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Regulating reactive oxygen species and inflammation are important for treating atherosclerosis. Here, the authors create a cell membrane coated zoledronic acid ceria nanocomposite loaded with probucol for synergistic drug and scavenging nanozyme treatment of atherosclerosis demonstrating application in vivo.

Quantitatively describing the atomic configuration of the catalytically active sites is challenging. Here the authors demonstrate that tuning crystal-phase of metal single-particle enables to precisely describe the atomic structure of the active sites and accurately identify the activation routes of the reacting molecules.

BackgroundChronic kidney disease (CKD) is a global health burden. However, the efficacy of different modes of eHealth care in facilitating self-management for patients with CKD is unclear. ObjectiveThe aim of this study was to evaluate the effectiveness of a mobile app–based intelligent care system in improving the kidney outcomes of patients with CKD. MethodsOur study was a retrospective analysis based on the KidneyOnline intelligent system developed in China. Patients with CKD but not dependent on dialysis who registered on the KidneyOnline app between January 2017 and January 2021 were screened. Patients in the the KidneyOnline intelligent system group and those in the conventional care group were 1:1 matched according to their baseline characteristics. The intervention group received center-based follow-up combined with the KidneyOnline intelligent patient care system, which was a nurse-led, patient-oriented collaborative management system. Health-related data uploaded by the patients were integrated using deep learning optical character recognition (OCR). Artificial intelligence (AI)–generated personalized recipes, lifestyle intervention suggestions, early warnings, real-time questions and answers, and personalized follow-up plans were also provided. Patients in the conventional group could get professional suggestions from the nephrologists through regular clinical visits, but they did not have access to the service provided by AI and the health coach team. Patients were followed for at least 3 months after recruitment or until death or start of renal replacement therapy. ResultsA total of 2060 eligible patients who registered on the KidneyOnline app from 2017 to 2021 were enrolled for the analysis. Of those, 902 (43.8%) patients were assessed for survival analysis after propensity score matching, with 451(50%) patients in the KidneyOnline intelligent patient care system group and 451(50%) patients in the conventional care group. After a mean follow-up period of 15.8 (SD 9.5) months, the primary composite kidney outcome occurred in 28 (6%) participants in the KidneyOnline intelligent patient care system group and 32 (7%) in the conventional care group, with a hazard ratio of 0.391 (95% CI 0.231-0.660; P

Anti-CD25 antibodies have been approved for renal transplantation and has been used prior to and during transplantation by the Food and Drug Administration (FDA). However, no reported bioassays have been reflected the mechanism of action (MOA) of anti-CD25 antibodies. Here, we describe the development and validation of a reporter gene assay (RGA) based on the engineered C8166-STAT5RE-Luc cells expressing endogenous IL-2 receptors and a STAT5-inducible element-driven firefly luciferase in C8166 cell lines. The RGA was fully validated according to the International Conference on the Harmonization of Technical Requirements for the Registration of Pharmaceuticals for the Human Use-Q2 (ICH-Q2). After optimization, the assay showed excellent specificity, linearity, accuracy, precision, and robustness. Due to the MOA relatedness and the excellent assay performance, the RGA is suitable for exploring the critical quality attributes (CQAs), release inspection, comparability and stability of anti-CD25 mAbs.

By distinguishing between two types of neutralizing antibodies that either exhibit or lack antibody-dependent enhancement (ADE) activity, FcγRIIB and bivalent binding are shown to be required for ADE in SARS-CoV-2 infection.

Constructed wetlands (CWs) widely applied for wastewater treatment release significant greenhouse gases (GHGs), contributing to global warming. It is essential to characterize the comprehensive source-sink effects and affecting factors of GHGs in CWs, offering references and guidance for designing and operating CWs to better control GHG emissions. However, current reviews focus on individual GHG emission mechanisms. With the aid of the Web of Science Core Collection database, the relevant literature on carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) emissions in CWs after 2010 was collected and organized. As highlighted in the review, CWs can produce and transmit these GHGs into the atmosphere, forming sources of GHGs and sequestration CO2 through plants photosynthesis, forming sinks of GHGs. Their overall performance depends on many factors. Hybrid CWs, Cyperus papyrus, Cyperus alternifolius, and Iris pseudacorus, adsorption substrates like Fe-C, low temperatures, and a C/N ratio of five are beneficial for GHG mitigation in CWs. Future studies should focus on in-depth research into the mechanisms and overall source-sink benefits of plants and microorganisms in relation to GHGs. This review provided a comprehensive understanding of the emission mechanisms and affecting factors of the major GHGs in CWs, bridging the research gap in this field, helping researchers to clarify the context, and providing valuable in-sights for further scientific investigations.

