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Alzheimer’s disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer’s disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer’s disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer’s disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer’s disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer’s disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer’s disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer’s disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer’s disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer’s disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer’s disease.

This is an article in the field of mineral processing engineering. Lithium ore is an important strategic resource in China. At present, flotation is the most commonly used method for the separation of lithium ore. In this article, the crystal structure characteristics of spodumene and its interaction mechanism with flotation agent are discussed from the point of view of spodumene crystal structure. This article describes it from seven aspects: metal cationic activator, organic inhibitor, inorganic inhibitor, anionic collector, cationic collector, mixed collector and new collector. It is of great significance to understand the characteristics of the interaction between spodumene and reagents, to develop new and efficient flotation reagents and to optimize the mineral processing process.

Aim Tripterygium wilfordii Hook F (TwHF) has been shown to substantially reduce proteinuria in patients with diabetic kidney disease (DKD); however, the effect of TwHF on renal outcomes in DKD remains unknown. Accordingly, we aimed to establish the effects of TwHF on renal outcomes in patients with DKD.Methods Overall, 124 patients with DKD, induced by type 2 diabetes mellitus, with 24-h proteinuria > 2 g, and an estimated glomerular filtration rate > 30 mL/min/1.73 m2 were retrospectively investigated. The renal outcomes were defined as doubling serum creatinine levels or end-stage kidney disease. Kaplan-Meier curves and Cox regression analyses were performed to analyze prognostic factors for renal outcomes.Results By the end of the follow-up, renal outcomes were observed in 23 and 11 patients in the non-TwHF and TwHF groups, respectively (p = 0.006). TwHF significantly reduced the risk of renal outcomes (adjusted hazard ratio [HR] 0.271, 95% confidence interval [CI] 0.111–0.660, p = 0.004) in patients with chronic kidney disease (CKD) G3 (adjusted HR 0.274, 95%CI 0.081–0.932, p = 0.039). Based on the Kaplan-Meier analysis, 1- and 3-year proportions of patients without renal outcomes were significantly lower in the non-TwHF group than those in the TwHF group (92.8% vs. 95.5% and 47.2% vs. 76.8%, respectively; p = 0.0018).Conclusion In DKD patients with severe proteinuria, TwHF could prevent DKD progression, especially in patients with CKD G3. A randomized clinical trial is needed to elucidate the benefits of TwHF on renal outcomes in patients with DKD.

The ongoing evolution and immune escape of SARS-CoV-2, alongside the potential threat of SARS-CoV-1 and other sarbecoviruses, underscore the urgent need for effective strategies against their infection and transmission. This study highlights the discovery of nanobodies from immunized alpacas, which demonstrate exceptionally broad and potent neutralizing capabilities against the recently emerged and more divergent SARS-CoV-2 Omicron subvariants including JD.1.1, JN.1, KP.3, KP.3.1.1, as well as SARS-CoV-1 and coronaviruses from bats and pangolins utilizing receptor ACE2. Among these, Tnb04-1 emerges as the most broad and potent, binding to a conserved hydrophobic pocket in the spike's receptor-binding domain, distinct from the ACE2 binding site. This interaction disrupts the formation of a proteinase K-resistant core, crucial for viral-cell fusion. Notably, intranasal administration of Tnb04-1 in Syrian hamsters effectively prevented respiratory infection and transmission of the authentic Omicron XBB.1.5 subvariant. Thus, Thb04-1 holds promise in combating respiratory acquisition and transmission of diverse sarbecoviruses.

Diabetes mellitus (DM), a major global health concern, is a chronic metabolic disorder. Bioactive compounds sourced from numerous marine natural products recently have drawn attention as novel therapeutic approaches. Considering these chemicals and their role in cellular redox modulation by involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway, the current study attempts to highlight their anti-diabetic effects and the molecular mechanisms involved. Reactive oxygen species (ROS)-mediated oxidative stress, inflammation, and cellular damage are linked to most human pathologies specifically DM. The Nrf2/HO-1 pathway is a key defense mechanism developed by the cells to combat ROS burst. Marine natural compounds have strong pharmacological potential in triggering cellular antioxidant defense mechanisms by declining oxidative damage and inflammation linked to DM. How marine natural products potentially alleviate DM specifically type 2 diabetes (T2D) and its related issues is especially focused on. The literature was thoroughly analyzed to open a discussion about specific marine compounds and their well-established anti-diabetic effects to elucidate possible therapeutic applications. Furthermore, opportunities and the pros and cons of using these marine bioactive compounds as complementary treatment for DM are also discussed. The diverse characteristics of marine natural products, specifically with regard to redox control, offer promising opportunities for drug discovery and therapeutic interventions in clinical trials.

Abstract Kidney injury is one of the detrimental consequences of primary malignant hypertension (pMHTN). There is a paucity of non-invasive biomarkers to enhance diagnosis and elucidate the underlying mechanisms. This study aims to explore urine protein biomarkers for pMHTN associated renal damage. In the discovery phase, urine samples were collected from 8 pMHTN, 19 disease controls (DCs), and 5 healthy controls (HCs). In-gel digestion combined with liquid chromatography–tandem mass spectrometry (LC–MS/MS) approach was used for identification of proteins associated with pMHTN. In the validation phase, the differentially expressed proteins were validated by ELISA assay in cohort with 10 pMHTN patients, 37 DCs, and 30 HCs. Compared to DCs and HCs, a specific band between 15 and 25 kDa was found in 7 out of 8 patients with pMHTN. Further LC–MS/MS analysis revealed 5 differentially expressed proteins. ELISA validation demonstrated that urinary complement factor D (CFD) was significantly up regulated in pMHTN. By receiver operating characteristic curve analysis, urinary CFD/Cr showed moderate potential in discriminating pMHTN from DCs (the area under curve: 0.822, 95% CI 0.618–0.962). Urinary CFD may be a potential biomarker for pMHTN with its elevation indicative of the activation of the alternative complement pathway in pMHTN.

BackgroundHypertensive disorders of pregnancy (HDP) are associated with an increased risk of stroke later in life in multiparous women. However, causality of these associations remains unclear. This study employed 2-sample univariate and multivariate Mendelian randomization (MR) to assess the causal connection between HDP and stroke.MethodsGenetic variants for HDP and two subtypes were identified from recent large-scale genome-wide association studies and the FinnGen consortium. Stroke summary data were obtained from the MEGASTROKE consortium. The primary analytical approach for univariate MR was the inverse variance weighting method. Sensitivity analyses incorporated methods such as MR-Egger regression, weighted median, and maximum likelihood to ascertain the robustness of the results. Additionally, multivariable MR analyses were conducted to account for potential associative effects of hypertension and type 2 diabetes.ResultsGenetically predicted HDP was associated with a high risk of large artery atherosclerosis (odds ratio [OR]=1.50, 95% confidence interval [CI]: 1.17–1.91, P=1.13×10-3) and small vessel stroke (OR=1.29, 95% CI: 1.20–1.50, P=1.52×10-3). HDP may also correlate with ischemic stroke (OR=1.13, 95% CI: 1.04–1.23, P=4.99×10-3) and stroke (OR=1.11, 95% CI: 1.03–1.20, P=8.85×10-3). An elevated risk of small vessel stroke (OR=1.20, 95% CI: 1.01–1.43, P=3.74×10-2) and large artery atherosclerosis (OR=1.22, 95% CI: 1.01–1.47, P=4.07×10-2) may be related with genetically predicted susceptibility to gestational hypertension. Genetically predicted susceptibility to preeclampsia or eclampsia may be associated with an increased risk of stroke (OR = 1.10, 95% CI: 1.02–1.19, P = 1.16×10-2) and ischemic stroke (OR = 1.10, 95% CI: 1.02–1.20, P = 1.84×10-2). Type 2 diabetes mellitus and hypertension were identified as significant factors contributing to the association between HDP and stroke.ConclusionsThis study provides genetic evidence supporting an association between HDP and increased stroke risk bolstering HDP as a cerebrovascular risk factor.

