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Geng Li

Publications and source records attributed to Geng Li.

At least 19 recordsLinked to original sources

The R203M and D377Y mutations of the nucleocapsid protein promote SARS-CoV-2 infectivity by impairing RIG-I-mediated antiviral signaling.

The viral protein mutations can modify virus-host interactions during virus evolution, and thus alter the extent of infection or pathogenicity. Studies indicate that nucleocapsid (N) protein of SARS-CoV-2 participates in viral genome assembly, intracellular signal regulation and immune interference. However, its biological function in viral evolution is not well understood. SARS-CoV-2 N protein mutations were analyzed in Delta, Omicron, and original strains. Two mutations with a methionine (M) residue at site 203 and a tyrosine (Y) residue at site 377 of the N protein were found in Delta strain but not in Omicron and original strains, and promoted SARS-CoV-2 infection therein. Those mutations, R203M and D377Y, enhanced the inhibitory impact of N protein on the impairment of RIG-I-mediated antiviral signaling, such as IRF3 phosphorylation and IFN-β activation. The viral RNA-binding activity of N protein was promoted by these mutations, effectively attenuating the recognition and interaction of RIG-I with viral RNA compared to the original or other variants. The R203M/D377Y mutations thus enhanced the suppressive activity of the N protein on RIG-I-mediated interferon induction both in vitro and in vivo, which in turn promoted viral replication. This study helps to understand the variability of SARS-CoV-2 in regulating host immunity.

SARS-CoV-2↗

Identification of a novel prostate cancer-associated tumor antigen.

BACKGROUND: The identification of antigens that distinguish cancer cells from normal cells is of major importance for the definition of therapeutic targets in human malignancies. Using sera from cancer patients, we have previously reported on the identification of immunologically recognized proteins that belong to the family of cancer testis antigens (CTAs). METHODS: A normal testicular cDNA library was screened with pooled allogeneic sera from patients with prostate cancer using a modified SEREX approach. Subsequently we have identified and characterized a novel antigen, T21, with an expression pattern similar to that of CTAs. mRNA expression of T21 was determined using a panel of whole tissues and prostate cell lines using Q-RT-PCR. For laser microdissection, fresh prostate cancer and benign tissue was obtained using our novel validated harvesting technique. Protein expression and cellular localization of T21 were assessed in prostate cell lines using Western blotting, confocal microscopy and flow cytometry. RESULTS: T21 showed tissue-restricted mRNA expression in gastric, kidney and prostate cancers, and in normal testis and prostate tissues. Following laser microdissection, T21 was significantly over-expressed in malignant compared to benign prostatic epithelium. We have demonstrated expression of T21 at the protein level and confocal microscopy on PC3 cells probed with a T21-monospecific antibody revealed cytoplasmic localization of T21 protein. CONCLUSIONS: The highly restricted expression pattern of T21 makes it an attractive vaccine target for prostate cancer. Several CTAs reportedly induce cytotoxic T-lymphocyte responses, therefore it is reasonable to assume that T21 will be a valuable target for cancer immunotherapy.

Adolescent↗

Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein.

This study was designed to test whether Coenzyme Q10 (CoQ10) supplementation has neuroprotective effect in aged, double-transgenic amyloid precursor protein (APP)/presenilin 1 (PS1), single transgenic APP and PS1 mice exposed to ischemic injury of the brain. Forty-eight mice (12 each of APP/PS1, APP, PS1 and wild-type) were studied. Half of each genotype groups (n=6 per group) was treated with CoQ10 (1200 mg/kg/day) after ischemic injury and the other half with placebo. Magnetic resonance (MR) images were used to measure the volume of induced infarction (IFV), as well as the volume of the hemispheres and hippocampi. Significantly greater volumes of infarction and lesser volumes of hemisphere/hippocampus on the ischemic side were observed in APP/PS1 and APP mice than in PS1 and wild-type mice. This is consistent with amplification of the effect of ischemia in APP carriers. After 28 days of CoQ10 treatment, APP/PS1 or APP mutations have smaller infarct volumes, while the volumes of hemisphere and hippocampus on the infarcted side were larger than those treated with placebo. No differences between CoQ10- and placebo-treated groups in volumes of infarct, hemisphere and hippocampus were observed in PS1 and wild-type mice. We conclude that CoQ10 has a protective effect on the brain from infarction and atrophy induced by ischemic injury in aged and susceptible transgenic mice.

