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1. The Infection Dynamics of Experimental Edwardsiella ictaluri and Flavobacterium covae Coinfection in Channel Catfish (Ictalurus punctatus)

   https://doi.org/10.3390/pathogens12030462  

   Wise, Allison L.; LaFrentz, Benjamin R.; Kelly, Anita M.; Liles, Mark R.; Griffin, Matt J.; Beck, Benjamin H.; Bruce, Timothy J. (March 2023, Pathogens)

   Edwardsiella ictaluri and Flavobacterium covae are pervasive bacterial pathogens associated with significant losses in catfish aquaculture. Bacterial coinfections have the potential to increase outbreak severity and can worsen on-farm mortality. A preliminary assessment of in vivo bacterial coinfection with E. ictaluri (S97-773) and F. covae (ALG-00-530) was conducted using juvenile channel catfish (Ictalurus punctatus). Catfish were divided into five treatment groups: (1) mock control; (2) E. ictaluri full dose (immersion; 5.4 × 105 CFU mL−1); (3) F. covae full dose (immersion; 3.6 × 106 CFU mL−1); (4) E. ictaluri half dose (immersion; 2.7 × 105 CFU mL−1) followed by half dose F. covae (immersion; 1.8 × 106 CFU mL−1); and (5) F. covae half dose followed by half dose E. ictaluri. In the coinfection challenges, the second inoculum was delivered 48 h after the initial exposure. At 21 days post-challenge (DPC), the single dose E. ictaluri infection yielded a cumulative percent mortality (CPM) of 90.0 ± 4.1%, compared with 13.3 ± 5.9% in the F. covae group. Mortality patterns in coinfection challenges mimicked the single dose E. ictaluri challenge, with CPM of 93.3 ± 5.4% for fish initially challenged with E. ictaluri followed by F. covae, and 93.3 ± 2.7% for fish exposed to F. covae and subsequently challenged with E. ictaluri. Despite similarities in the final CPM within the coinfection groups, the onset of peak mortality was delayed in fish exposed to F. covae first but was congruent with mortality trends in the E. ictaluri challenge. Catfish exposed to E. ictaluri in both the single and coinfected treatments displayed increased serum lysozyme activity at 4-DPC (p < 0.001). Three pro-inflammatory cytokines (il8, tnfα, il1β) were evaluated for gene expression, revealing an increase in expression at 7-DPC in all E. ictaluri exposed treatments (p < 0.05). These data enhance our understanding of the dynamics of E. ictaluri and F. covae coinfections in US farm-raised catfish. 

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2. The landscape of lysogeny across microbial community density, diversity and energetics

   https://doi.org/10.1111/1462-2920.15640  

   Silveira, Cynthia_B; Luque, Antoni; Rohwer, Forest (June 2021, Environmental Microbiology)

   Summary Lysogens are common at high bacterial densities, an observation that contrasts with the prevailing view of lysogeny as a low‐density refugium strategy. Here, we review the mechanisms regulating lysogeny in complex communities and show that the additive effects of coinfections, diversity and host energic status yield a bimodal distribution of lysogeny as a function of microbial densities. At high cell densities (above 10⁶ cells ml⁻¹or g⁻¹) and low diversity, coinfections by two or more phages are frequent and excess energy availability stimulates inefficient metabolism. Both mechanisms favour phage integration and characterize the Piggyback‐the‐Winner dynamic. At low densities (below 10⁵ cells ml⁻¹or g⁻¹), starvation represses lytic genes and extends the time window for lysogenic commitment, resulting in a higher frequency of coinfections that cause integration. This pattern follows the predictions of the refugium hypothesis. At intermediary densities (between 10⁵and 10⁶ cells ml⁻¹or g⁻¹), encounter rates and efficient energy metabolism favour lysis. This may involve Kill‐the‐Winner lytic dynamics and induction. Based on these three regimes, we propose a framework wherein phage integration occurs more frequently at both ends of the host density gradient, with distinct underlying molecular mechanisms (coinfections and host metabolism) dominating at each extreme. 

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3. Protection Generated by Prior Exposure to Pathogens Depends on both Priming and Challenge Dose

   https://doi.org/10.1128/IAI.00537-21  

   Weitzman, Chava L.; Ceja, Guadalupe; Leon, Ariel E.; Hawley, Dana M. (March 2022, Infection and Immunity)

   Pirofski, Liise-anne (Ed.)

   ABSTRACT Free-living hosts encounter pathogens at a wide range of frequencies and concentrations, including low doses that are largely aclinical, creating a varied landscape of exposure history and reinfection likelihood. While several studies show that higher priming doses result in stronger immunological protection against reinfection, it remains unknown how the reinfection challenge dose and priming dose interact to determine the likelihood and severity of reinfection. We manipulated both priming and challenge doses of Mycoplasma gallisepticum , which causes mycoplasmal conjunctivitis, in captive house finches ( Haemorhous mexicanus ), to assess reinfection probability and severity. We found a significant interaction between priming and challenge doses on reinfection probability, with the likelihood of reinfection by a high but not a low challenge dose decreasing exponentially at higher priming doses. While this interaction was likely driven by lower average infection probabilities for low-dose versus high-dose challenges, even the highest priming dose provided only negligible protection against reinfection from low-dose challenges. Similarly, pathogen loads during reinfection were significantly reduced with increasing priming doses only for birds reinfected at high but not low doses. We hypothesize that these interactions arise to some degree from fundamental differences in host immune responses across doses, with single low doses only weakly triggering host immune responses. Importantly, our results also demonstrate that reinfections can occur from a variety of exposure doses and across diverse degrees of standing immunity in this system. Overall, our study highlights the importance of considering both initial and subsequent exposure doses where repeated exposure to a pathogen is common in nature. 

