Hypoxia inducible factor 2α promotes tolerogenic macrophage development during cardiac transplantation through transcriptional regulation of colony stimulating factor 1 receptor.

Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice with conditional loss or gain of function, we uncovered that myeloid cell expression of HIF-2α was required for costimulatory blockade-induced transplantation tolerance. While HIF-2α was dispensable for mobilization of tolerogenic monocytes, which were sourced in part from the spleen, it promoted the expression of colony stimulating factor 1 receptor (CSF1R). CSF1R mediates monocyte differentiation into tolerogenic macrophages and was found to be a direct transcriptional target of HIF-2α in splenic monocytes. Administration of the HIF stabilizer, roxadustat, within micelles to target myeloid cells, increased HIF-2α in splenic monocytes, which was associated with increased CSF1R expression and enhanced cardiac allograft survival. These data support further exploration of HIF-2α activation in myeloid cells as a therapeutic strategy for transplantation tolerance.

Phytosulfokine promotes fruit ripening and quality via phosphorylation of transcription factor DREB2F in tomato.

Phytosulfokine (PSK), a plant peptide hormone with a wide range of biological functions, is recognized by its receptor PHYTOSULFOKINE RECEPTOR 1 (PSKR1). Previous studies have reported that PSK plays important roles in plant growth, development, and stress responses. However, the involvement of PSK in fruit development and quality formation remains largely unknown. Here, using tomato (Solanum lycopersicum) as a research model, we show that exogenous application of PSK promotes the initiation of fruit ripening and quality formation, while these processes are delayed in pskr1 mutant fruits. Transcriptomic profiling revealed that molecular events and metabolic pathways associated with fruit ripening and quality formation are affected in pskr1 mutant lines and transcription factors are involved in PSKR1-mediated ripening. Yeast screening further identified that DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN 2F (DREB2F) interacts with PSKR1. Silencing of DREB2F delayed the initiation of fruit ripening and inhibited the promoting effect of PSK on fruit ripening. Moreover, the interaction between PSKR1 and DREB2F led to phosphorylation of DREB2F. PSK improved the efficiency of DREB2F phosphorylation by PSKR1 at the tyrosine-30 site, and the phosphorylation of this site increased the transcription level of potential target genes related to the ripening process and functioned in promoting fruit ripening and quality formation. These findings shed light on the involvement of PSK and its downstream signaling molecule DREB2F in controlling climacteric fruit ripening, offering insights into the regulatory mechanisms governing ripening processes in fleshy fruits.

Glucose-G protein signaling plays a crucial role in tomato resilience to high temperature and elevated CO2.

Global climate change is accompanied by carbon dioxide (CO2) enrichment and high temperature (HT) stress; however, how plants adapt to the combined environments and the underlying mechanisms remain largely unclear. In this study, we show that elevated CO2 alleviated plant sensitivity to HT stress, with significantly increased apoplastic glucose (Glc) levels in tomato (Solanum lycopersicum) leaves. Exogenous Glc treatment enhanced tomato resilience to HT stress under ambient CO2 conditions. Cell-based biolayer interferometry, subcellular localization, and Split-luciferase assays revealed that Glc bound to the tomato regulator of G protein signaling 1 (RGS1) and induced RGS1 endocytosis and thereby RGS1-G protein α subunit (GPA1) dissociation in a concentration-dependent manner. Using rgs1 and gpa1 mutants, we found that RGS1 negatively regulated thermotolerance and was required for elevated CO2-Glc-induced thermotolerance. GPA1 positively regulated the elevated CO2-Glc-induced thermotolerance. A combined transcriptome and chlorophyll fluorescence parameter analysis further revealed that GPA1 integrated photosynthesis- and photoprotection-related mechanisms to regulate thermotolerance. These results demonstrate that Glc-RGS1-GPA1 signaling plays a crucial role in the elevated CO2-induced thermotolerance in tomato. This information enhances our understanding of the Glc-G protein signaling function in stress resilience in response to global climate change and will be helpful for genetic engineering approaches to improve plant resilience.

Nuclear Quantum Effects Accelerate Charge Recombination but Boost the Stability of Inorganic Perovskites in Mild Humidity.

