Cascadia Journal of Biomedical Research - Articles

Rao, V., Engel, L.

Previous work on chronic kidney disease has produced conflicting results, partly because of differences in design and data. We find a 23% relative reduction in the primary outcome, and we show that the result is stable under a range of perturbations of the assumptions. Together, these results contribute to a more complete picture and open the way to further applications.

Hu, B., Pang, C., Luo, D., Wang, Y., Sun, C., Zhou, J., Chen, J., Du, G., Zhong, F., Zhou, J., Wang, B., Zhao, X.

Willard, C., Puglisi, L., Ravi, D., Dmitrieva, M., Mattiesing, R., Barkhof, F., Alexander, D., Harlow, D., Piani-Meier, D., Eshaghi, A.

Multiple sclerosis (MS) is a highly heterogeneous disease in its clinical manifestation and progression. Predicting individual disease courses is key for aligning treatments with underlying pathobiology. We developed an unsupervised machine learning model integrating MRI-derived measures with serum neurofilament light chain (sNfL) levels to identify biologically informed MS subtypes and stages. Using a training cohort of patients with relapsing–remitting and secondary progressive MS (n = 189), with validation on a newly diagnosed population (n = 445), we discovered two distinct subtypes defined by the timing of sNfL elevation and MRI abnormalities (early- and late-sNfL types). In comparison to MRI-only models, incorporating sNfL with MRI improved correlations of data-derived stages with the Expanded Disability Status Scale in the training (Spearman’s ρ = 0.420 versus MRI-only ρ = 0.231, P = 0.001) and external test sets (ρ = 0.163 for MRI–sNfL, versus ρ = 0.067 for MRI-only). The early-sNfL subtype showed elevated sNfL, corpus callosum injury and early lesion accrual, reflecting more active inflammation and neurodegeneration, whereas the late-sNfL group showed early volume loss in the cortical and deep grey matter volumes, with later sNfL elevation. Cross-sectional subtyping predicted longitudinal radiological activity: the early-sNfL group showed a 144% increased risk of new lesion formation (hazard ratio = 2.44, 95% confidence interval 1.38–4.30, P < 0.005) compared with the late-sNfL group. Baseline subtyping, over time, predicted treatment effect on new lesion formation on the external test set (faster lesion accrual in early-sNfL compared with late-sNfL, P = 0.01), in addition to treatment effects on brain atrophy (early sNfL average percentage brain volume change: −0.41, late-sNfL = −0.31, P = 0.04). Integration of sNfL provides an improved framework in comparison to MRI-only subtyping of MS to stage disease progression and inform prognosis. Our model predicted treatment responsiveness in early, more active disease states. This approach offers a powerful alternative to conventional clinical phenotypes and supports future efforts to refine prognostication and guide personalized therapy in MS.

Zhao, Y., Duan, J., Seah, H., van de Leemput, J., Han, Z.

Chronic kidney disease is a major health issue and is gaining prevalence. Using a Drosophila model for chronic kidney disease, we show that a high-fat diet (HFD) disrupts the slit diaphragm filtration structure in nephrocytes, the fly functional equivalent of mammalian podocytes. The structural disruption resulted in reduced filtration function in the affected nephrocytes. We demonstrate that HFD activates the JAK-STAT pathway in nephrocytes, which has previously been linked to diabetic kidney disease. JAK-STAT activation was initiated by increased expression and release of the adipokine, Upd2, from the fat body. This leptin-like hormone is a known ligand of JAK-STAT. Both genetic and pharmacological inhibition of JAK-STAT restored nephrocyte HFD-associated dysfunction. Altogether, our study reveals the importance of the JAK-STAT signaling pathway in the adipose tissue−nephrocyte axis and its contribution to HFD-associated nephropathy. These findings open new avenues for intervention in treating diabetic nephropathy and chronic kidney disease.

Hu, B., Pang, C., Luo, D., Wang, Y., Sun, C., Zhou, J., Chen, J., Du, G., Zhong, F., Zhou, J., Wang, B., Zhao, X.

