Self-Assembled Nanocomposite DOX/TPOR4@CB[7]4 for Enhanced Synergistic Photodynamic Therapy and Chemotherapy in Neuroblastoma.

DOX/TPOR4@CB[7]4 was synthesized via self-assembly, and its physicochemical properties and ability to generate reactive oxygen species (ROS) were evaluated. The impact of photodynamic therapy on SH-SY5Y cells was assessed using the MTT assay, while flow cytometry analysis was employed to detect cell apoptosis. Confocal laser scanning microscopy was utilized to observe the intracellular distribution of DOX/TPOR4@CB[7]4 in SH-SY5Y cells. Additionally, fluorescence imaging of DOX/TPOR4@CB[7]4 in nude mice bearing SH-SY5Y tumors and examination of the combined effects of photodynamic and chemical therapies were conducted. The incorporation of CB[7] significantly enhanced the optical properties of DOX/TPOR4@CB[7]4, resulting in increased ROS production and pronounced toxicity towards SH-SY5Y cells. Moreover, both the apoptotic and mortality rates exhibited significant elevation. In vivo experiments demonstrated that tumor growth inhibition was most prominent in the DOX/TPOR4@CB[7]4 group. π-π interactions facilitated the binding between DOX and photosensitizer TPOR, with TPOR's naphthalene hydrophilic groups encapsulated within CB[7]'s cavity through host-guest interactions with CB[7]. Therefore, CB[7] can serve as a nanocarrier to enhance the combined application of chemical therapy and photodynamic therapy, thereby significantly improving treatment efficacy against neuroblastoma tumors.

Cucurbit[8]uril Mediated Supramolecular Heterodimerisation and Photoinduced [2+2] Heterocycloaddition to Generate Unexpected [2]Rotaxanes.

In contrast to the self-assembly of homosupramolecules, the self-assembly of heterosupramolecules is more challenging and significant in various fields. Herein, we design and investigate a cucurbit[8]uril-mediated heterodimerisation using an arene-fluoroarene strategy. Moreover, the resulting heteroternary complex is found to be able to undergo a photoinduced [2+2] heterocycloaddition, resulting in the formation of an unexpected [2]rotaxane structure. This work demonstrates a novel supramolecular heterodimerisation system, not only contributing to the development of photoisomerisation systems, but also enriching synthetic methodologies of mechanically interlocked molecules.

A Portable Fluorescent Lateral Flow Immunoassay Platform for Rapid Detection of FluA.

The spread of the FluA virus poses significant public health concerns worldwide. Fluorescent lateral flow immunoassay (LFIA) test strips have emerged as vital tools for the early detection and monitoring of influenza infections. However, existing quantitative virus-detection methods, particularly those utilizing smartphone-based sensing platforms, encounter accessibility challenges in resource-limited areas and among the elderly population. Despite their advantages in speed and portability, these platforms often lack user-friendliness for these demographics, impeding their widespread utilization. To address these challenges, this study proposes leveraging the optical pick-up unit (OPU) sourced from commercial optical drives as a readily available fluorescence excitation module for the quantitative detection of antibodies labeled with quantum-dot fluorescent microspheres. Additionally, we utilize miniaturized and high-performance optical components and 3D-printed parts, along with a customized control system, to develop an affordable point-of-care testing (POCT) device. Within the system, a stepping motor scans the test strip from the T-line to the C-line, enabling the calculation of the fluorescence-intensity ratio between the two lines. This simple yet effective design facilitates rapid and straightforward field or at-home testing for FluA. The proposed prototype platform demonstrates promising performance, achieving a limit of detection (LOD) of 2.91 ng/mL, a total detection time of no more than 15 min, and dimensions of 151 mm × 11.2 mm × 10.8 mm3. We believe that the proposed approach holds great potential for improving access to an accurate influenza diagnosis.

An ultrawide-range photochromic molecular fluorescence emitter.

Photocontrollable luminescent molecular switches capable of changing emitting color have been regarded as the ideal integration between intelligent and luminescent materials. A remaining challenge is to combine good luminescence properties with wide range of wavelength transformation, especially when confined in a single molecular system that forms well-defined nanostructures. Here, we report a π-expanded photochromic molecular photoswitch, which allows for the comprehensive achievements including wide emission wavelength variation (240 nm wide, 400-640 nm), high photoisomerization extent (95%), and pure emission color (<100 nm of full width at half maximum). We take the advantageous mechanism of modulating self-assembly and intramolecular charge transfer in the synthesis and construction, and further realize the full color emission by simple photocontrol. Based on this, both photoactivated anti-counterfeiting function and self-erasing photowriting films are achieved of fluorescence. This work will provide insight into the design of intelligent optical materials.

Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury.

BACKGROUND: Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models. METHODS: We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. RESULTS: Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice. CONCLUSIONS: The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.

Diatom cell-size composition as a novel tool for quantitative estimates of the water table in peatlands.

Diatom cell-size composition is an indicator of aquatic environmental changes but has been rarely investigated, especially in semi-terrestrial peatlands. In this study, both taxonomic composition and cell-size composition of diatoms were analysed in 41 samples from two montane peatlands, northeastern China. Redundancy analyses revealed that diatom taxonomic composition was significantly related to the depth to the water table (DWT) and Ca2+, while cell-size composition was significantly associated with DWT and Si. DWT was the most important factor and its sole effect explained 26.2% and 17.9% of the total variance in taxonomic composition and cell-size composition, respectively. Accordingly, diatom-based water-table transfer functions were developed based on taxonomic composition and cell-size composition, respectively. The maximum-likelihood (ML) model based on diatom taxonomic composition had the best performance, with a correlation coefficient value (R2) of 0.78 and the root mean squared error of prediction (RMSEP) of 6.66 cm. The ML model based on cell-size composition had similar performance, with an R2 of 0.78 and the RMSEP of 6.87 cm, suggesting that diatom cell-size composition can be a new quantitative means to track past water-table changes. This method requires further appraisal with palaeoecological data but offers a new option that deserves exploration.

Bioactive Metal Ion-Coordinated Dynamic Hydrogel with Antibacterial, Immunomodulatory, and Angiogenic Activities for Infected Wound Repair.

The repair of infected wounds is a complex physiopathologic process. Current studies on infected wound treatment have predominantly focused on infection treatment, while the factors related to delayed healing caused by vascular damage and immune imbalance are commonly overlooked. In this study, an extracellular matrix (ECM)-like dynamic and multifunctional hyaluronic acid (HA) hydrogel with antimicrobial, immunomodulatory, and angiogenic capabilities was designed as wound dressing for the treatment of infected skin wounds. The dynamic network in the hydrogel dressing was based on reversible metal-ligand coordination formed between sulfhydryl groups and bioactive metal ions. In our design, antibacterial silver and immunomodulatory zinc ions were employed to coordinate with sulfhydrylated HA and a vasculogenic peptide. In addition to the desired bioactivities for infected wounds, the hydrogel could also exhibit self-healing and injectable abilities. Animal experiments with infected skin wound models indicated that the hydrogel dressings enabled minimally invasive injection and seamless skin wound covering and then facilitated wound healing by efficient bacterial killing, continuous inflammation inhibition, and improved blood vessel formation. In conclusion, the metal ion-coordinated hydrogels with wound-infection-desired bioactivities and ECM-like dynamic structures represent a class of tissue bionic wound dressings for the treatment of infected and chronic inflammation wounds.

Cross-species transmission of a novel bisegmented orfanplasmovirus in the phytopathogenic fungus Exserohilum rostratum.

Mycoviruses have been found in various fungal species across different taxonomic groups, while no viruses have been reported yet in the fungus Exserohilum rostratum. In this study, a novel orfanplasmovirus, namely Exserohilum rostratum orfanplasmovirus 1 (ErOrfV1), was identified in the Exserohilum rostratum strain JZ1 from maize leaf. The complete genome of ErOrfV1 consists of two positive single-stranded RNA segments, encoding an RNA-dependent RNA polymerase and a hypothetical protein with unknown function, respectively. Phylogenetic analysis revealed that ErOrfV1 clusters with other orfanplasmoviruses, forming a distinct phyletic clade. A new family, Orfanplasmoviridae, is proposed to encompass this newly discovered ErOrfV1 and its associated orfanplasmoviruses. ErOrfV1 exhibits effective vertical transmission through conidia, as evidenced by its 100% presence in over 200 single conidium isolates. Moreover, it can be horizontally transmitted to Exserohilum turcicum. Additionally, the infection of ErOrfV1 is cryptic in E. turcicum because there were no significant differences in mycelial growth rate and colony morphology between ErOrfV1-infected and ErOrfV1-free strains. This study represents the inaugural report of a mycovirus in E. rostratum, as well as the first documentation of the biological and transmission characteristics of orfanplasmovirus. These discoveries significantly contribute to our understanding of orfanplasmovirus.

