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AIMS: To investigate alternative resistance mechanisms among seven ceftazidime-avibactam (CZA)-resistant carbapenem-resistant Klebsiella pneumoniae (CRKP) strains lacking common antimicrobial resistance genes (ARGs) using whole genome sequencing. METHODS AND RESULTS: ARG and virulence factors (VFs) were screened using the ARG database CARD and the VF database, respectively, and identified using genomic annotation data with BLAST+. Six strains were ST11 sequence types (STs), and one was ST2123. ST11 strains harbored more ARGs than the ST2123 strains. All seven strains carried multiple ARGs with efflux-mediated antibiotic resistance, including oqxA, oqxB, tet (A), qacEdltal, CRP, H-NS, Kpn-E, F, G, H, acrA, LptD, acrB, acrD, cpxA, mdtB, and mdtC. These efflux-mediated ARGs were identified in most strains and even all strains. Whole genome sequencing revealed that the ST11 strain carried multiple potential prophages, genomic islands, and integrative and conjugative elements, while the ST2123 strain carried an independent potential prophages and a genomic island. CONCLUSIONS: Whole genome sequencing analysis revealed that these seven CZA-resistant CRKP strains lacking common ARGs exhibited efflux-mediated antibiotic resistance-associated ARGs. The main mechanism by which CRKP resists CZA is antibiotic inactivation. Except for tet (A), no ARGs and validation experiments related to efflux were found. This study's results provide a new possibility for the resistance mechanism of CRKP to CZA, and we will verify this conclusion through experiments in the future.
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Antibacterianos , Compostos Azabicíclicos , Ceftazidima , Combinação de Medicamentos , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Sequenciamento Completo do Genoma , Ceftazidima/farmacologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efeitos dos fármacos , Compostos Azabicíclicos/farmacologia , Antibacterianos/farmacologia , Genoma Bacteriano , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Infecções por Klebsiella/microbiologia , Carbapenêmicos/farmacologia , Fatores de Virulência/genéticaRESUMO
Randomly distributed topological defects created during the spontaneous symmetry breaking are the fingerprints to trace the evolution of symmetry, range of interaction, and order parameters in condensed matter systems. However, the effective mean to manipulate topological defects into ordered form is elusive due to the topological protection. Here, we establish a strategy to effectively align the topological domain networks in hexagonal manganites through a mechanical approach. It is found that the nanoindentation strain gives rise to a threefold Magnus-type force distribution, leading to a sixfold symmetric domain pattern by driving the vortex and antivortex in opposite directions. On the basis of this rationale, sizeable mono-chirality topological stripe is readily achieved by expanding the nanoindentation to scratch, directly transferring the randomly distributed topological defects into an ordered form. This discovery provides a mechanical strategy to manipulate topological protected domains not only on ferroelectrics but also on ferromagnets/antiferromagnets and ferroelastics.
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Two-dimensional (2D) Fe chalcogenides with their rich structures and properties are highly desirable for revealing the torturous transition mechanism of Fe chalcogenides and exploring their potential applications in spintronics and nanoelectronics. Hydrostatic pressure can effectively stimulate phase transitions between various ordered states, allowing one to successfully plot a phase diagram for a given material. Herein, the structural evolution and transport characteristics of 2D FeTe were systematically investigated under extreme conditions by comparing two distinct symmetries, i.e., tetragonal (t) and hexagonal (h) FeTe. We found that t-FeTe presented a pressure-induced transition from an antiferromagnetic state to a ferromagnetic state at â¼3 GPa, corresponding to the tetragonal collapse of the layered structure. Contrarily, the ferromagnetic order of h-FeTe was retained up to 15 GPa, which was evidently confirmed by electrical transport and Raman measurements. Furthermore, T-P phase diagrams for t-FeTe and h-FeTe were mapped under delicate critical conditions. Our results can provide a unique platform to elaborate the extraordinary properties of Fe chalcogenides and further develop their applications.