Abstract Background Age-related cognitive decline has a significant impact on the health and longevity of older adults. Circulating very long-chain saturated fatty acids (VLSFAs) may actively contribute to the improvement of cognitive function. The objective of this study was to investigate the associations between arachidic acid (20:0), docosanoic acid (22:0), tricosanoic acid (23:0), and lignoceric acid (24:0) with cognitive function in older adults. Methods This study used a dataset derived from the 2011–2014 National Health and Nutrition Examination Survey (NHANES). A total of 806 adults (≥ 60 years) were included who underwent comprehensive cognitive testing and plasma fatty acid measurements. Multivariable linear regression, restricted cubic spline (RCS), and interaction analyses were used to assess associations between VLSFAs and cognitive function. Partial Spearman’ s correlation analysis was used to examine the correlations between VLSFAs and palmitic acid (16:0), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, systemic inflammatory markers, and dietary nutrients. Results Multivariable linear regression analysis, adjusting for sociodemographic, clinical conditions, and lifestyle factors, showed that 22:0 and 24:0 levels were positively associated with better global cognitive function (β = 0.37, 95% confidence interval [CI] = 0.01, 0.73; β = 0.73, 95% CI = 0.29, 1.2, respectively) as well as better CEARD-DR Z-score (β = 0.82, 95% CI = 0.36, 1.3 and β = 1.2, 95% CI = 0.63, 1.8, respectively). RCS analysis showed linear associations between higher 22:0 and 24:0 levels and better cognitive performance in both global cognitive function and CERAD-DR tests. Conclusions The study suggests that higher levels of 22:0 and 24:0 are associated with better global cognitive function in older adults. 22:0 and 24:0 may be important biomarkers for recognizing cognitive impairment, and supplementation with specific VLSFAs (22:0 and 24:0) may be an important intervention to improve cognitive function. Further studies are needed to elucidate the underlying biological mechanisms between VLSFAs and cognitive function.

Abstract Background This article reports an extremely rare case of lipoprotein glomerulopathy (LPG) with apolipoprotein E gene (APOE) Chicago mutation in a young Chinese male. Only five cases or families with APOE Chicago mutations have been reported in the literature. Case presentation The young male patient is manifested with nephrotic syndrome, accompanied by hyperlipidemia with a preferable increase in triglycerides and elevated ApoE level. Renal biopsy of the patient showed highly dilated glomerular capillaries filled with vacuolar lipids, segmentally fused podocyte foot processes, vacuolar degeneration of renal tubular epithelial cells and absence of electron-dense material, which indicates the diagnosis of LPG. Whole-exome gene sequencing identified the heterozygous mutation of NM_000041.4:c.494G > C (p.Arg165Pro), which is in the exon 4 of the APOE gene and also known as APOE Chicago mutation, a rare mutation of LPG. Further family pedigree gene analysis clarified that the mutation was inherited from the patient’s mother, who does not have high ApoE levels or renal manifestations. This is also consistent with the incomplete penetrance of APOE gene mutations in LPG. Under lipid-lowering treatments, including a low-fat diet and fenofibrate, the patient’s urinary protein was partially controlled, and the albumin level was recovered. Conclusion Patients with nephrotic syndrome and elevated ApoE levels should be prompted into renal biopsy to avoid delay of appropriate treatment and unnecessary use of glucocorticoids. This case of LPG was diagnosed by renal biopsy and further verified with genetic sequencing. The timely diagnosis and treatment improved the patient’s symptoms. This case is one of only six reported LPG cases or families with APOE Chicago mutation in the world.

BackgroundEvaluating cardiovascular risk in patients experiencing acute ST-elevation myocardial infarction (STEMI) and undergoing percutaneous coronary intervention (PCI) is crucial for early intervention and improving long-term outcomes. 24 h Holter monitoring provides continuous cardiac electrophysiological data, enabling the detection of arrhythmias and autonomic dysfunction that are not captured during routine examinations. This study aimed to examine the relationship between Holter monitoring metrics and the occurrence of out-of-hospital major adverse cardiovascular events (MACEs) following PCI in patients with STEMI, offering insights into cardiovascular risk evaluation.MethodsThis prospective cohort study included STEMI patients undergoing PCI. 24 h Holter monitoring data were recorded, including heart rate, heart rate variability (HRV) metrics such as SDNN and SDANN index, heart rate deceleration capacity (DC) at different time scales (DC2, DC4, DC8), and the frequency of premature ventricular contractions (PVCs). Independent correlations between these indices and MACEs, as well as cardiovascular deaths, were investigated using multifactorial logistic regression. Predictive capacities were assessed through receiver operating characteristic (ROC) curves.ResultsA total of 172 participants were enrolled in this study. Over the 3-year follow-up period, MACEs were observed in 57 patients, including 20 cases of cardiac death. In logistic regression models adjusted for confounding variables, SDNN [OR: 0.980; 95% CI: (0.967, 0.994); p = 0.005] and SDANN index [OR: 0.982; 95% CI: (0.969, 0.996); p = 0.009] were negatively associated with the incidence of MACEs. Conversely, the slowest heart rate [OR: 1.075; 95% CI: (1.022, 1.131); p = 0.005] and frequent PVCs [OR: 2.685; 95% CI: (1.204, 5.987); p = 0.016] demonstrated a positive association with MACEs. Furthermore, SDNN [OR: 0.957; 95% CI: (0.933, 0.981); p = 0.001], DC [OR: 0. 702; 95% CI: (0.526, 0.938); p = 0.017]) and DC4 [OR: 0.020; 95% CI: (0.001, 0.664); p = 0.029] were negatively associated with cardiac death. The ROC analysis results indicated that SDNN was an effective predictor of both MACEs [AUC: 0.688 (95% CI: 0.601–0.776)] and cardiac death [AUC: 0.752 (95% CI: 0.625–0.879)].ConclusionHRV, DC metrics, and frequent PVCs obtained by 24 h Holter monitoring were associated with the risk of MACEs in STEMI patients. These metrics can help clinicians identify at-risk patients early so that timely interventions.

The goal of this work was to better meet the demand for rapid detection of surface defects in sawn timber in forestry production. This paper introduces a two-way feature fusion network based on the YOLO-v8 algorithm and proposes a feature fusion network model that combines the attention mechanism and loss function optimization. In this way it increases the tiny target detection head in order to more effectively detect small defective targets in the wood, thus realizing the model's high-efficiency and low-consumption functional design. The results show that the improved TSW-YOLO-v8n model realized the identification of eight kinds of defects in sawn timber with a high efficiency of 91.10% mAP50 and an average detection 6 ms, which is 5.1% higher than the original model’s mAP50 and 1 ms shorter than the original model’s average detection time. The comparison of the original model and its mainstream algorithms shows that the model of this paper had better performance and better detection capability. Thus, the improved model achieved better overall performance and stronger detection ability, which provides a new idea for the development of detection technology in the forestry industry.

