Biomimetic NIR-II fluorescent proteins created from chemogenic protein-seeking dyes for multicolor deep-tissue bioimaging.

Near-infrared-I/II fluorescent proteins (NIR-I/II FPs) are crucial for in vivo imaging, yet the current NIR-I/II FPs face challenges including scarcity, the requirement for chromophore maturation, and limited emission wavelengths (typically < 800 nm). Here, we utilize synthetic protein-seeking NIR-II dyes as chromophores, which covalently bind to tag proteins (e.g., human serum albumin, HSA) through a site-specific nucleophilic substitution reaction, thereby creating proof-of-concept biomimetic NIR-II FPs. This chemogenic protein-seeking strategy can be accomplished under gentle physiological conditions without catalysis. Proteomics analysis identifies specific binding site (Cys 477 on DIII). NIR-II FPs significantly enhance chromophore brightness and photostability, while improving biocompatibility, allowing for high-performance NIR-II lymphography and angiography. This strategy is universal and applicable in creating a wide range of spectrally separated NIR-I/II FPs for real-time visualization of multiple biological events. Overall, this straightforward biomimetic approach holds the potential to transform fluorescent protein-based bioimaging and enables in-situ albumin targeting to create NIR-I/II FPs for deep-tissue imaging in live organisms.

Urban professionals' restorative tourism: exploring the role of perceived environmental restorativeness, push and pull motivations and destination attributes on tourism expectations.

Introduction: Urban professionals often seek respite from their daily routines through restorative tourism, driven by a complex interplay of motivations that include both internal "push" factors and external "pull" factors. This study investigates the intricate relationship between the perceived environmental restorativeness of tourist destinations and the expectations of urban professionals engaging in restorative tourism. Furthermore, it examines how push and pull motivations mediate this relationship while also considering the moderating effect of destination attributes. Methods: The multiple regression analyses on the survey data collected from 221 urban professionals with restorative tourism experiences provided quantitative evidence regarding the hypothesized relationships among perceived environmental restorativeness, push and pull motivations, destination attributes, and tourism expectations. Results: The results showed that perceived environmental restorativeness has a positive effect on urban professionals' tourism expectations; urban professionals' pull motivation and push motivation each play a mediating role between perceived environmental restorativeness and tourist expectations; and restorative tourism destination attributes have a moderating effect between perceived environmental restorativeness and push motivation, as well as the relationship between perceived environmental restorativeness and pull motivation. Discussion: This study provides essential theoretical contributions to restorative tourism and practical implications when designing restorative tourism destinations that target urban professionals.

Discovery of common molecular signatures and drug repurposing for COVID-19/Asthma comorbidity: ACE2 and multi-partite networks.

Angiotensin-converting enzyme 2 (ACE2) is identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global coronavirus disease-2019 (COVID-19) pandemic. This study aimed to elucidate potential therapeutic avenues by scrutinizing approved drugs through the identification of the genetic signature associated with SARS-CoV-2 infection in individuals with asthma. This exploration was conducted through an integrated analysis, encompassing interaction networks between the ACE2 receptor and common host (co-host) factors implicated in COVID-19/asthma comorbidity. The comprehensive analysis involved the identification of common differentially expressed genes (cDEGs) and hub-cDEGs, functional annotations, interaction networks, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and module construction. Interaction networks were used to identify overlapping disease modules and potential drug targets. Computational biology and molecular docking analyzes were utilized to discern functional drug modules. Subsequently, the impact of the identified drugs on the expression of hub-cDEGs was experimentally validated using a mouse model. A total of 153 cDEGs or co-host factors associated with ACE2 were identified in the COVID-19 and asthma comorbidity. Among these, seven significant cDEGs and proteins - namely, HRAS, IFNG, JUN, CDH1, TLR4, ICAM1, and SCD-were recognized as pivotal host factors linked to ACE2. Regulatory network analysis of hub-cDEGs revealed eight top-ranked transcription factors (TFs) proteins and nine microRNAs as key regulatory factors operating at the transcriptional and post-transcriptional levels, respectively. Molecular docking simulations led to the proposal of 10 top-ranked repurposable drug molecules (Rapamycin, Ivermectin, Everolimus, Quercetin, Estradiol, Entrectinib, Nilotinib, Conivaptan, Radotinib, and Venetoclax) as potential treatment options for COVID-19 in individuals with comorbid asthma. Validation analysis demonstrated that Rapamycin effectively inhibited ICAM1 expression in the HDM-stimulated mice group (p < 0.01). This study unveils the common pathogenesis and genetic signature underlying asthma and SARS-CoV-2 infection, delineated by the interaction networks of ACE2-related host factors. These findings provide valuable insights for the design and discovery of drugs aimed at more effective therapeutics within the context of lung disease comorbidities.

