An ultrasound-activated nanoplatform remodels tumor microenvironment through diverse cell death induction for improved immunotherapy.

Although nanomaterial-based nanomedicine provides many powerful tools to treat cancer, most focus on the "immunosilent" apoptosis process. In contrast, ferroptosis and immunogenic cell death, two non-apoptotic forms of programmed cell death (PCD), have been shown to enhance or alter the activity of the immune system. Therefore, there is a need to design and develop nanoplatforms that can induce multiple modes of cell death other than apoptosis to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment for cancer therapy. In this study, a new type of multifunctional nanocomposite mainly consisting of HMME, Fe3+ and Tannic acid, denoted HFT NPs, was designed and synthesized to induce multiple modes of cell death and prime the tumor microenvironment (TME). The HFT NPs consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O2 upon ultrasound irradiation, and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS ·OH through inorganic catalytic reactions. The administration of HFT NPs and subsequent ultrasound treatment caused cell death through the consumption of GSH, the generation of ROS, ultimately inducing apoptosis, ferroptosis, and immunogenic cell death (ICD). More importantly, the combination of HFT NPs and ultrasound irradiation could reshape the TME and recruit more T cell infiltration, and its combination with immune checkpoint blockade anti-PD-1 antibody could eradicate tumors with low immunogenicity and a cold TME. This new nano-system integrates sonodynamic and chemodynamic properties to achieve outstanding therapeutic outcomes when combined with immunotherapy. Collectively, this study demonstrates that it is possible to potentiate cancer immunotherapy through the rational and innovative design of relatively simple materials.

Deep insight into regulation mechanism of band distribution in phase junction CdS for enhanced photocatalytic H2 production.

An in-depth understanding of structure-activity relationship between the phase constitution and solar-to-hydrogen (STH) conversion efficiency is conducive to guiding the optimization route of targeted photocatalyst candidates, further establishing advanced photocatalytic systems. Herein, based on the concept of phase engineering, we encompassed the crystalline phase of CdS and achieved precise regulation of phase proportion as well as phase boundary width in the phase junction for the first time. The above cooperative effect not only modifies energy band distribution for sufficient redox potentials, but also guarantees the reverse migration orientation of photogenerated carriers in phase junction, thereby endowing photocarriers with a prolonged lifetime. Compared to pure cubic or hexagonal phase (72.6 or 101.1 µmol h-1 g-1), this CdS system with optimized phase junction demonstrates an improved photocatalytic hydrogen evolution activity of 1.04 mmol h-1 g-1 and favorable stability without cocatalyst assistance, which mainly stems from an efficient protons reduction process interacting with long-lived photogenerated electrons. This research explores the mechanism behind phase regulation and its relationship with junction capability, providing a powerful strategy to manipulate crystal phase distribution and paving a feasible avenue for other phase-dependent photocatalysts towards rational design of heterostructures based on different phases in solar energy conversion field.

Enhancing Electrocatalytic Kinetics via Synergy of Co Nanoparticles and Co/Ni-N4-C- and N-Doped Porous Carbon.

Transition-metal species embedded in carbon have sparked intense interest in the fields of oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). However, improvement of the electrocatalytic kinetics remains a challenge caused by the synergistic assembly. Here, we propose a biochemical strategy to fabricate the Co nanoparticles (NPs) and Co/Ni-N4-C co-embedded N-doped porous carbon (CoNPs&Co/Ni-N4-C@NC) catalysts via constructing the zeolitic imidazolate framework (ZIF)@yeast precursor. The rich amino groups provide the possibility for the anchorage of Co2+/Ni2+ ions as well as the construction of Co/Ni-ZIF@yeast through the yeast cell biomineralization effect. The functional design induces the formation of CoNPs and Co/Ni-N4-C sites in N-doped carbon as well as regulates the porosity for exposing such sites. Synergy of CoNPs, Co/Ni-N4-C, and porous N-doped carbon delivered excellent electrocatalytic kinetics (the ORR Tafel slope of 76.3 mV dec-1 and the OER Tafel slope of 80.4 mV dec-1) and a high voltage of 1.15 V at 10 mA cm-2 for the discharge process in zinc air batteries. It provides an effective strategy to fabricate high-performance catalysts.