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IL-6 plays an important role in oogenesis in humans. However, at the preimplantation stage, IL-6 production and the role in embryo development remain unclear. In this study, IL-6 concentrations in single-embryo media were analyzed. In addition, the association between IL-6 production and blastocyst formation was investigated. Single-embryo culture media from 194 embryos were collected on day 6 after fertilization and divided into four groups according to the developmental stage of the corresponding embryo, as follows: cleavage stage group, morula-early blastocyst group, unavailable full blastocyst group, and available full blastocyst group. IL-6 concentrations were significantly lower in the cleavage stage group than in the morula-early blastocyst group (p = 0.009), in the unavailable full blastocyst group (p = 0.003), and in the available full blastocyst group (p < 0.001). Logistic regression analysis showed that IL-6 concentration in single-embryo medium was significantly associated with blastocyst formation (odds ratios ß1 = 1.876, 95% CI 1.433 to 2.644, p < 0.0001). Therefore, IL-6 was produced by human preimplantation embryos throughout the preimplantation stage and may play a role in embryo development.
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Técnicas de Cultura Embrionária , Interleucina-6 , Humanos , Blastocisto , Embrião de Mamíferos , Desenvolvimento Embrionário , Fertilização in vitroRESUMO
2D layered magnets, such as iron chalcogenides, have emerged these years as a new family of unconventional superconductors and provided the key insights to understand the phonon-electron interaction and pairing mechanism. Their mechanical properties are of strategic importance for the potential applications in spintronics and optoelectronics. However, there is still a lack of efficient approach to tune the elastic modulus despite the extensive studies. Herein, the modulated elastic modulus of 2D magnetic FeTe and its thickness-dependence is reported via phase engineering. The grown 2D FeTe by chemical vapor deposition can present various polymorphs, that is tetragonal FeTe (t-FeTe, antiferromagnetic) and hexagonal FeTe (h-FeTe, ferromagnetic). The measured Young's modulus of t-FeTe by nanoindentation method shows an obvious thickness-dependence, from 290.9 ± 9.2 to 113.0 ± 8.7 GPa when the thicknesses increased from 13.2 to 42.5 nm, respectively. In comparison, the elastic modulus of h-FeTe remains unchanged. These results can shed light on the efficient modulation of mechanical properties of 2D magnetic materials and pave the avenues for their practical applications in nanodevices.
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[This corrects the article DOI: 10.1093/nsr/nwab232.].
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Hepatic ischemia/reperfusion (I/R) injury is an unavoidable complication of liver hepatectomy, transplantation, and systemic shock. Pectolinarigenin (Pec) is a flavonoid with many biological activities, which include anti-inflammatory, anti-apoptotic, and antioxidant stress. This study explored whether Pec pretreatment could reduce hepatic I/R injury and the potential mechanisms at play. After pretreatment of mice and AML12 cells with Pec, I/R and hypoxia/reoxygenation (H/R) models were established. By examining markers related to liver injury, cell viability, oxidative stress, inflammatory response, and apoptosis, the effect of Pec on important processes involved in hepatic I/R injury was assessed. Protein levels associated with the PI3K/AKT/Nrf2 pathway were analyzed by relative quantification to investigate possible pathways through which Pec plays a role in the I/R process. Pec treatment corrected abnormal transaminase levels resulting from I/R injury, improved liver injury, and increased AML12 cell viability. Moreover, Pec treatment inhibited oxidative stress, inflammation and apoptosis and could activate the PI3K/AKT/Nrf2 pathway during I/R and H/R. Further studies found that LY294002 (PI3K inhibitor) suppressed the protective effect of Pec on hepatic I/R injury. In summary, our results show that Pec inhibits oxidative stress, inflammatory responses, and apoptosis, thereby attenuating I/R-induced liver injury and H/R-induced cell damage via activation of the PI3K/AKT/Nrf2 pathway.
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Proteínas Proto-Oncogênicas c-akt , Traumatismo por Reperfusão , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Fígado/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/etiologia , Apoptose , Estresse Oxidativo , Isquemia/complicações , Isquemia/metabolismoRESUMO
Anisotropic two-dimensional layered materials with low-symmetry lattices have attracted increasing attention due to their unique orientation-dependent mechanical properties. Black arsenic (b-As), with the puckered structure, exhibits extreme in-plane anisotropy in optical, electrical, and thermal properties. However, experimental research on mechanical properties of b-As is very rare, although theoretical calculations predicted the exotic elastic properties of b-As, such as the anisotropic Young's modulus and negative Poisson's ratio. Herein, experimental observations on highly anisotropic elastic properties of b-As were demonstrated using our developed in situ tensile straining setup based on the effective microelectromechanical system. The cyclic and repeatable load-displacement curves proved that Young's modulus along the zigzag direction was â¼1.6 times greater than that along the armchair direction, while the anisotropic ratio of ultimate strain reached â¼2.5, attributed to the hinge structure in the armchair direction. This study could provide significant insights into the design of novel anisotropic materials and explore their potential applications in nanomechanics and nanodevices.
