A kinome-wide synthetic lethal CRISPR/Cas9 screen reveals that mTOR inhibition prevents adaptive resistance to CDK4/CDK6 blockade in HNSCC.

The comprehensive genomic analysis of the head and neck squamous cell carcinoma (HNSCC) oncogenome revealed the frequent loss of p16INK4A (CDKN2A) and amplification of cyclin D1 (CCND1) genes in most HPV negative HNSCC lesions. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown modest effects in the clinic. The aberrant activation of PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials have shown promising clinical efficacy of mTOR inhibitors (mTORi) in the neoadjuvant and adjuvant settings but not in advanced HNSCC patients. By a kinome-wide CRISPR/Cas9 screen, we identified cell cycle inhibition as a synthetic lethal target for mTORi. Combination of mTORi and palbociclib, a CDK4/6 specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor. Mechanistically, mTORi inhibits the formation of eIF4G-CCNE1 mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that mTORi reverts the adaptive resistance to palbociclib. This provides a multimodal therapeutic option for HNSCC by co-targeting mTOR and CDK4/6, which in turn may halt the emergence of palbociclib resistance.

Highly Anion-Conductive Viologen-based Two-Dimensional Polymer Membranes as Nanopower Generators.

Two-dimensional polymers (2DPs) and their layer-stacked 2D covalent organic frameworks (2D COFs) membranes hold great potential for harvesting sustainable osmotic energy. The nascent research has yet to simultaneously achieve high ionic flux and selectivity, primarily due to inefficient ion transport dynamics. This is directly related to ultrasmall pore size (<3 nm), much smaller than the duple Debye length in the diluted electrolyte (6~20 nm), as well as low charge density (<4.5 mC m-2). Here, we introduce a π-conjugated viologen-based 2DP (V2DP) membrane possessing a large pore size of 4.5 nm, strategically enhancing the overlapping of the electric double layer, coupled with an exceptional positive surface charge density (~6 mC m-2). These characteristics enable the membrane to facilitate high anion flux while maintaining ideal selectivity. Notably, V2DP membranes realize an impressive current density of 5.5×103 A m-2, surpassing  previously nanofluidic membranes. In practical application scenario involving the mixing of artificial seawater and river water, the V2DP membranes exhibit a considerable ion transference number of 0.70 towards Cl-, contributing to an outstanding power density of ~55 W m-2. Theoretical calculations reveal that the large quantity of anion transport sites act as binding sites evenly located in the positively charged N-containing pyridine rings.

A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death.

Glutamine is a conditionally essential amino acid for the growth and survival of rapidly proliferating cancer cells. Many cancers are addicted to glutamine, and as a result, targeting glutamine metabolism has been explored clinically as a therapeutic approach. Glutamine-catalyzing enzymes are highly expressed in primary and metastatic head and neck squamous cell carcinoma (HNSCC). However, the nature of the glutamine-associated pathways in this aggressive cancer type has not been elucidated. Here, we explored the therapeutic potential of a broad glutamine antagonist, DRP-104 (sirpiglenastat), in HNSCC tumors and aimed at shedding light on glutamine-dependent pathways in this disease. We observed a potent antitumoral effect of sirpiglenastat in HPV- and HPV + HNSCC xenografts. We conducted a whole-genome CRISPR screen and metabolomics analyses to identify mechanisms of sensitivity and resistance to glutamine metabolism blockade. These approaches revealed that glutamine metabolism blockade results in the rapid buildup of polyunsaturated fatty acids (PUFAs) via autophagy nutrient-sensing pathways. Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies.

Adaptive resistance of tumor cells to anti-vascular endothelial growth factor therapy: A reversible phenomenon.

Vascular endothelial growth factor (VEGF) inhibition is an essential targeted strategy for malignant tumors, but its efficacy is severely constrained by drug resistance. The traditional view holds that the target of VEGF inhibition is endothelial cells, and thus compensatory angiogenesis is considered the main mechanism of drug resistance. In this study, we found that tumor cells themselves could develop acquired resistance to VEGF therapy, indicating an independent resistance mechanism apart from angiogenesis. Notably, this acquired resistance was temporary, disappearing completely four days after discontinuing exposure to the drug in vitro. Our findings suggest that tumor cells may also be targets of VEGF inhibition, and their response to treatment should not be overlooked in contributing to drug resistance.

