SIRT5-Mediated Desuccinylation of RAB7A Protects Against Cadmium-Induced Alzheimer's Disease-Like Pathology by Restoring Autophagic Flux.

Cadmium (Cd) is a neurotoxic contaminant that induces cognitive decline similar to that observed in Alzheimer's disease (AD). Autophagic flux dysfunction is attributed to the pathogenesis of AD, and this study aimed to investigate the effect of autophagy on environmental Cd-induced AD progression and the underlying mechanism. Here, Cd exposure inhibited autophagosome-lysosome fusion and impaired lysosomal function, leading to defects in autophagic clearance and then to APP accumulation and nerve cell death. Proteomic analysis coupled with Ingenuity Pathway Analysis (IPA) identified SIRT5 as an essential molecular target in Cd-impaired autophagic flux. Mechanistically, Cd exposure hampered the expression of SIRT5, thus increasing the succinylation of RAB7A at lysine 31 and inhibiting RAB7A activity, which contributed to autophagic flux blockade. Importantly, SIRT5 overexpression led to the restoration of autophagic flux blockade, the alleviation of Aß deposition and memory deficits, and the desuccinylation of RAB7A in Cd-exposed FAD4T mice. Additionally, SIRT5 levels decrease mainly in neurons but not in other cell clusters in the brains of AD patients according to single-nucleus RNA sequencing data from the public dataset GSE188545. This study reveals that SIRT5-catalysed RAB7A desuccinylation is an essential adaptive mechanism for the amelioration of Cd-induced autophagic flux blockade and AD-like pathogenesis.

Comparison of the speed and quality of innovative and traditional pneumatic tube system transport outside of an emergency laboratory.

Background: Ensuring the rapidity and accuracy of emergency laboratory test results is especially important to save the lives of patients with acute and critical conditions. To better meet the needs of clinicians and patients, detection efficiency can be improved by reducing extra-laboratory sample turnaround times (TATs) through the use of innovative pneumatic tube system (PTS) transport for sample transport. However, concerns remain regarding the potential compromise of sample quality during PTS transit relative to that occurring with manual transportation. This study was performed to evaluate the efficacy of an innovative PTS (Tempus600 PTS) relative to a traditional PTS in terms of sample transit time, sample quality, and the concordance of analytical results with those obtained from manually transported samples. Methods: In total, 30 healthy volunteers aged >18 years were recruited for this study, conducted for five consecutive days. Venous blood samples were collected from six volunteers per day at fixed timepoints. From each volunteer, nine blood samples were collected into tubes with tripotassium ethylene diamine tetraacetic acid anticoagulant, tubes with 3.2 % sodium citrate, and serum tubes with separation gel (n = 3 each) and subjected to all tests conducted in the emergency laboratory in our hospital. 270 blood samples from 30 healthy volunteers were transported and analyzed, yielding 6300 test results. The blood samples were divided randomly into three groups (each containing one tube of each type) and transported to the emergency laboratory manually and with Tempus600 PTS and conventional Swisslog PTS, respectively. The extra-laboratory TATs, sample quality, and test results of the transported blood samples were compared. Results: The sample quality and test results did not differ according to the delivery method. The TAT was much shorter with the Tempus600 than with the other two transport modes (58.40 ± 1.52 s vs. 1711.20 ± 77.56 s for manual delivery and 146.60 ± 1.82 s for the Swisslog PTS; P = 0.002). Conclusion: Blood sample transport with the Tempus600 PTS significantly reduced the extra-laboratory TAT without compromising sample quality or test result accuracy, thereby improving the efficiency of sample analysis and the services provided to clinicians and patients.

Exploring and validating heating dynamics in a radio-frequency electromagnetic field-based resonant chamber for mouse hyperthermia research.

