Gene therapy for CNS disorders: modalities, delivery and translational challenges.

Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.

Multi-omics analysis reveals the potential pathogenesis and therapeutic targets of diabetic kidney disease.

Clinicians have long been interested in understanding the molecular basis of diabetic kidney disease (DKD)and its potential treatment targets. Its pathophysiology involves protein phosphorylation, one of the most recognizable post-transcriptional modifications, that can take part in many cellular functions and control different metabolic processes. In order to recognize the molecular and protein changes of DKD kidney, this study applied Tandem liquid chromatography-mass spectrometry (LC-MS/MS) and Next-Generation Sequencing, along with Tandem Mass Tags (TMT) labeling techniques to evaluate the mRNA, protein and modified phosphorylation sites between DKD mice and model ones. Based on Gene Ontology (GO) and KEGG pathway analyses of transcriptome and proteome, The molecular changes of DKD include accumulation of extracellular matrix, abnormally activated inflammatory microenvironment, oxidative stress and lipid metabolism disorders, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress has been emphasized as an important factor in DKD and progression to ESKD, which is directly related to podocyte injury, albuminuria and renal tubulointerstitial fibrosis. A histological study of phosphorylation further revealed that kinases were crucial. Three groups of studies have found that RAS signaling pathway, RAP1 signaling pathway, AMPK signaling pathway, PPAR signaling pathway and HIF-1 signaling pathway were crucial for the pathogenesis of DKD. Through this approach, it was discovered that targeting specific molecules, proteins, kinases and critical pathways could be a promising approach for treating DKD.

Comprehensive exploration of multi-modal and multi-branch imaging markers for autism diagnosis and interpretation: insights from an advanced deep learning model.

Autism spectrum disorder is a complex neurodevelopmental condition with diverse genetic and brain involvement. Despite magnetic resonance imaging advances, autism spectrum disorder diagnosis and understanding its neurogenetic factors remain challenging. We propose a dual-branch graph neural network that effectively extracts and fuses features from bimodalities, achieving 73.9% diagnostic accuracy. To explain the mechanism distinguishing autism spectrum disorder from healthy controls, we establish a perturbation model for brain imaging markers and perform a neuro-transcriptomic joint analysis using partial least squares regression and enrichment to identify potential genetic biomarkers. The perturbation model identifies brain imaging markers related to structural magnetic resonance imaging in the frontal, temporal, parietal, and occipital lobes, while functional magnetic resonance imaging markers primarily reside in the frontal, temporal, occipital lobes, and cerebellum. The neuro-transcriptomic joint analysis highlights genes associated with biological processes, such as "presynapse," "behavior," and "modulation of chemical synaptic transmission" in autism spectrum disorder's brain development. Different magnetic resonance imaging modalities offer complementary information for autism spectrum disorder diagnosis. Our dual-branch graph neural network achieves high accuracy and identifies abnormal brain regions and the neuro-transcriptomic analysis uncovers important genetic biomarkers. Overall, our study presents an effective approach for assisting in autism spectrum disorder diagnosis and identifying genetic biomarkers, showing potential for enhancing the diagnosis and treatment of this condition.

Enhanced group-level dorsolateral prefrontal cortex subregion parcellation through functional connectivity-based distance-constrained spectral clustering with application to autism spectrum disorder.

The dorsolateral prefrontal cortex (DLPFC) assumes a central role in cognitive and behavioral control, emerging as a crucial target region for interventions in autism spectrum disorder neuroregulation. Consequently, we endeavor to unravel the functional subregions within the DLPFC to shed light on the intricate functions of the brain. We introduce a distance-constrained spectral clustering (SC-DW) methodology that leverages functional connection to identify distinctive functional subregions within the DLPFC. Furthermore, we verify the relationship between the functional characteristics of these subregions and their clinical implications. Our methodology begins with principal component analysis to extract the salient features. Subsequently, we construct an adjacency matrix, which is constrained by the spatial properties of the brain, by linearly combining the distance matrix and a similarity matrix. The quality of spectral clustering is further optimized through multiple cluster evaluation coefficient. The results from SC-DW revealed four uniform and contiguous subregions within the bilateral DLPFC. Notably, we observe a substantial positive correlation between the functional characteristics of the third and fourth subregions in the left DLPFC with clinical manifestations. These findings underscore the unique insights offered by our proposed methodology in the realms of brain subregion delineation and therapeutic targeting.

