Monkeypox virus (MPXV) is a zoonotic virus endemic to Africa that has recently re-emerged, becoming the first orthopoxvirus with sustained human-to-human transmission since smallpox eradication. The 2022 global epidemic of MPXV was caused by Clade IIb virus (lineage B.1) that derived from the lineage A endemic to West Africa through APOBEC3 microevolution[1-3]. Here, comparison of lineage B.1 virus with its closest earlier A.1 ancestor reveals that despite only 46 nucleotide differences, lineage B.1 has attenuating phenotypic changes. Both viruses replicated equivalently in cell culture, but B.1 had defects in long-range spread, which mapped to APOBEC3 mutation E353K in OPG057 (F13L). MPXV B.1 was also defective in innate immune control, inducing higher IFNβ and innate immune signalling gene expression, and showing reduced capacity to suppress interleukin-1β-mediated responses, which mapped to APOBEC3 mutation R48C in OPG047 (F3L). Finally, MPXV B.1 had reduced virulence in a mouse model of MPXV infection relative to the ancestral A.1 strain. Our work demonstrates that the 2022 global outbreak MPXV was intrinsically attenuated, with attenuating mutations that are absent in concurrent, more severe clade IIb outbreaks. Our data also reveal that APOBEC3 editing is a mechanism of MPXV phenotypic variation, potentially contributing to clade evolution and competition.

Cancer therapies are often limited by poor cellular specificity and tumor microenvironment-mediated immunosuppression. We developed a dual-function graphene oxide (GO)-based gene delivery platform combining direct cancer cell elimination with stromal and immune reprogramming. CD47-targeting siRNA and ANT1-encoding plasmid DNA selectively induced apoptosis in tumor cells, while TGFβ-targeting siRNA altered cancer-associated fibroblasts (CAFs) phenotype and was associated with a shift in macrophage polarization toward a pro-inflammatory, tumor-restraining phenotype. We evaluated this approach in a 3D multicellular lung cancer model consisting of A549 cells, human lung fibroblasts, and THP1-derived macrophages. TGFβ silencing alone modulated stromal and immune features without direct cytotoxicity, whereas CD47/ANT1 modulation reduced overall cell viability to ∼51%. When both therapeutic functions were applied together, overall cell viability was further reduced to ∼29%. EGFR-targeted GO-CD47-ANT1 (GE11-peptide modified formulation) enhanced tumor-cell uptake and selective apoptosis in CK7[+] cancer cells to 91%, while sparing CK7[-] nonmalignant populations (16%). Mechanistically, combined therapy suppressed immunosuppressive macrophage markers (CD163, IL10, TGFβ), restored epithelial integrity (E-cadherin 3.5-fold), and attenuated CAF activation (αSMA 0.3-fold; vimentin 0.6-fold). GE11 peptide functionalization shifted nanocarrier internalization toward EGFR-mediated cancer cell uptake, minimizing off-target delivery to fibroblasts and macrophages. These findings demonstrate that synergistic modulation of cancer cells and the tumor microenvironment is essential for robust and selective tumor elimination. Our study establishes a modular, mechanism-informed GO platform integrating dual therapeutic functions-targeted cancer cell killing and microenvironmental reprogramming-highlighting its translational potential in physiologically relevant tumor models.

The recent spread of human monkeypox (mpox) beyond Africa has attracted global attention. Although mpox is a DNA virus with relatively lower pandemic potential, and smallpox vaccines and therapeutics may offer protection, the distinct clinical features observed in the current outbreak highlight the need for novel antiviral drugs. Here, we developed a drug repurposing workflow based on interspecies protein analysis and advanced virtual screening, integrating pre- and post-docking processes. After screening 6,074 approved or clinical-stage drugs against viral DNA topoisomerase, we expanded the analysis to viral DNA polymerase, increasing the compound library to 11,484 molecules, including approved or clinical-stage drugs and DNA polymerase inhibitors from ChEMBL. To assess dynamic stability, we performed molecular dynamics (MD) simulations and quantified protein-ligand contact occupancy, distinguishing stably bound candidates from transient docking poses. The MD and convolutional neural-network (GNINA) scoring analyses converged on vindesine for DNA topoisomerase and LY2090314 for DNA polymerase. Importantly, the workflow was applied to targets with distinct prior information, including a structurally characterized DNA polymerase supported by homologue inhibitor data and a less-characterized DNA topoisomerase requiring homology modelling. These results illustrate an adaptable repurposing pipeline for prioritizing therapeutic candidates against emerging infectious diseases, although experimental validation remains required.