Parasitic behavior and developmental morphology of Mesocomys trabalae (Hymenoptera: Eupelmidae), a promising parasitoid of the Japanese giant silkworm Caligula japonica (Lepidoptera: Saturniidae).

The egg parasitoid Mesocomys trabalae Yao, Yang, and Zhao is used as a biocontrol agent against the emerging defoliator pest Caligula japonica Moore in East Asia. It has been proven that the eggs of Antheraea pernyi Guérin-Méneville can be used as a factitious host for the mass production of M. trabalae. We examined the parasitic behavior and morphological characteristics of the developmental stages of M. trabalae reared on A. pernyi eggs. The parasitic behavior of M. trabalae encompasses 10 steps, involving searching, antennation, locating the oviposition site, drilling, probing, detecting, oviposition, host feeding, grooming, and resting, with the oviposition step further divided into 3 stages. We determined that the parasitoid released an egg during the second stage of the oviposition step, while her body remained in a relatively static state. Among all the steps in parasitic behavior, probing occupied the longest time, accounting for 26.33% of the entire parasitism process. It was followed by oviposition (15.88%), drilling (15.10%), antennation (13.09%), detecting (10.79%), host feeding (10.02%), and the remaining steps, each occupying less than 5.00% of the total time in steps. The pre-emergence of adult M. trabalae comprised of 4 stages: egg (0-1 day), larva (2-6 days), prepupa (7-11 days), pupa (12-20 days), followed by the development into an adult, and it usually took 20-22 days to develop from an egg into an adult at 25°C. This study advances our understanding of the biology of Mesocomys parasitoids and their mass-rearing for use in augmentation programs.

ATG5-mediated keratinocyte ferroptosis promotes M1 polarization of macrophages to aggravate UVB-induced skin inflammation.

Autophagy participates in the regulation of ferroptosis. Among numerous autophagy-related genes (ATGs), ATG5 plays a pivotal role in ferroptosis. However, how ATG5-mediated ferroptosis functions in UVB-induced skin inflammation is still unclear. In this study, we unveil that the core ferroptosis inhibitor GPX4 is significantly decreased in human skin tissue exposed to sunlight. We report that ATG5 deletion in mouse keratinocytes strongly protects against UVB-induced keratinocyte ferroptosis and skin inflammation. Mechanistically, ATG5 promotes the autophagy-dependent degradation of GPX4 in UVB-exposed keratinocytes, which leads to UVB-induced keratinocyte ferroptosis. Furthermore, we find that IFN-γ secreted by ferroptotic keratinocytes facilitates the M1 polarization of macrophages, which results in the exacerbation of UVB-induced skin inflammation. Together, our data indicate that ATG5 exacerbates UVB-induced keratinocyte ferroptosis in the epidermis, which subsequently gives rise to the secretion of IFN-γ and M1 polarization. Our study provides novel evidence that targeting ATG5 may serve as a potential therapeutic strategy for the amelioration of UVB-caused skin damage.

Suicidal ideation in adolescents with adiponectin receptor 2 rs12342 polymorphism affected by Wenchuan earthquake.

PURPOSE: The present study was to investigate prevalence of suicidal ideation and its associations with biological and environmental factors in adolescents with different genotypes of rs12342 at adiponectin receptor 2 gene (ADIPOR2). METHODS: Suicidal ideation, biological and environmental factors were evaluated by questionnaires in 669 high school students after Wenchuan earthquake in China. ADIPOR2 rs12342 was genotyped by polymerase chain reaction-restriction fragment length polymorphism and verified by DNA sequencing. RESULTS: Female adolescents had higher prevalence of suicidal ideation than male students in AG heterozygote and GG homozygote, but not AA homozygote. Prevalence of suicidal ideation was different in male, but not female, subjects with different genotypes. Genotype and allele frequencies were significantly different between male students with and without suicidal ideation, but not the female counterparts. Family history of mental disorders, extent of damage to property, carbohydrate intake and protein intake were associated with suicidal ideation in female subjects, while ADIPOR2 rs12342, father's educational level and previous trauma experience were associated with suicidal ideation in male subjects. CONCLUSION: ADIPOR2 rs12342 is associated with and has potential to interact with environmental factors on suicidal ideation in a gender-dependent manner in youth. These findings pave a novel way and perspective for precision inferences of suicidal ideation in subjects with different genetic backgrounds. ADIPOR2 rs12342 needs to be considered when intervening suicidal ideation, especially in adolescents.

Physiological occlusal force attenuates replacement root resorption of replanted teeth: an experimental animal study.

