The Salton Sea is a drying salt lake in an arid region with high aerosol particulate-matter concentrations. This region is plagued by a high incidence of asthma, attributed in part to the aerosols surrounding the Sea. But the connection between the Sea and asthma may be more than simple calculations of dust concentrations. While dusts might contain toxic substances that impact the lungs of residents, the complex dynamics related to the environmental degradation of the Salton Sea may be generating additional toxins relevant to public health, such as microcystins produced by algal blooms. This collection of pollutants may be driving inflammatory responses in the lungs of residents through multiple mechanisms. As such, examination of the full range of potential environmental triggers of lung inflammation promises to yield a better understanding of key mechanisms driving the high incidence of asthma in local residents. Our discussion provides a perspective aiming to re-frame the issue in the context of the historical theory of “miasma” and the linkages between environmental change and health impacts.
Reassortment between different influenza strains occurs when they co-infect the same host cell. The emergence of a reassortant virus depends on both its intrinsic fitness and extrinsic factors, including preexisting humoral immunity. The generation of pandemic strains, such as H2N2 and H3N2, and zoonotic influenza A viruses, such as H5N6, H5N8, and H7N9, in birds is suggested to be the result of extensive selection by preexisting antibodies. To further explore the role of humoral immunity in reassortment, we generated two divergent fluorescent protein-expressing viruses and used strain-specific and cross-reactive monoclonal antibodies (mAbs) to assess the impact of cross-immunity on reassortment. Our results indicate that all mAbs altered the genotypic diversity and significantly reduced the release of progeny virions in co-infected cells both in vitro and in vivo. Moreover, antibody transfer studies in mice revealed protection from challenge with divergent pathogenicity profiles. Notably, selection driven by a strain-specific mAb depended on its neutralizing specificity, whereas the selection driven by broadly reactive mAbs was independent of neutralization specificity. Our findings demonstrate that preexisting neutralizing antibodies shape reassortment and that strain-specific neutralizing antibodies promote antigenic shift during co-infection, which is not the case for broadly cross-reactive antibodies that recognize influenza viruses from different subtypes.
A zoonotic Babesia species previously referred to as Babesia sp. MO1 is formally described and named here as Babesia hegotelforum sp. nov. This taxon is distinct from Babesia divergens based on genome-wide sequence divergence, phylogenetic placement, host associations, and clinical presentation. The parasite infects erythrocytes of humans, and eastern cottontail rabbits (Sylvilagus floridanus), and is transmitted by Ixodes dentatus. The holotype consists of a Giemsa-stained thin blood smear and cryopreserved infected erythrocytes from the cloned isolate BML-Bh-B12 at ≤10 passages in continuous in vitro culture. Paratype material includes five additional clones (BML-Bh-H1, BML-Bh-F12, BML-Bh-H6, BML-Bh-A3, and BML-Bh-F1) derived from BEI Resources strain NR-50441, along with the original mixed isolate NR-50441. This species description meets the requirements of the International Code of Zoological Nomenclature and establishes Babesia hegotelforum sp. nov. as a distinct species of clinical and epidemiological significance in North America.
Host-pathogen interactions are shaped by cellular restriction factors that direct antiviral defenses. We built the first ovine genome-wide CRISPR knockout library in sheep testis (OA3.Ts) cells, targeting all protein-coding genes. Using this platform, we identified PEX11B, a peroxisomal membrane regulatory protein, as a strong restriction factor against orf virus (ORFV) infection. Removing PEX11B increased viral susceptibility and triggered severe cytopathic effects with membrane fusion and syncytia formation. Mechanistic studies showed that PEX11B knockout harmed peroxisomal integrity and disrupted lipid metabolism. This led to greater plasma membrane fluidity, creating a proviral environment that allowed more viral entry and replication. These results reveal a new antiviral function for PEX11B in blocking viral infection and underscore the importance of peroxisomal regulation in host-virus interactions.