Aging↗

Early prediction of sepsis-induced disseminated intravascular coagulation with interleukin-10, interleukin-6, and RANTES in preterm infants.

BACKGROUND: The progression to disseminated intravascular coagulation (DIC) in infected very low birth weight (VLBW; <1500 g) infants is difficult to predict with precision at the onset of sepsis. We investigated the immunologic profiles of preterm infants with sepsis, using chemokine and cytokine measurements to predict the development of sepsis-induced DIC at the onset of infection. METHODS: We measured a panel of chemokines and cytokines at 0 and 24 h after clinical presentation in VLBW infants with suspected infection requiring full sepsis screening. The chemokines measured were interleukin (IL)-8, interferon-gamma-inducible protein-10 (IP-10), monokine induced by interferon-gamma, monocyte chemoattractant protein-1, and regulated upon activation normal T-cell expressed and secreted (RANTES), and the cytokines were IL-6, IL-10, and tumor necrosis factor-alpha. RESULTS: Of 195 episodes of suspected clinical sepsis investigated, 62 were culture-confirmed septicemia or necrotizing enterocolitis (28 of these infants developed DIC), 22 were culture-negative clinical infections, and 111 involved noninfected episodes. All studied inflammatory mediators except RANTES showed significantly greater up-regulation in culture-positive infected infants than in noninfected infants at 0 and 24 h, whereas RANTES showed significant down-regulation. The model that used plasma IL-10 (>208 ng/L), IL-6 (>168 ng/L), and RANTES (<3110 ng/L) at 0 h had sensitivity, specificity, and positive and negative predictive values of 100%, 97%, 85%, and 100%, respectively, for identifying infected patients who subsequently developed DIC. CONCLUSIONS: IL-10, IL-6, and RANTES measured at clinical presentation sensitively and accurately predicted the development of DIC in severely infected infants. This information could be vital for early and effective treatment of neonatal sepsis.

Chemokine CCL5↗

The identification of human tumour antigens: Current status and future developments.

The biggest challenge facing us today in cancer control and prevention is the identification of novel biomarkers for detection and improved therapeutic interventions to reduce mortality and morbidity rates. Biomarkers are important indicators to inform us of the physiological state of the cell at a specific time. It is now clear that malignant transformation occurs by changes in cellular DNA and protein expression with subsequent clonal proliferation of the altered cells. The affected genes and their expressed protein products or biomarkers are those involved in the normal growth and maintenance of the cancerous cells. These biomarkers could prove pivotal for the identification of early cancer and people at risk of developing cancer. Altered proteins or changes in gene expression in malignant cells may lead to the expression of tumour antigens recognised by host immune system. In this review we discuss current research into the molecular technologies making possible the global genomic-wide analysis of changes in DNA (genotyping), RNA expression (transcriptomics) and protein expression (proteomics) that have accelerated the rate of new biomarker/tumour antigen discovery. To gain a comprehensive understanding of the physiology and pathophysiology of cancer an approach that harmoniously integrates the various 'omic' platforms are key to unraveling the complexity 'needle-in-a-haystack' quality of biomarker/tumour antigen discovery.

Antigens, Neoplasm↗

Cognitive processing in Chinese literate and illiterate subjects: an fMRI study.

Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) were used to map brain activation during language tasks. While previous studies have compared performance between alphabetic literate and illiterate subjects, there have been no such data in Chinese-speaking individuals. In this study, we used fMRI to examine the effects of education on neural activation associated with silent word recognition and silent picture-naming tasks in 24 healthy right-handed Chinese subjects (12 illiterates and 12 literates). There were 30 single Chinese characters in the silent word recognition task and 30 meaningful road-signs in the silent picture-naming task. When we compared literate and illiterate subjects, we observed education-related differences in activation patterns in the left inferior/middle frontal gyrus and both sides of the superior temporal gyrus for the silent word recognition task and in the bilateral inferior/middle frontal gyrus and left limbic cingulated gyrus for the silent picture-naming task. These results indicate that the patterns of neural activation associated with language tasks are strongly influenced by education. Education appears to have enhanced cognitive processing efficiency in language tasks.

