Population suppression with dominant female-lethal alleles is boosted by homing gene drive.

BACKGROUND: Methods to suppress pest insect populations using genetic constructs and repeated releases of male homozygotes have recently been shown to be an attractive alternative to older sterile insect techniques based on radiation. Female-specific lethal alleles have substantially increased power, but still require large, sustained transgenic insect releases. Gene drive alleles bias their own inheritance to spread throughout populations, potentially allowing population suppression with a single, small-size release. However, suppression drives often suffer from efficiency issues, and the most well-studied type, homing drives, tend to spread without limit. RESULTS: In this study, we show that coupling female-specific lethal alleles with homing gene drive allowed substantial improvement in efficiency while still retaining the self-limiting nature (and thus confinement) of a lethal allele strategy. Using a mosquito model, we show the required release sizes for population elimination in a variety of scenarios, including different density growth curves, with comparisons to other systems. Resistance alleles reduced the power of this method, but these could be overcome by targeting an essential gene with the drive while also providing rescue. A proof-of-principle demonstration of this system in Drosophila melanogaster was effective in both biasing its inheritance and achieving high lethality among females that inherit the construct in the absence of antibiotic. CONCLUSIONS: Overall, our study shows that substantial improvements can be achieved in female-specific lethal systems for population suppression by combining them with various types of gene drive.

Construction and preclinical evaluation of a 124I-labelled bispecific antibody targeting PD-L1 and PD-L2.

PURPOSE: NB12 is a bispecific antibody that consists of two anti-programmed cell death-ligand 1 (PD-L1) nanobodies and two anti-programmed cell death-ligand 2 (PD-L2) nanobodies. The aim of this study was to design a novel tracer, [124I]I-NB12, targeting PD-L1/2 and perform preclinical evaluations to dynamically monitor PD-L1/2 expression for determining cancer patient responsiveness to ICI therapy. METHODS: NB12 was labelled with the radionuclide 124I at room temperature (RT). An in vitro binding assay was performed to assess the affinity of [124I]I-NB12 for PD-L1 and PD-L2. Cellular uptake, pharmacokinetic, and biodistribution experiments were performed to evaluate the biological properties. Micro-PET/CT imaging with [124I]I-NB12 was conducted at different time points. Immunohistochemical and haematoxylin and eosin (HE) staining experiments were carried out using tumour tissues. Routine blood, biochemical indices and major organ pathology were used to evaluate the biosafety of the tracers. RESULTS: The radiochemical yield of [124I]I-NB12 was 84.62 ± 3.90%, and the radiochemical purity (RCP) was greater than 99%. [124I]I-NB12 had a high affinity for the PD-L1 (Kd = 19.82 nM) and PD-L2 (Kd = 2.93 nM). Cellular uptake experiments confirmed that the uptake of [124I]I-NB12 by A549-PDL1/2 cells was greater than that by A549 cells. The half-lives of the distribution phase and elimination phase were 0.26 h and 4.08 h, respectively. Micro-PET/CT showed significant [124I]I-NB12 uptake in the tumour region of A549-PDL1/2 tumour-bearing mice compared with A549 tumour-bearing mice 24 h postinjection. Immunohistochemical and HE staining experiments confirmed that tumour-bearing mice was successfully constructed. CONCLUSION: We constructed a bispecific antibody that targets PD-L1 and PD-L2, namely, [124I]I-NB12. Biological evaluation revealed its specificity and affinity for PD-L1/2, and micro-PET/CT confirmed the feasibility of visualizing tumour PD-L1/2 in vivo. Using [124I]I-NB12 may be a promising strategy for identifying cancer patients that can potentially benefit from ICI therapy.

Mitochondria-endoplasmic reticulum crosstalk in apoptosis: The interactions of cytochrome c with monooxygenase and its reductase.