BACKGROUND: Tooth avulsion represents the most severe form of dental trauma, necessitating tooth replantation as the primary treatment. However, the risk of replacement root resorption (RRR) poses a significant threat to tooth retention following replantation. This study preliminarily aimed to investigate the effect of physiological occlusal force on RRR after the replantation of avulsed teeth and to explore the potential underlying mechanisms. METHODS: Thirty-six 4-week-old male Sprague-Dawley rats underwent extraction and immediate replantation of their left maxillary molars. The rats were randomly divided into two major groups: the occluded (n = 18) group, where the opposite mandibular teeth were preserved; non-occluded (n = 18) group, where the opposite mandibular teeth were extracted. Within each major group, there were three subgroups corresponding to 7 days, 14 days, and 2 months, resulting in a total of six subgroups, (n = 6 per subgroup). The right maxillary first molars served as the normal control. Various periodontal characteristics were assessed using haematoxylin-eosin (H&E), tartrate-resistant acid phosphatase (TRAP) staining, and micro-computed tomography (micro-CT). RESULTS: Histological staining revealed that under occlusal force, the early stage (day 7) after tooth replantation mainly manifested as root surface resorption, especially in the non-occluded group, which gradually diminished over time. Cementum and periodontal ligament (PDL) repair was observed on day 14. Micro-CT analysis indicated a significant decrease in PDL width in the non-occluded group two months after replantation, consistent with the histological findings, signifying severe RRR in the non-occluded group. CONCLUSIONS: This study provides preliminary evidence that physiological occlusal force may attenuate osteoclastogenesis during the early stage of tooth replantation, thereby reducing the occurrence of RRR and promoting periodontal healing.

Shared and unique alterations of large-scale network connectivity in drug-free adolescent-onset and adult-onset major depressive disorder.

Differences in clinical manifestations and biological underpinnings between Major Depressive Disorder (MDD) onset during adolescence and adulthood have been posited in previous studies, implying an influential role of age of onset (AOO) in the clinical subtyping and therapeutic approaches to MDD. However, direct comparisons between the two cohorts and their age-matched controls have been lacking in extant investigations. In this investigation, 156 volunteers participated, comprising 46 adolescents with MDD (adolescent-onset group), 35 adults with MDD (adult-onset group), 19 healthy adolescents, and 56 healthy adults. Resting-state functional MRI scans were undergone by all participants. Large-scale network analyses were applied. Subsequently, a 2 × 2 ANOVA was employed to analyze the main effects of diagnosis, age, and their interaction effect on functional connectivity (FC). Furthermore, regression analysis was employed to scrutinize the association between anomalous FC and HAMD sub-scores. Increased FC in visual network (VN), limbic network (LN), VN-dorsal attention network (DAN), VN-LN, and LN-Default Mode (DMN) was found in both adolescent-onset and adult-onset MDD; however, the increased FC in DAN and LN were only found in adult-onset MDD and the decreased FC in DAN was only found in adolescent-onset MDD. Additionally, the relationship between HAMD factor 1 anxiety somatization and altered FC of DAN, VN, and VN-DAN was moderated by AOO. In conclusion, shared and distinctive large-scale network alterations in adolescent-onset and adult-onset MDD patients were suggested by our findings, providing valuable contributions towards refining clinical subtyping and treatment approaches for MDD.

Opioid Nonadherence Risk Prediction of Patients with Cancer-Related Pain Based on Five Machine Learning Algorithms.

Objectives: Opioid nonadherence represents a significant barrier to cancer pain treatment efficacy. However, there is currently no effective prediction method for opioid adherence in patients with cancer pain. We aimed to develop and validate a machine learning (ML) model and evaluate its feasibility to predict opioid nonadherence in patients with cancer pain. Methods: This was a secondary analysis from a cross-sectional study that included 1195 patients from March 1, 2018, to October 31, 2019. Five ML algorithms, such as logistic regression (LR), random forest, eXtreme Gradient Boosting, multilayer perceptron, and support vector machine, were used to predict opioid nonadherence in patients with cancer pain using 43 demographic and clinical factors as predictors. The predictive effects of the models were compared by the area under the receiver operating characteristic curve (AUC_ROC), accuracy, precision, sensitivity, specificity, and F1 scores. The value of the best model for clinical application was assessed using decision curve analysis (DCA). Results: The best model obtained in this study, the LR model, had an AUC_ROC of 0.82, accuracy of 0.82, and specificity of 0.71. The DCA showed that clinical interventions for patients at high risk of opioid nonadherence based on the LR model can benefit patients. The strongest predictors for adherence were, in order of importance, beliefs about medicines questionnaire (BMQ)-harm, time since the start of opioid, and BMQ-necessity. Discussion. ML algorithms can be used as an effective means of predicting adherence to opioids in patients with cancer pain, which allows for proactive clinical intervention to optimize cancer pain management. This trial is registered with ChiCTR2000033576.

Robot-assisted Radical Prostatectomy with the KangDuo Surgical System Versus the da Vinci Si System: A Prospective, Double-center, Randomized Controlled Trial.

BACKGROUND: The KangDuo Surgical Robot (KD-SR) is a newly developed surgical robot. OBJECTIVE: To compare the safety and efficacy of robot-assisted radical prostatectomy (RARP) using the KD-SR with those of the da Vinci Si Surgical System (DV-SS-Si). DESIGN, SETTING, AND PARTICIPANTS: A prospective double-center noninferiority randomized controlled trial was conducted among 18-75-yr-old patients with suspected T1-2N0M0 prostate cancer (PCa) scheduled for RARP. INTERVENTION: RARP with the KD-SR (KD-RARP) versus RARP with the DV-SS-Si (DV-RARP). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was surgical success, defined as follows: surgery can be performed according to the established protocol, without switching to other surgical modalities, and without secondary surgery due to surgical complications after surgery. The secondary outcome was short-term functional and oncological outcomes. The noninferiority threshold was set at 10%. RESULTS AND LIMITATIONS: Eighty patients were enrolled, while the full analysis set finally included 79 patients (40 with KD-RARP and 39 with DV-RARP). The success rate was 100% in both groups. We could not find differences in urinary continence rate at 1, 2, 3, and 4 wk after catheter removal between the groups (p > 0.05). The rate of Clavien-Dindo grade II adverse events was 20% in the KD-RARP group and 17.9% in the DV-RARP group (p = 0.82), and no grade ≥III adverse events occurred. The median operation time was significantly longer in the KD-RARP group than in the DV-RARP group (177.5 vs 145 min, p = 0.012). The main limitations were the short follow-up period and that survival was not considered as the primary outcome. CONCLUSIONS: The KD-SR is a viable option for RARP, with acceptable short-term outcomes compared with the DV-SS-Si for T1-2 PCa. PATIENT SUMMARY: This is the first prospective randomized controlled trial to compare the KangDuo Surgical Robot (KD-SR) versus the da Vinci Si Surgical System (DV-SS-Si) for robot-assisted radical prostatectomy, which determines that the KD-SR is noninferior to the DV-SS-Si regarding safety and efficacy for T1-T2 prostate cancer.

Stem Cell-Derived Nanovesicles Embedded in Dual-Layered Hydrogel for Programmed ROS Regulation and Comprehensive Tissue Regeneration in Burn Wound Healing.

Burn wounds often bring high risks of delayed healing process and even death. Reactive oxygen species (ROS) play a crucial role in burn wound repair. However, the dynamic process in wound healing requires both the generation of ROS to inhibit bacteria and the subsequent reduction of ROS levels to initiate and promote tissue regeneration, which calls for a more intelligent ROS regulation dressing system. Hence, a dual-layered hydrogel (Dual-Gel) tailored to the process of burn wound repair is designed: the inner layer hydrogel (Gel 2) first responds to bacterial hyaluronidase (Hyal) to deliver aggregation-induced emission photosensitizer functionalized adipose-derived stem cell nanovesicles, which generate ROS upon light irradiation to eliminate bacteria; then the outer layer hydrogel (Gel 1) continuously starts a long-lasting consumption of excess ROS at the wound site to accelerate tissue regeneration. Simultaneously, the stem cell nanovesicles trapped in the burns wound also provide nutrients and mobilize neighboring tissues to thoroughly assist in inflammation regulation, cell proliferation, migration, and angiogenesis. In summary, this study develops an intelligent treatment approach on burn wounds by programmatically regulating ROS and facilitating comprehensive wound tissue repair.

Chemical Constituents with Anti-Proliferative Activity on Pulmonary Arterial Smooth Muscle Cells from the Roots of Anthriscus sylvestris (L.) Hoffm.

A chemical investigation of Anthriscus sylvestris roots led to the isolation and characterization of two new nitrogen-containing phenylpropanoids (1-2) and two new phenol glycosides (8-9), along with fifteen known analogues. Structure elucidation was based on HRESIMS, 1D and 2D NMR spectroscopy, and electronic circular dichroism (ECD). In addition, compounds 3, 6, 9-10, 12, and 17 exhibited inhibitory effects against the abnormal proliferation of pulmonary arterial smooth muscle cells with IC50 values ranging from 10.7 ± 0.6 to 57.1 ± 1.1 µM.

Co-Immobilization of Alcalase/Dispase for Production of Selenium-Enriched Peptide from Cardamine violifolia.

Enzymatically derived selenium-enriched peptides from Cardamine violifolia (CV) can serve as valuable selenium supplements. However, the industrial application of free enzyme is impeded by its limited stability and reusability. Herein, this study explores the application of co-immobilized enzymes (Alcalase and Dispase) on amino resin for hydrolyzing CV proteins to produce selenium-enriched peptides. The successful enzyme immobilization was confirmed through scanning electron microscopy (SEM), energy dispersive X-ray (EDX), and Fourier-transform infrared spectroscopy (FTIR). Co-immobilized enzyme at a mass ratio of 5:1 (Alcalase/Dispase) exhibited the smallest pore size (7.065 nm) and highest activity (41 U/mg), resulting in a high degree of hydrolysis of CV protein (27.2%), which was obviously higher than the case of using free enzymes (20.7%) or immobilized Alcalase (25.8%). In addition, after a month of storage, the co-immobilized enzyme still retained a viability level of 41.93%, showing fairly good stability. Encouragingly, the selenium-enriched peptides from co-immobilized enzyme hydrolysis exhibited uniform distribution of selenium forms, complete amino acid fractions and homogeneous distribution of molecular weight, confirming the practicality of using co-immobilized enzymes for CV protein hydrolysis.

UV-B Radiation Disrupts Membrane Lipid Organization and Suppresses Protein Mobility of GmNARK in Arabidopsis.

While it is well known that plants interpret UV-B as an environmental cue and a potential stressor influencing their growth and development, the specific effects of UV-B-induced oxidative stress on the dynamics of membrane lipids and proteins remain underexplored. Here, we demonstrate that UV-B exposure notably increases the formation of ordered lipid domains on the plasma membrane (PM) and significantly alters the behavior of the Glycine max nodule autoregulation receptor kinase (GmNARK) protein in Arabidopsis leaves. The GmNARK protein was located on the PM and accumulated as small particles in the cytoplasm. We found that UV-B irradiation interrupted the lateral diffusion of GmNARK proteins on the PM. Furthermore, UV-B light decreases the efficiency of surface molecule internalization by clathrin-mediated endocytosis (CME). In brief, UV-B irradiation increased the proportion of the ordered lipid phase and disrupted clathrin-dependent endocytosis; thus, the endocytic trafficking and lateral mobility of GmNARK protein on the plasma membrane are crucial for nodule formation tuning. Our results revealed a novel role of low-intensity UV-B stress in altering the organization of the plasma membrane and the dynamics of membrane-associated proteins.

Integrated Anchored Stapling and Hierarchical Dynamics: MSICDA-Driven CREBBP Bromodomain Inhibition.

Despite recent success in the computational approaches of cyclic peptide design, current studies face challenges in modeling noncanonical amino acids and nonstandard cyclizations due to limited data. To address this challenge, we developed an integrated framework for the tailored design of stapled peptides (SPs) targeting the bromodomain of CREBBP (CREBBP-BrD). We introduce a powerful combination of anchored stapling and hierarchical molecular dynamics to design and optimize SPs by employing the MultiScale integrative conformational dynamics assessment (MSICDA) strategy, which involves an initial virtual screening of over 1.5 million SPs, followed by comprehensive simulations amounting to 154.54 µs across 5418 of instances. The MSICDA method provides a detailed and holistic stability view of peptide-protein interactions, systematically isolated optimized peptides and identified two leading candidates, DA#430 and DA#99409, characterized by their enhanced stability, optimized binding, and high affinity toward the CREBBP-BrD. In cell-free assays, DA#430 and DA#99409 exhibited 2- to 12-fold greater potency than inhibitor SGC-CBP30. Cell studies revealed higher peptide selectivity for cancerous versus normal cells over small molecules. DA#430 combined with (+)-JQ-1 showed promising synergistic effects. Our approach enables the identification of peptides with optimized binding, high affinity, and enhanced stability, leading to more precise and effective cyclic peptide design, thereby establishing MSICDA as a generalizable and transformative tool for uncovering novel targeted drug development in various therapeutic areas.