SLC22A17 as a Cell Death-Linked Regulator of Tight Junctions in Cerebral Ischemia.

BACKGROUND: Beyond neuronal injury, cell death pathways may also contribute to vascular injury after stroke. We examined protein networks linked to major cell death pathways and identified SLC22A17 (solute carrier family 22 member 17) as a novel mediator that regulates endothelial tight junctions after ischemia and inflammatory stress. METHODS: Protein-protein interactions and brain enrichment analyses were performed using STRING, Cytoscape, and a human tissue-specific expression RNA-seq database. In vivo experiments were performed using mouse models of transient focal cerebral ischemia. Human stroke brain tissues were used to detect SLC22A17 by immunostaining. In vitro experiments were performed using human brain endothelial cultures subjected to inflammatory stress. Immunostaining and Western blot were used to assess responses in SLC22A17 and endothelial tight junctional proteins. Water content, dextran permeability, and electrical resistance assays were used to assess edema and blood-brain barrier (BBB) integrity. Gain and loss-of-function studies were performed using lentiviral overexpression of SLC22A17 or short interfering RNA against SLC22A17, respectively. RESULTS: Protein-protein interaction analysis showed that core proteins from apoptosis, necroptosis, ferroptosis, and autophagy cell death pathways were closely linked. Among the 20 proteins identified in the network, the iron-handling solute carrier SLC22A17 emerged as the mediator enriched in the brain. After cerebral ischemia in vivo, endothelial expression of SLC22A17 increases in both human and mouse brains along with BBB leakage. In human brain endothelial cultures, short interfering RNA against SLC22A17 prevents TNF-α (tumor necrosis factor alpha)-induced ferroptosis and downregulation in tight junction proteins and disruption in transcellular permeability. Notably, SLC22A17 could repress the transcription of tight junctional genes. Finally, short interfering RNA against SLC22A17 ameliorates BBB leakage in a mouse model of focal cerebral ischemia. CONCLUSIONS: Using a combination of cell culture, human stroke samples, and mouse models, our data suggest that SLC22A17 may play a role in the control of BBB function after cerebral ischemia. These findings may offer a novel mechanism and target for ameliorating BBB injury and edema after stroke.

Regulating Interlayer-Spacing of Vanadium Phosphates for High-Capacity and Long-Life Aqueous Iron-Ion Batteries.

Although the research on aqueous batteries employing metal as the anode is still mainly focused on the aqueous zinc-ion battery, aqueous iron-ion batteries are considered as promising aqueous batteries owing to the lower cost, higher specific capacity, and better stability. However, the sluggish Fe2+ (de)intercalation leads to unsatisfactory specific capacity and poor electrochemical stability, which makes it difficult to find cathode materials with excellent electrochemical properties. Herein, phenylamine (PA)-intercalated VOPO4 materials with expanded interlayer spacing are synthesized and applied successfully in aqueous iron-ion batteries. Owing to enough diffusion space from the expanded interlayer, which can boost fast Fe2+ diffusion, the aqueous iron-ion battery shows a high specific capacity of 170 mAh g-1 at 0.2 A g-1 , excellent rate performance, and cycle stability (96.2% capacity retention after 2200 cycles). This work provides a new direction for cathode material design in the development of aqueous iron-ion batteries.

Irisin inhibits CCK-8-induced TNF-α production via integrin αVß5-NF-κB signaling pathways in Nile tilapia (Oreochromis niloticus).

