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Abstract Purpose This study aimed to identify and quantify the association and investigate whether serum vitamin B12 alone or vitamin B12 combined with folate and plasma total homocysteine (tHcy) levels could be used to predict the risk of acute ischemic stroke. Materials and methods This retrospective case-control study was conducted in the Department of Neurology, First Affiliated Hospital of Chongqing Medical University. It included 259 inpatients experiencing their first-ever acute ischemic stroke and 259 age-matched, sex-matched healthy controls. Patients were categorized into groups based on the etiology of their stroke: large-artery atherosclerosis (LAAS, n = 126), cardio embolism (CEI, n = 35), small vessel disease (SVD, n = 89), stroke of other determined etiology (ODE, n = 5), and stroke of undetermined etiology (UDE, n = 4). The associations of serum vitamin B12, folate, and plasma tHcy levels with the risk of ischemic stroke were evaluated using multivariable logistic regression analysis. Receiver operator characteristic (ROC) curves were used to assess the diagnostic power of vitamin B12, folate, and tHcy levels for ischemic stroke. Results Serum vitamin B12 and folate levels were significantly lower in ischemic stroke patients compared to controls, while plasma tHcy levels were significantly higher. The first quartile of serum vitamin B12 levels was significantly associated with an increased risk of LAAS (aOR = 2.289, 95% CI = 1.098–4.770), SVD (aOR = 4.471, 95% CI = 1.110–4.945) and overall ischemic stroke (aOR = 3.216, 95% CI = 1.733–5.966). Similarly, the first quartile of serum folate levels was associated with an increased risk of LAAS (aOR = 3.480, 95% CI = 1.954–6.449), CEI (aOR = 2.809, 95% CI = 1.073–4.991), SVD (aOR = 5.376, 95% CI = 1.708–6.924), and overall ischemic stroke (aOR = 3.381, 95% CI = 1.535–7.449). The fourth quartile of tHcy levels was also significantly associated with an increased risk of LAAS (aOR = 2.946, 95% CI = 1.008–5.148), CEI (aOR = 2.212, 95% CI = 1.247–5.946), SVD (aOR = 2.957, 95% CI = 1.324–6.054), and overall ischemic stroke (aOR = 2.233, 95% CI = 1.586–4.592). For predicting different types of ischemic stroke, vitamin B12 alone demonstrated the best diagnostic value for SVD, evidenced by a sensitivity of 71.0% and negative predictive value of 90.3%, along with the highest positive likelihood ratio (+ LR) for SVD. Vitamin B12 + tHcy + folate are valuable in predicting different types of ischemic stroke, with the most significant effect observed in SVD, followed by LAAS, and the weakest predictive effect in CEI. Additionally, vitamin B12 alone in combination with other indicators, such as folate alone, tHcy alone, and folate + tHcy could reduce negative likelihood ratio (-LR) and improve + LR. Conclusions Vitamin B12 was an independent risk factor for acute ischemic stroke. The risk calculation model constructed with vitamin B12 + tHcy + folate had the greatest diagnostic value for SVD.