Integration of mult-omics and nucleotide metabolism reprogramming signature analysis reveals gastric cancer immunological and prognostic features.

BACKGROUND: Gastric cancer is a frequent and lethal solid tumor that has a poor prognosis and treatment result. Reprogramming of nucleotide metabolism is a characteristic of cancer development and progression. METHODS: We used a variety of machine learning techniques to create a novel nucleotide metabolism-related index (NMRI) using gastric cancer sample data obtained from the TCGA and GEO databases. This index is based on genes associated to nucleotide metabolism. Gastric cancer patients were categorized into high and low NMRI groups based on NMRI results. The clinical features, tumor immune microenvironment, response to chemotherapy, and response to immunotherapy were then thoroughly examined. In vitro experiments were then used to confirm the biological role of SERPINE1 in gastric cancer. RESULTS: The four nucleotide metabolism-related genes that make up NMRI (GAMT, ORC1, CNGB3, and SERPINE1) were verified in an external dataset and are a valid predictor of prognosis for patients with gastric cancer. The high NMRI group was more responsive to immunotherapy and had greater levels of immune cell infiltration than the low NMRI group. The proliferation and migration of stomach cancer was shown to be decreased by SERPINE1 knockdown in vitro. CONCLUSIONS: This study's NMRI can reliably predict a patient's prognosis for stomach cancer and pinpoint the patient group that will benefit from immunotherapy, offering important new information on the clinical treatment of stomach cancer.

Activity-induced stiffness, entanglement network and dynamic slowdown in unentangled semidilute polymer solutions.

Active polymers possess numerous unique properties that are quite different from those observed in the system of small active molecules due to the intricate interplay between their activity and topological constraints. This study focuses on the conformational changes induced by activity, impacting effective stiffness and crucially influencing entanglement and dynamics. When the two terminals of a linear chain undergo active modification through coupling to a high-temperature thermal bath, there is a substantial increase in chain size, indicating a notable enhancement in effective stiffness. Unlike in passive semiflexible chains where stiffness predominantly affects local bond angles, activity-induced stiffness manifests at the scale of tens of monomers. While activity raises the ambient temperature, it significantly decreases diffusion by over an order of magnitude. The slowdown of the dynamics observed can be attributed to increased entanglement due to chain elongation.

Population genetic admixture and evolutionary history in the Shandong Peninsula inferred from integrative modern and ancient genomic resources.

BACKGROUND: Ancient northern East Asians (ANEA) from the Yellow River region, who pioneered millet cultivation, play a crucial role in understanding the origins of ethnolinguistically diverse populations in modern China and the entire landscape of deep genetic structure and variation discovery in modern East Asians. However, the direct links between ANEA and geographically proximate modern populations, as well as the biological adaptive processes involved, remain poorly understood. RESULTS: Here, we generated genome-wide SNP data for 264 individuals from geographically different Han populations in Shandong. An integrated genomic resource encompassing both modern and ancient East Asians was compiled to examine fine-scale population admixture scenarios and adaptive traits. The reconstruction of demographic history and hierarchical clustering patterns revealed that individuals from the Shandong Peninsula share a close genetic affinity with ANEA, indicating long-term genetic continuity and mobility in the lower Yellow River basin since the early Neolithic period. Biological adaptive signatures, including those related to immune and metabolic pathways, were identified through analyses of haplotype homozygosity and allele frequency spectra. These signatures are linked to complex traits such as height and body mass index, which may be associated with adaptations to cold environments, dietary practices, and pathogen exposure. Additionally, allele frequency trajectories over time and a haplotype network of two highly differentiated genes, ABCC11 and SLC10A1, were delineated. These genes, which are associated with axillary odor and bilirubin metabolism, respectively, illustrate how local adaptations can influence the diversification of traits in East Asians. CONCLUSIONS: Our findings provide a comprehensive genomic dataset that elucidates the fine-scale genetic history and evolutionary trajectory of natural selection signals and disease susceptibility in Han Chinese populations. This study serves as a paradigm for integrating spatiotemporally diverse ancient genomes in the era of population genomic medicine.

