Genomic Evidence for the Nonpathogenic State in HIV-1-Infected Northern Pig-Tailed Macaques.

HIV-1 is a highly host-specific retrovirus that infects humans but not most nonhuman primates. Thus, the lack of a suitable primate model that can be directly infected with HIV-1 hinders HIV-1/AIDS research. In the previous study, we have found that the northern pig-tailed macaques (NPMs) are susceptible to HIV-1 infection but show a nonpathogenic state. In this study, to understand this macaque-HIV-1 interaction, we assembled a de novo genome and longitudinal transcriptome for this species during the course of HIV-1 infection. Using comparative genomic analysis, a positively selected gene, Toll-like receptor 8, was identified with a weak ability to induce an inflammatory response in this macaque. In addition, an interferon-stimulated gene, interferon alpha inducible protein 27, was upregulated in acute HIV-1 infection and acquired an enhanced ability to inhibit HIV-1 replication compared with its human ortholog. These findings coincide with the observation of persistently downregulated immune activation and low viral replication and can partially explain the AIDS-free state in this macaque following HIV-1 infection. This study identified a number of unexplored host genes that may hamper HIV-1 replication and pathogenicity in NPMs and provided new insights into the host defense mechanisms in cross-species infection of HIV-1. This work will facilitate the adoption of NPM as a feasible animal model for HIV-1/AIDS research.

A Graph Theory Study of Resting-State Functional MRI Connectivity in Children With Carbon Monoxide Poisoning.

BACKGROUND: The effect of carbon monoxide (CO) poisoning on the topology of brain functional networks is unclear, especially in children whose brains are still developing. PURPOSE: To investigate the topological alterations of the whole-brain functional connectome in children with CO poisoning and characterize its relationship with disease severity. STUDY TYPE: Cross-sectional and prospective study. SUBJECTS: A total of 26 patients with CO poisoning and 26 healthy controls. FIELD STRENGTH/SEQUENCE: A 3.0 T MRI system/echo planar imaging (EPI) and 3D brain volume imaging (BRAVO) sequences. ASSESSMENT: We used the network-based statistics (NBS) method to explore between-group differences in functional connectivity strength and a graph-theoretical-based analytic method to explore the topology of brain networks. STATISTICAL TESTS: Student's t-test, chi-square test, NBS, Pearson correlation coefficient, and false discovery rate correction. The statistical significance threshold was set at P < 0.05. RESULTS: The case group's brain functional network topology was impaired in comparison to the control group (reduced global efficiency and small-worldness, increased characteristic path length). According to node and edge analyses, the case group showed topologically damaged regions in the frontal lobe and basal ganglia, as well as neuronal circuits with weaker connections. Also, there was a significant correlation between the patients' coma time and the degree (r = -0.4564), efficiency (r = -0.4625), and characteristic path length (r = 0.4383) of the nodes in the left orbital inferior frontal gyrus. Carbon monoxide hemoglobin content (COHb) concentration and right rolandic operculum node characteristic path length (r = -0.3894) were significantly correlated. The node efficiency and node degree of the right middle frontal gyrus (r = 0.4447 and 0.4539) and right pallidum (r = 0.4136 and 0.4501) significantly correlated with the MMSE score. DATA CONCLUSION: The brain network topology of CO poisoned children is damaged, which is manifested by reduced network integration and may lead to a series of clinical symptoms in patients. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.

Circular RNA PARG adjusts miR-140-3p to influence progression in sepsis.

