Plasma Proteomics Identify Biomarkers and Pathogenesis of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is a global public health crisis. However, little is known about the pathogenesis and biomarkers of COVID-19. Here, we profiled host responses to COVID-19 by performing plasma proteomics of a cohort of COVID-19 patients, including non-survivors and survivors recovered from mild or severe symptoms, and uncovered numerous COVID-19-associated alterations of plasma proteins. We developed a machine-learning-based pipeline to identify 11 proteins as biomarkers and a set of biomarker combinations, which were validated by an independent cohort and accurately distinguished and predicted COVID-19 outcomes. Some of the biomarkers were further validated by enzyme-linked immunosorbent assay (ELISA) using a larger cohort. These markedly altered proteins, including the biomarkers, mediate pathophysiological pathways, such as immune or inflammatory responses, platelet degranulation and coagulation, and metabolism, that likely contribute to the pathogenesis. Our findings provide valuable knowledge about COVID-19 biomarkers and shed light on the pathogenesis and potential therapeutic targets of COVID-19.

The subgenomic flaviviral RNA suppresses RNA interference through competing with siRNAs for binding RISC components.

During the life cycle of mosquito-borne flaviviruses, substantial subgenomic flaviviral RNA (sfRNA) is produced via incomplete degradation of viral genomic RNA by host XRN1. Zika virus (ZIKV) sfRNA has been detected in mosquito and mammalian somatic cells. Human neural progenitor cells (hNPCs) in the developing brain are the major target cells of ZIKV, and antiviral RNA interference (RNAi) plays a critical role in hNPCs. However, whether ZIKV sfRNA was produced in ZIKV-infected hNPCs as well as its function remains not known. In this study, we demonstrate that abundant sfRNA was produced in ZIKV-infected hNPCs. RNA pulldown and mass spectrum assays showed ZIKV sfRNA interacted with host proteins RHA and PACT, both of which are RNA-induced silencing complex (RISC) components. Functionally, ZIKV sfRNA can antagonize RNAi by outcompeting small interfering RNAs (siRNAs) in binding to RHA and PACT. Furthermore, the 3' stem loop (3'SL) of sfRNA was responsible for RISC components binding and RNAi inhibition, and 3'SL can enhance the replication of a viral suppressor of RNAi (VSR)-deficient virus in a RHA- and PACT-dependent manner. More importantly, the ability of binding to RISC components is conversed among multiple flaviviral 3'SLs. Together, our results identified flavivirus 3'SL as a potent VSR in RNA format, highlighting the complexity in virus-host interaction during flavivirus infection.IMPORTANCEZika virus (ZIKV) infection mainly targets human neural progenitor cells (hNPCs) and induces cell death and dysregulated cell-cycle progression, leading to microcephaly and other central nervous system abnormalities. RNA interference (RNAi) plays critical roles during ZIKV infections in hNPCs, and ZIKV has evolved to encode specific viral proteins to antagonize RNAi. Herein, we first show that abundant sfRNA was produced in ZIKV-infected hNPCs in a similar pattern to that in other cells. Importantly, ZIKV sfRNA acts as a potent viral suppressor of RNAi (VSR) by competing with siRNAs for binding RISC components, RHA and PACT. The 3'SL of sfRNA is responsible for binding RISC components, which is a conserved feature among mosquito-borne flaviviruses. As most known VSRs are viral proteins, our findings highlight the importance of viral non-coding RNAs during the antagonism of host RNAi-based antiviral innate immunity.

Key Residue in the Precursor Region of M Protein Contributes to the Neurovirulence and Neuroinvasiveness of the African Lineage of Zika Virus.

