Methods Mol Biol. 2024;2719:51-77. doi: 10.1007/978-1-0716-3461-5_4.

ABSTRACT

Growth is regulated by gene expression variation at different developmental stages of biological processes such as cell differentiation, disease progression, or drug response. In cancer, a stage-specific regulatory model constructed to infer the dynamic expression changes in genes contributing to tissue growth or proliferation is referred as a dynamic growth regulatory network (dGRN). Over the past decade, gene expression data has been widely used for reconstructing dGRN by computing correlations between the differentially expressed genes (DEGs). A wide variety of pipelines are available to construct the GRNs using DEGs and the choice of a particular method or tool depends on the nature of the study. In this protocol, we have outlined a step-by-step guide for the analysis of DEGs using RNA-Seq data, beginning from data acquisition, pre-processing, mapping to reference genome, and construction of a correlation-based co-expression network to further downstream analysis. We have also outlined the steps for the inclusion of publicly available interaction/regulation information into the dGRN followed by relevant topological inferences. This tutorial has been designed in a way that early researchers can refer to for an easy and comprehensive glimpse of methodologies used in the inference of dGRN using transcriptomics data.

PMID:37803112 | DOI:10.1007/978-1-0716-3461-5_4

Methods Mol Biol. 2024;2719:13-31. doi: 10.1007/978-1-0716-3461-5_2.

ABSTRACT

The discovery of potential disease-causing genes can aid medical progress. The post-genomic era has made this a more difficult task. Modern high-throughput methods have not solved the problem of identifying disease genes. Conventional methods cannot be used to investigate many rare or lethal diseases. Monitoring gene expression values in different samples using microarray technology is one of the best and most accurate ways to identify disease-causing genes. One of the most recent advances in experimental molecular biology is microarrays, which allow researchers to simultaneously monitor the expression levels of thousands of genes. Statistical analysis of microarray data might aid gene discovery by revealing pathways related to the target gene and facilitating identification of candidate genes. Systems biology, an interdisciplinary approach, has emerged as a crucial analytic tool with the potential to reveal previously unidentified causes and consequences of human illness. Genetic, environmental, immunological, or neurological factors have been implicated in the developing complex disorders like cancer. Because of this, it is important to approach the study of such disease from a novel perspective. The system biology approach allows us to rapidly identify disease-causing genes and assess their viability as therapeutic targets. This chapter demonstrates systems biology approaches to identify candidate genes using public database. Oral squamous cell carcinoma (OSCC) is used as a model disease to show how systems biology can be used successfully to identify and prioritize disease genes.

PMID:37803110 | DOI:10.1007/978-1-0716-3461-5_2

Trends Plant Sci. 2023 Oct 4:S1360-1385(23)00301-1. doi: 10.1016/j.tplants.2023.09.008. Online ahead of print.

NO ABSTRACT

PMID:37802694 | DOI:10.1016/j.tplants.2023.09.008

Anal Chem. 2023 Oct 6. doi: 10.1021/acs.analchem.3c03399. Online ahead of print.

ABSTRACT

Glass is by far the most common substrate for biomolecular arrays, including high-throughput sequencing flow cells and microarrays. The native glass hydroxyl surface is modified by using silane chemistry to provide appropriate functional groups and reactivities for either in situ synthesis or surface immobilization of biologically or chemically synthesized biomolecules. These arrays, typically of oligonucleotides or peptides, are then subjected to long incubation times in warm aqueous buffers prior to fluorescence readout. Under these conditions, the siloxy bonds to the glass are susceptible to hydrolysis, resulting in significant loss of biomolecules and concomitant loss of signal from the assay. Here, we demonstrate that functionalization of glass surfaces with dipodal silanes results in greatly improved stability compared to equivalent functionalization with standard monopodal silanes. Using photolithographic in situ synthesis of DNA, we show that dipodal silanes are compatible with phosphoramidite chemistry and that hybridization performed on the resulting arrays provides greatly improved signal and signal-to-noise ratios compared with surfaces functionalized with monopodal silanes.

PMID:37801728 | DOI:10.1021/acs.analchem.3c03399

Brief Funct Genomics. 2023 Oct 4:elad045. doi: 10.1093/bfgp/elad045. Online ahead of print.