In-situ imaging of heat-induced phase transition in a two-dimensional conjugated metal-organic framework.

Atomically-resolved in-situ high-resolution transmission electron microscopy (HRTEM) imaging of the structural dynamics in organic materials remains a major challenge. This difficulty persists even with aberration-corrected instruments, as HRTEM images necessitate a high electron dose that is generally intolerable for organic materials. In this study, we report the in-situ HRTEM imaging of heat-induced structural dynamics in a benzenehexathiol-based two-dimensional conjugated metal-organic framework (2D c-MOF, i.e., Cu3(BHT)). Leveraging its hydrogen-free structure and high electrical conductivity, Cu3(BHT) exhibits high electron beam resistance. We demonstrate atomic resolution imaging at an 80 kV electron accelerating voltage using our Cc/Cs-corrected SALVE instrument. However, continuous electron irradiation eventually leads to its amorphization. Intriguingly, under heating in a MEMS holder, the Cu3(BHT) undergoes a phase transition to a new crystalline phase and its phase transition, occurring within the temperature range of 480 °C to 620 °C in dependence on the electron beam illumination. Using HRTEM and energy-dispersive X-ray mapping, we identify this new phase as CuS. Our findings provide insights into the mechanisms governing structural transitions in purposefully engineered structures, potentially pivotal for future endeavours involving the production of metal oxide/sulfide nanoparticles from MOF precursors.

AcEXPA1, an α-expansin gene, participates in the aluminum tolerance of carpetgrass (Axonopus compressus) through root growth regulation.

KEY MESSAGE: AcEXPA1, an aluminum (Al)-inducible expansin gene, is demonstrated to be involved in carpetgrass (Axonopus compressus) root elongation under Al toxicity through analyzing composite carpetgrass plants overexpressing AcEXPA1. Aluminum (Al) toxicity is a major mineral toxicity that limits plant productivity in acidic soils by inhibiting root growth. Carpetgrass (Axonopus compressus), a dominant warm-season turfgrass widely grown in acidic tropical soils, exhibits superior adaptability to Al toxicity. However, the mechanisms underlying its Al tolerance are largely unclear, and knowledge of the functional genes involved in Al detoxification in this turfgrass is limited. In this study, phenotypic variation in Al tolerance, as indicated by relative root elongation, was observed among seventeen carpetgrass genotypes. Al-responsive genes related to cell wall modification were identified in the roots of the Al-tolerant genotype 'A58' via transcriptome analysis. Among them, a gene encoding α-expansin was cloned and designated AcEXPA1 for functional characterization. Observed Al dose effects and temporal responses revealed that Al induced AcEXPA1 expression in carpetgrass roots. Subsequently, an efficient and convenient Agrobacterium rhizogenes-mediated transformation method was established to generate composite carpetgrass plants with transgenic hairy roots for investigating AcEXPA1 involvement in carpetgrass root growth under Al toxicity. AcEXPA1 was successfully overexpressed in the transgenic hairy roots, and AcEXPA1 overexpression enhanced Al tolerance in composite carpetgrass plants through a decrease in Al-induced root growth inhibition. Taken together, these findings suggest that AcEXPA1 contributes to Al tolerance in carpetgrass via root growth regulation.

Fine mapping and candidate gene analysis of CRA8.1.6, which confers clubroot resistance in turnip (Brassica rapa ssp. rapa).

