Adaptive Immune Deficiency Impairs Neural Activity After Training and Retrieval.

Neuroimmune interactions have been studied for decades. Several neurodevelopmental disorders have been associated with immune dysfunction. However, the effects of immune system on neuronal function remain unknown. Herein, based on c-Fos protein expression, we characterized the brain areas that are activated after contextual fear conditioning (CFC) training or retrieval in severe combined immune deficiency (SCID) and wild-type mice. Further, we analyzed the interregional correlations of c-Fos activity that are affected by deficiency in adaptive immunity. Results showed significantly lower c-Fos density in learning and memory-associated brain regions of SCID mice after memory retrieval, but not during the CFC training. Moreover, SCID mice exhibited remarkably discordant interregional neuronal activities of learning neuron circuits after CFC training, which could be the cause of inefficient activation of the memory circuit after retrieval. These results provide a new perspective on how adaptive immunity affects neuronal function. Adaptive immune deficiency impairs the coordination of neural activity after training and retrieval, which might be a potential therapeutic target for neurodevelopmental disorders.

GABAergic neuronal IL-4R mediates T cell effect on memory.

Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying T cell effects on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long-term potentiation. Severe combined immune-deficient mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. Behaviors impacted by T cells were mediated via IL-4 receptors expressed on neurons. Exploration of snRNA-seq of neurons participating in memory processing provided insights into synaptic organization and plasticity-associated pathways regulated by immune cells. IL-4Rα knockout in inhibitory (but not in excitatory) neurons was sufficient to impair contextual fear memory, and snRNA-seq from these mice pointed to IL-4-driven regulation of synaptic function in promoting memory. These findings provide new insights into complex neuroimmune interactions at the transcriptional and functional levels in neurons under physiological conditions.

Clinical manifestations of blood cell parameters and inflammatory factors in 92 patients with COVID-19.

BACKGROUND: Although there are many COVID-19 case series studies, few studies report the relationship between variations in blood cell parameters and inflammatory factors and disease severity. This study aims to describe the dynamic trends in COVID-19 blood cell parameters and inflammatory factors. METHODS: Ninety-two patients with confirmed COVID-19 at Jingzhou Central Hospital, Hubei Province, China, between January 23, 2020, and April 10, 2020, were enrolled. Epidemiological data, clinical information, and laboratory test results were collected and analyzed. RESULTS: As patient age increased, disease severity increased (P<0.0001). The inflammatory factor C-reactive protein (CRP) showed a gradual increasing trend with disease aggravation. Based on dynamic change graphs, CRP in all patients with severe and critical COVID-19 initially increased and then decreased; however, CRP in patients with a good prognosis did not increase again after the initial decline (<20 mg/L). CRP in patients with a poor prognosis returned to a high level (>50 mg/L) 1 week after the initial decrease and continued to fluctuate at a high level. Lymphocyte count (LYM#) in patients with severe and critical disease was significantly lower (<1×109/L) than that in patients with moderate disease; LYM# was significantly increased 3 weeks after disease onset in patients with a good prognosis (>1×109/L), but patients with a poor prognosis continued to have a low LYM#. CONCLUSIONS: CRP and LYM# showed strong correlation with disease progression, suggesting that these parameters could be used to monitor changes in patient condition.

Red cell distribution width (RDW): a prognostic indicator of severe COVID-19.

BACKGROUND: The global mortality rate for coronavirus disease 2019 (COVID-19) is 3.68%, but the mortality rate for critically ill patients is as high as 50%. Therefore, the exploration of prognostic predictors for patients with COVID-19 is vital for prompt clinical intervention. Our study aims to explore the predictive value of hematological parameters in the prognosis of patients with severe COVID-19. METHODS: Ninety-eight patients who were diagnosed with COVID-19 at Jingzhou Central Hospital and Central Hospital of Wuhan, Hubei Province, were included in this study. RESULTS: The median age of the patients was 59 [28-80] years; the median age of patients with a good prognosis was 56 [28-79] years, and the median age of patients with a poor outcome was 67 [35-80] years. The patients in the poor outcome group were older than the patients in the good outcome group (P<0.05). The comparison of hematological parameters showed that lymphocyte count (Lym#), red blood cells (RBCs), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were significantly lower in the poor outcome group than in the good outcome group (P<0.05). Further, the red cell volume distribution width-CV (RDW-CV) and red cell volume distribution width-SD (RDW-SD) were significantly higher in the poor outcome group than in the good outcome group (P<0.0001). Receiver operating characteristic (ROC) curves showed RDW-SD, with an area under the ROC curve (AUC) of 0.870 [95% confidence interval (CI) 0.796-0.943], was the most significant single parameter for predicting the prognosis of severe patients. When the cut-off value was 42.15, the sensitivity and specificity of RDW-SD for predicting the prognosis of severe patients were 73.1% and 80.2%, respectively. Reticulocyte (RET) channel results showed the RET level was significantly higher in critical patients than in moderate patients and severe patients (P<0.05), which may be one cause of the elevated RDW in patients with a poor outcome. CONCLUSIONS: In this study, the hematological parameters of COVID-19 patients were statistically analyzed. RDW was found to be a prognostic predictor for patients with severe COVID-19, and the increase in RET may contribute to elevated RDW.

