Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment.

COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.

Activation of TIR signalling boosts pattern-triggered immunity.

Plant immune responses are mainly activated by two types of receptor. Pattern recognition receptors localized on the plasma membrane perceive extracellular microbial features, and nucleotide-binding leucine-rich repeat receptors (NLRs) recognize intracellular effector proteins from pathogens1. NLRs possessing amino-terminal Toll/interleukin-1 receptor (TIR) domains activate defence responses via the NADase activity of the TIR domain2,3. Here we report that activation of TIR signalling has a key role in pattern-triggered immunity (PTI) mediated by pattern recognition receptors. TIR signalling mutants exhibit attenuated PTI responses and decreased resistance against pathogens. Consistently, PTI is compromised in plants with reduced NLR levels. Treatment with the PTI elicitor flg22 or nlp20 rapidly induces many genes encoding TIR-domain-containing proteins, which is likely to be responsible for activating TIR signalling during PTI. Overall, our study reveals that activation of TIR signalling is an important mechanism for boosting plant defence during PTI.

S100A11 promotes focal adhesion disassembly via myosin II-driven contractility and Piezo1-mediated Ca2+ entry.

S100A11 is a small Ca2+-activatable protein known to localize along stress fibers (SFs). Analyzing S100A11 localization in HeLa and U2OS cells further revealed S100A11 enrichment at focal adhesions (FAs). Strikingly, S100A11 levels at FAs increased sharply, yet transiently, just before FA disassembly. Elevating intracellular Ca2+ levels with ionomycin stimulated both S100A11 recruitment and subsequent FA disassembly. However, pre-incubation with the non-muscle myosin II (NMII) inhibitor blebbistatin or with an inhibitor of the stretch-activatable Ca2+ channel Piezo1 suppressed S100A11 recruitment, implicating S100A11 in an actomyosin-driven FA recruitment mechanism involving Piezo1-dependent Ca2+ influx. Applying external forces on peripheral FAs likewise recruited S100A11 to FAs even if NMII activity was inhibited, corroborating the mechanosensitive recruitment mechanism of S100A11. However, extracellular Ca2+ and Piezo1 function were indispensable, indicating that NMII contraction forces act upstream of Piezo1-mediated Ca2+ influx, in turn leading to S100A11 activation and FA recruitment. S100A11-knockout cells display enlarged FAs and had delayed FA disassembly during cell membrane retraction, consistent with impaired FA turnover in these cells. Our results thus demonstrate a novel function for S100A11 in promoting actomyosin contractility-driven FA disassembly.

Tn5 tagments and transposes oligos to single-stranded DNA for strand-specific RNA sequencing.

Tn5 transposon tagments double-stranded DNA and RNA/DNA hybrids to generate nucleic acids that are ready to be amplified for high-throughput sequencing. The nucleic acid substrates for the Tn5 transposon must be explored to increase the applications of Tn5. Here, we found that the Tn5 transposon can transpose oligos into the 5' end of single-stranded DNA longer than 140 nucleotides. Based on this property of Tn5, we developed a tagmentation-based and ligation-enabled single-stranded DNA sequencing method called TABLE-seq. Through a series of reaction temperature, time, and enzyme concentration tests, we applied TABLE-seq to strand-specific RNA sequencing, starting with as little as 30 pg of total RNA. Moreover, compared with traditional dUTP-based strand-specific RNA sequencing, this method detects more genes, has a higher strand specificity, and shows more evenly distributed reads across genes. Together, our results provide insights into the properties of Tn5 transposons and expand the applications of Tn5 in cutting-edge sequencing techniques.

FUS reads histone H3K36me3 to regulate alternative polyadenylation.

Complex organisms generate differential gene expression through the same set of DNA sequences in distinct cells. The communication between chromatin and RNA regulates cellular behavior in tissues. However, little is known about how chromatin, especially histone modifications, regulates RNA polyadenylation. In this study, we found that FUS was recruited to chromatin by H3K36me3 at gene bodies. The H3K36me3 recognition of FUS was mediated by the proline residues in the ZNF domain. After these proline residues were mutated or H3K36me3 was abolished, FUS dissociated from chromatin and bound more to RNA, resulting in an increase in polyadenylation sites far from stop codons genome-wide. A proline mutation corresponding to a mutation in amyotrophic lateral sclerosis contributed to the hyperactivation of mitochondria and hyperdifferentiation in mouse embryonic stem cells. These findings reveal that FUS is an H3K36me3 reader protein that links chromatin-mediated alternative polyadenylation to human disease.

