Identification of hub genes and pathways associated with cellular senescence in diabetic foot ulcers via comprehensive transcriptome analysis.

This research aimed to find important genes and pathways related to cellular senescence (CS) in diabetic foot ulcers (DFU) and to estimate the possible pathways through which CS affects diabetic foot healing. The GSE80178 dataset was acquired from the Gene Expression Omnibus (GEO) database, containing six DFU and three diabetic foot skin (DFS) samples. The limma package was used to identify differentially expressed genes (DEGs). At the same time, DEGs associated with CS (CS-DEGs) were found using the CellAge database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the CS-DEGs. A protein-protein interaction (PPI) network was built using the String database, and the cytoHubba plug-in within Cytoscape helped identify hub genes. Lastly, the miRNA-TF-mRNA regulatory network for these hub genes was established. In total, 66 CS-DEGs were obtained. These genes mainly focus on CS, Kaposi sarcoma-associated herpesvirus infection and Toll-like receptor signalling pathway. Eight hub genes were identified to regulate cell senescence in DFU, including TP53, SRC, SIRT1, CCND1, EZH2, CXCL8, AR and CDK4. According to miRNA-TF-mRNA regulatory network, hsa-mir-132-3p/SIRT1/EZH2 axis is involved in senescence cell accumulation in DFU.

All-in-One Zinc-Doped Prussian Blue Nanozyme for Efficient Capture, Separation, and Detection of Copper Ion (Cu2+ ) in Complicated Matrixes.

Copper is a vital micronutrient for lives and an important ingredient for bactericides and fungicides. Given its indispensable biological and agricultural roles, there is an urgent need to develop simple, affordable, and reliable methods for detecting copper in complicated matrixes, particularly in underdeveloped regions where costly standardized instruments and sample dilution procedures hinder progress. The findings that zinc-doped Prussian blue nanoparticle (ZnPB NP) exhibits exceptional efficiency in capturing and isolating copper ions, and accelerates the generation of dissolved oxygen in a solution of H2 O2 with remarkable sensitivity and selectivity, the signal of which displays a positive correlation with the copper level due to the copper-enhanced catalase-like activity of ZnPB NP, are presented. Consequently, the ZnPB NP serves as an all-in-one sensor for copper ion. The credibility of the method for copper assays in human urine and farmland soil is shown by comparing it to the standard instrumentation, yielding a coefficient of correlation (R2 = 0.9890), but the cost is dramatically reduced. This ZnPB nanozyme represents a first-generation probe for copper ion in complicated matrixes, laying the groundwork for the future development of a practical copper sensor that can be applied in resource-constrained environments.

Spherical Assembly of Halloysite Clay Nanotubes as a General Reservoir of Hydrophobic Pesticides for pH-Responsive Management of Pests and Weeds.

The development of smart systems for pesticidal delivery presents a significant advancement in enhancing the utilization efficiency of pesticides and mitigating environmental risks. Here an acid-responsive pesticidal delivery system using microspheres formed by the self-assembly of halloysite clay nanotubes (HNTs) is proposed. Insecticide avermectin (AVM) and herbicide prometryn (PMT) are used as two models of hydrophobic pesticide and encapsulated within the porous microspheres, followed by a coating of tannic acid/iron (TA/FeIII) complex films to generate two controlled-release pesticides, named as HCEAT and HCEPT, resulting in the loading capacity of AVM and PMT being 113.3 and 120.3 mg g-1, respectively. Both HCEAT and HCEPT exhibit responsiveness to weak acid, achieving 24 h-release ratios of 85.8% and 80.5% at a pH of 5.5. The experiment and simulation results indicate that the coordination interaction between EDTA2- and Ca2+ facilitates the spherical aggregation of HNTs. Furthermore, these novel pesticide formulations demonstrate better resistance against ultraviolet (UV) irradiation, higher foliar affinity, and less leaching effect, with negligible impact of the carrier material on plants and terrestrial organisms. This work presents a promising approach toward the development of efficient and eco-friendly pesticide formulations, greatly contributing to the sustainable advancement of agriculture.

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2.

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

Association of elevated circulating monocyte-platelet aggregates with hypercoagulability in patients with nephrotic syndrome.

