Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR.

Despite the effectiveness of antiretroviral therapy (ART) in prolonging the lifespan of individuals infected with HIV-1, it does not offer a cure for acquired immunodeficiency syndrome (AIDS). The "block and lock" approach aims to maintain the provirus in a state of extended transcriptional arrest. By employing the "block and lock" strategy, researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART. The crux of this strategy lies in the utilization of latency-promoting agents (LPAs) that are suitable for impeding HIV-1 provirus transcription. However, previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients, underscoring the significance of identifying novel LPAs that yield substantial outcomes. In this study, we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs. We discovered ripretinib being an LPA candidate, which was validated and observed to hinder proviral activation in cell models harboring latent infections, as well as CD4+ T cells derived from infected patients. We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells, thereby suppressing the opening states of cellular chromatin. The results of this research offer a promising drug candidate for the implementation of the "block and lock" strategy in the pursuit of an HIV-1 cure.

Dynamic surface adapts to multiple service stages by orchestrating responsive polymers and functional peptides.

Control over the implant surface functions is highly desirable to enhance tissue healing outcomes but has remained unexplored to adapt to the different service stages. In the present study, we develop a smart titanium surface by orchestrating thermoresponsive polymer and antimicrobial peptide to enable dynamic adaptation to the implantation stage, normal physiological stage and bacterial infection stage. The optimized surface inhibited bacterial adhesion and biofilm formation during surgical implantation, while promoted osteogenesis in the physiological stage. The further temperature increase driven by bacterial infection induced polymer chain collapse to expose antimicrobial peptides by rupturing bacterial membranes, as well as protect the adhered cells from the hostile environment of infection and abnormal temperature. The engineered surface could inhibit infection and promote tissue healing in rabbit subcutaneous and bone defect infection models. This strategy enables the possibility to create a versatile surface platform to balance bacteria/cell-biomaterial interactions at different service stages of implants that has not been achieved before.

Inhalable GSH-Triggered Nanoparticles to Treat Commensal Bacterial Infection in In Situ Lung Tumors.

Bacterial infection has been considered one of the primary reasons for low survival rate of lung cancer patients. Herein, we demonstrated that a kind of mesoporous silica nanoparticles loaded with anticancer drug doxorubicin (DOX) and antimicrobial peptide HHC36 (AMP) (MSN@DOX-AMP) can kill both commensal bacteria and tumor cells under GSH-triggering, modulating the immunosuppressive tumor microenvironment, significantly treating commensal bacterial infection, and eliminating in situ lung tumors in a commensal model. Meanwhile, MSN@DOX-AMP encapsulated DOX and AMP highly efficiently via a combined strategy of physical adsorption and click chemistry and exhibited excellent hemocompatibility and biocompatibility. Importantly, MSN@DOX-AMP could be inhaled and accumulate in lung by a needle-free nebulization, achieving a better therapeutic effect. This system is expected to serve as a straightforward platform to treat commensal bacterial infections in tumors and promote the translation of such inhaled GSH-triggered MSN@DOX-AMP to clinical treatments of lung cancer.

Meta-Resolve of Risk Factors for Nosocomial Infection in Patients Undergoing Thoracic Surgery.

As we all know, various complications may occur after surgery, and postoperative bleeding and infection are the most common in clinical practice. Postoperative infection mainly manifests as abdominal abscess, peritonitis, and fungal infection. Thoracic surgery is a very common clinical operation. It can directly deal with the relevant lesions, so a better curative effect can usually be obtained. However, patients undergoing thoracic surgery are generally more severely ill, with low immune resistance, long duration, and complicated surgical treatment process. Therefore, the probability of nosocomial infection is high, and there are many risk factors for infection. After the occurrence of HAI, it not only increases the suffering and economic burden of patients and the workload of medical staff but also prolongs the hospitalization time of patients, reduces the turnover rate of hospital beds, causes unnecessary economic losses, and affects the social and economic benefits of hospitals. Based on this, this paper proposes to analyze the risk factors of nosocomial infection in patients undergoing thoracic surgery, so as to provide a reference for the prevention or control of nosocomial infection. This paper analyzes the actual situation of nosocomial infection in a city hospital and then uses meta-analysis to determine the factors of nosocomial infection from the perspective of relevant research literature. Meta-analysis results show that patients older than 60 years have twice the risk of postoperative infection compared with patients younger than 60 years.

