DNA-inspired nanomaterials for enhanced endosomal escape.

To realize RNA interference (RNAi) therapeutics, it is necessary to deliver therapeutic RNAs (such as small interfering RNA or siRNA) into cell cytoplasm. A major challenge of RNAi therapeutics is the endosomal entrapment of the delivered siRNA. In this study, we developed a family of delivery vehicles called Janus base nanopieces (NPs). They are rod-shaped nanoparticles formed by bundles of Janus base nanotubes (JBNTs) with RNA cargoes incorporated inside via charge interactions. JBNTs are formed by noncovalent interactions of small molecules consisting of a base component mimicking DNA bases and an amino acid side chain. NPs presented many advantages over conventional delivery materials. NPs efficiently entered cells via macropinocytosis similar to lipid nanoparticles while presenting much better endosomal escape ability than lipid nanoparticles; NPs escaped from endosomes via a "proton sponge" effect similar to cationic polymers while presenting significant lower cytotoxicity compared to polymers and lipids due to their noncovalent structures and DNA-mimicking chemistry. In a proof-of-concept experiment, we have shown that NPs are promising candidates for antiviral delivery applications, which may be used for conditions such as COVID-19 in the future.

Comparing the accuracies of freehand, static computer-assisted and robot-assisted dental implant placements: an in vitro study.

OBJECTIVE: To compare the accuracies among three oral implant surgical techniques: freehand (FH), static computer-assisted implant surgery (sCAIS), and robotic computer-assisted implant surgery (rCAIS). METHODS: The polyurethane and bovine femur implant models were fabricated, and 126 and 96 implant sites were designed on them. The implant sites were divided into three groups: FH, sCAIS, and rCAIS, according to the implantation method. The deviation between the actual implant position and the planned position was analyzed and compared by cone beam computed tomography. RESULTS: In the polyurethane model test, the entry deviation, entry-level deviation, apical deviation, apical level deviation, and angle deviation in sCAIS and rCAIS groups were significantly reduced compared with those in the FH group (P<0.05). No significant differences were observed in all kinds of deviations between the sCAIS and rCAIS groups (P>0.05). In the bovine femur model test, the entry deviation, entry-level deviation, apical deviation, apical level deviation, and angle deviation in both sCAIS and rCAIS groups were significantly reduced compared with those in the FH group (P<0.05). No significant differences were observed in all kinds of deviations between the sCAIS and rCAIS groups (P>0.05). CONCLUSION: This in vitro study shows that the rCAIS technique is superior to the freehand, but has the same accuracy as the sCAIS.

A structural and functional comparison between two recombinant human lubricin proteins: Recombinant human proteoglycan-4 (rhPRG4) vs ECF843.

Proteoglycan 4 (PRG4, lubricin) is a mucin-like glycoprotein present on the ocular surface that has both boundary lubricating and anti-inflammatory properties. Full-length recombinant human PRG4 (rhPRG4) has been shown to be clinically effective in improving signs and symptoms of dry eye disease (DED). In vitro, rhPRG4 has been shown to reduce inflammation-induced cytokine production and NFκB activity in corneal epithelial cells, as well as to bind to and inhibit MMP-9 activity. A different form of recombinant human lubricin (ECF843), produced from the same cell line as rhPRG4 but manufactured using a different process, was recently assessed in a DED clinical trial. However, ECF843 did not significantly improve signs or symptoms of DED compared to vehicle. Initial published characterization of ECF843 showed it had a smaller hydrodynamic diameter and was less negatively charged than native PRG4. Further examination of the structural and functional properties of ECF843 and rhPRG4 could contribute to the understanding of what led to their disparate clinical efficacy. Therefore, the objective of this study was to characterize and compare rhPRG4 and ECF843 in vitro, both biophysically and functionally. Hydrodynamic diameter and charge were measured by dynamic light scattering (DLS) and zeta potential, respectively. Size and molecular weight was determined for individual species by size exclusion chromatography (SEC) with in-line DLS and multi-angle light scattering (MALS). Bond structure was measured by Raman spectroscopy, and sedimentation properties were measured by analytical ultracentrifugation (AUC). Functionally, MMP-9 inhibition was measured using a commercial MMP-9 activity kit, coefficient of friction was measured using an established boundary lubrication test at a latex-glass interface, and collagen 1-binding ability was measured by quart crystal microbalance with dissipation (QCMD). Additionally, the ability of rhPRG4 and ECF843 to inhibit urate acid crystal formation and cell adhesion was assessed. ECF843 had a significantly smaller hydrodynamic diameter and was less negatively charged than rhPRG4, as assessed by DLS and zeta potential. Size was further explored with SEC-DLS-MALS, which indicated that while rhPRG4 had 3 main peaks, corresponding to monomer, dimer, and multimer as expected, ECF843 had 2 peaks that were similar in size and molecular weight compared to rhPRG4's monomer peak and a third peak that was significantly smaller in both size and molar mass than the corresponding peak of rhPRG4. Raman spectroscopy demonstrated that ECF843 had significantly more disulfide bonds, which are functionally determinant structures, relative to the carbon-carbon backbone compared to rhPRG4, and AUC indicated that ECF843 was more compact than rhPRG4. Functionally, ECF843 was significantly less effective at inhibiting MMP-9 activity and functioning as a boundary lubricant compared to rhPRG4, as well as being slower to bind to collagen 1. Additionally, ECF843 was significantly less effective at inhibiting urate acid crystal formation and at preventing cell adhesion. Collectively, these data demonstrate ECF843 and rhPRG4 are significantly different in both structure and function. Given that a protein's structure sets the foundation for its interactions with other molecules and tissues in vivo, which ultimately determine its function, these differences most likely contributed to the disparate DED clinical trial results.