Abstract Although treatments for myocardial infarction have advanced significantly, the global mortality due to ischemia and subsequent reperfusion injury remains high. Here, a platelet (PLT) membrane nanocarrier (PL720) that encapsulates L‐arginine and FTY720 to facilitate the cascade‐targeted delivery of these substances to the myocardial injury site and enable the controlled release of L‐arginine and FTY720 is developed. Such an innovative approach shows enhanced cardioprotection through multiple target strategies involved in ischemia–reperfusion injury and late reperfusion inflammation. During the ischemia–reperfusion phase, PL720 targets and accumulates in damaged coronary arteries. PL720 rapidly releases L‐arginine, stimulating endothelial cells to produce NO, thereby dilating blood vessels and promoting blood flow recovery, while FTY720's sustained release exerts anti‐apoptotic effects. During the late reperfusion inflammatory phase, PL720 is captured by circulating inflammatory monocytes and transported into a deeper ischemic myocardial lesion. PL720 promotes macrophage polarization and accelerates the inflammatory repair. Furthermore, the issue of bradycardia associated with the clinical use of FTY720 is innovatively relieved. Therefore, PL720 is a vascular injury and inflammation dual targeting strategy, exhibiting significant potential for multi‐targeted therapy and clinical translation for cardiac injury.

Straw mulching incorporation has a wide range of environmental benefits that make it an effective practice for sustainable agro-ecosystem in the semi-arid regions. There is an urgent need to improve the 13C-photosynthates distribution, water use efficiency (WUE) and maize canopy characteristics under the diverse tillage practices with straw mulched management strategies for sustainable intensification of maize production. The field study consists of three diverse tillage systems (RT: rotary tillage; CT, conventional tillage; MT, minimum tillage) with three straws mulching (NS: no straw mulch; SS: straw mulch on the soil surface; SI: straw incorporated into the soil) were assessed under the ridge-furrow rainfall harvesting system. Our results showed that the rotary tillage with straw incorporated into the soil significantly reduces the ET rate (11 %), and leaf rolling index; as a result considerably improves LAI, LEI, 13C-photosynthates distribution, N accumulation, and above ground biomass under various growth stages. The RTSI treatment significantly improved soil water storage, soil organic carbon (52 %, SOC), soil C storage (39 %, SCS), and NPK nutrients uptake (70 %, 62 %, and 69 %) of maize than observed for the rest of all other treatments, respectively. The RTSI treatment improves soil water balance, grain yield (53 %), biomass yield (37 %), WUEg (51 %), WUEb (35 %), nutrients uptake, and mitigating soil water depletion than the MTNS treatment. Although RTSS can achieve optimal soil water storage in the short term, RTSI has a great potential in improving soil carbon stability, canopy characteristics, soil water storage, and WUE, contributing to sustainable and intensive corn production in agricultural ecosystems in semi-arid regions.

BackgroundThe burden of metabolic syndrome (MetS) continues to rise globally and is associated with complications of multiple organ systems. We aimed to identify the association between changes in MetS status and accelerated renal function progression through a regional epidemiological survey in China, thus discovering influence factors with treatable potential.MethodsThis study was a population-based survey conducted in 2008 and 2014, assessing a representative sample of 5,225 individuals from rural areas of China. They were divided into four subgroups according to their MetS status in 2008 and 2014 (Never, Previously abnormal, New-onset, and Consistent). Multivariate logistic regression and stratification analysis evaluated the relationship between clinical factors and renal function decline under different MetS statuses. Smooth curve fitting further addressed the role of serum uric acid, illustrating the vital turning point of uric acid levels in the background of renal function deterioration.ResultsOf all groups of MetS states, the new-onset MetS showed the most significant eGFR decline, with a 6.66 ± 8.21 mL/min/1.73 m2 decrease over 6 years. The population with newly-onset MetS showed a considerable risk increase in delta eGFR with a beta coefficient of 1.66 (95%CI=1.09-2.23) after necessary correction. In searching for the drivers, the strength of the association was significantly reduced after additional adjustment for uric acid levels (β=0.91, 95%CI=0.35-1.45). Regarding the turning point, uric acid levels exceeding 426 μmol/L were more significantly associated with the stepped-up deterioration of kidney function for those with new-onset MetS.ConclusionMetabolic syndrome demonstrated a solid correlation with the progression of renal function, particularly in those with newly-onset MetS status. In addition to the diagnostic components of MetS, hyperuricemia could be used as a marker to identify the high risk of accelerating eGFR decline early. Furthermore, we suggested a potential renal benefit for the newly-onset MetS population when maintaining their serum uric acid level below the criteria for asymptomatic hyperuricemia.

Abstract Background The quality of learning and post-learning performances is critical for daily life. The behavioral flexibility is equally important for adapting the changing circumstances. The learning process requires repeated practices, which enhances prompt and proper behavioral responses, in turn, which promotes habits formation as well. Despite the well-documented sex differences in learning and performances, contradictory results were reported. A possible cause might be a systematic analysis due to specific research interests, regardless of the continuity of natural acquisition process. Here, we investigate the potential sex differences in learning, performances and adjustments of habited behaviors with regular and reversal Go/NoGo tasks. Methods Both male and female Sprague-Dawley rats were used in this study. All rats were trained for a regular rodent Go/NoGo task and a subset of rats were trained for a reversal rodent Go/NoGo task, both with strict elimination criteria. The behavioral performance data were stored in PC for off-line analysis. Multiple behavioral indices were analyzed for both passed and retired rats. Results The ability of learning the regular the reversal Go/NoGo tasks was similar for both male and female rats, however, the female rats took longer time to master the task principles in later stages for both tasks. In the regular Go/NoGo task, the female rats spent more time on completing the trial in performance optimization phases, which implied female rats were more cautious than male rats. Along with the progression of training, both male and female rats developed Go-preference strategies to perform the regular Go/NoGo task, which induced failure to meet the setting success criteria. The retired male rats exhibited shorter RTs and MTs than the retired female rats after developing Go-preference. Moreover, the time needed to complete the Go trials was significantly prolonged for male rats in the reversal Go/NoGo task. Conclusions Overall, we conclude that distinctive strategies were employed in performing Go/NoGo tasks for both male and female rats. Male rats required less time to stabilize the performance in behavioral optimization phase. In addition, male rats were more accurate in estimating time elapsing. In contrast, female rats took more cautious considerations in performing the task, through which minimal influences were manifested in the reversal version of task.

Escherichia coli is a major bacterial pathogen which causes diarrhea in the giant panda. This study investigated the biological characteristics of 100 E. coli strains isolated from fecal samples collected from 100 captive giant pandas of different age groups and sexes. A standard Kirby-Bauer disk diffusion antimicrobial susceptibility test was performed with the isolates and we then further evaluated the antibiotic resistance genes (ARGs) by high-throughput quantitative PCR. Additionally, we then analyzed O serogroups through a slide agglutination test, virulence genes and the multi-locus sequence typing (MLST) by PCR. Antimicrobial susceptibility testing demonstrated that the 100 E. coli strains were mainly resistant to ENR (68%), AM (56%), IPM (55%), AMX (54%) and CA (52%), but were susceptible to MEM and FOX. The resistance to TZP, AK, FEP, CAZ, AMS, AZM, AT and IPM was significantly related to age (p

Objective: The objective of this work is to design and fabricate a novel multifunctional nanocarrier combining thrombus-targeted imaging and ultrasound-mediated drug delivery for the theranostics of thrombotic diseases. Impact Statement: This study develops a new technology that can accurately visualize the thrombus and deliver drugs with controllable properties to diagnose and treat thrombotic diseases. Introduction: Thrombotic diseases are a serious threat to human life and health. The diagnosis and treatment of thrombotic diseases have always been a challenge. In recent years, nanomedicine has brought new ideas and new methods for the theranostics of thrombotic diseases. However, there are also many problems need to be solved, such as biosafety and stability of nanocarriers, early diagnosis, and timely treatment of thrombotic diseases, difficulty in clinical translation. Methods: The S1P@CD-PLGA-rtPA nanobubbles (NBs) were prepared by integrating sulfur hexafluoride (SF6)-loaded poly (D, L-lactide-co-glycolide) (PLGA) NBs, cyclodextrin (CD), sphingosine-1-phosphate (S1P), and recombinant tissue plasminogen activator (rtPA). Results: S1P@CD-PLGA-rtPA NBs had rapid and excellent thrombosis targeting imaging performance based on the specific interaction of S1P–S1PR1 (sphingosine-1-phosphate receptor 1). Furthermore, S1P@CD-PLGA-rtPA NBs that specifically targeting to the thrombosis regions could also respond to external ultrasound to achieve accurate and efficient delivery of rtPA to enhance the thrombolysis effectiveness and efficiency. Conclusion: This study proposes a new idea and strategy of targeting thrombus in rats via the specific interaction of S1P–S1PR1. On this basis, the acoustic response properties of bubble carriers could be fully utilized by combining thrombus-specific targeted imaging and ultrasound-mediated drug delivery for effective thrombolysis, which is expected to be applied in targeted diagnosis and treatment of thrombotic diseases in the future.

