Genes&Diseases

语种：英文出版周期：双月刊

E-ISSN：2352-3042P-ISSN：2352-4820

主管单位：重庆市教育委员会主办单位：重庆医科大学

Genes and Diseases是本由重庆医科大学于2014年创办的双月刊，也是国内第一本分子医学与转化医学相结合的全英文综合期刊，并入选“中国科技期刊卓越行动计划”高起点新刊项目。

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Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis. However, the underlying mechanism is still not completely understood. In this study, progranulin (PGRN) was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening. In addition, PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model. Furthermore, estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN. Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling. In addition, loss of PGRN led to the reduction of estrogen receptor α, the important estrogen receptor involved in estrogen regulation of osteoporosis, through enhancing its degradation via K48-linked ubiquitination. These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptor α.

Intervertebral disc degeneration (IDD) is a common chronic inflammatory degenerative disease that causes lower back pain. However, the underlying mechanisms of IDD remain unclear. Ferroptosis suppressor protein 1 (FSP1) is a newly identified suppressor for ferroptosis. This study aims to investigate the role of FSP1 in IDD. Nucleus pulposus (NP) tissues in humans were collected and NP cells from rats were isolated to detect FSP1 expression pattern. The relationship between FSP1-mediated ferroptosis and apoptosis was identified using FSP1 inhibitor iFSP1. RNA sequencing was utilized to seek downstream molecules and related signaling pathways. Moreover, both exogenous recombinant FSP1 protein and endogenous small interfering RNA were implemented in this study to clarify the role of FSP1 in tumor necrosis factor-alpha (TNFα)-mediated NP cell apoptosis. Ultimately, the underlying mechanisms of FSP1-related signaling pathway in IDD were uncovered both in vitro and in vivo. As a result, FSP1 was up-regulated in human degenerative NP tissues and after TNFα stimulation. FSP1 inhibition by iFSP1 fails to trigger ferroptosis in NP cells while inhibiting TNFα-mediated apoptosis. Further experiments demonstrated that FSP1 was closely related to TNFα-reliant caspase 3 activation and mitochondrial damage. However, the exogenous addition of recombinant protein FSP1 does not induce cell death or intensify the efficacy of TNFα. Mechanically, FSP1 is involved in TNFα-mediated NF-κB signaling activation to accelerate the development of IDD. This study demonstrated that FSP1 promotes IDD through TNFα-reliant NF-κB signaling activation and caspase 3-dependent apoptosis. These findings suggested a novel therapeutic target for the treatment of IDD.

Multiple myeloma (MM) patients with chromosome 1q gain (1q+) are clinically and biologically heterogeneous. The underlying molecular mechanisms are still under investigation, while the identification of targets for effective therapy of this subgroup of MM patients is urgently needed. We aimed to investigate the clinical significance and the regulatory mechanisms of insulin-like growth factor 2 messenger RNA (mRNA) binding protein 1 (IGF2BP1), a N6-methyladenosine (m6A) reader, in MM patients with 1q+. We found that MM patients with 1q+ exhibit a significantly higher level of IGF2BP1 mRNA than controls, while higher IGF2BP1 expression predicted a worse prognosis in MM patients with 1q+. IGF2BP1 overexpression promoted cell proliferation and G1-to-S phase transition of the cell cycle in NCI-H929 cells. Through comprehensive in silico analyses of existing public datasets and in-house generated high-throughput sequencing datasets, along with in vitro experiments, we identified CDC5L as a target of IGFBP1, which can bind to the m6A sites of CDC5L mRNA to up-regulate its protein abundance. Higher CDC5L expression also predicted a worse prognosis of MM patients with 1q+. Moreover, both knockdown and mutation of CDC5L attenuated the pro-proliferative effect of IGF2BP1. Furthermore, IGF2BP1 inhibitor BTYNB effectively inhibited CDC5L expression in MM cells with 1q+ and suppressed the proliferation of these cells in vitro and in vivo. Therefore, IGF2BP1 acts as a post-transcriptional enhancer of CDC5L in an m6A-dependent manner to promote the proliferation of MM cells with 1q+. Our work identified a novel IGF2BP1-CDC5L axis and provided new insight into developing targeted therapeutics for MM patients with 1q+.

MAFB is essential for regulating male-type urethral differentiation, and especially, its variation can contribute to hypospadias in mice. However, the potential mechanism is still unclear. Here we observed that the basic leucine zipper (bZIP) transcription factor MAFB and CCAAT/enhancer-binding protein alpha (CEBPA) could promote human urothelium SV-HUC-1 growth. Moreover, MAFB and CEBPA expression were reduced in the prepuce tissues of hypospadias patients. Based on transcriptome sequencing analysis and Western blot, MAFB knockdown was found to suppress CEBPA protein expression and repress Wnt/β-catenin signaling in urothelium cells. Meanwhile, we observed blocked cell-cycle progression from the G1 to the S phase, inhibited cell proliferation, and activated apoptosis. Furthermore, MAFB could facilitate CEBPA transcription and regulate the proliferation of urothelium. The above results indicated that MAFB-mediated inhibition of urothelial SV-HUC-1 growth resulted from inhibiting the Wnt/β-catenin signaling pathway by down-regulating CEBPA. Our findings provide new insight into the understanding of genes associated with hypospadias and the pathogenic mechanism of this disorder.

Naked cuticle homolog 2 (NKD2) has been recognized as an antagonist of Wnt/β-catenin signaling and a tumor suppressor. The role of NKD2 in osteoblast and osteoclast differentiation and the mechanism are not fully understood. In this study, we identified the up-regulation of NKD2 during osteoblast and adipocyte differentiation. Functional experiments revealed that NKD2 stimulated osteoblast differentiation and suppressed adipocyte formation. Furthermore, NKD2 down-regulated the expression of receptor activator of nuclear factor-κB ligand in bone marrow mesenchymal stem cells and inhibited osteoclast formation from osteoclast precursor cells. Mechanistic investigations revealed that the regulation of osteoblast and adipocyte differentiation by NKD2 involved Wnt/β-catenin and tuberous sclerosis complex subunit 1 (TSC1)/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways. Unlike in undifferentiated mesenchymal cells where NKD2 promoted Dishevelled-1 degradation, in the cells differentiating toward osteoblasts or adipocytes NKD2 down-regulated secreted frizzled related protein 1/4 expression and failed to destabilize Dishevelled-1, thereby activating Wnt/β-catenin signaling. Moreover, NKD2 bound to TSC1 and inhibited mTORC1 signaling. Further investigation uncovered an interplay between TSC1/mTORC1 and Wnt/β-catenin signaling pathways. Finally, transplantation of NKD2-overexpressing bone marrow mesenchymal stem cells into the marrow of mice increased osteoblasts, reduced osteoclasts and marrow fat, and partially prevented bone loss in ovariectomized mice. This study provides evidence that NKD2 in mesenchymal stem/progenitor cells reciprocally regulates the differentiation of osteoblasts and adipocytes by modulating Wnt/β-catenin and mTORC1 pathways and inhibits osteoclast formation by down-regulating receptor activator of nuclear factor-κB ligand. It suggests that NKD2 up-regulation may ameliorate postmenopausal bone loss.

