ß-blockades and the risk of atrial fibrillation in patients with cardiovascular diseases.

Background: ß-blockers have been widely used in patients with extensive cardiovascular disease (CVD) and have provided benefits. However, they are more likely to cause symptomatic bradycardia, hypotension, or glucose metabolism disorders, which may lead to an increased risk of atrial fibrillation (AF), but evidence is lacking. Aims: This study was to analyze the association between the use of ß-blockers and the risk of developing AF. Methods: This nationwide, prospective cohort study utilized data from the 2013-2020 National Health and Nutrition Examination Survey (NHANES). The patients were stratified into a ß-blocker treatment group (n = 2585) and a non-ß-blocker treatment group (n = 8525). Univariate and multivariate logistic regression analyses were performed to identify the relationship between ß-blockades and the risk of AF. Propensity matching analysis was used to balance patient baseline characteristics and to control for confounders. Results: A total of 11,110 subjects were included in this study (mean [SD] age, 59.89 [15.07] years; 5657 [49.7%] males). A total of 111/2585 subjects developed AF in the ß-blocker treatment group, and 75/8525 developed AF in the non-ß-blocker treatment group (incidence rate, 4.2% vs. 0.8%). Compared with the non-ß-blocker group, the ß-blocker group had an increased risk of incident AF (aOR, 2.339; 95% CI, 1.614-3.410). Some sensitivity analyses also revealed consistent findings of increased AF risk associated with ß-blocker treatment. Conclusion: The findings from this study suggest that ß-blocker treatment is associated with an increased risk of incident AF and may help physicians select a modest medication for patients while also assessing the risk of AF.

A fluorescent terbium-metal-organic framework material for high-sensitivity detection of vomitoxin and oxytetracycline hydrochloride in water.

A unique luminescent lanthanide metal-organic framework (LnMOF)-based fluorescence detection platform was utilized to achieve sensitive detection of vomitoxin (VT) and oxytetracycline hydrochloride (OTC-HCL) without the use of antibodies or biomolecular modifications. The sensor had a fluorescence quenching constant of 9.74 × 106 M-1 and a low detection limit of 0.68 nM for vomitoxin. Notably, this is the first example of a Tb-MOF sensor for fluorescence detection of vomitoxin. We further investigated its response to two mycotoxins, aflatoxin B1 and ochratoxin A, and found that their Stern-Volmer fluorescence quenching constants were lower than those of VT. In addition, the fluorescence sensor realized sensitive detection of OTC-HCL with a detection limit of 0.039 µM. In conclusion, the method has great potential as a sensitive and simple technique to detect VT and OTC-HCL in water.

Global level of methylation in the sea lamprey (jawless vertebrate) genome is intermediate between invertebrate and jawed vertebrate genomes.

In eukaryotes, cytosine methylation is a primary heritable epigenetic modification of the genome that regulates many cellular processes. In invertebrate, methylated cytosine generally located on specific genomic elements (e.g., gene bodies and silenced repetitive elements) to show a "mosaic" pattern. While in jawed vertebrate (teleost and tetrapod), highly methylated cytosine located genome-wide but only absence at regulatory regions (e.g., promoter and enhancer). Many studies imply that the evolution of DNA methylation reprogramming may have helped the transition from invertebrates to jawed vertebrates, but the detail remains largely elusive. In this study, we used the whole-genome bisulfite-sequencing technology to investigate the genome-wide methylation in three tissues (heart, muscle, and sperm) from the sea lamprey, an extant agnathan (jawless) vertebrate. Strikingly, we found that the methylation level of the sea lamprey is very similar to that in sea urchin (a deuterostome) and sea squirt (a chordate) invertebrates. In sum, the global pattern in sea lamprey is intermediate methylation level (around 30%), that is higher than methylation level in the genomes of pre-bilaterians and protostomes (1%-10%), but lower than methylation level appeared in jawed vertebrates (around 70%, teleost and tetrapod). We anticipate that, in addition to genetic dynamics such as genome duplications, epigenetic dynamics such as global methylation reprograming was also orchestrated toward the emergence and evolution of vertebrates.

Anciently duplicated genes continuously recruited to heart expression in vertebrate evolution are associated with heart chamber increase.

