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The tissue-specific targeted delivery and efficient cellular uptake of siRNAs are the main obstacles to their clinical application. Antibody-siRNA-conjugates (ARCs) can deliver siRNA by exploiting the targeting property of antibodies like antibody-drug conjugates (ADCs). However, the effective conjugation of antibodies and siRNAs and the release of siRNAs specifically at target sites have posed challenges to the development of ARCs. In this study, the successful conjugation of antibodies and siRNAs was achieved using a multifunctional peptide as a linker, composed of a cell-penetrating peptide (CPP) and a substrate peptide (SP), which is highly expressed in solid tumors. The resulting antibody-multifunctional peptide (SP-CPP)-siRNA system delivered the siRNA to target tumor cells by the specific binding of the antibody. Once the enzymes on the tumor cell surface hydrolyzed the substrate peptide linker, siRNA-CPP was released from ARCs. The released siRNA-CPP entered the targeted cells via the cellular penetrating ability of CPP, resulting in improved siRNA-mediated gene silencing efficiency, verified both in vitro and in vivo. After intravenous administration, the designed ARCs achieved approximately 66.7% EGFP (Enhanced Green Fluorescent Protein) downregulation efficiency in nude mice xenografted with the HCT116-EGFP tumor model. The proposed system provides a prospective choice for ARC production and the safe and efficient delivery of siRNAs.

Background The lower limb joints, including hip and knee, are the most commonly involved joints in haemophilic arthropathy. With a higher risk of transfusion, total hip and knee arthroplasty (THA and TKA) are still the first choice after failure of conservative treatment. In the present study, we aimed to analyze clinical outcomes and complications rate after total joint arthroplasty of the lower limbs using tranexamic acid (TXA) or not. Methods Thirty-four patients with haemophilia A undergoing 24 TKA and 18 THA were evaluated in this retrospective study (No. 201302009). Based on using TXA or not, they were divided into either TXA (12 knees and 10 hips) or Non-TXA groups (12 knees and 8 hips). Total blood loss, intraoperative blood loss, total amount of FVIII usage, range of motion, inflammatory biomarkers, joint function, pain status, complication rate and patient satisfaction were assessed and compared at a mean follow-up of 68 months. Results Usage of TXA can decrease not only the perioperative blood loss (p = 0.001), transfusion rate (p = 0.017) and supplemental amount of FVIII (p

A novel enhanced photoelectrochemical (PEC) DNA biosensor, based on a compact heterojunction g-C3N4/MoS2 and co-sensitization effect with CdSe quantum dots (QDs), was first proposed for simple and accurate analysis of a short ssDNA. In this work, the g-C3N4/MoS2 was successfully synthesized and used as the electrode matrix material to construct PEC biosensor. 2D/2D heterojunction was formed between g-C3N4 and MoS2, which could promote the separation of photogenerated electron-hole pairs resulting in an enhanced photocurrent. In the presence of target DNA, CdSe QDs labeled reporter DNA was complementary pairing with target DNA which was specific recognized by capture DNA loading on self-assembled CdS QDs film, leading to close contact between CdSe QDs and g-C3N4/MoS2 modified electrode surface, thereby resulting in the enhanced photocurrent intensity due to the co-sensitization effect. Under the optimal operating conditions, the photoelectrochemical biosensor demonstrated favorable accuracy and could respond to 0.32 pM (S/N = 3) with a linear concentration range from 1.0 pM to 2.0 μM. Moreover, the proposed PEC DNA biosensor exhibits high sensitivity, excellent specificity, acceptable reproducibility and accuracy, showing a promising potential in DNA bioanalysis and other relative fields.

