Analysis of Factors Related to the Efficacy of Consciousness-regaining Therapy for Prolonged Disorder of Consciousness: A Retrospective Cohort Study.

OBJECTIVE: To analyse the factors related to the efficacy of consciousness-regaining therapy for prolonged disorder of consciousness. METHODS: A retrospective analysis was conducted on the case data of 114 patients with pDOC admitted to the Department of Functional Neurosurgery of Tianjin Huanhu Hospital from January 2019 to January 2022 to explore the relevant factors that affect the efficacy of consciousness-regaining therapy (CRT) for prolonged disorder of consciousness (pDOC). Next, basic information on the cases, data on pDOC disease assessment, CRT methods, and efficacy evaluation were collected. RESULTS: These 114 patients were grouped, and a comparative analysis was done based on the efficacy at the end of treatment. Of these, 61 cases were allotted to the ineffective group and 53 cases to the effective group. There was a lack of statistical difference (P > 0.05) between the two groups based on gender, age, etiology, acute cerebral herniation, emergency craniotomy surgery, emergency decompressive craniectomy, time from onset to start of CRT, and CRT duration (P > 0.05). However, secondary hydrocephalus, CRT methods, CRS-R grading before treatment, and GOSE score at six months after treatment were found to be statistically different. The results of binary logistic regression analysis showed that the type of therapy (OR = 0.169, 95% CI: 0.057-0.508) affected the efficacy of CRT (P < 0.05). CONCLUSIONS: Personalized awakening therapy using various invasive CRT methods could improve the efficacy of therapy for pDOC compared with non-invasive therapy.

Highly precise FBG wavelength demodulation method with strong multiplexing ability and positioning function based on time-domain detection.

Based on the theory of the microwave photonic filter (MPF), to our knowledge, a novel fiber Bragg grating (FBG) wavelength demodulation method based on time-domain detection is proposed. The method uses VNA (vector network analyzer) to measure the S21 parameter of the sensor system, and converts them to the time-domain through inverse discrete Fourier transform (IDFT), The wavelength demodulation and positioning of FBG can be realized by measuring the amplitude and position of the time-domain peak. In order to improve the number of FBG multiplexes, a method is proposed to eliminate the effect of spectrum overlap by normalization in the case of two FBGs and three FBGs. The experimental results show that the temperature sensitivity is 0.00503 RAC/°C, the positioning resolution of the system is 1.25 cm, and the limit of the wavelength difference between two FBGs allowed by the system is 0.25 nm. This method has the advantages of high demodulation precision, strong multiplexing ability and high precision positioning, and has broad application prospects.

Rapid isolation of pan-neutralizing antibodies against Omicron variants from convalescent individuals infected with SARS-CoV-2.

Introduction: The emergence of SARS-CoV-2 Omicron subvariants has presented a significant challenge to global health, as these variants show resistance to most antibodies developed early in the pandemic. Therapeutic antibodies with potent efficacy to the Omicron variants are urgently demanded. Methods: Utilizing the rapid antibody discovery platform, Berkeley Lights Beacon, we isolated two monoclonal neutralizing antibodies, 2173-A6 and 3462-A4. These antibodies were isolated from individuals who recently recovered from Omicron infections. Results: Both antibodies, 2173-A6 and 3462-A4, demonstrated high affinity for the RBD and effectively neutralized pseudoviruses from various Omicron lineages, including BA.4/5, XBB.1.16, XBB.1.5, and EG.5.1. This neutralization was achieved through binding to identical or overlapping epitopes. Discussion: The use of the Beacon platform enabled the rapid isolation and identification of effective neutralizing antibodies within less than 10 days. This process significantly accelerates the development of novel therapeutic antibodies, potentially reducing the time required to respond to unknown infectious diseases in the future.

B cell receptor repertoire analysis in primary Sjogren's syndrome salivary glands identifies repertoire features associated with clinical activity.

