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Abstract Despite their efficacy, the currently available polio vaccines, oral polio vaccine (OPV) and inactivated polio vaccine (IPV), possess inherent flaws posing significant challenges in the global eradication of polio. OPV, which uses live Sabin attenuated strains, carries the risk of reversion to pathogenic forms and causing vaccine-associated paralytic poliomyelitis (VAPP) and vaccine-derived polio disease (VDPD) in incompletely vaccinated or immune-compromised individuals. Conventional IPVs, which are non-replicative, are more expensive to manufacture and introduce biohazard and biosecurity risks due to the use of neuropathogenic strains in production. These types of limitations have led to a call by the Global Polio Eradication Initiative and others for the development of updated polio vaccines. We are developing a novel Ultraviolet-C radiation (UVC) inactivation method that preserves immunogenicity and is compatible with attenuated strains of polio. The method incorporates an antioxidant complex, manganese-decapeptide-phosphate (MDP), derived from the radioresistant bacterium Deinococcus radiodurans. The inclusion of MDP protects the immunogenic neutralizing epitopes from damage during UVC inactivation. The novel vaccine candidate, ultraIPVTM, produced using these methods demonstrates three crucial attributes: complete inactivation, which precludes the risk of vaccine-associated disease; use of non-pathogenic strains to reduce production risks; and significantly enhanced yield of doses per milligram of input virus, which could increase vaccine supply while reducing costs. Additionally, ultraIPVTM retains antigenicity post-freeze–thaw cycles, a testament to its robustness.

Natural resource managers need innovative and cost-effective methodologies that enable the targeted removal of aquatic invasive species (AIS). Removing AIS before they establish and spread into critical habitat for native species can mitigate invasions in freshwater systems and preserve ecosystem integrity. To address this need, we established protocols using the detection of environmental DNA (eDNA) to guide deployment of traditional fisheries trapping methods for invasive fish species removal. In a pilot study during spring 2022, we set minnow traps (one per site) in a spatially stratified random design. We also developed a quantitative polymerase chain reaction (qPCR) assay to detect eDNA from multiple closely related invasive loach species (family Cobitidae) and compared detections of eDNA with detections of fish using minnow traps. At sites where both eDNA and minnow traps were deployed, the two methods agreed on the presence of loaches approximately 79% of the time (95% CI: 60%-90%). Based on the rate at which minnow traps failed to detect loaches when eDNA samples were positive (22%; 95% CI: 11%-40%), we estimated that setting three or more replicate traps per site would improve detections with gear. This information was used to inform a more comprehensive study in spring 2023. This main study consisted of two phases: (1) a fixed-point DNA study to calibrate a model of dispersal and attenuation rate, and (2) a loach removal phase. In the removal phase, we randomly selected sites to sample for loach eDNA, plotted eDNA concentration as a GIS layer to develop heatmaps, and then placed 10 replicate traps at sites with the highest concentrations. A total of 658 loaches were removed from 68 of 77 eDNA-positive trapped sites. Our results indicate that aquatic invasive species removal is more efficient when eDNA detection techniques are combined with traditional trapping methods.

Acinetobacter baumannii causes multi-system diseases in both nosocomial settings and a pre-disposed general population. The bacterium is not only desiccation-resistant but also notoriously resistant to multiple antibiotics and drugs of last resort including carbapenem, colistin, and sulbactam. The World Health Organization has categorized carbapenem-resistant A. baumannii at the top of its critical pathogen list in a bid to direct urgent countermeasure development. Several early-stage vaccines have shown a range of efficacies in healthy mice, but no vaccine candidates have advanced into clinical trials. Herein, we report our findings that both an ionizing γ-radiation-inactivated and a non-ionizing ultraviolet C-inactivated whole-cell vaccine candidate protects neutropenic mice from pulmonary challenge with virulent AB5075, a particularly pathogenic isolate. In addition, we demonstrate that a humoral response is sufficient for this protection via the passive immunization of neutropenic mice.