Clubroot disease poses a significant threat to Brassica crops, necessitating ongoing updates on resistance gene sources. In F2 segregants of the clubroot-resistant inbred line BrT18-6-4-3 and susceptible DH line Y510, the genetic analysis identified a single dominant gene responsible for clubroot resistance. Through bulk segregant sequencing analysis and kompetitive allele-specific polymerase chain reaction assays, CRA8.1.6 was mapped within 110 kb (12,255-12,365 Mb) between markers L-CR11 and L-CR12 on chromosome A08. We identified B raA08g015220.3.5C as the candidate gene of CRA8.1.6. Upon comparison with the sequence of disease-resistant material BrT18-6-4-3, we found 249 single-nucleotide polymorphisms, seven insertions, six deletions, and a long terminal repeat (LTR) retrotransposon (5,310 bp) at 909 bp of the first intron. However, the LTR retrotransposon was absent in the coding sequence of the susceptible DH line Y510. Given the presence of a non-functional LTR insertion in other materials, it showed that the LTR insertion might not be associated with susceptibility. Sequence alignment analysis revealed that the fourth exon of the susceptible line harbored two deletions and an insertion, resulting in a frameshift mutation at 8,551 bp, leading to translation termination at the leucine-rich repeat domain's C-terminal in susceptible material. Sequence alignment of the CDS revealed a 99.4% similarity to Crr1a, which indicate that CRA8.1.6 is likely an allele of the Crr1a gene. Two functional markers, CRA08-InDel and CRA08-KASP1, have been developed for marker-assisted selection in CR turnip cultivars. Our findings could facilitate the development of clubroot-resistance turnip cultivars through marker-assisted selection.

Circ_0000758 Facilitates Bladder Cancer Cell Growth, Migration and Angiogenesis Via Severing as miR-1236-3p Sponge.

Circular RNA (circRNA) has been reported to regulate the development of bladder cancer (BCa). However, the role of circ_0000758 in BCa progression is unknown. Circ_0000758 and miR-1236-3p expression, as well as ZEB2 mRNA expression were determined by qRT-PCR. BCa cell biological functions were determined by MTT assay, EdU assay, flow cytometry, wound healing assay and tube formation assay. Protein expression was detected by western blot analysis. RNA pull-down assay and dual-luciferase reporter assay were used to confirm RNA interaction. Xenograft mice models were constructed to assess the effect of circ_0000758 on BCa tumor growth. Circ_0000758 had increased expression in BCa tissues and cells. Circ_0000758 silencing could inhibit BCa cell growth, migration, angiogenesis in vitro, and tumor growth in vivo. Circ_0000758 served as a molecular sponge for miR-1236-3p, and miR-1236-3p inhibitor reversed circ_0000758 knockdown-mediated the inhibition effect on BCa cell progression. ZEB2 was targeted by miR-1236-3p, and its overexpression also revoked the suppressive effect of miR-1236-3p on BCa cell growth, migration, and angiogenesis. Besides, circ_0000758 knockdown also restrained BCa tumor growth. Circ_0000758 might promote BCa cell growth, migration, and angiogenesis by regulating the miR-1236-3p/ZEB2 axis.

Multiple Human Population Movements and Cultural Dispersal Events Shaped the Landscape of Chinese Paternal Heritage.

Large-scale genomic projects and ancient DNA innovations have ushered in a new paradigm for exploring human evolutionary history. However, the genetic legacy of spatiotemporally diverse ancient Eurasians within Chinese paternal lineages remains unresolved. Here, we report an integrated Y-chromosome genomic database encompassing 15,563 individuals from both modern and ancient Eurasians, including 919 newly reported individuals, to investigate the Chinese paternal genomic diversity. The high-resolution, time-stamped phylogeny reveals multiple diversification events and extensive expansions in the early and middle Neolithic. We identify four major ancient population movements, each associated with technological innovations that have shaped the Chinese paternal landscape. First, the expansion of early East Asians and millet farmers from the Yellow River Basin predominantly carrying O2/D subclades significantly influenced the formation of the Sino-Tibetan people and facilitated the permanent settlement of the Tibetan Plateau. Second, the dispersal of rice farmers from the Yangtze River Valley carrying O1 and certain O2 sublineages reshapes the genetic makeup of southern Han Chinese, as well as the Tai-Kadai, Austronesian, Hmong-Mien, and Austroasiatic people. Third, the Neolithic Siberian Q/C paternal lineages originated and proliferated among hunter-gatherers on the Mongolian Plateau and the Amur River Basin, leaving a significant imprint on the gene pools of northern China. Fourth, the J/G/R paternal lineages derived from western Eurasia, which were initially spread by Yamnaya-related steppe pastoralists, maintain their presence primarily in northwestern China. Overall, our research provides comprehensive genetic evidence elucidating the significant impact of interactions with culturally distinct ancient Eurasians on the patterns of paternal diversity in modern Chinese populations.

