Dampening of ISGylation of RIG-I by ADAP regulates type I interferon response of macrophages to RNA virus infection.

While macrophage is one of the major type I interferon (IFN-I) producers in multiple tissues during viral infections, it also serves as an important target cell for many RNA viruses. However, the regulatory mechanism for the IFN-I response of macrophages to respond to a viral challenge is not fully understood. Here we report ADAP, an immune adaptor protein, is indispensable for the induction of the IFN-I response of macrophages to RNA virus infections via an inhibition of the conjugation of ubiquitin-like ISG15 (ISGylation) to RIG-I. Loss of ADAP increases RNA virus replication in macrophages, accompanied with a decrease in LPS-induced IFN-ß and ISG15 mRNA expression and an impairment in the RNA virus-induced phosphorylation of IRF3 and TBK1. Moreover, using Adap-/- mice, we show ADAP deficiency strongly increases the susceptibility of macrophages to RNA-virus infection in vivo. Mechanically, ADAP selectively interacts and functionally cooperates with RIG-I but not MDA5 in the activation of IFN-ß transcription. Loss of ADAP results in an enhancement of ISGylation of RIG-I, whereas overexpression of ADAP exhibits the opposite effect in vitro, indicating ADAP is detrimental to the RNA virus-induced ISGylation of RIG-I. Together, our data demonstrate a novel antagonistic activity of ADAP in the cell-intrinsic control of RIG-I ISGylation, which is indispensable for initiating and sustaining the IFN-I response of macrophages to RNA virus infections and replication.

Modulation effect of low-intensity transcranial ultrasound stimulation on REM and NREM sleep.

Previous studies have shown that modulating neural activity can affect rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. Low-intensity transcranial ultrasound stimulation (TUS) can effectively modulate neural activity. However, the modulation effect of TUS on REM and NREM sleep is still unclear. In this study, we used ultrasound to stimulate motor cortex and hippocampus, respectively, and found the following: (i) In healthy mice, TUS increased the NREM sleep ratio and decreased the REM sleep ratio, and altered the relative power and sample entropy of the delta band and spindle in NREM sleep and that of the theta and gamma bands in REM sleep. (ii) In sleep-deprived mice, TUS decreased the ratio of REM sleep or the relative power of the theta band during REM sleep. (iii) In sleep-disordered Alzheimer's disease (AD) mice, TUS increased the total sleep time and the ratio of NREM sleep and modulated the relative power and the sample entropy of the delta and spindle bands during NREM and that of the theta band during REM sleep. These results demonstrated that TUS can effectively modulate REM and NREM sleep and that modulation effect depends on the sleep state of the samples, and can improve sleep in sleep-disordered AD mice.

Low-intensity ultrasound stimulation modulates time-frequency patterns of cerebral blood oxygenation and neurovascular coupling of mouse under peripheral sensory stimulation state.

Previous studies have demonstrated that transcranial ultrasound stimulation (TUS) not only modulates cerebral hemodynamics, neural activity, and neurovascular coupling characteristics in resting samples but also exerts a significant inhibitory effect on the neural activity in task samples. However, the effect of TUS on cerebral blood oxygenation and neurovascular coupling in task samples remains to be elucidated. To answer this question, we first used forepaw electrical stimulation of the mice to elicit the corresponding cortical excitation, and then stimulated this cortical region using different modes of TUS, and simultaneously recorded the local field potential using electrophysiological acquisition and hemodynamics using optical intrinsic signal imaging. The results indicate that for the mice under peripheral sensory stimulation state, TUS with a duty cycle of 50% can (1) enhance the amplitude of cerebral blood oxygenation signal, (2) reduce the time-frequency characteristics of evoked potential, (3) reduce the strength of neurovascular coupling in time domain, (4) enhance the strength of neurovascular coupling in frequency domain, and (5) reduce the time-frequency cross-coupling of neurovasculature. The results of this study indicate that TUS can modulate the cerebral blood oxygenation and neurovascular coupling in peripheral sensory stimulation state mice under specific parameters. This study opens up a new area of investigation for potential applicability of TUS in brain diseases related to cerebral blood oxygenation and neurovascular coupling.

Low-intensity pulsed ultrasound triggers a beneficial neuromodulation in dementia mice with chronic cerebral hypoperfusion via activation of hippocampal Fndc5/irisin signaling.