Cytochrome P450 enzymes are promising for synthesizing therapeutically beneficial bile acids murideoxycholic acid (MDCA) and ursodeoxycholic acid (UDCA) from lithocholic acid (LCA). However, the catalytic efficiency of P450 enzymes remains inadequate for large-scale production. Here, we address this limitation by engineering P450 OleP, achieving high activity for the efficient synthesis of MDCA and UDCA. Firstly, an improved high-throughput detection method for UDCA was developed to accelerate the screening process for mutants with improved UDCA synthesis capabilities. Next, the mutant S240A was generated through semi-rational design guided by the crystal structure of the OleP-LCA complex, resulting in an improvement in the MDCA conversion rate from 32.5% to 98.3% using 0.5 g L−1 of LCA as the substrate. Furthermore, the crystal structure of the S240A mutant was resolved and analyzed. Subsequently, the mutant F84Q/S240A/V291G/E89 N was developed through rational design, improving the UDCA conversion rate from 6.5% to 12.1% with 0.5 g L−1 of LCA as the substrate. Finally, molecular dynamics simulations were employed to elucidate the mechanisms underlying the enhanced catalytic activity of the S240A and F84Q/S240A/V291G/E89 N mutants. This study provides optimized P450 enzyme mutants for the synthesis of MDCA and UDCA and offers significant insights into the catalytic mechanisms underlying the production of hydroxylated, LCA-derived high-value-added compounds.

Zheng, Z., Shen, D., Shi, Y., Chai, L., Zhou, Y.

Objective The H1N1 influenza, a highly contagious acute respiratory disease, causes a significant burden on public health, especially during the winter season when the number of cases surges. Emergency department nurses, who are on the frontline of patient care during this period, are exposed to high - stress situations, increasing their risk of developing post - traumatic stress disorder (PTSD). Understanding the status of PTSD among them and its influencing factors is crucial for safeguarding their mental health and ensuring quality healthcare. This study aims to investigate the status of post-traumatic stress disorder (PTSD) among emergency department nurses in multiple tertiary hospitals in Shanghai, China during the winter H1N1 influenza season and analyze its influencing factors. Methods A cross - sectional study design was adopted from October 2023 to December 2023. A total of 116 emergency department nurses from multiple tertiary hospitals in Shanghai were selected as research subjects using cluster sampling during the peak period of winter H1N1 influenza. The Impact of Event Scale-Revised (IES-R), Maslach Burnout Inventory (MBI), Simplified Coping Style Questionnaire (SCSQ), Connor-Davidson Resilience Scale (CD-RISC), and Social Support Rating Scale (SSRS) were used for data collection. PTSD was defined as IES-R score ≥ 35, and participants were grouped as PTSD positive or negative. The relationship between PTSD and occupational burnout, coping styles, psychological resilience, and social support was analyzed. Results Among the 116 participants, the rate of PTSD positivity was 44.86% (48/107). The MBI scores in all dimensions were significantly higher in the PTSD positive group compared to the PTSD negative group. The positive coping scores in the SCSQ were lower in the positive group, while the negative coping scores were higher. The CD-RISC scores in all dimensions were significantly lower in the PTSD positive group, as were the SSRS scores in all dimensions. Higher emotional exhaustion was significantly associated with increased odds of PTSD (OR = 1.16), indicating that for each one-point increase in emotional exhaustion, the odds of PTSD increased by 16%. Greater reliance on negative coping strategies was also independently associated with PTSD (OR = 1.23). In contrast, higher levels of optimism (a resilience factor) and greater subjective social support were protective, significantly lowering the odds of PTSD (OR = 0.76 and OR = 0.70, respectively). Conclusion The occurrence of PTSD among emergency department nurses during the winter H1N1 influenza season is considerable and closely related to occupational burnout, psychological resilience, coping styles, and social support. These findings highlight the urgent need for attention to this issue. However, this study has several limitations. The sample was only from top - tier hospitals in Shanghai during the winter influenza season, which may limit the generalizability of the findings. Also, relying on self-reported questionnaires may be subject to recall bias and self - reporting subjectivity.

Xu, M., Li, X., Song, L.