Nematicidal activity and action mode of a methyl-accepting chemotaxis protein from Pseudomonas syringae against Caenorhabditis elegans.

The conventional phytopathogen Pseudomonas syringae reportedly possesses several virulence determinants against Caenorhabditis elegans; however, their action mechanisms remain elusive. This study reports the nematicidal activity and action receptor of a methyl-accepting chemotaxis protein (MCP03) of a wild-type P. syringae MB03 against C. elegans. Purified MCP03 exhibited nematicidal toxicity against C. elegans at a half-lethal concentration of 124.4 µg mL-1, alongside detrimental effects on the growth and brood size of C. elegans. Additionally, MCP03-treated worms exhibited severe pathological destruction of the intestine and depressed wrinkles of the cuticle. Yeast two-hybrid assays identified a subunit of COP9 signalosome, namely CSN-5, which functioned as an MCP03 action receptor. In vitro pull-down verified the binding interaction between MCP03 and CSN-5. RNA interference assays confirmed that MCP03 antagonizes CSN-5, thereby adversely affecting the brood size and cuticle integrity of C. elegans. Following MCP03 infection, the expression of genes related to reproduction, growth, and cuticle formation, such as kgb-1, unc-98, and col-117, was considerably downregulated, indicating pathological changes in MCP03-treated nematodes. Therefore, we proposed that MCP03 antagonizes CSN-5, causing lethality as well as detrimental effects on the fertility, growth, and morphogenesis of C. elegans, which can provide new insights into the signaling pathways and mechanisms underlying the nematicidal action of MCP03 toward C. elegans.

Extracting the winter wheat using the decision tree based on time series dual-polarization SAR feature and NDVI.

Winter wheat is one of the most important crops in the world. It is great significance to obtain the planting area of winter wheat timely and accurately for formulating agricultural policies. Due to the limited resolution of single SAR data and the susceptibility of single optical data to weather conditions, it is difficult to accurately obtain the planting area of winter wheat using only SAR or optical data. To solve the problem of low accuracy of winter wheat extraction only using optical or SAR images, a decision tree classification method combining time series SAR backscattering feature and NDVI (Normalized Difference Vegetation Index) was constructed in this paper. By synergy using of SAR and optical data can compensate for their respective shortcomings. First, winter wheat was distinguished from other vegetation by NDVI at the maturity stage, and then it was extracted by SAR backscattering feature. This approach facilitates the semi-automated extraction of winter wheat. Taking Yucheng City of Shandong Province as study area, 9 Sentinel-1 images and one Sentinel-2 image were taken as the data sources, and the spatial distribution of winter wheat in 2022 was obtained. The results indicate that the overall accuracy (OA) and kappa coefficient (Kappa) of the proposed method are 96.10% and 0.94, respectively. Compared with the supervised classification of multi-temporal composite pseudocolor image and single Sentinel-2 image using Support Vector Machine (SVM) classifier, the OA are improved by 10.69% and 5.66%, respectively. Compared with using only SAR feature for decision tree classification, the producer accuracy (PA) and user accuracy (UA) for extracting the winter wheat are improved by 3.08% and 8.25%, respectively. The method proposed in this paper is rapid and accurate, and provide a new technical method for extracting winter wheat.

Single-Shot Intensity- and Phase-Sensitive Compressive Sensing-Based Coherent Modulation Ultrafast Imaging.