Sepsis has been characterized as a frequent medical problem with high mortality and severe complication medical problem in the intensive care unit (ICU). Here, qRT-PCR was used to examine circRNA PARG expression levels in patients with sepsis and in human pulmonary microvascular endothelial cells (HPMEC). Lipopolysaccharide (LPS)-simulated HPMEC were hybridized using RNA-Fluorescence in situ hybridization to confirm the location of circRNA PARG and miR-140-3p. The biological role of downregulated circRNA PARGin cellular proliferation, apoptosis, and inflammatory and apoptosis responses was evaluated. performed A dual-luciferase reporter assay was performed to determine the relationship between the circRNA PARG with miR-140-3p. In this study,circRNA PARG aberrant expression was found, and the effects of circRNA PARG on lipopolysaccharide (LPS)-stimulated apoptosis of HPMEC cells were further investigated. Down-regulated circRNA PARG led to significant alleviation of LPS-simulated cell apoptosis via inhibition of inflammatory and apoptosis-related genes, while upregulated circRNA PARG exhibited the opposite effects. Further findings indicated that circRNA PARG positively modulated the relative level of miR-140-3p, which has been confirmed using the luciferase reporter assay. Upregulated circRNA PARG led to a reversal of LPS-simulated cells after transfection of miR-140-3p mimic. In general, a novel insight into understanding the important effects of circRNA PARG in sepsis is provided.

The Efficacy and Safety of Different Noninvasive Therapies in the Treatment of Central Poststroke Pain (CPSP): A Network Meta-Analysis and Systematic Review.

OBJECTIVE: To evaluate the efficacy and safety of noninvasive therapies in the treatment of central poststroke pain (CPSP) by network meta-analysis and to provide an evidence-based basis for clinical practice. METHODS: PubMed, Cochrane Library, EMBASE, CNKI, Wanfang, and VIP were searched for clinical randomized controlled studies on noninvasive therapy for CPSP. The retrieval time limit was from the establishment of each database to July 2022. The bias risk assessment tool recommended by Cochrane was used to evaluate the quality of the included randomized controlled trials (RCTs). Stata 14.0 was used for network meta-analysis, and Review Manager 5.3 software was used for traditional meta-analysis. RESULTS: Twelve RCTs involving 8 treatment schemes and 641 patients were finally included. The results of the network meta-analysis showed the following rankings in visual analysis scale (VAS): super laser injury on stellate ganglia (SLI) > transcranial direct current stimulation (tDCS) > music therapy (MT) > repetitive transcranial magnetic stimulation (rTMS) > continuous theta burst stimulation (cTBS) > transcutaneous acupoint electrical stimulation (TAES) > common therapy (CT). The total clinical efficiency ranked as follows: psychological training of mindfulness (PT) > rTMS > CT. Clinical adverse reactions ranked as follows: rTMS > MT > CT > SLI. CONCLUSIONS: Noninvasive complementary therapy can effectively alleviate the pain of CPSP patients, and the efficacy and safety of SLI are relatively significant. However, due to the limitations of this study, the efficacy ranking cannot fully explain the advantages and disadvantages of clinical efficacy. In the future, more multicentre, large sample, double-blind clinical randomized controlled trials are needed to supplement and demonstrate the results of this study.

Real-Time Target Detection System for Intelligent Vehicles Based on Multi-Source Data Fusion.

To improve the identification accuracy of target detection for intelligent vehicles, a real-time target detection system based on the multi-source fusion method is proposed. Based on the ROS melodic software development environment and the NVIDIA Xavier hardware development platform, this system integrates sensing devices such as millimeter-wave radar and camera, and it can realize functions such as real-time target detection and tracking. At first, the image data can be processed by the You Only Look Once v5 network, which can increase the speed and accuracy of identification; secondly, the millimeter-wave radar data are processed to provide a more accurate distance and velocity of the targets. Meanwhile, in order to improve the accuracy of the system, the sensor fusion method is used. The radar point cloud is projected onto the image, then through space-time synchronization, region of interest (ROI) identification, and data association, the target-tracking information is presented. At last, field tests of the system are conducted, the results of which indicate that the system has a more accurate recognition effect and scene adaptation ability in complex scenes.

Tree Shrew Cells Transduced with Human CD4 and CCR5 Support Early Steps of HIV-1 Replication, but Viral Infectivity Is Restricted by APOBEC3.

