Mouse Model Established by Early Renal Transplantation After Skin Allograft Sensitization Mimics Clinical Antibody-Mediated Rejection

Antibody-mediated rejection (AMR) is the main barrier to renal graft survival, and mouse renal AMR models are important to study this process. Current mouse models are established by priming the recipient to donor skin for over 7 days before kidney transplantation. The robustness of AMR in these cases is too strong to mimic clinical AMR and it is unclear why altering the priming times ranging from 7 to 91 days fails to reduce the AMR potency in these models. In the present study, we found that the donor-recipient combination and skin graft size were determinants of donor-specific antibody (DSA) development patterns after skin transplantation. DSA-IgG was sustained for over 100 days after skin challenge, accounting for an identical AMR robustness upon different skin priming times over 7 days. However, decreasing the skin priming time within 7 days attenuated the robustness of subsequent renal allograft AMR in C3H to Balb/c mice. Four-day skin priming guaranteed that recipients develop acute renal AMR mixed with a high ratio of graft-infiltrating macrophages, renal grafts survived for a mean of 6.4 ± 2.1 days, characterized by typical AMR histological changes, such as glomerulitis, peritubular capillary (PTC) dilation, and capillaritis, deposition of IgG and C3d in PTCs, but less prevalence of microthrombus, whereas the cellular rejection histological change of tubulitis was absent to mild. With this scheme, we also found that the renal AMR model can be developed using common mouse strains such as C57BL/6 and Balb/c, with mean prolonged renal graft survival times of 14.4 ± 5.0 days. Finally, we proved that donor-matched skin challenge after kidney transplantation did not strongly affect DSA development and kidney graft outcome. These findings may facilitate an understanding and establishment of mouse renal allograft AMR models and promote AMR-associated studies

Establishing thresholds of handgrip strength based on mortality using machine learning in a prospective cohort of Chinese population

BackgroundThe relative prognostic importance of handgrip strength (HGS) in comparison with other risk factors for mortality remains to be further clarified, and thresholds used for best identify high-risk individuals in health screening are not yet established. Using machine learning and nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), the study aimed to investigate the prognostic importance of HGS and establish sex-specific thresholds for health screening.MethodsA total of 6,762 participants from CHARLS were enrolled. A random forest model was built using 30 variables with all-cause mortality as outcome. SHapley Additive exPlanation values were applied to explain the model. Cox proportional hazard models and Harrell’s C index change were used to validate the clinical importance of the thresholds.ResultsAmong the participants, 3,102 (45.9%) were men, and 622 (9.1%) case of death were documented follow-up period of 6.78 years. The random forest model identified HGS as the fifth important prognostic variable, with thresholds for identifying high-risk individuals were < 32 kg in men and < 19 kg in women. Low HGS were associated with all-cause mortality [HR (95% CI): 1.77 (1.49–2.11), p < 0.001]. The addition of HGS thresholds improved the predictive ability of an established office-based risk score (C-index change: 0.022, p < 0.001).ConclusionOn the basis of our thresholds, low HGS predicted all-cause mortality better than other risk factors and improved prediction of a traditional office-based risk score. These results reinforced the clinical utility of measurement of HGS in health screening

Temporal Trends and Differences in Sexuality among Depressed and Non-Depressed Adults in the United States

This study aimed to examine temporal trends and differences in sexuality between depressed and non-depressed adults aged 18–59 in the United States from 2005 to 2016. A total of 21,437 people (5432 with depression) were enrolled in this cross-sectional study. From 2005–2008 to 2013–2016, the average age at first sexual intercourse decreased, while the proportion of normal frequency of sexual activity and heterosexual sexual orientation increased among all the participants. Some differences in sexuality were found between the depressed and non-depressed groups. The average age at first sexual intercourse (p < 0.001), the proportion of normal frequency of sexual activity (p < 0.001), and heterosexual sexual orientation (p < 0.001) were lower in depressed participants, and the differences did not change over time (pfor trend = 0.926 of average age at first sexual intercourse, pfor trend = 0.823 of normal frequency of sexual activity, pfor trend = 0.926 of heterosexual sexual orientation). Moreover, these differences were associated with marital status (pfor interaction < 0.001 by average age at first sexual intercourse), employment status (pfor interaction < 0.001 by average age at first sexual intercourse), education status (pfor interaction = 0.023 by heterosexual sexual orientation) and family income status (pfor interaction = 0.013 by average age at first sexual intercourse and pfor interaction = 0.017 by normal frequency of sexual activity). In conclusion, the study found that the age at first sexual intercourse decreased and the frequency of sexual intercourse increased in all the participants, and differences in sexuality between depressed and non-depressed participants were present; however, these differences had no further increase or decrease during the 12-year period. These differences were associated with marital status, employment status, education status, and family income status. These findings show differences in sexuality between depressed and non-depressed patients but are somewhat different from previous studies; the results may provide directions for future research and social work