ABSTACT: Pu-erh tea theabrownins (TBs) exert beneficial effect on egg quality and antioxidant properties of eggs, but the underlying mechanisms behind this response are unclear. In this study, we investigate the effect of TBs on egg antioxidative activity, amino acid and fatty acid profiles, and the underlying relationship between the TBs and oxidant-sensitive Nrf2 signaling pathway in laying hens. Eighty layers were fed a basal diet (control) and 400 mg/kg of TBs supplemented diet for 12 wk. TBs led to an increase in albumen height and Haugh unit (P < 0.05). The albumen lysine, valine, and tryptophan were higher in layers fed TBs, whereas yolk tryptophan, methionine, vitamin A, and α-tocopherol content were enhanced by TBs (P < 0.05). Eggs albumen and yolk showed higher total antioxidant capacity (T-AOC), reducing power (RP), and the scavenging rate of 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH), and lower MDA content than those of eggs from the control group (P < 0.05). Also, magnum Nrf2, hemeoxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and Bcl2 expression were up-regulated by TBs, whereas magnum proapoptotic gene (Bax, caspase 3, Cyt C) were down-regulated by TBs (P < 0.05). Our findings suggest that TBs improved egg albumen quality and antioxidant activity, and the Nrf2-ARE pathway were found to be involved in this process.

Abstract Background Consumption of high fructose corn syrup sweetened drinks and diet soft drinks has increased in the United States. However, the relationship between the intake of high fructose corn syrup sweetened drinks and diet soft drinks, and serum sodium has been scarcely studied. Our objective is to evaluate the relation between intake of high fructose corn syrup sweetened drinks and diet soft drinks, and serum sodium, and explore the possible effect modifiers in a nationally representative sample of adults from the United States. Methods We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey 2003–2006. The study participants included 6989 adults aged ≥18 years. Using survey-weighted generalized linear regression analyses, we investigated the relationship between high fructose corn syrup sweetened drink, diet soft drink consumption, and serum sodium. Consumption of high fructose corn syrup sweetened drinks and diet soft drinks was evaluated through a food-frequency questionnaire. Results Serum sodium levels increased as high fructose corn syrup sweetened drink intake increased. Serum sodium levels were higher in participants in the highest high fructose corn syrup sweetened drink consumption quantile, compared with those in the lowest high fructose corn syrup sweetened drink intake quantile (p = 0.020). The multivariate betas for serum sodium, according to the corresponding high fructose corn syrup sweetened drink intake quantiles, were 0.16, 0.19, and 0.21, respectively (P for trend = 0.051). We found no relationship between diet soft drink consumption and serum sodium after adjustment of confounding. (multivariate P > 0.05). Conclusion There was a a step-wise increase in serum sodium concentration with increasing consumption of HFCS sweetened beverages. Even moderate HFCS sweetened soft drink intake was associated with an elevated serum sodium level - a risk factor for hypertension.

The authors identify nanobodies from immunized alpaca with broadly neutralizing activity against SARS-CoV-1, SARS-CoV-2 variants, and major sarbecoviruses. One representative nanobody binds to a highly conserved epitope on RBD and protects K18-hACE2 mice from Omicron and Delta infection.

Abstract Background The cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 represses multiple cancer cells. However, its tumor-repressive efficiency in wild-type p53 breast cancer cells remains controversial. Methods We conducted various assays, including CCK8, colony formation, flow cytometry, western blotting, and lactate dehydrogenase release detection, to clarify whether p53 elevation sensitizes breast cancer cells to THZ1. Results We found that upregulating functional p53 contributes to the increased sensitivity of breast cancer cells to THZ1. Increased THZ1 sensitivity requires active p53 and an intact p53 pathway, which was confirmed by introducing exogenous wild-type p53 and the subsequent elevation of THZ1-mediated tumor suppression in breast cancer cells carrying mutant p53. We confirmed that p53 accumulates in the nucleus and mitochondria during cell death. Furthermore, we identified extensive transcriptional disruption, rather than solely CDK7 inhibition, as the mechanism underlying the nutlin-3 and THZ1-induced death of breast cancer cells. Finally, we observed the combined nutlin-3 and THZ1 treatment amplified gasdermin E cleavage. Conclusion Enhanced sensitivity of breast cancer cells to THZ1 can be achieved by increasing effective p53 expression. Our approach may serve as a potential treatment for patients with breast cancer resistant to regular therapies. Video Abstract

AimTo assess the individual effects of overweight/obesity and tobacco exposure, and their combined effects on hypertension in children.MethodsThis cross-sectional study included 6,339 children aged 6–17 years from National Health and Nutrition Examination Surveys 1999–2018. Participants’ height, weight and blood pressure (BP) were measured by trained technicians. Hypertension was defined as: mean systolic BP (SBP) and/or diastolic BP (DBP) ≥ 90th percentile for sex, age, and height (for children aged 1–13 years), and SBP ≥120 mmHg and/or a DBP ≥80 mmHg (for adolescents aged 13–17 years); or self-reported having been diagnosed with hypertension or taking antihypertensive medication. Gender- and age-specific body mass index (BMI) cut-points were used to define overweight/obesity: “overweight” was defined as a BMI > 1 standard deviation (SD); “obesity” was defined as BMI > 2SD; and “thinness” was defined as BMI 0.05 µg/L or reporting the presence of at least one smoker in the household. Weighted univariate and multivariate logistic regression models were used to assess overweight/obesity and tobacco exposure with the odds of hypertension, and the combined effects of overweight/ obesity and tobacco exposure on hypertension, followed by strata-specific analyses. Odds ratios (OR) with 95% confidence intervals (CI) were calculated.ResultsThe prevalence of overweight/obesity and tobacco exposure was significantly higher in the hypertension group than in the non-hypertension group. Overweight/obesity (OR = 1.67, 95%CI: 1.26–2.21/ OR = 2.38, 95%CI: 1.67–3.39) and tobacco exposure (OR = 1.58, 95%CI: 1.16–2.14) were associated with a higher odd of hypertension in children, respectively. Additionally, we also observed the combined effect between overweight (OR = 3.05, 95%CI: 1.96–4.75)/obesity (OR = 3.68, 95%CI: 2.24–6.03) and tobacco exposure were related to hypertension odds in children, with a significant effect in different populations.ConclusionThere may exist joint effect of overweight/obesity and tobacco exposure on the odds of hypertension in American children. These findings offer an insight that early weight control and reduction of tobacco exposure may be important to reduce odds of hypertension in children.