Effectiveness of different antithrombotic agents in combination with tranexamic acid for venous thromboembolism prophylaxis and blood management after total knee replacement: a prospective randomized study.

BACKGROUND: Tranexamic acid (TXA) has been widely applied in total knee arthroplasty (TKA) to significantly reduce perioperative blood loss and improve knee function recovery in patients after surgery. The choice of antithrombotic agents for venous thromboembolism (VTE) prevention after TKA is controversial. Therefore, this study aimed to compare the effects of different antithrombotic agents on patients after primary unilateral TKA in the context of applied TXA. METHODS: A total of 180 patients undergoing primary unilateral TKA from October 2020 to December 2021 were included in this study. All patients were given an intraoperative drip of 60 mg/kg TXA. Thereafter, patients were divided into three groups (n = 60 each). Baseline data were comparable among the three groups. The average follow-up time was 3.02 ± 0.09 months. Group 1 enrolled patients receiving oral rivaroxaban (RA) at 10 mg, Group 2 included patients who received subcutaneous Dalteparin sodium at 2500 IU, while Group 3 included patients taking oral aspirin (ASA) at 100 mg. Patients in all the three groups received treatment once a day for 30 days at 12 h postoperatively. The primary outcomes in this study were post-treatment drainage volume and thrombotic complication rate. The secondary outcomes included hematologic parameters, transfusion rate, intraoperative blood loss, total blood loss (TBL), and bleeding complication rate. RESULTS: The average drainage volume after treatment was significantly lower in Group 3 than in Group 1 and Group 2 (205.2 ± 69.0 vs 243.4 ± 72.5 vs 295.4 ± 72.5 ml, P < 0.001), and there was a significant difference between Group 1 and Group 2 (243.4 ± 72.5 mL vs 295.4 ± 72.5 mL, P < 0.001). The blood transfusion rate of Group 2 dramatically increased compared with Group 1 and Group 3 (20.0% vs 6.7% vs 5.0%, P = 0.01). The bleeding complication rate in Group 1 apparently increased relative to Group 2 and Group 3 (26.7% vs 10.0% vs 8.3%, P = 0.008). Besides, there was no significant difference in the thrombotic complication rate among the three groups. CONCLUSION: Under the background of TXA application, ASA, RA, and Dalteparin sodium were all effective on preventing VTE after TKA. In addition, ASA effectively reduced post-treatment Hemoglobin (Hb) loss, drainage volume, TBL, transfusion rate, and bleeding complications compared with RA and Dalteparin sodium. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200060169). Date of Registration: 21/05/2022.

Accuracy of an optical robotic computer-aided implant system and the trueness of virtual techniques for measuring robot accuracy evaluated with a coordinate measuring machine in vitro.