Experiments have demonstrated that mild humidity can enhance the stability of the CsPbBr3 perovskite, though the underlying mechanism remains unclear. Utilizing ab initio molecular dynamics, ring polymer molecular dynamics, and non-adiabatic molecular dynamics, our study reveals that nuclear quantum effects (NQEs) play a crucial role in stabilizing the lattice rigidity of the perovskite while simultaneously shortening the charge carrier lifetime. NQEs reduce the extent of geometric disorder and the number of atomic fluctuations, diminish the extent of hole localization, and thereby improve the electron-hole overlap and non-adiabatic coupling. Concurrently, these effects significantly suppress phonon modes and slow decoherence. As a result, these factors collectively accelerate charge recombination by a factor of 1.42 compared to that in scenarios excluding NQEs. The resulting sub-10 ns recombination time scales align remarkably well with experimental findings. This research offers novel insight into how moisture resistance impacts the stability and charge carrier lifetime in all-inorganic perovskites.

Enhancing the Toughness and Strength of Polymers Using Mechanically Interlocked Hydrogen Bonds.

The energy dissipative features of hydrogen bonds under conditions of mechanical strain have provided an ongoing incentive to explore hydrogen bonding units for the purpose of controlling and customizing the mechanical properties of polymeric materials. However, there remains a need for hydrogen bond units that (1) possess directionality, (2) provide selectivity, (3) dissipate energy effectively, and (4) can be incorporated readily into polymeric materials to regulate their mechanical properties. Here, we report mechanically interlocked hydrogen bond units that incorporate multiple hydrogen bonds within a [2]catenane structure. The conformational flexibility and associated spatial folding characteristics of the [2]catenane units allow for molecular scale motion under external stress, while the interlocked structure serves as a pivot that maintains the directionality and selectivity of the resultant hydrogen bonding units. When incorporated into polymers, these interlocked hydrogen bond motifs serve to strengthen and toughen the resulting materials. This study not only presents a novel hydrogen bond unit for creating polymeric materials with improved mechanical properties but also underscores the unique opportunities that mechanically interlocked hydrogen bond structures may provide across a diverse range of applications.

Altered kidney distribution and loss of ACE2 into the urine in acute kidney injury.

There are diverse pathophysiological mechanisms involved in acute kidney injury (AKI). Among them, overactivity of the renin-angiotensin system (RAS) has been described. Angiotensin-converting enzyme 2 (ACE2) is a tissue RAS enzyme expressed in the apical border of proximal tubules. Given the important role of ACE2 in the metabolism of angiotensin II, this study aimed to characterize kidney and urinary ACE2 in a mouse model of AKI. Ischemia-reperfusion injury (IRI) was induced in C57BL/6 mice by clamping of the left renal artery followed by removal of the right kidney. In kidneys harvested 48 h after IRI, immunostaining revealed a striking maldistribution of ACE2 including spillage into the tubular lumen and the presence of ACE2-positive luminal casts in the medulla. In cortical membranes, ACE2 protein and enzymatic activity were both markedly reduced (37 ± 4 vs. 100 ± 6 ACE2/ß-actin, P = 0.0004, and 96 ± 14 vs. 152 ± 6 RFU/µg protein/h, P = 0.006). In urine, full-length membrane-bound ACE2 protein (100 kDa) was markedly increased (1,120 ± 405 vs. 100 ± 46 ACE2/µg creatinine, P = 0.04), and casts stained for ACE2 were recovered in the urine sediment. In conclusion, in AKI caused by IRI, there is a marked loss of ACE2 from the apical tubular border with deposition of ACE2-positive material in the medulla and increased urinary excretion of full-length membrane-bound ACE2 protein. The deficiency of tubular ACE2 in AKI suggests that provision of this enzyme could have therapeutic applications and that its excretion in the urine may also serve as a diagnostic marker of severe proximal tubular injury.NEW & NOTEWORTHY This study provides novel insights into the distribution of kidney ACE2 in a model of AKI by IRI showing a striking detachment of apical ACE2 from proximal tubules and its loss in urine and urine sediment. The observed deficiency of kidney ACE2 protein and enzymatic activity in severe AKI suggests that administration of forms of this enzyme may mitigate AKI and that urinary ACE2 may serve as a potential biomarker for tubular injury.