The Zika virus (ZIKV) represents an important global health threat due to its unusual association with congenital Zika syndrome. ZIKV strains are phylogenetically grouped into the African and Asian lineages. However, the viral determinants underlying the phenotypic differences between the lineages remain unknown. Here, multiple sequence alignment revealed a highly conserved residue at position 21 of the premembrane (prM) protein, which is glutamic acid and lysine in the Asian and African lineages, respectively. Using reverse genetics, we generated a recombinant virus carrying an E21K mutation based on the genomic backbone of the Asian lineage strain FSS13025 (termed E21K). The E21K mutation significantly increased viral replication in multiple neural cell lines with a higher ratio of M to prM production. Animal studies showed E21K exhibited increased neurovirulence in suckling mice, leading to more severe defects in mouse brains by causing more neural cell death and destruction of hippocampus integrity. Moreover, the E21K substitution enhanced neuroinvasiveness in interferon alpha/beta (IFN-α/ß) receptor knockout mice, as indicated by the increased mortality, and enhanced replication in mouse brains. The global transcriptional analysis showed E21K infection profoundly altered neuron development networks and induced stronger antiviral immune response than wild type (WT) in both neural cells and mouse brains. More importantly, the reverse K21E mutation based on the genomic backbone of the African strain MR766 caused less mouse neurovirulence. Overall, our findings support the 21st residue of prM functions as a determinant for neurovirulence and neuroinvasiveness of the African lineage of ZIKV. IMPORTANCE The suspected link of Zika virus (ZIKV) to birth defects led the World Health Organization to declare ZIKV a Public Health Emergency of International Concern. ZIKV has been identified to have two dominant phylogenetic lineages, African and Asian. Significant differences exist between the two lineages in terms of neurovirulence and neuroinvasiveness in mice. However, the viral determinants underlying the phenotypic differences are still unknown. Here, combining reverse genetics, animal studies, and global transcriptional analysis, we provide evidence that a single E21K mutation of prM confers to the Asian lineage strain FSS130125 significantly enhanced replication in neural cell lines and more neurovirulent and neuroinvasiveness phenotypes in mice. Our findings support that the highly conserved residue at position 21 of prM functions as a determinant of neurovirulence and neuroinvasiveness of the African lineage of ZIKV in mice.

Kynurenine-3-monooxygenase (KMO) broadly inhibits viral infections via triggering NMDAR/Ca2+ influx and CaMKII/ IRF3-mediated IFN-ß production.

Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is well known to play a critical function in cancer, autoimmune and neurodegenerative diseases. However, its role in host-pathogen interactions has not been characterized yet. Herein, we identified that kynurenine-3-monooxygenase (KMO), a key rate-limiting enzyme in the KP, and quinolinic acid (QUIN), a key enzymatic product of KMO enzyme, exerted a novel antiviral function against a broad range of viruses. Mechanistically, QUIN induced the production of type I interferon (IFN-I) via activating the N-methyl-d-aspartate receptor (NMDAR) and Ca2+ influx to activate Calcium/calmodulin-dependent protein kinase II (CaMKII)/interferon regulatory factor 3 (IRF3). Importantly, QUIN treatment effectively inhibited viral infections and alleviated disease progression in mice. Furthermore, kmo-/- mice were vulnerable to pathogenic viral challenge with severe clinical symptoms. Collectively, our results demonstrated that KMO and its enzymatic product QUIN were potential therapeutics against emerging pathogenic viruses.

Daratumumab and venetoclax combined with CAGE for late R/R T-ALL/LBL patients: Single-arm, open-label, phase I study.

