Canopy FGF signaling regulator 3 affects prognosis, immune infiltration, and PI3K/AKT pathway in colon adenocarcinoma.

BACKGROUND: Colon adenocarcinoma (COAD) is a malignant tumor of the digestive system. The mechanisms underlying COAD development and progression are still largely unknown. AIM: To identify the role of canopy FGF signaling regulator 3 (CNPY3) in the development and progression of COAD by using bioinformatic tools and functional experiments. METHODS: Bioinformatic data were downloaded from public databases. The associations of clinicopathological features, survival, and immune function with the expression of CNPY3 were analyzed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis were used to explore the related pathways. Then, quantitative real-time PCR and immunohistochemistry were used for validation of CNPY3 expression in clinical samples and tumor cell lines. Cell lines with CNPY3 knockdown were constructed to further analyze gene functions. The functional experiments included proliferation, invasion, migration and apoptosis assays. RESULTS: In both the TCGA cohort and the merged dataset, elevated CNPY3 expression was observed in tumor tissues. High CNPY3 expression correlated with adverse survival and compromised immune functions. Functional enrichment analysis suggested that the pro-oncogenic properties of CNPY3 might be linked to the PI3K-AKT signaling pathway. CNPY3 expression was validated at both the RNA and protein levels. Functional assays indicated that cell proliferation, invasion, and migration were inhibited and cell apoptosis was promoted after CNPY3 knockdown. Additionally, Western blot results revealed the downregulation of key proteins in the PI3K/AKT pathway following CNPY3 knockdown. PI3K/AKT pathway activator reversed the decrease in proliferation, invasion, and migration and the increase in apoptosis. Notably, CNPY3 knockdown still affected the cells when the pathway was inhibited. CONCLUSION: This study showed that CNPY3 is upregulated in COAD and might regulate COAD development and progression by the PI3K/AKT pathway. Thus, CNPY3 might be a promising therapeutic target.

A Novel Joint Motion Compensation Algorithm for ISAR Imaging Based on Entropy Minimization.

Space targets move in orbit at a very high speed, so in order to obtain high-quality imaging, high-speed motion compensation (HSMC) and translational motion compensation (TMC) are required. HSMC and TMC are usually adjacent, and the residual error of HSMC will reduce the accuracy of TMC. At the same time, under the condition of low signal-to-noise ratio (SNR), the accuracy of HSMC and TMC will also decrease, which brings challenges to high-quality ISAR imaging. Therefore, this paper proposes a joint ISAR motion compensation algorithm based on entropy minimization under low-SNR conditions. Firstly, the motion of the space target is analyzed, and the echo signal model is obtained. Then, the motion of the space target is modeled as a high-order polynomial, and a parameterized joint compensation model of high-speed motion and translational motion is established. Finally, taking the image entropy after joint motion compensation as the objective function, the red-tailed hawk-Nelder-Mead (RTH-NM) algorithm is used to estimate the target motion parameters, and the joint compensation is carried out. The experimental results of simulation data and real data verify the effectiveness and robustness of the proposed algorithm.

Reprogramming macrophages with R848-loaded artificial protocells to modulate skin and skeletal wound healing.

After tissue injury, inflammatory cells are rapidly recruited to the wound where they clear microbes and other debris, and coordinate the behaviour of other cell lineages at the repair site in both positive and negative ways. In this study, we take advantage of the translucency and genetic tractability of zebrafish to evaluate the feasibility of reprogramming innate immune cells in vivo with cargo-loaded protocells and investigate how this alters the inflammatory response in the context of skin and skeletal repair. Using live imaging we show that protocells loaded with R848 cargo (which targets TLR7/8 signalling), are engulfed by macrophages resulting in their switching to a pro-inflammatory phenotype and altering their regulation of angiogenesis, collagen deposition and re-epithelialization during skin wound healing, as well as dampening osteoblast and osteoclast recruitment and bone mineralization during fracture repair. For infected skin wounds, R848-reprogrammed macrophages exhibited enhanced bactericidal activities leading to improved healing. We replicated our zebrafish studies in cultured human macrophages, and showed that R848-loaded protocells similarly reprogramme human cells, indicating how this strategy might be used to modulate wound inflammation in the clinic.

Synchronization transitions in phase oscillator populations with partial adaptive coupling.

