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Simple Summary: Pulmonary hypertension is a fatal comorbidity in dogs with left-sided heart disease. Various oral pulmonary vasodilators have been effective in treating canine pulmonary hypertension; however, no studies have compared their hemodynamic effects. This study compared the hemodynamic effects of selected pulmonary vasodilators (15 µg/kg beraprost, 1.0 mg/kg sildenafil, and their combination) in canine models of mitral regurgitation (the most common cardiac disease in dogs). Significant improvements in pulmonary hypertension were observed with all study drugs. Pulmonary vasodilating effects differed among the study's drugs. Sildenafil showed a more potent pulmonary vasodilating effect than beraprost; however, sildenafil significantly worsened the left-heart loading condition. Although beraprost showed a weaker pulmonary vasodilating effect than sildenafil, no significant worsening in the left-heart loading condition was observed. Combination therapy resulted in the strongest pulmonary and systemic vasodilating effects without worsening the left-heart loading condition. This study demonstrated the differences between beraprost and sildenafil in pulmonary and systemic vasodilating effects. Sildenafil involved the risk of worsening the left-heart load, although it was effective in treating pulmonary hypertension. Combination therapy with beraprost and sildenafil synergistically dilated the pulmonary and systemic vessels, indicating a more potent treatment option. Previous reports have shown that various oral pulmonary vasodilators are effective against canine pulmonary hypertension (PH). However, no studies have compared their hemodynamic effects. We aimed to compare the hemodynamic effects of 15 µg/kg beraprost sodium, 1.0 mg/kg sildenafil, and their combination, in dogs with experimentally induced mitral regurgitation. This experimental crossover study evaluated the hemodynamic and functional effects of oral pulmonary vasodilators by application of right-sided heart catheterization and echocardiography. Beraprost significantly decreased pulmonary and systemic vascular resistance. Additionally, beraprost increased right-ventricular stroke volume and left-ventricular cardiac output without worsening left-heart size and left-atrial pressure. The pulmonary vasodilatory effects of sildenafil were stronger, and its systemic vasodilatory effects were weaker than those of beraprost. However, sildenafil significantly increased the left-ventricular volume, left-atrial pressure indicator, and right-ventricular cardiac output. Combination therapy resulted in the strongest pulmonary and systemic vasodilating effects without worsening the left-heart size and left-atrial pressure indicators. Both beraprost and sildenafil were effective against canine PH; however, sildenafil was associated with the risk of worsening left-heart loading. Combination therapy with beraprost and sildenafil synergistically dilated pulmonary and systemic vessels, indicating a more potent treatment option for severe PH cases. [ABSTRACT FROM AUTHOR]

With the determination of numerous viral and bacterial genome sequences, sequence‐trait relationships, such as the evolution of virulence and associations to geographic location or host, are now being studied. In these studies, phylogenetic trees were first reconstructed, and trait data were analysed based on the trees. However, in some cases, such as fast evolution sequences and gene‐sharing network data, reconstructing the phylogenetic tree is challenging. Even in such cases, it is possible to quantify the similarity between sequences and construct an similarity network.Here, we propose a novel approach, Network‐Trait association with Graph Fourier Transform (NeTaGFT), to analyse network‐trait associations. NeTaGFT is inspired by graph signalling process techniques. The graph in this study corresponds to a similarity network representing the similarities between virus samples, and the graph signal corresponds to trait data. By using graph Fourier transform, NeTaGFT aims to identify trait signals and associations of various traits from a similarity network.We validated that NeTaGFT can find signals associated with network structures and associations of traits with the simulation dataset. We applied NeTaGFT for influenza type A and virome gene‐sharing datasets. As a result, we identified several network structures and their associated traits.Our approach is expected to provide novel insights into network‐based approach not only for typical sequence‐trait relationships but also for various biological data, such as antibody evolution. [ABSTRACT FROM AUTHOR]

Malaria infection elicits both protective and pathogenic immune responses, and IL‐27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL‐27. Neutralization of IL‐27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium‐specific CD4+ T cells in IL‐27‐neutralized mice consisted mainly of CD127+KLRG1− and CD127−KLRG1+ subpopulations that displayed distinct cytokine production, proliferative capacity, and are maintained in a manner independent of active infection. Single‐cell RNA‐seq analysis revealed that these CD4+ T cell subsets formed independent clusters that express unique Th1‐type genes. These IL‐27‐neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL‐27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4+ T cells, suggesting potential implications for the development of vaccines and other strategic interventions. Synopsis: IL‐27 inhibits the generation of parasite‐specific memory CD4+ T cells in a malaria infection model. Transient blockade of IL‐27 elicits high levels of unique CD127+ and KLRG1+ memory CD4+ T cells, elevates antibody production, and enhances protective immunity against secondary infection. IL‐27 produced during the acute phase of malaria infection is inhibitory for the generation of parasite‐specific memory CD4+ T cells.Two types of unique memory CD4+ T cells are generated in the absence of IL‐27: CD127+ and KLRG1+ cells expressing high levels of Ifng and Tbx21, respectively.Memory CD4+ T cells induced in the absence of IL‐27 can be maintained in the absence of persistent malaria infection.The absence of IL‐27 during the acute phase of malaria infection generates memory immune responses that are protective against challenge infection. [ABSTRACT FROM AUTHOR]

Background: Progression to combined post‐ and pre‐capillary pulmonary hypertension (PH) provides prognostic information in human patients with post‐capillary PH. Pulmonary vascular resistance estimated by echocardiography (PVRecho) is useful for the stratification of dogs with myxomatous mitral valve disease (MMVD) and detectable tricuspid regurgitation. Objectives: To evaluate the prognostic value of PVRecho in dogs with MMVD. Animals: Fifty‐four dogs with MMVD and detectable tricuspid regurgitation. Methods: Prospective cohort study. All dogs underwent echocardiography. The PVRecho was calculated based on tricuspid regurgitation and the velocity‐time integral of the pulmonary artery flow. To evaluate the influence of echocardiographic variables on cardiac‐related deaths, Cox proportional hazard analysis was performed. Additionally, Kaplan‐Meier curves classified by PVRecho tertiles were made and compared using log‐rank tests to evaluate the influence of PVRecho on all‐cause mortality and cardiac‐related death. Results: The median follow‐up time was 579 days. Forty‐one dogs with MMVD (PH severity [number]: no or mild, 21/33; moderate, 11/11; severe, 9/10) died during the study. In the multivariable Cox proportional hazard analysis adjusted for age, sildenafil administration, and American College of Veterinary Internal Medicine stage of MMVD, left atrial to aortic diameter ratio and PVRecho remained significant (adjusted hazard ratio [95% confidence interval]: 1.2 [1.1‐1.3] and 2.1 [1.6‐3.0], respectively). Higher PVRecho showed a significant association with lower survival rates. Conclusions and Clinical Importance: Left atrial enlargement and high PVRecho were independent prognostic factors in dogs with MMVD and detectable tricuspid regurgitation. [ABSTRACT FROM AUTHOR]