The host range of human immunodeficiency virus type 1 (HIV-1) is narrow. Therefore, using ordinary animal models to study HIV-1 replication, pathogenesis, and therapy is impractical. The lack of applicable animal models for HIV-1 research spurred our investigation on whether tree shrews (Tupaia belangeri chinensis), which are susceptible to many types of human viruses, can act as an animal model for HIV-1. Here, we report that tree shrew primary cells are refractory to wild-type HIV-1 but support the early replication steps of HIV-1 pseudotyped with the vesicular stomatitis virus glycoprotein envelope (VSV-G), which can bypass entry receptors. The exogenous expression of human CD4 renders the tree shrew cell line infectible to X4-tropic HIV-1IIIB, suggesting that tree shrew CXCR4 is a functional HIV-1 coreceptor. However, tree shrew cells did not produce infectious HIV-1 progeny virions, even with the human CD4 receptor. Subsequently, we identified tree shrew (ts) apolipoprotein B editing catalytic polypeptide 3 (tsAPOBEC3) proteins as active inhibitors of HIV-1 particle infectivity, with virus infectivity reduced 10- to 1,000-fold. Unlike human APOBEC3G, the tsA3Z2c-Z1b protein was not degraded by the HIV-1 viral infectivity factor (Vif) but markedly restricted HIV-1 replication through mutagenicity and reverse transcription inhibition. The pooled knockout of tsA3Z2c-Z1b partially restored the infectivity of the HIV-1 progeny. This work suggests that tsAPOBEC3 proteins serve as an additional barrier to the development of HIV-1 tree shrew models, even when virus entry is overcome by exogenous expression of human CD4. IMPORTANCE The development of animal models is critical for studying human diseases and their pathogenesis and for evaluating drug and vaccine efficacy. For improved AIDS research, the ideal animal model of HIV-1 infection should be a small laboratory mammal that closely mimics virus replication in humans. Tree shrews exhibit considerable potential as animal models for the study of human diseases and therapeutic responses. Here, we report that human CD4-expressing tree shrew cells support the early steps of HIV-1 replication and that tree shrew CXCR4 is a functional coreceptor of HIV-1. However, tree shrew cells harbor additional restrictions that lead to the production of HIV-1 virions with low infectivity. Thus, the tsAPOBEC3 proteins are partial barriers to developing tree shrews as an HIV-1 model. Our results provide insight into the genetic basis of HIV inhibition in tree shrews and build a foundation for the establishment of gene-edited tree shrew HIV-1-infected models.

Northern pig-tailed macaques (Macaca leonina) maintain superior CD4+ T-cell homeostasis during SIVmac239 infection.

Gradual depletion of CD4+ T cells is a typical characteristic of pathogenic SIV infection. Intriguingly, we find a spontaneous CD4+ T-cell homeostasis in northern pig-tailed macaques (Macaca leonina) during SIVmac239 infection.

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells.

Alternative splicing occurs frequently in many genes, especially those involved in immunity. Unfortunately, the functions of many alternatively spliced molecules from immunologically relevant genes remain unknown. Classical HLA-I molecules are expressed on almost all nucleated cells and play a pivotal role in both innate and adaptive immunity. Although splice variants of HLA-I genes have been reported, the details of their functions have not been reported. In the current study, we determined the characteristics, expression, and function of a novel splice variant of HLA-A11 named HLA-A11svE4 HLA-A11svE4 is located on the cell surface without ß2-microglobulin (ß2m). Additionally, HLA-A11svE4 forms homodimers as well as heterodimers with HLA-A open conformers, instead of combining with ß2m. Moreover, HLA-A11svE4 inhibits the activation of NK cells to protect target cells. Compared with ß2m and HLA-A11, the heterodimer of HLA-A11svE4 and HLA-A11 protected target cells from lysis by NK cells more effectively. Furthermore, HLA-AsvE4 expression was upregulated by HIV-1 in vivo and by HSV, CMV, and hepatitis B virus in vitro. In addition, our findings indicated that HLA-A11svE4 molecules were functional in activating CD8+ T cells through Ag presentation. Taken together, these results suggested that HLA-A11svE4 can homodimerize and form a novel heterodimeric complex with HLA-A11 open conformers. Furthermore, the data are consistent with HLA-A11svE4 playing a role in the immune escape of HIV-1.