STATEMENT OF PROBLEM: A unified standard for measuring robot implantation errors has not yet been established. A coordinate measuring machine (CMM) measures the coordinates of an object with high accuracy. However, evaluations of the accuracy of a robotic computer-assisted implant system (R-CAIS) using CMM are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the accuracy of an optics-based R-CAIS using a CMM and to assess the accuracy of cone beam computed tomography (CBCT), a laboratory scanner (LS), and an intraoral scanner (IOS) in measuring the accuracy of the R-CAIS. MATERIAL AND METHODS: Two 60×50×40-mm cubic models were prepared for the experiment. One master model and several replica models were used for the first part. Employing a robotic system software, virtual planning was performed on the digital imaging and communications in medicine (DICOM) image of the master model, and spatial mapping was performed by using an optical tracking marker (OT-marker) to ensure that virtual planning of the master model could be executed when replica casts were drilled and placed the implants. The actual placements of the implants in the replica casts were measured by using CMM. The errors between the actual and virtual-planned positions were calculated. In the second part, virtual planning was performed on the experimental model, and an optics-based R-CAIS was used to drill holes and place the implants. The actual positions of the implants were measured by using CMM, CBCT, LS, and IOS. The errors between the actual and virtual-planned positions were calculated, and the error results among groups were compared by 1-way analysis of variance or a nonparametric test. The Dunnett test was used for post hoc comparison (α=.05). RESULTS: In the first part, the entry, apical, and angle deviations were 0.33 ±0.10 mm, 0.41 ±0.11 mm, and 0.33 ±0.13 degrees, respectively. In the second part, as compared with CMM, no statistically significant differences were observed in the LS group (P>.05), whereas significant differences were observed in entry-depth, entry, apical-depth, apical, and angle deviations in the IOS group, as well as in entry-depth and apical-depth deviations in the CBCT group (all P<.05). CONCLUSIONS: The optical-based R-CAIS exhibited high accuracy. The application of CBCT for clinical implantation may be close to that of the true deviation.

High porosity 3D printed titanium mesh allows better bone regeneration.

BACKGROUND: Most patients with insufficient bone mass suffer from severe horizontal or vertical bone defects in oral implant surgery. The purpose of this study was to compare the bone regeneration effects of titanium meshes with different porosity in the treatment of bone defects. METHODS: Nine beagle dogs were equally divided into three groups based on execution time. Three months after the extraction of the first to fourth premolars of the mandible, three bone defects were randomly made in the mandible. Bone particles and three kinds of three-dimensional (3D) printed titanium nets with different porosities (low porosity group (LP), 55%; medium porosity group (MP), 62%; and high porosity group (HP), 68%) were replanted in situ. The beagles were killed 4, 8, and 12 weeks after surgery. Formalin-fixed specimens were embedded in acrylic resin. The specimens were stained with micro-CT, basic fuchsin staining, and toluidine blue staining. RESULTS: Micro-CT analysis showed that the trabecular thickness, trabecular number, and bone volume fraction of the HP group were higher than those of the other two groups. Moreover, the trabecular separation of the HP group decreased slightly and was lower than that of the MP and LP groups. Histological staining analysis showed that the trabecular number in the HP group was higher than in the other two groups at 8 and 12 weeks, and the bone volume fraction of the HP was higher than that in the other two groups at 12 weeks. Moreover, the trabecular thickness of the MP was higher than that of the LP group at 12 weeks and the trabecular separation was lower in the HP group at 4 and 8 weeks. The differences were statistically significant (p < 0.05). CONCLUSION: A 3D printed titanium mesh with HP in a certain range may have more advantages than a titanium mesh with LP in repairing large bone defects.

Ultra-low noise phase measurement of fiber optic sensors via weak value amplification.