Synchronously Sensitive Immunoassay and Efficient Inactivation of Living Zika Virus via DNAzyme Catalytic Amplification and In Situ Aggregation-Induced Emission Photosensitizer Generation.

Sensitive identification and effective inactivation of the virus are paramount for the early diagnosis and treatment of viral infections to prevent the risk of secondary transmission of viruses in the environment. Herein, we developed a novel two-step fluorescence immunoassay using antibody/streptavidin dual-labeled polystyrene nanobeads and biotin-labeled G-quadruplex/hemin DNAzymes with peroxidase-mimicking activity for sensitive quantitation and efficient inactivation of living Zika virus (ZIKV). The dual-labeled nanobeads can specifically bind ZIKV through E protein targeting and simultaneously accumulate DNAzymes, leading to the catalytic oxidation of Amplex Red indicators and generation of intensified aggregation-induced emission fluorescence signals, with a detection limit down to 66.3 PFU/mL and 100% accuracy. Furthermore, robust reactive oxygen species generated in situ by oxidized Amplex Red upon irradiation can completely kill the virus. This sensitive and efficient detection-inactivation integrated system will expand the viral diagnostic tools and reduce the risk of virus transmission in the environment.

Ion-Selective Micropipette Sensor for In Vivo Monitoring of Sodium Ion with Crown Ether-Encapsulated Metal-Organic Framework Subnanopores.

In vivo sensing of the dynamics of ions with high selectivity is essential for gaining molecular insights into numerous physiological and pathological processes. In this work, we report an ion-selective micropipette sensor (ISMS) through the integration of functional crown ether-encapsulated metal-organic frameworks (MOFs) synthesized in situ within the micropipette tip. The ISMS features distinctive sodium ion (Na+) conduction and high selectivity toward Na+ sensing. The selectivity is attributed to the synergistic effects of subnanoconfined space and the specific coordination of 18-crown-6 toward potassium ions (K+), which largely increase the steric hindrance and transport resistance for K+ to pass through the ISMS. Furthermore, the ISMS exhibits high stability and sensitivity, facilitating real-time monitoring of Na+ dynamics in the living rat brain during spreading of the depression events process. In light of the diversity of crown ethers and MOFs, we believe this study paves the way for a nanofluidic platform for in vivo sensing and neuromorphic electrochemical sensing.

Integrative single-cell transcriptomic analyses reveal the cellular ontological and functional heterogeneities of primary and metastatic liver tumors.

BACKGROUND: The global cellular landscape of the tumor microenvironment (TME) combining primary and metastatic liver tumors has not been comprehensively characterized. METHODS: Based on the scRNA-seq and spatial transcriptomic data of non-tumor liver tissues (NTs), primary liver tumors (PTs) and metastatic liver tumors (MTs), we performed the tissue preference, trajectory reconstruction, transcription factor activity inference, cell-cell interaction and cellular deconvolution analyses to construct a comprehensive cellular landscape of liver tumors. RESULTS: Our analyses depicted the heterogeneous cellular ecosystems in NTs, PTs and MTs. The activated memory B cells and effector T cells were shown to gradually shift to inhibitory B cells, regulatory or exhausted T cells in liver tumors, especially in MTs. Among them, we characterized a unique group of TCF7+ CD8+ memory T cells specifically enriched in MTs that could differentiate into exhausted T cells likely driven by the p38 MAPK signaling. With regard to myeloid cells, the liver-resident macrophages and inflammatory monocyte/macrophages were markedly replaced by tumor-associated macrophages (TAMs), with TREM2+ and UBE2C+ TAMs enriched in PTs, while SPP1+ and WDR45B+ TAMs in MTs. We further showed that the newly identified WDR45B+ TAMs exhibit an M2-like polarization and are associated with adverse prognosis in patients with liver metastases. Additionally, we addressed that endothelial cells display higher immune tolerance and angiogenesis capacity, and provided evidence for the source of the mesenchymal transformation of fibroblasts in tumors. Finally, the malignant hepatocytes and fibroblasts were prioritized as the pivotal cell populations in shaping the microenvironments of PTs and MTs, respectively. Notably, validation analyses by using spatial or bulk transcriptomic data in clinical cohorts concordantly emphasized the clinical significance of these findings. CONCLUSIONS: This study defines the ontological and functional heterogeneities in cellular ecosystems of primary and metastatic liver tumors, providing a foundation for future investigation of the underlying cellular mechanisms.