Predict disease progression from T-cell phenotypes in northern pig-tailed macaques (Macaca leonina) during SIVmac239 infection.

Macaca leonina (northern pig-tailed macaques, NPMs) have variable disease progression during SIVmac239 infection. In the present study, we analysed, for the first time, the correlations between T-cell phenotypes and disease progression in NPMs during SIVmac239 infection. In comparison to normal progressors (NPs), slow progressors (SPs) had lower chronic T-cell activation and exhaustion levels. In addition, SPs showed higher peripheral CD4+ T-cell count and CD4 : CD8 ratio, and lower plasma viral load than NPs. CD4+ T-cell count and CD4 : CD8 ratio decreased more sharply in NPs than in SPs. Furthermore, T cells in NPs were more highly differentiated, at least in acute infection, than in SPs. These results indicated that T-cell phenotypes were correlated with disease progression in SIVmac239-infected NPMs and these correlations may provide valuable guidance for the improvement of therapeutic strategies tested in NPMs.

Translocation of microbes and changes of immunocytes in the gut of rapid- and slow-progressor Chinese rhesus macaques infected with SIVmac239.

Human/simian immunodeficiency virus (HIV/SIV) infection can cause severe depletion of CD4(+) T cells in both plasma and mucosa; it also results in damage to the gut mucosa barrier, which makes the condition more conducive to microbial translocation. In this study, we used SIV-infected Chinese rhesus macaques to quantify the extent of microbial translocation and the function of immune cells in the entire gastrointestinal tract and to compare their differences between rapid and slow progressors. The results showed that in the slow progressors, microbial products translocated considerably and deeply into the lamina propria of the gut; the tissue macrophages had no significant differences compared with the rapid progressors, but there was a slightly higher percentage of mucosal CD8(+) T cells and a large amount of extracellular microbial products in the lamina propria of the intestinal mucosa of the slow progressors. The data suggested that although microbial translocation increased markedly, the mucosal macrophages and CD8(+) T cells were insufficient to clear the infiltrated microbes in the slow progressors. Also, therapies aimed at suppressing the translocation of microbial products in the mucosa could help to delay the progression of SIV disease.

Independent birth of a novel TRIMCyp in Tupaia belangeri with a divergent function from its paralog TRIM5.

The origin of novel genes and their evolutionary fates are long-standing questions in evolutionary biology. These questions become more complicated for genes conserved across various lineages, such as TRIM5, an antiretroviral restriction factor and a retrovirus capsid sensor in immune signaling. TRIM5 has been subjected to numerous pathogenic challenges and undergone dynamic evolution, making it an excellent example for studying gene diversification. Previous studies among several species showed that TRIM5 gained genetic and functional novelty in a lineage-specific manner, either through gene duplication or a cyclophilin A retrotransposing into the TRIM5 locus, creating the gene fusion known as TRIM5-Cyclophilin A (TRIMCyp). To date, the general pattern of TRIM5 across the mammalian lineage remains elusive. In this study, we surveyed 36 mammalian genomes to verify a potentially novel TRIM5 pattern that uniquely seems to have occurred in tree shrews (Tupaia belangeri), and found that both gene duplication and retrotransposition worked jointly to form a specific TRIM5/TRIMCyp cluster not found among other mammals. Evolutionary analyses showed that tree shrew TRIMCyp (tsTRIMCyp) originated independently in comparison with previously reported TRIMCyps and underwent strong positive selection, whereas no signal of positive selection was detected for other tree shrew TRIM5 (tsTRIM5) genes. Functional assay results suggest a functional divergence between tsTRIMCyp and its closest paralog TRIM5-4, likely reflecting different fates under diverse evolutionary forces. These findings present a rare example of novel gene origination resulting from a combination of gene duplication, retrotransposition, and exon shuffling processes, providing a new paradigm to study genetic innovations and evolutionary fates of duplicated genes.

High immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected Chinese rhesus macaques.

