Metformin reprograms tryptophan metabolism via gut microbiome-derived bile acid metabolites to ameliorate depression-Like behaviors in mice.

As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside.

STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease.

Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human kidney samples revealed that hypertension induced mtDNA leakage and promoted the expression of stimulator of interferon genes (STING) in renal epithelial cells. We used angiotensin II (AngII)- and 2K1C-treated mouse kidneys to elucidate the underlying mechanisms. Abnormal renal mtDNA packing caused by AngII promoted STING-dependent production of inflammatory cytokines, macrophage infiltration, and a fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation and immune cell infiltration, attenuating tubule atrophy and extracellular matrix accumulation in vivo and in vitro. These effects delayed CKD progression. Immunoprecipitation assays and liquid chromatography-tandem mass spectrometry showed that STING and ACSL4 were directly combined at the D53 and K412 amino acids of ACSL4. Furthermore, STING induced renal inflammatory response and fibrosis through ACSL4-dependent ferroptosis. Last, inhibition of ACSL4 using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent renal inflammation. These results suggest that targeting the STING/ACSL4 axis might represent a potential strategy for treating hypertension-associated CKD.

Sleep disturbances and intrinsic capacity trajectories among Chinese older adults: The Rugao Longevity and Ageing Study.

Age related decline of intrinsic capacity (IC) is the core of the functional ability and risk factor of adverse outcomes such as disability, hospitalization, and mortality. However, the relationship between sleep disturbance and IC decline are largely unknown. We conducted a longitudinal study and used data of 1514 community elders from the aging arm of the Rugao Longevity and Ageing Study. We found that poor sleep quality is cross-sectional associated with an increased risk of lower IC. In longitudinal analysis, sleep disturbances were inversely associated with composite IC score changes after adjusting for confounders (PSQI>5 vs. PSQI≤5: mean difference [-0.23], P = 0.0005), suggesting that poor sleep quality was associated with a decline in IC during the follow-up period. In conclusion, sleep disturbances were associated with worse IC changes. The results suggest that improving sleep health may help prevent IC decline and hence decreasing the burden of geriatric nursing practice.

CircKDM5B sponges miR-128 to regulate porcine blastocyst development by modulating trophectoderm barrier function.

Circular RNAs (circRNAs), which exert critical functions in the regulation of transcriptional and post-transcriptional gene expression, are found in mammalian cells but their functions in mammalian preimplantation embryo development remain poorly understood. Here, we showed that circKDM5B mediated miRNA-128 (miR-128) to regulate porcine early embryo development. We screened circRNAs potentially expressed in porcine embryos through an integrated analysis of sequencing data from mouse and human embryos, as well as porcine oocytes. An authentic circRNA originating from histone demethylase KDM5B (referred to as circKDM5B) was abundantly expressed in porcine embryos. Functional studies revealed that circKDM5B knockdown not only significantly reduced blastocyst formation but also decreased the number of total cells and trophectoderm (TE) cells. Moreover, the knockdown of circKDM5B resulted in the disturbance of tight junction assembly and impaired paracellular sealing within the TE epithelium. Mechanistically, miR-128 inhibitor injection could rescue the early development of circKDM5B knockdown embryos. Taken together, the findings revealed that circKDM5B functions as a miR-128 sponge, thereby facilitating early embryonic development in pigs through the modulation of gene expression linked to tight junction assembly.

Effects of Antibiotic Resistance Genes and Antibiotics on the Transport and Deposition Behaviors of Bacteria in Porous Media.