BACKGROUND: Hypercoagulability emerges as a central pathological feature and clinical complication in nephrotic syndrome. Increased platelet activation and aggregability are closely related to hypercoagulability in nephrotic syndrome. Monocyte-platelet aggregates (MPAs) have been proposed to represent a robust biomarker of platelet activation. The aim of this study was to investigate levels of the circulating MPAs and MPAs with the different monocyte subsets to evaluate the association of MPAs with hypercoagulability in nephrotic syndrome. METHODS: Thirty-two patients with nephrotic syndrome were enrolled. In addition, thirty-two healthy age and sex matched adult volunteers served as healthy controls. MPAs were identified by CD14 monocytes positive for CD41a platelets. The classical (CD14 + + CD16-, CM), the intermediate (CD14 + + CD16+, IM) and the non-classical (CD14 + CD16++, NCM) monocytes, as well as subset specific MPAs, were measured by flow cytometry. RESULTS: Patients with nephrotic syndrome showed a higher percentage of circulating MPAs as compared with healthy controls (p < 0.001). The percentages of MPAs with CM, IM, and NCM were higher than those of healthy controls (p = 0.012, p < 0.001 and p < 0.001, respectively). Circulating MPAs showed correlations with hypoalbuminemia (r=-0.85; p < 0.001), hypercholesterolemia (r = 0.54; p < 0.001), fibrinogen (r = 0.70; p < 0.001) and D-dimer (r = 0.37; p = 0.003), but not with hypertriglyceridemia in nephrotic syndrome. The AUC for the prediction of hypercoagulability in nephrotic syndrome using MPAs was 0.79 (95% CI 0.68-0.90, p < 0.001). The sensitivity of MPAs in predicting hypercoagulability was 0.71, and the specificity was 0.78. CONCLUSION: Increased MPAs were correlated with hypercoagulability in nephrotic syndrome. MPAs may serve as a potential biomarker for thrombophilic or hypercoagulable state and provide novel insight into the mechanisms of anticoagulation in nephrotic syndrome.

The cytotoxic natural compound erianin binds to colchicine site of ß-tubulin and overcomes taxane resistance.

Erianin, a natural compound derived from Dendrobium, has shown significant anticancer properties against a wide range of cancer cells. Despite the identification of multiple mechanisms of action for erianin, none of these mechanisms fully account for its broad-spectrum effect. In this study, we aimed to identify the cellular target and underlying mechanism responsible for the broad-spectrum antitumor effects of erianin. We found that erianin effectively inhibited tubulin polymerization in cancer cells and purified tubulin. Through competition binding assays and X-ray crystallography, it was revealed that erianin bound to the colchicine site of ß-tubulin. Importantly, the X-ray crystal structure of the tubulin-erianin complex was solved, providing clear insight into the orientation and position of erianin in the colchicine-binding site. Erianin showed activity against paclitaxel-resistant cells, evidenced by G2/M cell cycle arrest, apoptosis-related PARP and Caspase-3 cleavage, and in vivo xenograft studies. The study concluded that erianin bound reversibly to the colchicine site of ß-tubulin, inhibited tubulin polymerization, and displayed anticancer activity against paclitaxel-resistant cells, offering valuable insights for further exploration as potential anticancer agents.

Dynamic analyses of a soft tissue-implant interface: Biological responses to immediate versus delayed dental implants.

AIM: To qualitatively and quantitatively evaluate the formation and maturation of peri-implant soft tissues around 'immediate' and 'delayed' implants. MATERIALS AND METHODS: Miniaturized titanium implants were placed in either maxillary first molar (mxM1) fresh extraction sockets or healed mxM1 sites in mice. Peri-implant soft tissues were evaluated at multiple timepoints to assess the molecular mechanisms of attachment and the efficacy of the soft tissue as a barrier. A healthy junctional epithelium (JE) served as positive control. RESULTS: No differences were observed in the rate of soft-tissue integration of immediate versus delayed implants; however, overall, mucosal integration took at least twice as long as osseointegration in this model. Qualitative assessment of Vimentin expression over the time course of soft-tissue integration indicated an initially disorganized peri-implant connective tissue envelope that gradually matured with time. Quantitative analyses showed significantly less total collagen in peri-implant connective tissues compared to connective tissue around teeth around implants. Quantitative analyses also showed a gradual increase in expression of hemidesmosomal attachment proteins in the peri-implant epithelium (PIE), which was accompanied by a significant inflammatory marker reduction. CONCLUSIONS: Within the timeframe examined, quantitative analyses showed that connective tissue maturation never reached that observed around teeth. Hemidesmosomal attachment protein expression levels were also significantly reduced compared to those in an intact JE, although quantitative analyses indicated that macrophage density in the peri-implant environment was reduced over time, suggesting an improvement in PIE barrier functions. Perhaps most unexpectedly, maturation of the peri-implant soft tissues was a significantly slower process than osseointegration.