Workflow management systems (WMS) are essential for creating and automating multi-step data analyses and ensuring the reproducibility of biological insights. Although numerous WMS solutions exist, few provide deep integration of command-line software with the R and Bioconductor ecosystems, where a substantial portion of statistical modeling and downstream scientific analysis is performed by a large user base. systemPipeR addresses this gap by offering a unified environment that links R-based analytical steps with command-line tools through a standardized workflow specification. It enables the design and execution of reproducible workflows on both local and high-performance computing systems, while allowing users to select the most appropriate R or command-line tool for each analysis step. The latest version introduces a fully redesigned architecture that streamlines workflow construction, execution, monitoring, and reporting. Key enhancements include a flexible workflow management class object, integration of the Common Workflow Language (CWL), formal declaration and standardized execution of both R and command-line steps, utilities for metadata management, and automated generation of scientific and technical reports. Together, these advances establish systemPipeR as a general-purpose R-based WMS for building and executing end-to-end workflows for reproducible analysis of complex data in genomics and other data-intensive fields. The software is distributed as a free open-source Bioconductor package (https://bioconductor.org/packages/systemPipeR).
A critical component of evaluating whether a chemical can cause human neurotoxicity is hazard identification, which typically involves a comprehensive literature search to identify and synthesize epidemiological, animal, and mechanistic data for the chemical of interest. The key characteristics (KCs) concept has proven to be a useful tool for searching, organizing, and evaluating mechanistic data for hazard identification. KCs are the established chemical and biological properties of known human neurotoxic agents based on understanding of their mechanisms of neurotoxicity. KCs were originally developed for carcinogens but have now also been published for endocrine- and metabolism-disruptors and various organ-selective toxic chemicals. To identify KCs associated with neurotoxic chemicals, an expert committee was convened to consider current mechanistic understanding of chemicals known to be neurotoxic in humans with the goal of identifying established molecular and cellular actions of neurotoxic chemicals. After extensive discussion, the committee reached consensus on 10 KCs. Here, we describe the 10 proposed KCs and provide chemical-related examples to support their inclusion. Several important considerations emerged from the committee's deliberations including: (1) a mechanistic action need not be unique to neurotoxicity to be considered a KC of neurotoxic chemicals; (2) many, if not most, neurotoxic chemicals exhibit multiple KCs, and the relative importance of any specific KC and/or its causal relationship to other KCs may vary depending on life stage at the time of exposure and/or the exposure paradigm; and (3) data indicating a chemical exhibits one or more KCs of neurotoxic chemicals suggests that the chemical poses a neurotoxic hazard but does not necessarily identify the risk that the chemical presents to humans. These considerations, as well as potential applications of KCs in neurotoxicology, are discussed. The committee also strongly recommended that the list of proposed KCs of neurotoxic chemicals be viewed as a "living document" that is reviewed and revised in response to emerging insights on mechanisms of neurotoxicity, as well as lessons learned from the application of these proposed KCs, including but not limited to their use as a tool for the systemic identification and review of mechanistic data for assessment of neurotoxic hazards.
Virus-based nanocarriers have shown great potential for noninvasive delivery of drugs, diagnostics, and imaging agents to hard-to-reach anatomical locations. Yet, they largely depend on diffusion for transport, often lacking the force to actively penetrate biological barriers, and navigation to guide therapeutic agents. In these studies, the M13 bacteriophage, a linearly shaped virus, was converted from passive nanocarrier to actively propelled, fuel-driven nanomotor. Using the distinctive low symmetry of its capsid, a single Pt nanoparticle was added to one end of the M13 virus to form a tadpole-like structure. The Pt/M13 head/tail nanomotors exhibited notably enhanced diffusion in the presence of hydrogen peroxide fuel, and significantly improved uptake by SVOK3 ovarian cancer cells in vitro. Given the successes of the M13 bacteriophage as a nanocarrier, the demonstration of this simple, but comparatively mobile M13-based nanomotor platform represents an important step in advancing the potential therapeutic efficacy of viral nanocarriers.
