Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators in the Diagnosis and Subtype Classification of Rheumatoid Arthritis.

m6A modification is the most abundant mRNA modifications and plays an integral role in various biological processes in eukaryotes. However, the role of m6A regulators in rheumatoid arthritis remains unknown. To determine the expression of m6A RNA methylation regulators in rheumatoid arthritis and their possible functional and prognostic value. In this study, we performed differential analysis in the comprehensive gene expression database GSE93272 dataset between non-rheumatoid arthritis patients and rheumatoid arthritis patients to obtain 15 important m6A regulators. A random forest model and lasso regression were used to screen the five most important m6A regulators to predict the risk of developing rheumatoid arthritis. After further validation using in vitro qPCR experiments, a nomogram model was developed based on the four most important m6A regulators (ELAVL1, WTAP, YTHDF1, and ALKBH5). Immuno-infiltration analysis and consensus clustering analysis were then performed. An analysis of the decision curve showed that the nomogram model could be beneficial to patients. According to selected important m6A regulators, patients with rheumatoid arthritis were classified into two m6A models (ClusterA and ClusterB) via consensus approach. Activated B cells, CD56dim natural killer cells, immature B cells, monocytes, natural killer T cells, and T lymphocytes were associated with ClusterA in immune infiltration analysis. Importantly, immune infiltration in patients with high ELAVL1 expression was strikingly similar to ClusterA. m6A regulators play a non-negligible role in the development of rheumatoid arthritis. A study of m6A patterns may provide future therapeutic options for rheumatoid arthritis.

Comment on "Ultrastructure reveals ancestral vertebrate pharyngeal skeleton in yunnanozoans".

Tian et al. (Reports, 8 July 2022, p. 218) claim that Cambrian yunnanozoan animals are stem vertebrates, based partly on their observation at the nanometer scale of microfibrillar tissue located in the branchial arches. They interpret this to represent cellular cartilage with an extracellular matrix of microfibrils. Instead, we argue that the 'microfibrils' are more likely modern organic contamination.

Protomelission is an early dasyclad alga and not a Cambrian bryozoan.

The animal phyla and their associated body plans originate from a singular burst of evolution occurring during the Cambrian period, over 500 million years ago1. The phylum Bryozoa, the colonial 'moss animals', have been the exception: convincing skeletons of this biomineralizing clade have been absent from Cambrian strata, in part because potential bryozoan fossils are difficult to distinguish from the modular skeletons of other animal and algal groups2,3. At present, the strongest candidate4 is the phosphatic microfossil Protomelission5. Here we describe exceptionally preserved non-mineralized anatomy in Protomelission-like macrofossils from the Xiaoshiba Lagerstätte6. Taken alongside the detailed skeletal construction and the potential taphonomic origin of 'zooid apertures', we consider that Protomelission is better interpreted as the earliest dasycladalean green alga-emphasizing the ecological role of benthic photosynthesizers in early Cambrian communities. Under this interpretation, Protomelission cannot inform the origins of the bryozoan body plan; despite a growing number of promising candidates7-9, there remain no unequivocal bryozoans of Cambrian age.

Site-specific unnatural base excision via visible light.

Base excision (BE) is an important yet hard-to-control biological event. Unnatural base pairs are powerful tools to revolutionize biological studies in various areas. In this paper, we report a visible-light-induced method to construct site-specific unnatural BE and show the influence of its regulation on transcription and translation levels.

Mechanistic Insight into the Photoinduced Damage of an Unnatural Base Pair.

Chemical- and photostability of unnatural base pairs (UBPs) are important to maintain the genetic code integrity, and critical for developing healthy semisynthetic organisms. As reported, dTPT3 was less stable upon irradiation, and thus might act as a pervasive photosensitizer to induce oxidative damage within DNA, causing harm to living semi-synthetic organisms when exposed to UVA radiation. However, there was no knowledge about molecular-level understanding of this damage process. In this paper, we not only identified four photoproducts of dTPT3, including desulfur-dTPT3 (dTPT3H ), TPT3 sulphinate (TPT3SO2 ), TPT3 sulphonate (TPT3SO3 ) and TPT3-thioTPT3 (TPT3S TPT3), but also established a Type II photosensitized oxidation mechanism. In addition, the antioxidant (sodium ascorbate) was able to effectively inhibit the photoproducts formation of dTPT3 and dTPT3 in DNA, suggesting that a reductive environment might protect DNA bearing dTPT3 against UVA oxidation and ameliorate its adverse biological effects. The comprehensive understanding of TPT3' photochemical stability will give researchers helpful guidance to design more photostable UBPs and construct healthier semisynthetic organisms.

