Targeting mitochondrial double-stranded RNAs ameliorates autoimmune characteristics of Sjӧgren’s syndrome

Sjӧgren’s syndrome (SS) is a systemic autoimmune disease that targets the exocrine glands, resulting in impaired saliva and tear secretion. To date, type I interferons (IFNs) are increasingly recognized as pivotal mediators in SS, but their endogenous drivers have not been elucidated. Here, we investigate the role of mitochondrial double-stranded RNAs (mt-dsRNAs) in regulating type I IFN response in SS. We find that mt-dsRNAs are elevated in the saliva and tear of SS patients and in salivary glands of non-obese diabetic mice with salivary dysfunction. Using the in-house- developed 3D culture, we show that dsRNA stimulation increases mt-dsRNAs expression via JAK1/STAT pathway and facilitates their cytosolic export, which is accompanied by autoimmune signatures observed in SS. We further show that muscarinic receptor ligand acetylcholine or antioxidant resveratrol ameliorates autoimmune characteristics by preventing mt-dsRNA- mediated immune activation. In addition, direct suppression of mt-dsRNAs reverses the autoimmune signatures of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation and suggests mt-dsRNAs as an important key to the puzzle of SS.SummaryMitochondrial double-stranded RNA levels are elevated in the tear and saliva of SS patients. These RNAs promote type I interferon signature, as well as other autoimmune phenotypes in SS. Downregulation of mitochondrial dsRNAs alleviates autoimmune signatures of SS in salivary gland epithelial cells.Graphical Abstractmt-dsRNAs as the molecular mediator of autoimmune phenotypes in SS.mt-dsRNAs are elevated in both human samples and mouse model of SS and function to exacerbate dsRNA-induced autoimmune phenotypes in SS. Countering the accumulation of mt- dsRNAs alleviates the autoimmune phenotypes in SGECs.

Trichovariability in rhizosphere soil samples and their biocontrol potential against downy mildew pathogen in pearl millet

The present work is aimed to examine the genetic variability and the distribution pattern of beneficial Trichoderma spp. isolated from rhizosphere samples and their mode of action in improving the plant health. A total of 131 suspected fungi were isolated from the rhizospheric soil and 91 isolates were confirmed as Trichoderma spp. T. asperellum and T. harzianum were found high in the frequency of occurrence. Genetic diversity analysis using RAPD and ISSR revealed the diverse distribution pattern of Trichoderma spp. indicating their capability to adapt to broad agroclimatic conditions. Analysis of genetic diversity using molecular markers revealed intra-species diversity of isolated Trichoderma spp. The frequency of pearl millet (PM) root colonization by Trichoderma spp. was found to be 100%. However, they showed varied results for indole acetic acid, siderophore, phosphate solubilization, β-1,3-glucanase, chitinase, cellulase, lipase, and protease activity. Downy mildew disease protection studies revealed a strong involvement of Trichoderma spp. in direct suppression of the pathogen (mean 37.41) in the rhizosphere followed by inducing systemic resistance. Our findings highlights the probable distribution and diversity profile of Trichoderma spp. as well as narrate the possible utilization of Trichoderma spp. as microbial fungicides in PM cultivation across different agroclimatic zones of India.

Choosing between cocaine and sucrose under the influence: testing the effect of cocaine tolerance

Cocaine use not only depends on the reinforcing properties of the drug, but also on its intoxicating effects on alternative nondrug activities. In animal models investigating choice between cocaine and alternative sweet rewards, the latter influence can have a dramatic impact on choice outcomes. When cocaine intoxication at the moment of choice is prevented by imposing sufficiently long intervals between choice trials, animals typically prefer the sweet reward. However, when choosing under the drug influence is permitted, animals shift their preference in favor of cocaine. We previously hypothesized that this preference shift is mainly due to a direct suppression of responding for sweet reward by cocaine intoxication. Here we tested this hypothesis by making rats tolerant to this drug-induced behavioral suppression. Contrary to our expectation, tolerance did not prevent rats from shifting their preference to cocaine when choosing under the influence. Thus, other mechanisms must be invoked to explain the influence of cocaine intoxication on choice outcomes.

