Short-chain fatty acids directly exert anti-inflammatory responses in podocytes and tubular epithelial cells exposed to high glucose

Aims: Gut-microbiome derived short-chain fatty acids exert anti-inflammatory effects and delay progression of kidney disease in diabetic nephropathy. The aim of this study was to examine the impact in vivo and in vitro of short-chain fatty acid treatment on cellular pathways involved in the development of experimental diabetic nephropathy.Methods: To determine the effect of short-chain fatty acids in diabetic nephropathy, we compared wildtype, GPR43−/− and GPR109A−/− mice diabetic mice treated with acetate or butyrate and assessed variables of kidney damage. We also examined the impact of short-chain fatty acid treatment on gene expression in renal tubular cells and podocytes under high glucose conditions.Results: Short-chain fatty acid treatment with acetate or butyrate protected wild-type mice against development of diabetic nephropathy, exhibiting less glomerular hypertrophy, hypercellularity and interstitial fibrosis compared to diabetic controls. Acetate and butyrate treatment did not provide the same degree of protection in diabetic GPR43−/− and GPR109A−/− diabetic mice respectively. Consistent with our in vivo results, expression of pro-inflammatory genes in tubular epithelial cells exposed to high glucose were attenuated by acetate and butyrate treatment. Acetate did not reduce inflammatory or fibrotic responses in glucose stimulated GPR43−/− TECs. Butyrate mediated inhibition of pro-fibrotic gene expression in TECs through GPR109A, and in podocytes via GPR43.Conclusion: SCFAs protect against progression of diabetic nephropathy and diminish podocyte and tubular epithelial injury and interstitial fibrosis via direct, GPR-pathway dependent effects on intrinsic kidney cells. GPR43 and GPR109A are critical to short-chain fatty acid mediated reno-protection and have potential to be harnessed as a therapeutic target in diabetic nephropathy

An Efficient Virus-Induced Gene Silencing System for Functional Genomics Research in Walnut (Juglans regia L.) Fruits

The Persian walnut (Juglans regia L.) is a leading source of woody oil in warm temperate regions and has high nutritional and medicinal values. It also provides both tree nuts and woody products. Nevertheless, incomplete characterization of the walnut genetic system limits the walnut gene function analysis. This study used the tobacco rattle virus (TRV) vector to construct an infectious pTRV-JrPDS recombinant clone. A co-culture inoculation method utilizing Agrobacterium was screened out from four inoculation methods and optimized to set up an efficient virus-induced gene silencing (VIGS) system for J. regia fruit. The optimized VIGS-TRV system induced complete photobleaching phenotype on the walnut fruits of four cultivars, and the JrPDS transcript levels decreased by up to 88% at 8 days post-inoculation (dpi). While those of browning-related J. regia polyphenol oxidase (PPO) genes JrPPO1 and JrPPO2 decreased by 67 and 80% at 8 dpi, respectively, accompanied by a significant reduction in fruit browning phenotype. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis screening and Western Blot showed that the PPO protein levels were significantly reduced. Moreover, a model of TRV-mediated VIGS system for inoculating J. regia fruit with efficient silence efficiency via co-culture was developed. These results indicate that the VIGS-TRV system is an efficient tool for rapid gene function analysis in J. regia fruits

Changes in axial length in anisometropic children wearing orthokeratology lenses

PurposeThere is a particular anisometropia occurring in one eye with myopia, while the other eye has very low myopia, emmetropia, or very low hyperopia. It is unclear how the binocular axial length changes when these children wear unilateral OK lenses only in the more myopic eyes. This study investigates the changes in the axial elongation of both eyes.MethodsThis is a 1-year retrospective study. In total, 148 children with myopic anisometropia were included. The more myopic eyes were wearing orthokeratology lenses (treated eyes), whereas the contralateral eyes were not indicated for visual correction (untreated eyes). The untreated eyes were classified into three subgroups based on the spherical equivalent refraction (SER): low myopia (≤ -0.50 D, n = 37), emmetropia (+0.49 to −0.49 D, n = 76), and low hyperopia (≥0.50 D, n = 35). Changes in the axial length (AL) were compared between the untreated and treated eyes and among the three subgroups.ResultsThe axial elongation was 0.14 ± 0.18 mm and 0.39 ± 0.27 mm in all treated and untreated eyes, respectively (p < 0.001). The interocular AL difference decreased significantly from 1.09 ± 0.45 mm at the baseline to 0.84 ± 0.52 mm at 1 year (p < 0.001). The baseline median (Q1, Q3) SER of the untreated eyes were −0.75 D (−0.56, −0.88 D), 0.00 D (0.00, −0.25 D), and +0.75 D (+1.00, +0.62 D) in low myopia, emmetropia, and low hyperopia subgroups, respectively. The axial elongation was 0.14 ± 0.18 mm, 0.15 ± 0.17 mm, and 0.13 ± 0.21 mm (p = 0.92) in the treated eyes and 0.44 ± 0.25 mm, 0.35 ± 0.24 mm, and 0.41 ± 0.33 mm in the untreated eyes (p = 0.11) after 1 year. Multivariate linear regression analyses only showed significant differences in axial elongation between the emmetropia and low myopia subgroups of untreated eyes (p = 0.04; p > 0.05 between other subgroups).ConclusionUnilateral orthokeratology lenses effectively reduced axial elongation in the more myopic eyes and reduced interocular AL differences in children with myopic anisometropia. The refractive state of the untreated eyes did not affect the axial elongation of the more myopic eye wearing the orthokeratology lens. In the untreated eyes, AL increased faster in the low myopia subgroup than in the emmetropia subgroup

