Characterization of sensory and motor dysfunction and morphological alterations in late stages of type 2 diabetic mice.

Diabetic neuropathy is the most common complication of diabetes and lacks effective treatments. Although sensory dysfunction during the early stages of diabetes has been extensively studied in various animal models, the functional and morphological alterations in sensory and motor systems during late stages of diabetes remain largely unexplored. In the current work, we examined the influence of diabetes on sensory and motor function as well as morphological changes in late stages of diabetes. The obese diabetic Leprdb/db mice (db/db) were used for behavioral assessments and subsequent morphological examinations. The db/db mice exhibited severe sensory and motor behavioral defects at the age of 32 weeks, including significantly higher mechanical withdrawal threshold and thermal latency of hindpaws compared with age-matched nondiabetic control animals. The impaired response to noxious stimuli was mainly associated with the remarkable loss of epidermal sensory fibers, particularly CGRP-positive nociceptive fibers. Unexpectedly, the area of CGRP-positive terminals in the spinal dorsal horn was dramatically increased in diabetic mice, which was presumably associated with microglial activation. In addition, the db/db mice showed significantly more foot slips and took longer time during the beam-walking examination compared with controls. Meanwhile, the running duration in the rotarod test was markedly reduced in db/db mice. The observed sensorimotor deficits and motor dysfunction were largely attributed to abnormal sensory feedback and muscle atrophy as well as attenuated neuromuscular transmission in aged diabetic mice. Morphological analysis of neuromuscular junctions (NMJs) demonstrated partial denervation of NMJs and obvious fragmentation of acetylcholine receptors (AChRs). Intrafusal muscle atrophy and abnormal muscle spindle innervation were also detected in db/db mice. Additionally, the number of VGLUT1-positive excitatory boutons on motor neurons was profoundly increased in aged diabetic mice as compared to controls. Nevertheless, inhibitory synaptic inputs onto motor neurons were similar between the two groups. This excitation-inhibition imbalance in synaptic transmission might be implicated in the disturbed locomotion. Collectively, these results suggest that severe sensory and motor deficits are present in late stages of diabetes. This study contributes to our understanding of mechanisms underlying neurological dysfunction during diabetes progression and helps to identify novel therapeutic interventions for patients with diabetic neuropathy.

Benefits and risks of PD-1/PD-L1 inhibitors for recurrent small cell lung cancer: A systematic review and meta-analysis.

The development of immune checkpoint inhibitors(ICIs) has revolutionized the progress of solid tumors. Ongoing clinical trials are exploring the use of checkpoint inhibitors in recurrent small-cell lung cancer and achieving specific results. Although studies have been conducted to systematically review this issue, we conducted this single-arm meta-analysis in light of the emergence of several new clinical studies. In total, 854 individuals from 11 clinical investigations were enrolled in this single-arm meta-analysis. Median progression-free survival, median overall survival, and objective response rate were 1.65 months, 6.83 months, and 20.5%, respectively, according to pooled analyses. The best treatment regimen in the subgroup analysis was a dual checkpoint inhibitor combined with other treatments, and the drug that worked well for treatment was pembrolizumab. The benefit of programmed death 1/programmed cell death-ligand 1(PD-1/PD-L1) inhibitors alone is limited, and their combination with other therapies is a promising treatment option. Among PD-1/PD-L1 inhibitors, pembrolizumab is the recommended drug.

Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2).

Enzymatic breakdown of sphingomyelin by sphingomyelinase (SMase) is the main source of the membrane lipids, ceramides, which are involved in many cellular physiological processes. However, the full-length structure of human neutral SMase has not been resolved; therefore, its catalytic mechanism remains unknown. Here, we resolve the structure of human full-length neutral SMase, sphingomyelinase 1 (SMPD2), which reveals that C-terminal transmembrane helices contribute to dimeric architecture of hSMPD2 and that D111 - K116 loop domain is essential for substrate hydrolysis. Coupled with molecular docking, we clarify the binding pose of sphingomyelin, and site-directed mutagenesis further confirms key residues responsible for sphingomyelin binding. Hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamic (MD) simulations are utilized to elaborate the catalysis of hSMPD2 with the reported in vitro substrates, sphingomyelin and lyso-platelet activating fator (lyso-PAF). Our study provides mechanistic details that enhance our knowledge of lipid metabolism and may lead to an improved understanding of ceramide in disease and in cancer treatment.

