Activation of β-catenin signaling in aggrecan-expressing cells in temporomandibular joint causes osteoarthritis-like defects

β-Catenin plays a critical role in cartilage formation and development. To further understand the role of β-catenin in osteoarthritis（OA） development in temporomandibular joint（TMJ）, we have generated β-catenin conditional activation mice（β-cat（ex3）^Agc1CreER）by breeding Agc1-CreER mice with β-catenin^flox（ex3/＋）mice. Results of histologic analysis showed the progressive TMJ defects in 3-and 6-month-old β-cat（ex3）^Agc1CreERmice（tamoxifen induction was performed at 2 weeks of age）, including decreased chondrocyte numbers in the superficial layer associated with less Alcian blue staining, increased numbers of hypertrophic chondrocytes in deep layers, and rough articular surface. Compared to the TMJ phenotype of β-cat（ex3）^（Col2CreER）mice, β-cat（ex3）^（Agc1CreER）mice showed much severe morphological defects in the superficial layer of TMJ. This may reflect that Agc1-CreER mice could efficiently target cells in the superficial layer of TMJ. Results of immunostaining showed significantly increased expression of MMP13, Col-X, Adamts4,and Adamts5 in TMJ of β-cat（ex3）^（Agc1CreER）mice. Results of proliferating cell nuclear antigen（PCNA）, Ki67, and terminal deoxinucleotidyl transferase-mediated d UTP-fluorescein nick end labeling（TUNEL） staining further demonstrated that cell proliferation was decreased and cell apoptosis was increased in condylar cartilage of β-cat（ex3）^Agc1CreERmice. Our findings indicate that abnormal upregulation of β-catenin in TMJ leads to defects assembling to OA-like phenotype, further demonstrating that β-catenin plays a critical role in TMJ pathogenesis.

The Hedgehog signalling pathway in bone formation

The Hedgehog（Hh） signalling pathway plays many important roles in development,homeostasis and tumorigenesis.The critical function of Hh signalling in bone formation has been identified in the past two decades.Here,we review the evolutionariiy conserved Hh signalling mechanisms with an emphasis on the functions of the Hh signalling pathway in bone development,homeostasis and diseases.In the early stages of embryonic limb development,Sonic Hedgehog（Shh） acts as a major morphogen in patterning the limb buds.Indian Hedgehog（Ihh） has an essential function in endochondral ossification and induces osteoblast differentiation in the perichondrium.Hh signalling is also involved intramembrane ossification.Interactions between Hh and Wnt signalling regulate cartilage development,endochondral bone formation and synovial joint formation.Hh also plays an important role in bone homeostasis,and reducing Hh signalling protects against age-related bone loss.Disruption of Hh signalling regulation leads to multiple bone diseases,such as progressive osseous heteroplasia.Therefore,understanding the signalling mechanisms and functions of Hh signalling in bone development,homeostasis and diseases will provide important insights into bone disease prevention,diagnoses and therapeutics.

Spatial signalling mediated by the transforming growth factor-β signalling pathway during tooth formation

Tooth development relies on sequential and reciprocal interactions between the epithelial and mesenchymal tissues, and it is continuously regulated by a variety of conserved and specific temporal-spatial signalling pathways. It is well known that suspensions of tooth germ cells can form tooth-like structures after losing the positional information provided by the epithelial and mesenchymal tissues. However, the particular stage in which the tooth germ cells start to form tooth-like structures after losing their positional information remains unclear. In this study, we investigated the reassociation of tooth germ cells suspension from different morphological stages during tooth development and the phosphorylation of Smad2/3 in this process. Four tooth morphological stages were designed in this study. The results showed that tooth germ cells formed odontogenic tissue at embryonic day （E） 14.5, which is referred to as the cap stage, and they formed tooth-like structures at E16.5, which is referred to as the early bell stage, and E18.5, which is referred to as the late bell stage. Moreover, the transforming growth factor-β signalling pathway might play a role in this process.