Aged↗

An fMRI study of somatosensory-implicated acupuncture points in stable somatosensory stroke patients.

PURPOSE: To assess differences in brain responses between stroke patients and controls to tactile and electrical acupuncture stimulation using functional MRI (fMRI). MATERIALS AND METHODS: A total of 12 male, clinically stable stroke patients with left side somatosensory deficits, and 12 age-matched male control subjects were studied. fMRI was performed with two different paradigms; namely, tactile stimuli and electrical stimulation at acupuncture points LI4 and LI11 on the affected side of the body. fMRI data were analyzed using SPM99. RESULTS: Tactile stimulation in both patients and controls produced significant activation in primary and secondary sensory and motor cortical areas and cerebellum. Greater activation was present in patients than controls in the somatosensory cortex with both the tactile task and the acupuncture point (acupoint) stimulation. Activation was greater during the tactile task than the acupuncture stimulation in patients and normal controls. CONCLUSION: Differences observed between patients and controls on both tasks may indicate compensatory over recruitment of neocortical areas involved in somatosensory perception in the stroke patients. The observed differences between patients and controls on the acupoint stimulation task may also indicate that stimulation of acupoints used therapeutically to enhance recovery from stroke, selectively activates areas thought to be involved in mediating recovery from stroke via functional plasticity. fMRI of acupoint stimulation may illustrate the functional substrate of the therapeutically beneficial effect of acupuncture in stroke rehabilitation.

Acupuncture Therapy↗

Melatonin reduces infarction volume in a photothrombotic stroke model in the wild-type but not cyclooxygenase-1-gene knockout mice.

Cyclooxygenase (COX)-2 plays a harmful role in cerebral ischemic/reperfusion injury, but the role of COX-1 is uncertain. In the present study, cerebral infarct was induced by photothrombosis. Intraperitoneal injections of melatonin at 15 g/kg or its vehicle were made at 0.5 hr before stroke and 24 and 48 hr after stroke. Cerebral blood flow (CBF) in the penumbra was monitored during stroke using a laser Doppler flowmeter. Sensorimotor behavior was evaluated using the turning in an alley and falling from a pole tests at 1 hr before stroke and 24 and 48 hr after stroke. Infarct volume was determined from the T2-weighted magnetic resonance images at 72 hr after stroke. During the first 15 min of stroke, CBF decreased in the penumbra in both homozygous COX-1-gene knockout and wild-type mice. Melatonin treatment improved the penumbral CBF in the wild-type mice. Mild poststroke impairment in sensorimotor behavior was detected by the turning in an alley test in which the COX-1-gene knockout mice performed better. Melatonin treatment did not affect the poststroke sensorimotor behavior. The relative infarct volume at 72 hr after stroke was 8.1% and 8.4% in the COX-1-gene knockout and wild-type mice, respectively. Melatonin treatment reduced the relative infarct volume to 6.3% in the latter but not in the former (8.2%). Thus, COX-1-gene knockout does not affect the brain's susceptibility to photothrombotic stroke. Melatonin treatment reduces infarct size in the wild-type mice following photothrombotic stroke partly via maintenance of penumbral CBF in which the COX-1-gene may play a role.

Animals↗

[Experimental studies on hepatotoxicity of rats induced by Fructus Gardeniae].

OBJECTIVE: To study the hepatotoxicity effects in rats with different extract of Fructus Gardeniae. METHOD: Observe the change of appearance, behavior and weight of rats through oral gavage daily for 3 d. Weigh the liver and calculate the liver index. Detect the ALT, AST and TBIL. Observe the liver tissue by optical microscope. RESULT: The weight and index of liver were increased by 3.08 g x kg(-1) aqueous extract, 1.62 g x kg(-1) alcoholic extract and 0.28 g x kg(-1) geniposide, compared to those of the blank group (P < 0.005, P < 0.001) and the activities of ALT, AST and the content of TBIL were also increased, compared to those of the blank group (P < 0.05, P < 0.001). The liver cells were obviously swell, necrotic and changed with inflammatory infiltrate. CONCLUSION: Aqueous extract, alcoholic extract and geniposide displayed hepatotoxicity, and the geniposide which was the main substance of the Fructus Gardeniae might be mainly responsible for the hepatotoxicity.