BACKGROUND: Exercise-related signaling Fndc5/irisin expresses in brain and acts as a crucial regulator of cognitive function, but its detailed roles in vascular dementia (VaD) are still unclear. Low intensity pulsed ultrasound (LIPUS), a novel brain stimulation approach, has been suggested as a promising treatment for dementia. Here, we investigated the activity and efficacy of Fndc5/irisin in experimental VaD, further explored whether the potential effects of LIPUS on VaD is related to Fndc5/irisin. METHODS: Mouse model of VaD was established with chronic cerebral hypoperfusion (CCH) using bilateral common carotid arteries stenosis (BCAS). Transcranial LIPUS was applied 24 h after BCAS and subsequently daily with a stimulation time of 5 min at an ultrasound pressure of 0.51 MPa for a period of 28 days. The levels of Fndc5/irisin in different brain regions, the hippocampal long-term potentiation and anti-inflammatory cytokines were investigated at day 28 after cognitive evaluation. Global Fndc5 knock-out (F5KO), forced expression or knockdown of Fndc5, and recombinant irisin application were respectively employed for mechanism exploration. The neuron dendritic spine density and astrocyte phenotype were detected in vitro. RESULTS: Fndc5/irisin was reduced in hippocampus of BCAS mice, forced expression hippocampal Fndc5 or bilateral intrahippocampal injection of recombinant irisin respectively improved hippocampal synaptic plasticity or inflammatory microenvironment, and then alleviated the cognitive impairments. LIPUS existed a positive efficacy in enhancing hippocampal Fndc5/irisin in BCAS mice, thus triggering a beneficial neuromodulation for VaD protection. Importantly, the neurorestorative effects of LIPUS on CCH-induced damages were totally reversed by knockdown the expression of hippocampal Fndc5 in WT mice, or in F5KO mice. Moreover, Fndc5 mediated the upregulated effects of LIPUS on spine density as well as irisin secretion of hippocampal neurons. The neuron-secreted irisin further drove reactive astrocytes to a neuroprotective phenotype. CONCLUSION: LIPUS induced a neurorestorative stimulation against VaD may be through upregulation of the hippocampal Fndc5/irisin levels. Hippocampal Fndc5/irisin signaling might be a promising strategic target for VaD.

Low-intensity transcranial ultrasound stimulation modulates neural activities in mice under propofol anaesthesia.

BACKGROUND: Previous studies have reported that transcranial focused ultrasound stimulation can significantly decrease the time to emergence from intraperitoneal ketamine-xylazine anaesthesia in rats. However, how transcranial focused ultrasound stimulation modulates neural activity in anaesthetized rats is unclear. METHODS: In this study, to answer this question, we used low-intensity transcranial ultrasound stimulation (TUS) to stimulate the brain tissue of propofol-anaesthetized mice, recorded local field potentials (LFPs) in the mouse motor cortex and electromyography (EMG) signals from the mouse neck, and analysed the emergence and recovery time, mean absolute power, relative power and entropy of local field potentials. RESULTS: We found that the time to emergence from anaesthesia in the TUS group (20.3 ± 1.7 min) was significantly less than that in the Sham group (32 ± 2.6 min). We also found that compared with the Sham group, 20 min after low-intensity TUS during recovery from anaesthesia, (1) the absolute power of local field potentials in mice was significantly reduced in the [1-4 Hz] and [13-30 Hz] frequency bands and significantly increased in the [55-100 Hz], [100-140 Hz] and [140-200 Hz] frequency bands; (2) the relative power of local field potentials in mice was enhanced at [30-45 Hz], [100-140 Hz] and [140-200 Hz] frequency bands; (3) the entropy of local field potentials ([1-200 Hz]) was increased. CONCLUSION: These results demonstrate that low-intensity TUS can effectively modulate neural activities in both awake and anaesthetized mice and has a positive effect on recovery from propofol anaesthesia in mice.

[Modulation of motor responses and neural activities with transcranial ultrasound stimulation based on closed-loop control].

Closed-loop transcranial ultrasound stimulation technology is based on real-time feedback signals, and has the potential for precise regulation of neural activity. In this paper, firstly the local field potential (LFP) and electromyogram (EMG) signals of mice under different intensities of ultrasound stimulation were recorded, then the mathematical model of ultrasound intensity and mouse LFP peak/EMG mean was established offline based on the data, and the closed-loop control system of LFP peak and EMG mean based on PID neural network control algorithm was simulated and built to realize closed-loop control of LFP peak and EMG mean of mice. In addition, using the generalized minimum variance control algorithm, the closed-loop control of theta oscillation power was realized. There was no significant difference between the LFP peak, EMG mean and theta power under closed-loop ultrasound control and the given value, indicating a significant control effect on the LFP peak, EMG mean and theta power of mice. Transcranial ultrasound stimulation based on closed-loop control algorithms provides a direct tool for precise modulation of electrophysiological signals in mice.