Abstract Background Esophageal cancer is the fifth most common cancer affecting men in China. The primary treatment options are surgery and traditional radio-chemotherapy; no effective targeted therapy exists yet. Self-assembled RNA nanocarriers are highly stable, easily functionally modified, and have weak off-tumor targeting effects. Thus, they are among the most preferred carriers for mediating the targeted delivery of anti-tumor drugs. miR-375 was found to be significantly down-regulated in esophageal squamous cell carcinoma (ESCC) tissues and its overexpression effectively inhibits the proliferation, migration, and invasion of ESCC cells. Moreover, epidermal growth factor receptor (EGFR) was overexpressed in ESCC cells, and accumulation of RNA nanoparticles in ESCC tumors was enhanced by EGFR-specific aptamer (EGFRapt) modification. Results Herein, a novel four-way junction RNA nanocarrier, 4WJ-EGFRapt-miR-375-PTX simultaneously loaded with miR-375, PTX and decorated with EGFRapt, was developed. In vitro analysis demonstrated that 4WJ-EGFRapt-miR-375-PTX possesses strong thermal and pH stabilities. EGFRapt decoration facilitated tumor cell endocytosis and promoted deep penetration into 3D-ESCC spheroids. Xenograft mouse model for ESCC confirmed that 4WJ-EGFRapt-miR-375-PTX was selectively distributed in tumor sites via EGFRapt-mediating active targeting and targeted co-delivery of miR-375 and PTX exhibited more effective therapeutic efficacy with low systemic toxicity. Conclusion This strategy may provide a practical approach for targeted therapy of ESCC. Graphical Abstract

Introduction: Zoledronic acid (ZA) is a widely used bisphosphonate compound for the prevention of skeletal metastasis-associated osteolysis and treatment of post-menopause osteoporosis. Acute kidney injury is one of the commonly described renal complications. Electrolytes disorder has also been reported relevant to ZA exposure and nephrotoxicity. Syndrome of persistent hypophosphatemia, hypokalemia and metabolic acidosis is regarded as the initial signs of acute kidney injury. Case presentation: We reported a 64-year-old female with bone metastasis from lung adenocarcinoma who received a 5-year history of 4-week cycle ZA infusion. She initially presented symptomatic severe hypophosphatemia and was finally identified with ZA-induced generalized tubular dysfunction as Fanconi’s syndrome and distal renal tubular acidosis. Renal pathological findings revealed toxic renal tubular necrosis. The ZA infusion was thus extended to an 8-week cycle with oral phosphate supplementation and alfacalcidol. Although periodic changes pre- and post-ZA infusion existed yet, hypophosphatemia was effectively improved and the rapid decline of eGFR was partially delayed. We reviewed the literature and mainly summarized the characteristics of bisphosphonates-associated hypophosphatemia. Moderate hypophosphatemia was more frequently mentioned in contrast to severe cases being predisposed to be reported. And progressive hypophosphatemia serves as an early sign of kidney injury. Conclusion: Progressive electrolyte disorders and CKD were the long-term renal outcome of the current patient. We would like to arouse more attention to electrolytes imbalance related to early ZA-induced kidney injury and emphasize the significance of close monitoring.

The aim of the present experiment was to study the effects of duo-strain probiotics (DSP, Bacillus subtilis and Lactobacillus plantarum) culture supplemented by post-spraying technology on the growth performance, digestive enzyme activity, antioxidant capacity and intestinal microbiota of grass carp, as well as the viability of the DSP in the post-spraying and storage process. In the present experiment, 900 of Grass carp (41.4 ± 1.8 g) were fed with a basal diet (control group) and the DSP diet containing 105 CFU/g (T1 group) or 106 CFU/g (T2 group) probiotics supplemented by the post-spraying technology in 9 cages for 6 weeks. Meanwhile, the amount of DSP in the diets was monitored for 30 days. The results revealed that the viability of the B. subtilis and L. plantarum was 98.14% and 98.09% after the post-spraying and there were no significant differences among 30 days of storage in comparison with final viability of 99.13% and 99.10%. The result of the feed experiment indicated that the diet supplemented DSP significantly increased the percent weight gain (PWG), specific growth rate (SGR) and survival rate (SR) of grass carp, and decreased the feed conversion ratio (FCR) (P

Abstract Tumor cells require high levels of cholesterol for membrane biogenesis for rapid proliferation during development. Beyond the acquired cholesterol from low-density lipoprotein (LDL) taken up from circulation, tumor cells can also biosynthesize cholesterol. The molecular mechanism underlying cholesterol anabolism in esophageal squamous cell carcinoma (ESCC) and its effect on patient prognosis are unclear. Dysregulation of lipid metabolism is common in cancer. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been implicated in various cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we identified that LPCAT1 is highly expressed in ESCC and that LPCAT1 reprograms cholesterol metabolism in ESCC. LPCAT1 expression was negatively correlated with patient prognosis. Cholesterol synthesis in ESCC cells was significantly inhibited following LPCAT1 knockdown; cell proliferation, invasion, and migration were significantly reduced, along with the growth of xenograft subcutaneous tumors. LPCAT1 could regulate the expression of the cholesterol synthesis enzyme, SQLE, by promoting the activation of PI3K, thereby regulating the entry of SP1/SREBPF2 into the nucleus. LPCAT1 also activates EGFR leading to the downregulation of INSIG-1 expression, facilitating the entry of SREBP-1 into the nucleus to promote cholesterol synthesis. Taken together, LPCAT1 reprograms tumor cell cholesterol metabolism in ESCC and can be used as a potential treatment target against ESCC.