Alanine Transaminase↗

Immunotherapeutic potential of DISC-HSV and OX40L in cancer.

Several vectors, viral and bacterial, have been developed over the past few years for means of generating an effective antitumor immune response. We have developed and studied a "model for immunotherapy" using a viral vector disabled infectious single cycle-herpes simplex virus (DISC-HSV), which efficiently transduces various tumor cell lines and offers a useful vehicle for the further development of cell-based vaccines. The immunotherapeutic potential of DISC-HSV encoding granulocyte macrophage colony stimulating factor (GM-CSF) was demonstrated in a number of murine carcinoma models, leading to complete regression of well-established tumors in up to 70% of the mice. Moreover, the therapeutic potential of DISC-HSV-GM-CSF was significantly enhanced when used in combination therapy with either OX40L or dendritic cells (DC), even in a poorly immunogenic tumor model. The ability of this vector to accept large gene inserts, its good safety profile, its ability to undergo only a single round of infection, the inherent viral immunostimulatory properties and its ability to infect various tumor cell lines efficiently, make DISC-HSV an ideal candidate vector for immunotherapy. The DISC- CT-26 tumor model was used to investigate the mechanisms associated with immunotherapy induced tumor rejection. Although CTL induction, was positively correlated with regression, MHC class I down regulation and accumulation of immature Gr1+ myeloid cells were shown to be the main immuno-suppressor mechanisms operating against regression and associated with progressive tumor growth. The CTL response was associated with the immuno-dominant AH-1 peptide of the retroviral glycoprotein gp70. This model of immunotherapy has provided an opportunity to dissect further the immunological events associated with tumor-rejection and escape. Since other antigens may be important in initiating tumor rejection, we have investigated the expression of MTA-1, an antigen that appears to be expressed widely in human and murine tumors. The immunogenicity of MTA-1 was studied and its potential as a tumor rejection antigen is under investigation.

Animals↗

Quantitative measurement of monocyte HLA-DR expression in the identification of early-onset neonatal infection.

BACKGROUND: This study aimed to evaluate the diagnostic utilities of monocyte HLA-DR as an infection marker in the identification of early-onset clinical infection and pneumonia in newborn infants. METHODS: Term newborns in whom infection was suspected when they were <72 h of age were eligible for enrollment in the study. C-reactive protein (CRP), monocyte HLA-DR and neutrophil CD64 expressions were quantitatively measured at the time of sepsis evaluation (0 h) and 24 h afterwards by flow cytometry and standard laboratory method. RESULTS: A total of 288 infants with suspected sepsis were investigated, and 93 were found to be clinically infected. There were no significant differences in monocyte HLA-DR expression between the infected, non-infected and control groups at 0 h (median (interquartile range): 13,986 (10,994-18,544), 14,234 (12,045-17,474) and 18,441 (14,250-21,537) antibody phycoerythrin (PE) molecules bound/cell), and between infected and non-infected infants at 24 h (median (interquartile range): 17,772 (12,933-25,167) and 19,406 (14,885-24,225) antibody PE molecules bound/cell). The areas under the receiver operating characteristics (ROC) curves for HLA-DR, CD64 and CRP were 0.52-0.54, 0.88-0.94 and 0.75-0.77, respectively. We were unable to determine an optimal cutoff value for HLA-DR, as the diagnostic utilities of any cutoff point on the ROC curves were unable to satisfy the criteria (i.e. sensitivity and specificity >or=80%) for consideration as an useful diagnostic marker of infection. CONCLUSIONS: Our findings did not support the use of monocyte HLA-DR alone or in combination with other infection markers in the diagnosis of early-onset clinical infection and pneumonia in term newborns.

Biomarkers↗

Proton-density-weighted spinal fMRI with sensorimotor stimulation at 0.2 T.

