Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, highly aggressive hematologic malignancy characterized by frequent cutaneous involvement, rapid systemic dissemination, and poor clinical outcomes. Although initially misclassified due to overlapping morphologic and immunophenotypic features with other acute leukemias, lymphomas, and NK-cell neoplasms, BPDCN is now recognized as a distinct hematologic malignancy. Advances in immunophenotyping, transcriptional profiling, and genomic analysis have clarified the cellular origin of BPDCN and revealed that the disease commonly arises from hematopoietic stem or progenitor cells harboring clonal hematopoiesis (CH)-associated mutations. Subsequent transcriptionally regulated lineage commitment to the pDC program and acquisition of cooperating genetic and epigenetic lesions drive malignant transformation. Recurrent alterations affecting epigenetic regulators, RNA splicing factors, transcriptional networks, and chromatin organization disrupt interferon signaling, promote immune evasion, and stabilize malignant identity. A defining clinical and biological feature of BPDCN is its marked skin tropism, mediated by aberrant expression of adhesion molecules and chemokine receptors and shaped by ultraviolet light-associated mutational selection within the cutaneous microenvironment. This review integrates the current knowledge of BPDCN ontogeny, morphologic and immunophenotypic features, genetic and epigenetic architecture, immune dysregulation, and mechanisms of skin tropism into a proposed unified model of leukemogenesis with implications for diagnosis, prognostication, and biology-driven therapeutic strategies.

The clustered regularly interspaced short palindromic repeats CRISPR-associated protein 9 (CRISPR/Cas9) system has emerged as a versatile platform for genome editing, transcriptional regulation, and chromosomal imaging. Recent advances in synthetic biology have enabled the engineering of single guide RNA (sgRNA) to confer conditional responsiveness on the CRISPR/Cas9 system. By integrating functional nucleic acid elements, such as aptamers, ribozymes, and aptazymes, into specific structural regions of the sgRNA, researchers have developed systems that respond to a variety of molecular signals, including small molecules, proteins, and endogenous metabolites. These engineered sgRNAs enable spatiotemporal control of gene editing, activation, repression, and imaging in both prokaryotic and eukaryotic cells. This review summarizes the structural principles, design strategies, and applications of condition-responsive CRISPR/Cas9 systems, highlighting their potential in synthetic biology, disease modeling, and therapeutic development. Current challenges and future directions for improving the specificity, efficiency, and applicability of these systems are also discussed.

Monkeypox (Mpox), a zoonotic disease caused by the mpox virus, has been endemic mainly in West and Central Africa for a long time, with only a few cases in other parts of the world. However, recent multi-country outbreaks in non-endemic areas have escalated Mpox into a significant global public health concern. The rapid transmission highlights the urgent need for robust strategies governing diagnosis, treatment, and prevention. In this review, we synthesized advanced approaches addressing the Mpox challenge, focusing on the application of emerging technologies. We examined the integration of nanotechnology, nucleic acid amplification techniques (NAATs), gene editing technology and sequencing technology in Mpox prevention and control. These platforms offered promising solutions to critical limitations in current Mpox control, including high detection costs, poor drug specificity, and suboptimal vaccine efficacy. Finally, we outlined the outlook and potential development trajectories for sustained Mpox prevention and control.

MFSD6 is a newly identified receptor that mediates the invasion of respiratory cells by enterovirus D68 (EV-D68), a non-polio enterovirus that causes severe respiratory disease and poliomyelitis-like illness in children. Here, we report near-atomic-resolution cryo-electron microscopy (cryo-EM) structures of historical and contemporary AFM-associated EV-D68 strains, together with their complexes bound to the third extracellular loop of MFSD6 (MFSD6-L3). These structures uncover a previously unrecognized "binary gating switch" mechanism of virus-receptor engagement that differs from the reported model. In this mechanism, the N200-V208 segment of MFSD6, carrying a glycosylated Asn207, inserts into one capsomer, whereas the sialyl-Gal-terminated glycan of MFSD6 engages an adjacent capsomer. Neu5Ac binding induces conformational rearrangements that expel the pocket factor, destabilize the virion, and prime infection. Functional analyses further define the contributions of the receptor-contacting residues and glycans to viral attachment and entry. Together, our findings refine the molecular basis of EV-D68 recognition of MFSD6 and reveal a glycan-mediated dual-lock mechanism that may enhance receptor specificity, prevent premature uncoating, and ensure productive infection only upon engagement of the correct host receptor. These results provide broader insight into enterovirus tropism and establish a framework for structure-guided antiviral design.

