Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model

We examined the impact of gut inflammation on the expression of cytochrome P450 (P450) and other biotransformation genes in male mice using a dextran sulfate sodium (DSS)-induced colitis model. Several P450 isoforms, including CYP1A, CYP2B, CYP2C, and CYP3A, were down-regulated, accompanied by decreases in microsomal metabolism of diclofenac and nifedipine, in the liver and small intestine. The impact of the colitis on in vivo clearance of oral drugs varied for four different drugs tested: a small decrease for nifedipine, a relatively large decrease for lovastatin, but no change for pravastatin, and a large decrease in the absorption of cyclosporine A. To further assess the scope of influence of gut inflammation on gene expression, we performed genome-wide expression analysis using RNA-seq, which showed down-regulation of many CYPs, non-CYP phase-I enzymes, phase-II enzymes and transporters, and up-regulation of many other members of these gene families, in both liver and intestine of adult C57BL/6 mice, by DSS-induced colitis. Overall, our results indicate that gut inflammation suppresses the expression of many P450s and other biotransformation genes in the intestine and liver, and alters the pharmacokinetics for some but not all drugs, potentially affecting therapeutic efficacy or causing adverse effects in a drug-specific fashion.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Transient expression of fluorescently tagged proteins in developing maize aleurone cells

publishedVersio

A Demand-Supply Cooperative Responding Strategy in Power System with High Renewable Energy Penetration

Industrial demand response (IDR) plays an important role in promoting the utilization of renewable energy (RE) in power systems. However, it will lead to power adjustments on the supply side, which is also a non-negligible factor in affecting RE utilization. To comprehensively analyze this impact while enhancing RE utilization, this paper proposes a power demand-supply cooperative response (PDSCR) strategy based on both day-ahead and intraday time scales. The day-ahead PDSCR determines a long-term scheme for responding to the predictable trends in RE supply. However, this long-term scheme may not be suitable when uncertain RE fluctuations occur on an intraday basis. Regarding intraday PDSCR, we formulate a profit-driven cooperation approach to address the issue of RE fluctuations. In this context, unreasonable profit distributions on the demand-supply side would lead to the conflict of interests and diminish the effectiveness of cooperative responses. To mitigate this issue, we derive multi-individual profit distribution marginal solutions (MIPDMSs) based on satisfactory profit distributions, which can also maximize cooperative profits. Case studies are conducted on an modified IEEE 24-bus system and an actual power system in China. The results verify the effectiveness of the proposed strategy for enhancing RE utilization, via optimizing the coordination of IDR flexibility with generation resources.Comment: Accepted by IEEE Transactions on Control Systems Technolog

Fabrication and Characterization of Collagen/PVA Dual-Layer Membranes for Periodontal Bone Regeneration

Guided tissue regeneration (GTR) is a promising treatment for periodontal tissue defects, which generally uses a membrane to build a mechanical barrier from the gingival epithelium and hold space for the periodontal regeneration especially the tooth-supporting bone. However, existing membranes possess insufficient mechanical properties and limited bioactivity for periodontal bone regenerate. Herein, fish collagen and polyvinyl alcohol (Col/PVA) dual-layer membrane were developed via a combined freezing/thawing and layer coating method. This dual-layer membrane had a clear but contact boundary line between collagen and PVA layers, which were both hydrophilic. The dual membrane had an elongation at break of 193 ± 27% and would undergo an in vitro degradation duration of more than 17 days. Further cell experiments showed that compared with the PVA layer, the collagen layer not only presented good cytocompatibility with rat bone marrow-derived mesenchymal stem cells (BMSCs), but also promoted the osteogenic genes (RUNX2, ALP, OCN, and COL1) and protein (ALP) expression of BMSCs. Hence, the currently developed dual-layer membranes could be used as a stable barrier with a stable degradation rate and selectively favor the bone tissue to repopulate the periodontal defect. The membranes could meet the challenges encountered by GTR for superior defect repair, demonstrating great potential in clinical applications

The intergenerational impact of house prices on education: evidence from China

We investigate heterogeneous and nonlinear intergenerational transmission of education and the impact on this of house prices. Using the China Household Finance Survey, we construct household history of property purchases and educational investment over the past 16 years with current filial educational achievement. High house prices tighten the household's credit constraints, resulting in the concave slopes of filial education as a function of father's education. On average one standard deviation in father's (mother's) education accounts for 0.375 (0.098) standard deviations of filial education. Decomposition reveals the “glass ceiling” and the “glass floor” in two tails of education distribution

