve injury (PNI) often leads to significant movement disorders and intractable pain. Therefore, promoting nerve regeneration while avoiding neuropathic pain is crucial for the clinical treatment of PNI patients. However, established animal models for peripheral neuropathy fail to accurately recapitulate the clinical features of PNI. Additionally, researchers usually investigate neuropathic pain and axonal regeneration separately, leaving the intrinsic relationship between the development of neuropathic pain and nerve regeneration after PNI unclear. To explore the underlying connections between pain and regeneration after PNI and provide potential molecular targets, we performed single-cell RNA sequencing and functional verification in an established rat model, allowing simultaneous study of the neuropathic pain and axonal regeneration after PNI. RESULTS: First, a novel rat model named spared nerve crush (SNC) was created. In this model, two branches of the sciatic nerve were crushed, but the epineurium remained unsevered. This model successfully recapitulated both neuropathic pain and axonal regeneration after PNI, allowing for the study of the intrinsic link between these two crucial biological processes. Dorsal root ganglions (DRGs) from SNC and naïve rats at various time points after SNC were collected for single-cell RNA sequencing (scRNA-seq). After matching all scRNA-seq data to the 7 known DRG types, we discovered that the PEP1 and PEP3 DRG neuron subtypes increased in crushed and uncrushed DRG separately after SNC. Using experimental design scRNA-seq processing (EDSSP), we identified Adcyap1 as a potential gene contributing to both pain and nerve regeneration. Indeed, repeated intrathecal administration of PACAP38 mitigated pain and facilitated axonal regeneration, while Adcyap1 siRNA or PACAP6-38, an antagonist of PAC1R (a receptor of PACAP38) led to both mechanical hyperalgesia and delayed DRG axon regeneration in SNC rats. Moreover, these effects can be reversed by repeated intrathecal administration of PACAP38 in the acute phase but not the late phase after PNI, resulting in alleviated pain and promoted axonal regeneration. CONCLUSIONS: Our study reveals that Adcyap1 is an intrinsic protective factor linking neuropathic pain and axonal regeneration following PNI. This finding provides new potential targets and strategies for early therapeutic intervention of PNI.

Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil.

Epilepsy is a common neurological disorder that is primarily treated with antiseizure medications (ASMs). Although dozens of ASMs are available in the clinic, approximately 30% of epileptic patients have medically refractory seizures; other limitations in most traditional ASMs include poor tolerability and drug-drug interactions. Therefore, there is an urgent need to develop alternative ASMs. Levetiracetam (LEV) is a first-line ASM that is well tolerated, has promising efficacy, and has little drug-drug interaction. Although it is widely accepted that LEV acts through a unique therapeutic target synaptic vesicle protein (SV) 2A, the molecular basis of its action remains unknown. Even so, the next-generation SV2A ligands against epilepsy based on the structure of LEV have achieved clinical success. This review highlights the research and development (R&D) process of LEV and its analogs, brivaracetam and padsevonil, to provide ideas and experience for the R&D of novel ASMs.

Temporal and spatial variations of disinfection by-products in South Taihu's drinking water, Zhejiang Province, China.

Some disinfection by-products (DBPs) in drinking water present a potential safety concern. This study focuses on the elements influencing DBPs formation. A total of 120 water samples were collected from 10 different drinking water facilities spanning 5 counties within Huzhou, Zhejiang Province, China. Concentrations of trihalomethanes (THMs) and haloacetic acids (HAAs) were observed to be 14.5 and 27.4 µg/L, respectively, constituting 34 and 64% of the total DBPs. Seasonal fluctuations demonstrated that HAAs, THMs, halonitromethanes (HNMs), and haloacetonitriles (HANs) followed a similar pattern with higher levels in summer or autumn compared to spring. Importantly, the concentrations of HAAs and THMs were markedly higher in Taihu-sourced water compared to other sources. Geographically, Nanxun exhibited the highest levels of total DBPs, HAAs, and THMs, while Deqing and Changxing demonstrated significantly lower levels. Correlation studies between water quality parameters and DBPs revealed that factors such as chloride content, temperature, and residual chlorine positively influenced DBPs formation, whereas turbidity negatively affected it. Principal component analysis suggested similar formation processes for HANs, haloketones (HKs), HNMs, and THMs. Factors such as temperature, chemical oxygen demand (COD), and residual chlorine were identified as significant contributors to the prevalence of HAAs.

Electron density effect of aromatic carboxylic acids in naphthalenediimide-based coordination polymers: from thermal electron transfer and charge transfer to photoinduced electron transfer.

Various naphthalenediimide (NDI) based electron donor-acceptor coordination polymers (D-A CPs) have been constructed and used to explore charge transfer (CT) and electron transfer (ET) behaviors. Up to now, significant progress has been made in the interface contact and electron donor-acceptor ability matching mechanism, while the electronic density effect of the electron donors on the CT and ET behaviors is still not known. Herein, two NDI-based D-A CPs, [Cd2(H2NDI)(IPA)2(H2O)2] (1) and [Cd2(H2NDI)(IPA-OH)2(H2O)2] (2), are constructed using an NDI-based ligand and two aromatic carboxylic acid ligands (H2NDI = 2,7-bis(3,5-dimethyl) dipyrazol-1,4,5,8-naphthalene tetracarboxydiimide, H2IPA = isophthalic acid; and H2IPA-OH = 5-hydroxyisophthalic acid). UV-vis and EPR spectroscopy and DFT calculations analyses reveal that the occurrence of themal electron transfer (TET) in 1 and 2 results from the HOMO of the IPA and IPA-OH lying higher than the LUMO of the NDI. Meanwhile, compared to 1, the UV-vis absorption spectrum of 2 exhibits a significant red shift, which suggests higher electron density of the donor and more electron transfer pathways are beneficial for the occurrence of intermolecular CT. After UV light irradiation, the comparison of the photochromic behavior of 1 and 2 confirms the negative effect of the stronger CT on photoinduced electron transfer (PET). The present study illustrates the delicate modulating effect of electron density on the CT and ET behaviors in D-A CPs.