Association of plasma lactoferrin levels with disease severity in glaucoma patients.

Objective: To explore the relationship between plasma lactoferrin (Lf) and glaucoma, assessing the clinical utility of Lf in glaucoma. Methods: A cross-sectional study involved 161 glaucoma patients and 115 healthy controls, with a follow-up of 14 subjects after approximately 2 years. Plasma Lf markers were quantified using ELISA, comparing levels between glaucoma patients and healthy controls, and analyzing plasma Lf across different glaucoma severity grades. Results: Glaucoma patients had significantly elevated plasma Lf levels compared to healthy controls (p < 0.001). Higher plasma Lf levels correlated with more severe disease stages (HPA grades showed ρ = 0.435, p < 0.001; AGIS grades showed ρ = 0.436, p < 0.001) and reduced retinal nerve fiber layer (RNFL) thickness (RNFL thickness showed ρ = -0.204, p = 0.024). ROC curve analysis demonstrated the efficacy of glaucoma markers in differentiating early-stage from advanced glaucoma. Conclusion: Plasma Lf levels are significantly associated with glaucoma severity and may be involved in the pathogenic progression of the disease.

Capture of armA by a novel ISCR element, ISCR28.

ISCR28 is a fully functional and active member of the IS91-like family of insertion sequences. ISCR28 is 1,708-bp long and contains a 1,293-bp long putative open reading frame that codes a transposase. Sixty ISCR28-containing sequences from GenBank generated 27 non-repeat genetic contexts, all of which represented naturally occurring biological events that had occurred in a wide range of gram-negative organisms. Insertion of ISCR28 into target DNA preferred the presence of a 5'-GXXT-3' sequence at its terIS (replication terminator) end. Loss of the first 4 bp of its oriIS (origin of replication) likely caused ISCR28 to be trapped in ISApl1-based transposons or similar structures. Loss of terIS and fusion with a mobile element upstream likely promoted co-transfer of ISCR28 and the downstream resistance genes. ArmA and its downstream intact ISCR28 can be excised from recombinant pKD46 plasmids forming circular intermediates, further elucidating its activity as a transposase.

[Reversal Effect of NVP-BEZ235 on Doxorubicin-Resistance in Burkitt Lymphoma RAJI Cell Line].

OBJECTIVE: To study the reversal effect of NVP-BEZ235 on doxorubicin resistance in Burkitt lymphoma RAJI cell line. METHODS: The doxorubicin-resistant cell line was induced by treating RAJI cells with a concentration gradient of doxorubicin. The levels of Pgp, p-AKT, and p-mTOR in cells were detected by Western blot. Cell viability was detected by MTT assay. IC50 was computed by SPSS. RESULTS: The doxorubicin-resistant Burkitt lymphoma cell line, RAJI/DOX, was established successfully. The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. CONCLUSION: The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway.

Corrigendum: Genomic evolution of BA.5.2 and BF.7.14 derived lineages causing SARS-CoV-2 outbreak at the end of 2022 in China.

[This corrects the article DOI: 10.3389/fpubh.2023.1273745.].

Th1 cells contribute to retinal ganglion cell loss in glaucoma in a VCAM-1-dependent manner.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.

[Mechanism about LMP1 of EB Virus Promoting Plasma Blast Differentiation of DLBCL Cell via mTORC1].