Context Baicalin is an active compound which demonstrates cardioprotection effects against myocardial ischaemia/reperfusion injury (MI/RI). Objective To investigate how baicalin protects against myocardial injury and to explore its potential mechanism. We hypothesized that baicalin-modulated macrophages change from M1 (pro-inflammatory subset) to M2 (anti-inflammatory subset) under I/R stress. Materials and methods We established an ischaemia/reperfusion (I/R) model using Sprague Dawley (SD) rat, then baicalin was intragastric administration (20, 60 or 120 mg/kg) for 24 h. The rats were randomly divided into five groups (n = 10): control, I/R, I/R + baicalin (20 mg/kg), I/R + baicalin (60 mg/kg) and I/R + baicalin (120 mg/kg). Cardiac function was detected by echocardiography, HE staining and ELISA, respectively. Macrophage phenotype was examined by flow cytometry. Furthermore, IHC, qRT-PCR and WB were employed to analyse the related mechanisms. Results The study showed that baicalin (20, 60 or 120 mg/kg) significantly improved cardiac function and impeded cardiac apoptosis in rats. In addition, the repair of myocardial morphology (reduced neutrophil infiltration) further confirmed its cardiacprotective effect. Moreover, baicalin effectively decreased iNOS, IL-1β and IL-6, and up-regulated Arg-1, IL-10 and TGF-β via changing the macrophage phenotype (from M1 towards M2). Notably, treatment with baicalin also inhibited the phosphorylation levels of JAK2 and STAT3. Discussion and conclusions: It was confirmed that baicalin alleviated post-I/R myocardial injury and reduced inflammation via JAK/STAT pathway, and baicalin treatment might be recommended as a new approach for myocardial ischaemic complications.

Zheng, Z., Shen, D., Shi, Y., Chai, L., Zhou, Y.

Objective The H1N1 influenza, a highly contagious acute respiratory disease, causes a significant burden on public health, especially during the winter season when the number of cases surges. Emergency department nurses, who are on the frontline of patient care during this period, are exposed to high - stress situations, increasing their risk of developing post - traumatic stress disorder (PTSD). Understanding the status of PTSD among them and its influencing factors is crucial for safeguarding their mental health and ensuring quality healthcare. This study aims to investigate the status of post-traumatic stress disorder (PTSD) among emergency department nurses in multiple tertiary hospitals in Shanghai, China during the winter H1N1 influenza season and analyze its influencing factors. Methods A cross - sectional study design was adopted from October 2023 to December 2023. A total of 116 emergency department nurses from multiple tertiary hospitals in Shanghai were selected as research subjects using cluster sampling during the peak period of winter H1N1 influenza. The Impact of Event Scale-Revised (IES-R), Maslach Burnout Inventory (MBI), Simplified Coping Style Questionnaire (SCSQ), Connor-Davidson Resilience Scale (CD-RISC), and Social Support Rating Scale (SSRS) were used for data collection. PTSD was defined as IES-R score ≥ 35, and participants were grouped as PTSD positive or negative. The relationship between PTSD and occupational burnout, coping styles, psychological resilience, and social support was analyzed. Results Among the 116 participants, the rate of PTSD positivity was 44.86% (48/107). The MBI scores in all dimensions were significantly higher in the PTSD positive group compared to the PTSD negative group. The positive coping scores in the SCSQ were lower in the positive group, while the negative coping scores were higher. The CD-RISC scores in all dimensions were significantly lower in the PTSD positive group, as were the SSRS scores in all dimensions. Higher emotional exhaustion was significantly associated with increased odds of PTSD (OR = 1.16), indicating that for each one-point increase in emotional exhaustion, the odds of PTSD increased by 16%. Greater reliance on negative coping strategies was also independently associated with PTSD (OR = 1.23). In contrast, higher levels of optimism (a resilience factor) and greater subjective social support were protective, significantly lowering the odds of PTSD (OR = 0.76 and OR = 0.70, respectively). Conclusion The occurrence of PTSD among emergency department nurses during the winter H1N1 influenza season is considerable and closely related to occupational burnout, psychological resilience, coping styles, and social support. These findings highlight the urgent need for attention to this issue. However, this study has several limitations. The sample was only from top - tier hospitals in Shanghai during the winter influenza season, which may limit the generalizability of the findings. Also, relying on self-reported questionnaires may be subject to recall bias and self - reporting subjectivity.

Nguyễn, M., Okafor, T., Johansson, S.

Hypertension have attracted growing attention because of their relevance to both theory and practice. In contrast to earlier studies, our approach accounts for heterogeneity and avoids the usual simplifying assumptions. We find a distinct transcriptional program in the responding group. We discuss limitations of the present study and outline how the methods can be extended.