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Two-dimensional (2D) materials have aroused considerable research interest owing to their potential applications in nanoelectronics and optoelectronics. Thermodynamic stability of 2D structures inevitably affects the performance and power consumption of the fabricated nanodevices. Black arsenic (b-As), as a cousin of black phosphorus, has presented extremely high anisotropy in physical properties. However, systematic research on structural stability of b-As is still lacking. Herein, we demonstrated the detailed analysis on structural metastability of the natural b-As, and determined its existence conditions in terms of two essential thermodynamic variables, hydrostatic pressure and temperature. Our results confirmed that b-As can survive only below 0.7 GPa, and then irreversibly transforms to gray arsenic, consistent with our theoretical calculations. Furthermore, a thermal annealing strategy was developed to precisely control the thickness of the b-As flake, and it sublimates at 300 °C. These results could pave the way for 2D b-As in many promising applications.
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The epithelial sodium channel (ENaC) is a heterotrimer and is widely distributed throughout the kidneys, blood vessels, lungs, colons, and many other organs. The basic role of the ENaC is to mediate the entry of Na+ into cells; the ENaC also has an important regulatory function in blood pressure, airway surface liquid (ASL), and endothelial cell function. Aldosterone, serum/glucocorticoid kinase 1 (SGK1), shear stress, and posttranslational modifications can regulate the activity of the ENaC; some ion channels also interact with the ENaC. In recent years, it has been found that the ENaC can lead to immune cell activation, endothelial cell dysfunction, aggravated inflammation involved in high salt-induced hypertension, cystic fibrosis, pseudohypoaldosteronism (PHA), and tumors; some inflammatory cytokines have been reported to have a regulatory role on the ENaC. The ENaC hyperfunction mediates the increase of intracellular Na+, and the elevated exchange of Na+ with Ca2+ leads to an intracellular calcium overload, which is an important mechanism for ENaC-related inflammation. Some of the research on the ENaC is controversial or unclear; we therefore reviewed the progress of studies on the role of ENaC-related inflammation in human diseases and their mechanisms.
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Canais Epiteliais de Sódio , Hipertensão , Humanos , Canais Epiteliais de Sódio/metabolismo , Transdução de Sinais , Sódio/metabolismo , InflamaçãoRESUMO
CONTEXT AND RESULTS: 2,4,6-triazide-1,3,5-triazine (TAT) has received widespread attention for its great potential to synthesize or convert to nitrogen-rich high energy density materials (HEDMs). The TAT structure alteration in the compression process up to 30 GPa has characteristics as follows: (a) [N3] groups straighten; (b) [N3] groups gather toward the six-membered C-N heterocycles. At about 5 GPa, Raman peak split at 700 cm-1 was observed both in calculation and in-situ Raman experiment, which is caused by pressure-induced intramolecular stress. Besides, the broad band of the amorphous two-dimensional C=N network (centered at 1630 cm-1) occurred at about 12 GPa. Meantime, the study on electronic features suggests the pressure-induced deformation in TAT molecular structure cause the discontinuous change of band gap at about 4.5 GPa and 8.0 GPa, respectively. COMPUTATIONAL AND THEORETICAL TECHNIQUES: The static compression process of TAT was explored in the range of 0-30 GPa by using dispersion corrected density functional theory (DFT-D) calculations combined with in-situ Raman experiment. The GGA/PBE+G06 method that has less errors than other calculation methods was used to predict the geometry structure, vibrational properties and electronic structure of TAT under pressure.