OBJECTIVE: To investigate possible mechanism on protien LMP1 expressed by EBV inducing plasmablast differentiation of DLBCL cell via the mTORC1 pathway. METHODS: The expression levels of LMP1 protein, CD38 and the phosphorylation levels of p70S6K in EBV+ and EBV- DLBCL cell lines were detected by Western blot. Cell lines overexpressing LMP1 gene stablely were constructed and LMP1 gene was silenced by RNAi. The expression of LMP1 gene was verified by RT-qPCR. The expression levels of LMP1 and CD38 and the phosphorylation levels of p70S6K in each group were detected by Western blot. RESULTS: Compared with EBV-DLBCL cells, the expression of LMP1 was detected on EBV +DLBCL cells (P =0.0008), EBV +DLBCL cells had higher phosphorylation levels of p70S6K (P =0.0072) and expression levels of CD38(P =0.0091). Compared with vector group, the cells of LMP1OE group had higher expression levels of LMP1 and CD38 (P =0.0353; P <0.0001), meanwhile molecular p70S6K was phosphorylated much more(P =0.0065); expression of LMP1 mRNA was verified(P <0.0001). Compared with si-NC group, expression level of LMP1 protein(P =0.0129) was not detected and phosphorylated p70S6K disappeared of LMP1KO group (P =0.0228); meanwhile, expression of CD38 decreased,although there was no significant difference (P =0.2377). CONCLUSION: LMP1 promotes DLBCL cells plasmablast differentiation via activating mTORC1 signal pathway.

Synthesis of silyl indenes by ruthenium-catalyzed aldehyde- and acylsilane-enabled C-H alkylation/cyclization.

A ruthenium-catalyzed C-H alkylation/cyclization sequence is presented to prepare silyl indenes with atom and step-economy. This domino reaction is triggered by acyl silane-directed C-H activation, and an aldehyde controlled the following enol cyclization/condensation other than ß-H elimination. The protocol tolerates a broad substitution pattern, and the further synthetic elaboration of silyl indenes allows access to a diverse range of interesting indene and indanone derivatives.

Genomic evolution of BA.5.2 and BF.7.14 derived lineages causing SARS-CoV-2 outbreak at the end of 2022 in China.

Since the end of 2022, when China adjusted its COVID-19 response measures, the SARS-CoV-2 epidemic has rapidly grown in the country. It is very necessary to monitor the evolutionary dynamic of epidemic variants. However, detailed reports presenting viral genome characteristics in China during this period are limited. In this study, we examined the epidemiological, genomic, and evolutionary characteristics of the SARS-CoV-2 genomes from China. We analyzed nearly 20,000 genomes belonging to 17 lineages, predominantly including BF.7.14 (22.3%), DY.2 (17.3%), DY.4 (15.5%), and BA.5.2.48 (11.9%). The Rt value increased rapidly after mid-November 2022, reaching its peak at the end of the month. We identified forty-three core mutations in the S gene and forty-seven core mutations in the ORF1ab gene. The positive selection of all circulating lineages was primarily due to non-synonymous substitutions in the S1 region. These findings provide insights into the genomic characteristics of SARS-CoV-2 genomes in China following the relaxation of the 'dynamic zero-COVID' policy and emphasize the importance of ongoing genomic monitoring.

Kaempferol and ginsenoside Rg1 ameliorate acute hypobaric hypoxia induced lung injury based on network pharmacology analysis.

Acute hypobaric hypoxia at high altitude can cause fatal non-cardiogenic high altitude pulmonary edema. Anti-inflammatory and anti-oxidant treatments appear to be a prospective way to alleviate acute hypoxia lung injury. Kaempferol (KA) and ginsenoside Rg1 (GRg1) can be isolated and purified from ginseng with anti-inflammatory, antioxidant, anti-carcinogenic, neuroprotective, and antiaging effects. However, their effects and pharmacological mechanisms on lung injury remains unclear. Network pharmacology analyses were used to explore potential targets of KA and GRg1 against acute hypobaric hypoxia induced lung injury. Rat lung tissues were further used for animal experiment verification. Among the putative targets of KA and GRg1 for inhibition of acute hypobaric hypoxia induced lung injury, AKT1, PIK3R1, PTK2, STAT3, HSP90AA1 and AKT2 were recognized as higher interrelated targets. And PI3K-AKT signaling pathway is considered to be the most important and relevant pathway. The rat experimental results showed that KA and GRg1 significantly improved histopathological changes and decreased pulmonary edema in rats with lung injury caused by acute hypobaric hypoxia. The concentrations of IL-6, TNF-α, MDA, SOD and CAT in rats treated with KA and GRg1 were significantly ameliorated. Protein and mRNA levels of PI3K and AKTI were significantly inhibited after KA administration. KA and GRg1 can lower lung water content, improve lung tissue damage, reduce the production of pro-inflammatory cytokines and the oxidative stress level.