Antibiotics present in the natural environment would induce the generation of antibiotic-resistant bacteria (ARB), causing great environmental risks. The effects of antibiotic resistance genes (ARGs) and antibiotics on bacterial transport/deposition in porous media yet are unclear. By using E. coli without ARGs as antibiotic-susceptible bacteria (ASB) and their corresponding isogenic mutants with ARGs in plasmids as ARB, the effects of ARGs and antibiotics on bacterial transport in porous media were examined under different conditions (1-4 m/d flow rates and 5-100 mM NaCl solutions). The transport behaviors of ARB were comparable with those of ASB under antibiotic-free conditions, indicating that ARGs present within cells had negligible influence on bacterial transport in antibiotic-free solutions. Interestingly, antibiotics (5-1000 µg/L gentamicin) present in solutions increased the transport of both ARB and ASB with more significant enhancement for ASB. This changed bacterial transport induced by antibiotics held true in solution with humic acid, in river water and groundwater samples. Antibiotics enhanced the transport of ARB and ASB in porous media via different mechanisms (ARB: competition of deposition sites; ASB: enhanced motility and chemotaxis effects). Clearly, since ASB are likely to escape sites containing antibiotics, these locations are more likely to accumulate ARB and their environmental risks would increase.

Inhibitory Effects of 3-Methylcholanthrene Exposure on Porcine Oocyte Maturation.

3-methylcholanthrene (3-MC) is a highly toxic environmental pollutant that impairs animal health. 3-MC exposure can cause abnormal spermatogenesis and ovarian dysfunction. However, the effects of 3-MC exposure on oocyte maturation and embryo development remain unclear. This study revealed the toxic effects of 3-MC exposure on oocyte maturation and embryo development. 3-MC with different concentrations of 0, 25, 50, and 100 µM was applied for in vitro maturation of porcine oocytes. The results showed that 100 µM 3-MC significantly inhibited cumulus expansion and the first polar body extrusion. The rates of cleavage and blastocyst of embryos derived from 3-MC-exposed oocytes were significantly lower than those in the control group. Additionally, the rates of spindle abnormalities and chromosomal misalignments were higher than those in the control group. Furthermore, 3-MC exposure not only decreased the levels of mitochondria, cortical granules (CGs), and acetylated α-Tubulin, but also increased the levels of reactive oxygen species (ROS), DNA damage, and apoptosis. The expression of cumulus expansion and apoptosis-related genes was abnormal in 3-MC-exposed oocytes. In conclusion, 3-MC exposure disrupted the nuclear and cytoplasmic maturation of porcine oocytes through oxidative stress.

Double profound enhancements of Cu2O nano-octahedrons connected by intertwined Ag nanovines for elevating SERS activity toward ultrasensitive pesticide detection.

Recently, hybrid plasmonic metal/semiconductor-based surface-enhanced Raman scattering (SERS) has attracted ever-increasing attention due to its combined characteristics of electromagnetic (EM) enhancement and chemical (CM) enhancement, holding great potential for trace molecular detection. Herein, we demonstrate an interesting heterostructure by linking Cu2O nano-octahedrons with intertwined Ag nanovines (NVs). The obtained Ag NVs/Cu2O heterostructures exhibit excellent SERS activity, which is about 2.7 and 7.0 times higher than that of monodispersed Ag or Au nanoparticles (NPs) modified Cu2O. The intertwined Ag NVs among adjacent Cu2O octahedrons serve as efficient electron transport channels, which can obviously promote the separation of electrons and holes, reduce the recombination of photogenerated carriers, and then improve the CM enhancement effect. Meanwhile, the accumulated electrons on plasmonic NVs can effectively optimize the collective oscillation of electrons and further improve the EM enhancement. The optimal SERS substrate possesses fascinating multifunctional SERS properties, including ultra-low detection limit (CV, 10-14 M), excellent anti-interference capability and selectivity. Finally, the established nanosensor can be effectively applied for the quantitative detection of pesticide thiram molecules in soil and biological samples, with low detection limits of 0.48 ng g-1 and 10-7 M, respectively. The proposed work demonstrates a high-performance SERS heterostructure with both improved CM enhancement and enhanced EM effect by linking adjacent Cu2O nano-octahedrons with Ag NVs, which is particularly suitable for ultrasensitive residual pesticide detection in real-world environment.

Extraordinary approach to further boost plasmonic NIR-SERS by cryogenic temperature-suppressed non-radiative recombination.