A novel ultrasensitive photoelectrochemical aptasensing was developed to detect mucin 1 (MUC1) based on TiO2/CdS:Eu nanocomposite. The TiO2/CdS:Eu nanocomposite modified fluorine-doped tin oxide (FTO) electrode was prepared by successive ionic layer adsorption and reaction technique (SILAR) and then was employed as matrix for immobilization of SH-DNA (DNA1). After 6-mercaptohexanol (MCH) blocked unbound sites of the electrode surface, the MUC1 aptamer(DNA2) was introduced, allowing MUC1 aptamer to hybridize with DNA1. Subsequently, CdS-COOH QDs as signal amplification elements were successively labeled on the terminal of MUC1 aptamer. In this case, the target MUC1 detection was based upon the photocurrent change originated from quantities change of the signal amplification elements CdS. In the presence of MUC1, the MUC1 aptamer was specifically bound with MUC1, and meanwhile MUC1/DNA2/CdS was released from the electrode surface, resulting in significantly decreased photocurrent intensity. The novel ultrasensitive photoelectrochemical aptasensing presented a highly selective, sensitive and reproductive detection of MUC1 from 1 nM to 5 μM with a lower detection limit of 0.3 nM. At the same time, it also provided a good specificity, reproducibility, stability and promising strategy to detect a variety of other protein targets for early clinical diagnosis of different diseases.

In this paper, hydrothermal method was used for the synthesis of SnO

Additional file 1: Table S1. Regional incident cases and ASIR of the three urologic benign diseases in 2019. Table S2 Regional deaths and ASMR of urinary tract infections and urolithiasis in 2019. Table S3 Regional DALYs and ASDR of the three urologic benign diseases in 2019. Table S4 Incidence, mortality, and DALYs of the three urologic benign diseases among the top three and bottom three countries in 2019. Table S5 EAPC of ASIR for the three urologic benign diseases in 203 countries and territories from 1990 to 2019. Table S6 EAPC of ASMR for urinary tract infections and urolithiasis in 203 countries and territories from 1990 to 2019. Table S7 EAPC of ASDR for the three urologic benign diseases in 203 countries and territories from 1990 to 2019.

Additional file 2: Fig. S1. Age-standardized DALYs rates for urolithiasis for 21 regions by SDI from 1990 to 2019. SDI sociodemographic index; DALYs disability-adjusted life-years. Fig. S2 Age-standardized mortality rates for urolithiasis for 21 regions by SDI from 1990 to 2019. SDI sociodemographic index. Fig. S3 Age-standardized incidence rates for urinary tract infections for 203 countries and territories by SDI in 2019. SDI sociodemographic index. Fig. S4 Age-standardized incidence rates for benign prostatic hyperplasia for 203 countries and territories by SDI in 2019.SDI sociodemographic index. Fig. S5 Age-standardized DALYs rates for urolithiasis for 203 countries and territories by SDI in 2019. SDI sociodemographic index; DALYs disability-adjusted life-years. Fig. S6 Age-standardized DALYs rates for benign prostatic hyperplasia for 203 countries and territories by SDI in 2019. SDI sociodemographic index; DALYs disability-adjusted life-years. Fig. S7 Age-standardized DALYs rates for urinary tract infections for 203 countries and territories by SDI in 2019. SDI sociodemographic index; DALYs disability-adjusted life-years. Fig. S8 Age-standardized mortality rates for urinary tract infections for 203 countries and territories by SDI in 2019. SDI sociodemographic index. Fig. S9 Age-standardized DALYs rates for urinary tract infections for 21 regions by SDI from 1990 to 2019. SDI sociodemographic index; DALYs disability-adjusted life-years. Fig. S10 Age-standardized mortality rates for urinary tract infections for 21 regions by SDI from 1990 to 2019. SDI sociodemographic index. Fig. S11 Age-standardized mortality rates for urolithiasis for 203 countries and territories by SDI in 2019. SDI sociodemographic index. Fig. S12 Age-standardized incidence rates for urinary tract infections for 21 regions by SDI from 1990 to 2019. SDI sociodemographic index. Fig. S13 Age-standardized incidence rates for benign prostatic hyperplasia for 21 regions by SDI from 1990 to 2019. SDI sociodemographic index. Fig. S14 Age-standardized DALYs rates for benign prostatic hyperplasia for 21 regions by SDI from 1990 to 2019. SDI sociodemographic index; DALYs disability-adjusted life-years. Fig. S15 Global incidence of the three urologic benign diseases by age and sex in 2019. a Urinary tract infections. b Urolithiasis. c Benign prostatic hyperplasia. Fig. S16 Global mortality of urinary tract infections and urolithiasis by age and sex in 2019. a Urinary tract infections. b Urolithiasis. Fig. S17 Global DALYs of the three urologic benign diseases by age and sex in 2019. a Urinary tract infections. b Urolithiasis. c Benign prostatic hyperplasia.