Mild whole-body hyperthermia has been shown to have anti-tumor effects through an immune-modulating mechanism. Before it is widely applied in the clinic, tremendous mechanistic research in animals is necessary to adhere to evidence-based principles. The radio frequency electromagnetic field (RF-EMF) based heating facility could be a good choice for hyperthermia treatment, but the heating characteristics of a facility, including structure design, electromagnetic and thermal dosimetry, and the biologic effects of hyperthermia, need to be well elucidated. Here, we reported the heating characteristic study on a resonant chamber (RC) excited by a 1800 MHz solid source. The EMF in the RC was stirred by 24 static reflectors, which resulted in the standard deviation of electric field intensity being below 3 dB in the EM homogeneity evaluation. For the exposure scenario, six free-moving mice were loaded into separate cases and exposed simultaneously in the RC. The EMF energy absorption and distribution in exposed mice were calculated with the 12-plane-waves method of numerical simulation. Different levels of core body temperature increment in exposed mice were achieved through regulation of the source output power. Overexpression of heat shock proteins (HSPs) was detected in the liver, lung and muscle, but not in the brain of the exposed mice. The levels of representative inflammatory cytokines in the serum, TNF-α and IL-10 increased post RC exposure. Based on the heating characteristic study and validation, the applied RC would be a qualified heating system for mild whole-body hyperthermia effect research in mice.

Mild whole-body hyperthermia has potential anti-tumor effects by modulating the immune system. A radio frequency electromagnetic field (RF-EMF)-based heating facility emerges as a suitable option for hyperthermia treatment. However, a qualified heating facility for scientific research must elucidate its heating characteristics and validate the biological effects associated with hyperthermia. In this study, we report the characteristics of a rodent heating chamber using EMF energy. The special structure of the chamber not only achieved efficient EMF usage but also ensured the homogeneity in EMF spatial distribution, animal EM absorption, and EMF-caused biological effects. Our work may offer insights for designing a low-cost yet reliable heating facility for scientific research.

Optimization, characterization and evaluation of sodium alginate nanoparticles for Ganoderic acid DM encapsulation: Inhibitory activity on tyrosinase activity and melanin formation.

The efficacy of nanoencapsulation as a technology for enhancing the solubility of active substances has been demonstrated. In this particular investigation, Ganoderic acid DM (GA-DM) was encapsulated within sodium alginate nanoparticles (NPs) using the ionic crosslinking method. The confirmation of the successful loading of GA-DM was ascertained through the analysis of Fourier transform infrared spectrum (FTIR). Empirical evidence derived from the examination of scanning electron microscope (SEM) images, transmission electron microscope (TEM) images, atomic force microscope (AFM) images, and dynamic light scattering (DLS) demonstrated a regular distribution and spherical morphology, with an average particle size of approximately 133 nm. The investigation yielded an encapsulation efficiency of 95.27 ±â€¯0.11 % and a drug loading efficiency of 21.17 ±â€¯0.02 % for the prepared sample. The release kinetics of SGPN was fitted with the Korsmeyer-Peppas kinetic model corresponding to diffusion-controlled release. The incorporation of GA-DM into sodium alginate nanocarriers exhibited a mitigating effect on the cytotoxicity of HaCat and B16, while also demonstrating inhibitory properties against tyrosinase activity and melanin formation.

PLIN5 Suppresses Lipotoxicity and Ferroptosis in Cardiomyocyte via Modulating PIR/NF-κB Axis.

Cardiomyocyte lipotoxicity and ferroptosis are the key to the development of diabetic cardiomyopathy (DCM). Perilipin 5 (PLIN5) is perceived as a significant target of DCM. This study aimed to focus on the role and mechanism of PLIN5 on lipotoxicity and ferroptosis in DCM.Following transfection, mouse cardiomyocytes HL-1 were induced by 0.1 mM palmitic acid (PA) to set up lipotoxic cardiomyocyte models. The cell viability and lipid accumulation were evaluated by cell counting kit-8 assay and Oil red O staining, respectively. Ferrous ion (Fe2+), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) levels were determined to verify the effects of PLIN5 or Pirin (PIR) on ferroptosis. Quantitative real-time reverse transcription polymerase chain reaction or Western blot was performed for quantitative analysis.PLIN5 overexpression promoted the viability, GSH level, and expression of GPX4/PIR/intracellular P65, yet suppressed lipid accumulation, level of Fe2+/MDA/ROS, and expression of interleukin (IL)-1ß/IL-18/intranuclear P65 in PA-stimulated HL-1 cells. PIR silencing counteracted the roles of PLIN5 overexpression in PA-stimulated HL-1 cells.PLIN5 suppresses lipotoxicity and ferroptosis in cardiomyocyte via modulating PIR/NF-κB axis, hinting its potential as a therapeutic target in DCM.