Green tea and its active extracts have been widely used in a variety of dietary supplements. However, to date, the interaction of these bioactive compounds in green tea and their protein targets are not well studied. We first used the bioinformatics analysis of the relevant diabetes-related targets with the green tea bioactive compounds target proteins to construct a protein interaction (PPI) network to screen the core targets. The results of in vitro experiments showed that EGCG, a major polyphenolic component of green tea, inhibited HG-induced cardiomyocyte hypertrophy, inflammation, oxidative stress response, and cellular senescence. It was found that the PPARG-dependent pathways were involved in the protective effects of EGCG against HG-induced myocardial injury and senescence. This study comprehensively explored the role of EGCG in high glucose-induced myocardial cell injury and aging.

Abstract Background The impact of maternal pre-pregnancy bodyweight on gestational diabetes mellitus (GDM) following assisted reproductive technology (ART) treatment has been insufficiently investigated. The aim of this study was to investigate the association between maternal pre-pregnancy bodyweight and GDM following ART. Methods From January 2014 to March 2019, this population-based retrospective cohort study included pregnancies achieved by ART treatment in a pregnancy registration database in China. Multivariate regression analysis and restricted cubic splines were used to explore the association between bodyweight and GDM. Results A total of 6,598 pregnancies were included. The incidence of GDM was 26.0% (1715/6598). A total of 868 (13.2%) pregnant women were underweight, 665 (10.8%) were overweight, and 145 (2.20%) were obesity. We found a linear dose–response relation between maternal body mass index and GDM by restricted cubic splines, where one unit body mass index increase was associated with the 15% elevated risk of GDM (adjusted odds ratio [OR] 1.15, 95% CI 1.08–1.22). Compared to the normal weight group, maternal underweight was associated with lower risk of GDM (adjusted OR 0.68, 95% CI 0.57–0.82), while increased risk was found for overweight (adjusted OR 1.54 95% CI 1.29–1.84) and obesity (adjusted OR 1.74, 95% CI 1.23–2.47). Conclusions Our study found a linear dose–effect relationship between pre-pregnancy bodyweight and GDM following ART treatment. The findings in this study support the clinical recommendation of advising women with overweight or obesity to lose weight prior to ART treatment.

Aim IgA nephropathy (IgAN) is one of the leading causes of end-stage renal disease (ESRD). Urine testing is a non-invasive way to track the biomarkers used for measuring renal injury. This study aimed to analyse urinary complement proteins during IgAN progression using quantitative proteomics. Methods In the discovery phase, we analysed 22 IgAN patients who were divided into three groups (IgAN 1-3) according to their estimated glomerular filtration rate (eGFR). Eight patients with primary membranous nephropathy (pMN) were used as controls. Isobaric tags for relative and absolute quantitation (iTRAQ) labelling, coupled with liquid chromatography-tandem mass spectrometry, was used to analyse global urinary protein expression. In the validation phase, western blotting and parallel reaction monitoring (PRM) were used to verify the iTRAQ results in an independent cohort (N = 64). Results In the discovery phase, 747 proteins were identified in the urine of IgAN and pMN patients. There were different urine protein profiles in IgAN and pMN patients, and the bioinformatics analysis revealed that the complement and coagulation pathways were most activated. We identified a total of 27 urinary complement proteins related to IgAN. The relative abundance of C3, the membrane attack complex (MAC), the complement regulatory proteins of the alternative pathway (AP), and MBL (mannose-binding lectin) and MASP1 (MBL associated serine protease 2) in the lectin pathway (LP) increased during IgAN progression. This was especially true for MAC, which was found to be involved prominently in disease progression. Alpha-N-acetylglucosaminidase (NAGLU) and α-galactosidase A (GLA) were validated by western blot and the results were consistent with the iTRAQ results. Ten proteins were validated in a PRM analysis, and these results were also consistent with the iTRAQ results. Complement factor B (CFB) and complement component C8 alpha chain (C8A) both increased with the progression of IgAN. The combination of CFB and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) also showed potential as a urinary biomarker for monitoring IgAN development. Conclusion There were abundant complement components in the urine of IgAN patients, indicating that the activation of AP and LP is involved in IgAN progression. Urinary complement proteins may be used as biomarkers for evaluating IgAN progression in the future.

PurposeIntravitreal vascular endothelial growth factor (VEGF) blockade is essential in many macular edema diseases treatment. However, intravitreal VEGF treatment has been reported to lead to deteriorated proteinuria and renal function. This study aimed to explore the relationship between renal adverse events (AEs) and the intravitreal use of VEGF inhibitors.MethodIn the FDA’s Adverse Event Reporting System (FAERS) database, we searched for renal AEs of patients receiving various anti-VEGF drugs. We performed statistics on renal AEs in patients treated with Aflibercept, Bevacizumab, Ranibizumab, and Brolucizumab (from January 2004 to September 2022) using disproportionate and Bayesian analysis. We also investigated the time to onset, fatality, and hospitalization rates of renal AEs.ResultsWe identified 80 reports. Renal AEs were most frequently associated with Ranibizumab (46.25%) and Aflibercept (42.50%). However, the association between intravitreal anti-VEGFs and renal AEs was insignificant since the reporting odds ratio of Aflibercept, Bevacizumab, Ranibizumab, and Brolucizumab were 0.23 (0.16, 0.32), 0.24 (0.11, 0.49), 0.37 (0.27, 0.51) and 0.15 (0.04, 0.61), respectively. The median time to renal AEs onsets was 37.5 (interquartile range 11.0–107.3) days. The hospitalization and fatality rates in patients who developed renal AEs were 40.24 and 9.76%, respectively.ConclusionThere are no clear signals for the risk of renal AEs following various intravitreal anti-VEGF drugs based on FARES data.

Abstract A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is urgently needed to tackle the COVID-19 global pandemic. Here, we describe the development of chimpanzee adenovirus serotypes 6 and 68 (AdC6 and AdC68) vector-based vaccine candidates expressing the full-length transmembrane spike glycoprotein. We assessed the vaccine immunogenicity, protective efficacy, and immune cell profiles using single-cell RNA sequencing in mice. Mice were vaccinated via the intramuscular route with the two vaccine candidates using prime-only regimens or heterologous prime-boost regimens. Both chimpanzee adenovirus-based vaccines elicited strong and long-term antibody and T cell responses, balanced Th1/Th2 cell responses, robust germinal center responses, and provided effective protection against SARS-CoV-2 infection in mouse lungs. Strikingly, we found that heterologous prime-boost immunization induced higher titers of protective antibodies, and more spike-specific memory CD8+ T cells in mice. Potent neutralizing antibodies produced against the highly transmissible SARS-CoV-2 variants B.1.1.7 lineage (also known as N501Y.V1) and B.1.351 lineage (also known as N501Y.V2) were detectable in mouse sera over 6 months after prime immunization. Our results demonstrate that the heterologous prime-boost strategy with chimpanzee adenovirus-based vaccines is promising for further development to prevent SARS-CoV-2 infection.

Neutralizing monoclonal antibodies (mAbs) against highly pathogenic coronaviruses represent promising candidates for clinical intervention. Here, we isolated a potent neutralizing monoclonal antibody, MERS-S41, from a yeast displayed scFv library using the S protein as a bait. To uncover the neutralization mechanism, we determined structures of MERS-S41 Fab in complex with the trimeric spike glycoprotein by cryoelectron microscopy (cryo-EM). We observed four distinct classes of the complex structure, which showed that the MERS-S41 Fab bound to the “up” receptor binding domain (RBD) with full saturation and also bound to an accessible partially lifted “down” RBD, providing a structural basis for understanding how mAbs bind to trimeric spike glycoproteins. Structure analysis of the epitope and cell surface staining assays demonstrated that virus entry is blocked predominantly by direct competition with the host receptor, dipeptidyl peptidase-4 (DPP4).