The prognosis of patients diagnosed with relapsed or refractory (R/R) T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) has consistently been unsatisfactory, with limited treatment options. As reports, the CAG regimen can serve as a salvage treatment for R/R T-ALL/LBL, but there remains a subset of patients who do not benefit from it. Recent studies have indicated that daratumumab (Dara) and venetoclax (Ven) may offer promising therapeutic benefits for T-ALL/LBL. In light of these findings, we conducted a safety and efficacy evaluation of the enhanced treatment regimen, combining Dara and Ven with aclarubicin, cytarabine, granulocyte colony-stimulating factor, and etoposide (CAGE), in patients suffering from R/R T-ALL/LBL. The participants in this phase I trial were patients with R/R T-ALL/LBL who fail to standard treatment regimens. During each 28-day cycle, the patients were treated by Dara, Ven, cytarabine, aclarubicin, granulocyte colony-stimulating factor, etoposide. The primary endpoint of this study was the rate of remission. This report presents the prospective outcomes of 21 patients who received the salvage therapy of Dara and Ven combined with the CAGE regimen (Dara + Ven + CAGE). The objective remission rate (ORR) was determined to be 57.1%, while the complete remission (CR) rate was 47.6%. Notably, patients with the early T-cell precursor (ETP) subtype exhibited a significantly higher remission rate in the bone marrow compared to non-ETP patients (100% vs. 44.4%, p = 0.044). The Dara + Ven + CAGE regimen demonstrated a favorable remission rate in patients with R/R T-ALL/LBL. Moreover, the treatment was well-tolerated.

NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression.

Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.

Transcriptome analysis of Schizothorax oconnori (Cypriniformes: Cyprinidae) oocytes: The role of K+ in promoting yolk globule fusion and regulating oocyte maturation.

Schizothorax oconnori (S. oconnori) is an economically important fish in Tibet. Oocyte maturation is a physiological process that is of great significance to reproduction and seed production in S. oconnori, yet little is currently known regarding the molecular mechanisms of oocyte development in this species. To identify candidate genes involved in reproduction of female fish, a combination of PacBio and Illumina HiSeq technologies was employed to provide deep coverage of the oocyte transcriptome. Transcriptome analysis revealed several candidate genes that are potentially involved in the regulation of oocyte maturation in S. oconnori, including GIRK1, CHRM3, NPY2R, GABRA3, GnRH3, mGluR1α, GPER1, GDF9, HSP90, and ESR2. Genes that are significantly expressed during oocyte maturation mainly contribute to the GPCR signaling pathway and the estrogen signaling pathway. Neurotransmitter (Ach, NPY, and GABA) and peptide hormone (GnRH3) binding to G protein-coupled receptors (GPCRs) frees G-protein ßγ subunits to interact with the G protein-gated inward rectifier K+ channel 1 (GIRK1). This process helps release K+ from granulosa cells to maturing oocytes, allowing yolk globule fusion. This mechanism may play an important role in oocyte maturation in S. oconnori. In conclusion, this study provides a valuable basis for deciphering the reproductive system in S. oconnori during the oocyte maturation process.

HMGB1 is a promising therapeutic target for asthma.

High-mobility group box protein 1 (HMGB1) is a non-histone deoxyribonucleic acid-binding nuclear protein. In physiological state it is involved in gene transctioripn regulation and cell replication, differentiation and maturation. HMGB1 is actively secreted into the extracellular space in the form of intracellular vesicles, upon stimulation of inflammation and infection, by monocytes, macrophages, dendritic cells (DCs), and other immune cells, and can also be passively released by necrotic or injured cells. After binding with the corresponding receptors, HMGB1 can activate the downstream substrate and trigger a series of biological effects. HMGB1 was mainly dependent on toll-like re ceptors (TLR) 2 and 4, and receptors for advanced glycation end products (RAGE) to trigger intracellular signal transduction, and mediate innate and adoptive immune responses. Besides these, studies have reported the participation of TLR3, TLR9, T-cell immunoglobulin mucin (TIM) 3, CD24, anti-N-methyl-D-aspartate receptor (NMDAR) in Th2 inflammatory response, eosinophilic airway inflammation, and airway hyperresponsiveness, mediated by HMGB1 in asthma. Both clinical and experimental studies suggested that HMGB1 was involved in the pathogenesis of asthma probably by regulating the downstream signaling pathways via corresponding receptors. This article reviews the role of HMGB1 in pathogenesis of asthma, and provides a new theoretical basis for the diagnosis and treatment of asthma.

NLRC3 Participates in Inhibiting the Pulmonary Inflammatory Response of Sepsis-Induced Acute Lung Injury.