Although gene/genome duplications in the early stage of vertebrates have been thought to provide major resources of raw genetic materials for evolutionary innovations, it is unclear whether they continuously contribute to the evolution of morphological complexity during the course of vertebrate evolution, such as the evolution from two heart chambers (fishes) to four heart chambers (mammals and birds). We addressed this issue by our heart RNA-Seq experiments combined with published data, using 13 vertebrates and one invertebrate (sea squirt, as an outgroup). Our evolutionary transcriptome analysis showed that number of ancient paralogous genes expressed in heart tends to increase with the increase of heart chamber number along the vertebrate phylogeny, in spite that most of them were duplicated at the time near to the origin of vertebrates or even more ancient. Moreover, those paralogs expressed in heart exert considerably different functions from heart-expressed singletons: the former are functionally enriched in cardiac muscle and muscle contraction-related categories, whereas the latter play more basic functions of energy generation like aerobic respiration. These findings together support the notion that recruiting anciently paralogous genes that are expressed in heart is associated with the increase of chamber number in vertebrate evolution.

Co-delivery of drugs by adhesive transdermal patches equipped with dissolving microneedles for the treatment of rheumatoid arthritis.

In this study, a dosage form consisting of dissolving (D) microneedles (M) and an adhesive (A) transdermal patch (P; DMAP) was designed and pre-clinically evaluated for the treatment of rheumatoid arthritis (RA). The tip of the dissolving microneedles (DMNs) was loaded with the macromolecular drug melittin (Mel@DMNs), this to treat joint inflammation and bone damage, while the adhesive transdermal patches contained the low molecular weight drug diclofenac sodium (DS; DS@AP) for pain relief. Mel@DMNs and DS@AP were ingeniously connected through an isolation layer for compounding Mel-DS@DMAP for the simultaneous delivery of the drugs. In vitro and in vivo experiments showed that DS@AP did not affect the mechanical properties and dissolution process of Mel@DMNs while the pores formed by the microneedles promoted the skin penetration of DS. Treatment of rats suffering from RA with Mel-DS@DMAP reduced paw swelling and damage of the synovium, joint and cartilage, suggesting that the 'patch-microneedle' dosage form might be promising for the treatment and management of RA.

Synthesis of multifunctional amorphous metallic shell on crystalline metallic nanoparticles.

Colloidal nanoparticles can be coated with a conformal shell to form multifunctional nanoparticles. For instance, plasmonic, magnetic, and catalytic properties, chemical stability and biocompatibility can be mixed and matched. Here, a facile synthesis for depositing metal boride amorphous coatings on colloidal metallic nanocrystals is introduced. The synthesis is independent of core size, shape, and composition. We have found that the shell synthesis is limited to nanoparticles capped with short molecular weight and low binding energy ligands, and does not work with polyvinylpyrrolidone (PVP)-coated Ag nanoparticles or thiol-coated Au nanoparticles. Shell thickness can be as thin as 3 nm with no apparent pinholes. High pressure studies show that the coatings are highly resistant to crystallization and are strongly bonded to the crystalline core. By choosing either CoB or NiB for the coating, the composite nanoparticles can be either ferromagnetic or paramagnetic at room temperature, respectively.

Simvastatin nanocrystals-based dissolving microneedles for wound healing.

Currently, one of the main problems encountered in wound healing therapy is related to inefficient drug delivery. However, dissolving microneedles (DMNs) can be administered percutaneously to effectively deliver a drug to a deep wound area. Simvastatin (SIM) can promote wound healing, albeit its insolubility in water limits its application. Here, we designed a DMNs (SIM-NC@DMNs) drug delivery system loaded with SIM nanocrystals (SIM-NC) and evaluated its efficacy in wound healing. Based on our observations, the dissolution performance of insoluble SIM is significantly improved after the preparation of SIM-NC. For example, the saturation solubility of SIM-NC in deionized water and PBS increased by 150.57 times and 320.14 times, respectively. After the SIM-NC@DMNs are deeply inserted into the wound, the needle portion, which is composed of hyaluronic acid (HA), dissolves rapidly, and the SIM-NC loaded on the needle portion is efficiently released into the deep wound area for optimal therapeutic efficacy. The combination of NC and DMNs makes this system further effective for wound healing. Our cumulative work suggests that the newly developed SIM-NC@DMNs possess great potential in accelerating wound healing. By day 12 after treatment, the residual wound area in the Control group was 21.34 %, while the residual wound area in the SIM-NC@DMNs group was only 2.36 %. This result as well as provides certain evidence of its efficacy for wound healing therapy. The SIM-NC@DMNs drug delivery system may become an efficient treatment modality that promotes wound healing, with a promising potential in the field of wound healing research.