Abstract Background Epithelioid hemangioma is a rare, benign vascular lesion classically presenting with painless nodules in the head and neck region. Hemangioma lesions are typically small, located within the dermis and subcutaneous tissue, and rarely exceed 10 cm in size. Complete surgical excision, with negative margins, is the recommended treatment as local recurrence is common. We describe an unusual presentation of epithelioid hemangioma that, to our knowledge, has not been previously described in the literature, epithelioid. Case presentation We report an atypical case of a large epithelioid hemangioma lesion with deep intramuscular involvement in a 16-year-old male. Ultrasound and MRI showed a hypervascular mass on the patient’s left upper back, and biopsy confirmed the diagnosis. Treatment consisted of preoperative embolization followed by excision and local tissue rearrangement. Conclusions Epithelioid hemangiomas are considered uncommon in the pediatric population. Moreover, it is challenging to diagnose these lesions due to their similarities to other vascular anomalies. We aim to increase awareness of this condition and obtain more precision in diagnosis, thus standardizing the approach for those treating individuals with vascular anomalies.

Describes a resonant method based on a tunnel-diode oscillator for precision measurements of relative radio-frequency impedance changes in materials. Integration of the measurement system with the commercially available Physical Property Measurement System; Circuit design and operation; Computer interface and data acquisition.

Abstract Plant chromatin dynamics are generally recognized as playing a role in the genomic response to environmental stress. Although stress‐induced transcriptional activities of LTR‐retrotransposons have been reported, whether the stress response can be detected at the level of chromatin structure for LTR‐retrotransposons is largely unknown. Using differential nuclease sensitivity profiling, we identified that two out of 29 maize LTR‐retrotransposon families change their chromatin structure in response to drought stress in leaf tissue. The two LTR‐retrotransposon families, uloh and vegu, are classified as nonautonomous LTR‐retrotransposons. Differently from other families, the chromatin structure of these two families shifted from more open in normal conditions to more closed following drought stress. Although uloh and vegu lack sequence similarity, most of them shared an intriguing feature of having a new and uncharacterized insertion of a DNA sequence near one side of an LTR. In the uloh family, nine members with a strong drought response also exhibited a drought‐induced reduction of published H3K4me3 histone modification in the inserted DNA region, implicating this modification in the chromatin structural changes. Our results provide new insight into how LTR‐retrotransposons can alter their chromatin structure following stress response in plants.

Background and purpose: In neuro-oncology, high spatial accuracy is needed for clinically acceptable high-precision radiation treatment planning (RTP). In this study, the clinical applicability of anatomically optimised 7-Tesla (7T) MR images for reliable RTP is assessed with respect to standard clinical imaging modalities. Materials and methods: System- and phantom-related geometrical distortion (GD) were quantified on clinically-relevant MR sequences at 7T and 3T, and on CT images using a dedicated anthropomorphic head phantom incorporating a 3D grid-structure, creating 436 points-of-interest. Global GD was assessed by mean absolute deviation (MADGlobal). Local GD relative to the magnetic isocentre was assessed by MADLocal. Using 3D displacement vectors of individual points-of-interest, GD maps were created. For clinically acceptable radiotherapy, 7T images need to meet the criteria for accurate dose delivery (GD