ABSTRACT The erythromycin resistance RNA methyltransferase (erm) confers cross-resistance to all therapeutically important macrolides, lincosamides, and streptogramins (MLS phenotype). The expression of erm is often induced by the macrolide-mediated ribosome stalling in the upstream co-transcribed leader sequence, thereby triggering a conformational switch of the intergenic RNA hairpins to allow the translational initiation of erm. We investigated the evolutionary emergence of the upstream erm regulatory elements and the impact of allelic variation on erm expression and the MLS phenotype. Through systematic profiling of the upstream regulatory sequences across all known erm operons, we observed that specific erm subfamilies, such as ermB and ermC, have independently evolved distinct configurations of small upstream ORFs and palindromic repeats. A population-wide genomic analysis of the upstream ermB regions revealed substantial non-random allelic variation at numerous positions. Utilizing machine learning-based classification coupled with RNA structure modeling, we found that many alleles cooperatively influence the stability of alternative RNA hairpin structures formed by the palindromic repeats, which, in turn, affects the inducibility of ermB expression and MLS phenotypes. Subsequent experimental validation of 11 randomly selected variants demonstrated an impressive 91% accuracy in predicting MLS phenotypes. Furthermore, we uncovered a mixed distribution of MLS-sensitive and MLS-resistant ermB loci within the evolutionary tree, indicating repeated and independent evolution of MLS resistance. Taken together, this study not only elucidates the evolutionary processes driving the emergence and development of MLS resistance but also highlights the potential of using non-coding genomic allele data to predict antibiotic resistance phenotypes.IMPORTANCEAntibiotic resistance (AR) poses a global health threat as the efficacy of available antibiotics has rapidly eroded due to the widespread transmission of AR genes. Using Erm-dependent MLS resistance as a model, this study highlights the significance of non-coding genomic allelic variations. Through a comprehensive analysis of upstream regulatory elements within the erm family, we elucidated the evolutionary emergence and development of AR mechanisms. Leveraging population-wide machine learning (ML)-based genomic analysis, we transformed substantial non-random allelic variations into discernible clusters of elements, enabling precise prediction of MLS phenotypes from non-coding regions. These findings offer deeper insight into AR evolution and demonstrate the potential of harnessing non-coding genomic allele data for accurately predicting AR phenotypes.

Rice is an important dietary source of the toxic mineral cadmium (Cd) for populations in which rice is the main staple food. When grown in agricultural soils that are contaminated with Cd, rice often accumulates excessive Cd into the grains, which is a serious threat to agricultural sustainability and human health. To limit Cd accumulation in rice grains, studies on the genetic basis of Cd accumulation in rice have been carried out extensively, and some low-Cd rice varieties have also been developed in recent years. However, the challenges in low-Cd rice breeding still exist because the outcomes of the current genetic improvements for low-Cd rice cannot fully meet the requirements for the development of Cd-safe rice at present. In this review, we outline the progress in understanding the physiological mechanisms and the genetic nature of Cd accumulation in rice and summarize the strategies and outcomes of low-Cd rice breeding over the past decade. By graphing the physiological mechanism of Cd transport in the rice plant, three key steps and some underlying genes are summarized and discussed. Also, two genetic features of the natural variation in rice grain-Cd accumulation, the phenotypic plasticity and subspecies divergence, and the potential genetic explanations for these features are also discussed. Finally, we summarize and discuss current progress and the potential issues in low-Cd rice breeding using different breeding strategies. We hope to propose strategies for future success in the breeding of low-Cd rice varieties over the next decade.

Abstract Disrupting protein–protein interactions (PPIs) has emerged as a promising strategy for cancer drug development. Interfering peptides disrupting PPIs can be rationally designed based on the structures of natural sequences mediating these interactions. Transcription factor FOXM1 overexpresses in multiple cancers and is considered an effective target for cancer therapeutic drug development. Using a rational design approach, we have generated a peptide library from the FOXM1 C-terminal sequence and screened FOXM1-binding peptides. Combining FOXM1 binding and cell inhibitory results, we have obtained a FOXM1-targeting interfering peptide M1-20 that is optimized from the natural parent peptide to the D-retro-inverso peptide. With improved stability characteristics, M1-20 inhibits proliferation and migration, and induces apoptosis of cancer cells. Mechanistically, M1-20 inhibits FOXM1 transcriptional activities by disrupting its interaction between the MuvB complex and the transcriptional co-activator CBP. These are consistent with the results that M1-20 suppresses cancer progression and metastasis without noticeable toxic and side effects in wild-type mice. These findings reveal that M1-20 has the potential to be developed as an anti-cancer drug candidate targeting FOXM1.