Safety and benefit of modified mesohepatectomy in the treatment of bilobar involvement congenital biliary dilatation.

BACKGROUND: The diseased bile duct in bilobar congenital biliary dilatation is extensive and often requires major hepatectomy or liver transplantation associated with a higher risk. We aimed to evaluate the safety and benefit of modified mesohepatectomy, in comparison with trisectionectomy, to treat bilobar congenital biliary dilatation. METHODS: This study included 28 patients with type IV and V bilobar congenital biliary dilatation. An innovative mesohepatectomy comprising the hepatectomy technique beyond the P/U point and bile duct shaping was applied to 14 patients to address the extensively diseased bile duct and difficulty in hepaticojejunostomy. Another 14 patients received trisectionectomy. The perioperative and long-term outcomes of these patients were compared. RESULTS: The ratio of residual liver volume to standard liver volume in the mesohepatectomy group was higher (78.68% vs. 40.90%, p = 0.005), while the resection rate of the liver parenchyma was lower (28.25% vs. 63.97%, p = 0.000), than that in trisectionectomy group. The mesohepatectomy group had a lower severe complication (>Clavein III, 0% vs. 57.70%, p = 0.019) and incidence of posthepatectomy liver failure (7.14% vs. 42.86%, p = 0.038). No significant difference was observed in blood loss and bile leakage (p > 0.05). All the patients in the mesohepatectomy group achieved optimal results in the long-term follow-up. CONCLUSIONS: mesohepatectomy provides an efficient treatment option for bilobar congenital biliary dilatation and can achieve radical resection, retain more liver parenchyma, and reduce the difficulty of hepaticojejunostomy, especially for patients that are not eligible for major hepatectomy and liver transplantation.

Distribution, risk evaluation, and source allocation of cesium and strontium in surface soil in a mining city.

Radioactive nuclides cesium (Cs) and strontium (Sr) possess long half-lives, with 135Cs at approximately 2.3 million years and 87Sr at about 49 billion years. Their persistent accumulation can result in long-lasting radioactive contamination of soil ecosystems. This study employed geo-accumulation index (Igeo), pollution load index (PLI), potential ecological risk index (PEPI), health risk assessment model (HRA), and Monte Carlo simulation to evaluate the pollution and health risks of Cs and Sr in the surface soil of different functional areas in a typical mining city in China. Positive matrix factorization (PMF) model was used to elucidate the potential sources of Cs and Sr and the respective contribution rates of natural and anthropogenic sources. The findings indicate that soils in the mining area exhibited significantly higher levels of Cs and Sr pollution compared to smelting factory area, agricultural area, and urban residential area. Strontium did not pose a potential ecological risk in any studied functional area. The non-carcinogenic health risk of Sr to the human body in the study area was relatively low. Because of the lack of parameters for Cs, the potential ecological and human health risks of Cs was not calculated. The primary source of Cs in the soil was identified as the parent material from which the soil developed, while Sr mainly originated from associated contamination caused by mining activities. This research provides data for the control of Cs and Sr pollution in the surface soil of mining city.

Advances in methane emissions from agricultural sources: Part I. Accounting and mitigation.

Methane is one of the major greenhouse gases (GHGs) and agriculture is recognized as its primary emitter. Methane accounting is a prerequisite for developing effective agriculture mitigation strategies. In this review, methane accounting methods and research status for various agricultural emission source including rice fields, animal enteric fermentation and livestock and poultry manure management were overview, and the influencing factors of each emission source were analyzed and discussed. At the same time, it analyzes the different research efforts involving agricultural methane accounting and makes recommendations based on the actual situation. Finally, mitigation strategies based on accounting results and actual situation are proposed. This review aims to provide basic data and reference for agriculture-oriented countries and regions to actively participate in climate action and carry out effective methane emission mitigation.