Genome distance and phylogenetic inference accommodating gene duplication, loss and new gene input.

With the rapid growth of entire genome data, phylogenomics focuses on analyzing evolutionary histories and relationships of species, i.e., the tree of life. For decades it has been realized that the genome-wide phylogenetic inference can be approached based upon the dynamic pattern of gene content (the presence/absence of gene families), or extended gene content (absence, presence as a single-copy, or duplicates). Those methods, conceptually or technically, invoked the birth-and-death process to model the evolutionary process (gene duplication or gene loss. One common drawback is that the mechanism of new gene input, including de novo origin of new genes and the lateral gene transfer, has not been explicitly considered. In this paper, the author developed a new genome distance approach for genome phylogeny inference under the origin-birth-death stochastic process. The model takes gene duplication, gene loss and new gene input into account simultaneously. Computer simulations found that the two-genome approach is statistically difficult to distinguish between two proliferation parameters, i.e., the rate of gene duplication and the rate of new gene input. Nevertheless, it has also demonstrated the statistical feasibility for using the loss-genome distance to infer the genome phylogeny, which can avoid the large sampling problem. The strategy to study the universal tree of life was discussed and exemplified by an example.

MATTE: a pipeline of transcriptome module alignment for anti-noise phenotype-gene-related analysis.

A phenotype may be associated with multiple genes that interact with each other in the form of a gene module or network. How to identify these relationships is one important aspect of comparative transcriptomics. However, it is still a challenge to align gene modules associated with different phenotypes. Although several studies attempted to address this issue in different aspects, a general framework is still needed. In this study, we introduce Module Alignment of TranscripTomE (MATTE), a novel approach to analyze transcriptomics data and identify differences in a modular manner. MATTE assumes that gene interactions modulate a phenotype and models phenotype differences as gene location changes. Specifically, we first represented genes by a relative differential expression to reduce the influence of noise in omics data. Meanwhile, clustering and aligning are combined to depict gene differences in a modular way robustly. The results show that MATTE outperformed state-of-the-art methods in identifying differentially expressed genes under noise in gene expression. In particular, MATTE could also deal with single-cell ribonucleic acid-seq data to extract the best cell-type marker genes compared to other methods. Additionally, we demonstrate how MATTE supports the discovery of biologically significant genes and modules, and facilitates downstream analyses to gain insight into breast cancer. The source code of MATTE and case analysis are available at https://github.com/zjupgx/MATTE.

Unraveling the Drivers of Tumorigenesis in the Context of Evolution: Theoretical Models and Bioinformatics Tools.

Cancer originates from somatic cells that have accumulated mutations. These mutations alter the phenotype of the cells, allowing them to escape homeostatic regulation that maintains normal cell numbers. The emergence of malignancies is an evolutionary process in which the random accumulation of somatic mutations and sequential selection of dominant clones cause cancer cells to proliferate. The development of technologies such as high-throughput sequencing has provided a powerful means to measure subclonal evolutionary dynamics across space and time. Here, we review the patterns that may be observed in cancer evolution and the methods available for quantifying the evolutionary dynamics of cancer. An improved understanding of the evolutionary trajectories of cancer will enable us to explore the molecular mechanism of tumorigenesis and to design tailored treatment strategies.

5-aminolevulinic acid-loaded dissolving microneedle array for photodynamic therapy of rheumatoid arthritis on rats.