BACKGROUND: Primary Sjogren's syndrome (pSS) is a complex autoimmune disease featuring damage to salivary and lacrimal glands, with the possibility of manifestations across multiple organs. Antibody-producing B cells have long been appreciated to play a significant role in pSS pathogenesis, with a number of autoreactive antibody species having been identified to be elevated in pSS patients. While several studies have attempted to characterize the BCR repertoires of peripheral blood B cells in pSS patients, much remains unknown about the repertoire characteristics of gland-infiltrating B cells. METHODS: Through paired scRNAseq and scBCRseq, we profiled the BCR repertoires of both infiltrating and circulating B cells in a small cohort of patients. We further utilize receptor reconstruction analyses to further investigate repertoire characteristics in a wider cohort of pSS patients previously profiled through RNAseq. RESULTS: Via integrated BCR and transcriptome analysis of B cell clones, we generate a trajectory progression pattern for infiltrated memory B cells in pSS. We observe significant differences in BCR repertoires between the peripheral blood and labial gland B cells of pSS patients in terms of relative expansion, isotype usage, and BCR clustering. We further observe significant decreases in IgA2 isotype usage among pSS patient labial and parotid gland B cells these analyses relative to controls as well as a positive correlation between kappa/lambda light chain usage and clinical disease activity. CONCLUSIONS: Through BCR repertoire analysis of pSS patient salivary glands, we identify a number of novel repertoire characteristics that may serve as useful indicators of clinical disease and disease activity. By collecting these BCR repertoires into an accessible database, we hope to also enable comparative analysis of patient repertoires in pSS and potentially other autoimmune disorders.

The Association Between Trajectory-Skull Angle and Accuracy of Stereoelectroencephalography Electrode Implantation in Drug-Resistant Epilepsy.

OBJECTIVE: To analyze the relationship between trajectory-skull angle and stereoelectroencephalography electrode implantation accuracy in drug-resistant epilepsy patients, aiming to guide clinical electrode placement and enhance surgical precision and safety. METHODS: We conducted a retrospective analysis of medical records and surgical characteristics of 32 consecutive patients diagnosed with drug-resistant epilepsy, who underwent stereoelectroencephalography procedures at our center from June 2020 to June 2023. To evaluate the accuracy of electrode implantation, we utilized preoperative and postoperative computed tomography scans fused with SinoPlan software-planned trajectories. Entry radial error and target vector error were assessed as measurements of electrode implantation accuracy. RESULTS: After adjusting for confounders, we found a significant positive correlation between trajectory-skull angle and entry radial error (ß = 0.02, 95% CI: 0.01-0.03, P < 0.001). Likewise, a significant positive correlation existed between trajectory-skull angle and target vector error in all three models (ß = 0.03, 95% CI: 0.01-0.04, P < 0.001). Additionally, a U-shaped relationship between trajectory-skull angle and target vector error was identified using smooth curve fitting. This U-shaped pattern persisted in both frame-based and robot-guided stereotactic techniques. According to the two-piecewise linear regression model, the inflection points were 9° in the frame-based group and 16° in the robot-guided group. CONCLUSIONS: This study establishes a significant positive linear correlation between trajectory-skull angle and entry radial error, along with a distinctive U-shaped pattern in the relationship between trajectory-skull angle and target vector error. Our findings suggest that trajectory-skull angles of 9° (frame-based) and 16° (robot-guided) may optimize the accuracy of target vector error.

Transcriptional profile of human thymus reveals IGFBP5 is correlated with age-related thymic involution.

Thymus is the main immune organ which is responsible for the production of self-tolerant and functional T cells, but it shrinks rapidly with age after birth. Although studies have researched thymus development and involution in mouse, the critical regulators that arise with age in human thymus remain unclear. We collected public human single-cell transcriptomic sequencing (scRNA-seq) datasets containing 350,678 cells from 36 samples, integrated them as a cell atlas of human thymus. Clinical samples were collected and experiments were performed for validation. We found early thymocyte-specific signaling and regulons which played roles in thymocyte migration, proliferation, apoptosis and differentiation. Nevertheless, signaling patterns including number, strength and path completely changed during aging, Transcription factors (FOXC1, MXI1, KLF9, NFIL3) and their target gene, IGFBP5, were resolved and up-regulated in aging thymus and involved in promoting epithelial-mesenchymal transition (EMT), responding to steroid and adipogenesis process of thymic epithelial cell (TECs). Furthermore, we validated that IGFBP5 protein increased at TECs and Hassall's corpuscle in both human and mouse aging thymus and knockdown of IGFBP5 significantly increased the expression of proliferation-related genes in thymocytes. Collectively, we systematically explored cell-cell communications and regulons of early thymocytes as well as age-related differences in human thymus by using both bioinformatic and experimental verification, indicating IGFBP5 as a functional marker of thymic involution and providing new insights into the mechanisms of thymus involution.

Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner.

Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora.

Exploring the heterogeneity of community and function and correspondence of "species-enzymes" among three types of Daqu with different fermentation peak-temperature via high-throughput sequencing and metagenomics.

The enzyme activity of Daqu is an important prerequisite for defining it as a Baijiu starter. However, little is known about the functional species related to enzymes in different types of Daqu at the metagenomic level. Therefore, we analyzed the differences in enzymatic properties, microbial composition and metabolic function of three types of Daqu, namely high-, medium- and low-temperature Daqus (HTD, MTD and LTD), by combining chemical feature and multi-dimensional sequencing. The results showed that both liquefaction, saccharification, fermentation and esterification powers were remarkably weaker in HTD compared to MTD and LTD. Totally, 30 bacterial and 5 fungal phyla were identified and significant differences in community structures were also observed among samples, with Brevibacterium/Microascus, Pseudomonas, and Lactobacillus/Saccharomycopsis identified as biomarkers for HTD, MTD and LTD, respectively. Additionally, the importance of deterministic assembly in bacterial communities was proportional to the fermentation peak-temperature, while stochastic assembly dominated in fungal ones. Metagenomics analysis indicated eukaryota (>80 %, mainly Ascomycota) predominated in HTD and MTD while bacteria (54.3 %, mainly Actinobacteriota) were more abundant in LTD. However, the functional profiles and pathways of MTD and LTD were more similar, and the synthesis and metabolism of carbohydrates and amino acids were the crucial biological functions of all samples. Finally, the relationship between species and enzymes in different samples was constructed and the functional species in LTD and MTD were more diverse than HTD, which elucidated the functional species associated with enzyme activity in each type of Daqu. These results will greatly enrich our understanding of the core functional species in three typical Daqu, which provide available information for rational regulation of Daqu quality and the Baijiu fermentation.

Hepatitis B virus-mediated sodium influx contributes to hepatic inflammation via synergism with intrahepatic danger signals.

The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome has been involved in the pathogenesis of various chronic liver diseases. However, its role in hepatitis B virus (HBV)-associated hepatitis remains unknown. Here we demonstrate the synergistic effect of HBV with potential intrahepatic danger signals on NLRP3 inflammasome activation. HBV exposure at the appropriate temporal points enhances potassium efflux-dependent NLRP3 inflammasome activation in macrophages and also increases NLRP3 inflammasome-mediated inflammation in HBV-transgenic mouse model. HBV-mediated synergism with intrahepatic signals represented by ATP molecules on NLRP3 activation was observed via relevance analysis, confocal microscopy, and co-immunoprecipitation, and its effector cytokines exhibit positive associations with hepatic inflammation in patients with severe hepatitis B. Furthermore, the synergism of HBV on NLRP3 inflammasome activation owes to increased sodium influx into macrophages. Our data demonstrate that HBV contributes to hepatic inflammation via sodium influx-dependent synergistic activation of NLRP3 inflammasome, which provides a deeper understanding of immune pathogenesis in HBV-associated hepatitis.

STAT3 and SOX-5 induce BRG1-mediated chromatin remodeling of RORCE2 in Th17 cells.

