Augmenter of liver regeneration knockout aggravates tubular ferroptosis and macrophage activation by regulating carnitine palmitoyltransferase-1A-induced lipid metabolism in diabetic nephropathy.

AIM: Ferroptosis is a novel type of programmed cell death that performs a critical function in diabetic nephropathy (DN). Augmenter of liver regeneration (ALR) exists in the inner membrane of mitochondria, and inhibits inflammation, apoptosis, and oxidative stress in acute kidney injury; however, its role in DN remains unexplored. Here, we aimed to identify the role of ALR in ferroptosis induction and macrophage activation in DN. METHODS: The expression of ALR was examined in DN patients, db/db DN mice, and HK-2 cells treated with high glucose (HG). The effects of ALR on ferroptosis and macrophage activation were investigated with ALR conditional knockout, lentivirus transfection, transmission electron microscopy, qRT-PCR and western blotting assay. Mass spectrometry and rescue experiments were conducted to determine the mechanism of ALR. RESULTS: ALR expression was reduced in the kidney tissues of DN patients and mice, serum of DN patients, and HG-HK-2 cells. Moreover, the inhibition of ALR promoted ferroptosis, macrophage activation, and DN progression. Mechanistically, ALR can directly bind to carnitine palmitoyltransferase-1A (CPT1A), the key rate-limiting enzyme of fatty acid oxidation (FAO), and inhibit the expression of CPT1A to regulate lipid metabolism involving FAO and lipid droplet-mitochondrial coupling in DN. CONCLUSION: Taken together, our findings revealed a crucial protective role of ALR in ferroptosis induction and macrophage activation in DN and identified it as an alternative diagnostic marker and therapeutic target for DN.

STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.

Microbial imidazole propionate affects glomerular filtration rate in patients with diabetic nephropathy through association with HSP90α.

Imidazole propionate (ImP) is a detrimental metabolite produced by the fermentation of histidine intermediates via the intestinal flora. Here, the untargeted metabolite analysis of plasma metabolites from patients with diabetic nephropathy (DN), in combination with the Human Metabolome Database, revealed significantly increased levels of ImP in patients with DN, with a positive correlation with patients' blood creatinine concentration and urinary albumin-to-creatinine ratio, and a negative correlation with the glomerular filtration rate. RNA-seq was applied to detect the effects of ImP on renal tissue transcriptome in mice with DN. It demonstrated that ImP exacerbated renal injury in mice with DN and promoted renal tubular epithelial-mesenchymal transition (EMT), leading to renal mesenchymal fibrosis and renal impairment. Furthermore, ImP was found to directly target HAP90α and activate the PI3K-Akt signalling pathway, which is involved in EMT, by the drug affinity response target stability method. The findings showed that ImP may provide a novel target for DN quality, as it can directly bind to and activate HSP90, thereby facilitating the development of DN while acting as a potential indicator for the clinical diagnosis of DN.

Circadian syndrome is associated with the development of chronic kidney disease and rapid decline in kidney function in middle-aged and elder adults: a China nationwide cohort study.

PURPOSE: The correlation between circadian syndrome (CircS) and kidney outcomes is currently supported by limited empirical evidence. Thus, the objective of this study was to determine the potential relationship between CircS and the development of chronic kidney disease (CKD), as well as the rapid decline in renal function. MATERIALS AND METHODS: We utilized data from the 2011 China Health and Retirement Longitudinal Study (CHARLS), which involved 6002 Chinese adults ≥40 years of age. Among these participants, 3670 subsequently had follow-up evaluations in the 2015 survey. The primary outcome was the development of CKD, as defined by an estimated glomerular filtration rates decrease to a level <60 ml/min/1.73 m2, while the secondary outcome was rapid decline in renal function, as defined by an estimated glomerular filtration rates decrease of >5 ml/min/1.73 m2 per year. Multivariable logistic regression analysis was utilized to determine the association between CircS and kidney outcomes. RESULTS: Compared to participants without CircS, those with CircS had a higher risk of CKD in the cross-sectional studies conducted in 2011 (OR, 1.292; 95% CI, 1.053-1.585) and 2015 (OR, 1.860; 95% CI, 1.469-2.355). Participants with CircS in the longitudinal cohort study had a higher risk of progressing to CKD (OR, 3.050; 95% CI, 2.052-4.534) and a rapid decline in renal function (OR, 1.959; 95% CI, 1.433-2.677) after 4 years of follow-up evaluations and adjustment for covariates. Moreover, participants who had CircS with ≥6 CirS components had the highest risk of a rapid decline in renal function (OR, 1.703; 95% CI, 1.054-2.753). CONCLUSION: CirS significantly increased the risk of CKD progression and rapid decline in renal function among middle-aged and elder individuals. Our study findings highlights the importance of recognizing and managing CirC as a preventative strategy for CKD.

GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression.

Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time at which GLIS3 target genes, such as Slc5a5 (Nis), become expressed. This, together with observations showing that ubiquitous Glis3KO mice do not display major changes in prenatal thyroid gland morphology, indicated that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of GLIS3 in postnatal thyroid suggested a link between GLIS3 protein expression and blood TSH levels. This was supported by data showing that treatment with TSH, cAMP, or adenylyl cyclase activators or expression of constitutively active PKA enhanced GLIS3 protein stability and transcriptional activity, indicating that GLIS3 activity is regulated at least in part by TSH/TSHR-mediated activation of PKA. The TSH-dependent increase in GLIS3 transcriptional activity would be critical for the induction of GLIS3 target gene expression, including several thyroid hormone (TH) biosynthetic genes, in thyroid follicular cells of mice fed a low iodine diet (LID) when blood TSH levels are highly elevated. Like TH biosynthetic genes, the expression of cell cycle genes is suppressed in ubiquitous Glis3KO mice fed a LID; however, in thyroid-specific Glis3 knockout mice, the expression of cell cycle genes was not repressed, in contrast to TH biosynthetic genes. This indicated that the inhibition of cell cycle genes in ubiquitous Glis3KO mice is dependent on changes in gene expression in GLIS3 target tissues other than the thyroid.

Loss of nephric augmenter of liver regeneration facilitates acute kidney injury via ACSL4-mediated ferroptosis.

Ferroptosis, characterized by lipid accumulation in intracellular compartments, is related to acute kidney injury (AKI), but the mechanism remains obscure. In our previous study, the protective effect of augmenter of liver regeneration (ALR) on AKI was not fully clarified. In this study, we established an AKI mouse model by knocking out proximal tubule-specific ALR and an AKI cell model by inducing hypoxia, as well as enrolled AKI patients, to investigate the effects of ALR on ferroptosis and the progression of AKI. We found that ALR knockout aggravated ferroptosis and increased ROS accumulation and mitochondrial damage, whereas ALR overexpression attenuated ferroptosis through clearance of ROS and maintenance of mitochondrial morphology. Mechanistically, we demonstrated that ALR could directly bind to long-chain-fatty-acid-CoA ligase 4 (ACSL4) and further inhibit the expression of ACSL4 by interacting with certain regions. By resolution liquid chromatography coupled with triple quadruple mass spectrometry, we found that ALR could reduce the contents of polyunsaturated fatty acids, especially arachidonic acid. In addition, we showed that ALR binds to ACSL4 and attenuates oxylipin accumulation, exerting a protective effect against ferroptosis in AKI. Therefore, targeting renal ALR can attenuate ferroptosis and can offer a promising strategy for the treatment of AKI.

Sfrp2 promotes renal dysfunction of diabetic kidney disease via modulating Fzd5-induced cytosolic calcium ion concentration and CaMKII/Mek/Erk pathway in mesangial cells.

OBJECTIVE: Mesangial cells (MCs) in the kidney play central role in maintaining glomerular integrity, and their abnormal proliferation leads to major glomerular diseases including diabetic kidney disease (DKD). Although high blood glucose elicits MCs impairment, the underlying molecular mechanism is poorly understood. The present study aimed to investigate the effect of secreted frizzled-related protein 2 (Sfrp2) from single-nucleus RNA profiling on MC proliferation of DKD in vitro and in vivo and explored the specific mechanisms. RESULTS: By snRNA-seq analysis of isolated renal cells from leptin receptor-deficient db/db mice and control db/m mice, we found that Sfrp2 was increased in the MCs of DKD in comparison to other intrinsic renal cells, which was further verified in vitro and in vivo. We also found that the expression of Sfrp2 was significantly upregulated in DKD patients and correlated with renal function, demonstrating that Sfrp2 might serve as an independent biomarker for DKD patients. Functionally, we showed the loss and acquisition of Sfrp2 affected cytosolic Ca2+ concentration, cell proliferation and fibrosis of MC, albuminuria and kidney injury in vitro and in vivo. Mechanistically, we identify c-Jun as a transcription factor of Sfrp2 promoting its transcription, and the Ca2+ signaling related protein frizzled receptor 5 (Fzd5) as the binding protein of Sfrp2. And we further found Sfrp2 promoted Fzd5-induced cytosolic Ca2+ concentration and the downstream CaMKII/Mek/Erk pathway activation, leading to MC proliferation and fibrosis in DKD. CONCLUSION: Our study revealed a novel involvement for Sfrp2 in the regulation of MC function and the effect of Sfrp2 on cell proliferation and fibrosis of MC via the Fzd5/Ca2+/CaMKII/Mek/Erk pathway, implying that Sfrp2 may be a possible biomarker and therapeutic target for DKD.