Peptide-Engineered AIE Nanofibers with Excellent and Precisely Adjustable Antibacterial Activity.

Photosensitizers with aggregation-induced emission properties (AIEgens) can produce reactive oxygen species (ROS) under irradiation, showing great potential in the antibacterial field. However, due to the limited molecular skeletons, the development of AIEgens with precisely adjustable antibacterial activity is still a daunting challenge. Herein, a series of AIE nanofibers (AIE-NFs) based on the AIEgen of DTPM as the inner core and rationally designed peptides as bacterial recognition ligands (e.g., antimicrobial peptide (AMP) HHC36, ditryptophan, polyarginine, and polylysine) is developed. These AIE-NFs show precisely adjustable antibacterial behaviors simply by changing the decorated peptides, which can regulate the aggregation and inhibition of different bacteria. By mechanistic analysis, it is demonstrated that this effect can be attributed to the synergistic antibacterial activities of the ROS and the peptides. It is noteworthy that the optimized AIE-NFs, NFs-K18, can efficiently aggregate bacteria to cluster and kill four types of clinical bacteria under irradiation in vitro, inhibit the infection of methicillin-resistant Staphylococcus aureus (MRSA) and promote wound healing in vivo. To the authors' knowledge, this is the first report of AIE-NFs with precisely adjustable antibacterial activity, providing new opportunities for photodynamic therapy (PDT) treatment of infection.

Associations between I/D polymorphism in the ACE gene and lung cancer: an updated systematic review and a meta-analysis.

BACKGROUND: We evaluated the association between the I/D polymorphism in the ACE gene and lung cancer risk by performing a meta-analysis. METHODS: The heterogeneity in the study was tested using the Cochran χ2-based Q statistic test and I2 test, and then the random ratio or fixed effect was utilized to merge the odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the strength of the association between ACE polymorphisms and susceptibility to lung cancer. Sensitivity analysis was also performed. Using funnel plot and Begg's rank test, we investigated the publication bias. All statistical analyses were performed using Stata 12.0 and RevMan 5.3. RESULTS: A total of 4307 participants (2181 patients; 2126 controls) were included in the 12 case-control studies. No significant association was found between the ACE I/D polymorphism and lung cancer risk (II vs. ID + DD: OR = 1.22, 95% CI = 0.89-1.68; II + ID vs. DD: OR = 1.21, 95% CI = 0.90-1.63; I vs. D: OR = 1.15, 95% CI = 0.95-1.39). In the subgroup analysis by ethnicity, no significant association between the ACE I/D polymorphism and lung cancer risk was found among Asian and Caucasian populations for the comparisons of II vs. ID + DD, II + ID vs. DD, and I vs. D genetic models. CONCLUSION: The ACE I/D polymorphism is not associated with the risk of lung cancer.

Endogenous Aß induces osteoporosis through an mTOR-dependent inhibition of autophagy in bone marrow mesenchymal stem cells (BMSCs).

BACKGROUND: It has previously been suggested that Alzheimer's disease (AD) and osteoporosis (OP) were related. However, the connection between these 2 disorders is poorly understood. This study aimed to investigate the relationship between amyloid ß peptide (Aß) and the osteoporotic deficit observed in AD patients. METHODS: We used the APP/PS1ΔE9 transgenic mouse model of AD for in vivo study and extracted bone marrow mesenchymal stem cells (BMSCs) for in vitro studies. For in vivo experiments, mice femurs were put through a µ-computer tomography (µ-CT) scanning and after which, sliced for hematoxylin/eosin (HE), Masson and Goldner staining for detection of bone changes. For in vitro experiments, BMSCs were placed in an osteogenic inducing medium with or without rapamycin. After induction, alkaline phosphatase (ALP) staining, alizarin red staining, quantitative real-time PCR (qPCR) and western-blot were used to identify osteogenic differentiation, calcium deposition and protein expression differences respectively. RESULTS: We observed that pathological changes characteristic of AD and OP occurred in vivo in APP/PS1ΔE9 mice. In BMSCs producing endogenous Aß, mammalian target of rapamycin (mTOR) activation and subsequent inhibition of autophagy suppressed bone formation. Further, the addition of the mTOR inhibitor rapamycin into the inducing medium reversed the inhibition of osteogenesis. CONCLUSIONS: Our results suggested that endogenous Aß might have induced osteoporosis through an mTOR-dependent inhibition of autophagy in BMSCs, which may explain the OP changes observed in AD patients.

