Matrine reverses the resistance of Haemophilus parasuis to cefaclor by inhibiting the mutations in penicillin-binding protein genes (ftsI and mrcA).

Introduction: Matrine (MT) is a potential resistance reversal agent. However, it remains unclear whether MT can reverse the resistance of Haemophilus parasuis (H. parasuis) to ß-lactams, and, if so, by what mechanism MT works. Methods: We screened one cefaclor (CEC)-resistant strain (clinical strain C7) from eight clinical (H. parasuis) strains and determined the underlying resistance mechanism. Then, we investigated the reversal effect of MTon the resistance of this strain to CEC. Results and Discussion: The production of ß-lactamase, overexpression of AcrAB-TolC system, and formation of biofilm might not be responsible for the resistance of clinical strain C7 to CEC. Fourteen mutation sites were found in four PBP genes (ftsI, pbp1B, mrcA, and prcS) of clinical strain C7, among which the mutation sites located in ftsI (Y103D and L517R) and mrcA (A639V) genes triggered the resistance to CEC. The minimum inhibitory concentration (MIC) of CEC against clinical strain C7 was reduced by two to eight folds after MT treatment, accompanied by the significant down-regulated expression of mutated ftsI and mrcA genes. Based on such results, we believed that MT could reverse the resistance of H. parasuis to CEC by inhibiting the mutations in ftsI and mrcA genes. Our research would provide useful information for restoring the antimicrobial activity of ß-lactams and improving the therapeutic efficacy of Glässer's disease.

Teacher-student guided knowledge distillation for unsupervised convolutional neural network-based speckle tracking in ultrasound strain elastography.

Accurate and efficient motion estimation is a crucial component of real-time ultrasound elastography (USE). However, obtaining radiofrequency ultrasound (RF) data in clinical practice can be challenging. In contrast, although B-mode (BM) data is readily available, elastographic data derived from BM data results in sub-optimal elastographic images. Furthermore, existing conventional ultrasound devices (e.g., portable devices) cannot provide elastography modes, which has become a significant obstacle to the widespread use of traditional ultrasound devices. To address the challenges above, we developed a teacher-student guided knowledge distillation for an unsupervised convolutional neural network (TSGUPWC-Net) to improve the accuracy of BM motion estimation by employing a well-established convolutional neural network (CNN) named modified pyramid warping and cost volume network (MPWC-Net). A pre-trained teacher model based on RF is utilized to guide the training of a student model using BM data. Innovations outlined below include employing spatial attention transfer at intermediate layers to enhance the guidance effect of the model. The loss function consists of smoothness of the displacement field, knowledge distillation loss, and intermediate layer loss. We evaluated our method on simulated data, phantoms, and in vivo ultrasound data. The results indicate that our method has higher signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) values in axial strain estimation than the model trained on BM. The model is unsupervised and requires no ground truth labels during training, making it highly promising for motion estimation applications.

Cascade Reactions Catalyzed by Gold Hybrid Nanoparticles Generate CO Gas Against Periodontitis in Diabetes.

The treatment of diabetic periodontitis poses a significant challenge due to the presence of local inflammation characterized by excessive glucose concentration, bacterial infection, and high oxidative stress. Herein, mesoporous silica nanoparticles (MSN) are embellished with gold nanoparticles (Au NPs) and loaded with manganese carbonyl to prepare a carbon monoxide (CO) enhanced multienzyme cooperative hybrid nanoplatform (MSN-Au@CO). The Glucose-like oxidase activity of Au NPs catalyzes the oxidation of glucose to hydrogen peroxide (H2O2) and gluconic acid，and then converts H2O2 to hydroxyl radicals (•OH) by peroxidase-like activity to destroy bacteria. Moreover, CO production in response to H2O2, together with Au NPs exhibited a synergistic anti-inflammatory effect in macrophages challenged by lipopolysaccharides. The underlying mechanism can be the induction of nuclear factor erythroid 2-related factor 2 to reduce reactive oxygen species, and inhibition of nuclear factor kappa-B signaling to diminish inflammatory response. Importantly, the antibacterial and anti-inflammation effects of MSN-Au@CO are validated in diabetic rats with ligature-induced periodontitis by showing decreased periodontal bone loss with good biocompatibility. To summarize, MSN-Au@CO is fabricate to utilize glucose-activated cascade reaction to eliminate bacteria, and synergize with gas therapy to regulate the immune microenvironment, offering a potential direction for the treatment of diabetic periodontitis.