Irisin, a secreted myokine generated by fibronectin type III domain-containing protein 5, has recently shown the potential to alleviate inflammation. Cholecystokinin-octapeptide (CCK-8) is closely associated with the inflammatory factor TNF-α, a central cytokine in inflammatory reactions. However, the interactions between irisin and CCK-8 in regulating TNF-α production and the underlying mechanism have not yet been elucidated. In the present study, irisin treatment inhibited the basal and the CCK-8-induced TNF-α production in vivo. Additionally, neutralizing circulating irisin using an irisin antiserum significantly augmented the CCK-8-induced stimulation of TNF-α levels. Moreover, the incubation of head kidney cells with irisin or CCK-8 has opposite effects on TNF-α secretion. Notably, irisin treatment inhibited basal and CCK-8-stimulated TNF-α release and gene transcription in head kidney cells. Mechanistically, the inhibitory actions of irisin on basal and CCK-8-induced TNF-α production could be negated by co-administered with the selective integrin αVß5 inhibitor cilengitide. In addition, the inhibitory effect of irisin on basal and CCK-8-triggered TNF-α production could be abolished by the inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, irisin impeded CCK-8-induced phosphorylation and degradation of IκBα, simultaneously inhibiting NF-κB phosphorylation, preventing its translocation into the nucleus, and suppressing its DNA-binding activity induced by CCK-8. Collectively, these results suggest that the inhibitory effect of irisin on TNF-α production caused by CCK-8 is mediated via the integrin αVß5-NF-κB signaling pathways in tilapia.

Machine Learning-Based Integrated Analysis of PANoptosis Patterns in Acute Myeloid Leukemia Reveals a Signature Predicting Survival and Immunotherapy.

Objective: We conducted a meticulous bioinformatics analysis leveraging expression data of 226 PANRGs obtained from previous studies, as well as clinical data from AML patients derived from the HOVON database. Methods: Through meticulous data analysis and manipulation, we were able to categorize AML cases into two distinct PANRG clusters and subsequently identify differentially expressed genes (PRDEGs) with prognostic significance. Furthermore, we organized the patient data into two corresponding gene clusters, allowing us to investigate the intricate relationship between the risk score, patient prognosis, and the immune landscape. Results: Our findings disclosed significant associations between the identified PANRGs, gene clusters, patient survival, immune system, and cancer-related biological processes and pathways. Importantly, we successfully constructed a prognostic signature comprising nineteen genes, enabling the stratification of patients into high-risk and low-risk groups based on individually calculated risk scores. Furthermore, we developed a robust and practical nomogram model, integrating the risk score and other pertinent clinical features, to facilitate accurate patient survival prediction. Our comprehensive analysis demonstrated that the high-risk group exhibited notably worse prognosis, with the risk score proving to be significantly correlated with infiltration of most immune cells. The qRT-PCR results revealed significant differential expression patterns of LGR5 and VSIG4 in normal and human leukemia cell lines (HL-60 and MV-4-11). Conclusions: Our findings underscore the potential utility of PANoptosis-based molecular clustering and prognostic signatures as predictive tools for assessing patient survival in AML.

Precise coordination of cell-ECM adhesion is essential for efficient melanoblast migration during development.

Melanoblasts disperse throughout the skin and populate hair follicles through long-range cell migration. During migration, cells undergo cycles of coordinated attachment and detachment from the extracellular matrix (ECM). Embryonic migration processes that require cell-ECM attachment are dependent on the integrin family of adhesion receptors. Precise regulation of integrin-mediated adhesion is important for many developmental migration events. However, the mechanisms that regulate integrin-mediated adhesion in vivo in melanoblasts are not well understood. Here, we show that autoinhibitory regulation of the integrin-associated adapter protein talin coordinates cell-ECM adhesion during melanoblast migration in vivo Specifically, an autoinhibition-defective talin mutant strengthens and stabilizes integrin-based adhesions in melanocytes, which impinges on their ability to migrate. Mice with defective talin autoinhibition exhibit delays in melanoblast migration and pigmentation defects. Our results show that coordinated integrin-mediated cell-ECM attachment is essential for melanoblast migration and that talin autoinhibition is an important mechanism for fine-tuning cell-ECM adhesion during cell migration in development.

Understanding the Super-Theoretical Capacity Behavior of VO2 in Aqueous Zn Batteries.