The noise floor is a vital specification that determines the minimum detectable signal in the phase measurement. However, the noise floor in optical phase measurement conducted via conventional optical interferometry tends to approach the intrinsic limit. In this study, a low noise phase measurement of a fiber optic sensor conducted via weak value amplification is experimentally demonstrated. The system has a flat, wideband frequency response from 0.1 Hz to 10 kHz, as well as adequate linearity. The operating band is wider than the present sensor using the same mechanism. In particular, the system noise floor is measured to be -98 dB at 1 Hz and -155 dB at 1 kHz. The results indicate that the minimum detectable signal can reach as low as 5.6 × 10-6 rad at 1 Hz and 8 × 10-9 rad at 1 kHz. In addition, it is demonstrated that the noise result of the proposed system is two-order of magnitude lower than that of the typical interferometric fiber optic sensors through the comparison experiment. With the characteristic of low-noise, the system is promising in the field of weak signal detection such as underwater acoustic signal detection, seismic wave detection, and mineral resource exploration.

Effect of Exposure Rates With Customized Versus Conventional Titanium Mesh on Guided Bone Regeneration: Systematic Review and Meta-Analysis.

Titanium mesh exposure is the main complication of bone regeneration. In this study, a meta-analysis was performed to clarify the effect of customized titanium mesh versus conventional titanium mesh complications and the time of mesh exposure on edentulous alveolar ridge guided bone regeneration (GBR). Databases, including PubMed, EMBASE, Web of Science, and Cochrane Central Register Controlled Trials, were searched by 2 independent reviewers to retrieve articles published from January 2010 to March 2020, regarding the incidence of complications after GBR surgery, with language limited to English articles. A total of 705 articles were found, and 9 articles were quantitatively analyzed. A funnel plot was made for 10 comprehensive data sets. The combined value of the total exposure rate of titanium mesh was 0.44 (44%, 95% CI = 0.30∼0.58). The results of subgroup analysis showed that the combined value of the customized titanium mesh exposure rate was 0.31 (31%, 95% CI = 0.15∼0.51), and the combined value of the conventional titanium mesh exposure rate was 0.51 (51%, 95% CI = 0.33∼0.69). Based on the findings of the present study, the exposure rate of customized titanium mesh is lower than that of conventional titanium mesh. The design of three-dimensional printing customized titanium mesh avoids nerves and blood vessels, which is of great significance to improve the accurate reconstruction of GBR and provides enough space for implantation and reducing the exposure rate. Soft tissue management (ie, technical sensitivity) is also an important factor to avoid soft tissue fractures.

Circ-PTK2 promotes the proliferation and suppressed the apoptosis of acute myeloid leukemia cells through targeting miR-330-5p/FOXM1 axis.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by malignant clonal disorder of blood cells with high relapse rate and low survival rate. Circular RNAs (circRNAs) have shown their important regulatory roles in AML progression. Here, we intended to disclose the role of circular RNA protein tyrosine kinase 2 (circ-PTK2) in the progression of AML and illustrate the potential working mechanisms. METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay were conducted to analyze cell proliferation ability, and the apoptosis rate was assessed by flow cytometry. Dual-luciferase reporter assay was used to validate the direct interaction between microRNA-330-5p (miR-330-5p) and circ-PTK2 or forkhead box M1 (FOXM1). RESULTS: Circ-PTK2 was highly expressed in AML. Circ-PTK2 interference suppressed the proliferation and triggered the apoptosis of AML cells. Circ-PTK2 directly bound to miR-330-5p. Si-circ-PTK2-mediated inhibition on the malignant behaviors of AML cells was partly counteracted by the addition of anti-miR-330-5p. MiR-330-5p directly interacted with FOXM1 messenger RNA (mRNA), and FOXM1 overexpression partly reversed miR-330-5p-induced influence in AML cells. Circ-PTK2 up-regulated FOXM1 expression through sponging miR-330-5p in AML cells. CONCLUSION: Circ-PTK2 promoted the proliferation and hampered the apoptosis of AML cells through targeting miR-330-5p/FOXM1 axis.

Therapeutic Considerations and Conjugated Polymer-Based Photosensitizers for Photodynamic Therapy.

Conjugated polymers have recently attracted a great deal of attention for applications in photodynamic therapy (PDT) because of their light-harvesting capability, efficient energy transfer, and singlet oxygen generation properties. This review describes recent advances in PDT development, including therapeutic mechanisms of PDT in cancer treatments, light excitation methods, and especially recent advances of conjugated polyelectrolytes and conjugated polymer nanoparticles as photosensitizers. The future direction on PDT and further development of conjugated polymer photosensitizers are discussed. The aim of this review is to stimulate innovative ideas to synthesize a new generation of conjugated polymer photosensitizers and promote their translation to clinical applications of PDT.