Chinese rhesus macaques (CRMs) are ideal experimental animals for studying the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and for vaccine research. SHIV89.6 has been reported to be an attenuated virus because, in most cases, SHIV89.6 infection only causes limited alteration of immune cells and tissues, and it has been used commonly for vaccine research. After two serial passages in vivo, SHIV (SHIV-89.6P) induces CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections. However, the pathogenic ability of SHIV89.6 is not well understood. In this study, we found that 6 of 14 SHIV89.6-infected CRMs died within 127 weeks after infection. We found especially high immune activation, low IFN-α expression, and distinctive cytokine expression profiles in the infected and dead (ID) group of monkeys, while there was only few change in the CD4(+) T counts and distribution of T cell subsets in the ID group monkeys. Also, there was a similar dynamic of viral load between infected and surviving (IS) and ID group monkeys. Furthermore, we found various correlations among immune activation, IFN-α expression, and frequencies of cytokine-secreting cells. These results suggest that SHIV89.6 infections have pathogenic potential in CRMs and that high immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected CRMs. This also implies that high immune activation may be relevant to dysfunction of immune cells. It is proposed that high immune activation and dysfunction of immune cells may be good predictors for disease progression and markers for therapy.

Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models.

The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019 (COVID-19) immunobiology, often resulting in a lack of reproducibility when extrapolated to the whole organism. Consequently, developing animal models is imperative for a comprehensive understanding of the pathology and immunology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This review summarizes current progress related to COVID-19 animal models, including non-human primates (NHPs), mice, and hamsters, with a focus on their roles in exploring the mechanisms of immunopathology, immune protection, and long-term effects of SARS-CoV-2 infection, as well as their application in immunoprevention and immunotherapy of SARS-CoV-2 infection. Differences among these animal models and their specific applications are also highlighted, as no single model can fully encapsulate all aspects of COVID-19. To effectively address the challenges posed by COVID-19, it is essential to select appropriate animal models that can accurately replicate both fatal and non-fatal infections with varying courses and severities. Optimizing animal model libraries and associated research tools is key to resolving the global COVID-19 pandemic, serving as a robust resource for future emerging infectious diseases.

Dynamic Dysregulation of the Triple Network of the Brain in Mild Traumatic Brain Injury and Its Relationship With Cognitive Performance.

A triple network model consisting of a default network, a salience network, and a central executive network has recently been used to understand connectivity patterns in cognitively normal versus dysfunctional brains. This study aimed to explore changes in the dynamic connectivity of triplet network in mild traumatic brain injury (mTBI) and its relationship to cognitive performance. In this work, we acquired resting-state functional magnetic resonance imaging (fMRI) data from 30 mTBI patients and 30 healthy controls (HCs). Independent component analysis, sliding time window correlation, and k-means clustering were applied to resting-state fMRI data. Further, we analyzed the relationship between changes in dynamic functional connectivity (FC) parameters and clinical variables in mTBI patients. The results showed that the dynamic functional connectivity of the brain triple network was clustered into five states. Compared with HC, mTBI patients spent longer in state 1, which is characterized by weakened dorsal default mode network (DMN) and anterior salience network (SN) connectivity, and state 3, which is characterized by a positive correlation between DMN and SN internal connectivity. Mild TBI patients had fewer metastases in different states than HC patients. In addition, the mean residence time in state 1 correlated with Montreal Cognitive Assessment scores in mTBI patients; the number of transitions between states correlated with Glasgow Coma Score in mTBI patients. Taken together, our findings suggest that the dynamic properties of FC in the triple network of mTBI patients are abnormal, and provide a new perspective on the pathophysiological mechanism of cognitive impairment from the perspective of dynamic FC.

Nonnegligible Contribution of Nonlymphoid Tissue to Viral Reservoir During the Short-Term Early cART in SIVmac239-Infected Chinese Rhesus Macaques.

