Fully Integrated and High-Throughput Microfluidic System for Multiplexed Point-Of-Care Testing.

For every epidemic outbreak, the prevention and treatments in resource-limited areas are always out of reach. Critical to this is that high accuracy, stability, and more comprehensive analytical techniques always rely on expensive and bulky instruments and large laboratories. Here, a fully integrated and high-throughput microfluidic system is proposed for ultra-multiple point-of-care immunoassay, termed Dac system. Specifically, the Dac system only requires a handheld portable device to automatically recycle repetitive multi-step reactions including on-demand liquid releasing, dispensing, metering, collecting, oscillatory mixing, and discharging. The Dac system performs high-precision enzyme-linked immunosorbent assays for up to 17 samples or targets simultaneously on a single chip. Furthermore, reagent consumption is only 2% compared to conventional ELISA, and microbubble-accelerated reactions shorten the assay time by more than half. As a proof of concept, the multiplexed detections are achieved by detecting at least four infection targets for two samples simultaneously on a singular chip. Furthermore, the barcode-based multi-target results can rapidly distinguish between five similar cases, allowing for accurate therapeutic interventions. Compared to bulky clinical instruments, the accuracy of clinical inflammation classification is 92.38% (n = 105), with a quantitative correlation coefficient of R2 = 0.9838, while the clinical specificity is 100% and the sensitivity is 98.93%.

Effect of partial substitution of complex phosphates with sodium bicarbonate on aggregation, conformation and gel properties of beef-pork-chicken complex myofibrillar proteins.

BACKGROUND: Complex phosphates (CP) can improve the physicochemical properties and gelation properties of myofibrillar fibrous protein (MP) in mixed meat products, but an excessive intake of phosphates over a long period of time is harmful to health. The present study investigated the effects of partial or complete substitution of CP with sodium bicarbonate (SB) on the physicochemical properties and gel properties of beef-pork-chicken mixed myofibrillar protein (BPC-MP), aiming to evaluate the feasibility of this method in reducing the amount of phosphate in mixed meat products. RESULTS: Under the optimal substitution conditions, the turbidity of BPC-MP was reduced by 37.8%, the net negative potential was increased by 28.9% and the modulus of elasticity (G') was increased. The tertiary structure indexes of protein (including fluorescence intensity, surface hydrophobicity and active thiol content) were significantly changed, whereas the α-helix and ß-turn angle contents in the secondary structure of protein were significantly increased. In addition, the water retention ability and strength of gel were also improved, which were increased by 20.7% and 42.6%, respectively. The results of scanning electron microscopy showed that the SB substitution group had a more compact and ordered microstructure. CONCLUSION: The results showed that partial substitution of CP with SB reduced the amount of phosphate added to BPC-MP and had a positive effect on the physicochemical and gel properties of BPC-MP. © 2024 Society of Chemical Industry.

An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema.

Hereditary angioedema (HAE) is a genetic disorder mostly caused by mutations in the C1 esterase inhibitor gene (C1INH) that results in poor control of contact pathway activation and excess bradykinin generation. Bradykinin increases vascular permeability and is ultimately responsible for the episodes of swelling characteristic of HAE. We hypothesized that the use of RNA interference (RNAi) to reduce plasma Factor XII (FXII), which initiates the contact pathway signaling cascade, would reduce contact pathway activation and prevent excessive bradykinin generation. A subcutaneously administered GalNAc-conjugated small-interfering RNA (siRNA) targeting F12 mRNA (ALN-F12) was developed, and potency was evaluated in mice, rats, and cynomolgus monkeys. The effect of FXII reduction by ALN-F12 administration was evaluated in two different vascular leakage mouse models. An ex vivo assay was developed to evaluate the correlation between human plasma FXII levels and high-molecular weight kininogen (HK) cleavage. A single subcutaneous dose of ALN-F12 led to potent, dose-dependent reduction of plasma FXII in mice, rats, and NHP. In cynomolgus monkeys, a single subcutaneous dose of ALN-F12 at 3 mg/kg resulted in >85% reduction of plasma FXII. Administration of ALN-F12 resulted in dose-dependent reduction of vascular permeability in two different mouse models of bradykinin-driven vascular leakage, demonstrating that RNAi-mediated reduction of FXII can potentially mitigate excess bradykinin stimulation. Lastly, ex vivo human plasma HK cleavage assay indicated FXII-dependent bradykinin generation. Together, these data suggest that RNAi-mediated knockdown of FXII by ALN-F12 is a potentially promising approach for the prophylactic treatment of HAE.