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4. Exploring spatial dose information in the parotid gland for xerostomia prediction and local dose patterns in head and neck cancer radiotherapy

   https://doi.org/10.1088/2057-1976/adb15e  

   Chao, Ming; Tomalin, Lewis; Wei, Jie; Liu, Tian; Zhang, Jiahan; Liu, Jerry; Peñagarícano, José A (February 2025, Biomedical Physics & Engineering Express)

   Abstract Purpose. To investigate the relationship between spatial parotid dose and the risk of xerostomia in patients undergoing head-and-neck cancer radiotherapy, using machine learning (ML) methods.Methods. Prior to conducting voxel-based ML analysis of the spatial dose, two steps were taken: (1) The parotid dose was standardized through deformable image registration to a reference patient; (2) Bilateral parotid doses were regrouped into contralateral and ipsilateral portions depending on their proximity to the gross tumor target. Individual dose voxels were input into six commonly used ML models, which were tuned with ten-fold cross validation: random forest (RF), ridge regression (RR), support vector machine (SVM), extra trees (ET), k-nearest neighbor (kNN), and naïve Bayes (NB). Binary endpoints from 240 patients were used for model training and validation: 0 (N = 119) for xerostomia grades 0 or 1, and 1 (N = 121) for grades 2 or higher. Model performance was evaluated using multiple metrics, including accuracy, F₁score, areas under the receiver operating characteristics curves (auROC), and area under the precision–recall curves (auPRC). Dose voxel importance was assessed to identify local dose patterns associated with xerostomia risk.Results. Four models, including RF, SVM, ET, and NB, yielded average auROCs and auPRCs greater than 0.60 from ten-fold cross-validation on the training data, except for a lower auROC from NB. The first three models, along with kNN, demonstrated higher accuracy and F₁scores. A bootstrapping analysis confirmed test uncertainty. Voxel importance analysis from kNN indicated that the posterior portion of the ipsilateral gland was more predictive of xerostomia, but no clear patterns were identified from the other models.Conclusion. Voxel doses as predictors of xerostomia were confirmed with some ML classifiers, but no clear regional patterns could be established among these classifiers, except kNN. Further research with a larger patient dataset is needed to identify conclusive patterns. 

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5. Growth Performance, Survival, Blood Chemistry, and Immune Gene Expression of Channel Catfish (Ictalurus punctatus) Fed Probiotic-Supplemented Diets

   https://doi.org/10.3390/vetsci9120701  

   Nguyen, Khanh Q.; Bruce, Timothy J.; Afe, Oluwafunmilola E.; Liles, Mark R.; Beck, Benjamin H.; Davis, Donald Allen (December 2022, Veterinary Sciences)

   The channel catfish (Ictalurus punctatus) farming industry is the largest and one of the oldest aquaculture industries in the United States. Despite being an established industry, production issues stemming from disease outbreaks remain problematic for producers. Supplementing fish diets with probiotics to enhance the immune system and growth potential is one approach to mitigating disease. Although considerable laboratory data demonstrate efficacy, these results do not always translate to natural modes of disease transmission. Hence, the present work was conducted in the laboratory but incorporated flow-through water from large catfish pond production systems, allowing for natural exposure to pathogens. Two feeding trials were conducted in an 18-tank aquaria system housing two different sizes, 34.8 ± 12.5 g and 0.36 ± 0.03 g, of channel catfish. Channel catfish in the first trial were fed three experimental diets over six weeks. Commercial diets were top-coated with two selected spore-forming Bacillus spp. probiotics, Bacillus velezensis AP193 (1 × 106 CFU g−1) and BiOWiSH (3.6 × 104 CFU g−1), or a basal diet that contained no dietary additive. In the second eight-week trial, diets were top-coated with BiOWiSH at three concentrations (1.8, 3.6, and 7.3 × 104 CFU g−1), along with one basal diet (no probiotic). At the completion of these studies, growth performance, survival, hematocrit, blood chemistry, and immune expression of interleukin 1β (il1β), tumor necrosis factor-alpha (tnf-α), interleukin-8 (il8), transforming-growth factor β1 (tgf-β1), and toll-like receptor 9 (tlr9) were evaluated using qPCR. Trial results revealed no differences (p > 0.05) among treatments concerning growth, survival, or hematological parameters. For immune gene expression, interesting trends were discerned, with substantial downregulation observed in B. velezensis AP193-fed fish for il1β, tnf-α, and tlr9 expression within splenic tissue, compared to that of the basal and BiOWiSH diets (p < 0.05). However, the results were not statistically significant for anterior kidney tissue in the first trial. In the second trial, varied levels of probiotic inclusion revealed no significant impact of BiOWiSH’s products on the expression of il1β, tnf-α, il8, and tgf-β1 in both spleen and kidney tissue at any rate of probiotic inclusion (p > 0.05). Based on these findings, more research on utilizing probiotics in flow-through systems with natural infection conditions is crucial to ensure consistency from a controlled laboratory scale to real-world practices. 

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