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.

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.

Flexible and Dynamic Scheduling of Mixed-Criticality Systems.

A mixed-criticality system refers to an integrated embedded system in which tasks with different criticality levels run on a shared computing platform. In the design and development of mixed-criticality systems, how to schedule tasks to ensure that high-criticality tasks are executed in time and low-criticality tasks are served as much as possible is a major problem to be studied. Existing studies tend to consider pessimistic processing strategies to ensure the schedulability of functional tasks with high-criticality requirements. However, excessive pessimistic processing can lead to waste of system resources, thereby reducing the performance of functional tasks with low-criticality requirements. In this paper, we propose an adaptive-service-level adjustment strategy for low-criticality tasks, which solves the problem of waste of resources caused by invalid compensation in the low-criticality task compensation method of flexible mixed-criticality systems. In view of the problem that the existing methods mostly use static budget allocation and static independent mode switching without considering the actual operation of the task, this paper also proposes a flexible and dynamic mixed-criticality system scheduling scheme and designs a system execution framework, scheduling algorithm, and dynamic allocation strategy of maximum execution budget, in order to reduce unnecessary redundant resource expenditures and system switching costs and to improve the performance of low-criticality tasks. Experiments show that the proposed methods are effective compared to the state-of-the-art.

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.

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.

Aggregation-Induced Emission Active Probe for Light-Up Detection of Anionic Surfactants and Wash-Free Bacterial Imaging.

Anionic surfactants are widely used in daily life and industries, but their residues can cause serious damage to the environment. The current detection methods for anionic surfactants suffer from various limitations and a new detection strategy is highly desirable. Based on 2-(2-hydroxyphenyl)benzothiazole fluorogen with aggregation-induced emission characteristics, we have developed a fluorescent probe HBT-C18 for selective and sensitive detection of anionic surfactants. By in situ formation of catanionic aggregates or micelles with anionic surfactants, the emission intensity of the HBT-C18 probe can increase with increasing keto/enol emission ratio through restriction of intramolecular motion and excited-state intramolecular proton-transfer mechanisms. The probe can also be used for wash-free imaging of bacteria enveloped by a negatively charged outer membrane. The results of this study provide a new strategy for sensitive detection of anionic surfactants and wash-free bacterial imaging.

Driving forces of heavy metal changes in agricultural soils in a typical manufacturing center.

Heavy metal concentrations in 2002 and 2012 in agricultural soils in Dongguan, a manufacturing center in southern China, were analyzed to determine the impact of rapid economic development on soil pollution. The level of pollution was assessed using the Nemerow synthetic pollution index (NPI), and its changing characteristics and driving forces were analyzed using multivariate statistical and geostatistical methods. The results indicate that the mean NPI was 0.79 in 2002 and 0.84 in 2012, which indicates aggravated heavy metal contamination in the agricultural soils. The concentrations of Cd and Zn increased 54.7 and 20.8 %, respectively, whereas Hg and Pb decreased 35.3 and 24.5 %, respectively. Cr, As, Cu, and Ni remained relatively stable. The Hg and Cd concentrations were highly correlated with soil types (P < 0.01), the secondary industrial output per unit of land (P < 0.01), proportion of cereal fields (P < 0.01), proportion of vegetable fields (P < 0.01), population density (P < 0.05), and road density (P < 0.05). The Pb and As concentrations were greatly influenced by soil types (P < 0.01), river density (P < 0.01), fertilizer rate (P < 0.01), and road density (P < 0.05). Cr, Zn, Cu, and Ni concentrations were primarily driven by soil types (P < 0.01), river density (P < 0.01), and fertilizer rate (P < 0.05).

A 3D anthropometry-based quantified comfort model for children's eyeglasses design.

Modeling the quantified relationships between anthropometric/product parameters and human perceptions provides research-driven guidelines for mass customization and personalization of ergonomic products. In particular, such models are critical for designing children's eyeglasses; however, they are still underexplored. This study examined children's comfort perceptions for eyeglasses with two variables (i.e., nose pads width and temple clamping force), and established quantified linkage models between subjective human perceptions and objective 3D anthropometric/product parameters. To the best of our knowledge, this is the first work to quantify these relationships for ergonomic eyeglasses design. A psychological experiment with thirty child participants was performed, and our analyses showed that two eyeglasses variables significantly influenced the children's comfort perceptions; static vs. dynamic conditions caused slight differences. The mathematical trendlines and trend surfaces established by our findings can estimate perceived component-specific and overall comfort scores based on 3D anthropometric/product parameters. This also allows for calculation of parameter's allowances for sizing and grading eyeglasses while maintaining satisfactory comfort.