Mouse models susceptible to HCoV-229E and HCoV-NL63 and cross protection from challenge with SARS-CoV-2.

Human coronavirus 229E (HCoV-229E) and NL63 (HCoV-NL63) are endemic causes of upper respiratory infections such as the "common cold" but may occasionally cause severe lower respiratory tract disease in the elderly and immunocompromised patients. There are no approved antiviral drugs or vaccines for these common cold coronaviruses (CCCoV). The recent emergence of COVID-19 and the possible cross-reactive antibody and T cell responses between these CCCoV and SARS-CoV-2 emphasize the need to develop experimental animal models for CCCoV. Mice are an ideal experimental animal model for such studies, but are resistant to HCoV-229E and HCoV-NL63 infections. Here, we generated 229E and NL63 mouse models by exogenous delivery of their receptors, human hAPN and hACE2 using replication-deficient adenoviruses (Ad5-hAPN and Ad5-hACE2), respectively. Ad5-hAPN- and Ad5-hACE2-sensitized IFNAR-/- and STAT1-/- mice developed pneumonia characterized by inflammatory cell infiltration with virus clearance occurring 7 d post infection. Ad5-hAPN- and Ad5-hACE2-sensitized mice generated virus-specific T cells and neutralizing antibodies after 229E or NL63 infection, respectively. Remdesivir and a vaccine candidate targeting spike protein of 229E and NL63 accelerated viral clearance of virus in these mice. 229E- and NL63-infected mice were partially protected from SARS-CoV-2 infection, likely mediated by cross-reactive T cell responses. Ad5-hAPN- and Ad5-hACE2-transduced mice are useful for studying pathogenesis and immune responses induced by HCoV-229E and HCoV-NL63 infections and for validation of broadly protective vaccines, antibodies, and therapeutics against human respiratory coronaviruses including SARS-CoV-2.

Plasma cell-free RNA characteristics in COVID-19 patients.

The pathogenesis of COVID-19 is still elusive, which impedes disease progression prediction, differential diagnosis, and targeted therapy. Plasma cell-free RNAs (cfRNAs) carry unique information from human tissue and thus could point to resourceful solutions for pathogenesis and host-pathogen interactions. Here, we performed a comparative analysis of cfRNA profiles between COVID-19 patients and healthy donors using serial plasma. Analyses of the cfRNA landscape, potential gene regulatory mechanisms, dynamic changes in tRNA pools upon infection, and microbial communities were performed. A total of 380 cfRNA molecules were up-regulated in all COVID-19 patients, of which seven could serve as potential biomarkers (AUC > 0.85) with great sensitivity and specificity. Antiviral (NFKB1A, IFITM3, and IFI27) and neutrophil activation (S100A8, CD68, and CD63)-related genes exhibited decreased expression levels during treatment in COVID-19 patients, which is in accordance with the dynamically enhanced inflammatory response in COVID-19 patients. Noncoding RNAs, including some microRNAs (let 7 family) and long noncoding RNAs (GJA9-MYCBP) targeting interleukin (IL6/IL6R), were differentially expressed between COVID-19 patients and healthy donors, which accounts for the potential core mechanism of cytokine storm syndromes; the tRNA pools change significantly between the COVID-19 and healthy group, leading to the accumulation of SARS-CoV-2 biased codons, which facilitate SARS-CoV-2 replication. Finally, several pneumonia-related microorganisms were detected in the plasma of COVID-19 patients, raising the possibility of simultaneously monitoring immune response regulation and microbial communities using cfRNA analysis. This study fills the knowledge gap in the plasma cfRNA landscape of COVID-19 patients and offers insight into the potential mechanisms of cfRNAs to explain COVID-19 pathogenesis.

The Proteome and Phosphoproteome Uncovers Candidate Proteins Associated With Vacuolar Phosphate Signal Multipled by Vacuolar Phosphate Transporter 1 (VPT1) in Arabidopsis.