Fusion peptide engineered "statically-versatile" titanium implant simultaneously enhancing anti-infection, vascularization and osseointegration.

Although antimicrobial titanium implants can prevent biomaterial-associated infection (BAI) in orthopedics, they display cytotoxicity and delayed osseointegration. Therefore, versatile implants are desirable for simultaneously inhibiting BAI and promoting osseointegration, especially "statically-versatile" ones with nonessential external stimulations for facilitating applications. Herein, we develop a "statically-versatile" titanium implant by immobilizing an innovative fusion peptide (FP) containing HHC36 antimicrobial sequence and QK angiogenic sequence via sodium borohydride reduction promoted Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC-SB), which shows higher immobilization efficiency than traditional CuAAC with sodium ascorbate reduction (CuAAC-SA). The FP-engineered implant exhibits over 96.8% antimicrobial activity against four types of clinical bacteria (S. aureus, E. coli, P. aeruginosa and methicillin-resistant S. aureus), being stronger than that modified with mixed peptides. This can be mechanistically attributed to the larger bacterial accessible surface area of HHC36 sequence. Notably, the implant can simultaneously enhance cellular proliferation, up-regulate expressions of angiogenesis-related genes/proteins (VEGF and VEGFR-2) of HUVECs and osteogenesis-related genes/proteins (ALP, COL-1, RUNX-2, OPN and OCN) of hBMSCs. In vivo assay with infection and non-infection bone-defect model reveals that the FP-engineered implant can kill 99.63% of S. aureus, and simultaneously promote vascularization and osseointegration. It is believed that this study presents an excellent strategy for developing "statically-versatile" orthopedic implants.

On-demand storage and release of antimicrobial peptides using Pandora's box-like nanotubes gated with a bacterial infection-responsive polymer.

Background: Localized delivery of antimicrobial agents such as antimicrobial peptides (AMPs) by a biomaterial should be on-demand. Namely, AMPs should be latent and biocompatible in the absence of bacterial infection, but released in an amount enough to kill bacteria immediately in response to bacterial infection. Methods: To achieve the unmet goal of such on-demand delivery, here we turned a titanium implant with titania nanotubes (Ti-NTs) into a Pandora's box. The box was loaded with AMPs (HHC36 peptides, with a sequence of KRWWKWWRR) inside the nanotubes and "closed" (surface-modified) with a pH-responsive molecular gate, poly(methacrylic acid) (PMAA), which swelled under normal physiological conditions (pH 7.4) but collapsed under bacterial infection (pH ≤ 6.0). Thus, the PMAA-gated Ti-NTs behaved just like a Pandora's box. The box retarded the burst release of AMPs under physiological conditions because the gate swelled to block the nanotubes opening. However, it was opened to release AMPs to kill bacteria immediately when bacterial infection occurred to lowering the pH (and thus made the gate collapse). Results: We demonstrated such smart excellent bactericidal activity against a panel of four clinically important bacteria, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus. In addition, this box was biocompatible and could promote the osteogenic differentiation of human mesenchymal stem cells. Both in vitro and in vivo studies confirmed the smart "on-demand" bactericidal activity of the Pandora's box. The molecularly gated Pandora's box design represents a new strategy in smart drug delivery.

Temperature-Controlled Reversible Exposure and Hiding of Antimicrobial Peptides on an Implant for Killing Bacteria at Room Temperature and Improving Biocompatibility in Vivo.