Expert consensus on difficulty assessment of endodontic therapy

Endodontic diseases are a kind of chronic infectious oral disease. Common endodontic treatment concepts are based on the removal of inflamed or necrotic pulp tissue and the replacement by gutta-percha. However, it is very essential for endodontic treatment to debride the root canal system and prevent the root canal system from bacterial reinfection after root canal therapy(RCT). Recent research, encompassing bacterial etiology and advanced imaging techniques, contributes to our understanding of the root canal system’s anatomy intricacies and the technique sensitivity of RCT. Success in RCT hinges on factors like patients, infection severity, root canal anatomy, and treatment techniques. Therefore, improving disease management is a key issue to combat endodontic diseases and cure periapical lesions. The clinical difficulty assessment system of RCT is established based on patient conditions, tooth conditions, root canal configuration, and root canal needing retreatment, and emphasizes pre-treatment risk assessment for optimal outcomes. The findings suggest that the presence of risk factors may correlate with the challenge of achieving the high standard required for RCT. These insights contribute not only to improve education but also aid practitioners in treatment planning and referral decision-making within the field of endodontics.

Knowledge Reasoning Method Based on Deep Transfer Reinforcement Learning:DTRLpath

In recent years,with the continuous development of deep learning and knowledge graph reasoning methods,more and more researchers have shown great interest in improving knowledge graph reasoning methods by inferring missing facts through reasoning.By searching paths on the knowledge graph and making fact and link predictions based on these paths,deep learning-based Reinforcement Learning(RL)agents can demonstrate good performance and interpretability.Therefore,deep reinforcement learning-based knowledge reasoning methods have rapidly emerged in recent years and have become a hot research topic.However,even in a small and fixed knowledge graph reasoning action space,there are still a large number of invalid actions.It often leads to the interruption of RL agents’wandering due to the selection of invalid actions,resulting in a significant decrease in the success rate of path mining.In order to improve the success rate of RL agents in the early stages of path search,this article proposes a knowledge reasoning method based on Deep Transfer Reinforcement Learning path(DTRLpath).Before supervised pre-training and retraining,a pre-task of searching for effective actions in a single step is added.The RL agent is first trained in the pre-task to improve its ability to search for effective actions.Then,the trained agent is transferred to the target reasoning task for path search training,which improves its success rate in searching for target task paths.Finally,based on the comparative experimental results on the FB15K-237 and NELL-995 datasets,it can be concluded that the proposed method significantly improves the success rate of path search and outperforms similar methods in most reasoning tasks.

Transcriptomic and cellular decoding of scaffolds-induced suture mesenchyme regeneration

Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration.Despite extensive studies on mineralized parenchymal tissue rebuilding,regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet.Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage.But to date,the absence of promising therapeutic biomaterials/scaffolds remains.The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds.To address these issues,in this study,we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds.Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses.A feasible scaffold,polylactic acid electrospinning membrane(PLA),was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center,meanwhile supporting proper osteointegration with defect bony edges.Especially,transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered.This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing,offering clinicians potential choices for regenerating such complicated injuries.

Aberrant activation of latent transforming growth factor-β initiates the onset of temporomandibular joint osteoarthritis

There is currently no effective medical treatment for temporomandibular joint osteoarthritis(TMJ-OA) due to a limited understanding of its pathogenesis. This study was undertaken to investigate the key role of transforming growth factor-β(TGF-β)signalling in the cartilage and subchondral bone of the TMJ using a temporomandibular joint disorder(TMD) rat model, an ageing mouse model and a Camurati–Engelmann disease(CED) mouse model. In the three animal models, the subchondral bone phenotypes in the mandibular condyles were evaluated by μCT, and changes in TMJ condyles were examined by TRAP staining and immunohistochemical analysis of Osterix and p-Smad2/3. Condyle degradation was confirmed by Safranin O staining, the Mankin and OARSI scoring systems and type X collagen(Col X), p-Smad2/3 a and Osterix immunohistochemical analyses. We found apparent histological phenotypes of TMJ-OA in the TMD, ageing and CED animal models, with abnormal activation of TGF-βsignalling in the condylar cartilage and subchondral bone. Moreover, inhibition of TGF-β receptor I attenuated TMJ-OA progression in the TMD models. Therefore, aberrant activation of TGF-β signalling could be a key player in TMJ-OA development.

