A novel protein elicitor (Cs08297) from Ciboria shiraiana enhances plant disease resistance.

Ciboria shiraiana is a necrotrophic fungus that causes mulberry sclerotinia disease resulting in huge economic losses in agriculture. During infection, the fungus uses immunity elicitors to induce plant tissue necrosis that could facilitate its colonization on plants. However, the key elicitors and immune mechanisms remain unclear in C. shiraiana. Herein, a novel elicitor Cs08297 secreted by C. shiraiana was identified, and it was found to target the apoplast in plants to induce cell death. Cs08297 is a cysteine-rich protein unique to C. shiraiana, and cysteine residues in Cs08297 were crucial for its ability to induce cell death. Cs08297 induced a series of defence responses in Nicotiana benthamiana, including the burst of reactive oxygen species (ROS), callose deposition, and activation of defence-related genes. Cs08297 induced-cell death was mediated by leucine-rich repeat (LRR) receptor-like kinases BAK1 and SOBIR1. Purified His-tagged Cs08297-thioredoxin fusion protein triggered cell death in different plants and enhanced plant resistance to diseases. Cs08297 was necessary for sclerotial development, oxidative-stress adaptation, and cell wall integrity but negatively regulated virulence of C. shiraiana. In conclusion, our results revealed that Cs08297 is a novel fungal elicitor in fungi inducing plant immunity. Furthermore, its potential to enhance plant resistance provides a new target to control agricultural diseases biologically.

Advanced Predictive Modeling of Concrete Compressive Strength and Slump Characteristics: A Comparative Evaluation of BPNN, SVM, and RF Models Optimized via PSO.

This study presents the development of predictive models for concrete performance, specifically targeting the compressive strength and slump value, utilizing the quantities of individual raw materials in the concrete mix design as input variables. Three distinct machine learning approaches-Backpropagation Neural Network (BPNN), Support Vector Machine (SVM), and Random Forest (RF)-were employed to establish the prediction models independently. In the model construction process, the Particle Swarm Optimization (PSO) algorithm was integrated with cross-validation to fine-tune the hyperparameters of each model, ensuring optimal performance. Following the completion of training and modeling, a comprehensive comparison of the predictive accuracy among the three models was conducted, with the aim of selecting the most suitable model for incorporation into an optimized objective function. The findings reveal that among the chosen machine learning techniques, BPNN exhibited superior predictive capabilities for the compressive strength of concrete. Specifically, in the validation set, BPNN achieved a high correlation coefficient (R) of 0.9531 between the predicted and actual outputs, accompanied by a low Root Mean Square Error (RMSE) of 4.2568 and a Mean Absolute Error (MAE) of 2.6627, indicating a precise and reliable prediction. Conversely, for the prediction of the concrete slump value, RF outperformed the other two models, demonstrating a correlation coefficient (R) of 0.8986, an RMSE of 9.4906, and an MAE of 5.5034 in the validation set. This underscores the effectiveness of RF in capturing the complexity and variability inherent in slump behavior. Overall, this research highlights the potential of integrating advanced machine learning algorithms with optimization techniques for enhancing the accuracy and efficiency of concrete performance predictions. The identified optimal models, BPNN for compressive strength and RF for slump, can serve as valuable tools for engineers and researchers in the field of construction materials, facilitating the design of concrete mixes tailored to specific performance requirements.

Effects of arthroscopic outside-in sutures versus all-inside sutures in the treatment of lateral disc meniscus injury of the knee joint under arthroscopy.