Preliminary study to identify severe from moderate cases of COVID-19 using combined hematology parameters.

BACKGROUND: The third fatal coronavirus is the novel coronavirus (SARS-CoV-2) that causes novel coronavirus pneumonia (COVID-19) which first broke out in December 2019. Patients will develop rapidly if there is no any intervention, so the risk identification of severe patients is critical. The aim of this study was to investigate the characteristics and rules of hematology changes in patients with COVID-19, and to explore the possibility differentiating moderate and severe patients using conventional hematology parameters or combined parameters. METHODS: The clinical data of 45 moderate and severe type patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Jingzhou Central Hospital from January 23 to February 13, 2020 were collected. The epidemiological indexes, clinical symptoms, and laboratory test results of the patients were retrospectively analyzed. Those parameters with significant differences between moderate and severe cases were analyzed, and the combination parameters with the best diagnostic performance were selected using the linear discriminant analysis (LDA) method. RESULTS: Of the 45 patients with the novel 2019 corona virus (COVID-19) (35 moderate and 10 severe cases), 23 were male and 22 were female, with ages ranging from 16 to 62 years. The most common clinical symptoms were fever (89%) and dry cough (60%). As the disease progressed, white blood cell count (WBC), neutrophil count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), red blood cell distribution width-coefficient of variation (RDW-CV), and red cell volume distribution width-standard deviation (RDW-SD) parameters in the severe group were significantly higher than those in the moderate group (P<0.05); meanwhile, lymphocyte count (Lym#), eosinophil count (Eos#), high fluorescent cell percentage (HFC%), red blood cell count (RBC), hemoglobin (HGB), and hematocrit (HCT) parameters in the severe group were significantly lower than those in the moderate group (P<0.05). For NLR parameter, it's area under the curve (AUC), cutoff, sensitivity and specificity were 0.890, 13.39, 83.3% and 82.4% respectively; meanwhile, for PLR parameter, it's AUC, cutoff, sensitivity and specificity were 0.842, 267.03, 83.3% and 74.0% respectively. The combined parameters of NLR and RDW-SD had the best diagnostic efficiency (AUC =0.938), and when the cutoff value was 1.046, the sensitivity and the specificity were 90.0% and 84.7% respectively, followed by the combined parameter NLR&RDW-CV (AUC =0.923). When the cut-off value was 0.62, the sensitivity and the specificity for distinguishing severe type from moderate cases of COVID-19 were 90.0% and 82.4% respectively. CONCLUSIONS: The combined NLR and RDW-SD parameter is the best hematology index. It may help clinicians to predict the severity of COVID-19 patients and can be used as a useful indicator to help prevent and control the epidemic.

The Meningeal Lymphatic System: A New Player in Neurophysiology.

The nature of fluid dynamics within the brain parenchyma is a focus of intensive research. Of particular relevance is its participation in diseases associated with protein accumulation and aggregation in the brain, such as Alzheimer's disease (AD). The meningeal lymphatic vessels have recently been recognized as an important player in the complex circulation and exchange of soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). In aging mammals, for example, impaired functioning of the meningeal lymphatic vessels can lead to accelerated accumulation of toxic amyloid beta protein in the brain parenchyma, thus aggravating AD-related pathology. Given that meningeal lymphatic vessels are functionally linked to paravascular influx/efflux of the CSF/ISF, and in light of recent findings that certain cytokines, classically perceived as immune molecules, exert neuromodulatory effects, it is reasonable to suggest that the activity of meningeal lymphatics could alter the accessibility of CSF-borne immune neuromodulators to the brain parenchyma, thereby altering their effects on the brain. Accordingly, in this Perspective we propose that the meningeal lymphatic system can be viewed as a novel player in neurophysiology.

Dendritic mitoflash as a putative signal for stabilizing long-term synaptic plasticity.