CircUBXN7 promotes macrophage infiltration and renal fibrosis associated with the IGF2BP2-dependent SP1 mRNA stability in diabetic kidney disease.

Introduction: Inflammatory cell infiltration is a novel hallmark of diabetic kidney disease (DKD), in part, by activated macrophages. Macrophage-to-tubular epithelial cell communication may play an important role in renal fibrosis. Circular RNAs (circRNAs) have been reported in the pathogenesis of various human diseases involving macrophages activation, including DKD. However, the exact mechanism of circRNAs in macrophage infiltration and renal fibrosis of DKD remains obscure. Methods: In our study, a novel circRNA circUBXN7 was identified in DKD patients using microarray. The function of circUBXN7 in vitro and in vivo was investigated by qRT-PCR, western blot, and immunofluorescence. Finally, a dual-luciferase reporter assay, ChIP, RNA pull-down, RNA immunoprecipitation and rescue experiments were performed to investigate the mechanism of circUBXN7. Results: We demonstrated that the expression of circUBXN7 was significantly upregulated in the plasma of DKD patients and correlated with renal function, which might serve as an independent biomarker for DKD patients. According to investigations, ectopic expression of circUBXN7 promoted macrophage activation, EMT and fibrosis in vitro, and increased macrophage infiltration, EMT, fibrosis and proteinuria in vivo. Mechanistically, circUBXN7 was transcriptionally upregulated by transcription factor SP1 and could reciprocally promote SP1 mRNA stability and activation via directly binding to the m6A-reader IGF2BP2 in DKD. Conclusion: CircUBXN7 is highly expressed in DKD patients may provide the potential biomarker and therapeutic target for DKD.

ASIC1a affects hypothalamic signaling and regulates the daily rhythm of body temperature in mice.

The body temperature of mice is higher at night than during the day. We show here that global deletion of acid-sensing ion channel 1a (ASIC1a) results in lower body temperature during a part of the night. ASICs are pH sensors that modulate neuronal activity. The deletion of ASIC1a decreased the voluntary activity at night of mice that had access to a running wheel but did not affect their spontaneous activity. Daily rhythms of thyrotropin-releasing hormone mRNA in the hypothalamus and of thyroid-stimulating hormone ß mRNA in the pituitary, and of prolactin mRNA in the hypothalamus and pituitary were suppressed in ASIC1a-/- mice. The serum thyroid hormone levels were however not significantly changed by ASIC1a deletion. Our findings indicate that ASIC1a regulates activity and signaling in the hypothalamus and pituitary. This likely leads to the observed changes in body temperature by affecting the metabolism or energy expenditure.

Role of GLIS3 in thyroid development and in the regulation of gene expression in thyroid specific Glis3KO mice.

Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time when GLIS3 target genes, such as Slc5a5 (Nis), become also expressed. We further show that Glis3KO mice do not display any major changes in prenatal thyroid gland morphology indicating that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of thyroid-specific Glis3 knockout (Glis3-Pax8Cre) mice fed either a normal or low-iodine diet (ND or LID) revealed that, in contrast to ubiquitous Glis3KO mice, thyroid follicular cell proliferation and the expression of cell cycle genes were not repressed suggesting that the inhibition of thyroid follicular cell proliferation in ubiquitous Glis3KO mice is related to loss of GLIS3 function in other cell types. However, the expression of several thyroid hormone biosynthesis-, extracellular matrix (ECM)-, and inflammation-related genes was still suppressed in Glis3-Pax8Cre mice particularly under conditions of high blood levels of thyroid stimulating hormone (TSH). We further demonstrate that treatment with TSH, protein kinase A (PKA) or adenylyl cyclase activators or expression of constitutively active PKA enhances GLIS3 protein and activity, suggesting that GLIS3 transcriptional activity is regulated in part by TSH/TSHR-mediated activation of the PKA pathway. This mechanism of regulation provides an explanation for the dramatic increase in GLIS3 protein expression and the subsequent induction of GLIS3 target genes, including several thyroid hormone biosynthetic genes, in thyroid follicular cells of mice fed a LID.