Robot-assisted versus laparoscopic-assisted gastrectomy among malnourished patients with gastric cancer based on textbook outcome.

BACKGROUND: Textbook outcome (TO) has been widely employed as a comprehensive indicator to assess the short-term prognosis of patients with cancer. Preoperative malnutrition is a potential risk factor for adverse surgical outcomes in patients with gastric cancer (GC). This study aimed to compare the TO between robotic-assisted gastrectomy (RAG) and laparoscopic-assisted gastrectomy (LAG) in malnourished patients with GC. METHODS: According to the diagnostic consensus of malnutrition proposed by Global Leadership Initiative on Malnutrition (GLIM) and Nutrition Risk Index (NRI), 895 malnourished patients with GC who underwent RAG (n = 115) or LAG (n = 780) at a tertiary referral hospital between January 2016 and May 2021 were included in the propensity score matching (PSM, 1:2) analysis. RESULTS: After PSM, no significant differences in clinicopathological characteristics were observed between the RAG (n = 97) and LAG (n = 194) groups. The RAG group had significantly higher operative time and lymph nodes harvested, as well as significantly lower blood loss and hospital stay time compared to the LAG group. More patients in the RAG achieved TO. Logistic regression analysis revealed that RAG was an independent protective factor for achieving TO. There were more adjuvant chemotherapy (AC) cycles in the RAG group than in the LAG group. After one year of surgery, a higher percentage of patients (36.7% vs. 22.8%; P < 0.05) in the RAG group recovered from malnutrition compared to the LAG group. CONCLUSIONS: For malnourished patients with GC, RAG performed by experienced surgeons can achieved a higher rate of TO than those of LAG, which directly contributed to better AC compliance and a faster restoration of nutritional status.

[A multi-center epidemiological study on pneumococcal meningitis in children from 2019 to 2020]. / 2019­2020å¹´160ä¾‹å„¿ç«¥è‚ºç‚Žé“¾çƒèŒè„‘è†œç‚Žä¸´åºŠæµè¡Œç— å­¦å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the clinical characteristics and prognosis of pneumococcal meningitis (PM), and drug sensitivity of Streptococcus pneumoniae (SP) isolates in Chinese children. METHODS: A retrospective analysis was conducted on clinical information, laboratory data, and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country. RESULTS: Among the 160 children with PM, there were 103 males and 57 females. The age ranged from 15 days to 15 years, with 109 cases (68.1%) aged 3 months to under 3 years. SP strains were isolated from 95 cases (59.4%) in cerebrospinal fluid cultures and from 57 cases (35.6%) in blood cultures. The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87) and 27% (21/78), respectively. Fifty-five cases (34.4%) had one or more risk factors for purulent meningitis, 113 cases (70.6%) had one or more extra-cranial infectious foci, and 18 cases (11.3%) had underlying diseases. The most common clinical symptoms were fever (147 cases, 91.9%), followed by lethargy (98 cases, 61.3%) and vomiting (61 cases, 38.1%). Sixty-nine cases (43.1%) experienced intracranial complications during hospitalization, with subdural effusion and/or empyema being the most common complication [43 cases (26.9%)], followed by hydrocephalus in 24 cases (15.0%), brain abscess in 23 cases (14.4%), and cerebral hemorrhage in 8 cases (5.0%). Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old, with rates of 91% (39/43) and 83% (20/24), respectively. SP strains exhibited complete sensitivity to vancomycin (100%, 75/75), linezolid (100%, 56/56), and meropenem (100%, 6/6). High sensitivity rates were also observed for levofloxacin (81%, 22/27), moxifloxacin (82%, 14/17), rifampicin (96%, 25/26), and chloramphenicol (91%, 21/23). However, low sensitivity rates were found for penicillin (16%, 11/68) and clindamycin (6%, 1/17), and SP strains were completely resistant to erythromycin (100%, 31/31). The rates of discharge with cure and improvement were 22.5% (36/160) and 66.2% (106/160), respectively, while 18 cases (11.3%) had adverse outcomes. CONCLUSIONS: Pediatric PM is more common in children aged 3 months to under 3 years. Intracranial complications are more frequently observed in children under 1 year old. Fever is the most common clinical manifestation of PM, and subdural effusion/emphysema and hydrocephalus are the most frequent complications. Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates. Adverse outcomes can be noted in more than 10% of PM cases. SP strains are high sensitivity to vancomycin, linezolid, meropenem, levofloxacin, moxifloxacin, rifampicin, and chloramphenicol.