Detection accuracy and clinical applications of DP-TOF mass spectrometry.

OBJECTIVE: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is currently used in clinical microbiology laboratories. This study aimed to determine whether dual-polarity time-of-flight mass spectrometry (DP-TOF MS) could be applied to clinical nucleotide detection. METHODS: This prospective study included 40 healthy individuals and 110 patients diagnosed with cardiovascular diseases. We used DP-TOF MS and Sanger sequencing to evaluate 17 loci across 11 genes associated with cardiovascular drug responses. In addition, we used DP-TOF MS to test 998 retrospectively collected clinical DNA samples with known results. RESULTS: A, T, and G nucleotide detection by DP-TOF MS and Sanger sequencing revealed 100% concordance, whereas the C nucleotide concordance was 99.86%. Genotyping based on the results of the two methods showed 99.96% concordance. Regarding clinical applications, DP-TOF MS yielded a 99.91% concordance rate for known loci. The minimum detection limit for DNA was 0.4 ng; the inter-assay and intra-assay precision rates were both 100%. Anti-interference analysis showed that aerosol contamination greater than 1013 copies/µL in the laboratory environment could influence the results of DP-TOF MS. CONCLUSIONS: The DP-TOF MS platform displayed good detection performance, as demonstrated by its 99.96% concordance rate with Sanger sequencing. Thus, it may be applied to clinical nucleotide detection.

Paraquat disrupts KIF5A-mediated axonal mitochondrial transport in midbrain neurons and its antagonism by melatonin.

Paraquat (PQ) is a broad-spectrum herbicide used worldwide and is a hazardous chemical to human health. Cumulative evidence strengthens the association between PQ exposure and the development of Parkinson's disease (PD). However, the underlying mechanism and effective interventions against PQ-induced neurotoxicity remain unclear. In this study, C57BL/6 J mice were treated with PQ (i.p., 10 mg/kg, twice a week) and melatonin (i.g., 20 mg/kg, twice a week) for 8 weeks. Results showed that PQ-induced motor deficits and midbrain dopaminergic neuronal damage in C57BL/6 J mice were protected by melatonin pretreatment. In isolated primary midbrain neurons and SK-N-SH cells, reduction of cell viability, elevation of total ROS levels, axonal mitochondrial transport defects and mitochondrial dysfunction caused by PQ were attenuated by melatonin. After screening of expression of main motors driving axonal mitochondrial transport, data showed that PQ-decreased KIF5A expression in mice midbrain and in SK-N-SH cell was antagonized by melatonin. Using the in vitro KIF5A-overexpression model, it was found that KIF5A overexpression inhibited PQ-caused neurotoxicity and mitochondrial dysfunction in SK-N-SH cells. In addition, application of MTNR1B (MT2) receptor antagonist, 4-P-PDOT, significantly counteracted the protection of melatonin against PQ-induced neurotoxicity. Further, Kif5a-knockdown diminished melatonin-induced alleviation of motor deficits and neuronal damage against PQ in C57BL/6 J mice. The present study establishes a causal link between environmental neurotoxicants exposure and PD etiology and provides effective interventive targets in the pathogenesis of PD.

Transcriptomic analysis provides insights into the molecular mechanism of melatonin-mediated cadmium tolerance in Medicago sativa L.

Cadmium (Cd), a toxic element, often makes a serious threat to plant growth and development. Previous studies found that melatonin (Mel) reduced Cd accumulation and reestablished the redox balance to alleviate Cd stress in Medicago sativa L., however, the complex molecular mechanisms are still elusive. Here, comparative transcriptome analysis and biochemical experiments were conducted to explore the molecular mechanisms of Mel in enhancing Cd tolerance. Results showed that 7237 differentially expressed genes (DEGs) were regulated by Mel pretreatment to Cd stress compared to the control condition in roots of Medicago sativa L. Besides, in comparison with Cd stress alone, Mel upregulated 1081 DEGs, and downregulated 1085 DEGs. These DEGs were mainly involved in the transcription and translation of genes and folding, sorting and degradation of proteins, carbohydrate metabolism, and hormone signal network. Application of Mel regulated the expression of several genes encoding ribosomal protein and E3 ubiquitin-protein ligase involved in folding, sorting and degradation of proteins. Moreover, transcriptomic analyse suggested that Mel might regulate the expression of genes encoding pectin lyase, UDP-glucose dehydrogenase, sucrose-phosphate synthase, hexokinase-1, and protein phosphorylation in the sugar metabolism. Therefore, these could promote sucrose accumulation and subsequently alleviate the Cd damage. In conclusion, above findings provided the mining of important genes and molecular basis of Mel in mitigating Cd tolerance and genetic cultivation of Medicago sativa L.

