AttentionPert: accurately modeling multiplexed genetic perturbations with multi-scale effects.

MOTIVATION: Genetic perturbations (e.g. knockouts, variants) have laid the foundation for our understanding of many diseases, implicating pathogenic mechanisms and indicating therapeutic targets. However, experimental assays are fundamentally limited by the number of measurable perturbations. Computational methods can fill this gap by predicting perturbation effects under novel conditions, but accurately predicting the transcriptional responses of cells to unseen perturbations remains a significant challenge. RESULTS: We address this by developing a novel attention-based neural network, AttentionPert, which accurately predicts gene expression under multiplexed perturbations and generalizes to unseen conditions. AttentionPert integrates global and local effects in a multi-scale model, representing both the nonuniform system-wide impact of the genetic perturbation and the localized disturbance in a network of gene-gene similarities, enhancing its ability to predict nuanced transcriptional responses to both single and multi-gene perturbations. In comprehensive experiments, AttentionPert demonstrates superior performance across multiple datasets outperforming the state-of-the-art method in predicting differential gene expressions and revealing novel gene regulations. AttentionPert marks a significant improvement over current methods, particularly in handling the diversity of gene perturbations and in predicting out-of-distribution scenarios. AVAILABILITY AND IMPLEMENTATION: Code is available at https://github.com/BaiDing1234/AttentionPert.

H2Se-evolving bio-heterojunctions promote cutaneous regeneration in infected wounds by inhibiting excessive cellular senescence.

Pathogenic infection leads to excessive senescent cell accumulation and stagnation of wound healing. To address these issues, we devise and develop a hydrogen selenide (H2Se)-evolving bio-heterojunction (bio-HJ) composed of graphene oxide (GO) and FeSe2 to deracinate bacterial infection, suppress cellular senescence and remedy recalcitrant infected wounds. Excited by near-infrared (NIR) laser, the bio-HJ exerts desired photothermal and photodynamic effects, resulting in rapid disinfection. The crafted bio-HJ could also evolve gaseous H2Se to inhibit cellular senescence and dampen inflammation. Mechanism studies reveal the anti-senescence effects of H2Se-evolving bio-HJ are mediated by selenium pathway and glutathione peroxidase 1 (GPX1). More critically, in vivo experiments authenticate that the H2Se-evolving bio-HJ could inhibit cellular senescence and potentiate wound regeneration in rats. As envisioned, our work not only furnishes the novel gasotransmitter-delivering bio-HJ for chronic infected wounds, but also gets insight into the development of anti-senescence biomaterials.

Does curve of Spee affect the precision of 3D-printed curvature-adaptive splints?

OBJECTIVES: This study aimed to propose a standardized protocol for the fabrication of three-dimensionally (3D)-printed curvature-adaptive splints (CASs) and assess the precision of CASs on dentitions with different depths of the curve of Spee (COS). METHODS: 76 lower dental resin models, each exhibiting one of the four types of COS (0-, 2-, 4-, and 6-mm deep), were selected and digitally scanned. CASs were designed, 3D printed, and grouped into C0, C2, C4, and C6, corresponding to the four types of COS depths. To assess precision, the CASs occluded with the resin model were scanned as a whole and compared with the originally designed ones. RESULTS: In terms of translational deviations observed in the CASs, the mean value of absolute sagittal deviation (0.136 mm) was significantly higher than those of vertical (0.091 mm) and transversal deviations (0.045 mm) (P < 0.01). Regarding rotational deviations of the CASs, the mean deviation in pitch (0.323°) was significantly higher than those in yaw (0.083°) and roll (0.110°) (P < 0.01). However, when comparing the accuracy of CASs across C0, C2, C4, and C6 groups, no statistically significant difference was found. Additionally, the translational deviations, rotational deviations, and RMSE of all groups were significantly lower than the clinically acceptable limits of 0.5 mm, 1°, and 0.25 mm, respectively (P < 0.01). CONCLUSIONS: The depth of the COS has no significant impact on the precision of CASs, as evidenced by the absence of statistically significant differences in translational, rotational deviations, and RMSE among all groups (C0, C2, C4, and C6). Moreover, despite relatively high deviations in the sagittal dimension and pitch, all dimensional deviations and RMSE remained statistically significantly lower than the corresponding clinically acceptable limits (CALs) in all groups. CLINICAL SIGNIFICANCE: This standardized protocol incorporating "curvature-adaptation" represents an optimized approach to fabricating diverse 3D-printed splints tailored to dentitions with different anatomical features in contemporary digital dentistry.