OBJECTIVE: To compare the clinical efficacy of arthroscopic outside-in suturing and all-inside suturing in the treatment of discoid lateral meniscus (DLM) injury, and to analyze the influencing factors for clinical efficacy. METHODS: We retrospectively selected 30 patients with DLM injury who received arthroscopic all-inside suturing at Wuzhou Workers' Hospital from January 2020 to December 2022 as the observation group. Another 30 patients who received arthroscopic outside-in suturing during the same period were enrolled as the control group. The surgical indicators, pre- and post-operative knee scores and proprioception difference of knee joint, postoperative complications and clinical efficacy were compared between the two groups. Factors affecting clinical efficacy of patients with DLM injury were identified using Logistic regression analysis. RESULTS: Significant differences were observed in operation time, hospital stay, blood loss and clinical efficacy between the two groups (all P<0.05); however, there was no significant difference in complications (P>0.05). The visual analog score (VAS) scores of both groups decreased over time at 1, 3, 5, 7, 15, and 30 days post-surgery, with the observation group scoring lower than the control group (all P<0.05). At 1, 3, and 6 months after the surgery, the international knee documentation committee (IKDC), Lysholm, and Tegner scores of both groups increased over time, with the observation group scoring higher than the control group (all P<0.05). Six months post-surgery, proprioception differences at 15°, 45°, and 75° of knee flexion were significantly decreased, with greater improvements observed in the observation group (P<0.05). Univariate analysis showed that operation time, IKDC and Lysholm scores at 6 months post-operation, postoperative complications, and suture method were factors influencing treatment outcomes in patients with DLM injury (all P<0.05). Multivariate Logistic regression analysis identified postoperative complications as an independent risk factor for poor treatment outcome in patients with DLM injury (P<0.05). CONCLUSION: Arthroscopic all-inside suturing for DLM injury offers significant clinical benefits, including shorter operation time and hospital stay, less blood loss, and improved knee joint function with fewer complications. Prolonged operation time, low IKDC and Lysholm scores at 6 months post-operation, postoperative complications and outside-in suturing technique are associated with poorer treatment outcomes in patients with DLM injury.

Skeletal muscle-derived exosomes prevent osteoporosis by promoting osteogenesis.

Skeletal muscle and bone are the major organs for physical activity, in which there is a parallel correlation between muscle mass and bone density throughout a lifetime. Osteoporosis is a systemic bone metabolic disorder caused by reduced bone formation and increased bone resorption. Based on the metabolic symbiosis relationship between skeletal muscle and bone, we hypothesis that skeletal muscle secretory factors could play constructive roles in osteoporosis. Exosomes have been verified to transfer bioactive factors among cells. However, the role of skeletal muscle derived-exosomes (SM-Exos) in osteoporosis is still unclear. In this study, we performed neuromuscular electrical stimulation (NMES) intervention on denervated skeletal muscles and subsequently extracted exosomes (DN + ES-Exo) from the skeletal muscles, and then injected these DN + ES-Exo into sarco-osteoporotic rats through tail vein. In vitro studies, we cocultured SM-Exos from different states with differentiated MC3T3-E1 osteoblasts. In brief, our research findings demonstrate that SM-Exos could partially promote osteogenesis both in vivo and in vitro. Further, our findings indicate that skeletal muscle contraction induced by NMES can reverse the incidence of sarco-osteoporosis to a certain degree, and DN + ES-Exo contributes to the improvement in osteoporosis by facilitating osteoblast differentiation. Then, we revealed that NMES might regulate several miRNAs in skeletal muscle, the miRNAs that are encapsulated by SM-Exos might be involved in osteogenic differentiation in a network manner. All in all, this study confirmed the effect of NMES on sarco-osteoporosis and explored the role of SM-Exos in the improvement of osteoporosis, which provide an effective theoretical support for the physical therapy of clinical sarco-osteoporosis.

Superior osmotic stress tolerance in oilseed rape transformed with wild-type Rhizobium rhizogenes.

