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Timely evaluation of the protective effects of Coronavirus Disease 2019 (COVID-19) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern is urgently needed to inform pandemic control planning. Based on 78 vaccine efficacy or effectiveness (VE) data from 49 studies and 1,984,241 SARS-CoV-2 sequences collected from 31 regions, we analyzed the relationship between genetic distance (GD) of circulating viruses against the vaccine strain and VE against symptomatic infection. We found that the GD of the receptor-binding domain of the SARS-CoV-2 spike protein is highly predictive of vaccine protection and accounted for 86.3% (P = 0.038) of the VE change in a vaccine platform-based mixed-effects model and 87.9% (P = 0.006) in a manufacturer-based model. We applied the VE-GD model to predict protection mediated by existing vaccines against new genetic variants and validated the results by published real-world and clinical trial data, finding high concordance of predicted VE with observed VE. We estimated the VE against the Delta variant to be 82.8% (95% prediction interval: 68.7–96.0) using the mRNA vaccine platform, closely matching the reported VE of 83.0% from an observational study. Among the four sublineages of Omicron, the predicted VE varied between 11.9% and 33.3%, with the highest VE predicted against BA.1 and the lowest against BA.2, using the mRNA vaccine platform. The VE-GD framework enables predictions of vaccine protection in real time and offers a rapid evaluation method against novel variants that may inform vaccine deployment and public health responses.

Cancer-related genes have evolved specific genetic and genomic features to favor tumor suppression. Previously we reported that tumor suppressor genes (TSGs) acquired high promoter CpG dinucleotide frequencies during evolution to maintain high expression in normal tissues and resist cancer-specific downregulation. In this study, we investigated whether 3'untranslated regions (3'UTRs) of TSGs have evolved specific features to carry out similar functions. We found that 3'UTRs of TSGs, especially those involved in multiple histological types and pediatric cancers, are longer than those of non-cancer genes. 3'UTRs of TSGs also exhibit higher density of binding sites for RNA-binding proteins (RBPs), particularly those having high affinities to C-rich motifs. Both longer 3'UTR length and RBP binding sites enrichment are correlated with higher gene expression in normal tissues across tissue types. Moreover, both features together with the correlated N

Supplementary Table from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution

Supplementary Figure from Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution

Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation.Significance:This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1β/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited. Published version This work was supported by The TUYF Charitable Trust and Shenzhen Science and Technology Programme (JCYJ20180508161604382).

Clostridioides difficile infection (CDI) is a common cause of nosocomial diarrhea. TcdB is a major C. difficile exotoxin that activates macrophages to promote inflammation and epithelial damage. Lysosome impairment is a known trigger for inflammation. Herein, we hypothesize that TcdB could impair macrophage lysosomal function to mediate inflammation during CDI. Effects of TcdB on lysosomal function and the downstream pro-inflammatory SQSTM1/p62-NFKB (nuclear factor kappa B) signaling were assessed in cultured macrophages and in a murine CDI model. Protective effects of two lysosome activators (i.e., vitamin D3 and carbamazepine) were assessed. Results showed that TcdB inhibited CTNNB1/β-catenin activity to downregulate MITF (melanocyte inducing transcription factor) and its direct target genes encoding components of lysosomal membrane vacuolar-type ATPase, thereby suppressing lysosome acidification in macrophages. The resulting lysosomal dysfunction then impaired autophagic flux and activated SQSTM1-NFKB signaling to drive the expression of IL1B/IL-1β (interleukin 1 beta), IL8 and CXCL2 (chemokine (C-X-C motif) ligand 2). Restoring MITF function by enforced MITF expression or restoring lysosome acidification with 1α,25-dihydroxyvitamin D3 or carbamazepine suppressed pro-inflammatory cytokine expression in vitro. In mice, gavage with TcdB-hyperproducing C. difficile or injection of TcdB into ligated colon segments caused prominent MITF downregulation in macrophages. Vitamin D3 and carbamazepine lessened TcdB-induced lysosomal dysfunction, inflammation and histological damage. In conclusion, TcdB inhibits the CTNNB1-MITF axis to suppress lysosome acidification and activates the downstream SQSTM1-NFKB signaling in macrophages during CDI. Vitamin D3 and carbamazepine protect against CDI by restoring MITF expression and lysosomal function in mice. Abbreviations: ATP6V0B: ATPase H+ transporting V0 subunit b; ATP6V0C: ATPase H+ transporting V0 subunit c; ATP6V0E1: ATPase H+ transporting V0 subunit e1; ATP6V1H: ATPase H+ transporting V1 subunit H; CBZ: carbamazepine; CDI: C. difficile infection; CXCL: chemokine C-X-X motif ligand; IL: interleukin; LAMP1: lysosomal-associated membrane protein 1; LC3: microtubule-associated protein 1 light chain 3; LEF: lymphoid enhancer binding factor 1; MITF: melanocyte inducing transcription factor; NFKB: nuclear factor kappa B; PMA: phorbol 12-myristate 13-acetate; TcdA: Clostridial toxin A; TcdB: Clostridial toxin B; TFE3: transcription factor E3; TFEB: transcription factor EB. Published version This work was supported by the National Natural Science Foundation of China [82070576] and the Hong Kong Food and Health Bureau (FHB) Commissioned Health and Medical Research Fund [CID-CUHK-C].