Isolated Proteinuria Caused by CUBN Gene Mutations: A Case Report and Review of the Literature.

Mutations in the cubilin (CUBN) gene commonly cause Imerslund-Gräsbeck syndrome, while isolated proteinuria as a result of CUBN variations is rarely reported. The clinical manifestation is mainly chronic isolated proteinuria in the non-nephrotic range. However, findings to date suggest that isolated proteinuria associated with abnormalities in the CUBN gene is benign and does not affect long-term prognosis of kidney function. We identified 2 patients with isolated proteinuria triggered by compound heterozygous CUBN mutations. Renal functions of both patients remained normal over a 10-year follow-up period, supporting the benign nature of proteinuria caused by CUBN gene variations. Two novel mutation sites were detected, expanding the genotypic spectrum of CUBN variations. In addition, etiology, pathogenesis, clinical manifestations, auxiliary examination, and treatment of the condition were reviewed, with the aim of providing further guidance for clinical management.

Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.

Defects in endoplasmic reticulum (ER) proteostasis have been linked to diseases in multiple organ systems. Here we examined the impact of perturbation of ER proteostasis in mice bearing thyrocyte-specific knockout of either HRD1 (to disable ER-associated protein degradation [ERAD]) or ATG7 (to disable autophagy) in the absence or presence of heterozygous expression of misfolded mutant thyroglobulin (the most highly expressed thyroid gene product, synthesized in the ER). Misfolding-inducing thyroglobulin mutations are common in humans but are said to yield only autosomal-recessive disease - perhaps because misfolded thyroglobulin protein might undergo disposal by ERAD or ER macroautophagy. We find that as single defects, neither ERAD, nor autophagy, nor heterozygous thyroglobulin misfolding altered circulating thyroxine levels, and neither defective ERAD nor defective autophagy caused any gross morphological change in an otherwise WT thyroid gland. However, heterozygous expression of misfolded thyroglobulin itself triggered significant ER stress and individual thyrocyte death while maintaining integrity of the surrounding thyroid epithelium. In this context, deficiency of ERAD (but not autophagy) resulted in patchy whole-follicle death with follicular collapse and degeneration, accompanied by infiltration of bone marrow-derived macrophages. Perturbation of thyrocyte ER proteostasis is thus a risk factor for both cell death and follicular demise.

Effect of the Fetal THRB Genotype on the Placenta.

CONTEXT: Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high thyroid hormone (TH) levels shown to be detrimental to a normal fetus (NlFe) but not to an affected fetus (AfFe). However, no information is available about differences in placental TH regulators. OBJECTIVE: To investigate whether there are differences in placentas associated with a NlFe compared with an AfFe, we had the unique opportunity to study placentas from 2 pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. METHODS: Sections of placentas were collected and frozen at -80 °C after term delivery of a NlFe and an AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. Expression of following genes was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. RESULTS: The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the TH transporters MCT10, LAT1 and LAT2, and THRA. CONCLUSION: We present the first study of the effect of the fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of TH regulators in the placenta.

Iodotyrosines Are Biomarkers for Preclinical Stages of Iodine-Deficient Hypothyroidism in Dehal1-Knockout Mice.