Background: Pelvic inflammatory disease (PID) is a polymicrobial infection of the upper female genital tract affecting women globally. The study aimed to assess the global prevalence and years lived with disability (YLDs) of PID from 1990 to 2021 and analyze influencing factors. Methods: The 2021 Global Burden of Disease (GBD) dataset provided data on the PID statistics of women of childbearing age (15-49 years), including case counts and age-standardized rates (ASRs). Trends were assessed using estimated annual percentage changes (EAPCs), while the relation of regions, nations and Socio-demographic Index (SDI) was examined using local weighted regression (Lowess). To predict the burden, the Bayesian age-period-cohort (BAPC) model was devised. Results: The GBD data show PID burden negatively correlated with SDI: the age-standardized prevalence rate (ASPR) and the agestandardized years lived with disability rate (ASYR) were higher in low-SDI regions (eg, sub-Saharan Africa) and lower in high-SDI regions (eg, Western Europe). In 2021, rates were 27.02 and 3.68 per 100,000, respectively. Country disparities are marked (Guinea-Bissau highest). Burden peaks at ages 30-39. Projections show persistent increases in both rates across childbearing ages through 2050. Conclusion: Through severity-stratified estimations, detailed cause-specific burden analysis, and BAPC projection modeling, this study provides a comprehensive and detailed description of the global burden and epidemiological trends of PID. Despite overall progress, persistent disparities remain notably the disproportionately high burden in low-SDI regions such as sub-Saharan Africa and Eastern Europe. These projections underscore an urgent need for context-specific prevention strategies, including strengthened STI screening and treatment, improved antibiotic access, and community-based sexual health education tailored to local health system capacity.

BACKGROUND:Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative treatment for pediatric patients with SAA. The chimeric anti-CD20 monoclonal antibody rituximab (RTX) is the most widely used agent to deplete circulating B cells for preventing the complication of donor-specific human leukocyte antigen antibodies and treating Epstein-Barr virus (EBV) reactivation in patients who undergo allo-HSCT. However, RTX efficacy and safety in allo-HSCT recipients with SAA remain unclear in pediatric patients. METHODS:This study included 105 pediatric patients with SAA who underwent allo-HSCT at Wuhan Children's Hospital. The patients' basic characteristics, stem cell transplantation, survival, GVHD occurrence, CMV and EBV reactivation and amounts of lymphocytes was compared in the patients with RTX (RTX+) and without RTX (RTX-) treatment. RESULTS:Compared with the RTX-, the RTX+ showed a significantly higher incidence of GVHD (16.6% vs 4%; P = 0.02). The RTX+ was associated with a markedly higher rate of CMV reactivation (76.7% vs 38.7%; P < 0.001) and lower rate of EBV reactivation (60.0% vs 89.3%; P < 0.001). Among 1 month after HSCT, the RTX+ exhibited lower T-cell (P = 0.04), B-cell (P < 0.001), and NK-cell (P = 0.01) counts, which exhibit no significant difference in the long-term period. CONCLUSION:The pre-treatment of RTX exhibits beneficial effects on the overall and long-term response, indicated by 100% successful implantation, lower risk of EBV reactivation, and little influence on lymphocyte regeneration. More emphasis should be placed on preventing CMV reactivation among RTX-treated pediatric SAA patients undergoing allo-HSCT.