Viewing-Angle-Enhanced and Dual-View Compatible Integral Imaging 3D Display Based on a Dual Pinhole Array.

Conventional integral imaging (InIm) three-dimensional (3D) display has the defect of a small viewing angle and usually presents a single 3D image. In this paper, we propose a viewing-angle-enhanced and dual-view compatible InIm 3D display system. The crosstalk pixel areas within the conventional elemental images (EIs) that result in image crosstalk were effectively utilized either for viewing angle enhancement or for dual-view 3D display. In the viewing-angle-enhanced 3D display mode, a composite elemental image (CEI) that consisted of a normal EI and two view-enhanced EIs was imaged by a dual pinhole array and formed an extended 3D viewing area. A precisely designed mask array was introduced to block the overlapped rays between adjacent viewing areas to eliminate image crosstalk. While in the dual-view 3D display mode, a CEI was composed of image information of two different 3D scenes. With the help of the dual pinhole array and mask array, two different 3D images were reconstructed for the left and right perspectives. Experiments demonstrated that both the left and right sides were increased by 6 degrees from the conventional 3D viewing angle, and also, a dual-view 3D display effect that retains the same viewing angle as the conventional system was achieved. The proposed system has a compact structure and can be freely switched between two display modes.

Identification of Hedyotis diffusa Willd-specific mRNA-miRNA-lncRNA network in rheumatoid arthritis based on network pharmacology, bioinformatics analysis, and experimental verification.

Hedyotis diffusa Willd (HDW) possesses heat-clearing, detoxification, anti-cancer, and anti-inflammatory properties. However, its effects on rheumatoid arthritis (RA) remain under-researched. In this study, we identified potential targets of HDW and collected differentially expressed genes of RA from the GEO dataset GSE77298, leading to the construction of a drug-component-target-disease regulatory network. The intersecting genes underwent GO and KEGG analysis. A PPI protein interaction network was established in the STRING database. Through LASSO, RF, and SVM-RFE algorithms, we identified the core gene MMP9. Subsequent analyses, including ROC, GSEA enrichment, and immune cell infiltration, correlated core genes with RA. mRNA-miRNA-lncRNA regulatory networks were predicted using databases like TargetScan, miRTarBase, miRWalk, starBase, lncBase, and the GEO dataset GSE122616. Experimental verification in RA-FLS cells confirmed HDW's regulatory impact on core genes and their ceRNA expression. We obtained 11 main active ingredients of HDW and 180 corresponding targets, 2150 RA-related genes, and 36 drug-disease intersection targets. The PPI network diagram and three machine learning methods screened to obtain MMP9, and further analysis showed that MMP9 had high diagnostic significance and was significantly correlated with the main infiltrated immune cells, and the molecular docking verification also showed that MMP9 and the main active components of HDW were well combined. Next, we predicted 6 miRNAs and 314 lncRNAs acting on MMP9, and two ceRNA regulatory axes were obtained according to the screening. Cellular assays indicated HDW inhibits RA-FLS cell proliferation and MMP9 protein expression dose-dependently, suggesting HDW might influence RA's progression by regulating the MMP9/miR-204-5p/MIAT axis. This innovative analytical thinking provides guidance and reference for the future research on the ceRNA mechanism of traditional Chinese medicine in the treatment of RA.

