Bioscience Research

Despite significant advances in the treatment of clear cell renal cell carcinoma (ccRCC) over the past two decades, therapeutic intervention for patients at advanced or metastatic stages remains a clinical hurdle. Emerging evidence highlights aberrant CD70 expression during tumor progression, supporting its potential as a therapeutic target in advanced ccRCC. However, the molecular mechanisms underlying CD70-mediated metastatic processes remain poorly defined. CD70 was knocked out or overexpressed in three ccRCC cell lines, and its role in tumor progression was assessed using in vitro migration and invasion assays, as well as in vivo tumorigenesis and metastasis models. Mass spectrometry-based proteomics was performed to identify differentially expressed proteins and potential pathway dysregulation following CD70 depletion. Co-immunoprecipitation (Co-IP) assays confirmed the CD70-NF1 interaction, and NF1 knockdown in CD70-knockout cells was conducted to reverse the effects of CD70 depletion on Ras/ERK signaling, migration, invasion, and epithelial-mesenchymal transition (EMT)-related features. Expression of EMT-related marks were evaluated by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC). CD70 was significantly upregulated in ccRCC tissues and correlated with poor survival outcomes. CD70 knockout markedly inhibited in vitro cell migration and invasion, as well as in vivo tumor growth and metastasis. Mechanistically, CD70 depletion was associated with increased neurofibromin 1 (NF1) expression in ccRCC cells; CD70 knockout resulted in robust NF1 induction, which in turn suppressed Ras/ERK signaling and downstream EMT-related molecular alterations. Notably, NF1 knockdown largely reversed the inhibitory effects of CD70 knockout on these key molecular and functional phenotype changes. Our findings uncover a novel CD70-NF1-Ras/ERK axis that contributes to ccRCC progression and metastasis, involving suppression of NF1 and subsequent activation of the Ras/ERK signaling pathway, which further promotes EMT and enhances metastatic capacity. These insights provide a mechanistic foundation for targeting CD70 as a potential therapeutic strategy in advanced ccRCC. Notably, we propose that CD70-targeted therapy may be more effective when combined with agents blocking adaptive escape pathways (e.g., Ras/ERK inhibitors), a hypothesis generated by mechanistic rescue and pharmacologic inhibition in vitro, which require further preclinical validation to confirm synergistic efficacy and clinical viability.

The design of artificial photoenzymes by incorporating synthetic chromophores into proteins represents a promising strategy to achieve non-natural biocatalytic transformations with high levels of stereocontrol. Selecting an appropriate protein scaffold is a crucial step in this approach, which so far has been limited to naturally occurring proteins. Here, we tested the suitability of computationally designed scaffolds for this purpose. We chose a de novo helical bundle protein that has a central cavity for small molecule binding but no inherent catalytic activity. To generate a starting point for photoenzyme engineering, we installed a thioxanthone-based triplet sensitizer via cysteine bioconjugation. Guided by computational modeling and molecular dynamics (MD) simulations, three rounds of directed evolution toward the [2 + 2] photocycloaddition of a 3-alkenyloxy-substituted quinolone resulted in enzyme variants with catalytic efficiencies of kcat/Km > 1000 M–1 s–1 and opposite enantioselectivity. Upon visible-light irradiation, both product enantiomers were accessible with quantitative yield and >90:10 enantiomeric ratio. Furthermore, we obtained high-resolution crystal structures of the evolved designer enzymes. When exposing crystals of substrate-bound protein to blue light, we observed product formation in crystallo and could rationalize the enantioselectivity. Our work highlights the potential of de novo designed protein scaffolds to efficiently generate and evolve stereoselective artificial photoenzymes.

Fire blight, caused by Erwinia amylovora, severely impacts global apple and pear production. Current control measures rely heavily on conventional antibiotics like streptomycin, oxytetracycline, and kasugamycin, which raise concerns regarding resistance development and environmental impacts. This research introduces RejuAgro A (RAA), an antimicrobial produced by Pseudomonas soli 0617-T307, showing potent activity against E. amylovora, including streptomycin-resistant strains. RAA demonstrates efficacy comparable to streptomycin in field trials, effectively reducing fire blight incidence. Studies on the antimicrobial mechanism reveal that RAA inhibits RNA, DNA, and protein synthesis, distinguishing from that of conventional antibiotics. Furthermore, RAA displays broad-spectrum activity against diverse plant bacterial and fungal pathogens. The RAA biosynthesis gene cluster in P. soli is identified, revealing key genes essential for its production. RAA presents an alternative to traditional antibiotics, potentially enhancing sustainable apple and pear production and addressing antibiotic resistance concerns.

