Antagonistic roles of tau and MAP6 in regulating neuronal development.

Association of tau (encoded by Mapt) with microtubules causes them to be labile, whereas association of MAP6 with microtubules causes them to be stable. As axons differentiate and grow, tau and MAP6 segregate from one another on individual microtubules, resulting in the formation of stable and labile domains. The functional significance of the yin-yang relationship between tau and MAP6 remains speculative, with one idea being that such a relationship assists in balancing morphological stability with plasticity. Here, using primary rodent neuronal cultures, we show that tau depletion has opposite effects compared to MAP6 depletion on the rate of neuronal development, the efficiency of growth cone turning, and the number of neuronal processes and axonal branches. Opposite effects to those seen with tau depletion were also observed on the rate of neuronal migration, in an in vivo assay, when MAP6 was depleted. When tau and MAP6 were depleted together from neuronal cultures, the morphological phenotypes negated one another. Although tau and MAP6 are multifunctional proteins, our results suggest that the observed effects on neuronal development are likely due to their opposite roles in regulating microtubule stability.

NeoDesign: A Computational Tool for Optimal Selection of Polyvalent Neoantigen Combinations.

MOTIVATION: Tumor polyvalent neoantigen mRNA vaccines are gaining prominence in immunotherapy. The design of sequences in vaccine development is crucial for enhancing both the immunogenicity and safety of vaccines. However, a major challenge lies in selecting the optimal sequences from the large pools generated by multiple peptide combinations and synonymous codons. RESULTS: We introduce NeoDesign, a computational tool designed to tackle the challenge of sequence design. NeoDesign comprises four modules: Library Construction, Optimal Path Filtering, Linker Addition, and λ-Evaluation. It aims to identify the optimal protein sequence for tumor polyvalent neoantigen vaccines by minimizing linker usage, avoiding unexpected neoantigens and functional domains, and simplifying the structure. It also provides a preference scheme to balance mRNA stability and protein expression when designing mRNA sequences for the optimal protein sequence. This tool can potentially improve the sequence design of tumor polyvalent neoantigen mRNA vaccines, thereby significantly advancing immunotherapy strategies. AVAILABILITY: NeoDesign is freely available on https://github.com/HuangLab-Fudan/neoDesign and https://figshare.com/projects/NeoDesign/221704. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Global Epidemiology of Gallstones in the 21st Century: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Gallstones are common and associated with substantial health and economic burden. We aimed to comprehensively evaluate the prevalence and incidence of gallstones in the 21st century. METHODS: We systematically searched PubMed and Embase to identify studies reporting the prevalence and/or incidence of gallstones between January 1, 2000, and November 18, 2023. Pooled prevalence and incidence were calculated using DerSimonian and Laird's random-effects model. We performed subgroup analyses and meta-regression based on age, sex, geographic location, population setting, and modality of detection to examine sources of heterogeneity. RESULTS: Based on 115 studies with 32,610,568 participants, the pooled prevalence of gallstones was 6.1% (95% CI, 5.6-6.5). Prevalence was higher in females vs males (7.6% vs 5.4%), in South America vs Asia (11.2% vs 5.1%), in upper-middle-income countries vs high-income countries (8.9% vs 4.0%), and with advancing age. On sensitivity analysis of population-based studies, the prevalence of gallstones was 5.5% (95% CI, 4.1-7.4; n = 44 studies), and when limiting subgroup analysis to imaging-based detection modalities, the prevalence was 6.7% (95% CI, 6.1-7.3; n = 101 studies). Prevalence has been stable over the past 20 years. Based on 12 studies, the incidence of gallstones was 0.47 per 100 person-years (95% CI, 0.37-0.51), without differences between males and females, and with increasing incidence in more recent studies. CONCLUSIONS: Globally, 6% of the population have gallstones, with higher rates in females and in South America. The incidence of gallstones may be increasing. Our findings call for prioritizing research on the prevention of gallstones.

Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets.

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.

A novel log odds of positive lymph nodes-based nomogram for predicting overall survival in patients with colorectal signet ring cell carcinoma: a SEER population-based study.