Background: Iodine is required for the synthesis of thyroid hormone (TH), but its natural availability is limited. Dehalogenase1 (Dehal1) recycles iodine from mono- and diiodotyrosines (MIT, DIT) to sustain TH synthesis when iodine supplies are scarce, but its role in the dynamics of storage and conservation of iodine is unknown. Methods: Dehal1-knockout (Dehal1KO) mice were generated by gene trapping. The timing of expression and distribution was investigated by X-Gal staining and immunofluorescence using recombinant Dehal1-beta-galactosidase protein produced in fetuses and adult mice. Adult Dehal1KO and wild-type (Wt) animals were fed normal and iodine-deficient diets for 1 month, and plasma, urine, and tissues were isolated for analyses. TH status was monitored, including thyroxine, triiodothyronine, MIT, DIT, and urinary iodine concentration (UIC) using a novel liquid chromatography with tandem mass spectrometry method and the Sandell-Kolthoff (S-K) technique throughout the experimental period. Results: Dehal1 is highly expressed in the thyroid and is also present in the kidneys, liver, and, unexpectedly, the choroid plexus. In vivo transcription of Dehal1 was induced by iodine deficiency only in the thyroid tissue. Under normal iodine intake, Dehal1KO mice were euthyroid, but they showed negative iodine balance due to a continuous loss of iodotyrosines in the urine. Counterintuitively, the UIC of Dehal1KO mice is twofold higher than that of Wt mice, indicating that S-K measures both inorganic and organic iodine. Under iodine restriction, Dehal1KO mice rapidly develop profound hypothyroidism, while Wt mice remain euthyroid, suggesting reduced retention of iodine in the thyroids of Dehal1KO mice. Urinary and plasma iodotyrosines were continually elevated throughout the life cycles of Dehal1KO mice, including the neonatal period, when pups were still euthyroid. Conclusions: Plasma and urine iodotyrosine elevation occurs in Dehal1-deficient mice throughout life. Therefore, measurement of iodotyrosines predicts an eventual iodine shortage and development of hypothyroidism in the preclinical phase. The prompt establishment of hypothyroidism upon the start of iodine restriction suggests that Dehal1KO mice have low iodine reserves in their thyroid glands, pointing to defective capacity for iodine storage.

Clinical application of flexible ureteroscopic sheath with controllable intraluminal pressure in treating ureteral stones.

Objective: The purpose of the study was to assess the clinical efficacy and safety of a combined perfusion suction platform with pressure feedback control function and an ureteroscopic suction sheath that can measure the ureteropelvic pressure in implementing lithotripsies. Methods: Fifty-two patients who underwent lithotripsy under intelligent monitoring of ureteral intraluminal pressure from June 2016 to January 2018 were retrospectively recruited. The inclusion standard was stone diameter >1.5 cm but <2.5 cm. After the 12/14 Fr suction sheath was placed, manometer interface and suction interface of the sheath were connected to the platform via the pressure sensor and suction tube, respectively. The ureteroscope was connected to the platform perfusion pump, and the crushed stones were aspirated out under negative pressure. Results: According to the location of the stone, 21 (40.4%) cases were classified as upper ureteral stones, 19 (36.5%) were midureteral stones, and 12 (23.1%) were lower ureteral stones. Forty-seven patients underwent successful primary sheath placement and lithotripsy with a mean operative time of 34.5 (standard deviation 18.3) min. Retrograde stone migration did not occur. There were eight patients with hematuria postoperatively. Serious complication was 1.9% with one case of ureteral perforation. Stone clearance was 95.7% at Day 1-2 postoperatively, and 100% at Day 30 postoperatively. Conclusion: Ureteroscopic lithotripsy with intelligent pressure control using our device improved the efficiency of the lithotripsy and rate of stone clearance. The safety of the operation can be ensured. It is worth popularization and application in clinical practice.

Cellular and Humoral Responses to Recombinant and Inactivated SARS-CoV-2 Vaccines in CKD Patients: An Observational Study.