Influenza A virus infection disrupts the function of syncytiotrophoblast cells and contributes to adverse pregnancy outcomes.

Pregnancy heightens susceptibility to influenza A virus (IAV) infection, thereby increasing the risk of severe pneumonia and maternal mortality. It also raises the chances of adverse outcomes in offspring, such as fetal growth restriction, preterm birth, miscarriage, and stillbirth in offsprings. However, the underlying mechanisms behind these effects remain largely unknown. Syncytiotrophoblast cells, crucial in forming the placental barrier, nutrient exchange and hormone secretion, have not been extensively studied for their responses to IAV. In our experiment, we used Forskolin-treated BeWo cells to mimic syncytiotrophoblast cells in vitro, and infected them with H1N1, H5N1 and H7N9 virus stains. Our results showed that syncytiotrophoblast cells, with their higher intensity of sialic acid receptors, strongly support IAV infection and replication. Notably, high-dose viral infection and prolonged exposure resulted in a significant decrease in fusion index, as well as gene and protein expression levels associated with trophoblast differentiation, ß-human chorionic gonadotropin secretion, estrogen and progesterone biosynthesis, and nutrient transport. In pregnant BALB/c mice infected with the H1N1 virus, we observed significant decreases in trophoblast differentiation and hormone secretion gene expression levels. IAV infection also resulted in preterm labor, fetal growth restriction, and increased maternal and fetal morbidity and mortality. Our findings indicate that IAV infection in syncytiotrophoblastic cells can result in adverse pregnancy outcomes by altering trophoblast differentiation, suppressing of ß-hCG secretion, and disrupting placental barrier function.

NrCAM activates the NF-κB signalling pathway by competitively binding to SUMO-1 and promotes Th17 cell differentiation in Graves' disease.

This study aimed to explore the molecular mechanism of neuronal cell adhesion molecule (NrCAM) by regulating Th17 cell differentiation in the pathogenesis of Graves' disease (GD). Naïve CD4+ T cells were isolated from peripheral blood mononuclear cells of GD patients and healthy control (HC) subjects. During the differentiation of CD4+ T cells into Th17 cells, NrCAM level in GD group was improved. Interference with NrCAM in CD4+ T cells of GD patients decreased the percentage of Th17 cells. NrCAM overexpression in CD4+ T cells of HC subjects increased the percentage of Th17 cells and upregulated p-IκBα, p50, p65, c-Rel protein expressions, and NF-κB inhibitor BAY11-7082 partially reversed NrCAM effect. NrCAM overexpression promoted the degradation of IκBα, and overexpression of small ubiquitin-related modifier 1 (SUMO-1) inhibited IκBα degradation. NrCAM overexpression reduced IκBα binding to SUMO-1. During Th17 cell differentiation in HC group, NrCAM overexpression increased IL-21 levels and secretion, and IL-21 neutralizing antibody reversed this effect. IL-21 level was decreased after p65 interference in CD4+ T cells of HC subjects. p65 interacts with IL-21 promoter region. In conclusion, NrCAM binds to SUMO-1 and increases phosphorylation of IκBα, leading to activation of NF-κB pathway, which promotes Th17 cell differentiation.

Psychological well-being trajectories preceding incident mild cognitive impairment and dementia.

BACKGROUND: Poorer psychological well-being has been related to an increased dementia risk, but changes in psychological well-being along the dementia course are unclear. We explored psychological well-being trajectories before and after the diagnosis of mild cognitive impairment (MCI) and dementia. METHODS: Within the Rush Memory and Aging Project, 910 cognitively intact older adults were followed annually for up to 14 years to detect incident MCI and dementia. Psychological well-being and its six components (self-acceptance, autonomy, environmental mastery, purpose in life, positive relation with others, and personal growth) were annually measured based on Ryff's Scales of Psychological Well-Being. Data were analysed using mixed-effect models with a backward timescale. RESULTS: Compared with participants who remained cognitively intact, those who developed incident MCI had a faster decline in psychological well-being (ß -0.015, 95% CI -0.027 to -0.003), leading to lower well-being 2 years before MCI diagnosis (mean difference at year -2, -0.099, 95% CI -0.187 to -0.012). Considering different well-being components, those who developed MCI had lower levels of purpose in life and personal growth beginning 3 years (-0.126, 95% CI -0.251 to -0.001) and 6 years (-0.139, 95% CI -0.268 to -0.009) before MCI, respectively. The slope of psychological well-being decline was similar before and after MCI diagnosis for each component except for positive relation with others, which had an accelerated decline after MCI (ß -0.042, 95% CI-0.075 to -0.009). Well-being trajectories remained similar for individuals with MCI regardless of whether they later developed dementia. CONCLUSIONS: Psychological well-being (specifically purpose in life and personal growth) became significantly lower before MCI diagnosis.