Modification of implants by antimicrobial peptides (AMPs) can improve the antimicrobial activity of the implants. However, AMPs have some cytotoxicity in vivo when they are exposed at body temperature. To tackle this challenge, we propose to develop a new approach to generating a smart antimicrobial surface through exposure of AMPs on the surface. A polydopamine film was first formed on the substrates, followed by the conjugation of a temperature-sensitive polymer, poly( N-isopropylacrylamide) (pNIPAM), to the film through atom transfer radical polymerization (ATRP). Then, AMPs were conjugated to the NIPAM on the resultant pNIPAM-modified surface through a click chemistry reaction. Because of the temperature-sensitive property of pNIPAM, the AMPs motif was more exposed to the external environment at room temperature (25 °C) than at body temperature (37 °C), making the surface present a higher antimicrobial activity at room temperature than at body temperature. More importantly, such a smart behavior is accompanied with the increased biocompatibility of the surface at body temperature when compared to the substrates unmodified or modified by AMPs or pNIPAM alone. Our in vivo study further verified that pNIPAM-AMP dual modified bone implants showed increased biocompatibility even when they were challenged with the bacteria at room temperature before implantation. These results indicate that the implants are antibacterial at room temperature and can be safely employed during surgery, resulting in no infection after implantations. Our work represents a new promising strategy to fully explore the antimicrobial property of AMPs, while improving their biocompatibility in vivo. The higher exposure of AMPs at room temperature (the temperature for storing the implants before surgery) will help decrease the risk of bacterial infection, and the lower exposure of AMPs at body temperature (the temperature after the implants are placed into the body by surgery) will improve the biocompatibility of AMPs.

Prognostic value of lncRNA ROR expression in various cancers: a meta-analysis.

Background: There is a dispute on the prognostic value of long non-coding RNA regulator of reprogramming (lncRNA ROR) in cancers. The purpose of the present study was to evaluate the prognostic significance of lncRNA ROR expression in human cancers. Methods: PubMed, Embase, and Cochrane Library were searched to look for relevant studies. The meta-analyses of prognostic and clinicopathological parameters (CPs) were conducted. Results: A total of ten studies were finally included into the meta-analysis. High lncRNA ROR expression was significantly associated with shorter overall survival (hazard ratio [HR] = 2.88, 95% confidence interval [CI] = 2.16-3.84, P<0.01) and disease-free survival (HR = 3.25, 95% CI = 2.30-4.60, P<0.01) compared with low lncRNA ROR expression. Besides, high lncRNA ROR expression was obviously related to more advanced clinical stage (P<0.01), earlier tumor metastasis (P=0.02), lymph node metastasis (P<0.01), and vascular invasion (P<0.01) compared with low lncRNA ROR expression. However, there was no significant correlation between lncRNA ROR expression and other CPs, including age (P=0.18), gender (P=0.33), tumor size (P=0.25), or tumor differentiation (P=0.13). Conclusion: High lncRNA ROR expression was associated with worse prognosis in cancers. LncRNA ROR expression could serve as an unfavorable prognostic factor in various cancers.

Quantifying compressive forces between living cell layers and within tissues using elastic round microgels.

Increasing evidence shows that mechanical stresses are critical in regulating cell functions, fate, and diseases. However, no methods exist that can quantify isotropic compressive stresses. Here we describe fluorescent nanoparticle-labeled, monodisperse elastic microspheres made of Arg-Gly-Asp-conjugated alginate hydrogels (elastic round microgels, ERMGs). We generate 3D displacements and calculate strains and tractions exerted on an ERMG. Average compressive tractions on an ERMG are 570 Pa within cell layers and 360 Pa in tumor-repopulating cell (TRC) colonies grown in 400-Pa matrices. 3D compressive tractions on a 1.4-kPa ERMG are applied by surrounding cells via endogenous actomyosin forces but not via mature focal adhesions. Compressive stresses are substantially heterogeneous on ERMGs within a uniform cell colony and do not increase with TRC colony sizes. Early-stage zebrafish embryos generate spatial and temporal differences in local normal and shear stresses. This ERMG method could be useful for quantifying stresses in vitro and in vivo.

Soft matrices downregulate FAK activity to promote growth of tumor-repopulating cells.