Reverse atrial remodeling in heart failure with recovered ejection fraction

Background Heart failure with recovered ejection fraction (HFrecEF) has been a newly recognized entity since 2020. However, the concept has primarily focused on left ventricular ejection fraction improvement, with less focus on the recovery of the left atrium. In this study, we investigated changes in left atrial (LA) echocardiographic indices in HFrecEF. Methods and Results An inpatient cohort with heart failure with reduced ejection fraction (HFrEF) was identified retrospectively and followed up prospectively in a single tertiary hospital. The enrolled patients were classified into HFrecEF and persistent HFrEF groups. Alternations in LA parameters by echocardiography were calculated. The primary outcome was a composite of cardiovascular death or heart failure rehospitalization. A total of 699 patients were included (HFrecEF: n=228; persistent HFrEF: n=471). Compared with persistent HFrEF, the HFrecEF group had greater reductions in LA diameter, LA transverse diameter, LA superior–inferior diameter, LA volume, and LA volume index but not in LA sphericity index. Cox regression analysis showed that the HFrecEF group experienced lower risks of prespecified end points than the persistent HFrEF group after adjusting for confounders. Additionally, 136 (59.6%) and 62 (13.0%) patients showed LA reverse remodeling (LARR) for the HFrecEF and persistent HFrEF groups, respectively. Among the HFrecEF subgroup, patients with LARR had better prognosis compared with those without LARR. Multivariate logistic analysis demonstrated that age and coronary heart disease were 2 independent negative predictors for LARR. Conclusions In HFrecEF, both left ventricular systolic function and LA structure remodeling were improved. Patients with HFrecEF with LARR had improved clinical outcomes, indicating that the evaluation of LA size provides a useful biomarker for risk stratification of heart failure

Safety and efficacy of ex vivo expanded CD34 stem cells in murine and primate models

Background: Hematopoietic stem cell (HSC) transplantation has been widely applied to the treatment of malignant blood diseases. However, limited number of functional HSCs hinders successful transplantation. The purpose of our current study is to develop a new and cost-efficient medium formulation that could greatly enhance the expansion of HSCs while retaining their long-term repopulation and hematopoietic properties for effective clinical transplantation. Methods: Enriched human CD34(+) cells and mobilized nonhuman primate peripheral blood CD34(+) cells were expanded with a new, cost-efficient expansion medium formulation, named hematopoietic expansion medium (HEM), consisting of various cytokines and nutritional supplements. The long-term repopulation potential and hematologic-lineage differentiation ability of expanded human cells were studied in the non-obese diabetic/severe combined immunodeficiency mouse model. Furthermore, the efficacy and safety studies were performed by autologous transplantation of expanded primate cells in the nonhuman primate model. Results: HEM could effectively expand human CD34(+) cells by up to 129 fold within 9 days. Expanded HSCs retained long-term repopulation potential and hematologic-lineage differentiation ability, as indicated by (1) maintenance (over unexpanded HSCs) of immunophenotypes of CD38(-)CD90(+)CD45RA(-)CD49f(+) in CD34(+) cells after expansion; (2) significant presence of multiple human hematopoietic lineages in mouse peripheral blood and bone marrow following primary transplantation; (3) enrichment (over unexpanded HSCs) in SCID-repopulating cell frequency measured by limiting dilution analysis; and (4) preservation of both myeloid and lymphoid potential among human leukocytes from mouse bone marrow in week 24 after primary transplantation or secondary transplantation. Moreover, the results of autologous transplantation in nonhuman primates demonstrated that HEM-expanded CD34(+) cells could enhance hematological recovery after myelo-suppression. All primates transplanted with the expanded autologous CD34(+) cells survived for over 18 months without any noticeable abnormalities. Conclusions: Together, these findings demonstrate promising potential for the utility of HEM to improve expansion of HSCs for clinical application.State Scientific Key Projects for New Drug Research and Development [2011ZX09102-010-04, 2011ZX09401-027]; International Cooperation and Exchange Program, China [2013DFA30830]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Efficacy of guideline-directed medical treatment in heart failure with mildly reduced ejection fraction.

Heart failure with mildly reduced ejection fraction (HFmrEF) has received increasing attention following the publication of the latest ESC guidelines in 2021. However, it remains unclear whether patients with HFmrEF could benefit from guideline-directed medical treatment (GDMT), referring the combination of ACEI/ARB/ARNI, β-blockers, and MRAs, which are recommended for those with reduced ejection fraction. This study explored the efficacy of GDMT in HFmrEF patients. This was a retrospective cohort study of HFmrEF patients admitted to The First Affiliated Hospital of Dalian Medical University between 1 September 2015 and 30 November 2019. Propensity score matching (1:2) between patients receiving triple-drug therapy (TT) and non-triple therapy (NTT) based on age and sex was performed. The primary outcome was all cause death, cardiac death, rehospitalization from any cause, and rehospitalization due to worsening heart failure. Of the 906 patients enrolled in the matched cohort (TT group, n = 302; NTT group, N = 604), 653 (72.08%) were male, and mean age was 61.1 ± 11.92. Survival analysis suggested that TT group experienced a significantly lower incidence of prespecified primary endpoints than NTT group. Multivariable Cox regression showed that TT group had a lower risk of all-cause mortality (HR 0.656, 95% CI 0.447-0.961, P = 0.030), cardiac death (HR 0.599, 95% CI 0.380-0.946, P = 0.028), any-cause rehospitalization (HR 0.687, 95% CI 0.541-0.872, P = 0.002), and heart failure rehospitalization (HR 0.732, 95% CI 0.565-0.948, P = 0.018). In patients with HFmrEF, combined use of neurohormonal antagonists produces remarkable effects in reducing the occurrence of the primary outcome of rehospitalization and death. Thus, the treatment of HFmrEF should be categorized as HFrEF due to the similar benefit of neurohormonal blocking therapy in HFrEF and HFmrEF. [Abstract copyright: © 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.