Quantitatively predicting effects of exercise on pharmacokinetics of drugs using a physiologically based pharmacokinetic model.

Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow, decreasing glomerular filtration rate (GFR) and liver blood flow, thereby, altering absorption, distribution, metabolism and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g. muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. Pharmacokinetics of midazolam, quinidine, digoxin and lidocaine during exercise were predicted by a whole body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within 5th-95th percentiles of the simulations, and the estimated peak concentrations and area under the curve of drugs were also within 0.5-2.0 folds of observations. Sensitivity analysis showed that exercise intensity, exercise duration, medication time and alterations in physiological parameters significantly affected drug pharmacokinetics, and the net effect depending on drug characteristics and exercise conditions. In conclusion, pharmacokinetics of drugs during exercise could be quantitatively predicted using the developed WB-PBPK model and database of physiological parameters. Significance Statement This study simulated real-time changes of human physiological parameters during exercise in the WB-PBPK model and comprehensively investigated pharmacokinetic changes during exercise following oral and intravenous administration. Furthermore, the factors affecting pharmacokinetics during exercise were also revealed.

Dietary Quality and Diet-Related Factors Among Emerging Adults (18-23 y) in the United States Are a Cause for Concern: National Health and Nutrition Examination Survey 2015-2018.

BACKGROUND: Poor dietary quality is a risk factor for diet-related chronic disease and suboptimal nutritional patterns often begin early in the life course. Although the dietary intakes of young children, adolescents, and middle-aged and older adults are well established, much less is known about emerging adults, who represent a unique time point in life, as they are undergoing significant changes in food environments, autonomy, finances, and caregiver and parental involvement. OBJECTIVES: This study aimed to examine dietary quality, as assessed via the Healthy Eating Index (HEI), by demographic, socioeconomic, and health-related characteristics among emerging adults (18-23 y) in the United States who participated in the 2015-2018 National Health and Nutrition Examination Survey (NHANES). METHODS: NHANES data were collected via a household interview and 2 24-h dietary recalls (24HR). Usual dietary intakes from the 24HRs were approximated using the multivariate National Cancer Institute Method to compute mean HEI-2015 overall and component scores (range: 0-100; higher scores indicating higher dietary quality). RESULTS: Overall dietary quality among emerging adults (HEI-2015: 50.3 ± 1.3) was significantly lower than other adults (≥24 y) (HEI-2015: 56.3 ± 0.5; P < 0.0001) in the United States, with differences primarily driven by lower intakes of whole fruit, vegetables, and whole grains and higher intakes of sodium, refined grains, and saturated fat. Few differences in HEI-2015 scores were noted across population subgroups by sex, food security, family income, and food assistance program participation, except for added sugar; intakes of added sugar were significantly higher among women, food insecure, and food assistance program participants than those in their counterparts, respectively. CONCLUSIONS: Dietary quality is poor among emerging adults in the United States and persists across all population subgroups, suggesting a significant need for tailored public health interventions to improve dietary quality among this population. Future research investigating to what extent emerging adults prioritize healthful behaviors and exploring other indicators for identifying nutritionally vulnerable subgroups may be impactful for identifying disparities among this life stage.

Combined targeting of Hedgehog/GLI1 and Wnt/ß-catenin pathways in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. Challenges in its treatment include relapse, drug resistance, and a short survival period. The Hedgehog/GLI1 (Hh/GLI1) and Wnt/ß-catenin pathways are crucial in cancer cell proliferation, survival, and drug resistance, making them significant targets for anticancer research. This study aimed to assess the effectiveness of combining inhibitors for both pathways against MCL and investigate the underlying molecular mechanisms. The co-expression of key proteins from the Hh/GLI1 and Wnt/ß-catenin pathways was observed in MCL. Targeting the Hh/GLI1 pathway with the GLI1 inhibitor GANT61 and the Wnt/ß-catenin pathway with the CBP/ß-catenin transcription inhibitor ICG-001, dual-target therapy was demonstrated to synergistically suppressed the activity of MCL cells. This approach promoted MCL cell apoptosis, induced G0/G1 phase blockade, decreased the percentage of S-phase cells, and enhanced the sensitivity of MCL cells to the drugs adriamycin and ibrutinib. Both GANT61 and ICG-001 downregulated GLI1 and ß-catenin while upregulating GSK-3ß expression. The interaction between Hh/GLI1 and Wnt/ß-catenin pathways was mediated by GANT61-dependent Hh/GLI1 inhibition. Moreover, GLI1 knockdown combined with ICG-001 synergistically induced apoptosis and increased drug sensitivity of MCL cells to doxorubicin and ibrutinib. GANT61 attenuated the overexpression of ß-catenin and decreased the inhibition of GSK-3ß in MCL cells. Overall, the combined targeting of both the Hh/GLI1 and Wnt/ß-catenin pathways was more effective in suppressing proliferation, inducing G0/G1 cycle retardation, promoting apoptosis, and increasing drug sensitivity of MCL cells than mono treatments. These findings emphasize the potential of combinatorial therapy for treating MCL patients.