HIV/AIDS cannot be cured because of the persistence of the viral reservoir. Because of the complexity of the cellular composition and structure of the human organs, HIV reservoirs of anatomical site are also complex. Recently, although a variety of molecules have been reported to be involved in the establishment and maintenance of the viral reservoirs, or as marker of latent cells, the research mainly focuses on blood and lymph nodes. Now, the characteristics of the viral reservoir in tissue are not yet fully understood. In this study, various tissues were collected from SIVmac239-infected monkeys, and the level of total SIV DNA, SIV 2-LTR DNA, and cell-associated virus RNA in them were compared with character of the anatomical viral reservoir under early treatment. The results showed that short-term combination antiretroviral therapy (cART) starting from 3 days after infection could significantly inhibit viremia and reduce the size of the anatomical viral reservoir, but it could not eradicate de novo infections and ongoing replication of virus. Moreover, the effects of early cART on the level of total SIV DNA, SIV 2-LTR DNA, and cell-associated virus RNA in different tissues were different, which changed the size distribution of viral reservoir in anatomical site. Finally, the contribution of nonlymphoid tissues, especially liver and lung, to the viral reservoir increased after treatment, while the contribution of intestinal lymphoid to the viral reservoir significantly reduced. These results suggested that early treatment effectively decreased the size of viral reservoir, and that the effects of cART on the tissue viral reservoir varied greatly by tissue type. The results implied that persistent existence of virus in nonlymphoid tissues after short-term treatment suggested that the role of nonlymphoid tissues cannot be ignored in development strategies for AIDS therapy.

Treatment outcomes amongst older people with HIV infection receiving antiretroviral therapy.

OBJECTIVES: There is conflicting data regarding the response of older people with HIV (PWH) to antiretroviral therapy (ART). The objective of this study was to evaluate the long-term immunological and virological responses, changes in regimen, and adverse drug reactions (ADRs) in older participants (50+ years) compared with younger (18-34 years) and middle-aged (35-49 years) PWH. METHODS: A retrospective review of medical records was conducted on 1622 participants who received ART in Yunnan Province, China, from 2010 to 2019. The study compared CD4+ T-cell counts, CD4+/CD8+ ratio, and relative numbers between different groups using the Kruskal-Wallis test. Cox proportional hazards regression models were used to identify variables associated with the occurrence of immune reconstitution insufficiency. The rates of immune reconstitution, incidence of ADRs, and rates of treatment change were analyzed using the chi-squared test or Fisher's exact test. RESULTS: Over 95% achieved viral load 200 copies/ml or less, with no age-related difference. However, older participants exhibited significantly lower CD4+ T-cell counts and CD4+/CD8+ recovery post-ART (P < 0.001), with only 32.21% achieving immune reconstitution (compared with young: 52.16%, middle-aged: 39.29%, P < 0.001) at the end of follow-up. Middle-aged and elderly participants changed ART regimens more because of ADRs, especially bone marrow suppression and renal dysfunction. CONCLUSION: Although the virological response was consistent across age groups, older individuals showed poorer immune responses and higher susceptibility to side effects. This underscores the need for tailored interventions and comprehensive management for older patients with HIV.

Imaging of nerve injury in neonatal acute bilirubin encephalopathy using 1H-MRS and Glu-CEST techniques.

Objectives: To investigate the significance of proton magnetic resonance spectroscopy (1H-MRS) and glutamate chemical exchange saturation transfer (Glu-CEST) techniques in assessing the condition and prognosis of acute bilirubin encephalopathy patients and to understand the mechanism of nerve injury in this disease. Materials and methods: From September 2019 to February 2021, 31 neonates with acute bilirubin encephalopathy and 16 healthy neonates were enrolled in this study. All the quantitative results of 1H-MRS, Glu-CEST, and conventional magnetic resonance imaging (MRI) of all neonates were analyzed. The associations between statistically significant indicators of imaging and developmental quotients (DQ) were analyzed. Results: The 31 cases were assigned to the mild subgroup (n = 21) and moderate and severe subgroup (n = 10) according to the bilirubin-induced neurologic dysfunction (BIND) scores. The case group had elevated Cho and GABA absolute concentrations compared to the normal control group (all p < 0.05). Compared with the normal control group, the absolute concentration of GABA of the moderate and severe subgroup was significantly larger (p < 0.05). Compared with the normal control group, the Glu-CEST% values in the left basal ganglia, right thalamus, left frontal cortex and bilateral medial geniculate body of the case group was significantly larger (all p < 0.05). The moderate and severe subgroup had higher Glu-CEST% values in the left basal ganglia, right thalamus, and bilateral medial geniculate body than the normal control group (all p < 0.05). A negative association was revealed between the DQ scores and the Glu-CEST% values in the left basal ganglia (r = -0.888, p < 0.05). Conclusion: The combination of 1H-MRS and Glu-CEST techniques can monitor the intracerebral metabolite level of acute bilirubin encephalopathy and evaluate the illness severity.