microRNAs (miRNAs) are short single-stranded non-coding RNAs between 21 and 25 nt in length in eukaryotic organisms, which control post-transcriptional gene expression. Through complementary base pairing, miRNAs generally bind to their target messenger RNAs and repress protein production by destabilizing the messenger RNA and translational silencing. They regulate almost all life activities, such as cell proliferation, differentiation, apoptosis, tumorigenesis, and host–pathogen interactions. Methylation modification is the most common RNA modification in eukaryotes. miRNA methylation exists in different types, mainly N6-methyladenosine, 5-methylcytosine, and 7-methylguanine, which can change the expression level and biological mode of action of miRNAs and improve the activity of regulating gene expression in a very fine-tuned way with flexibility. In this review, we will summarize the recent findings concerning methylation modifications of miRNA, focusing on their biogenesis and the potential role of miRNA fate and functions.

Although cell-cycle arrest, senescence, and apoptosis are well accepted as the classic barriers in tumorigenesis, recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer development. It is well accepted that ferroptosis, an iron-dependent programmed cell death, acts as a new type of tumor suppression mechanism tightly linked with numerous metabolic pathways. SLC7A11 is a transmembrane cystine/glutamate transporter protein that plays a vital role in controlling ferroptosis in vivo. The levels of SLC7A11 are dynamically regulated by various types of stresses, such as oxidative stress, nutrient deprivation, endoplasmic reticulum stress, radiation, oncogenic stress, DNA damage, and immune stress. SLC7A11 can be transcriptionally regulated by both activators such as ATF4, NRF2, and ETS1, and repressors including BACH1, p53, ATF3, and STAT1 during stress responses. Moreover, SLC7A11 activity and its protein stability and cellular localization are also modulated upon stress. Patients' data show that SLC7A11 is overexpressed in various types of human cancers, and higher levels of SLC7A11 predict poorer overall survival. Growing evidence also suggests that targeting SLC7A11 is a promising approach in cancer therapy by effectively inhibiting tumor proliferation, invasion, and metastasis, as well as counteracting cancer stem cells and overcoming chemoresistance. This review highlights the regulation of SLC7A11 as an unconventional checkpoint in tumorigenesis through modulating ferroptotic responses under various types of stress.

In precision cancer therapy, addressing intra-tumor heterogeneity poses a significant obstacle. Due to the heterogeneity of each cell subtype and between cells within the tumor, the sensitivity and resistance of different patients to targeted drugs, chemotherapy, etc., are inconsistent. Concerning a specific tumor type, many feasible treatments or combinations can be used by specifically targeting the tumor microenvironment. To solve this problem, it is necessary to further study the tumor microenvironment. Single-cell sequencing techniques can dissect distinct tumor cell populations by isolating cells and using statistical computational methods. This technology may assist in the selection of targeted combination therapy, and the obtained cell subset information is crucial for the rational application of targeted therapy. In this review, we summarized the research and application advances of single-cell sequencing technology in the tumor microenvironment, including the most commonly used single-cell genomic and transcriptomic sequencing, and their future development direction was proposed. The application of single-cell sequencing technology has been expanded to include epigenomics, proteomics, metabolomics, and microbiome analysis. The integration of these different omics approaches has significantly advanced the development of single-cell multiomics sequencing technology. This innovative approach holds immense potential for various fields, such as biological research and medical investigations. Finally, we discussed the advantages and disadvantages of using single-cell sequencing to explore the tumor microenvironment.

Posttranscriptional RNA modification is an important mode of epigenetic regulation in various biological and pathological contexts. N6, 2′-O-dimethyladenosine (m6Am) is one of the most abundant methylation modifications in mammals and usually occurs at the first transcribed nucleotide. Accumulating evidence indicates that m6Am modifications have important roles in RNA metabolism and physiological and pathological processes. PCIF1 (phosphorylated C-terminal domain interacting factor 1) is a protein that can bind to the phosphorylated C-terminal domain of RNA polymerase II through its WW domain. PCIF1 is named after this binding ability. Recently, PCIF1 has been identified as a cap-specific adenine N6-methyltransferase responsible for m6Am formation. Discovered as the sole m6Am methyltransferase for mammalian mRNA, PCIF1 has since received more extensive and in-depth study. Dysregulation of PCIF1 contributes to various pathological processes. Targeting PCIF1 may hold promising therapeutic significance. In this review, we provide an overview of the current knowledge of PCIF1. We explore the current understanding of the structure and the biological characteristics of PCIF1. We further review the molecular mechanisms of PCIF1 in cancer and viral infection and discuss its therapeutic potential.

Osteoarthritis (OA) is a debilitating chronic joint disease affecting large populations of patients, especially the elderly. The pathological mechanisms of OA are currently unknown. Multiple risk factors are involved in OA development. Among these risk factors, alterations of mechanical loading in the joint leading to changes in biological signaling pathways have been known as a key event in OA development. The importance of AMPK-β-catenin-Runx2 signaling in the initiation and progression of OA has been recognized in recent years. In this review, we discuss the recent progress in understanding the role of this signaling pathway and the underlying interaction mechanisms during OA development. We also discuss the drug development aiming to target this signaling pathway for OA treatment.

Human hepatitis B virus (HBV) infection is the major cause of acute and chronic hepatitis B, liver cirrhosis, and hepatocellular carcinoma. Although the application of prophylactic vaccination programs has successfully prevented the trend of increasing HBV infection prevalence, the number of HBV-infected people remains very high. Approved therapeutic management efficiently suppresses viral replication; however, HBV infection is rarely completely resolved. The major reason for therapeutic failure is the persistence of covalently closed circular DNA (cccDNA), which forms viral minichromosomes by combining with histone and nonhistone proteins in the nucleus. Increasing evidence indicates that chromatin-modifying enzymes, viral proteins, and noncoding RNAs are essential for modulating the function of cccDNA. Therefore, a deeper understanding of the regulatory mechanism underlying cccDNA transcription will contribute to the development of a cure for chronic hepatitis B. This review summarizes the current knowledge of cccDNA biology, the regulatory mechanisms underlying cccDNA transcription, and novel anti-HBV approaches for eliminating cccDNA transcription.