Single-cell transcriptomic analysis reveals a systemic immune dysregulation in COVID-19-associated pediatric encephalopathy.

Unraveling the molecular mechanisms for COVID-19-associated encephalopathy and its immunopathology is crucial for developing effective treatments. Here, we utilized single-cell transcriptomic analysis and integrated clinical observations and laboratory examination to dissect the host immune responses and reveal pathological mechanisms in COVID-19-associated pediatric encephalopathy. We found that lymphopenia was a prominent characteristic of immune perturbation in COVID-19 patients with encephalopathy, especially those with acute necrotizing encephalopathy (AE). This was characterized a marked reduction of various lymphocytes (e.g., CD8+ T and CD4+ T cells) and significant increases in other inflammatory cells (e.g., monocytes). Further analysis revealed activation of multiple cell apoptosis pathways (e.g., granzyme/perforin-, FAS- and TNF-induced apoptosis) may be responsible for lymphopenia. A systemic S100A12 upregulation, primarily from classical monocytes, may have contributed to cytokine storms in patients with AE. A dysregulated type I interferon (IFN) response was observed which may have further exacerbated the S100A12-driven inflammation in patients with AE. In COVID-19 patients with AE, myeloid cells (e.g., monocytic myeloid-derived suppressor cells) were the likely contributors to immune paralysis. Finally, the immune landscape in COVID-19 patients with encephalopathy, especially for AE, were also characterized by NK and T cells with widespread exhaustion, higher cytotoxic scores and inflammatory response as well as a dysregulated B cell-mediated humoral immune response. Taken together, this comprehensive data provides a detailed resource for elucidating immunopathogenesis and will aid development of effective COVID-19-associated pediatric encephalopathy treatments, especially for those with AE.

Case report: A toxoplasmic encephalitis in an immunocompromised child detected through metagenomic next-generation sequencing.

There exist numerous pathogens that are capable of causing infections within the central nervous system (CNS); however, conventional detection and analysis methods prove to be challenging. Clinical diagnosis of CNS infections often depends on clinical characteristics, cerebrospinal fluid (CSF) analysis, imaging, and molecular detection assays. Unfortunately, these methods can be both insensitive and time consuming, which can lead to missed diagnoses and catastrophic outcomes, especially in the case of infrequent diseases. Despite the application of appropriate prophylactic regimens and evidence-based antimicrobial agents, CNS infections continue to result in significant morbidity and mortality in hospital settings. Metagenomic next-generation sequencing (mNGS) is a novel tool that enables the identification of thousands of pathogens in a target-independent manner in a single run. The role of this innovative detection method in clinical pathogen diagnostics has matured over time. In this particular research, clinicians employed mNGS to investigate a suspected CNS infection in a child with leukemia, and unexpectedly detected Toxoplasma gondii. Case: A 3-year-old child diagnosed with T-cell lymphoblastic lymphoma was admitted to our hospital due to a 2-day history of fever and headache, along with 1 day of altered consciousness. Upon admission, the patient's Glasgow Coma Scale score was 14. Brain magnetic resonance imaging revealed multiple abnormal signals. Due to the patient's atypical clinical symptoms and laboratory test results, determining the etiology and treatment plan was difficulty.Subsequently, the patient underwent next-generation sequencing examination of cerebrospinal fluid. The following day, the results indicated the presence of Toxoplasma gondii. The patient received treatment with a combination of sulfamethoxazole (SMZ) and azithromycin. After approximately 7 days, the patient's symptoms significantly improved, and they were discharged from the hospital with oral medication to continue at home. A follow-up polymerase chain reaction (PCR) testing after about 6 weeks revealed the absence of Toxoplasma. Conclusion: This case highlights the potential of mNGS as an effective method for detecting toxoplasmic encephalitis (TE). Since mNGS can identify thousands of pathogens in a single run, it may be a promising detection method for investigating the causative pathogens of central nervous system infections with atypical features.