BACKGROUND: It remains unclear what B cell and humoral responses are mounted by chronic kidney disease (CKD) patients in response to recombinant and inactivated SARS-CoV-2 vaccines. In this study, we aimed to explore the cellular and humoral responses, and the safety of recombinant and inactivated SARS-CoV-2 vaccines in CKD patients. METHODS: 79 CKD and 420 non-CKD individuals, who completed a full course of vaccination, were enrolled in the study. Adverse events (AEs) were collected via a questionnaire. Cellular and humoral responses were detected at 1, 3, and 6 months, including IgG antibody against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (anti-RBD-IgG), neutralizing antibodies (NAbs), the positive rate of NAbs and anti-RBD-IgG, RBD-atypical memory B cells (MBCs) (CD3 - CD19 + RBD + CD21 - CD27-), RBD-activated MBCs (CD3 - CD19 + RBD + CD21 - CD27+), RBD-resting MBCs (CD3 - CD19 + RBD + CD21 + CD27+), and RBD-intermediate MBCs (CD3 - CD19 + RBD + CD21 + CD27-). RESULTS: We found no differences in the positivity rates of NAbs (70.89% vs. 79.49%, p = 0.212) and anti-RBD IgG (72.15% vs. 83.33%, p = 0.092) between the CKD and control groups. A total of 22 CKD individuals completed the full follow-up (1, 3, and 6 months). Significant and sustained declines were found at 3 months in anti-RBD IgG (26.64 BAU/mL vs. 9.08 BAU/mL, p < 0.001) and NAbs (161.60 IU/mL vs. 68.45 IU/mL p < 0.001), and at 6 months in anti-RBD IgG (9.08 BAU/mL vs. 5.40 BAU/mL, p = 0.064) and NAbs (68.45 IU/mL vs. 51.03 IU/mL, p = 0.001). Significant differences were identified in MBC subgroups between CKD patients and healthy controls, including RBD-specific atypical MBCs (60.5% vs. 17.9%, p < 0.001), RBD-specific activated MBCs (36.3% vs. 14.8%, p < 0.001), RBD-specific intermediate MBCs (1.24% vs. 42.6%, p < 0.001), and resting MBCs (1.34% vs. 22.4%, p < 0.001). Most AEs in CKD patients were mild (grade 1 and 2) and self-limiting. One patient with CKD presented with a recurrence of nephrotic syndrome after vaccination. CONCLUSIONS: The recombinant and inactivated SARS-CoV-2 vaccine was well-tolerated and showed a good response in the CKD cohort. Our study also revealed differences in MBC subtypes after SARS-CoV-2 vaccination between CKD patients and healthy controls.

Specific and Long-Term Luminescent Monitoring of Hydrogen Peroxide in Tumor Metastasis.

Luminescent monitoring of endogenous hydrogen peroxide (H2 O2 ) in tumors is conducive to understanding metastasis and developing novel therapeutics. The clinical transformation is obstructed by the limited light penetration depth, toxicity of nano-probes, and lack of long-term monitoring modes of up to days or months. New monitoring modes are introduced via specific probes and implantable devices, which can achieve real-time monitoring with a readout frequency of 0.01 s or long-term monitoring for months to years. Near-infrared dye-sensitized upconversion nanoparticles (UCNPs) are fabricated as the luminescent probes, and the specificity to reactive oxygen species is subtly regulated by the self-assembled monolayers on the surfaces of UCNPs. Combined with the passive implanted system, a 20-day monitoring of H2 O2 in the rat model of ovarian cancer with peritoneal metastasis is achieved, in which the limited light penetration depth and toxicity of nano-probes are circumvented. The developed monitoring modes show great potential in accelerating the clinical transformation of nano-probes and biochemical detection methods.

Risk of waning humoral responses after inactivated or subunit recombinant SARS-CoV-2 vaccination in patients with chronic diseases: Findings from a prospective observational study in China.

Heterogeneity of antibody responses has been reported in SARS-CoV-2 vaccination recipients with underlying diseases. We investigated the impact of the presence of comorbidities on the humoral response to SARS-CoV-2 vaccination in patients with chronic disease (PWCD) and assessed the effect of the number of comorbidities on the humoral response to vaccination. In this study, neutralizing antibodies (NAbs) and IgG antibodies against the receptor-binding domain (RBD-IgG) were monitored following a full-course vaccination. In total, 1400 PWCD (82.7%, inactivated vaccines; 17.3%, subunit recombinant vaccine) and 245 healthy controls (65.7% inactivated vaccines, 34.3% subunit recombinant vaccine) vaccinated with inactivated or subunit recombinant SARS-CoV-2 vaccines, were included. The seroconversion and antibody levels of the NAbs and RBD-IgG were different in the PWCD group compared with those in the control group. Chronic hepatitis B (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46-0.93), cancer (OR: 0.65; 95% CI: 0.42-0.99), and diabetes (OR: 0.50; 95% CI: 0.28-0.89) were associated with lower seroconversion of NAbs. Chronic kidney disease (OR: 0.29; 95% CI: 0.11-0.76), cancer (OR: 0.38; 95% CI: 0.23-0.62), and diabetes (OR: 0.37; 95% CI: 0.20-0.69) were associated with lower seroconversion of RBD-IgG. Only the presence of autoimmune disease showed significantly lower NAbs and RBD-IgG titers. Patients with most types of chronic diseases showed similar responses to the controls, but humoral responses were still significantly associated with the presence of ≥2 coexisting diseases. Our study suggested that humoral responses following SARS-CoV-2 vaccination are impaired in patients with certain chronic diseases.