Retinoid-related orphan receptor gamma t (RORγt) is the lineage-specific transcription factor for T helper 17 (Th17) cells. Our previous study demonstrated that STAT3 likely participates in the activation of RORCE2 (a novel enhancer of the RORγt gene) in Th17 cells. However, the detailed mechanism is still unclear. Here, we demonstrate that both STAT3 and SOX-5 mediate the enhancer activity of RORCE2 in vitro. Deletion of the STAT3 binding site (STAT3-BS) in RORCE2 impaired RORγt expression and Th17 differentiation, resulting in reduced severity of experimental autoimmune encephalomyelitis (EAE). Mechanistically, STAT3 and SOX-5 bind the RORCE2 region and recruit the chromatin remodeling factor BRG1 to remodel the nucleosomes positioned at this region. Collectively, our data suggest that STAT3 and SOX-5 mediate the differentiation of Th17 cells through the induction of BRG1-mediated chromatin remodeling of RORCE2 in Th17 cells.

Screening single-cell trajectories via continuity assessments for cell transition potential.

Advances in single-cell sequencing and data analysis have made it possible to infer biological trajectories spanning heterogeneous cell populations based on transcriptome variation. These trajectories yield a wealth of novel insights into dynamic processes such as development and differentiation. However, trajectory analysis relies on an assumption of trajectory continuity, and experimental limitations preclude some real-world scenarios from meeting this condition. The current lack of assessment metrics makes it difficult to ascertain if/when a given trajectory deviates from continuity, and what impact such a divergence would have on inference accuracy is unclear. By analyzing simulated breaks introduced into in silico and real single-cell data, we found that discontinuity caused precipitous drops in the accuracy of trajectory inference. We then generate a simple scoring algorithm for assessing trajectory continuity, and found that continuity assessments in real-world cases of intestinal stem cell development and CD8 + T cells differentiation efficiently identifies trajectories consistent with empirical knowledge. This assessment approach can also be used in cases where a priori knowledge is lacking to screen a pool of inferred lineages for their adherence to presumed continuity, and serve as a means for weighing higher likelihood trajectories for validation via empirical studies, as exemplified by our case studies in psoriatic arthritis and acute kidney injury. This tool is freely available through github at qingshanni/scEGRET.

Exploring the network effects of deep brain stimulation for rapid eye movement sleep behavior disorder in Parkinson's disease.

BACKGROUND: The research findings on the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) with Rapid Eye Movement Sleep Behavior Disorder (RBD) are inconsistent, and there is a lack of research on DBS electrode sites and their network effects for the explanation of the differences. Our objective is to explore the optimal stimulation sites (that is the sweet spot) and the brain network effects of STN-DBS for RBD in PD. METHODS: In this study, among the 50 PD patients who underwent STN-DBS treatment, 24 PD patients with RBD were screened. According to clinical scores and imaging data, the sweet spot of STN-DBS was analyzed in PD patients with RBD, and the optimal structure and functional network models of subthalamic stimulation were constructed. RESULTS: Bilateral STN-DBS can effectively improve the symptoms of RBD and other non-motor symptoms in 24 PD patients with RBD. RBD Questionnaire-Hong Kong (RBDQ-HK) score was 41.33 ± 17.45 at baseline and 30.83 ± 15.83 at 1-year follow-up, with statistical significance between them (P < 0.01). However, the MoCA score was an exception with a baseline of 22.04 ± 4.28 and a 1-year follow-up of 21.58 ± 4.33, showing no statistical significance (P = 0.12). The sweet spot and optimal network connectivity models for RBD improvement have been validated as effective. CONCLUSIONS: Bilateral STN-DBS can improve the symptoms of RBD in PD. There exist the sweet spot and brain network effects of bilateral STN-DBS in the treatment of PD with RBD. Our study also demonstrates that RBD is a brain network disease.

