Cryptochrome 2 Suppresses Epithelial-Mesenchymal Transition by Promoting Trophoblastic Ferroptosis in Unexplained Recurrent Spontaneous Abortion.

Unexplained recurrent spontaneous abortion (URSA) is a serious reproductive issue that affects women of childbearing age. Studies have shown a close association between disrupted circadian rhythm and impaired epithelial-mesenchymal transition (EMT) in trophoblasts during URSA, although the underlying mechanism is not known. The current study investigated the regulatory relationship between circadian rhythm gene cryptochrome 2 (CRY2) and ferroptosis on the migratory ability of trophoblast cells. Cell proliferation experiments, wound-healing assays, and expression of related markers were conducted to study EMT. Trophoblastic ferroptosis was confirmed by the expressions of malondialdehyde, glutathione, mitochondrial membrane potential, divalent iron ions, and related genes. The results showed significant increased expression of CRY2 and decreased expression of brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) in the URSA villous tissues, accompanied by iron-dependent oxidative changes and abnormal expression of ferroptosis-related proteins. CRY2 and BMAL1 were co-localized and functioned as a feedback loop, which regulated the dynamic changes of EMT-related markers in trophoblast cells. CRY2 promoted trophoblastic ferroptosis, whereas BMAL1 had the opposite effect. Particularly, the ferroptosis inhibitor (ferrostatin-1) effectively reversed the trophoblastic ferroptosis and EMT inhibition caused by CRY2 overexpression. Collectively, these results suggest that CRY2 regulates trophoblastic ferroptosis and hinders cellular EMT and migratory ability by suppressing BMAL1 expression.

A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization.

Nuclear receptor-binding SET domain-containing 2 (NSD2) is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two proline-tryptophan-tryptophan-proline (PWWP) domains and five plant homeodomains (PHDs) believed to serve as chromatin reading modules. Here, we report a chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1, antagonizes PWWP1 interaction with nucleosomal H3K36me2 and selectively engages endogenous NSD2 in cells. UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 that result from translocations prevalent in multiple myeloma (MM). Mutations of other NSD2 chromatin reader domains also increase NSD2 nucleolar localization and enhance the effect of UNC6934. This chemical probe and the accompanying negative control UNC7145 will be useful tools in defining NSD2 biology.

Chemically modified microRNA delivery via DNA tetrahedral frameworks for dental pulp regeneration.

Dental pulp regeneration is a promising strategy for addressing tooth disorders. Incorporating this strategy involves the fundamental challenge of establishing functional vascular networks using dental pulp stem cells (DPSCs) to support tissue regeneration. Current therapeutic approaches lack efficient and stable methods for activating DPSCs. In the study, we used a chemically modified microRNA (miRNA)-loaded tetrahedral-framework nucleic acid nanostructure to promote DPSC-mediated angiogenesis and dental pulp regeneration. Incorporating chemically modified miR-126-3p into tetrahedral DNA nanostructures (miR@TDNs) represents a notable advancement in the stability and efficacy of miRNA delivery into DPSCs. These nanostructures enhanced DPSC proliferation, migration, and upregulated angiogenesis-related genes, enhancing their paracrine signaling effects on endothelial cells. This enhanced effect was substantiated by improvements in endothelial cell tube formation, migration, and gene expression. Moreover, in vivo investigations employing matrigel plug assays and ectopic dental pulp transplantation confirmed the potential of miR@TDNs in promoting angiogenesis and facilitating dental pulp regeneration. Our findings demonstrated the potential of chemically modified miRNA-loaded nucleic acid nanostructures in enhancing DPSC-mediated angiogenesis and supporting dental pulp regeneration. These results highlighted the promising role of chemically modified nucleic acid-based delivery systems as therapeutic agents in regenerative dentistry and tissue engineering.

Identification of a novel de novo mutation in SOX4 for syndromic tooth agenesis.

OBJECTIVES: Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms. MATERIALS AND METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4. RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing. CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis. CLINICAL RELEVANCE: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.

