FAdV-4-induced ferroptosis affects fat metabolism in LMH cells.

Ferroptosis is a form of controlled cell death that was first described relatively recently and that is dependent on the formation and accumulation of lipid free radicals through an iron-mediated mechanism. A growing body of evidence supports the close relationship between pathogenic infections and ferroptotic cell death, particularly for viral infections. Ferroptosis is also closely tied to the pathogenic development of hepatic steatosis and other forms of liver disease. Fowl adenovirus serotype 4 (FAdV-4) is a hepatotropic aviadenovirus causing hydropericardium syndrome (HPS) that is capable of impacting fat metabolism. However, it remains uncertain as to what role, if any, ferroptotic death plays in the context of FAdV-4 infection. Here, FAdV-4 was found to promote ferroptosis via the p53-SLC7A11-GPX4 axis, while ferrostain-1 was capable of inhibiting this FAdV-4-mediated ferroptotic death through marked reductions in lipid peroxidation. The incidence of FAdV-4-induced fatty liver was also found to be associated with the activation of ferroptotic activity. Together, these results offer novel insights regarding potential approaches to treating HPS.

Lapatinib combined with doxorubicin causes dose-dependent cardiotoxicity partially through activating the p38MAPK signaling pathway in zebrafish embryos.

Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies.

Integrated analysis of gut microbiota and metabolomic profiling in colorectal cancer metastasis.

Colorectal cancer (CRC) is characterized by its heterogeneity and complex metastatic mechanisms, presenting significant challenges in treatment and prognosis. This study aimed to unravel the intricate interplay between the gut microbiota and metabolic alterations associated with CRC metastasis. By employing high-throughput sequencing and advanced metabolomic techniques, we identified distinct patterns in the gut microbiome and fecal metabolites across different CRC metastatic sites. The differential gene analysis highlighted significant enrichment in biological processes related to immune response and extracellular matrix organization, with key genes playing roles in the complement and clotting cascades, and staphylococcus aureus infections. Protein-protein interaction networks further elucidated the potential mechanisms driving CRC spread, emphasizing the importance of extracellular vesicles and the PPAR signaling pathway in tumor metastasis. Our comprehensive microbiota analysis revealed a relatively stable alpha diversity across groups but identified specific bacterial genera associated with metastatic stages. Metabolomic profiling using OPLS-DA models unveiled distinct metabolic signatures, with differential metabolites enriched in pathways crucial for cancer metabolism and immune modulation. Integrative analysis of the gut microbiota and metabolic profiles highlighted significant correlations, suggesting a complex interplay that may influence CRC progression and metastasis. These findings offer novel insights into the microbial and metabolic underpinnings of CRC metastasis, paving the way for innovative diagnostic and therapeutic strategies targeting the gut microbiome and metabolic pathways.

Scalable Polyimide-Organosilicate Hybrid Films for High-Temperature Capacitive Energy Storage.

High-temperature polymer dielectrics have broad application prospects in next-generation microelectronics and electrical power systems. However, the capacitive energy densities of dielectric polymers at elevated temperatures are severely limited by carrier excitation and transport. Herein, a molecular engineering strategy is presented to regulate the bulk-limited conduction in the polymer by bonding amino polyhedral oligomeric silsesquioxane (NH2 -POSS) with the chain ends of polyimide (PI). Experimental studies and density functional theory (DFT) calculations demonstrate that the terminal group NH2 -POSS with a wide-bandgap of Eg ≈ 6.6 eV increases the band energy levels of the PI and induces the formation of local deep traps in the hybrid films, which significantly restrains carrier transport. At 200 °C, the hybrid film exhibits concurrently an ultrahigh discharged energy density of 3.45 J cm-3 and a high gravimetric energy density of 2.74 J g-1 , with the charge-discharge efficiency >90%, far exceeding those achieved in the dielectric polymers and nearly all other polymer nanocomposites. Moreover, the NH2 -POSS terminated PI film exhibits excellent charge-discharge cyclability (>50000) and power density (0.39 MW cm-3 ) at 200 °C, making it a promising candidate for high-temperature high-energy-density capacitors. This work represents a novel strategy to scalable polymer dielectrics with superior capacitive performance operating in harsh environments.