A 'hermit' shell-dwelling lifestyle in a Cambrian priapulan worm.

The Cambrian 'explosion', about 530 million years ago, marks a rapid diversification of the major animal lineages1. A concomitant increase in the complexity of ecosystems is believed to have accelerated this evolutionary radiation2, but direct evidence of the ecological modes of Cambrian taxa is nevertheless scarce - even in exceptional Burgess Shale-type deposits3. Here, we present new fossil material from the Cambrian (Stage 4) Guanshan biota in southern China that reveals the consistent occurrence of the priapulan worm ?Eximipriapulus4 within the conical shells of hyoliths. This represents the first direct evidence of a 'hermiting' life strategy - the adoption of a different organism's exoskeleton - in the priapulans and within the Palaeozoic era. It highlights the intense degree of convergent evolution during the Cambrian radiation. Hermiting behaviour has previously been linked with the escalation of predation pressure during the Mesozoic marine revolution5; such intensity of predation may also have characterised early Cambrian oceans.

New multipodomerous appendages of stem-group euarthropods from the Cambrian (Stage 4) Guanshan Konservat-Lagerstätte.

Stem-group euarthropods are important for understanding the early evolutionary and ecological history of the most species-rich animal phylum on Earth. Of particular interest are fossil taxa that occupy a phylogenetic position immediately crownwards of radiodonts, for this part of the euarthropod tree is associated with the appearance of several morphological features that characterize extant members of the group. Here, we report two new euarthropods from the Cambrian Stage 4 Guanshan Biota of South China. The fuxianhuiid Alacaris? sp. is represented by isolated appendages composed of a gnathobasic protopodite and an endite-bearing endopod of at least 20 podomeres. This material represents the youngest occurrence of the family Chengjiangocarididae, and its first record outside the Chengjiang and Xiaoshiba biotas. We also describe Lihuacaris ferox gen. et sp. nov. based on well-preserved and robust isolated appendages. Lihuacaris ferox exhibits an atypical combination of characters including an enlarged rectangular base, 11 endite-bearing podomeres and a hypertrophied distal element bearing 8-10 curved spines. Alacaris? sp. appendages display adaptations for macrophagy. Lihuacaris ferox appendages resemble the frontal appendages of radiodonts, as well as the post-oral endopods of chengjiangocaridid fuxianhuids and other deuteropods with well-documented raptorial/predatory habits. Lihuacaris ferox contributes towards the record of endemic biodiversity in the Guanshan Biota.

Long non-coding RNA taurine upregulated gene 1 is downregulated in osteoporosis and influences the osteogenic differentiation of bone marrow mesenchymal stem cells.

BACKGROUND: With aging, an imbalance in bone remodeling leading to increased bone resorption and decreased bone formation is thought to contribute to osteoporosis. Osteoblastic differentiation of bone marrow mesenchymal stem cells (BMMSCs) plays a vital role in the pathogenesis of osteoporosis. However, the detailed molecular mechanisms of osteoporosis remain incompletely understood. Given that long non-coding RNA taurine upregulated gene 1 (lnc TUG1) plays a critical role in the osteogenic differentiation, and microRNA-23b (miR-23b) as a putative sponge for lnc TUG1 has upregulated expression in osteoporosis. Therefore, this study investigated the roles of TUG1/miR-23b in osteoporotic pathology. MATERIAL AND METHODS: TUG1 and miR-23b expression in the plasma of osteoporotic patients were evaluated by quantitative real-time PCR (qRT-PCR). The osteogenic differentiation in human BMMSCs was evaluated by qRT-PCR, western blot, Alizarin red staining after knockdown of TUG1 by small interfering RNA (siRNA) treatment. RESULTS: Decreased expression of TUG1 and increased expression of miR-23b evident in the plasma of patients with osteoporosis than in that of age- and sex-matched healthy controls. Additionally, increased miR-23b expression inhibited runt-related transcription factor 2 (RUNX2), osteocalcin, and osteopontin expression and reduced calcified nodule formation based on the results of qRT-PCR, western blot, and Alizarin Red S staining. CONCLUSION: The study for the first time reported that silence of lncRNA TUG1 significantly suppressed the osteogenic differentiation of BMMSCs possibly by targeting the miR-23b/RUNX2 signaling pathway. This mechanism of TUG1/miR-23b/RUNX2 signaling within the osteogenic differentiation of BMMSCs might provide new insight for the development of lncRNA-directed diagnostic and therapeutic strategies for osteoporosis.