The clinical and immunological characteristics of COVID-19 patients with delayed SARS-CoV-2 virus clearance.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a great threat to human health. Some severe COVID-19 patients still carried detectable levels of SARS-CoV-2 even after prolonged intensive care unit treatment. However, the immunological features of these COVID-19 patients with delayed virus clearance (CDVC) are still unclear. METHODS: We retrospectively reviewed the clinical and immunological data of 13 CDVC cases, who were admitted into one hospital in Wuhan from February to April 2020. These data were also compared to those of perished (n = 9) and recovered (n = 52) cases. The expression of the exhaustion marker PD-1 on circulating T cells of these patients was measured by flow cytometry. RESULTS: High levels of serum interleukin-6 (IL-6), IL-1ß, IL-8, as well as other inflammatory mediators, were seen in CDVC cases. Severe lymphopenia was observed in CDVC patients with the counts of total lymphocytes (0.9 × 109 /L), CD4+ T cells (0.35 × 109 /L), and CD8+ T cells (0.28 × 109 /L) below their corresponding lower limits of normal range. Similar to the perished group, CDVC cases have higher percentages of CD25+ Foxp3+ regulatory T cells (Treg) in circulation. Moreover, enhanced expression of the exhaustion marker PD-1 on CCR7- CD45RA+ effector, CCR7+ CD45RA- central memory, and CCR7- CD45RA- effector memory CD4+ and CD8+ T cells were also observed in CDVC cases. CONCLUSION: CDVC patients still have SARS-CoV-2 and these cases manifest with severe clinical symptoms due to persistent inflammation. Augmentation of the frequency of circulating Treg, severe lymphopenia, and functional exhaustion of T cells might lead to inefficient clearance of SARS-CoV-2. Therefore, enhancing lymphocyte counts and reversing T-cell exhaustion might be key methods to boost immune responses and eliminate SARS-CoV-2 in CDVC patients.

Serum levels of type I interferon (IFN-I) is associated with the severity of COVID-19.

Introduction. Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, coronavirus disease 2019 (COVID-19) has threatened global public health. Immune damage mechanisms are essential guidelines for clinical treatment and immune prevention.Hypothesis. The dysregulated type I interferon (IFN-I) responses, lymphocytopenia and hypercytokinemia during SARS-CoV-2 infection have been reported. However, whether there is a correlation between levels of IFN-I and the severity of COVID-19 has not been reported yet.Aim. To investigate the source of IFN-I and detect the exact roles of them in the pathogenesis of COVID-19.Methodology. Here ELISA was used to detect serum IFN-I (IFN-α and IFN-ß) for 137 cases with laboratory-confirmed COVID-19 admitted into one hospital in Wuhan from December 2019 to March 2020, and the relationships between IFN-α/ß concentrations and patients' clinical parameters were conducted by statistical analysis.Results. Both IFN-α and IFN-ß concentrations dramatically increased in COVID-19 patients, especially in old patients (>80 years) and severe cases. Statistical analysis demonstrated that serum IFN-α/ß concentrations were negatively correlated with the counts of total CD3+T, CD4+ and CD8+T cells, especially in critically ill cases. Moreover, serum IFN-α levels were positively correlated to IL-6 and TNF-α. Finally, immunofluorescent double staining showed that IFN-α and IFN-ß are major secretions from macrophages and dendritic cells (DCs) in lymph nodes from COVID-19 autopsies.Conclusion. These results demonstrate that macrophages and DCs are the main origination of IFN-I, and serum levels of IFN-I are positively associated with lymphopenia and cytokine storm, suggesting that IFN-α/ß deteriorated the severity of COVID-19. Anti-interferon or IFN-I signalling block drugs are needed to treat ICU patients.

Single-cell Clonal Tracing of Glandular and Circulating T cells identifies a population of CD9+CD8+T cells in primary Sjogren's Syndrome.

Primary Sjogren's syndrome (pSS) is a complex chronic autoimmune disease in which local tissue damage in exocrine glands are combined with broader systemic involvement across the body in tissues including the skin. These combined manifestations negatively impact patient health and quality of life. While studies have previously reported differences in immune cell composition in the peripheral blood of pSS patients relative to healthy controls, a detailed immune cell landscape of the damaged exocrine glands of these patients remains lacking. Through single-cell transcriptomics and repertoire sequencing of immune cells in paired peripheral blood samples and salivary gland biopsies, we present here a preliminary picture of adaptive immune response in pSS. We characterize a number of points of divergence between circulating and glandular immune responses that have been hitherto underappreciated, and identify a novel population of CD8+CD9+ cells with tissue-residential properties that are highly enriched in the salivary glands of pSS patients. Through comparative analyses with other sequencing data, we also observe a potential connection between these cells and the tissue-resident memory cells found in cutaneous vasculitis lesions. Together, these results indicate a potential role for CD8+CD9+ cells in mediating glandular and systemic effects associated with pSS and other autoimmune disorders.