We report an effective strategy to promote the near-infrared surface-enhanced Raman scattering spectroscopy (NIR-SERS) activity by boosting the photon-induced charge transfer (PICT) efficiency at cryogenic temperature. Based on as-prepared Au/Ag nano-urchins (NUs) with abundant surface defects, the extremely low temperature (77 K) can significantly weaken the metallic lattice vibration and reduce the recombination of thermal phonons and photoexcited electrons, then accelerate the migration of energetic electrons. It enables the NIR-SERS detection limit of dye molecules to be achieved at 10-17 M, which is nearly three orders of magnitude better than that at room temperature. The present work provides a new, to the best of our knowledge, approach for ultra-trace NIR-SERS bioanalysis.

A novel resveratrol analog upregulates sirtuin 1 and inhibits inflammatory cell infiltration in acute pancreatitis.

Acute pancreatitis (AP), an inflammatory disorder of the pancreas, is a complicated disease without specific drug therapy. (R)-4,6-dimethoxy-3-(4-methoxy phenyl)-2,3-dihydro-1H-indanone [(R)-TML104] is a synthesized analog of the natural product resveratrol sesquiterpenes (±) -isopaucifloral F. This study aimed to investigate the effect and underlying mechanism of (R)-TML104 on AP. The experimental AP model was induced by caerulein hyperstimulation in BALB/c mice. (R)-TML104 markedly attenuated caerulein-induced AP, as evidenced by decreased pancreatic edema, serum amylase levels, serum lipase levels, and pancreatic myeloperoxidase activity. In addition, (R)-TML104 significantly inhibited the expression of pancreatic chemokines C-C motif chemokine ligand 2 and macrophage inflammatory protein-2 and the infiltration of neutrophils and macrophages. Mechanistically, (R)-TML104 activated AMP-activated protein kinase and induced sirtuin 1 (SIRT1) expression. (R)-TML104 treatment markedly induced the SIRT1-signal transducer and activator of transcription 3 (STAT3) interaction and reduced acetylation of STAT3, thus inhibiting the inflammatory response mediated by the interleukin 6-STAT3 pathway. The effect of (R)-TML104 on SIRT1-STAT3 interaction was reversed by treatment with a SIRT1 inhibitor selisistat (EX527). Together, our findings indicate that (R)-TML104 alleviates experimental pancreatitis by reducing the infiltration of inflammatory cells through modulating SIRT1.

Epigenetic restoration of voltage-gated potassium channel Kv1.2 alleviates nerve injury-induced neuropathic pain.

Voltage-gated potassium channels (Kv) are important regulators of neuronal excitability for its role of regulating resting membrane potential and repolarization. Recent studies show that Kv channels participate in neuropathic pain, but the detailed underlying mechanisms are far from being clear. In this study, we used siRNA, miR-137 agomir, and antagomir to regulate the expression of Kv1.2 in spinal cord and dorsal root ganglia (DRG) of naïve and chronic constriction injury (CCI) rats. Kv currents and neuron excitability in DRG neurons were examined by patch-clamp whole-cell recording to verify the change in Kv1.2 function. The results showed that Kv1.2 was down-regulated in DRG and spinal dorsal horn (SDH) by CCI. Knockdown of Kv1.2 by intrathecally injecting Kcna2 siRNA induced significant mechanical and thermal hypersensitivity in naïve rats. Concomitant with the down-regulation of Kv1.2 was an increase in the expression of the miR-137. The targeting and regulating of miR-137 on Kcna2 was verified by dual-luciferase reporter system and intrathecal injecting miR-137 agomir. Furthermore, rescuing the expression of Kv1.2 in CCI rats, achieved through inhibiting miR-137, restored the abnormal Kv currents and excitability in DRG neurons, and alleviated mechanical allodynia and thermal hyperalgesia. These results indicate that the miR-137-mediated Kv1.2 impairment is a crucial etiopathogenesis for the nerve injury-induced neuropathic pain and can be a novel potential therapeutic target for neuropathic pain management.

Therapeutic effects of CXCL9-overexpressing human umbilical cord mesenchymal stem cells on liver fibrosis in rats.