The crosstalk between endoplasmic reticulum and mitochondria is of significance in apoptosis, in which cytochrome b5 (Cyt b5) is thought to be a major target for cytochrome c (Cyt c) upon its release from the mitochondria. In the absence of Cyt b5, the role of interactions of Cyt c with CYP-dependent monooxygenase system in apoptotic regulation was explored in this study. NADPH-dependent and Cyt c-induced formation of reactive oxygen species (ROS) and NADPH-independent Cyt c unfolding were revealed. With the aid of a CPR inhibitor and CYP antibodies, the interactions among Cyt c, cytochrome P450 reductase (CPR) and cytochrome P450 (CYP) are evidenced, which are found crucial for monooxygenase-derived ROS formation. The underlying structural basis of Cyt c-CYP complex was unveiled by molecular dynamics simulations. This study provides novel insights into how Cyt c regulates ROS formation through the interactions with CPR and CYP, and is implicated for a deeper understanding of the regulation mechanism in the mitochondria-endoplasmic reticulum apoptotic pathway.

Winter wheat ear counting based on improved YOLOv7x and Kalman filter tracking algorithm with video streaming.

Accurate and real-time field wheat ear counting is of great significance for wheat yield prediction, genetic breeding and optimized planting management. In order to realize wheat ear detection and counting under the large-resolution Unmanned Aerial Vehicle (UAV) video, Space to depth (SPD) module was added to the deep learning model YOLOv7x. The Normalized Gaussian Wasserstein Distance (NWD) Loss function is designed to create a new detection model YOLOv7xSPD. The precision, recall, F1 score and AP of the model on the test set are 95.85%, 94.71%, 95.28%, and 94.99%, respectively. The AP value is 1.67% higher than that of YOLOv7x, and 10.41%, 39.32%, 2.96%, and 0.22% higher than that of Faster RCNN, SSD, YOLOv5s, and YOLOv7. YOLOv7xSPD is combined with the Kalman filter tracking and the Hungarian matching algorithm to establish a wheat ear counting model with the video flow, called YOLOv7xSPD Counter, which can realize real-time counting of wheat ears in the field. In the video with a resolution of 3840×2160, the detection frame rate of YOLOv7xSPD Counter is about 5.5FPS. The counting results are highly correlated with the ground truth number (R2 = 0.99), and can provide model basis for wheat yield prediction, genetic breeding and optimized planting management.

Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy.

BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

Development and Validation of a Machine Learning Algorithm to Predict the Risk of Blood Transfusion after Total Hip Replacement in Patients with Femoral Neck Fractures: A Multicenter Retrospective Cohort Study.

OBJECTIVE: Total hip arthroplasty (THA) remains the primary treatment option for femoral neck fractures in elderly patients. This study aims to explore the risk factors associated with allogeneic blood transfusion after surgery and to develop a dynamic prediction model to predict post-operative blood transfusion requirements. This will provide more accurate guidance for perioperative humoral management and rational allocation of medical resources. METHODS: We retrospectively analyzed data from 829 patients who underwent total hip arthroplasty for femoral neck fractures at three third-class hospitals between January 2017 and August 2023. Patient data from one hospital were used for model development, whereas data from the other two hospitals were used for external validation. Logistic regression analysis was used to screen the characteristic subsets related to blood transfusion. Various machine learning algorithms, including logistic regression, SVA (support vector machine), K-NN (k-nearest neighbors), MLP (multilayer perceptron), naive Bayes, decision tree, random forest, and gradient boosting, were used to process the data and construct prediction models. A 10-fold cross-validation algorithm facilitated the comparison of the predictive performance of the models, resulting in the selection of the best-performing model for the development of an open-source computing program. RESULTS: BMI (body mass index), surgical duration, IBL (intraoperative blood loss), anticoagulant history, utilization rate of tranexamic acid, Pre-Hb, and Pre-ALB were included in the model as well as independent risk factors. The average area under curve (AUC) values for each model were as follows: logistic regression (0.98); SVA (0.91); k-NN (0.87) MLP, (0.96); naive Bayes (0.97); decision tree (0.87); random forest (0.96); and gradient boosting (0.97). A web calculator based on the best model is available at: (https://nomo99.shinyapps.io/dynnomapp/). CONCLUSION: Utilizing a computer algorithm, a prediction model with a high discrimination accuracy (AUC > 0.5) was developed. The logistic regression model demonstrated superior differentiation and reliability, thereby successfully passing external validation. The model's strong generalizability and applicability have significant implications for clinicians, aiding in the identification of patients at high risk for postoperative blood transfusion.