Mechanism of fibroblast growth factor 1 regulating fatty liver disorder in mule ducks.

Mule ducks tend to accumulate abundant fat in their livers via feeding, which leads to the formation of a fatty liver that is several times larger than a normal liver. However, the mechanism underlying fatty liver formation has not yet been elucidated. Fibroblast growth factor 1 (FGF1), a member of the FGF superfamily, is involved in cellular lipid metabolism and mitosis. This study aims to investigate the regulatory effect of FGF1 on lipid metabolism disorders induced by complex fatty acids in primary mule duck liver cells and elucidate the underlying molecular mechanism. Hepatocytes were induced by adding 1,500:750 µmol/L oleic and palmitic acid concentrations for 36 h, which were stimulated with FGF1 concentrations of 0, 10, 100, and 1000 ng/mL for 12 h. The results showed that FGF1 significantly reduced the hepatic lipid droplet deposition and triglyceride content induced by complex fatty acids; it also reduced oxidative stress; decreased reactive oxygen species fluorescence intensity and malondialdehyde content; upregulated the expression of antioxidant factors nuclear factor erythroid 2 related factor 2 (Nrf2), HO-1, and NQO-1; significantly enhanced liver cell activity; promoted cell cycle progression; inhibited cell apoptosis; upregulated cyclin-dependent kinase 1 (CDK1) and BCL-2 mRNA expression; and downregulated Bax and Caspase-3 expression. In addition, FGF1 promoted AMPK phosphorylation, activated the AMPK pathway, upregulated AMPK gene expression, and downregulated the expression of SREBP1 and ACC1 genes, thereby alleviating excessive fat accumulation in liver cells induced by complex fatty acids. In summary, FGF1 may alleviate lipid metabolism disorders induced by complex fatty acids in primary mule duck liver cells by activating the AMPK signaling pathway.

Altered expression of transfer RNAs and their possible roles in brain white matter injury.

Transfer RNAs (tRNAs) can regulate cell behavior and are associated with neurological disorders. Here, we aimed to investigate the expression levels of tRNAs in oligodendrocyte precursor cells (OPCs) and their possible roles in the regulation of brain white matter injury (WMI). Newborn Sprague-Dawley rats (postnatal day 5) were used to establish a model that mimicked neonatal brain WMI. RNA-array analysis was performed to examine the expression of tRNAs in OPCs. psRNAtarget software was used to predict target mRNAs of significantly altered tRNAs. Gene ontology (GO) and KEGG were used to analyze the pathways for target mRNAs. Eighty-nine tRNAs were changed after WMI (fold change absolute ≥1.5, P  < 0.01), with 31 downregulated and 58 upregulated. Among them, three significantly changed tRNAs were identified, with two being significantly increased (chr10.trna1314-ProTGG and chr2.trna2771-ProAGG) and one significantly decreased (chr10.trna11264-GlyTCC). Further, target mRNA prediction and GO/KEGG pathway analysis indicated that the target mRNAs of these tRNAs are mainly involved in G-protein coupled receptor signaling pathways and beta-alanine metabolism, which are both related to myelin formation. In summary, the expression of tRNAs in OPCs was significantly altered after brain WMI, suggesting that tRNAs may play important roles in regulating WMI. This improves the knowledge about WMI pathophysiology and may provide novel treatment targets for WMI.

Does clinical experience affect the bracket bonding accuracy of guided bonding devices in vitro?