Umbilical cord mesenchymal stem cells (UC-MSCs) transplantation has become a promising treatment for liver fibrosis. However, UC-MSCs have limited anti-fibrosis ability, and their homing ability of UC-MSCs to the injured liver seems to be poor. In our study, we aimed to determine if the CXCL9-overexpressing UC-MSCs could have synergistic anti-fibrosis effects and whether it can promote the homing ability of UC-MSCs. Overexpression of CXCL9 in UC-MSCs (CXCL9-UC-MSCs) was attained by transfecting the lenti-CXCL9-mCherry to naive UC-MSCs. The therapeutic effect of transducted CXCL9-UC-MSCs on both repairing of hepatic fibrosis and target homing were evaluated by comparing with the control of UC-MSCs transfected with empty lenti-mCherry vector. The results revealed that the liver function of CXCL9-UC-MSCs treated group was significantly improved when compared with that of control UC-MSCs (P < 0.05), and the histopathology indicated an obvious decrease of the collagen fiber content and significant disappearing of pseudo-lobules with basically normal morphology of hepatic lobules. Furthermore, liver frozen sections confirmed that CXCL9-UC-MSCs have significantly stronger chemotaxis and stable persistence in the injured liver tissues. In summary, overexpression of CXCL9 could improve the efficacy of UC-MSCs therapy for liver fibrosis repairing on account of an enhanced ability of UC-MSCs in homing to and staying in the injured sites of liver fibrosis in rat models.

Silk fibroin fibers decorated with urchin-like Au/Ag nanoalloys: a flexible hygroscopic SERS sensor for monitoring of folic acid in human sweat.

Surface-enhanced Raman scattering (SERS) spectroscopy has become a powerful and sensitive analytical tool for the detection and assessment of chemical/biological molecules in special scenarios. Herein we propose a flexible hygroscopic SERS biocompatible sensor based on the silk fibroin fibers (SFF) decorated with urchin-like Au/Ag nanoalloys (NAs). The hybrid SFF-Au/Ag NAs with a stronger absorbance capacity (500∼1100 nm) and excellent hygroscopicity provide a remarkable higher near-infrared (NIR)-SERS activity than that of bare urchin-like Au/Ag NAs. The interesting NIR-SERS sensor enables the limit of detection (LOD) of folic acid (FA) to be achieved at nanomolar (nM, 10-9 M) level, facilitating the ultrasensitive monitoring of FA in human sweat and offering reliable real-time personal health management in the near future.

Flagella and Their Properties Affect the Transport and Deposition Behaviors of Escherichia coli in Quartz Sand.

The effects of flagella and their properties on bacterial transport and deposition behaviors were examined by using four types of Escherichia coli (E. coli) with or without flagella, as well as with normal or sticky flagella. Packed column, quartz crystal microbalance with dissipation, visible parallel-plate flow chamber system, and visible flow chamber packed with porous media system were employed to investigate the deposition mechanisms of bacteria with different properties of flagella. We found that the presence of flagella favored E. coli deposition onto quartz sand/silica surfaces. Moreover, by changing the porous media porosity and directly observing the bacterial deposition process, local sites with high roughness, narrow flow channels, and grain-to-grain contacts were found to be the major sites for bacterial deposition. Particularly, flagella could help bacteria swim near and then deposit at these sites. In addition, we found that due to the stronger adhesive forces, sticky flagella could further enhance bacterial deposition onto quartz sand/silica surfaces. Elution experiments indicated that flagella could help bacteria attach onto sand surfaces more irreversibly. Clearly, flagella and their properties would have obvious impacts on the transport/deposition behaviors of bacteria in porous media.

Hesperetin ameliorates diabetes-associated anxiety and depression-like behaviors in rats via activating Nrf2/ARE pathway.