Ultrafast imaging can capture the dynamic scenes with a nanosecond and even femtosecond temporal resolution. Complementarily, phase imaging can provide the morphology, refractive index, or thickness information that intensity imaging cannot represent. Therefore, it is important to realize the simultaneous ultrafast intensity and phase imaging for achieving as much information as possible in the detection of ultrafast dynamic scenes. Here, we report a single-shot intensity- and phase-sensitive compressive sensing-based coherent modulation ultrafast imaging technique, shortened as CS-CMUI, which integrates coherent modulation imaging, compressive imaging, and streak imaging. We theoretically demonstrate through numerical simulations that CS-CMUI can obtain both the intensity and phase information of the dynamic scenes with ultrahigh fidelity. Furthermore, we experimentally build a CS-CMUI system and successfully measure the intensity and phase evolution of a multimode Q-switched laser pulse and the dynamical behavior of laser ablation on an indium tin oxide thin film. It is anticipated that CS-CMUI enables a profound comprehension of ultrafast phenomena and promotes the advancement of various practical applications, which will have substantial impact on fundamental and applied sciences.

Enhancing stem cell therapy efficacy with functional lignin modified cerium-iron nanozyme through magnetic resonance imaging tracking and apoptosis protection in inflammatory environment.

Stem cell transplantation provides a promising approach for addressing inflammation and functional disorders. Nonetheless, the viability of these transplanted cells diminishes significantly within pathological environments, limiting their therapeutic potential. Moreover, the non-invasive tracking of these cells in vivo remains a considerable challenge, hampering the assessment of their therapeutic efficacy. Transition-metal oxide nanocrystals, known for their unique "enzyme-like" catalytic property and imaging capability, provide a new avenue for clinical application. In this study, the lignin as a biocompatible macromolecule was modified with poly (ethylene glycol) through chain-transfer polymerization, and then it was utilized to incorporate superparamagnetic iron oxide and cerium oxide nanocrystals creating a functional nanozyme. The iron oxide nanocrystals self-assembled into the hydrophobic core of nano system, while the in-situ mineralization of cerium oxide particles was carried out with the assistance of peripheral phenolic hydroxyl groups. The product, cerium­iron core-shell nanozyme, enabled effective stem cells labeling through endocytosis and exhibited catalase and superoxide dismutase activities within the cells. As a result, it could scavenge highly destructive hydroxyl radicals and peroxyl radicals, shielding stem cells from apoptosis in inflammatory environment and maintaining their differentiation ability. Additionally, when these functionalized stem cells were administered to mice with acute inflammation, not only did they alleviate disease symptoms, but they also allowed for the visualization using T2-weighted magnetic resonance imaging. This innovative therapeutic approach provides a new strategy for combatting diseases.

Effects of different mylohyoid muscle stimulations on swallowing cortex excitability in healthy subjects.

BACKGROUND: Dysphagia has been recognized by the World Health Organization as a medical disability. Improving mylohyoid muscle function plays an important role in pharyngeal dysphagia. The aim of this study was to evaluate the treatment of transcranial magnetic stimulation (TMS), peripheral magnetic stimulation (PMS), and electrical stimulation (ES) for dysphagia. METHODS: Forty healthy subjects were randomly divided into four groups: TMS+PMS, TMS, PMS, and ES. TMS stimulated the cortical representative area of the mylohyoid muscle and the PMS was directly stimulating the mylohyoid muscle, both of them at a frequency of 10 Hz for a total of 1,800 pulses. The intensity of ES was based on the subject's tolerance level, usually 2-5 mA. Functional near infrared spectroscopy (fNIRS) and motor evoked potential (MEP) of the mylohyoid muscle were used to evaluate the immediate effects of stimulation on swallowing cortex excitability of healthy subjects before and after intervention. RESULTS: The fNIRS results revealed notable activation across multiple channels in the four groups of healthy subjects both pre- and post- the intervention. Among these channels, the activation levels were most pronounced in the TMS+PMS group, followed by the TMS, PMS, and ES groups, respectively. Regarding the MEP results, post-intervention observations indicated a reduction in bilateral latency and an increase in bilateral amplitude in the TMS+PMS group. Additionally, the left amplitude exhibited an increase in the TMS group. CONCLUSIONS: In fNIRS, all four stimulation methods significantly activated the swallowing cortex of healthy subjects, and the activation of TMS+PMS was the most obvious, followed by TMS, PMS, and ES.

[Research progress on mechanism of traditional Chinese medicine intervention in angiogenesis in prevention and treatment of nontraumatic avascular necrosis of femoral head].