Separable neural mechanisms support intentional forgetting and thought substitution

Psychological and neuroscientific experiments have established that people can intentionally forget information via different strategies: direct suppression and thought substitution. However, few studies have directly compared the effectiveness of these strategies in forgetting specific items, and it remains an open question if the neural mechanisms supporting these strategies differ. Here, we developed a novel item-method directed forgetting paradigm with Remember, Forget, and Imagine cues, and recorded EEG to directly compare these strategies. Behaviorally, Forget and Imagine cues produced similar forgetting compared to Remember cues, but through separable neural processes; Forget cues elicited frontal oscillatory power changes that were predictive of future forgetting, whereas item-cue representational similarity was predictive of later accuracy for Imagine cues. These results suggest that both strategies can lead to intentional forgetting, but directed forgetting may rely on frontally-mediated suppression, while thought substitution may lead to contextual shifting, impairing successful retrieval.

Duple extinguishment of COVID-19: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

The virus replication and lung inflammation are basic targets for COVID-19 treatment. To effectively treat COVID-19, the best chemical drug should combine inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokine expression together. Our SARS-CoV-2 main protease (Mpro) crystal structure studies revealed Au(I), derived from auranofin (AF) or gold cluster (GA), could specifically bind thiolate of Cys145 of SARS-CoV-2 Mpro. GA or AF could well inhibit Mpro activity and significantly decrease SARS-CoV-2 replication in cell. Cell studies showed that either AF or GA could down-regulate NFκB pathway, therefore significantly inhibit inflammatory cytokine level of IL-6, IL-1β, TNF-α in macrophage and bronchial epithelial cell, respectively. The lung viral load in GA treated COVID-19 mice (15mg/kg.bw) is significantly lower than that in normal saline (NS, 0.9% NaCl) treated COVID-19 mice, and pathological studies revealed GA treatment (score ~1.8) significantly reduced lung inflammatory injury compared with NS treated COVID-19 mice (score ~3). After normal mice were treated by GA (15mg/kg), the Au ingredient well distributed into lungs and there are no pathological changes in main organs when compared with control mice. The toxicity results revealed GA is more safety than auranofin for cell/mice/rat. The rat pharmacokinetics studies show GA is with high bioavailability (> 90%) in vivo.One Sentence SummarySingle gold compound not only significantly inhibits SARS-CoV-2 replication in lung and but also directly suppress lung inflammatory injury in COVID-19 mice, it is with great potential to effectively treat COVID-19.

Dienogest exerts its anti-endometriotic effect throughthe direct suppression of matrix metallopeptidases

Background: Endometriosis, which affects up to 10% women of reproductive age, is defined by the presence of ectopic endometrial tissue outside the uterus. The current key drug of hormonal therapies for endometriosis is dienogest, which is a progestin with high specificity for the progesterone receptor. Although many findings about the anti-endometriotic effect of dienogest on endometriosis have been reported, the precise mechanisms of dienogest's anti-endometriotic effect remain unknown. Methods: To investigate the direct anti-endometriotic effect of dienogest on endometriotic cells, we determined and compared the genome-wide gene expression profiles of endometriotic stromal cells treated with dienogest (Dienogest group) and those not treated with dienogest (Control group) and then performed a pathway analysis using these data. To test the microarray data, we performed real-time RT-PCRs for matrix metallopeptidase (MMP)-1, MMP-3, MMP-10, and TIMP-4.Results: Six-hundred forty-seven genes were revealed to be differentially expressed between the Dienogest and Control groups. Of them, 314 genes were upregulated and 333 genes were downregulated in the Dienogest group compared to the Control group. We identified 20 canonical pathways that are significantly distinct in the Dienogest group versus the Control group. Among the 20 canonical pathways, MMPs including MMP-1, -3, and -10 were found to be the most involved genes. Conclusions: Our results suggest that dienogest may exert its anti-endometriotic effect through the direct suppression of MMPs.