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BACKGROUND: To analyze the polymorphism distribution of low density lipoprotein receptor rs688, AvaII, NcoI gene in ischemic stroke, and explore the linkage disequilibrium among them. The correlation between the linkage disequilibrium and ischemic stroke was further analyzed. METHODS: The levels of serum lipid (triglyceride, cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoprotein A1, apolipoprotein B) and rs688, AvaII, NcoI polymorphism of low density lipoprotein receptor gene were tested in patients with ischemic stroke (n = 140), healthy control (n = 129) and patients with other cerebrovascular diseases (n = 122). Chi-square test was used to compare the gene frequency and allele frequency of each group. Both the linkage disequilibrium of the three genes and the alleles correlated with ischemic stroke were analyzed. The correlation of linkage disequilibrium gene and ischemic stroke was analyzed with logistic binary regression. RESULTS: In the ischemic stroke group, significant difference was observed in frequencies and allelic frequencies of low density lipoprotein receptor (LDLR) rs688 and AvaII. No difference of NcoI was found. Linkage disequilibrium was found for rs688 and AvaII (D' = 0.927, R2 = 0.509). Allelic genes correlate with ischemic stroke included T of rs688 (X2 = 46.105, p < 0.001) and C of AvaII (X2 = 20.436, p < 0.001). CONCLUSIONS: Linkage disequilibrium existed between LDLR rs688 and AvaII genes. With the wild type gene (WT) (rs688/AvaII: CC/TT) as reference, rs688/AvaII: CT/TC, CT/CC and TT/CC increased the risk of ischemic stroke, which might be a genetic marker used for the screen of high-risk population contributing to the prevention of the disease.
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AVC Isquêmico , Humanos , Frequência do Gene , Predisposição Genética para Doença , Desequilíbrio de Ligação , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Receptores de LDL/genéticaRESUMO
Deterministic control of ferroelectric domain is critical in the ferroelectric functional electronics. Ferroelectric polarization can be manipulated mechanically with a nano-tip through flexoelectricity. However, it usually occurs in a very localized area in ultrathin films, with possible permanent surface damage caused by a large tip-force. Here it is demonstrated that the deliberate engineering of transverse flexoelectricity offers a powerful tool for improving the mechanical domain switching. Sizable-area domain switching under an ultralow tip-force can be realized in suspended van der Waals ferroelectrics with the surface intact, due to the enhanced transverse flexoelectric field. The film thickness range for domain switching in suspended ferroelectrics is significantly improved by an order of magnitude to hundreds of nanometers, being far beyond the limited range of the substrate-supported ones. The experimental results and phase-field simulations further reveal the crucial role of the transverse flexoelectricity in the domain manipulation. This large-scale mechanical manipulation of ferroelectric domain provides opportunities for the flexoelectricity-based domain controls in emerging low-dimensional ferroelectrics and related devices.
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BACKGROUND: Our study aims to evaluate the performance of the combination of Sysmex urine dry chemistry analyzer UC-3500 and urine particle analyzer UF-5000 in screening bacterial urinary tract infection (UTI). METHODS: We analyzed 2000 urine specimens from patients with suspected UTI by using a urine dry chemistry analyzer (UC-3500) and a fully automated sediment analyzer (UF-5000). After being tested by the instrument, all specimens were sent to our clinical microbiology laboratory for culture. In addition, 600 urine specimens were selected to evaluate the accuracy of the six screening strategies established in this study. RESULTS: The consistency of UF-5000 bacterial classification and bacterial culture was fair (Kappa = 0.339). The counts of WBC and BACT elevated with sequential group designs (P < 0.001). The cut-off value of WBC was 32.20/µL for males (AUC, 0.942, 95%CI, 0.930-0.955) and 39.15/µL for females (AUC, 0.931, 95%CI, 0.914-0.948). The sensitivity and specificity of WBC were relatively higher than those of BACT. Strategy⣠and Strategy⥠in all six strategies had a good negative predictive value (NPV) which was 98.73%. CONCLUSION: UF-5000 bacterial classification cannot be used as a practical reference. 32.20/µL (male) and 39.15/µL (female) for WBC as well as 22.35/µL (male) and 127.25/µL (female) for BACT were used as cut-off values to effectively determine whether UTI occurs. WBC, BACT and LEU joint screening programs were suitable to rapidly and effectively exclude bacterial UTI.