Hashimoto's encephalopathy (HE), also known as steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), has a variety of clinical manifestations, with various neuropsychiatric characteristics, including tremors, transient aphasia, seizures, altered consciousness, myoclonus, cognitive impairment, and psychiatric manifestations. The hallmark presenting feature is a non-specific encephalopathy characterized by alteration of mental status and consciousness ranging from confusion to coma and impaired cognitive function, while those with cerebellar ataxia as the main manifestation is rare. We reported a case of Hashimoto's encephalopathy with cerebellar ataxia as the main manifestation, elevated anti-thyroid antibodies (anti-TPO/TG), and normal thyroid function. The symptoms of cerebellar ataxia improved after steroid treatment. Meanwhile, we reviewed the clinical features of 20 representative cases of HE with cerebellar ataxia as the core symptoms. In conclusion, based on our case findings and literature review, the diagnosis of HE should be suspected in cases of encephalopathy without an obvious cause, to quickly start an effective treatment.

Background and aimsRecently, various hemocyte and blood cell ratios have garnered researchers' attention, as a low-cost, widely prevalent, and easy-to-measure index for diagnosing and predicting disease. Therefore, we sought to investigate the effect and predictive value of the peripheral blood neutrophil percentage and neutrophil-lymphocyte ratio (NLR) in the acute phase of ischemic stroke (AIS) in post-stroke cognitive impairment (PSCI).MethodsWe selected 454 patients with mild AIS and acquired general clinical data. The patients were divided into PSCI and post-stroke no cognitive impairment (PSNCI) groups according to their Montreal Cognitive Assessment (MOCA) scores. We assessed whether there were differences in clinical data, peripheral blood neutrophil percentage, and NLR values between the different groups. We also analyzed the independent influences on the occurrence of PSCI using a binary logistic regression. Receiver operating characteristic (ROC) curves were used to analyze the predictive value of the above inflammatory indicators and models containing different inflammatory indicators for PSCI.ResultsIn total, 454 patients were included, of whom 253 (55.7%) patients were in the PSCI group, with a mean age of 62.15 ± 7.34 years and median neutrophil percentage and NLR of 0.64 (0.32–0.95) and 2.39 (0.71–54.46), respectively. Both neutrophil percentage (adjusted OR = 1.025; 95% confidence interval: 1.005–1.406) and NLR as a categorical variable (Q5, adjusted OR = 2.167; 95% CI: 1.127–4.166) were independent risk factors for PSCI, and the Q5 group (NLR ≥ 4.05) had significantly worse overall cognition and executive function.ConclusionsNeutrophil percentage and NLR in the acute phase of AIS were independently associated with PSCI, and a high NLR was strongly associated with executive function. In addition, neutrophil percentage and NLR have diagnostic values for PSCI.

The difference in microbiota was examined for breeders with different egg-laying rates, and the impact of dietary Enterococcus faecium (EF) was also determined in the present study. A total of 256 Arbor Acres broiler breeders (48-wk-old) were used in a 2 × 2 factorial design, which encompassed 2 egg-laying rate levels [average (average egg laying: AP, 80.45 ± 0.91%) and low (lower egg laying: LP, 70.61 ± 1.16%)] and 2 different dietary groups [control (no additive), 6 × 108 cfu/kg EF]. The results showed that the AP breeders presented a lower egg weight, feed conversion ratio, abdominal fat rate, and serum leptin level (P(laying) ≤ 0.05) as well as a higher egg-laying rate (P(laying)

Epigallocatechin-3-gallate (EGCG), a frequently studied catechin in green tea, has been shown involved in the anti-proliferation and apoptosis of human nasopharyngeal carcinoma (NPC) cells. However, the underlying molecular mechanism of the apoptotic effects of EGCG has not been fully investigated. Recent literature emphasized the importance of Sirtuin 1 (SIRT1), an NAD+-dependent protein deacetylase, in regulating cellular stress responses, survival, and organismal lifespan. Herein, the study showed that EGCG could significantly inhibit cell proliferation and promote apoptosis of 2 NPC (CNE-2 and 5-8F) cell lines. Moreover, it was also found that SIRT1 is down-regulated by EGCG, and the SIRT1-p53 signaling pathway participates in the effects of EGCG on CNE-2 and 5-8 F cells. Taken together, the findings of this study provided evidence that EGCG could inhibit the growth of NPC cell lines and is linked with the inhibition of the SIRT1-p53 signaling pathway, suggesting the therapeutic potential of EGCG in human NPC.

Summary: With the rapid emergence and spread of SARS-CoV-2 variants, development of vaccines with broad and potent protectivity has become a global priority. Here, we designed a lipid nanoparticle-encapsulated, nucleoside-unmodified mRNA (mRNA-LNP) vaccine encoding the trimerized receptor-binding domain (RBD trimer) and showed its robust capability in inducing broad and protective immune responses against wild-type and major variants of concern (VOCs) in the mouse model of SARS-CoV-2 infection. The protectivity was correlated with RBD-specific B cell responses especially the long-lived plasma B cells in bone marrow, strong ability in triggering BCR clustering, and downstream signaling. Monoclonal antibodies isolated from vaccinated animals demonstrated broad and potent neutralizing activity against VOCs tested. Structure analysis of one representative antibody identified a novel epitope with a high degree of conservation among different variants. Collectively, these results demonstrate that the RBD trimer mRNA vaccine serves as a promising vaccine candidate against SARS-CoV-2 variants and beyond.

Background: Aberrant O-glycosylation of IgA1 plays an important role in IgA nephropathy pathogenesis. Previous proteomic studies analyzed O-glycans of the circulating IgA1 hinge region and found that the N-acetylgalactosamine (GalNAc) and galactose numbers in the hinge region of IgA1 of patients with IgA nephropathy were lower than those in healthy participants. However, the diagnostic performance of the O-glycosylation traits in the hinge region of plasma IgA1 for IgA nephropathy remains unelucidated. The present study aimed to determine the difference in plasma IgA1 hinge region O-glycoforms among IgA nephropathy, non-IgA nephropathy disease controls, and healthy participants, and to further evaluate the diagnostic performance of plasma IgA1 glycosylation traits.Methods: Sixty-two patients with biopsy-proven primary IgA nephropathy, 30 age- and sex-matched non-IgA nephropathy disease controls (10 patients with membranous nephropathy, 10 with focal segmental glomerulosclerosis, and 10 with minimal change disease), and 30 healthy participants were prospectively recruited. Plasma galactose deficient-IgA1 levels were measured using a KM55 kit. Plasma IgA was extracted using IgA immunoaffinity beads. After de-N-glycosylation, reduction, alkylation, trypsin digestion, and O-glycopeptide enrichment via hydrophilic interaction liquid chromatography, liquid chromatography tandem mass spectrometry (LC-MS/MS) was applied to analyze the IgA1 O-glycosylation patterns and we derived the plasma IgA1 O-glycosylation traits.Results: Plasma IgA1 O-glycosylation patterns were significantly changed in IgA nephropathy patients compared to those with non-IgA nephropathy disease controls and healthy participants. The GalNAc number was lowest in IgA nephropathy patients. In addition, a similar result was observed for the galactose number in the IgA1 hinge region. These values showed moderate potential for discriminating between IgA nephropathy and the controls. When these values were combined, the area under the curve increased compared to when they were considered individually. When further adding a clinical indicator, the area under the curve of the GalNAc-galactose-IgA panel exceed 0.9 in discriminating IgA nephropathy from the controls.Conclusion: The amount of GalNAc and galactose in plasma IgA1 hinge region identified by glycoproteomics could be used as a diagnostic biomarker for IgA nephropathy. The panel containing GalNAc, galactose, and circulating IgA displayed excellent diagnostic performance and is promising for practical clinical applications.