OBJECTIVES: To study whether and how the clinical experience of the operator affects the accuracy of bracket placement using guided bonding devices (GBDs) in vitro. MATERIALS AND METHODS: Five resin models were bonded virtually with brackets, and the corresponding GBDs were generated and three-dimensionally printed. Nine operators, which included three dental students, three orthodontic students, and three orthodontists, bonded the brackets on the resin models using GBDs on a dental mannequin. After being bonded with brackets, the models were scanned, and the actual and designed positions of the brackets were compared. RESULTS: There was no immediate debonding. The orthodontists spent a significantly shorter time (22.36 minutes) in bracket bonding than the dental students (24.62 minutes; P < .05). The brackets tended to deviate to the buccal side in the dental student group. Linear deviations tended to be smallest in the orthodontic student group, but no significant difference was found among operators with different clinical experience (P > .5). All linear and angular deviations in each group were under 0.5 mm and 2°, respectively. CONCLUSIONS: Clinical experience was positively related to the bonding accuracy using GBDs, especially in the buccolingual dimension. Inexperience also led to longer bonding duration. However, bonding accuracy was clinically acceptable in general.

Engineered Bio-Heterojunction Confers Extra- and Intracellular Bacterial Ferroptosis and Hunger-Triggered Cell Protection for Diabetic Wound Repair.

Nanomaterial-mediated ferroptosis has garnered considerable interest in the antibacterial field, as it invokes the disequilibrium of ion homeostasis and boosts lipid peroxidation in extra- and intracellular bacteria. However, current ferroptosis-associated antibacterial strategies indiscriminately pose damage to healthy cells, ultimately compromising their biocompatibility. To address this daunting issue, this work has designed a precise ferroptosis bio-heterojunction (F-bio-HJ) consisting of Fe2 O3 , Ti3 C2 -MXene, and glucose oxidase (GOx) to induce extra-intracellular bacteria-targeted ferroptosis for infected diabetic cutaneous regeneration. Fe2 O3 /Ti3 C2 -MXene@GOx (FMG) catalytically generates a considerable amount of ROS which assaults the membrane of extracellular bacteria, facilitating the permeation of synchronously generated Fe2+ /Fe3+ into bacteria under near-infrared (NIR) irradiation, causing planktonic bacterial death via ferroptosis, Fe2+ overload, and lipid peroxidation. Additionally, FMG facilitates intracellular bacterial ferroptosis by transporting Fe2+ into intracellular bacteria via inward ferroportin (FPN). With GOx consuming glucose, FMG creates hunger protection which helps macrophages escape cell ferroptosis by activating the adenosine 5'-monophosphate (AMP) activated protein kinase (AMPK) pathway. In vivo results authenticate that FMG boosts diabetic infectious cutaneous regeneration without triggering ferroptosis in normal cells. As envisaged, the proposed tactic provides a promising approach to combat intractable infections by precisely terminating extra-intracellular infection via steerable ferroptosis, thereby markedly elevating the biocompatibility of therapeutic ferroptosis-mediated strategies.

Customized planning of the visible maxillary arch width in harmony with interparopia width and smile width for female facial aesthetics.

BACKGROUND: The visible maxillary arch width (VAW) is an important aesthetic-determining feature. To date, there is no well-established methodology to determine the aesthetically optimal VAW in customized treatment planning. METHODS: In this study, the common traits of the dentofacial configuration were investigated in most attractive Asian and Caucasian female smiles. The smiling photo of a subject was digitally modified based on combined variations of VAW, smile width (SW), transverse facial dimensions (TFD), and vertical facial dimensions. These modified photos were assessed for aesthetics. The aesthetically essential parameters were identified, and their mathematic correlations and reference ranges were determined for different vertical facial patterns. Using the obtained results, a mathematic guidance was constructed for customized smile designing. The applicability of this guidance was tested in Asian females. RESULTS: The most attractive Asian and Caucasian female smiles have intraracial and interracial commonalities in the VAW-to-TFD ratios. The interparopia width (IPD) predominated over facial widths in determining well-matched VAW and SW. For optimal smile aesthetics, the VAW and SW were correlated as simulated by the formula 1.92 IPD ≤ VAW + 2.3 SW ≤ 2.17 IPD, plus the VAW-to-IPD ratio within 0.54 to 0.62 and the SW-to-IPD ratio within 0.61 to 0.71, ranges tailored to vertical facial patterns. This constitutes a mathematic guidance for customized planning of the aesthetically optimal VAW. This guidance was preliminarily validated to be applicable to Asian females. CONCLUSIONS: The VAW-to-TFD ratios were essential for Caucasian and Asian female smile aesthetics. The mathematic guidance could serve as a reference for customized smile designs for Asian females.