Abstract Background Transcription factor FOXM1 is a potential target for anti-cancer drug development. An interfering peptide M1-21, targeting FOXM1 and FOXM1-interacting proteins, is developed and its anti-cancer efficacy is evaluated. Methods FOXM1 C-terminus-binding peptides are screened by in silico protocols from the peptide library of FOXM1 (1-138aa) and confirmed by cellular experiments. The selected peptide is synthesized into its D-retro-inverso (DRI) form by fusing a TAT cell-penetrating sequence. Anti-cancer activities are evaluated in vitro and in vivo with tumor-grafted nude mice, spontaneous breast cancer mice, and wild-type metastasis-tracing mice. Anti-cancer mechanisms are analyzed. Distribution and safety profiles in mice are evaluated. Results With improved stability and cell inhibitory activity compared to the parent peptide, M1-21 binds to multiple regions of FOXM1 and interferes with protein-protein interactions between FOXM1 and its various known partner proteins, including PLK1, LIN9 and B-MYB of the MuvB complex, and β-catenin. Consequently, M1-21 inhibits FOXM1-related transcriptional activities and FOXM1-mediated nuclear importation of β-catenin and β-catenin transcriptional activities. M1-21 inhibits multiple types of cancer (20 µM in vitro or 30 mg/kg in vivo) by preventing proliferation, migration, and WNT signaling. Distribution and safety profiles of M1-21 are favorable (broad distribution and > 15 h stability in mice) and the tested non-severely toxic dose reaches 200 mg/kg in mice. M1-21 also has low hemolytic toxicity and immunogenicity in mice. Conclusions M1-21 is a promising interfering peptide targeting FOXM1 for the development of anti-cancer drugs.

Macrolides, lincosamides, and streptogramin B (MLS) are structurally distinct molecules that are among the safest antibiotics for prophylactic use and for the treatment of bacterial infections. The family of erythromycin resistance methyltransferases (Erm) invariantly install either one or two methyl groups onto the N6,6-adenosine of 2058 nucleotide (m6A2058) of the bacterial 23S rRNA, leading to bacterial cross-resistance to all MLS antibiotics. Despite extensive structural studies on the mechanism of Erm-mediated MLS resistance, how the m6A epitranscriptomic mark affects ribosome function and bacterial physiology is not well understood. Here, we show that Staphylococcus aureus cells harboring m6A2058 ribosomes are outcompeted by cells carrying unmodified ribosomes during infections and are severely impaired in colonization in the absence of an unmodified counterpart. The competitive advantage of m6A2058 ribosomes is manifested only upon antibiotic challenge. Using ribosome profiling (Ribo-Seq) and a dual-fluorescence reporter to measure ribosome occupancy and translational fidelity, we found that specific genes involved in host interactions, metabolism, and information processing are disproportionally deregulated in mRNA translation. This dysregulation is linked to a substantial reduction in translational capacity and fidelity in m6A2058 ribosomes. These findings point to a general "inefficient translation" mechanism of trade-offs associated with multidrug-resistant ribosomes.

Abstract Ischemic stroke is one of the major causes of death and disability in the world. Currently, most patients cannot choose intravenous thrombolysis or intravascular mechanical thrombectomy because of narrow therapeutic windows and severe complications. Stem cell transplantation is an emerging treatment and has been studied in various central nervous system diseases. Animal and clinical studies showed that transplantation of mesenchymal stem cells (MSCs) could alleviate neurological deficits and bring hope for ischemic stroke treatment. This article reviewed biological characteristics, safety, feasibility and efficacy of MSCs therapy, potential therapeutic targets of MSCs, and production process of Good Manufacturing Practices-grade MSCs, to explore the potential therapeutic targets of MSCs in the process of production and use and provide new therapeutic directions for ischemic stroke.

Summary: Transposable elements (TEs) are abundant in metazoan genomes and have multifaceted effects on host fitness. However, the mechanisms underlying the functions of TEs are still not fully understood. Here, we combine Hi-C, ATAC-seq, and ChIP-seq assays to report the existence of multimegabase supersized loop (SSL) clusters in the Xenopus tropicalis sperm. We show that SSL anchors are inaccessible and devoid of the architectural protein CTCF, RNA polymerase II, and modified histones. Nearly all SSL anchors are marked by Helitrons, a class II DNA transposon. Molecular dynamics simulations indicate that SSL clusters are likely formed via a molecular agent-mediated chromatin condensation process. However, only slightly more SSL anchor-associated genes are expressed at late embryo development stages, suggesting that SSL anchors might only function in sperm. Our work shows an evolutionarily distinct and sperm-specific genome structure marked by a subset of Helitrons, whose establishment and function remain to be explored.