Clinical Outcomes of Fusion in Type II Accessory Naviculars With or Without Asymptomatic Flatfeet.

BACKGROUND: Few studies have reported the clinical outcomes of fusion surgeries for type II accessory naviculars. Whether the combination of accessory naviculars and asymptomatic flatfoot will result in worse outcomes in accessory navicular surgeries remains to be elucidated. Our study aims to report the clinical outcomes of fusion for type II accessory naviculars and make a subgroup comparison among accessory navicular patients with or without asymptomatic flatfeet. METHODS: From May 2017 to June 2021, all painful type II accessory naviculars with or without asymptomatic flatfeet in our inpatient center were reviewed, and those who only underwent fusion surgeries were included in the retrospective study. Visual analog scale (VAS) scores, American Orthopaedic Foot & Ankle Society (AOFAS) midfoot scores, Tegner activity level scores, complications, patient-reported satisfaction, and imaging results (Meary angle in the weightbearing lateral view, talo-first metatarsal angle and talonavicular coverage angle in the weightbearing anteroposterior view) were used to describe outcomes. RESULTS: Thirty-two eligible patients responded to the latest follow-up request and were included in this study. The mean follow-up duration was 37.1 ± 16.0 months. The average VAS pain score improved from 4.7 ± 1.8 preoperatively to 0.9 ± 1.2 at the latest follow-up (P<.001). The average AOFAS midfoot score improved from 67.1 ± 8.5 preoperatively to 90.2 ± 10.7 at the latest follow-up (P<.001). The preoperative and postoperative Tegner activity level scores were similar (3.3 ± 1.5 vs 3.5 ± 1.6, P=.136). The overall complication rate was 37.5%. The most common complication was nonunion (31.3%). The overall satisfaction rate was 90.6%. Similar outcomes were observed between the flatfoot and the nonflatfoot subgroups. CONCLUSION: Fusion for painful type II accessory naviculars resulted in good symptom relief, function improvement, and patient satisfaction at midterm follow-up, but the nonunion rate was relatively high. Fusion for painful type II accessory naviculars with or without asymptomatic mild to moderate flatfoot brought about similar clinical outcomes. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

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.

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.

Marriage of High-Throughput Gradient Surface Generation With Statistical Learning for the Rational Design of Functionalized Biomaterials.

Functional biomaterial is already an important aspect in modern therapeutics; yet, the design of novel multi-functional biomaterial is still a challenging task nowadays. When several biofunctional components are present, the complexity that arises from their combinations and interactions will lead to tedious trial-and-error screening. In this work, a novel strategy of biomaterial rational design through the marriage of gradient surface generation with statistical learning is presented. Not only can parameter combinations be screened in a high-throughput fashion, but also the optimal conditions beyond the experimentally tested range can be extrapolated from the models. The power of the strategy is demonstrated in rationally designing an unprecedented ternary functionalized surface for orthopedic implant, with optimal osteogenic, angiogenic, and neurogenic activities, and its optimality and the best osteointegration promotion are confirmed in vitro and in vivo, respectively. The presented strategy is expected to open up new possibilities in the rational design of biomaterials.

Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility.

Broadly neutralizing antibodies (bnAbs) against HIV-1 target conserved epitopes, thereby inhibiting viral entry. Yet surprisingly, those recognizing linear epitopes in the HIV-1 gp41 membrane proximal external region (MPER) are elicited neither by peptide nor protein scaffold vaccines. Here, we observe that while Abs generated by MPER/liposome vaccines may exhibit human bnAb-like paratopes, B-cell programming without constraints imposed by the gp160 ectodomain selects Abs unable to access the MPER within its native "crawlspace". During natural infection, the flexible hinge of IgG3 partially mitigates steric occlusion of less pliable IgG1 subclass Abs with identical MPER specificity, until affinity maturation refines entry mechanisms. The IgG3 subclass maintains B-cell competitiveness, exploiting bivalent ligation resulting from greater intramolecular Fab arm length, offsetting weak antibody affinity. These findings suggest future immunization strategies.

Inadequate structural constraint on Fab approach rather than paratope elicitation limits HIV-1 MPER vaccine utility.

Broadly neutralizing antibodies (bnAbs) against HIV-1 target conserved envelope (Env) epitopes to block viral replication. Here, using structural analyses, we provide evidence to explain why a vaccine targeting the membrane-proximal external region (MPER) of HIV-1 elicits antibodies with human bnAb-like paratopes paradoxically unable to bind HIV-1. Unlike in natural infection, vaccination with MPER/liposomes lacks a necessary structure-based constraint to select for antibodies with an adequate approach angle. Consequently, the resulting Abs cannot physically access the MPER crawlspace on the virion surface. By studying naturally arising Abs, we further reveal that flexibility of the human IgG3 hinge mitigates the epitope inaccessibility and additionally facilitates Env spike protein crosslinking. Our results suggest that generation of IgG3 subtype class-switched B cells is a strategy for anti-MPER bnAb induction. Moreover, the findings illustrate the need to incorporate topological features of the target epitope in immunogen design.