A predictive model in patients with chronic hydrocephalus following aneurysmal subarachnoid hemorrhage: a retrospective cohort study.

Objective: Our aim was to develop a nomogram that integrates clinical and radiological data obtained from computed tomography (CT) scans, enabling the prediction of chronic hydrocephalus in patients with aneurysmal subarachnoid hemorrhage (aSAH). Method: A total of 318 patients diagnosed with subarachnoid hemorrhage (SAH) and admitted to the Department of Neurosurgery at the Affiliated People's Hospital of Jiangsu University between January 2020 and December 2022 were enrolled in our study. We collected clinical characteristics from the hospital's medical record system. To identify risk factors associated with chronic hydrocephalus, we conducted both univariate and LASSO regression models on these clinical characteristics and radiological features, accompanied with penalty parameter adjustments conducted through tenfold cross-validation. All features were then incorporated into multivariate logistic regression analyses. Based on these findings, we developed a clinical-radiological nomogram. To evaluate its discrimination performance, we conducted Receiver Operating Characteristic (ROC) curve analysis and calculated the Area Under the Curve (AUC). Additionally, we employed calibration curves, and utilized Brier scores as an indicator of concordance. Additionally, Decision Curve Analysis (DCA) was performed to determine the clinical utility of our models by estimating net benefits at various threshold probabilities for both training and testing groups. Results: The study included 181 patients, with a determined chronic hydrocephalus prevalence of 17.7%. Univariate logistic regression analysis identified 11 potential risk factors, while LASSO regression identified 7 significant risk factors associated with chronic hydrocephalus. Multivariate logistic regression analysis revealed three independent predictors for chronic hydrocephalus following aSAH: Periventricular white matter changes, External lumbar drainage, and Modified Fisher Grade. A nomogram incorporating these factors accurately predicted the risk of chronic hydrocephalus in both the training and testing cohorts. The AUC values were calculated as 0.810 and 0.811 for each cohort respectively, indicating good discriminative ability of the nomogram model. Calibration curves along with Hosmer-Lemeshow tests demonstrated excellent agreement between predicted probabilities and observed outcomes in both cohorts. Furthermore, Brier scores (0.127 for the training and 0.09 for testing groups) further validated the predictive performance of our nomogram model. The DCA confirmed that this nomogram provides superior net benefit across various risk thresholds when predicting chronic hydrocephalus. The decision curve demonstrated that when an individual's threshold probability ranged from 5 to 62%, this model is more effective in predicting the occurrence of chronic hydrocephalus after aSAH. Conclusion: A clinical-radiological nomogram was developed to combine clinical characteristics and radiological features from CT scans, aiming to enhance the accuracy of predicting chronic hydrocephalus in patients with aSAH. This innovative nomogram shows promising potential in assisting clinicians to create personalized and optimal treatment plans by providing precise predictions of chronic hydrocephalus among aSAH patients.

Single-Nucleus Transcriptomic Atlas of Human Pericoronary Epicardial Adipose Tissue in Normal and Pathological Conditions.