ABSTRACT

Embryonic stem cells (ESCs) preserve the unique ability to differentiate into any somatic cell lineage while maintaining their self-renewal potential, relying on a complex interplay of extracellular signals regulating the expression/activity of pluripotency transcription factors and their targets. Leukemia inhibitory factor (LIF)-activated STAT3 drives ESCs' stemness by a number of mechanisms, including the transcriptional induction of pluripotency factors such as Klf4 and the maintenance of a stem-like epigenetic landscape. However, it is unknown if STAT3 directly controls stem-cell specific non-coding RNAs, crucial to balance pluripotency and differentiation. Applying a bioinformatic pipeline, here we identify Lncenc1 in mouse ESCs as an STAT3-dependent long non-coding RNA that supports pluripotency. Lncenc1 acts in the cytoplasm as a positive feedback regulator of the LIF-STAT3 axis by competing for the binding of microRNA-128 to the 3'UTR of the Klf4 core pluripotency factor mRNA, enhancing its expression. Our results unveil a novel non-coding RNA-based mechanism for LIF-STAT3-mediated pluripotency.

PMID:37801430 | DOI:10.1093/bfgp/elad045

Cell Rep. 2023 Oct 4;42(10):113189. doi: 10.1016/j.celrep.2023.113189. Online ahead of print.

ABSTRACT

Host-pathogen interactions are complex by nature, and the host developmental stage increases this complexity. By utilizing Caenorhabditis elegans larvae as the host and the bacterium Pseudomonas aeruginosa as the pathogen, we investigated how a developing organism copes with pathogenic stress. By screening 36 P. aeruginosa isolates, we found that the CF18 strain causes a severe but reversible developmental delay via induction of reactive oxygen species (ROS) and mitochondrial dysfunction. While the larvae upregulate mitophagy, antimicrobial, and detoxification genes, mitochondrial unfolded protein response (UPRmt) genes are repressed. Either antioxidant or iron supplementation rescues the phenotypes. We examined the virulence factors of CF18 via transposon mutagenesis and RNA sequencing (RNA-seq). We found that non-phenazine toxins that are regulated by quorum sensing (QS) and the GacA/S system are responsible for developmental slowing. This study highlights the importance of ROS levels and mitochondrial health as determinants of developmental rate and how pathogens can attack these important features.

PMID:37801396 | DOI:10.1016/j.celrep.2023.113189

Int J Oncol. 2023 Nov;63(5):128. doi: 10.3892/ijo.2023.5576. Epub 2023 Oct 6.

ABSTRACT

T cell acute lymphoblastic leukemia (T‑ALL), a neoplasm derived from T cell lineage‑committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ‑secretase. γ‑secretase inhibitors (GSIs) are a NOTCH‑targeted therapy for T‑ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ‑secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH‑associated T‑ALL. The present study assessed the efficacy of nelfinavir against T‑ALL cells and investigated mechanisms of action in vitro and in preclinical treatment studies using a SCL‑LMO1 transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ‑secretase activity as well as the NOTCH1 pathway, thus suppressing T‑ALL cell viability. Additionally, microarray analysis of nelfinavir‑treated T‑ALL cells showed that nelfinavir upregulated mRNA levels of CHAC1 (glutathione‑specific γ‑glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (SESN2; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T‑ALL cells. Moreover, nelfinavir suppressed NOTCH1 mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating NOTCH1 mRNA expression, upregulating CHAC1 and suppressing γ‑secretase via presenilin 1 inhibition and the mTOR pathway by upregulating SESN2 via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T‑ALL in an SCL‑LMO1 transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T‑ALL.

PMID:37800623 | DOI:10.3892/ijo.2023.5576

Front Bioeng Biotechnol. 2023 Sep 20;11:1193424. doi: 10.3389/fbioe.2023.1193424. eCollection 2023.