VO2 material, as a promising intercalation host, is widely investigated not only in aqueous lithium-ion batteries, but also in aqueous zinc-ion batteries (AZIBs) owing to its stable tunnel-like framework and multivalence of vanadium. Different from lithium-ion storage, VO2 can provide higher capacity when storing zinc ions, even exceeding its theoretical capacity (323 mAh g-1 ), but the specific reason for this unconventional performance in AZIBs is still unclear. The present study proposes a catalytic oxygen evolution reaction (OER) coupled with an interface oxidation mechanism of VO2 during the initial charging to a high voltage. This coupling induces a phase transformation of VO2 into a high oxidation state of V5 O12 ∙6H2 O, enabling a nearly two-electron reaction and providing additional zinc storage sites to achieve super-theoretical capacity. Furthermore, it is demonstrated that these vanadium oxide cathodes (V2 O3 , VO2 , and V2 O5 ) will all undergo phase change after the first charge or short cycle. Notably, water molecules participate in the final formation of layered vanadium-based hydrate, highlighting their crucial role as "pillars" for stabilizing the structure. This work significantly enhances the understanding of vanadium-based oxide cathodes.

Metal Halides for High-Capacity Energy Storage.

High-capacity electrochemical energy storage systems are more urgently needed than ever before with the rapid development of electric vehicles and the smart grid. The most efficient way to increase capacity is to develop electrode materials with low molecular weights. The low-cost metal halides are theoretically ideal cathode materials due to their advantages of high capacity and redox potential. However, their cubic structure and large energy barrier for deionization impede their rechargeability. Here, the reversibility of potassium halides, lithium halides, sodium halides, and zinc halides is achieved through decreasing their dimensionality by the strong π-cation interactions between metal cations and reduced graphene oxide (rGO). Especially, the energy densities of KI-, KBr-, and KCl-based materials are 722.2, 635.0, and 739.4 Wh kg-1 , respectively, which are higher than those of other cathode materials for potassium-ion batteries. In addition, the full-cell with 2D KI/rGO as cathode and graphite as anode demonstrates a lifespan of over 150 cycles with a considerable capacity retention of 57.5%. The metal halides-based electrode materials possess promising application prospects and are worthy of more in-depth researches.

Antileukemic effect of venetoclax and hypomethylating agents via caspase-3/GSDME-mediated pyroptosis.

BACKGROUND: The identifying of B-cell lymphoma 2 (Bcl-2) as a therapeutic target has led to a paradigm shift in acute myeloid leukemia (AML) treatment. Pyroptosis is a novel antitumor therapeutic mechanism due to its cytotoxic and immunogenic effects. The combination of venetoclax and hypomethylating agents (HMAs) has been shown to lead to durable responses and significantly improve prognosis in patients with AML. However, our understanding of the mechanisms underlying this combinatorial activity is evolving. METHODS: We investigated whether the Bcl-2 inhibitor venetoclax induces AML cell pyroptosis and identified pyroptosis effector proteins. Via using western blotting, immunoprecipitation, RNA interference, CCK8 assays, and LDH assays, we explored the mechanism underlying the pyroptotic effect. The relationship between the expression of the pyroptosis effector protein GSDME and AML prognosis was investigated. The effect of GSDME demethylation combined with venetoclax treatment on pyroptosis was investigated and confirmed in mouse models and clinical samples. RESULTS: Venetoclax induces pyroptosis that is mediated by caspase-3-dependent GSDME cleavage. Mechanistically, venetoclax upregulates caspase-3 and GSDME cleavage by activating the intrinsic apoptotic pathway. GSDME is downregulated in AML by promoter methylation, and low GSDME expression is significantly associated with poor prognosis, based on public databases and patient sample analysis. In vivo and in vitro experiments showed that GSDME overexpression or HMAs-mediated restoration of GSDME expression significantly increased venetoclax-induced pyroptosis in AML. CONCLUSION: GSDME-mediated pyroptosis may be a novel aspect of the antileukemic effect of Bcl-2 inhibitors. This finding offers new insights into potential biomarkers and therapeutic strategies, identifying an important mechanism explaining the clinical activity of venetoclax and HMAs in AML.

[Dose-response relationship between age and Streptococcus pneumoniae vaccination coverage in kindergarten children]. / 幼儿园儿童年龄与肺炎链球菌疫苗覆盖率间的剂量-ååº”å ³ç³».