Heat stress enhances the occurrence of erythromycin resistance of Enterococcus isolates in mice feces.

Heat stress is a common environmental factor in livestock breeding that has been shown to impact the development of antibiotic resistance within the gut microbiota of both human and animals. However, studies investigating the effect of temperature on antibiotic resistance in Enterococcus isolates remain limited. In this study, specific pathogen free (SPF) mice were divided into a control group maintained at normal temperature and an experimental group subjected to daily 1-h heat stress at 38 °C, respectively. Gene expression analysis was conducted to evaluate the activation of heat shock responsive genes in the liver of mice. Additionally, the antibiotic-resistant profile and antibiotic resistant genes (ARGs) in fecal samples from mice were analyzed. The results showed an upregulation of heat-inducible proteins HSP27, HSP70 and HSP90 following heat stress exposure, indicating successful induction of cellular stress within the mice. Furthermore, heat stress resulted in an increase in the proportion of erythromycin-resistant Enterococcus isolates, escalating from 0 % to 0.23 % over a 30-day duration of heat stress. The resistance of Enterococcus isolates to erythromycin also had a 128-fold increase in minimum inhibitory concentration (MIC) within the heated-stressed group compared to the control group. Additionally, a 2∼8-fold rise in chloramphenicol MIC was observed among these erythromycin-resistant Enterococcus isolates. The acquisition of ermB genes was predominantly responsible for mediating the erythromycin resistance in these Enterococcus isolates. Moreover, the abundance of macrolide, lincosamide and streptogramin (MLS) resistant-related genes in the fecal samples from the heat-stressed group exhibited a significant elevation compared to the control group, primarily driven by changes in bacterial community composition, especially Enterococcaceae and Planococcaceae, and the transfer of mobile genetic elements (MGEs), particularly insertion elements. Collectively, these results highlight the role of environmental heat stress in promoting antibiotic resistance in Enterococcus isolates and partly explain the increasing prevalence of erythromycin-resistant Enterococcus isolates observed among animals in recent years.

Response of garlic (Allium sativum L.) to the combined toxicity of microplastics and arsenic.

The extensive utilization of mulch films in agricultural settings, coupled with the persistence of microplastic remnants in soil following the natural degradation of plastics, has given rise to detrimental microplastic impacts on crops. Arsenic (As) contamination in the environment is known to accumulate in crops through aquatic pathways or soil. Garlic (Allium sativum L.), a globally popular crop and seasoning, contains alliin, a precursor of its flavor compounds with medicinal properties. While alliin exhibits antimicrobial and antioxidant effects in garlic, its response to microplastics and arsenic has not been thoroughly investigated, specifically in terms of microplastic or As uptake. This study aimed to explore the impact of varied stress concentrations of microplastics on the toxicity, migration, and accumulation of As compounds. Results demonstrated that polystyrene (PS) fluorescent microspheres, with an 80 nm diameter, could permeate garlic bulbs through the root system, accumulating within vascular tissues and intercellular layers. Low concentrations of PS (10 and 20 mg L-1) and As (2 mg L-1) mitigated the production and accumulation of reactive oxygen species (ROS) and antioxidant enzymes in garlic. Conversely, garlic exhibited reduced root vigor, substance uptake, and translocation when treated with elevated As concentrations (4 mg L-1) in conjunction with PS concentrations of 40 and 80 mg L-1. An escalation in PS concentration facilitated As transport into bulbs but led to diminished As accumulation and biomass in the root system. Notably, heightened stress levels weakened garlic's antioxidant defense system, encompassing sulfur allicin and phytochelatin metabolism, crucial for combating the phytotoxicity of PS and As. In summary, PS exerted a detrimental influence on garlic, exacerbating As toxicity. The findings from this study offer insights for subsequent investigations involving Liliaceae plants.

Influence of Spider Silk Protein Structure on Mechanical and Biological Properties for Energetic Material Detection.

Spider silk protein, renowned for its excellent mechanical properties, biodegradability, chemical stability, and low immune and inflammatory response activation, consists of a core domain with a repeat sequence and non-repeating sequences at the N-terminal and C-terminal. In this review, we focus on the relationship between the silk structure and its mechanical properties, exploring the potential applications of spider silk materials in the detection of energetic materials.