The adaptation underlying many realistic processes plays a pivotal role in shaping the collective dynamics of diverse systems. Here, we untangle the generic conditions for synchronization transitions in a system of coupled phase oscillators incorporating the adaptive scheme encoded by the feedback between the coupling and the order parameter via a power-law function with different weights. We mathematically argue that, in the subcritical and supercritical correlation scenarios, there exists no critical adaptive fraction for synchronization transitions converting from the first (second)-order to the second (first)-order. In contrast to the synchronization transitions previously deemed, the explosive and continuous phase transitions take place in the corresponding regions as long as the adaptive fraction is nonzero, respectively. Nevertheless, we uncover that, at the critical correlation, the routes toward synchronization depend crucially on the relative adaptive weights. In particular, we unveil that the emergence of a range of interrelated scaling behaviors of the order parameter near criticality, manifesting the subcritical and supercritical bifurcations, are responsible for various observed phase transitions. Our work, thus, provides profound insights for understanding the dynamical nature of phase transitions, and for better controlling and manipulating synchronization transitions in networked systems with adaptation.

TNFAIP1 promotes macrophage lipid accumulation and accelerates the development of atherosclerosis through the LEENE/FoxO1/ABCA1 pathway.

Macrophage lipid accumulation is a critical contributor to foam cell formation and atherosclerosis. Tumor necrosis factor-α-induced protein 1 (TNFAIP1) is closely associated with cardiovascular disease. However, its role and molecular mechanisms in atherogenesis remain unclear. TNFAIP1 was knocked down in THP-1 macrophage-derived foam cells and apolipoprotein-deficient (apoE-/-) mice using lentiviral vector. The expression of lncRNA enhancing endothelial nitric oxide synthase expression (LEENE), Forkhead box O1 (FoxO1) and ATP binding cassette transporter A1 (ABCA1) was evaluated by qRT-PCR and/or western blot. Lipid accumulation in macrophage was assessed by high-performance liquid chromatography and Oil red O staining. RNA immunoprecipitation and RNA pull-down assay were performed to verify the interaction between LEENE and FoxO1 protein. Atherosclerotic lesions were analyzed using HE, Oil red O and Masson staining. Our results showed that TNFAIP1 was significantly increased in THP-1 macrophages loaded with oxidized low-density lipoprotein. Knockdown of TNFAIP1 enhanced LEENE expression, promoted the direct interaction of LEENE with FoxO1 protein, stimulated FoxO1 protein degradation through the proteasome pathway, induced ABCA1 transcription, and finally suppressed lipid accumulation in THP-1 macrophage-derived foam cells. TNFAIP1 knockdown also up-regulated ABCA1 expression, improved plasma lipid profiles, enhanced the efficiency of reverse cholesterol transport and attenuated lesion area in apoE-/- mice. Taken together, these results provide the first direct evidence that TNFAIP1 aggravates atherosclerosis by promoting macrophage lipid accumulation via the LEENE/FoxO1/ABCA1 signaling pathway. TNFAIP1 may represent a promising therapeutic target for atherosclerotic cardiovascular disease.

Characterization, hazard identification, and risk assessment of volatile organic compounds in Poly(butylene adipate-co-terephthalate)-based food contact articles.

The chemical safety of poly (butylene adipate-co-terephthalate) (PBAT) based food contact articles (FCAs) has aroused increasing toxicological concerns in recent years, but the chemical characterization and associated risk assessment still remain inadequate as it fails to elucidate the distribution pattern and discern the potential genotoxic and carcinogenic hazards of the identified substances. Herein, the volatile organic compounds (VOCs) in 50 batches of PBAT-based FCAs of representative categories and 10 batches of PLA and PBAT pellets were characterized, by which 237 VOCs of 10 chemical categories were identified and exhibited characteristic distribution patterns in the chemical spaces derived from their molecular descriptors. Chemical hazards associated with the identified VOCs were discerned by a hazard-driven classification scheme integrating hazard-related knowledge from multiple publicly available sources, and 34 VOCs were found to bear genotoxic or carcinogenic hazards and to feature higher average molecular weight than the other VOCs. Finally, the Risk and hazard quotient (HQ) calculated as the metrics of risk suggested that all identified VOCs posed acceptable risks (Risk<10-4 or HQ < 1), whereas oxolane, butyrolactone, N,N-dimethylacetamide, 2-butoxyethanol, benzyl alcohol, and 1,2,3-trichloropropane posed non-negligible (Risk>10-6) genotoxic or carcinogenic risk and thus should be of prioritized concern to promote the chemical safety of PBAT-based FCAs.

Cytarabine prevents neuronal damage by enhancing AMPK to stimulate PINK1 / Parkin-involved mitophagy in Parkinson's disease model.