BACKGROUND: Pericoronary epicardial adipose tissue (EAT) is a unique visceral fat depot that surrounds the adventitia of the coronary arteries without any anatomic barrier. Clinical studies have demonstrated the association between EAT volume and increased risks for coronary artery disease (CAD). However, the cellular and molecular mechanisms underlying the association remain elusive. METHODS: We performed single-nucleus RNA sequencing on pericoronary EAT samples collected from 3 groups of subjects: patients undergoing coronary bypass surgery for severe CAD (n=8), patients with CAD with concomitant type 2 diabetes (n=8), and patients with valvular diseases but without concomitant CAD and type 2 diabetes as the control group (n=8). Comparative analyses were performed among groups, including cellular compositional analysis, cell type-resolved transcriptomic changes, gene coexpression network analysis, and intercellular communication analysis. Immunofluorescence staining was performed to confirm the presence of CAD-associated subclusters. RESULTS: Unsupervised clustering of 73 386 nuclei identified 15 clusters, encompassing all known cell types in the adipose tissue. Distinct subpopulations were identified within primary cell types, including adipocytes, adipose stem and progenitor cells, and macrophages. CD83high macrophages and FOSBhigh adipocytes were significantly expanded in CAD. In comparison to normal controls, both disease groups exhibited dysregulated pathways and altered secretome in the primary cell types. Nevertheless, minimal differences were noted between the disease groups in terms of cellular composition and transcriptome. In addition, our data highlight a potential interplay between dysregulated circadian clock and altered physiological functions in adipocytes of pericoronary EAT. ANXA1 and SEMA3B were identified as important adipokines potentially involved in functional changes of pericoronary EAT and CAD pathogenesis. CONCLUSIONS: We built a complete single-nucleus transcriptomic atlas of human pericoronary EAT in normal and diseased conditions of CAD. Our study lays the foundation for developing novel therapeutic strategies for treating CAD by targeting and modifying pericoronary EAT functions.

Head Impact Kinematics and Brain Tissue Strains in High School Lacrosse.

Male lacrosse and female lacrosse have differences in history, rules, and equipment. There is current debate regarding the need for enhanced protective headwear in female lacrosse like that worn by male lacrosse players. To inform this discussion, 17 high school lacrosse players (6 female and 11 male) wore the Stanford Instrumented Mouthguard during 26 competitive games over the 2021 season. Time-windowing and video review were used to remove false-positive recordings and verify head acceleration events (HAEs). The HAE rate in high school female lacrosse (0.21 per athlete exposure and 0.24 per player hour) was approximately 35% lower than the HAE rate in high school male lacrosse (0.33 per athlete exposure and 0.36 per player hour). Previously collected kinematics data from the 2019 high school male and female lacrosse season were combined with the newly collected 2021 kinematics data, which were used to drive a finite element head model and simulate 42 HAEs. Peak linear acceleration (PLA), peak angular velocity (PAV), and 95th percentile maximum principal strain (MPS95) of brain tissue were compared between HAEs in high school female and male lacrosse. Median values for peak kinematics and MPS95 of HAEs in high school female lacrosse (PLA, 22.3 g; PAV, 10.4 rad/s; MPS95, 0.05) were lower than for high school male lacrosse (PLA, 24.2 g; PAV, 15.4 rad/s; MPS95, 0.07), but the differences were not statistically significant. Quantifying a lower HAE rate in high school female lacrosse compared to high school male lacrosse, but similar HAE magnitudes, provides insight into the debate regarding helmets in female lacrosse. However, due to the small sample size, additional video-verified data from instrumented mouthguards are required.

A commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response.

Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain unclear. Here, we show that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1ß secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host's arginine-ornithine metabolic pathway, but also shaping the metabolic environment for the microbial community in the host's intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile's virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest interactions between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolism in the regulation of pathogenesis and provide further insights for treating CDI.

Lipoic acid-mediated oral drug delivery system utilizing changes on cell surface thiol expression for the treatment of diabetes and inflammatory diseases.