Plant vacuoles serve as the primary intracellular compartments for inorganic phosphate (Pi) storage. Passage of Pi across vacuolar membranes plays a critical role in buffering the cytoplasmic Pi level against fluctuations of external Pi and metabolic activities. To gain new insights into the proteins and processes, vacuolar Pi level regulated by vacuolar phosphate transporter 1 (VPT1) in Arabidopsis, we carried out tandem mass tag labeling proteome and phosphoproteome profiling of Arabidopsis WT and vpt1 loss-of-function mutant plants. The vpt1 mutant had a marked reduced vacuolar Pi level and a slight increased cytosol Pi level. The mutant was stunted as reflected in the reduction of the fresh weight compared with WT plants and bolting earlier under normal growth conditions in soil. Over 5566 proteins and 7965 phosphopeptides were quantified. About 146 and 83 proteins were significantly changed at protein abundance or site-specific phosphorylation levels, but only six proteins were shared between them. Functional enrichment analysis revealed that the changes of Pi states in vpt1 are associated with photosynthesis, translation, RNA splicing, and defense response, consistent with similar studies in Arabidopsis. Except for PAP26, EIN2, and KIN10, which were reported to be associated with phosphate starvation signal, we also found that many differential proteins involved in abscisic acid signaling, such as CARK1, SnRK1, and AREB3, were significantly changed in vpt1. Our study illuminates several new aspects of the phosphate response and identifies important targets for further investigation and potential crop improvement.

Genome-wide association study for cashmere traits in Inner Mongolia cashmere goat population reveals new candidate genes and haplotypes.

BACKGROUND: The cashmere goat industry is one of the main pillars of animal husbandry in Inner Mongolia Autonomous Region, and plays an irreplaceable role in local economic development. With the change in feeding methods and environment, the cashmere produced by Inner Mongolia cashmere goats shows a tendency of coarser, and the cashmere yield can not meet the consumption demand of people. However, the genetic basis behind these changes is not fully understood. We measured cashmere traits, including cashmere yield (CY), cashmere diameter (CD), cashmere thickness (CT), and fleece length (FL) traits for four consecutive years, and utilized Genome-wide association study of four cashmere traits in Inner Mongolia cashmere goats was carried out using new genomics tools to infer genomic regions and functional loci associated with cashmere traits and to construct haplotypes that significantly affect cashmere traits. RESULTS: We estimated the genetic parameters of cashmere traits in Inner Mongolia cashmere goats. The heritability of cashmere yield, cashmere diameter, and fleece length traits of Inner Mongolia cashmere goats were 0.229, 0.359, and 0.250, which belonged to the medium heritability traits (0.2 ~ 0.4). The cashmere thickness trait has a low heritability of 0.053. We detected 151 genome-wide significantly associated SNPs with four cashmere traits on different chromosomes, which were very close to the chromosomes of 392 genes (located within the gene or within ± 500 kb). Notch3, BMPR1B, and CCNA2 have direct functional associations with fibroblasts and follicle stem cells, which play important roles in hair follicle growth and development. Based on GO functional annotation and KEGG enrichment analysis, potential candidate genes were associated with pathways of hair follicle genesis and development (Notch, P13K-Akt, TGF-beta, Cell cycle, Wnt, MAPK). We calculated the effective allele number of the Inner Mongolia cashmere goat population to be 1.109-1.998, the dominant genotypes of most SNPs were wild-type, the polymorphic information content of 57 SNPs were low polymorphism (0 < PIC < 0.25), and the polymorphic information content of 79 SNPs were moderate polymorphism (0.25 < PIC < 0.50). We analyzed the association of SNPs with phenotypes and found that the homozygous mutant type of SNP1 and SNP3 was associated with the highest cashmere yield, the heterozygous mutant type of SNP30 was associated with the lowest cashmere thickness, the wild type of SNP76, SNP77, SNP78, SNP80, and SNP81 was associated with the highest cashmere thickness, and the wild type type of SNP137 was associated with the highest fleece length. 21 haplotype blocks and 68 haplotype combinations were constructed. Haplotypes A2A2, B2B2, C2C2, and D4D4 were associated with increased cashmere yield, haplotypes E2E2, F1F1, G5G5, and G1G5 were associated with decreased cashmere fineness, haplotypes H2H2 was associated with increased cashmere thickness, haplotypes I1I1, I1I2, J1J4, L5L3, N3N2, N3N3, O2O1, P2P2, and Q3Q3 were associated with increased cashmere length. We verified the polymorphism of 8 SNPs by KASP, and found that chr7_g.102631194A > G, chr10_g.82715068 T > C, chr1_g.124483769C > T, chr24_g.12811352C > T, chr6_g.114111249A > G, and chr6_g.115606026 T > C were significantly genotyped in verified populations (P < 0.05). CONCLUSIONS: In conclusion, the genetic effect of single SNP on phenotypes is small, and SNPs are more inclined to be inherited as a whole. By constructing haplotypes from SNPs that are significantly associated with cashmere traits, it will help to reveal the complex and potential causal variations in cashmere traits of Inner Mongolia cashmere goats. This will be a valuable resource for genomics and breeding of the cashmere goat.