Extrachromosomal circular DNA (eccDNA), a chromosome-independent circular DNA, has garnered significant attention due to its widespread distribution and intricate biogenesis in carcinoma. Existing research findings propose that multiple eccDNAs contribute to drug resistance in cancer treatments through complex and interrelated regulatory mechanisms. The unique structure and genetic properties of eccDNA increase tumor heterogeneity. This increased diversity is a result of eccDNA's ability to stimulate oncogene remodeling and participate in anomalous splicing processes through chimeric cyclization and the reintegration of loop DNA back into the linear genome. Such actions promote oncogene amplification and silencing. eccDNA orchestrates protein interactions and modulates protein degradation by acting as a regulatory messenger. Moreover, it plays a pivotal role in modeling the tumor microenvironment and intensifying the stemness characteristics of tumor cells. This review presented detailed information about the biogenesis, distinguishing features, and functions of eccDNA, emphasized the role and mechanisms of eccDNA during cancer treatment, and further proposed the great potential of eccDNA in inspiring novel strategies for precision cancer therapy and facilitating the discovery of prognostic biomarkers for cancer.

Digestive-system cancers represent major threats to human health; however, the mechanisms underlying tumorigenesis and radiochemotherapy resistance have remained elusive. Therefore, an urgent need exists for identifying key drivers of digestive system tumorigenesis and novel targeted therapeutics. The checkpoint kinase 2 (Chk2) regulates cell-cycle progression, and Chk2 dysregulation or Chk2 mutations can lead to the development of various cancers, which makes Chk2 an important research topic. This review summarizes the roles of Chk2 in DNA-damage responses, cell-cycle regulation, autophagy, and homeostasis maintenance. We describe relationships between tumorigenesis and cell-cycle dysregulation induced by Chk2 mutations. In addition, we summarize evidence indicating that Chk2 can serve as a novel therapeutic target, based on its contributions to radiochemotherapy-resistance reversion and progress made in developing antitumor agents against Chk2. The prevailing evidence supports the conclusion that further research on Chk2 will provide a deeper understanding of digestive-system tumorigenesis and should suggest novel therapeutic targets.

Exosomes, extracellular vesicles originating from endosomes, were discovered in the late 1980s and their function in intercellular communication has since garnered considerable interest. Exosomes are lipid bilayer-coated vesicles that range in size from 30 to 150 nm and appear as sacs under the electron microscope. Exosome secretion is crucial for cell-to-cell contact in both normal physiology and the development and spread of tumors. Furthermore, cancer cells can secrete more exosomes than normal cells. Scientists believe that intercellular communication in the complex tissue environment of the human body is an important reason for cancer cell invasion and metastasis. For example, some particles containing regulatory molecules are secreted in the tumor microenvironment, including exosomes. Then the contents of exosomes can be released by donor cells into the environment and interact with recipient cells to promote the migration and invasion of tumor cells. Therefore, in this review, we summarized the biogenesis of exosome, as well as exosome cargo and related roles. More importantly, this review introduces and discusses the factors that have been reported to affect exosome secretion in tumors and highlights the important role of exosomes in tumors.

Sepsis, a life-threatening condition triggered by a dysregulated host response to infection, remains a major challenge for therapeutic intervention. Despite the growing interest in immunomodulatory strategies for sepsis treatment, the effects and mechanisms of these approaches on the organ-specific inflammatory and immunosuppressive states induced by sepsis are poorly understood. According to existing studies, capsaicin (CPS) has pharmacological effects such as analgesic, antipruritic, hypolipidemia, hypoglycemia, anti-inflammatory and antibacterial, and anti-tumor activity.1 However, the effectiveness of CPS in treating sepsis is still unknown. Here, we applied single-cell RNA sequencing (scRNA-seq) to reveal how CPS, a natural compound with anti-inflammatory properties, modulates the splenic microenvironment in a mouse model for sepsis induced by cecal ligation and puncture (CLP). We found that CPS improved survival and reduced inflammation in septic mice. Additionally, scRNA-seq analysis revealed that CPS plays an antioxidant and anti-inflammatory role in the body by regulating plasma cells derived from B cells. Moreover, CPS activated cytotoxic T cells and natural killer cells. Furthermore, we have observed that CPS has the potential to regulate cytokine production but exerts limited influence on the chemotactic activity of neutrophils during sepsis. Lastly, CPS enhanced the polarization of inflammatory macrophages during sepsis. Hence, our findings imply that CPS holds the potential to harmonize immune homeostasis, thereby dampening the inflammatory and/or immunosuppressive milieu observed in septic conditions. Our investigation presents a comprehensive scrutiny of CPS's role in orchestrating the spleen microenvironment in the context of septic infection, offering a foundational rationale for considering CPS as a prospective therapeutic intervention against sepsis.

Age-related clonal hematopoiesis is defined as the presence of somatic mutations of genes known to be recurrently mutated in hematologic malignancies in the peripheral blood of healthy individuals.1 When clonal hematopoiesis is associated with a mutation at a variant allele frequency of 0.02 or greater, it is termed “clonal hematopoiesis of indeterminate potential” (CHIP). Classical CHIP genes include epigenetic modifiers such as Dnmt3a, Tet2, and Asxl1, and DNA repair genes such as Tp53 and Ppm1d.2 Although CHIP-associated mutations are most frequent in myeloid neoplasm, some, such as those in Dnmt3a and Tet2, are recurrently observed in lymphoid malignancies as well. Tiacci et al described a case of sequential onset of angioimmunoblastic T-cell lymphoma possessing Tet2 mutations and acute myeloid leukemia within two years in a 45-year-old man.3 This suggested the potential roles of CHIP in the molecular pathogenesis of the sequential/simultaneous onset of two hematologic malignancies, also termed hematological composite malignancies (HCM). However, till now, the association of CHIP mutations with the clone evolution of HCM remains poorly clarified probably due to a low incidence.

Oral cancer, primarily oral squamous cell carcinoma (OSCC), is one of the most common cancer types worldwide. The incidence of OSCC continues to rise, with approximately 377,713 new cases and 177,757 deaths reported worldwide by 2020.1 Despite advancements in diagnosis and treatment, the 5-year survival rate for OSCC patients has remained at 60%–67% over the last two decades (SEER database: https://seer.cancer.gov/). This consistent rise in morbidity and lack of survival improvement have made OSCC a public concern.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness and atrophy.1 The widespread implementation of next-generation sequencing in clinical practice has facilitated the identification of over 40 ALS-associated genes, among which copper/zinc-superoxide dismutase 1 (SOD1) assumes a pivotal role in East Asian populations.1 Moreover, it is increasingly apparent that the intricate interplay between genetic predisposition and exposome over time may contribute significantly to the etiology of this debilitating disease. While the precise pathogenic role of copper (Cu) in ALS remains elusive, accumulating evidence suggests that Cu deficiency may be linked to SOD1-associated ALS, possibly mediated through the promotion of the hydrophobicity of mutant SOD1, ultimately exacerbating its neurotoxic aggregation.2 Furthermore, a novel form of regulated cell death, termed cuproptosis, has emerged as an intriguing phenomenon. Cuproptosis is characterized by the direct binding of Cu to the lipoylated enzymes of the tricarboxylic acid cycle, leading to mitochondrial lipoylated protein aggregation and consequent proteotoxic stress.3 Given that mitochondrial dysfunction constitutes a critical pathophysiological hallmark in ALS, the perturbation of Cu homeostasis may possibly play a prominent role in the context of SOD1-induced neurodegeneration.