Effect of varying auxiliaries on maxillary incisor torque control with clear aligners: A finite element analysis.

INTRODUCTION: This study aimed to evaluate the effects of varying auxiliaries on tooth movement and stress distribution when maxillary central incisors were torqued 1° with a clear aligner through finite element analysis. METHODS: Three-dimensional finite element models, including maxillary alveolar bone, periodontal ligament, dentition, and clear aligner, were constructed. According to the auxiliaries designed on the maxillary central incisor, 5 models were created: (1) without auxiliaries (control model), (2) with the power ridge, (3) with the semi-ellipsoid attachment, (4) with the horizontal rectangular attachment, and (5) with the horizontal cylinder attachment. The tooth movement and periodontal ligament stress distribution after a palatal root torque of 1° were analyzed for each of the 5 models. RESULTS: With 1° torque predicted, the maxillary central incisor without auxiliaries showed a tendency of labial tipping, mesial tipping, and intrusion. The rotation center moved occlusally in the power ridge model. The labiolingual inclination variation increased in the semi-ellipsoid attachment model but decreased in the power ridge model. The maxillary central incisor is twisted in the distal direction in the power ridge model. The maxillary central incisor of the horizontal rectangular attachment and the horizontal cylinder attachment model behaved similarly to the control model. Periodontal stresses were concentrated in the cervical and apical areas. The maximum von Mises stresses were 11.6, 12.4, 3.81, 1.14, and 11.0 kPa in the 5 models. The semi-ellipsoid attachment model exhibited a more uniform stress distribution than the other models. CONCLUSIONS: Semi-ellipsoid attachment performed better efficacy on labiolingual inclination, and power ridge performed better efficacy on root control. However, a distal twist of maxillary incisors could be generated by the power ridge.

Structural basis for the recognition of methylated histone H3 by the Arabidopsis LHP1 chromodomain.

Arabidopsis LHP1 (LIKE HETEROCHROMATIN PROTEIN 1), a unique homolog of HP1 in Drosophila, plays important roles in plant development, growth, and architecture. In contrast to specific binding of the HP1 chromodomain to methylated H3K9 histone tails, the chromodomain of LHP1 has been shown to bind to both methylated H3K9 and H3K27 histone tails, and LHP1 carries out its function mainly via its interaction with these two epigenetic marks. However, the molecular mechanism for the recognition of methylated histone H3K9/27 by the LHP1 chromodomain is still unknown. In this study, we characterized the binding ability of LHP1 to histone H3K9 and H3K27 peptides and found that the chromodomain of LHP1 binds to histone H3K9me2/3 and H3K27me2/3 peptides with comparable affinities, although it exhibited no binding or weak binding to unmodified or monomethylated H3K9/K27 peptides. Our crystal structures of the LHP1 chromodomain in peptide-free and peptide-bound forms coupled with mutagenesis studies reveal that the chromodomain of LHP1 bears a slightly different chromodomain architecture and recognizes methylated H3K9 and H3K27 peptides via a hydrophobic clasp, similar to the chromodomains of human Polycomb proteins, which could not be explained only based on primary structure analysis. Our binding and structural studies of the LHP1 chromodomain illuminate a conserved ligand interaction mode between chromodomains of both animals and plants, and shed light on further functional study of the LHP1 protein.

The intricate relationship between autoimmunity disease and neutrophils death patterns: a love-hate story.

Autoimmune diseases are pathological conditions that result from the misidentification of self-antigens in immune system, leading to host tissue damage and destruction. These diseases can affect different organs and systems, including the blood, joints, skin, and muscles. Despite the significant progress made in comprehending the underlying pathogenesis, the complete mechanism of autoimmune disease is still not entirely understood. In autoimmune diseases, the innate immunocytes are not functioning properly: they are either abnormally activated or physically disabled. As a vital member of innate immunocyte, neutrophils and their modes of death are influenced by the microenvironment of different autoimmune diseases due to their short lifespan and diverse death modes. Related to neutrophil death pathways, apoptosis is the most frequent cell death form of neutrophil non-lytic morphology, delayed or aberrant apoptosis may contribute to the development anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). In addition, NETosis, necroptosis and pyroptosis which are parts of lytic morphology exacerbate disease progression through various mechanisms in autoimmune diseases. This review aims to summarize recent advancements in understanding neutrophil death modes in various autoimmune diseases and provide insights into the development of novel therapeutic approaches for autoimmune diseases.