Using Zebrafish Animal Model to Study the Genetic Underpinning and Mechanism of Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is largely an autosomal dominant genetic disorder manifesting fibrofatty infiltration and ventricular arrhythmia with predominantly right ventricular involvement. ACM is one of the major conditions associated with an increased risk of sudden cardiac death, most notably in young individuals and athletes. ACM has strong genetic determinants, and genetic variants in more than 25 genes have been identified to be associated with ACM, accounting for approximately 60% of ACM cases. Genetic studies of ACM in vertebrate animal models such as zebrafish (Danio rerio), which are highly amenable to large-scale genetic and drug screenings, offer unique opportunities to identify and functionally assess new genetic variants associated with ACM and to dissect the underlying molecular and cellular mechanisms at the whole-organism level. Here, we summarize key genes implicated in ACM. We discuss the use of zebrafish models, categorized according to gene manipulation approaches, such as gene knockdown, gene knock-out, transgenic overexpression, and CRISPR/Cas9-mediated knock-in, to study the genetic underpinning and mechanism of ACM. Information gained from genetic and pharmacogenomic studies in such animal models can not only increase our understanding of the pathophysiology of disease progression, but also guide disease diagnosis, prognosis, and the development of innovative therapeutic strategies.

Tailoring Poly(Styrene-co-maleic anhydride) Networks for All-Polymer Dielectrics Exhibiting Ultrahigh Energy Density and Charge-Discharge Efficiency at Elevated Temperatures.

Polymer film capacitors have been widely used in electronics and electrical power systems due to their advantages of high power densities, fast charge-discharge speed, and great stability. However, the exponential increase of electrical conduction with temperature and applied electric field substantially degrades the capacitive performance of dielectric polymers at elevated temperatures. Here, the first example of controlling the energy level of charge traps in all-organic crosslinked polymers by tailoring molecular structures that significantly inhibit high-field high-temperature conduction loss, which largely differs from current approaches based on the introduction of inorganic fillers, is reported. The polymer network with optimized crosslinking structures exhibits an ultrahigh discharged energy density of 7.02 J cm-3 with charge/discharge efficiencies of >90% at 150 °C, far outperforming current dielectric polymers and composites. The charge-trapping effects in different crosslinked structures, as the origins of the marked improvements in the high-temperature capacitive performance, are comprehensively investigated experimentally and confirmed computationally. Moreover, excellent cyclability and self-healing features are demonstrated in the polymer film capacitors. This work offers a promising pathway of molecular structure design to scalable high-energy-density polymer dielectrics capable of operating under harsh environments.

Cinnamaldehyde causes developmental neurotoxicity in zebrafish via the oxidative stress pathway that is rescued by astaxanthin.

Toxicology studies provide a reliable dose range for the use of compounds. Zebrafish show unique advantages in toxicology research. Cinnamaldehyde (Cin) is one of the main active compounds isolated from Cinnamon trees and other species of the genus Cinnamomum. In this study, we investigated the developmental neurotoxicity of cinnamaldehyde in zebrafish and preliminarily explored its underlying mechanism. Cinnamaldehyde causes developmental neurotoxicity in zebrafish, as evidenced by the damage to ventricular structures, eye malformations, shortened body length, trunk curvature, decreased neuronal fluorescence, and pericardial oedema. Moreover, it can induce abnormal behaviour and gene expression in zebrafish. After treatment with the oxidative stress inhibitor astaxanthin, the behaviour and abnormal gene expression were reversed. All of these data demonstrated that the developmental neurotoxicity of cinnamaldehyde might be attributed to oxidative stress. In addition, this study also confirmed that zebrafish is a reliable model for toxicity studies.

TMT-based quantitative proteomics analysis reveals the role of Notch signaling in FAdV-4-infected LMH cell.

Fowl adenovirus serotype 4 (FAdV-4) is recognized as a pathogen that causes hydropericardium syndrome. Irrespective of the pathway used by the virus to invade the chicken, the pathological characteristics of the disease include degeneration and necrosis of hepatocytes, formation of intranuclear inclusions, as well as inflammatory cell infiltration. Liver dysfunction constitutes one of the critical factors leading to death. Therefore, it is vital to investigate the virus-mediated severe pathological liver damage to further understand the pathogenesis of FAdV-4. Here, proteomics, a tandem mass tag (TMT)-based approach to directly analyze protein expression, was used to determine the protein expression during FAdV-4 proliferation in leghorn male hepatoma (LMH) cells. We identified 177 differentially expressed proteins associated with various biological processes and pathways. The functional enrichment analysis revealed that FAdV-4 could downregulate some signaling pathways in LMH cells, including NOD-like receptor signaling, RIG-I-like receptor signaling, NF-κB signaling, TNF signaling pathway, and Notch signaling, FoxO signaling, PI3K-Akt signaling, and autophagy. The results of proteomics screening suggested an association between FAdV-4 infection and Notch signaling in LMH in vitro, indicating that Notch signaling regulated the expression of inflammatory cytokines and interferons but not viral replication in LMH cells. These data contributed to the understanding of the immunopathogenesis and inflammopathogenesis of FAdV-4 infection and also provided valuable information for the further analysis of the molecular mechanisms underlying viral pathogenesis.