Antibacterial and Angiogenic (2A) Bio-Heterojunctions Facilitate Infectious Ischemic Wound Regeneration via an Endogenous-Exogenous Bistimulatory Strategy.

In infectious ischemic wounds, a lack of blood perfusion significantly worsens microbe-associated infection symptoms and frequently complicates healing. To overcome this daunting issue, antibacterial and angiogenic (2A) bio-heterojunctions (bio-HJs) consisting of CuS/MXene heterojunctions and a vascular endothelial growth factor (VEGF)-mimicking peptide (VMP) are devised and developed to accelerate infectious cutaneous regeneration by boosting angiogenesis via an endogenous-exogenous bistimulatory (EEB) strategy. Assisted by near-infrared irradiation, the bio-HJ platform exhibits versatile synergistic photothermal, photodynamic, and chemodynamic effects for robust antibacterial efficacy. In addition, copper ions liberated from 2A bio-HJs elevate VEGF secretion from fibroblasts, which provokes VEGF receptors (VEGFR) activation through an endogenous pathway, whereas VMP itself promotes an exogenous pathway to facilitate endothelial cell multiplication and tube formation by directly activating the VEGFR signaling pathway. Moreover, employing an in vivo model of infectious ischemic wounds, it is confirmed that the EEB strategy can considerably boost cutaneous regeneration through pathogen elimination, angiogenesis promotion, and collagen deposition. As envisaged, this work leads to the development of a powerful 2A bio-HJ platform that can serve as an effective remedy for bacterial invasion-induced ischemic wounds through the EEB strategy.

Optimal settings for different tooth types in the virtual bracket removal technique.

OBJECTIVES: To determine the optimal settings for reconstructing the buccal surfaces of different tooth types using the virtual bracket removal (VBR) technique. MATERIALS AND METHODS: Ten postbonded digital dentitions (with their original prebonded dentitions) were enrolled. The VBR protocol was carried out under five settings from three commonly used computer-aided design (CAD) systems: OrthoAnalyzer (O); Meshmixer (M); and curvature (G2), tangent (G1), and flat (G0) from Geomagic Studio. The root mean squares (RMSs) between the reconstructed and prebonded dentitions were calculated for each tooth and compared with the clinically acceptable limit (CAL) of 0.10 mm. RESULTS: The overall prevalences of RMSs below the CAL were 66.80%, 70.08%, 62.30%, 94.83%, and 56.15% under O, M, G2, G1, and G0, respectively. For the upper dentition, the mean RMSs were significantly lower than the CAL for all tooth types under G1 and upper incisors and canines under M and G2. For the lower dentition, the mean RMSs were significantly lower than the CAL for all tooth types under G1 and lower incisors and canines under M, G2, and G0 (all P < .05). Additionally, the mean RMSs of all teeth under G1 were significantly lower than those under the other settings (all P < .001). CONCLUSIONS: The optimal settings varied among different tooth types. G1 performed best for most tooth types compared to the other four settings.

Assessment tools for stigma in breast cancer patients based on COSMIN guidelines: a systematic review.

OBJECTIVE: The objective of this study was to conduct a systematic review of the measurement properties and methodological quality of stigma assessment tools designed for breast cancer patients. The aim was to provide clinical medical staff with a foundation for selecting high-quality assessment tools. METHODS: A comprehensive computer search was carried out across various databases, including SinoMed, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database(VIP), Embase, PubMed, Web of Science, The Cochrane Library, and Scopus, which were searched from the inception of the databases until March 20, 2023. Literature screening and data extraction were performed independently by two researchers, adhering to predefined inclusion and exclusion criteria. The assessment tools were evaluated using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) systematic evaluation guidelines. RESULTS: In the final analysis, a total of 9 assessment tools were included. However, none of these tools addressed measurement error, cross-cultural validity, criterion validity, and responsiveness. Following the COSMIN guidelines, BCSS and CSPDS were assigned to Class A recommendations, while the remaining tools received Class B recommendations. CONCLUSION: The BCSS and CSPDS scales demonstrated comprehensive assessment in terms of their measurement characteristics, exhibiting good methodological quality, measurement attribute quality, and supporting evidence. Therefore, it is recommended to utilize these scales for evaluating breast cancer stigma. However, further validation is required for the remaining assessment tools.