Abstract Background Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare in Asians, and patients with CLL/SLL seldomly undergo kidney biopsy. The histopathological features and clinical relevance of tubulointerstitial injury in CLL/SLL have not been extensively characterized. Hence, we attempted to describe the clinical characteristics, renal pathology and clinical outcome of a well-characterized population of CLL/SLL patients with CLL cell infiltration in the renal interstitium from a large single center in China. Methods Between January 1st, 2010 and September 31st, 2020, 31946renal biopsies were performed at Peking University First Hospital, and 10 CLL/SLL patients with CLL cell infiltration in the renal interstitium were included. Complete clinical data were collected from these 10 patients, and renal specimens were examined by routine light microscopy, immunofluorescence and electron microscopy. Results The extent of the infiltrating CLL cells in patients with CLL/SLL varied among different patients and ranged from 10 to 90% of kidney parenchyma. Six (60%) of 10 patients presented with an extent of infiltrating CLL cells ≥50%. Interestingly, we found that three patients (3/10, 30%) expressed monoclonal immunoglobulins in the infiltrating CLL cells, and special cytoplasmic crystalline structures were found in two of the three patients by electron microscopy for the first time. Severe renal insufficiency (Scr ≥200 μmol/L) was associated with ≥50% interstitial infiltration of CLL cells in the renal interstitium. Conclusions The current study confirmed that CLL cells infiltrating the renal interstitium can directly secrete monoclonal immunoglobulins, indicating that the interstitial infiltrating CLL cells possibly cause renal injury directly by secreting monoclonal immunoglobulins in situ. This finding may prove a new clue to elucidate the pathogenetic mechanism of renal injury involved with CLL/SLL.

BackgroundAcute oxalate nephropathy (AON) is an uncommon condition that causes acute kidney injury (AKI), characterized by the massive deposition of calcium oxalate crystals in the renal parenchyma. In previous studies, urinary oxalate excretion has been found to be increased in patients with diabetes mellitus (DM). Here, we report a case series of diabetic patients with AKI with biopsy-proven AON, aiming to alert physicians to the potential of AON as a trigger of AKI in diabetic patients in clinical practice.Materials and methodsCases with pathological diagnosis of AON who presented with AKI clinically and had DM between January 2016 and December 2020 were retrospectively enrolled. Their clinical and pathological manifestations, treatment, and prognosis were collected.ResultsSix male patients with biopsy-proven AON out of a total of 5,883 native kidney biopsies were identified, aged 58.3 ± 9.1 years at the time of kidney biopsy. Only one patient who had received Roux-en-Y gastric bypass surgery took oxalate-rich food before the onset of the disease. None of them had clinical features of enteric malabsorption. Three patients were currently on renin-angiotensin system inhibitor treatment for hypertension, and 5 of them received non-steroidal anti-inflammatory drugs. Three patients presented with oliguria and 4 patients needed dialysis at the beginning with none requiring dialysis at discharge. Four patients received a course of corticosteroid treatment empirically. Among them, two patients had estimated glomerular filtration rate (eGFR) recovered to over 60 ml/min/1.73 m2, while the other two patients remained with kidney dysfunction at the last follow-up. In two patients without corticosteroid treatment, one patient fully recovered with eGFR over 90 ml/min/1.73 m2 and the other patient remained with kidney dysfunction at the last follow-up.ConclusionAON might be a rare but potentially trigger of AKI in patients with DM. A kidney biopsy could help physicians to make the correct diagnosis. The proper treatment to alleviate oxalate-induced injury needs to be further studied.

Lipid nanoparticles (LNPs) are widely used as delivery systems for mRNA vaccines. The stability and bilayer fluidity of LNPs are determined by the properties and contents of the various lipids used in the formulation system, and the delivery efficiency of LNPs largely depends on the lipid composition. For the quality control of such vaccines, here we developed and validated an HPLC-CAD method to identify and determine the contents of four lipids in an LNP-encapsulated COVID-19 mRNA vaccine to support lipid analysis for the development of new drugs and vaccines.

Diabetic wounds have an extremely complex microenvironment of hyperglycemia, hypoxia and high reactive oxygen species (ROS). Therefore, the regulation and management of this microenvironment may provide a new and improved treatment method for chronic diabetic wound healing. Herein, a glucose/ROS cascade-responsive nanozyme (CHA@GOx) was developed for diabetic wound treatment based on Ce-driven coassembly by a special dual ligand (alendronic acid and 2-methylimidazole) and glucose oxidase (GOx). It possesses superoxide dismutase and catalase mimic activities, which effectively remove excess ROS. In particular, it can catalyze excessive hydrogen peroxide generated by the glucose oxidation reaction to produce oxygen, regulate the oxygen balance of the wound, and reduce the toxic side effects of GOx, thus achieving the purpose of synergistically repairing diabetic wounds. In vitro experiments show that CHA@GOx assists mouse fibroblast migration and promotes human umbilical vein endothelial cell tube formation. In vivo, it can induce angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. Taken together, this study indicates that the coassembly of multifunctional nanozymes has implications in diabetic wound healing.