BACKGROUND:Endometriosis is a debilitating gynaecological disorder with an elusive pathogenesis. While gut microbiota dysbiosis has been implicated, the causal role of gut-peritoneum microbial translocation and the specific mechanisms driving disease progression remain elusive. Notably, the role of peritoneal neutrophils and neutrophil extracellular traps (NETs) in the development of endometriosis remains unknown. OBJECTIVE:This study aims to delineate the pathogenic pathway linking gut microbiota to peritoneal neutrophil activation and the development of endometriosis. DESIGN:We combined single-cell RNA sequencing of clinical peritoneal fluid immune cells with functional validation in heterologous and homologous mice models. We further adopted microbial source-tracking analysis of patient cohorts and interventional strategies, including faecal microbiota transplantation (FMT) and administration of green fluorescent protein (GFP)-tagged Pseudomonas aeruginosa. RESULTS:We identified a unique membrane metalloendopeptidase (MME) positive neutrophil subset (Neu_MME) that is expanded in endometriosis and primed for NETs formation (NETosis). These Neu_MME released NETs in response to bacterial lipopolysaccharides (LPS), which directly captured endometrial cells and enhanced their proliferation and migration, driving lesion development. Accordingly, inhibiting NETosis or degrading NETs significantly suppressed endometriosis in mice. Furthermore, FMT from patients with endometriosis to mice disrupted the intestinal barrier, promoting the translocation of gut microbiota, particularly Pseudomonas, into the peritoneal cavity and the lesions. This translocated Pseudomonas was identified as a key driver of LPS-induced NETosis and disease progression. CONCLUSION:Our findings define a gut-peritoneum axis in endometriosis, where gut-derived Pseudomonas triggers NETosis in peritoneal Neu_MME to promote disease, suggesting that targeting this bacterium or NETosis represents a viable therapeutic strategy.

BACKGROUND:Prostate-specific membrane antigen (PSMA) represents an ideal therapeutic target for prostate cancer. However, the clinical efficacy of PSMA-targeted chimeric antigen receptor T (CAR-T) cell therapy remains unsatisfactory. Strategies to enhance anti-tumor activity-such as optimizing CAR antigen-binding design-are critical for maximizing the clinical benefits of this treatment. METHODS:We constructed CARs targeting membrane-proximal (MP) and membrane-distal (MD) epitopes of PSMA to evaluate how epitope location influences CAR-T cell anti-tumor function. We systematically evaluated the antitumor efficacy of MP CAR-T and MD CAR-T cells both in vitro and in xenograft mouse models in vivo. Furthermore, by integrating transcriptomic and proteomic datasets, we postulated the underlying antitumor mechanism of MP CAR-T cells. RESULTS:Despite comparable antigen affinity and phenotypic profiles, MP CAR-T cells demonstrated superior in vitro cytotoxicity and inflammatory cytokine secretion. In vivo, MP CAR-T cells exhibited significantly stronger control of tumor growth and prolonged survival in both solid tumor and bone metastasis models. Transcriptomic and proteomic analysis revealed that MP CAR-T cells had enhanced activation of immune synapse-related pathways and a unique upregulation of the STING-mediated interferon signaling pathway. CONCLUSION:Targeting the proximal membrane protease domain of PSMA generates functionally superior CAR-T cells. The enhanced efficacy is associated with more robust immunological synapse formation and the concomitant activation of the STING innate immune pathway, offering a novel mechanistic insight for optimizing CAR-T cell design.

NUP98 rearrangements (NUP98r) are often cryptic and define a high-risk subgroup of pediatric myeloid neoplasms, predominantly acute myeloid leukemia (AML). Despite their clinical significance, the immunophenotypic signatures that enable early recognition of NUP98r remain incompletely characterized. We retrospectively studied 62 pediatric and young adult patients (aged ≤21 years at diagnosis) with NUP98-rearranged myeloid neoplasms diagnosed from 1994 to 2025. We integrated flow cytometry, morphology, cytogenetics, and molecular data and grouped cases based on fusion partner-NUP98::NSD1 (n = 35), NUP98::KDM5A (n = 12), and other NUP98 fusions (NUP98::X; n = 15)-and flow-defined differentiation patterns. NUP98::NSD1 accounted for 56% of cases and was found in older children, with a median age at diagnosis of 13.2 years. These cases displayed an immature myeloid phenotype, with frequent expression of CD34 (33/35; 94%), CD117 (31/35; 89%), HLA-DR (34/34; 100%), and uniform CD123 positivity in all evaluable cases (22/22; 100%), along with FLT3-ITD and WT1 alterations (22/34 each; 65%) and mostly diploid karyotypes (61%). NUP98::KDM5A occurred in younger children (median age at diagnosis, 1.9 years) and was associated with erythroid/megakaryocytic differentiation, including CD41/CD61 positivity in 8 of 10 (80%) and glycophorin A positivity in 3 of 9 (33%) evaluable cases. Chromosome 13 abnormalities and RB1 alterations were identified in 60% and 55% of evaluable cases, respectively, and complex karyotypes were present in 63% of cases. Other NUP98 fusions (NUP98::X; n = 15, 24%) showed diverse phenotypes and were enriched for 11p abnormalities (79% of evaluable NUP98::X cases). Most 11p abnormalities were evident on conventional cytogenetics when karyotype data were available, in contrast to NUP98::NSD1 and NUP98::KDM5A cases, which were often cytogenetically cryptic. In summary, the NUP98 fusion partner was associated with recurring, diagnostically useful immunophenotypic, cytogenetic, and molecular patterns. These patterns can facilitate prioritization of RNA-based fusion testing, anticipate partner-specific differentials, and design flow cytometry follow-up strategies.

