Physiological temperature drives TRPM4 ligand recognition and gating.

Temperature profoundly affects macromolecular function, particularly in proteins with temperature sensitivity1,2. However, its impact is often overlooked in biophysical studies that are typically performed at non-physiological temperatures, potentially leading to inaccurate mechanistic and pharmacological insights. Here we demonstrate temperature-dependent changes in the structure and function of TRPM4, a temperature-sensitive Ca2+-activated ion channel3-7. By studying TRPM4 prepared at physiological temperature using single-particle cryo-electron microscopy, we identified a 'warm' conformation that is distinct from those observed at lower temperatures. This conformation is driven by a temperature-dependent Ca2+-binding site in the intracellular domain, and is essential for TRPM4 function in physiological contexts. We demonstrated that ligands, exemplified by decavanadate (a positive modulator)8 and ATP (an inhibitor)9, bind to different locations of TRPM4 at physiological temperatures than at lower temperatures10,11, and that these sites have bona fide functional relevance. We elucidated the TRPM4 gating mechanism by capturing structural snapshots of its different functional states at physiological temperatures, revealing the channel opening that is not observed at lower temperatures. Our study provides an example of temperature-dependent ligand recognition and modulation of an ion channel, underscoring the importance of studying macromolecules at physiological temperatures. It also provides a potential molecular framework for deciphering how thermosensitive TRPM channels perceive temperature changes.

Molecular determinants of pH sensing in the proton-activated chloride channel.

In response to acidic pH, the widely expressed proton-activated chloride (PAC) channel opens and conducts anions across cellular membranes. By doing so, PAC plays an important role in both cellular physiology (endosome acidification) and diseases associated with tissue acidosis (acid-induced cell death). Despite the available structural information, how proton binding in the extracellular domain (ECD) leads to PAC channel opening remains largely unknown. Here, through comprehensive mutagenesis and electrophysiological studies, we identified several critical titratable residues, including two histidine residues (H130 and H131) and an aspartic acid residue (D269) at the distal end of the ECD, together with the previously characterized H98 at the transmembrane domain-ECD interface, as potential pH sensors for human PAC. Mutations of these residues resulted in significant changes in pH sensitivity. Some combined mutants also exhibited large basal PAC channel activities at neutral pH. By combining molecular dynamics simulations with structural and functional analysis, we further found that the ß12 strand at the intersubunit interface and the associated "joint region" connecting the upper and lower ECDs allosterically regulate the proton-dependent PAC activation. Our studies suggest a distinct pH-sensing and gating mechanism of this new family of ion channels sensitive to acidic environment.

Femtosecond laser direct writing large-area fiber Bragg grating based on diaphragm shaping.

We propose and demonstrate a new method of direct writing large-area fiber Bragg grating by femtosecond laser through the coating. By adding an adjustable diaphragm before the focusing objective, we can precisely control the length of the refractive index modulation line along the femtosecond laser incident direction up to 29.1 µm. In combination with femtosecond laser scanning fabrication technology, a uniform refractive index modulation plane can be inscribed in the fiber in a single scanning. Based on the plane-by-plane inscription method, we have fabricated a high-quality high-reflectivity fiber Bragg grating and a chirped fiber Bragg grating on 20/400 double-clad fiber core. The reflectivity of both gratings is greater than 99%, and the insertion loss is as low as 0.165 dB and 0.162 dB, respectively. The thermal slope of chirped fiber Bragg grating without any refrigeration is 0.088 °C/W and there is no obvious temperature increase when using the water cooling. Therefore, the fabrication method of large-area fiber Bragg grating based on diaphragm shaping can efficiently fabricate high-quality fiber Bragg grating in the large core diameter fiber, which has an important application prospect in high-power all-fiber oscillators, especially all-fiber oscillators in special wavebands.

Simultaneous superresolution reconstruction and distortion correction for single-shot EPI DWI using deep learning.