Soil salinity is one of the major abiotic stresses that negatively affect plant growth and agricultural productivity. For many crop species, the germination stage is one of the most sensitive stages to salinity stress. This study evaluated salt tolerance in 200 Brassica napus L. germplasms using hierarchical cluster analysis based on multiple morphological parameters, including germination rate, root length, fresh weight of root, shoot length, fresh weight of shoot, and total fresh weight. Membership function was used as a comprehensive index to select and evaluate salt tolerance of these germplasms, identifying 8 highly salt-tolerant germplasms, 40 salt-tolerant germplasms, 65 moderate salt-tolerant germplasms, 52 salt-sensitive germplasms, and 35 highly saltsensitive germplasms lines. The responses of rapeseed germplasm to salt stress indicate differences in morphological parameters. Furthermore, NaCl showed a positive effect on total fresh weight and biomass production of some germplasms at a concentration of 100 mmol L–1. Since the correlation value of salt tolerance with total fresh weight was highest under 200 mmol L–1 NaCl, it can be considered the most reliable parameter to evaluate salt tolerance. Therefore, the findings of this study can be applied as an effective and reliable method for mass screening and evaluation of Brassica napus germplasm at the germination stage for breeding salt-tolerant rapeseed genotypes. Highlights - The salinity tolerance of 200 varieties of B. napus germplasms was investigated. - B. napus is more vulnerable to saline conditions during the germination and early reproductive stages than the vegetative and flowering periods. - Based on hierarchical cluster analysis, there was a wide variability of salinity tolerance among rapeseed germplasm. - Low concentration of sodium chloride had a positive effect on shoot and root growth, germination and total weight in some B. napus seedlings. - Total fresh weight can be utilized as the most efficient index for mass screening of salt tolerance in B. napus germplasms at the germination stage.

Owing to the limitation of in vitro culture of human noroviruses (HuNoVs), the development of HuNoV vaccines has to depend on the self-assembling virus-like particles (VLPs) with capsid protein expression. The heterogeneity of artificial VLPs exert an impact on the immunogenicity, and should be considered as one of the factors in vaccine evaluation. In this study, we biochemically finger print the HuNoV VLPs with different genogroups, genotypes and sub-genotypes which constitute for a candidate vaccine, by using capillary isoelectric focusing with whole column imaging detection (cIEF-WCID). The electropherograms of GI.1, GII.3, GII.4 and GII.17 VLPs in fluorescence signal were described in the monomer VP1 forms after degenerated by 8 M urea. The four HuNoV VLPs showed different properties in electropherogram finger prints. The finger prints were also reproducible within a certain concentration range (approx. 150 ∼ 20 ug/ml). This method can also tell the changes of pI finger-print patterns when the expired HoNoV VLPs were tested. In conclusion, cIEF-WCID shows great promise for evaluating the production consistency of HuNoV VLP vaccine.

BackgroundAmyloidosis refers to an etiologically heterogeneous group of protein misfolding diseases characterized by extracellular deposition in organs and tissues of amyloid fibers, leading to severe organ dysfunction and death. Systemic amyloidosis often involves multiple organs. Heart and kidney are the most commonly affected organs, whereas skeletal muscle involvement is rare and often accompanied by other organs’ involvement.Case SummaryWe reported a 70-year-old man manifested with myopathy followed by heart failure who was suspected of transthyretin amyloidosis clinically, after the pathological results and the 99mTc-pyrophosphate (99mTc-PYP) scintigraphy, light-chain (AL) amyloidosis involving the heart and skeletal muscle was confirmed.ConclusionThe patient’s unique presentation gives insight into a rare but debilitating disorder and the potential link between various types of amyloidosis. In addition, myopathy in amyloidosis should be recognized.

Abstract Background Multiple myeloma causes different types of renal injury. C3 glomerulonephritis (C3GN) is characterised by an abnormal deposition of complement C3 in the glomeruli due to abnormal activation of the alternative pathway of the complement system. While the association between C3GN and multiple myeloma has been well established, mild renal injury by C3GN in multiple myeloma patients with high levels of light chain has not been reported. Case presentation A 55-year-old Chinese man presented with proteinuria. Combined with immunofixation electrophoresis, bone marrow biopsy, and renal biopsy, he was diagnosed with IgA-type multiple myeloma accompanied by C3GN and light chain proximal tubulopathy without crystal deposits. Although he had a higher level of lambda serum-free light chain, the renal injury in this patient was mild. After treatment with four courses of BD, one course of PAD, and autologous stem cell transplantation, he achieved a very good partial hematologic response with stable renal function. Conclusions In multiple myeloma, the light chain reaches a certain level and persists, resulting in C3GN renal impairment. Early diagnosis and early intensive treatment are critical for the prognosis of such patients.