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Infecções Bacterianas , Infecções Urinárias , Humanos , Masculino , Feminino , Citometria de Fluxo/métodos , Infecções Urinárias/diagnóstico , Infecções Urinárias/microbiologia , Bactérias , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/microbiologia , Sensibilidade e Especificidade , Urinálise/métodos , Contagem de LeucócitosRESUMO
Aortic aneurysm (AA), a potentially lethal condition with the characteristic of aortic dilatation, can only be treated by surgical or endovascular procedures. The underlying mechanisms of AA are unclear and early preventive treatment is still insufficient due to segmental aortic heterogeneity and the limitations of current disease models. Here, we firstly established a comprehensive lineage-specific vascular smooth muscle cell (SMC)-on-a-chip model using human induced pluripotent stem cells to yield cell lineages representing different segments of the aorta and tested the constructed organ-on-a-chip model under various tensile stress conditions. Bulk RNA sequencing, RT-qPCR, immunofluorescence, western blot and FACS analyses were performed to discover the segmental aortic heterogeneity of response for tensile stress and drug testing. The appropriate stretching frequency for all lineages of SMCs was 1.0 Hz, paraxial mesoderm (PM) SMCs were more sensitive to tensile stress than lateral mesoderm (LM) SMCs and neural crest (NC) SMCs. These differences may be related to the different transcriptional profiles of the tension-stressed distinct lineage-specific vascular SMCs, specifically in relation to the PI3K-Akt signaling pathway. Also, the organ-on-a-chip displayed contractile physiology, perfect fluid coordination, and was conducive to drug testing, displaying heterogeneous segmental aortic responses. Compared with LM-SMCs and NC-SMCs, PM-SMCs were more sensitive to ciprofloxacin. The model is evaluated as a novel and suitable supplement to AA animal models for determining differential physiology and drug response in different parts of the aorta. Furthermore, this system could pave the way for disease modeling, drug testing, and the personalized treatment of patients with AA in the future.
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Células-Tronco Pluripotentes Induzidas , Animais , Humanos , Diferenciação Celular , Músculo Liso Vascular , Fosfatidilinositol 3-Quinases/metabolismo , Aorta , Dispositivos Lab-On-A-Chip , Miócitos de Músculo LisoRESUMO
Twisted stacking of van der Waals materials with moiré superlattices offers a new way to tailor their physical properties via engineering of the crystal symmetry. Unlike well-studied twisted bilayers, little is known about the overall symmetry and symmetry-driven physical properties of continuously supertwisted multilayer structures. Here, using polarization-resolved second harmonic generation (SHG) microscopy, we report threefold (C3) rotational symmetry breaking in supertwisted WS2 spirals grown on non-Euclidean surfaces, contrasting the intact symmetry of individual monolayers. This symmetry breaking is attributed to a geometrical magnifying effect in which small relative strain between adjacent twisted layers (heterostrain), verified by Raman spectroscopy and multiphysics simulations, generates significant distortion in the moiré pattern. Density-functional theory calculations can explain the C3 symmetry breaking and unusual SHG response by the interlayer wave function coupling. These findings thus pave the way for further developments in the so-called "3D twistronics".
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OBJECTIVES: This study is aimed to evaluate if automated urine sediment analysis UN2000 can be used to screen lupus nephritis. METHODS: UN2000 was used to examine 160 urine samples from patients with systemic lupus erythematosus and 124 urine samples from Lupus nephritis. The result of protein/creatinine ratio(P/C) and renal tubular epithelial cells (RTEC) were evaluated. With biochemical analysis and microscopic examination as the gold standard, the Kappa consistency test was used to analyze the accuracy of P/C and RTEC. Analysis was to evaluate the accuracy of P/C single item or RTEC single item and both screening lupusnephritis. RESULTS: The consistency of P/C and the gold standard, and that of RTEC and the gold standard are respectively strong and good (0.858 vs. 0.673). The specificity, positive predictive value, and coincidence were the highest when P/C ≥ 2 + was set as the only screening standard for lupus nephritis. When the standard was selected between P/C ≥ 2 + or RTEC > 2.8 cells/µl, the sensitivity and negative predictive value were the highest. CONCLUSION: UN 2000 can be used to screen lupus nephritis by detecting P/C and RTEC.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Creatinina/urina , Células Epiteliais , Humanos , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/urina , UrináliseRESUMO
Small-cell lung cancer (SCLC) is a recalcitrant cancer characterized by high metastasis. However, the exact cell type contributing to metastasis remains elusive. Using a Rb1 L/L /Trp53 L/L mouse model, we identify the NCAMhiCD44lo/- subpopulation as the SCLC metastasizing cell (SMC), which is progressively transitioned from the non-metastasizing NCAMloCD44hi cell (non-SMC). Integrative chromatin accessibility and gene expression profiling studies reveal the important role of the SWI/SNF complex, and knockout of its central component, Brg1, significantly inhibits such phenotypic transition and metastasis. Mechanistically, TAZ is silenced by the SWI/SNF complex during SCLC malignant progression, and its knockdown promotes SMC transition and metastasis. Importantly, ectopic TAZ expression reversely drives SMC-to-non-SMC transition and alleviates metastasis. Single-cell RNA-sequencing analyses identify SMC as the dominant subpopulation in human SCLC metastasis, and immunostaining data show a positive correlation between TAZ and patient prognosis. These data uncover high SCLC plasticity and identify TAZ as the key molecular switch in orchestrating SCLC phenotypic transition and metastasis.