Proton-density-weighted fMRI at low field (0.2 T) was carried out in the cervical spinal cord of healthy volunteers in this study to examine the feasibility of detecting proton density alteration accompanying activation in the spinal cord. Subjects were asked to grip both hands simultaneously, providing sensorimotor simulation for spinal fMRI. Over 70% subjects recruited had activation localized at C6-C7 spinal levels with discrete activation detected in both the anterior and posterior horns of the cervical spinal cord, and the average fractional signal change was 4.06%. The 0.2 T low magnetic field and the 24 ms short TE used in this study diminished the BOLD effect to a negligible level, thus the observed signal change was believed to be mainly attributable to proton density increase during neuronal stimulation. Our results suggested the existence of task-driven proton density change in the cervical spinal cord.

Adult↗

Regulation of CTL responses to MHC-restricted class I peptide of the gp70 tumour antigen by splenic parenchymal CD4+ T cells in mice failing immunotherapy with DISC-mGM-CSF.

Direct intratumour injection of the disabled infectious single-cycle-herpes simplex virus-encoding murine granulocyte/macrophage colony-stimulating factor (DISC-HSV-mGM-CSF) into established colon carcinoma CT26 tumours induced complete tumour rejection in up to 70% of treated animals (regressors), while the remaining mice developed progressive tumours (progressors). This murine Balb/c model was used to dissect the cellular mechanisms involved in tumour regression or progression following immunotherapy. CTLs were generated by coculturing lymphocytes and parenchymal cells from the same spleens of individual regressor or progressor animals in the presence of the relevant AH-1 peptide derived from the gp70 tumour-associated antigens expressed by CT26 tumours. Tumour regression was correlated with potent CTL responses, spleen weight and cytokine (IFN-gamma) production. Conversely, progressor splenocytes exhibited weak to no CTL activity and poor IFN-gamma production, concomitant with the presence of a suppressor cell population in the progressor splenic parenchymal cell fraction. Further fractionation of this parenchymal subpopulation demonstrated that cells inhibitory to the activation of AH-1-specific CTLs, restimulated in vitro with peptide, were present in the nonadherent parenchymal fraction. In vitro depletion of progressor parenchymal CD3+/CD4+ T cells restored the CTL response of the cocultured splenocytes (regressor lymphocytes and progressor parenchymal cells) and decreased the production of IL-10, suggesting that CD3+CD4+ T lymphocytes present in the parenchymal fraction regulated the CTL response to AH-1. We examined the cellular responses associated with tumour rejection and progression, identifying regulatory pathways associated with failure to respond to immunotherapy.

Animals↗

Coenzyme Q10 protects SHSY5Y neuronal cells from beta amyloid toxicity and oxygen-glucose deprivation by inhibiting the opening of the mitochondrial permeability transition pore.

Coenzyme Q10 (CoQ10) is an essential biological cofactor which increases brain mitochondrial concentration and exerts neuroprotective effects. In the present study, we exposed SHSY5Y neuroblastoma cells to neurotoxic beta amyloid peptides (Abeta) and oxygen glucose deprivation (OGD) to investigate the neuroprotective effect of 10 microM CoQ10 by measuring (i) cell viability by the MTT assay, (ii) opening of the mitochondrial permeability transition pore via the fluorescence intensity of calcein-AM, and (iii) superoxide anion concentration by hydroethidine. Cell viability (mean +/- S.E.M.) was 55.5 +/- 0.8% in the group exposed to Abeta + OGD, a value lower than that in the Abeta or OGD group alone (P < 0.01). CoQ10 had no neuroprotective effect on cell death induced by either Abeta or OGD, but increased cell survival in the Abeta + OGD group to 57.3 +/- 1.7%, which was higher than in the group treated with vehicle (P < 0.05). The neuroprotective effect of CoQ10 was blocked by administration of 20 microM atractyloside. Pore opening and superoxide anion concentration were increased in the Abeta + OGD group relative to sham control (P < 0.01), and were attenuated to the sham level (P > 0.05) when CoQ10 was administered. Our results demonstrate that CoQ10 protects neuronal cells against Abeta neurotoxicity together with OGD by inhibiting the opening of the pore and reducing the concentration of superoxide anion.

Amyloid beta-Peptides↗

Spinal effects of acupuncture stimulation assessed by proton density-weighted functional magnetic resonance imaging at 0.2 T.