Safety evaluation of 2'-deoxy-2'-fluoro nucleotides in GalNAc-siRNA conjugates.

For oligonucleotide therapeutics, chemical modifications of the sugar-phosphate backbone are frequently used to confer drug-like properties. Because 2'-deoxy-2'-fluoro (2'-F) nucleotides are not known to occur naturally, their safety profile was assessed when used in revusiran and ALN-TTRSC02, two short interfering RNAs (siRNAs), of the same sequence but different chemical modification pattern and metabolic stability, conjugated to an N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Exposure to 2'-F-monomer metabolites was low and transient in rats and humans. In vitro, 2'-F-nucleoside 5'-triphosphates were neither inhibitors nor preferred substrates for human polymerases, and no obligate or non-obligate chain termination was observed. Modest effects on cell viability and mitochondrial DNA were observed in vitro in a subset of cell types at high concentrations of 2'-F-nucleosides, typically not attained in vivo. No apparent functional impact on mitochondria and no significant accumulation of 2'-F-monomers were observed after weekly administration of two GalNAc-siRNA conjugates in rats for ∼2 years. Taken together, the results support the conclusion that 2'-F nucleotides can be safely applied for the design of metabolically stabilized therapeutic GalNAc-siRNAs with favorable potency and prolonged duration of activity allowing for low dose and infrequent dosing.

Synergistic heat/UV activated persulfate for the treatment of nanofiltration concentrated leachate.

Nanofiltration concentration leachate is a high concentration organic wastewater with low biodegradability and high toxicity. To explore the feasibility of a combined Heat/UV activated persulfate process on nanofiltration concentrated leachate, the effects of persulfate concentration, initial solution pH before reaction, UV-lamp power and reaction temperature on the removal of organic pollutant were systematically investigated. Results indicated that the maximum rate of chemical oxygen demand (COD), ammonia-nitrogen (NH3-N) and absorbance of organic matter under UV light at 254 nm (UV254) removal from the leachate were 65.4%, 51.4% and 98.1%, respectively, at a persulfate concentration of 18 g L-1, initial solution pH before reaction of 9.0, UV-lamp power of 60 W and temperature of 80 °C. The results of three-dimensional fluorescence and UV254 showed that the removal rates of humic substances contained in the nanofiltration concentrated leachate were over 98%. In addition, the results of free radical scavenging showed that hydroxyl radicals were dominant under alkaline conditions. The results of this study demonstrated that coupling heat and ultraviolet activated persulfate oxidation is a promising technique for the treatment of nanofiltration concentrated leachate.

Development of arsenic trioxide sustained-release pellets for reducing toxicity and improving compliance.

Arsenic trioxide (ATO) is first-line drug for acute promyelocytic leukemia. Clinically, the continuously slow intravenous infusion is adopted to maintain effective blood concentration and reduce toxic effects, but it causes poor patient' compliance for a considerable infusion period. To overcome these disadvantages, we developed an oral ATO sustained-release preparation which was constructed via the ATO core pellets prepared by extrusion spheronization and followed by a coating membrane by fluid-bed technology. The prepared coated pellets displayed a round surface and uniform particle size. All in vitro release profiles of ATO pellets in different pH media and rotation speeds had no statistical difference. Importantly, the coated pellets can release completely in 12 h without obvious burst release. There was no distinct change in appearance and release behaviors in stability experiments. In vivo pharmacokinetics was studied by one-time intragastric administration of rats. Compared with free drug, the AUC0-∞ of the ATO coated pellets was 2.3-fold higher, indicating the oral bioavailability was significantly increased. Cmax decreased by about a half and Tmax extended about 15 h. In particularly, the ATO level at 96 h only decreased about 20% of Cmax , suggesting that the ATO sustained-release preparation could not only decrease the peak concentration, but also maintain a relatively constant blood concentration for a long period. Further, the in vivo absorption could be well predicted by in vitro release experiments. Therefore, the ATO sustained-release preparation formulated by the mature preparation technology, possessing satisfactory stability and improving bioavailability, had great application potentials for industrialization.