Objective The aim of the present study was to evaluate the 10‐year outcomes of cementless total hip arthroplasty (THA) in adult patients with the late sequelae of septic arthritis of the hip. Methods We followed 166 consecutive patients (168 hips) who underwent cementless THA between March 2001 and December 2011. There were 79 men and 87 women, with a mean age of 50.4 years (range 21–76 years) at the time of index THA, all of whom had hip osteoarthritis secondary to hip pyogenic infection. The average duration of follow up was 10.6 years (range 6.9–17.2 years). Preoperative and postoperative clinical ratings were evaluated, including the hip dysfunction and osteoarthritis outcome score (HOOS), the Harris hip score (HHS), range of motion, a 100‐point visual analog scale for hip pain, and the severity of limp and limb length discrepancy (LLD). The anteroposterior and lateral radiographs of the hip and full‐length view of the lower extremities were obtained to assess the position of the components, radiolucent lines, osteolysis, loosening of components, and heterotopic ossification. The intraoperative and postoperative complications were also recorded. Results The mean HSS and hip pain score were 44.2 points (range 29–66 points) and 42.5 points (range 32–64 points), respectively, before the index surgery and significantly improved to 88.1 points (range 78–96 points) and 15.1 points (range 10–26 points), respectively, at final follow‐up examination. The HOOS and range of motion also improved significantly. The mean limb length discrepancy was reduced from 2.6 to 0.8 cm. The limp at last follow‐up examination was moderate in 3 cases because of hip osteoarthritis in the other limb, slight in 26, and absent in 137. A radiolucent line was observed in 12 hips (7.1%) around the acetabular or femoral components. A progressive radiolucent line around the undersized femoral stem in all zones was seen in 1 hip, resulting in aseptic loosening and breakage of the femoral component. There were 8 cases of intraoperative fracture, 7 cases of dislocation, and 7 cases of transient nerve palsy. Recurrence of infection occurred in 2 hips. Revision surgery was conducted in 2 hips because of isolated loosening of the acetabular cup and the femoral stem, respectively. Kaplan–Meier survival was 97% at 10 years, with revision for any reason with any component as an end‐point. Conclusion Improved surgical techniques and development of components with various sizes provided favorable results for cementless THA conducted for late sequelae of sepsis in these young and active patients. Although the incidence of complications was relatively high, the complications were treated successfully., Favorable results can be obtained from cementless THA for late sequelae of pyogenic arthritis. Although the incidence of complications is relatively high, the complications can be treated successfully.

To study the distribution and drug resistance of pathogens causing periprosthetic infections after hip and knee arthroplasty, and to formulate prevention and treatment strategies for drug-resistant bacteria.The data of 146 cases of periprosthetic infection after primary hip and knee arthroplasty from 2010 to 2015 were collected, including 111 cases of periprosthetic infection after hip arthroplasty and 35 cases of periprosthetic infection after knee arthroplasty. The culture positive rate, pathogenic bacteria composition and drug resistance rate were counted over the years, and the change trend of pathogen distribution and drug resistance was analyzed.One hundredand eight strains of pathogenic bacteria were detected in 146 cases, and the positive rate of culture was 73.97%. Gram positive bacteria accounted for 55.48%, Staphylococcus epidermidis and Staphylococcus aureus accounted for 25.34% and 15.07% respectively. Gram negative bacteria accounted for 13.01%, including Enterobacter cloacae, Pseudomonas aeruginosa and Escherichia coli. There were 4 cases of Mycobacterium tuberculosis infection and mixed infection. The results of culture over the years showed that the constituent ratio of Gram positive bacteria had an increasing trend, fluctuating from 39.13% to 76.47%. The results of drug sensitivity showed that the pathogens were highly resistant to β-lactams, quinolones, clindamycin and gentamicin, and the drug resistance rate was increasing, but it was still sensitive to rifampicin, nitrofurantoin, tigecycline, linezolid and vancomycin.Gram positive bacteria are the main pathogens of periprosthetic infection, and the proportion is increasing gradually.The pathogens have high resistance to many kinds of antibiotics, and the resistance rate is still increasing. To strengthen the monitoring of the distribution and drug resistance of pathogenic bacteria is helpful to grasp its change trend and formulate targeted prevention and control strategies.