ObjectiveUsing faecal shotgun metagenomic sequencing, we identified the depletion ofLactobacillus gallinarumin patients with colorectal cancer (CRC). We aimed to determine the potential antitumourigenic role ofL. gallinarumin colorectal tumourigenesis.DesignThe tumor-suppressive effect ofL. gallinarumwas assessed in murine models of CRC. CRC cell lines and organoids derived from patients with CRC were cultured withL. gallinarumorEscherichia coliMG1655 culture-supernatant to evaluate cell proliferation, apoptosis and cell cycle distribution. Gut microbiota was assessed by 16S ribosomal DNA sequencing. Antitumour molecule produced fromL. gallinarumwas identified by liquid chromatography mass spectrometry (LC-MS/MS) and targeted mass spectrometry.ResultsL. gallinarumsignificantly reduced intestinal tumour number and size compared withE. coliMG1655 and phosphate-buffered saline in both male and female murine intestinal tumourigenesis models. Faecal microbial profiling revealed enrichment of probiotics and depletion of pathogenic bacteria inL. gallinarum-treated mice. Culturing CRC cells withL. gallinarumculture-supernatant (5%, 10% and 20%) concentration-dependently suppressed cell proliferation and colony formation.L. gallinarumculture-supernatant significantly promoted apoptosis in CRC cells and patient-derived CRC organoids, but not in normal colon epithelial cells. OnlyL. gallinarumculture-supernatant with fraction size L. gallinarumculture-supernatant and the gut ofL. gallinarum-treated mice. ILA displayed anti-CRC growthin vitroand inhibited intestinal tumourigenesisin vivo.ConclusionL. gallinarumprotects against intestinal tumourigenesis by producing protective metabolites that can promote apoptosis of CRC cells.

Digestive system tumours are the most common malignancies worldwide, causing huge number of deaths each year. With the increases in morbidity and mortality, it is imperative to identify new therapeutic targets. Melanoma-associated antigen-A6 (MAGEA6) is a member of the cancer/testicular antigen (CTA) family. There are increasing amount of evidence supporting that MAGEA6 plays an important role in the development of solid tumours. However, there has been no comprehensive analysis of MAGEA6 in digestive system tumours. Therefore, our objective was to investigate the expression level, clinical significance and related biological functions of MAGEA6 in digestive system tumours. In this study, we integratively analysed the data from multiple databases of patients with digestive system tumours. Our results showed that MAGEA6 was highly expressed in most digestive system tumours as compared with normal tissues, whereas patients with higher expression of MAGEA6 had a worse prognosis. Based on co-expression analysis, there was a close interaction between MAGEA6 and MAGEA3. Furthermore, differential gene enrichment analysis indicated that MAGEA6 was mainly involved in the formation of extracellular structure, DNA replication, mitosis and the p53 signalling pathway. These results suggest that MAGEA6 is as a prognostic factor with functional importance in digestive system tumours.