Efficiency of Different Treatment Regimens Combining Anti-tumor and Anti-inflammatory Liposomes for Metastatic Breast Cancer.

Nanomedicines such as liposomes have been widely exploited in the treatment of tumors, and are also involved in combination therapies to enhance anti-tumor efficacy and reduce side effects. However, few studies have systematically discussed the significance and optimized regimens for nanomedicine-based combination therapy. In this study, we used anti-inflammatory and anti-tumor liposomes for co-administration, and compared three regimens: intermittent, metronomic, or sequential administration (IA, MA, and SA). The anti-inflammatory liposome HA/TN-CCLP was constructed in our previous research, which co-loaded curcumin (CUR) and celecoxib (CXB), modified with TAT-NBD peptide (TN) and finally coated with hyaluronic acid (HA), thereby inhibiting NF-κB and STAT3 pathways in the treatment of metastatic breast cancer. Furthermore, doxorubicin liposomes with and without TN modification (namely TN-DOXLP and DOXLP) were constructed and administrated with HA/TN-CCLP. The anti-tumor and anti-metastasis efficacy of different regimens was investigated. Results showed that in vitro cytotoxicity of DOXLP and TN-DOXLP was significantly enhanced when combined with HA/TN-CCLP. In vivo experiments also revealed the superiority of three combination therapies in inhibiting tumor growth, prolonging the survival of tumor-bearing mice, inducing apoptosis, and reducing lung metastases. In particular, the combination therapy could reduce MDSCs (Gr-1+/CD11b+) and CSCs (CD44+/CD24+) infiltration, which are two important factors in tumor metastasis and recurrence. Among three regimens, sequential administration (SA) showed the best therapeutic outcome and was especially effective for the inhibition of CSCs. In general, the results demonstrated that combination therapy, particularly the sequential administration of anti-inflammatory and anti-tumor liposome, was superior to monotherapy in inhibiting the development and metastasis of inflammation-related tumors.

On-chip two-step microwave frequency measurement with high accuracy and ultra-wide bandwidth using add-drop micro-disk resonators.

An on-chip two-step microwave frequency measurement method with high accuracy and an ultra-wide frequency measurement range is reported. A silicon photonic integrated micro-disk resonator (MDR) array is used to coarsely measure the signal frequency via an array of add-drop MDRs with smaller disk radii; then an MDR with a larger radius is used to finely measure the signal frequency, which is done by monitoring the optical powers of the optical signals from the through port and drop port of the MDRs. The proposed system features a very compact structure, ultra-wide frequency measurement range, and high frequency measurement accuracy, which is verified by a proof-of-concept experiment using two MDRs with radii of 6 and 10 µm. A frequency measurement of microwave signals from 1.6 to 40 GHz is implemented with a measurement error of less than 60 MHz. The stability of the system is also evaluated.

Real-time random grating sensor array for quasi-distributed sensing based on wavelength-to-time mapping and time-division multiplexing.

A real-time random grating sensor array for quasi-distributed sensing based on spectral-shaping and wavelength-to-time (SS-WTT) mapping and time-division multiplexing is proposed and experimentally demonstrated. The sensor array consists of multiple random gratings written in a single-mode fiber (SMF) at different physical locations. When the temperature or strain applied to a particular random grating is changed, the central wavelength of the reflection spectrum of the random grating will change, which is converted to the time domain as a time shift based on SS-WTT using a linearly chirped fiber Bragg grating. After detection at a photodetector, an electrical waveform with the time shift information encoded in the random waveform is obtained, which is further compressed by correlation to increase the time resolution. As a demonstration, a real-time quasi-distributed sensing system based on a two-random-grating array is implemented. The results show that the sensing resolutions for temperature and strain are 0.23°C and 2.5 µÏµ, respectively, and the accuracies for temperature and strain are 0.11°C and 1.2 µÏµ, respectively. Compared with a conventional quasi-distributed sensor, our proposed sensing system has key advantages, including real-time sensing, high-resolution interrogation, and large scalability.

The molecular mechanism underlying anthocyanin metabolism in apple using the MdMYB16 and MdbHLH33 genes.