Divergent determinants on interannual variability of terrestrial water cycle across the globe.

Intensifying variability in precipitation under a changing climate is projected to amplify fluctuation in terrestrial hydrological cycle, leading to more severe water-related disasters. The connections between interannual variability of hydrological components and factors influencing these connections have not been clearly defined yet. Based on terrestrial water budget from Climate Data Record, we identify dominant factors influencing partitioning interannual variability of precipitation (P) into that of evapotranspiration (E), runoff (Q), and water storage deviation (ΔS) across the globe by employing geographical detector model (GDM). Sensitivities of the variability partitioning to dominant factors are quantified for different hydroclimate regions by linear regression model and law of total differential. Results show that dominant factors influencing precipitation variability partitioning (VP) are different across distinct hydroclimate conditions. Comparing the statistical index (q value) of the GDM, it can be seen that surface air temperature (Ta), snow water equivalent (SWE) and water storage capacity (Smax) are dominant factors of VP in humid, semi-arid and arid regions, respectively. Changes in P variability largely can transfer into Q variability in humid region. The P variability partitioned into Q variability is dramatically reduced in semi-arid region with SWE decreasing, while P variability partitioned into ΔS variability increases with Smax increasing in arid region. Joint effects of Ta and coefficient of variation of precipitation (Pcv) are found to be the most important interaction in determining VP across the globe. Furthermore, warmer temperatures in humid region cause >90 % of the change in precipitation variability to be transferred to Q variability change. In semi-arid region with snowfall, decreased SWE has strong effect on changes in ΔS (30-40 %) and Q (20-40 %) variability. Our findings imply a changing VP and more severe impacts of hydrological extremes under future climate, where intensive changes in Ta, SWE and land cover are projected.

The roles and mechanisms of SREBP1 in cancer development and drug response.

Cancer occurrence and development are closely related to increased lipid production and glucose consumption. Lipids are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition, signal transduction, and energy supply, which are vital for cancer cell rapid proliferation, invasion, and metastasis. Sterol regulatory element-binding transcription factor 1 (SREBP1) is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis, lipid homeostasis, and fatty acid synthesis. In addition, SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases, particularly cancer. However, no review of SREBP1 in cancer biology has yet been published. Herein, we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells, including SREBP1 modification, lipid metabolism and reprogramming, glucose and mitochondrial metabolism, immunity, and tumor microenvironment, epithelial-mesenchymal transition, cell cycle, apoptosis, and ferroptosis. Additionally, we discussed the potential role of SREBP1 in cancer prognosis, drug response such as drug sensitivity to chemotherapy and radiotherapy, and the potential drugs targeting SREBP1 and its corresponding pathway, elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.

Mitochondria-Specific Molecular Crosstalk between Ferroptosis and Apoptosis Revealed by In Situ Raman Spectroscopy.

Ferroptosis and apoptosis are two types of regulated cell death that are closely associated with the pathophysiological processes of many diseases. The significance of ferroptosis-apoptosis crosstalk in cell fate determination has been reported, but the underlying molecular mechanisms are poorly understood. Herein mitochondria-mediated molecular crosstalk is explored. Based on a comprehensive spectroscopic investigation and mass spectrometry, cytochrome c-involved Fenton-like reactions and lipid peroxidation are revealed. More importantly, cytochrome c is found to induce ROS-independent and cardiolipin-specific lipid peroxidation depending on its redox state. In situ Raman spectroscopy unveiled that erastin can interrupt membrane permeability, specifically through cardiolipin, facilitating cytochrome c release from the mitochondria. Details of the erastin-cardiolipin interaction are determined using molecular dynamics simulations. This study provides novel insights into how molecular crosstalk occurs around mitochondrial membranes to trigger ferroptosis and apoptosis, with significant implications for the rational design of mitochondria-targeted cell death reducers in cancer therapy.

A comprehensive study on the co-removal of Cr (VI) and ciprofloxacin via microbial-photocatalytic coupling: Mechanistic insights and performance evaluation.