PURPOSE: Considering the poor prognosis and high lymph node (LN) involvement rate of colorectal signet ring cell carcinoma (SRCC), this study aimed to construct a prognostic nomogram to predict overall survival (OS) with satisfactory accuracy and utility, based on LN status indicators with superior predictability. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, we obtained cases of colorectal SRCC patients and employed univariate and multivariate Cox analyses to determine independent prognostic factors. Kaplan-Meier curves were utilized to visualize survival differences among these factors. Receiver operating characteristic curves were generated to assess predictive performances of models incorporating various LN status indicators. A novel nomogram, containing optimal LN status indicators and other prognostic factors, was developed to predict OS, whose discriminatory ability and accuracy were evaluated using calibration curves and decision curve analysis. RESULTS: A total of 1663 SRCC patients were screened from SEER database. Older patients and those with grades III-IV, tumor sizes > 39 mm, T3/T4 stage, N1/N2 stage, M1 stage, and higher log odds of positive lymph nodes (LODDS) values exhibited poorer prognoses. Age, grade, tumor size, TNM stage, and LODDS were independent prognostic factors. The model containing N stage and LODDS outperformed the one relying solely on N stage as LN status indicator, resulting in a validated nomogram for accurately predicting OS in SRCC patients. CONCLUSION: The integration of LODDS, N stage, and other risk factors into a nomogram offered precise OS predictions, enhancing therapeutic decision-making and tailored follow-up management for colorectal SRCC patients.

Non-heme Iron Single-Atom Nanozymes as Peroxidase Mimics for Tumor Catalytic Therapy.

Single-atom nanozymes (SAzymes) open new possibilities for the development of artificial enzymes that have catalytic activity comparable to that of natural peroxidase (POD). So far, most efforts have focused on the structural modulation of the Fe-N4 moiety to mimic the metalloprotein heme center. However, non-heme-iron POD with much higher activity, for example, HppE, has not been mimicked successfully due to its structural complexity. Herein, carbon dots (CDs)-supported SAzymes with twisted, nonplanar Fe-O3N2 active sites, highly similar to the non-heme iron center of HppE, was synthesized by exploiting disordered and subnanoscale domains in CDs. The Fe-CDs exhibit an excellent POD activity of 750 units/mg, surpassing the values of conventional SAzymes with planar Fe-N4. We further fabricated an activatable Fe-CDs-based therapeutic agent with near-infrared enhanced POD activity, a photothermal effect, and tumor-targeting ability. Our results represent a big step in the design of high-performance SAzymes and provide guidance for future applications for synergistic tumor therapy.

[Establishment and Validation of a Predictive Model for Gallstone Disease in the General Population: A Multicenter Study]. / èƒ†ç»“çŸ³æ‚£ç— é£Žé™©é¢„æµ‹æ¨¡åž‹çš„æž„å»ºå’Œå¤šä¸­å¿ƒéªŒè¯ç ”ç©¶.