Signal changes can be detected by proton density-weighted functional imaging in both the brain and the spinal cord. These are attributed to changes in extravascular water proton (signal enhancement by extravascular protons) density during neuronal activation. In this study, we used this technique to detect correlations between acupoint stimulation and neural activity in the spinal cord. Stimulation of acupoints associated with treatment of sensorimotor deficits (LI4 and LI11) was performed on 11 volunteers. During stimulation, 8 of the 11 subjects had consistent functional activations in C6/C7. A bilateral activation pattern was common. Our findings show that acupoint stimulation modulates activity in the spinal cord.

Acupuncture↗

Immunity to tumour antigens.

During the last decade, a large number of human tumour antigens have been identified. These antigens are classified as tumour-specific shared antigens, tissue-specific differentiation antigens, overexpressed antigens, tumour antigens resulting from mutations, viral antigens and fusion proteins. Antigens recognised by effectors of immune system are potential targets for antigen-specific cancer immunotherapy. However, most tumour antigens are self-proteins and are generally of low immunogenicity and the immune response elicited towards these tumour antigens is not always effective. Strategies to induce and enhance the tumour antigen-specific response are needed. This review will summarise the approaches to discovery of tumour antigens, the current status of tumour antigens, and their potential application to cancer treatment.

Antigens, Neoplasm↗

Peptide immunisation of HLA-DR-transgenic mice permits the identification of a novel HLA-DRbeta1*0101- and HLA-DRbeta1*0401-restricted epitope from p53.

Because of the central role of CD4(+) T cells in antitumour immunity, the identification of the MHC class II-restricted peptides to which CD4(+) T cells respond has become a priority of tumour immunologists. Here, we describe a strategy permitting us to rapidly determine the immunogenicity of candidate HLA-DR-restricted peptides using peptide immunisation of HLA-DR-transgenic mice, followed by assessment of the response in vitro. This strategy was successfully applied to the reported haemaglutinin influenza peptide HA(307-319), and then extended to three candidate HLA-DR-restricted p53 peptides predicted by the evidence-based algorithm SYFPEITHI to bind to HLA-DRbeta1*0101 (HLA-DR1) and HLA-DRbeta1*0401 (HLA-DR4) molecules. One of these peptides, p53(108-122), consistently induced responses in HLA-DR1- and in HLA-DR4-transgenic mice. Moreover, this peptide was naturally processed by dendritic cells (DCs), and induced specific proliferation in the splenocytes of mice immunised with p53 cDNA, demonstrating that immune responses could be naturally mounted to the peptide. Furthermore, p53(108-122) peptide was also immunogenic in HLA-DR1 and HLA-DR4 healthy donors. Thus, the use of this transgenic model permitted the identification of a novel HLA-DR-restricted epitope from p53 and constitutes an attractive approach for the rapid identification of novel immunogenic MHC class II-restricted peptides from tumour antigens, which can ultimately be incorporated in immunotherapeutic protocols.

Aged↗

Neutrophil CD64 is a sensitive diagnostic marker for early-onset neonatal infection.

This prospective study aimed to evaluate the diagnostic utilities of neutrophil CD64 expression for the identification of early-onset clinical infection and pneumonia in term infants and to define the optimal cutoff value so that it may act as a reference with which future studies can be compared. Term newborns in whom infection was suspected when they were <72 h of age were recruited into the study. C-reactive protein (CRP) and expression of CD64 on neutrophils were measured at 0 h (at the time of sepsis evaluation) and 24 h. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of CRP, CD64, and the combination of these two markers for predicting neonatal sepsis were determined. A total of 338 infants with suspected clinical sepsis were investigated, 115 of whom were found to be clinically infected. CRP and CD64 in infected infants were both significantly elevated at 0 and 24 h compared with noninfected infants (p < 0.001). The calculated optimal cutoff value for CD64 was 6136 antibody-phycoerythrin molecules bound/cell. CD64 has a very high sensitivity (96%) and NPV (97%) at 24 h. The addition of CRP only marginally enhanced the sensitivity and NPV (97 and 98%, respectively). In conclusion, neutrophil CD64 is a very sensitive diagnostic marker for the identification of early-onset clinical infection and pneumonia in term newborns. The results strongly suggest that measurement of neutrophil CD64 may allow neonatal clinicians to discontinue antibiotic treatment at 24 h in infants who are clinically stable and whose CD64 expressions are below the optimal cutoff level.

Age of Onset↗