In recent years, mpox has emerged as a significant global public health threat. The widespread distribution of the virus, coupled with the legacy of historical smallpox vaccination, has underscored the critical need to serologically distinguish between natural mpox infection and vaccine-induced humoral immune responses. However, the high antigenic similarity among Orthopoxvirus species leads to the production of cross-reactive antibodies, limiting the differentiation capacity of conventional serological assays. This mini-review evaluates current serological approaches aimed at discriminating between mpox infection and vaccine-induced immunity. Specifically, we analyze multiplexed immunoassays, comparative ratios based on orthologous antigens, machine learning-supported serological models, peptide-based platforms, and recombinant protein-based enzyme-linked immunosorbent assay (ELISA) methods. The findings of this review indicate that multiplex immunoassays, orthologous antigen ratio-based approaches, and machine learning algorithms exhibit the highest discriminatory potential for distinguishing natural mpox infection from vaccine-induced immune responses. In addition, MPXV A27L and ATI-N-CPXV antigens may be considered promising candidates for serological differentiation, although their performance requires further investigation.

Guinea worm disease is approaching eradication, with only 10 human cases reported worldwide in 2025, the lowest annual total recorded. Yet the final phase of eradication presents complex clinical and public health challenges that differ from earlier stages of control. Persistent animal infections, particularly in dogs, civil conflict, fragile health systems, financing disruptions, and the need for prolonged surveillance threaten progress at the point when global attention may wane. Unlike smallpox, Guinea worm has been driven to near-eradication without a vaccine, curative drug, or rapid diagnostic test, relying instead on safe water, filtration, vector control, case containment, community education, reporting incentives, and sustained field operations. This Perspective argues that eradication remains achievable but requires a specific policy agenda: protected financing for surveillance, animal-source transmission control, safe-water measures, operational access, and certification through 2030. Completing the final mile would represent a permanent preventive achievement and a durable victory for neglected populations too often overlooked.

This article discusses the intersections between vaccination and slavery in colonial Brazil, highlighting the arrival of the smallpox vaccine in Bahia and its spread to other regions of the Portuguese Empire including its holdings in Africa. We highlight the story of enslaved boys, who were primarily inoculated and vaccinated between the late eighteenth and early nineteenth centuries, through analysis of bibliographical and documentary sources that illustrate the actions of historical figures such as Felisberto Caldeira Brant, Francisco da Cunha Menezes and Francisco Ignácio Sequeira Nobre. These activities reveal the initiative of slave owners in the search for solutions against smallpox, highlighting the complex relationships between slavery, science and health.

This interview with retired Casa de Oswaldo Cruz/Fiocruz researcher Tania Maria Dias Fernandes explores her academic trajectory, which covers studies on the history of science, public health and vaccines. Notable topics include the institutionalization of the smallpox vaccine, the eradication of smallpox, the role of health surveillance and the historical and contemporary challenges faced by marginalized communities. The interview also addresses strategies adopted during the vaccination process, scientific debates that influenced health policy, and the importance of understanding public health through an interdisciplinary approach.

Smallpox, eradicated globally in 1980, remains a major biodefense concern due to retained Variola virus stocks and the absence of population immunity following cessation of routine vaccination. Monkeypox virus (MPXV), a related orthopoxvirus, has reemerged as a global public health threat, with major outbreaks in 2022 and renewed spread from 2024 onward.

The collapse of the Dzungar Khanate in the 1750s marked the end of the world's last nomadic empire and reshaped Eurasian geopolitics. However, whether environmental and societal factors interplayed and contributed to its collapse remains unclear. Here, we reconstructed steppe productivity variability across the Dzungar heartland since 1625 using 441 tree-ring series based on an extreme growth ratio. Our record shows that the Khanate's collapse coincided with the lowest steppe productivity in the past four centuries during 1751-1761. The weakening societal resilience approaching a tipping point intensified the effects of the rapid steppe productivity decline, which cascaded into famine, conflict, and trade breakdown. Smallpox then reemerged and escalated into a catastrophic epidemic, transforming the environmental crisis into the collapse of the Dzungar Khanate. Our findings underscore the urgent need to strengthen pastoral resilience and epidemic surveillance in steppe regions as climate stress intensifies and cross-border epidemic threats escalate.