Mitochondrial flashes (mitoflashes) are recently discovered excitable mitochondrial events in many cell types. Here we investigate their occurrence in the context of structural long-term potentiation (sLTP) at hippocampal synapses. At dendritic spines stimulated by electric pulses, glycine, or targeted glutamate uncaging, induction of sLTP is associated with a phasic occurrence of local, quantized mitochondrial activity in the form of one or a few mitoflashes, over a 30-min window. Low-dose nigericin or photoactivation that elicits mitoflashes stabilizes otherwise short-term spine enlargement into sLTP. Meanwhile, scavengers of reactive oxygen species suppress mitoflashes while blocking sLTP. With targeted photoactivation of mitoflashes, we further show that the stabilization of sLTP is effective within the critical 30-min time-window and a spatial extent of ~2 µm, similar to that of local diffusive reactive oxygen species. These findings indicate a potential signaling role of dendritic mitochondria in synaptic plasticity, and provide new insights into the cellular function of mitoflashes.Mitoflashes are dynamic events in mitochondria, associated with depolarization and release of reactive oxygen species, and have been associated with several cellular functions. The authors now show that in neurons, dendritic mitoflashes are involved in structural postsynaptic changes during LTP.

Alteration of N-glycan expression profile and glycan pattern of glycoproteins in human hepatoma cells after HCV infection.

BACKGROUND: Hepatitis C virus (HCV) infection causes chronic liver diseases, liver fibrosis and even hepatocellular carcinoma (HCC). However little is known about any information of N-glycan pattern in human liver cell after HCV infection. METHODS: The altered profiles of N-glycans in HCV-infected Huh7.5.1 cell were analyzed by using mass spectrometry. Then, lectin microarray, lectin pull-down assay, reverse transcription-quantitative real time PCR (RT-qPCR) and western-blotting were used to identify the altered N-glycosylated proteins and glycosyltransferases. RESULTS: Compared to uninfected cells, significantly elevated levels of fucosylated, sialylated and complex N-glycans were found in HCV infected cells. Furthermore, Lens culinaris agglutinin (LCA)-binding glycoconjugates were increased most. Then, the LCA-agarose was used to precipitate the specific glycosylated proteins and identify that fucosylated modified annexin A2 (ANXA2) and heat shock protein 90 beta family member 1 (HSP90B1) was greatly increased in HCV-infected cells. However, the total ANXA2 and HSP90B1 protein levels remained unchanged. Additionally, we screened the mRNA expressions of 47 types of different glycosyltransferases and found that α1,6-fucosyltransferase 8 (FUT8) was the most up-regulated and contributed to strengthen the LCA binding capability to fucosylated modified ANXA2 and HSP90B1 after HCV infection. CONCLUSIONS: HCV infection caused the altered N-glycans profiles, increased expressions of FUT8, fucosylated ANXA2 and HSP90B1 as well as enhanced LCA binding to Huh7.5.1. GENERAL SIGNIFICANCE: Our results may lay the foundation for clarifying the role of N-glycans and facilitate the development of novel diagnostic biomarkers and therapeutic targets based on the increased FUT8, fucosylated ANXA2 and HSP90B1 after HCV infection.

Hydroxysafflor Yellow A Protects Neurons From Excitotoxic Death through Inhibition of NMDARs.

Excessive glutamate release causes overactivation of N-methyld-aspartate receptors (NMDARs), leading to excitatory neuronal damage in cerebral ischemia. Hydroxysafflor yellow A (HSYA), a compound extracted from Carthamus tinctorius L., has been reported to exert a neuroprotective effect in many pathological conditions, including brain ischemia. However, the underlying mechanism of HSYA's effect on neurons remains elusive. In the present study, we conducted experiments using patch-clamp recording of mouse hippocampal slices. In addition, we performed Ca(2+) imaging, Western blots, as well as mitochondrial-targeted circularly permuted yellow fluorescent protein transfection into cultured hippocampal neurons in order to decipher the physiological mechanism underlying HSYA's neuroprotective effect.Through the electrophysiology experiments, we found that HSYA inhibited NMDAR-mediated excitatory postsynaptic currents without affecting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and γ-aminobutyric acid A-type receptor-mediated currents. This inhibitory effect of HSYA on NMDARs was concentration dependent. HSYA did not show any preferential inhibition of either N-methyld-aspartate receptor subtype 2A- or N-methyld-aspartate receptor subtype 2B- subunit-containing NMDARs. Additionally, HSYA exhibits a facilitatory effect on paired NMDAR-mediated excitatory postsynaptic currents. Furthermore, HSYA reduced the magnitude of NMDAR-mediated membrane depolarization currents evoked by oxygen-glucose deprivation, and suppressed oxygen-glucose deprivation-induced and NMDAR-dependent ischemic long-term potentiation, which is believed to cause severe reperfusion damage after ischemia. Through the molecular biology experiments, we found that HSYA inhibited the NMDA-induced and NMDAR-mediated intracellular Ca(2+)concentration increase in hippocampal cultures, reduced apoptotic and necrotic cell deaths, and prevented mitochondrial damage. Together, our data demonstrate for the first time that HSYA protects hippocampal neurons from excitotoxic damage through the inhibition of NMDARs. This novel finding indicates that HSYA may be a promising pharmacological candidate for the treatment of brain ischemia.