Fecal calprotectin as an intestinal inflammation marker is elevated in glaucoma.

Objective: The aim of this study was to investigate the potential association between glaucoma and fecal calprotectin. Methods: A total of 144 glaucomatous patients and 66 healthy controls were enlisted for this study. The fecal calprotectin was assessed using enzyme-linked immunosorbent assay. Results: The median fecal calprotectin levels were significantly elevated in glaucoma (73.67 vs 41.97 µg/g; p < 0.001), primary angle-closure glaucoma (76.85 µg/g; p < 0.001) and primary open-angle glaucoma (69.29 µg/g; p = 0.016) groups compared with controls. A notable proportion of the glaucoma (24%; p < 0.001), primary angle-closure glaucoma (21%; p < 0.001) and primary open-angle glaucoma (24%; p < 0.001) subgroups exhibited highly abnormal fecal calprotectin levels (≥250 µg/g). Conclusion: Elevated fecal calprotectin might indicate potential intestinal inflammation in glaucoma.

Electrolyte-Impregnated Mesoporous Hollow Microreactor to Supplement an Inner Reaction Pathway for Boosting the Cyclability of Li-CO2 Batteries.

Li-CO2 batteries that integrate energy storage with greenhouse gas fixation have received a great deal of attention in the pursuit of carbon neutrality. However, cyclic accumulation of the insulative and insoluble Li2CO3 on the cathode surface severely restrains the battery cyclability, especially under a high depth of discharge/charge. Herein, we design and fabricate a microreactor-type catalyst by embedding Ru nanoparticles into the shells of mesoporous hollow carbon spheres. We show that both the hollow cavity and mesoporous shell are indispensable for concertedly furnishing a high activity to catalyze reversible Li2CO3 formation/decomposition. This unique structure ensures that the Ru sites masked by exterior Li2CO3 deposits during charging can resume the redox process of discharge by working with the prestored electrolyte to establish an inner reaction path. The thus fabricated Li-CO2 batteries demonstrate remarkable cyclability of 1085 cycles under 0.5 Ah g-1 and 326 cycles under 2 Ah g-1 at 1 A g-1, outshining most of the literature reports. This study highlights a smart catalyst design to boost the reversibility and cyclability of Li-CO2 batteries through an "in & out" strategy.

Gut-licensed ß7+ CD4+ T cells contribute to progressive retinal ganglion cell damage in glaucoma.

Glaucoma is the leading cause of irreversible blindness. Currently, most therapeutic strategies aim to reduce elevated intraocular pressure (EIOP), but this does not always halt disease progression. Evidence suggests a role for T cells in glaucoma pathogenesis, but the underlying mechanisms remain largely unknown. Here, we found that the percentage of circulating CD4+ T cells expressing a gut-homing integrin ß7 was increased in patients with glaucoma and was associated with disease stage. In an EIOP-triggered glaucoma mouse model, ß7+ CD4+ T cells infiltrated the retina in the progressive phase of glaucoma via eliciting retinal endothelial cell expression of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). MAdCAM-1 was minimally detected in retinas of healthy mice, and neutralization with an MAdCAM-1 antibody ameliorated retinal ganglion cell (RGC) loss and glial activity in mice with glaucoma. We furthermore found that EIOP-induced ß7+ CD4+ T cells homed to the gut during the acute phase of glaucoma, which was essential for progressive RGC damage in diseased mice. Gut-homing ß7+ CD4+ T cells underwent transcriptional reprogramming, showing up-regulated pathways enriched in autoimmune diseases, bacteria responses, mucosal immunity, and glial activity. Gut-homing ß7+ CD4+ T cells gained the competence to induce retinal MAdCAM-1 expression and to cross the blood-retina barrier. Together, our study reveals a role of gut-licensed ß7+ CD4+ T cells and MAdCAM-1 in RGC degeneration and emphasizes the importance of the "gut-retina" axis in glaucoma.