Protective role of nitric oxide donors on endothelium in ischemia-reperfusion injury: a meta-analysis of randomized controlled trials

Abstract Background Decreased bioavailability of nitric oxide (NO) under hypoxic conditions can lead to endothelial dysfunction. NO supplementation may protect endothelial function in ischemia-reperfusion (IR) injury. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to verify the protective effect of NO donors on endothelium in IR injury. Methods Medline, Embase, Cochrane Library, and Web of Science databases were searched from inception to April 1, 2023. The specific inclusion criteria were as follows: (1) RCTs; (2) trials comparing NO donors with placebo control groups; and (3) trials reporting the effects of these interventions on vascular endothelial functional outcomes in IR injury. Random-effects models were used to assess pooled effect sizes, which were expressed as standardized mean differences (SMD). Results Seven studies satisfied the inclusion criteria and consisted of a total of 149 participants. NO donors were protective of endothelial function in IR injury (SMD: − 1.60; 95% confidence interval [CI]: − 2.33, − 0.88, P < 0.0001; heterogeneity [I2 = 66%, P = 0.001]). Results of the subgroup analysis showed the following: absence of protective effect of NO donor use following ischemia on endothelial function in IR injury − 1.78 (95% CI: − 2.50, − 1.07) and loss of protective effect on endothelial function after prolonged NO donor use − 0.89 (95% CI: − 2.06, 0.28). Conclusion The short-period use of NO donors before the onset of ischemia can protect endothelial function in IR injury

A Comprehensive Assessment of the Chinese Version of the Duke Activity Status Index in Patients with Cardiovascular Diseases

Background: Exercise capacity serves as a direct representation of cardiac function. The Duke Activity Status Index (DASI), a self-administered 12-item questionnaire, covers aspects of daily living, household tasks, sexual function, and physical activity. Although widely used to evaluate exercise capacity, its validation in Chinese cardiovascular disease (CVD) patients has not been thoroughly explored. Considering the significant cultural and lifestyle differences between China and Western countries, which may influence Chinese patients’ comprehension and responses to DASI, our objective is to culturally adapt DASI for Chinese patients with CVD to ensure its precision in assessing exercise capacity. Methods: The cultural adaptation of the original DASI questionnaire into Chinese followed a rigorous process to ensure its validity, reliability, and sensitivity to Chinese CVD patients. The study included 107 outpatients diagnosed with CVD who completed the DASI and cardiopulmonary exercise testing (CPET). Cronbach’s alpha, Spearman correlation, and factor analysis were utilized to test reliability and validity. Receiver operating characteristic (ROC) curve analysis was employed to assess the prognostic utility of the DASI. Results: Participants had a mean DASI score of 39.40 ± 10.75 and a peak oxygen uptake (Peak VO2) of 19.53 ± 5.89 mL/min/kg. The Chinese version of the DASI exhibited satisfactory reliability and validity in CVD patients, with a Chronbach’s alpha coefficient of 0.706. The DASI score demonstrated a moderate correlation with Peak VO2 measured by CPET (r = 0.67, p < 0.001). Factor analysis yielded three factors, accounting for 56.76% of the total variance, with factor 1 contributing to 26.38% of the variance. ROC curve analysis demonstrated that the DASI exhibited discriminative utility in the identification of patients with improved long-term prognosis (p < 0.001). The ROC curve had an area of 0.788 [95% confidence interval (CI) = 0.704–0.871]. The DASI score ≥36.85 served as the optimal threshold for enhanced long-term prognosis, exhibiting a sensitivity of 0.80 and a specificity of 0.69. Conclusions: The culturally adapted DASI questionnaire is a straightforward and efficient tool for reasonably evaluating exercise capacity in Chinese CVD patients

Noninvasive and quantitative measurement of C4d deposition for the diagnosis of antibody-mediated cardiac allograft rejectionResearch in context