Imaging of glutamate in acute carbon monoxide poisoning using chemical exchange saturation transfer.

Aims: This study adopted the Glutamate Chemical Exchange Saturation Transfer (GluCEST) imaging technique to quantitatively analyze cranial glutamate and discussed the effectiveness of GluCEST values in identifying the pathogenesis of encephalopathy after CO poisoning. Methods: The routine MRI and functional MRI scans of two cohorts of subjects (CO group, n = 29; Control group, n = 21) were performed. Between-group comparisons were conducted for GluCEST% in regions of interest (ROI), including the basal ganglia, the thalamus, the frontal lobe, the occipital lobe, the genu of corpus callosum, the cingulate gyrus, and the cuneus. Moreover, an age-stratified subgroup analysis was devised, and a correlational analysis was performed for GluCEST% in each ROI, including the time in coma, Simple Mini-Mental State Examination Scale (MMSE) score, Hamilton Anxiety Scale score, and blood COHb%. Results: As compared to the healthy control, the CO group led to significantly increasing GluCEST% in the basal ganglia, the occipital lobe, the genu of the corpus callosum, the cingulate gyrus, and the cuneus (p < 0.05). In the subgroup analysis for age, adult patients had higher GluCEST% in the basal ganglia, the thalamus, the occipital lobe, the cingulate gyrus, and the cuneus compared to healthy adults (p < 0.05). In addition, the correlational analysis of CO-poisoned patients revealed a statistical association between the GluCEST% and the MMSE in the thalamus and the genu of the corpus callosum. Conclusion: The GluCEST technique is superior to routine MRI in that it can identify the cerebral biochemical changes sooner after acute CO poisoning, which is significant for our understanding of the role of neurotransmitters in the pathological basis of this disease. Brain injury caused by CO poisoning may be different in adults and children.

Extracellular vesicles mediate antibody-resistant transmission of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Antibody resistance dampens neutralizing antibody therapy and threatens current global Coronavirus (COVID-19) vaccine campaigns. In addition to the emergence of resistant SARS-CoV-2 variants, little is known about how SARS-CoV-2 evades antibodies. Here, we report a novel mechanism of extracellular vesicle (EV)-mediated cell-to-cell transmission of SARS-CoV-2, which facilitates SARS-CoV-2 to escape from neutralizing antibodies. These EVs, initially observed in SARS-CoV-2 envelope protein-expressing cells, are secreted by various SARS-CoV-2-infected cells, including Vero E6, Calu-3, and HPAEpiC cells, undergoing infection-induced pyroptosis. Various SARS-CoV-2-infected cells produce similar EVs characterized by extra-large sizes (1.6-9.5 µm in diameter, average diameter > 4.2 µm) much larger than previously reported virus-generated vesicles. Transmission electron microscopy analysis and plaque assay reveal that these SARS-CoV-2-induced EVs contain large amounts of live virus particles. In particular, the vesicle-cloaked SARS-CoV-2 virus is resistant to neutralizing antibodies and able to reinfect naïve cells independent of the reported receptors and cofactors. Consistently, the constructed 3D images show that intact EVs could be taken up by recipient cells directly, supporting vesicle-mediated cell-to-cell transmission of SARS-CoV-2. Our findings reveal a novel mechanism of receptor-independent SARS-CoV-2 infection via cell-to-cell transmission, provide new insights into antibody resistance of SARS-CoV-2 and suggest potential targets for future antiviral therapeutics.

Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection.

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.