RNA helicases and E3 ubiquitin ligases mediate many critical functions in cells, but their actions have largely been studied in distinct biological contexts. Here, we uncover evolutionarily conserved ...rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immunity. Using cryoelectron microscopy and biochemistry, we show that RIG-I-like receptors (RLRs), viral RNA receptors with helicase domains, interact with their cognate TRIM/TRIM-like E3 ligases through similar epitopes in the helicase domains. Their interactions are avidity driven, restricting the actions of TRIM/TRIM-like proteins and consequent immune activation to RLR multimers. Mass spectrometry and phylogeny-guided biochemical analyses further reveal that similar rules of engagement may apply to diverse RNA helicases and TRIM/TRIM-like proteins. Our analyses suggest not only conserved substrates for TRIM proteins but also, unexpectedly, deep evolutionary connections between TRIM proteins and RNA helicases, linking ubiquitin and RNA biology throughout animal evolution.
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•TRIM65 selectively recognizes MDA5 filaments using PSpry bivalency•TRIM65 PSpry binds α1/α3 helices in the Hel2 domain of MDA5•RIPLET recognizes RIG-I using a similar epitope in the helicase domain•Distinct TRIM proteins recognize common epitopes in diverse helicases using bivalency
Proper immune function requires multiple layers of checks and balances. Kato et al. show a conserved mechanism by which the antiviral proteins RIG-I-like receptors collaborate with a family of E3 ligases, TRIM-like proteins, to ensure high fidelity and robustness of the antiviral immune response.
Background: Estimates of the clinical-onset serial interval of human influenza infection (time between onset of symptoms in an index case and a secondary case) are used to inform public health policy ...and to construct mathematical models of influenza transmission. We estimate the serial interval of laboratory-confirmed influenza transmission in households. Methods: Index cases were recruited after reporting to a primary healthcare center with symptoms. Members of their households were followed-up with repeated home visits. Results: Assuming a Weibull model and accounting for selection bias inherent in our field study design, we used symptom-onset times from 14 pairs of infector/infectee to estimate a mean serial interval of 3.6 days (95% confidence interval = 2.9-4.3 days), with standard deviation 1.6 days. Conclusion: The household serial interval of influenza may be longer than previously estimated. Studies of the complete serial interval, based on transmission in all community contexts, are a priority.
Toll-like receptors (TLRs) play key roles in innate immune recognition of pathogen-associated molecular patterns of invading microbes. Among the 10 TLR family members identified in humans, TLR10 ...remains an orphan receptor without known agonist or function. TLR10 is a pseudogene in mice and mouse models are noninformative in this regard. Using influenza virus infection in primary human peripheral blood monocyte-derived macrophages and a human monocytic cell line, we now provide previously unidentified evidence that TLR10 plays a role in innate immune responses following viral infection. Influenza virus infection increased TLR10 expression and TLR10 contributed to innate immune sensing of viral infection leading to cytokine induction, including proinflammatory cytokines and interferons. TLR10 induction is more pronounced following infection with highly pathogenic avian influenza H5N1 virus compared with a low pathogenic H1N1 virus. Induction of TLR10 by virus infection requires active virus replication and de novo protein synthesis. Culture supernatants of virus-infected cells modestly up-regulate TLR10 expression in nonvirus-infected cells. Signaling via TLR10 was activated by the functional RNAprotein complex of influenza virus leading to robust induction of cytokine expression. Taken together, our findings identify TLR10 as an important innate immune sensor of viral infection and its role in innate immune defense and immunopathology following viral and bacterial pathogens deserves attention.
Exosomes are 30-120nm bio particles transferred from donor to recipient cells leading to modification in their regulatory mechanisms depending upon the coded message in the form of loaded ...biomolecule. Cancer cells derived exosomes the true representatives of the parent cells have been found to modify the tumor surrounding/distinct regions and participate in metastasis, angiogenesis and immune suppression. Tis study was aimed to study the effects of tumor mice derived exosomes on the normal mice spleen isolated T cells by using co-culture experiments and flow cytometer analysis. We mainly focused on some of the T cells population and cytokines including IFN-γ, FOXP3+ regulatory T (Treg) cells and KI67 (proliferation marker). Overall results indicated random changes in different set of experiments, where the cancer derived exosomes reduced the IFN-γ expression in both CD4 and CD8 T cells, similarly the Treg cells were also found decreased in the presence of cancer exosomes. No significant changes were observed on the Ki67 marker expression. Such studies are helpful in understanding the role of cancer exosomes in immune cells suppression in tumor microenvironment. Cancer exosomes will need to be validated in vivo and in vitro on a molecular scale in detail for clinical applications.