KEY MESSAGE: Natural transformation with R. rhizogenes enhances osmotic stress tolerance in oilseed rape through increasing osmoregulation capacity, enhancing maintenance of hydraulic integrity and total antioxidant capacity. Transformation of plants using wild strains of agrobacteria is termed natural transformation and is not covered by GMO legislation in, e.g., European Union and Japan. In this study, offspring lines of Rhizobium rhizogenes naturally transformed oilseed rape (Brassica napus), i.e., A11 and B3 (termed root-inducing (Ri) lines), were investigated for osmotic stress resilience. Under polyethylene glycol 6000 (PEG) 10% (w/v)-induced osmotic stress, the Ri lines, particularly A11, had less severe leaf wilting, higher stomatal conductance (8.2 times more than WT), and a stable leaf transpiration rate (about 2.9 mmol m-2 s-1). Although the leaf relative water content and leaf water potential responded similarly to PEG treatment between the Ri lines and WT, a significant reduction of the turgid weight to dry weight ratio in A11 and B3 indicated a greater capacity of osmoregulation in the Ri lines. Moreover, the upregulation of plasma membrane intrinsic proteins genes (PIPs) in roots and downregulation of these genes in leaves of the Ri lines implied a better maintenance of hydraulic integrity in relation to the WT. Furthermore, the Ri lines had greater total antioxidant capacity (TAC) than the WT under PEG stress. Collectively, the enhanced tolerance of the Ri lines to PEG-induced osmotic stress could be attributed to the greater osmoregulation capacity, better maintenance of hydraulic integrity, and greater TAC than the WT. In addition, Ri-genes (particularly rolA and rolD) play roles in response to osmotic stress in Ri oilseed rape. This study reveals the potential of R. rhizogenes transformation for application in plant drought resilience.

Enhanced root system architecture in oilseed rape transformed with Rhizobium rhizogenes.

Transformation of plants using wild strains of agrobacteria is termed natural transformation and is not covered by GMO legislation in e.g. European Union and Japan. In the current study, offspring lines (A11 and B3) of Rhizobium rhizogenes naturally transformed oilseed rape (Brassica napus) were randomly selected to characterize the morphological traits, and analyze the implications of such morphological changes on plant drought resilience. It was found that the introduction of Ri-genes altered the biomass partitioning to above- and under-ground parts of oilseed rape plants. Compared to the wild type (WT), the A11 and B3 lines exhibited 1.2-4.0 folds lower leaf and stem dry weight, leaf area and plant height, but had 1.3-5.8 folds greater root dry weight, root length and root surface area, resulting in a significantly enhanced root: shoot dry mass ratio and root surface area: leaf area ratio. In addition, the introduction of Ri-genes conferred reduced stomatal pore aperture and increased stomatal density in the B3 line, and increased leaf thickness in A11 line, which could benefit plant drought resilience. Finally, the modulations in morphological traits as a consequence of transformation with Ri-genes are discussed concerning resilience in water-limited conditions. These findings reveal the potential of natural transformation with R. rhizogenes for drought-targeted breeding in crops.

Facile synthesis, release mechanism, and life cycle assessment of amine-modified lignin for bifunctional slow-release fertilizer.

Biomass-based slow-release fertilizers (SRFs) are a sustainable solution for addressing food scarcity, improving fertilizer efficiency, and reducing pollution, whereas they still face complex preparation, high costs, and low release characteristics. This study introduces a simple and innovative approach to producing bifunctional green SRFs with controlled release and conditioning properties for saline soils and harsh environments. The method involves a one-pot preparation of microsphere-structured amine-modified lignin slow-release fertilizer (L-UX) using biomass lignin as the starting material. The L-UX demonstrates an exceptional fertilizer loading rate (66.2 %) and extended slow-release performance (288 h), effectively enhancing the fertilizer's release ability. Compared to traditional fertilizers, the bifunctional L-UX significantly improves soil water retention capacity (824.3 %), plant growth, and germination percentage in challenging soil conditions (133 %). These findings highlight the potential of L-UX as a large-scale controlled-release fertilizer in harsh environments. A life cycle assessment (LCA) was also conducted to evaluate the environmental impact of L-UX from its production to disposal. This revealed that L-UX has a minimal environmental footprint compared to conventional inorganic fertilizers. This study further supports the widespread application of L-UX as an environmentally friendly alternative.

Enhancing flame retardancy and heat insulation performances of polyamide 66 composite film by adding CNC/Al2O3 nanohybrids.