Negative Life Events on Depression of Vocational Undergraduates in the Partial Least Squares Structural Equation Modeling Approach Perspective: A Mediated Moderation Model.

BACKGROUND: Following China's strategy of developing applied and compound social talents, vocational undergraduates are surging rapidly, and it is essential to understand the causes of their depression to effectively prevent and intervene in schools. OBJECTIVE: We aimed to investigate the relationship between negative life events (NLEs) and depression among vocational undergraduates in China, along with the mediating role of loneliness and the moderating role of socioeconomic status (SES). METHODS: A convenience sample survey was conducted at a vocational education university (N = 1487), and analyzed using partial least squares structural equation modeling. RESULTS: Findings showed that NLEs directly predicted depression (ß = 0.399, 95% CI [0.339, 0.452], p < 0.001) among vocational undergraduates. Furthermore, this relationship was partially mediated by loneliness (ß = 0.182, 95% CI [0.145, 221], p < 0.001); SES moderated the link between NLEs and depression (ß = 0.051, 95% CI [0.004, 092], p < 0.05), but not between NLEs and loneliness (p > 0.05). CONCLUSIONS: The current study highlights the impact of NLEs on depression among vocational undergraduates, indicating the importance of addressing NLEs and consequent feelings of loneliness to promote mental health. In addition, the moderating role of SES underscores the necessity of targeted interventions to mitigate the impact of NLEs on depression. The present study contributes to our understanding of the unique characteristics of depression in vocational undergraduates and has practical implications for psychological support services. Moreover, it probably has broader implications for addressing mental health challenges in global education settings for vocational undergraduates.

A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.

Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module. A high-resolution cryo-EM structure of feeblin with SLC15A4 reveals that the inhibitor binds a lysosomal outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to degradation of TASL. This mechanism of action exploits a conformational switch and converts a target-binding event into proteostatic regulation of the effector protein TASL, interrupting the TLR7/8-IRF5 signaling pathway and preventing downstream proinflammatory responses. Considering that all components involved have been genetically associated with systemic lupus erythematosus and that feeblin blocks responses in disease-relevant human immune cells from patients, the study represents a proof-of-concept for the development of therapeutics against this disease.

Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.

Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.

Research on river water quality evaluation based on the GA-PP and improved fuzzy model.

To ensure the water quality of rivers, it is crucial to scientifically evaluate their water quality status. This study takes a river in Jiangsu, China, as an example to establish six targeted main indicators for river water quality evaluation and uses a projection pursuit model optimized by the genetic algorithm to determine weights. Applying the improved fuzzy evaluation model to the final evaluation of water quality, the results indicate that this article adopts a weight calculation model that reduces dimensionality without losing data features, and the comprehensive evaluation model is also more complete, resulting in more accurate evaluation results. According to model analysis, the summer water quality is good and peaks from June to July. This article proposes corresponding measures and suggestions in response to the reasons behind this seasonal change. The evaluation model used in this article is superior to other models in terms of accuracy and portability, making it an excellent choice for river water quality evaluation. It can provide valuable technical guidance for similar river water quality evaluations.

Molecular basis of ClC-6 function and its impairment in human disease.

ClC-6 is a late endosomal voltage-gated chloride-proton exchanger that is predominantly expressed in the nervous system. Mutated forms of ClC-6 are associated with severe neurological disease. However, the mechanistic role of ClC-6 in normal and pathological states remains largely unknown. Here, we present cryo-EM structures of ClC-6 that guided subsequent functional studies. Previously unrecognized ATP binding to cytosolic ClC-6 domains enhanced ion transport activity. Guided by a disease-causing mutation (p.Y553C), we identified an interaction network formed by Y553/F317/T520 as potential hotspot for disease-causing mutations. This was validated by the identification of a patient with a de novo pathogenic variant p.T520A. Extending these findings, we found contacts between intramembrane helices and connecting loops that modulate the voltage dependence of ClC-6 gating and constitute additional candidate regions for disease-associated gain-of-function mutations. Besides providing insights into the structure, function, and regulation of ClC-6, our work correctly predicts hotspots for CLCN6 mutations in neurodegenerative disorders.

Comparing Depression Prevalence and Associated Symptoms with Intolerance of Uncertainty among Chinese Urban and Rural Adolescents: A Network Analysis.

