Liposomal nanocarriers of preassembled glycocalyx restore normal venular permeability and shear stress sensitivity in sepsis: assessed quantitatively with a novel microchamber system.

The endothelial glycocalyx (EG), covering the luminal side of endothelial cells, regulates vascular permeability and senses wall shear stress. In sepsis, EG undergoes degradation leading to increased permeability and edema formation. We hypothesized that restoring EG integrity using liposomal nanocarriers of preassembled glycocalyx (LNPG) will restore normal venular permeability in lipopolysaccharide (LPS)-induced sepsis model of mice. To test this hypothesis, we designed a unique perfusion microchamber in which the permeability of isolated venules could be assessed by measuring the concentration of Evans blue dye (EBD) in microliter samples of extravascular solution (ES). Histamine-induced time- and dose-dependent increases in EBD in the ES could be measured, confirming the sensitivity of the microchamber system. Notably, the histamine-induced increase in permeability was significantly attenuated by histamine receptor (H1) antagonist, triprolidine hydrochloride. Subsequently, mice were treated with LPS or LPS + LNPG. When compared with control mice, venules from LPS-treated mice showed a significant increased permeability, which was significantly reduced by LNPG administration. Moreover, in the presence of wall shear stress, intraluminal administration of LNPG significantly reduced the permeability in isolated venules from LPS-treated mice. We have found no sex differences. In conclusion, our newly developed microchamber system allows us to quantitatively measure the permeability of isolated venules. LPS-induced sepsis increases permeability of mesenteric venules that is attenuated by in vivo LNPG administration, which also reestablished endothelial responses to shear stress. Thus, LNPG presents a promising therapeutic potential for restoring EG function and thereby mitigating vasogenic edema due to increased permeability in sepsis.NEW & NOTEWORTHY In sepsis, the degradation of the endothelial glycocalyx leads to increased venular permeability. In this study, we developed a potentially new therapeutic approach by in vivo administration of liposomal nanocarriers of preassembled glycocalyx to mice, which restored venular sensitivity to wall shear stress and permeability in lipopolysaccharide-induced sepsis, likely by restoring the integrity of the endothelial glycocalyx. Using a new microchamber system, the permeability of Evans blue dye could be quantitatively determined.

Long-term efficacy of liposomal nanocarriers of preassembled glycocalyx in restoring cerebral endothelial glycocalyx in sepsis.

The endothelial glycocalyx (EG) undergoes early degradation in sepsis. Our recent work introduced a novel therapeutic approach involving liposomal nanocarriers of preassembled glycocalyx (LNPG) to restore EG in lipopolysaccharide (LPS)-induced sepsis model of mice. While short-term effects were promising, this study focuses on the long-term impact of LNPG on mouse cerebral microcirculation. Utilizing cranial window, we assessed the stability of vascular density (VD) and perfused boundary region (PBR), an index of EG thickness, over a five-day period in normal control mice. In septic groups (LPS, LPS + 1-dose LNPG, and LPS + 2-dose LNPG), the exposure of mice to LPS significantly reduced VD and increased PBR within 3 h. Without LNPG treatment, PBR returned to the normal control level by endogenous processes at 48 h, associated with the recovery of VD to the baseline level at 72 h. However, mice receiving LNPG treatment significantly reduced the increment of PBR at 3 h. The therapeutic effect of 1-dose LNPG persisted for 6 h while the 2-dose LNPG treatment further reduced PBR and significantly increased VD at 12 h compared to LPS group. This study provides valuable insights into the potential therapeutic benefits of LNPG in mitigating EG degradation in sepsis.

The Protective Role of Magnoliae Flos in Preventing Ovotoxicity and Managing Ovarian Function: An In Vitro and In Vivo Study.