Bacteria have developed several molecular conflict systems to facilitate kin recognition and non-kin competition to gain advantages in the acquisition of growth niches and of limited resources. One such example is a large class of so-called polymorphic toxin systems (PTSs), which comprise a variety of the toxin proteins secreted via T2SS, T5SS, T6SS, T7SS and many others. These systems are highly divergent in terms of sequence/structure, domain architecture, toxin-immunity association, and organization of the toxin loci, which makes it difficult to identify and characterize novel systems using traditional experimental and bioinformatic strategies. In recent years, we have been developing and utilizing unique genome-mining strategies and pipelines, based on the organizational principles of both domain architectures and genomic loci of PTSs, for an effective and comprehensive discovery of novel PTSs, dissection of their components, and prediction of their structures and functions. In this study, we present our systematic discovery of a new type of PTS (S8-PTS) in several gram-positive bacteria. We show that the S8-PTS contains three components: a peptidase of the S8 family (subtilases), a polymorphic toxin, and an immunity protein. We delineated the typical organization of these polymorphic toxins, in which a N-terminal signal peptide is followed by a potential receptor binding domain, BetaH, and one of 16 toxin domains. We classified each toxin domain by the distinct superfamily to which it belongs, identifying nine BECR ribonucleases, one Restriction Endonuclease, one HNH nuclease, two novel toxin domains homologous to the VOC enzymes, one toxin domain with the Frataxin-like fold, and several other unique toxin families such as Ntox33 and HicA. Accordingly, we identified 20 immunity families and classified them into different classes of folds. Further, we show that the S8-PTS-associated peptidases are analogous to many other processing peptidases found in T5SS, T7SS, T9SS, and many proprotein-processing peptidases, indicating that they function to release the toxin domains during secretion. The S8-PTSs are mostly found in animal and plant-associated bacteria, including many pathogens. We propose S8-PTSs will facilitate the competition of these bacteria with other microbes or contribute to the pathogen-host interactions.

Globins constitute an ancient superfamily of proteins, exhibiting enormous structural and functional diversity, as demonstrated by many heme-binding families and two non-heme binding families that were discovered in bacterial stressosome component RsbR and in light-harvesting phycobiliproteins (phycocyanin) in cyanobacteria and red algae. By comprehensively exploring the globin repertoire using sensitive computational analyses of sequences, structures, and genomes, we present the identification of the third family of non-heme binding globins—the photoglobin. By conducting profile-based comparisons, clustering analyses, and structural modeling, we demonstrate that photoglobin is related to, but distinct from, the phycocyanin family. Photoglobin preserves a potential ligand-binding pocket, whose residue configuration closely resembles that of phycocyanin, indicating that photoglobin potentially binds to a comparable linear tetrapyrrole. By exploring the contextual information provided by the photoglobin’s domain architectures and gene-neighborhoods, we found that photoglobin is frequently associated with the B12-binding light sensor domain and many domains typical of prokaryotic signal transduction systems. Structural modeling using AlphaFold2 demonstrated that photoglobin and B12-binding domains form a structurally conserved hub among different domain architecture contexts. Based on these strong associations, we predict that the coupled photoglobin and B12-binding domains act as a light-sensing regulatory bundle, with each domain sensing different wavelengths of light resulting in switch-like regulation of downstream signaling effectors. Thus, based on the above lines of evidence, we present a distinct non-heme binding globin family and propose that it may define a new type of light sensor, by means of a linear tetrapyrrole, in complex prokaryotic signal transduction systems.

Ischemic stroke is a common cerebrovascular disease that seriously affects human health. However, most patients do not practice self-care and cannot rely on the current clinical treatment for guaranteed functional recovery. Stem cell transplantation is an emerging treatment studied in various central nervous system diseases. More importantly, animal studies show that transplantation of mesenchymal stem cells (MSCs) can alleviate neurological deficits and bring hope to patients suffering from ischemic stroke. This paper reviews the biological characteristics of MSCs and discusses the mechanism and progression of MSC transplantation to provide new therapeutic directions for ischemic stroke.