Tracking the first SARS-CoV-2 Omicron BA.5.1.3 outbreak in China.

The SARS-CoV-2 is still undergoing rapid evolution, resulting in the emergence of several variants of concern, especially the Omicron variants (B.1.1.529), which are surging worldwide. In this study, we tracked Omicron subvariant BA.5.1.3 as the causative agent in the Hainan Province wave in China, which started on 1 August 2022. This was China's first case of Omicron subvariant BA.5.1.3 and led to an indefinite total lockdown in Hainan with more than 8,500 confirmed cases. We obtained 391 whole genomes from positive nasopharyngeal swab samples in the city of Sanya in Hainan Province, which was the center of this outbreak. More than half of the infected cases were female (58%, 227/391) with a median age of 37.0 years (IQR 23.0-53.0). Median Ct values were 24.9 (IQR 22.6-27.3) and 25.2 (IQR 22.9-27.6) for ORF1ab and N genes, respectively. The total single-nucleotide polymorphism (SNP) numbers of Omicron BA.5.1.3 sampled in Sanya (median 69.0, IQR = 69.0-70.0) compared to those worldwide (median 63.0, IQR = 61.0-64.0) showed a significant difference (p < 0.05). Unique core mutations, including three non-synonymous mutations in ORF1ab (Y1064N, S2844G, and R3574K) and one synonymous mutation in ORF3a (S74S), were found. Phylogenetic analysis showed that virus from Sanya formed an independent sub-clade within the BA.5.1.3 subvariant, and could be divided into 15 haplotypes based on the S gene. The most recent common ancestor for the virus from Sanya was estimated as appearing on 5 July 2022, with 95% HPD ranging from 15 May to 20 September 2022. Thanks to our results, we were also able to delineate the mutational profile of this outbreak and highlight the importance of global genomic surveillance and data sharing.

Design, Synthesis and Biological Evaluation of 7-Substituted-1,3-diaminopyrrol[3,2-f]quinazolines as Potential Antibacterial Agents.

The evolution of drug-resistant bacteria poses a serious threat to public health; hence, it is imperative to develop new and efficient antibiotics. Irresistin-16 (IRS-16) is a dual-target antibacterial candidate that affects folate biosynthesis and membrane integrity and exhibits potent lethality against various bacteria. In this study, a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (DAPQ) derivatives based on IRS-16 was designed and synthesized to identify outstanding antibacterial candidates. The most promising compound, 7-(4-(4-methylpiperazin-1-yl) benzyl)-7H-pyrrol[3,2-f] quinazoline-1,3-diamine (18 e), displayed excellent antibacterial activity against both gram-positive and gram-negative bacteria (minimum inhibitory concentrations=1-4 µg/mL), improved water solubility, poor hemolytic activity and low cytotoxicity. Compound 18 e exhibited rapid bactericidal properties and prevented bacterial resistance in laboratory simulations. These results provide a basis for the development of new DAPQ-based compounds to combat emerging bacterial resistance.

IRF4 rearrangement may predict favorable prognosis in children and young adults with primary head and neck large B-cell lymphoma.