Bamboo part preference plays a critical role in influencing the nutrient utilization and gastrointestinal microbiota composition of captive giant pandas. However, the effects of bamboo part consumption on the nutrient digestibility and gut microbiome of geriatric giant pandas remain unknown. A total of 11 adult and 11 aged captive giant pandas were provided with bamboo shoots or bamboo leaves in the respective single-bamboo-part consumption period, and the nutrient digestibility and fecal microbiota of both adult and aged giant pandas in each period were evaluated. Bamboo shoot ingestion increased the crude protein digestibility and decreased the crude fiber digestibility of both age groups. The fecal microbiome of the bamboo shoot-fed giant pandas exhibited greater alpha diversity indices and significantly different beta diversity index than the bamboo leaf-fed counterparts regardless of age. Bamboo shoot feeding significantly changed the relative abundance of predominant taxa at both phylum and genus levels in adult and geriatric giant pandas. Bamboo shoot-enriched genera were positively correlated with crude protein digestibility and negatively correlated with crude fiber digestibility. Taken together, these results suggest that bamboo part consumption dominates over age in affecting the nutrient digestibility and gut microbiota composition of giant pandas.

Abstract Background To evaluate renal expression of C4d, a complement component in the classical/mannose binding lectin (MBL) pathway, in patients with primary Sjögren’s syndrome (pSS)-associated renal impairments. Methods We retrospectively reviewed the clinical and pathological data from 39 patients with pSS presenting with renal impairments. C4d was examined in paraffin-embedded biopsy tissues using immunohistochemistry. Glomerular C4d positive was defined when > 75% glomeruli were globally stained. Tubulointerstitial C4d (TI-C4d) were scored semi-quantitatively as 0 (absent), 1 (spotty or weak), 2 (patchy) and 3 (diffuse). A TI-C4d score ≥ 2 was considered TI-C4d positive and included in the TI-C4d+ group and vice versa. Peritubular capillary (PTC) C4d was scored as 0 (absent), 1 (0~10%, minimal), 2 (10%~ 50%, focal), and 3 (> 50%, diffuse). Results Glomerular C4d deposition was observed in all 8 patients with pSS-related membranous nephropathy (MN) without obvious C1q deposition. Two of 5 patients with mesangial proliferative glomerulonephritis and 1 of 2 patients with IgA nephropathy had mild mesangial C4d deposition. Sixteen patients (6 glomerular dominant and 10 tubulointerstitial dominant) presented TI-C4d score ≥ 2. Patients in the TI-C4d+ group exhibited a higher serum creatinine level at the time of renal biopsy (TI-C4d+ 132.5 [89.7, 165.5] vs. TI-C4d− 83.0 [70.7, 102.0] μmol/L, P = 0.008). PTC C4d was observed in 12 patients, with each of minimal, focal and diffuse staining being noted in 4 patients. Conclusions The MBL pathway of complement activation was potentially involved in pSS-related MN. Tubulointerstitial C4d might be a pathological marker of severe renal injury in patients with pSS-related renal impairments.

The development of a safe and effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we aim to develop novel SARS-CoV-2 vaccines based on a derivative of less commonly used rare adenovirus serotype AdC68 vector. Three vaccine candidates were constructed expressing either the full-length spike (AdC68-19S) or receptor-binding domain (RBD) with two different signal sequences (AdC68-19RBD and AdC68-19RBDs). Single-dose intramuscular immunization induced robust and sustained binding and neutralizing antibody responses in BALB/c mice up to 40 weeks after immunization, with AdC68-19S being superior to AdC68-19RBD and AdC68-19RBDs. Importantly, immunization with AdC68-19S induced protective immunity against high-dose challenge with live SARS-CoV-2 in a golden Syrian hamster model of SARS-CoV-2 infection. Vaccinated animals demonstrated dramatic decreases in viral RNA copies and infectious virus in the lungs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in rhesus macaques. Taken together, these results confirm that AdC68-19S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.

Background and purpose Detection of atrial fibrillation (AF) after acute ischaemic stroke is pivotal for the timely initiation of anticoagulation to prevent recurrence. Besides heart rhythm monitoring, various blood biomarkers have been suggested as complimentary diagnostic tools for AF. We aimed to summarise data on the performance of cardiac natriuretic peptides for the diagnosis of covert AF after acute ischaemic stroke and to assess their potential clinical utility.Methods We searched PubMed and Embase for prospective studies reporting the performance of B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) for the diagnosis of covert AF after acute ischaemic stroke. Summary diagnostic performance measures were pooled using bivariate meta-analysis with a random-effect model.Results We included six studies focusing on BNP (n=1930) and three studies focusing on NT-proBNP (n=623). BNP had a sensitivity of 0.83 (95% CI 0.64 to 0.93), a specificity of 0.74 (0.67 to 0.81), a positive likelihood ratio of 3.2 (2.6 to 4.0) and a negative likelihood ratio of 0.23 (0.11 to 0.49). NT-proBNP had a sensitivity of 0.91 (0.65 to 0.98), a specificity of 0.77 (0.52 to 0.91), a positive likelihood ratio of 3.9 (1.8 to 8.7) and a negative likelihood ratio of 0.12 (0.03 to 0.48). Considering a pretest probability of 20%, BNP and NT-proBNP had post-test probabilities of 45% and 50%.Conclusions NT-proBNP has a better performance than BNP for the diagnosis of covert AF after acute ischaemic stroke. Both biomarkers have low post-test probabilities and may not be used as a stand-alone decision-making tool for the diagnosis of covert AF in patients with acute ischaemic stroke. However, they may be useful for a screening strategy aiming to select patients for long-term monitoring of the heart rhythm.

Background and aims: Monoclonal immunoglobulin light chain associated Fanconi syndrome (LC-FS) is a rare disease that involves proximal tubules. As most of the reported cases came from western countries, we aimed to analyze the clinicopathological characteristics of Asian LC-FS and its treatment responses to chemotherapy. Methods: A total of 26 LC-FS patients in a single-center were retrospectively studied. Results: At diagnosis, the mean age of the 26 Asian LC-FS patients was 54.7 ± 14.7 years, with females accounting for 57.7%. They presented with different degrees of proximal tubular dysfunctions with normoglycemic glycosuria (88.0%), hyperphosphaturia (84.2%) and aminoaciduria (84.0%) as the most common features. The mean estimated glomerular filtration rate (eGFR) was (68.0 ± 26.4) ml/min per 1.73 m 2 . After chemotherapy, renal response was achieved in 58.3% cases, which was accompanied by hematological response, and tubular response was acquired in 66.7% cases. During 3 years of follow-up, the eGFR levels significantly decreased in the monoclonal gammopathy of renal significance patients, few of whom (21.4%) had received chemotherapy. Conclusion: Asian LC-FS patients had mild renal function disorder. The chemotherapy could improve both renal and tubular functions, which may be related to the hematological response.

ABSTRACTThe recently identified Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe and fatal acute respiratory illness in humans. However, no approved prophylactic and therapeutic interventions are currently available. The MERS-CoV envelope spike protein serves as a crucial target for neutralizing antibodies and vaccine development, as it plays a critical role in mediating viral entry through interactions with the cellular receptor, dipeptidyl peptidase 4 (DPP4). Here, we constructed a recombinant rare serotype of the chimpanzee adenovirus 68 (AdC68) that expresses full-length MERS-CoV S protein (AdC68-S). Single intranasal immunization with AdC68-S induced robust and sustained neutralizing antibody and T cell responses in BALB/c mice. In a human DPP4 knock-in (hDPP4-KI) mouse model, it completely protected against lethal challenge with a mouse-adapted MERS-CoV (MERS-CoV-MA). Passive transfer of immune sera to naïve hDPP4-KI mice also provided survival advantages from lethal MERS-CoV-MA challenge. Analysis of sera absorption and isolated monoclonal antibodies from immunized mice demonstrated that the potent and broad neutralizing activity was largely attributed to antibodies targeting the receptor binding domain (RBD) of the S protein. These results show that AdC68-S can induce protective immune responses in mice and represent a promising candidate for further development against MERS-CoV infection in both dromedaries and humans.