ABSTRACT Liberibacter pathogens are the causative agents of several severe crop diseases worldwide, including citrus Huanglongbing and potato zebra chip. These bacteria are endophytic and nonculturable, which makes experimental approaches challenging and highlights the need for bioinformatic analysis in advancing our understanding about Liberibacter pathogenesis. Here, we performed an in-depth comparative phylogenomic analysis of the Liberibacter pathogens and their free-living, nonpathogenic, ancestral species, aiming to identify major genomic changes and determinants associated with their evolutionary transitions in living habitats and pathogenicity. Using gene neighborhood analysis and phylogenetic classification, we systematically uncovered, annotated, and classified all prophage loci into four types, including one previously unrecognized group. We showed that these prophages originated through independent gene transfers at different evolutionary stages of Liberibacter and only the SC-type prophage was associated with the emergence of the pathogens. Using ortholog clustering, we vigorously identified two additional sets of genomic genes, which were either lost or gained in the ancestor of the pathogens. Consistent with the habitat change, the lost genes were enriched for biosynthesis of cellular building blocks. Importantly, among the gained genes, we uncovered several previously unrecognized toxins, including new toxins homologous to the EspG/VirA effectors, a YdjM phospholipase toxin, and a secreted endonuclease/exonuclease/phosphatase (EEP) protein. Our results substantially extend the knowledge of the evolutionary events and potential determinants leading to the emergence of endophytic, pathogenic Liberibacter species, which will facilitate the design of functional experiments and the development of new methods for detection and blockage of these pathogens. IMPORTANCE Liberibacter pathogens are associated with several severe crop diseases, including citrus Huanglongbing, the most destructive disease to the citrus industry. Currently, no effective cure or treatments are available, and no resistant citrus variety has been found. The fact that these obligate endophytic pathogens are not culturable has made it extremely challenging to experimentally uncover the genes/proteins important to Liberibacter pathogenesis. Further, earlier bioinformatics studies failed to identify key genomic determinants, such as toxins and effector proteins, that underlie the pathogenicity of the bacteria. In this study, an in-depth comparative genomic analysis of Liberibacter pathogens along with their ancestral nonpathogenic species identified the prophage loci and several novel toxins that are evolutionarily associated with the emergence of the pathogens. These results shed new light on the disease mechanism of Liberibacter pathogens and will facilitate the development of new detection and blockage methods targeting the toxins.

IbMYB1 was one of the major anthocyanin biosynthesis regulatory genes that has been identified and utilized in purple-fleshed sweet potato breeding. At least three members of this gene, namely, IbMYB1-1, -2a, and -2b, have been reported. We found that IbMYB1-2a and -2b are not necessary for anthocyanin accumulation in a variety of cultivated species (hexaploid) with purple shoots or purplish rings/spots of flesh. Transcriptomic and quantitative reverse transcription PCR (RT-qPCR) analyses revealed that persistent and vigorous expression of IbMYB1 is essential to maintain the purple color of leaves and storage roots in this type of cultivated species, which did not contain IbMYB1-2 gene members. Compared with IbbHLH2, IbMYB1 is an early response gene of anthocyanin biosynthesis in sweet potato. It cannot exclude the possibility that other MYBs participate in this gene regulation networks. Twenty-two MYB-like genes were identified from 156 MYBs to be highly positively or negatively correlated with the anthocyanin content in leaves or flesh. Even so, the IbMYB1 was most coordinately expressed with anthocyanin biosynthesis genes. Differences in flanking and coding sequences confirm that IbMYB2s, the highest similarity genes of IbMYB1, are not the members of IbMYB1. This phenomenon indicates that there may be more members of IbMYB1 in sweet potato, and the genetic complementation of these members is involved in the regulation of anthocyanin biosynthesis. The 3′ flanking sequence of IbMYB1-1 is homologous to the retrotransposon sequence of TNT1-94. Transposon movement is involved in the formation of multiple members of IbMYB1. This study provides critical insights into the expression patterns of IbMYB1, which are involved in the regulation of anthocyanin biosynthesis in the leaf and storage root. Notably, our study also emphasized the presence of a multiple member of IbMYB1 for genetic improvement.