OBJECTIVES: To investigate the potential relationship between age and Streptococcus pneumoniae vaccination coverage in kindergarten children, and to provide a basis for guiding vaccination and developing new protein vaccines. METHODS: The stratified cluster random sampling method was used to select 1 830 healthy children from six kindergartens in Shunde District, Foshan City, China, and nasopharyngeal swabs were collected for the isolation and identification of Streptococcus pneumoniae. The logistic regression model based on restricted cubic spline was used to analyze the dose-response relationship between age and Streptococcus pneumoniae vaccination coverage. RESULTS: The rate of nasal Streptococcus pneumoniae carriage was 22.46% (411/1 830) among the kindergarten children, with the predominant serotypes of 6B, 19F, 15A, 23A, 34, and 23F. The coverage rates of 10-valent pneumococcal conjugate vaccine (PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13) were 53.0% and 57.9%, respectively, and there was a significant non-linear dose-response relationship between age and the coverage rates of PCV10 and PCV13 (P<0.05), with a higher coverage rate of PCV10 (88.0%) and PCV13 (91.1%) in the children aged 2 years. There was a significant non-linear dose-response relationship between age and the coverage rates of pilus islet 1 (PI-1) and pilus islet 2 (PI-2) (P<0.05), with a lower vaccination coverage rate for PI-1 (37.7%) and PI-2 (16.1%). The coverage rates of PI-1 (13.0%-58.5%) and PI-2 (6.0%-29.4%) were lower in all age groups. The virulence genes lytA (99.5%) and ply (99.0%) associated with candidate protein vaccines showed higher vaccination coverage rates. CONCLUSIONS: There is a significant non-linear dose-response relationship between the age of kindergarten children and the coverage rates of PCV10 and PCV13 serotypes, and kindergarten children aged 2 years have a relatively high coverage rate of PCV. The high prevalence of the virulence genes lytA and ply shows that they are expected to become candidate virulence factors for the development of a new generation of recombinant protein vaccines.

Biomolecular Regulation of Zinc Deposition to Achieve Ultra-Long Life and High-Rate Zn Metal Anodes.

Aqueous zinc-ion batteries (ZIBs) have been extensively studied due to their inherent safety and high energy density for large-scale energy storage. However, the practical application is significantly limited by the growing Zn dendrites on metallic Zn anode during cycling. Herein, an environmental biomolecular electrolyte additive, fibroin (FI), is proposed to guide the homogeneous Zn deposition and stabilize Zn anode. This work demonstrates that the FI molecules with abundant electron-rich groups (NH, OH, and CO) can anchor on Zn anode surface to provide more nucleation sites and suppress the side reactions, and the strong interaction with water molecules can simultaneously regulate the Zn2+ coordination environment facilitating the uniform deposition of Zn. As a consequence, only 0.5 wt% FI additive enables a highly reversible Zn plating/stripping over 4000 h at 1 mA cm-2 , indicating a sufficient advance in performance over state-of-the-art Zn anodes. Furthermore, when applied to a full battery (NaVO/Zn), the cell exhibits excellent capacity retention of 98.4% after 1000 cycles as well as high Coulombic efficiency of 99%, whereas the cell only operates for 68 cycles without FI additive. This work offers a non-toxic, low-cost, effective additive strategy to solve dendrites problems and achieve long-life and high-performance rechargeable aqueous ZIBs.

Comprehensive analysis of CXCR family members in lung adenocarcinoma with prognostic values.