Herein, a label-free photoelectrochemical immunosensor based on a g-C3N4/CdSe nanocomposite was established and applied to detect carcinoembryonic antigen (CEA). The prepared nanocomposite materials were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), ultraviolet-visible absorption spectroscopy (UV-vis), X-ray photoelectron spectroscopy (XPS), fourier transform infrared spectrometer (FT-IR) and photoluminescence spectroscopy (PL). The results indicate that g-C3N4/CdSe nanocomposite materials were successfully synthesized. In a typical assembly process, the immunosensor was constructed by modifying a fluorine-doped tin oxide (FTO) electrode with poly dimethyl diallyl ammonium chloride (PDDA), the g-C3N4/CdSe nanocomposite, the anti-carcinoembryonic antigen antibody (Ab) and the blocking agent bovine serum albumin (BSA) successively. In the presence of CEA, the photocurrent signal of the prepared immunosensor decreased significantly. Accordingly, under the optimal conditions, a label-free photoelectrochemical immunosensor was established, and it exhibited excellent selectivity and repeatability for CEA detection. The detection limit was 0.21 ng mL-1, and the range was 10 ng mL-1-100 μg mL-1. Simultaneously, the immunosensor also provides a likely sensing device for detecting other protein targets, which is of great significance for early clinical diagnosis.

In this paper, carboxylated C3N4 (g-C3N4-COOH) was prepared by a new method, and then combined with ZnSe quantum dots (QDs) through amide reaction to form g-C3N4-COOH/ZnSe nanocomposite and used for detecting kanamycin. The prepared g-C3N4-COOH/ZnSe nanocomposite was used as the subatrate of aptasensor. Then, the g-C3N4-COOH/ZnSe nanocomposite-modified electrode was incubated with aptamer DNA (NH2-DNA), after cholamine blocked the unbond sites of the electrode surface, the ferrocene-labled quenching probe (Fc-DNA) as electrochemiluminescence (ECL) signal quencher was incubated on the electrode surface through base complementation with aptamer DNA. In the absence of kanamycin, the ECL signal was quenched effectively by Fc-DNA. On the contrary, kanamycin was specifically bond with aptamer DNA, and Fc-DNA was detached from the aptasensor electrode surface because of the deformation of aptamer DNA, generating an effectively enhanced ECL signal. The aptasensor exhibited a wide detection range for detecting kanamycin (1.0 nM − 100 μM) with a low limit of detection (0.7982 nM). The prepared aptasensor displayed a stable and selective detection for kanamycin, and also provided a promising strategy for a variety of other protein target.

Herein, an ultra-sensitive photoelectrochemical biosensor based on Ti

Background We designed the current study to understand the normal trajectories of interleukin-6 (IL-6) and C-reactive protein (CRP) in the immediate hours and days after primary total knee arthroplasty (TKA) under the management of an enhanced recovery after surgery (ERAS) protocol and examined whether one or the other returned to normal more quickly. Methods In this prospective cross-sectional study, we examined the plasma IL-6 and CRP levels in 100 patients undergoing primary TKA at the following time points: 12 h preoperatively as well as postoperatively 12 h, 48 h, 3 days and 2 weeks. Patients were followed up for 1 year to monitor the postoperative complications, especially the infection. Results IL-6 peaked at 48 h postoperatively. Then IL-6 started to decline at 3 days postoperatively and went back to baseline level at 2 weeks (p = 0.950). CRP peaked at 3 days postoperatively. At 2 weeks, CRP declined to a normal range, without being significantly different from the baseline level (p = 0.816). Conclusion We found that under the ERAS scenario, the postoperative peak of IL-6 and CRP was deferred compared with previous studies. Compared to IL-6, CRP showed a gradual rise after surgery. Both of these two biomarkers returned to normal under the ERAS scenario. Future multiple-center studies with larger sample size can help define the thresholds of IL-6 and CRP for periprosthetic joint infection (PJI) early diagnosis. With these reference data, a clinician can make a quicker decision to perform aspiration to diagnose early PJI and benefits more patients.