Clinical evaluation of endoscopic resection for treatment of large gastric stromal tumors

BACKGROUND Gastric stromal tumor is a digestive tract mesenchymal tumor with malignant potential, and endoscopic techniques have been widely used in the treatment of gastric stromal tumors, but there is still controversy over their use for large gastric stromal tumors(≥ 3 cm).AIM To evaluate the clinical long-term efficacy and safety of endoscopic resection for large(≥ 3 cm) gastric stromal tumors.METHODS All patients who underwent endoscopic resection or surgery at our hospital from 2012 to 2017 for pathologically confirmed gastric stromal tumor with a maximum diameter of ≥ 3 cm were collected. The clinical data, histopathologic characteristics of the tumors, and long-term outcomes were recorded.RESULTS A total of 261 patients were included, including 37 patients in the endoscopy group and 224 patients in the surgical group. In the endoscopy group, the maximum tumor diameter was 3-8 cm; the male: Female ratio was 21/16; 34 cases had low-risk tumors, 3 had intermediate-risk, and 0 had high-risk; the mean follow-up time was 30.29 ± 19.67 mo, no patient was lost to follow-up, and no patient received chemotherapy after operation; two patients with recurrence had low-risk stromal tumors, and neither had complete resection under endoscopy. In the surgical group, the maximum tumor diameter was 3-22 cm; the male: Female ratio was 121/103; 103 cases had low-risk tumors, 75 had intermediate-risk, and 46 had high-risk; the average follow-up time was 38.83 ± 21.50 mo, 53 patients were lost to follow-up, and 8 patients had recurrence after operation(6 cases had high-risk tumors, 1 had intermediate-risk, and 1 had low-risk). The average tumor volume of the endoscopy group was 26.67 ± 26.22 cm^3(3.75-120), all of which were less than 125 cm^3. The average volume of the surgical group was 273.03 ± 609.74 cm^3(7-4114). Among all patients with a tumor volume < 125 cm^3,7 with high-risk stromal tumors in the surgical group(37.625 cm^3 to 115.2 cm^3)accounted for 3.8%(7/183); of those with a tumor volume < 125 cm^3, high-risk patients accounted for 50%(39/78). We found that 57.1%(12/22) of patients with high-risk stromal tumors also had endoscopic surface ulcer bleeding and tumor liquefaction on ultrasound or abdominal computed tomography; the ratio of tumors positive for both in high-risk stromal tumors with a volume < 125 cm^3 was 60%(3/5).CONCLUSION Endoscopic treatment is safe for 95.5% of patients with gastric stromal tumors with a tumor diameter ≥ 3 cm and a volume of < 125 cm^3 without endoscopic surface ulcer bleeding or CT liquefaction.

Neuroglobin expression in rats after traumatic brain injury

In this study, we used a rat model of severe closed traumatic brain injury to explore the relationship between neuroglobin, brain injury and neuronal apoptosis. Real-time PCR showed that neuroglobin mRNA expression rapidly increased in the rat cerebral cortex, and peaked at 30 minutes and 48 hours following traumatic brain injury. Immunohistochemical staining demonstrated that neuroglobin expression increased and remained high 2 hours to 5 days following injury. The rate of increase in the apoptosis-related Bax/Bcl-2 ratio greatly decreased between 30 minutes and 1 hour as well as between 48 and 72 hours post injury. Expression of neuroglobin and the anti-apoptotic factor Bcl-2 greatly increased, while that of the proapoptotic factor decreased, in the cerebral cortex post severe closed traumatic brain injury. It suggests that neuroglobin might protect neurons from apoptosis after traumatic injury by regulating Bax/Bcl-2 pathway.