Acute lung injury (ALI) progresses rapidly, is difficult to treat, and has a high fatality rate. The excessive inflammatory response is an important pathological mechanism of ALI. NLRC3 (NLR family CARD domain-containing 3), a non-inflammasome member of the NLR family, has been found that it could negatively regulates various biological pathways associated with inflammatory response, such as NF-κB (nuclear factor kappa B), PI3K (Phosphatidylinositol 3'-kinase)-Akt (protein kinase B)-mTOR (mammalian target of the rapamycin), and STING (stimulator of interferon genes) pathways, which are responsible for the progression of pulmonary inflammation and participate in regulating the pathological progression of ALI. However, the effects of NLRC3 in sepsis-induced pathological injury of lung tissue remain unclear. In this study, we aimed to investigate the potential effects of NLRC3 in the sepsis-induced ALI. To investigate whether NLRC3 participates in inhibiting the pulmonary inflammatory response of sepsis-induced ALI. Sepsis-induced ALI mice models were established by intrabronchial injection of lipopolysaccharide (LPS) or cecum ligation and puncture (CLP). The lentivirus with overexpression of NLRC3 (LV-NLRC3) and downregulation of NLRC3 (LV-NLRC3-RNAi) were transfected to LPS-induced ALI mice. The expression of NLRC3 was upregulated or downregulated in the lung tissue of sepsis-induced ALI mice. Transfection with NLRC3-overexpression lentivirus significantly decreased inflammatory response in the lung of LPS-induced ALI mice in contrast to the control group. By transfection with NLRC3-silencing lentivirus, the inflammatory response in LPS-induced ALI mice was aggravated. Our study provides evidence of the protective effect of NLRC3 in sepsis-induced ALI by inhibiting excessive inflammatory response of the lung tissue.AbbreviationsAcute lung injury: ALI; intensive care units: ICU; lipopolysaccharide: LPS; acute respiratory distress syndrome: ARDS; bronchoalveolar lavage fluid: BALF; nucleotide-binding oligomerization domain-like receptors: NLRs; NLR family CARD domain containing 3: NLRC3; nuclear factor kappa B: NF-κB; tumor necrosis factor receptor-associated factor 6: TRAF6; Phosphatidylinositol 3'-kinase: PI3K; protein kinase B: Akt; mammalian target of the rapamycin: mTOR; stimulator of interferon genes: STING; TANK-binding kinase 1: TBK1; type I interferon: IFN-I; toll-like receptors: TLRs; tumor necrosis factor: TNF; interleukin: IL; NOD-like receptor protein 3: NLRP3; enhanced green fluorescent protein: EGFP; lentivirus: LV; phosphate-buffered saline: PBS; intrabronchial: i.t.; cecum ligation and puncture: CLP; wet/dry: W/D; Real time polymerase chain reaction: RT-PCR; enzyme-linked immunosorbent assay: ELISA; hematoxylin and eosin: H&E; radio immunoprecipitation assay: RIPA; sodium dodecyl sulfate polyacrylamide gel electrophoresis: SDS-PAGE; polyvinylidene fluoride: PVDF; glyceraldehyde 3-phosphate dehydrogenase: GAPDH; bovine serum albumin: BSA; Tris buffered saline containing Tween 20: TBST; standard deviation: SD; one-way analysis of variance: ANOVA; janus kinase 2: JAK2; activators of transcription 3: STAT3; pathogen associated molecular patterns: PAMPs; danger associated molecular patterns: DAMPs.

Effects of airway pressure release ventilation on lung physiology assessed by electrical impedance tomography in patients with early moderate-to-severe ARDS.