Nontraumatic avascular necrosis of the femoral head(NANFH) is a common and refractory femoral head disease that causes bone death due to interruption of blood supply. Early clinical symptoms are atypical, such as hip pain and limited joint function. In the late stage, severe pain, shortening of the affected limb, claudication, and other serious symptoms are common, which se-riously affects the quality of life of patients. Therefore, it is of great significance to actively improve the clinical symptoms of NANFH to enhance the quality of life of patients. The pathogenesis of NANFH is complex, such as traumatic vascular circulatory disorders, the use of hormones or other drugs, alcoholism, and diabetes mellitus. These factors directly or indirectly lead to femoral head vascular damage, thrombosis, and coagulation system disorders, which reduce the blood supply to the acetabulum and femoral head, thus causing ischaemic death of the femoral head or even femoral head collapse. NANFH is mainly categorized as "bone impotence" and "bone paralysis" in traditional Chinese medicine(TCM). The treatment of NANFH with TCM has the characteristics and advantages of a long history, stable and reliable therapeutic effect, fewer adverse reactions, good patient tolerance, and high acceptance. Previous studies have shown that the promotion of angiogenesis is a key initiative in the prevention and treatment of NANFH, and TCM can promote fe-moral head angiogenesis by interfering with the expression of angiogenesis-related factors, which in turn can help to restore the blood supply of the femoral head and thus improve clinical symptoms of NANFH and prevent and treat NANFH. This article described the roles of blood supply interruption and angiogenesis in NANFH and the accumulated knowledge and experience of TCM in NANFH and summarized the role of angiogenesis-related factors in NANFH and the research progress on TCM intervention, so as to provide an idea for the subsequent research and a new basis for the clinical application of TCM in the treatment of NANFH.

Comparison of Fracture Behavior in Single-Edge Notched Beams Reinforced with Steel Bars or CFRP Bars.

To explore and compare the failure modes, deformation behaviors, and load-bearing capacities of single-edge notched (SEN) beams strengthened with carbon fiber-reinforced polymer (CFRP) and steel bars, static and dynamic three-point bending tests on both types of concrete beams have been carried out in this study. During the static tests, the electro-hydraulic servo machine served as a loading device to apply pressure to CFRP beams and reinforced concrete (RC) beams. During the impact experiments, different impact velocities were imparted by adjusting the drop hammer's height. Thus, information regarding crack propagation, energy absorption, and deformation was obtained. The results from the static tests showed that the RC beams predominantly experienced shear failure. In contrast, the CFRP beams primarily exhibited bending-shear failure, attributed to the relatively weaker bond strength between the bars and the concrete. Impact tests were conducted at three different velocities in this study. As the impact velocity increased, both types of concrete beams transitioned from bending failure to bending-shear failure. At the lowest velocity, the difference in energy absorption between beams reinforced with different materials was insignificant during the bending process. However, at the highest velocity, CFRP beams absorbed less energy than RC beams. The study of structures' impact failure modes and their mechanical characteristics offers valuable references for the anti-collision design and protection of structures.

TriLA: Triple-Level Alignment based Unsupervised Domain Adaptation for Joint Segmentation of Optic Disc and Optic Cup.

Cross-domain joint segmentation of optic disc and optic cup on fundus images is essential, yet challenging, for effective glaucoma screening. Although many unsupervised domain adaptation (UDA) methods have been proposed, these methods can hardly achieve complete domain alignment, leading to suboptimal performance. In this paper, we propose a triple-level alignment (TriLA) model to address this issue by aligning the source and target domains at the input level, feature level, and output level simultaneously. At the input level, a learnable Fourier domain adaptation (LFDA) module is developed to learn the cut-off frequency adaptively for frequency-domain translation. At the feature level, we disentangle the style and content features and align them in the corresponding feature spaces using consistency constraints. At the output level, we design a segmentation consistency constraint to emphasize the segmentation consistency across domains. The proposed model is trained on the RIGA+ dataset and widely evaluated on six different UDA scenarios. Our comprehensive results not only demonstrate that the proposed TriLA substantially outperforms other state-of-the-art UDA methods in joint segmentation of optic disc and optic cup, but also suggest the effectiveness of the triple-level alignment strategy.