Diabetes-associated affective disorders are of wide concern, and oxidative stress plays a vital role in the pathological process. This study was to investigate the cerebroprotective effects of hesperetin against anxious and depressive disorders caused by diabetes, exploring the potential mechanisms related to activation of Nrf2/ARE pathway. Streptozotocin-induced diabetic rats were intragastrically administrated with hesperetin (0, 50, and 150 mg/kg) for 10 weeks. Forced swimming test, open field test, and elevated plus maze were used to evaluate the anxiety and depression-like behaviors of rats. The brain was collected for assays of Nrf2/ARE pathway. Moreover, high glucose-cultured SH-SY5Y cells were used to further examine the neuroprotective effects of hesperetin and underlying mechanisms. Hesperetin showed anxiolytic and antidepressant effects in diabetic rats according to the behavior tests, and increased p-Nrf2 in cytoplasm and Nrf2 in nucleus followed by elevations in mRNA levels and protein expression of glyoxalase 1 (Glo-1) and γ-glutamylcysteine synthetase (γ-GCS) in brain, known target genes of Nrf2/ARE signaling. Moreover, hesperetin attenuated high glucose-induced neuronal damages through activation of the classical Nrf2/ARE pathway in SH-SY5Y cells. Further study indicated that PKC inhibition or GSK-3ß activation pretreatment attenuated even abolished the effect of hesperetin on the protein expression of Glo-1 and γ-GCS in high glucose-cultured SH-SY5Y cells. In summary, hesperetin ameliorated diabetes-associated anxiety and depression-like behaviors in rats, which was achieved through activation of the Nrf2/ARE pathway. Furthermore, an increase in nuclear Nrf2 phosphorylation from PKC activation and GSK-3ß inhibition contributed to the activation of Nrf2/ARE pathway by hesperetin.

Functional network dynamics in a neurodevelopmental disorder of known genetic origin.

Dynamic connectivity in functional brain networks is a fundamental aspect of cognitive development, but we have little understanding of the mechanisms driving variability in these networks. Genes are likely to influence the emergence of fast network connectivity via their regulation of neuronal processes, but novel methods to capture these rapid dynamics have rarely been used in genetic populations. The current study redressed this by investigating brain network dynamics in a neurodevelopmental disorder of known genetic origin, by comparing individuals with a ZDHHC9-associated intellectual disability to individuals with no known impairment. We characterised transient network dynamics using a Hidden Markov Model (HMM) on magnetoencephalography (MEG) data, at rest and during auditory oddball stimulation. The HMM is a data-driven method that captures rapid patterns of coordinated brain activity recurring over time. Resting-state network dynamics distinguished the groups, with ZDHHC9 participants showing longer state activation and, crucially, ZDHHC9 gene expression levels predicted the group differences in dynamic connectivity across networks. In contrast, network dynamics during auditory oddball stimulation did not show this association. We demonstrate a link between regional gene expression and brain network dynamics, and present the new application of a powerful method for understanding the neural mechanisms linking genetic variation to cognitive difficulties.

Automated reconstruction of multiple objects with individual movement based on PSP.

Many methods have been proposed to reconstruct the moving object based on phase shifting profilometry. Quality reconstruction results can be achieved when a single moving object or multiple objects with same movement are measured. However, errors will be introduced when multiple objects with individual movements are reconstructed. This paper proposes an automated method to track and reconstruct the multiple objects with individual movement. First, the objects are identified automatically and their bounding boxes are obtained. Second, with the identified objects' images before movement, the objects are tracked by the KCF algorithm in the successive fringe pattern after movement. Third, the SIFT method is applied on the tracked object images and the objects' movement is described individually by the rotation matrix and translation vector. Finally, the multiple objects are reconstructed based on the different movement information. Experiments are presented to verify the effectiveness.

Mapping differential responses to cognitive training using machine learning.

We used two simple unsupervised machine learning techniques to identify differential trajectories of change in children who undergo intensive working memory (WM) training. We used self-organizing maps (SOMs)-a type of simple artificial neural network-to represent multivariate cognitive training data, and then tested whether the way tasks are represented changed as a result of training. The patterns of change we observed in the SOM weight matrices implied that the processes drawn upon to perform WM tasks changed following training. This was then combined with K-means clustering to identify distinct groups of children who respond to the training in different ways. Firstly, the K-means clustering was applied to an independent large sample (N = 616, Mage  = 9.16 years, range = 5.16-17.91 years) to identify subgroups. We then allocated children who had been through cognitive training (N = 179, Mage  = 9.00 years, range = 7.08-11.50 years) to these same four subgroups, both before and after their training. In doing so, we were able to map their improvement trajectories. Scores on a separate measure of fluid intelligence were predictive of a child's improvement trajectory. This paper provides an alternative approach to analysing cognitive training data that go beyond considering changes in individual tasks. This proof-of-principle demonstrates a potentially powerful way of distinguishing task-specific from domain-general changes following training and of establishing different profiles of response to training.