Magnoliae Flos (MF) is a medicinal herb widely employed in traditional medicine for relieving sinusitis, allergic rhinitis, headaches, and toothaches. Here, we investigated the potential preventive effects of MF extract (MFE) against 4-vinylcyclohexene diepoxide (VCD)-induced ovotoxicity in ovarian cells and a mouse model of premature ovarian insufficiency (POI). The cytoprotective effects of MFE were assessed using CHO-K1 or COV434 cells. In vivo, B6C3F1 female mice were intraperitoneally injected with VCD for two weeks to induce POI, while MFE was orally administered for four weeks, beginning one week before VCD administration. VCD led to a significant decline in the viabilities of CHO-K1 and COV434 cells and triggered excessive reactive oxygen species (ROS) production and apoptosis specifically in CHO-K1 cells. However, pretreatment with MFE effectively prevented VCD-induced cell death and ROS generation, while also activating the Akt signaling pathway. In vivo, MFE increased relative ovary weights, follicle numbers, and serum estradiol and anti-Müllerian hormone levels versus controls under conditions of ovary failure. Collectively, our results demonstrate that MFE has a preventive effect on VCD-induced ovotoxicity through Akt activation. These results suggest that MFE may have the potential to prevent and manage conditions such as POI and diminished ovarian reserve.

Liposomal nanocarriers of preassembled glycocalyx expeditiously restore endothelial glycocalyx in endotoxemia.

The endothelial glycocalyx (EG) is degraded early during sepsis, and currently available treatments are not effective in promptly restoring it. Here, we created liposomal nanocarriers of preassembled glycocalyx (LNPG) by synthesizing glycosylated syndecan-1 and inserting it into the lipid membrane of unilamellar liposomes. We hypothesized that LNPG would fuse with the endothelial cells where EG is degraded and restore EG in sepsis. We induced endotoxemia in C57BL/6J mice using lipopolysaccharides (LPS) and treated them with LNPG, saline, syndecan-1, or liposomes. LNPG significantly prolonged the survival time of LPS-treated mice compared with the other treatments. Immunostaining of en face mesenteric arteries of LPS-treated mice showed that syndecan-1 was fully restored after LNPG administration. In addition, EG height in microvasculature of mouse cremaster muscle was monitored using sidestream dark field imaging. LNPG restored the perfused boundary region (PBR), which is inversely related to EG dimensions, to the control level after LPS administration. Furthermore, flow-induced dilation in isolated mouse mesenteric arterioles was fully recovered after LNPG treatment in LPS-treated mice. In summary, our findings provide evidence of the therapeutic efficacy of LNPG in the LPS-induced mouse model of sepsis, achieved by expeditiously restoring EG through fusion of LNPG with the endothelial plasma membrane and recovery of endothelial function.NEW & NOTEWORTHY Vascular endothelial cells represent the first line of exposure to bacterial endotoxins. Here, we propose a novel therapeutic strategy using liposomes to deliver preassembled glycocalyx to vascular endothelial cell surface and consequently restore endothelial glycocalyx (EG). We tested liposomal nanocarriers of preassembled glycocalyx (LNPG) in vivo and ex vivo to establish for the first time their expeditious therapeutic efficacy in improving survival of lipopolysaccharides (LPS)-treated mice, as achieved by the restoration of EG and recovery of endothelial function.

A Multidrug Delivery Microrobot for the Synergistic Treatment of Cancer.

Multidrug combination therapy provides an effective strategy for malignant tumor treatment. This paper presents the development of a biodegradable microrobot for on-demand multidrug delivery. By combining magnetic targeting transportation with tumor therapy, it is hypothesized that loading multiple drugs on different regions of a single magnetic microrobot can enhance a synergistic effect for cancer treatment. The synergistic effect of using two drugs together is greater than that of using each drug separately. Here, a 3D-printed microrobot inspired by the fish structure with three hydrogel components: skeleton, head, and body structures is demonstrated. Made of iron oxide (Fe3 O4 ) nanoparticles embedded in poly(ethylene glycol) diacrylate (PEGDA), the skeleton can respond to magnetic fields for microrobot actuation and drug-targeted delivery. The drug storage structures, head, and body, made by biodegradable gelatin methacryloyl (GelMA) exhibit enzyme-responsive cargo release. The multidrug delivery microrobots carrying acetylsalicylic acid (ASA) and doxorubicin (DOX) in drug storage structures, respectively, exhibit the excellent synergistic effects of ASA and DOX by accelerating HeLa cell apoptosis and inhibiting HeLa cell metastasis. In vivo studies indicate that the microrobots improve the efficiency of tumor inhibition and induce a response to anti-angiogenesis. The versatile multidrug delivery microrobot conceptualized here provides a way for developing effective combination therapy for cancer.