Dietary Factors and Incidence of Hydatidiform Mole: An Ecological Study.

The current ecological study aims to explore the association between dietary factors and hydatidiform mole (HM) incidence in Japan and China. HM incidence in Japan gradually declined from 1970s to 1990s, while the dietary structure also changed during the same period, mainly characterized by a decrease in the consumption of cereals and an increase in the consumption of meat, eggs, and dairy products. In China, HM incidence varied by regions, and it positively correlated with the per capita intake of rice, fish and shrimp, and animal fat, as well as the proportion of GDP of primary industry; and negatively correlated with the per capita intake of wheat flour, starch and sugar, protein, and iron, and the proportion of protein in the caloric nutrients and the proportion of nonagricultural population. In partial analysis, the correlations of HM incidence with rice, fish and shrimp, iron, and the proportion of protein in caloric nutrients remained significant. Meanwhile, alcoholic beverage consumption and the proportion of empty calories in caloric food were also found to be positively correlated with HM incidence, while phosphorus consumption was negatively correlated. Our results suggested that HM incidence could be influenced by dietary factors.

Management of relapsed gestational trophoblastic neoplasia: What can help to reduce the re-recurrence rate?

AIM: To explore the risk factors for re-recurrence in relapsed gestational trophoblastic neoplasia (GTN) and therapeutic approaches to reduce the re-recurrence rate. METHODS: Data of relapsed GTN treated in the Obstetrics and Gynecology Hospital of Fudan University from January 1, 2015, to December 31, 2020, were reviewed retrospectively. Risk factors associated with re-recurrence were analyzed using Logistic regression analysis. RESULTS: A total of 39 relapsed GTN patients were included in our study. At the time of the first relapse, 14 patients received single-agent chemotherapy and 25 patients received multi-agent chemotherapy. Surgery was performed in 19 patients. Complete remission was achieved in all of the patients. Re-recurrence occurred in 21 patients. Univariate analysis suggested that unifocal recurrence was the only factor significantly associated with re-recurrence (OR = 0.25, p = 0.04). Recurrence pattern-based subgroup analysis showed that the proportion of re-recurrence was lower in patients who received both surgery and chemotherapy compared to those who received only chemotherapy in the unifocal recurrence group (3/11 vs. 2/4), but not in the non-unifocal recurrence group (7/8 vs. 9/16). The results of the multivariate analysis showed that there was no significant difference in re-recurrence rates between the surgical approaches and that the non-unifocal recurrence pattern was an independent risk factor for re-recurrence. CONCLUSIONS: For relapsed GTN with unifocal recurrence pattern, surgical removal of the lesion can effectively reduce the re-recurrence rate.

Influence of behavioral state on the neuromodulatory effect of low-intensity transcranial ultrasound stimulation on hippocampal CA1 in mouse.

In process of brain stimulation, the influence of any external stimulus depends on the features of the stimulus and the initial state of the brain. Understanding the state-dependence of brain stimulation is very important. However, it remains unclear whether neural activity induced by ultrasound stimulation is modulated by the behavioral state. We used low-intensity focused ultrasound to stimulate the hippocampal CA1 regions of mice with different behavioral states (anesthesia, awake, and running) and recorded the neural activity in the target area before and after stimulation. We found the following: (1) there were different spike firing rates and response delays computed as the time to reach peak for all behavioral states; (2) the behavioral state significantly modulates the spike firing rate linearly increased with an increase in ultrasound intensity under different behavioral states; (3) the mean power of local field potential induced by TUS significantly increased under anesthesia and awake states; (4) ultrasound stimulation enhanced phase-locking between spike and ripple oscillation under anesthesia state. These results suggest that ultrasound stimulation-induced neural activity is modulated by the behavioral state. Our study has great potential benefits for the application of ultrasound stimulation in neuroscience.

Low-Intensity Pulsed Ultrasound Stimulation Induces Coupling Between Ripple Neural Activity and Hemodynamics in the Mouse Visual Cortex.