Tumor-repopulating cells (TRCs) are a tumorigenic sub-population of cancer cells that drives tumorigenesis. We have recently reported that soft fibrin matrices maintain TRC growth by promoting histone 3 lysine 9 (H3K9) demethylation and Sox2 expression and that Cdc42 expression influences H3K9 methylation. However, the underlying mechanisms of how soft matrices induce H3K9 demethylation remain elusive. Here we find that TRCs exhibit lower focal adhesion kinase (FAK) and H3K9 methylation levels in soft fibrin matrices than control melanoma cells on 2D rigid substrates. Silencing FAK in control melanoma cells decreases H3K9 methylation, whereas overexpressing FAK in tumor-repopulating cells enhances H3K9 methylation. Overexpressing Cdc42 or RhoA in the presence of FAK knockdown restores H3K9 methylation levels. Importantly, silencing FAK, Cdc42, or RhoA promotes Sox2 expression and proliferation of control melanoma cells in stiff fibrin matrices, whereas overexpressing each gene suppresses Sox2 expression and reduces growth of TRCs in soft but not in stiff fibrin matrices. Our findings suggest that low FAK mediated by soft fibrin matrices downregulates H3K9 methylation through reduction of Cdc42 and RhoA and promotes TRC growth.

Long-Term Tracking of the Osteogenic Differentiation of Mouse BMSCs by Aggregation-Induced Emission Nanoparticles.

Bone marrow-derived mesenchymal stem cells (BMSCs) have shown great potential for bone repair due to their strong proliferation ability and osteogenic capacity. To evaluate and improve the stem cell-based therapy, long-term tracking of stem cell differentiation into bone-forming osteoblasts is required. However, conventional fluorescent trackers such as fluorescent proteins, quantum dots, and fluorophores with aggregation-caused quenching (ACQ) characteristics have intrinsic limitations of possible interference with stem cell differentiation, heavy metal cytotoxicity, and self-quenching at a high labeling intensity. Herein, we developed aggregation-induced emission nanoparticles decorated with the Tat peptide (AIE-Tat NPs) for long-term tracking of the osteogenic differentiation of mouse BMSCs without interference of cell viability and differentiation ability. Compared with the ability of the commercial Qtracker 655 for tracking of only 6 passages of mouse BMSCs, AIE-Tat NPs have shown a much superior performance in long-term tracking for over 12 passages. Moreover, long-term tracking of the osteogenic differentiation process of mouse BMSCs was successfully conducted on the biocompatible hydroxyapatite scaffold, which is widely used in bone tissue engineering. Thus, AIE-Tat NPs have promising applications in tracking stem cell fate for bone repair.

Efficient extravasation of tumor-repopulating cells depends on cell deformability.

Cancer metastasis is the most deadly stage in cancer progression. Despite significant efforts over the past decades, it remains elusive why only a very small fraction of cancer cells is able to generate micrometastasis and metastatic colonization. Recently we have shown that tumor-repopulating cells (TRCs), a highly tumorigenic subpopulation of mouse melanoma cells, can be selected by being cultured and grown in 3D soft fibrin gels. Here we show that when injected into the yolk of a 2 day-post-fertilization (dpf) embryo of Tg (fli1:EGFP or kdrl:mCherry) zebrafish, TRCs are much more efficient in surviving and growing at various secondary sites to generate micrometastasis and metastatic colonization than control melanoma cells that are grown on rigid plastic. The metastasis of TRCs is dependent on the presence of Sox2, a self-renewal gene, and silencing Sox2 leads to the inhibition of TRC metastasis. High-resolution of 3D confocal images of the TRCs at the secondary sites show that extravasation and formation of micrometastases by TRCs are more efficient than by the control cells. Remarkably, efficient extravasation of TRCs in vivo and transmigration in vitro are determined by TRC deformability, as a result of low Cdc42 and high Sox2. Our findings suggest that tumor cell deformability is a key factor in controlling extravasation dynamics during metastasis.

Gossypium barbadense genome sequence provides insight into the evolution of extra-long staple fiber and specialized metabolites.