Association of cognitive reserve with the risk of dementia in the UK Biobank: role of polygenic factors.

BACKGROUND: It remains unclear whether cognitive reserve can attenuate dementia risk among people with different genetic predispositions. AIMS: We aimed to examine the association between cognitive reserve and dementia, and further to explore whether and to what extent cognitive reserve may modify the risk effect of genetic factors on dementia. METHOD: Within the UK Biobank, 210 631 dementia-free participants aged ≥60 years were followed to detect incident dementia. Dementia was ascertained through medical and death records. A composite cognitive reserve indicator encompassing education, occupation and multiple cognitively loaded activities was created using latent class analysis, categorised as low, moderate and high level. Polygenic risk scores for Alzheimer's disease were constructed to evaluate genetic risk for dementia, categorised by tertiles (high, moderate and low). Data were analysed using Cox models and Laplace regression. RESULTS: In multi-adjusted Cox models, the hazard ratio (HR) of dementia was 0.66 (95% confidence interval (CI) 0.61-0.70) for high cognitive reserve compared with low cognitive reserve. In Laplace regression, participants with high cognitive reserve developed dementia 1.62 (95% CI 1.35-1.88) years later than those with low cognitive reserve. In stratified analysis by genetic risk, high cognitive reserve was related to more than 30% lower dementia risk compared with low cognitive reserve in each stratum. There was an additive interaction between low cognitive reserve and high genetic risk on dementia (attributable proportion 0.24, 95% CI 0.17-0.31). CONCLUSIONS: High cognitive reserve is associated with reduced risk of dementia and may delay dementia onset. Genetic risk for dementia may be mitigated by high cognitive reserve. Our findings underscore the importance of enhancing cognitive reserve in dementia prevention.

Epidemiology and genotypes analysis of human papillomavirus infection in Beijing, China.

BACKGROUND: This study aimed to investigate the epidemiology of high-risk human papillomavirus (HPV) in the female population in Beijing, China, and identify the relationship between HPV genotypes and host factors. METHODS: HPV testing was performed on women aged 15-89 (mean age 38.0 ± 10.9 years) from Beijing in 2020. High-risk HPV genotyping real-time polymerase chain reaction was used to determine HPV genotypes. The overall prevalence, age-specific prevalence, genotype distribution, and the correlation between HPV genotypes and cervical cytology were analyzed. RESULTS: Among the 25,344 study participants, the single and double infection rates were 18.8% (4,777/25,344) and 4.2% (1,072/25,344), respectively. A total of 6,119 HPV-positive individuals were found to have 91.6% negative results for intraepithelial lesion or malignancy (NILM), 5.8% atypical squamous cells of undetermined significance (ASC-US), 0.9% low-grade squamous intraepithelial lesion (LSIL), and 1.7% high-grade squamous intraepithelial lesion (HSIL). In single HPV infections, the HPV16 genotype was highly associated with cervical cytology severity (χ2 trend = 172.487, P < 0.001). Additionally, HPV infection rates increased gradually with age, and statistical differences were observed across age groups (χ2 = 180.575; P < 0.001). High-risk HPV genotypes were highly prevalent in women below 25 years of age and those aged 55-59 years. Cluster analysis revealed that the 13 HPV genotypes could be roughly divided into two groups in a single infection; however, patterns of infection consistent with biological characteristics were not observed. CONCLUSION: High-risk HPV was found in 24.1% of outpatients, with HPV52, HPV58, HPV16, HPV39, and HPV51 being the most common high-risk genotypes. Single high-risk HPV infection was predominant. HPV16, HPV39, HPV51, and HPV52 were associated with cervical lesion progression. HPV16 infection was especially worrying since it aggravates cervical lesions. Because the infection rates of the 13 HPV genotypes differed by age, the peak HPV infection rate should not guide vaccination, screening, and prevention programs. Instead, these initiatives should be tailored based on the regional HPV distribution characteristics. Moreover, it was determined that Beijing's populace needed to receive treatment for HPV39 infection.