Photodynamic therapy (PDT) is a noninvasive technique that can be used to treat rheumatoid arthritis (RA) by irradiating photosensitizers with specific wavelengths of light to generate reactive oxygen species (ROS), thus leading to targeted cell necrosis. However, efficient delivery of photosensitizers with low side effects is a key issue. We developed a 5-aminolevulinic acid-loaded dissolving microneedle array (5-ALA@DMNA) that can locally and efficiently deliver photosensitizers for RA treatment by PDT. 5-ALA@DMNA was fabricated through a two-step molding process, which was characterized. The effects of 5-ALA-mediated PDT on RA fibroblast-like synoviocytes (RA-FLs) were investigated via in vitro experiments. Adjuvant arthritis rat models were established to evaluate the therapeutic effect of 5-ALA@DMNA-mediated PDT on RA. The results showed that 5-ALA@DMNA could penetrate the skin barrier and efficiently deliver photosensitizers. 5-ALA-mediated PDT can significantly inhibit the migration ability and selectively induce apoptosis of RA-FLs. Moreover, 5-ALA-mediated PDT had a significant therapeutic effect on rats with adjuvant arthritis, which may be related to the upregulation of interleukin (IL)- 4 and IL-10 and downregulation of TNF-α, IL-6, and IL-17. Thus, 5-ALA@DMNA-mediated PDT may be a potential therapy for RA.

The hydrogen bond between tryptophan and the host molecule induced fluorescence enhancement.

Tryptophan is one of important amino acids in the human body, therefore its detection is particularly important. The 3,5-bis(4-pyridyl)-4-amino-1,2,4-triazole (BPAT) organic molecule was designed to be used as fluorescence detectors to detect tryptophan molecules for the interaction between the host and the guest. BPAT shows good sensitivity and selectivity towards tryptophan compared with other amino acid molecules. The limit of detection obtained from formula 3δ/KSV is considered to be 5.43 × 10-7  mol/L. We speculated that this change is mainly caused by the hydrogen bond between tryptophan and the host molecule BPAT. This conjecture was verified by the controlled experiments with other host molecules.

TSNAdb v2.0: The Updated Version of Tumor-specific Neoantigen Database.

In recent years, neoantigens have been recognized as ideal targets for tumor immunotherapy. With the development of neoantigen-based tumor immunotherapy, comprehensive neoantigen databases are urgently needed to meet the growing demand for clinical studies. We have built the tumor-specific neoantigen database (TSNAdb) previously, which has attracted much attention. In this study, we provide TSNAdb v2.0, an updated version of the TSNAdb. TSNAdb v2.0 offers several new features, including (1) adopting more stringent criteria for neoantigen identification, (2) providing predicted neoantigens derived from three types of somatic mutations, and (3) collecting experimentally validated neoantigens and dividing them according to the experimental level. TSNAdb v2.0 is freely available at https://pgx.zju.edu.cn/tsnadb/.

MODIG: integrating multi-omics and multi-dimensional gene network for cancer driver gene identification based on graph attention network model.

MOTIVATION: Identifying genes that play a causal role in cancer evolution remains one of the biggest challenges in cancer biology. With the accumulation of high-throughput multi-omics data over decades, it becomes a great challenge to effectively integrate these data into the identification of cancer driver genes. RESULTS: Here, we propose MODIG, a graph attention network (GAT)-based framework to identify cancer driver genes by combining multi-omics pan-cancer data (mutations, copy number variants, gene expression and methylation levels) with multi-dimensional gene networks. First, we established diverse types of gene relationship maps based on protein-protein interactions, gene sequence similarity, KEGG pathway co-occurrence, gene co-expression patterns and gene ontology. Then, we constructed a multi-dimensional gene network consisting of approximately 20 000 genes as nodes and five types of gene associations as multiplex edges. We applied a GAT to model within-dimension interactions to generate a gene representation for each dimension based on this graph. Moreover, we introduced a joint learning module to fuse multiple dimension-specific representations to generate general gene representations. Finally, we used the obtained gene representation to perform a semi-supervised driver gene identification task. The experiment results show that MODIG outperforms the baseline models in terms of area under precision-recall curves and area under the receiver operating characteristic curves. AVAILABILITY AND IMPLEMENTATION: The MODIG program is available at https://github.com/zjupgx/modig. The code and data underlying this article are also available on Zenodo, at https://doi.org/10.5281/zenodo.7057241. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Celecoxib nanocrystal-loaded dissolving microneedles with highly efficient for osteoarthritis treatment.