Polyamide 66 (PA66) has garnered significant attention due to its exceptional properties; unfortunately, its flammability is challenging. Adding flame retardants (FRs) is a primary approach to enhance PA66 flame retardancy. This study developed a highly flame-retardant PA66 composite film by adding corn-like functional nanohybrids (CNC/Al2O3). Interestingly, CNC/Al2O3 nanohybrids not only formed hydrogen bond interactions with PA66 but also improved crystallization properties as heterogeneous nucleating agents, resulting in the excellent mechanical properties of PA66 composite film. Remarkably, the incorporation of 3 wt% CNC/Al2O3 nanohybrids into PA66 matrix contributed to increasing the LOI to 28.5 %. The pHRR, THR, and TSR were reduced obviously by 55.7 %, 15.3 %, and 65.2 %, respectively. The excellent flame retardancy of PA66 composite film was attributed to the forming of a compact carbon layer catalyzed by the CNC/Al2O3 nanohybrids. Besides, the homogeneous distribution of CNC/Al2O3 nanohybrids endowed the composite film with excellent heat insulation, and the heat insulation rate was up to 31.9 %. Thus, such PA66 composite films with excellent flame retardancy, heat insulation, and mechanical properties could meet the broader application requirements.

Identification of differentially expressed genes of blood leukocytes for Schizophrenia.

Background: Schizophrenia (SCZ) is a severe neurodevelopmental disorder with brain dysfunction. This study aimed to use bioinformatic analysis to identify candidate blood biomarkers for SCZ. Methods: The study collected peripheral blood leukocyte samples of 9 SCZ patients and 20 healthy controls for RNA sequencing analysis. Bioinformatic analyses included differentially expressed genes (DEGs) analysis, pathway enrichment analysis, and weighted gene co-expression network analysis (WGCNA). Results: This study identified 1,205 statistically significant DEGs, of which 623 genes were upregulated and 582 genes were downregulated. Functional enrichment analysis showed that DEGs were mainly enriched in cell chemotaxis, cell surface, and serine peptidase activity, as well as involved in Natural killer cell-mediated cytotoxicity. WGCNA identified 16 gene co-expression modules, and five modules were significantly correlated with SCZ (p < 0.05). There were 106 upregulated genes and 90 downregulated genes in the five modules. The top ten genes sorted by the Degree algorithm were RPS28, BRD4, FUS, PABPC1, PCBP1, PCBP2, RPL27A, RPS21, RAG1, and RPL27. RAG1 and the other nine genes belonged to the turquoise and pink module respectively. Pathway enrichment analysis indicated that these 10 genes were mainly involved in processes such as Ribosome, cytoplasmic translation, RNA binding, and protein binding. Conclusion: This study finds that the gene functions in key modules and related enrichment pathways may help to elucidate the molecular pathogenesis of SCZ, and the potential of key genes to become blood biomarkers for SCZ warrants further validation.

Efficient cellulose dissolution and derivatization enabled by oxalic/sulfuric acid for high-performance cellulose films as food packaging.

The performance of cellulose-based materials is highly dependent on the choice of solvent systems. Exceptionally, cellulose dissolution and derivatization by efficient solvent have been considered as a key factor for large-scale industrial applications of cellulose. However, cellulose dissolution and derivatization often requires harsh reaction conditions, high energy consumption, and complex solubilizing, resulting in environmental impacts and low practical value. Here we address these limitations by using a low-temperature oxalic acid/sulfuric acid solvent to enable cellulose dissolution and derivatization for high-performance cellulose films. The dissolution and derivatization mechanism of the mixed acid is studied, demonstrating that cellulose is firstly socked by oxalic acid, then more hydrogen bonds ionized by sulfuric acid break cellulose chain, and finally the esterification reaction between oxalic acid and cellulose is catalyzed by sulfuric acid. Solutions containing 8 %-10 % cellulose are obtained and can be stored for a long time at -18 °C without significant degradation. Moreover, the cellulose film exhibits a higher tensile strength of up to 66.1 MPa, thermal stability, and degree of polymerization compared to that fabricated by sulfuric acid. These unique advantages provide new paths to utilize renewable resources for alternative food packaging materials at an industrial scale.