Differentiated metabolomic profiling reveals plasma amino acid signatures for primary glomerular disease.

Primary glomerular disease (PGD) is an idiopathic cause of renal glomerular lesions that is characterized by proteinuria or hematuria and is the leading cause of chronic kidney disease (CKD). The identification of circulating biomarkers for the diagnosis of PGD requires a thorough understanding of the metabolic defects involved. In this study, ultra-high performance liquid chromatography-tandem mass spectrometry was performed to characterize the amino acid (AA) profiles of patients with pathologically diagnosed PGD, including minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), membranous nephropathy, and immunoglobulin A nephropathy. The plasma concentrations of asparagine and ornithine were low, and that of aspartic acid was high, in patients with all the pathologic types of PGD, compared to healthy controls. Two distinct diagnostic models were generated using the differential plasma AA profiles using logistic regression and receiver operating characteristic analyses, with areas under the curves of 1.000 and accuracies up to 100.0% in patients with MCD and FSGS. In conclusion, the progression of PGD is associated with alterations in AA profiles, The present findings provide a theoretical basis for the use of AAs as a non-invasive, real-time, rapid, and simple biomarker for the diagnosis of various pathologic types of PGD.

The cell cycle, autophagy, and cell wall integrity pathway jointly governed by MoSwe1 in Magnaporthe oryzae.

The cell cycle is pivotal to cellular differentiation in plant pathogenic fungi. Cell wall integrity (CWI) signaling plays an essential role in coping with cell wall stress. Autophagy is a degradation process in which cells decompose their components to recover macromolecules and provide energy under stress conditions. However, the specific association between cell cycle, autophagy and CWI pathway remains unclear in model pathogenic fungi Magnaporthe oryzae. Here, we have identified MoSwe1 as the conserved component of the cell cycle in the rice blast fungus. We have found that MoSwe1 targets MoMps1, a conserved critical MAP kinase of the CWI pathway, through protein phosphorylation that positively regulates CWI signaling. The CWI pathway is abnormal in the ΔMoswe1 mutant with cell cycle arrest. In addition, we provided evidence that MoSwe1 positively regulates autophagy by interacting with MoAtg17 and MoAtg18, the core autophagy proteins. Moreover, the S phase initiation was earlier, the morphology of conidia and appressoria was abnormal, and septum formation and glycogen degradation were impaired in the ΔMoswe1 mutant. Our research defines that MoSWE1 regulation of G1/S transition, CWI pathway, and autophagy supports its specific requirement for appressorium development and virulence in plant pathogenic fungi. Video Abstract.

Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway.

AIM: To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD). METHODS: Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 106 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro. RESULTS: The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1ß) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance. CONCLUSION: We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.

Renal aging and mitochondrial quality control.

Mitochondria are dynamic organelles that participate in different cellular process that control metabolism, cell division, and survival, and the kidney is one of the most metabolically active organs that contains abundant mitochondria. Perturbations in mitochondrial homeostasis in the kidney can accelerate kidney aging, and maintaining mitochondrial homeostasis can effectively delay aging in the kidney. Kidney aging is a degenerative process linked to detrimental processes. The significance of aberrant mitochondrial homeostasis in renal aging has received increasing attention. However, the contribution of mitochondrial quality control (MQC) to renal aging has not been reviewed in detail. Here, we generalize the current factors contributing to renal aging, review the alterations in MQC during renal injury and aging, and analyze the relationship between mitochondria and intrinsic renal cells. We also introduce MQC in the context of renal aging, and discuss the study of mitochondria in the intrinsic cells of the kidney, which is the innovation of our paper. In addition, during kidney injury and repair, the specific functions and regulatory mechanisms of MQC systems in resident and circulating cell types remain unclear. Currently, most of the studies we reviewed are based on animal and cellular models, the relationship between renal tissue aging and mitochondria has not been adequately investigated in clinical studies, and there is still a long way to go.