Psittacosis caused severe community-acquired pneumonia accompanied by acute hypoxic respiratory failure: a multicenter retrospective cohort study from China.

INTRODUCTION: Psittacosis can cause severe community-acquired pneumonia (CAP). The clinical manifestations of psittacosis range from subclinical to fulminant psittacosis with multi-organ failure. It is essential to summarize the clinical characteristic of patients with severe psittacosis accompanied by acute hypoxic respiratory failure (AHRF). METHODS: This retrospective study included patients with severe psittacosis caused CAP accompanied by AHRF from 19 tertiary hospitals of China. We recorded the clinical data, antimicrobial therapy, respiratory support, complications, and outcomes. Chlamydia psittaci was detected on the basis of metagenomic next-generation sequencing performed on bronchoalveolar lavage fluid samples. Patient outcomes were compared between the treatment methods. RESULTS: This study included 45 patients with severe CAP and AHRF caused by psittacosis from April 2018 to May 2021. The highest incidence of these infections was between September and April. There was a history of poultry contact in 64.4% of the patients. The median PaO2/FiO2 of the patients was 119.8 (interquartile range, 73.2 to 183.6) mmHg. Four of 45 patients (8.9%) died in the ICU, and the median ICU duration was 12 days (interquartile range, 8 to 21) days. There were no significant differences between patients treated with fluoroquinolone initially and continued after the diagnosis, fluoroquinolone initially followed by tetracycline, and fluoroquinolone combined with tetracycline. CONCLUSION: Psittacosis caused severe CAP seems not rare, especially in the patients with the history of exposure to poultry or birds. Empirical treatment that covers atypical pathogens may benefit such patients, which fluoroquinolones might be considered as an alternative.

The LRP5 high-bone-mass mutation causes alveolar bone accrual with minor craniofacial alteration.

BACKGROUND AND OBJECTIVE: Mutations in low-density lipoprotein receptor-related protein 5 (LRP5) cause various bone diseases. Several mouse models were generated to study the role of LRP5 in bone development. But most of the studies were confined to the appendicular skeleton. The role of LRP5 in the axial skeleton, especially in the craniofacial skeleton, is largely unknown. The aim of this study was to investigate the craniofacial phenotype with the LRP5G171V mutation. METHODS: To understand how LRP5 affects craniofacial bone properties, we analyzed LRP5 high-bone-mass mutant mice carrying the G171V missense mutation (LRP5HBM ). Quantitative microcomputed tomographic imaging and histomorphometric analyses were used to study craniofacial phenotypes and bone density. Histology, immunohistochemistry, and in vivo fluorochrome labeling were used to study molecular mechanisms. RESULTS: LRP5HBM mice showed overall minor changes in the craniofacial bone development but with increased bone mass in the interradicular alveolar bone, edentulous ridge, palatine bone, and premaxillary suture. Elevated osteocyte density was observed in LRP5HBM mice, along with increased Runx2 expression and unmineralized bone surrounding osteocytes. Meanwhile, LRP5HBM mice exhibited increased osteoprogenitors, but no significant changes were observed in osteoclasts. This led to a high-bone-mass phenotype, and an increased osteocyte density in the alveolar bone and edentulous ridge. CONCLUSION: LRP5HBM mice display increased bone mass in the alveolar bone with minor changes in the craniofacial morphology. Collectively, these data elucidated the important role of LRP5 in axial bone development and homeostasis and provided clues into the therapeutical potential of LRP5 signaling in treating alveolar bone loss.

N6-methyladenosine demethylase FTO related to hyperandrogenism in PCOS via AKT pathway.