BACKGROUND: The expression profiles and molecular mechanisms of CXC chemokine receptors (CXCRs) in Lung adenocarcinoma (LUAD) have been extensively explored. However, the comprehensive prognostic values of CXCR members in LUAD have not yet been clearly identified. METHODS: Multiple available datasets, including Oncomine datasets, the cancer genome atlas (TCGA), HPA platform, GeneMANIA platform, DAVID platform and the tumor immune estimation resource (TIMER) were used to detect the expression of CXCRs in LUAD, as well as elucidate the significance and value of novel CXCRs-associated genes and signaling pathways in LUAD. RESULTS: The mRNA and/or protein expression of CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CXCR6 displayed predominantly decreased in LUAD tissues as compared to normal tissues. On the contrary, compared with the normal tissues, the expression of CXCR7 was significantly increased in LUAD tissues. Subsequently, we constructed a network including CXCR family members and their 20 related genes, and the related GO functions assay showed that CXCRs connected with these genes participated in the process of LUAD through several signal pathways including Chemokine signaling pathway, Cytokine-cytokine receptor interaction and Neuroactive ligand-receptor interaction. TCGA and Timer platform revealed that the mRNA expression of CXCR family members was significantly related to individual cancer stages, cancer subtypes, patient's gender and the immune infiltration level. Finally, survival analysis showed that low mRNA expression levels of CXCR2 (HR = 0.661, and Log-rank P = 1.90e-02), CXCR3 (HR = 0.674, and Log-rank P = 1.00e-02), CXCR4 (HR = 0.65, and Log-rank P = 5.01e-03), CXCR5 (HR = 0.608, and Log-rank P = 4.80e-03) and CXCR6 (HR = 0.622, and Log-rank P = 1.85e-03) were significantly associated with shorter overall survival (OS), whereas high CXCR7 mRNA expression (HR = 1.604, and Log-rank P = 4.27e-03) was extremely related with shorter OS in patients. CONCLUSION: Our findings from public databases provided a unique insight into expression characteristics and prognostic values of CXCR members in LUAD, which would be benefit for the understanding of pathogenesis, diagnosis, prognosis prediction and targeted treatment in LUAD.

[Application value of metagenomic next-generation sequencing for pathogen detection in childhood agranulocytosis with fever]. / ç— åŽŸä½“å®åŸºå› ç»„äºŒä»£æµ‹åºåœ¨å„¿ç«¥ç²’ç»†èƒžç¼ºä¹ä¼´å‘çƒ­ä¸­çš„åº”ç”¨ä»·å€¼.

OBJECTIVES: To study the application value of metagenomic next-generation sequencing (mNGS) for pathogen detection in childhood agranulocytosis with fever. METHODS: A retrospective analysis was performed on the mNGS results of pathogen detection of 116 children with agranulocytosis with fever who were treated from January 2020 to December 2021. Among these children, 38 children with negative mNGS results were enrolled as the negative group, and 78 children with positive results were divided into a bacteria group (n=22), a fungal group (n=23), and a viral group (n=31). Clinical data were compared between groups. RESULTS: For the 116 children with agranulocytosis and fever, the median age was 8 years at diagnosis, the median turnaround time of mNGS results was 2 days, and the positive rate of mNGS testing was 67.2% (78/116). Compared with the negative group, the bacterial group had a higher procalcitonin level (P<0.05), the fungal group had higher level of C-reactive protein and positive rate of (1,3)-ß-D glucan test/galactomannan test (P<0.05), and the fungal group had a longer duration of fever (P<0.05). Among the 22 positive microbial culture specimens, 9 (41%) were consistent with the mNGS results. Among the 17 positive blood culture specimens, 8 (47%) were consistent with the mNGS results. Treatment was adjusted for 28 children (36%) with the mNGS results, among whom 26 were cured and discharged. CONCLUSIONS: The mNGS technique has a shorter turnaround time and a higher sensitivity for pathogen detection and can provide evidence for the pathogenic diagnosis of children with agranulocytosis and fever.

Co-carriage of Streptococcus pneumoniae and Moraxella catarrhalis among preschool children and its influencing factors. / å­¦é¾„å‰å„¿ç«¥è‚ºç‚Žé“¾çƒèŒå’Œå¡ä»–èŽ«æ‹‰èŒæºå¸¦çŠ¶æ€åŠå½±å“å› ç´ åˆ†æž.