KEY MESSAGE: MdMYB16 forms homodimers and directly inhibits anthocyanin synthesis via its C-terminal EAR repressor. It weakened the inhibitory effect of MdMYB16 on anthocyanin synthesis when overexpressing MdbHLH33 in callus overexpressing MdMYB16. MdMYB16 could interact with MdbHLH33. Anthocyanins are strong antioxidants that play a key role in the prevention of cardiovascular disease, cancer, and diabetes. The germplasm of Malus sieversii f. neidzwetzkyana is important for the study of anthocyanin metabolism. To date, only limited studies have examined the negative regulatory mechanisms underlying anthocyanin synthesis in apple. Here, we analyzed the relationship between anthocyanin levels and MdMYB16 expression in mature Red Crisp 1-5 apple (M. domestica) fruit, generated an evolutionary tree, and identified an EAR suppression sequence and a bHLH binding motif of the MdMYB16 protein using protein sequence analyses. Overexpression of MdMYB16 or MdMYB16 without bHLH binding sequence (LBSMdMYB16) in red-fleshed callus inhibited MdUFGT and MdANS expression and anthocyanin synthesis. However, overexpression of MdMYB16 without the EAR sequence (LESMdMYB16) in red-fleshed callus had no inhibitory effect on anthocyanin. The yeast one-hybrid assay showed that MdMYB16 and LESMdMYB16 interacted the promoters of MdANS and MdUFGT, respectively. Yeast two-hybrid, pull-down, and bimolecular fluorescence complementation assays showed that MdMYB16 formed homodimers and interacted with MdbHLH33, however, the LBSMdMYB16 could not interact with MdbHLH33. We overexpressed MdbHLH33 in callus overexpressing MdMYB16 and found that it weakened the inhibitory effect of MdMYB16 on anthocyanin synthesis. Together, these results suggested that MdMYB16 and MdbHLH33 may be important part of the regulatory network controlling the anthocyanin biosynthetic pathway.

5'-(E)-Vinylphosphonate: A Stable Phosphate Mimic Can Improve the RNAi Activity of siRNA-GalNAc Conjugates.

Small interfering RNA (siRNA)-mediated silencing requires siRNA loading into the RNA-induced silencing complex (RISC). Presence of 5'-phosphate (5'-P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid-domain of the Argonaute2 (Ago2) protein. Phosphorylation of exogenous duplex siRNAs is thought to be accomplished by cytosolic Clp1 kinase. However, although extensive chemical modifications are essential for siRNA-GalNAc conjugate activity, they can significantly impair Clp1 kinase activity. Here, we further elucidated the effect of 5'-P on the activity of siRNA-GalNAc conjugates. Our results demonstrate that a subset of sequences benefit from the presence of exogenous 5'-P. For those that do, incorporation of 5'-(E)-vinylphosphonate (5'-VP), a metabolically stable phosphate mimic, results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability.

Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity.

All pancreatic endocrine cell types arise from a common endocrine precursor cell population, yet the molecular mechanisms that establish and maintain the unique gene expression programs of each endocrine cell lineage have remained largely elusive. Such knowledge would improve our ability to correctly program or reprogram cells to adopt specific endocrine fates. Here, we show that the transcription factor Nkx6.1 is both necessary and sufficient to specify insulin-producing beta cells. Heritable expression of Nkx6.1 in endocrine precursors of mice is sufficient to respecify non-beta endocrine precursors towards the beta cell lineage, while endocrine precursor- or beta cell-specific inactivation of Nkx6.1 converts beta cells to alternative endocrine lineages. Remaining insulin(+) cells in conditional Nkx6.1 mutants fail to express the beta cell transcription factors Pdx1 and MafA and ectopically express genes found in non-beta endocrine cells. By showing that Nkx6.1 binds to and represses the alpha cell determinant Arx, we identify Arx as a direct target of Nkx6.1. Moreover, we demonstrate that Nkx6.1 and the Arx activator Isl1 regulate Arx transcription antagonistically, thus establishing competition between Isl1 and Nkx6.1 as a critical mechanism for determining alpha versus beta cell identity. Our findings establish Nkx6.1 as a beta cell programming factor and demonstrate that repression of alternative lineage programs is a fundamental principle by which beta cells are specified and maintained. Given the lack of Nkx6.1 expression and aberrant activation of non-beta endocrine hormones in human embryonic stem cell (hESC)-derived insulin(+) cells, our study has significant implications for developing cell replacement therapies.