Parkinson's disease (PD) is a common age-related neurodegenerative disorder, which may be largely due to the mitochondrial dysfunction and impaired mitophagy. Thus, it is of great importance to seek novel therapeutic strategies for PD targeting mitochondrial function and mitophagy. Cytarabine is a marine-derived antimetabolite used in the treatment of acute leukemia, which is also used in the study of the nervous system. In this study, we found that cytarabine pretreatment significantly inhibited the apoptosis and necrosis in the ROT-induced SH-SY5Y cell PD model and reduced the oxidative stress, as evidenced by the reduced MDA levels and the increased levels of SOD, GSH, and total antioxidant capacity. Cytarabine can also enhance mitochondrial vitality, improve mitochondrial respiratory function, and preserve mitochondrial morphology. Cytarabine also enhanced the expression of the mitophagy-related proteins PINK1, Parkin, VDAC1, and DJ-1, and its actions can be reversed by treatment with AMPK inhibitor - Compound C (CC), suggesting that AMPK activation may be involved in cytarabine-enhanced mitophagy. Furthermore, cytarabine can also ameliorate the motor symptoms in the MPTP-induced PD-like mice model, and attenuate the neuropathy in the substantia nigra (SN) of PD mice, while Compound C antagonized cytarabine's beneficial effects. In summary, marine-derived compound cytarabine could resist neurological damage both in vitro and in vivo by activating AMPK to increase PINK1/Parkin-induced mitophagy, serving as a promising disease modulator for treating neurodegenerative disease.

Comprehensive understanding of glioblastoma molecular phenotypes: classification, characteristics, and transition.

Among central nervous system-associated malignancies, glioblastoma (GBM) is the most common and has the highest mortality rate. The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide. In precision medicine, research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity, as well as the refractory nature of GBM toward therapy. Deep understanding of the different molecular expression patterns of GBM subtypes is critical. Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes. The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors. These subtypes also exhibit high plasticity in their regulatory pathways, oncogene expression, tumor microenvironment alterations, and differential responses to standard therapy. Herein, we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype. Furthermore, we review the mesenchymal transition mechanisms of GBM under various regulators.

Protein-nanoparticle co-assembly supraparticles for drug delivery: Ultrahigh drug loading and colloidal stability, and instant and complete lysosomal drug release.

Two frequent problems hindering clinical translation of nanomedicine are low drug loading and low colloidal stability. Previous efforts to achieve ultrahigh drug loading (>30 %) introduce new hurdles, including lower colloidal stability and others, for clinical translation. Herein, we report a new class of drug nano-carriers based on our recent finding in protein-nanoparticle co-assembly supraparticle (PNCAS), with both ultrahigh drug loading (58 % for doxorubicin, i.e., DOX) and ultrahigh colloidal stability (no significant change in hydrodynamic size after one year). We further show that our PNCAS-based drug nano-carrier possesses a built-in environment-responsive drug release feature: once in lysosomes, the loaded drug molecules are released instantly (<1 min) and completely (∼100 %). Our PNCAS-based drug delivery system is spontaneously formed by simple mixing of hydrophobic nanoparticles, albumin and drugs. Several issues related to industrial production are studied. The ultrahigh drug loading and stability of DOX-loaded PNCAS enabled the delivery of an exceptionally high dose of DOX into a mouse model of breast cancer, yielding high efficacy and no observed toxicity. With further developments, our PNCAS-based delivery systems could serve as a platform technology to meet the multiple requirements of clinical translation of nanomedicines.

Enzyme-responsive liposomes for controlled drug release.

Compared to other nanovectors, liposomes exhibit unique advantages, such as good biosafety and high drug-loading capacity. However, slow drug release from conventional liposomes makes most payloads unavailable, restricting the therapeutic efficacy. Therefore, in the last ∼20 years, enzyme-responsive liposomes have been extensively investigated, which liberate drugs under the stimulation of enzymes overexpressed at disease sites. In this review, we elaborate on the research progress on enzyme-responsive liposomes. The involved enzymes mainly include phospholipases, particularly phospholipase A2, matrix metalloproteinases, cathepsins, and esterases. These enzymes can cleave ester bonds or specific peptide sequences incorporated in the liposomes for controlled drug release by disrupting the primary structure of liposomes, detaching protective polyethylene glycol shells, or activating liposome-associated prodrugs. Despite decades of efforts, there are still a lack marketed products of enzyme-responsive liposomes. Therefore, more efforts should be made to improve the safety and effectiveness of enzyme-responsive liposomes and address the issues associated with production scale-up.