Objective: Gallstone disease (GSD) is one of the common digestive tract diseases with a high worldwide prevalence. The effects of GSD on patients include but are not limited to the symptoms of nausea, vomiting, and biliary colic directly caused by GSD. In addition, there is mounting evidence from cohort studies connecting GSD to other conditions, such as cardiovascular diseases, biliary tract cancer, and colorectal cancer. Early identification of patients at a high risk of GSD may help improve the prevention and control of the disease. A series of studies have attempted to establish prediction models for GSD, but these models could not be fully applied in the general population due to incomplete prediction factors, small sample sizes, and limitations in external validation. It is crucial to design a universally applicable GSD risk prediction model for the general population and to take individualized intervention measures to prevent the occurrence of GSD. This study aims to conduct a multicenter investigation involving more than 90000 people to construct and validate a complete and simplified GSD risk prediction model. Methods: A total of 123634 participants were included in the study between January 2015 and December 2020, of whom 43929 were from the First Affiliated Hospital of Chongqing Medical University (Chongqing, China), 11907 were from the First People's Hospital of Jining City (Shandong, China), 1538 were from the Tianjin Medical University Cancer Institute and Hospital (Tianjin, China), and 66260 were from the People's Hospital of Kaizhou District (Chongqing, China). After excluding patients with incomplete clinical medical data, 35976 patients from the First Affiliated Hospital of Chongqing Medical University were divided into a training data set (n=28781, 80%) and a validation data set (n=7195, 20%). Logistic regression analyses were performed to investigate the relevant risk factors of GSD, and a complete risk prediction model was constructed. Factors with high scores, mainly according to the nomograms of the complete model, were retained to simplify the model. In the validation data set, the diagnostic accuracy and clinical performance of these models were validated using the calibration curve, area under the curve (AUC) of the receiver operating characteristic curve, and decision curve analysis (DCA). Moreover, the diagnostic accuracy of these two models was validated in three other hospitals. Finally, we established an online website for using the prediction model (The complete model is accessible at https://wenqianyu.shinyapps.io/Completemodel/, while the simplified model is accessible at https://wenqianyu.shinyapps.io/Simplified/). Results: After excluding patients with incomplete clinical medical data, a total of 96426 participants were finally included in this study (35876 from the First Affiliated Hospital of the Chongqing Medical University, 9289 from the First People's Hospital of Jining City, 1522 from the Tianjin Medical University Cancer Institute, and 49639 from the People's Hospital of Kaizhou District). Female sex, advanced age, higher body mass index, fasting plasma glucose, uric acid, total bilirubin, gamma-glutamyl transpeptidase, and fatty liver disease were positively associated with risks for GSD. Furthermore, gallbladder polyps, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and aspartate aminotransferase were negatively correlated to risks for GSD. According to the nomograms of the complete model, a simplified model including sex, age, body mass index, gallbladder polyps, and fatty liver disease was constructed. All the calibration curves exhibited good consistency between the predicted and observed probabilities. In addition, DCA indicated that both the complete model and the simplified model showed better net benefits than treat-all and treat-none. Based on the calibration plots, DCA, and AUCs of the complete model (AUC in the internal validation data set=74.1% [95% CI: 72.9%-75.3%], AUC in Shandong=71.7% [95% CI: 70.6%-72.8%], AUC in Tianjin=75.3% [95% CI: 72.7%-77.9%], and AUC in Kaizhou=72.9% [95% CI: 72.5%-73.3%]) and the simplified model (AUC in the internal validation data set=73.7% [95% CI: 72.5%-75.0%], AUC in Shandong=71.5% [95% CI: 70.4%-72.5%], AUC in Tianjin=75.4% [95% CI: 72.9%-78.0%], and AUC in Kaizhou=72.4% [95% CI: 72.0%-72.8%]), we concluded that the complete and simplified risk prediction models for GSD exhibited excellent performance. Moreover, we detected no significant differences between the performance of the two models (P>0.05). We also established two online websites based on the results of this study for GSD risk prediction. Conclusions: This study innovatively used the data from 96426 patients from four hospitals to establish a GSD risk prediction model and to perform risk prediction analyses of internal and external validation data sets in four cohorts. A simplified model of GSD risk prediction, which included the variables of sex, age, body mass index, gallbladder polyps, and fatty liver disease, also exhibited good discrimination and clinical performance. Nonetheless, further studies are needed to explore the role of low-density lipoprotein cholesterol and aspartate aminotransferase in gallstone formation. Although the validation results of the complete model were better than those of the simplified model to a certain extent, the difference was not significant even in large samples. Compared with the complete model, the simplified model uses fewer variables and yields similar prediction and clinical impact. Hence, we recommend the application of the simplified model to improve the efficiency of screening high-risk groups in practice. The use of the simplified model is conducive to enhancing the self-awareness of prevention and control in the general population and early intervention for GSD.

[New Progress in Longitudinal Research on the Risk Factors for Cholelithiasis]. / åŸºäºŽçºµå‘ç ”ç©¶çš„èƒ†å›Šç»“çŸ³å‘ç— é£Žé™©å› ç´ ç ”ç©¶æ–°è¿›å±•.