Hepatitis B surface antigen expression impairs endoplasmic reticulum stress-related autophagic flux by decreasing LAMP2.

Background & Aims: Hepatitis B surface antigen (HBsAg) drives hepatocarcinogenesis. Factors and mechanisms involved in this progression remain poorly defined, hindering the development of effective therapeutic strategies. Therefore, the mechanisms involved in the HBsAg-induced transformation of normal liver into hepatocellular carcinoma (HCC) were investigated. Methods: Hemizygous Tg(Alb1HBV)44Bri/J mice were examined for HBsAg-induced carcinogenic events. Gene set-enrichment analysis identified significant signatures in HBsAg-transgenic mice that correlated with endoplasmic reticulum (ER) stress, unfolded protein response, autophagy and proliferation. These events were investigated by western blotting, immunohistochemical and immunocytochemical staining in 2-, 8- and 12-month-old HBsAg-transgenic mice. The results were verified in HBsAg-overexpressing Hepa1-6 cells and validated in human HBV-related HCC samples. Results: Increased BiP expression in HBsAg-transgenic mice indicated induction of the unfolded protein response. In addition, early-phase autophagy was enhanced (increased BECN1 and LC3B) and late-phase autophagy blocked (increased p62) in HBsAg-transgenic mice. Finally, HBsAg altered lysosomal acidification via ATF4- and ATF6-mediated downregulation of lysosome-associated membrane protein 2 (LAMP2) expression. In patients, HBV-related HCC and adjacent tissues showed increased BiP, p62 and downregulated LAMP2 compared to uninfected controls. In vitro, the use of ER stress inhibitors reversed the HBsAg-related suppression of LAMP2. Furthermore, HBsAg promoted hepatocellular proliferation as indicated by Ki67, cleaved caspase-3 and AFP staining in paraffin-embedded liver sections from HBsAg-transgenic mice. These results were further verified by colony formation assays in HBsAg-expressing Hepa1-6 cells. Interestingly, inhibition of ER stress in HBsAg-overexpressing Hepa1-6 cells suppressed HBsAg-mediated cell proliferation. Conclusions: These data showed that HBsAg directly induces ER stress, impairs autophagy and promotes proliferation, thereby driving hepatocarcinogenesis. In addition, this study expanded the understanding of HBsAg-mediated intracellular events in carcinogenesis. Impact and implications: Factors and mechanisms involved in hepatocarcinogenesis driven by hepatitis B surface antigen (HBsAg) are poorly defined, hindering the development of effective therapeutic strategies. This study showed that HBsAg-induced endoplasmic reticulum stress suppressed LAMP2, thereby mediating autophagic injury. The present data suggest that restoring LAMP2 function in chronic HBV infection may have both antiviral and anti-cancer effects. This study has provided insights into the role of HBsAg-mediated intracellular events in carcinogenesis and thereby has relevance for future drug development.

Batoclimab vs Placebo for Generalized Myasthenia Gravis: A Randomized Clinical Trial.