BACKGROUND: Polycystic ovary syndrome (PCOS) was known as the common endocrine disease in women, featured as hyperandrogenism, ovulation disorders, etc. Fat mass and obesity-associated protein (FTO), a m6A demethylase, is abnormal in the occurrence of ovarian diseases. However, the mechanism of FTO in the pathogenesis of PCOS is still unclear. METHODS: The level of FTO in clinical samples, PCOS rat with hyperandrogenism and granulosa cells (GCs) lines effected by DHT were investigated by ELISA, qRT-PCR, WB, and IHC, while m6A RNA methylation level was studied by m6A Colorimetric and androgen level was tested through ELISA. Changes in steroid hormone synthetase and androgen receptor (AR)/prostate-specific antigen (PSA) levels in vitro were visualized by WB after transient transfection silenced FTO. The effect of DHT combined with FTO inhibitor meclofenamic acid (MA) on FTO, AR/PSA, and AKT phosphorylation were also demonstrated by WB. The co-localization of FTO and AR in KGN cells was analyzed by confocal microscopy, and the physiological interaction between FTO and AR was studied by Co-IP assay. The effect of FTO-specific inhibitor MA, AKT phosphorylation inhibitor LY294002, and the combined them on GCs proliferation and cell cycle were evaluated by drug combination index, EDU assay, and flow cytometry analysis. RESULTS: FTO expression was upregulated in follicular fluid and GCs in PCOS patients clinically. The high FTO expression in patients was negative with the level of m6A, but positive with the level of androgen. The upregulation of FTO was accompanied with a decrease in the level of m6A in PCOS rat with hyperandrogenism. Dihydrotestosterone (DHT) promoted the FTO expression and inhibited m6A content as a dose-dependent way in vitro. In contrast, suppression of FTO with siRNA attenuated the expression of steroid hormone synthetase such as CYP11A1, CYP17A1, HSD11B1, HSD3B2 except CYP19A1 synthetase, ultimately inducing the decrease of androgen level. Suppression of FTO also decreased the biological activity of androgen through downregulation AR/PSA. MA treatment as the specific FTO antagonist decreased cell survival in time- and dose-dependent way in GCs lines. Correspondingly, MA treatment decreased the expression of FTO, AR/PSA expression, and AKT phosphorylation in the presence of DHT stimulation. Additionally, we also speculate there is a potential relation between FTO and AR according to FTO was co-localized and interacted with AR in KGN cells. Compared with AKT phosphorylation inhibitor LY294002 or MA alone, LY294002 combined with MA synergistically inhibited cell survival and increased G2/M phase arrest in GC line. CONCLUSIONS: We first evaluated the correlation of FTO and m6A in PCOS clinically, and further explored the mechanism between FTO and hyperandrogenism in PCOS animal and cell models. These findings contributed the potential therapy by targeting the FTO for hyperandrogenism in PCOS.

Comparison of the efficacy and safety of different surgical procedures for patients with hemorrhoids: a network meta-analysis.

PURPOSE: This study used a network meta-analysis to evaluate the efficacy and safety of different surgical approaches in patients with hemorrhoids. METHODS: PubMed, Embase, Web of science, and Cochrane Library were searched for randomized controlled trials on patients with hemorrhoids treated by different surgical procedures. The search was conducted until January 15, 2023. Two investigators independently screened the resulting literature, extracted information, evaluated the risk of bias of the included studies, and performed a network meta-analysis. RESULT: A total of 23 randomized controlled studies were included and involved 3573 patients and 10 interventions, namely L (Ligasure), M-M (Milligan-Morgan), F (Ferguson), H (Harmonic), OH (open Harmonic), CH (closed Harmonic), PPH (procedure for prolapse and hemorrhoids), TST (tissue selecting technique), T-S (TST STARE+; tissue selection therapy stapled transanal rectal resection plus), and STARR (stapled transanal rectal resection). Network meta-analysis results showed that L has the shortest mean operating time and STARR has the longest mean operating time, F and H have the longest length of hospitalization and T-S has the shortest length of hospitalization, PPH has the most intraoperative blood loss and L has the least intraoperative blood loss, TST has the shortest time to first defecation and M-M has the longest time to first defecation, STARR had the least recurrence and PPH had the most recurrence, PPH had the least anal stenosis and L had the most anal stenosis, and F had the least postoperative pain after 24 h and PPH had the most postoperative pain after 24 h. CONCLUSION: Current evidence suggests that L is best at reducing mean operative time and intraoperative bleeding, T-S is best at reducing mean length of stay, TST has the shortest time to first defecation, STARR is best at reducing recurrence rates, PPH is best at reducing postoperative anal stricture, and F is best at reducing postoperative pain after 24 h.