FOXP2, a member of forkhead box transcription factor family, was first identified as a language-related gene that played an important role in language learning and facial movement. In addition, FOXP2 was also suggested regulating the progression of cancer cells. In previous studies, we found that FOXA2 inhibited epithelial-mesenchymal transition (EMT) in breast cancer cells. In this study, by identifying FOXA2-interacting proteins from FOXA2-pull-down cell lysates with Mass Spectrometry Analysis, we found that FOXP2 interacted with FOXA2. After confirming the interaction between FOXP2 and FOXA2 through Co-IP and immunofluorescence assays, we showed a correlated expression of FOXP2 and FOXA2 existing in clinical breast cancer samples. The overexpression of FOXP2 attenuated the mesenchymal phenotype whereas the stable knockdown of FOXP2 promoted EMT in breast cancer cells. Even though FOXP2 was believed to act as a transcriptional repressor in most cases, we found that FOXP2 could activate the expression of tumor suppressor PHF2. Meanwhile, we also found that FOXP2 could endogenously bind to the promoter of E-cadherin and activate its transcription. This transcriptional activity of FOXP2 relied on its interaction with FOXA2. Furthermore, the stable knockdown of FOXP2 enhanced the metastatic capacity of breast cancer cells in vivo. Together, the results suggested that FOXP2 could inhibit EMT by activating the transcription of certain genes, such as E-cadherin and PHF2, in concert with FOXA2 in breast cancer cells.

ABSTRACT A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was recently identified as the causative agent for the coronavirus disease 2019 (COVID-19) outbreak that has generated a global health crisis. We use a combination of genomic analysis and sensitive profile-based sequence and structure analysis to understand the potential pathogenesis determinants of this virus. As a result, we identify several fast-evolving genomic regions that might be at the interface of virus-host interactions, corresponding to the receptor binding domain of the Spike protein, the three tandem Macro fold domains in ORF1a, and the uncharacterized protein ORF8. Further, we show that ORF8 and several other proteins from alpha- and beta-CoVs belong to novel families of immunoglobulin (Ig) proteins. Among them, ORF8 is distinguished by being rapidly evolving, possessing a unique insert, and having a hypervariable position among SARS-CoV-2 genomes in its predicted ligand-binding groove. We also uncover numerous Ig domain proteins from several unrelated metazoan viruses, which are distinct in sequence and structure but share comparable architectures to those of the CoV Ig domain proteins. Hence, we propose that SARS-CoV-2 ORF8 and other previously unidentified CoV Ig domain proteins fall under the umbrella of a widespread strategy of deployment of Ig domain proteins in animal viruses as pathogenicity factors that modulate host immunity. The rapid evolution of the ORF8 Ig domain proteins points to a potential evolutionary arms race between viruses and hosts, likely arising from immune pressure, and suggests a role in transmission between distinct host species. IMPORTANCE The ongoing COVID-19 pandemic strongly emphasizes the need for a more complete understanding of the biology and pathogenesis of its causative agent SARS-CoV-2. Despite intense scrutiny, several proteins encoded by the genomes of SARS-CoV-2 and other SARS-like coronaviruses remain enigmatic. Moreover, the high infectivity and severity of SARS-CoV-2 in certain individuals make wet-lab studies currently challenging. In this study, we used a series of computational strategies to identify several fast-evolving regions of SARS-CoV-2 proteins which are potentially under host immune pressure. Most notably, the hitherto-uncharacterized protein encoded by ORF8 is one of them. Using sensitive sequence and structural analysis methods, we show that ORF8 and several other proteins from alpha- and beta-coronavirus comprise novel families of immunoglobulin domain proteins, which might function as potential immune modulators to delay or attenuate the host immune response against the viruses.