OBJECTIVE: The aim of this study was to investigate the physiological impact of airway pressure release ventilation (APRV) on patients with early moderate-to-severe acute respiratory distress syndrome (ARDS) by electrical impedance tomography (EIT). METHODS: In this single-center prospective physiological study, adult patients with early moderate-to-severe ARDS mechanically ventilated with APRV were assessed by EIT shortly after APRV (T0), and 6 h (T1), 12 h (T2), and 24 h (T3) after APRV initiation. Regional ventilation and perfusion distribution, dead space (%), shunt (%), and ventilation/perfusion matching (%) based on EIT measurement at different time points were compared. Additionally, clinical variables related to respiratory and hemodynamic condition were analyzed. RESULTS: Twelve patients were included in the study. After APRV, lung ventilation and perfusion were significantly redistributed to dorsal region. One indicator of ventilation distribution heterogeneity is the global inhomogeneity index, which decreased gradually [0.61 (0.55-0.62) to 0.50 (0.42-0.53), p < 0.001]. The other is the center of ventilation, which gradually shifted towards the dorsal region (43.31 ± 5.07 to 46.84 ± 4.96%, p = 0.048). The dorsal ventilation/perfusion matching increased significantly from T0 to T3 (25.72 ± 9.01 to 29.80 ± 7.19%, p = 0.007). Better dorsal ventilation (%) was significantly correlated with higher PaO2/FiO2 (r = 0.624, p = 0.001) and lower PaCO2 (r = -0.408, p = 0.048). CONCLUSIONS: APRV optimizes the distribution of ventilation and perfusion, reducing lung heterogeneity, which potentially reduces the risk of ventilator-induced lung injury.

Remimazolam besylate versus propofol for deep sedation in critically ill patients: a randomized pilot study.

OBJECTIVE: To compare the efficacy and safety of remimazolam besylate and propofol for deep sedation in critically ill patients. METHODS: In this single-center, prospective, randomized, controlled pilot study, patients in the intensive care unit (ICU) requiring deep sedation were randomized to receive remimazolam besylate or propofol intravenously. Deep sedation was defined as a Richmond Agitation and Sedation Scale (RASS) score of - 4 or - 5. Sedation depth was monitored using RASS and Narcotrend Index (NI). The primary outcome was the percentage of time within the target sedation range without rescue sedation. The secondary outcomes included ventilator-free hours within 7 days, successful extubation, length of ICU stay, and 28-day mortality. Adverse events during the interventional period were also recorded. RESULTS: Thirty patients were assigned to each group. The median (IQR) RASS score was - 5.0 (- 5.0, - 4.0), and the median (IQR) NI value was 29.0 (21.0, 37.0) during the intervention period. Target RASS was reached a median of 100% of the sedation time in the two groups. No significant differences were observed in ventilator-free hours within 7 days, successful extubation, length of ICU stay, or 28-day mortality among groups. Hypotension occurred in 16 (53.3%) patients of remimazolam group and 18 (60.0%) patients of propofol group (p > 0.05). No patient experienced bradycardia. CONCLUSIONS: Remimazolam besylate appears to be an effective and safe agent for short-term deep sedation in critically ill patients. Our findings warrant large sample-sized randomized clinical trials.

Genetic effect of an InDel in the promoter region of the NUDT15 and its effect on myoblast proliferation in chickens.

BACKGROUND: Molecular breeding accelerates the speed of animal breeding. Screening molecular markers that can affect economic traits through genome-wide association studies (GWAS) can provide a theoretical basis for molecular breeding. At present, a large number of molecular markers have been screened in poultry research, but few reports on how molecular markers affect economic traits exist. It is particularly important to reveal the action mechanisms of molecular markers, which can provide more accurate information for molecular breeding. RESULTS: The aim of this study was to investigate the relationships between two indels (NUDT15-indel-2777 and NUDT15-indel-1673) in the promoter region of NUDT15 and growth and carcass traits in chickens and to explore the regulatory mechanism of NUDT15. Significant differences were found in genotype and allele frequencies among commercial broilers, commercial laying hens and dual-purpose chickens. The results of association analyses showed that these two indel loci could significantly affect growth traits, such as body weight, and carcass traits. Tissue expression profiling at E12 showed that the expression of NUDT15 was significantly higher in skeletal muscle, and time-expression profiling of leg muscle showed that the expression of NUDT15 in myoblasts was significantly higher in the E10 and E12 proliferation stages than in other stages. Promoter activity analysis showed that pro-1673-I and pro-1673-D significantly inhibited promoter activity, and the promoter activity of pro-1673-D was significantly lower than that of pro-1673-I. In addition, when NUDT15 was overexpressed or underwent interference in chicken primary myoblasts (CPMs), NUDT15 could inhibit the proliferation of CPMs. CONCLUSION: The results suggest that the studied indels in the promoter region of NUDT15 may regulate the proliferation of CPMs by affecting NUDT15 expression, ultimately affecting the growth and carcass traits of chickens. These indel polymorphisms may be used together as molecular markers for improving economic traits in chickens.