ABSTRACT

The burgeoning human population has resulted in an augmented demand for raw materials and energy sources, which in turn has led to a deleterious environmental impact marked by elevated greenhouse gas (GHG) emissions, acidification of water bodies, and escalating global temperatures. Therefore, it is imperative that modern society develop sustainable technologies to avert future environmental degradation and generate alternative bioproduct-producing technologies. A promising approach to tackling this challenge involves utilizing natural microbial consortia or designing synthetic communities of microorganisms as a foundation to develop diverse and sustainable applications for bioproduct production, wastewater treatment, GHG emission reduction, energy crisis alleviation, and soil fertility enhancement. Microalgae, which are photosynthetic microorganisms that inhabit aquatic environments and exhibit a high capacity for CO2 fixation, are particularly appealing in this context. They can convert light energy and atmospheric CO2 or industrial flue gases into valuable biomass and organic chemicals, thereby contributing to GHG emission reduction. To date, most microalgae cultivation studies have focused on monoculture systems. However, maintaining a microalgae monoculture system can be challenging due to contamination by other microorganisms (e.g., yeasts, fungi, bacteria, and other microalgae species), which can lead to low productivity, culture collapse, and low-quality biomass. Co-culture systems, which produce robust microorganism consortia or communities, present a compelling strategy for addressing contamination problems. In recent years, research and development of innovative co-cultivation techniques have substantially increased. Nevertheless, many microalgae co-culturing technologies remain in the developmental phase and have yet to be scaled and commercialized. Accordingly, this review presents a thorough literature review of research conducted in the last few decades, exploring the advantages and disadvantages of microalgae co-cultivation systems that involve microalgae-bacteria, microalgae-fungi, and microalgae-microalgae/algae systems. The manuscript also addresses diverse uses of co-culture systems, and growing methods, and includes one of the most exciting research areas in co-culturing systems, which are omic studies that elucidate different interaction mechanisms among microbial communities. Finally, the manuscript discusses the economic viability, future challenges, and prospects of microalgal co-cultivation methods.

PMID:37799812 | PMC:PMC10548143 | DOI:10.3389/fbioe.2023.1193424

Biomicrofluidics. 2023 Oct 3;17(5):051301. doi: 10.1063/5.0170050. eCollection 2023 Sep.

ABSTRACT

Microfluidic technology has largely benefited both fundamental biological research and translational clinical diagnosis with its advantages in high-throughput, single-cell resolution, high integrity, and wide-accessibility. Despite the merits we obtained from microfluidics in the last two decades, the current requirement of intelligence in biomedicine urges the microfluidic technology to process biological big data more efficiently and intelligently. Thus, the current readout technology based on the direct detection of the signals in either optics or electrics was not able to meet the requirement. The implementation of artificial intelligence (AI) in microfluidic technology matches up with the large-scale data usually obtained in the high-throughput assays of microfluidics. At the same time, AI is able to process the multimodal datasets obtained from versatile microfluidic devices, including images, videos, electric signals, and sequences. Moreover, AI provides the microfluidic technology with the capability to understand and decipher the obtained datasets rather than simply obtaining, which eventually facilitates fundamental and translational research in many areas, including cell type discovery, cell signaling, single-cell genetics, and diagnosis. In this Perspective, we will highlight the recent advances in employing AI for single-cell biology and present an outlook on the future direction with more advanced AI algorithms.

PMID:37799809 | PMC:PMC10550334 | DOI:10.1063/5.0170050

Bioinform Adv. 2023 Sep 14;3(1):vbad125. doi: 10.1093/bioadv/vbad125. eCollection 2023.

ABSTRACT

MOTIVATION: Leishmaniasis is a global concern especially in underdeveloped and developing subtropical and tropical regions. The extent of infectivity in host is majorly dependent on functional polarization of macrophages. Classically activated M1 macrophage can eliminate parasite through production of iNOS and alternatively activated M2 macrophages can promote parasite growth through by providing shelter and nutrients to parasite. The biological processes involved in immune signaling and metabolism of host and parasite might be responsible for deciding fate of parasite.

RESULTS: Using systems biology approach, we constructed two mathematical models and inter-regulatory immune-metabolic networks of M1 and M2 state, through which we identified crucial components that are associated with these phenotypes. We also demonstrated how parasite may modulate M1 phenotype for its growth and proliferation and transition to M2 state. Through our previous findings as well as from recent findings we could identify SHP-1 as a key component in regulating the immune-metabolic characterization of M2 macrophage. By targeting SHP-1 at cellular level, it might be possible to modulate immuno-metabolic mechanism and thereby control parasite survival.

AVAILABILITY AND IMPLEMENTATION: Mathematical modeling is implemented as a workflow and the models are deposited in BioModel database. FactoMineR is available at: https://github.com/cran/FactoMineR/tree/master.