Anemia and testosterone deficiency risk: insights from NHANES data analysis and a Mendelian randomization analysis.

BACKGROUND: Previous research has shown that testosterone deficiency (TD) increases the risk of anemia, but it is unclear whether anemia affects testosterone levels. This study investigated the influence of anemia on testosterone levels. METHODS: Utilizing data from six NHANES cycles, including demographic, testosterone levels, and hemoglobin concentrations, we employed multivariable-adjusted logistic regression to investigate the relationship between anemia and testosterone levels. Moreover, a two-sample Mendelian randomization (MR) study employing genome-wide association study (GWAS) data examined the causal relationship. Kaplan-Meier survival estimation was used to compared the overall survival (OS) of anemic and nonanemic patients with low testosterone and normal testosterone levels. RESULTS: The inclusion of 21,786 participants (2318 with anemia and19,468 without anemia) revealed that nonanemic patients exhibited higher testosterone levels than did anemic patients (ß = 22.616, 95% CI: 3.873-41.359, p = 0.01807). MR analysis confirmed anemia as a cause of TD (OR = 1.045, 95% CI: 1.020-1.071, p < 0.001). Anemic males with low testosterone had reduced OS compared to those with normal levels (p < 0.001). CONCLUSIONS: Anemia emerged as a potential risk factor for TD, highlighting a bidirectional relationship between these conditions. Additional prospective investigations are essential for the validation and reinforcement of our findings.

Activation of D2-like dopamine receptors improves the neuronal network and cognitive function of PPT1KI mice.

Palmitoyl-protein thioesterase 1 (PPT1) is a lysosomal depalmitoylation enzyme that mediates protein posttranslational modifications. Loss-of-function mutation of PPT1 causes a failure of the lysosomal degradation of palmitoylated proteins and results in a congenital disease characterized by progressive neuronal degeneration referred to as infantile neuronal ceroid lipofuscinosis (INCL). A mouse knock-in model of PPT1 (PPT1-KI) was established by introducing the R151X mutation into exon 5 of the PPT1 gene, which exhibited INCL-like pathological lesions. We previously reported that hippocampal γ oscillations were impaired in PPT1 mice. Hippocampal γ oscillations can be enhanced by selective activation of the dopamine D4 receptor (DR4), a dopamine D2-like receptor. In this study, we investigated the changes in DR expression and the effects of dopamine and various DR agonists on neural network activity, cognition and motor function in PPT1KI mice. Cognition and motor defects were evaluated via Y-maze, novel object recognition and rotarod tests. Extracellular field potentials were elicited in hippocampal slices, and neuronal network oscillations in the gamma frequency band (γ oscillations) were induced by perfusion with kainic acid (200 nM). PPT1KI mice displayed progressive impairments in γ oscillations and hippocampus-related memory, as well as abnormal expression profiles of dopamine receptors with preserved expression of DR1 and 3, increased membrane expression of DR4 and decreased DR2 levels. The immunocytochemistry analysis revealed the colocalization of PPT1 with DR4 or DR2 in the soma and large dendrites of both WT and PPT1KI mice. Immunoprecipitation confirmed the interaction between PPT1 and DR4 or DR2. The impaired γ oscillations and cognitive functions were largely restored by the application of exogenous dopamine, the selective DR2 agonist quinpirole or the DR4 agonist A412997. Furthermore, the administration of A412997 (0.5 mg/kg, i.p.) significantly upregulated the activity of CaMKII in the hippocampus of 5-month-old PPT1KI mice. Collectively, these results suggest that the activation of D2-like dopamine receptors improves cognition and network activity in PPT1KI mice and that specific DR subunits may be potential targets for the intervention of neurodegenerative disorders, such as INCL.