Iodine-Oxidized Diene-Based Rubbers as Anti-icing and Deicing Polymer Coatings.

In an effort to prevent or minimize icing hazards, techniques and materials for icing inhibition and deicing have always been highly favored throughout human history. This work discovers the integrated anti-icing and deicing effects of poly(styrene-b-butadiene-b-styrene) triblock rubber (SBS) after its easy oxidation in iodine vapor. Iodine oxidation happens on the block of polybutadiene, featured by the conversion of SBS from hydrophobic to amphiphilic and the improved capability of photothermal conversion. The oxidized SBS can serve as a polymer coating, which possesses intriguing abilities to delay the kinetics of icing on its surface and repel the ice under light illumination. According to characterizations of surface chemistry and mechanical performance, iodine oxidation is assumed to involve the processes of iodine coordination to unsaturated bonds, the formation of radical cations as a result of the redox reaction between iodine and unsaturated carbon-carbon bonds, improved light absorption owing to the formation of polyiodide anions, and intermolecular coupling of radical cations. The appearance of polar moieties/species within the oxidized SBS is attributed to the delayed ice nucleation. The significant photothermal capacity in visible and near-infrared windows enables the iodine-oxidized SBS coating to remove the adhered ice by melting under light illumination when the icing process is inevitable, even at an extremely low temperature (-25 °C).

Application of POCUS in patients with COVID-19 for acute respiratory distress syndrome management: a narrative review.

COVID-19 has inflicted the world for over two years. The recent mutant virus strains pose greater challenges to disease prevention and treatment. COVID-19 can cause acute respiratory distress syndrome (ARDS) and extrapulmonary injury. Dynamic monitoring of each patient's condition is necessary to timely tailor treatments, improve prognosis and reduce mortality. Point-of-care ultrasound (POCUS) is broadly used in patients with ARDS. POCUS is recommended to be performed regularly in COVID-19 patients for respiratory failure management. In this review, we summarized the ultrasound characteristics of COVID-19 patients, mainly focusing on lung ultrasound and echocardiography. Furthermore, we also provided the experience of using POCUS to manage COVID-19-related ARDS.

Role of Cholinergic Anti-Inflammatory Pathway in Protecting Sepsis-Induced Acute Lung Injury through Regulation of the Conventional Dendritic Cells.