The ionome of the rice grain is crucial for the health of populations that consume rice as a staple food. However, the contribution of phenotypic plasticity to the variation of rice grain ionome and the genetic architecture of phenotypic plasticity are poorly understood. In this study, we investigated the rice grain ionome of a rice diversity panel in up to eight environments. A considerable proportion of phenotypic variance can be attributed to phenotypic plasticity. Then, phenotypic plasticity and mean phenotype were quantified using Bayesian Finlay-Wilkinson regression, and a significant correlation between them was observed. However, the genetic architecture of mean phenotype was distinct from that of phenotypic plasticity. Also, the correlation between them was mainly attributed to the phenotypic divergence between rice subspecies. Furthermore, the results of whole-genome regression analysis showed that the genetic loci related to phenotypic plasticity can explain a considerable proportion of the phenotypic variance in some environments, especially for Cd, Cu, Mn, and Zn. Our study not only sheds light on the genetic architecture of phenotypic plasticity of the rice grain ionome but also suggests that the genetic loci which related to phenotypic plasticity are valuable in rice grain ionome improvement breeding.

Activation of signal transducer and activator of transcription 3 (Stat3) by leukemia inhibitory factor (LIF) is required for maintaining self-renewal and pluripotency of mouse embryonic stem cells (mESCs). Here, we have confirmed transcription factor Forkhead Box m1 (Foxm1) as a LIF/Stat3 downstream target that mediates LIF/Stat3-dependent mESC self-renewal. The expression of Foxm1 relies on LIF signaling and is stimulated by Stat3 directly in mESCs. The knockdown of Foxm1 results in the loss of mESC pluripotency in the presence of LIF, and the overexpression of Foxm1 alone maintains mESC pluripotency in the absence of LIF and feeder layers, indicating that Foxm1 is a mediator of LIF/Stat3-dependent maintenance of pluripotency in mESCs. Furthermore, the inhibition of Foxm1 expression prevents the reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells (iPSCs), suggesting that Foxm1 is essential for the reprogramming of somatic cells into iPSCs. Our results reveal an essential function of Foxm1 in the LIF/Stat3-mediated mESC self-renewal and the generation of iPSCs.

To conduct the association between vitamin B12 and mental health in children and adolescents. Five databases were searched for observational studies in any language reporting on mental health and vitamin B12 levels or intake in children and adolescents from inception to March 18, 2022. Two authors independently extracted data and assessed study quality. Qualitative and quantitative analysis of data were performed. The review was registered in the PROSPERO database (CRD42022345476). Fifty six studies containing 37,932 participants were identified in the review. Vitamin B12 levels were lower in participants with autism spectrum disorders (ASD) (standardized mean difference [SMD], -1.61; 95% confidence interval [95% CI], -2.44 to -0.79; p < 0.001), attention deficit hyperactivity disorders (SMD, -0.39; 95% CI, -0.78 to -0.00; p = 0.049) compared with control group. Vitamin B12 intake were lower in participants with ASDs (SMD, -0.86; 95% CI, -1.48 to -0.24; p = 0.006) compared with control group, but showed no difference between depression group (SMD, -0.06; 95% CI, -0.15 to 0.03; p = 0.17) and the control group. Higher vitamin B12 intake were associated with lower risk of depression (odds ratio [OR], 0.79; 95% CI, 0.63-0.98; p = 0.034) and behavioral problems (OR, 0.83; 95% CI, 0.69-0.99; p = 0.04). The vast majority of included studies supported potential positive influence of vitamin B12 on mental health, and vitamin B12 deficiency may be a reversible cause for some mental health disorders in children and adolescents. [ABSTRACT FROM AUTHOR]

Macrophage-myofibroblast transformation (MMT) transforms macrophages into myofibroblasts in a specific inflammation or injury microenvironment. MMT is an essential biological process in fibrosis-related diseases involving the lung, heart, kidney, liver, skeletal muscle, and other organs and tissues. This process consists of interacting with various cells and molecules and activating different signal transduction pathways. This review deeply discussed the molecular mechanism of MMT, clarified crucial signal pathways, multiple cytokines, and growth factors, and formed a complex regulatory network. Significantly, the critical role of transforming growth factor-β (TGF-β) and its downstream signaling pathways in this process were clarified. Furthermore, we discussed the significance of MMT in physiological and pathological conditions, such as pulmonary fibrosis and cardiac fibrosis. This review provides a new perspective for understanding the interaction between macrophages and myofibroblasts and new strategies and targets for the prevention and treatment of MMT in fibrotic diseases.