BackgroundRural communities were disproportionately impacted by the COVID-19 pandemic. Current and future pandemic preparedness in rural areas could be aided by serological (antibody) testing. However, benefits to be gained from serosurveillance are challenged both by the accessibility of serological testing resources in hard-to-reach rural areas, and by likely hesitancy towards their use in many rural communities. Trials are needed to evaluate outreach and health communication strategies that can increase rural receptivity towards serosurveillance.MethodsWe conducted a two-arm randomized controlled trial that recruited N = 194 participants from rural northern Michigan. In a single online session lasting approximately 45 min, participants were randomly assigned to view either a general SARS-CoV-2 antibody testing didactic video, or a rural targeted didactic video co-created with a rural community advisory board and containing unique rural messaging. Primary self-report outcomes included receptivity to antibody testing, as well as activation of medical mistrust and concern for rural-discrimination in future SARS-CoV-2 antibody testing. We also developed and provided an opportunity to participate in a home-based salivary antibody screening program. In addition to assessing the feasibility and fidelity of this program, we assessed interest and full participation in the serosurveillance program as behavioral outcomes.DiscussionFindings from this study can guide the use of home-based screening programs and targeted health communication strategies to promote greater uptake of health resources in rural communities. In doing so, study results can also guide public health strategies to reduce pandemic-related and other rural health disparities.

Breast cancer remains a leading global health concern in women, while screening is still limited by imaging accessibility and reduced sensitivity in dense breasts. Here we conduct a multicenter case-control study including 503 breast cancer patients and 289 benign controls to develop TuFEst, a machine learning model based on genome-wide cell-free DNA fragmentomic features. TuFEst achieves high sensitivity (95%) and specificity (78.3%) for early cancer detection and reliably identifies malignancies missed by conventional imaging. Extension of this framework enables non-invasive molecular subtyping (TuFEst-MS) and lymph node status prediction (TuFEst-LN), with strong performance in independent validation cohorts and imaging-pathology discordant cases. Transcriptomic profiling of paired bulk tumor samples (n = 79) demonstrates that elevated TuFEst-derived cancer scores reflect tumor aggressiveness and immune-related biological programs. Together, these findings support cfDNA fragmentomics as an integrated liquid biopsy strategy for breast cancer management, enabling concurrent detection, molecular subtyping, and lymph node evaluation with potential clinical utility.

BackgroundNo neoadjuvant treatment has been considered to be standard therapy for patients with resectable intrahepatic cholangiocarcinoma with high-risk factors for recurrence. The GOLP regimen (gemcitabine–oxaliplatin, lenvatinib, and an anti–programmed death 1 antibody) has shown promising efficacy with a manageable safety profile in advanced intrahepatic cholangiocarcinoma and biliary tract cancer.MethodsIn a phase 2–3 trial, we randomly assigned, in a 1:1 ratio, patients with resectable high-risk intrahepatic cholangiocarcinoma to the neoadjuvant group (intravenous gemcitabine–oxaliplatin plus toripalimab every 3 weeks for three cycles and oral lenvatinib once daily for 9 weeks, followed by curative resection) or the control group (curative resection and no neoadjuvant treatment). All patients received adjuvant capecitabine for eight cycles after surgery. The primary end point was event-free survival. Secondary end points included overall survival and safety.ResultsA total of 178 patients underwent randomization (88 patients to the neoadjuvant group and 90 to the control group). At the interim analysis at a median follow-up of 16.9 months, the median event-free survival was significantly longer in the neoadjuvant group (18.0 months; 95% confidence interval [CI], 13.8 to 27.6) than in the control group (8.7 months; 95% CI, 7.2 to 12.4) (P<0.001). Overall survival at 24 months was 79% (95% CI, 70 to 90) in the neoadjuvant group and 61% (95% CI, 50 to 75) in the control group (hazard ratio for death, 0.43; 95% CI, 0.23 to 0.79; P=0.005, which did not meet the significance criterion [two-sided alpha, 0.0019]). Across all treatment phases, adverse events occurred in 97% of the patients in the neoadjuvant group and in 70% of those in the control group. During the neoadjuvant phase, adverse events of grade 3 or higher occurred in 28% of the patients, and treatment-related adverse events of grade 3 or higher in 26%. No treatment-related adverse event led to death.ConclusionsNeoadjuvant GOLP led to significantly longer event-free survival than control therapy, with mainly low-grade adverse events, among patients with resectable high-risk intrahepatic cholangiocarcinoma. (Funded by the Clinical Research Plan of Shanghai Hospital Development Center and others; ZSAB-neoGOLP ClinicalTrials.gov number, NCT04669496.)