Genetic Susceptibility and Mechanisms Underlying the Pathogenesis of Anthracycline-Associated Cardiotoxicity.

Anthracyclines are chemotherapeutic agents widely used to treat a variety of cancers, and these drugs have revolutionized our management of cancer patients. The dose-dependent cardiotoxicity of anthracyclines, however, remains one of the leading causes of chemotherapy treatment-associated mortality in cancer survivors. Patient threshold doses leading to anthracycline-induced cardiotoxicity (AIC) are highly variable among affected patients. This variability is largely ascribed to genetic variants in individuals' genomes. Here, we briefly discuss the prevailing mechanisms underlying the pathogenesis of AIC, and then, we review the genetic variants, mostly identified through human genetic approaches and identified in cancer survivors. The identification of all genetic susceptibilities and elucidation of underlying mechanisms of AIC can help improve upfront risk prediction assessment for potentially severe cardiotoxicity disease and provide valuable insights into the understanding of AIC pathophysiology, which can be further leveraged to develop targeted pharmacogenetic therapies for those at high risk.

FAdV-4 induce autophagy via the endoplasmic reticulum stress-related unfolded protein response.

Hydropericardium syndrome caused by the fowl adenovirus serotype 4 (FAdV-4) is prevalent disease in China with a high mortality rate. Many studies have demonstrated some viral infections to induce stress in the endoplasmic reticulum (ER). When the ER stress exceeds or persists, it activates autophagy, eventually triggering the onset of diseases. However, no report has ever stated FAdV-4 infection to induce ER stress-mediated autophagy. Previous studies have identified FAdV-4 infection in triggering autophagy in the hepatocytes; however, the underlying mechanism of this induction remains unknown. This study investigated the mechanism of ER stress-mediated autophagy induced by FAdV-4 infection. Here, ER stress was found to be triggered by FAdV-4 infection, as evident from the increased expression of the ER stress marker glucose-regulated protein 78, and the dilated morphology of the ER. Three pathways linked with the unfolded protein response (UPR) were found to be triggered in the hepatocellular carcinoma cell line, which included the PKR-like ER protein kinase (PERK), transcription factor 6, and inositol-requiring enzyme 1 (IRE1) pathways, respectively. Additionally, our results demonstrated that autophagy is involved in the PERK-eukaryotic initiation factor 2 subunit - C/EBP homologous protein and IRE1-c-Jun-N-terminal kinase pathways. Furthermore, treatment with the small interfering RNAs, or specific chemical inhibitors for the two pathways were found to reduce the interfering activity and could suppress the FAdV-4 replication. Collectively, these results developed new insight into the mechanisms of FAdV-4-induced autophagy by activating the ER stress-related UPR pathway and provided the experimental bases and novel ideas for developing antiviral drugs.

An EGFP Knock-in Zebrafish Experimental Model Used in Evaluation of the Amantadine Drug Safety During Early Cardiogenesis.