PMID:37799190 | PMC:PMC10548086 | DOI:10.1093/bioadv/vbad125

J Am Acad Dermatol. 2023 Oct 3:S0190-9622(23)02881-5. doi: 10.1016/j.jaad.2023.08.105. Online ahead of print.

ABSTRACT

BACKGROUND: The recent expansion of immunotherapy for stage IIB/IIC melanoma highlights a growing clinical need to identify patients at high risk of metastatic recurrence and, therefore, most likely to benefit from this therapeutic modality.

OBJECTIVE: To develop time-to-event risk prediction models for melanoma metastatic recurrence.

METHODS: Patients diagnosed with stage I/II primary cutaneous melanoma between 2000 and 2020 at Mass General Brigham and Dana-Farber Cancer Institute were included. Melanoma recurrence date and type were determined by chart review. Thirty clinicopathologic factors were extracted from electronic health records. Three types of time-to-event machine-learning models were evaluated internally and externally in the distant versus locoregional/non-recurrence prediction.

RESULTS: This study included 954 melanomas (155 distant, 163 locoregional, and 636 1:2 matched non-recurrences). Distant recurrences were associated with worse survival compared to locoregional/non-recurrences (HR: 6.21, p<0.001) and to locoregional recurrences only (HR: 5.79, p<0.001). The Gradient Boosting Survival model achieved the best performance (concordance index: 0.816; time-dependent AUC: 0.842; Brier score: 0.103) in the external validation.

LIMITATIONS: Retrospective nature and cohort from one geography.

CONCLUSIONS: These results suggest that time-to-event machine-learning models can reliably predict the metastatic recurrence from localized melanoma and help identify high-risk patients who are most likely to benefit from immunotherapy.

PMID:37797836 | DOI:10.1016/j.jaad.2023.08.105

J Hosp Infect. 2023 Oct 3:S0195-6701(23)00316-X. doi: 10.1016/j.jhin.2023.08.026. Online ahead of print.

ABSTRACT

The COVID-19 (SARS-CoV-2) pandemic increased the attention for preventing contamination with airborne pathogens (e.g. viruses, bacteria and fungi) by reducing their concentration. Filtration, UV or ionization technologies could contribute to air purification of the indoor environment and inactivation of microorganisms. The aim of this study is to identify the relevant literature and review the scientific evidence presented on the efficacy of filter and germicidal technologies (e.g. non-physical technologies) in air purification applications used to capture and inactivate microorganisms and airborne viruses (e.g. SARS-CoV-2, rhinovirus, influenzavirus) in practice. A scoping review was performed to collect literature. Adopting exclusion criteria resulted in a final number of 75 studies to be included in this research. Discussion is presented on inactivation efficiencies of ultraviolet germicidal irradiation (UVGI) and ionization applications in laboratory studies and in practice. Specific attention is given to studies relating the use of UVGI and ionization to inactivation of the SARS-CoV-2 virus. Based on the consulted literature, no unambiguous conclusions can be drawn for the effectiveness of air purification technologies in practice. The documented and well controled laboratory studies are not adequately representing the practical situation in which the purifier systems are used.

PMID:37797657 | DOI:10.1016/j.jhin.2023.08.026

Cell Rep Methods. 2023 Sep 27:100599. doi: 10.1016/j.crmeth.2023.100599. Online ahead of print.

ABSTRACT

For large libraries of small molecules, exhaustive combinatorial chemical screens become infeasible to perform when considering a range of disease models, assay conditions, and dose ranges. Deep learning models have achieved state-of-the-art results in silico for the prediction of synergy scores. However, databases of drug combinations are biased toward synergistic agents and results do not generalize out of distribution. During 5 rounds of experimentation, we employ sequential model optimization with a deep learning model to select drug combinations increasingly enriched for synergism and active against a cancer cell line-evaluating only ∼5% of the total search space. Moreover, we find that learned drug embeddings (using structural information) begin to reflect biological mechanisms. In silico benchmarking suggests search queries are ∼5-10× enriched for highly synergistic drug combinations by using sequential rounds of evaluation when compared with random selection or ∼3× when using a pretrained model.