The prevalence of depression among adolescents is increasing, which can hinder their healthy development and is intricately linked to the intolerance of uncertainty (IU). IU involves both prospective anxiety and inhibitory anxiety. However, the precise relationship between depressive symptoms and these two components of IU remains unclear, particularly when considering the specific context of rural adolescents in China. A total of 1488 adolescents (male, 848; Meanage = 20, SDage = 1.51, age range from 16 to 24) in China were recruited and divided into urban adolescents (N = 439) and rural adolescents (N = 1049) groups. The Patient Health Questionnaire-9 and Intolerance of Uncertainty Scale-12 were utilized to measure depression and IU. The symptom network approach and the flow network approach were employed. The prevalence of depression was significantly higher (χ2 = 4.09, p = 0.04) among rural adolescents (N = 419, 40.1%) than urban adolescents (N = 152, 34.8%). The node strength of "motor" demonstrated some discrepancy between rural and urban adolescents, while there was no notable disparity in the global strength and structure of the network between the two groups. However, rural adolescents exhibited a significantly higher global strength in the flow network (including depression and IU) than their urban counterparts. In the flow networks of rural adolescents, "guilt" was directly associated with prospective and inhibitory anxiety. These findings highlight the urgent need for interventions that enhance the ability of rural adolescents to cope with uncertainty and prevent their depressive symptoms more effectively.

Intolerance of uncertainty fuels preservice teachers' smartphone dependence through rumination and anxiety during the COVID-19 pandemic: A cross-sectional study.

Objectives: We aimed to explore the relationship among intolerance of uncertainty (IU), rumination, anxiety, and smartphone dependence (SPD) in preservice teachers during the COVID-19 pandemic. Methods: Two cross-sectional studies were conducted with Chinese preservice teachers, using questionnaires on IU, rumination, anxiety, and SPD. Data were analyzed using AMOS 24.0 and SPSS 25.0, and the mediating mechanism was tested using the macro program Model 6. Study 1 recruited participants who were forcibly sequestered in a university due to an anti-epidemic policy during the COVID-19 crisis. Study 2 was surveyed online from different universities to replicate and enhance the reliability of Study 1 finding. Results: Study 1 (N = 553, Mage = 20.8 ± 2.3, 30.0% female) and Study 2 (N = 1610, Mage = 21.1 ± 2.1, 51.4% female) both found that IU affected SPD through the independent mediators of rumination and anxiety, as well as the chain mediation of rumination→ anxiety. In Study 1, the indirect effect of IU on SPD was significant through rumination (ß = 0.16, 95% CI [0.03, 0.06]), anxiety (ß = 0.11, 95% CI [0.03, 0.06]), and the chain mediation (ß = 0.02, 95% CI [0.01, 0.04]); in Study 2, the indirect effect of IU on SPD was significant through rumination (ß = 0.08, 95% CI [0.05, 0.11]), anxiety (ß = 0.10, 95% CI [0.08, 0.13]), and the chain mediation (ß = 0.02, 95% CI [0.02, 0.03]). Conclusion: Two cross-sectional studies found that preservice teachers' SPD is indirectly connected to IU, mediated by rumination and anxiety, and weakly mediated by the chain mediation of rumination and anxiety. Our findings may help educators understand the impact of anti-epidemic policies on preservice teachers and possible inclusive later interventions.

Soil enzyme activities, soil physical properties, photosynthetic physical characteristics and water use of winter wheat after long-term straw mulch and organic fertilizer application.

Introduction: Inappropriate residue and nutrient management leads to soil degradation and the decline of soil quality and water storage capacity. Methods: An ongoing field experiment has been conducted since 2011 to investigate the effects of straw mulching (SM), and straw mulching combined with organic fertilizer (SM+O), on winter wheat yield, including a control treatment (CK, no straw). We studied the effects of these treatments on soil microbial biomass nitrogen and carbon, soil enzyme activity in 2019, photosynthetic parameters, evapotranspiration (ET), water use efficiency (WUE), and yields over five consecutive years (2015-2019). We also analyzed the soil organic carbon, soil structure, field capacity, and saturated hydraulic conductivity in 2015 and 2019. Results: Results indicate that compared with CK, SM and SM+O treatments increased the proportion of >0.25mm aggregates, soil organic carbon, field capacity, and saturated hydraulic conductivity, but decreased the soil bulk density. In addition, the SM and SM+O treatments also increased soil microbial biomass nitrogen and carbon, the activity of soil enzymes, and decreased the carbon-nitrogen ratio of microbial biomass. Therefore, SM and SM+O treatments both increased the leaf water use efficiency (LWUE) and photosynthetic rate (Pn), and improved the yields and water use efficiency (WUE) of winter wheat. The combination SM (4.5 t/ha)+O (0.75 t/ha) was more effective than SM alone, and both treatments were superior to the control. Conclusion: Based on the results of this study, SM+O is recommended as the most effective cultivation practice.