PURPOSE: Single-shot (SS) EPI is widely used for clinical DWI. This study aims to develop an end-to-end deep learning-based method with a novel loss function in an improved network structure to simultaneously increase the resolution and correct distortions for SS-EPI DWI. THEORY AND METHODS: Point-spread-function (PSF)-encoded EPI can provide high-resolution, distortion-free DWI images. A distorted image from SS-EPI can be described as the convolution between a PSF function with a distortion-free image. The deconvolution process to recover the distortion-free image can be achieved with a convolution neural network, which also learns the mapping function between low-resolution SS-EPI and high-resolution reference PSF-EPI to achieve superresolution. To suppress the oversmoothing effect, we proposed a modified generative adversarial network structure, in which a dense net with gradient map guidance and a multilevel fusion block was used as the generator. A fractional anisotropy loss was proposed to utilize the diffusion anisotropy information among diffusion directions. In vivo brain DWI data were used to test the proposed method. RESULTS: The results show that distortion-corrected high-resolution DWI images with restored structural details can be obtained from low-resolution SS-EPI images by taking advantage of the high-resolution anatomical images. Additionally, the proposed network can improve the quantitative accuracy of diffusion metrics compared with previously reported networks. CONCLUSION: Using high-resolution, distortion-free EPI-DWI images as references, a deep learning-based method to simultaneously increase the perceived resolution and correct distortions for low-resolution SS-EPI was proposed. The results show that DWI image quality and diffusion metrics can be improved.

Comparison of uniform-density, variable-density, and dual-density spiral samplings for multi-shot DWI.

PURPOSE: To compare the performances of uniform-density spiral (UDS), variable-density spiral (VDS), and dual-density spiral (DDS) samplings in multi-shot diffusion imaging, and determine a sampling strategy that balances reliability of shot navigator and overall DWI image quality. THEORY AND METHODS: UDS, VDS, and DDS trajectories were implemented to achieve four-shot diffusion-weighted spiral imaging. First, the static B0 off-resonance effects in UDS, VDS, and DDS acquisitions were analyzed based on a signal model. Then, in vivo experiments were performed to verify the theoretical analyses, and fractional anisotropy (FA) fitting residuals were used to quantitatively assess the quality of spiral diffusion data for tensor estimation. Finally, the SNR performances and g-factor behavior of the three spiral samplings were evaluated using a Monte Carlo-based pseudo multiple replica method. RESULTS: Among the three spiral trajectories with the same readout duration, UDS sampling exhibited the least off-resonance artifacts. This was most evident when the static B0 off-resonance effect was severe. The UDS diffusion images had higher anatomical fidelity and lower FA fitting residuals than the other two counterparts. Furthermore, the four-shot UDS acquisition achieved the best SNR performance in diffusion imaging with 12.11% and 40.85% improvements over the VDS and DDS acquisitions with the same readout duration, respectively. CONCLUSION: UDS sampling is an efficient spiral acquisition scheme for high-resolution diffusion imaging with reliable navigator information. It provides superior off-resonance performance and SNR efficiency over the VDS and DDS samplings for the tested scenarios.

Raman suppression in high-power fiber oscillators by femtosecond-written chirped and tilted fiber Bragg gratings.

Realizing stimulated Raman scattering (SRS) suppression is a key topic for high-power fiber lasers. Here, we report an effective and simple strategy for SRS suppression using chirped and tilted fiber Bragg gratings (CTFBGs) in high-power fiber oscillators while maintaining the compactness and stability of the system. The CTFBG is inserted on the side of a cavity mirror FBG without cutting the gain fiber. To improve power handling capability, the CTFBG and cavity mirror FBGs are inscribed by femtosecond (fs) lasers. The optimal SRS suppression effect can be realized when the CTFBG is inserted into the resonant cavity and on the side of the output coupler FBG. The SRS threshold is increased by approximately 11% with an SRS suppression ratio of nearly 14 dB. Moreover, the output power of the fiber oscillator is improved to 3.5 kW, which is the maximum power achieved in fiber oscillators with SRS suppression using CTFBGs, to the best of our knowledge. The temperature of the air-cooled CTFBG is 50.2 °C, which has the potential to handle higher power. This work provides new insights for suppressing SRS in fiber oscillators, promoting the application of CTFBGs in high-power lasers.

Femtosecond laser fabrication of chirped and tilted fiber Bragg gratings for stimulated Raman scattering suppression in kilowatt-level fiber lasers.