Californium-252 neutron brachytherapy combined with external pelvic radiotherapy plus concurrent chemotherapy for cervical cancer: a retrospective clinical study

Background:Cervical cancer is the sixth most common cancer in Chinese women.A standard treatment modal?ity for cervical cancer is the combination of surgery,chemotherapy,external?beam radiotherapy and intracavitary brachytherapy.The aim of this study was to retrospectively assess the long?term treatment outcomes of patients with cervical cancer who were treated with californium?252 neutron brachytherapy combined with external?beam radio?therapy plus concurrent chemotherapy.Methods:We retrospectively analyzed the medical records of 150 patients with primary stages IB?IVB cervical cancer who received neutron brachytherapy combined with external?beam radiotherapy concurrently with cisplatin chemo?therapy.All patients were followed up.Using an actuarial analysis,patient outcomes and treatment?related adverse effects were evaluated and compared.Results:The median overall survival(OS)was 33.2 months.The 3?year progression?free survival rates for patients with stages I–II,III,and IV diseases were 81.0%(68/84),65.0%(39/60),and 0%(0/6),respectively;the 3?year OS rates were 90.5%(76/84),85.0%(51/60),and 16.7%(1/6),respectively.Vaginal bleeding was controlled within the median time of4.0 days.One month after treatment,97.3%of patients achieved short?term local control.The local recurrence rates for patients with stages I–II,III,and IV disease were 4.8%(4/84),11.7%(7/60),and 33.3%(2/6),respectively,and the occurrence rates of distant metastasis were 16.7%(14/84),25.0%(15/60),and 100.0%(6/6),respectively.Cancer stage,tumor size,and lymph node metastasis were identified as prognostic risk factors,but only lymph node metastasis was found to be an independent prognostic factor.The most common adverse effects during treatment were grades 1 and 2 irradiation?related proctitis and radiocystitis.Conclusion:For patients with cervical cancer,neutron brachytherapy combined with external?beam radiotherapy plus concurrent chemotherapy produces a rapid response and greatly improves local control and long?term survival rates with tolerable adverse effects.

Comparison of Effects of Mechanical Stretching on Osteogenic Potential of ASCs and BMSCs

Mechanical forces play critical roles in the development and remodeling processes of bone. As an alternative cell source for bone engineering, adipose-derived stem cells （ASCs） should be fully investigated for their responses to mechanical stress. Similarly, the osteogenic potential, stimulated by mechanical stress, should be compared with bone marrow stromal cells （BMSCs）, which have been clinically used for bone tissue engineering. In this study, ASCs and BMSCs were osteogenic-induced for 48 hours, and then subjected to uniaxial mechanical stretching for 2 or 6 hours. Cell orientation, osteogenic regulatory genes, osteogenic genes and ALP activities were measured and compared between ASCs and BMSCs. ASCs could align in a perpendicular way to the direction of stretching stress, while BMSCs did not present a specific alignment. Both 2 and 6 hours mechanical stretching could enhance the mRNA expression of Osx and Runx2 in BMSCs and ASCs, while OCN mRNA only increased in ASCs after 6 hours mechanical loading. Mechanical stretching enhanced the BMP-2 mRNA expression in ASCs, while only after 6 hours of mechanical loading significantly increased the BMP-2 gene expression in BMSCs. Significant differences only exist between ASCs and BMSCs loaded at 2 hours of mechanical stretching. It is concluded that ASCs are more rapid responders to mechanical stress, and have greater potential than BMSCs in osteogenesis when stimulated by mechanical stretching, indicating their usefulness for bone study in a rat model.

NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts

The adaptor protein NUMB is involved in asymmetric division and cell fate determination and recognized as an antagonist of Notch.Previous studies have proved that Notch activation in osteoblasts contributes to a high bone mass. In this study, however, an osteopenic phenotype was found in 9-week-old mice using osteoblastic specific Col1a1–2.3-Cre to ablate both Numb and its homologue Numbl. The trabecular bone mass decreased dramatically while the cortical bone mass was unaffected. Here, the Notch signal was not activated,while the tensin homologue deleted on human chromosome 10(PTEN), which dephosphorylates phosphatidylinositide 3-kinases, was elevated, attenuating protein kinase B(Akt). The ubiquitination assay revealed that NUMB may physiologically promote PTEN ubiquitination in the presence of neural precursor cell-expressed developmentally downregulated protein 4–1. In addition, the deficiency of Numb/Numbl also activated the Hedgehog pathway through GLI1. This process was found to improve the ratio of the receptor activator of nuclear factor-k B ligand to osteoprotegerin, which enhanced the differentiation of osteoclasts and bone resorption. In conclusion, this study provides an insight into new functons of NUMB and NUMBL on bone homeostasis.

Bone morphogenetic protein 2-induced human dental pulp cell differentiation involves p38 mitogen-activated protein kinase-activated canonical WNT pathway

Both bone morphogenetic protein 2（BMP2） and the wingless-type MMTV integration site（WNT）/p-catenin signalling pathway play important roles in odontoblast differentiation and dentinogenesis.Cross-talk between BMP2 and WNT/p-catenin in osteoblast differentiation and bone formation has been identified.However,the roles and mechanisms of the canonical WNT pathway in the regulation of BMP2 in dental pulp injury and repair remain largely unknown.Here,we demonstrate that BMP2 promotes the differentiation of human dental pulp cells（HDPCs） by activating WNT/p-catenin signalling,which is further mediated by p38mitogen-activated protein kinase（MAPK） in vitro.BMP2 stimulation upregulated the expression of p-catenin in HDPCs,which was abolished by SB203580 but not by Noggin or LDN193189.Furthermore,BMP2 enhanced cell differentiation,which was not fully inhibited by Noggin or LDN193189.Instead,SB203580 partially blocked BMP2-induced p-catenin expression and cell differentiation.Taken together,these data suggest a possible mechanism by which the elevation of p-catenin resulting from BMP2 stimulation is mediated by the p38 MAPK pathway,which sheds light on the molecular mechanisms of BMP2-mediated pulp reparative dentin formation.

Diverse microbiota in palatal radicular groove analyzed by Illumina sequencing:Four case reports

BACKGROUND A palatal radicular groove is an unusual developmental deformity of the tooth,which may serve as a channel linking the periodontal and periapical inflammation,and yet no literature could be obtained analyzing microbiota within the palatal radicular grooves.CASE SUMMARY Four patients diagnosed with palatal radicular groove and concomitant periodontal-endodontic deformity in permanent maxillary lateral incisors were enrolled in this work.Twelve bacterial samples from 4 patients were collected from different parts of the palatal radicular groove during intentional replantation surgery.Illumina sequencing was performed to analyze the taxonomical composition and microbiome structure inside the palatal grooves,and 1162 operational taxonomic units were obtained.The phyla of Firmicutes and Proteobacteria predominated in most of the samples.An unknown genus from the Bacillaceae family,Lactococcus,and Porphyromonas were the most abundant genera identified.There was no difference in the microbiota richness and diversity in three sections of the groove.CONCLUSION The unique ecological niches inside the palatal grooves harbored bacterial communities that shared some component features of both the endodontic and periodontal infections.The existence of palatal groove may play an interaction bridge between the root apex and tooth cervix and thus impair the outcome of traditional therapeutic methods such as root canal treatment and periodontal management.