Night-time surgery for type a aortic dissection: Immediate or delaying?

OBJECTIVES: This study aims to investigate whether surgery performed during night compared with daytime were associated with an increased risk of operative mortality of type A aortic dissection (TAAD) patients. METHODS: A total of 2015 TAAD patients who underwent surgical repair were collected from two cardiovascular centers from Jan 2015 to Jan 2021. According to the start time of surgery, patients were divided into daytime group (06:01 a.m. to 06:00 p.m.) and night-time group (06:01 p.m. to 06:00 a.m.), and retrospective analyses were performed between them. RESULTS: The operative mortality of night-time group (12.2%, 43/352) was dramatically higher than daytime group (6.9%, 115/1663; p = 0.001). There was significant difference between night-time and daytime groups in terms of 30-days mortality (5.8% vs 10.8%; p = 0.001) and in-hospital mortality (3.5% vs 6.0%; p = 0.03). The night-time group had a longer duration of intensive care unit stay (4 vs two; days; p < 0.001) and ventilation support (34 vs 19; hours; p < 0.001), compared with daytime group. The risk factors for operative mortality were night-time surgery (odds ratio [OR], 1.545; p = 0.027), age (odds ratio, 1.152; p < 0.001), total arch replacement (OR, 2.265; p < 0.001) and previous aortic surgery (OR, 2.376; p = 0.003). CONCLUSION: Night-time surgical repair may be associated with higher operative mortality of patients with TAAD. Nevertheless, it is reasonable to offer emergency surgery at night-time for such patients who were more likely to present disastrous complications with delayed surgical intervention, as outcomes indicate acceptable operative mortality.

Concentration Scaling on Linear Viscoelastic Properties of Cellular Suspensions and Effects of Equilibrium Phase Behavior.

Concentration scaling on linear viscoelastic properties of cellular suspensions has been studied by rheometric characterisation of Phormidium suspensions and human blood in a wide range of volume fraction under small amplitude oscillatory shear experiments. The rheometric characterisation results are analysed by the time-concentration superposition (TCS) principle and show a power law scaling of characteristic relaxation time, plateau modulus and the zero-shear viscosity over the concentration ranges studied. The results show that the concentration effect of Phormidium suspensions on their elasticity is much stronger than that of human blood due to its strong cellular interactions and a high aspect ratio. For human blood, no obvious phase transition could be observed over the range of hematocrits studied here and with respect to a high-frequency dynamic regime, only one concentration scaling exponent could be identified. For Phormidium suspensions with respect to a low-frequency dynamic regime, three concentration scaling exponents in the volume fraction Region I (0.36≤ϕ/ϕref≤0.46), Region II (0.59≤ϕ/ϕref≤2.89) and Region III (3.11≤ϕ/ϕref≤3.44) are identified. The image observation shows that the network formation of Phormidium suspensions occurs as the volume fraction is increased from Region I to Region II; the sol-gel transition takes place from Region II to Region III. In combination with analysis of other nanoscale suspensions and liquid crystalline polymer solutions reported in the literature, it is revealed that such a power law concentration scaling exponent depends on colloidal or molecular interactions mediated with solvent and is sensitive to the equilibrium phase behaviour of complex fluids. The TCS principle is an unambiguous tool to give a quantitative estimation.

Degrading FLT3-ITD protein by proteolysis targeting chimera (PROTAC).

Clinical FLT3 mutations caused poor therapeutic benefits toward the present FLT3 inhibitors, and degradation of the FLT3 mutant protein may be a promising alternative approach to protect against acute myeloid leukemia (AML). Herein, we report the discovery of small molecule FLT3 degraders based on the proteolysis targeting chimera (PROTAC). FLT3 degraders were designed, synthesized, and evaluated for FLT3 degradation. Promising PF15 significantly inhibited the proliferation of FLT3-ITD-positive cells, induced FLT3 degradation and downregulated the phosphorylation of FLT3 and STAT5. An in vivo xenograft model and survival period evaluation verified the efficacy of PROTAC. These findings laid a robust foundation for FLT3-PROTAC molecules as an effective strategy for treating AML.

Design, synthesis and biological evaluation of novel FAK inhibitors with better selectivity over IR than TAE226.