Deep-targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma.

AIMS: To investigate the key factors influencing glioma progression and the emergence of treatment resistance by examining the intrinsic connection between mutations in DNA damage and repair-related genes and the development of chemoresistance in gliomas. METHODS: We conducted a comprehensive analysis of deep-targeted gene sequencing data from 228 glioma samples. This involved identifying differentially mutated genes across various glioma grades, assessing their functions, and employing I-TASSER for homology modeling. We elucidated the functional changes induced by high-frequency site mutations in these genes and investigated their impact on glioma progression. RESULTS: The analysis of sequencing mutation results of deep targeted genes in integration revealed that ARID1A gene mutation occurs frequently in glioblastoma and alteration of ARID1A could affect the tolerance of glioma cells to temozolomide treatment. The deletion of proline at position 16 in the ARID1A protein affected the stability of binding of the SWI/SNF core subunit BRG1, which in turn affected the stability of the SWI/SNF complex and led to altered histone modifications in the CDKN1A promoter region, thereby affecting the biological activity of glioma cells, as inferred from modeling and protein interaction analysis. CONCLUSION: The ARID1A gene is a critical predictive biomarker for glioma. Mutations at the ARID1A locus alter the stability of the SWI/SNF complex, leading to changes in transcriptional regulation in glioma cells. This contributes to an increased malignant phenotype of GBM and plays a pivotal role in mediating chemoresistance.

Base Editors-Mediated Gene Therapy in Hematopoietic Stem Cells for Hematologic Diseases.

Base editors, developed from the CRISPR/Cas system, consist of components such as deaminase and Cas variants. Since their emergence in 2016, the precision, efficiency, and safety of base editors have been gradually optimized. The feasibility of using base editors in gene therapy has been demonstrated in several disease models. Compared with the CRISPR/Cas system, base editors have shown great potential in hematopoietic stem cells (HSCs) and HSC-based gene therapy, because they do not generate double-stranded breaks (DSBs) while achieving the precise realization of single-base substitutions. This precise editing mechanism allows for the permanent correction of genetic defects directly at their source within HSCs, thus promising a lasting therapeutic effect. Recent advances in base editors are expected to significantly increase the number of clinical trials for HSC-based gene therapies. In this review, we summarize the development and recent progress of DNA base editors, discuss their applications in HSC gene therapy, and highlight the prospects and challenges of future clinical stem cell therapies.

Analysis of brain structural covariance network in Cushing disease.

Background: Cushing disease (CD) is a rare clinical neuroendocrine disease. CD is characterized by abnormal hypercortisolism induced by a pituitary adenoma with the secretion of adrenocorticotropic hormone. Individuals with CD usually exhibit atrophy of gray matter volume. However, little is known about the alterations in topographical organization of individuals with CD. This study aimed to investigate the structural covariance networks of individuals with CD based on the gray matter volume using graph theory analysis. Methods: High-resolution T1-weighted images of 61 individuals with CD and 53 healthy controls were obtained. Gray matter volume was estimated and the structural covariance network was analyzed using graph theory. Network properties such as hubs of all participants were calculated based on degree centrality. Results: No significant differences were observed between individuals with CD and healthy controls in terms of age, gender, and education level. The small-world features were conserved in individuals with CD but were higher than those in healthy controls. The individuals with CD showed higher global efficiency and modularity, suggesting higher integration and segregation as compared to healthy controls. The hub nodes of the individuals with CD were Short insular gyri (G_insular_short_L), Anterior part of the cingulate gyrus and sulcus (G_and_S_cingul-Ant_R), and Superior frontal gyrus (G_front_sup_R). Conclusions: Significant differences in the structural covariance network of patients with CD were found based on graph theory. These findings might help understanding the pathogenesis of individuals with CD and provide insight into the pathogenesis of this CD.

Consensus statements on endoscopic ultrasound-guided tissue acquisition. Guidelines from the Asian Endoscopic Ultrasound Group.