Advancements in biomaterials have transformed the field of endodontics, shifting treatment approaches from mechanical interventions to biologically driven regenerative therapies. This narrative review explores the evolving landscape of endodontic biomaterials, emphasizing their roles in disinfection, obturation, root repair, surgical procedures, and regenerative endodontics. Key materials such as mineral trioxide aggregate (MTA), Biodentine, and calcium-enriched mixture (CEM) cement demonstrate superior sealing, biocompatibility, and osteogenic potential compared to traditional materials. The integration of nanotechnology, bioactive components, and smart drug delivery systems has further enhanced antimicrobial properties and tissue interaction. Clinical applications, including regenerative procedures using platelet-rich fibrin and case-based biomaterial usage, are discussed to illustrate their relevance and effectiveness in real-world practice. Despite significant progress, challenges such as regulatory hurdles, economic limitations, and translational gaps persist. Emerging trends such as 3D printing, personalized medicine, and multifunctional scaffolds offer promising directions for future endodontic care. Continued interdisciplinary collaboration is essential to overcome current barriers and facilitate widespread adoption of next-generation biomaterials. Unlike prior reviews that categorize endodontic biomaterials descriptively by material class or technological advancement, this review introduces an indication-based comparative framework aligning biomaterial properties with specific clinical decision points and corresponding levels of evidence. By integrating biological mechanisms, translational considerations, and clinical application within a structured decision-oriented model, the manuscript offers analytical synthesis rather than a purely descriptive overview.

Purpose In the last decade, there has been a growing consensus that expanding gender diversity in the workplace can improve productivity and work quality. However, the well-being of female workers continues to be a challenge for companies. This study aims to evaluate the influence of some work practices (remote work, participation, flex-time, and work autonomy) on work engagement and work-life balance of European workers in the logistics sector, distinguishing male from female workers. The analysis is grounded in the job demands-resources (JD-R) model and social exchange theory (SET). Design/methodology/approach To this end, we used a quantitative methodology, carrying out a multi-group analysis and applying the partial least square method to a sample of 4,806 European workers in the logistics sector. Findings The results reveal significant gender differences in the intensity of influence of work practices on work engagement and work-life balance. Participation and flex-time practices positively influence the work engagement of female workers, and remote work practices their work-life balance, but with less intensity when compared to male workers. The relationship between work engagement and work-life balance is negative, being more intense in the case of female workers. Finally, when the association between workplace practices and work-life balance is mediated by work engagement, there is a positive influence of remote work and participation in work practices in the case of female workers. Originality/value This study contributes to deepening knowledge about gender differences in the workplace by integrating the JD-R model and SET to reveal gendered pathways between workplace practices, work engagement, and work-life balance in the logistics sector. It demonstrates that workplace practices appropriate to workers' gender should be promoted to enhance work engagement and work-life balance, which are valued by workers and could lead to greater worker proficiency.

Parkinson's disease (PD) pathogenesis is driven by α-synuclein (α-syn) amyloid aggregation, with the flexible C-terminal region mediating pathological interactions with cellular receptors and facilitating disease propagation and neuroinflammation. Through immunization with human α-syn fibrils and iterative neuronal binding and propagation assays, we identify H21 as a high-affinity fibril-specific monoclonal antibody. H21 selectively binds to α-syn fibrils and specifically targets the C-terminal region. H21 competitively blocks interactions between α-syn fibrils and established receptors and binding partners, including FAM171A2, RAGE, LAG3, and LC3B. Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) studies reveal that H21 engages α-syn fibrils in a periodic manner, inducing conformational remodeling in the fibril architecture. In a PD mouse model, H21 treatment reduces pathological α-syn spreading, suppresses neuroinflammation, and significantly improves motor outcomes. These findings underscore the rational design and therapeutic potential of fibril-specific antibodies targeting the C-terminal region of α-syn to halt PD progression.