Ubiquitin-specific protease 7 prevents recurrent spontaneous abortion by targeting enhancer of zeste homolog 2 to regulate trophoblast proliferation, apoptosis, migration, and invasion through the Wnt/ß-catenin pathway†.

Trophoblasts are significant components of the placenta and play crucial roles in maternal-fetal crosstalk. Adequate trophoblast migration and invasion are essential for embryo implantation and healthy pregnancy. Ubiquitin-specific protease 7 (USP7), a member of the deubiquitinating enzyme family, regulates the processes of migration and invasion in multiple tumor cells. However, the effects of USP7 on trophoblasts and its possible mechanism in the development of recurrent spontaneous abortion (RSA) are still unclear. In this study, we analyzed the expression of USP7 in villous tissues obtained from RSA patients and healthy controls, and then GNE-6776 (a USP7-specific inhibitor) and USP7 siRNA were used in a trophoblast cell line, HTR-8/SVneo, to further assess the effect of USP7 on the biological function of trophoblasts. Our results provide convincing evidence that USP7 is downregulated in the placental villous tissues of RSA patients. USP7 was found to have a crucial role in the proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) process of trophoblast cells. Further experiments revealed that USP7 directly interacted with the enhancer of zeste homolog 2 (EZH2) and regulated the Wnt/ß-catenin signaling pathway in trophoblasts. Taken together, these findings indicate the vital role of USP7 in regulating trophoblast proliferation, migration and invasion, thus affecting the pathogenesis of RSA, providing new insights into the important role of USP7 in the maternal-fetal interface.

Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron.

Proteome integrity depends on the ubiquitin-proteasome system to degrade unwanted or abnormal proteins. In addition to the N-degrons, C-terminal residues of proteins can also serve as degradation signals (C-degrons) that are recognized by specific cullin-RING ubiquitin ligases (CRLs) for proteasomal degradation. FEM1C is a CRL2 substrate receptor that targets the C-terminal arginine degron (Arg/C-degron), but the molecular mechanism of substrate recognition remains largely elusive. Here, we present crystal structures of FEM1C in complex with Arg/C-degron and show that FEM1C utilizes a semi-open binding pocket to capture the C-terminal arginine and that the extreme C-terminal arginine is the major structural determinant in recognition by FEM1C. Together with biochemical and mutagenesis studies, we provide a framework for understanding molecular recognition of the Arg/C-degron by the FEM family of proteins.

Efficacy and Safety of Direct Oral Anticoagulants (DOACs) Versus Warfarin in Atrial Fibrillation Patients with Prior Stroke: a Systematic Review and Meta-analysis.

BACKGROUND: The purpose of this meta-analysis was to compare efficacy and safety of direct oral anticoagulants (DOACs) to warfarin for secondary stroke prevention among adult patients with atrial fibrillation and prior stroke. METHODS: Major repositories were screened for randomized controlled trials (RCTs), RCT subgroups, and observational studies (OBSs, divided in claims and non-claims). Occurrences of ischemic stroke or transient ischemic attack, systemic embolism, all-cause mortality, intracranial hemorrhage (ICH), and major bleeding were outcomes of interest. Hazard ratios (HRs) and their confidence intervals (95%CIs) were pooled using random-effects models for each study design. Claims studies were analyzed separately from non-claims, while RCT subgroups were grouped with OBSs (non-claims) as the randomization was broken. RESULTS: Of 8647 articles, 20 were included (one RCT, six RCT subgroups, nine claims, and four non-claims). Comparing DOACs to warfarin, pooled HRs (95%CI) were consistently in favor of DOACs although some did not reach statistical significance: for ischemic stroke, 0.84 (0.66-1.07) in claims; 0.90 (0.77-1.06) in non-claims and RCT subgroups; for systemic embolism, 0.77 (0.62-0.96) in claims; 0.86 (0.77-0.96) in non-claims and RCT subgroups; for all-cause mortality, 0.57 (0.33-0.99) in claims; 0.87 (0.79-0.96) in non-claims and RCT subgroups; for ICH, 0.72 (0.39-1.33) in claims; 0.51 (0.38-0.67) in non-claims and RCT subgroups; and for major bleeding, 0.86 (0.71-1.03) in claims; 0.90 (0.76-1.08) for non-claims and RCT subgroups. CONCLUSION: DOACs were associated with better efficacy and safety profiles than warfarin in atrial fibrillation patients with prior stroke, more specifically a lower risk of systemic embolism, all-cause mortality, and ICH.