Aberrant NF-κB activation in odontoblasts orchestrates inflammatory matrix degradation and mineral resorption

Inflammation-associated proteinase functions are key determinants of inflammatory stromal tissues deconstruction.As a specialized inflammatory pathological process,dental internal resorption(IR)includes both soft and hard tissues deconstruction within the dentin-pulp complex,which has been one of the main reasons for inflammatory tooth loss.Mechanisms of inflammatory matrix degradation and tissue resorption in IR are largely unclear.In this study,we used a combination of Cre-loxP reporter,flow cytometry,cell transplantation,and enzyme activities assay to mechanistically investigate the role of regenerative cells,odontoblasts(ODs),in inflammatory mineral resorption and matrices degradation.We report that inflamed ODs have strong capabilities of matrix degradation and tissue resorption.Traditionally,ODs are regarded as hard-tissue regenerative cells;however,our data unexpectedly present ODs as a crucial population that participates in IR-associated tissue deconstruction.Specifically,we uncovered that nuclear factor-kappa b(NF-κB)signaling orchestrated Tumor necrosis factorα(TNF-α)-induced matrix metalloproteinases(Mmps)and Cathepsin K(Ctsk)functions in ODs to enhance matrix degradation and tissue resorption.Furthermore,TNF-αincreases Rankl/Opg ratio in ODs via NF-κB signaling by impairing Opg expression but increasing Rankl level,which utterly makes ODs cell line 17IIA11(A11)become Trap^(+) and Ctsk^(+) multinucleated cells to perform resorptive actions.Blocking of NF-κB signaling significantly rescues matrix degradation and resorptive functions of inflamed ODs via repressing vital inflammatory proteinases Mmps and Ctsk.Utterly,via utilizing NF-κB specific small molecule inhibitors we satisfactorily attenuated inflammatory ODs-associated human dental IR in vivo.Our data reveal the underlying mechanisms of inflammatory matrix degradation and resorption via proteinase activities in IR-related pathological conditions.

Bivalent histone modifications during tooth development

Histone methylation is one of the most widely studied post-transcriptional modifications. It is thought to be an important epigenetic event that is closely associated with cell fate determination and differentiation. To explore the spatiotemporal expression of histone H3 lysine 4trimethylation（H3K4me3） and histone H3 lysine 27 trimethylation（H3K27me3） epigenetic marks and methylation or demethylation transferases in tooth organ development, we measured the expression of SET7, EZH2, KDM5 B and JMJD3 via immunohistochemistry and quantitative polymerase chain reaction（qP CR） analysis in the first molar of BALB/c mice embryos at E13.5, E15.5, E17.5, P0 and P3, respectively. We also measured the expression of H3K4me3 and H3K27me3 with immunofluorescence staining. During murine tooth germ development, methylation or demethylation transferases were expressed in a spatial–temporal manner. The bivalent modification characterized by H3K4me3 and H3K27me3 can be found during the tooth germ development, as shown by immunofluorescence. The expression of SET7, EZH2 as methylation transferases and KDM5 B and JMJD3 as demethylation transferases indicated accordingly with the expression of H3K4me3 and H3K27me3 respectively to some extent. The bivalent histone may play a critical role in tooth organ development via the regulation of cell differentiation.

Correlation between prion protein gene codon 129 polymorphism and late-onset Alzheimer's disease

