Risk hotspots and influencing factors identification of heavy metal(loid)s in agricultural soils using spatial bivariate analysis and random forest.

Heavy metal(loid)s (HMs) in agricultural soils not only affect soil function and crop security, but also pose health risks to residents. However, previous concerns have typically focused on only one aspect, neglecting the other. This lack of a comprehensive approach challenges the identification of hotspots and the prioritization of factors for effective management. To address this gap, a novel method incorporating spatial bivariate analysis with random forest was proposed to identify high-risk hotspots and the key influencing factors. A large-scale dataset containing 2995 soil samples and soil HMs (As, Cd, Cr, Cu, Mn, Ni, Pb, Sb, and Zn) was obtained from across Henan province, central China. Spatial bivariate analysis of both health risk and ecological risks revealed risk hotspots. Positive matrix factorization model was initially used to investigate potential sources. Twenty-two environmental variables were selected and input into random forest to further identify the key influencing factors impacting soil accumulation. Results of local Moran's I index indicated high-high HM clusters at the western and northern margins of the province. Hotspots of high ecological and health risk were primarily observed in Xuchang and Nanyang due to the widespread township enterprises with outdated pollution control measures. As concentration and exposure frequency dominated the non-carcinogenic and carcinogenic risks. Anthropogenic activities, particularly vehicular traffic (contributing ~37.8 % of the total heavy metals accumulation), were the dominant sources of HMs in agricultural soils. Random forest modeling indicated that soil type and PM2.5 concentrations were the most influencing natural and anthropogenic variables, respectively. Based on the above findings, control measures on traffic source should be formulated and implemented provincially; in Xuchang and Nanyang, scattered township enterprises with outdated pollution control measures should be integrated and upgraded to avoid further pollution from these sources.

Clinical Features and a Prediction Model for Early Prediction of Composite Outcome in Chlamydia psittaci Pneumonia: A Multi-Centre Retrospective Study in China.

Introduction: C. psittaci pneumonia has atypical clinical manifestations and is often ignored by clinicians. This study analyzed the clinical characteristics, explored the risk factors for composite outcome and established a prediction model for early prediction of composite outcome among C. psittaci pneumonia patients. Methods: A multicenter, retrospective, observational cohort study was conducted in ten Chinese tertiary hospitals. Patients diagnosed with C. psittaci pneumonia were included, and their clinical data were collected and analyzed. The composite outcome of C. psittaci pneumonia included death during hospitalization, ICU admission, and mechanical ventilation. Univariate and multivariable logistic regression analyses were conducted to determine the significant variables. A ten-fold cross-validation was performed to internally validate the model. The model performance was evaluated using various methods, including receiver operating characteristics (ROC), C-index, sensitivity, specificity, positive/negative predictive value (PPV/NPV), decision curve analysis (DCA), and clinical impact curve analysis (CICA). Results: In total, 83 patients comprised training cohorts and 36 patients comprised validation cohorts. CURB-65 was used to establish predictive Model 1. Multivariate logistic regression analysis identified three independent prognostic factors, including serum albumin, CURB-65, and white blood cells. These factors were employed to construct model 2. Model 2 had acceptable discrimination (AUC of 0.898 and 0.825 for the training and validation sets, respectively) and robust internal validity. The specificity, sensitivity, NPV, and PPV for predicting composite outcome in the nomogram model were 91.7%, 84.5%, 50.0%, and 98.4% in the training sets, and 100.0%, 64.7%, 14.2%, and 100.0% in the validation sets. DCA and CICA showed that the nomogram model was clinically practical. Conclusion: This study constructs a refined nomogram model for predicting the composite outcome in C. psittaci pneumonia patients. This nomogram model enables early and accurate C. psittaci pneumonia patients' evaluation, which may improve clinical outcomes.

Zeaxanthin dipalmitate-enriched wolfberry extract improves vision in a mouse model of photoreceptor degeneration.

Zeaxanthin dipalmitate (ZD) is a chemical extracted from wolfberry that protects degenerated photoreceptors in mouse retina. However, the pure ZD is expensive and hard to produce. In this study, we developed a method to enrich ZD from wolfberry on a production line and examined whether it may also protect the degenerated mouse retina. The ZD-enriched wolfberry extract (ZDE) was extracted from wolfberry by organic solvent method, and the concentration of ZD was identified by HPLC. The adult C57BL/6 mice were treated with ZDE or solvent by daily gavage for 2 weeks, at the end of the first week the animals were intraperitoneally injected with N-methyl-N-nitrosourea to induce photoreceptor degeneration. Then optomotor, electroretinogram, and immunostaining were used to test the visual behavior, retinal light responses, and structure. The final ZDE product contained ~30mg/g ZD, which was over 9 times higher than that from the dry fruit of wolfberry. Feeding degenerated mice with ZDE significantly improved the survival of photoreceptors, enhanced the retinal light responses and the visual acuity. Therefore, our ZDE product successfully alleviated retinal morphological and functional degeneration in mouse retina, which may provide a basis for further animal studies for possible applying ZDE as a supplement to treat degenerated photoreceptor in the clinic.

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.

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.

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.

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.

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.

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.