Elevated intraocular pressure (IOP) is recognized as a significant contributor to the development of various ocular diseases, especially glaucoma. The delicate balance between the generation and drainage of aqueous humor (AH) in the anterior chamber angle regulates the real IOP level. Despite extensive research, our understanding of the cellular components, tissue structure, and functional heterogeneity within the AH circulatory system (AHCS) remains incomplete, hindering the progression of effective and accessible treatment strategies for IOP intervention. Therefore, the state-of-the-art spatiotemporal single-cell omics stands poised to furnish an invaluable spatial cellular map of the AHCS, thereby laying the foundation for subsequent in-depth investigations. Meanwhile, this innovative approach promises to offer novel insights into the pathogenesis and management of IOP regulation. Here, we utilized nanoscale resolution-spatial enhanced resolution omics-sequencing (Stereo-seq1) to obtain in situ gene expression profiles of AHCS in human eyes (Fig. S1A). We generated two optimal cutting temperature compound-embedded chips of the trabecular meshwork (TM) and surrounding tissue from four samples (Table S1), which were later cut into layers of 10-μm-thickness cryosections for Stereo-seq and hematoxylin-eosin staining. Considering that transcript capture was performed at a subcellular level using a DNA nanoball sequencing technique, we integrated a semi-automated spatial omics methodology with cell segmentation using the GEM3D-toolkit (https://github.com/BGI-Qingdao/GEM3D_toolkit) to acquire a single-cell resolved transcript of AHCS in spatial scenarios. This method allowed us to partition two Stereo-seq chips into 60,638 putative single cells by assigning transcripts to each defined cell area at single-cell resolution (detailed in supplementary methods and materials and Fig. S1B). After the following quality control, we finally detected 978.5 DNA nanoball spots per cell area on average, with the per-cell detection of 885.4 unique molecular identifiers and 445.3 genes. Chip1 and Chip2 were composed of 32,081 and 28,557 cells, respectively, covering 24,775 genes (Fig. S1C and Table S2).

Gray matter heterotopia (GMH) is caused by malformation of cortical development, which exhibits as gray matter nodules abnormally located within the white matter region, and most GMH patients have concomitant epilepsy. Although antiepileptic drugs can control seizures, over 40% of patients still require surgery to pursue a cure for the disease. Previous researchers have studied GMH from the genetic perspective, and several disease-specific gene modifications were identified to elucidate the pathogenesis.1 However, to acquire a deeper understanding of the disease progression, it is essential to comprehensively explore the transcriptional alterations caused by GMH. Here, we sought to analyze the cell types and their distinct transcriptional changes in GMH. Thus, we studied the lesional tissues from GMH patients using single-cell RNA sequencing, which captured the cell-type specific transcriptome at single-cell resolution.

Gastric cancer has a high incidence worldwide; the incidence of gastric cancer ranks fifth among all malignant tumors, and the mortality rate ranks fourth.1 The immune microenvironment plays an important role in the occurrence, progression, and metastasis of gastric cancer.2 Immunotherapy has been recognized as the most effective treatment for a variety of human cancers. Among immunotherapy strategies, the blockade of immune checkpoints is becoming the most common cutting-edge cancer immunotherapy method, and also the most effective method.3 Given the high incidence and mortality of gastric cancer, identifying new immune checkpoints in the process of gastric cancer formation is urgently needed, as it provides a new theoretical basis for the diagnosis and treatment of gastric cancer. Thus, we conducted single-cell sequencing analysis of three pairs of primary gastric cancer and adjacent normal tissues to search for genes related to the immune escape of gastric cancer cells. The detailed case data are shown in Table S1. Our results revealed that the VSIR gene plays an important role in the development of gastric cancer. However, the mechanism by which the VSIR gene helps gastric cancer cells achieve immune escape during gastric cancer formation is still unclear, and further research is needed.

Calpain3 is one of the calpain protease family members that are predominantly expressed in skeletal muscle. Loss-of-function mutations in Calpain3 have been related to autosomal recessive limb-girdle muscular dystrophy 1 (LGMDR1), a common form of muscular dystrophy. Recently, the heterozygous 21-bp deletion mutation of the Calpain3 gene has been reported to cause autosomal dominant limb-girdle muscular dystrophy 4 (LGMDD4) which suggests that the mutant proteins act in a dominant-negative manner. Therefore, we examined whether the mutant protein could suppress the activity of wild-type Calpain3 using a cell culture model and a Drosophila model. The mutant Calpain3 resulted in catalytic inactivation, which did not inhibit wild-type Calpain3 autolytic and catalytic activities in HeLa cells. Overexpression of wild-type and mutant Calpain3 in Drosophila's eyes and muscles did not exhibit significant dominant toxicity. We provide evidence that mutant Calpain3 does not suppress wild-type Calpain3 activity. Rather, it is a mutant lacking autocatalytic activity like many other loss-of-function Calpain3 mutants causing LGMDR1. Our results implicate that the stability of the heteromeric mutant and wild-type Calpain3 complexes may be affected without inhibiting the wild-type activity per se. However, a thorough investigation is necessary to understand the molecular mechanism and dominant inheritance of the heterozygous 21-bp deletion mutation in LGMDD4.

SLC7A11, as the core component of system xc−, protects cancer cells from oxidative-stress-induced cell death like ferroptosis by mediating cystine uptake. Recent studies revealed that SLC7A11 is widely overexpressed in various types of cancer, and inhibition of SLC7A11 could inhibit tumor growth.1 Consistently, SLC7A11 was overexpressed in cervical cancer, and the expression of SLC7A11 was associated with the severity of cervical cancer (Fig. 1A; Fig. S1A), making SLC7A11 a promising anti-tumor target. However, SLC7A11 inhibitor imidazole ketone erastin (IKE) alone exerts weak antiproliferative effects in cervical cancer cells (Fig. S1D). Oridonin is isolated from the traditional Chinese herbal Rabdosia rubescens and exhibits mild anti-cancer activity against multiple types of tumor cells, including cervical cancer cells. However, the low bioavailability and dose-dependent toxicity of oridonin hinder its clinical application.2 Here, we first discovered that combination of SLC7A11 inhibitors and oridonin synergistically inhibited cervical cancer cell growth. Then the pharmacological effect and underlying mechanism of the combination of SLC7A11 inhibitors and oridonin were explored.