The increasing contamination of water systems by antibiotics and heavy metals has become a growing concern. The intimately coupled photocatalysis and biodegradation (ICPB) approach offers a promising strategy for the effective removal of mixed pollutants. Despite some prior research on ICPB applications, the mechanism by which ICPB eliminates mixed pollutants remains unclear. In our current study, the ICPB approach achieved approximately 1.53 times the degradation rate of ciprofloxacin (CIP) and roughly 1.82 times the reduction rate of Cr (VI) compared to photocatalysis. Remarkably, after 30 days, the ICPB achieved a 96.1% CIP removal rate, and a 97.8% reduction in Cr (VI). Our investigation utilized three-dimensional fluorescence analysis and photo-electrochemical characterization to unveil the synergistic effects of photocatalysis and biodegradation in removal of CIP and Cr (VI). Incorporation of B-Bi3O4Cl (B-BOC) photocatalyst facilitated electron-hole separation, leading to production of ·O2-, ·OH, and h+ species which interacted with CIP, while electrons reduced Cr (VI). Subsequently, the photocatalytic products were biodegraded by a protective biofilm. Furthermore, we observed that CIP, acting as an electron donor, promoted the reduction of Cr (VI). The microbial communities revealed that the number of bacteria favoring pollutant removal increased during ICPB operation, leading to a significant enhancement in performance.

In Situ Raman Spectroscopy Reveals Cytochrome c Redox-Controlled Modulation of Mitochondrial Membrane Permeabilization That Triggers Apoptosis.

The selective interaction of cytochrome c (Cyt c) with cardiolipin (CL) is involved in mitochondrial membrane permeabilization, an essential step for the release of apoptosis activators. The structural basis and modulatory mechanism are, however, poorly understood. Here, we report that Cyt c can induce CL peroxidation independent of reactive oxygen species, which is controlled by its redox states. The structural basis of the Cyt c-CL binding was unveiled by comprehensive spectroscopic investigation and mass spectrometry. The Cyt c-induced permeabilization and its effect on membrane collapse, pore formation, and budding are observed by confocal microscopy. Moreover, cytochrome c oxidase dysfunction is found to be associated with the initiation of Cyt c redox-controlled membrane permeabilization. These results verify the significance of a redox-dependent modulation mechanism at the early stage of apoptosis, which can be exploited for the design of cytochrome c oxidase-targeted apoptotic inducers in cancer therapy.

In Situ Monitoring of Membrane Protein Electron Transfer via Surface-Enhanced Resonance Raman Spectroscopy.

In situ analysis of membrane protein-ligand interactions under physiological conditions is of significance for both fundamental and applied science, but it is still a big challenge due to the limits in sensitivity and selectivity. Here, we demonstrate the potential of surface-enhanced resonance Raman spectroscopy (SERRS) for the investigation of membrane protein-protein interactions. Lipid biolayers are successfully coated on silver nanoparticles through electrostatic interactions, and a highly sensitive and biomimetic membrane platform is obtained in vitro. Self-assembly and immobilization of the reduced cytochrome b5 on the coated membrane are achieved and protein native biological functions are preserved. Owing to resonance effect, the Raman fingerprint of the immobilized cytochrome b5 redox center is selectively enhanced, allowing for in situ and real-time monitoring of the electron transfer process between cytochrome b5 and their partners, cytochrome c and myoglobin. This study provides a sensitive analytical approach for membrane proteins and paves the way for in situ exploration of their structural basis and functions.

Super-small zwitterionic micelles enable the improvement of blood-brain barrier crossing for efficient orthotopic glioblastoma combinational therapy.