Chirped and tilted fiber Bragg gratings (CTFBGs) are important all-fiber filtering components in high-power fiber lasers for stimulated Raman scattering (SRS) suppression. The fabrication of CTFBGs in large-mode-area double-cladding fibers (LMA-DCFs) by femtosecond (fs) laser is reported for the first time to the best of our knowledge. The chirped and tilted grating structure is obtained by scanning the fiber obliquely and moving the fs-laser beam relative to the chirped phase mask at the same time. By this method, the CTFBGs with different chirp rates, grating lengths, and tilted angles are fabricated, and the maximum rejection depth and bandwidth are ∼25 dB and ∼12 nm, respectively. To test the performance of the fabricated CTFBGs, one is inserted between the seed laser and the amplifier stage of a 2.7 kW fiber amplifier, and an SRS suppression ratio of ∼4 dB is achieved with no reduction in laser efficiency and degradation in beam quality. This work provides a highly fast and flexible method to fabricate large-core CTFBGs, which is of great significance to the development of high-power fiber laser systems.

Robust femtosecond-written chirped and tilted fiber Bragg gratings for Raman filtering in multi-kW fiber lasers.

We present a robust chirped and tilted fiber Bragg grating (CTFBG) in a large-mode-area double-cladding fiber (LMA-DCF) written by a femtosecond (fs) laser. By implementing the fs-CTFBG into the output end of a high-power fiber laser for Raman filtering, a power handling capability of 4 kW is achieved with a Raman filtering ratio of ∼13 dB. To the best of our knowledge, this is the maximum handling power of a CTFBG for Raman filtering. The signal loss of the fs-CTFBG is 0.03 dB, which has little effect on the output laser beam quality. The air-cooled fs-CTFBG has a minimum temperature slope of 7.8°C/kW due to a self-annealing effect. This work proves the excellent performance of the fs-CTFBG, promoting the development of high-power CTFBGs.

Nanoscale Investigation into Dynamics of Thin Liquid Films during Bouncing and Attachment of Rising Air Bubbles on Hydrophilic and Hydrophobic Surfaces.

Investigations on bouncing and attachment of free-rising air bubbles on hydrophobic surfaces have been limited to side-view, high-speed photography of the bubble-plate attachment process. In this work, an investigation of the dynamics as well as stability of thin liquid films (TLFs) between free-rising air bubbles and quartz surfaces was performed using a newly developed multiple-wavelength synchronized reflection interferometry microscopy (SRIM) technique. The effect of surface hydrophobicity on both the stability and critical rupture thickness of TLFs was investigated. Results showed that the TLF ruptured at a critical rupture thickness of 100-1000 nm or beyond during bubble's impact on hydrophobic quartz surfaces. The critical rupture thicknesses varied depending on the surface hydrophobicity as well as surface asperity. A higher surface hydrophobicity, in general, contributed to a higher critical rupture thickness. In addition, the effect of n-octanol on the stability of the TLFs was investigated. Results showed that film stability increased with increasing the concentration of n-octanol, which was accompanied by a significant decrease in the critical rupture thickness. The present result illustrates, for the first time, the dynamics of TLFs on hydrophobic surfaces under a dynamic condition compared with previous studies under a quasi-equilibrium condition. The information revealed from the present work has a significant implication to many industrial applications, including froth flotation and other biological and semiconductor applications.

Slab boundary artifact correction in multislab imaging using convolutional-neural-network-enabled inversion for slab profile encoding.

PURPOSE: This study aims to propose a novel algorithm for slab boundary artifact correction in both single-band multislab imaging and simultaneous multislab (SMSlab) imaging. THEORY AND METHODS: In image domain, the formation of slab boundary artifacts can be regarded as modulating the artifact-free images using the slab profiles and introducing aliasing along the slice direction. Slab boundary artifact correction is the inverse problem of this process. An iterative algorithm based on convolutional neural networks (CNNs) is proposed to solve the problem, termed CNN-enabled inversion for slab profile encoding (CPEN). Diffusion-weighted SMSlab images and reference images without slab boundary artifacts were acquired in 7 healthy subjects for training. Images of 5 healthy subjects were acquired for testing, including single-band multislab and SMSlab images with 1.3-mm or 1-mm isotropic resolution. CNN-enabled inversion for slab profile encoding was compared with a previously reported method (i.e., nonlinear inversion for slab profile encoding [NPEN]). RESULTS: CNN-enabled inversion for slab profile encoding reduces the slab boundary artifacts in both single-band multislab and SMSlab images. It also suppresses the slab boundary artifacts in the diffusion metric maps. Compared with NPEN, CPEN shows fewer residual artifacts in different acquisition protocols and more significant improvements in quantitative assessment, and it also accelerates the computation by more than 35 times. CONCLUSION: CNN-enabled inversion for slab profile encoding can reduce the slab boundary artifacts in multislab acquisitions. It shows better slab boundary artifact correction capacity, higher robustness, and computation efficiency when compared with NPEN. It has the potential to improve the accuracy of multislab acquisitions in high-resolution DWI and functional MRI.