Lipoic acid (LA), which has good safety and oral absorption, is obtained from various plant-based food sources and needs to be supplemented through human diet. Moreover, substances with a disulfide structure can enter cells through dynamic covalent disulfide exchange with thiol groups on the cell membrane surface. Based on these factors, we constructed LA-modified nanoparticles (LA NPs). Our results showed that LA NPs can be internalized into intestinal epithelial cells through surface thiols, followed by intracellular transcytosis via the endoplasmic reticulum-Golgi pathway. Further mechanistic studies indicated that disulfide bonds within the structure of LA play a critical role in this transport process. In a type I diabetes rat model, the oral administration of insulin-loaded LA NPs exhibited a more potent hypoglycemic effect, with a pharmacokinetic bioavailability of 5.42 ± 0.53%, representing a 1.6 fold enhancement compared to unmodified PEG NPs. Furthermore, a significant upregulation of surface thiols in inflammatory macrophages was reported. Thus, we turned our direction to investigate the uptake behavior of inflammatory macrophages with increased surface thiols towards LA NPs. Inflammatory macrophages showed a 2.6 fold increased uptake of LA NPs compared to non-inflammatory macrophages. Surprisingly, we also discovered that the antioxidant resveratrol facilitates the uptake of LA NPs in a concentration-dependent manner. This is mainly attributed to an increase in glutathione, which is involved in thiol uptake. Consequently, we employed LA NPs loaded with resveratrol for the treatment of colitis and observed a significant alleviation of colitis symptoms. These results suggest that leveraging the variations of thiol expression levels on cell surfaces under both healthy and diseased states through an oral drug delivery system mediated by the small-molecule nutrient LA can be employed for the treatment of diabetes and certain inflammatory diseases.

Ivermectin ameliorates acute myocarditis via the inhibition of importin-mediated nuclear translocation of NF-κB/p65.

BACKGROUND: Myocarditis is an important clinical issue which lacks specific treatment by now. Ivermectin (IVM) is an inhibitor of importin α/ß-mediated nuclear translocation. This study aimed to explore the therapeutic effects of IVM on acute myocarditis. METHODS: Mouse models of coxsackie B3 virus (CVB3) infection-induced myocarditis and experimental autoimmune myocarditis (EAM) were established to evaluate the effects of IVM. Cardiac functions were evaluated by echocardiography and Millar catheter. Cardiac inflammatory infiltration was assessed by histological staining. Cytometric bead array and quantitative real-time PCR were used to detect the levels of pro-inflammatory cytokines. The macrophages and their M1/M2 polarization were analyzed via flow cytometry. Protein expression and binding were detected by co-immunoprecipitation, Western blotting and histological staining. The underlying mechanism was verified in vitro using CVB3-infected RAW264.7 macrophages. Cyclic polypeptide (cTN50) was synthesized to selectively inhibit the nuclear translocation of NF-κB/p65, and CVB3-infected RAW264.7 cells were treated with cTN50. RESULTS: Increased expression of importin ß was observed in both models. IVM treatment improved cardiac functions and reduced the cardiac inflammation associated with CVB3-myocarditis and EAM. Furthermore, the pro-inflammatory cytokine (IL-1ß/IL-6/TNF-α) levels were downregulated via the inhibition of the nuclear translocation of NF-κB/p65 in macrophages. IVM and cTN50 treatment also inhibited the nuclear translocation of NF-κB/p65 and downregulated the expression of pro-inflammatory cytokines in RAW264.7 macrophages. CONCLUSIONS: Ivermectin inhibits the nuclear translocation of NF-κB/p65 and the expression of major pro-inflammatory cytokines in myocarditis. The therapeutic effects of IVM on viral and non-viral myocarditis models suggest its potential application in the treatment of acute myocarditis.

Chloride-induced corrosion of steel in concrete-insights from bimodal neutron and X-ray microtomography combined with ex-situ microscopy.

The steel-concrete interface (SCI) is known to play a major role in corrosion of steel in concrete, but a fundamental understanding is still lacking. One reason is that concrete's opacity complicates the study of internal processes. Here, we report on the application of bimodal X-ray and neutron microtomography as in-situ imaging techniques to elucidate the mechanism of steel corrosion in concrete. The study demonstrates that the segmentation of the specimen components of relevance-steel, cementitious matrix, aggregates, voids, corrosion products-obtained through bimodal X-ray and neutron imaging is more reliable than that based on the results of each of the two techniques separately. Further, we suggest the combination of tomographic in-situ imaging with ex-situ SEM analysis of targeted sections, selected based on the segmented tomograms. These in-situ and ex-situ characterization techniques were applied to study localized corrosion in a very early stage under laboratory chloride-exposure conditions, using reinforced concrete cores retrieved from a concrete bridge. Several interesting observations were made. First, the acquired images revealed the formation of several corrosion sites close to each other. Second, the morphology of the corrosion pits was relatively shallow. Finally, only about half of the total 31 corrosion initiation spots were in close proximity to interfacial macroscopic air voids, and > 90% of the more than 160 interfacial macroscopic air voids were free from corrosion. The findings have implications for the mechanistic understanding of corrosion of steel in concrete and suggest that multimodal in-situ imaging is a valuable technique for further related studies. Supplementary Information: The online version contains supplementary material available at 10.1617/s11527-024-02337-7.