Glioblastoma multiforme (GBM) remains incurable in clinical, nanotechnology-based drug delivery strategies show promising perspective in alleviating GBM, while limited blood-brain-barrier (BBB) permeation, short blood half-live accompanied by the poor tumor accumulation and penetration, significantly restrict the therapeutic outcomes. Herein, a versatile super-small zwitterionic nano-system (MCB(S)) based on carboxybetaine (CB) zwitterion functionalized hyperbranched polycarbonate (HPCB) is developed to overcome the brain delivery challenges. After grafting with amino-functionalized IR780 (free IR780), the ultimate paclitaxel (PTX)-encapsulated micelles (MCB(S)-IR@PTX) are precisely activated by near-infrared (NIR) for accelerated drug release and effective combinational GBM therapy. Importantly, MCB(S)-IR@PTX with the crosslinked structure and CB zwitterion prolongs blood-circulation, and CB-zwitterion further facilitates BBB-traversing through betaine/γ-aminobutyric acid (GABA) transporter-1 (BGT-1) pathway. Combined with the benefit of super small-size, MCB(S)-IR@PTX highly accumulates at tumor sites and penetrates deeply, thus efficiently inhibiting tumor growth and strikingly improving survival time in U87MG orthotopic GBM-bearing mouse model. The ingenious nanoplatform furnishes a versatile strategy for delivering therapeutics into the brain and realizing efficient brain cancer therapy.

Construction and preclinical evaluation of a zirconium-89 labelled monoclonal antibody targeting PD-L2 in lung cancer.

OBJECTIVES: The aim of this study was to design a novel tracer targeting programmed cell death-ligand 2 (PD-L2) to dynamically monitor PD-L2 expression and perform preclinical screening to identify patients who may benefit from immune checkpoint inhibitor therapy (ICI) therapy. METHODS: 89Zr labelling of DFO-conjugated PD-L2 antibody (ATL2) was carried out in Na2CO3 buffer at pH 7 (37 °C, 1 h). In vitro stability was analysed using radio-thin layer chromatography (radio-TLC). The affinity of [89Zr]Zr-DFO-ATL2 was evaluated by radio-ELISA. Cell uptake, pharmacokinetic, and biodistribution experiments were used to evaluate the biological properties. Micro-PET/CT imaging with [89Zr]Zr-DFO-ATL2 was conducted at different time points. Immunohistochemical and HE staining studies were carried out using tumour tissues from tumour-bearing mice. RESULTS: The radiochemical yield of [89Zr]Zr-DFO-ATL2 was 65.6 ± 3.9%, and the radiochemical purity (RCP) of the tracer was greater than 99%. The tracer maintained relatively high stability and had a high affinity for the PD-L2 protein (Kd = 31.85 nM, R2 = 0.94). The uptake of [89Zr]Zr-DFO-ATL2 in A549-PD-L2 cells was higher than that in A549 cells at each time point. Micro-PET/CT showed significant uptake in the tumour region of mice bearing tumours derived from A549-PD-L2 (SUVmax = 3.53 ± 0.09 at 96 h) and H2228 (SUVmax = 2.30 ± 0.12 at 48 h) cells. CONCLUSION: The high tumour uptake at early imaging time points demonstrates the feasibility of applying [89Zr]Zr-DFO-ATL2 to image PD-L2 expression in tumours and is encouraging for further clinical application in the screening of patients who may benefit from ICI therapy.

The effect and mechanism of iodophors on the adhesion and virulence of Staphylococcus aureus biofilms attached to artificial joint materials.

BACKGROUND: Iodophors are known to be a treatment for biofilm-related periprosthetic joint infection. However, the efficacy and mechanism of eradicating biofilms from different artificial joint materials after iodophor treatment are unknown. This study was conducted to understand the effect and mechanism of iodophors with respect to the adhesion and virulence of Staphylococcus aureus biofilms attached to artificial joint materials. METHODS: Biofilms of Staphylococcus aureus strains were grown on titanium alloy, cobalt chromium molybdenum and polyethylene coupons, which are commonly used materials for artificial joints, for 24 h. Afterward, all coupons were divided into experimental and control groups: (1) exposed to a 0.5 ± 0.05% iodophor for 5 min and (2) exposed to phosphate-buffered saline for 5 min. To gauge the level of biofilm, colony forming units (CFU), live/dead staining confocal microscopy and crystal violet staining were used. Meanwhile, the expression of icaACDR and clfA, which are related to virulence and adhesion, was examined in both the experimental and control groups. RESULTS: A roughly three-log decrease in CFU/cm2 was seen in the viable plate count compared to the control group. Confocal imaging and crystal violet staining verified the CFU data. Moreover, the expression of icaACDR was reduced on three different orthopaedic implant materials, and the expression of clfA was also inhibited on titanium alloy coupons exposed to the iodophor. CONCLUSIONS: Our results indicated that exposure to an iodophor for 5 min could significantly eliminate biofilms. When Staphylococcus aureus that had adhered to these three materials, which were used for artificial joints, was treated with an iodophor for 5 min, the expression of icaACDR was significantly reduced. This provides strong evidence for clinically clearing periprosthetic joint infections without removing the artificial joints.