Silicosis is a chronic interstitial lung disease caused by prolonged exposure to inhalable silica particles. The initiation and progression of silicosis involve a dynamic process encompassing various cell types and molecules. Although the effector cells in different stages of silicosis undergo constant switching with disease progression, immune cells play a dominant role throughout the entire process.1 Therefore, comprehensively exploring cellular and molecular mechanisms underlying immune responses in silicosis becomes a prerequisite for unraveling its pathogenesis. Immune checkpoints (ICs) are crucial immunomodulatory factors that contribute significantly to the maintenance of immune tolerance and homeostasis.2 Our previous studies have also demonstrated that the development of experimental silicosis is accompanied by dysregulation of IC expression.3 Therefore, a systematic description of the dynamic expression profile of ICs in silicosis can provide a basis for subsequent experimental research. In this study, we established a mouse model of silicosis and collected lung tissue samples at various stages for transcriptome sequencing analysis. By integrating bioinformatics analysis techniques with time series-based trend analysis, we mapped out pulmonary IC atlas to highlight the critical role played by ICs in orchestrating immune responses at distinct stages of silicosis progression.

In recent years, molecular diagnostics has become pivotal in the detection of polycystic kidney disease (PKD).1 Nevertheless, given the extensive genomic architecture, allelic heterogeneity, and dispersed mutations in affiliated genes, the translation of its clinical prospects is constrained.2 Moreover, summarizing the pertinent literature within the past decade reveals that the majority of studies predominantly focus on three main genes (PKD1, PKD2, and PKHD1), resulting in a limited scope of genes considered (Table S1). In the present investigation, endeavoring to supersede the limitations of traditional genetic diagnosis methods, we employed next-generation sequencing to meticulously interrogate the entire coding domains and exon-intron junctions of 15 pre-eminent genes (Table S2).

CARM1 (coactivator-associated arginine methyltransferase 1) is a type I protein arginine methyltransferase and a binding protein of the p160 coactivator family.1 Moreover, the research shows that the absence of CARM1 leads to impaired adipocyte differentiation2 and disrupts normal differentiation of embryonic T cells.3 In addition, other studies have confirmed that CARM1 induces the expression of pluripotent genes Oct4 and Sox2 through methylation modification of histone H3, thereby damaging embryonic stem cell differentiation.4 Furthermore, it can be indicated that CARM1 plays an important role in different types of tumors through various pathways.5 Notably, it is well known that ARAF (v-raf murine sarcoma 3611 viral oncogene homolog) regulates cell proliferation and differentiation abilities. In this study, it is revealed that CARM1 affects the epigenetic modification, transcriptome, and proteome to regulate the expression of related genes in liver cancer, thus regulating cell proliferation, cell metabolism, cell cycle, and other biological processes in liver cancer cells. These results provide a valuable theoretical basis for further exploring the cellular and molecular mechanisms of CARM1 promoting the occurrence and development of liver cancer at the cellular and molecular levels.

Colorectal cancer (CRC) is a significant global health concern, ranking third in incidence and second in mortality among all cancer-related diseases.1 Therefore, it is imperative to prioritize research efforts focused on CRC prevention and treatment to effectively reduce the associated incidence and mortality rates. Synthetic lethality (SL) refers to the phenomenon in which cells harboring two specific gene mutations simultaneously undergo cell death, whereas cells with a single mutation in either of the genes can survive normally. SL strategies are widely concerned in personalized cancer treatment, with the application of PARP inhibitors marking a significant milestone.2

Chimeric RNAs, hybrid transcripts containing exons from two originally separate genes, have been extensively studied in various cancer types and non-cancerous tissues.1,2 The hybrid transcripts can arise through different mechanisms, such as chromosomal rearrangements, trans-splicing events, or read-through transcription. The investigation into chimeric RNA landscape across various cancer types as well as in normal physiology processes has highlighted their potential roles in regulating gene expression and cellular functions. However, the specific landscape and functional relevance of chimeric RNAs in pregnancy-related conditions, such as gestational complications, fetal growth abnormalities, or preterm birth, are still not fully understood. Preeclampsia is one of the most high-risk pregnancy complications that lack early diagnosis and precise treatment.3,4 Here, we explored chimeric RNAs in placenta tissues and their potential clinical implications in preeclampsia. Firstly, we identified 272 placenta-specific chimeric RNAs by analyzing the placenta RNA-seq data. We then validated the candidate chimeric RNAs using a combination of bioinformatic analyses and experimental validations. To further explore their potential as biomarkers for preeclampsia, we conducted bioinformatic analysis on the expression of candidate chimeric RNAs in placenta RNA-seq data, comparing preeclampsia samples with age-matched healthy pregnancies. We discovered three chimeric RNAs that exhibited a higher or specific expression pattern in preeclampsia placental samples. We then validated their expression in clinical samples of preeclampsia placentas and healthy controls. PGBD2-SZT2 chimeric RNA was discovered as a potential diagnostic biomarker due to its significantly higher expression in preeclampsia placentas. These findings uncover a new repertoire of pregnancy-specific chimeric RNAs and highlight their potential as novel diagnostic biomarkers or therapeutic targets for preeclampsia.

Doxorubicin (Dox), an anthracycline chemotherapy drug, is used extensively in cancer chemotherapy and has been studied in depth in relation to cancers including leukemia, small-cell lung cancer, and ovarian cancer.1 However, the dose-dependent cardiotoxicity of Dox seriously limits its clinical application.2 As a type of noncoding RNA with a covalent cyclic structure, circular RNA (circRNA) has emerged as a new and exciting topic. Growing evidence has shown that circRNA is linked to the pathogenesis of various cardiovascular diseases, including Doxorubicin-induced cardiotoxicity (DIC).3 The function of circRNA is closely associated with its cellular sublocalization. CircRNAs distributed in the cytoplasm primarily serve as microRNA (miRNA) sponges that competitively adsorb miRNA and reduce the binding and degradation of the target mRNA by miRNA, leading to indirect up-regulation of the target gene and increased execution of its function.4 In the present research, a novel circRNA named mmu_circ_0000153 with a length of 840 bp was identified in DIC through circRNA sequencing. It is derived from the precursor Akap7 mRNA through the back-splicing of exons and is therefore also referred to as circAkap7. Functionally, circAkap7 serves as an endogenous protective factor for the heart, as it was activated and increased in abundance to resist Dox-stimulated cardiomyocyte damage, whereas its knockdown intensified Dox-induced cardiomyocyte apoptosis. To examine the mechanism, the circAkap7‒miRNA‒mRNA (messenger RNA) ceRNA (competing endogenous RNA) network was constructed through miRNA prediction and mRNA sequencing based on circAkap7 knockdown.