Enhanced oral and pulmonary delivery of biomacromolecules via amplified transporter targeting.

Ligand-modified nanocarriers can promote oral or inhalative administration of macromolecular drugs across the intestinal or pulmonary mucosa. However, enhancing the unidirectional transport of the nanocarriers through "apical uptake→intracellular transport→basolateral exocytosis" route remains a hot topic and challenge in current research. Forskolin is a naturally occurring diterpenoid compound extracted from the roots of C. forskohlii. In our studies, we found that forskolin could increase the transcellular transport of butyrate-modified nanoparticles by 1.67-fold and 1.20-fold in Caco-2 intestinal epithelial cell models and Calu-3 lung epithelial cell models, respectively. Further mechanistic studies revealed that forskolin, on the one hand, promoted the cellular uptake of butyrate-modified nanoparticles by upregulating the expression of monocarboxylic acid transporter-1 (MCT-1) on the apical membrane. On the other hand, forskolin facilitated the binding of MCT-1 to caveolae, thereby mediating butyrate-modified nanoparticles hijacking caveolae to promote the basolateral exocytosis of butyrate-modified nanoparticles. Studies in normal mice model showed that forskolin could promote the transmucosal absorption of butyrate-modified nanoparticles by >2-fold, regardless of oral or inhalative administration. Using semaglutide as the model drug, both oral and inhalation delivery approaches demonstrated significant hypoglycemic effects in type 2 diabetes mice model, in which inhalative administration was more effective than oral administration. This study optimized the strategies aimed at enhancing the transmucosal absorption of ligand-modified nanocarriers in the intestinal or pulmonary mucosa.

Bacterial cellulose-based hydrogel with regulated rehydration and enhanced antibacterial activity for wound healing.

Bacterial cellulose (BC) hydrogels are promising medical biomaterials that have been widely used for tissue repair, wound healing and cartilage engineering. However, the high water content of BC hydrogels increases the difficulty of storage and transportation. Moreover, they will lose their original hydrogel structure after dehydration, which severely limits their practical applications. Introducing the bio-based polyelectrolytes is expected to solve this problem. Here, we modified BC and combined it with quaternized chitosan (QCS) via a chemical reaction to obtain a dehydrated dialdehyde bacterial cellulose/quaternized chitosan (DBC/QCS) hydrogel with repeated swelling behavior and good antibacterial properties. The hydrogel can recover the initial state on the macro scale with a swelling ratio over 1000 % and possesses excellent antimicrobial properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) with a killing rate of 80.8 % and 81.3 %, respectively. In addition, the hydrogel has excellent biocompatibility, which is conducive to the stretching of L929 cells. After 14 d of in vivo wound modeling in rats, it was found that the hydrogel loaded with pirfenidone (PFD) could promote collagen deposition and accelerate wound healing with scar prevention. This rehydratable hydrogel can be stored and transported under dry conditions, which is promising for practical applications.

Tumor-targeted gypenoside nanodrug delivery system with double protective layers.

OBJECTIVES: Gypenoside (Gyp) is easily degraded in the gastrointestinal tract, resulting in its low bioavailability. We aimed to develop a tumor-targeted Gyp nanodrug delivery system and to investigate its antitumor effect in vitro. MATERIALS AND METHODS: We used Gyp as the therapeutic drug molecule, mesoporous silica (MSN) and liposome (Lipo) as the drug carrier and protective layers, and aptamer SYL3C as the targeting element to establish a tumor-targeted nanodrug delivery system (i.e., SYL3C-Lipo@Gyp-MSN). The characteristics of SYL3C-Lipo@Gyp-MSN were investigated, and its drug release performance, cell uptake, and antitumor activity in vitro were evaluated. RESULTS: A tumor-targeted Gyp nanodrug delivery system was successfully prepared. The SYL3C-Lipo@Gyp-MSN was spherical or ellipsoidal; had good dispersion, which enabled it to specifically target and kill the liver tumor cell HepG2; and effectively protected the early leakage of Gyp. CONCLUSIONS: We have established a tumor-targeted nanodrug delivery system that can target and kill liver cancer cells and may provide a strategy for preparing new nanodrug-loaded preparations of traditional Chinese medicine.