Background: C4d is a specific biomarker for the diagnosis of antibody-mediated rejection (AMR) after cardiac transplantation. Although strongly recommended, routine C4d surveillance is hindered by the invasive nature of endomyocardial biopsy. Targeted ultrasound (US) has high sensitivity, and C4d is abundantly expressed within the graft of patients experiencing AMR, which makes it possible to visualize C4d deposition in vivo using targeted US. Methods: We designed a serial dilution of C4d-targeted microbubbles (MBC4d) using a streptavidin-biotin conjugation system. A rat model of AMR with C4d deposition was established by pre-sensitization with skin transplantation before cardiac transplantation. MBC4d were injected into recipients and then qualitatively and quantitatively analyzed using the destruction-replenishment method with a clinical US imaging system and analyzed by software. Findings: We successfully obtained qualitative images of C4d deposition in a wide cardiac allograft section, which, for the first time, reflected real-time C4d distribution. Moreover, normal intensity difference was used for quantitative analysis and exhibited an almost nearly linear correlation with the grade of C4d deposition according to the pathologic evidence. In addition, MBC4d injection did not affect the survival and aggravate injury, which demonstrates its safety. Interpretation: This study demonstrates a noninvasive, quantitative and safe evaluation method for C4d. As contrast-enhanced US has been widely used in clinical settings, this technology is expected to be applied quickly to clinical practice. Fund: National Natural Science Foundation of China and Guangdong Province, Leading Scientific Talents of Guangdong special support program, the Science and Technology Project of Guangdong Province and Guangzhou City. Keywords: Noninvasive, Antibody-mediated rejection, C4d, Cardiac transplantation, Targeted microbubble

In Vivo Attenuation of Antibody-Mediated Acute Renal Allograft Rejection by Ex Vivo TGF-β-Induced CD4+Foxp3+ Regulatory T Cells

Antibody-mediated rejection (AMR) has emerged as the major cause of renal allograft dysfunction, and more effective strategies need to be explored for improving transplant outcomes. Regulatory T cells (Tregs), consisting of at least natural and induced Treg subsets, suppress effector responses at multiple levels and play a key role in transplantation tolerance. In this study, we investigated the effect of induced Tregs (iTregs) on preventing antibody-mediated renal injury and rejection in a mouse model. We observed that infusion of iTregs markedly attenuated histological graft injury and rejection and significantly improved renal allograft survival. iTregs exhibited a comprehensive ability to regulate immunological disorders in AMR. First, iTreg treatment decreased the levels of circulating antidonor antibody and the antibody deposition within allografts. Second, iTregs significantly reduced cell infiltration including CD4+ T cells (including Th1, Th17, and Tfh), CD8+IFN-γ+ cells, natural killer cells, B cells, and plasma cells, which are involved in the process of AMR. Our results also highlight a predominance of M1 macrophage infiltration in grafts with acute AMR, and M1 macrophage could be reduced by iTreg treatment. Collectively, our data demonstrate, for the first time, that TGF-β-induced Tregs can attenuate antibody-mediated acute renal allograft injury through targeting multiple effectors. Thus, use of iTregs in prevention of AMR in clinical practice could be expected

Distinct Geographical Distribution of the <i>Miscanthus</i> Accessions with Varied Biomass Enzymatic Saccharification

<div><p><i>Miscanthus</i> is a leading bioenergy candidate for biofuels, and it thus becomes essential to characterize the desire natural <i>Miscanthus</i> germplasm accessions with high biomass saccharification. In this study, total 171 natural <i>Miscanthus</i> accessions were geographically mapped using public database. According to the equation [P(H/L| East) = P(H/L∩East)/P(East)], the probability (P) parameters were calculated on relationships between geographical distributions of <i>Miscanthus</i> accessions in the East of China, and related factors with high(H) or low(L) values including biomass saccahrification under 1% NaOH and 1% H₂SO₄ pretreatments, lignocellulose features and climate conditions. Based on the maximum P value, a golden cutting line was generated from 42°25’ N, 108°22’ E to 22°58’ N, 116°28’ E on the original locations of <i>Miscanthus</i> accessions with high P(H|East) values (0.800–0.813), indicating that more than 90% <i>Miscanthus</i> accessions were originally located in the East with high biomass saccharification. Furthermore, the averaged insolation showed high P (H|East) and P(East|H) values at 0.782 and 0.754, whereas other climate factors had low P(East|H) values, suggesting that the averaged insolation is unique factor on <i>Miscanthus</i> distributions for biomass saccharification. In terms of cell wall compositions and wall polymer features, both hemicelluloses level and cellulose crystallinity (CrI) of <i>Miscanthus</i> accessions exhibited relative high P values, suggesting that they should be the major factors accounting for geographic distributions of <i>Miscanthus</i> accessions with high biomass digestibility.</p></div

Variation of biomass saccharification in four <i>Miscanthus</i> species.

<p>Variation of biomass saccharification in four <i>Miscanthus</i> species.</p

Variation of meteorological factors in four major <i>Miscanthus</i> species.

<p>Variation of meteorological factors in four major <i>Miscanthus</i> species.</p