Lung cancer is an exceedingly prevalent form of cancer, frequently diagnosed, and holds the unfortunate distinction of being the primary cause of cancer-related fatalities on a global scale.1 Non-small cell lung cancer (NSCLC) accounts for 85 % of all lung cancer cases and has a low 5-year survival rate.2 Previous studies have revealed that CircDONSON plays a pivotal role in promoting the growth and invasion of gastric cancer by activating the NURF complex-dependent transcription factor SOX4.3 However, the function significance of CircDONSON in lung cancer remains unexplored. Mechanistically, we demonstrate that CircDONSON interacts with HNRNPC and subsequently inhibits the downstream MAPK signaling pathway. To summarize, our study demonstrates that CircDONSON acts as a tumor suppressor in lung cancer and exhibits potential as both a prognostic marker and therapeutic target for NSCLC.

Breast cancer (BRCA) is the dominating form of cancer affecting women, with an estimated 2.3 million newly diagnosed cases and 685,000 deaths in 2020.1 An emerging study has proposed a novel metabolism-related regulated cell death modality called disulfidptosis induced by abnormal accumulation of intracellular disulfides in SLC7A11high tumor cells.2 However, research on disulfidptosis remains in its infancy. The study presents for the first time a comprehensive investigation on disulfidptosis in BRCA. Diversity and complexity somatic mutations and copy number variations of disulfidptosis genes and their aberrant expression were found in breast tumors. Three disulfidptosis-based consensus clusters were established, with heterogeneous clinical, molecular, and immunogenomic features. A disulfidptosis-relevant signature (FHOD1, IL1R1, SPRY4, DOK4, TNN, ZMAT3, FEZ1, EMP1, WLS, ENPEP, RGS3, CCDC92, C11orf95, PTTG1IP, and SDC1) was proposed for reliably improving prognosis estimation. Low-risk patients more possibly responded to immune-checkpoint blockade, while high-risk patients were more sensitive to docetaxel. Disulfidptosis-relevant genes were proven to present abnormal expression in breast tumors. Disulfidptosis-relevant PTTG1IP overexpression led to aggressiveness and actin cytoskeleton formation in BRCA cells. Additionally, its overexpression induced tumor growth. These new findings proposed innovative disulfidptosis-based classification and signature for reflecting the heterogeneity of disulfidptosis in breast tumors, which might assist clinical-decision making.

Loss of excessive hair growth causes psychological distress in many people, seriously affecting their social confidence and quality of life. The dermal papilla (DP) plays a pivotal role in regulating hair follicle (HF) morphogenesis and hair growth. However, the genes that govern the DP function in HF have not been extensively investigated. Genome-wide association studies have reported that two single-nucleotide polymorphisms (rs929626 and rs1081073) of the transcription factor EBF1 (early B-cell factor 1) are associated with male pattern baldness.1 Additionally, in Ebf1 whole-body knockout mice, hair follicles fail to reenter the anagen phase after the first hair cycle, presumably because of the lack of intradermal adipocyte precursors.2 These findings suggested that EBF1 plays a vital role in hair loss-related diseases.

Vascular calcification is a pathophysiological change characterized by abnormal deposition of hydroxyapatite crystals in the vascular walls, contributing to increased morbidity and mortality from cardiovascular diseases.1 Currently, there are no effective therapeutic strategies to prevent or impede the progression of vascular calcification. Recent studies have elucidated that inhibiting the phenotypic transition of vascular smooth muscle cells (VSMCs) from contractile to osteo/chondrogenic phenotype represents a pivotal strategy for restraining vascular calcification.2 Diet and lifestyle are strongly linked to arterial calcification.3 Green tea is the second most popular beverage globally besides water. Studies have substantiated the favorable impact of tea beverages on cardiovascular ailments.4 However, the potential of green tea in the investigation of treating and preventing vascular calcification has not been fully explored yet. In this study, we have discovered that (-)-epigallocatechin gallate (EGCG), a prominent catechin present in green tea, exhibits the potential to mitigate vascular calcification both in vivo and in vitro. Mechanistically, EGCG effectively mitigates vascular calcification by inhibiting mineral deposition and osteogenic differentiation of VSMCs through the MAPK-JunB signaling axis.

Mycoplasma hyopneumoniae (Mhp) and Mycoplasma ovipneumoniae (Mo), similar to Mycoplasma pneumoniae (Mp), initiate a chronic respiratory infection with concomitant pulmonary disease, causing substantial harm worldwide.1 A mouse model with genetic consistency helped to elucidate the unknown pathogenic mechanism of respiratory mycoplasmas in large animals and humans. While the intraperitoneal route would facilitate dissemination of infectious agents to the adventitia, combined challenge or immunization would promote replication of microorganisms or vaccine immune effects; for example, intraperitoneal combined intranasal route increased gamma interferon-specific CD8 T cells by more than 60 times after influenza infection.2

Nowadays, although the treatment and diagnostic approaches have been improved, lung adenocarcinoma (LUAD) is still the leading cause of cancer-related death in the world with overall survival of less than five years1. Diagnosis of LUAD in the early stage is still a challenge, resulting from that early symptoms are not obvious2, which leads to the fact that most patients eventually die from cancer progression and chemotherapy resistance. LUAD is reported to be associated with the MAPK pathway, however, the mechanism at the cellular and genetic levels has not been clearly elucidated. Therefore, functional exploration of LUAD- and MAPK pathway-related genes is essential for understanding the pathogenesis of LUAD and exploring therapeutic measures. Figure S1 illustrates the flowchart of this study.

Mesenchymal stem cells (MSCs) are somatic adult stem cells derived from the mesoderm, possessing robust multipotency and regenerative properties. These cells are found in various tissues, including bone marrow, adipose tissue, the placenta, and the umbilical cord. The vascular wall serves as a reservoir for different types of stem and progenitor cells, contributing to tissue regeneration and vascular wall remodeling under pathological and environmental stress. Previous studies have reported the presence of MSCs or MSC-like cells in abdominal aortic aneurysm (AAA).1 However, due to the lack of exclusive and specific makers, identification and confirmation of vascular MSCs of patients with AAA remains challenging. Accurately determining the quantity and function of resident MSCs in patients with AAA holds immense importance in unraveling the pathogenesis and progression of the disease. Although Ciavarella and colleagues have successfully isolated arterial wall MSCs in patients with AAA,2,3 it is important to note that their findings have not been independently replicated in other centers. Therefore, the presence of vascular MSCs in patients with AAA requires validation using precise and powerful tools. Single-cell RNA sequencing (scRNA-seq) is an advanced technique that allows for the distinction and characterization of tissue stem cells. Despite the limited studies utilizing scRNA-seq on AAA samples, none have defined an MSC cluster. Thus, this investigation aimed to determine the plausibility of MSC existence in AAA samples using diverse methods.