Of the two cultivated species of allopolyploid cotton, Gossypium barbadense produces extra-long fibers for the production of superior textiles. We sequenced its genome (AD)2 and performed a comparative analysis. We identified three bursts of retrotransposons from 20 million years ago (Mya) and a genome-wide uneven pseudogenization peak at 11-20 Mya, which likely contributed to genomic divergences. Among the 2,483 genes preferentially expressed in fiber, a cell elongation regulator, PRE1, is strikingly At biased and fiber specific, echoing the A-genome origin of spinnable fiber. The expansion of the PRE members implies a genetic factor that underlies fiber elongation. Mature cotton fiber consists of nearly pure cellulose. G. barbadense and G. hirsutum contain 29 and 30 cellulose synthase (CesA) genes, respectively; whereas most of these genes (>25) are expressed in fiber, genes for secondary cell wall biosynthesis exhibited a delayed and higher degree of up-regulation in G. barbadense compared with G. hirsutum, conferring an extended elongation stage and highly active secondary wall deposition during extra-long fiber development. The rapid diversification of sesquiterpene synthase genes in the gossypol pathway exemplifies the chemical diversity of lineage-specific secondary metabolites. The G. barbadense genome advances our understanding of allopolyploidy, which will help improve cotton fiber quality.

Transfer of cadmium from soil to vegetable in the Pearl River Delta area, South China.

The purpose of this study was to investigate the regional Cadmium (Cd) concentration levels in soils and in leaf vegetables across the Pearl River Delta (PRD) area; and reveal the transfer characteristics of Cadmium (Cd) from soils to leaf vegetable species on a regional scale. 170 paired vegetables and corresponding surface soil samples in the study area were collected for calculating the transfer factors of Cadmium (Cd) from soils to vegetables. This investigation revealed that in the study area Cd concentration in soils was lower (mean value 0.158 mg kg(-1)) compared with other countries or regions. The Cd-contaminated areas are mainly located in west areas of the Pearl River Delta. Cd concentrations in all vegetables were lower than the national standard of Safe vegetables (0.2 mg kg(-1)). 88% of vegetable samples met the standard of No-Polluted vegetables (0.05 mg kg(-1)). The Cd concentration in vegetables was mainly influenced by the interactions of total Cd concentration in soils, soil pH and vegetable species. The fit lines of soil-to-plant transfer factors and total Cd concentration in soils for various vegetable species were best described by the exponential equation (y = ax(b)), and these fit lines can be divided into two parts, including the sharply decrease part with a large error range, and the slowly decrease part with a low error range, according to the gradual increasing of total Cd concentrations in soils.

Matrix softness regulates plasticity of tumour-repopulating cells via H3K9 demethylation and Sox2 expression.

Tumour-repopulating cells (TRCs) are a self-renewing, tumorigenic subpopulation of cancer cells critical in cancer progression. However, the underlying mechanisms of how TRCs maintain their self-renewing capability remain elusive. Here we show that relatively undifferentiated melanoma TRCs exhibit plasticity in Cdc42-mediated mechanical stiffening, histone 3 lysine residue 9 (H3K9) methylation, Sox2 expression and self-renewal capability. In contrast to differentiated melanoma cells, TRCs have a low level of H3K9 methylation that is unresponsive to matrix stiffness or applied forces. Silencing H3K9 methyltransferase G9a or SUV39h1 elevates the self-renewal capability of differentiated melanoma cells in a Sox2-dependent manner. Mechanistically, H3K9 methylation at the Sox2 promoter region inhibits Sox2 expression that is essential in maintaining self-renewal and tumorigenicity of TRCs both in vitro and in vivo. Taken together, our data suggest that 3D soft-fibrin-matrix-mediated cell softening, H3K9 demethylation and Sox2 gene expression are essential in regulating TRC self-renewal.

The promotion of antimicrobial activity on silicon substrates using a "click" immobilized short peptide.

We demonstrated, for the first time, that the short antimicrobial peptide Tet213 could be conjugated onto the silicon surface by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The modified surface exhibited excellent antimicrobial activity against S. aureus and E. coli, and low cytotoxicity to rat bone mesenchymal stem cells (rBMSCs).