Osteoporosis Is Characterized by Altered Expression of Exosomal Long Non-coding RNAs.

Osteoporosis is a metabolic bone disease characterized by a decrease in bone mass and degradation of the bone microstructure, which increases bone fragility and risk of fracture. However, the molecular mechanisms of osteoporosis remain unclear. The current study attempts to elucidate the role of exosomal long non-coding RNA in the pathology of osteoporosis. Peripheral blood was collected from persons with (OP) or without (NC) osteoporosis, and the serum exosomes were extracted using ultra centrifugation process. Total RNA of exosomes was isolated, and the lncRNAs profiling was done using RNA-Seq experiments. In silico analysis resulted in identification of 393 differentially expressed (DE) lncRNAs in OP vs. NC, with 296 that were up-regulated and 97 were down-regulated. Bioinformatics analysis of potential target mRNAs of lncRNAs with cis-acting mechanism showed that mRNAs co-located with DE lncRNAs were highly enriched in osteoporosis-related pathways, including regulation of insulin secretion, activation of MAPK activity, cellular response to metal ions, fucosylation and proteolysis. Together these results suggest that lncRNAs of serum exosomes could play a significant role in development of osteoporosis and such information may be helpful in developing diagnostic markers and therapeutic modules for osteoporosis.

Robust Waterborne Superhydrophobic Coatings with Reinforced Composite Interfaces.

Waterborne superhydrophobic coatings have attracted tremendous attention recently, but their practical applications are severely limited by hydrophobic instability and poor mechanical durability. Herein, a novel robust waterborne PTFE-CP&MgO-AOP superhydrophobic coating was successfully fabricated by reinforcing composite interfaces. Combined with the self-polymerization of dopamine and the in situ grown MgO, CNTs-polydopamine&MgO (CP&MgO) particles with improved interfacial compatibility were obtained. Through the cross-linking and hydrogen bonding interactions, phosphate networks (CP&MgO-AOP) with the aluminum orthophosphate (AOP) binder were formed during dehydration polymerization. The phosphate networks not only enhanced the interfacial interaction among CP&MgO to form coral-like structures but also strengthened the interfacial binding force between the waterborne polytetrafluoroethylene (PTFE) coating and the substrate. With the enhanced composite interfacial strength, the waterborne PTFE-CP&MgO-AOP coating exhibited excellent wear-resistance, which can withstand more than 1.27 × 105 abrasion cycles. Moreover, the chemical bonding between the functional groups of phosphate networks and metal substrate improved the adhesion strength from grade 5 to 1. Furthermore, the prepared coating surface with the reticular/coral-like composite structures can lock the stable gas layer to maintain excellent hydrophobic stability, even under the conditions of strong acidic/alkaline, high-temperature, xenon lamp irradiation, and mechanical wear. Thus, this study is expected to open new insights into interfacial enhancement of robust waterborne superhydrophobic coatings.

The Analysis for Anemia Increasing Fracture Risk.