Genetic diversity analysis of Inner Mongolia cashmere goats (Erlangshan subtype) based on whole genome re-sequencing.

BACKGROUND: Inner Mongolia cashmere goat (IMCG), renowned for its superior cashmere quality, is a Chinese indigenous goat breed that has been developed through natural and artificial selection over a long period. However, recently, the genetic resources of IMCGs have been significantly threatened by the introduction of cosmopolitan goat breeds and the absence of adequate breed protection systems. RESULTS: In order to assess the conservation effectiveness of IMCGs and efficiently preserve and utilize the purebred germplasm resources, this study analyzed the genetic diversity, kinship, family structure, and inbreeding of IMCGs utilizing resequencing data from 225 randomly selected individuals analyzed using the Plink (v.1.90), GCTA (v.1.94.1), and R (v.4.2.1) software. A total of 12,700,178 high-quality SNPs were selected through quality control from 34,248,064 SNP sites obtained from 225 individuals. The average minor allele frequency (MAF), polymorphic information content (PIC), and Shannon information index (SHI) were 0.253, 0.284, and 0.530, respectively. The average observed heterozygosity (Ho) and the average expected heterozygosity (He) were 0.355 and 0.351, respectively. The analysis of the identity by state distance matrix and genomic relationship matrix has shown that most individuals' genetic distance and genetic relationship are far away, and the inbreeding coefficient is low. The family structure analysis identified 10 families among the 23 rams. A total of 14,109 runs of homozygosity (ROH) were identified in the 225 individuals, with an average ROH length of 1014.547 kb. The average inbreeding coefficient, calculated from ROH, was 0.026 for the overall population and 0.027 specifically among the 23 rams, indicating a low level of inbreeding within the conserved population. CONCLUSIONS: The IMCGs exhibited moderate polymorphism and a low level of kinship with inbreeding occurring among a limited number of individuals. Simultaneously, it is necessary to prevent the loss of bloodline to guarantee the perpetuation of the IMCGs' germplasm resources.

Influence of storage solution, temperature, assay time and concentration on RT-qPCR nucleic acid detection for SARS-CoV-2 detection of SARS-CoV-2 by the RT-qPCR.

Real-time reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) is an important method for the early diagnosis of coronavirus disease 2019 (COVID-19). This study investigated the effects of storage solution, temperature and detection time on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid detection by RT-qPCR. Various concentrations of SARS-CoV-2 were added to inactive and non-inactive storage solution and the viral suspensions were stored at various temperatures (room temperature, 4, -20 and -80 °C). Then, at five different detection time points, the Ct values were determined by RT-qPCR. Active and inactive storage solutions and storage temperature have a great impact on the detection of N gene of SARS-CoV-2 at different concentration corridors but have little impact on the ORF gene. The storage time has a greater impact on the N gene and ORF gene at high concentrations but has no effect on the two genes at low concentrations. In conclusion, storage temperature, storage time and storage status (inactivated, non-inactivated) have no effect on the nucleic acid detection of SARS-CoV-2 at the same concentration. For different concentrations of SARS-CoV-2, the detection of N gene is mainly affected.

Relationship of serum 25-hydroxyvitamin D, obesity with new-onset obstructive sleep apnea.