Monkeypox virus (MPXV) is transmitted through respiratory mucosa and close contact, including sexual transmission, especially among men who have sex with men (MSM). Using bioengineering, we constructed an inhaled bacterial outer membrane vesicles (OMVs) vaccine, ABM@OMV, to block MPXV transmission. This nanovaccine consists of OMVs from ΔlpxM EcN strain that co-expressing three MPXV antigens (A9R, B6R and M1R). Our results show that OMVs vector enhances antigen uptake, mediates endosomal escape, and promotes APC maturation. Due to the adjuvant activity of OMVs and the synergistic effects of multi-antigen, ABM@OMV elicits robust systemic and mucosal immunity in both respiratory and vaginal, following intranasal immunization. This is demonstrated by the induction of three high-titer antigen-specific IgG and significant levels of SIgA. Moreover, ABM@OMV with A9R elicited stronger CD4+ and CD8+ T cell responses. The vaccine conferred complete protection against lethal vaccinia virus (VACV, replacing MPXV) challenge, and 100% survival. ABM@OMV is simple to produce, scalable, and easily standardized, offering a novel strategy for needle-free mucosal vaccines against emerging infectious diseases.

The chimeric antigen receptor (CAR)-T cell therapy has shown promise for the treatment of hematological and solid tumors. Although CAR-T cells targeting PSMA showed robust antitumor efficacy for prostate cancer in preclinical studies, the clinical benefits of PSMA CAR-T cells are unsatisfactory. To maximize the efficacy of this immunotherapy, we combined zoledronic acid (ZOL), a first-line prophylactic drug against skeletal-related events (SREs) and for bone pain management in patients with advanced prostate cancer, with PSMA CAR-T cells for the treatment of prostate cancer. In mice with intratibial inoculation of 22Rv1 prostate tumor, ZOL treatment after PSMA CAR-T cells infusion inhibited growth of the primary intratibial tumor, while it increased the extraskeletal metastasis, demonstrating that ZOL impedes the long-term immunosurveillance, albeit it enhances the short-term antitumor capability of the CAR-T cells. Mechanistically, ZOL showed no increase in the frequency of γδT cell phenotype. Finally, we found that ZOL induced hyperactivation and eventually led to exhaustion of the PSMA CAR-T cells, elucidating the impediment clues of ZOL on the T cell therapy. Our study demonstrates the necessity to balance the contribution of ZOL when combined with CAR-T cell therapy for prostate cancer.

Curing tuberculosis (TB) remains challenging due to treatment complexity and high recurrence rates. Through bioinformatic analyses of the immune microenvironment within clinical non-tuberculous granulomas (NTBG)/tuberculous granulomas (TBG) samples, and peripheral blood from drug-resistant/sensitive, recurrent/non-recurrent TB patients, we identify suppression of innate immune responses, especially downregulated Toll-like receptor/NF-kappa B pathways in macrophages/dendritic cells and elevated B/T cell negative regulation, contributing to treatment failure and recurrence. Building on these insights, we develop mannose-modified organic semiconducting nano-immunostimulants (manSNI) for precise TB sono-immunotherapy. Under optimized ultrasound condition, manSNI generates massive reactive oxygen species (ROS) to eradicate Mycobacterium tuberculosis (M.tb) within lung granulomas/macrophages, while simultaneously promoting in situ release of M.tb-derived antigens. The released antigens and TLR7 agonist R837 synergistically induce potent innate/adaptive anti-TB immunity and long-lasting immune memory. This granulomas microenvironment-guided sono-immunotherapy strategy demonstrates efficient TB control and relapse/reinfection prevention, which provides a promising direction for customized therapy against high-pathogenic infections.