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PURPOSE: To investigate the level of sdLDL and the frequency of LDLR rs688 polymorphisms, as well as the correspondence between them, and to analyze the risk factors for stroke. METHODS: Between March 2019 and November 2019, 232 patients diagnosed with stroke and 96 health volunteers were enrolled in Quanzhou First Hospital. Subjects were divided into control group, ischemic stroke group (n=120) and hemorrhagic stroke group (n=112). The level of sdLDL and the genotypes and allele frequencies of LDLR rs688 were compared between groups, the correspondence was analyzed with Spearman method. Risk factors were analyzed with Binary logistic regression. RESULTS: The level of sdLDL was highest in ischemic group, followed by hemorrhagic stroke group and lowest control group. The differences of genotypes and allele frequencies of LDLR rs688 were significant in ischemic stroke group (p=0.0000 and 0.0000 respectively), while were not significant in hemorrhagic group (p=0.184 and .0137). There was no obvious correlation between the level of sdLDL and LDLR rs688 genotype by Spearman analysis (p=0.116). CONCLUSION: Elevated sdLDL level and the C>T mutation of LDLR rs688 are independent risk factors for ischemic stroke, while they are not correlative to hemorrhagic stroke. The surveillance and regulatory of sdLDL level, the detection of LDLR rs688 gene polymorphisms may contribute to the prevention of ischemic stroke.
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Acidente Vascular Cerebral Hemorrágico , AVC Isquêmico , Receptores de LDL , Humanos , Acidente Vascular Cerebral Hemorrágico/genética , AVC Isquêmico/genética , Mutação , Polimorfismo de Nucleotídeo Único , Receptores de LDL/genética , Fatores de RiscoRESUMO
The integration of multi-omics data makes it possible to understand complex biological organisms at the system level. Numerous integration approaches have been developed by assuming a common underlying data space. Due to the noise and heterogeneity of biological data, the performance of these approaches is greatly affected. In this work, we propose a novel deep neural network architecture, named Deep Latent Space Fusion (DLSF), which integrates the multi-omics data by learning consistent manifold in the sample latent space for disease subtypes identification. DLSF is built upon a cycle autoencoder with a shared self-expressive layer, which can naturally and adaptively merge nonlinear features at each omics level into one unified sample manifold and produce adaptive representation of heterogeneous samples at the multi-omics level. We have assessed DLSF on various biological and biomedical datasets to validate its effectiveness. DLSF can efficiently and accurately capture the intrinsic manifold of the sample structures or sample clusters compared with other state-of-the-art methods, and DLSF yielded more significant outcomes for biological significance, survival prognosis and clinical relevance in application of cancer study in The Cancer Genome Atlas. Notably, as a deep case study, we determined a new molecular subtype of kidney renal clear cell carcinoma that may benefit immunotherapy in the viewpoint of multi-omics, and we further found potential subtype-specific biomarkers from multiple omics data, which were validated by independent datasets. In addition, we applied DLSF to identify potential therapeutic agents of different molecular subtypes of chronic lymphocytic leukemia, demonstrating the scalability of DLSF in diverse omics data types and application scenarios.