Tetraspan MS4A6D is a coreceptor of MHC class II antigen (MHC-II) that promotes macrophages-derived inflammation.

Our previous research demonstrated that the tetraspan MS4A6D is an adapter of VSIG4 that controls NLRP3 inflammasome activation (Sci Adv. 2019: eaau7426); however, the expression, distribution and biofunction of MS4A6D are still poorly understood. Here, we showed that MS4A6D is restricted to mononuclear phagocytes and that its gene transcript is controlled by the transcription factor NK2 homeobox-1 (NKX2-1). Ms4a6d-deficient (Ms4a6d-/-) mice showed normal macrophage development but manifested a greater survival advantage against endotoxin (lipopolysaccharide) challenge. Mechanistically, MS4A6D homodimers crosslinked with MHC class II antigen (MHC-II) to form a surface signaling complex under acute inflammatory conditions. MHC-II occupancy triggered Tyr241 phosphorylation in MS4A6D, leading to activation of SYK-CREB signaling cascades, further resulting in augmenting the transcription of proinflammatory genes (Il1b, Il6 and Tnfa) and amplifying the secretion of mitochondrial reactive oxygen species (mtROS). Deletion of Tyr241 or interruption of Cys237-mediated MS4A6D homodimerization in macrophages alleviated inflammation. Importantly, both Ms4a6dC237G and Ms4a6dY241G mutation mice phenocopied Ms4a6d-/- animals to prevent endotoxin lethality, highlighting MS4A6D as a novel target for treating macrophage-associated disorders.

Crystal structures and solution conformations of HtrA from Helicobacter pylori reveal pH-dependent oligomeric conversion and conformational rearrangements.

Helicobacter pylori is a Gram-negative microaerophilic bacterium that infects over 50 % of the world's population, making it a major risk factor for chronic gastritis, ulcer diseases of the stomach and duodenum, MALT lymphoma, and gastric cancer. The clinical consequences of H. pylori infection are closely linked with the expression of virulence factors secreted by the bacterium. One such virulence factor is high temperature requirement A (HtrA), which possesses chaperone and serine protease activity. In the host stomach, HtrA secreted from H. pylori (HpHtrA) disrupts intercellular adhesions by cleaving epithelial adhesion proteins including E-cadherin and desmoglein-2. This disruption causes intercellular junctions to open, allowing the bacterium to pass through the epithelial barrier, access the intercellular space, and colonize the gastric mucosa. HtrA proteases are well known for their structural complexity, reflected in their diverse oligomer forms and multi-tasking activities in both prokaryotes and eukaryotes. In this study, we determined crystal structures and solution conformations of HpHtrA monomer and trimer, which revealed large domain rearrangements between them. Notably, this is the first report of a monomeric structure in the HtrA family. We further found a pH-dependent dynamic trimer-to-monomer conversion and concurrent conformational changes that seem closely linked with a pH-sensing ability through the protonation of certain Asp residues. These results advance our understanding of the functional roles and the related mechanisms of this protease in bacterial infection, which may shed light on the development of HtrA-targeted therapies for H. pylori-associated diseases.

Electroencephalogram-Based Brain Connectivity Analysis in Prolonged Disorders of Consciousness.