AimsTo explore clinical features and outcome of 2019 novel coronavirus(2019-nCoV)-infected patients with high BNP levelsMethods and resultsData were collected from patients’ medical records, and we defined high BNP according to the plasma BNP was above > 100 pg/mL. In total,34 patients with corona virus disease 2019(COVID-19)were included in the analysis. Ten patients had high plasma BNP level. The median age for these patients was 60.5 years(interquartile range, 40-80y), and 6/10 (60%) were men. Underlying comorbidities in some patients were coronary heart disease (n=2, 20%), hypertesion (n=3,30%), heart failure (n=1,10%)and diabetes (n=2, 20%). Six (60%) patients had a history of Wuhan exposure. The most common symptoms at illness onset in patients were fever (n=7, 70%), cough (n=3, 30%), headache or fatigue(n=4,40%). These patients had higher aspartate aminotransferase(AST), troponin I, C reactive protein and lower hemoglobin, and platelet count,compared with patients with normal BNP, respectively. Compared with patients with normal BNP, patients with high BNP were more likely to develop severe pneumonia, and receive tracheal cannula, invasive mechanical ventilation, continuous renal replacement therapy, extracorporeal membrane oxygenation, and be admitted to the intensive care unit. One patient with high BNP died during the study.ConclusionHigh BNP is a common condition among patients infected with 2019-nCoV. Patients with high BNP showed poor clinical outcomes

AimsTo explore the epidemiological and clinical features of 2019 novel coronavirus(2019-nCoV)-infected patients with cardiac injury.Methods and resultsData were collected from patients’ medical records, and we defined cardiac injury according to cardiac biomarker troponin I level > 0.03 μg/L. Among the 291 patients, 15 (5.2%) showed evidence of cardiac injury. Of 15 hospitalized patients with cardiac injury, the median age was 65 years, and 11/15 (73.3%) were men. Underlying cardiovascular diseases in some patients were hypertension (n=7, 46.7%), coronary heart disease (n=3, 20%) and diabetes (n=3, 20%). The most common symptoms at illness onset in patients with cardiac injury were fever (n=11, 73.3%), cough (n=7, 46.7%), headache or fatigue (n=5, 33.3%) and dyspnea (n=4, 26.7%). These patients had higher systolic pressures, white blood cell count, neutrophil count, troponin I, brain natriuretic peptide, D-dimer and lower lymphocyte count, and platelet count, compared with patients without cardiac injury, respectively. Bilateral infiltrates on chest X-ray and elevated C-reactive protein occurred in all patients with cardiac injury. Compared with patients without cardiac injury, patients with cardiac injury were more likely to develop acute respiratory distress syndrome, and receive mechanical ventilation, continuous renal replacement therapy, extracorporeal membrane oxygenation and vasopressor therapy and be admitted to the intensive care unit.ConclusionCardiac injury is a common condition among patients infected with 2019-nCoV. Compared with patients without cardiac injury, the clinical outcomes of patients with cardiac injury are relatively worse.