Haplotype-resolved chromosomal-level genome assembly reveals regulatory variations in mulberry fruit anthocyanin content.

Understanding the intricate regulatory mechanisms underlying the anthocyanin content (AC) in fruits and vegetables is crucial for advanced biotechnological customization. In this study, we generated high-quality haplotype-resolved genome assemblies for two mulberry cultivars: the high-AC 'Zhongsang5801' (ZS5801) and the low-AC 'Zhenzhubai' (ZZB). Additionally, we conducted a comprehensive analysis of genes associated with AC production. Through genome-wide association studies (GWAS) on 112 mulberry fruits, we identified MaVHAG3, which encodes a vacuolar-type H+-ATPase G3 subunit, as a key gene linked to purple pigmentation. To gain deeper insights into the genetic and molecular processes underlying high AC, we compared the genomes of ZS5801 and ZZB, along with fruit transcriptome data across five developmental stages, and quantified the accumulation of metabolic substances. Compared to ZZB, ZS5801 exhibited significantly more differentially expressed genes (DEGs) related to anthocyanin metabolism and higher levels of anthocyanins and flavonoids. Comparative analyses revealed expansions and contractions in the flavonol synthase (FLS) and dihydroflavonol 4-reductase (DFR) genes, resulting in altered carbon flow. Co-expression analysis demonstrated that ZS5801 displayed more significant alterations in genes involved in late-stage AC regulation compared to ZZB, particularly during the phase stage. In summary, our findings provide valuable insights into the regulation of mulberry fruit AC, offering genetic resources to enhance cultivars with higher AC traits.

Effector Cs02526 from Ciboria shiraiana induces cell death and modulates plant immunity.

Sclerotinia disease is one of the most devastating fungal diseases worldwide, as it reduces the yields of many economically important crops. Pathogen-secreted effectors play crucial roles in infection processes. However, key effectors of Ciboria shiraiana, the pathogen primarily responsible for sclerotinia disease in mulberry (Morus spp.), remain poorly understood. In this study, we identified and functionally characterized the effector Cs02526 in C. shiraiana and found that Cs02526 could induce cell death in a variety of plants. Moreover, Cs02526-induced cell death was mediated by the central immune regulator brassinosteroid insensitive 1-associated receptor kinase 1, dependent on a 67-amino acid fragment. Notably, Cs02526 homologs were widely distributed in hemibiotrophic and necrotrophic phytopathogenic fungi, but the homologs failed to induce cell death in plants. Pretreatment of plants with recombinant Cs02526 protein enhanced resistance against both C. shiraiana and Sclerotinia sclerotiorum. Furthermore, the pathogenicity of C. shiraiana was diminished upon spraying plants with synthetic dsRNA-Cs02526. In conclusion, our findings highlight the cell death-inducing effector Cs02526 as a potential target for future biological control strategies against plant diseases.

Targeting bacterial nickel transport with aspergillomarasmine A suppresses virulence-associated Ni-dependent enzymes.

Microbial Ni2+ homeostasis underpins the virulence of several clinical pathogens. Ni2+ is an essential cofactor in urease and [NiFe]-hydrogenases involved in colonization and persistence. Many microbes produce metallophores to sequester metals necessary for their metabolism and starve competing neighboring organisms. The fungal metallophore aspergillomarasmine A (AMA) shows narrow specificity for Zn2+, Ni2+, and Co2+. Here, we show that this specificity allows AMA to block the uptake of Ni2+ and attenuate bacterial Ni-dependent enzymes, offering a potential strategy for reducing virulence. Bacterial exposure to AMA perturbs H2 metabolism, ureolysis, struvite crystallization, and biofilm formation and shows efficacy in a Galleria mellonella animal infection model. The inhibition of Ni-dependent enzymes was aided by Zn2+, which complexes with AMA and competes with the native nickelophore for the uptake of Ni2+. Biochemical analyses demonstrated high-affinity binding of AMA-metal complexes to NikA, the periplasmic substrate-binding protein of the Ni2+ uptake system. Structural examination of NikA in complex with Ni-AMA revealed that the coordination geometry of Ni-AMA mimics the native ligand, Ni-(L-His)2, providing a structural basis for binding AMA-metal complexes. Structure-activity relationship studies of AMA identified regions of the molecule that improve NikA affinity and offer potential routes for further developing this compound as an anti-virulence agent.