Brain functional activity-based classification of autism spectrum disorder using an attention-based graph neural network combined with gene expression.

Autism spectrum disorder (ASD) is a complex brain neurodevelopmental disorder related to brain activity and genetics. Most of the ASD diagnostic models perform feature selection at the group level without considering individualized information. Evidence has shown the unique topology of the individual brain has a fundamental impact on brain diseases. Thus, a data-constructing method fusing individual topological information and a corresponding classification model is crucial in ASD diagnosis and biomarker discovery. In this work, we trained an attention-based graph neural network (GNN) to perform the ASD diagnosis with the fusion of graph data. The results achieved an accuracy of 79.78%. Moreover, we found the model paid high attention to brain regions mainly involved in the social-brain circuit, default-mode network, and sensory perception network. Furthermore, by analyzing the covariation between functional magnetic resonance imaging data and gene expression, current studies detected several ASD-related genes (i.e. MUTYH, AADAT, and MAP2), and further revealed their links to image biomarkers. Our work demonstrated that the ASD diagnostic framework based on graph data and attention-based GNN could be an effective tool for ASD diagnosis. The identified functional features with high attention values may serve as imaging biomarkers for ASD.

Classification of major depressive disorder using an attention-guided unified deep convolutional neural network and individual structural covariance network.

Major depressive disorder (MDD) is the second leading cause of disability worldwide. Currently, the structural magnetic resonance imaging-based MDD diagnosis models mainly utilize local grayscale information or morphological characteristics in a single site with small samples. Emerging evidence has demonstrated that different brain structures in different circuits have distinct developmental timing, but mature coordinately within the same functional circuit. Thus, establishing an attention-guided unified classification framework with deep learning and individual structural covariance networks in a large multisite dataset could facilitate developing an accurate diagnosis strategy. Our results showed that attention-guided classification could improve the classification accuracy from primary 75.1% to ultimate 76.54%. Furthermore, the discriminative features of regional covariance connectivities and local structural characteristics were found to be mainly located in prefrontal cortex, insula, superior temporal cortex, and cingulate cortex, which have been widely reported to be closely associated with depression. Our study demonstrated that our attention-guided unified deep learning framework may be an effective tool for MDD diagnosis. The identified covariance connectivities and structural features may serve as biomarkers for MDD.

Shared and distinct patterns of dynamic functional connectivity variability of thalamo-cortical circuit in bipolar depression and major depressive disorder.

Evidence has indicated abnormalities of thalamo-cortical functional connectivity (FC) in bipolar disorder during a depressive episode (BDD) and major depressive disorder (MDD). However, the dynamic FC (dFC) within this system is poorly understood. We explored the thalamo-cortical dFC pattern by dividing thalamus into 16 subregions and combining with a sliding-window approach. Correlation analysis was performed between altered dFC variability and clinical data. Classification analysis with a linear support vector machine model was conducted. Compared with healthy controls (HCs), both patients revealed increased dFC variability between thalamus subregions with hippocampus (HIP), angular gyrus and caudate, and only BDD showed increased dFC variability of the thalamus with superior frontal gyrus (SFG), HIP, insula, middle cingulate gyrus, and postcentral gyrus. Compared with MDD and HCs, only BDD exhibited enhanced dFC variability of the thalamus with SFG and superior temporal gyrus. Furthermore, the number of depressive episodes in MDD was significantly positively associated with altered dFC variability. Finally, the disrupted dFC variability could distinguish BDD from MDD with 83.44% classification accuracy. BDD and MDD shared common disrupted dFC variability in the thalamo-limbic and striatal-thalamic circuitries, whereas BDD exhibited more extensive and broader aberrant dFC variability, which may facilitate distinguish between these 2 mood disorders.

The association between shift work, shift work sleep disorders and premature ejaculation in male workers.