Feasibility of myocardial blood flow quantification to detect flow-limited coronary artery disease with a one-day rest/stress continuous rapid imaging protocol on cardiac-dedicated cadmium zinc telluride single photon emission computed tomography.

BACKGROUND: It is clinically needed to explore a more efficient imaging protocol for single photon emission computed tomography (SPECT) myocardial blood flow (MBF) quantitation derived from cadmium zinc telluride (CZT) SPECT camera for the routine clinical utilization. METHODS: One hundred and twenty patients with matched clinical characteristics and angiographic findings who completed one-day rest/stress SPECT imaging with either the intermittently sequential imaging (ISI) protocol (two dynamic and two electrocardiography (ECG)-gated scans) or the continuous rapid imaging (CRI) protocol (two dynamic/ECG-gated scans) were included. MBF quantitation adopted residual activity correction (RAC) to correct for rest residual activity (RRA) in the stress dynamic SPECT scan for the detection of flow-limited coronary artery disease. RESULTS: The CRI protocol reduced about 6.2 times shorter than the ISI protocol (25.5 min vs 157.6 min), but slightly higher than the RRA (26.7% ± 3.6% vs 22.3% ± 4.9%). With RAC, both protocols demonstrated close stress MBF (2.18 ± 1.13 vs 2.05 ± 1.10, P > 0.05) and myocardial flow reserve (MFR) (2.42 ± 1.05 vs 2.48 ± 1.11, P > 0.05) to deliver comparable diagnostic performance (sensitivity = 82.1%-92.3%, specificity = 81.2%-91.2%). Myocardial perfusion and left ventricular function overall showed no significant difference (all P > 0.26). CONCLUSION: One-day rest/stress SPECT with the CRI protocol and rest RAC is feasible to warrant the diagnostic performance of MBF quantitation with a shortened examination time and enhanced patient comfort. Further evaluation on the impact of extracardiac activity to regional MBF and perfusion pattern is required. Additional evaluation is needed in a patient population that is typical of those referred for SPECT MPI, including those with known or suspected coronary microvascular disease.

Exploitation of multiple host-derived nutrients by the yellow catfish epidermal environment facilitates Vibrio mimicus to sustain infection potency and susceptibility.

Infection with Vibrio mimicus in the Siluriformes has demonstrated a rapid and high infectivity and mortality rate, distinct from other hosts. Our earlier investigations identified necrosis, an inflammatory storm, and tissue remodeling as crucial pathological responses in yellow catfish (Pelteobagrus fulvidraco) infected with V. mimicus. The objective of this study was to further elucidate the impact linking these pathological responses within the host during V. mimicus infection. Employing metabolomics and transcriptomics, we uncovered infection-induced dense vacuolization of perimysium; Several genes related to nucleosidase and peptidase activities were significantly upregulated in the skin and muscles of infected fish. Concurrently, the translation processes of host cells were impaired. Further investigation revealed that V. mimicus completes its infection process by enhancing its metabolism, including the utilization of oligopeptides and nucleotides. The high susceptibility of yellow catfish to V. mimicus infection was associated with the composition of its body surface, which provided a microenvironment rich in various nucleotides such as dIMP, dAMP, deoxyguanosine, and ADP, in addition to several amino acids and peptides. Some of these metabolites significantly boost V. mimicus growth and motility, thus influencing its biological functions. Furthermore, we uncovered an elevated expression of gangliosides on the surface of yellow catfish, aiding V. mimicus adhesion and increasing its infection risk. Notably, we observed that the skin and muscles of yellow catfish were deficient in over 25 polyunsaturated fatty acids, such as Eicosapentaenoic acid, 12-oxo-ETE, and 13-Oxo-ODE. These substances play a role in anti-inflammatory mechanisms, possibly contributing to the immune dysregulation observed in yellow catfish. In summary, our study reveals a host immune deviation phenomenon that promotes bacterial colonization by increasing nutrient supply. It underscores the crucial factors rendering yellow catfish highly susceptible to V. mimicus, indicating that host nutritional sources not only enable the establishment and maintenance of infection within the host but also aid bacterial survival under immune pressure, ultimately completing its lifecycle.