Objects This study aimed to analyze the clinicopathological features of acute kidney disease (AKD) with renal oxalosis. Methods Data for biopsy-proven AKD with oxalosis diagnosed from Jan 2011 to Oct 2018 was collected. The underlying diseases, dietary habits, clinical and pathological characteristics of newly emerging kidney disease were analyzed. The long-term renal prognosis was observed. Results A total of 23 patients were included, comprised of 18 men and 5 women with a mean age of 51.6 ± 15.9 years. The peak Scr was 669.9 ± 299.8 μmol/L, and 95.7% of patients had stage 3 acute kidney injury (AKI). Drug-induced tubulointerstitial nephritis (TIN) was the most common cause (65.2%) of AKD, followed by severe nephrotic syndrome (17.4%). All patients had pathological changes indicating TIN, and 11 patients were complicated with the newly emerging glomerular disease (GD). The risk of oxalosis caused by increased enterogenous oxalate absorption accounted for only 26.1%, and others came from new kidney diseases. The majority (75%) of abundant (medium to severe) oxalosis occurred in patients without GD. There were no significant differences in the score for tubular injury (T-IS) and interstitial inflammation with different severities of oxalosis. Rate of Scr decrease (ΔScr%) at 2 weeks was negatively correlated with the severity of oxalosis (R = −0.542, p = 0.037), score for T-IS (R = −0.553, p = 0.033), and age (R = −0.736, p = 0.002). The decrease in Scr at 4 weeks was correlated with T-IS (R = −0.433), but had no correlation with oxalosis. Conclusions The present findings revealed that 95.7% of AKD with secondary renal oxalosis occurred in critically ill patients. AKD from tubular injury was the prominent cause. Severe oxalosis contributed to delayed early recovery of AKD.

Introduction Extracorporeal shock wave lithotripsy (ESWL) is a noninvasive modality to treat urolithiasis, with complications including tissue damage and hematoma of kidney parenchyma. Anti-glomerular basement membrane (GBM) disease is suggested to be a rare complication of ESWL since it was reported in several cases to occur after ESWL. However, the clinical and immunological features of the ESWL-associated anti-GBM disease have not been fully investigated so far. Case Presentation Here, we present the clinical, pathological, and immunological characteristics of three patients with the post-ESWL anti-GBM disease in our hospital. Anti-GBM disease occurred within a median of 22 months after ESWL treatment. It presented with similar clinical features to the classic anti-GBM disease, including fever, gross hematuria, and rapidly progressive glomerulonephritis (RPGN) with poor renal prognosis. Sera from all patients recognized the α3(IV)NC1 in GBM, but with IgG2 and IgG4 as the dominant IgG subclasses. Conclusion Although further exploration is required to prove the causal relationship in this rare condition, our study reminds physicians that patients developing acute renal insufficiency after ESWL should lead to the suspicion of anti-GBM disease and in-time diagnosis and treatment.

Lipidomic analyses have suggested that palmitic acid (PA) is linked to gastric cancer. However, its effects and action mechanisms remain unclear. Therefore, we evaluated the effects of PA on cell proliferation, invasion, and apoptosis in human gastric cancer, as well as the role of p-STAT3 in mediating its effects. The results of the MTT and colony formation assays revealed that PA blocked gastric cancer cell proliferation in a concentration-dependent manner. The EdU-DNA assay indicated that 50 μM of PA could block gastric cell proliferation by 30.6–80.0%. The Transwell assay also confirmed the concentration dependence of PA-induced inhibitory effect on cell invasion. The flow cytometry analysis indicated that PA treatment for 18 h could induce gastric cancer cell apoptosis. The immunohistochemical staining revealed that p-STAT3 levels were higher in the gastric cancer tissues than in the control tissues. We demonstrated that PA treatment for 12 h decreased the expressions of p-STAT3, p-JAK2, N-cadherin, and vimentin, and inhibited the nuclear expression of p-STAT3 in gastric cancer cells. Finally, PA treatment (50 mg/kg) decreased gastric cancer growth (54.3%) in the xenograft models. Collectively, these findings demonstrate that PA inhibits cell proliferation and invasion and induces human gastric cancer cell apoptosis.

Aliphatic α,ω-dicarboxylic acids (DCAs) are widely used chemicals that are synthesised by multistage chemical oxidations. Here, the authors report an artificially designed biocatalytic cascade for the oxidation of cycloalkanes or cycloalkanols to DCAs in the form of microbial consortia, composed of three Escherichia coli cell modules.