Desmin is a muscle-specific intermediate filament protein, which plays a significant role in providing structural integrity of cardiomyocytes by connecting different cell organelles and multi-protein complexes.1 Pathogenic DES mutations cause different cardiomyopathies and skeletal myopathies.2 The most obvious hallmark of pathogenic DES mutations is an aberrant cytoplasmic desmin accumulation.3 However, driven by a broad clinical application of next-generation sequencing techniques and advanced classification criteria, the number of variants of unknown significance increased significantly during the last years. Especially, the impact of DES variants within the N-terminal head domain on the filament assembly is widely unknown.

KRAS mutations occur in approximately 40% of metastatic colorectal cancer (CRC), leading to disrupted hydrolysis of guanosine triphosphate and tumor cell proliferation.1 Genetic features and clinical outcomes of CRCs depend on KRAS mutation subtypes,2, 3, 4 and molecular biomarkers for prognosis prediction are under development. We supposed that mutational signatures offering an additional layer of genomic information might aid in understanding the differences in treatment efficacy among KRAS-mutated CRCs.

Triple-negative breast cancer (TNBC) is an inherently heterogeneous malignancy at the biological and clinical levels, occupying around 15% of diagnosed breast cancer cases and being the most lethal breast cancer subtype to combat.1 Anoikis is a programmed cell death that occurs when cells detach from the correct extracellular matrix, thereby destroying integrin connections.2 However, the role of anoikis expression pattern and prognosis in TNBC is still unrevealed. Here, TNBC presented three heterogeneous phenotypes in anoikis, and each subtype owned unique molecular, and clinical characteristics as well as diverse responses to chemotherapy, targeted therapies, and immune checkpoint blockade. The anoikis-based scoring system can accurately estimate patient survival, which was remarkably superior to well-established clinical parameters. Patients with a low anoikis score were predicted to well respond to immune checkpoint blockade, and compounds were identified to be appropriate for those with a high anoikis score. The genes from the anoikis-based scoring system were aberrantly expressed in bulk TNBC versus normal tissues, and specifically expressed in TNBC single cells. Each of them was linked with a TNBC prognosis. Altogether, our study sheds light on the anoikis landscape of TNBC, which will contribute to further understanding of anoikis and formulating an appropriate treatment choice to defeat TNBC.

It is estimated that infertility impacts 8%–12% of reproductive-aged couples worldwide. Female infertility accounts for 37% of causes among infertile couples, and ovulatory dysfunction is regarded as its most common factor.1 CUL4B belongs to the Cullin family, whose members are the scaffolding proteins of Cullin-RING E3 ligases (CRLs). Human CUL4B gene mutations result in X-linked mental retardation syndromes. In addition to mental retardation, patients have symptoms such as short stature, obesity, and hypogonadism. Global (Sox2-Cre) or germ cell-specific (Vasa-Cre) Cul4b knockout male mice are infertile with impaired spermatozoa motility and spermatogonial stemness. DDB1 and DCAF1, two members of the CRL4A/B complex, can regulate oocyte survival, reprogramming,2 and meiotic maturation of oocytes.3 In this study, we generated Sox2-Cre+/−;Cul4bf/+ heterozygous female mice and found that these mice were infertile due to anovulation. CUL4B affects granulosa cell number and follicle development by regulating the follicle-stimulating hormone (FSH)/aromatase/estrogen loop. These results reveal a new function of CUL4B in follicular development and ovulation and provide a novel theoretical basis for the diagnosis and treatment of ovulation dysfunction and female infertility.

Krabbe disease, also known as globoid cell leukodystrophy, is a rare lysosomal storage disorder. It is primarily caused by mutations in the GALC gene on chromosome 14q31, leading to GALC enzyme deficiency in lysosomes. This results in the accumulation of toxic substrate psychosine in the nervous systems.1 Currently, hematopoietic stem cell transplantation is the only available treatment, offering only a delay in neurological deterioration. Gene therapy, particularly using recombinant adeno-associated viruses (AAVs), shows promise for treating genetic diseases by introducing functional genes into target cells.2

Bone mesenchymal stem cells (BMSCs) are stem cells located in the bone marrow matrix that have a variety of differentiation potentials and biological functions. They play an important role in bone regenerative medicine. The senescence of BMSCs might cause accelerated degeneration of bone tissue. Autophagy is a process in which cellular homeostasis is maintained by autophagosomes and lysosomes. It could control the function and senescence of BMSCs during bone aging and might be a therapeutic target for treating diseases during aging.1 Ferroptosis is a regulated cell death process.2 The inhibition of ferroptosis in mesenchymal stem cells could reduce cell injury and might have great therapeutic value.3, 4, 5

Sepsis affects approximately 20%–30% of patients admitted to the intensive care unit.1 Acute respiratory distress syndrome (ARDS) is recognized as one of the earliest and most common complications of sepsis, occurring when sepsis triggers a systemic infection and provokes an uncontrolled inflammatory response that can lead to severe lung damage.2 Studies have demonstrated that patients with sepsis-induced ARDS face not only a mortality risk ranging from 30% to 40%3 but also long-term outcomes such as cognitive impairment and memory loss.4 Moreover, patients with sepsis-associated ARDS have a higher mortality rate compared with those with ARDS caused by other factors and tend to have suboptimal treatment outcomes once ARDS develops.5 Therefore, early identification and treatment initiation are crucial to prevent ARDS in sepsis, reduce mortality, and minimize healthcare costs. In this study, we aimed to develop a predictive model for assessing the likelihood of ARDS development in sepsis patients by integrating bulk RNA sequencing and single-cell RNA sequencing data (materials & methods can be found in supplementary data).

The coronavirus disease 2019 (COVID-19) is still a global threat today. SARS-CoV-2 is the etiologic agent of COVID-19, the culprit behind the current pandemic. Its life cycle is dependent on hijacking host-cell biological processes to facilitate entry, replication, assembly, and budding. The recognition that a suite of mammalian host proteins is required for SARS-CoV-2 infection and replication presents additional targeting strategies that may be less prone to deflections by the quickly mutating viral genome. In this study, we conducted an integrative network analysis to identify pivotal host genes and pathways for SARS-CoV-2 infection.