[Anti-HBs persistence after revaccination with three doses of hepatitis B vaccines among non-responsive adults: 24-month of follow-up].

OBJECTIVE: To access the antibody persistence 24-month after revaccination with 3-dose of hepatitis B vaccine (HepB) among non-response adults. METHODS: A total of 24 237 healthy adults who had no histories of hepatitis B infection and hepatitis B vaccination, resided in the local area for more than six months and were aged 18-49 years were selected from 79 villages of Zhangqiu county, Shandong province, China in 2009. Blood samples were obtained and hepatitis B surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were detected using ELISA method. A total of 11 590 persons who were negative for all of these indicators were divided into four groups by cluster sampling methods. Each group was vaccinated with one of the following four types of HepB at 0-, 1-, 6-months schedule: 20 µg HepB derived in Saccharomyces Cerevisiae (HepB-SC), 20 µg HepB derived in Chinese hamster ovary cell (HepB-CHO), 10 µg HepB-SC and 10 µg HepB derived in Hansenula Polymorpha (HepB-HP). Blood samples were collected one month after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay (CMIA). The non-responders were revaccinated with three doses of HepB at 0-, 1-, 6-months schedule and the type of HepB was the same as which was used for primary immunization. Blood samples were collected one month (T1) and two years (T24) after revaccination and anti-HBs, antibody against hepatitis B core antigen (anti-HBc) and hepatitis B surface angtigen (HBsAg) (if anti-HBs < 10 mU/ml) were detected by CMIA. χ(2) test was used to compared age, gender and body mass index (BMI) between different groups and the anti-HBs positive rate at T1 and T24; analysis of variance (ANOVA) was used to compare the geometric mean concentration (GMC) of anti-HBs between difference groups. The risk factors associated with positive rate of anti-HBs and GMC of anti-HBs were identified by multiple logistic regression analysis and multifactor linear regression model analysis respectively. RESULTS: A total of 900 non-responders were identified and 71.7% (645/900) of them completed three-dose revaccination and blood collection after revaccination. 467 (72.4%) non-responsive adults were followed up at T24. The anti-HBs positive rate decreased from 85.65% (95% CI: 82.14%-88.71%) at T1 to 60.60% (95% CI: 56.01%-65.06%) at T24 and the corresponding GMC decreased from 175.62 (95% CI: 139.03-221.84) mU/ml to 21.43 (95% CI: 17.62-26.06) mU/ml. Multivariate analysis showed that positive rate of anti-HBs at T24 was associated with gender, HepB type for revaccination and anti-HBs level at T1, but only anti-HBs level at T1 was associated with the anti-HBs titer at T24. No subject showed HBsAg seroconversion and anti-HBc conversion rate was 3.64% (17/467) at T24. CONCLUSION: Anti-HBs titer decreases rapidly two years after HepB revaccination among non-responsive adults, but more than half non-responderd still kept anti-HBs above protective level. The immunity durability after revaccination was associated with gender, HepB type for revaccination and anti-HBs titer one month after revaccination.

[Antibody persistence following booster vaccination with three doses of hepatitis B vaccines among low-response adults in Zhangqiu county of Shandong province: 24-month of follow-up from 2009].