Characterization of a group of germacrene A synthases involved in the biosynthesis of ß-elemene from Atractylodis macrocephala.

ß-Elemene, an important component of the volatile oil of Atractylodis macrocephala, has been widely utilized as an antitumor drug for over 20 years. However, the germacrene A synthase (GAS) genes responsible for the biosynthesis of ß-elemene in A. macrocephala were previously unidentified. In this study, two new AmGASs were identified from the A. macrocephala transcriptome, demonstrating their capability to convert farnesyl pyrophosphate into germacrene A, which subsequently synthesizes ß-elemene through Cope rearrangement. Additionally, two highly catalytic AmGAS1 mutations, I307A and E392A, resulted in a 2.23-fold and 1.57-fold increase in ß-elemene synthesis, respectively. Furthermore, precursor supply and fed-batch strategies were employed to enhance the precursor supply, resulting in ß-elemene yields of 7.3 mg/L and 33.3 mg/L, respectively. These findings identify a promising candidate GAS for ß-elemene biosynthesis and lay the foundation for further functional studies on terpene synthases in A. macrocephala.

Enhancement of mineral density and mechanical properties in root caries treated with silver diammine fluoride and glass ionomer cement, with emphasis on silver ion distribution.

OBJECTIVES: This study aimed to measure the distribution of silver ion (Ag+), mineral recovery, and nanohardness in carious lesions and comprehensively evaluate the degree of dentin restoration. METHODS: Sixty human teeth with root caries were randomly assigned to the control, silver diammine fluoride (SDF) [Safo], and SDF+Glass ionomer cement (GIC) treatment [Safo+Fuji] groups. Micro-computed tomography (micro-CT) was performed at five time points for each sample before/after treatment to evaluate mineral density within and around carious lesions. Three months following treatment, 12 samples were selected for synchrotron radiation X-ray fluorescence analysis to evaluate Ag+ distribution, while 15 samples were selected for nanoindentation. Data were analyzed using Dunnett's T3 test for micro-CT and Wilcoxon rank sum test with Bonferroni correction (p = 0.017) for nanoindentation. The correlation between hardness and mineral change was analyzed using the Spearman rank correlation coefficient. RESULTS: The Safo and Safo+Fuji groups showed significantly higher mineral recovery rates than did the control group (p < 0.001). In the Safo group, Ag+ accumulated in the deeper layers rather than the superficial layer of caries. In the Safo+Fuji group, Ag+ was found evenly distributed throughout caries, with only a few Ag+ detected in the GIC layer. Hardness in the Safo+Fuji group was significantly higher compared with the Safo group at depths in the range of 10-50 µm. CONCLUSION: In the presence of GICs, SDF exhibited high remineralization capacity when diffusing throughout carious lesions over time. Combined treatment with SDF and GIC could strengthen root dentin even in the presence of caries. CLINICAL SIGNIFICANCE: We found that combination treatment with SDF and GIC could increase mineral density in caries and improve the hardness of the tooth structure compared with fluoride-based agents alone. These findings might pave the way for future clinical trials to determine the therapeutic potential of nanotechnology-based restorative materials.

Further delineation of phenotype and genotype of Kenny-Caffey syndrome type 2 (phenotype and genotype of KCS type 2).

BACKGROUND: Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention. METHODS: We present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father-to-daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases. RESULTS: There were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases. CONCLUSION: We provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father-to-daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention.