OBJECTIVES: To investigate the carriage status of Streptococcus pneumoniae (S.pneumoniae) and Moraxella catarrhalis (M. catarrhalis) in preschool children and the influencing factors for the carriage status. METHODS: The stratified cluster sampling method was used to select 2 031 healthy children from seven kindergartens in Shunde District of Foshan in Guangdong, China. Nasal swabs were collected from all children for the isolation and identification of S. pneumoniae and M. catarrhalis. The carriage status of S. pneumoniae and M. catarrhalis was analyzed in terms of its association with demographic features and hospital- and community-related factors. RESULTS: The carriage rates of S. pneumoniae and M. catarrhalis were 21.81% and 52.44%, respectively among the children. The co-carriage rate of S. pneumoniae and M. catarrhalis was 14.87%. The correspondence analysis showed that the factors such as lower grade, non-local registered residence, living in rural areas, small living area, history of respiratory tract infection but no history of antibiotic use, allergic skin diseases, and no hospital-related exposure history were significantly associated with the co-carriage of S. pneumoniae and M. catarrhalis among the children (P<0.05). CONCLUSIONS: Co-carriage of S. pneumoniae and M. catarrhalis can be observed in preschool children. Young age, poor living environment, a history of respiratory tract infection but no history of antibiotic use, allergic skin diseases, and no hospital-related exposure history are important risk factors for the co-carriage of S. pneumoniae and M. catarrhalis in preschool children.

[Clinical features and prognosis in 20 children with rhabdomyosarcoma]. / 20例横纹肌肉瘤患儿的临床特点及预后分析.

OBJECTIVES: To study the clinical features of children with rhabdomyosarcoma (RMS) and the influencing factors for prognosis. METHODS: A retrospective analysis was performed on the clinical and follow-up data of 20 children with RMS who were admitted to the Department of Pediatric Hematology, Xiangya Hospital of Central South University, from June 2014 to September 2020. RESULTS: The most common clinical symptoms of the 20 children with RMS at the first visit were painless mass (13/20, 65%), exophthalmos (4/20, 20%), and abdominal pain (3/20, 15%). According to the staging criteria of Intergroup Rhabdomyosarcoma Study Group (IRSG), there was 1 child (5%) with stage I RMS, 4 (20%) with stage II RMS, 9 (45%) with stage III RMS, and 6 (30%) with stage IV RMS. The median follow-up time was 19 months for the 20 children (range: 3-93 months), with a 2-year overall survival (OS) rate of 79.5% (95%CI: 20.1-24.3) and a 2-year event-free survival (EFS) rate of 72.0% (95%CI: 19.5-23.9). Pleomorphic RMS was associated with the reduced 2-year OS rate (P<0.05), and distant metastasis, IRSG stage IV RMS, and high-risk RMS were associated with the reduced 2-year EFS rate (P<0.05). CONCLUSIONS: RMS has no specific clinical symptoms at the first visit, with painless mass as the most common symptom. Distant metastasis, IRSG stage, and risk degree may be associated with the prognosis of children with RMS.

Residual Shunt After Patent Foramen Ovale Closure and Long-Term Stroke Recurrence: A Prospective Cohort Study.

BACKGROUND: Residual shunt is observed in up to 25% of patients after patent foramen ovale (PFO) closure, but its long-term influence on stroke recurrence currently is unknown. OBJECTIVE: To investigate the association of residual shunt after PFO closure with the incidence of recurrent stroke and transient ischemic attack (TIA). DESIGN: Prospective cohort study comparing stroke or TIA recurrence in patients with and without residual shunt after PFO closure. SETTING: Single hospital center. PARTICIPANTS: 1078 consecutive patients (mean age, 49.3 years) with PFO-attributable cryptogenic stroke who were undergoing percutaneous PFO closure were followed for up to 11 years. MEASUREMENTS: Residual shunt was evaluated by transthoracic echocardiography with saline contrast. Primary outcome was a composite of the first recurrent ischemic stroke or TIA after PFO closure. RESULTS: Compared with complete closure, the presence of residual shunt after PFO closure was associated with an increased incidence of recurrent stroke or TIA: 2.32 versus 0.75 events per 100 patient-years (hazard ratio [HR], 3.05 [95% CI, 1.65 to 5.62]; P < 0.001). This result remained robust after adjustment for important covariates, namely age; study period; device; presence of atrial septal aneurysm, hypertension, hyperlipidemia, diabetes, hypercoagulability, or hypermobile septum; and medication use (HR, 3.01 [CI, 1.59 to 5.69]; P < 0.001). Further stratification based on shunt size revealed that moderate or large residual shunts were associated with a higher risk for stroke or TIA recurrence (HR, 4.50 [CI, 2.20 to 9.20]; P < 0.001); the result for small residual shunts was indeterminate (HR, 2.02 [CI, 0.87 to 4.69]; P = 0.102). LIMITATION: Nonrandomized study with potential unmeasured confounding. CONCLUSION: Among patients undergoing PFO closure to prevent future stroke, the presence of residual shunt, particularly a moderate or large residual shunt, was associated with an increased risk for stroke or TIA recurrence. PRIMARY FUNDING SOURCE: National Institutes of Health.