PURPOSE: Large B-cell lymphoma with IRF4 rearrangement (LBCL, IRF4+) has been recently recognized as a specific entity that is frequently associated with young age and favorable prognosis. However, whether the good outcome of the disease is due to IRF4+ or other factors remains obscure. We thus analyzed 100 young patients with primary head and neck LBCL to see the clinicopathologic correlates of IRF4+. METHODS: The histopathology, immunophenotype, IRF4 status of the tumors, and clinical data were reviewed. RESULTS: Twenty-one tumors were diagnosed as LBCL, IRF4+, which were more frequently associated with a follicular growth pattern, medium-sized blastoid cytology, germinal center B-cell-like, and CD5+ phenotype, compared with IRF4- ones. While most of the patients received chemotherapy with or without radiation, eight IRF4+ patients received mere surgical resection of the tumor and exhibited excellent outcome. IRF4+ cases featured a significantly higher complete remission rate, and better survivals compared with IRF4- ones. Multivariate analysis confirmed IRF4+ correlates with a better survival. CONCLUSION: Our work confirmed the unique clinicopathologic features of LBCL, IRF4+, and disclosed for the first time the independent favorable prognostic impact of IRF4+. These findings may further unravel the heterogeneity of LBCL occurring in youth, and aid in risk stratification and tailoring the therapeutic strategy.

Cholesterol homeostasis regulated by ABCA1 is critical for retinal ganglion cell survival.

Genome-wide association studies have suggested a link between primary open-angle glaucoma and the function of ABCA1. ABCA1 is a key regulator of cholesterol efflux and the biogenesis of high-density lipoprotein (HDL) particles. Here, we showed that the POAG risk allele near ABCA1 attenuated ABCA1 expression in cultured cells. Consistently, POAG patients exhibited lower ABCA1 expression, reduced HDL, and higher cholesterol in white blood cells. Ablation of Abca1 in mice failed to form HDL, leading to elevated cholesterol levels in the retina. Counting retinal ganglion cells (RGCs) by using an artificial intelligence (AI) program revealed that Abca1-deficient mice progressively lost RGCs with age. Single-cell RNA sequencing (scRNA-seq) revealed aberrant oxidative phosphorylation in the Abca1-/- retina, as well as activation of the mTORC1 signaling pathway and suppression of autophagy. Treatment of Abca1-/- mice using atorvastatin reduced the cholesterol level in the retina, thereby improving metabolism and protecting RGCs from death. Collectively, we show that lower ABCA1 expression and lower HDL are risk factors for POAG. Accumulated cholesterol in the Abca1-/- retina causes profound aberrant metabolism, leading to a POAG-like phenotype that can be prevented by atorvastatin. Our findings establish statin use as a preventive treatment for POAG associated with lower ABCA1 expression.

Influenza vaccination features revealed by a single-cell transcriptome atlas.

Emerging and re-emerging viruses like influenza virus pose a continuous global public health threat. Vaccines are one of the most effective public health strategies for controlling infectious diseases. However, little is known about the immunological features of vaccination at the single-cell resolution, including for influenza vaccination. Here, we report the single-cell transcriptome atlas of longitudinally collected peripheral blood mononuclear cells (PBMCs) in individuals immunized with an inactivated influenza vaccine. Overall, vaccination with the influenza vaccine only had a small impact on the composition of peripheral immune cells, but elicited global transcriptional changes in multiple immune cell subsets. In plasma and B cell subsets, transcriptomic changes, which were mostly involved in antibody production as well as B cell activation and differentiation, were observed after influenza vaccinations. In influenza-vaccinated individuals, we found a reduction in multiple biological processes (e.g., interferon response, inflammatory response, HLA-I/II molecules, cellular apoptosis, migration, and cytotoxicity, etc.,) 7 days postvaccination in multiple immune cell subsets. However, 14 days postvaccination, these levels returned to similar levels observed in prevaccination samples. Additionally, we did not observe significant upregulation of pro-inflammatory response genes and key thrombosis-related genes in influenza-vaccinated individuals. Taken together, we report a cell atlas of the peripheral immune response to influenza vaccination and provide a resource for understanding the immunological response mechanisms of influenza vaccination.