An electrochemiluminescence (ECL) biosensor was fabricated for the evaluation of prostate specific antigen (PSA). The sensor was developed by successively modifying glassy carbon electrode (GCE) electrodes with CdS/Chito/g-C3N4 nanocomposites and DNA1 was labeled at the 5′ end with thiol. The aptamer DNA was labeled at the 3′ end with a quencher ferrocene (Fc) was ligated to DNA1 by the principle of complementary base pairing. In the absence of PSA, the ECL intensity signal is effectively quenches through the energy transfer and photoexcitation electron transfer between CdS/Chito/g-C3N4 emitter and quencher Fc. After incubation with target PSA, the aptamer DNA interacts with PSA and then moved away from the electrode surface together, which will recover the ECL intensity. Under the optimal conditions, the ECL intensity increases linearly with the logarithm of PSA concentration in the range of 1 pg·mL−1 to 100 ng·mL−1, and the detection limit is 0.14 pg·mL−1 (S/N = 3). The biosensor has been successfully applied to the determination of PSA in serum sample.

The original version of this article unfortunately contained a spelling mistake in the first author’s affiliation. The university name “Shangdong University of Science and Technology” should be amended to “Shandong University of Science and Technology”. The correct affiliations are given below.

A novel enhanced photoelectrochemical DNA sensor, based on a TiO2/Au hybrid electrode structure, was developed to detect target DNA. The sensor was developed by successively modifying fluorine-tin oxide (FTO) electrodes with TiO2 nanoparticles, gold (Au) nanoparticles, hairpin DNA (DNA1), and CdSe-COOH quantum dots (QDs), which acted as signal amplification factors. In the absence of target DNA, the incubated DNA1 hairpin and the CdSe-COOH QDs were in close contact with the TiO2/Au electrode surface, leading to an enhanced photocurrent intensity due to the sensitization effect. After incubation of the modified electrode with the target DNA, the hairpin DNA changed into a double helix structure, and the CdSe QDs moved away from the TiO2/Au electrode surface, leading to a decreased sensitization effect and photoelectrochemical signal intensity. This novel DNA sensor exhibited stable, sensitive and reproducible detection of DNA from 0.1 μM to 10 fM, with a lower detection limit of 3 fM. It provided good specificity, reproducibility, stability and is a promising strategy for the detection of a variety of other DNA targets, for early clinical diagnosis of various diseases.

Herein, we established a novel ultrasensitive photoelectrochemical biosensor for detecting urokinase-type plasminogen activator (u-PA), based on a g-C3N4/CdS nanocomposite. The prepared nanocomposite was characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, ultraviolet–visible absorption spectroscopy, and Fourier transform infrared spectroscopy, thus indicating that the nanocomposite was prepared successfully. In the typical process, the prepared nanocomposite was deposited on the surface of a bare FTO electrode. After being air-dried, the g-C3N4/CdS nanocomposite modified electrode was successively incubated with antibody against urokinase-type plasminogen activator and the blocking agent BSA to produce a photoelectrochemical biosensor for u-PA. In the presence of target u-PA antigen, the photocurrent response of the prepared biosensor electrode decreased significantly. The proposed novel photoelectrochemical biosensor exhibited good sensitivity, specificity, and reproducibility for u-PA detection, and a low detection limit of 33 fg mL−1, ranging from 1 μg mL−1–0.1 pg mL−1. The proposed strategy should provide a promising method for detection of other biomarkers.

Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease, associated with significant risk of limb loss, morbidity and mortality; however, there remains unmet therapeutic needs for arterial revascularization and ischemic tissue repair. Stem cell therapies have emerged as compelling candidates due to beneficial proangiogenic and immunosuppressive function. Nevertheless, in vivo efficacy was insufficient in proliferation, differentiation and survival/engraftment rate. Cardiac stem cells (CSCs) was firstly attempted for CLI as a novel therapeutic modality to provide superior angiogenic potency to bone marrow-derived stem cells (BMSCs). It was noted that CSCs demonstrated 3.2-fold in HGF, 2.9-fold in VEGF and 8.7-fold in PDGF-B higher gene expressions compared to BMSCs. To enhance the hypoxia-induced proangiogenic effect, CSCs were transfected with hypoxia-inducible factor-1 alpha (HIF-1α) by using electroporation method, specifically optimized for CSCs yielding 45.77% of transfection efficiency and 89.75% of viability. HIF-1α overexpression significantly increased CSC survival in hypoxia, proangiogenic factors production and endothelial differentiation. In mouse hind limb ischemia model, local intramuscular delivery of CSC overexpressing HIF-1α (HIF-CSC) significantly improved the blood flow recovery. Histological analysis revealed that muscle degeneration and fibrosis in the ischemic limb were attenuated. Local delivery of HIF-CSC might be a promising option for ischemic tissue restoration.