Little is known about the risk for acquiring a concordant human papillomavirus (HPV) infection in a genital (or anal) site after an anal (or genital) HPV infection. We collected 3 sets of anogenital specimens at 6-month intervals from 2,309 men and 2,378 women in Liuzhou, China, and tested these specimens for HPV. The risk for sequential anal HPV infection in participants with a previous genital HPV infection was higher than for participants without an infection (hazard ratio [HR] 4.4, 95% CI 3.4–5.8 for women and HR 2.6, 95% CI 1.4–4.6 for men). For sequential genital HPV infection, women with a previous anal infection had a higher risk (HR 1.9, 95% CI 1.2–3.1), but no major difference was found for men (HR 0.7, 95% CI 0.2–1.9). Our study indicates that autoinoculation might play a major role in anogenital HPV transmission, in addition to direct sexual intercourse, especially for anal infection in women.

BackgroundComplement dysregulation has been implicated in the pathogenesis of malignant nephrosclerosis with typical pathological manifestation as thrombotic microangiopathy (TMA) in recent studies. The aim of the present study was to evaluate the potential role of complement activation in arterionephrosclerosis, the major pathological change in benign hypertensive nephrosclerosis.MethodsPatients with biopsy-proven arterionephrosclerosis from 2010 to 2018 in our center were retrospectively enrolled in the present study. The clinical data were retrieved from the medical chart record. The pathological changes of renal biopsy were semiquantitatively evaluated. The ratio of inner-/outer-luminal diameter of the arterioles was calculated to evaluate the degree of arteriosclerosis. Immunohistochemical staining of CD34 and CD68 was adopted to evaluate peritubular capillary (PTC) density and macrophage infiltration, respectively. Complement components, including C3d, C4d, C1q, and C5b-9, were detected by immunohistochemical staining in paraffin-embedded sections. IgM and albumin were detected by immunofluorescence staining in frozen renal tissues.ResultsFifty-two patients were enrolled. The mean age was 45.0 ± 12.7 years, with 39 (75%) males. The median duration of hypertension was 66 months (IQR: 24–138 months). A total of 950 arterioles were evaluated, with a mean ratio of the inner/outer luminal diameter of 0.43 ± 0.05. The ratio of the inner-/outer-luminal diameter correlated with eGFR (r = 0.341, p = 0.013), sclerotic/ischemic glomerular lesions (r = –0.364, p = 0.008) and PTC density (r = 0.426, p = 0.002). Seventy-four percent (703/950) of the evaluated arterioles had C3d deposition with various patterns and intensities. The percentage of C3d-positive arterioles ranged from 63.6 to 100.0% in each specimen. The ratio of the inner/outer luminal diameter of arterioles correlated with the intensity of C3d deposition (r = –0.174, p = 0.001). Infiltration of macrophages was observed around C3d-positive arterioles. The percentage of C3d-positive arterioles was correlated with macrophage infiltration in each specimen (r = 0.330, p = 0.018). Occasional C4d-positive staining on arterioles was observed with no deposition of C1q or C5b-9 in arterionephrosclerosis specimens.ConclusionOur findings provide evidence for potential complement activation in the pathogenesis of vascular lesions in arterionephrosclerosis.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a serious public health crisis worldwide, and considering the novelty of the disease, preventative and therapeutic measures alike are urgently needed. To accelerate such efforts, the development of JS016, a neutralizing monoclonal antibody directed against the SARS-CoV-2 spike protein, was expedited from a typical 12- to 18-month period to a 4-month period. During this process, transient Chinese hamster ovary cell lines are used to support preclinical, investigational new drug-enabling toxicology research, and early Chemistry, Manufacturing and Controls development; mini-pool materials to supply Phase 1 clinical trials; and a single-clone working cell bank for late-stage and pivotal clinical trials were successively adopted. Moreover, key process performance and product quality investigations using a series of orthogonal and state-of-the-art techniques were conducted to demonstrate the comparability of products manufactured using these three processes, and the results indicated that, despite observed variations in process performance, the primary and high-order structures, purity and impurity profiles, biological and immunological functions, and degradation behaviors under stress conditions were largely comparable. The study suggests that, in particular situations, this strategy can be adopted to accelerate the development of therapeutic biopharmaceuticals and their access to patients.

Large granular T lymphocyte leukemia (T-LGLL) is a rare indolent lymphocyte leukemia. The clonal proliferation of T cells, which is related to STAT3 gene mutation and abnormal Fas-mediated apoptosis pathway after cell activation, plays a major role in disease progression. Some studies have found that the exogenous and continuous stimulation of endogenous antigens, such as virus infection, is related to the pathogenesis of T-LGLL. The renal pathological manifestations of T-LGLL have rarely been described. In this study, we report a case of T-LGLL with kidney involvement as proteinuria, acute kidney injury, with the appearance of circulating T-LGL infiltrating intra-glomerular capillaries, and endocapillary glomerulopathy. We also summarize reported cases of renal injury associated with LGLL.