Efficacy of upper-incisor torque control with clear aligners: a retrospective study using cone-beam computed tomography.

OBJECTIVES: The objectives of this retrospective clinical study were to evaluate the efficacy of clear aligners on upper-incisor torque control, with the expectation of providing guidance for clinics. MATERIALS AND METHODS: Pretreatment (T0) and posttreatment (T1) cone-beam computed tomography (CBCT) scans of 47 patients with a nonextraction treatment using clear aligners were obtained and 120 upper-incisors with torque ≥5° were selected. Voxel-based superimpositions were performed using Dolphin imaging software and achieved movements were then measured. Difference between achieved and predicted movement (DAPM) and the efficiency for upper-incisor torque were used to evaluate the torque control efficacy. RESULTS: The achieved torque movement with clear aligners was lower than predicted significantly, as the mean efficiency was 46.81±33.95%. Additionally, the achieved incisor movement of the crown and root differed significantly from the predicted movement, especially root movement. CONCLUSIONS: Clear aligners struggle to control upper-incisor torque, particularly root movement. In that case, overcorrection is necessary to prevent torque loss. CLINICAL RELEVANCE: Clear aligners remain a limitation on torque control and overcorrection should be considered.

Integrating network pharmacology and experimental validation to decipher the mechanism of the Chinese herbal prescription modified Shen-Yan-Fang-Shuai formula in treating diabetic nephropathy.

CONTEXT: Diabetic nephropathy (DN) is the main cause of end-stage renal disease. Modified Shen-Yan-Fang-Shuai formula (M-SYFSF) has excellent clinical efficacy in treating diabetic kidney disease. However, the potential mechanism of M-SYFSF remains unknown. OBJECTIVE: To investigate the mechanism of M-SYFSF against DN by network pharmacological analysis and biological experiments. MATERIALS AND METHODS: Utilizing a web-based pharmacology database, the potential mechanisms of M-SYFSF against DN were identified. In vivo experiments, male SD rats were injected with streptozotocin (50 mg/kg) and got uninephrectomy to construct a model of DN. M-SYFSF (11.34 g/kg/d) was gavaged once per day for 12 weeks after model establishment. In vitro experiments, human proximal tubular cells (HK-2) were performed with advanced glycation end-products (AGEs) (100 µg/mL), then intervened with M-SYFSF freeze-dried powder. Pathological staining, WB, IHC, ELISA were conducted to explore the mechanism of M-SYFSF against DN. RESULTS: Network pharmacological analysis showed that MAPK pathway was the potential pathway. Results showed that compared with the Model group, M-SYFSF significantly reduced 24h urine albumin, UACR, and serum creatinine levels (54.90 ± 26.67 vs. 111.78 ± 4.28, 8.87 ± 1.69 vs. 53.94 ± 16.01, 11.56 ± 1.70 vs. 118.70 ± 49.57, respectively), and improved renal pathological changes. Furthermore, the intervention of M-SYFSF reduced the expression of pro-inflammatory cytokines and inhibited the activation of MAPK pathway in AGEs-treated HK-2 cells. DISCUSSION AND CONCLUSION: M-SYFSF is likely to reduce inflammation in DN by inhibiting the MAPK pathway. It provides a theoretical basis for the clinical application of M-SYFSF in the treatment of DN.