OBJECTIVE: The prospective association between vitamin D and obstructive sleep apnea (OSA) remains uncertain. We aimed to assess the association between serum 25-hydroxyvitamin D (25(OH)D), a major circulating form of vitamin D, and new-onset OSA, and examine the modifying effect of obesity. MATERIALS AND METHODS: This prospective cohort study included 444,975 participants from UK Biobank without prior OSA. The primary outcome was new-onset OSA. RESULTS: During a median follow-up duration of 12.0 years, 6051 (1.4%) participants occurred new-onset OSA. Overall, there was an inverse relation of serum 25(OH)D concentrations with the risk of new-onset OSA (per SD increment, HR, 0.92; 95%CI: 0.89-0.95). In the analysis of the interactions of serum 25(OH)D with the combination of BMI (<25, 25- < 30, and ≥30 kg/m2) and waist circumference (WC) (<90 and ≥90 cm) categories on new-onset OSA, the significantly inverse association of serum 25(OH)D and new-onset OSA was mainly found in participants with both BMI ≥ 25 kg/m2 and WC ≥ 90 cm (BMI 25-30 kg/m2 and WC ≥ 90 cm: per SD increment, HR, 0.90; 95%CI: 0.84-0.95; BMI ≥ 30 kg/m2 and WC ≥ 90 cm: per SD increment, HR, 0.85; 95%CI: 0.81-0.88), but not in other four groups with BMI < 25 kg/m2 or WC < 90 cm (P -interaction = 0.004). CONCLUSIONS: There was an inverse relation of serum 25(OH)D with the risk of new-onset OSA in participants with both BMI ≥ 25 kg/m2 and WC ≥ 90 cm. Our findings suggest the importance of maintaining a higher serum 25(OH)D concentration for primary prevention of OSA in a population with obesity.

Sequential activation of strigolactone and salicylate biosynthesis promotes leaf senescence.

Leaf senescence is a complex process strictly regulated by various external and endogenous factors. However, the key signaling pathway mediating leaf senescence remains unknown. Here, we show that Arabidopsis SPX1/2 negatively regulate leaf senescence genetically downstream of the strigolactone (SL) pathway. We demonstrate that the SL receptor AtD14 and MAX2 mediate the age-dependent degradation of SPX1/2. Intriguingly, we uncover an age-dependent accumulation of SLs in leaves via transcriptional activation of SL biosynthetic genes by the transcription factors (TFs) SPL9/15. Furthermore, we reveal that SPX1/2 interact with the WRKY75 subclade TFs to inhibit their DNA-binding ability and thus repress transcriptional activation of salicylic acid (SA) biosynthetic gene SA Induction-Deficient 2, gating the age-dependent SA accumulation in leaves at the leaf senescence onset stage. Collectively, our new findings reveal a signaling pathway mediating sequential activation of SL and salicylate biosynthesis for the onset of leaf senescence in Arabidopsis.

Dual pH and Ca2+-Responsive PEG-Modified Pillar[5]arene-Based Supramolecular Nanodrug Delivery System: Excellent Cargo Encapsulation and Minimal Drug Toxicity.

Chemotherapy is one of the most employed strategies in clinical treatment of cancer. However, reducing medication adverse effects and improving the biological activity remains a significant issue for chemotherapy. We developed a pH and Ca2+-responsive pillar[5]arene-based supramolecular nanodrug delivery system (NDDS) WP5⊃EV@DOX to address the aforementioned challenges. The formation of this NDDS began with the spontaneous formation of supramolecular nanodrug carrier WP5⊃EV in water from PEG-modified pillar[5]arene and the bipyridilium salt derivative EV through simple host-guest interaction. Then the antitumor drug doxorubicin DOX was efficiently loaded with a high encapsulation rate of 84.6%. Cytotoxicity results indicated that the constructed nanoplatform not only reduced DOX toxicity and side effects on normal cell (293T), but also significantly enhanced the antitumor activity on cancer cell (HepG2). Moreover, in vivo experiments showed that WP5⊃EV@DOX had a longer half-life and higher bioavailability in the blood of mice compared to the nake drug DOX, with increases to 212% and 179%, respectively. Therefore, WP5⊃EV@DOX has great potential in tumor therapy and provides a new idea for host-guest drug delivery system.

Investigation of ENO2 as a promising novel marker for the progression of colorectal cancer with microsatellite instability-high.