BACKGROUND: The cholinergic anti-inflammatory pathway connects the immune response system and the nervous system via the vagus nerve. The key regulatory receptor is the α7-subtype of the nicotinic acetylcholine receptor (α7nAChR). Cholinergic anti-inflammatory pathway has been proved to be effective in suppressing the inflammation responses in acute lung injury (ALI). Dendritic cells (DCs), the important antigen-presenting cells, also express the α7nAChR. Past studies have indicated that reducing the quantity of mature conventional DCs and inhibiting the maturation of pulmonary DCs may prove effective for the treatment of ALI. However, the effects of cholinergic anti-inflammatory pathway on maturation, function, and quantity of DCs and conventional DCs in ALI remain unclear. OBJECTIVE: It was hypothesized that cholinergic anti-inflammatory pathway may inhibit the inflammatory response of ALI by regulating maturation, phenotype, and quantity of DCs and conventional DCs. METHODS: GTS-21 (GTS-21 dihydrochloride), an α7nAchR agonist, was prophylactically administered in sepsis-induced ALI mouse model and LPS-primed bone marrow-derived dendritic cells. The effects of GTS-21 were observed with respect to maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2 (type 2 conventional DCs) and the release of DC-related proinflammatory cytokines in vivo and in vitro. RESULTS: The results of the present study revealed that GTS-21 treatment decreased the maturation of DCs and the production of DC-related proinflammatory cytokines in vitro and in sepsis-induced ALI mouse model; it reduced the quantity of CD11c+MHCII+ conventional DCs and CD11c+CD11b+ conventional DCs2 in vivo experiment. CONCLUSIONS: Cholinergic anti-inflammatory pathway contributes to the reduction in the inflammatory response in ALI by regulating maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2.

Deconvoluting the Optical Response of Biocompatible Photonic Pigments.

To unlock the widespread use of block copolymers as photonic pigments, there is an urgent need to consider their environmental impact (cf. microplastic pollution). Here we show how an inverse photonic glass architecture can enable the use of biocompatible bottlebrush block copolymers (BBCPs), which otherwise lack the refractive index contrast needed for a strong photonic response. A library of photonic pigments is produced from poly(norbornene-graft-polycaprolactone)-block-poly(norbornene-graft-polyethylene glycol), with the color tuned via either the BBCP molecular weight or the processing temperature upon microparticle fabrication. The structure-optic relationship between the 3D porous morphology of the microparticles and their complex optical response is revealed by both an analytical scattering model and 3D finite-difference time domain (FDTD) simulations. Combined, this allows for strategies to enhance the color purity to be proposed and realized with our biocompatible BBCP system.

Overall trend towards headache remission during the COVID-19 pandemic among Chinese patients with pre-existing headache highlights the role of family support.

BACKGROUND: The global status of the COVID-19 pandemic is not optimistic. This is a particularly vulnerable time for patients with pre-existing headache disorders. The present study aimed to investigate the impact of the COVID-19 pandemic on headache patients in China. METHODS: A survey was conducted through an online survey platform on June 6, 2020. Demographic characteristics, the PHQ-9, the ISI, a COVID-19 questionnaire and a headache profile survey were included in the online questionnaire. RESULTS: Eventually, a total of 15,000 participants from China completed the online questionnaire. Among them, 2806 participants had pre-existing headache disorders. Our analysis showed reductions in the duration of headaches (3.414 ± 6.859 vs 4.033 ± 7.325 h, P<0.001), number of headache days per month (1.788 ± 2.989 vs 2.092 ± 3.694, P<0.001), and headache intensity (4.110 ± 1.609 vs 4.290 ± 1.680, P<0.001) during the COVID-19 pandemic. Smoking (OR = 1.397, 95% CI 1.090 to 1.790, P = 0.008) and getting support from family members during social isolation (OR = 1.656, 95% CI 1.075 to 2.550, P = 0.022) were independent factors affecting the reduction in the duration of headaches. Education level (OR = 1.478, 95% CI 1.103 to 1.980, P = 0.009) and having a relative or acquaintance who contracted COVID-19 (OR = 0.643, 95% CI 0.458 to 0.902, P = 0.011) were the independent factors affecting the reduction in headache severity. Living in the Wuhan area, having symptoms or a diagnosis of COVID-19 and having relatives or acquaintances who had contracted COVID-19 were associated with the worsening of headaches. CONCLUSIONS: Participants experienced an overall trend towards the improvement of headaches during the COVID-19 pandemic. Family support might play an important role in the improvement of headaches.

ATP/P2X7r axis mediates the pathological process of allergic asthma by inducing M2 polarization of alveolar macrophages.