In Situ and Real-Time Monitoring of Mitochondria-Endoplasmic Reticulum Crosstalk in Apoptosis via Surface-Enhanced Resonance Raman Spectroscopy.

The crosstalk between mitochondria and endoplasmic reticula plays a crucial role in apoptotic pathways in which reactive oxygen species (ROS) produced by microsomal monooxygenase (MMO) are believed to accelerate cytochrome c release. Herein, we successfully demonstrate the potential of surface-enhanced resonance Raman spectroscopy (SERRS) for monitoring MMO-derived ROS formation and ROS-mediated cytochrome c release. Silver nanoparticles coated with nickel shells are used as both Raman signal enhancers and electron donors for cytochrome c. SERRS of cytochrome c is found to be sensitive to ROS, allowing for in situ probing of ROS formation with a cell death inducer. Label-free evaluation of ROS-induced apoptosis is achieved by SERRS-based monitoring of cytochrome c release in living cells. This study verifies the capability of SERRS for label-free, in situ, and real-time monitoring of the mitochondria-endoplasmic reticulum crosstalk in apoptosis and provides a novel strategy for the rational design and screening of ROS-inducing drugs for cancer treatment.

Hypomethylation of Tumor necrosis factor-like cytokine 1A(TL1A) and its decoy receptor 3 expressive level increase has diagnostic value in HBV-associated cirrhosis.

For patients with cirrhosis, early diagnosis is the key to delaying the development of liver fibrosis and improving prognosis. This study aimed to investigate the clinical significance of TL1A, which is a susceptibility gene for hepatic fibrosis, and DR3 in the development of cirrhosis and fibrosis. We analyzed the expression of TL1A, DR3, and other inflammatory cytokines associated with liver fibrosis in serum and PBMCs in 200 patients.TL1A methylation level was lower in patients with HBV-associated LC than in the other groups. In addition, the mRNA level and serum of TL1A and DR3 expression levels were found to increase in the LC. Hypomethylation of the TL1A promoter is present in HBV-associated LC, and TL1A and DR3 are highly expressed in HBV-associated cirrhosis. These results indicate that TL1A and DR3 may play an important role in the pathogenesis of LC and TL1A methylation levels may serve as a noninvasive biomarker for early diagnosis and progression of LC.

Multimodal Image Fusion Offers Better Spatial Resolution for Mass Spectrometry Imaging.

High-resolution reconstruction has attracted increasing research interest in mass spectrometry imaging (MSI), but it remains a challenging ill-posed problem. In the present study, we proposed a deep learning model to fuse multimodal images to enhance the spatial resolution of MSI data, namely, DeepFERE. Hematoxylin and eosin (H&E) stain microscopy imaging was used to pose constraints in the process of high-resolution reconstruction to alleviate the ill-posedness. A novel model architecture was designed to achieve multi-task optimization by incorporating multi-modal image registration and fusion in a mutually reinforced framework. Experimental results demonstrated that the proposed DeepFERE model is able to produce high-resolution reconstruction images with rich chemical information and a detailed structure on both visual inspection and quantitative evaluation. In addition, our method was found to be able to improve the delimitation of the boundary between cancerous and para-cancerous regions in the MSI image. Furthermore, the reconstruction of low-resolution spatial transcriptomics data demonstrated that the developed DeepFERE model may find wider applications in biomedical fields.

PhoPQ Regulates Quinolone and Cephalosporin Resistance Formation in Salmonella Enteritidis at the Transcriptional Level.