Combined endoscope and low-temperature plasma knife for bilateral nasal vestibular cyst with sinus tract formation.

BACKGROUND: Nasal vestibular cyst is a non-dental cystic mass that occurs under the skin at the base of the nasal vestibule. The primary treatment is a transnasal endoscopic excision of the cyst wall at the base of the nose to open the cyst wall at the base of the nasal cavity, namely, marsupialization. METHODS: We present a patient with bilateral nasal vestibular cysts with sinus tract formation. This patient underwent marsupialization under general anesthesia because of the presence of facial swelling and other symptoms. RESULTS: After a 4-year follow-up, our studied case show a significantly improved radiological outcome and clinical prognosis. CONCLUSIONS: Compared to unilateral lesions, bilateral nasal vestibular cysts are more likely to be underdiagnosed due to the deceptive nature of the bilateral anatomy observed from the radiological findings. With this rare clinical case reported in this study, we hope our experience in diagnosis and treatment will provide a reference for otolaryngologist surgeons managing similar patients.

Differential Mobility Spectrometry-Tandem Mass Spectrometry with Multiple Ion Monitoring Coupled with in Source-Collision Induced Dissociation: A New Strategy for the Quantitative Analysis of Pharmaceutical Polymer Excipients in Rat Plasma.

Polylactic acids (PLAs) are synthetic polymers composed of repeating lactic acid subunits. For their good biocompatibility, PLAs have been approved and widely applied as pharmaceutical excipients and scaffold materials. Liquid chromatography-tandem mass spectrometry is a powerful analytical tool not only for pharmaceutical ingredients but also for pharmaceutical excipients. However, the characterization of PLAs presents particular problems for mass spectrometry techniques. In addition to their high molecular weights and wide polydispersity, multiple charging and various adductions are intrinsic features of electrospray ionization. In the present study, a strategy combining of differential mobility spectrometry (DMS), multiple ion monitoring (MIM) and in-source collision-induced dissociation (in source-CID) has been developed and applied to the characterization and quantitation of PLAs in rat plasma. First, PLAs will be fragmented into characteristic fragment ions under high declustering potential in the ionization source. The specific fragment ions are then screened twice by quadrupoles to ensure a high signal intensity and low interference for mass spectrometry detection. Subsequently, DMS technique has been applied to further reduce the background noise. The appropriately chosen surrogate specific precursor ions could be utilized for the qualitative and quantitative analysis of PLAs, which provided results with the advantages of low endogenous interference, sufficient sensitivity and selectivity for bioassay. The linearity of the method was evaluated over the concentration range 3-100 µg/mL (r2 = 0.996) for PLA 20,000. The LC-DMS-MIM coupled with in source-CID strategy may contribute to the pharmaceutical studies of PLAs and the possible prospects of other pharmaceutical excipients.

Recent advances in the bioanalytical methods of polyethylene glycols and PEGylated pharmaceuticals.