Association between insulin resistance, metabolic syndrome and its components and lung cancer: a systematic review and meta-analysis.

BACKGROUND: A growing body of evidence points to the association between insulin resistance (IR), metabolic syndrome (MetS) and its components and lung cancer incidence, but remains controversial and unknown. METHODS: A systematic search was conducted through PubMed, Embase, Cochrane Library, the China National Knowledge Infrastructure (CNKI) and Wanfang databases for the corresponding studies. Each study reported the risk estimate and 95% confidence intervals (CI) for lung cancer, and a fixed effects model or random effects model was used for outcome. RESULTS: We included 31 publications involving 6,589,383 people with 62,246 cases of lung cancer. Diabetes mellitus (DM) (RR = 1.11, 95% CI 1.06-1.16, P = 0.000) and IR (RR = 2.35, 95% CI 1.55-3.58, P = 0.000) showed a positive association with lung cancer risk. BMI (RR = 0.66, 95% CI 0.54-0.81, P = 0.000) and HDL-C (RR = 0.88, 95% CI 0.79-0.97, P = 0.010) were negatively correlated with lung cancer. MetS(RR = 0.99, 95% CI 0.90-1.09, P = 0.801), TC (RR = 0.93, 95% CI 0.81-1.06, P = 0.274), TG (RR = 0.99, 95% CI 0.88-1.12,P = 0.884), LDL-C (RR = 1.01, 95% CI 0.87-1.16, P = 0.928), hypertension (RR = 1.01, 95% CI 0.88-1.15, P = 0.928), FBG (RR = 1.02, 95% CI 0.92-1.13, P = 0.677) and obesity (RR = 1.11, 95% CI 0.92-1.35, P = 0.280) were not associated with lung cancer. CONCLUSION: Our study showed that the risk of lung cancer is correlated with DM, IR, BMI, and HDL-C. Timely control of these metabolic disorders may have a positive effect on preventing lung cancer. Trial registration Our study has been registered in the Prospective Register of Systematic Reviews (PROSPERO), ID: CRD42023390710.

The preparation of gallic acid-grafted cationic chitosan as effective salt-tolerant flocculants.

In this work, gallic acid was successfully grafted onto quaternary aminated chitosan to prepare a high efficiency cationic flocculant. The mechanism of flocculation and different influencing factors were studied in detail. The prepared flocculant only needs 60 mg L-1 to achieve a 98.7% and 94.5% removal rate on methyl blue (MB) and Congo red (CR), respectively. The high removal rate (93.2%) of a CR-MB mixed dye also confirms the universality of flocculation. In addition, kaolin as a simulated suspended solid was removed at a rate of 97% in the experiment at a dosage of 3 mg L-1. A zeta potential test showed that it worked best when the potential of the flocculation system was zero; this was because an electrostatic balance was reached between the flocculant and pollutant. Importantly, the three-functional molecules can provide more possibilities to form hydrogen bonds with water molecules, which is conducive to the stretching of flocculant molecular chains in salt water. The flocculant maintained a high stability in four different salt environments and has a positive industrial application significance. Furthermore, the flocculation experiment of the actual wastewater of the printing and dyeing plant found that the dye wastewater changed obviously from turbidity to clarification, which proved the practical application potential of the flocculant. This work provides a feasible idea for the preparation of bio-based flocculants.

Consumption of Apigenin Prevents Radiation-induced Gut Dysbiosis in Male C57BL/6J Mice Exposed to Silicon Ions.

The search for medical treatments to prevent radiation-induced damage to gastrointestinal tissue is crucial as such injuries can be fatal. This study aimed to investigate the effects of apigenin (AP) on the gut microbiome of irradiated mice, as it is a promising radiation countermeasure. Male C57BL/6J mice were divided into four groups, with six mice in each group. Two groups were given food with apigenin (20 mg/kg body weight or AP 20) before and after exposure to 0 or 50 cGy of silicon (28Si) ions, while another two groups of mice received regular diet without apigenin (0 mg/kg body weight or AP 0) before and after irradiation. The duodenum, the primary site for oral AP absorption, was collected from each mouse seven days after radiation exposure. Using 16S rRNA amplicon sequencing, we found significant differences in microbial diversity among groups. Firmicutes and Bacteroidetes were the major phyla for all groups, while actinobacterial and proteobacterial sequences represented only a small percentage. Mice not given dietary apigenin had a higher Firmicutes and Bacteroidetes (F/B) ratio and an imbalanced duodenal microbiota after exposure to radiation, while irradiated mice given apigenin had maintained homeostasis of the microbiota. Additionally, irradiated mice not given apigenin had decreased probiotic bacteria abundance and increased inflammation, while apigenin-supplemented mice had reduced inflammation and restored normal histological structure. In conclusion, our results demonstrate the potential of dietary apigenin as a countermeasure against radiation-induced gut injuries due to its anti-inflammatory activity, reduction of gut microbiota dysbiosis, and increase in probiotic bacteria (e.g., Lachnospiraceae, Muribaculaceae and Bifidobacteriaceae).