The two-component system (TCS) PhoPQ has been demonstrated to be crucial for the formation of resistance to quinolones and cephalosporins in Salmonella Enteritidis (S. Enteritidis). However, the mechanism underlying PhoPQ-mediated antibiotic resistance formation remains poorly understood. Here, it was shown that PhoP transcriptionally regulated an assortment of genes associated with envelope homeostasis, the osmotic stress response, and the redox balance to confer resistance to quinolones and cephalosporins in S. Enteritidis. Specifically, cells lacking the PhoP regulator, under nalidixic acid and ceftazidime stress, bore a severely compromised membrane on the aspects of integrity, fluidity, and permeability, with deficiency to withstand osmolarity stress, an increased accumulation of intracellular reactive oxygen species, and dysregulated redox homeostasis, which are unfavorable for bacterial survival. The phosphorylated PhoP elicited transcriptional alterations of resistance-associated genes, including the outer membrane porin ompF and the aconitate hydratase acnA, by directly binding to their promoters, leading to a limited influx of antibiotics and a well-maintained intracellular metabolism. Importantly, it was demonstrated that the cavity of the PhoQ sensor domain bound to and sensed quinolones/cephalosporins via the crucial surrounding residues, as their mutations abrogated the binding and PhoQ autophosphorylation. This recognition mode promoted signal transduction that activated PhoP, thereby modulating the transcription of downstream genes to accommodate cells to antibiotic stress. These findings have revealed how bacteria employ a specific TCS to sense antibiotics and combat them, suggesting PhoPQ as a potential drug target with which to surmount S. Enteritidis. IMPORTANCE The prevalence of quinolone and cephalosporin-resistant S. Enteritidis is of increasing clinical concern. Thus, it is imperative to identify novel therapeutic targets with which to treat S. Enteritidis-associated infections. The PhoPQ two-component system is conserved across a variety of Gram-negative pathogens, by which bacteria adapt to a range of environmental stimuli. Our earlier work has demonstrated the importance of PhoPQ in the resistance formation in S. Enteritidis to quinolones and cephalosporins. In the current work, we identified a global profile of genes that are regulated by PhoP under antibiotic stresses, with a focus on how PhoP regulated downstream genes, either positively or negatively. Additionally, we established that PhoQ sensed quinolones and cephalosporins in a manner of directly binding to them. These identified genes and pathways that are mediated by PhoPQ represent promising targets for the development of a drug potentiator with which to neutralize antibiotic resistance in S. Enteritidis.

MRI characteristics of lumbosacral dural arteriovenous fistulas.

Background and purpose: Spinal dural arteriovenous fistulas located in the lumbosacral region are rare and present with nonspecific clinical signs. The purpose of this study was to find out the specific radiologic features of these fistulas. Methods: We retrospectively reviewed the clinical and radiological data of 38 patients diagnosed with lumbosacral spinal dural arteriovenous fistulas in our institution from September 2016 to September 2021. All patients underwent time-resolved contrast-enhanced three-dimensional MRA and DSA examinations, and were treated with either endovascular or neurosurgical strategies. Results: Most of the patients (89.5%) had motor or sensory disorders in both lower limbs as the first symptoms. On MRA, the dilated filum terminale vein or radicular vein was seen in 23/30 (76.7%) patients with lumbar spinal dural arteriovenous fistulas and 8/8 (100%) patients with sacral spinal dural arteriovenous fistulas. T2W intramedullary abnormally high signal intensity areas were found in all lumbosacral spinal dural arteriovenous fistula patients, with involvement of the conus present in 35/38 (92.1%) patients. The "missing piece sign" in the intramedullary enhancement area was seen in 29/38 (76.3%) patients. Conclusion: Dilatation of the filum terminale vein or radicular vein is powerful evidence for diagnosis of lumbosacral spinal dural arteriovenous fistulas, especially for sacral spinal dural arteriovenous fistulas. T2W intramedullary hyperintensity in the thoracic spinal cord and conus, and the missing-piece sign could be indicative of lumbosacral spinal dural arteriovenous fistula.