Sepsis is defined as life-threatening organ dysfunction caused by the host immune dysregulation to infection. It is a highly heterogeneous syndrome with complex pathophysiological mechanisms. The host immune response to sepsis can be divided into hyper-inflammatory and immune-suppressive phases which could exist simultaneously. In the initial stage, systemic immune response is activated after exposure to pathogens. Both innate and adaptive immune cells undergo epigenomic, transcriptomic, and functional reprogramming, resulting in systemic and persistent inflammatory responses. Following the hyper-inflammatory phase, the body is in a state of continuous immunosuppression, which is related to immune cell apoptosis, metabolic failure, and epigenetic reprogramming. Immunosuppression leads to increased susceptibility to secondary infections in patients with sepsis. RNA N6-Methyladenosine (m6A) has been recognized as an indispensable epitranscriptomic modification involved in both physiological and pathological processes. Recent studies suggest that m6A could reprogram both innate and adaptive immune cells through posttranscriptional regulation of RNA metabolism. Dysregulated m6A modifications contribute to the pathogenesis of immune-related diseases. In this review, we summarize immune cell changes and the potential role of m6A modification in sepsis. This article is categorized under: RNA in Disease and DevelopmentRNA in Disease RNA ProcessingRNA Editing and Modification.

Large-scale fecal shotgun metagenomic sequencing revealed the high abundance of Parvimonas micra in colorectal cancer (CRC) patients. We investigated the role and clinical significance of P. micra in colorectal tumorigenesis. The abundance of P. micra was examined in 309 fecal samples and 165 colon biopsy tissues of CRC patients and healthy subjects. P. micra was significantly enriched in fecal samples from 128 CRC patients compared to 181 healthy subjects (P P P. micra is an independent risk factor of poor survival in CRC patients (Hazard Ratio: 1.93). P. micra strain was isolated from feces of a CRC patient. Apcmin/+ mice gavaged with P. micra showed significantly higher tumor burden and tumor load (both P P. micra significantly promoted colonocyte proliferation in conventional mice, which was further confirmed by germ-free mice. P. micra colonization up-regulated genes involved in cell proliferation, stemness, angiogenesis and invasiveness/metastasis; and enhanced Th17 cells infiltration and expression of Th17 cells-secreted cytokines (Il-17, Il-22, and Il-23) in the colon of Apcmin/+, conventional and germ-free mice. P. micra-conditioned medium significantly promoted the differentiation of CD4+ T cells to Th17 cells (IL-17+CD4+ phenotype) and enhanced the oncogenic Wnt signaling pathway. In conclusion, P. micra promoted colorectal tumorigenesis in mice by inducing colonocyte proliferation and altering Th17 immune response. P. micra may act as a prognostic biomarker for poor survival of CRC patients.

Multi-population cohorts offer unprecedented opportunities for profiling disease risk in large samples, however, heterogeneous risk effects underlying complex traits across populations make integrative prediction challenging. In this study, we propose a novel Bayesian probability framework, the Prism Vote (PV), to construct risk predictions in heterogeneous genetic data. The PV views the trait of an individual as a composite risk from subpopulations, in which stratum-specific predictors can be formed in data of more homogeneous genetic structure. Since each individual is represented by a composition of subpopulation memberships, the framework enables individualized risk characterization. Simulations demonstrated that the PV framework applied with alternative prediction methods significantly improved prediction accuracy in mixed and admixed populations. The advantage of PV enlarges as the sample size, genetic heterogeneity, and population diversity increase. In two real genome-wide association data consists of multiple populations, we showed that the framework enhanced prediction accuracy of the linear mixed model by up to 12.1% in five-group cross validations. The proposed framework offers a new aspect to analyze individual’s disease risk and improve accuracy for predicting complex traits in genome data.