An online survey on public awareness of drug clinical trials in inland cities of northern China.

Objective: The aims of this survey were to investigate the public awareness of drug clinical trials (DCTs) and willingness to participate the DCTs, and provide references for propaganda and science popularization of DCTs. Methods: A self-designed questionnaire named "an online survey questionnaire on public awareness of DCTs" was used to conduct an online survey from January to March 2022. The demographic characteristics and the response of participants to the awareness and willingness to participate the DCTs were collected. The factors affecting the public awareness of DCTs were analyzed by single factor and binary logistic regression analysis. Results: One thousand three hundred eighty valid questionnaires were collected, and the respondents' awareness rate of DCTs was 61.1%. Thirteen demographic characteristics including age, gender, education, occupation, work fields, household type, marital status, city type, income, medical insurance, medical expenditure, pressure to seek medical care, financial pressure, both significantly affected the qualified rate of participants' awareness of DCTs (p < 0.001) by single factor analysis. Binary logistic regression analysis indicated that education level, work fields, city type, medical insurance, and medical expenditure affected independently the participants' awareness rate of DCTs (p < 0.001). 52.9% of the participants were willing to take part in DCTs. "to promote medical progress" (54.4%) or "believe doctors" (31.1%) were the most frequent reasons for subjects participating in DCTs. Conclusion: The public awareness rate of DCTs and the willingness to participate in drug clinical were significantly affected by the demographic characteristics of subjects. Thus, targeting the needs of the public, propaganda, and science popularization of DCTs should be carried out and served public health.

Development of 1 Month Sustained-Release Microspheres Containing Liraglutide for Type 2 Diabetes Treatment.

Liraglutide has been extensively applied in the treatment of type 2 diabetes mellitus (T2DM), but its 11-15 h half-life resulted in daily administration, which led to poor patient compliance. This study aimed to solve this problem by developing liraglutide-loaded microspheres with a 1 month sustained release prepared by the W1/O/W2 method combined with the premix membrane emulsification technique to improve therapeutic efficacy. Remarkably, we found that the amphiphilic properties of liraglutide successfully reduced the oil-water interfacial tension, resulting in a stable primary emulsion and decreasing the level of drug leakage into the external water phase. As a result, exceptional drug loading (>8%) and encapsulation efficiency (>85%) of microspheres were achieved. Furthermore, the uniformity in microsphere size facilitated an in-depth exploration of the structural characteristics of liraglutide-loaded microspheres. The results indicated that the dimensions of the internal cavities of the microspheres were significantly influenced by the size of the inner water droplets in the primary emulsion. A denser and more uniform cavity structure decreased the initial burst release, improving the release process of liraglutide from the microspheres. To evaluate the release behavior of liraglutide from microspheres, a set of in vitro release assays and in vivo pharmacodynamics were performed. The liraglutide-loaded microspheres effectively decreased fasting blood glucose (FBG) levels and hemoglobin A1c (HbA1c) levels while enhancing the pancreatic and hepatic functions in db/db mice. In conclusion, liraglutide sustained-release microspheres showed the potential for future clinical applications in the management of T2DM and provided an effective therapeutic approach to overcoming patient compliance issues.

Particle sizes crucially affected the release of additives from tire wear particles during UV irradiation and mechanical abrasion.