Recent progress and challenges in the treatment of spinal cord injury.

Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI.

Effect of long term application of super absorbent polymer on soil structure, soil enzyme activity, photosynthetic characteristics, water and nitrogen use of winter wheat.

Introduction: Water scarcity and seasonal drought are major constraints on agricultural development globally. Super absorbent polymer (SAP) is a good amendment that can improve soil structure, increase soil water retention, and promote crop growth even with less soil moisture. We hypothesize that long term application of SAP has a better effect on soil organic carbon, soil enzyme activity, photosynthetic characteristics, yield, and water and nitrogen use than short term application. Methods: A long term field experiment with different application rates (0 (CK), 15 (L), 30 (M), 45 (H) kg ha-1) of SAP was conducted at the Yuzhou water conservation agriculture base of the Henan Academy of Agricultural Sciences from 2011 to 2019. Results and Discussion: The results indicate that applying SAP increases > 0.25 mm aggregates and decreased<0.25 mm aggregates in the soil after one year (2011) and 9 years (2019) of application. In addition, soil organic carbon, soil microbial biomass carbon, soil sucrase and cellulase activities, soil water consumption, water consumption, net photosynthetic rate (Pn), leaf water use efficiency (LWUE) of wheat and yield, all increased after SAP application. SAP also boosts water use efficiency and nitrogen use efficiency. Correlation analyses show that SAP promotes the growth of wheat, and improves the utilization rate of soil water and nutrients by improving the soil structure and increasing soil organic carbon and microbial enzyme activity. Conclusion: Based on our research, SAP treatment at a dosage of 45 kg ha-1 is most effective and is thus recommended.

The influence of gratitude on pre-service teachers' career goal self-efficacy: Chained intermediary analysis of meaning in life and career calling.

Objective: The aim of the study was to explore the relationship among gratitude, meaning in life (MIL), career calling, and career goal self-efficacy (CGSE) of the pre-service teachers in the Free Teacher Education program in China and the internal mechanism of action. Methods: In this study, gratitude, MIL, career calling, and CGSE questionnaires were used to investigate 801 pre-service teachers. IBM SPSS 25.0 and AMOS 24.0 were used for data processing, and SPSS macro program Model 6 was used for the mediating mechanism. Results: (1) Gratitude was positively correlated with MIL and career calling. MIL was positively correlated with career calling. Gratitude, MIL, and career calling were significantly and positively associated with CGSE. (2) Gratitude influences pre-service teachers' CGSE mainly through the independent intermediary of MIL and career calling, and the chain intermediary of MIL→career calling, three indirect effects. Conclusion: Gratitude indirectly predicts CGSE of pre-service teachers not only through the independent intermediary of MIL and career calling but also through the chain intermediary of MIL and career calling.

Rice OsUBR7 modulates plant height by regulating histone H2B monoubiquitination and cell proliferation.

Plant height is an important agronomic trait for lodging resistance and yield. Here, we report a new plant-height-related gene, OsUBR7 in rice (Oryza sativa L.); knockout of OsUBR7 caused fewer cells in internodes, resulting in a semi-dwarf phenotype. OsUBR7 encodes a putative E3 ligase containing a plant homeodomain finger and a ubiquitin protein ligase E3 component N-recognin 7 (UBR7) domain. OsUBR7 interacts with histones and monoubiquitinates H2B (H2Bub1) at lysine148 in coordination with the E2 conjugase OsUBC18. OsUBR7 mediates H2Bub1 at a number of chromatin loci for the normal expression of target genes, including cell-cycle-related and pleiotropic genes, consistent with the observation that cell-cycle progression was suppressed in the osubr7 mutant owing to reductions in H2Bub1 and expression levels at these loci. The genetic divergence of OsUBR7 alleles among japonica and indica cultivars affects their transcriptional activity, and these alleles may have undergone selection during rice domestication. Overall, our results reveal a novel mechanism that mediates H2Bub1 in plants, and UBR7 orthologs could be utilized as an untapped epigenetic resource for crop improvement.

Structural basis for the catalytic activity of filamentous human serine beta-lactamase-like protein LACTB.