Glycyrrhetinic acid and its derivatives as potential alternative medicine to relieve symptoms in nonhospitalized COVID-19 patients.

SARS-CoV-2 is highly infectious, and infection by this virus results in COVID-19, manifesting predominantly symptoms in the lower respiratory system. Detection of viral genomic materials by RT-PCR is the gold standard for diagnosis. Suspected COVID-19 patients who had a documented history of exposure and exhibited symptoms, but did not have positive PCR test results, were generally self-quarantined with prescriptions aiming to help attenuate their symptoms. These prescriptions are however neither specific nor highly effective for COVID-19 treatment. Given the rapidly growing pandemic and the overwhelmed medical system, the number of self-quarantined patients is increasing. There is an urgent need of alternative medicine to help patients relieve symptoms during self-quarantine, and to potentially help increase their chances of survival and recovery from the infection. We report here a case of severe COVID-19 that never had a positive PCR test result during disease progression but was confirmed with antibody test post recovery. This patient was self-quarantined and received diammonium glycyrrhizinate (DG), a steroid-like molecule, in combination with vitamin C as alternative medicine. This patient went through severe COVID-19 but eventually recovered upon the implementation of this treatment regimen, suggesting potential therapeutic effects of DG as alternative medicine to help relieve COVID-19 symptoms.

A lipid transfer protein variant with a mutant eight-cysteine motif causes photoperiod- and thermo-sensitive dwarfism in rice.

Plant height is an important trait for architecture patterning and crop yield improvement. Although the pathways involving gibberellins and brassinosteroids have been well studied, there are still many gaps in our knowledge of the networks that control plant height. In this study, we determined that a dominant photoperiod- and thermo-sensitive dwarf mutant is caused by the active role of a mutated gene Photoperiod-thermo-sensitive dwarfism 1 (Ptd1), the wild-type of which encodes a non-specific lipid transfer protein (nsLTP). Ptd1 plants showed severe dwarfism under long-day and low-temperature conditions, but grew almost normal under short-day and high-temperature conditions. These phenotypic variations were associated with Ptd1 mRNA levels and accumulation of the corresponding protein. Furthermore, we found that the growth inhibition in Ptd1 may result from the particular protein conformation of Ptd1 due to loss of two disulfide bonds in the eight-cysteine motif (8-CM) that is conserved among nsLTPs. These results contribute to our understanding of the novel function of disulfide bonds in the 8-CM, and provide a potential new strategy for regulation of cell development and plant height by modifying the amino acid residues involved in protein conformation patterning.

Effects of aging, hypertension and diabetes on the mouse brain and heart vasculomes.