Harnessing instability for work hardening in multi-principal element alloys.

The strength-ductility trade-off has long been a Gordian knot in conventional metallic structural materials and it is no exception in multi-principal element alloys. In particular, at ultrahigh yield strengths, plastic instability, that is, necking, happens prematurely, because of which ductility almost entirely disappears. This is due to the growing difficulty in the production and accumulation of dislocations from the very beginning of tensile deformation that renders the conventional dislocation hardening insufficient. Here we propose that premature necking can be harnessed for work hardening in a VCoNi multi-principal element alloy. Lüders banding as an initial tensile response induces the ongoing localized necking at the band front to produce both triaxial stress and strain gradient, which enables the rapid multiplication of dislocations. This leads to forest dislocation hardening, plus extra work hardening due to the interaction of dislocations with the local-chemical-order regions. The dual work hardening combines to restrain and stabilize the premature necking in reverse as well as to facilitate uniform deformation. Consequently, a superior strength-and-ductility synergy is achieved with a ductility of ~20% and yield strength of 2 GPa during room-temperature and cryogenic deformation. These findings offer an instability-control paradigm for synergistic work hardening to conquer the strength-ductility paradox at ultrahigh yield strengths.

Targeted Liposomes Sensitize Plastic Melanoma to Ferroptosis via Senescence Induction and Coenzyme Depletion.

Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.

Lactate coordinated with exercise promoted the browning of inguinal white adipose tissue.

Lactate, an important exercise metabolite, induces white adipose tissue browning by upregulated uncoupling protein 1 (UCP1) expression. However, the function of lactate during browning of inguinal white adipose tissue (iWAT) caused by exercise is unclear. Here, we considered lactate as an exercise supplement and investigated the effects of chronic pre-exercise lactate administration on energy metabolism and adipose tissue browning. C57B/L6 male mice (5 weeks of age) were divided into six groups. We evaluated the changes in blood lactate levels in each group of mice after the intervention. Energy expenditure was measured after the intervention immediately by indirect calorimetry. The marker protein levels and gene expressions were determined by western-blot and quantitative real-time PCR. HIIT significantly decreased adipose tissue weight while increased energy expenditure and the expression of UCP1 in iWAT; however, these regulations were inhibited in the DCA+HIIT group. Compared with the MICT and LAC groups, long-term lactate injection before MICT led to lower WAT weight to body weight ratios and higher energy expenditure in mice. Furthermore, the marker genes of browning in iWAT, such as Ucp1 and Pparγ, were significantly increased in the LAC+MICT group than in the other groups, and the expression of monocarboxylate transporter-1 (Mct1) mRNA was also significantly increased. Lactate was involved in exercise-mediated browning of iWAT, and its mechanism might be the increased of lactate transport through MCT1 or PPARγ upregulation induced by exercise. These findings suggest exogenous lactate may be a new exercise supplement to regulate metabolism.

Deep insights into biodegradability mechanism and growth cycle adaptability of polylactic acid/hyperbranched cellulose nanocrystal composite mulch.

The widespread use of petroleum-based plastic mulch in agriculture has accelerated white and microplastic pollution while posing a severe agroecological challenge due to its difficulty in decomposing in the natural environment. However, endowing mulch film with degradability and growth cycle adaptation remains elusive due to the inherent non-degradability of petroleum-based plastics severely hindering its applications. This work reports polylactic acids hyperbranched composite mulch (PCP) and measured biodegradation behavior under burial soil, seawater, and ultraviolet (UV) aging to understand the biodegradation kinetics and to increase their sustainability in the agriculture field. Due to high interfacial interactions between polymer and nanofiler, the resultant PCP mulch significantly enhances crystallization ability, hydrophilicity, and mechanical properties. PCP mulch can be scalable-manufactured to exhibit modulated degradation performance under varying degradation conditions and periods while concurrently enhancing crop growth (wheat). Thus, such mulch with excellent performance can reduce labor costs and the environmental impact of waste mulch disposal to replace traditional mulch for sustainable agricultural production.