Polyethylene glycols are synthetic polymers composed of repeating oxyethylene subunits, which have been known for non-toxic, non-immunogenic, non-antigenic, good solubility in water and therefore approved for pharmaceutical applications. Recently, attachment or amalgamation of polyethylene glycols to therapeutic small molecules, peptides, proteins, or nanoparticles has become a mature technology for the sake of improving their pharmacokinetic and pharmacological profiles, also referred to as PEGylation. By comparison, there are only a few PEGylated pharmaceuticals have been registered for further clinical trials and even less was approved for marketing. High failure rate of PEGylated pharmaceuticals in pre-clinical and clinical trials could be majorly attributed to their unclear pharmacokinetic behaviors. Therefore, the in vivo fate of the PEGylated pharmaceuticals for the various routes of administration needs to be thoroughly investigated An accurate in vivo pharmacological study thereof highly depends on the precise detection of polyethylene glycols as well as their fragments in biological matrixes. The goal of this review is to highlight the analytical methods that were developed and applied to evaluate the polyethylene glycols in pharmaceutical ingredients and excipients, which bring us closer to bridging the gap between the development of polyethylene glycol-based drug delivery systems and their clinical application.

Do I sound dry? Comparative voice analysis of primary Sjögren's syndrome.

OBJECTIVES: Desiccation of the vocal tract can cause many voice problems. Therefore, we aimed to investigate whether patients with primary Sjögren's syndrome (pSS) with dry mouth have more voice-related problems than controls without the disease and to determine the factors affecting voice in pSS patients. METHODS: Patients with pSS and controls complaining of voice-related symptoms underwent acoustic analysis, aerodynamic study and stroboscopic analysis. They also completed the voice handicap index (VHI) questionnaire and perceptual voice analysis (GRBAS). Various disease-related parameters were obtained from pSS registry data. RESULTS: Fifty-five pSS patients and 52 controls were analysed. The subjects were all female, and mean age was 53.9 years. VHI score was significantly higher in the pSS patient group (median [interquartile range], 11 [3-30] vs. 5.5 [0- 15.75], p=0.014). However, the results of acoustic analysis aerodynamic study and stroboscopic findings were not different between the two groups. Disease-related parameters were available in 47 pSS patients. Correlation analysis revealed that jitter value positively correlated with ESSDAI (spearman's rho = 0.29, p=0.048) and patient global assessment (rho=0.3, p= 0.04). High VHI score was associated with low quality of life measured by EQ5D (rho=-0.493, p=0.0001). Of note, patients with longer disease duration (≥ 40 months) showed higher noise-to-harmonics ratio (NHR). CONCLUSIONS: Patients with pSS had higher VHI score, which was associated with low quality of life and longer disease duration was associated with increased noise in pSS patients. The likelihood of voice problems should be addressed with pSS patients, and vocal hygiene education will be important in those patients.

Engineered bone scaffolds with Dielectrophoresis-based patterning using 3D printing.

Patterning of cells into a specific pattern is an important procedure in tissue engineering to facilitate tissue culture and ingrowth. In this paper, a new type of 3D-printed scaffold utilizing dielectrophoresis (DEP) for active cell seeding and patterning was proposed. This scaffold adopted a concentric-ring design that is similar to native bone tissues. The scaffold was fabricated with a commercial three-dimensional (3D) printer. Polylactic Acid (PLA) was selected as the material for the printer and the fabricated scaffold was coated with gold to enhance the conductivity for DEP manipulation. Simulation from COMSOL confirmed that non-uniform electric fields were successfully generated under a voltage input. The properties of the scaffold were first characterized through a series of experiments. Then, preosteoblast MC3T3-E1 cells were seeded onto the coated scaffold and multiple cellular rings were observed under the microscope. The biocompatibility of the material was also examined and mineralized bone nodules were detected using Alizarin Red S Staining after 28 days of culture. The proposed scaffold design can enable formation of multiple ring patterns via DEP and the properties of the scaffold are suitable for bone tissue culture. This new type of 3D-printed scaffold with cell seeding mechanism offers a new and rapid approach for fabricating engineered scaffolds that can arrange cells into different patterns for various tissue engineering applications.

Development of a Physiologically Relevant Population Pharmacokinetic in Vitro-in Vivo Correlation Approach for Designing Extended-Release Oral Dosage Formulation.