Cholelithiasis is a common disease of the digestive system. The risk factors for cholelithiasis have been reported and summarized many times in the published literature, which primarily focused on cross-sectional studies. Due to the inherent limitations of the study design, the reported findings still need to be validated in additional longitudinal studies. Moreover, a number of new risk factors for cholelithiasis have been identified in recent years, such as bariatric surgery, hepatitis B virus infection, hepatitis C virus infection, kidney stones, colectomy, osteoporosis, etc. These new findings have not yet been included in published reviews. Herein, we reviewed the 101 cholelithiasis-associated risk factors identified through research based on longitudinal investigations, including cohort studies, randomized controlled trials, and nested case control studies. The risk factors associated with the pathogenesis of cholelithiasis were categorized as unmodifiable and modifiable factors. The unmodifiable factors consist of age, sex, race, and family history, while the modifiable factors include 37 biological environmental factors, 25 socioenvironmental factors, and 35 physiochemical environmental factors. This study provides thorough and comprehensive ideas for research concerning the pathogenesis of cholelithiasis, supplying the basis for identifying high-risk groups and formulating relevant prevention strategies.

Extracellular vesicles long RNA profiling identifies abundant mRNA, circRNA and lncRNA in human bile as potential biomarkers for cancer diagnosis.

Extracellular vesicles (EVs) are bilayered membrane vesicles produced by living cells and secreted into the extracellular matrix. Bile is a special body fluid that is secreted by the liver cells, and extracellular vesicles long RNAs (exLRs) have not been explored in bile. In this study, exLR sequencing (exLR-seq) was performed on 19 bile samples from patients with malignant cancer or patients with biliary stones. A total of 8649 mRNAs, 13 823 circRNAs and 1105 lncRNAs were detected. The KEGG pathway analysis revealed that differentially expressed exLRs were enriched in mTOR and AMPK signaling pathway. We identified five mRNAs (EID2, LLPH, ATP6V0A2, RRP9 and MTRNR2L10), three lncRNAs (AC015922.2, AL135905.1 and LINC00921) and six circRNAs (circASH1L, circATP9A, circCLIP1, circRNF138, circTIMMDC1 and circANKRD12) were enriched in bile EV samples with cancer, and these exLRs may be potential markers used to distinguish malignant cancers from benign biliary diseases. Moreover, the tissue/cellular source components of EVs were analyzed using the EV-origin algorithm. The absolute abundance of CD4_naive and Th1 cell source in bile EVs from cancer patients were significantly increased. In summary, our study presented abundant exLRs in human bile EVs and provides some basis for the selection of tumor diagnostic markers.

Not all Rectal Cancer Patients Could Benefit From the Surgery on the Primary Site.

AIM: Previous studies have provided evidence that primary site surgery can improve the prognosis of rectal cancer patients, even in those with advanced age and distant metastasis, though results have been inconsistent. The current study aims to determine if all rectal cancer patients are likely to benefit from surgery in terms of overall survival. METHODS: This study examined the impact of primary site surgery on the prognosis of rectal cancer patients diagnosed between 2010 and 2019 using multivariable Cox regression analysis. The study also stratified patients by age group, M stage, chemotherapy, radiotherapy, and number of distant metastatic organs. The propensity score matching method was used to balance observed covariates between patients who received and did not receive surgery. The Kaplan-Meier method was used to analyze the data, and the log-rank test was used to determine differences between patients who did and did not undergo surgery. RESULTS: The study included 76,941 rectal cancer patients, with a median survival of 81.0 months (95% CI: 79.2-82.8 months). Of these patients, 52,360 (68.1%) received primary site surgery, and they tended to be younger, have higher differentiated grade, earlier T, N, M stage, and lower rates of bone, brain, lung, and liver metastasis, chemotherapy, and radiotherapy than those without surgery. Multivariable Cox regression analysis revealed that surgery had a protective effect on the prognosis of rectal cancer patients, including those with advanced age, distant metastasis, and multiple organ metastasis, but not in patients with four organ metastases. The results were also confirmed using propensity score matching. CONCLUSION: Not all rectal cancer patients could benefit from the surgery on the primary site, especially the patients with more than four distant metastases. The results could help the clinicians to tailor targeted treatment regimens and provide a guideline for making surgical decisions.

DNA damage-inducible transcript 3 deficiency promotes bone resorption in murine periodontitis models.