In the environment, tire wear particles (TWPs) could release various additives to induce potential risk, while the effects of particle size on the additive release behavior and ecological risk from TWPs remain unknown. This study investigated the effects and mechanisms of particle sizes (>2 mm, 0.71-1 mm, and <0.1 mm) on the release behavior of TWPs additives under mechanical abrasion and UV irradiation in water. Compared to mechanical abrasion, UV irradiation significantly increased the level of additives released from TWPs. Especially, the additive releasing characteristics were critically affected by the particle sizes of TWPs, manifested as the higher release in the smaller-size ones. After 60 d of UV irradiation, the concentration of antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) reached 10.79 mg/L in the leachate of small-sized TWPs, 2.78 and 5.36 times higher than that of medium-sized and large-sized TWPs. The leachate of the small-sized TWPs also showed higher cytotoxicity. •OH and O2•- were identified as the main reactive oxygen species (ROS), which exhibited higher concentrations and dramatic attack on small-sized TWPs to cause pronounced fragmentation and oxidation, finally inducing the higher release of additives. This paper sheds light on the crucial effects and mechanism of particle sizes in the release behavior of TWPs additives, provides useful information to assess the ecological risk of TWPs.

COVID-19 lockdown stress and problematic social networking sites use among quarantined college students in China: A chain mediation model based on the stressor-strain-outcome framework.

The COVID-19 pandemic has coincided with a global increase in problematic social networking sites use (PSNSU). By drawing on transactional stress theory and applying the stressor-strain-outcome (SSO) framework, we proposed and verified a chain mediation model to explore the mediating roles of fear of missing out (FoMO) and future anxiety (FA) in the relationship between COVID-19 lockdown stress (CL stress) and PSNSU. Our sample of 670 quarantined college students in China responded to a COVID-19 student stress questionnaire, a social network addiction scale, a fear of missing out scale, and a dark future scale. The results revealed that (1) CL stress significantly positively predicted PSNSU, (2) both FoMO and FA mediated the relationship between CL stress and PSNSU, (3) FoMO significantly positively predicted FA, and (4) a full chain mediation was observed between CL stress and PSNSU.

Efficacy and safety of the surgical treatments for lower calyceal stones: a systematic review and network meta-analysis.

OBJECTIVE: Efficacy and safety of five common surgical treatments for lower calyceal (LC) stones were assessed for LC stones 20 mm or less. METHODS: A systematic literature search was conducted up to June 2020 using PubMed, EMBASE, and Cochrane Library. The study has been registered in PROSPERO, CRD42021228404. Randomized controlled trials evaluating the efficacy and safety of five common surgical treatments for LC stones were collected, including percutaneous nephrolithotomy (PCNL), mini-PCNL (MPCNL), ultramini-PCNL (UMPCNL), extracorporeal shock wave lithotripsy (ESWL), and retrograde intrarenal surgery (RIRS). Heterogeneity among studies was assessed by using global inconsistency and local inconsistency. Both pooled odds ratio, along with 95% credible interval (CI) and the surface under the cumulative ranking curve values were calculated to assess the outcomes, paired comparisons of efficacy and safety of five treatments. RESULTS: Nine peer-reviewed randomized controlled trials, comprising 1674 patients in recent 10 years, were included. Heterogeneity tests showed no statistical significance, and a consistency model was chosen, respectively. The order of surface under the cumulative ranking curve values for efficacy was as follows: PCNL (79.4), MPCNL (75.2), UMPCNL (66.3), RIRS (29), and eSWL (0). For safety: eSWL (84.2), UMPCNL (82.2), RIRS (52.9), MPCNL (16.6), and PCNL (14.1). CONCLUSION: In the current study, all five treatments are both effective and safe. Many factors must be considered to choose surgical treatments for LC stones 20 mm or less; the results that we separate conventional PCNL into PCNL, MPCNL, and UMPCNL make the questions even more controversial. However, relative judgments are still needed to be used as reference data in clinical management. For efficacy, PCNL>MPCNL>UMPCNL>RIRS>ESWL, ESWL is statistically inferior to the other four treatments, respectively. RIRS is statistically inferior to PCNL and MPCNL, respectively. For safety, ESWL>UMPCNL>RIRS>MPCNL>PCNL, ESWL is statistically superior to RIRS, MPCNL, and PCNL, respectively. RIRS is statistically superior to PCNL. We cannot reach conclusions about which surgical treatment is the best choice for all patients with LC stones 20 mm or less; therefore, tailored treatments based on individual patients still demand more attention than ever before for both patients and urologists.