Structural basis of the TAM domain of BAZ2A in binding to DNA or RNA independent of methylation status.

Bromodomain adjacent to zinc finger domain protein 2A (BAZ2A) (also called transcription termination factor-1 interacting protein 5), a key component of the nucleolar remodeling complex, recruits the nucleolar remodeling complex to ribosomal RNA genes, leading to their transcriptional repression. In addition to its tandem plant homeodomain-bromodomain that is involved in binding to acetylated histone H4, BAZ2A also contains a methyl-CpG-binding domain (MBD)-like Tip5/ARBP/MBD (TAM) domain that shares sequence homology with the MBD. In contrast with the methyl-CpG-binding ability of the canonical MBD, the BAZ2A TAM domain has been shown to bind to promoter-associated RNAs of ribosomal RNA genes and promoter DNAs of other genes independent of DNA methylation. Nevertheless, how the TAM domain binds to RNA/DNA mechanistically remains elusive. Here, we characterized the DNA-/RNA-binding basis of the BAZ2A TAM domain by EMSAs, isothermal titration calorimetry binding assays, mutagenesis analysis, and X-ray crystallography. Our results showed that the TAM domain of BAZ2A selectively binds to dsDNA and dsRNA and that it binds to the backbone of dsDNA in a sequence nonspecific manner, which is distinct from the base-specific binding of the canonical MBD. Thus, our results explain why the TAM domain of BAZ2A does not specifically bind to mCG or TG dsDNA like the canonical MBD and also provide insights for further biological study of BAZ2A acting as a transcription factor in the future.

Patient Acceptability of a Novel Technological Solution (Ambient Intelligent Geriatric Management System) to Prevent Falls in Geriatric and General Medicine Wards: A Mixed-Methods Study.

INTRODUCTION: As effective interventions to prevent inpatient falls are lacking, a novel technological intervention was trialed. The Ambient Intelligent Geriatric Management (AmbIGeM) system used wearable sensors that detected and alerted staff of patient movements requiring supervision. While the system did not reduce falls rate, it is important to evaluate the acceptability, usability, and safety of the AmbIGeM system, from the perspectives of patients and informal carers. METHODS: We conducted a mixed-methods study using semistructured interviews, a pre-survey and post-survey. The AmbIGeM clinical trial was conducted in two geriatric evaluation and management units and a general medical ward, in two Australian hospitals, and a subset of participants were recruited. Within 3 days of being admitted to the study wards and enrolling in the trial, 31 participants completed the pre-survey. Prior to discharge (post-intervention), 30 participants completed the post-survey and 27 participants were interviewed. Interview data were thematically analyzed and survey data were descriptively analyzed. RESULTS: Survey and interview participants had an average age of 83 (SD 9) years, 65% were female, and 41% were admitted with a fall. Participants considered the AmbIGeM system a good idea. Most but not all thought the singlet and sensor component as acceptable and comfortable, with no privacy concerns. Participants felt reassured with extra monitoring, although sometimes misunderstood the purpose of AmbIGeM as detecting patient falls. Participants' acceptability was strongly positive, with median 8+ (0-10 scale) on pre- and post-surveys. DISCUSSION/CONCLUSION: Patients' acceptability is important to optimize outcomes. Overall older patients considered the AmbIGeM system as acceptable, usable, and improving safety. The findings will be important to guide refinement of this and other similar technology developments.

Histone and DNA binding ability studies of the NSD subfamily of PWWP domains.

The NSD proteins, namely NSD1, NSD2 and NSD3, are lysine methyltransferases, which catalyze mono- and di-methylation of histone H3K36. They are multi-domain proteins, including two PWWP domains (PWWP1 and PWWP2) separated by some other domains. These proteins act as potent oncoproteins and are implicated in various cancers. However the biological functions of these PWWP domains are still largely unknown. To better understand the functions of these proteins' PWWP domains, we cloned, expressed and purified all the PWWP domains of these NSD proteins to characterize their interactions with methylated histone peptides and dsDNA by quantitative binding assays and crystallographic analysis. Our studies indicate that all these PWWP domains except NSD1_PWWP1 bind to trimethylated H3K36, H3K79 peptides and dsDNA weakly. Our crystal structures uncover that the NDS3_PWWP2 and NSD2_PWWP1 domains, which hold an extremely long α-helix and α-helix bundle, respectively, need a conformation adjustment to interact with nucleosome.

Crystal structure of chromo barrel domain of RBBP1.

RBBP1 is a retinoblastoma protein (pRb) binding protein acting as a repressor of gene transcription. RBBP1 is a multidomain protein including a chromo barrel domain, and its chromo barrel domain has been reported to recognize histone H4K20me3 weakly, and this binding is enhanced by the simultaneous binding of DNA. However, the molecular basis of this DNA-mediated histone binding by the chromo barrel domain of RBBP1 is unclear. Here we attempted to co-crystallize the chromo barrel domain of RBBP1 with either a histone H4K20me3 peptide alone or with both a histone H4K20me3 peptide and DNA, but only solved the peptide/DNA unbound crystal structure. Our structural analysis indicates that RBBP1 could interact with histone H4K20me3 similar to other histone binding chromo barrel domains, and the surface charge representation analysis of the chromo barrel domain of RBBP1 suggests that the chromo barrel domain of RBBP1 does not have a typical DNA binding surface, indicating that it might not bind to DNA. Consistently, our ITC assays also showed that DNA does not significantly enhance the histone binding ability of the chromo barrel domain of RBBP1.

USP22 is required for human endometrial stromal cell proliferation and decidualization by deubiquitinating FoxM1.

Despite significant advances in assisted reproductive technology (ART), recurrent implantation failure (RIF) still occurs in some patients. Poor endometrial receptivity and abnormal human endometrial stromal cell (HESC) proliferation and decidualization have been identified as the major causes. Ubiquitin-specific protease 22 (USP22) has been reported to participate in the decidualization of endometrial stromal cells in mice. However, the role of USP22 in HESC function and RIF development remains unknown. In this study, clinical endometrial tissue samples were gathered to investigate the involvement of USP22 in RIF, and HESCs were utilized to examine the molecular mechanisms of USP22 and Forkhead box M1 (FoxM1). The findings indicated a high expression of USP22 in the secretory phase of the endometrium. Knockdown of USP22 led to a notable reduction in the proliferation and decidualization of HESCs, along with a decrease in FoxM1 expression, while overexpression of USP22 yielded opposite results. Furthermore, USP22 was found to deubiquitinate FoxM1 in HESCs. Moreover, both USP22 and FoxM1 were downregulated in the endometria of patients with RIF. In conclusion, these results suggest that USP22 may have a significant impact on HESCs proliferation and decidualization through its interaction with FoxM1, potentially contributing to the underlying mechanisms of RIF pathogenesis.

Targeting fusion proteins of the interleukin family: A promising new strategy for the treatment of autoinflammatory diseases.

As a means of communication between immune cells and non-immune cells, Interleukins (ILs) has the main functions of stimulating the proliferation and activation of inflammatory immune cells such as dendritic cells and lymphocytes, promote the development of blood cells and so on. However, dysregulation of ILs expression is a major feature of autoinflammatory diseases. The drugs targeting ILs or IL-like biologics have played an important role in the clinical treatment of autoinflammatory diseases. Nevertheless, the widespread use of IL products may result in significant off-target adverse reactions. Thus, there is a clear need to develop next-generation ILs products in the biomedical field. Fusion proteins are proteins created through the joining of two or more genes that originally coded for separate proteins. Over the last 30 years, there has been increasing interest in the use of fusion protein technology for developing anti-inflammatory drugs. In comparison to single-target drugs, fusion proteins, as multiple targets drugs, have the ability to enhance the cytokine therapeutic index, resulting in improved efficacy over classical drugs. The strategy of preparing ILs or their receptors as fusion proteins is increasingly used in the treatment of autoimmune and chronic inflammation. This review focuses on the efficacy of several fusion protein drugs developed with ILs or their receptors in the treatment of autoinflammatory diseases, in order to illustrate the prospects of this new technology as an anti-inflammatory drug development protocol in the future.