Stable Picodisc Assemblies from Saposin Proteins and Branched Detergents.

Methods for maintaining membrane proteins in their native state after removal from the lipid bilayer are essential for the study of this important class of biomacromolecules. Common solubilization strategies range from the use of detergents to more complex systems that involve a polypeptide working in concert with lipids or detergents, such as nanodiscs, picodiscs, and peptidiscs, in which an engineered protein or synthetic peptide surrounds the membrane protein along with a lipid sheath. Picodiscs employ the protein saposin A, which naturally functions to facilitate lipid degradation in the lysozome. Saposin A-amphiphile complexes therefore tend to be most stable at acidic pH, which is not optimal for most membrane protein applications. In search of new picodisc assemblies, we have explored pairings of saposin A or other saposin proteins with a range of detergents, and we have identified a number of combinations that spontaneously co-assemble at neutral pH. The resulting picodiscs are stable for weeks and have been characterized by size-exclusion chromatography, native mass spectrometry, and small angle X-ray scattering. The new assemblies are formed by double-tail detergents rather than more traditional single-tail detergents; the double-tail detergents can be seen as structurally intermediate between single-tail detergents and common lipids. In addition to saposin A, an engineered variant of saposin B (designated saposin BW) forms picodisc assemblies. These findings provide a framework for future efforts to solubilize membrane proteins with multiple picodisc systems that were previously unknown.

Cs2MnF6 Red Phosphor with Ultrahigh Absorption Efficiency.

To improve absorption efficiency (AE) and subsequently improve external quantum efficiency (EQE) remains one of the significant challenges for Mn4+-doped red-emitting fluoride phosphors. In this study, we propose to use Mn4+ as a part of matrix to enhance the AE of fluoride phosphors. Red-emission phosphors Cs2MnF6, Cs2MnF6:Sc3+, and Cs2MnF6:Si4+ were synthesized successfully by a coprecipitation method. The Rietveld refinement of X-ray diffraction reveals that this red phosphor exhibits a cubic structure in Fm3̅m space group. Owing to Mn4+ being a part of matrix, this kind of red phosphor possesses an extremely high AE, which can be promoted to 88%. The doping of Sc3+ and Si4+ ions into Cs2MnF6 can effectively increase the luminescence intensity to 253 and 232%, respectively, relative to that of Cs2MnF6. The relative emission intensity of Cs2MnF6:5%Si4+ red phosphor preserves about 115% when temperature rises to 175 °C. By employing Cs2MnF6:5%Si4+ as a red-emitting component, high-performance LED-1 with Ra = 86.2, R9 = 82.1 and CCT = 3297 K, and LED-2 with an ultrawide color gamut (NTSC value of 122.3% and rec. 2020 value of 91.3%) are obtained. This work may provide a new idea to explore a new type of fluoride phosphor with high EQE for high-performance white-light-emitting diodes.

Sensitivity improvement induced by thermal response behavior for temperature sensing applications.

Overcoming the restriction of the energy gap (700-800 cm-1) in Er3+-doped upconversion (UC) materials to achieve high detection accuracy is crucial for practical temperature detection applications. Herein, we design a feasible route based on the different thermal response behaviors of various hosts to enhance the SA value in a double perovskite NaLaMgWO6:Er,Mo system. The maximum SA value is 222.8 × 10-4@423 K in the NLMW:5%Er3+ host, and this can be promoted to 275.4 × 10-4 K-1@323 K in the NaLaMgWO6:Er,Mo system. The SR values decrease monotonously as the temperature rises, and this is due to the dependency of the SR values on the energy gap. A mechanism that is ascribed to the different thermal response behaviors of the various hosts is proposed, and this mechanism is further proved by investigating the temperature sensing properties of barium gadolinium zincate phosphors that possess the same thermal response behaviors. In addition, this study introduces the idea that a host with a high emission intensity for the 2H11/2 level and a lower emission intensity for the 4S3/2 level is highly suitable for temperature measurements. A thorough investigation of this system offers a strategy to acquire a high SA value and reveals the broad prospects of NaLaMgWO6:Er,Mo in the temperature detection field.

Transgenic Wucai (Brassica campestris L.) produced via Agrobacterium-mediated anther transformation in planta.