BACKGROUND Fractures are a major public health problem for elderly people throughout the world. Anemia is also a common, important health problem among elderly populations. The aim of this article was to estimate the association between anemia and fracture incidence via a systematic review and meta-analysis. MATERIAL AND METHODS The participant, intervention, observation, and study design (PICOS) reporting guidelines were followed, and databases were searched from their inception to May 2020 to identify relevant studies. When heterogeneity was significant, and a random-effects model was used. Subgroup analysis was conducted to explore the source of heterogeneity based on sex, study design, and region. RESULTS We found that anemia significantly increased fracture risk [relative risk (RR)=1.26, 95% confidence interval (CI)=1.14-1.39, P<0.001], specifically, hip fracture (RR=1.44, 95% CI=1.29-1.61), spine fracture (RR=1.15, 95% CI=1.08-1.23), and nonspine fracture (RR=1.42, 95% CI=1.33-1.52). Males with anemia had a 1.51-fold higher fracture risk, females had a 1.09-fold higher fracture risk. And the association was stronger in Asian (RR=1.22, 95% CI=1.07-1.40), but not in American and European study populations. CONCLUSIONS In conclusion, a significantly increased fracture risk was observed, and anemia can be a predictor of fracture risk.

An updated analysis of opioids increasing the risk of fractures.

OBJECTIVE: To assess the relationship between opioid therapy for chronic noncancer pain and fracture risk by a meta-analysis of cohort studies and case-control studies. METHODS: The included cohort studies and case-control studies were identified by searching the PubMed and EMBASE databases from their inception until May 24, 2019. The outcome of interest was a fracture. This information was independently screened by two authors. When the heterogeneity among studies was significant, a random effects model was used to determine the overall combined risk estimate. RESULTS: In total, 12 cohort studies and 6 case-control studies were included. We used the Newcastle-Ottawa Scale (NOS) to evaluate the quality of the included literature, and 14 of the studies were considered high-quality studies. The overall relative risk of opioid therapy and fractures was 1.78 (95% confidence interval (CI) 1.53-2.07). Subgroup analyses revealed sources of heterogeneity, sensitivity analysis was stable, and no publication bias was observed. CONCLUSIONS: The meta-analysis showed that the use of opioids significantly increased the risk of fracture.

Ecdysis in a stem-group euarthropod from the early Cambrian of China.

Moulting is a fundamental component of the ecdysozoan life cycle, but the fossil record of this strategy is susceptible to preservation biases, making evidence of ecdysis in soft-bodied organisms extremely rare. Here, we report an exceptional specimen of the fuxianhuiid Alacaris mirabilis preserved in the act of moulting from the Cambrian (Stage 3) Xiaoshiba Lagerstätte, South China. The specimen displays a flattened and wrinkled head shield, inverted overlap of the trunk tergites over the head shield, and duplication of exoskeletal elements including the posterior body margins and telson. We interpret this fossil as a discarded exoskeleton overlying the carcass of an emerging individual. The moulting behaviour of A. mirabilis evokes that of decapods, in which the carapace is separated posteriorly and rotated forward from the body, forming a wide gape for the emerging individual. A. mirabilis illuminates the moult strategy of stem-group Euarthropoda, offers the stratigraphically and phylogenetically earliest direct evidence of ecdysis within total-group Euarthropoda, and represents one of the oldest examples of this growth strategy in the evolution of Ecdysozoa.

New Therapeutic Approach for Targeting Hippo Signalling Pathway.

Nuclear localization signals are short amino acid sequences that target proteins for nuclear import. In this manuscript, we have generated a chimeric tri-functional peptide composed of a cell penetrating peptide (CPP), a nuclear localization sequence and an interfering peptide blocking the interaction between TEAD and YAP, two transcription factors involved in the Hippo signalling pathway, whose deregulation is related to several types of cancer. We have validated the cell penetration and nuclear localization by flow cytometry and fluorescence microscopy and shown that the new generated peptide displays an apoptotic effect in tumor cell lines thanks to the specific nuclear delivery of the cargo, which targets a protein/protein interaction in the nucleus. In addition, the peptide has an anti-tumoral effect in vivo in xenograft models of breast cancer. The chimeric peptide designed in the current study shows encouraging prospects for developing nuclear anti- neoplastic drugs.

A soft-bodied euarthropod from the early Cambrian Xiaoshiba Lagerstätte of China supports a new clade of basal artiopodans with dorsal ecdysial sutures.