The emerging concept of the vasculome suggests that microvessels contribute to function and dysfunction in every organ. In the brain, aging and comorbidities such as hypertension and diabetes significantly influence a wide variety of neurodegenerative and cerebrovascular disorders, but the underlying mechanisms are complex and remain to be fully elucidated. Here, we hypothesize that aging, hypertension and diabetes perturb gene networks in the vasculome. Microvascular endothelial cells were isolated from mouse brain and heart, and their transcriptomes were profiled with microarrays. For aging, we compared 5 mo vs 15 mo old C57BL6 male mice. For hypertension, we compared 4 mo old normotensive BPN vs hypertensive BPH male mice. For diabetes, we compared 3 mo old diabetic db/db mice with their matching C57BLKS controls. Four overall patterns arose from these comparative analyses. First, organ differences between brain and heart were larger than effects of age and co-morbidities per se. Second, across all conditions, more genes were altered in the brain vasculome compared with the heart. Third, age, hypertension and diabetes perturbed the brain and heart vasculomes in mostly distinct ways, with little overlap. Fourth, nevertheless, a few common pathways were detected in the brain, expressed mostly as a suppression of immune response. These initial drafts of the brain and heart vasculomes in the context of aging and vascular comorbidities should provide a framework for designing future investigations into potential targets and mechanisms in CNS disease.

MCPIP1 is a positive regulator of type I interferons antiviral activity.

Type-I interferons (IFN-I) are widely used for antiviral immunotherapy in clinic. Therefore, identification of the regulators of IFN-I antiviral activity is important for developing novel targets for IFN-based antiviral therapy. Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1) is critical for cellular inflammatory responses. However, the roles of MCPIP1 in interferons (IFNs)-mediated antiviral immunity are unexplored. In this study, we demonstrate for the first time that MCPIP1 is an important positive regulator of IFNs antiviral activity. We found that MCPIP1 can promote innate antiviral immunity independently of both its RNase and deubiquitinase activity. Furthermore, we reveal that MCPIP1 is an IFN-induced positive feedback signal molecule which promotes IFN-I-mediated antiviral efficacy. Mechanistically, MCPIP1 does not affect the activation of JAK/STAT upstream of IFN-I signaling, but significantly promotes IFN-I signaling by enhancing ISRE promoter activity and expression of interferon-stimulated genes (ISGs). And MCPIP1-mediated activation of IFN-I signaling is independently of its RNase and deubiquitinase activity. These findings uncover a novel innate antiviral mechanism mediated by the IFN-MCPIP1 axis, and may provide potential targets for enhancing IFNs antiviral therapy.

A potential gliovascular mechanism for microglial activation: differential phenotypic switching of microglia by endothelium versus astrocytes.

BACKGROUND: Activation of microglia can result in phenotypic and functional diversity. However, the pathways that trigger different states of microglial activation remain to be fully understood. Here, we hypothesized that after injury, astrocytes and endothelium may contribute to a gliovascular switch for microglial activation. METHODS: Astrocytes or cerebral endothelial cells were subjected to oxygen glucose deprivation, then conditioned media were transferred to microglia. The release of TNFα, IL-1ß, IL-10, and IGF-1 was measured using ELISA. Surface markers of CD11b, CD45, CD86, and MHC class II were detected by flow cytometry. mRNA expression of iNOS, CD86, CD206, Arginase1, and transcription factors was measured using real-time PCR. Microglial function including migration and phagocytosis was assessed. Dendritogenesis was determined by counting the number of primary dendrites, secondary dendrites, and dendritic ends in the neurons exposed to either endothelial- or astrocyte-activated microglia. RESULTS: Exposure to conditioned media from oxygen-glucose-deprived cerebral endothelial cells or oxygen-glucose-deprived astrocytes activated microglia into different forms. The endothelium converted ramified microglia into amoeboid shapes; increased the release of TNFα, IL-1ß, and IL-10; decreased IGF-1; upregulated iNOS expression; and inhibited microglial migration and phagocytosis. In contrast, astrocytes increased microglial production of IGF-1, upregulated CD206 expression, and enhanced microglial phagocytosis. These opposing effects of the endothelium versus astrocyte crosstalk partly mirror potentially deleterious versus potentially beneficial microglial phenotypes. Consistent with this idea, endothelial-activated microglia were neurotoxic, whereas astrocyte-activated microglia did not affect neuronal viability but instead promoted neuronal dendritogenesis. CONCLUSION: These findings provide proof of concept that endothelial cells and astrocytes provide differing signals to microglia that influence their activation states and suggest that a gliovascular switch may be involved in the balance between beneficial versus deleterious microglial properties.