KEY MESSAGE: We developed a novel Agrobacterium-mediated anther transformation for Wucai in planta, and in this procedure, the male germ line was the predominant target. Wucai (Brassica campestris L.), a variant of non-heading Chinese cabbage, is widely cultured in China and only improved by classic breeding methods. Here, a novel and efficient in planta Agrobacterium-mediated anther transformation method is developed based on the optimization of several factors that affect anther transformation. After optimization, transformation with the manual pollination application led to increased transient GUS expression in anthers (reaching 91.59%) and the transformation efficacies in planta (0.59-1.56% for four commercial cultivars). The stable integration and inheritance of the transgenes were further examined by molecular and genetic analyses. Three T2 transgenic lines presented a segregation ratio of 3:1, which was consistent with the Mendelian feature of a single dominant gene. In addition, the GUS histochemical assay and genetic crossing analysis revealed that the male germ line was the predominant target in this transformation. This optimized transformation system could provide a useful tool for both the improvement of cultivar qualities and investigation of functional genes in Wucai.

Comparative Transcriptome Analysis between Fertile and CMS Flower Buds in Wucai (Brassica campestris L.).

BACKGROUND: Wucai (Brassica campestris L. ssp. chinensis var. rosularis Tsen) is a variant of nonheading Chinese cabbage (Brassica campestris L.), which is one of the major vegetables in China. Cytoplasmic male sterility (CMS) has been used for Wucai breeding in recent years. However, the underlying molecular mechanism of Wucai CMS remains unclear. In this study, the phenotypic and cytological features of Wucai CMS were observed by anatomical analysis, and a comparative transcriptome analysis was carried out to identify genes related to male sterility using Illumina RNA sequencing technology (RNA-Seq). RESULTS: Microscopic observation demonstrated that tapetum development was abnormal in the CMS line, which failed to produce fertile pollen. Bioinformatics analysis detected 4430 differentially expressed genes (DEGs) between the fertile and sterile flower buds. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to better understand the functions of these DEGs. Among the DEGs, 35 genes (53 DEGS) were implicated in anther and pollen development, and 11 genes were involved in pollen cell wall formation and modification; most of these showed downregulated expression in sterile buds. In addition, several genes related to tapetum development (A6, AMS, MS1, MYB39, and TSM1) and a few genes annotated to flowering (CO, AP3, VIN3, FLC, FT, and AGL) were detected and confirmed by qRT-PCR as being expressed at the meiosis, tetrad, and uninucleate microspore stages, thus implying possible roles in specifying or determining the fate and development of the tapetum, male gametophyte and stamen. Moreover, the top four largest transcription factor families (MYB, bHLH, NAC and WRKY) were analyzed, and most showed reduced expression in sterile buds. These differentially expressed transcription factors might result in abortion of pollen development in Wucai. CONCLUSION: The present comparative transcriptome analysis suggested that many key genes and transcription factors involved in anther development show reduced gene expression patterns in the CMS line, which might contribute to male sterility in Wucai. This study provides valuable information for a better understanding of CMS molecular mechanisms and functional genome studies in Wucai.

Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers.

This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 µg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 µg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 µg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 µg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

Potential biomarkers of acute myocardial infarction based on the composition of the blood microbiome.

BACKGROUND: It is difficult to distinguish between acute myocardial infarction (AMI) and unstable angina (UA) due to their similar clinical features. In recent years, studies have shown that microbiomes have great potential in distinguishing diseases. The purpose of this study is to describe the composition of serum microbiome in the AMI and UA by 16S rDNA sequencing. METHODS: Based on the high-throughput detection platform and 16S rDNA amplification sequencing technology, this study detected the blood microbial composition of 55 patients with AMI and 62 patients with UA. Alpha diversity and Beta diversity analysis were used to compare the differences in microbial composition and bacterial colony structure between AMI and UA groups. We perform PCoA (Principal Co-ordinates Analysis) based on Unweighted Unifrac distance. In addition, various statistical methods were employed to examine the significance of differences in microbial composition and genus between the two groups. PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) was employed to predict KEGG (Kyoto Encyclopedia of Genes and Genomes) function from 16S sequencing data. Random forest was applied to identify biomarkers and construct the diagnostic model. Subsequently, the stability of the model was verified by 10-fold cross and the diagnostic effectiveness was evaluated through ROC (Receiver Operating Characteristic). RESULTS: In this study, we found that alpha diversity index of serum microbiome in AMI group was significantly higher than in UA group. T-test analysis demonstrated that the UA group presented a higher abundance of Ralstonia, Faecalibaculum and Gammaproteobacteria, while Bacteroides, Sphingomonas, Faecalibaculum, Haemophilus, Serratia, Bifidobacterium and Chloroplast were more abundant in the AMI group. The LefSe (LDA Effect Size) analysis showed that the Gammaproteobacteria, Proteobacteria, Ralstonia pickettli, Ralstonia, Burkholderiaceae and Burkholderiales were enriched in UA group, and Bacteroidales, Bacteroidia, Bacteroidota, Clostridia and Firmicutes were more abundant in the AMI group. Ten bacterial diagnostic models were constructed in the random forest. The area under the curve (AUC) in the training set was 88.01%, and the AUC value in the test set was 95.04%. CONCLUSION: In this study, the composition of blood microorganisms in the groups of patients with AMI and UA has been analyzed, providing novel insights for understanding the pathogenesis of AMI; Blood microbiome may serve as novel diagnostic biomarkers of AMI.