Influence of microsurgical varicocelectomy on human sperm mitochondrial DNA copy number: a pilot study.

BACKGROUND: There is good evidence to show that varicocele repair can improve conventional sperm parameters, as well as, sperm DNA integrity, in infertile men with a clinical varicocele. OBJECTIVE: To examine the effect of varicocelectomy on sperm quality, specifically, sperm nuclear chromatin integrity and sperm mitochondrial DNA (mtDNA) copy number. DESIGN, SETTING, AND PARTICIPANTS: A prospective study done between March 2007 and January 2008. We evaluated a consecutive series of infertile men (n = 14) presenting to Ovo clinic with one year or more history of infertility, a clinically palpable varicocele and poor motility (<25 % rapid progressive and <50 % progressive). SURGICAL PROCEDURE: Microsurgical sub-inguinal varicocelectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Conventional sperm parameters, sperm mtDNA copy number (by real time PCR) and sperm chromatin structure assay (SCSA) parameters (%DFI,% HDS) before and 4 months after microsurgical varicocelectomy. RESULTS AND LIMITATIONS: Sperm concentration and SCSA parameters (%DFI and %HDS) improved significantly after surgery (P < 0.05). Sperm mitochondrial DNA copy number decreased significantly after surgery (27 ± 30 to 9 ± 6 copies per sperm, respectively, P = 0.032). There was a significant negative correlation between mitochondrial DNA copy number and sperm motility (r = - 0.71, P = 0.002). CONCLUSION: These findings support the concept that correction of a varicocele can improve spermatogenesis and sperm function, as mitochondrial DNA copy number has been suggested to reflect the efficiency of spermatogenesis and has been inversely related to sperm motility.

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.

Dynamic HIV-1 spike motion creates vulnerability for its membrane-bound tripod to antibody attack.

Vaccines targeting HIV-1's gp160 spike protein are stymied by high viral mutation rates and structural chicanery. gp160's membrane-proximal external region (MPER) is the target of naturally arising broadly neutralizing antibodies (bnAbs), yet MPER-based vaccines fail to generate bnAbs. Here, nanodisc-embedded spike protein was investigated by cryo-electron microscopy and molecular-dynamics simulations, revealing spontaneous ectodomain tilting that creates vulnerability for HIV-1. While each MPER protomer radiates centrally towards the three-fold axis contributing to a membrane-associated tripod structure that is occluded in the upright spike, tilting provides access to the opposing MPER. Structures of spike proteins with bound 4E10 bnAb Fabs reveal that the antibody binds exposed MPER, thereby altering MPER dynamics, modifying average ectodomain tilt, and imposing strain on the viral membrane and the spike's transmembrane segments, resulting in the abrogation of membrane fusion and informing future vaccine development.

Mitochondrial DNA damage is sensitive to exogenous H(2)O(2) but independent of cellular ROS production in prostate cancer cells.

Intrinsic oxidative stress through enhanced production of reactive oxygen species (ROS) in prostate and other cancers may contribute to cancer progression due to its stimulating effect on cancer growth. In this study, we investigate differential responses to exogenous oxidative stimuli between aggressive prostate cancer and normal cell lines and explore potential mechanisms through interactions between cytotoxicity, cellular ROS production and oxidative DNA damage. The circular, multi-copy mitochondrial DNA (mtDNA) is used as a sensitive surrogate to oxidative DNA damage. We demonstrate that exogenous H(2)O(2) induces preferential cytotoxicity in aggressive prostate cancer than normal cells; a cascade production of cellular ROS, composed mainly of superoxide (O(2)(-)), is shown to be a critical determinant of H(2)O(2)-induced selective toxicity in cancer cells. In contrast, mtDNA damage and copy number depletion, as measured by a novel two-phase strategy of the supercoiling-sensitive qPCR method, are very sensitive to exogenous H(2)O(2) exposure in both cancer and normal cell lines. Moreover, we demonstrate for the first time that the sensitive mtDNA damage response to exogenous H(2)O(2) is independent of secondary cellular ROS production triggered by several ROS modulators regardless of cell phenotypes. These new findings suggest different mechanisms underpinning cytotoxicity and DNA damage induced by oxidative stress and a susceptible phenotype to oxidative injury associated with aggressive prostate cancer cells in vitro.