OBJECTIVE: Shift work and Shift Work Sleep Disorder (SWSD) are known to affect the secretion of several neurotransmitters and hormones associated with premature ejaculation (PE). However, their specific influence on the regulation of male ejaculation remains unclear. This study explores the relationship between shift work, SWSD, and PE. METHODS: From April to October 2023, a cross-sectional survey was conducted across five regions of China to explore the work schedules, sleep quality, and sexual function of male workers. Participants' sleep quality was evaluated using a validated SWSD questionnaire, and their erectile function and ejaculatory control were assessed with the International Inventory of Erectile Function (IIEF-5) scores and Premature Ejaculation Diagnostic Tool (PEDT) scores, respectively. Univariate and multivariate linear regression analyses were employed to identify risk factors associated with PE. Confounders were controlled using multiple regression models, and clinical prediction models were developed to predict PE onset and assess the contribution of risk factors. RESULTS: The study included 1239 eligible participants, comprising 840 non-shift workers and 399 shift workers (148 with SWSD and 251 without SWSD). Compared to non-shift working males, those involved in shift work (ß 1.58, 95% CI 0.75 - 2.42, p < 0.001) and those suffering from SWSD (ß 2.86, 95% CI 1.86 - 3.85, p < 0.001) they had significantly higher PEDT scores. Additionally, we identified daily sleep of less than six hours, depression, anxiety, diabetes, hyperlipidemia, frequent alcohol consumption (more than twice a week), and erectile dysfunction as risk factors for PE. The predictive model for PE demonstrated commendable efficacy. CONCLUSION: Both shift work and SWSD significantly increase the risk of premature ejaculation, with the risk magnifying in tandem with the duration of shift work. This study reveals the potential impact of shift work and SWSD on PE and provides new theoretical foundations for the risk assessment and prevention of this condition.

Zafirlukast ameliorates lipopolysaccharide and bleomycin-induced lung inflammation in mice.

Acute lung injury (ALI) is the result of damage to the capillary endothelia and the alveolar epithelial cell caused by various direct and indirect factors, leading to significant pulmonary interstitial and alveolar edema and acute hypoxic respiratory insufficiency. A subset of ALI cases progresses to irreversible pulmonary fibrosis, a condition with fatal implications. Zafirlukast is a leukotriene receptor antagonist licensed for asthma prevention and long-term treatment. This study demonstrated a significant improvement in lung tissue pathology and a reduction in inflammatory cell infiltration in models of lipopolysaccharide (LPS)-induced ALI and bleomycin (BLM)-induced lung inflammation following zafirlukast administration, both in vivo and in vitro. Moreover, zafirlukast was found to suppress the inflammatory response of alveolar epithelial cells in vitro and lung inflammation in vivo by reducing the activation of the TLR4/NF-κB/NLRP3 inflammasome pathway. In conclusion, zafirlukast relieved lung injury and the infiltration of inflammatory cells in the lung by regulating the TLR4/NF-κB/NLRP3 pathway.

Implications of neuromuscular electrical stimulation on gait ability, balance and kinematic parameters after stroke: a systematic review and meta-analysis.

INTRODUCTIN: Improper gait patterns, impaired balance and foot drop consistently plague stroke survivors, preventing them from walking independently and safely. Neuromuscular electrical stimulation (NMES) technology can help patients reactivate their muscles and regain motor coordination. This study aims to systematically review and summarize the evidence for the potential benefits of NMES on the improvement of gait patterns after stroke. EVIDENCE ACQUISITION: PubMed, Cochrane Library, Embase, Science Direct and Web of Science were systematically searched until April 2024, to identify randomized controlled trials with the following criteria: stroke survivors as participants; NMES as intervention; conventional rehabilitation as a comparator; and gait assessment, through scales or quantitative parameters, as outcome measures. EVIDENCE SYNTHESIS: 29 publications involving 1711 patients met the inclusion criteria. Meta-analysis showed no significant differences in Ten-meter walk test, Fugl-Meyer assessment lower extremity, Modified Ashworth Assessment and asymmetry between the NMES group and the control group. Besides, NMES was associated with changes in outcome indicators such as quantitative gait analysis speed [SMD = 0.53, 95% CI (0.20, 0.85), P = 0.001], cadence [SMD = 0.76, 95% CI (0.32, 1.20), P = 0.0008], affected side step length [SMD = 0.73, 95% CI (0.16, 1.31), P = 0.01], angle of ankle dorsiflexion [WMD = 1.57, 95% CI (0.80, 2.33), P < 0.0001], Six-Minute Walk Test [WMD = 14.83, 95% CI (13.55, 16.11), P<0.00001]. According to the PEDro scale, 21 (72.4%) studies were of high quality and 8 were of moderate quality (27.6%). CONCLUSIONS: Taken together, the review synthesis indicated that NMES might play a potential role in stroke-induced walking dysfunction. And NMES may be superior for survivors in the chronic phase than the acute and subacute phases, and the efficacy of short sessions received by patients was greater than that of those who participated in a longer session. Additionally, further comparisons of the effects of NMES with different types or stimulation frequencies may provide unexpected benefits.