BACKGROUND: Microsatellite instability-high (MSI-H) has emerged as a significant biological characteristic of colorectal cancer (CRC). Studies reported that MSI-H CRC generally had a better prognosis than microsatellite stable (MSS)/microsatellite instability-low (MSI-L) CRC, but some MSI-H CRC patients exhibited distinctive molecular characteristics and experienced a less favorable prognosis. In this study, our objective was to explore the metabolic transcript-related subtypes of MSI-H CRC and identify a biomarker for predicting survival outcomes. METHODS: Single-cell RNA sequencing (scRNA-seq) data of MSI-H CRC patients were obtained from the Gene Expression Omnibus (GEO) database. By utilizing the copy number variation (CNV) score, a malignant cell subpopulation was identified at the single-cell level. The metabolic landscape of various cell types was examined using metabolic pathway gene sets. Subsequently, functional experiments were conducted to investigate the biological significance of the hub gene in MSI-H CRC. Finally, the predictive potential of the hub gene was assessed using a nomogram. RESULTS: This study revealed a malignant tumor cell subpopulation from the single-cell RNA sequencing (scRNA-seq) data. MSI-H CRC was clustered into two subtypes based on the expression profiles of metabolism-related genes, and ENO2 was identified as a hub gene. Functional experiments with ENO2 knockdown and overexpression demonstrated its role in promoting CRC cell migration, invasion, glycolysis, and epithelial-mesenchymal transition (EMT) in vitro. High expression of ENO2 in MSI-H CRC patients was associated with worse clinical outcomes, including increased tumor invasion depth (p = 0.007) and greater likelihood of perineural invasion (p = 0.015). Furthermore, the nomogram and calibration curves based on ENO2 showed potential prognosis predictive performance. CONCLUSION: Our findings suggest that ENO2 serves as a novel prognostic biomarker and is associated with the progression of MSI-H CRC.

Multiomics analyses reveal the mechanisms of the responses of subalpine treeline trees to phenology and winter low-temperature stress.

Withstanding extreme cold stress is a prerequisite for alpine treeline trees to persist and survive. However, the underlying mechanism by which treeline trees sense phenological changes and survive hard winters has not been fully elucidated. Here, we investigated the physiology, transcriptome, and metabolome of the subalpine treeline species Larix chinensis to identify the molecular mechanism of phenological and cold resistance. Calcium and antioxidant enzyme activities (e.g., superoxide dismutase and glutathione peroxidase) are essential for coping with winter cold stress in L. chinensis. Transcriptome analysis revealed that circadian rhythm and phytohormone signalling transduction played important roles in regulating L. chinensis phenological changes and cold stress responses. The variations in the transcriptome identified were accompanied by the specific accumulation of flavones, flavonols, and monosaccharides. The flavonoid biosynthesis and phenylpropanoid biosynthesis pathways played important roles in the adaptation of L. chinensis to the extreme winter environment, and flavone and flavonol biosynthesis was an important pathway involved in bud burst. In addition, temperature and photoperiod had synergistic influences on the formation and release of bud dormancy. Thus, our findings provided new insights into the mechanism of subalpine treeline formation.

A Porous Carbazolic Al-MOF for Efficient Aerobic Photo-Oxidation of Sulfides into Sulfoxides under Air.

A robust, microporous, and photoactive aluminum-based metal-organic framework (Al-MOF, LCU-600) has been assembled by an in situ-formed [Al3O(CO2)6] trinuclear building unit and a tritopic carbazole ligand. LCU-600 shows a high water stability and permanent porosity for N2 and CO2 adsorption. Notably, the incorporation of photoresponsive carbazole moieties into LCU-600 makes it a highly efficient and recyclable photocatalyst for aerobic photo-oxidation of sulfides into sulfoxides under an air atmosphere at room temperature. Mechanism investigations unveil that photogenerated holes (h+), superoxide radical anion (O2•-), and singlet oxygen (1O2) are critical active spices for the photo-oxidation reaction performed in an air atmosphere.

Alterations in oxidative stress biomarkers and helper T-cell subgroups in patients with periodontitis and IgA nephropathy.

OBJECTIVE: Investigating the changes in the oxidative stress levels and helper T lymphocyte (Th) subsets in patients with periodontitis and IgA nephropathy (IgAN) to determine their relationship. BACKGROUND: IgAN has a high prevalence, poor prognosis, and no effective cure. Accumulating evidence has implicated a close relationship between periodontitis and chronic kidney diseases, in which both IgAN and chronic periodontitis show chronic inflammation and abnormal metabolism. However, few studies have been conducted on the relationship between the two diseases from this perspective. METHODS: We divided 86 IgAN patients into patients with healthy periodontium (IgAN-H, n = 34) and patients with periodontitis IgAN (IgAN-P, n = 52); moreover, we divided 72 systemically healthy participants into patients with periodontitis (H-P, n = 35) and participants with healthy periodontium (H-H, n = 37). The proportions of Th subsets in peripheral blood were estimated using flow cytometry. Cytokine levels in plasma were assessed using cytokine assay kits. Enzyme-linked immunosorbent assay was used to evaluate the plasma levels of oxidative stress. RESULTS: Our results from analyzing the Th cell subsets indicated that Th2 cell counts in the IgAN-P group were significantly lower than those in the IgAN-H group, while Th17 cell counts were increased (p < 0.05). Moreover, the Th1/Th2 ratio and interleukin-6 levels in the IgAN-P group were significantly higher than those in the H-H group (p < 0.01). Compared with that in the H-H group, in the remaining three groups, plasma total oxidation state (TOS) levels were increased (p < 0.01), while plasma total antioxidant state (TAS) levels were decreased (p < 0.05). Furthermore, estimated glomerular filtration rate was negatively correlated with the probing depth and gingival bleeding index. IgAN was a risk factor for periodontitis, while TAS was a protective factor for periodontitis. The oxidative stress index (OSI) might be valuable for distinguishing periodontitis patients from healthy controls (area under the receiver operator characteristic curve = 0.951). CONCLUSION: IgAN is an independent risk factor of periodontitis, and the Th17 cell-mediated inflammatory response might be associated with the occurrence of periodontitis in patients with IgAN. Patients with coexisting IgAN and periodontitis exhibit increased oxidative stress, in which TOS and OSI are potential biomarkers for diagnosing periodontitis.