Importance: Myasthenia gravis (MG) is caused by autoantibodies that disrupt the neuromuscular junction. The neonatal fragment crystallizable receptor (FcRn) antagonists, efgartigimod and rozanolixizumab, reduce immunoglobulin G (IgG) level in the circulation and alleviate symptoms in patients with generalized MG. Objective: To examine the efficacy and safety profile of batoclimab, a monoclonal IgG1 antibody, in patients with generalized MG. Design, Setting, and Participants: This was a multicenter randomized clinical trial conducted from September 15, 2021, to June 29, 2022, at 27 centers in China. Adult patients 18 years or older with generalized MG were screened, and those who were antibody positive were enrolled. Intervention: Eligible patients received batoclimab or matching placebo in addition to standard of care. Each treatment cycle consisted of 6 weekly subcutaneous injections of batoclimab, 680 mg, or matching placebo followed by 4 weeks of observation. A second treatment cycle was conducted in patients who required continuing treatment. Main Outcome and Measure: The primary outcome was sustained improvement, as defined by a 3-point or greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score from baseline for 4 or more consecutive weeks in the first cycle in individuals who were positive for acetylcholine receptor or muscle-specific kinase antibodies. Results: A total of 178 adult patients with generalized MG were screened, 132 were randomly assigned, 131 tested positive for antibodies, and 1 tested negative for antibodies. A total of 132 patients (mean [SE] age, 43.8 [13.6] years; 88 women [67.2%]) were enrolled. The rate of sustained MG-ADL improvement in the first cycle in antibody-positive patients was 31.3% (20 of 64) in the placebo group vs 58.2% (39 of 67) in the batoclimab group (odds ratio, 3.45; 95% CI, 1.62-7.35; P = .001). The MG-ADL score diverged between the 2 groups as early as week 2. The mean (SE) maximum difference in MG-ADL score reduction occurred 1 week after the last dose (day 43, 1.7 [0.3] in the placebo group vs 3.6 [0.3] in the batoclimab group; group difference, -1.9; 95% CI, -2.8 to -1.0; nominal P < .001). The rates of treatment-related and severe treatment-emergent adverse events in patients were 36.9% (24 of 65) and 7.7% (5 of 65) in the placebo group vs 70.1% (47 of 67) and 3.0% (2 of 67) in the batoclimab group, respectively. Conclusions and Relevance: Batoclimab increased the rate of sustained MG-ADL improvement and was well tolerated in adult patients with generalized MG. Clinical effects and the extent of IgG reduction were similar to those previously reported for efgartigimod and rozanolixizumab. Future studies of large sample size are needed to further understand the safety profile of batoclimab. Trial Registration: ClinicalTrials.gov Identifier: NCT05039190.

Tunable Single-Photon Emission with Wafer-Scale Plasmonic Array.

Bright, scalable, and deterministic single-photon emission (SPE) is essential for quantum optics, nanophotonics, and optical information systems. Recently, SPE from hexagonal boron nitride (h-BN) has attracted intense interest because it is optically active and stable at room temperature. Here, we demonstrate a tunable quantum emitter array in h-BN at room temperature by integrating a wafer-scale plasmonic array. The transient voltage electrophoretic deposition (EPD) reaction is developed to effectively enhance the filling of single-crystal nanometals in the designed patterns without aggregation, which ensures the fabricated array for tunable performances of these single-photon emitters. An enhancement of ∼500% of the SPE intensity of the h-BN emitter array is observed with a radiative quantum efficiency of up to 20% and a saturated count rate of more than 4.5 × 106 counts/s. These results suggest the integrated h-BN-plasmonic array as a promising platform for scalable and controllable SPE photonics at room temperature.

Immune-cell-mediated tissue engineering strategies for peripheral nerve injury and regeneration.

During the process of peripheral nerve repair, there are many complex pathological and physiological changes, including multi-cellular responses and various signaling molecules, and all these events establish a dynamic microenvironment for axon repair, regeneration, and target tissue/organ reinnervation. The immune system plays an indispensable role in the process of nerve repair and function recovery. An effective immune response not only involves innate-immune and adaptive-immune cells but also consists of chemokines and cytokines released by these immune cells. The elucidation of the orchestrated interplay of immune cells with nerve regeneration and functional restoration is meaningful for the exploration of therapeutic strategies. This review mainly enumerates the general immune cell response to peripheral nerve injury and focuses on their contributions to functional recovery. The tissue engineering-mediated strategies to regulate macrophages and T cells through physical and biochemical factors combined with scaffolds are discussed. The dynamic immune responses during peripheral nerve repair and immune-cell-mediated tissue engineering methods are presented, which provide a new insight and inspiration for immunomodulatory therapies in peripheral nerve regeneration.