In this study, 28 novel focal adhesion kinase (FAK) inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 18b displayed good inhibition of FAK (IC50 = 45 nM) with at least 22 fold of selectivity over insulin receptor (IR, IC50 > 1000 nM) and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC50 values of 0.27, 0.19 and 0.26 µM respectively, compared to TAE226 (2.68, 0.64 and 4.19 µM respectively). 18b also inhibited the clone formation and migration of HCT-116 cells, tube formation of HUVECs, and stimulated cell cycle arrest in the G2/M phase, inducing apoptosis by promoting ROS production. The FAK-Src-ERK signaling pathway was inhibited by 18b in a dose-dependent manner. Moreover, 18b showed adequate oral bioavailability of 16.37% and 75.90% tumor growth inhibition in the HCT116 xenograft model was observed. These results indicate that 18b is a promising selective inhibitor of FAK.

A Predicted Stem Loop in Coat Protein-Coding Sequence of Tobacco Vein Banding Mosaic Virus Is Required for Efficient Replication.

Potyviral coat protein (CP) is involved in the replication and movement of potyviruses. However, little information is available on the roles of CP-coding sequence in potyviral infection. Here, we introduced synonymous substitutions to the codon C574G575C576 coding conserved residue arginine at position 192 (R192) of tobacco vein banding mosaic virus (TVBMV) CP. Substitution of the codon C574G575C576 to A574G575A576 or A574G575G576, but not C574G575A576, C574G575T576, or C574G575G576, reduced the replication, cell-to-cell movement, and accumulation of TVBMV in Nicotiana benthamiana plants, suggesting that C574 was critical for replication of TVBMV. Nucleotides 531 to 576 of the TVBMV CP-coding sequence were predicted to form a stem-loop structure, in which four consecutive C-G base pairs (C576-G531, C532-G575, C574-G533, and C534-G573) were located at the stem. Synonymous substitutions of R178-codon C532G533C534 to A532G533A534 and A532G533G534, but not C532G533A534, C532G533T534, or C532G533G534, reduced the replication levels, cell-to-cell, and systemic movement of TVBMV, suggesting that C532 was critical for TVBMV replication. Synonymous substitutions disrupting base pairs C576-G531 and C534-G573 did not affect viral accumulation. After three serial-passage inoculations, the accumulation of spontaneous mutant viruses was restored, and codons A532G533A534, A532G533G534, A574G575A576, or A574G575G576 of mutants were each separately changed to C532G533A534, C532G533G534, C574G575A576, or C574G575G576. Synonymous mutation of R178 and R192 also reduced viral accumulation in N. tabacum plants. Therefore, we concluded that the two consecutive C532-G575 and C574-G533 base pairs played critical roles in TVBMV replication via maintaining the stability of the stem-loop structures formed by nucleotides 531 to 576 of the CP-coding sequence.

Effects of masticatory loading on bone remodeling around teeth versus implants: Insights from a preclinical model.

OBJECTIVES: Teeth connect to bone via a periodontal ligament, whereas implants connect to bone directly. Consequently, masticatory loads are distributed differently to periodontal versus peri-implant bone. Our objective was to determine how masticatory loading of an implant versus a tooth affected peri-implant versus periodontal bone remodeling. Our hypothesis was that strains produced by functional loading of an implant would be elevated compared with the strains around teeth, and that this would stimulate a greater degree of bone turnover around implants versus in periodontal bone. MATERIALS AND METHODS: Sixty skeletally mature mice were divided into two groups. In the implant group, maxillary first molars (mxM1) were extracted, and after socket healing, titanium alloy implants were positioned subocclusally. After osseointegration, implants were exposed, resin crowns were placed, and masticatory loading was initiated. In the control group, the dentition was left intact. Responses of peri-implant and periodontal bone were measured using micro-CT, histology, bone remodeling assays, and quantitative histomorphometry while bone strains were estimated using finite element (FE) analyses. CONCLUSIONS: When a submerged osseointegrated implant is exposed to masticatory forces, peri-implant strains are elevated, and peri-implant bone undergoes significant remodeling that culminates in new bone accrual. The accumulation of new bone functions to reduce both peri-implant strains and bone remodeling activities, equivalent to those observed around the intact dentition.