Cumulative Exposure to Lead in Relation to Cognitive Function in Older Women

Background: Recent data indicate that chronic low-level exposure to lead is associated with accelerated declines in cognition in older age, but this has not been examined in women. Objective: We examined biomarkers of lead exposure in relation to performance on a battery of cognitive tests among older women. Methods: Patella and tibia bone lead—measures of cumulative exposure over many years—and blood lead, a measure of recent exposure, were assessed in 587 women 47–74 years of age. We assessed their cognitive function 5 years later using validated telephone interviews. Results: Mean ± SD lead levels in tibia, patella, and blood were 10.5 ± 9.7 μg/g bone, 12.6 ± 11.6 μg/g bone, and 2.9 ± 1.9 μg/dL, respectively, consistent with community-level exposures. In multivariable-adjusted analyses of all cognitive tests combined, levels of all three lead biomarkers were associated with worse cognitive performance. The association between bone lead and letter fluency score differed dramatically from the other bone lead-cognitive score associations, and exclusion of this particular score from the combined analyses strengthened the associations between bone lead and cognitive performance. Results were statistically significant only for tibia lead: one SD increase in tibia lead corresponded to a 0.051-unit lower standardized summary cognitive score (95% confidence interval: −0.099 to −0.003; p = 0.04), similar to the difference in cognitive scores we observed between women who were 3 years apart in age. Conclusions: These findings suggest that cumulative exposure to lead, even at low levels experienced in community settings, may have adverse consequences for women’s cognition in older age

SARS-CoV-2 bivalent mRNA vaccine with broad protection against variants of concern

IntroductionThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has rapidly spread around the globe. With a substantial number of mutations in its Spike protein, the SARS-CoV-2 Omicron variant is prone to immune evasion and led to the reduced efficacy of approved vaccines. Thus, emerging variants have brought new challenges to the prevention of COVID-19 and updated vaccines are urgently needed to provide better protection against the Omicron variant or other highly mutated variants.Materials and methodsHere, we developed a novel bivalent mRNA vaccine, RBMRNA-405, comprising a 1:1 mix of mRNAs encoding both Delta-derived and Omicron-derived Spike proteins. We evaluated the immunogenicity of RBMRNA-405 in BALB/c mice and compared the antibody response and prophylactic efficacy induced by monovalent Delta or Omicron-specific vaccine with the bivalent RBMRNA-405 vaccine in the SARSCoV-2 variant challenge.ResultsResults showed that the RBMRNA-405 vaccine could generate broader neutralizing antibody responses against both Wuhan-Hu-1 and other SARS-CoV-2 variants, including Delta, Omicron, Alpha, Beta, and Gamma. RBMRNA-405 efficiently blocked infectious viral replication and lung injury in both Omicron- and Delta-challenged K18-ACE2 mice.ConclusionOur data suggest that RBMRNA-405 is a promising bivalent SARS-CoV-2 vaccine with broad-spectrum efficacy for further clinical development

Single Endemic Genotype of Measles Virus Continuously Circulating in China for at Least 16 Years

The incidence of measles in China from 1991 to 2008 was reviewed, and the nucleotide sequences from 1507 measles viruses (MeV) isolated during 1993 to 2008 were phylogenetically analyzed. The results showed that measles epidemics peaked approximately every 3 to 5 years with the range of measles cases detected between 56,850 and 140,048 per year. The Chinese MeV strains represented three genotypes; 1501 H1, 1 H2 and 5 A. Genotype H1 was the predominant genotype throughout China continuously circulating for at least 16 years. Genotype H1 sequences could be divided into two distinct clusters, H1a and H1b. A 4.2% average nucleotide divergence was found between the H1a and H1b clusters, and the nucleotide sequence and predicted amino acid homologies of H1a viruses were 92.3%–100% and 84.7%–100%, H1b were 97.1%–100% and 95.3%–100%, respectively. Viruses from both clusters were distributed throughout China with no apparent geographic restriction and multiple co-circulating lineages were present in many provinces. Cluster H1a and H1b viruses were co-circulating during 1993 to 2005, while no H1b viruses were detected after 2005 and the transmission of that cluster has presumably been interrupted. Analysis of the nucleotide and predicted amino acid changes in the N proteins of H1a and H1b viruses showed no evidence of selective pressure. This study investigated the genotype and cluster distribution of MeV in China over a 16-year period to establish a genetic baseline before MeV elimination in Western Pacific Region (WPR). Continuous and extensive MeV surveillance and the ability to quickly identify imported cases of measles will become more critical as measles elimination goals are achieved in China in the near future. This is the first report that a single endemic genotype of measles virus has been found to be continuously circulating in one country for at least 16 years