Background: Prolonged disorders of consciousness (pDOC) are common in neurology and place a heavy burden on families and society. This study is aimed at investigating the characteristics of brain connectivity in patients with pDOC based on quantitative EEG (qEEG) and extending a new direction for the evaluation of pDOC. Methods: Participants were divided into a control group (CG) and a DOC group by the presence or absence of pDOC. Participants underwent magnetic resonance imaging (MRI) T1 three-dimensional magnetization with a prepared rapid acquisition gradient echo (3D-T1-MPRAGE) sequence, and video EEG data were collected. After calculating the power spectrum by EEG data analysis tool, DTABR ((δ + θ)/(α + ß) ratio), Pearson's correlation coefficient (Pearson r), Granger's causality, and phase transfer entropy (PTE), we performed statistical analysis between two groups. Finally, receiver operating characteristic (ROC) curves of connectivity metrics were made. Results: The proportion of power in frontal, central, parietal, and temporal regions in the DOC group was lower than that in the CG. The percentage of delta power in the DOC group was significantly higher than that in the CG, the DTABR in the DOC group was higher than that in the CG, and the value was inverted. The Pearson r of the DOC group was higher than that of CG. The Pearson r of the delta band (Z = -6.71, P < 0.01), theta band (Z = -15.06, P < 0.01), and alpha band (Z = -28.45, P < 0.01) were statistically significant. Granger causality showed that the intensity of directed connections between the two hemispheres in the DOC group at the same threshold was significantly reduced (Z = -82.43, P < 0.01). The PTE of each frequency band in the DOC group was lower than that in the CG. The PTE of the delta band (Z = -42.68, P < 0.01), theta band (Z = -56.79, P < 0.01), the alpha band (Z = -35.11, P < 0.01), and beta band (Z = -63.74, P < 0.01) had statistical significance. Conclusion: Brain connectivity analysis based on EEG has the advantages of being noninvasive, convenient, and bedside. The Pearson r of DTABR, delta, theta, and alpha bands, Granger's causality, and PTE of the delta, theta, alpha, and beta bands can be used as biological markers to distinguish between pDOC and healthy people, especially when behavior evaluation is difficult or ambiguous; it can supplement clinical diagnosis.

Anti-PD-1 therapy achieves favorable outcomes in HBV-positive non-liver cancer.

Anti-PD-1 therapy has shown promising outcomes in the treatment of different types of cancer. It is of fundamental interest to analyze the efficacy of anti-PD-1 therapy in cancer patients infected with hepatitis B virus (HBV) since the comorbidity of HBV and cancer is widely documented. We designed a multicenter retrospective study to evaluate the efficacy of anti-PD-1 therapy on non-liver cancer patients infected with HBV. We found anti-PD-1 therapy achieved much better outcomes in HBV+ non-liver cancer patients than their HBV- counterparts. We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from esophageal squamous cell carcinoma (ESCC) patients. We found both cytotoxicity score of T cells and MHC score of B cells significantly increased after anti-PD-1 therapy in HBV+ ESCC patients. We also identified CX3CR1high TEFF, a subset of CD8+ TEFF, associated with better clinical outcome in HBV+ ESCC patients. Lastly, we found CD8+ TEFF from HBV+ ESCC patients showing higher fraction of Exhaustionhi T than their HBV- counterpart. In summary, anti-PD-1 therapy on HBV+ non-liver cancer patients is safe and achieves better outcomes than that on HBV- non-liver cancer patients, potentially because HBV+ patients had higher fraction of Exhaustionhi T, which made them more efficiently respond to anti-PD-1 therapy.

Immune damage mechanisms of COVID-19 and novel strategies in prevention and control of epidemic.

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has diverse clinical manifestations, which is the main feature of the disease, and the fundamental reason is the different immune responses in different bodies among the population. The damage mechanisms of critical illness by SARS-CoV-2 and its variants, such as hyperinflammatory response, a double-edged function of type I interferon, and hyperactivation of the complement system, are the same as other critical illnesses. Targeting specific immune damage mechanisms of COVID-19, we scored the first to put forward that the responses of T cells induced by acute virus infection result in "acute T-cell exhaustion" in elderly patients, which is not only the peripheral exhaustion with quantity reduction and dysfunction of T cells but also the central exhaustion that central immune organs lost immune homeostasis over peripheral immune organs, whereas the increased thymic output could alleviate the severity and reduce the mortality of the disease with the help of medication. We discovered that immune responses raised by SARS-CoV-2 could also attack secondary lymphoid organs, such as the spleen, lymphoid nodes, and kidneys, in addition to the lung, which we generally recognize. Integrated with the knowledge of mechanisms of immune protection, we developed a coronavirus antigen diagnostic kit and therapeutic monoclonal antibody. In the future, we will further investigate the mechanisms of immune damage and protection raised by coronavirus infection to provide more scientific strategies for developing new vaccines and immunotherapies.