OBJECTIVES: This consensus was developed by the Asian EUS Group (AEG), who aimed to formulate a set of practice guidelines addressing various aspects of endoscopic ultrasound-guided tissue acquisition (EUS-TA). METHODS: The AEG initiated the development of consensus statements and formed an expert panel comprising surgeons, gastroenterologists, and pathologists. Three online consensus meetings were conducted to consolidate the statements and votes. The statements were presented and discussed in the first two consensus meetings and revised according to comments. Final voting was conducted at a third consensus meeting. The Grading of Recommendations, Assessment, Development, and Evaluation system was adopted to define the strength of the recommendations and quality of evidence. RESULTS: A total of 20 clinical questions and statements regarding EUS-TA were formulated. The committee recommended that fine-needle biopsy (FNB) needles be preferred over conventional fine-needle aspiration (FNA) needles for EUS-TA of subepithelial lesions. For solid pancreatic masses, rapid on-site evaluation is not routinely recommended when FNB needles are used. For dedicated FNB needles, fork-tip and Franseen-tip needles have essentially equivalent performance. CONCLUSION: This consensus provides guidance for EUS-TA, thereby enhancing the quality of EUS-TA.

The short-term outcome of intracranial stenosis with distal thrombosis treated with balloon-assisted tracking.

Background and purposes: Treating intracranial stenosis with distal thrombosis (IS&DT) using traditional mechanical thrombectomy (MT) techniques has proven challenging. This study aimed to summarize the experience of utilizing the balloon-assisted tracking (BAT) technique for IS&DT. Methods: Demographic and morphologic characteristics of patients with IS&DT were collected for this study. The BAT technique, involving a half-deflated balloon outside the intermediate catheter tip, was used in all patients to navigate through the proximal stenosis. Various parameters were recorded, including the sequence of vascular reperfusion, the puncture-to-reperfusion time (PRT), the residual stenosis rate, and the occurrence of re-occlusion. The thrombolysis in cerebral infarction (TICI) scale was used to assess the reperfusion of intracranial vessels, with a TICI score of ≥2b considered as successful perfusion. The clinical status of patients was evaluated at three time points: pre-procedure, post-procedure, and at discharge using the modified Rankin score (mRS). Results: In this study, a total of 10 patients were diagnosed with IS&DT, consisting of 9 male patients (90.0%) and 1 female patient (10.0%). The patients' mean age was 63.10 years (ranging from 29 to 79 years). The mean National Institute of Health Stroke Scale (NIHSS) score before treatment was 24.3 (ranging from 12 to 40), indicating the severity of their condition. Following the procedure, all patients achieved successful reperfusion with a thrombolysis in cerebral infarction (TICI) score of ≥2b. The average puncture-to-reperfusion time (PRT) was 51.8 min (ranging from 25 to 100 min), indicating the time taken for the procedure. During the perioperative period, three patients (30.0%) experienced complications. One patient had hemorrhage, while two patients had contrast extravasation. Among these cases, only the patient with hemorrhage (10%) suffered from a permanent neurological function deficit. At discharge, the patient's condition showed improvement. The mean NIHSS score decreased to 13.2 (ranging from 1 to 34), indicating a positive response to treatment. The mean mRS score at discharge was 3.2 (ranging from 1 to 5), showing some level of functional improvement. Conclusion: In conclusion, the use of the balloon-assisted tracking (BAT) technique for treating intracranial stenosis with distal thrombosis (IS&DT) showed promising results. However, a moderate rate of perioperative complications was observed, warranting further investigation and refinement of the procedure.

FeCoCuMnRuB Nanobox with Dual Driving of High-Entropy and Electron-Trap Effects as the Efficient Electrocatalyst for Water Oxidation.

High-entropy borides hold potential as electrocatalysts for water oxidation. However, the synthesis of the tailored nanostructures remains a challenge due to the thermodynamic immiscibility of polymetallic components. Herein, a FeCoCuMnRuB nanobox decorated with a nanosheet array was synthesized for the first time by a "coordination-etch-reduction" method. The FeCoCuMnRuB nanobox has various structural characteristics to express the catalytic performance; meanwhile, it combines the high-entropy effect of multiple components with the electron trap effect induced by electron-deficient B, synergistically regulating its electronic structure. As a result, FeCoCuMnRuB nanobox exhibits enhanced OER activity with a low overpotential (η10 = 233 mV), high TOF value (0.0539 s-1), small Tafel slope (61 mV/dec), and a satisfactory stability for 200 h, outperforming the high-entropy alloy and low-entropy borides. This work develops a high entropy and electron-deficient B-driven strategy for motivating the catalytic performance of water oxidation, which broadens the structural diversity and category of high-entropy materials.

SiATG5-loaded cancer cell membrane-fused liposomes induced increased uptake of albumin-bound chemotherapeutics by pancreatic cancer cells.