Background: Drug exposure during gestation or in prematurely born children represents a significant risk to congenital heart disease (CHD). Amantadine is an antiviral agent also effective in the treatment of Parkinson's disease. However, while its potential side effects associated with tetralogy of fallot (ToF) and birth defects were implicated, its underlying etiologic mechanisms of action remain unknown. Here, we report teratogenic effects of amantadine drug during early cardiogenesis through developing a novel zebrafish (Danio rerio) knock-in (KI) animal model and explore the underlying mechanisms. Methods: Homologous recombination (HR) pathway triggered by CRISPR/Cas9 system was utilized to generate an enhanced green fluorescent protein (EGFP) KI zebrafish animal model. Dynamic fluorescence imaging coupled with a whole-mount in-situ hybridization (WISH) assay was employed to compare the spatial and temporal expression patterns of the EGFP reporter in the KI animal model with the KI-targeted endogenous gene. Heart morphology and EGFP expression dynamics in the KI animal models were monitored to assess cardiac side effects of different doses of amantadine hydrochloride. Expression of key genes required for myocardium differentiation and left-right (LR) asymmetry was analyzed using WISH and quantitative reverse transcription-PCR (RT-PCR). Results: A novel EGFP KI line targeted at the ventricular myosin heavy chain (vmhc) gene locus was successfully generated, in which EGFP reporter could faithfully recapitulate the endogenous expression dynamics of the ventricle chamber-specific expression of the vmhc gene. Amantadine drug treatment-induced ectopic expression of vmhc gene in the atrium and caused cardiac-looping or LR asymmetry defects to dose-dependently during early cardiogenesis, concomitant with dramatically reduced expression levels of key genes required for myocardium differentiation and LR asymmetry. Conclusion: We generated a novel zebrafish KI animal model in which EGFP reports the ventricle chamber-specific expression of vmhc gene dynamics that is useful to effectively assess drug safety on the cardiac morphology in vivo. Specifically, this study identified teratogenic effects of amantadine drug during early cardiogenesis dose dependent, which could be likely conveyed by inhibiting expression of key genes required for cardiac myocardium differentiation and LR asymmetry.

Failure mode and effects analysis on the control effect of multi-drug-resistant bacteria in ICU patients.

OBJECTIVE: The failure mode and effect analysis of the prevention and control in intensive care unit (ICU) patients with multi-drug-resistant (MDR) bacterial infection were explored and analyzed in this research. METHODS: A total of 251 critically ill patients who were hospitalized in the ICU from June to December 2019 were selected as the control group, and another 258 patients who were hospitalized in the ICU from January to June 2020 were set as the observation group. The control-group patients received conventional ICU care, the observation group was treated by the failure mode and effects analysis (FMEA), and then the prevention and control effect of the two nursing modes on multi-drug-resistant bacteria infection in the two groups were compared accordingly. RESULTS: The RPN values of the five highest-level factors in the nursing process were critically lower after the improved interventions than before the improvement. The infection rate of MDR bacteria in the observation group was obviously lower than that in the control group (14.73%, 26.69%, χ2 =11.1233, P=0.0009). In addition, the mortality rate of patients with MDR in the observation group was remarkably lower than that in the control group, and the difference was statistically significant (5.26%, 22.39%, χ2 =5.2405, P=0.0221). The satisfaction of the observation group with the ICU treatment was critically higher than that of the control group, and the difference was statistically significant (89.53%, 76.49%, χ2 =15.4094, P=0.0001). CONCLUSION: Through the application of FMEA to prevent MDR bacterial infection in ICU patients, nursing staff can accurately pay attention to the keynotes in nursing process, and as such reduce the proportion and mortality of MDR infection in ICU patients and promote the patients' satisfaction with nursing, which are all worthy of clinical application.

Nursing effect of continuous blood purification therapy in treatment of severe sepsis.

OBJECTIVE: To explore the nursing effect of continuous blood purification therapy in the treatment of severe sepsis patients. METHODS: A total of 142 patients with severe sepsis in our hospital were divided into two groups, 70 patients in the experimental group who received an optimize nursing plan, while 72 patients in the control group were given routine nursing intervention. The SF-36 questionnaire, nursing satisfaction and serious adverse events and complications were collected. RESULTS: The nursing intervention effect of the two groups after intervention were improved before intervention (P<0.05), and the patient's quality of life between the two groups (SF-36 questionnaire) in the experimental group was increased compared to that of the control group after nursing intervention. The nursing satisfaction scores of the experimental group were obviously improved after receiving optimize nursing intervention, and the scores in the experimental group were much higher than in the control group after receiving the intervention, namely (P<0.05). Moreover, the occurrence of serious adverse events and complications in the experimental group was decreased compared to that in the control group, especially the occurrence of acid base imbalance (P<0.05). CONCLUSION: The patients with severe sepsis who received continuous blood purification therapy and optimized nursing intervention had shortened ICU hospitalization time, reduced mortality and complication rates, and improved nursing satisfaction and quality of life.

Disruption of MAP7D1 Gene Function Increases the Risk of Doxorubicin-Induced Cardiomyopathy and Heart Failure.