Association between lung function and risk of microvascular diseases in patients with diabetes: A prospective cohort and Mendelian randomization study.

BACKGROUND AND AIMS: To investigate causal relationships of lung function with risks microvascular diseases among participants with diabetes, type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM), respectively, in prospective and Mendelian randomization (MR) study. METHODS AND RESULTS: 14,617 participants with diabetes and without microvascular diseases at baseline from the UK Biobank were included in the prospective analysis. Of these, 13,421 had T2DM and 1196 had T1DM. The linear MR analyses were conducted in the UK Biobank with 6838 cases of microvascular diseases and 10,755 controls. Lung function measurements included forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The study outcome was microvascular diseases, a composite outcome including chronic kidney diseases, retinopathy and peripheral neuropathy. During a median follow-up of 12.1 years, 2668 new-onset microvascular diseases were recorded. FVC (%predicted) was inversely associated with the risk of new-onset microvascular diseases in participants with diabetes (Per SD increment, adjusted HR = 0.86; 95%CI:0.83-0.89), T2DM (Per SD increment, adjusted HR = 0.86; 95%CI:0.82-0.90) and T1DM (Per SD increment, adjusted HR = 0.87; 95%CI: 0.79-0.97), respectively. Similar results were found for FEV1 (%predicted). In MR analyses, genetically predicted FVC (adjusted RR = 0.55, 95%CI:0.39-0.77) and FEV1 (adjusted RR = 0.48, 95%CI:0.28-0.83) were both inversely associated with microvascular diseases in participants with T1DM. No significant association was found in those with T2DM. Similar findings were found for each component of microvascular diseases. CONCLUSION: There was a causal inverse association between lung function and risks of microvascular diseases in participants with T1DM, but not in those with T2DM.

Positive association between dietary manganese intake and new-onset hypertension: A nationwide cohort study in China.

BACKGROUND AND AIM: To date, few studies have investigated the association between dietary manganese intake and the risk of hypertension, so the prospective relationship of dietary manganese intake and new-onset hypertension remains uncertain. We aimed to investigate the association between dietary manganese intake and the risk of new-onset hypertension in the general Chinese population. METHODS AND RESULTS: This prospective cohort study included 12,177 participants who were free of hypertension at baseline from China Health and Nutrition Survey (CHNS). Dietary intake was measured by 3 consecutive 24-h dietary recalls combined with a household food inventory. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or diagnosed by a physician or under antihypertensive treatment during the follow-up. During a median follow-up duration of 6.1 years, 4269 (44.9 per 1000 person-years) participants developed new-onset hypertension. Overall, there was a positive association between dietary manganese intake and new-onset hypertension. The adjusted HRs (95%CIs) of new-onset hypertension were 1.00 (reference), 0.97 (0.87, 1.08), 1.24 (1.10, 1.39) and 1.75 (1.52, 2.01) across the quartiles of dietary manganese intake, respectively. Accordingly, a significantly higher risk of new-onset hypertension (HR, 1.38; 95%CI: 1.27, 1.50) was found in participants in quartiles 3-4 of dietary manganese intake (≥6.0 mg/day), compared with those in quartiles 1-2 (<6.0 mg/day). CONCLUSIONS: In the general Chinese population, dietary manganese intake was positively associated with the risk of new hypertension, independent of sodium intake and other important covariates.