Introduction Coronavirus disease 2019 (COVID-19) has led to radical changes in social distancing awareness and affected social relationships. Owing to large-scale lockdown, home quarantine and social distancing requirements, it was anticipated that sexual activities would be severely impacted. However, retrospective self-report studies showed that pornography use and autoerotism increased during the pandemic. Aim This study used big-data databases available on the Internet to investigate factors that modulated pornography use during the pandemic. Methods Daily relative search volume (RSV) data from Google Trends for the period from 24 February 2020 to 13 July 2020 were extracted. Pornhub traffic data were extracted from the Pornhub Insights website, for the period from 24 February 2020 to 13 July 2020. The parameter was defined as ‘percent change in traffic compared to an average day in 2019’. The number of daily new cases of COVID-19 was extracted from the database on Our World in Data. Outcome measures The normality of the data was examined using the Shapiro-Wilk test. All variables included in this study were non-normally distributed. Therefore, non-parametric tests or parametric tests with bootstrapping were adopted where appropriate. Results According to Google Trends, the RSV for ‘pornography’ increased after late March 2020, which is close to the date when the World Health Organization declared COVID-19 a global pandemic. The number of daily new cases of COVID-19 was positively correlated with the traffic of Pornhub, a popular pornography website, and the RSV for ‘pornography’. Moderation analysis demonstrated a significant main effect of daily new cases of COVID-19 and the RSV for ‘social distancing’ in predicting Pornhub traffic/RSV for ‘pornography’. Furthermore, the RSV for ‘social distancing’ significantly moderated the relationship between daily new cases and Pornhub traffic/RSV for ‘pornography’. A stronger COVID-pornography use association was observed with increased social distancing awareness. Conclusion Increased pornography consumption during the pandemic was observed, and it was associated with the severity of the pandemic. Social distancing awareness could be a key factor influencing interest in and use of pornography. Further studies on the changes in sexual desire and birth-rate control are worthwhile because long-term public health may be affected by the changes in sexual behaviour during the pandemic.

Spinal cord injury (SCI) is a disabling condition for which therapeutic options are limited. Increasing number of microarray and next-generation sequencing studies have demonstrated that SCI coincides with altered expression of circular RNAs (circRNAs) in the damaged tissue. Emerging functional evidence further pinpointed specific differentially expressed circRNAs (e.g., circ-HIPK3, cicRNA.7079, circRNA_01477, circRNA-2960, and circ_0001723) for their effects on cellular processes relevant to SCI repair and regeneration, including neuronal apoptosis, astrocyte activation, and neuroinflammation, via sponging SCI-related microRNAs. Although circRNAs and their target microRNAs appear to be good candidates for therapeutic exploitation in SCI, further investigation into the efficient delivery of these regulatory molecules in a cell-type specific manner is a pre-requisite for translating these basic discoveries into clinical benefits.

Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation. Significance: This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.

To investigate the antibiofilm and remineralising effects of the dual-action peptide GA-KR12 on artificial enamel caries.Enamel blocks with artificial caries were treated with sterilised deionised water as control or GA-KR12. The blocks underwent biochemical cycling with Streptococcus mutans for 3 weeks. The architecture, viability, and growth kinetics of the biofilm were determined, respectively, by scanning electron microscopy (SEM), confocal laser scanning microscopy, and quantitative (culture colony-forming units, CFUs). The mineral loss, calcium-to-phosphorus ratio, surface morphology, and crystal characteristics of the enamel surface were determined, respectively, using micro-computed tomography, energy dispersive spectroscopy, SEM, and X-ray diffraction (XRD).SEM showed confluent growth of S. mutans in the control group but not in the GA-KR12-treated group. The dead-to-live ratios of the control and GA-KR12-treated groups were 0.42 ± 0.05 and 0.81 ± 0.08, respectively (p 0.001). The log CFUs of the control and GA-KR12-treated groups were 8.15 ± 0.32 and 6.70 ± 0.49, respectively (p 0.001). The mineral losses of the control and GA-KR12-treated groups were 1.39 ± 0.09 gcmThe dual-action peptide GA-KR12 inhibited the growth of S. mutans biofilm and promoted the remineralisation of enamel caries.GA-KR12 potentially is applicable for managing enamel caries.

Osteonecrosis of the femoral head (ONFH) is a potentially disabling orthopedic condition that, in most late-stage cases, requires total hip arthroplasty. Although direct trauma to the hip (e.g. femoral neck fracture, hip dislocation) that leads to vascular interruption is a strong risk factor for ONFH, there are many non-traumatic risk factors (e.g. use of corticosteroid, alcohol abuse) which molecular mechanisms in ONFH still remain obscured. Long non-coding RNAs (lncRNAs) is a class of regulatory RNAs that play crucial roles in various cellular functions, including cell proliferation, invasion, metabolism, apoptosis and stem cell differentiation. Recent studies also suggested their participation in bone development and regeneration, and a direct involvement in the pathogenesis of numerous of orthopaedic conditions, such as ONFH. LncRNAs are differentially expressed in ONFH tissues as well as bone marrow-mesenchymal stem cells and bone microvascular endothelial cells isolated from ONFH patients. Functional studies further established their critical roles in regulating biological processes, such as osteoblast survival and osteogenic differentiation of bone marrow-mesenchymal stem cells, which are closely related to ONFH. The current review aims at summarizing the recent advancement in this field and discussing the potential diagnostic, prognostic and therapeutic utilities of lncRNAs in the clinical management of ONFH.