Establishing a level A in vitro-in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on population pharmacokinetic (POP-PK) modeling that incorporated physiologically relevant absorption kinetics. To prepare three extended release (ER) tablets of loxoprofen, three types of hydroxypropyl methylcellulose (HPMC 100, 4000, and 15000 cps) were used as drug release modifiers, while lactose and magnesium stearate were used as the diluent and lubricant, respectively. An in vitro dissolution test in various pH conditions showed that loxoprofen dissolution was faster at higher pH. The in vivo pharmacokinetics of loxoprofen was assessed following oral administration of the different loxoprofen formulations to Beagle dogs (n = 22 in total). Secondary peaks or shoulders were observed in many of the individual plasma concentration vs time profiles after ER tablet administration, which may result from secondary absorption in the intestine due to a dissolution rate increase under intestinal pH compared to that observed at stomach pH. In addition, in vivo oral bioavailability was found to decrease with prolonged drug dissolution, indicating site-specific absorption. Based on the in vitro dissolution and in vivo absorption data, a POP-PK IVIVC model was developed using S-ADAPT software. pH-dependent biphasic dissolution kinetics, described using modified Michaelis-Menten kinetics with varying Vmax, and site-specific absorption, modeled using a changeable absorbed fraction parameter, were applied to the POP-PK IVIVC model. To experimentally determine the biphasic dissolution profiles of the ER tablets, another in vitro dissolution test was conducted by switching dissolution medium pH based on an in vivo estimate of gastric emptying time. The model estimated, using linear regression, that in vivo initial maximum dissolution rate (Vmax(0)in vivo) was highly correlated (r2 > 0.998) with in vitro (Vmax(0)in vitro), indicating that in vivo dissolution profiles obtained from POP-PK modeling could be converted to in vitro dissolution profiles and vice versa. Monte Carlo simulations were performed for model validation, and prediction errors for Cmax and AUC were all within the acceptable range (90 to 110%) according to the FDA guidelines. The developed model was successfully applied for the prediction of in vivo pharmacokinetics of a loxoprofen double-layered tablet using the in vitro dissolution profile. In conclusion, a level A IVIVC approach was developed and validated using population modeling that accounted for pH-dependent dissolution and site-specific absorption. Excellent correlations were observed between in vitro and in vivo dissolution profiles. This new approach holds great promise for the establishment of IVIVCs for drug and formulation development where absorption kinetics strongly depend on complex physiologically absorption processes.

Effects of direct current electric fields on lung cancer cell electrotaxis in a PMMA-based microfluidic device.

Tumor metastasis is the primary cause of cancer death. Numerous studies have demonstrated the electrotactic responses of various cancer cell types, and suggested its potential implications in metastasis. In this study, we used a microfluidic device to emulate endogenous direct current electric field (dcEF) environment, and studied the electrotactic migration of non-small cell lung cancer cell lines (H460, HCC827, H1299, and H1975) and the underlying mechanisms. These cell lines exhibited greatly different response in applied dcEFs (2-6 V/cm). While H460 cells (large cell carcinoma) showed slight migration toward cathode, H1299 cells (large cell carcinoma) showed increased motility and dcEF-dependent anodal migration with cell reorientation. H1975 cells (adenocarcinoma) showed dcEF-dependent cathodal migration with increased motility, and HCC827 cells (adenocarcinoma) responded positively in migration speed and reorientation but minimally in migrating directions to dcEF. Activation of MAPK and PI3K signaling pathways was found to be associated with the realignment and directed migration of lung cancer cells. In addition, both Ca2+ influx through activated stretch-activated calcium channels (SACCs) (but not voltage-gated calcium channels, VGCCs) and Ca2+ release from intracellular storage were involved in lung cancer cell electrotactic responses. The results demonstrated that the microfluidic device provided a stable and controllable microenvironment for cell electrotaxis study, and revealed that the electrotactic responses of lung cancer cells were heterogeneous and cell-type dependent, and multiple signals contributed to lung cancer cells electrotaxis.