OBJECTIVE: To assess the 24-month efficacy after booster vaccination with 3 doses of hepatitis B vaccine among low-response adults in Zhangqiu county of Shandong province. METHODS: A total of 24 237 adults aged 18-49 years old, never received HepB vaccination, without HBV infection history, and had been living at 3 towns of Zhangqiu county in Shandong province for more than half a year in september, 2009, were collected blood samples of 3-5 ml. A total of 11 590 adults who were negative for hepatitis B virus (HBV) surface antigen (HBsAg) , antibody to HBsAg (Anti-HBs) and antibody to HBV core antigen (Anti-HBc), were divided into four groups randomly and were vaccinated following the schedule of 0-1-6 with 20 µg hepatitis B vaccine made by recombinant deoxyribonucleic acid techniques in Saccharomyces cerevisiae (HepB-SC), 20 µg hepatitis B vaccine made by Chinese hamster ovary cell (HepB-CHO), 10 µg HepB-SC and 10 µg hepatitis B vaccine made by recombinant deoxyribonucleic acid techniques in Hansenula Polymorpha (HepB-HP), respectively. The adults who were low-response to the primary hepatitis B vaccination (10 mU/ml ≤ anti-HBs<100 mU/ml) were divided into four groups by cluster random sampling. These groups were revaccinated with 3-dose of above-mentioned four kinds of HepB respectively. Blood samples were drawn from 1 month (T1) and 24 month (T24) after the 3 dose revaccination, respectively. Anti-HBs and anti-HBc was detected by Chemiluminescence Microparticle Imunoassay (CMIA). RESULTS: Out of the 8 592 adults who have accepted the primary vaccination of hepatitis B and been collected the blood samples, 1 306 subjects showed low-response. A total of 718 low-response subjects were collected blood samples after T1 and T24 following 3 doses of booster vaccination. The proportion of the four groups was 32.3% (232/718), 25.8% (185/718) , 19.3% (139/718) , 22.6% (162/718) , respectively. The average proportion of anti-HBs ≥ 100 mIU/ml were decreased from 77.58% after T1 to 35.63% after T24 (χ² = 256.87, P < 0.01). The proportion of anti-HBs ≥ 100 mIU/ml in T24 were 38.8% (90/177), 39.5% (73/185), 25.2% (35/139) and 35.8% (58/162) in four groups, respectively. The proportion of anti-HBs>100 mIU/ml in T24 was significantly different among groups (χ² = 8.81, P = 0.032). The average geometric mean concentration (GMC) was significantly reduced from 443.53 mIU/ml after T1 to 48.98 mIU/ml after T24 (F = 439.41, P < 0.01). The GMC was 60.26 (45.71-77.62), 1.29 (38.90-69.18) , 35.48 (25.70-48.98) and 46.77 (33.88-6.07) mIU/ml in four groups, respectively (F = 1.97, P = 0.117) . Compared with vaccinated 20 µg HepB-SC, the proportion of anti-HBs ≥ 100 mIU/ml and GMC was 0.56 (0.35-0.91) and -0.20 (-0.39--0.02) times. The positive of HBsAg was not found and the positive rate of anti-HBc was 2.6% (18/692) in T24. CONCLUSION: Protective antibody following booster vaccination with three doses of hepatitis B vaccines among low-response adults after 2 years fade faster. Antibody level of anti-HBs in T24 was corrected with the booster vaccine type and age. 20 µgHepB-SC seemed better than 10 µg HepB-SC.

Effects of endoplasmic reticulum stress on chondrocyte apoptosis via the PI3K/AKT signaling pathway.

Chondrocytes undergo endoplasmic reticulum stress (ERS)-induced apoptosis under abnormal stimulation. However, the underlying molecular mechanism remains unclear. We investigated the regulatory effect of the PI3K/AKT signaling pathway on ERS and its effect on chondrocyte apoptosis. In addition, we established a unilateral anterior crossbite (UAC) model in rats to induce temporomandibular joint osteoarthritis (TMJOA). Chondrocytes were isolated from the temporomandibular joints and treated with lipopolysaccharide (LPS) in vitro. Protein expression of ERS and apoptosis markers (GRP78 and CASP12) was analyzed by immunohistochemistry and western blotting. The expression of GRP78, CASP12, p-PI3K, and p-AKT significantly increased in the UAC group. LY294002, a PI3K/AKT signaling pathway inhibitor, reduced the protein expression of GRP78, ATF4, CHOP, and CASP12, whereas 740 Y-P, an activation agent, elevated the expression of proteins GRP78, ATF4, CHOP, and CASP12. In the present study, UAC and LPS stimulation induced apoptosis of chondrocytes in the ERS pathway. Inhibition of the PI3K/AKT signaling pathway reduced ERS-induced chondrocyte apoptosis.

Bone and Extracellular Signal-Related Kinase 5 (ERK5).