PMID:37797618 | DOI:10.1016/j.crmeth.2023.100599

Nat Neurosci. 2023 Oct 5. doi: 10.1038/s41593-023-01452-y. Online ahead of print.

ABSTRACT

The amygdala processes positive and negative valence and contributes to addiction, but the cell-type-specific gene regulatory programs involved are unknown. We generated an atlas of single-nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with high and low cocaine addiction-like behaviors following prolonged abstinence. Differentially expressed genes between the high and low groups were enriched for energy metabolism across cell types. Rats with high addiction index (AI) showed increased relapse-like behaviors and GABAergic transmission in the amygdala. Both phenotypes were reversed by pharmacological inhibition of the glyoxalase 1 enzyme, which metabolizes methylglyoxal-a GABAA receptor agonist produced by glycolysis. Differences in chromatin accessibility between high and low AI rats implicated pioneer transcription factors in the basic helix-loop-helix, FOX, SOX and activator protein 1 families. We observed opposite regulation of chromatin accessibility across many cell types. Most notably, excitatory neurons had greater accessibility in high AI rats and inhibitory neurons had greater accessibility in low AI rats.

PMID:37798411 | DOI:10.1038/s41593-023-01452-y

Nat Commun. 2023 Oct 5;14(1):6173. doi: 10.1038/s41467-023-41836-z.

ABSTRACT

The relative abundance of Wnt receptors plays a crucial role in controlling Wnt signaling in tissue homeostasis and human disease. While the ubiquitin ligases that ubiquitylate Wnt receptors are well-characterized, the deubiquitylase that reverses these reactions remains unclear. Herein, we identify USP46, UAF1, and WDR20 (USP46 complex) as positive regulators of Wnt signaling in cultured human cells. We find that the USP46 complex is similarly required for Wnt signaling in Xenopus and zebrafish embryos. We demonstrate that Wnt signaling promotes the association between the USP46 complex and cell surface Wnt coreceptor, LRP6. Knockdown of USP46 decreases steady-state levels of LRP6 and increases the level of ubiquitylated LRP6. In contrast, overexpression of the USP46 complex blocks ubiquitylation of LRP6 by the ubiquitin ligases RNF43 and ZNFR3. Size exclusion chromatography studies suggest that the size of the USP46 cytoplasmic complex increases upon Wnt stimulation. Finally, we show that USP46 is essential for Wnt-dependent intestinal organoid viability, likely via its role in LRP6 receptor homeostasis. We propose a model in which the USP46 complex increases the steady-state level of cell surface LRP6 and facilitates the assembly of LRP6 into signalosomes via a pruning mechanism that removes sterically hindering ubiquitin chains.

PMID:37798301 | DOI:10.1038/s41467-023-41836-z

Nat Commun. 2023 Oct 5;14(1):6174. doi: 10.1038/s41467-023-41843-0.

ABSTRACT

The control of Wnt receptor abundance is critical for animal development and to prevent tumorigenesis, but the mechanisms that mediate receptor stabilization remain uncertain. We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow and enhances the sensitivity of target cells to stimulation by the Wingless morphogen, thereby increasing the amplitude and spatial range of signaling responses. Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/β-catenin, and attenuates or abolishes Wingless target gene activation, which prevents the concentration-dependent regulation of signaling strength. Consequently, Wingless-dependent developmental patterning and tissue homeostasis are disrupted. These results reveal an evolutionarily conserved mechanism that mediates Wnt/Wingless receptor stabilization and underlies the precise activation of signaling throughout the spatial range of the morphogen gradient.

PMID:37798281 | DOI:10.1038/s41467-023-41843-0

Naunyn Schmiedebergs Arch Pharmacol. 2023 Oct 5. doi: 10.1007/s00210-023-02741-w. Online ahead of print.