Environment-Sensitive Fluorescent Probe Enables Assessment of Anaplastic Lymphoma Kinase Activity in Nonsmall Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK) rearrangements have been identified as key oncogenic drivers of a subset of nonsmall cell lung cancer (NSCLC). The final chimeric protein of the fusion gene can be constitutively activated, which accounts for the growth and proliferation of ALK-rearranged tumors and thus strongly associates with cancer invasion and metastasis. Diagnostic tools enabling the visualization of ALK activity in a structure-function-based approach are highly desirable to determine ALK status and guide ALK tyrosine kinase inhibitor (ALK-TKI) treatment making. Here, we describe the design, synthesis, and application of a new environment-sensitive fluorescent probe HX16 by introducing an environment-sensitive fluorophore 4-sulfonamidebenzoxadiazole to visualize ALK activity in living cancer cells and tumor tissue slices (mouse model and human biopsy sample). HX16 is a multifunctional chemical tool based on the pharmacophore of ALK-TKI (ceritinib) and can specifically target the kinase domain of ALK with a high sensitivity. Using flow cytometry and confocal microscopy, HX16 enables visualization of ALK activity in various cancer cells with distinct ALK fusion genes, as well as xenograft mouse models. Importantly, HX16 was also applied to visualize ALK activity in a tumor biopsy from a NSCLC patient with ALK-echinoderm microtubule-associated protein-like-4 fusion gene for prediction of ALK-TKI sensitivity. These results demonstrate that strategically designed ALK-TKI-based probe allows the assessment of ALK activity in tumor tissues and hold promise as a useful diagnostic tool in predicting ALK-TKI therapy response.

Impact of microplastics on microbial-mediated soil sulfur transformations in flooded conditions.

As emerging environmental pollutants, microplastics have become a crucial focus in environmental science research. Despite this, the impact of microplastics on soil in flooding conditions remains largely unexplored. Addressing this gap, our study examined the influence of polystyrene (PS) and polyphenylene sulfide (PPS) on the microbial populations in black soil, meadow soil, and paddy soil under flooded conditions. Given the significant regulatory influence exerted by microorganisms on sulfur transformations, our study was primarily focused on evaluating the microbial contributions to alterations in soil sulfur species. Our findings revealed several notable trends: In black soil, both PS and PPS led to a marked increase in the abundance of γ-proteobacteria and Subgroup_6, while reducing Clostridia. Ignavibacteria were found to be lower under PPS compared to PS. In meadow soil, the introduction of PPS resulted in increased levels of KD4-96 and γ-proteobacteria, while α-proteobacteria decreased. Chloroflexia under PPS was observed to be lower than under PS conditions. In paddy soil, our study identified a significant rise in Bacteroidia and Ignavibacteria, accompanied by a decrease in α-proteobacteria and γ-proteobacteria. γ-proteobacteria levels under PPS were notably higher than those under PS conditions. These shifts in microbial communities induced by both PS and PPS had a direct impact on adenosine 5'-phosphosulfate reductase, sulfite reductase, and polysulfide dioxygenase. Consequently, these changes led to soil organic sulfur decrease and sulfide increase. This study not only offers a theoretical framework but also provides empirical evidence for understanding the effects of microplastics on soil microorganisms and their role in regulating nutrient cycling, particularly in flood-prone conditions. Furthermore, this study underscores the importance of ensuring an adequate supply of sulfur in agricultural practices, such as rice and lotus root cultivation, to support optimal crop growth in the presence of microplastic pollution.

Enantiomer-Dependent Supramolecular Immunosuppressive Modulation for Tissue Reconstruction.

Modulating the properties of biomaterials in terms of the host immune response is critical for tissue repair and regeneration. However, it is unclear how the preference for the cellular microenvironment manipulates the chiral immune responses under physiological or pathological conditions. Here, we reported that in vivo and in vitro oligopeptide immunosuppressive modulation was achieved by manipulation of macrophage polarization using chiral tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested that chiral FFFK nanofibers can serve as a defense mechanism in the restoration of tissue homeostasis by upregulating macrophage M2 polarization via the Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce a sustained polarization program, then passes the baton to EGR2, thereby continuously maintaining the M2 polarization program. It is worth noting that the L-chirality exhibits a more potent effect in inducing macrophage M2 polarization than does the D-chirality, leading to enhanced tissue reconstruction. These findings elucidate the crucial molecular signals that mediate chirality-dependent supramolecular immunosuppression in damaged tissues while also providing an effective chiral supramolecular strategy for regulating macrophage M2 polarization and promoting tissue injury repair based on the self-assembling chiral peptide design.