Bones are vital for anchoring muscles, tendons, and ligaments, serving as a fundamental element of the human skeletal structure. However, our understanding of bone development mechanisms and the maintenance of bone homeostasis is still limited. Extracellular signal-related kinase 5 (ERK5), a recently identified member of the mitogen-activated protein kinase (MAPK) family, plays a critical role in the pathogenesis and progression of various diseases, especially neoplasms. Recent studies have highlighted ERK5's significant role in both bone development and bone-associated pathologies. This review offers a detailed examination of the latest research on ERK5 in different tissues and diseases, with a particular focus on its implications for bone health. It also examines therapeutic strategies and future research avenues targeting ERK5.

Computation-aided Design of Rod-Shaped Janus Base Nanopieces for Improved Tissue Penetration and Therapeutics Delivery.

Despite the development of various drug delivery technologies, there remains a significant need for vehicles that can improve targeting and biodistribution in "hard-to-penetrate" tissues. Some solid tumors, for example, are particularly challenging to penetrate due to their dense extracellular matrix (ECM). In this study, we have formulated a new family of rod-shaped delivery vehicles named Janus base nanopieces (Rod JBNps), which are more slender than conventional spherical nanoparticles, such as lipid nanoparticles (LNPs). These JBNp nanorods are formed by bundles of DNA-inspired Janus base nanotubes (JBNts) with intercalated delivery cargoes. To develop this novel family of delivery vehicles, we employed a computation-aided design (CAD) methodology that includes molecular dynamics and response surface methodology. This approach precisely and efficiently guides experimental designs. Using an ovarian cancer model, we demonstrated that JBNps markedly improve penetration into the dense ECM of solid tumors, leading to better treatment outcomes compared to FDA-approved spherical LNP delivery. This study not only successfully developed a rod-shaped delivery vehicle for improved tissue penetration but also established a CAD methodology to effectively guide material design.

The positive relationship between androgen receptor splice variant-7 expression and the risk of castration-resistant prostate cancer: A cumulative analysis.

Background: At present, androgen deprivation therapy (ADT) is still the standard regimen for patients with metastatic and locally advanced prostate cancer (PCa). The level of androgen receptor splice variant-7 (AR-V7) in men with castration-resistant prostate cancer (CRPC) has been reported to be elevated compared with that in patients diagnosed with hormone-sensitive prostate cancer (HSPC). Aim: Herein, we performed a systematic review and cumulative analysis to evaluate whether the expression of AR-V7 was significantly higher in patients with CRPC than in HSPC patients. Methods: The commonly used databases were searched to identify the potential studies reporting the level of AR-V7 in CRPC and HSPC patients. The association between CRPC and the positive expression of AR-V7 was pooled by using the relative risk (RR) with the corresponding 95% confidence intervals (CIs) under a random-effects model. For detecting the potential bias and the heterogeneity of the included studies, sensitivity analysis and subgroup analysis were performed. Publication bias was assessed Egger's and Begg's tests. This study was registered on PROSPERO (ID: CRD42022297014). Results: This cumulative analysis included 672 participants from seven clinical trials. The study group contained 354 CRPC patients, while the other group contained 318 HSPC patients. Pooled results from the seven eligible studies showed that the expression of positive AR-V7 was significantly higher in men with CRPC compared to those with HSPC (RR = 7.55, 95% CI: 4.61-12.35, p < 0.001). In the sensitivity analysis, the combined RRs did not change substantially, ranging from 6.85 (95% CI: 4.16-11.27, p < 0.001) to 9.84 (95% CI: 5.13-18.87, p < 0.001). In the subgroup analysis, a stronger association was detected in RNA in situ hybridization (RISH) measurement in American patients, and those studies were published before 2011 (all p < 0.001). There was no significant publication bias identified in our study. Conclusion: Evidence from the seven eligible studies demonstrated that patients with CRPC had a significantly elevated positive expression of AR-V7. More investigations are still warranted to clarify the association between CRPC and AR-V7 testing. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022297014.

Event-triggered adaptive optimal tracking control for nonlinear stochastic systems with dynamic state constraints.

This paper investigates the issue of event-triggered adaptive optimal tracking control for uncertain nonlinear systems with stochastic disturbances and dynamic state constraints. To handle the dynamic state constraints, a novel unified tangent-type nonlinear mapping function is proposed. A neural networks (NNs)-based identifier is designed to cope with the stochastic disturbances. By utilizing adaptive dynamic programming (ADP) of identifier-actor-critic architecture and event triggering mechanism, the adaptive optimized event-triggered control (ETC) approach for the nonlinear stochastic system is first proposed. It is proven that the designed optimized ETC approach guarantees the robustness of the stochastic systems and the semi-globally uniformly ultimately bounded in the mean square of the NNs adaptive estimation error, and the Zeno behavior can be avoided. Simulations are offered to illustrate the effectiveness of the proposed control approach.