Doxorubicin is a cornerstone chemotherapeutic drug widely used to treat various cancers; its dose-dependent cardiomyopathy, however, is one of the leading causes of treatment-associated mortality in cancer survivors. Patients' threshold doses leading to doxorubicin-induced cardiomyopathy (DIC) and heart failure are highly variable, mostly due to genetic variations in individuals' genomes. However, genetic susceptibility to DIC remains largely unidentified. Here, we combined a genetic approach in the zebrafish (Danio rerio) animal model with a genome-wide association study (GWAS) in humans to identify genetic susceptibility to DIC and heart failure. We firstly reported the cardiac and skeletal muscle-specific expression and sarcomeric localization of the microtubule-associated protein 7 domain-containing protein 1b (Map7d1b) in zebrafish, followed by expression validation in mice. We then revealed that disruption of the map7d1b gene function exaggerated DIC effects in adult zebrafish. Mechanistically, the exacerbated DIC are likely conveyed by impaired autophagic degradation and elevated protein aggregation. Lastly, we identified 2 MAP7D1 gene variants associated with cardiac functional decline and heart failure in cancer patients who received doxorubicin therapy. Together, this study identifies MAP7D1 as a clinically relevant susceptibility gene to DIC and heart failure, providing useful information to stratify cancer patients with a high risk of incurring severe cardiomyopathy and heart failure after receiving chemotherapy.

Genetic risk of clozapine-induced leukopenia and neutropenia: a genome-wide association study.

BACKGROUND: Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). METHODS: A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). RESULTS: The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10-8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10-8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. CONCLUSIONS: The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.

Metabolomic Profiling Reveals New Insight of Fowl Adenovirus Serotype 4 Infection.

Highly pathogenic fowl adenovirus serotype 4 (FAdV-4) is the causative agent of hydropericardium syndrome (HPS), which is characterized by pericardial effusion and hepatitis, and is one of the foremost causes of economic losses to the poultry industry over the last 30 years. However, the metabolic changes in cells in response to FAdV-4 infection remain unclear. In order to understand the metabolic interactions between the host cell and virus, we utilized ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry to analyze the metabolic profiles with hepatocellular carcinoma cell line (LMH) infected with FAdV-4. The results showed that FAdV-4 could restore metabolic networks in LMH cells and tricarboxylic acid cycle, glycolysis, and metabolism of purines, pyrimidines, alanine, aspartate, glutamate, and amino sugar and nucleotide sugar moieties. Moreover, FAdV-4 production was significantly reduced in LMH cells cultured in glucose or glutamine-deficient medium. These observations highlighted the importance of host cell metabolism in virus replication. Therefore, similarities and disparities in FAdV-4-regulation of the metabolism of host cells could help improve targeted drug and reduce infection.

The amino acid variants in HLA II molecules explain the major association with adult-onset Still's disease in the Han Chinese population.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.

The pathogenicity of duck hepatitis A virus types 1 and 3 on ducklings.

Duck hepatitis A virus (DHAV) is one of the pathogens that cause fatal duck viral hepatitis (DVH) in ducklings, which is an acute and contagious disease with a high mortality rate. Despite a continuing official duck vaccination program, DHAV infection remains a major threat to the duck industry. Considerable changes were observed in the epidemiology of DHAV-1/-3 in China over time. Therefore, comparing the pathogenicity of different DHAV serotypes can provide a theoretical basis for the diagnosis and prevention of DVH. In this study, we systematically investigated the effects of infection with DHAV-1/-3 field strains on clinical signs, gross lesions, histopathological changes, viral RNA detection, enzymatic systems, and metabolite concentrations. The results demonstrated that the major macroscopic and microscopic lesions in ducks infected with DHAV-1/-3 in the liver, brain, spleen, pancreas, and kidneys exhibited no significant differences. After 24 h of infection, DHAV quickly appeared in blood and major organs. Significant changes in clinical chemical markers together with histopathological lesions and viral RNA detection indicated that the liver is the major target organ for both viruses, resulting in impaired of liver integrity and function. In addition, we found that both viruses were able to invade both central and peripheral immune organs. Also lipase plasma activity was substantially affected by DHAV-1/-3, indicating that the integrity and function of the pancreas was compromised. However, there was no significant difference in pathogenicity between DHAV-1 and -3. The results of this study provide new insights into the pathogenesis of DHAV-1/3, two viruses that cause serious depression, metabolic disorders, and immunosuppression.