Several studies have separately investigated neural activities and hemodynamic responses induced by low-intensity pulsed ultrasound stimulation (LIPUS), less is known about their coupling under LIPUS. This study aims to investigate the neurovascular coupling with LIPUS by measuring neural activity and hemodynamics. We found that the relative power and sample entropy of local field potential at the ripple band have a significant correlation to relative cerebral blood flow over time (correlation coefficients: 0.66 ± 0.13 [P < 0.01] and -0.58 ± 0.11 [P < 0.05]). These results demonstrate that LIPUS can induce neurovascular coupling in the mouse visual cortex.

The effect of anesthetic dose on the motor response induced by low-intensity pulsed ultrasound stimulation.

BACKGROUND: Low-intensity pulsed ultrasound stimulation (LIPUS) has been proven to be a noninvasive method with high spatial resolution and deep penetration. Previous studies have qualitatively demonstrated that the electromyographic response caused by LIPUS in the mouse motor cortex is affected by the anesthetic state of the mice. However, the quantitative relationship between motor response and anesthetic dose remains unclear. RESULTS: Experimental results show that the success rate decreases stepwise as the isoflurane concentration/mouse weight ratio increases (ratios: [0.004%/g, 0.01%/g], success rate: ~ 90%; [0.012%/g, 0.014%/g], ~ 40%; [0.016%/g, 0.018%/g], ~ 7%; 0.024%/g, 0). The latency and duration of EMG increase significantly when the ratio is more than 0.016%/g. Compared with that at ratios from 0.004 to 0.016%/g, normalized EMG amplitude decreases significantly at ratios of 0.018%/g and 0.020%/g. CONCLUSIONS: Quantitative calculations indicate that the anesthetic dose has a significant regulatory effect on the motor response of mice during LIPUS. Our results have guiding significance for the selection of the anesthetic dose for LIPUS in mouse motor cortex experiments.

Effect of pulsed transcranial ultrasound stimulation at different number of tone-burst on cortico-muscular coupling.

BACKGROUND: Pulsed transcranial ultrasound stimulation (pTUS) can modulate the neuronal activity of motor cortex and elicit muscle contractions. Cortico-muscular coupling (CMC) can serve as a tool to identify interaction between the oscillatory activity of the motor cortex and effector muscle. This research aims to explore the neuromodulatory effect of low-intensity, pTUS with different number of tone burst to neural circuit of motor-control system by analyzing the coupling relationship between motor cortex and tail muscle in mouse. The motor cortex of mice was stimulated by pulsed transcranial ultrasound with different number of tone bursts (NTB = 100 150 200 250 300). The local field potentials (LFPs) in tail motor cortex and electromyography (EMG) in tail muscles were recorded simultaneously during pTUS. The change of integral coupling strength between cortex and muscle was evaluated by mutual information (MI). The directional information interaction between them were analyzed by transfer entropy (TE). RESULTS: Almost all of the MI and TE values were significantly increased by pTUS. The results of MI showed that the CMC was significantly enhanced with the increase of NTB. The TE results showed the coupling strength of CMC in descending direction (from LFPs to EMG) was significantly higher than that in ascending direction (from EMG to LFPs) after stimulation. Furthermore, compared to NTB = 100, the CMC in ascending direction were significantly enhanced when NTB = 250, 300, and CMC in descending direction were significantly enhanced when NTB = 200, 250, 300. CONCLUSION: These results confirm that the CMC between motor cortex and the tail muscles in mouse could be altered by pTUS. And by increasing the NTB (i.e. sonication duration), the coupling strength within the cortico-muscular circuit could be increased, which might further influence the motor function of mice. It demonstrates that, using MI and TE method, the CMC could be used for quantitatively evaluating the effect of pTUS with different NTBs, which might provide a new insight into the effect of pTUS neuromodulation in motor cortex.

Effect of follicle cell autophagy on gonadal development of triploid female rainbow trout (Oncorhynchus mykiss).

Autophagy is a cellular process which occurs in eukaryotic cells. To study the mechanism regulating polyploid fish growth and development is of significance in genetic, because of its growth advantages and economic values. This study focused on triploid female rainbow trout (RBT) which discusses the effects of autophagy on gonadal development of polyploid fish. Autophagy-related genes of RBT lc3b, atg12, atg4b, gabarap1, and bcl2 were cloned, and autophagy gene expressions in gonads were analyzed at different developmental period. Gonadal ultrastructures were observed under transmission electron microscopy. To detect autophagy protein expression and localization, antibodies of RBT-LC3B and RBT-ATG12 were produced. Results showed clear evidence that autophagy-related genes were highly expressed during 200-300 days post fertilization (dpf), in which autophagosome structures were identified. In this stage, the conversion of LC3B-I to LC3B-II was greater than those in other stages. Immunolabeling-manifested autophagy occurred intensively in the cytoplasm of follicular cells. The morphology of follicular cells was gradually changed, leading to gonadal fibrosis and regression. This autophagic research is a new study area on gonadal development of polyploid fish.