Spreading false information or distorted news on social media with the intention of harming a person, group, or governmental entity is known as fake news. Gathering information from an online ...platform is an effortless process due to its speed, user-friendliness, and continuous updates. Nevertheless, this data is susceptible to personal biases or preferences, posing potential drawbacks for individuals or organizations involved. Consequently, it becomes crucial to employ computational techniques for identifying the dissemination of misinformation. Therefore, this study explored different machine learning models to classify the veracity of information by utilizing a dataset consisting of fake and real news. The analysis encompassed approximately 40,000 items, with roughly 20,000 items from each dataset category. The study utilized a combination of ensemble learning models, such as support vector machine, logistic regression, catboost, Xgboost, multinomial, naive Bayes, and random forest. The performance of these models was assessed using diverse evaluation metrics, including recall, accuracy, false rejection rate, F1 score, precision, negative predictive value, false discovery rate, and Matthews' correlation coefficient. Following these analyses, the deep auto_ViML model and passive-aggressive classifier were calculated alongside the best learning models. After calculations, the deep Auto_ViML model was found to have the highest accuracy, precision, recall, and F1 score of 99%. On the other hand, the hybrid learning model achieved the most favorable false rejection rate at 71%. In terms of computational efficiency, the support vector machine proved to be the fastest, taking only 0.245 ms to compute.
In March and early April 2009, a new swine-origin influenza A (H1N1) virus (S-OIV) emerged in Mexico and the United States. During the first few weeks of surveillance, the virus spread worldwide to ...30 countries (as of May 11) by human-to-human transmission, causing the World Health Organization to raise its pandemic alert to level 5 of 6. This virus has the potential to develop into the first influenza pandemic of the twenty-first century. Here we use evolutionary analysis to estimate the timescale of the origins and the early development of the S-OIV epidemic. We show that it was derived from several viruses circulating in swine, and that the initial transmission to humans occurred several months before recognition of the outbreak. A phylogenetic estimate of the gaps in genetic surveillance indicates a long period of unsampled ancestry before the S-OIV outbreak, suggesting that the reassortment of swine lineages may have occurred years before emergence in humans, and that the multiple genetic ancestry of S-OIV is not indicative of an artificial origin. Furthermore, the unsampled history of the epidemic means that the nature and location of the genetically closest swine viruses reveal little about the immediate origin of the epidemic, despite the fact that we included a panel of closely related and previously unpublished swine influenza isolates. Our results highlight the need for systematic surveillance of influenza in swine, and provide evidence that the mixing of new genetic elements in swine can result in the emergence of viruses with pandemic potential in humans.
The kinetochore is a multiprotein complex that mediates the attachment of a eukaryotic chromosome to the mitotic spindle. The protein composition of kinetochores is similar across species as ...divergent as yeast and human. However, recent findings have revealed an unexpected degree of compositional diversity in kinetochores. For example, kinetochore proteins that are essential in some species have been lost in others, whereas new kinetochore proteins have emerged in other lineages. Even in lineages with similar kinetochore composition, individual kinetochore proteins have functionally diverged to acquire either essential or redundant roles. Thus, despite functional conservation, the repertoire of kinetochore proteins has undergone recurrent evolutionary turnover.
The purpose of the present study was to obtain estimates of variance components and genetic parameters for direct and maternal effects on various growth traits in Beetal goat by fitting four animal ...models, attempting to separate direct genetic, maternal genetic and maternal permanent environmental effects under restricted maximum likelihood procedure. The data of 3,308 growth trait records of Beetal kids born during the period from 2004 to 2019 were used in the present study. Based on best fitted models, the direct additive h2 estimates were 0.06, 0.27, 0.37, 0.17 and 0.10 for birth weight (BWT), weight at 3 (WT3), 6 (WT6), 9 (WT9) and 12 (WT12) months of age, respectively. Maternal permanent environmental effects significantly contributed for 10% and 7% of total variance for BWT and WWT, respectively, which reduced direct heritability by 40 and 10% for respective traits from the models without these effects. For average daily gain (ADG1) and Kleiber ratios (KR1) up to weaning period (3 months) traits, maternal permanent environmental effects accounted for 7% and 8% of phenotypic variance, respectively, and resulted in a reduction of 6.6% and 5.4% in direct h2 of respective traits. For post‐weaning traits, the maternal effects were non‐significant (p > .05) which indicates diminishing influence of mothering ability for these traits. High and positive genetic correlations were obtained among WT3‐WT6, WT6‐WT9 and WT9‐WT12 with correlations of 0.96 ± 0.25, 0.84 ± 0.23 and 0.90 ± 0.13, respectively. Thus, early selection at weaning age can be practised taking into consideration maternal variation for effective response to selection in Beetal goat.
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