Osteoarthritis (OA) is a prevalent degenerative disease that has a significant impact on patients' lives. Celecoxib (CXB) is now primarily used to treat OA with oral dosing. CXB's limited water solubility, on the other hand, restricts its therapeutic application. We developed a delivery system of dissolving microneedles (DMNs) loaded with CXB-nanocrystals (CXB-NCs) for the treatment of OA. Oral administration's inefficiency and injectable administration's poor compliance might be solved using DMNs. Furthermore, carrier-free NCs may dramatically increase the dissolution of drugs with poorly water-solubility, as well as the drug load of DMNs. Antisolvent precipitation was used to make CXB-NCs. CXB-NC@DMNs were prepared by mixing CXB-NCs with hyaluronic acid (HA) that had high mechanical qualities and could permeate the skin efficiently in vitro. The therapeutic effect of oral CXB-NCs was substantially better than that of the same dose of oral CXB in an in vivo pharmacodynamic trial, demonstrating that the preparation of CXB into NCs might greatly increase CXB bioavailability. Furthermore, we discovered that DMNs loaded with low-dose CXB-NCs had similar or even better efficacy than the oral CXB-NCs group. The findings suggested that CXB-NC@DMNs may be a very efficient and promising drug delivery strategy in the treatment of OA.

dN/dS-H, a New Test to Distinguish Different Selection Modes in Protein Evolution and Cancer Evolution.

One of the most popular measures in the analysis of protein sequence evolution is the ratio of nonsynonymous distance (dN) to synonymous distance (dS). Under the assumption that synonymous substitutions in the coding region are selectively neutral, the dN/dS ratio can be used to statistically detect the adaptive evolution (or purifying selection) if dN/dS > 1 (or dN/dS < 1) significantly. However, due to strong structural constraints and/or variable functional constraints imposed on amino acid sites, most encoding genes in most species have demonstrated dN/dS < 1. Consequently, the statistical power for testing dN/dS = 1 may be insufficient to distinguish between different selection modes. In this paper, we propose a more powerful test, called dN/dS-H, in which a new parameter H, a relative measure of rate variation among sites, was introduced. Given the condition of strong purifying selections at some sites, the dN/dS-H model predicts dN/dS = 1-H for neutral evolution, dN/dS < 1-H for nearly neutral selection, and dN/dS > 1-H for adaptive evolution. The potential of this new method for resolving the neutral-adaptive debates is illustrated by the protein sequence evolution in vertebrates, Drosophila and yeasts, as well as somatic cancer evolution (specialized as the CN/CS-H test).

Autophagy promotes membrane trafficking of NR2B to alleviate depression by inhibiting AQP4 expression in mice.

Depression is a high-incidence mental illness that seriously affects human health. AQP4 has been reported to be closely associated with depression, while the underlying mechanism is still unclear. This work aimed to investigate the functional role of AQP4 in depression. Depression mouse model was constructed by administration of chronic social defeat stress (CSDS). We found that AQP4 was highly expressed in the hippocampal tissues of CSDS mice. AQP4 knockdown alleviated depression and enhanced the expression of NR2B and PSD95 in CSDS mice. Moreover, primary hippocampal neurons were treated with N-methyl-d-aspartate (NMDA) to induce neuron injury. AQP4 overexpression repressed cell viability and promoted apoptosis of NMDA-treated primary hippocampal neurons. AQP4 up-regulation repressed the expression of NR2B (surface), and enhanced the expression of NR2B (intracellular), P-NR2B, CaMK II and CK2 in the NMDA-treated primary hippocampal neurons. The influence conferred by AQP4 up-regulation was abolished by KN-93 (CaMK II inhibitor) or TBB (CK2 inhibitor) treatment. Rapamycin treatment enhanced the expression of NR2B (surface), and repressed the expression of AQP4, NR2B (intracellular) and P-NR2B in the primary hippocampal neurons by activating autophagy. The activated autophagy alleviated depression in CSDS mice by repressing AQP4 expression. In conclusion, our data demonstrated that autophagy ameliorated depression by repressing AQP4 expression in mice, and AQP4 knockdown promoted membrane trafficking of NR2B and inhibited phosphorylation of NR2B via CaMK II/CK2 pathway. Thus, our work suggests that AQP4 may be a promising molecular target for the development of antidepressant drugs.