Abnormal mechanical stress induced chondrocyte senescence by YAP loss-mediated METTL3 upregulation.

OBJECTIVES: Abnormal mechanical stress is the pivotal risk factor of temporomandibular joint osteoarthritis (TMJOA). This study investigated the pathogenic mechanism by which abnormal mechanical stress induced chondrocyte senescence. MATERIALS AND METHODS: Cellular senescence was investigated in the rodent model of unilateral anterior crossbite and in the chondrocytes subjected to mechanical overloading in vitro. The effects of Yes-associated protein (YAP) in chondrocyte senescence and its correlation with methyltransferase-like 3 (METTL3) and N6 -methyladenosine (m6 A) modification were evaluated. The role of m6 A modification in chondrocyte senescence was determined. The therapeutic effects of m6 A inhibition in TMJOA were investigated. RESULTS: Senescent chondrocytes were accumulated in the mechanically induced TMJOA lesions in rats and mechanical overloading could trigger chondrocyte senescence in vitro. This mechanical stress-induced cellular senescence was revealed to be mediated by YAP deficiency that promoted METTL3-dependent m6 A modification. Moreover, inhibition of m6 A modification rescued chondrocyte senescence in vitro and in vivo, and suppressed TMJOA progression in rats. CONCLUSIONS: This study uncovered the underlying mechanism of mechanically induced senescence in TMJOA from the perspective of epitranscriptomics and revealed the therapeutic potential of m6 A inhibition in TMJOA.

Reliability and validity of the Chinese version of the trauma-specific frailty index (TSFI) for geriatric trauma patients.

BACKGROUND: Pre-traumatic frailty in geriatric trauma patients has caught attention from emergency medical workers and the assessment of it thus become one of the important aspects of risk management. Several tools are available to identify frailty, but limited tools have been validated for geriatric trauma patients in China to assess pre-traumatic frailty.The aim of this study is to translate the Trauma-Specific Frailty Index(TSFI) into Chinese, and to evaluate the reliability and validity of the translated version in geriatric trauma patients. METHODS: A cross-sectional study was conducted. The TSFI was translated with using the Brislin model, that included forward and backward translation. A total of 184 geriatric trauma patients were recruited by a convenience sampling between October and December 2020 in Hospital of Chengdu University of Traditional Chinese Medicine, Sichuan. Using reliability or internal consistency tests assessed with Cronbach's alpha coefficient, split-half reliability and test-retest reliability. Content validity and construct validity analysis were both performed. Sensitivity, specificity and maximum Youden index(YI) were used to determine the optimal cut-off value. The screening performance was examined by Kappa value. RESULTS: The total study population included 184 subjects, of which 8 participants were excluded, resulting in a study sample size of 176 elderly trauma patients (the completion rate was 95.7%). The Chinese version of Trauma-Specific Frailty Index(C-TSFI) have 15 items with 5 dimensions. Cronbach's alpha coefficient of the C-TSFI was 0.861, Cronbach's alpha coefficient of dimensions ranged from 0.837 to 0.875, the split-half reliability of the C-TSFI were 0.894 and 0.880 respectively, test-retest reliability ranged from 0.692 to 0.862. The correlation coefficient between items and the C-TSFI ranged from 0.439 to 0.761. The content validity index for items (I-CVI) of the C-TSFI scale was 0.86~1.00, and the scale of content validity index (S-CVI) was 0.93. The area under curve (AUC) of the C-TSFI was 0.932 (95%CI 0.904-0.96, P < 0.05), the maximum YI was 0.725, the sensitivity was 80.2%, the specificity was 92.3%, and the critical value was 0.31. Kappa value was 0.682 (P < 0.05). CONCLUSIONS: The Chinese version of TSFI could be used as a general assessment tool in geriatric trauma patients, and both its reliability and validity have been demonstrated.