Background: The syndrome of tubulointerstitial nephritis and uveitis (TINU) is an uncommon and multisystemic autoimmune disorder. This review reports a rare case of TINU being superimposed on thrombotic microangiopathy (TMA) and, by comparing with the available literature, also summarizes the clinical features, associated conditions, treatment, and outcome of patients with TINU. Summary: Herein, we report the case of a 37-year-old male patient with acute kidney injury (AKI) clinicopathologically identified as malignant hypertension-induced TMA superimposed by acute tubulointerstitial nephritis, which was suspected to be related to drug hypersensitivity. After treatment with oral prednisone combined with a renin-angiotensin system inhibitor, the patient achieved partial renal recovery and was withdrawn from hemodialysis. Recurrent AKI concomitant with new-onset asymptomatic uveitis was detected during routine clinical follow-up after cessation of prednisone. TINU was then diagnosed, and prednisone followed by cyclophosphamide was prescribed. The patient achieved better renal recovery than in the first round of treatment and maintained stable renal function afterward. By reviewing the literature, 36 cases were reported as TINU superimposed on other conditions, including thyroiditis, osteoarthropathy, and sarcoid-like noncaseating granulomas. Key messages: TINU could be complicated by many other conditions, among which TMA is very rare. When presented as AKI, kidney biopsy is important for differential diagnosis. The case also shows that recurrent AKI with concomitant uveitis after prednisone withdrawal strongly suggested the need for long-term follow-up and elongated prednisone therapy for TINU syndrome.

Abstract Steroids are the most widely marketed products by the pharmaceutical industry after antibiotics. Steroid hydroxylation is one of the most important functionalizations because their derivatives enable a higher biological activity compared to their less polar non-hydroxylated analogs. Bacterial cytochrome P450s constitute promising biocatalysts for steroid hydroxylation due to their high expression level in common workhorses like Escherichia coli. However, they often suffer from wrong or insufficient regio- and/or stereoselectivity, low activity, narrow substrate range as well as insufficient thermostability, which hampers their industrial application. Fortunately, these problems can be generally solved by protein engineering based on directed evolution and rational design. In this work, an overview of recent developments on the engineering of bacterial cytochrome P450s for steroid hydroxylation is presented.

Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously impede their development. Peripherally-restricted KOR agonists have a poor ability to penetrate into the CNS system, so that CNS-related adverse effects can be ameliorated or even abolished. However, the only approved peripherally-restricted KOR agonist CR845 remains some frequent CNS adverse events. In the present study, we aim to address pharmacological profiles of HSK21542, with an expectation to provide a safe and effective alternative for patients who are suffering from pain and pruritus. The in vitro experimental results showed that HSK21542 was a selective and potent KOR agonist with higher potency than CR845, and had a brain/plasma concentration ratio of 0.001, indicating its peripheral selectivity. In animal models of pain, HSK21542 significantly inhibited acetic acid-, hindpaw incision- or chronic constriction injury-induced pain-related behaviors, and the efficacy was comparable to CR845 at 15 min post-dosing. HSK21542 had a long-lasting analgesic potency with a median effective dose of 1.48 mg/kg at 24 h post-drug in writhing test. Meanwhile, the antinociceptive activity of HSK21542 was effectively reversed by a KOR antagonist nor-binaltorphimine. In addition, HSK21542 had powerful antipruritic activities in compound 48/80-induced itch model. On the other hand, HSK21542 had a weak ability to produce central antinociceptive effects in a hot-plate test and fewer effects on the locomotor activity of mice. HSK21542 didn’t affect the respiratory rate of mice. Therefore, HSK21542 might be a safe and effective KOR agonist and promising candidate for treating pain and pruritus.

In this research, we described a very rare case of secondary lupus nephritis associated with B-cell lymphoma. An 84-year-old man was hospitalized at our institute for lower extremity edema persisting for over 2 months. He was diagnosed with systemic lupus erythematosus based on clinical and laboratory criteria, which showed impaired renal function and nephrotic syndrome with predominant hematuria. Renal biopsy showed IV+V lupus nephritis with highly infiltrated lymphoid cells in the kidney. Secondary lupus nephritis was suspected based on the possible pathogenesis of glomerular injury due to mantle cell lymphoma. Low-dose dexamethasone, rituximab, and lenalidomide were immediately started on the patient, and his renal function was improved after the first cycle of chemotherapy.

ObjectivesThis study aimed to determine the prevalence and localization of complement factor C4d in renal biopsies from patients with lupus nephritis (LN), as well as its associations with the disease’s clinico-pathological features. The correlation between arteriolar C4d deposition and renal microvascular lesions (RVLs) was further analyzed.MethodsA total of 325 biopsy-proven LN patients were enrolled, and their clinico-pathological data were collected. C4d staining of renal biopsies was performed by immunohistochemistry. The associations between C4d deposition and the clinico-pathological features were further analyzed.ResultsC4d deposition was present in most (98.8%) renal specimens in our cohort. These deposits were localized in the glomeruli (98.2%), tubular basement membrane (TBM) (43.7%), arterioles (31.4%), and peritubular capillary (33.8%). Patients with TBM C4d staining had higher disease activity (measured with the Systemic Lupus Erythematous Disease Activity Index) and higher National Institutes of Health pathological activity and chronicity indices (all P < 0.01). Patients with arteriolar C4d deposition were more likely to develop RVLs (91.2%) compared to those with no arteriolar C4d deposition (78.0%; P = 0.004), especially with two or more types of RVLs (P < 0.001). During the mean follow-up of 55.8 months, arteriolar C4d was related to worse renal outcomes [hazard ration (HR): 2.074, 95% confidence interval (CI) 1.056–4.075, P = 0.034]. Multivariate Cox hazard analysis showed that co-deposition of arteriolar C4d and C3c was an independent risk factor (HR: 3.681, 95% CI 1.519–8.921, P = 0.004) for predicting renal outcomes.ConclusionsC4d deposition was common in renal tissues from LN patients. TBM C4d deposition was related to the disease activity, and arteriolar C4d deposition was associated with RVLs and worse renal outcomes.