We describe the exceptionally well-preserved non-trilobite artiopodan Zhiwenia coronata gen. et sp. nov. from the Cambrian Stage 3 Xiaoshiba Lagerstätte in Yunnan, China. The exoskeleton consists of a cephalic shield with dorsal sutures expressed as lateral notches that accommodate stalked lateral eyes, an elongate trunk composed of 20 tergites-the first of which is reduced-and a short tailspine with marginal spines. Appendicular data include a pair of multi-segmented antennae, and homonomous biramous trunk limbs consisting of an endopod with at least seven podomeres and a flattened exopod with lamellae. Although the presence of cephalic notches and a reduced first trunk tergite invites comparisons with the petalopleurans Xandarella, Luohiniella and Cindarella, the proportions and exoskeletal tagmosis of Zhiwenia do not closely resemble those of any major group within Trilobitomorpha. Parsimony and Bayesian phylogenetic analyses consistently support Zhiwenia as sister-taxon to the Emu Bay Shale artiopodan Australimicola spriggi, and both of them as closely related to Acanthomeridion from the Chengjiang. This new monophyletic clade, Protosutura nov., occupies a basal phylogenetic position within Artiopoda as sister-group to Trilobitomorpha and Vicissicaudata, illuminates the ancestral organization of these successful euarthropods, and leads to a re-evaluation of the evolution of ecdysial dorsal sutures within the group.

SEMA3B-AS1-inhibited osteogenic differentiation of human mesenchymal stem cells revealed by quantitative proteomics analysis.

Human mesenchymal stem cells (hMSCs) are fibroblastoid multipotent adult stem cells with capacities of differentiation into osteoblasts and chondrocytes and show great potential in new bone formation and bone repair-related clinical settings, such as osteoporosis. Long noncoding RNAs (lncRNAs) have been demonstrated to play important roles in various biological processes. Here, we report an antisense lncRNA SEMA3B-AS1 regulating hMSCs osteogenesis. SEMA3B-AS1 is proximal to a member of the semaphorin family Sema3b. Overexpression of SEMA3B-AS1 using the lentivirus system markedly inhibits the proliferation of hMSCs and meanwhile reduces osteogenic differentiation. Using a comprehensive proteomic technique named isobaric tag for relative and absolute quantitation, we found that SEMA3B-AS1 significantly alters the process of osteogenesis through downregulating the expression of proteins involved in actin cytoskeleton, focal adhesion, and extracellular matrix-receptor interaction, while increasing the expression of proteins in the spliceosome. Collectively, we find that SEMA3B-AS1 is a target for controlling osteogenesis of hMSCs.

Fuxianhuiids.

Ortega-Hernández et al. introduce fuxianhuiids, Cambrian arthropods that are important for our understaindg how the largest animal phylum evolved.

miR-142-5p in Bone Marrow-Derived Mesenchymal Stem Cells Promotes Osteoporosis Involving Targeting Adhesion Molecule VCAM-1 and Inhibiting Cell Migration.

Osteoporosis is a systemic bone metabolic disease that is highly prevalent in the elderly population, particularly in postmenopausal women, which results in enhanced bone fragility and an increased susceptibility to fractures. However, the underlying molecular pathogenesis mechanisms still remain to be further elucidated. In this study, in a rat ovariectomy- (OVX-) induced postmenopausal osteoporosis model, aberrant expression of a microRNA miR-142-5p and vascular cell adhesion molecule 1 (VCAM-1) was found by RNA sequencing analysis and qRT-PCR. Using a dual-luciferase reporter assay, we found that miR-142-5p can bind to and decrease expression of VCAM-1 mRNA. Such reduction was prohibited when the miR-142-5p binding site in VCAM-1 3'UTR was deleted, and Western blotting analyses validated the fact that miR-142-5p inhibited the expression of VCAM-1 protein. Bone marrow-derived mesenchymal stem cells (BMMSCs) transfected with miR-142-5p showed a significantly decreased migration ability in a Transwell migration assay. Collectively, these data indicated the important role of miR-142-5p in osteoporosis development involving targeting VCAM-1 and inhibiting BMMSC migration.