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking.

Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic acid and adrenic acid. These PUFAs then accumulate in phospholipids, particularly ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools dictates their sensitivity to ferroptosis.

DKK1 affects survival of patients with head and neck squamous cell carcinoma by inducing resistance to radiotherapy and immunotherapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been approved to treat various types of tumors, including head and neck squamous cell carcinoma (HNSC). However, most HNSC patients do not respond to ICIs. Radioimmunotherapy has been proposed to enhance the immune response rate in HNSC. Dickkopf-1 (DKK1), a secreted protein, plays important roles in the Wnt signaling pathways. Herein, we aimed to explore the effect of DKK1 on radioimmunotherapy in HNSC. METHODS: We collected the gene expression profile and clinical information of HNSC patients from TCGA and GEO databases. The immune cell infiltration and immune score were assessed using R package CIBERSORT and ESTIMATE. The level of related pathways and biological processes were analyzed by GSEA. The signature scores of gene sets of interest were calculated by GSVA. We also performed cell viability and apoptosis assay, and clonogenic assay to investigate the radiation sensitivity of HSC-3 cells and CNE-2 cells after silencing DKK1 by siRNA. RESULTS: We found DKK1 was significantly higher expressed in HNSC, and closely correlated with patients' survival time, especially the patients who received radiotherapy. DKK1-knockdown HSC-3 cells or CNE-2 cells showed a decrease in cell viability and colony formation, and an increase in apoptotic rate after radiation. DKK1high tumors showed a more immunosuppressive microenvironment with lower infiltration of T cells and higher infiltration of marrow-derived suppressor cells (MDSCs). CONCLUSION: Our data show that DKK1 can affect both radiotherapy and immunotherapy in HNSC, suggesting that DKK1 can be a potential target for radioimmunology in HNSC.

CCGL-YOLOV5:A cross-modal cross-scale global-local attention YOLOV5 lung tumor detection model.

BACKGROUND: Multimodal medical image detection is a key technology in medical image analysis, which plays an important role in tumor diagnosis. There are different sizes lesions and different shapes lesions in multimodal lung tumor images, which makes it difficult to effectively extract key features of lung tumor lesions. METHODS: A Cross-modal Cross-scale Clobal-Local Attention YOLOV5 Lung Tumor Detection Model (CCGL-YOLOV5) is proposed in this paper. The main works are as follows: Firstly, the Cross-Modal Fusion Transformer Module (CMFTM) is designed to improve the multimodal key lesion feature extraction ability and fusion ability through the interactive assisted fusion of multimodal features; Secondly, the Global-Local Feature Interaction Module (GLFIM) is proposed to enhance the interaction ability between multimodal global features and multimodal local features through bidirectional interactive branches. Thirdly, the Cross-Scale Attention Fusion Module (CSAFM) is designed to obtain rich multi-scale features through grouping multi-scale attention for feature fusion. RESULTS: The comparison experiments with advanced networks are done. The Acc, Rec, mAP, F1 score and FPS of CCGL-YOLOV5 model on multimodal lung tumor PET/CT dataset are 97.83%, 97.39%, 96.67%, 97.61% and 98.59, respectively; The experimental results show that the performance of CCGL-YOLOV5 model in this paper are better than other typical models. CONCLUSION: The CCGL-YOLOV5 model can effectively use the multimodal feature information. There are important implications for multimodal medical image research and clinical disease diagnosis in CCGL-YOLOV5 model.