BACKGROUND AND OBJECTIVE: Periodontitis is a multifactorial inflammatory disease that leads to the destruction of supporting structures of the teeth. DNA damage-inducible transcript 3 (DDIT3) plays crucial roles in cell survival and differentiation. DDIT3 regulates bone mass and osteoclastogenesis in femur. However, the role of DDIT3 in periodontitis has not been elucidated. This research aimed to explore the role and mechanisms of DDIT3 in periodontitis. METHODS: DDIT3 gene knockout (KO) mice were generated using a CRISPR/Cas9 system. Experimental periodontitis models were established to explore the role of DDIT3 in periodontitis. The expression of DDIT3 in periodontal tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The alveolar bone phenotypes were observed by micro-CT and stereomicroscopy. The inflammation levels and osteoclast activity were examined by histological staining, immunostaining, and qRT-PCR. Bone marrow-derived macrophages (BMMs) were isolated to confirm the effects of DDIT3 on osteoclast formation and function in vitro. RESULTS: The increased expression of DDIT3 in murine inflamed periodontal tissues was detected. DDIT3 knockout aggravated alveolar bone loss and enhanced expression levels of inflammatory cytokines in murine periodontitis models. Increased osteoclast formation and higher expression levels of osteoclast-specific markers were observed in the inflamed periodontal tissues of KO mice. In vitro, DDIT3 deficiency promoted the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts and the bone resorption activity of mature osteoclasts. CONCLUSIONS: Our results demonstrate that DDIT3 deletion aggravated alveolar bone loss in experimental periodontitis through enhanced inflammatory reactions and osteoclastogenesis. The anti-inflammation and the inhibition of bone loss by DDIT3 in murine periodontitis provides a potential novel therapeutic strategy for periodontitis.

Network Pharmacology and Mechanism Studies of the Protective Effect of Ginseng against Alzheimer's Disease Based on Aß Pathogenesis.

Alzheimer's disease (AD) is a critical neurodegenerative disease that manifests as progressive intellectual decline and is pathologically characterized by a progressive loss of neurons in the brain. Despite extensive research on this topic, the pathogenesis of AD is not fully understood, while the beta-amyloid (Aß) hypothesis remains the dominant one and only a few symptomatic drugs are approved for the treatment of AD. Ginseng has been widely reported as an effective herbal medicine for the treatment of neurodegenerative diseases such as dementia. Therefore, we explore the protective effects of ginseng in AD by a network pharmacological approach based on the pathogenesis of Aß. Twenty-one major ginsenosides are screened based on ultraperformance liquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) data. Among them, MAPK8, MAPK9, BACE1, FLT1, CDK2, and CCR5 are the core targets. By molecular docking and validation with the in vitro cell model APPswe-SH-SY5Y, we find that ginsenosides Rg3 and Ro have good neuroprotective effects and can reduce the expression of Aß 1 - 42 in APPswe-SH-SY5Y. Finally, through RT-qPCR experiment, we find that ginsenoside Rg3 targeted MAPK8, FLT1, and CCR5, while ginsenoside Ro targeted MAPK8, MAPK9, FLT1, and CCR5 for its potential anti-AD efficacy.

Biomechanical Analysis of Different Framework Design, Framework Material and Bone Density in the Edentulous Mandible With Fixed Implant-Supported Prostheses: A Three-Dimensional Finite Element Study.

PURPOSE: The objective of this finite element study was to investigate the effect of different framework designs, framework materials, and bone densities on the stress distribution of fixed implant-supported prostheses for edentulous mandibles. MATERIALS AND METHODS: Under the condition of 2-mm cortical bone, 16 models were created in the edentulous mandible to simulate different framework designs (1-piece or 3-piece frameworks) with different framework material (pure titanium, zirconia, polyetheretherketone, or carbon fiber-reinforced polyetheretherketone) in-high or low-density trabecular bone. Then, vertical loading and oblique loading at 75° were applied to the anterior and posterior regions. The stress distribution and stress concentration region of implant and peri-implant bone with different combinations were compared by finite element analysis. RESULTS: The use of the 1-piece zirconia framework in high-density trabecular bone improved stress distribution on implants and peri-implant bone. The region of stress concentration is located in the buccal cervix of the distal implants and the distobuccal portion of the cortical bone in all models. To improve the stress distribution on fixed implant-supported dentures for edentulous mandibles, the 1-piece framework and zirconia represent the better combination. CONCLUSION: Under the condition of 2-mm cortical bone thickness, the full-arch zirconia framework had minimum von Mises stress on implants and peri-implant bone in all models, and high trabecular bone density greatly decreased the stress on cortical bone.