Waste paper recycling decision system based on material flow analysis and life cycle assessment: A case study of waste paper recycling from China.

China's paper industry development is rapid, but the recycling rate of China's waste paper has been low all the time. Meanwhile, material flow analysis can help determine the flow of waste paper, and life cycle assessment (LCA) is the methodological framework for quantifying greenhouse gas emissions. Therefore, present study integrates these two methods into the model construction of China's waste paper recycling decision system. Present study constructs a benchmark model of China's waste paper recycling decision system in 2017, focusing on the impact of nonstandard waste paper recycling on the economic and environmental benefits of China's domestic waste paper recycling system. This model construction is followed by sensitivity analysis of the relevant parameters affecting the efficiency of the waste paper recycling system. Finally, present study forecasts the system's economic benefits and greenhouse gas (GHG) emissions in the context of integrating and regulating nonstandard recycling vendors. The results show that the economic benefit of China's waste paper recycling in 2017 is approximately 458.3 yuan/t and that the GHG emissions are 901.1 kgCO2eq. The standard recovery rate and nonstandard recovery acceptance rate will both have a significant impact on the system's economic benefits and improve the GHG emissions structure. In the context of integrating nonstandard recycling enterprises and individual recycling vendors, the economic benefits will rise to 3312.5 yuan/t in 2030, while GHG emissions will rise to 942.9 kgCO2eq. Present study can play a certain guiding role for policy makers in formulating waste paper recycling industry specifications and formulating relevant policies.

Cotransport and Deposition of Iron Oxides with Different-Sized Plastic Particles in Saturated Quartz Sand.

The present study was designed to investigate the cotransport and deposition of different-sized plastic particle from nano- (0.02 µm) to micrometer-scale (0.2 and 2 µm) with goethite and hematite (two types of representative iron oxides abundant in natural environment) in porous media at both low (5 mM) and high ionic strength (25 mM) in NaCl solutions. We found that through different mechanisms (i.e., modification of surface properties of iron oxides, steric repulsion, or alteration in deposition sites on quartz sand), different-sized plastic particles induced different effects on the transport and deposition behaviors of iron oxides in quartz sand. Likewise, via different mechanisms such as change of surface properties or alteration in deposition sites on quartz sand, different transport behaviors for different sized plastic particles induced by the copresence of iron oxides were also observed. The results of this study suggested that cotransport of iron oxides and plastic particles in porous media is far more complex than those of individual colloid transport. Since both plastic particles and iron oxides are ubiquitous presence in natural environment, it is expected that they would interact with each other and thus alter the surface properties, leading to the change of transport behaviors in porous media.

Virtual Antenna Array and Fractional Fourier Transform-Based TOA Estimation for Wireless Positioning.

In this paper, a novel virtual antenna array and fractional Fourier transform (FRFT)-based 2-dimension super-resolution time-of-arrival (TOA) estimation algorithm for OFDM WLAN systems has been proposed. The proposed algorithm employs channel frequency responses (CFRs) at the equi-spaced positions on a line or quasi-line moving trajectory, i.e., the CFRs of a virtual antenna array, to extract multipaths' TOA information. Meanwhile, a new chirp-like quadratic function is used to approximate the channel multipaths' phase variation across the space dimension, which is more reasonable than the traditional linear function, especially for relatively big virtual antenna array sizes. By exploiting the property of chirp-like multipaths' energy concentration in the FRFT domain, the FRFT can be first used to separate chirp-like multipath components, then the existing TOA estimation methods in frequency domain can be further employed on the separated multipath components to obtain the multipaths' TOA estimates. Therefore, the proposed algorithm can make more use of the multipaths' characteristics in the space dimension, thus it can efficiently enhance the multipath resolution and achieve better multipaths' TOA estimation performance without requiring a real antenna array. Simulation results demonstrate the effectiveness of the proposed algorithm.