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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

High-throughput screening and rational design of biofunctionalized surfaces with optimized biocompatibility and antimicrobial activity.

Peptides are widely used for surface modification to develop improved implants, such as cell adhesion RGD peptide and antimicrobial peptide (AMP). However, it is a daunting challenge to identify an optimized condition with the two peptides showing their intended activities and the parameters for reaching such a condition. Herein, we develop a high-throughput strategy, preparing titanium (Ti) surfaces with a gradient in peptide density by click reaction as a platform, to screen the positions with desired functions. Such positions are corresponding to optimized molecular parameters (peptide densities/ratios) and associated preparation parameters (reaction times/reactant concentrations). These parameters are then extracted to prepare nongradient mono- and dual-peptide functionalized Ti surfaces with desired biocompatibility or/and antimicrobial activity in vitro and in vivo. We also demonstrate this strategy could be extended to other materials. Here, we show that the high-throughput versatile strategy holds great promise for rational design and preparation of functional biomaterial surfaces.

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.

Deep Temporal-Spatial Feature Learning for Motor Imagery-Based Brain-Computer Interfaces.

Motor imagery (MI) decoding is an important part of brain-computer interface (BCI) research, which translates the subject's intentions into commands that external devices can execute. The traditional methods for discriminative feature extraction, such as common spatial pattern (CSP) and filter bank common spatial pattern (FBCSP), have only focused on the energy features of the electroencephalography (EEG) and thus ignored the further exploration of temporal information. However, the temporal information of spatially filtered EEG may be critical to the performance improvement of MI decoding. In this paper, we proposed a deep learning approach termed filter-bank spatial filtering and temporal-spatial convolutional neural network (FBSF-TSCNN) for MI decoding, where the FBSF block transforms the raw EEG signals into an appropriate intermediate EEG presentation, and then the TSCNN block decodes the intermediate EEG signals. Moreover, a novel stage-wise training strategy is proposed to mitigate the difficult optimization problem of the TSCNN block in the case of insufficient training samples. Firstly, the feature extraction layers are trained by optimization of the triplet loss. Then, the classification layers are trained by optimization of the cross-entropy loss. Finally, the entire network (TSCNN) is fine-tuned by the back-propagation (BP) algorithm. Experimental evaluations on the BCI IV 2a and SMR-BCI datasets reveal that the proposed stage-wise training strategy yields significant performance improvement compared with the conventional end-to-end training strategy, and the proposed approach is comparable with the state-of-the-art method.

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.

Mechanistic Insights and Rational Design of a Versatile Surface with Cells/Bacteria Recognition Capability via Orientated Fusion Peptides.

Hospital-acquired infection causes many deaths worldwide and calls for the urgent need for antibacterial biomaterials used in clinic that can selectively kill harmful bacteria. The present study rationally designs fusion peptides capable of undergoing 2D self-assembly on the poly(methyl methacrylate) surface to form a smart surface, which can maintain a desirable orientation via electrostatic interactions. The in vitro assay shows that the smart surface can recognize bacteria to exert antibacterial activity and is nontoxic toward mouse bone mesenchymal stem cells. Excitingly, the smart surface can distinguish different bacterial strains. This selective feature, from being broad-spectrum to being highly selective against S. aureus, can be altered by varying the number of amino acids in the recognition sequences. By all-atom molecular dynamics simulations, it is also found that the recognition sequence in the peptide is critical for the selectivity toward specific bacterial strains, in which a less accessible surface area for the bacteria in the antimicrobial peptide sequence is responsible for such selectivity. Finally, the smart surface can inhibit S. aureus infection in vivo with much more rapid tissue-healing compared to the control.