Effect of offset on the precision of 3D-printed orthognathic surgical splints.

OBJECTIVE: This study evaluated the effect of offset on the precision of three-dimensional (3D)-printed splints, proposing to optimize the splint design to compensate for systematic errors. MATERIALS AND METHODS: 14 resin model sets were scanned and offset as a whole by given distances (0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, and 0.40 mm). Intermediate splints (ISs) and final splints (FSs) were generated from the non-offset and offset models and grouped correspondingly, named as splint type-offset value, IS-0.05, for instance. Dentitions occluded with the splint were scanned. Translational and rotational deviations of the lower dentition relative to the upper dentition were 3D measured. RESULTS: Deviations of ISs and FSs were more evident in the vertical and pitch dimensions, and were mostly acceptable in other dimensions. ISs with offset ≥ 0.05 mm showed vertical deviations significantly below 1 mm (P < 0.05) while ISs with 0.10- to 0.30-mm offsets had pitch rotations significantly lower than 1° (P < 0.05). The Pitch of IS-0.35 was significantly larger than ISs with 0.15- to 0.30-mm offsets (P < 0.05). Meanwhile, FSs fit better as the offset increased and FSs with offsets ≥ 0.15 mm all had deviations significantly lower than 1 mm (for translation) or 1° (for rotation) (P < 0.05). CONCLUSIONS: Offset affects the precision of 3D-printed splints. Moderate offset values of 0.10 to 0.30 mm are recommendable for ISs. Offset values ≥ 0.15 mm are recommended for FSs in cases with stable final occlusion. CLINICAL RELEVANCE: This study found the optimal offset ranges for 3D-printed ISs and FSs via a standardized protocol.

A 3D-printed orthopedic implant with dual-effect synergy based on MoS2 and hydroxyapatite nanoparticles for tumor therapy and bone regeneration.

Treatments for malignant bone tumors are urgently needed to be developed due to the dilemma of precise resection of tumor tissue and subsequent bone defects. Although polyether-ether-ketone (PEEK) has widely attracted attention in the orthopedic field, its bioinertness and poor osteogenic properties significantly restrict its applications in bone tumor treatment. To tackle the daunting issue, we use a hydrothermal technique to fabricate novel PEEK scaffolds modified with molybdenum disulfide (MoS2) nanosheets and hydroxyapatite (HA) nanoparticles. Our dual-effect synergistic PEEK scaffolds exhibit perfect photothermal therapeutic (PTT) property dependent on molybdous ion (Mo2+) concentration and laser power density, superior to conventional PEEK scaffolds. Under near-infrared (NIR) irradiation, the viability of MG63 osteosarcoma cells is significantly reduced by modified PEEK scaffolds, indicating a tumor-killing potential in vitro. Furthermore, the incorporation of HA nanoparticles on the surface of PEEK bolsters proliferation and adherence of MC3T3-E1 cells, boosting mineralization for further bone defect repair. The results of micro-computed tomography (micro-CT) and histological analysis of 4-week treated rat femora demonstrate the preeminent photothermal and osteogenesis capacity of 3D-printed modified scaffolds in vivo. In conclusion, the dual-effect synergistic orthopedic implant with photothermal anticancer property and osteogenic induction activity strikes a balance between tumor treatment and bone development promotion, offering a promising future therapeutic option.

YAP/TEAD1 and ß-catenin/LEF1 synergistically induce estrogen receptor α to promote osteogenic differentiation of bone marrow stromal cells.