Nanoproteases: Alternatives to Natural Protease for Biotechnological Applications.

Some nanomaterials with intrinsic protease-like activity have the advantages of good stability, biosafety, low price, large-scale preparation and unique property of nanomaterials, which are promising alternatives for natural proteases in various applications. An especial term, "nanoprotease", has been coined to stress the intrinsic proteolytic property of these nanomaterials. As a new generation of artificial proteases, they have become a burgeoning field, attracting many researchers to design and synthesize high performance nanoproteases. In this review, we summarize recent progress on all types of nanoproteases with regard of their activity, mechanism and application and introduce a new and effective strategy for engineering high-performance nanoproteases. In addition, we discuss the challenges and opportunities of nanoprotease research in the future.

MiR-2284b regulation of α-s1 casein synthesis in mammary epithelial cells of dairy goats.

The lactation character of dairy goats is the most important characteristic, and milk protein is an important index to evaluate milk quality. Casein accounts for more than 80% of the total milk protein in goat milk and is the main component of milk protein. Using GMECs (goat mammary epithelial cells) as the research object, the CHECK2 vector of the CSN1S1 gene and the overexpression vector of pcDNA 3.1 were constructed, and the mimics of miR-2284b and the interfering RNA of CSN1S1 were synthesized. Using PCR, RT-qPCR, a dual luciferase activity detection system, EdU, CCK8, cell apoptosis detection and ELISA detection, we explored the regulatory mechanism and molecular mechanism of miR-2284b regulation of αs1-casein synthesis in GMECs. miR-2284b negatively regulates proliferation and apoptosis of GMECs and αs1-casein synthesis. Two new gene sequences of CSN1S1 were discovered. CSN1S1-1/-2 promoted the proliferation of GMECs and inhibited cell apoptosis. However, it had no effect on αs1-casein synthesis. MiR-2284b negatively regulates αs1-casein synthesis in GMECs by inhibiting the CSN1S1 gene. These results all indicated that miR-2284b could regulate αs1-casein synthesis, thus playing a theoretical guiding role in the future breeding process of dairy goats and accelerating the development of dairy goat breeding.

Structural insights into the Clp protein degradation machinery.

The Clp protease system is important for maintaining proteostasis in bacteria. It consists of ClpP serine proteases and an AAA+ Clp-ATPase such as ClpC1. The hexameric ATPase ClpC1 utilizes the energy of ATP binding and hydrolysis to engage, unfold, and translocate substrates into the proteolytic chamber of homo- or hetero-tetradecameric ClpP for degradation. The assembly between the hetero-tetradecameric ClpP1P2 chamber and the Clp-ATPases containing tandem ATPase domains from the same species has not been studied in depth. Here, we present cryo-EM structures of the substrate-bound ClpC1:shClpP1P2 from Streptomyces hawaiiensis, and shClpP1P2 in complex with ADEP1, a natural compound produced by S. hawaiiensis and known to cause over-activation and dysregulation of the ClpP proteolytic core chamber. Our structures provide detailed information on the shClpP1-shClpP2, shClpP2-ClpC1, and ADEP1-shClpP1/P2 interactions, reveal conformational transition of ClpC1 during the substrate translocation, and capture a rotational ATP hydrolysis mechanism likely dominated by the D1 ATPase activity of chaperones.IMPORTANCEThe Clp-dependent proteolysis plays an important role in bacterial homeostasis and pathogenesis. The ClpP protease system is an effective drug target for antibacterial therapy. Streptomyces hawaiiensis can produce a class of potent acyldepsipeptide antibiotics such as ADEP1, which could affect the ClpP protease activity. Although S. hawaiiensis hosts one of the most intricate ClpP systems in nature, very little was known about its Clp protease mechanism and the impact of ADEP molecules on ClpP. The significance of our research is in dissecting the functional mechanism of the assembled Clp degradation machinery, as well as the interaction between ADEP1 and the ClpP proteolytic chamber, by solving high-resolution structures of the substrate-bound Clp system in S. hawaiiensis. The findings shed light on our understanding of the Clp-dependent proteolysis in bacteria, which will enhance the development of antimicrobial drugs targeting the Clp protease system, and help fighting against bacterial multidrug resistance.