Case report: Immunotherapy-based combination therapy achieving complete remission and prolonged survival in nasopharyngeal carcinoma with extensive bone marrow metastasis.

Nasopharyngeal carcinoma with bone marrow metastasis presents a rare and challenging clinical scenario associated with exceedingly poor prognosis. While standard treatment regimens offer limited efficacy and tolerability in such cases, individualized approaches are increasingly necessary. We present the case of a 64-year-old male diagnosed with recurrent nonkeratinizing undifferentiated nasopharyngeal carcinoma with extensive bone marrow metastasis (rTxN0M1). Treatment was initiated with immunotherapy-based combination therapy, consisting of pembrolizumab and low-dose cisplatin, which resulted in an initial response. Subsequently, there was a transition to standard-dose nab-paclitaxel-cisplatin chemotherapy in combination with pembrolizumab, followed by maintenance therapy with pembrolizumab plus fruquintinib. The patient achieved a sustained response with renormalization of tumor markers, imaging findings, and bone biopsies, resulting in complete remission. This case highlights the successful management of nasopharyngeal carcinoma with extensive bone marrow metastasis through an individualized treatment approach incorporating immunotherapy.

Modulation effect of non-invasive transcranial ultrasound stimulation in an ADHD rat model.

Objective.Previous studies have demonstrated that transcranial ultrasound stimulation (TUS) with noninvasive high penetration and high spatial resolution has an effective neuromodulatory effect on neurological diseases. Attention deficit hyperactivity disorder (ADHD) is a persistent neurodevelopmental disorder that severely affects child health. However, the neuromodulatory effects of TUS on ADHD have not been reported to date. This study aimed to investigate the neuromodulatory effects of TUS on ADHD.Approach.TUS was performed in ADHD model rats for two consecutive weeks, and the behavioral improvement of ADHD, neural activity of ADHD from neurons and neural oscillation levels, and the plasma membrane dopamine transporter and brain-derived neurotrophic factor (BDNF) in the brains of ADHD rats were evaluated.Main results.TUS can improve cognitive behavior in ADHD rats, and TUS altered neuronal firing patterns and modulated the relative power and sample entropy of local field potentials in the ADHD rats. In addition, TUS can also enhance BDNF expression in the brain tissues.Significance. TUS has an effective neuromodulatory effect on ADHD and thus has the potential to clinically improve cognitive dysfunction in ADHD.

GDNF-Loaded Polydopamine Nanoparticles-Based Anisotropic Scaffolds Promote Spinal Cord Repair by Modulating Inhibitory Microenvironment.

Spinal cord injury (SCI) is a devastating injury that causes permanent loss of sensation and motor function. SCI repair is a significant challenge due to the limited regenerating ability of adult neurons and the complex inflammatory microenvironment. After SCI, the oxidative stress induced by excessive reactive oxygen species (ROS) often leads to prolonged neuroinflammation that results in sustained damage to the spinal cord tissue. Polydopamine (PDA) shows remarkable capability in scavenging ROS to treat numerous inflammatory diseases. In this study, glial cell-derived neurotrophic factor (GDNF)-loaded PDA nanoparticle-based anisotropic scaffolds for spinal cord repair are developed. It is found that mesoporous PDA nanoparticles (mPDA NPs) in the scaffolds efficiently scavenge ROS and promote microglia M2 polarization, thereby inhibiting inflammatory response at the injury site and providing a favorable microenvironment for nerve cell survival. Furthermore, the GDNF encapsulated in mPDA NPs promotes corticospinal tract motor axon regeneration and its locomotor functional recovery. Together, findings from this study reveal that the GDNF-loaded PDA/Gelatin scaffolds hold potential as an effective artificial transplantation material for SCI treatment.

Mesenchymal Stromal Cell Therapy in Spinal Cord Injury: Mechanisms and Prospects.