Background/Aims: While systolic blood pressure variability (SBPV) is an independent risk factor for mortality in the general population, its association with outcomes in hemodialysis patients has been less well-investigated. Methods: In this retrospective study, we enrolled 99 eligible HD patients from 2006 to 2016. Predialysis blood pressure measurements obtained over 1-year period were used to determine each patient’s BPV. The standard deviation (SD), the coefficient of variation (CV) and the variation independent of the mean (VIM) were used as metrics of BPV. Results: During a median follow-up period of 68 months, 52 patients died, and cardiovascular disease (31.3%) was the primary cause of death in these patients. After adjusting for covariates, the hazard ratios (HRs) for all-cause and cardiovascular mortality were 1.80 (95% confidence interval (CI) 1.11-2.92) and 1.71 (95% CI 1.01-2.90), respectively, for a one percent increase in CV. Variability in the volume removed per session and predialysis serum albumin and calcium levels were identified as factors associated with BPV. Conclusion: In this study, we demonstrate that greater variability in predialysis SBP is associated with long-term mortality in hemodialysis patients. Controlling volume variation, avoiding hypoalbuminemia and reducing blood calcium levels might reduce SBP variability and thereby improve prognoses in these patients.

Abstract Background Chronic kidney disease patients have an increased prevalence of subclinical cerebrovascular diseases. Dialysis patients have severe vascular diseases burden. The cerebral small vessel diseases (CSVD) are difficult to find by clinical assessment. The evaluation of CVSD needs MRI. Cognitive impairment is a consequence of CVSD which is diagnosed by cognitive testing. These limited the study of CVSD and cognitive function in dialysis patients. Peritoneal dialysis (PD) patients are minority of dialysis population. We know even fewer about the CVSD in this special population. Methods In this cross-sectional study, we enrolled 72 PD patients who received care at the Peking Union Medical College hospital peritoneal dialysis center. CSVD were assessed by brain MR images. Cognitive function was evaluated with the Chinese version of the MMSE and MoCA. Results In our PD patients, the brain MRI showed the prevalence different signs of CSVD were: lacunar infarcts 38.9%, microbleeds 36.1%, abnormal brain white matter hyperintensities (WMHs) 48.6%, and intracerebral hemorrhage 4.2%. 25% and 86.8%of our patients could be diagnosed as cognitive impairment, according to the MMSE and MoCA test, respectively. nPCR was lower in patients with a lacunar infarct or intracerebral hemorrhage, and relative to the MMSA/MoCA score; hsCRP was higher in patients with lacunar infarct or abnormal WMHs and negative relative to the MMSA/MoCA score. In logistic regression analyses, nPCR was an independent risk factor for lacunar infarcts and impaired cognitive function. The presence of lacunar infarct was an independent risk factor for cognitive function decline. Conclusion We demonstrated a high prevalence of CSVD and cognitive impairment in our PD patients. Lacunar infarct was the main kind of CVSD responsible for PD patients cognitive function decline. Our novel observation also revealed an association between malnutrition-inflammation and CSVD.

Abstract Biomarkers are measurable changes associated with the disease. Urine can reflect the changes of the body while blood is under control of the homeostatic mechanisms; thus, urine is considered an important source for early and sensitive disease biomarker discovery. A comprehensive profile of the urinary proteome will provide a basic understanding of urinary proteins. In this paper, we present an in-depth analysis of the urinary proteome based on different separation strategies, including direct one dimensional liquid chromatography–tandem mass spectrometry (LC/MS/MS), two dimensional LC/MS/MS, and gel-eluted liquid fraction entrapment electrophoresis/liquid-phase isoelectric focusing followed by two dimensional LC/MS/MS. A total of 6085 proteins were identified in healthy urine, of which 2001 were not reported in previous studies and the concentrations of 2571 proteins were estimated (spanning a magnitude of 106) with an intensity-based absolute quantification algorithm. The urinary proteins were annotated by their tissue distribution. Detailed information can be accessed at the “Human Urine Proteome Database” (www.urimarker.com/urine).

Abstract Background This study reports the clinical and pathological features of 12 cases of primary Sjogren syndrome (pSS) with renal involvement presenting with proximal tubular dysfunction in a single center, and investigates the possible correlation of ectopic germinal center formation and megalin/cubilin down-expression. Method Clinical and pathological records were reviewed. Immunohistochemistry was carried out to detect megalin, cubilin, CD21 and IL-17 expression. Results Patients presented with different degrees of proximal renal tubule lesion and decreased estimated glomerular filtration rate (eGFR). Renal biopsy revealed tubulointerstitial nephritis, with tubular epithelial cell degeneration, tubular atrophy, interstitial inflammation and focal fibrosis. Immunohistochemistry revealed decreased expression of megalin and cubilin, two important multiligand protein receptors on the brush border of proximal tubular epithelial cells. IL-17 secreted by Th17 subtype effector T cells was diffusely detected in the renal proximal tubule, with a negative correlation of IL-17 and megalin expression. In addition, ectopic germinal centers characterized by CD21+ follicular dendritic cells were present in the renal interstitium. In patients with a decreased eGFR, treatment with 4 weeks of glucocorticoid therapy resulted in an improved eGFR in 75% of patients. Conclusion We report 12 cases of pSS characterized by Fanconi syndrome. The decreased megalin and cubilin expression may contribute to the proximal tubular reabsorption defect, possibly secondary to Th17 infiltration and formation of ectopic germinal centers.

Pomegranate (Punica granatum L.) fruit is being cultivated since the civilization is known, and its production and consumption have been increased since the last century due to the scientific confirmation of its health benefits. Pomegranate fruits, fruit juice, its seeds, and peels are known to have higher contents of bioactive compounds, viz., phenolic acids, flavonoids, and hydrolysable tannins. The peels of pomegranate fruits are the major by-products produced during food processing of pomegranate enriched in antioxidants and broad-spectrum antimicrobial agents and can prevent food deterioration even. This health potential of pomegranate is known to vary significantly upon the varieties, growing conditions, cultivation practices, stages of the development, and the extraction methods. Herein, the biochemical composition of the pomegranate peel extract (PPE), its efficacy in food preservation, and antimicrobial activities are discussed to provide a comprehensive guide for farmers, food processing, and storage sectors and academia.

Intracerebral hemorrhage (ICH) is a devastating disease that is characterized by high morbidity and high mortality. ICH has an annual incidence of 10–30/100,000 people and accounts for approximately 10%–30% of all types of stroke. ICH mostly occurs at the basal ganglia, which is rich in nerve fibers; thus, hemiplegia is quite common in ICH patients with partial sensory disturbance and ectopic blindness. In the clinic, those symptoms are considered to originate from the white matter injury in the area, but the exact mechanisms are unknown, and currently, no effective drug treatments are available to improve the prognosis. Clarifying the mechanisms will contribute to the development of new treatment methods for patients. The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel that plays a role in inflammatory pain sensation and nociception and may be a potential regulator in emotion, cognition and social behavior. Here, we report that TRPA1 is involved in myelin damage and oxidative stress injury in a mouse ICH model. Intervention with the TRPA1 channel may be a new method to improve the motor function of patients in the early stage of ICH.