BACKGROUND： Studies addressing the correlation between prion protein gene codon 129 polymorphism, Alzheimer＇s disease, and cognitive disorders have mainly focused on Caucasians. However, prion protein gene codon 129 polymorphism is thought to also affect the Chinese Han and Wei populations. OBJECTIVE： To analyze the differences of prion protein gene codon 129 distribution among the elderly Chinese Han, East Asian, and Caucasian populations, and to study the correlation between prion protein gene codon 129 distribution and late-onset Alzheimer＇s disease. DESIGN, TIME AND SETTING： A gene polymorphism analysis was performed in the Institute of Geriatrics, General Hospital of Chinese PLA between January 2006 and January 2007. PARTICIPANTS： A total of 152 elderly Chinese Han people were selected from the Beijing Troop Cadre＇s Sanitarium. Among them, 60 patients with late-onset Alzheimer＇s disease, with a mean age of （82 ± 7） years （range 67-94 years） and disease course of （5.9 ± 4.4） years, comprising 44 males with a mean age of （83 ± 7） years and 16 females with a mean age of （78 ±7） years, were selected for the case group. An additional 92 healthy elderly subjects, with a mean of （76 ± 9） years （range 60-94 years）, comprising 76 males with a mean age of （77 ± 9） years and 16 females with a mean age of （70 ± 8） years, were selected for the control group. There were no significant differences in age and gender between the two groups （P〉 0.05）. METHODS： DNA was extracted from peripheral blood leukocytes using routine phenol/chloroform methodology. Prion protein gene codon 129 potymorphism and ApoE polymorphism were measured using PCR-restriction fragment length polymorphism. The ApoEε allele was considered the standard for analyzing correlations between prion protein gene codon 129 polymorphism and late-onset Alzheimer＇s disease. MAIN OUTCOME MEASURES： Prion protein gene codon 129 distribution; correlation between genotypic frequency and allele frequency of prion protein gene codon 129 with Alzheimer＇s disease; relationship between methionine/methionine genotype of priori protein gene, ApoEε4 allele, gender, and age of Alzheimer＇s disease patients. RESULTS： Methionine/methionine genotypic frequency of prion protein gene codon 129 was 94.08% in the Chinese elderly population, and the methionine/valine genotypic frequency was 5.92%. However, valine/valine homozygotes were not determined. There was no significant difference in prion protein gene codon 129 polymorphism between the Chinese elderly and East Asian populations （P〉 0.05）. However, there was a significant difference between the Chinese elderly and the Caucasian population （P 〈 0.05）. The methionine/methionine genotype for the positive and negative ApoEε4 alleles was a risk factor for increased incidence of Alzheimer＇s disease, but there was no significant difference between the positives and the negatives （odds ratio = 1.33, 95% confidence interval = 0.32-6.49, P〉 0.05）. CONCLUSION： Prion protein gene codon 129 distribution in the Chinese elderly was different from the Caucasian population, which suggested that the methionine/methionine genotype of prion protein gene codon 129 negatively correlated with late-onset Alzheimer＇s disease.

Giant tumor resection under ultrasound-guided nerve block in a patient with severe asthma:A case report

BACKGROUND General anesthesia in critically ill patients is associated with increased risk of complications.Nerve block anesthesia is an alternative,but could be challenging in cases with surgical field that involves multiple dermatomes.CASE SUMMARY We report resection of a giant lipoma in the left shoulder and upper back under supraclavicular brachial plexus block plus T3-4 paravertebral block in an older patient with severe asthma.A 70-year-old patient presented with a slow-growing giant mass(25,15 and 5 cm in length,width and depth,respectively)that extended from the lateral side of the left scapula to the axillary midline,and from the T5 thoracic vertebra intercostal to the mid-medial section of the left upper arm.He had sharp intermittent pain over the mass for the past 7 d.The patient also had severe bronchial asthma for the past 8 years.A pulmonary function test revealed only 20%of the predicted forced expiratory volume in 1 second(FEV1,0.49 L).After controlling asthma with glucocorticoid,the tumor was resected under ultrasound-guided supraclavicular brachial plexus block and T3-4 paravertebral block.The surgery was completed without incident.CONCLUSION Ultrasound-guided regional nerve block is a viable alternative for patients with poor cardiopulmonary function undergoing shoulder,back and axillary surgery.

Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties

Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmacophores within a single-molecule framework.To address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a wellknown local anesthetic.DeepSA integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound generation.This framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent constraints.Through a sequence of local editing to navigate the molecular space,DeepSA successfully identified AT-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models.Mechanistic insights into AT-17 revealed its dual mode of action:selective inhibition of NaV1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway.These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.

Wnt/β-catenin signaling in cancers and targeted therapies

Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals.Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence,advancement of malignant progression,development of poor prognostics,and even ascendence of the cancer-associated mortality.Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers.Up to date,many therapies targeting Wnt/β-catenin signaling in cancers have been developed,which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling.