Lipid droplets (LDs) are dynamic cytoplasmic lipid-storing organelles that play a pivotal role in maintaining cellular energy balance, lipid homeostasis, and metabolic signaling. Dysregulation of lipid metabolism, particularly excessive lipogenesis, contributes to the abnormal accumulation of LDs in the nervous system, which is associated with several neurodegenerative diseases. Circular RNAs (circRNAs) are a new class of non-coding and regulatory RNAs that are widely expressed in eukaryotes. However, only a subset has been functionally characterized. Here, we identified and functionally characterized a new circular RNA circbabo(5,6,7,8S) that regulates lipogenesis and neuronal integrity in Drosophila melanogaster.

The peripheral nervous system significantly determines the fate of solid tumors and their microenvironment. In neurotropic malignancies such as pancreatic and prostate cancer, denervation in animal models demonstrate significantly delays in tumor initiation and progression, underscoring the critical neural dependency of these cancers. While tumor innervation establishes a structural basis for the neuromodulatory effects, the degree of innervation exhibits marked heterogeneity across tumor types, and its regulatory mechanisms remain poorly characterized. In this study, we screened genes associated with innervation status in pancreatic cancer and identified the splicing factor SRSF12 as a critical gene related to tumor innervation. In clinical samples, SRSF12 was expressed at low levels in pancreatic cancer tissues, and its downregulation was linked to poor prognosis in patients. Then we crossed Kras mutation and Srsf12 knockout mice (KrasG12DSrsf12 fl/fl) together with Srsf12 fl/flPdx1cre mice and found that depletion of Srsf12 accelerated Kras-driven pancreatic tumorigenesis and enhanced tumor innervation. Furthermore, we demonstrated that SRSF12 inhibits neurite outgrowth primarily by generating a LAMA3 splice isoform that lacks the fourth and fifth LG (G45) domains. Mechanistically, G45 promotes tumor innervation by activating ITGB1 and FAK in neurons. Together, our findings delineate SRSF12 as a novel suppressor of tumor innervation and pancreatic tumorigenesis, while also identifying a tumor-specific target for SRSF12-deficient pancreatic cancer.

Our previous study revealed that mesenchymal stem cells (MSCs) can secrete large amounts of the chemokine CCL2 under inflammatory conditions and alleviate idiopathic pneumonia syndrome (IPS) by promoting regulatory CCR2 + CD4 + T-cell formation through the CCL2‒CCR2 axis. Given the abundance of macrophages in lung tissue, how these macrophages are regulated by MSC-based prophylaxis via IPS and their interactions with T cells in lung tissue during allo-HSCT are still not fully understood.

The mechanisms driving the progression of moyamoya disease (MMD) remain unrecognized. There is evidence suggesting that genetic and environmental factors may be associated with intracranial artery stenosis. Here, we aimed to investigate the characteristics of infectious exposure and the association of the RNF213 (RING finger protein 213) variant and infectious burden (IB) with intracranial artery stenosis of MMD.

Asialoglycoprotein receptor 1 (ASGR1) deficiency has been implicated in enhancing liver insulin sensitivity and reducing systemic insulin resistance, thus highlighting its pivotal role in glucose metabolism. However, the association between serum soluble asialoglycoprotein receptor 1 (sASGR1) and type 2 diabetes mellitus (T2DM) remains elusive. Therefore, we conducted a study to delve into this association.

Alzheimer's disease (AD) is a complex neurodegenerative disorder with multifaceted pathogenesis, which has been extensively investigated, yet effective treatments remain lacking. Splicing factor proline and glutamine rich (SFPQ) is known to play a crucial role in neurodegenerative diseases, including antioxidant-related functions and regulating gene expression within brain neurons. However, the specific role of SFPQ in AD pathology is not well understood. In this study, an AD mouse model was established through lateral ventricular injection of amyloid-beta1-42 (Aβ 1-42). Subsequently, adeno-associated virus was administered to overexpress SFPQ in the hippocampus of AD mice. The results demonstrate that SFPQ overexpression improves recognition and memory in AD mice, while reducing AD-related marker proteins such as amyloid precursor protein (APP) and Tau. Additionally, synaptic and memory-associated proteins, as well as antioxidant proteins like glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), were upregulated. The ratio of antiapoptotic protein Bcl-2 to proapoptotic protein Bax also increased. Furthermore, phosphorylated phosphoinositide 3-kinase (p-PI3K)/PI3K and phosphorylated protein kinase B (p-AKT)/AKT ratios were elevated, indicating activation of the PI3K/AKT signaling pathway. These findings suggest that SFPQ may serve as a promising molecular target for the prevention and treatment of AD.

Glioblastoma (GBM) is a primary brain tumor known for its high levels of aggressiveness and resistance to current treatments such as radiotherapy and chemotherapy. As a result, there is a pressing need for innovative therapeutic approaches to combat GBM. Thus, we have developed an engineered multifunctional extracellular vesicle (EV) delivery system that offers an "all-in-one" strategy for GBM therapy. Our approach involved the use of genetic engineering to the long-lasting production of PD-1 and the brain-specific peptide angiopep-2 on the surface of EVs. These modified EVs were then utilized to rejuvenate exhausted CD8+ T cells blocking PD-L1, resulting in significant therapeutic benefits for GBM treatment. Furthermore, the EVs contained Cas9 protein and sgRNA for precise and minimally invasive gene therapy, which addressing the key barriers associated with in vivo CRISPR‒Cas9 gene editing treatment. The multigene editing of EVs resulted in efficient intratumor multisite gene editing (PLK1: 58.6%, VEGF: 52.7%), leading to the successful apoptosis of tumor cells in vivo and demonstrating an antiangiogenic effect. This research introduces a promising universal platform for combining immune checkpoint blockade therapy with gene editing treatment.

Denervated muscle atrophy, a common outcome of nerve injury, often results in irreversible fibrosis due to the limited effectiveness of current therapeutic interventions. While extracellular vesicles (EVs) offer promise for treating muscle atrophy, their therapeutic potential is hindered by challenges in delivery and bioactivity within the complex microenvironment of the injury site. To address this issue, an injectable hydrogel is developed that is responsive to both ultrasound and pH, with inherent anti-inflammatory and antioxidant properties, designed to improve the targeted delivery of stem cell-derived EVs. This hydrogel system allows for controlled release of EVs from human umbilical cord mesenchymal stem cells (HUC-MSCs), adapting to the specific conditions of the injury environment. In vivo studies using a rat model of nerve injury demonstrated that the EV-loaded hydrogel (EVs@UR-gel) significantly preserved muscle function. Six weeks post-nerve reconstruction, treated rats exhibited muscle strength, circumference, and wet weight reaching 89.53 ± 0.96%, 76.02 ± 7.49%, and 88.0 ± 2.65% of healthy controls, respectively, alongside an improvement in the sciatic nerve index (-0.11 ± 0.09). This platform presents a novel therapeutic approach by maintaining EV bioactivity, enabling tunable release based on the disease state, and facilitating the restoration of muscle structure and function.

DEAD-box ATPase 10 (DDX10), a prominent RNA-binding protein in the DDX family, has a critical function in cancer progression. Nevertheless, its well-defined mechanisms in oral squamous cell carcinoma (OSCC) are still not well understood. Here, we identify that DDX10 is substantially increased in OSCC, which is positively correlated with poor prognosis and malignant behavior. Mechanistically, we found that DDX10 had physical interaction with Rab27b by undergoing phase separation. Knockdown of DDX10 inhibited Rab27b-mediated exosome secretion and the expression of programmed cell death-ligand 1 (PD-L1) within its contents. Furthermore, knocking down DDX10 could restore the function and infiltration of T cells, hence inhibiting the progression of OSCC. These findings highlight that the oncogenic role of DDX10 in promoting exosomal PD-L1 secretion via phase separation with Rab27b has been preliminarily validated in T cell exhaustion in OSCC. A potential strategy for improving OSCC immunotherapy may involve the inhibition of DDX10.

As an important regulatory protein phosphatase in the abscisic acid (ABA) signal transduction pathway and mitogen-activated protein kinases (MAPK) cascade, type-2C protein phosphatase (PP2C) plays crucial roles in plant responses to abiotic stresses. However, the PP2C gene family's responses to abiotic stress in litchi (Litchi chinensis Sonn.) have not been systematically studied. In this study, we predicted the 68 PP2C (designated LcPP2C) genes randomly distributed across fourteen chromosomes in the litchi genome. Phylogenetic tree analysis among litchi, Arabidopsis (Arabidopsis thaliana), and rice (Oryza sativa) revealed that the phylogenetic tree was divided into thirteen groups (A, B, C, D, E, F1, F2, G, H, I, J, K, and L). Closely linked LcPP2C genes within the same group exhibited various similarities in gene structures and motif compositions. Collinearity analysis demonstrated that segmental duplication (SD) events were the main dramatically increasing numbers in the LcPP2C gene family members. Cis-acting element analysis revealed that the 68 LcPP2C genes contained hormone and stress response elements with varying quantities, implying their potential in litchi stress resistance. Expression analysis showed that all the LcPP2C genes exhibited varying expression levels across nine different litchi tissues, more than 50% of genes within each group displayed similar tissue-specific expression patterns. The expression intensity, duration and regulation direction (up- or down-regulation) of the LcPP2C genes were varied under different abiotic stresses (cold, heat, and drought). The physiological and biochemical tests indicated that eight activation indexes (peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), proline (PRO), soluble protein (SP), hydrogen peroxide (H2O2), and soluble sugar (SS)) increase at different level. Additionally, we analyzed physicochemical properties, subcellular locations, and secondary structures of the LcPP2C family members. Notably, the extensive connectivity of LcPP2C32/60/9/37 underscored their vital roles in orchestrating and regulating biomolecular networks. These results provide valuable information for the identification of the LcPP2C genes and ideas for the cultivation of its transgenic induction lines in litchi.

Brucella is a successful pathogen that employs a plethora of immune evasion mechanisms. This contributes to pathogenesis and persistence and limits the efficacy of available treatments. An increasing understanding of host‒pathogen interactions suggests that integrating host-directed strategies with existing anti-Brucella treatments could lead to more effective bacterial clearance and a reduction in drug-resistant strains. SIRT2 is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase found in mammals. It can deacetylate various transcription factors and regulatory proteins, playing crucial roles in host‒pathogen interactions and pathogen infection-induced apoptosis. In this study, we investigated the role of SIRT2 in Brucella-induced cell apoptosis using bovine placental trophoblast cells. Our results indicate that B. abortus A19 infection upregulates SIRT2 protein expression and significantly induces mitochondrial apoptosis in these cells. Furthermore, inhibition of SIRT2 exacerbates B. abortus A19-induced mitochondrial apoptosis and markedly inhibits intracellular bacterial survival. These results prove the role of SIRT2 in Brucella pathogenesis and the mechanism of action.

The family Anaplasmataceae, reclassified under the order Rickettsiales, represents a highly complex group that poses an increasing global threat. However, their infection risk remains poorly understood. We aimed to map the diversity, distribution, and potential infection risk of Anaplasmataceae members.

Inflammation is a principal cause of sensorineural hearing loss resulting from cochlear injury. However, current research investigating the mechanisms of sensorineural inflammatory injury remains inadequate.

Enterotoxigenic Escherichia coli (ETEC) is one of the primary pathogens causing diarrhea in piglets, causing significant economic losses in the swine farming industry. Due to the numerous serotypes of ETEC, traditional vaccines fail to provide sufficient cross-protection, and subunit vaccines based on epitope design have emerged as a safer and more effective approach for prevention and control. Unlike vaccine development strategies that involve the tandem arrangement of multiple antigenic epitopes, this study used the K88-FaeG protein as a backbone and incorporated the antigenic epitopes of K99-FanC to achieve a better immunogenicity. By using bioinformatics software to predict B-cell linear epitopes (score of over 0.6), B-cell epitopes from three-dimensional structures (50% amino acid score of ≥0.2), and B-cell epitope IgG antibody subtypes, as well as docking analysis with Sus scrofa aminopeptidase N (APN) receptors, six antigenic epitopes of K99-FanC were selected. Through Western blotting and competitive ELISA, we confirmed that all six recombinant proteins exhibited binding capabilities to K88- and K99-positive serum. The ELISA results showed that the serum levels of specific IgG and IgA antibodies increased after immunization, with FaeG-Ep3 and FaeG-Ep5 inducing the highest antibody titers against FanC-IgG (Log2 = 14.96) and FaeG-IgG (Log2 = 17.96), respectively. Bacterial adhesion assays revealed that only FaeG-Ep3 effectively blocked the adhesion of both K99 and K88 to IPEC-J2 cells. Immunization challenge experiments showed that, in the unimmunized group, mice infected with K88 and K99 experienced weight loss (p < 0.05) with intestinal villus shedding and intestinal wall structural damage. However, in the FaeG-Ep3-immunized group, no significant weight loss occurred after infection, and the villus protection rate (83%) was the same as that in the FaeG and FanC immunized groups. Overall, the FaeG-Ep3 recombinant protein identified in this study shows potential vaccine application value and provides new insights for developing multivalent vaccines against ETEC.

Dental caries is a global oral dilemma leading to demineralization of tooth hard tissues and exposure of dentinal tubules (DTs). Multifunctional restorative strategies, including remineralization, antibacterial properties, and DT occlusion, are urgently needed for dental caries management but remain a significant challenge. Herein, the polyaspartic acid-calcium-lanthanum suspension (5 g L-1-3.06 м-0.34 м) followed by phosphate solution (2.04 м) is adopted to conduct polyelectrolyte-cation complexes pre-precursor process. This strategy, for the first time, successfully induces La-doped intrafibrillar mineralization of collagen fibrils with lanthanum-doped hydroxyapatite (La-HAp). After sequential application of two mineralization media, the demineralized dentin is fully remineralized and the DTs are deeply occluded to a depth of 100 µm with La-HAp after 7 d of incubation in artificial saliva or oral cavity of rabbit. The remineralized dentin demonstrates antibacterial properties against cariogenic bacteria (Streptococcus mutans) both in vitro and in vivo, and its mechanical properties are almost restored to those of intact dentin. The mineralization media cause no apparent irritation to oral mucosa or dental pulp. Hence, this multifunctional strategy confers the remineralized dentin surface with antibacterial properties and blocks the invasion of cariogenic bacteria through DTs, providing insight into the clinical management of dentin caries accompanied by dentin hypersensitivity.

This study analyzes the expression and functional role of activating transcription factor 6 (ATF6) in diffuse large B-cell lymphoma (DLBCL) and its effects on disease progression. ATF6, a core component of the unfolded protein response (UPR) pathway, participates in many cellular activities and notably contributes to tumorigenesis. Through a combination of techniques, including immunohistochemistry (IHC) staining to assess ATF6 and pS6K levels, siRNA-mediated ATF6 knockdown, cytotoxicity assays, flow cytometry, quantitative real-time PCR (qRT-PCR), as well as Western blotting, this study clarified the functioning mechanisms of ATF6 in DLBCL and its potential clinical relevance. Further exploration of ATF6's involvement in the mTORC1 pathway was achieved through RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA). Our findings demonstrate that ATF6 expression is upregulated in DLBCL and linked to poor prognosis, particularly in people aged over 60 with Ann Arbor stage III-IV disease, B symptoms, non-GCB subtype, an international prognostic index (IPI) score greater than 2, and extranodal involvement. Notably, the ATF6 inhibitor ceapinA7 was shown to suppress ATF6 and mTORC1 activation, leading to less cell proliferation and the induction of apoptosis in DLBCL cells. Additionally, ceapinA7 increased the sensitivity of DLBCL cells to adriamycin. The foregoing results underscore the critical role of ATF6 in DLBCL and lay a theoretical and experimental foundation for future targeted therapies and drug development aimed at improving treatment outcomes for DLBCL.

Large granular lymphocytic leukemia (LGLL) is characterized by the clonal proliferation of cytotoxic T lymphocytes or NK cells. Standard first-line immunosuppressive treatments have limitations, achieving complete remission (CR) rates of up to 50%. Immune system dysregulation is implicated in LGLL. Promising results for thalidomide, an immunomodulatory drug, combined with prednisone and methotrexate (TPM), were observed in our pilot study. This multicenter study evaluated the efficacy and safety of a thalidomide, prednisone, and methotrexate (TPM) regimen in 52 symptomatic, methotrexate- and thalidomide-naive LGLL patients from June 2020 to August 2022. Thalidomide (100 mg daily for up to 24 months), prednisone (0.5-1.0 mg/kg every other day, tapered after 3 months), and methotrexate (10 mg/m2 weekly for up to 12 months) were administered. The primary objective was to determine the CR rate. The median follow-up duration was 29.0 months (range: 4.0-42.0). Forty-seven patients (90.4%) achieved hematological and symptomatic responses. Thirty-nine patients (75.0%) achieved CR. The median time to response was 3.0 months (range: 3.0-9.0). The median progression-free survival was 40.0 months (95% confidence interval (CI): 38.0-42.0), and the median duration of response was 39.0 months (95% CI: 36.1-41.9). The most common adverse event was peripheral neuropathy (24.1%), most of which (84.6%) were grades 1-2. Four patients experienced grade ≥3 adverse events. In conclusion, the TPM regimen was an effective and safe treatment for symptomatic LGLL patients, with a particularly high CR rate. This trial was registered at www.clinicaltrials.gov (#NCT04453345).

Robotic-assisted dental implantation represents a transformative innovation in modern dentistry, offering enhanced surgical precision and reduced variability. Despite its clinical adoption, the impact of anatomical and bone-related factors on placement accuracy remains underexplored. This retrospective study evaluated 54 implants placed in 30 patients using cone-beam computed tomography (CBCT) and virtual planning software to analyze deviations in crown position, apex position, and angulation. Significant regional variations in accuracy were observed, with higher angular deviations in the anterior maxilla (mean ± SD: 3.21° ± 2.22°) and greater positional deviations in the posterior mandible (1.09 mm ± 0.51 mm) (p < 0.05). Implant diameter significantly influenced global deviation (p = 0.019), while implant length and bone density (classified by Misch's system) showed no significant effects (p > 0.05). However, denser bone types (D1) exhibited a trend toward increased deviations, potentially due to insertion resistance. These findings underscore the need for region-specific and bone-quality considerations in robotic-assisted implantation. Refining robotic navigation and feedback mechanisms is critical to optimizing accuracy, particularly in anatomically complex regions.

Tendon injuries are often exacerbated by persistent inflammation, which hampers tissue regeneration. In this study, we developed a noninvasive, wirelessly controlled, and self-powered piezoelectric nanofilm fabricated by coaxial electrospinning of polycaprolactone (PCL) and tetragonal barium titanate nanoparticles (BTO), and investigated its roles in modulating inflammation and repairing Achilles tendon defects as well as the mechanism in a rat model. In vitro study and in vivo study upon subcutaneous implantation showed that the piezoelectric PCL/BTO nanofilms could inhibit M1 macrophage polarization and reduce the secretion of inflammatory factors. Moreover, when bridging an Achilles tendon defect, the nanofilms could promote tenogenic gene expression including collagen deposition, and collagen remodeling, facilitate functional tendon recovery and significantly reduce tissue inflammation by suppressing M1 macrophage polarization and promoting M2 polarization. Moreover, the piezoelectric stimulation could also enhance tendon regeneration by inhibiting angiogenesis, reducing lipid deposition, and decreasing ectopic ossification. Mechanistically, the piezoelectric nanofilms reduced tissue inflammation mainly via inhibiting the nuclear factor (NF)-κB signaling pathway that is mediated by interleukin (IL)-17A secreted from CD3+ T cells, and thus to reduce proinflammatory factors, such as IL-1β and IL-6, inducible nitric oxide synthase, monocyte chemoattractant protein-1, and tumor necrosis factor-α. These findings indicate the potential of piezoelectric stimulation in immunomodulation, and in promoting tendon regeneration via IL-17A/NF-κB-mediated pathway.

In breast cancer patients treated with pencil-beam scanning proton therapy (PBS), the increased linear energy transfer (LET) near the end of the proton range can affect nearby ribs. This may associate with a higher risk of rib fractures.