Spinal cord injury (SCI) often leads to severe motor, sensory, and autonomic dysfunction in patients and imposes a huge economic cost to individuals and society. Due to its complicated pathophysiological mechanism, there is not yet an optimal treatment available for SCI. Mesenchymal stromal cells (MSCs) are promising candidate transplant cells for use in SCI treatment. The multipotency of MSCs, as well as their rich trophic and immunomodulatory abilities through paracrine signaling, are expected to play an important role in neural repair. At the same time, the simplicity of MSCs isolation and culture and the bypassing of ethical barriers to stem cell transplantation make them more attractive. However, the MSCs concept has evolved in a specific research context to encompass different populations of cells with a variety of biological characteristics, and failure to understand this can undermine the quality of research in the field. Here, we review the development of the concept of MSCs in order to clarify misconceptions and discuss the controversy in MSCs neural differentiation. We also summarize a potential role of MSCs in SCI treatment, including their migration and trophic and immunomodulatory effects, and their ability to relieve neuropathic pain, and we also highlight directions for future research.

Preventive and Therapeutic Effects of Low-Intensity Ultrasound Stimulation on Migraine in Rats.

This study sought to systematically evaluate the prophylactic and therapeutic effects of low-intensity transcranial ultrasound stimulation on migraine in rats. We used video recordings to assess the head scratching behavior and laser speckle contrast imaging to record the changes in cerebral blood flow velocity of freely moving rats in a healthy group, migraine group, migraine group with ultrasound prevention, and migraine group with ultrasound therapy. Results demonstrated that (1) head scratching during migraine attacks in rats was accompanied by an decrease in cerebral blood flow; (2) both ultrasound prevention and therapy significantly reduced the number of head scratches but did not reduce the cerebral blood flow velocity; and (3) the number of head scratches in the ultrasound stimulation groups was not affected by the auditory effect. These results reveal that low-intensity ultrasound has the potential to be used clinically in the prevention and therapeutic treatment of migraine.

Collagen Modified Anisotropic PLA Scaffold as a Base for Peripheral Nerve Regeneration.

Reconstruction of damaged nerves remains a significant unmet challenge in clinical medicine. Topographical and mechanical stimulations play important roles to repair peripheral nerve injury. The synergistic effects of topography and mechanical rigidity may significantly accelerate nerve regeneration. In this work, a nerve-guiding collagen/polylactic acid (PLA) electrospun scaffold is developed to facilitate peripheral nerve repair. The obtained anisotropic PLA electrospun scaffolds simulate the directional arranged structure of nerve realistically and promote axonal regeneration after sciatic nerve injury when compared with the isotropic PLA electrospun scaffolds. Moreover, the collagen-modified PLA electrospun scaffolds further provide sufficient mechanical support and favorable microenvironment for axon regeneration. In addition, it is observed that collagen-modified PLA electrospun scaffolds facilitate the axon regeneration by regulating Yes-associated protein (YAP) molecular pathway. Taken together, the engineered collagen-modified anisotropic PLA electrospun scaffolds may be a potential candidate to combine topography and mechanical rigidity for peripheral nerve regeneration is engineered.

Sera Metabolomics Characterization of Patients at Different Stages in Wuhan Identifies Critical Biomarkers of COVID-19.

We have witnessed the 2-year-long global rampage of COVID-19 caused by the wide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, knowledge about biomarkers of the entire COVID-19 process is limited. Identification of the systemic features of COVID-19 will lead to critical biomarkers and therapeutic targets for early intervention and clinical disease course prediction. Here, we performed a comprehensive analysis of clinical measurements and serum metabolomics in 199 patients with different stages of COVID-19. In particular, our study is the first serum metabolomic analysis of critical rehabilitation patients and critical death patients. We found many differential metabolites in the comparison of metabolomic results between ordinary, severe, and critical patients and uninfected patients. Through the metabolomic results of COVID-19 patients in various stages, and critical rehabilitation patients and critical death patients, we identified a series of differential metabolites as biomarkers, a separate queue and precise distinction, and predicted COVID-19 verification. These differentially expressed metabolites, included 1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphate, propylparaben, 20-hydroxyeicosatetraenoic acid, triethanolamine, chavicol, disialosyl galactosyl globoside, 1-arachidonoylglycerophosphoinositol, and alpha-methylstyrene, all of which have been identified for the first time as biomarkers in COVID-19 progression. These biomarkers are involved in many pathological and physiological pathways of COVID-19, for example, immune responses, platelet degranulation, and metabolism which might result in pathogenesis. Our results showed valuable information about metabolites obviously altered in COVID-19 patients with different stages, which could shed light on the pathogenesis as well as serve as potential therapeutic agents of COVID-19.