Transoral endoscopic thyroidectomy via the tri-vestibular routes: results of a preclinical cadaver feasibility study.

The concept of natural orifice transluminal endoscopic surgery (NOTES) is an emerging experimental alternative to conventional surgery that eliminates skin incisions using an endoscope passed through a natural orifice (e.g., mouth, urethra, or anus). This study was designed to evaluate the feasibility and safety of thyroid resection via an entirely transoral tri-vestibular route using endoscopy, and to introduce NOTES to the head and neck area of medicine. We performed ten complete endoscopic thyroid lobectomies with central lymph node dissection via a tri-vestibular approach in fresh-frozen cadavers. A 5-mm endoscope with a deflectable tip was used to visualize the surgical field. Three cannulas were inserted through the midline and bilateral incision sites in the vestibule to position the instruments and endoscope. We refined and described the surgical technique in each step using video clips. We identified and preserved neighboring critical structures during surgery. We also confirmed that there were no obvious remnant thyroid tissues and no injury to the neighboring structures after exploration. The transoral tri-vestibular approach seems to provide a good view and surgical field for endoscopic thyroidectomy. However, the transoral approach for thyroidectomy remains experimental, and the detailed surgical technique should be refined via further clinical studies.

Curved carbon-plated shoe may further reduce forefoot loads compared to flat plate during running.

Using a curved carbon-fiber plate (CFP) in running shoes may offer notable performance benefit over flat plates, yet there is a lack of research exploring the influence of CFP geometry on internal foot loading during running. The objective of this study was to investigate the effects of CFP mechanical characteristics on forefoot biomechanics in terms of plantar pressure, bone stress distribution, and contact force transmission during a simulated impact peak moment in forefoot strike running. We employed a finite element model of the foot-shoe system, wherein various CFP configurations, including three stiffnesses (stiff, stiffer, and stiffest) and two shapes (flat plate (FCFP) and curved plate (CCFP)), were integrated into the shoe sole. Comparing the shoes with no CFP (NCFP) to those with CFP, we consistently observed a reduction in peak forefoot plantar pressure with increasing CFP stiffness. This decrease in pressure was even more notable in a CCFP demonstrating a further reduction in peak pressure ranging from 5.51 to 12.62%, compared to FCFP models. Both FCFP and CCFP designs had a negligible impact on reducing the maximum stress experienced by the 2nd and 3rd metatarsals. However, they greatly influenced the stress distribution in other metatarsal bones. These CFP designs seem to optimize the load transfer pathway, enabling a more uniform force transmission by mainly reducing contact force on the medial columns (the first three rays, measuring 0.333 times body weight for FCFP and 0.335 for CCFP in stiffest condition, compared to 0.373 in NCFP). We concluded that employing a curved CFP in running shoes could be more beneficial from an injury prevention perspective by inducing less peak pressure under the metatarsal heads while not worsening their stress state compared to flat plates.

[Numerical simulation on cycle change form of the pressure and wall shear in human upper respiratory tract].

The research on cycle change form of the pressure and the wall shear in human upper respiratory tract can strengthen understanding of the characteristics of the airflow in the place and provide us with a scientific basis for analyzing the diffusion, transition and deposition patterns of aerosol there. In our study, we used large eddy simulation to emulate the pressure and wall shear in human upper respiratory tract in conditions of the low intensive respiratory patterns, and discussed the distributing disciplinarian of the pressure and wall shear in mouth-throat model and trachea-triple bifurcation. The results showed that the pressure gradient variation in human upper respiratory tract was mainly fastened from root of epiglottis to trachea. The minimum pressure at the interim of inspiration was a duplication of the interim of expiration, and located on the posterior wall of the glottis. The pressure gradient variation was evident on trachea and its fork. The wall shear changed with the velocity of the air flow, and its direction changed periodically with breath cycle.

Tuning the Poisson's ratio of poly(ethylene glycol) diacrylate/cellulose nanofibril aerogel scaffold precisely for cultivation of bone marrow mesenchymal stem cell.

Tissue engineering (TE) scaffolds with appropriate Poisson's ratio (PR) are suitable for mimicking the environment of native tissues on which cells could survive and thrive better. Herein, cellular structured scaffolds are made by a new composite poly(ethylene glycol) diacrylate/cellulose nanofibril aerogel, with prototypes of the hexagonal, reentrant, and semireentrant models. Scaffolds with different geometry parameters (l, t, α) are designed and simulated by COMSOL to enable precise regulation of their PR. Then, nine groups of scaffolds with different PRs ranging from -0.5 to 0.85 are designed by adjusting geometry parameters and fabricated by using stereolithography and freeze-drying techniques. Subsequently, bone marrow mesenchymal stem cells (BMSc) are cultured on these scaffolds for 21 days, during which CCK8 assay, fluorescence microscope observation, and real-time polymerase chain reaction experiments are performed to characterize the proliferation and differentiation of BMSc. The results reflect that the scaffolds with different PR can provide various stress environments for cells, and the scaffold with zero PR is the most suitable for BMSc differentiating into chondrocytes during early culture experiments. This study suggests that tuning PR precisely is an attractive and effective strategy to provide a cells-suitable environment for scaffold fabrication for TE.

Carbonized Polymer Dot Probe for Two-Photon Fluorescence Imaging of Lipid Droplets in Living Cells and Tissues.

As a dynamic and multifunctional organelle, lipid droplets (LDs) are essential in maintaining lipid balance and transducing biological signals. LD accumulation and catabolism are closely associated with energy metabolism and cell signaling. In order to easily trace LDs in living cells, a novel carbonized polymer dot (CPD)-based fluorescent nanoprobe is reported to serve the needs of LD-targeting imaging. This probe exhibits the advantages of excellent biocompatibility, simple preparation, good lipophilicity, and high compatibility with commercial dyes. Transient absorption spectroscopy was employed to discuss the luminescence mechanism of CPDs, and the results indicate that the excellent fluorescence property and the environment-responsive feature of our CPDs are derived from the intramolecular charge transfer (ICT) characteristics and the D-π-A structure that possibly formed in CPD. This nanoprobe is available for one-photon fluorescence (OPF) and two-photon fluorescence (TPF) imaging and is also practicable for staining LDs in living/fixed cells and lipids in tissue sections. The staining process is completed within several seconds, with no washing step. The intracellular LDs involving the intranuclear LDs (nLDs) can be selectively lit up. This probe is feasible for visualizing dynamic interactions among LDs, which suggests its great potential in revealing the secret of LD metabolism. The in situ TPF spectra were analyzed to determine surrounding microenvironment according to the polarity-responsive feature of our CPDs. This work expands the applications of CPDs in biological imaging, helps design new LD-selective fluorescent probes, and has implications for studying LD-related metabolism and diseases.

The influence of running shoe with different carbon-fiber plate designs on internal foot mechanics: A pilot computational analysis.

A carbon-fiber plate (CFP) embedded into running shoes is a commonly applied method to improve running economy, but little is known in regard the effects of CFP design features on internal foot mechanics. This study aimed to explore how systematic changes in CFP geometrical variations (i.e., thickness and location) can alter plantar pressure and strain under the forefoot as well as metatarsal stress state through computational simulations. A foot-shoe finite element (FE) model was built and different CFP features including three thicknesses (1 mm, 2 mm, and 3 mm) and three placements (high-loaded (just below the insole), mid-loaded (in between the midsole), and low-loaded (just above the outsole)) were further modulated within the shoe sole. Simulations were conducted at the impact peak instant during forefoot strike running. Compared with the no-CFP shoe, peak plantar pressure and compressive strain under the forefoot consistently decreased when the CFP thickness increased, and the low-loaded conditions were found more effective (peak pressure decreased up to 31.91% and compressive strain decreased up to 18.61%). In terms of metatarsal stress, CFP designs resulted in varied effects and were dependent on their locations. Specifically, high-loaded CFP led to relatively higher peak metatarsal stress without the reduction trend as thickness increased (peak stress increased up to 12.91%), while low-loaded conditions showed a gradual reduction in peak stress, decreasing by 0.74%. Therefore, a low-loaded thicker CFP should be considered to achieve the pressure-relief effects of running shoes without the expense of increased metatarsal stress.