Cataract is the most common cause of blindness worldwide. Multiple factors such as aging, eye injury, diabetes mellitus, ultraviolet exposure, drug use and other ocular diseases are etiologically linked to cataractogenesis. Due to a rapid increase in aging population, age-related cataract has become the leading cause of blindness. Therefore, it is urgent to understand the molecular mechanism underlying cataractogenesis. MicroRNAs (miRNAs) are a group of endogenous, small noncoding RNAs that regulate gene expression at the post-translational level through binding with the 3’-untranslated regions of target mRNAs. Studies have shown that miRNAs play important roles in multiple cellular functions, including apoptosis, cell proliferation, senescence and stress response. Deregulated expression of miRNAs is also linked to the pathogenesis of many diseases, including ocular diseases. In our review, we focus on miRNAs that are involved in cataract development and discuss their potential applications as novel diagnostic markers and therapeutic targets.

PAQR3, also known as RKTG (Raf kinase trapping to Golgi), is a member of the progestin and adipoQ receptor (PAQR) family. The role of PAQR3 as a tumor suppressor has recently been established in different types of human cancer in which PAQR3 exerts its biological function through negative regulation of the oncogenic Raf/MEK/ERK signaling. Multiple studies have found that PAQR3 downregulation frequently occurs in human cancers and is very often associated with tumor progression and shortened patients’ survival. Moreover, restoring the expression of PAQR3 could induce apoptosis and inhibit proliferation and invasiveness of cancer cells. Downregulation of PAQR3 by oncogenic microRNAs has also been reported. In this review, we summarized current knowledge concerning the role of PAQR3 in tumor development. To our knowledge, this is the first review on the role of this novel tumor suppressor.

Leptin affects a number of cell signaling pathways, at present, the mechanism(s) by which leptin affects the cartilage cells in OA patient is not well understood. The current study seeks to elucidate whether leptin induces cytoskeletal remodeling in chondrocytes and the possible involvement of the RhoA/ROCK pathway and its downstream mediators in this process. Fluorescent resonance energy transfer (FRET) and western analysis were used to determine the activations of the key proteins in the RhoA/LIMK1/Cofilin pathway. Accompanying cytoskeletal remodeling was elucidated. Upon leptin stimulation, a substantial increase of RhoA activity localized at one end of the cell was observed from 2 to 30 min post-stimulation. The results of Western blot showed leptin significantly increased LIMK1 and cofilin-2 phosphorylation in a time-dependent manner with maximal stimulation attained 60 min and 24 h post-stimulation, respectively. Chondrocytes stimulated with leptin exhibited an epithelioid morphology with increased cellular spreading. F-actin in leptin-stimulated chondrocytes also showed more intense cytoplasmic staining with occasional localization along filamentous structures. The results indicate that leptin activates the RhoA/ROCK/LIMK/cofilin pathway, which results in cytoskeletal reorganization in chondrocytes. These findings provide novel evidence supporting the possible involvement of leptin and the RhoA pathway in the pathogenesis of OA.

ErbB receptors and their cognate ligands are implicated in cancer progression. Their expression in gastrointestinal cancer, however, has not been systemically studied.The expression of four ErbB receptors and a panel of ErbB ligands were determined by reverse transcription-PCR in two gastric (TMK1, MKN-45) and two colon (SW1116, HT-29) cancer cell lines. Cell proliferation was measured by MTT assay while gene knockdown was achieved by RNA interference.ErbB1, ErbB2 and ErbB3 receptors and five known or putative ErbB ligands, namely, epiregulin, epidermal growth factor (EGF), heparin-binding EGF, transforming growth factor alpha (TGFalpha) and neuroglycan-C were expressed in all four cell lines. Knockdown of neuroglycan-C, however, did not affect cell proliferation.This study profiles the expression of ErbB receptors and their cognate ligands in gastric and colon cancer cells. These findings might lay the basis for the development of ErbB pathway-directed therapeutics for gastrointestinal cancer.