Chemotherapeutic efficacy for pancreatic cancer is severely compromised by limited drug availability to tumor cells. Herein, we constructed a cancer cell membrane-fused liposome containing a siATG5-loaded calcium phosphate (CaP) core, termed CLip@siATG5. Through cancer cell membrane camouflage, the liposomes evaded immune clearance, actively infiltrated tumor tissues, and were preferentially taken up by homotypic tumor cells. Then, siATG5 escaped from the endosomes and was liberated in the cytoplasm, mainly benefiting from CaP dissolution-induced endosome rupture and liposome disassembly in acidic endosomes. The released siATG5 silenced autophagy protein 5 (ATG5) to inhibit autophagy, starving tumor cells. An alternative nutrient procurement pathway, macropinocytosis, was then upregulated in the cells, leading to increased uptake of the albumin-bound chemotherapeutic agent (nanoparticle albumin-bound paclitaxel (Nab-PTX)). Finally, in a murine pancreatic cancer model, CLip@siATG5 combined with Nab-PTX exerted superior efficacy to a twofold dose of Nab-PTX while avoiding its toxicity. Overall, we justified enhancing chemotherapeutic delivery by modulating the pancreatic cancer cell metabolism, which will enlighten the development of more effective chemotherapeutic adjuvants for pancreatic cancer in the future.

DNA as a universal chemical substrate for computing and data storage.

DNA computing and DNA data storage are emerging fields that are unlocking new possibilities in information technology and diagnostics. These approaches use DNA molecules as a computing substrate or a storage medium, offering nanoscale compactness and operation in unconventional media (including aqueous solutions, water-in-oil microemulsions and self-assembled membranized compartments) for applications beyond traditional silicon-based computing systems. To build a functional DNA computer that can process and store molecular information necessitates the continued development of strategies for computing and data storage, as well as bridging the gap between these fields. In this Review, we explore how DNA can be leveraged in the context of DNA computing with a focus on neural networks and compartmentalized DNA circuits. We also discuss emerging approaches to the storage of data in DNA and associated topics such as the writing, reading, retrieval and post-synthesis editing of DNA-encoded data. Finally, we provide insights into how DNA computing can be integrated with DNA data storage and explore the use of DNA for near-memory computing for future information technology and health analysis applications.

Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design.

Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed. Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery, inspiring the development of more high-performance RNA lipid nanovesicles in the future.

Biomechanical effects of Evans versus Hintermann osteotomy for treating adult acquired flatfoot deformity: a patient-specific finite element investigation.

BACKGROUND: Evans and Hintermann lateral column lengthening (LCL) procedures are both widely used to correct adult acquired flatfoot deformity (AAFD), and have both shown good clinical results. The aim of this study was to compare these two procedures in terms of corrective ability and biomechanics influence on the Chopart and subtalar joints through finite element (FE) analysis. METHODS: Twelve patient-specific FE models were established and validated. The Hintermann osteotomy was performed between the medial and posterior facets of the subtalar joint; while, the Evans osteotomy was performed on the anterior neck of the calcaneus around 10 mm from the calcaneocuboid joint surface. In each procedure, a triangular wedge of varying size was inserted at the lateral edge. The two procedures were then compared based on the measured strains of superomedial calcaneonavicular ligaments and planter facia, the talus-first metatarsal angle, and the contact characteristics of talonavicular, calcaneocuboid and subtalar joints. RESULTS: The Hintermann procedure achieved a greater correction of the talus-first metatarsal angle than Evans when using grafts of the same size, indicating that Hintermann had stronger corrective ability. However, its distributions of von-Mises stress in the subtalar, talonavicular and calcaneocuboid joints were less homogeneous than those of Evans. In addition, the strains of superomedial calcaneonavicular ligaments and planter facia of Hintermann were also greater than those of Evans, but both generally within the safe range (less than 6%). CONCLUSION: This FE analysis study indicates that both Evans and Hintermann procedures have good corrective ability for AAFD. Compared to Evans, Hintermann procedure can provide a stronger corrective effect while causing greater disturbance to the biomechanics of Chopart joints, which may be an important mechanism of arthritis. Nevertheless, it yields a better protection to the subtalar joint than Evans osteotomy. CLINICAL RELEVANCE: Both Evans and Hintermann LCL surgeries have a considerable impact on adjacent joints and ligament tissues. Such effects alongside the overcorrection problem should be cautiously considered when choosing the specific surgical method. LEVEL OF EVIDENCE: Level III, case-control study.