Effect of Fluid Therapy in Early Morning on the Incidence of Post-Induction Hypotension During Non-Cardiac Surgery After Noon: A Single-Center Retrospective Study.

Purpose: Post-induction hypotension (PIH) is a common clinical phenomenon linked to increased morbidity and mortality in various non-cardiac surgeries. Patients with surgery in the afternoon may have preoperative hypovolemia caused by prolonged fasting and dehydration, which increases the risk of hypotension during the induction period. However, studies on the fluid therapy in early morning combating PIH remain inadequate. Therefore, we aimed to investigate the influence of prophylactic high-volume fluid in the early morning of the operation day on the incidence of PIH during non-cardiac surgery after noon. Patients and Methods: We reviewed the medical records of patients who underwent non-cardiac surgery after noon between October 2021 and October 2022. The patients were divided into two groups based on whether they received a substantial volume of intravenous fluid (high-volume group) or not (low-volume group) in the early morning of the surgery day. We investigated the incidence of PIH and intraoperative hypotension (IOH) as well as the accumulated duration of PIH in the first 15 minutes. In total, 550 patients were included in the analysis. Results: After propensity score matching, the incidence of PIH was 39.7% in the high-volume group and 54.1% in the low-volume group. Multivariate logistic regression analysis showed that patients in the high-volume group had lower incidence of hypotension after induction compared with the low-volume group (odds ratio, 0.55; 95% CI, 0.34-0.89; p = 0.016). The high-volume fluid infusion in the preoperative morning was significantly correlated with the decreased duration of PIH (p = 0.013), but no statistical difference was observed for the occurrence of IOH between the two groups (p = 0.075). Conclusion: The fluid therapy of more than or equal to 1000 mL in the early morning of the surgery day was associated with a decreased incidence of PIH compared with the low-volume group in patients undergoing non-cardiac surgery after noon.

Evolution of illness severity in hospital admissions due to COVID-19, Québec, Canada, January to April 2022.

Background: The coronavirus disease 2019 (COVID-19) severity is influenced by multiple factors, such as age, underlying medical conditions, individual immunity, infecting variant, and clinical practice. The highly transmissible Omicron variants resulted in decreased COVID-19 screening capacity, which limited disease severity surveillance. Objective: To report on the temporal evolution of disease severity among patients admitted to Québec hospitals due to COVID-19 between January 2, 2022, and April 23, 2022, which corresponded to the peak period of hospitalizations due to Omicron. Methods: Retrospective population-based cohort study of all hospital admissions due to COVID-19 in Québec, between January 2, 2022, and April 23, 2022. Study period was divided into four-week periods, corresponding roughly to January, February, March and April. Regression using Cox and Poisson generalized estimating equations (GEEs) was used to quantify temporal variations in length of stay and risk of complications (intensive care admission or in-hospital death) through time, using the Omicron peak (January 2022) as reference. Measures were adjusted for age, sex, vaccination status, presence of chronic diseases, and clustering by hospital. Results: During the study period, 9,178 of all 18,272 (50.2%) patients hospitalized with a COVID-19 diagnosis were admitted due to COVID-19. Of these, 1,026 (11.2%) were admitted to intensive care and 1,523 (16.6%) died. Compared to January, the risk of intensive care admission was 25% and 31% lower in March and April respectively, while in-hospital fatality continuously decreased by 45% lower in April. The average length of stay was temporarily lower in March (9%). Conclusion: Severity of admissions due to COVID-19 decreased in the first months of 2022, when predominant circulating variants were considered to be of similar severity. Monitoring hospital admissions due to COVID-19 can contribute to disease severity surveillance.