Background In the past decade, the zebrafish community has widely embraced targeted mutagenesis technologies, resulting in an abundance of mutant lines. While many lines have proven to be useful for investigating gene function, many have also shown no apparent phenotype, or phenotypes not of interest to the originating lab. In order for labs to document and share information about these lines, we have created ZebraShare as a new resource offered within ZFIN. Methods ZebraShare involves a form-based submission process generated by ZFIN. The ZebraShare interface (https://zfin.org/action/zebrashare) can be accessed on ZFIN under “Submit Data”. Users download the Submission Workbook and complete the required fields, then submit the completed workbook with associated images and captions, generating a new ZFIN publication record. ZFIN curators add the submitted phenotype and mutant information to the ZFIN database, provide mapping information about mutations, and cross reference this information across the appropriate ZFIN databases. We present here examples of ZebraShare submissions, including phf21aa, kdm1a, ctnnd1, snu13a, and snu13b mutant lines. Results Users can find ZebraShare submissions by searching ZFIN for specific alleles or line designations, just as for alleles submitted through the normal process. We present several potential examples of submission types to ZebraShare including a phenotypic mutants, mildly phenotypic, and early lethal mutants. Mutants for kdm1a show no apparent skeletal phenotype, and phf21aa mutants show only a mild skeletal phenotype, yet these genes have specific human disease relevance and therefore may be useful for further studies. The p120-catenin encoding gene, ctnnd1, was knocked out to investigate a potential role in brain development or function. The homozygous ctnnd1 mutant disintegrates during early somitogenesis and the heterozygote has localized defects, revealing vital roles in early development. Two snu13 genes were knocked out to investigate a role in muscle formation. The snu13a;snu13b double mutant has an early embryonic lethal phenotype, potentially related to a proposed role in the core splicing complex. In each example, the mutants submitted to ZebraShare display phenotypes that are not ideally suited to their originating lab’s project directions but may be of great relevance to other researchers. Conclusion ZebraShare provides an opportunity for researchers to directly share information about mutant lines within ZFIN, which is widely used by the community as a central database of information about zebrafish lines. Submissions of alleles with a phenotypic or unexpected phenotypes is encouraged to promote collaborations, disseminate lines, reduce redundancy of effort and to promote efficient use of time and resources. We anticipate that as submissions to ZebraShare increase, they will help build an ultimately more complete picture of zebrafish genetics and development.

Development of novel anti-tuberculosis combination regimens that increase efficacy and reduce treatment timelines will improve patient compliance, limit side-effects, reduce costs, and enhance cure rates. Such advancements would significantly improve the global TB burden and reduce drug resistance acquisition. Bioenergetics has received considerable attention in recent years as a fertile area for anti-tuberculosis drug discovery. Targeting the electron transport chain (ETC) and oxidative phosphorylation machinery promises not only to kill growing cells but also metabolically dormant bacilli that are inherently more drug tolerant. Over the last two decades, a broad array of drugs targeting various ETC components have been developed. Here, we provide a focused review of the current state of art of bioenergetic inhibitors of Mtb with an in-depth analysis of the metabolic and bioenergetic disruptions caused by specific target inhibition as well as their synergistic and antagonistic interactions with other drugs. This foundation is then used to explore the reigning theories on the mechanisms of antibiotic-induced cell death and we discuss how bioenergetic inhibitors in particular fail to be adequately described by these models. These discussions lead us to develop a clear roadmap for new lines of investigation to better understand the mechanisms of action of these drugs with complex mechanisms as well as how to leverage that knowledge for the development of novel, rationally-designed combination therapies to cure TB.

Many microbes of concern to human health remain without vaccines. We have developed a whole-microbe inactivation technology that enables us to rapidly inactivate large quantities of a pathogen while retaining epitopes that were destroyed by previous inactivation methods. The method that we call UVC-MDP inactivation can be used to make whole-cell vaccines with increased potency. We and others are exploring the possibility of using improved irradiation-inactivation technologies to develop whole-cell vaccines for numerous antibiotic-resistant microbes. Here, we apply UVC-MDP to produce candidate MRSA vaccines which we test in a stringent tibia implant model of infection challenged with a virulent MSRA strain. We report high levels of clearance in the model and observe a pattern of protection that correlates with the immunogen protein profile used for vaccination.

A concerted action on the part of international agencies and national governments has resulted in the near-eradication of poliomyelitis. However, both the oral polio vaccine (OPV) and the inactivated polio vaccine (IPV) have deficiencies which make them suboptimal for use after global eradication. OPV is composed of attenuated Sabin strains and stimulates robust immunity, but may revert to neurovirulent forms in the intestine which can be shed and infect susceptible contacts. The majority of IPV products are manufactured using pathogenic strains inactivated with formalin. Upon eradication, the production of large quantities of pathogenic virus will present an increased biosecurity hazard. A logical ideal endgame vaccine would be an inactivated form of an attenuated strain that could afford protective immunity while safely producing larger numbers of doses per unit of virus stock than current vaccines. We report here the development of an ionizing radiation (IR)-inactivated Sabin-based vaccine using a reconstituted Mn-decapeptide (MDP) antioxidant complex derived from the radioresistant bacterium Deinococcus radiodurans. In bacteria, Mn2+-peptide antioxidants protect proteins from oxidative damage caused by extreme radiation exposure. Here we show for the first time, that MDP can protect immunogenic neutralizing epitopes in picornaviruses. MDP protects epitopes in Polio Virus 1 and 2 Sabin strains (PV1-S and PV2-S, respectively), but viral genomic RNA is not protected during supralethal irradiation. IR-inactivated Sabin viruses stimulated equivalent or improved neutralizing antibody responses in Wistar rats compared to the commercially used IPV products. Our approach reduces the biosecurity risk of the current PV vaccine production method by utilizing the Sabin strains instead of the wild type neurovirulent strains. Additionally, the IR-inactivation approach could provide a simpler, faster and less costly process for producing a more immunogenic IPV. Gamma-irradiation is a well-known method of virus inactivation and this vaccine approach could be adapted to any pathogen of interest.