Genome-wide chromatin accessibility landscape and dynamics of transcription factor networks during ovule and fiber development in cotton.

BACKGROUND: The development of cotton fiber is regulated by the orchestrated binding of regulatory proteins to cis-regulatory elements associated with developmental genes. The cis-trans regulatory dynamics occurred throughout the course of cotton fiber development are elusive. Here we generated genome-wide high-resolution DNase I hypersensitive sites (DHSs) maps to understand the regulatory mechanisms of cotton ovule and fiber development. RESULTS: We generated DNase I hypersensitive site (DHS) profiles from cotton ovules at 0 and 3 days post anthesis (DPA) and fibers at 8, 12, 15, and 18 DPA. We obtained a total of 1185 million reads and identified a total of 199,351 DHSs through ~ 30% unique mapping reads. It should be noted that more than half of DNase-seq reads mapped multiple genome locations and were not analyzed in order to achieve a high specificity of peak profile and to avoid bias from repetitive genomic regions. Distinct chromatin accessibilities were observed in the ovules (0 and 3 DPA) compared to the fiber elongation stages (8, 12, 15, and 18 DPA). Besides, the chromatin accessibility during ovules was particularly elevated in genomic regions enriched with transposable elements (TEs) and genes in TE-enriched regions were involved in ovule cell division. We analyzed cis-regulatory modules and revealed the influence of hormones on fiber development from the regulatory divergence of transcription factor (TF) motifs. Finally, we constructed a reliable regulatory network of TFs related to ovule and fiber development based on chromatin accessibility and gene co-expression network. From this network, we discovered a novel TF, WRKY46, which may shape fiber development by regulating the lignin content. CONCLUSIONS: Our results not only reveal the contribution of TEs in fiber development, but also predict and validate the TFs related to fiber development, which will benefit the research of cotton fiber molecular breeding.

Mechanistic insights into temperature-driven retention and speciation changes of heavy metals (HMs) in ash residues from Co-combustion of refuse-derived fuel (RDF) and red mud.

Red mud is a promising candidate for promoting the incineration of Refuse Derived Fuel (RDF) and stabilizing the resulting incineration ash. The combustion conditions, notably temperature, significantly steers the migration and transformation of harmful metal components during combustion, and ultimately affect their retention and speciation in the ash residue. The study attempted to investigate the effect of co-combustion temperature on the enrichment and stability of Cr, Ni, Cu, Zn, Cd and Pb within bottom ashes, and to reveal the underlined promotion mechanism of red mud addition. As temperature increased, red mud's active components formed a robust matrix, helping the formation, melting, and vitrification of silicates and aluminosilicates in the bottom ashes. The process significantly contributed to the encapsulation and stabilization of heavy metals such as Ni, Cu, Zn, Cd, and Pb, with their residual fractions ascending to 71.37%, 55.75%, 74.78%, 84.24%, and 93.54%, respectively. Conversely, high temperatures led to an increase in the proportion of Cr in the extremely unstable acid-soluble fraction of the bottom ashes, reaching 31.52%, posing a heightened risk of environmental migration. Considering the stability of heavy metals in the bottom ashes and the combustion characteristics, 800 °C is identified as the optimal temperature for the co-combustion of RDF and red mud, balancing efficiency and environmental safety. The findings will provide valuable insights for the co-utilization strategy of RDF and red mud, contributing to more informed decision-making in waste-to-energy processes.

AQP4-A25Q Point Mutation in Mice Depolymerizes Orthogonal Arrays of Particles and Decreases Polarized Expression of AQP4 Protein in Astrocytic Endfeet at the Blood-Brain Barrier.