Therapeutic effects of clonazepam in patients with burning mouth syndrome and various symptoms or psychological conditions.

Burning mouth syndrome (BMS) is frequently accompanied by dysgeusia and xerostomia. Clonazepam has been widely prescribed and is effective, but it is unclear whether clonazepam also affects the symptoms that accompany BMS, or whether such symptoms affect treatment outcomes. Here, we investigated the therapeutic outcomes in BMS patients with various symptoms or comorbidities. We retrospectively reviewed 41 patients diagnosed with BMS between June 2010 and June 2021 at a single institution. Patients were instructed to take clonazepam for 6 weeks. Before the first dose, burning pain intensity was measured using a visual analog scale (VAS); the unstimulated salivary flow rate (USFR), psychologic characteristics, site(s) of pain, and any taste disturbance were evaluated. Burning pain intensity was measured again after 6 weeks. Thirty-one of the 41 patents (75.7%) exhibited a depressed mood, whereas more than 67.8% of the patients exhibited anxiety. Subjective xerostomia was reported by ten patients (24.3%). The mean salivary flow rate was 0.69 mL/min and hyposalivation (an unstimulated salivary flow rate ≤ 0.5 mL/min) was apparent in ten patients (24.3%). Dysgeusia was present in 20 patients (48.7%); a bitter taste (n = 15, 75%) was reported by the largest proportion of patients. Patients who reported a bitter taste responded best in terms of burning pain reduction after 6 weeks (n = 4, 26.6%). Overall, 32 patients (78%) reported decreased oral burning pain after clonazepam (mean VAS score changed from 6.56 to 5.34) use. Patients who reported taste disturbances exhibited a significantly greater decrease in burning pain, compared with other patients (mean VAS score changed from 6.41 to 4.58) (p = 0.02). Clonazepam significantly improved burning pain in BMS patients who had taste disturbances.

CYP2C29 produces superoxide in response to shear stress.

OBJECTIVE: Activation of CYP2C29 releases superoxide during shear stress-induced dilation (SSID). METHODS: Mesenteric arteries isolated from female eNOS-KO and WT mice were cannulated and pressurized. Vasodilation and superoxide production in response to shear stress were assessed. RESULTS: Shear stress-induced dilation was significantly attenuated in vessels of eNOS-KO compared with WT mice, which was normalized by tempol and PEG-Catalase, in a PPOH (inhibitor of CYP2C29)-sensitive manner, but remained unaffected by VAS2870 and allopurinol, inhibitors of NADPH oxidase and xanthine oxidase, respectively. NaNO(2)-induced dilation was comparable in both strains of mice. Confocal microscopy shows that SS-stimulated superoxide was increased particularly in the endothelium of eNOS-KO mice. HPLC analysis of 2-EOH indicated an increase in SS-stimulated superoxide in vessels of eNOS-KO mice, a response that was sensitive to PPOH. Inhibition of soluble epoxide hydrolase significantly enhanced SSID without affecting SS-stimulated superoxide production. CYP2C29 and catalase were upregulated, and exogenous H(2)O(2) caused vasoconstriction in vessels of eNOS-KO mice. CONCLUSIONS: CYP2C29 synthesizes EETs to mediate SSID, and simultaneously releases superoxide and sequential H(2)O(2), which in turn impair SSID.