A Simple Evolutionary Model of Genetic Robustness After Gene Duplication.

When a dispensable gene is duplicated (referred to the ancestral dispensability denoted by O+), genetic buffering and duplicate compensation together maintain the duplicate redundancy, whereas duplicate compensation is the only mechanism when an essential gene is duplicated (referred to the ancestral essentiality denoted by O-). To investigate these evolutionary scenarios of genetic robustness, I formulated a simple mixture model for analyzing duplicate pairs with one of the following states: double dispensable (DD), semi-dispensable (one dispensable one essential, DE), or double essential (EE). This model was applied to the yeast duplicate pairs from a whole-genome duplication (WGD) occurred about 100 million years ago (mya), and the mouse duplicate pairs from a WGD occurred about more than 500 mya. Both case studies revealed that the proportion of essentiality for those duplicates with ancestral essentiality [PE(O-)] was much higher than that for those with ancestral dispensability [PE(O+)]. While it was negligible in the yeast duplicate pairs, PE(O+) (about 20%) was shown statistically significant in the mouse duplicate pairs. These findings, together, support the hypothesis that both sub-functionalization and neo-functionalization may play some roles after gene duplication, though the former may be much faster than the later.

Assembly of 97 Novel Bacterial Genomes in the Microbial Community Affiliated with Polyvinyl Alcohol in Soil of Northern China.

BACKGROUND: Undeveloped ecosystems belong to rich source of microbial population, of which resources remain unearthed. A kind of polymeric compound system with high polyvinyl alcohol (PVA) content has been reported and named Taisui. Marker gene amplification showed that Taisui harbored little-explored microbial communities. AIM: To address this issue, our study attempted to recover draft genomes and functional potential from microbial communities in Taisui using the metagenomic approach. Material and Methods. Taisui communities provided 97 novel bacterial genomes from 13 bacterial phyla, including bacteria candidate phylum. Two novel genus-level lineages were recovered from Planctomycetes and Chloroflexi. Based on the draft genomes, we expanded the number of taxa with potential productions of PKS and NRPS in phyla including Candidatus Dadabacteria, Chloroflexi, and Planctomycetes. RESULTS: A rich diversity of PVA dehydrogenase genes from 4 phyla, involving Proteobacteria, Acidobacteria, Acitinobacteria, and Planctomycetes, were identified. The phylogenetic tree of PVA dehydrogenase showed the possibility of horizontal gene transfer between microbes. CONCLUSION: Our study underscores the substantial microbial diversity and PVA degradation potential in the previously unexplored Taisui system.

MicroRNA-155-5p Targets SKP2, Activates IKKß, Increases Aß Aggregation, and Aggravates a Mouse Alzheimer Disease Model.

The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase ß (IKKß) are involved in Alzheimer disease (AD) pathogenesis. This study explored the mechanisms underlying IKKß-mediated Aß aggregation and neuron regeneration in APP.PS1 mice. Adenoviral transduction particles were injected into the hippocampal CA1 region of the mice to knock down or inhibit target genes. Morris water maze was performed to evaluate the cognitive function of the mice. Aß deposition was determined by histological examination. sh-IKKß plasmids and microRNA (miR)-155-5p inhibitor were transfected into Aß1-42-induced N2a cells. The expressions of AD-related proteins were detected by Western blot. The interaction between S-phase kinase-associated protein 2 (SKP2) and IKKß was assessed by co-immunoprecipitation. IKKß knockdown (KD) and miR-155-5p inhibition ameliorated cognitive impairment, improved neuron regeneration, and attenuated Aß deposition in APP/PS1 mice. SKP2 KD aggravated cognitive impairment, inhibited neuron regeneration, and promoted Aß deposition in the mice. SKP2 regulated the stability of IKKß protein via ubiquitination. MiR-155-5p regulates Aß deposition and the expression of Aß generation-related proteins in N2a cells via targeting SKP2. These results indicate that the miR-155-5p/SKP2/IKKß axis was critical for pathogenesis in this AD model and suggest the potential of miR-155-5p as a target for AD treatment.