Alternative polyadenylation (APA) is a post-transcriptional process that typically determines the length of mature mRNAs' 3' untranslated region (3'UTR). The global shortened 3'UTR alters mRNA stability, localization, and translation and contributes to cancer progression.1 The APA characteristics and its effects on acute myeloid leukemia (AML) remain to be comprehensively described. Here, we identified churchill domain containing 1 (CHURC1) as an up-regulated gene with a lengthened 3'UTR in CD34+ enriched AML cells compared with healthy hematopoietic stem and progenitor cells. As for APA regulation of CHURC1, we found that rs6745 and RNA binding protein TIA1 potentially contribute to the distal poly(A) site usage in cis- and trans-ways, respectively. Mechanistically, a lengthened CHURC1 3'UTR affected the apoptosis of AML cells by disrupting the expression of DICER1 by sponging miR-186–5p. The chemotherapeutic sensitivity of 8 drugs was associated with CHURC1 poly(A) site usage. Overall, our analysis indicated a previously undetected gene, CHURC1, that affected AML progression through 3'UTR length change resulting from APA. Data collection and detailed analysis methods were described in the supplementary material.

Combined oxidative phosphorylation deficiency 23 (COXPD23, MIM# 616198) is a rare autosomal-recessive mitochondrial disorder with variable disease severity ranging from death in early infancy to survival into the second decade of life,1 with the clinical symptoms of hypertrophic cardiomyopathy (HCM) and/or neurological symptoms with onset in early childhood, hypotonia, delayed psychomotor development, lactic acidosis,1 abnormal lesions in the basal ganglia, thalamus, and brainstem. COXPD23 is caused by homozygous or compound heterozygous mutations in the GTP-binding protein 3 (GTPBP3, OMIM∗ 608536) gene. Except for COXPD23, mutations in GTPBP3 are also associated with other diseases2, 3, 4 (Table S1).

Pontocerebellar hypoplasia type 7 (PCH7) (OMIM #614969) stands as a rare and severe neurodegenerative syndrome marked by distinct characteristics, including neurological decline, hypoplasia in the pons and cerebellum, muscle hypotonia, irregular breathing, and hypogonadism.1 Furthermore, individuals with 46, XY karyotypes display feminine genitalia, whereas those with 46, XX karyotypes exhibit atrophic ovaries and lack menarche in PCH7 patients.2 Recent investigations have pinpointed variants in the EGR1 protein 1 gene (TOE1) as the genetic culprits behind PCH7 onset.3 TOE1 primarily situated within the Cajal bodies of the nucleus has been identified. In this cellular compartment, TOE1 functions as a 3-exonuclease, aiding in the maturation of small nuclear RNAs (snRNAs) and the processing of snRNA 3′-tails.4 Disruptions in snRNA processing may contribute to severe neurodegenerative disorders.

Salmonella is a notorious foodborne pathogen that comprises strains that exhibit varied ability to cause human infection. To date, this pathogen still causes over one million cases of foodborne infections annually in the United States alone.1 The systemic infections of high-virulence Salmonella strains are often seen in the nosocomial environment. The increased prevalence of antimicrobial-resistant genes in highly virulent Salmonella causes their invasive infection more difficult to treat. Therefore, understanding the mechanism of Salmonella virulence is important for solving public health issues. According to the information from the US CDC, Salmonella enteritidis (S. enteritidis) infection is the most common cause of Salmonella infection in clinical cases among different serotypes.1 We collected a set of high- and low-virulence S. enteritidis isolates and subjected them to comparative genomic, transcriptomic, and phenotypic analyses. The tested strains exhibited almost identical genetic composition, but over-expression of genes involved in various physiological functions was observed in the high-virulence strains. Importantly, these genes include those responsible for maltose transport, citrate metabolism, VitB12 biosynthesis, propanediol utilization, nitrite reduction, and hydrogen production. The gene knockout experiment confirmed that the deletion of these genes resulted in decreased invasiveness, reduced survival inside macrophages, reduced invasion of different organs, and lower mortality in animal experiments.

Multiple myeloma (MM) is the second most common hematologic malignancy and is characterized by the expansion of clonally plasma cells and related organ or tissue damage.1 The clinical behavior, response, and survival of MM are heterogeneous, and much of this variability may be driven by acquired genetic factors, including primary immunoglobulin translocations, hyperdiploid, and additional copy number gains and losses.2 The abnormalities of chromosome 1q (+1q) were found in about 30%–40% of patients with newly diagnosed MM and at a higher proportion at the refractory/relapse stage.3 The gain/amplification of 1q (1q gain/amp) has been reported to relate to poor outcomes due to the dysregulation of lots of genes located in 1q including CKS1B, ANP32E, and ADAR1.3 However, the other prognostic genes on 1q and the underlying mechanisms remain elusive.

In mammalian cells, the nucleolus serves as a factory for organizing ribosomal RNA (rRNA) synthesis and ribosomal biogenesis. Moreover, by interacting with rRNA genes and heterochromatin, nucleolus also functions in chromatin organization and reprogramming. Differing from somatic cells, nucleolus undergoes distinct morphological changes during oocyte and early embryo development, while playing an indispensable role in orchestrating chromatin remodeling.1 However, the structural change and function of nucleolus in male germ cell development are still waiting for exploration. We recently reported that the role of Peter Pan Homolog (PPAN), a key rRNA processing factor, in mouse oocyte and preimplantation development.2 Here, we further constructed a male germ cell-conditional PPAN knockout (PPAN-cKO) mouse model to disturb nucleolar function in spermatogenesis. Our data showed that depletion of PPAN severely disrupts germ cell development by inducing aberrant nucleolar structure and function, resulting in an oligoasthenoteratozoospermia phenotype in mice.

As one amino acid can often be encoded by multiple codons, the genetic code is redundant, which accounts for synonymous mutations in protein-coding regions.1 Since synonymous mutations do not cause any alterations in amino acid sequence, it was previously believed that they do not change the structure and function of the proteins and thus are functionally silent.1 However, evidence is emerging that synonymous mutations can affect messenger RNA (mRNA) stability, splicing and translation, and thereby influencing protein biogenesis.1 Nevertheless, the detailed mechanisms underlying the impacts of synonymous mutations on mRNA metabolism and protein biogenesis remain elusive. N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNA, has been shown to play important roles in gene regulation in both normal and disease cells, through post-transcriptional regulation of mRNA stability, splicing and translation.2 Therefore, we assumed that if synonymous mutations occur in RNA m6A modification sites, synonymous mutations could change mRNA m6A modifications, which in turn would affect mRNA stability, splicing and translation. Indeed, through overlapping synonymous mutations in the classic m6A motif DRACH (D = A, G or U; R = G/A; H = A, C or U) sites in human cancers listed in the COSMIC (the Catalogue of Somatic Mutations in Cancer) database (https://cancer.sanger.ac.uk)3 with the detected m6A peaks listed in the RMBase database,4 we found that around 4500 synonymous mutations in over 3000 genes occurred at the “A” site of the classic m6A motifs DRACH with detected m6A peaks. Thus, our data reveals the prevalence of overlapping between synonymous mutations and m6A sites in genes in human cancers, suggesting that synonymous mutations-mediated m6A modification changes may contribute to the changes in the expression of the target genes in human cancers.