Therapeutic potential of targeting polo-like kinase 4.

Polo-like kinase 4 (PLK4), a highly conserved serine/threonine kinase, masterfully regulates centriole duplication in a spatiotemporal manner to ensure the fidelity of centrosome duplication and proper mitosis. Abnormal expression of PLK4 contributes to genomic instability and associates with a poor prognosis in cancer. Inhibition of PLK4 is demonstrated to exhibit significant efficacy against various types of human cancers, further highlighting its potential as a promising therapeutic target for cancer treatment. As such, numerous small-molecule inhibitors with distinct chemical scaffolds targeting PLK4 have been extensively investigated for the treatment of different human cancers, with several undergoing clinical evaluation (e.g., CFI-400945). Here, we review the structure, distribution, and biological functions of PLK4, encapsulate its intricate regulatory mechanisms of expression, and highlighting its multifaceted roles in cancer development and metastasis. Moreover, the recent advancements of PLK4 inhibitors in patent or literature are summarized, and their therapeutic potential as monotherapies or combination therapies with other anticancer agents are also discussed.

Role of reactive oxygen species in ultraviolet-induced photodamage of the skin.

Reactive oxygen species (ROS), such as superoxides (O2 •-) and hydroxyl groups (OH·), are short-lived molecules containing unpaired electrons. Intracellular ROS are believed to be mainly produced by the mitochondria and NADPH oxidase (NOX) and can be associated with various physiological processes, such as proliferation, cell signaling, and oxygen homeostasis. In recent years, many studies have indicated that ROS play crucial roles in regulating ultraviolet (UV)-induced photodamage of the skin, including exogenous aging, which accounts for 80% of aging. However, to the best of our knowledge, the detailed signaling pathways, especially those related to the mechanisms underlying apoptosis in which ROS are involved have not been reviewed previously. In this review, we elaborate on the biological characteristics of ROS and its role in regulating UV-induced photodamage of the skin.

The structural transformation reversibility of biogas slurry derived dissolved organic matter and its binding properties with norfloxacin under temperature fluctuation.

The widespread use of biogas slurry could potentially raise the environmental risk of antibiotics. Dissolved organic matter (DOM), as the most active part of biogas slurry, was able to interact with antibiotics and play a crucial role in the structure and function of soil and aquatic ecosystems. The recent shifts in global climate patterns have garnered significant attention due to their substantial impact on temperature, thereby exerting a direct influence on the characteristics of DOM and subsequently on the environmental behavior of antibiotics. However, there is limited research concerning the impact of temperature on the binding of DOM and antibiotics. Thus, this study aimed to explore the temperature-dependent structural transformation and driving factors of biogas slurry-derived DOM (BSDOM). Additionally, the binding characteristics between BSDOM and the commonly used antibiotic norfloxacin (NOR) at different temperatures were studied by using multi spectroscopic methods and two-dimensional correlation spectroscopy (2D-COS) analysis. The results suggested that the temperature-dependent structural transformation of BSDOM was reversible, with a slight lag in the transition temperature under cooling (13 °C for heating and 17 °C for cooling). Heating promoted the conversion of protein-like to humic-like substances while cooling favored the decomposition of humic-like substances. BSDOM and NOR were static quenching, with oxygen-containing functional groups such as C-O and -OH playing an important role. Temperature influenced the order of binding, the activity of the protein fraction, and its associated functional groups. At temperatures of 25 °C and 40 °C, the fluorescent components were observed to exhibit consistent binding preferences, whereby the humic-like component demonstrated a greater affinity for NOR compared to the protein-like component. However, the functional group binding order exhibited an opposite trend. At 10 °C, a new protein-like component appeared and bound preferentially to NOR, when no C-O stretch corresponding to the amide was observed. The finding will contribute to a comprehensive understanding of the interaction mechanisms between DOM and antibiotics under climate change, as well as providing a theoretical basis to reduce the environmental risks of biogas slurry and antibiotics.