Semi or fully automatic tooth segmentation in CBCT images: a review.

Cone beam computed tomography (CBCT) is widely employed in modern dentistry, and tooth segmentation constitutes an integral part of the digital workflow based on these imaging data. Previous methodologies rely heavily on manual segmentation and are time-consuming and labor-intensive in clinical practice. Recently, with advancements in computer vision technology, scholars have conducted in-depth research, proposing various fast and accurate tooth segmentation methods. In this review, we review 55 articles in this field and discuss the effectiveness, advantages, and disadvantages of each approach. In addition to simple classification and discussion, this review aims to reveal how tooth segmentation methods can be improved by the application and refinement of existing image segmentation algorithms to solve problems such as irregular morphology and fuzzy boundaries of teeth. It is assumed that with the optimization of these methods, manual operation will be reduced, and greater accuracy and robustness in tooth segmentation will be achieved. Finally, we highlight the challenges that still exist in this field and provide prospects for future directions.

The efficacy and safety of molidustat for anemia in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients: A systematic review and meta-analysis.

Objective: Molidustat is a novel agent investigated for the treatment of anemia in both dialysisdependent (DD) and non-dialysis-dependent (NDD) patients. Its efficacy and safety are still unclear. Methods: We searched five databases to identify randomized controlled trials comparing molidustat to erythropoiesis-stimulating agents (ESAs) or placebo in patients with anemia. Results: Six studies containing 2025 eligible participants were identified. For NDD patients, the change in Hb levels from baseline (ΔHb) was significantly higher for molidustat than for placebo [mean difference (MD) = 1.47 (95 % CI: 1.18 to 1.75), P < 0.00001] and ΔHb was also significantly higher for molidustat than for ESAs [MD = 0.25 (95 % CI 0.09 to 0.40), P = 0.002]. For NDD patients, Δhepcidin was significantly lower for molidustat than for placebo [MD = -20.66 (95 % CI: -31.67 to -9.66), P = 0.0002] and Δhepcidin was also significantly lower for molidustat than for ESAs [MD = -24.51 (95 % CI: -29.12 to -19.90), P < 0.00001]. For NDD patients, Δiron was significantly lower for molidustat than for ESAs [MD = -11.85 (95 % CI: -15.52 to -8.18), P < 0.00001], and ΔTSAT was also significantly lower for molidustat than for ESAs [MD = -5.29 (95 % CI: -6.81 to -3.78), P < 0.00001]. For NDD patients, Δferritin was significantly lower for molidustat than for placebo [MD = -90.01 (95 % CI: -134.77 to -45.25), P < 0.00001]. However, for DD-CKD patients, molidustat showed an effect similar to that of ESAs on increasing the Hb level [MD = -0.18 (95 % CI: -0.47 to 0.11), P = 0.23], Δiron level [MD = 3.78 (95 % CI: -7.21 to 14.76), P = 0.5], Δferritin level [MD = 25.03 (95 % CI: -34.69 to 84.75), P = 0.41], and Δhepcidin level [MD = 1.20 (95 % CI: -4.36 to 6.76), P = 0.67]. For DD-CKD patients, compared with the placebo or ESA group, molidustat showed a significantly higher level on ΔTSAT[MD = 3.88 (95 % CI: 2.10 to 5.65), P < 0.0001] and a slightly increased level on ΔTIBC level [MD = 1.08 (95 % CI: -0.07 to 2.23), P = 0.07]. There was no significant difference in the incidence of severe adverse events (SAEs), death, and cardio-related adverse events between molidustat and the ESAs groups. Conclusions: Moricizine can effectively improves Hb levels in NDD patients and corrects anemia in DD patients without increasing adverse event incidence.