Development of a TGF-ß signaling-related genes signature to predict clinical prognosis and immunotherapy responses in clear cell renal cell carcinoma.

Background: Transforming growth factor (TGF)-ß signaling is strongly related to the development and progression of tumor. We aimed to construct a prognostic gene signature based on TGF-ß signaling-related genes for predicting clinical prognosis and immunotherapy responses of patients with clear cell renal cell carcinoma (ccRCC). Methods: The gene expression profiles and corresponding clinical information of ccRCC were collected from the TCGA and the ArrayExpress (E-MTAB-1980) databases. LASSO, univariate and multivariate Cox regression analyses were conducted to construct a prognostic signature in the TCGA cohort. The E-MTAB-1980 cohort were used for validation. Kaplan-Meier (K-M) survival and time-dependent receiver operating characteristic (ROC) were conducted to assess effectiveness and reliability of the signature. The differences in gene enrichments, immune cell infiltration, and expression of immune checkpoints in ccRCC patients showing different risks were investigated. Results: We constructed a seven gene (PML, CDKN2B, COL1A2, CHRDL1, HPGD, CGN and TGFBR3) signature, which divided the ccRCC patients into high risk group and low risk group. The K-M analysis indicated that patients in the high risk group had a significantly shorter overall survival (OS) time than that in the low risk group in the TCGA (p < 0.001) and E-MTAB-1980 (p = 0.012). The AUC of the signature reached 0.77 at 1 year, 0.7 at 3 years, and 0.71 at 5 years in the TCGA, respectively, and reached 0.69 at 1 year, 0.72 at 3 years, and 0.75 at 5 years in the E-MTAB-1980, respectively. Further analyses confirmed the risk score as an independent prognostic factor for ccRCC (p < 0.001). The results of ssGSEA that immune cell infiltration degree and the scores of immune-related functions were significantly increased in the high risk group. The CIBERSORT analysis indicated that the abundance of immune cell were significantly different between two risk groups. Furthermore, The risk score was positively related to the expression of PD-1, CTLA4 and LAG3.These results indicated that patients in the high risk group benefit more from immunotherapy. Conclusion: We constructed a novel TGF-ß signaling-related genes signature that could serve as an promising independent factor for predicting clinical prognosis and immunotherapy responses in ccRCC patients.

Cigarette Smoke Mediates Nasal Epithelial Barrier Dysfunction via TNF-α.

BACKGROUND: Extensive data suggest that exposure to cigarette smoke can induce pulmonary epithelial barrier dysfunction. However, the effects of cigarette smoke on the nasal epithelial barrier are still unclear. Here, we investigated the consequence and mechanism of cigarette smoke on the nasal epithelial barrier. METHODS: Sprague Dawley rats were exposed to cigarette smoke for 3 or 6 months, and changes in inflammatory markers and nasal barrier function were evaluated. Moreover, underlying mechanisms were explored. Finally, normal human bronchial epithelial cells were cultured with or without tumor necrosis factor-alpha (TNF-α) in vitro, and the levels of continuity and tight junction-associated proteins were measured. RESULTS: In vivo experiments showed that the nasal mucosal barrier function of rats exposed to cigarette smoke was disturbed. Indeed, proteins associated with tight junctions were decreased, and the levels of inflammatory factors, such as IL-8, IL-6, and TNF-α, were dramatically increased in comparison to those of control animals. In vitro, TNF-α was shown to disrupt the continuity of proteins associated with tight junctions and to downregulate the expression of these proteins in bronchial epithelial cells. CONCLUSIONS: We found that cigarette smoke disrupted the nasal mucosal barrier, and the extent of the damage was correlated with the duration of cigarette smoke exposure. We showed that TNF-α can disrupt the continuity and attenuate the expression of tight junction proteins in human bronchial epithelial cells. Therefore, cigarette smoke may induce nasal epithelial barrier dysfunction through TNF-α.