BACKGROUND: Crimean-Congo hemorrhagic fever virus (CCHFV), a zoonotic agent in the Nairoviridae family (genus Orthonairovirus), is a high-priority pathogen. CCHFV infection causes Crimean-Congo hemorrhagic fever (CCHF), a human disease with case fatality rates of up to 40%. Serological surveillance of CCHFV in animals and humans is crucial for ecological studies and public health. METHODS: We developed CCHFV mix-and-read assays utilizing split-NanoLuc technology (NanoBiT) to detect anti-CCHFV antibodies against the nucleoprotein (NP) stalk region and the GP38 glycoprotein. These species- and isotype-agnostic assays provide results in ∼30 min. Using serum samples from RT-PCR-confirmed CCHF cases collected during and after hospitalization, we investigated anti-NP and anti-GP38 antibody development. The performance of the mix-and-read assays was compared to the NP-based IDScreen® CCHF commercial assay using human sera, and cross-reactivity potential was evaluated using a diverse panel of anti-orthonairovirus antisera raised in mice. FINDINGS: In human convalescent cases (n = 21), mix-and-read assay concordance between anti-GP38 and anti-NP antibody detection was 100%. Both mix-and-read assays and IDScreen® CCHF demonstrated identical sensitivity of 95.2% in convalescent patients. The specificity of the NP assay was 98.9%, and that of GP38 was 99.7%, both comparable to IDScreen® CCHF (specificity: 99.7%). Cross-reactivity against CCHF NP and GP38, regardless of assay type, was primarily observed in antisera raised against other orthonairoviruses within the Nairobi sheep disease genogroup. INTERPRETATION: The simplicity and robust performance of the CCHFV mix-and-read assays make them ideal tools for supporting serological surveillance in humans and animals. Furthermore, the inclusion of the GP38 antigen alongside NP enhances the precise identification of retrospective CCHF cases, further strengthening broad surveillance efforts. FUNDING: CDC Emerging Infectious Disease Research Core Funds, funding for reagent, CDC personal, travel. Defence Threat Reduction Agency (HDTRA12210007): E.K. salary. Oak Ridge Institute for Science and Education (ORISE): E.K. salary and travel. National Institute of Allergy and Infectious Diseases (1R01AI180125-01A1): sample acquisition. Funding sources did not have a role in the writing or decision to submit the publication.
Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). Iron deficiency is the most frequent cause of anemia in IBD; however, the mechanisms involved are still poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), in regulating iron homeostasis. Proteomic analyses were performed on serum from IBD patients genotyped for the IBD-associated loss-of-function rs1893217 PTPN2 variant. Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) mice were analyzed for iron content, blood parameters, and expression of iron handling proteins. Iron absorption was assessed through radiotracer assays. Serum proteomic analyses revealed that the "iron homeostasis signaling pathway" was the main pathway downregulated in Crohn's disease (CD) patients carrying the PTPN2 risk allele, independent of disease activity. Ptpn2-KO mice showed characteristics of anemia, including reduced hemoglobin concentrations along with serum and tissue iron deficiency and elevated serum hepcidin levels vs. Ptpn2-WT and Het mice. 55Fe absorption via oral gavage was significantly impaired in Ptpn2-KO mice. Correspondingly, Ptpn2-KO mice showed reduced apical membrane expression of the iron transporter DMT1. CD patients with the PTPN2 loss-of-function rs1893217 variant display alterations in serum iron handling proteins. Loss of Ptpn2 in mice caused features of anemia, including iron deficiency associated with reduced apical membrane expression of DMT1. These findings identify an important role for PTPN2 in regulating systemic iron homeostasis.
BACKGROUND: Clinical trials should benefit all people. Consequently, the National Cancer Institute expects cancer centers to accrue individuals to clinical trials in proportion to the cancer burden experienced by populations that live in their respective catchment areas; unfortunately, many cancer centers fail to meet this expectation. The person who gives consent for individuals in clinical trials frequently has significant contact with potential trial participants. We hypothesized that the race, ethnicity, and language of the consenter may have an important bearing on whether an individual chooses to participate in a clinical trial. METHODS: We used mixed methods to investigate the impact of the socio-cultural background of the consenter on the decision of a potential research subject to participate in a clinical trial. Between 01/2018 and 02/2020, 205 women were approached in the sequential order they appeared in our breast clinic; of the 181 participants who agreed to complete the survey questionnaire, 94 (52%) were Northern European, non-Hispanic White (NE White), and 87 (48%) were Women-of-Color (WOC); this category includes participants who self-identified as Asian, Black, Hispanic/Latina, or Native American. RESULTS: There were statistically significant differences according to the importance of the consenter's characteristics in the decision to enroll or decline participation in the BCT. No NE White enroller (0%, n = 0) reported that consenter race was important versus 11% (n = 9) of WOC enrollers (p = 0.0009). Similarly, none of the NE White enrollers rated the consenter "looking like people in my community" as important versus 12% (n = 10) of the WOC enrollers (p = 0.0004). CONCLUSIONS: We find that consenter race and ethnicity are important for clinical trial diversity. Larger studies are needed to evaluate the generalizability of this finding.