ABSTRACT

Honesty of publications is fundamental in science. Unfortunately, science has an increasing fake paper problem with multiple cases having surfaced in recent years, even in renowned journals. There are companies, the so-called paper mills, which professionally fake research data and papers. However, there is no easy way to systematically identify these papers. Here, we show that scanning for exchanged authors in resubmissions is a simple approach to detect potential fake papers. We investigated 2056 withdrawn or rejected submissions to Naunyn-Schmiedeberg's Archives of Pharmacology (NSAP), 952 of which were subsequently published in other journals. In six cases, the stated authors of the final publications differed by more than two thirds from those named in the submission to NSAP. In four cases, they differed completely. Our results reveal that paper mills take advantage of the fact that journals are unaware of submissions to other journals. Consequently, papers can be submitted multiple times (even simultaneously), and authors can be replaced if they withdraw from their purchased authorship. We suggest that publishers collaborate with each other by sharing titles, authors, and abstracts of their submissions. Doing so would allow the detection of suspicious changes in the authorship of submitted and already published papers. Independently of such collaboration across publishers, every scientific journal can make an important contribution to the integrity of the scientific record by analyzing its own pool of withdrawn and rejected papers versus published papers according to the simple algorithm proposed in the present paper.

PMID:37796310 | DOI:10.1007/s00210-023-02741-w

J Biomol Struct Dyn. 2023 Oct 4:1-10. doi: 10.1080/07391102.2023.2262596. Online ahead of print.

ABSTRACT

Adipose tissue is the major storage site of lipids and plays a vital role in energy homeostasis. Adipogenesis is a well-regulated process wherein preadipocytes differentiate into adipocytes. It requires the sequential activation of numerous transcription factors, including peroxisome proliferator activated receptor-γ (PPAR-γ). Phytochemicals have been reported to regulate adipogenesis and flavonoids represent the most researched groups of phytochemicals with regard to their effect on adipogenesis. Chrysin is a naturally occurring flavone and is reported to have anti-inflammatory effects in obese conditions. The present study was aimed to examine the effect of chrysin on adipogenesis. In silico Molecular docking, dynamic simulation studies and in vitro cell-based assays showed that chrysin inhibited adipogenesis by modulating key adipogenic transcription factor PPARγ. Enhanced adipogenesis leads to obesity and targeting adipogenesis is potential in regulating adipose tissue development. So, these investigations may provide important information for designing therapeutic interventions to control adiposity.Communicated by Ramaswamy H. Sarma.

PMID:37794770 | DOI:10.1080/07391102.2023.2262596

Cell. 2023 Sep 28:S0092-8674(23)00980-7. doi: 10.1016/j.cell.2023.09.002. Online ahead of print.

ABSTRACT

Regulation of viral RNA biogenesis is fundamental to productive SARS-CoV-2 infection. To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified proteins bound to genomic and subgenomic SARS-CoV-2 RNAs. We find that the host protein SND1 binds the 5' end of negative-sense viral RNA and is required for SARS-CoV-2 RNA synthesis. SND1-depleted cells form smaller replication organelles and display diminished virus growth kinetics. We discover that NSP9, a viral RBP and direct SND1 interaction partner, is covalently linked to the 5' ends of positive- and negative-sense RNAs produced during infection. These linkages occur at replication-transcription initiation sites, consistent with NSP9 priming viral RNA synthesis. Mechanistically, SND1 remodels NSP9 occupancy and alters the covalent linkage of NSP9 to initiating nucleotides in viral RNA. Our findings implicate NSP9 in the initiation of SARS-CoV-2 RNA synthesis and unravel an unsuspected role of a cellular protein in orchestrating viral RNA production.

PMID:37794589 | DOI:10.1016/j.cell.2023.09.002

Nat Rev Immunol. 2023 Oct 4. doi: 10.1038/s41577-023-00943-0. Online ahead of print.

ABSTRACT

Regular physical activity is associated with lower cancer incidence and mortality, as well as with a lower rate of tumour recurrence. The epidemiological evidence is supported by preclinical studies in animal models showing that regular exercise delays the progression of cancer, including highly aggressive malignancies. Although the mechanisms underlying the antitumorigenic effects of exercise remain to be defined, an improvement in cancer immunosurveillance is likely important, with different immune cell subtypes stimulated by exercise to infiltrate tumours. There is also evidence that immune cells from blood collected after an exercise bout could be used as adoptive cell therapy for cancer. In this Perspective, we address the importance of muscular activity for maintaining a healthy immune system and discuss the effects of a single bout of exercise (that is, 'acute' exercise) and those of 'regular' exercise (that is, repeated bouts) on anticancer immunity, including tumour infiltrates. We also address the postulated mechanisms and the clinical implications of this emerging area of research.

PMID:37794239 | DOI:10.1038/s41577-023-00943-0