An Opto- and Thermal-Rewrite PCM/CNF-IR 780 Energy Storage Nanopaper with Mechanical Regulated Performance.

In spite of efforts to fabricate self-assembled energy storage nanopaper with potential applications in displays, greenhouses, and sensors, few studies have investigated their multiple stimuli-sensitivities. Here, an opto- and thermal-rewrite phase change material/cellulose nanofibril (PCM/CNF) energy storage nanopaper with mechanical regulated performance is facilely fabricated, through 5 min sonication of PCMs and CNFs in an aqueous system. The combination of PCM and CNF not only guarantees the recyclability of PCM without leakage, but also offers nanopaper adaptive properties by leveraging the mobility and optical variation accompanying solid-to-liquid transition of PCM. Besides, trace near-infrared (NIR) dye (IR 780) in it imparts a PCM-embedded nanopaper photothermal effect to modulate the local transparency via time- and position-controlled laser exposure, leading to a reusable opto-writing nanopaper. Furthermore, since the synergistic effect of stick-and-slip function attributes from PCMs and pore structures are produced by calcium ions, the PCM/CNF energy storage nanopaper exhibits excellent mechanically regulated performance from rigid to flexible, which greatly enriches their application in energy-efficient smart buildings and displays.

Biomechanical analysis of inclined and cantilever design with different implant framework materials in mandibular complete-arch implant restorations.

STATEMENT OF PROBLEM: Inclined distal implants with posterior framework cantilevers are an alternative to straight implants for the treatment of edentulous jaws, avoiding grafting procedures and utilizing pre-existing bone. However, little is known about the implant, framework, and peri-implant bone stresses exerted by this design. PURPOSE: The purpose of this finite element analysis study was to assess the biomechanical properties of the inclined versus straight design, with different implant framework material to generate implant-supported complete-arch fixed mandibular prostheses. MATERIAL AND METHODS: A finite element model of the edentulous mandible was generated by using 4 implants in 2 distinct configurations: the inclined design and the straight design. Different framework materials were tested: pure titanium, cobalt-chromium alloy, type IV gold alloy, zirconia, polyetheretherketone (PEEK), and carbon fiber-reinforced polyetheretherketone (CFR-PEEK). A 300-N load at a 75-degree angle was applied to the occlusal plane from the lingual side of the buccal cusps of the 2 premolars and the first molar teeth. Subsequently, stresses on the implant, surrounding bone, and framework were measured and analyzed quantitatively and qualitatively. RESULTS: In terms of implant configurations, the inclined design demonstrated less stress on the posterior cortical bone, implants, and framework than the straight design. Comparing the framework materials, zirconia and metal exhibited reduced cortical bone and implants stresses but elevated framework stress when compared with the polymeric frameworks. CONCLUSIONS: From a biomechanical viewpoint, in edentulous patients with excessive posterior alveolar bone resorption, the inclined design exhibited more favorable stress distribution around the posterior implants than the straight design. In implant-supported complete-arch fixed mandibular prostheses, zirconia and metal, particularly cobalt-chromium alloy, distributed the stresses more effectively to the implants and supporting bone than polymeric materials.

Programmable Assembly of Multivalent DNA-Protein Superstructures for Tumor Imaging and Targeted Therapy.

Programmable DNA materials hold great potential in biochemical and biomedical researches, yet the complicated synthesis, and the low stability and targeting efficacy in complex biological milieu limit their clinical translations. Here we show a one-pot assembly of DNA-protein superstructures as drug vehicles with specifically high affinity and stability for targeted therapy. This is achieved by biomimetic assembly of programmable polymer DNA wire into densely packed DNA nanosphere with an alkaline protein, protamine. Multivalent DNA nanostructures encoded with different types and densities of aptamers exhibit high affinity to targeted cells through polyvalent interaction. Our results show high cancer cell selectivity, reduced side effect, excellent therapeutic efficacy, and sensitive tumor imaging in both subcutaneous and orthotopic non-small-cell lung cancer murine models. This biomimetic assembly approach provides practical DNA nanomaterials for further clinical trials and may advance oligonucleotide drug delivery.

Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse.

Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of HSP (not observed in spastin knockout mice) were adult onset, as is typical of human patients. Results of histological and tracer studies on the mouse are consistent with progressive dying back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin. These results on the SPASTC448Y mouse are consistent with a gain-of-function mechanism underlying HSP, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone.

Precision Spherical Nucleic Acids Enable Sensitive FEN1 Imaging and Controllable Drug Delivery for Cancer-Specific Therapy.

Accurate diagnosis and targeted therapy are essential to precision theranostics. However, nonspecific response of theranostic agents in healthy tissues impedes their practical applications. Here, we design an activatable DNA nanosphere for specifically in situ sensing of cancer biomarker flap endonuclease 1 (FEN1) and spatiotemporally modulating drug release. The gold nanostar-conjugated FEN1 substrate acts as spherical nucleic acid and induces a fluorescence signal upon a FEN1 stimulus for diagnosis. Guided by the nanoflare, external NIR light then triggers a controlled release of carried drugs at desired sites. This DNA nanosphere not only exhibits good stability, sensitivity, and specificity toward FEN1 assay but also serves as a precision theranostic agent for targeted and controlled drug delivery. Our study provides a reliable method for FEN1 imaging in vitro and in vivo and suggests a powerful strategy for precision medicine.

Insights into oral bioavailability enhancement of therapeutic herbal constituents by cytochrome P450 3A inhibition.

Herbal plants typically have complex compositions and diverse mechanisms. Among them, bioactive constituents with relatively high exposure in vivo are likely to exhibit therapeutic efficacy. On the other hand, their bioavailability may be influenced by the synergistic effects of different bioactive components. Cytochrome P450 3A (CYP3A) is one of the most abundant CYP enzymes, responsible for the metabolism of 50% of approved drugs. In recent years, many therapeutic herbal constituents have been identified as CYP3A substrates. It is more evident that CYP3A inhibition derived from the herbal formula plays a critical role in improving the oral bioavailability of therapeutic constituents. CYP3A inhibition may be the mechanism of the synergism of herbal formula. In this review, we explored the multiplicity of CYP3A, summarized herbal monomers with CYP3A inhibitory effects, and evaluated herb-mediated CYP3A inhibition, thereby providing new insights into the mechanisms of CYP3A inhibition-mediated oral herb bioavailability.

Polysaccharide CM1 from Cordyceps militaris hinders adipocyte differentiation and alleviates hyperlipidemia in LDLR(+/-) hamsters.

BACKGROUND: Cordyceps militaris is cultured widely as an edible mushroom and accumulating evidence in mice have demonstrated that the polysaccharides of Cordyceps species have lipid-lowering effects. However, lipid metabolism in mice is significantly different from that in humans, making a full understanding of the mechanisms at play critical. METHODS: After 5 months, the hamsters were weighed and sampled under anesthesia after overnight fasting. The lipid-lowering effect and mechanisms of the polysaccharide CM1 was investigated by cellular and molecular technologies. Furthermore, the effect of the polysaccharide CM1 (100 µg/mL) on inhibiting adipocyte differentiation was investigated in vitro. RESULTS: CM1, a polysaccharide from C. militaris, significantly decreased plasma total cholesterol, triglyceride and epididymal fat index in LDLR(+/-) hamsters, which have a human-like lipid profile. After 5 months' administration, CM1 decreased the plasma level of apolipoprotein B48, modulated the expression of key genes and proteins in liver, small intestine, and epididymal fat. CM1 also inhibited preadipocyte differentiation in 3T3-L1 cells by downregulating the key genes involved in lipid droplet formation. CONCLUSIONS: The polysaccharide CM1 lowers lipid and adipocyte differentiation by several pathways, and it has potential applications for hyperlipidemia prevention.