Bone remodeling is vital to the maintenance of bone homeostasis and may lead to destructive skeletal diseases once the balance is disrupted. Crosstalk between Wnt and estrogen receptor (ER) signaling has been proposed in bone remodeling, but the underlying mechanism remains unclear. This study was designed to explore the effect of Wnt-ER signaling during the osteogenic differentiation of bone marrow stromal cells (BMSCs). Rat BMSCs were isolated and identified using flow cytometry and stimulated with Wnt3a. Wnt3a treatment promoted osteogenic differentiation and mineralization of the BMSCs. Meanwhile, Wnt3a enhanced the expression of ERα as well as the canonical Wnt signaling mediator ß-catenin and the alternative Wnt signaling effector Yes-associated protein 1 (YAP1). Interestingly, DNA pulldown assay revealed direct binding of transcriptional enhanced associate domain 1 (TEAD1) and lymphoid enhancer binding factor 1 (LEF1), transcriptional partners of YAP1 and ß-catenin, respectively, to the promoter region of ERα. In addition, inhibition of TEAD1 and LEF1 suppressed Wnt3-promoted BMSC osteogenic differentiation and blocked Wnt3a-induced ERα expression. Furthermore, an in vivo model of femoral bone defect also supported that Wnt3a facilitated bone healing in an ERα-dependent way. Together, we suggest that Wnt3a promotes the osteogenic activity of BMSCs through YAP1 and ß-catenin-dependent activation of ERα, via direct binding of TEAD1 and LEF1 to the ERα promoter.

Targeting bromodomain-containing proteins: research advances of drug discovery.

Bromodomain (BD) is an evolutionarily conserved protein module found in 46 different BD-containing proteins (BCPs). BD acts as a specific reader for acetylated lysine residues (KAc) and serves an essential role in transcriptional regulation, chromatin remodeling, DNA damage repair, and cell proliferation. On the other hand, BCPs have been shown to be involved in the pathogenesis of a variety of diseases, including cancers, inflammation, cardiovascular diseases, and viral infections. Over the past decade, researchers have brought new therapeutic strategies to relevant diseases by inhibiting the activity or downregulating the expression of BCPs to interfere with the transcription of pathogenic genes. An increasing number of potent inhibitors and degraders of BCPs have been developed, some of which are already in clinical trials. In this paper, we provide a comprehensive review of recent advances in the study of drugs that inhibit or down-regulate BCPs, focusing on the development history, molecular structure, biological activity, interaction with BCPs and therapeutic potentials of these drugs. In addition, we discuss current challenges, issues to be addressed and future research directions for the development of BCPs inhibitors. Lessons learned from the successful or unsuccessful development experiences of these inhibitors or degraders will facilitate the further development of efficient, selective and less toxic inhibitors of BCPs and eventually achieve drug application in the clinic.

Enhanced virulence of genetically engineered Autographa californica nucleopolyhedrovirus owing to accelerated viral DNA replication aided by inserted ascovirus genes.

Genetic engineering technology is an ideal method to improve insecticidal efficiency by combining the advantages of different pathogenic microorganisms. Thus, six ascovirus genes were introduced into the genomic DNA of Autographa californica nucleopolyhedrovirus (AcMNPV) to possibly transfer the intrinsically valuable insecticidal properties from ascovirus to baculovirus. The viral budded virus (BV) production and viral DNA replication ability of AcMNPV-111 and AcMNPV-165 were significantly stronger than that of AcMNPV-Egfp (used as the wild-type virus in this study), whereas AcMNPV-33 had reduced ones. AcMNPV-111 and AcMNPV-165 also exhibited excellent insecticidal efficiency in the in vivo bioassays: AcMNPV-111 showed a 24.1% decrease in the LT50 value and AcMNPV-165 exhibited a 56.3% decrease in the LD50 value compared with AcMNPV-Egfp against the 3rd instar of Spodoptera exigua larvae, respectively. Furthermore, the size of the occlusion bodies (OBs) of AcMNPV-33, AcMNPV-111, and AcMNPV-165 were significantly increased compared to that of AcMNPV-Egfp. AcMNPV-111 and AcMNPV-165 had stable virulence against the 2nd to 4th instars tested larvae and higher OB yield than AcMNPV-Egfp in the 3rd and 4th instar larvae. Correlation and regression analyses indicated that it is better to use 5 OBs/larva virus to infect the 2nd instar larvae to produce AcMNPV-111 and 50 OBs/larva virus to infect the 3rd instar larvae to produce AcMNPV-165. The results of this study obtained recombinant viruses with enhanced virulence and exhibited a diversity of ascovirus gene function based on the baculovirus platform, which provided a novel strategy for the improvement of baculovirus as a biological insecticide.