Focus on Upper Urinary Tract Stones Combined with Parenchymal Infiltrative Renal Pelvis Cancer.

INTRODUCTION: Upper urinary tract stones combined with parenchymal infiltrative renal pelvic cancer are challenging to detect on imaging and to evaluate the differential diagnosis. CASE PRESENTATION: The symptoms and diagnoses in three cases of parenchymal infiltrative renal pelvic cancer and upper urinary tract stones that occurred between June 2019 and June 2022 were reviewed. Primary symptoms of lumbar discomfort and hematuria were evident in all 3 patients. Preoperative computed tomography (CT) abdominal imaging revealed that all three cases had hydronephrosis along with renal stones, while the other two cases only had localized hypoenhancement of the renal parenchyma, which was only thought to be limited inflammatory changes in the renal cortex as a result of the combination of renal pelvis infection. After percutaneous nephrolithotomy or ureteroscopic lithotripsy, a combined renal pelvis tumor was discovered in all of these instances. Radical tumor surgery was later performed. One patient who had several tumor metastases passed away 6 months after surgery. A case with multiple metastases was discovered 15 months after surgery and survived with the help of the current chemotherapy. A case with a bladder tumor recurrence was discovered 16 months after surgery and had transurethral bladder tumor electrosurgery and routine bladder perfusion chemotherapy. CONCLUSION: Upper urinary tract stones and parenchymal infiltrative pyel carcinoma have atypical imaging, easily confused with infectious diseases. CT or computed tomography urography (CTU) must be considered by urologists. Patients who have a CT with local renal parenchyma density should be suspected of having parenchymal invasive renal pelvis carcinoma; a needle biopsy ought to be performed; and repeat biopsies may be performed if necessary. High-risk individuals need multiple, sufficient biopsies as needed and a comprehensive intraoperative assessment of the renal pelvic mucosa.

Adult head and neck rhabdomyosarcoma: radiotherapy- based treatment, outcomes, and predictors of survival.

BACKGROUND: Adult head and neck rhabdomyosarcoma (HNRMS) is an exceptionally rare malignancy, and there is a paucity of data and research dedicated to understanding its characteristics and management in adult populations. This study aimed to assess the outcomes and identify survival predictors in adult HNRMS. METHODS: We retrospectively evaluated 42 adult patients (> 16 years) with HNRMS who received radiotherapy (RT)-based treatment at our institute between 2008 and 2022. We analysed the clinical characteristics and prognosis of these patients, including the locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS), using the Kaplan-Meier method. The chi-square and Fisher's exact tests were used to analyse differences between groups for dichotomous and categorical variables, respectively. Survival rates were calculated using the Kaplan-Meier method. Prognostic variables were assessed through univariate Cox analyses. RESULTS: The median patient age was 28 years (range, 16-82 years). Alveolar RMS was the most common histological type, observed in 21 patients (50.0%), followed by embryonal in 16 patients (38.1%). The anatomic sites of origin were orbital in one (2.4%), parameningeal in 26 (61.9%), and non-orbital/non-parameningeal in 15 (35.7%) patients. Nineteen patients (45.2%) had regional lymph node metastasis, and five patients (11.9%) presented with distant metastatic disease. Distant metastasis (n = 17) was the primary cause of treatment failure. At a median follow-up of 47.0 months, the 5-year LRFS, PFS, and OS rates were 69.0%, 39.7%, and 41.0%, respectively. Univariate analysis revealed that tumour size, lymph node involvement, and the local treatment pattern (surgery and RT vs. RT alone) were significant predictors of survival. CONCLUSIONS: The main failure pattern in patients with HNRMS receiving RT-based treatment was distant metastasis. Tumour size > 5 cm and lymph node involvement were predictors of worse LRFS. Multimodality local treatment, combining surgery and RT, is effective and provides survival benefits.

Yinhuang buccal tablet alters airway microbiota composition and metabolite profile in healthy humans.

ETHNOPHARMACOLOGICAL RELEVANCE: Perturbations in airway microbiota composition and disruption of microbe-metabolite interactions have been observed in respiratory infectious diseases (RIDs). The Yinhuang (YH) buccal tablet, as an ancient Chinese medicinal formula, has been traditionally employed for the management of upper RIDs. However, there is a lack of evidence for the effects of YH buccal tablets on upper respiratory tract microbiota and circulating metabolites. AIM OF THE STUDY: The aim of this study was to analyze the changes in respiratory microbiota composition and circulating metabolite profile after YH buccal tablets administration. MATERIALS AND METHODS: Throat swab samples and serum samples were collected from 60 healthy subjects for high-throughput 16S ribosomal RNA gene (16S rRNA) sequencing and non-targeted Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. RESULTS: Airway microbial composition changed significantly after YH administration. The abundance of Actinomyces and Prevotella_7 increased, while the abundance of potentially pathogenic Pseudomonas and Corynebacterium decreased. A total of 168 significant HMDB taxonomic metabolites were identified in serum samples, of which lipid metabolites accounted for the largest proportion. Correlation analysis showed that circulatory metabolites were significantly correlated with changes in airway microbiota composition. CONCLUSIONS: YH buccal tablets can inhibit opportunistic pathogens, increase beneficial microorganisms in the upper respiratory tract, and regulate the body's metabolic pathways. These findings provide insights into the mechanism of action of YH buccal tablets in the treatment and prevention of respiratory diseases.

A decentralized and security-enhanced professional title evaluation system in universities under mobile Internet of Things.

Digital online application is a commonly used method for professional title evaluation in colleges and universities. With the rapid development of the mobile Internet of Things, the fastest way for users to access the evaluation system is through mobile devices. However, this also poses security challenges to the traditional professional title evaluation system. Therefore, this paper proposes a decentralized and security-enhanced digital title evaluation system in mobile IoT. Since the system uses blockchain to implement a decentralized review process, the transparency and fairness of the review process are guaranteed. At the same time, the review data and reviewer information in the system are encrypted and stored in the distributed network to ensure the security and non-tamperability of the data. All review records are recorded on the blockchain, and anyone can view and verify the legitimacy of the review results. Additionally, the system incorporates security enhancement mechanisms such as identity verification, smart contracts, and auditing functions to improve the credibility of the evaluation process and prevent cheating under mobile IoT. Experiments have shown that this system has important application value in the field of professional title review in universities, which can improve review efficiency, reduce human intervention, and provide strong support for the credibility of review results.

A real-world evaluation of tislelizumab in patients with head and neck cancer.

Background: Various studies support the use of programmed cell death protein 1 (PD-1) blockades, also known as immune checkpoint inhibitors (ICIs), to treat head and neck cancer (HNC). Tislelizumab is a humanised immunoglobulin G4 (IgG4) monoclonal antibody with a high affinity and specificity for PD-1. However, the "real-world" clinical evidence of tislelizumab for HNC is limited. Methods: In this study, the medical records of 39 patients with head and neck squamous cell carcinoma (HNSCC) or nasopharyngeal carcinoma (NPC) who received tislelizumab between January 2021 and March 2022 were reviewed retrospectively. Tislelizumab was administered to 15 patients during neoadjuvant therapy (Group 1), five patients during adjuvant therapy (Group 2), 14 patients during consolidation therapy (Group 3), and five patients during salvage therapy (Group 4). The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS). Results: The median age of enrolled patients was 55 (range, 28-83) years. The median follow-up time was 27.1, 26.1, 28.6, and 20.9 months for Groups 1, 2, 3, and 4, respectively. The mean PFS and OS of Groups 1, 2, 3, and 4 were 21.5 and 22.8; 24.1 and 24.2; 26.9 and 28.1; and 13.9 and 17.1 months, respectively. In Groups 1 and 4, the objective response rate (ORR) was 86.7% and 60%, respectively. Meanwhile, except for one (2.6%) patient with grade 4 enteritis, the other observed non-haematological adverse events (AEs) were ≤ grade 2. Conclusions: Tislelizumab demonstrated promising efficacy and tolerability in patients with HNSCC or NPC in a real-world setting, consistent with previous reports.

Therapeutic effects of finasteride: inhibition of disease progression and serum prostate-specific antigen reduction in patients with prostatic intraepithelial neoplasia.

The objective of this study was to evaluate the impact of finasteride on the progression of prostate intraepithelial neoplasia and levels of prostate-specific antigen (PSA) in patients. A total of 120 patients with high-grade prostatic intraepithelial neoplasia were included in this study from January 2013 to January 2018. All patients underwent prostate biopsies. Among them, 60 patients were assigned to the observation group and received a daily dosage of 5 mg finasteride for 60 months, while the remaining 60 patients were assigned to the control group and did not receive finasteride. PSA levels were measured every six months, and imaging scans were conducted throughout the five-year study period. Additional biopsies were performed if PSA levels exceeded 10 ng/mL or imaging suggested the presence of prostate cancer. Statistical analysis was applied to the collected data. In total, 25 cases of prostate cancer were identified in this study. Of these cases, 7 patients belonged to the observation group, whereas the remaining 18 patients were from the control group. The observation group exhibited significantly lower levels of total serum PSA (p < 0.001) and Gleason scores (p < 0.001) compared to the control group. Our study, which involved 120 participants, demonstrated that finasteride effectively reduces serum PSA levels and mitigates the severity of prostate cancer. These findings suggest that finasteride holds potential as a treatment option for patients with -high-grade prostatic intraepithelial neoplasia.

A historical controlled study of domestic trastuzumab and pertuzumab in combination with docetaxel for the neoadjuvant treatment of early HER2-positive breast cancer.

Background: HER2-positive molecular breast cancer subtypes are characterized by high aggressiveness and malignancy, and their metastasis and mortality rates are among the highest of all types of breast cancer. The use of anti-HER2-targeted agents in neoadjuvant therapy has significantly improved the prognosis of patients with HER2-positive breast cancer. In this study, we investigated the efficacy and safety of a neoadjuvant Chinese THP regimen (docetaxel, trastuzumab biosimilar TQB211 plus the pertuzumab biosimilar TQB2440 or pertuzumab) for ER/PR-negative and HER2-positive breast cancer in China. Method: All enrolled patients received the THP regimen (T: docetaxel 75 mg/m2 per cycle; H: trastuzumab biosimilar TQB211 8 mg/kg in the first cycle and 6 mg/kg maintenance dose in cycles 2 to 4; P: pertuzumab biosimilar TQB2440 or pertuzumab 840 mg in the first cycle, maintenance dose 420 mg in cycles 2 to 4) every 3 weeks for 4 cycles. The biosimilar TQB2440 pertuzumab and pertuzumab were randomly assigned to patients. Docetaxel, TQB211, and TQB2440 were all developed by Chiatai Tianqing. The primary endpoint was the complete pathological response (pCR) in the breast, and the secondary endpoint was cardiac safety. Results: Of the 28 eligible patients, 19 (67.9%) achieved tpCR. The tpCR rate was higher than in the NeoSphere trial (pCR63.2%) and the PEONY study (tpCR52.5%). The adverse events that occurred most frequently were leukopenia and neutropenia, with incidence rates of 82.1% and 75.0%, respectively. Of these, grade 3 leukopenia and neutropenia occupied 46.4% and 35.7%. Other grade 3 or higher adverse events were bone marrow suppression (7.1%), lymphopenia (3.6%), and anemia (3.6%). There were no events of heart failure in patients and no patient died during the neoadjuvant phase. Conclusion: Domestic dual-target HP has a more satisfactory efficacy and safety in the neoadjuvant phase of treatment. Clinical trial registration: https://clinicaltrials.gov/study/NCT05985187, NCT05985187.

Nomograms for assessing the rupture risk of anterior choroid artery aneurysms based on clinical, morphological, and hemodynamic features.

Background and purpose: A notable prevalence of subarachnoid hemorrhage is evident among patients with anterior choroidal artery aneurysms in clinical practice. To evaluate the risk of rupture in unruptured anterior choroidal artery aneurysms, we conducted a comprehensive analysis of risk factors and subsequently developed two nomograms. Methods: A total of 120 cases of anterior choroidal artery aneurysms (66 unruptured and 54 ruptured) from 4 medical institutions were assessed utilizing computational fluid dynamics (CFD) and digital subtraction angiography (DSA). The training set, consisting of 98 aneurysms from 3 hospitals, was established, with an additional 22 cases from the fourth hospital forming the external validation set. Statistical differences between the two data sets were thoroughly compared. The significance of 9 clinical baseline characteristics, 11 aneurysm morphology parameters, and 4 hemodynamic parameters concerning aneurysm rupture was evaluated within the training set. Candidate selection for constructing the nomogram models involved regression analysis and variance inflation factors. Discrimination, calibration, and clinical utility of the models in both training and validation sets were assessed using area under curves (AUC), calibration plots, and decision curve analysis (DCA). The DeLong test, net reclassification index (NRI), and integrated discrimination improvement (IDI) were employed to compare the effectiveness of classification across models. Results: Two nomogram models were ultimately constructed: model 1, incorporating clinical, morphological, and hemodynamic parameters (C + M + H), and model 2, relying primarily on clinical and morphological parameters (C + M). Multivariate analysis identified smoking, size ratio (SR), normalized wall shear stress (NWSS), and average oscillatory shear index (OSIave) as optimal candidates for model development. In the training set, model 1 (C + M + H) achieved an AUC of 0.795 (95% CI: 0.706 ~ 0.884), demonstrating a sensitivity of 95.6% and a specificity of 54.7%. Model 2 (C + M) had an AUC of 0.706 (95% CI: 0.604 ~ 0.808), with corresponding sensitivity and specificity of 82.4 and 50.3%, respectively. Similarly, AUCs for models 1 and 2 in the external validation set were calculated to be 0.709 and 0.674, respectively. Calibration plots illustrated a consistent correlation between model evaluations and real-world observations in both sets. DCA demonstrated that the model incorporating hemodynamic parameters offered higher clinical benefits. In the training set, NRI (0.224, p = 0.007), IDI (0.585, p = 0.002), and DeLong test (change = 0.089, p = 0.008) were all significant. In the external validation set, NRI, IDI, and DeLong test statistics were 0.624 (p = 0.063), 0.572 (p = 0.044), and 0.035 (p = 0.047), respectively. Conclusion: Multidimensional nomograms have the potential to enhance risk assessment and patient-specific treatment of anterior choroidal artery aneurysms. Validated by an external cohort, the model incorporating clinical, morphological, and hemodynamic features may provide improved classification of rupture states.

PANoptosis-related signature in melanoma: Transcriptomic mapping and clinical prognostication.

Programmed cell death plays a pivotal role in maintaining tissue homeostasis, and recent advancements in cell biology have uncovered PANoptosis-a novel paradigm integrating pyroptosis, apoptosis, and necroptosis. This study investigates the implications of PANoptosis in melanoma, a formidable skin cancer known for its metastatic potential and resistance to conventional therapies. Leveraging bulk and single-cell transcriptome analyses, machine learning modeling, and immune correlation assessments, we unveil the molecular intricacies of PANoptosis in melanoma. Single-cell sequencing identifies diverse cell types involved in PANoptosis, while bulk transcriptome analysis reveals key gene sets correlated with PANoptosis. Machine learning algorithms construct a robust prognostic model, demonstrating consistent predictive power across diverse cohorts. Patients with different cohorts can be divided into high-risk and low-risk groups according to this PANoptosis score, with the high-risk group having a significantly worse prognosis. Immune correlation analyses unveil a link between PANoptosis and immunotherapy response, with potential therapeutic implications. Mutation analysis and enrichment studies provide insights into the mutational landscape associated with PANoptosis. Finally, we used cell experiments to verify the expression and function of key gene PARVA, showing that PARVA was highly expressed in melanoma cell lines, and after PARVA is knocked down, cell invasion, migration, and colony formation ability were significantly decreased. This study advances our understanding of PANoptosis in melanoma, offering a comprehensive framework for targeted therapeutic interventions and personalized medicine strategies in combating this aggressive malignancy.

Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system.

Argonaute (Ago) proteins are ubiquitous across all kingdoms of life. Eukaryotic Agos (eAgos) use small RNAs to recognize transcripts for RNA silencing in eukaryotes. In contrast, the functions of prokaryotic counterparts (pAgo) are less well known. Recently, short pAgos in conjunction with the associated TIR or Sir2 (SPARTA or SPARSA) were found to serve as antiviral systems to combat phage infections. Herein, we present the cryo-EM structures of nicotinamide adenine dinucleotide (NAD+)-bound SPARSA with and without nucleic acids at resolutions of 3.1 Å and 3.6 Å, respectively. Our results reveal that the APAZ (Analogue of PAZ) domain and the short pAgo form a featured architecture similar to the long pAgo to accommodate nucleic acids. We further identified the key residues for NAD+ binding and elucidated the structural basis for guide RNA and target DNA recognition. Using structural comparisons, molecular dynamics simulations, and biochemical experiments, we proposed a putative mechanism for NAD+ hydrolysis in which an H186 loop mediates nucleophilic attack by catalytic water molecules. Overall, our study provides mechanistic insight into the antiphage role of the SPARSA system.

Synthesis, biological activity evaluation and mechanism of action of novel bis-isatin derivatives as potential anti-liver cancer agents.

A series of bis-isatin conjugates with lysine linker were synthesized with the aim of probing their antiproliferative potential. All the newly synthesized derivatives (0-100 µM) were first screened against liver cancer cell lines(Huh1, H22, Huh7, Hepa1-6, HepG2, Huh6 and 97H) using CCK-8 assay. Results indicated that the derivative 4d exhibited the most potent activity against Huh1 (IC50 = 17.13 µM) and Huh7(IC50 = 8.265 µM). In vivo anti-tumor study showed that compound 4d effectively inhibited tumor growth in Huh1-induced xenograft mouse model; the anti-tumor effect of compound 4d (15 mg/kg) was comparable with sorafenib (20 mg/kg). H&E staining analysis and routine blood test and blood serum biochemistry examination was performed to confirm the safety of compound 4d in xenograft models. The mechanism of action of 4d on tumor growth inhibition was further investigated by RNA-Seq analysis, which indicates a positive regulation of autophagy signaling pathway, which was further confirmed with key biomarker expression of autophagy after 4d treatment. Our results suggest that the bis-isatin conjugate compound 4d is a promising tumor inhibitory agent for some liver cancer.

Inertial migration of polymer micelles in a square microchannel.

Using a hybrid simulation approach that combines a lattice-Boltzmann method for fluid flow and a molecular dynamics model for polymers, we investigate the inertial migration of star-like and crew-cut polymer micelles in a square microchannel. It is found that they exhibit two types of equilibrium positions, which shift further away from the center of the microchannel when the Reynolds number (Re) increases, as can be observed for soft particles. What differs from the behaviors of soft particles is that here, the blockage ratio is no longer the decisive factor. When the sizes are the same, the star-like micelles are always relatively closer to the microchannel wall as they gradually transition from spherical to disc-like with the increase of Re. In comparison, the crew-cut micelles are only transformed into an ellipsoid. Conversely, when the hydrophobic core sizes are the same, the equilibrium position of the star-like micelles becomes closer to that of the crew-cut micelles. Our results demonstrate that for polymer micelles with a core-shell structure, the equilibrium position is no longer solely determined by their overall dimensions but depends on the core and shell's specific dimensions, especially the hydrophobic core size. This finding opens up a new approach for achieving the separation of micelles in inertial migration.

Fe, N, S co-doped carbon network derived from acetate-modified Fe-ZIF-8 for oxygen reduction reaction.

In this work, potassium acetate (KAc) was added during the synthesis of a Zn-Fe based metal-organic framework (Fe-ZIF-8) to increase the fixed amount of Fe while simultaneously enhancing the number of pores. Electrospinning was utilized to embed KAc-modified Fe-ZIF-8 (Fe-ZIF-8-Ac) into the polyacrylonitrile nanofiber mesh, to obtain a network composite (Fe@NC-Ac) with hierarchical porous structure. Fe@NC-Ac was co-pyrolyzed with thiourea, resulting in Fe, N, S co-doped carbon electrocatalyst. The electrochemical tests indicated that the prepared catalyst displayed relatively remarkable oxygen reduction reaction (ORR) catalytic activity, with an onset potential (Eonset) of 1.08 V (vs. reversible hydrogen electrode, RHE) and a half-wave potential (E1/2) of 0.94 V, both higher than those of the commercial Pt/C (Eonset = 0.95 V and E1/2 = 0.84 V), respectively. Assembled into Zn-air batteries, the optimized catalyst exhibited higher open circuit voltage (1.698 V) and peak power density (90 mW cm-2) than those of the commercial 20 wt% Pt/C (1.402 V and 80 mW cm-2), respectively. This work provided a straightforward manufacturing strategy for the design of hierarchical porous carbon-based ORR catalysts with desirable performance.

Mechanism of Shenfu injection in suppressing inflammation and preventing sepsis-induced apoptosis in murine cardiomyocytes based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu injection(SFI), as a famous classical Chinese patent medicine injection for the treatment of sepsis, has achieved good curative effects in clinical practice. However, its specific ingredients and molecular mechanisms is still unclear. AIM OF THE STUDY: To analyze the effective ingredients and molecular mechanisms of SFI in the treatment of sepsis via network pharmacology technology and experimental validation. MATERIALS AND METHODS: A total of 198 mice were used in this experiment. Septic mice model was performed by cecal ligation and puncture (CLP). First, Survival rates were calculted to screen the dosage and the treatment time window of SFI. Cardiac function was evaluated by echocardiography. The potential targets and pathways of SFI in the treatment of sepsis were predicted by network pharmacology. Myocardial tissue samples were harvest from different groups after CLP surgery. Hematoxylin-eosin (H&E) and TUNEL staining were used to examine the injury of heart. Western-blot analysis was performed to determine the protein expression of apoptosis. Meanwhile, the structural changes and mitochondrial membrane potential in the mitochondria of cardiomyocytes were also observed by transmission electron microscopy. RESULTS: The Kaplan-Meier survival analysis showed that SFI significantly improved the 7-day survival rate as compared with that of CLP mice (P < 0.05). Echocardiography analysis found that LVEF and FS were significantly reduced in CLP mice compared with Sham mice, while SFI significantly increased LVEF (P < 001). Network pharmacology analysis indicated that the potential targets with higher degrees include IL2, BCL2, BAX, CASP7, BID, CASP8. Pathways with higher degrees include apoptosis, TNF signaling pathway, mitochondrial pathway apoptosis, PI3K-AKT signaling pathway. SFI treatment markedly attenuated the quantity of apoptotic cells as compared with the CLP group (P < 0.01). Western blot analysis indicated that CLP surgery decreased the expression of Bcl-2 (anti-apoptotic) but improved the protein expression of Bid, t-Bid, Cyc (pro-apoptotic) as compared with the Sham group (P < 0.01). While, SFI treatment markedly prevent the expression of Bid, t-Bid, Cyc and Caspase-9. The myocardial mitochondrial membrane potential of CLP group decreased after CLP surgery, while the mitochondrial membrane potential of SFI group increased significantly. Compared with the CLP group, in SFI group, the Z-line of the sarcomere was clear and distinguishable, and swollen mitochondria were significantly improved. CONCLUSIONS: The present study demonstrated that SFI improved survival rate and cardiac function of septic mice mainly by suppressing inflammation and apoptosis.