Aquaporin-4 (AQP4) is characterized by the formation of orthogonal arrays of particles (OAPs) comprising its M1 and M23 isoforms in the plasma membrane. However, the biological importance of OAP formation is obscure. Here, we developed an OAP depolymerization male mouse model by transgenic knock-in of an AQP4-A25Q mutation. Analyses of the mutant brain tissue using blue native polyacrylamide gel electrophoresis, super-resolution imaging, and immunogold electron microscopy revealed remarkably reduced OAP structures and glial endfeet localization of the AQP4-A25Q mutant protein without effects on its overall mRNA and protein expression. AQP4A25Q/A25Q mice showed better survival and neurologic deficit scores when cerebral edema was induced by water intoxication or middle cerebral artery occlusion/reperfusion. The brain water content and swelling of pericapillary astrocytic endfeet processes in AQP4A25Q/A25Q mice were significantly reduced, functionally supporting decreased AQP4 protein expression at the blood-brain barrier. The infarct volume and neuronal damage were also reduced in AQP4A25Q/A25Q mice in the middle cerebral artery occlusion/reperfusion model. Astrocyte activation in the brain was alleviated in AQP4A25Q/A25Q mice, which may be associated with decreased cell swelling. We conclude that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood-brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.SIGNIFICANCE STATEMENT Aquaporin-4 (AQP4) is characterized by orthogonal arrays of particles (OAPs) comprising the M1 and M23 isoforms in the membrane. Here, an OAP depolymerization male mouse model induced by AQP4-A25Q mutation was first established, and the functions of OAP depolymerization in cerebral edema have been studied. The results revealed that AQP4 lost its OAP structure without affecting AQP4 mRNA and protein levels in AQP4-A25Q mice. AQP4-A25Q mutation mice has neuroprotective effects on cerebral edema induced by water intoxication and middle cerebral artery occlusion/reperfusion through relieving the activation of astrocytes and suppressed microglia-mediated neuroinflammation. We concluded that the OAP structure of AQP4 plays a key role in its polarized expression in astrocytic endfeet processes at the blood-brain barrier. Therefore, our study provided new insights into intervention of cerebral cellular edema caused by stroke and traumatic brain injury through regulating AQP4 OAP formation.

Path sampling and integration method to calculate speckle patterns.

A stable speckle pattern is generated when a coherent beam illuminates a stationary scattering medium that contains numerous scatterers with fixed positions. To date, there has been no valid method to the best of our knowledge for calculating the speckle pattern of a macro medium with a large number of scatterers. Here, a new method based on possible path sampling with corresponding weights and coherent superposition is presented for the simulation of optical field propagation in a scattering medium and output speckle patterns. In this method, a photon is launched onto a medium with fixed scatterers. It propagates in one direction; upon collision with a scatterer, its direction is updated. The procedure is repeated until it exits the medium. A sampled path is obtained in this manner. By repeatedly launching photons, numerous independent optical paths can be sampled. A speckle pattern, corresponding to the probability density of the photon, is formed by the coherent superposition of sufficiently sampled path lengths ending on a receiving screen. This method can be used in sophisticated studies of the influences of medium parameters, motion of scatterers, sample distortions on speckle distributions, and morphological appearances. It can be used for micro-examination of optical fields in scattering media and may inspire new methods and techniques for non-invasive precision detection and diagnosis of scattering media.

A Freestanding 3D Skeleton with Gradationally Distributed Lithiophilic Sites for Realizing Stable Lithium Anodes.

Lithium (Li) metal anodes are drawing considerable attention owing to their ultrahigh theoretical capacities and low electrochemical reduction potentials. However, their commercialization has been hampered by safety hazards induced by continuous dendrite growth. These issues can be alleviated using the ZnO-modified 3D carbon-based host containing carbon nanotubes (CNTs) and carbon felt (CF) fabricated by electroplating in the present study (denoted as ZnO/CNT@CF). The constructed skeleton has lithiophilic ZnO that is gradationally distributed along its thickness. The utilization of an inverted ZnO/CNT@CF-Li anode obtained by flipping over the carbon skeleton after Li electrodeposition is also reported herein. The synergistic effect of the Li metal and lithiophilic sites reduces the nucleation overpotential, thus inducing Li+ to preferentially deposit inside the porous carbon-based scaffold. The composite electrode compels Li to grow away from the separator, thereby significantly improving battery safety. A symmetric cell with the inverted ZnO/CNT@CF-Li electrode operates steadily for 700 cycles at 1 mA cm-2 and 1 mAh cm-2 . Moreover, the ZnO/CNT@CF-Li|S cell exhibits an initial areal capacity of 10.9 mAh cm-2 at a S loading of 10.4 mg cm-2 and maintains a capacity of 3.0 mAh cm-2 after 320 cycles.