Recent studies revealed that macrophages are polarized towards the M2 phenotype in an ovalbumin (OVA)-induced asthmatic model. Alveolar macrophages (AMs) are immune barriers in alveoli to various pathogens in the respiratory tract; AMs suppress Th2 cell proliferation, inhibit interleukin (IL)-4, IL-5, and IL-13 secretion, and protect against airway hyperresponsiveness in allergic asthma. However, the polarization status and effects of different types of AMs in the pathogenesis of asthma are not known. ATP/P2X7r, expressed mainly on macrophages and dendritic cells, is associated with acute and chronic asthmatic airway inflammation and Th2 immune responses in mice and humans and functions by activating the NLRP3 inflammasome complex and inducing proinflammatory cytokine release (IL-1ß and IL-18). Therefore, we evaluated the association between the ATP/P2X7r axis and different types of AMs in the pathology of allergic asthma. A murine AM-depleted asthma model was established by administration of clodronate-encapsulated liposomes, and M1-or M2-AMs were adoptively transferred to confirm the effects of different AMs in allergic asthma. Brilliant Blue G and BzATP were administered to OVA/HDM-induced mice in vivo. Lipopolysaccharide + OVA, ATP, Brilliant Blue G, and BzATP were used to stimulate AMs isolated from control and asthmatic mice. We found that selective depletion of AMs aggravated lung inflammation in asthmatic mice. Further, M2-type AMs may play a key role in mediating asthmatic inflammatory responses via the adoptive transfer of M2-type AMs to AM-depleted asthmatic mice, and the phenotype of AMs differentiated to M2 type in asthma. P2X7r expression in M2-type AMs was higher than that in M1-type AMs. Activating P2X7r induced polarization of M2-type AMs and inhibited polarization of M1-type AMs, while blockage of P2X7r had the opposite effect. The ATP/P2X7r axis may participate in the pathogenesis of asthma by mediating the M2-type AM polarization.

The role of prepotent response inhibition and interference control in depression.

INTRODUCTION: The ability to suppress inappropriate prepotent response and to overcome the interference of irrelevant information are two important components of inhibitory control. Little is known, however, about the relevant contributions in these two components of inhibitory control to depression. The aim of the present study was to assess the prepotent response inhibition and interference control simultaneously in a group of patients diagnosed with major depression disorder (MDD). METHODS: A clinical group of patients with MDD (n = 41) and a control group of healthy volunteers (n = 39) were recruited and assessed using the stop-signal task and the Flanker task respectively. RESULTS: The results showed longer stop-signal reaction time in patients with MDD in the stop-signal task. Regarding the interference control function, the analysis showed the response accuracy under the incongruent condition was significantly lower in patients with MDD than healthy individuals. CONCLUSIONS: In conclusion, patients with MDD showed impairments both in prepotent response inhibition and interference control. The present findings provide a better understanding of the mechanism of depression-related deficits in inhibition and have great implications for the development of cognitive training programmes to remediate cognitive dysfunction in depression.

Deficits in maintenance and interference control of working memory in major depression: evidence from the visuospatial change detection task.

INTRODUCTION: Recent theories in cognitive psychology suggest that working memory (WM) processing involves a set of specific functions, in particular the WM functions of maintenance and interference control. Previous findings on WM impairments in patients with major depressive disorder (MDD) had been inconsistent, partly because earlier studies did not take into account these two different functions of WM. METHOD: Forty-two participants with MDD and 39 controls completed the visuospatial change detection task. We estimated the WM function of maintenance, based on performance in trials using the targets only, and the WM function of interference control, based on performance in trials with distractor rectangles. RESULTS: Our results showed that participants with MDD had poorer WM function of maintenance and interference control than controls. However, the results of filtering efficiency did not show significant group difference, thus patients with MDD showed comparable impairments in WM function of maintanance as well as in WM function of interference control. CONCLUSION: Our findings suggested that patients with MDD appear to show generalised impairments on visuospatial WM function of maintenance and interference control. Future studies should use refined paradigms to assess the different functions of WM and their distinctive contributions to symptomatology of depression.