Purpose: Aggressively growing tumors are characterized by significant variations in metabolites, including lipids, and can involve the elevated synthesis ofde novo fatty acids. Methods: Ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS)-based metabolomics and lipidomics were performed to compare human gastric cancer tissues and adjacent normal tissues from clinical patients. A series of cellular and molecular biological methods were applied to validate the lipidomics results. Results: Palmitic acid (PA) was found to be significantly downregulated in gastric cancer tissues, and it was found that a high concentration of PA specifically inhibited cell proliferation and impaired cell invasiveness and migrationin vitro in AGS, SGC-7901, and MGC-803 gastric cancer cell lines. Moreover, sterol regulatory element-binding protein 1 (SREBP-1c) was activated in human gastric cancer tissues, and it promoted the expression of a series of genes associated with the synthesis of fatty acids, such as SCD1 and FASN. SREBP-1c knockdown rescued the migration and invasion defects in AGS and SGC-7901 gastric cancer cells. Conclusion: Taken together, our findings confirmed the variation in fatty acid synthesis in gastric cancer and identified SREBP-1c as a promising target for gastric cancer treatment.

Attempting to correlate the characteristics of the fractionated components from bamboo to its susceptibility to enzyme is often inconclusive depending on the parameters of pretreatment conditions. Based on the integrated analysis of chemical components, cellulose bioconversion, characteristic property of isolated hemicellulose, and lignin, the optimal mild pretreatment operation for Moso bamboo was 4% NaOH in 20% ethanol aqueous solution. A total of 91.9% mass was successfully recovered, and 66% bioconversion efficiency of the cellulosic sample was finally achieved. Meanwhile, over 25% hemicelluloses and 7% lignin were isolated, and the characteristic analysis indicated that the fractionated biomacromolecule maintained the original core structure, which is a benefit to be further utilized for the production of chemicals or polymers.

Polyurethane (PU) foams reinforced with bamboo fiber sources in China, i.e. , bamboo fiber, bamboo α -cellulose fiber, and bamboo nanocellulose fiber, were prepared and their physico-mechanical properties were analyzed in this work. The bamboo fiber sources and PU foams were characterized by Fourier transform infrared spectroscopy (FTIR), Scanning electron microscope (SEM), Thermal gravimetric analysis (TGA) and universal compression testing. The results indicated that the hydroxyl groups on the fiber surfaces were enhanced by removing non-celluloses in the preparation of α -cellulose and nanocellulose. With the addition of small particle size α -cellulose and nanocellulose, the cell sizes of PU foams were reduced due to more nucleating agents being introduced. The FTIR spectra confirmed that the bamboo fiber sources were involved in the foaming reaction. The PU foams with bamboo fiber sources had a higher thermal stability than neat foam, and they were satisfactory enough to be used as insulation. PU foams reinforced with 5% bamboo fiber, 3% α -cellulose fiber and 3% nanocellulose fiber had better physico-mechanical performance than other foams. The reinforcement performance of 3% bamboo α -cellulose fiber on PU foam was comparable with that of high-cost nanocellulose. Accordingly, bamboo α -cellulose fiber was demonstrated to be a promising candidate to reinforce PU foam, which could be used in the reinforcement of foam insulation.

Adeno-associated virus (AAV) is one of the most extensively studied and utilized viral vectors in clinical gene transfer research. However, the serum instability and immunogenicity of AAV vectors significantly limit their application. Here, we endeavored to overcome these limitations by developing a straightforward approach for site-specific PEGylation of AAV via genetic code expansion. This technique includes incorporation of the azide moiety into the AAV capsid protein followed by orthogonal and stoichiometric conjugation of a variety of polyethylene glycols (PEGs) through click chemistry. Using this approach, only the chosen site(s) was consistently PEGylated under mild conditions, preventing nonselective conjugation. Upon a series of in vitro examinations, AAVs conjugated with 20-kD PEG at sites Q325+1, S452+1, and R585+1 showed a 1.7- to 2.4-fold stability improvement in pooled human serum and a nearly twofold reduction in antibody recognition. Subsequent animal research on Sprague Dawley rats displayed a promising 20% reduction in antibody inducement and a higher virus titer in the blood. Together, our data demonstrate successful protection of an AAV vector from antibody neutralization and blood clearance, thereby increasing the efficiency of therapeutic gene delivery.