In this work, an electrochemiluminescence (ECL) biosensor was fabricated for the selective detection of vascular endothelial growth factor (VEGF

Pyroptosis is a type of programmed cell death, which has been associated with multiple inflammatory diseases including diabetic atherosclerosis (DA). This study aims to explore the role of sinapic acid (SA) in the pyroptosis of macrophages in DA. Our results from the in vivo experiments showed that low-dose (≤50 mg/kg) chronic SA administration suppressed serum endothelin 1 (ET-1) and interleukin-1β (IL-1β) contents, pyroptotic death of bone marrow-derived macrophages, and the expression of pyroptotic proteins ASC, NRLP3, and caspase-1. Besides, lncRNA-metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was robustly upregulated in the macrophages of rats with DA and could be lowered by low-dose SA administration. Gene overexpression and knockdown experiments showed that MALAT1 had a modestly positive effect on the pyroptosis of normal macrophages. Moreover, in macrophages incubated with high-glucose and Ox-LDL, 1-μM SA treatment displayed a suppressive effect on the cell pyroptosis similar to that of MALAT1 knockdown. Transfection of the pcDNA-MALAT1 expression vector counteracted the decrease in MALAT1 expression and macrophage pyroptosis caused by SA. In conclusion, low-dose SA can abate the pyroptosis of macrophages by downregulation of lncRNA-MALAT1 in rats with DA.

When comets interacting with solar wind, straight and narrow plasma tails will be often formed. The most remarkable phenomenon of the plasma tails is the disconnection event, in which a plasma tail is uprooted from the comet’s head and moves away from the comet. In this paper, the interaction process between a comet and solar wind is simulated by using a laser-driven plasma cloud to hit a cylinder obstacle. A disconnected plasma tail is observed behind the obstacle by optical shadowgraphy and interferometry. Our particle-in-cell simulations show that the difference in thermal velocity between ions and electrons induces an electrostatic field behind the obstacle. This field can lead to the convergence of ions to the central region, resulting in a disconnected plasma tail. This electrostatic-field-induced model may be a possible explanation for the disconnection events of cometary tails.

Immune checkpoint therapy encounters significant challenges in clinic, including low response rate, acquired resistance and immune-related adverse events. Combination immunotherapy targeting multiple independent but complementary pathways in immune evasion has the potential to enhance therapeutic efficacy. Herein, a combination therapeutic strategy that dually inhibiting FGL1, a recently discovered main ligand for immune checkpoint LAG-3, and TGF-β1, an immunosuppressive cytokine, is firstly reported for colorectal cancer immunotherapy by blocking immune checkpoint and modulating tumor microenvironment simultaneously. We established a cRGD-modified exosome with high siFGL1 and siTGF-β1 loading efficiency (cRGD-Exo/siMix) to realize the co-silence of FGL1 and TGF-β1. The constructed cRGD-Exo/siMix showed a significant anti-tumor effect both in vitro and in vivo. Analysis of the tumor immune microenvironment demonstrated an increased number of tumor infiltration CD8+ T cells while a decreased number of immunosuppressive cells, implying that this therapeutic approach boosted anti-tumor immunity by reshaping the tumor microenvironment. This work provides a new strategy for siRNA delivery and its applications in combined cancer immunotherapy.

RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides (CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine (LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS–PEG–OPSS as a crosslinker to synthesize LMWP–siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation., Graphical abstract A monomeric covalent conjugate of low molecular weight protamine (LMWP, a well-established CPP) and siRNA were developed via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Three different synthetic and purification methods were compared and hetero-bifunctional NHS–PEG–OPSS was the optimized crosslinker.fx1