Serine beta-lactamase-like protein (LACTB) is a mammalian mitochondrial serine protease that can specifically hydrolyze peptide bonds adjacent to aspartic acid residues and is structurally related to prokaryotic penicillin-binding proteins. Here, we determined the cryoelectron microscopy structures of human LACTB (hLACTB) filaments from wild-type protein, a middle region deletion mutant, and in complex with the inhibitor Z-AAD-CMK at 3.0-, 3.1-, and 2.8-Å resolution, respectively. Structural analysis and activity assays revealed that three interfaces are required for the assembly of hLACTB filaments and that the formation of higher order helical structures facilitates its cleavage activity. Further structural and enzymatic analyses of middle region deletion constructs indicated that, while this region is necessary for substrate hydrolysis, it is not required for filament formation. Moreover, the inhibitor-bound structure showed that hLACTB may cleave peptide bonds adjacent to aspartic acid residues. These findings provide the structural basis underlying hLACTB catalytic activity.

Cryo-EM structures and transport mechanism of human P5B type ATPase ATP13A2.

Polyamines are important polycations that play critical roles in mammalian cells. ATP13A2 belongs to the orphan P5B adenosine triphosphatases (ATPase) family and has been established as a lysosomal polyamine exporter to maintain the normal function of lysosomes and mitochondria. Previous studies have reported that several human neurodegenerative disorders are related to mutations in the ATP13A2 gene. However, the transport mechanism of ATP13A2 in the lysosome remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structures of three distinct intermediates of the human ATP13A2, revealing key insights into the spermine (SPM) transport cycle in the lysosome. The transmembrane domain serves as a substrate binding site and the C-terminal domain is essential for protein stability and may play a regulatory role. These findings advance our understanding of the polyamine transport mechanism, the lipid-associated regulation, and the disease-associated mutants of ATP13A2.

Brain and Retinal Abnormalities in the 5xFAD Mouse Model of Alzheimer's Disease at Early Stages.

One of the major challenges in treating Alzheimer's disease (AD) is its early diagnosis. Increasing data from clinical and animal research indicate that the retina may facilitate an early diagnosis of AD. However, a previous study on the 5xFAD (a fast AD model), showing retinal changes before those in the brain, has been questioned because of the involvement of the retinal degeneration allele Pde6brd1. Here, we tested in parallel, at 4 and 6 months of age, both the retinal and the brain structure and function in a 5xFAD mouse line that carries no mutation of rd1. In the three tested regions of the 5xFAD brain (hippocampus, visual cortex, and olfactory bulb), the Aß plaques were more numerous than in wild-type (WT) littermates already at 4 months, but deterioration in the cognitive behavioral test and long-term potentiation (LTP) lagged behind, showing significant deterioration only at 6 months. Similarly in the retina, structural changes preceded functional decay. At 4 months, the retina was generally normal except for a thicker outer nuclear layer in the middle region than WT. At 6 months, the visual behavior (as seen by an optomotor test) was clearly impaired. While the full-field and pattern electroretinogram (ERG) responses were relatively normal, the light responses of the retinal ganglion cells (measured with multielectrode-array recording) were decreased. Structurally, the retina became abnormally thick with few more Aß plaques and activated glia cells. In conclusion, the timeline of the degenerative processes in the retina and the brain is similar, supporting the use of non-invasive methods to test the retinal structure and function to reflect changes in the brain for early AD diagnosis.

Molecular insights into the human ABCB6 transporter.

ABCB6 plays a crucial role in energy-dependent porphyrin transport, drug resistance, toxic metal resistance, porphyrin biosynthesis, protection against stress, and encoding a blood group system Langereis antigen. However, the mechanism underlying porphyrin transport is still unclear. Here, we determined the cryo-electron microscopy (cryo-EM) structures of nanodisc-reconstituted human ABCB6 trapped in an apo-state and an ATP-bound state at resolutions of 3.6 and 3.5 Å, respectively. Our structures reveal a unique loop in the transmembrane domain (TMD) of ABCB6, which divides the TMD into two cavities. It restrains the access of substrates in the inward-facing state and is removed by ATP-driven conformational change. No ligand cavities were observed in the nucleotide-bound state, indicating a state following substrate release but prior to ATP hydrolysis. Structural analyses and functional characterizations suggest an "ATP-switch" model and further reveal the conformational changes of the substrate-binding pockets triggered by the ATP-driven regulation.

Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis.

Pannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.