As aberrant Notch signaling has been linked to cancerous growth, Notch inhibitors represent a novel category of targeted oncological therapy. Notch pathways in tumor cells may contribute to proliferation or limit apoptosis and differentiation. Healthy skin differentiation and homeostasis are reliant on normal Notch expression, and disruption of this signaling has been implicated in dermatological conditions such as hidradenitis suppurativa, psoriasis, atopic dermatitis, and lichen planus. Here, we describe two cases of patients with cutaneous side effects from Notch inhibitor treatment for adenoid cyst carcinoma (ACC) and review the role of Notch signaling in skin disease. By illuminating connections between medication side effects and disease pathogenesis, our goal is to increase awareness of the cutaneous side effects of Notch inhibitor treatment.

The role of frontal lobes in speech perception is controversial. Here, the authors show that neurodegeneration of frontal speech regions delays prediction reconciliation in temporal cortex and results in inflexible prior expectations, indicating that fronto-temporal interactions determine predictive processes in speech.

Background Histone deacetylases (HDACs) are epigenetic factors that function to repress gene transcription by removing acetyl groups from the N-terminal of histone lysines. Histone deacetylase 4 (HDAC4), a class IIa HDAC, has previously been shown to regulate the process of endochondral ossification in mice via repression of Myocyte enhancer factor 2c (MEF2C), a transcriptional activator of Runx2, which in turn promotes chondrocyte maturation and production of bone by osteoblasts. Methods & Materials In this study, we generated two zebrafish lines with mutations in hdac4 using CRISPR/Cas9 and analyzed mutants for skeletal phenotypes and expression of genes known to be affected by Hdac4 expression. Results Lines have insertions causing a frameshift in a proximal exon of hdac4 and a premature stop codon. Mutations are predicted to result in aberrant protein sequence and a truncated protein, eliminating the Mef2c binding domain and Hdac domain. Zygotic mutants from two separate lines show a significant increase in ossification of pharyngeal ceratohyal cartilages at 7 days post fertilization (dpf) (p

Acinetobacter baumannii is a bacterial pathogen that is often multidrug-resistant (MDR) and causes a range of life-threatening illnesses, including pneumonia, septicemia, and wound infections. Some antibiotic treatments can reduce mortality if dosed early enough before an infection progresses, but there are few other treatment options when it comes to MDR-infection. Although several prophylactic strategies have been assessed, no vaccine candidates have advanced to clinical trials or have been approved. Herein, we rapidly produced protective whole-cell immunogens from planktonic and biofilm-like cultures of A. baumannii, strain AB5075 grown using a variety of methods. After selecting a panel of five cultures based on distinct protein profiles, replicative activity was extinguished by exposure to 10 kGy gamma radiation in the presence of a Deinococcus antioxidant complex composed of manganous (Mn2+) ions, a decapeptide, and orthophosphate. Mn2+ antioxidants prevent hydroxylation and carbonylation of irradiated proteins, but do not protect nucleic acids, yielding replication-deficient immunogenic A. baumannii vaccine candidates. Mice were immunized and boosted twice with 1.0 × 107 irradiated bacterial cells and then challenged intranasally with AB5075 using two mouse models. Planktonic cultures grown for 16 h in rich media and biofilm cultures grown in static cultures underneath minimal (M9) media stimulated immunity that led to 80–100% protection.