Mapping structural covariance networks of emotional withdrawal symptoms in males with methamphetamine use disorder during abstinence.

Individuals with methamphetamine use disorder (MUD) often experience anxiety and depressive symptoms during abstinence, which can worsen the likelihood of relapse. Thus, it is essential to understand the neuro-mechanism behind methamphetamine use and its associated emotional withdrawal symptoms in order to develop effective clinical strategies. This study aimed to evaluate associations between emotional withdrawal symptoms and structural covariance networks (SCNs) based on cortical thickness (CTh) across the brain. The CTh measures were obtained from Tl-weighted MRI data from a sample of 48 males with MUD during abstinence and 48 male healthy controls. The severity of anxiety and depressive symptoms was assessed by the Hamilton Anxiety Scale (HAMA) and depression (HAMD) scales. Two important nodes belonging to the brain reward system, the right rostral anterior cingulate cortex (rACC) and medial prefrontal cortex (medPFC), were selected as seeds to conduct SCNs and modulation analysis by emotional symptoms. MUDs showed higher structural covariance between the right rACC and regions in the dorsal attention, right frontoparietal, auditory, visual and limbic networks. They also displayed higher structural covariance between the right medPFC and regions in the limbic network. Moreover, the modulation analysis showed that higher scores on HAMA were associated with increased covariance between the right rACC and the left parahippocampal and isthmus cingulate cortex in the default mode network. These outcomes shed light on the complex neurobiological mechanisms underlying methamphetamine use and its associated emotional withdrawal symptoms and may provide new insights into the development of effective treatments for MUD.

Design of composite puncture blood collection system and research on puncture force.

Venous blood collection testing is one of the most commonly used medical diagnostic methods. Compared with conventional venous blood collection, robotic collection can reduce needle-stick injuries, medical staff workload, and infection risk; allow doctor-patient isolation; and improve collection reliability. Existing venous blood collection robots use rigid puncture needles, which can easily puncture the lower wall of blood vessels, causing vessel damage and collection failure. This paper proposes a bionic blood collection strategy based on a composite puncture needle that mimics the structure and function of mosquito mouthparts. A bionic composite puncture needle insertion system with puncture-force sensing was designed, and venipuncture forces were simulated and mathematically modelled. A prototype insertion system was built and used in an experiment, which demonstrated effective composite puncture blood collection and explored the factors influencing puncture force. Puncture force decreases with increased puncture speed and angle and with a decreased needle diameter. This provides a basis for optimising the parameters of blood collection robots.

Coupled Interface and Oxygen-Defect Engineering in Co3O4/CoMoO4 Heterostructures toward Active Oxidation of Ethylbenzene.

The catalytic oxidation of ethylbenzene (EB) is a promising route to produce acetophenone (AcPO). Unfortunately, it remains a great challenge to achieve the highly efficient oxidation of EB under solvent-free conditions using molecular oxygen as the sole oxidant. In this contribution, we present a facile strategy to construct hierarchical oxygen vacancy-rich Co3O4/CoMoO4 heterostructures (Vö-CCMO), which delivers a high yield value of 74.5% at 83.2% conversion of EB and selectivity of 89.6% to AcPO. Both experimental studies and theoretical calculations substantiate the important role of oxygen-defect engineering triggered by the modified chemistry environment at the interfaces between the biphasic phases, which contributes to the good catalytic performance. This work illustrates a promising paradigm for the exploit of advanced catalysts toward boosting EB oxidation reaction in a more practical way.

Progress in the Elimination of Organic Contaminants in Wastewater by Activation Persulfate over Iron-Based Metal-Organic Frameworks.

The release of organic contaminants has grown to be a major environmental concern and a threat to the ecology of water bodies. Persulfate-based Advanced Oxidation Technology (PAOT) is effective at eliminating hazardous pollutants and has an extensive spectrum of applications. Iron-based metal-organic frameworks (Fe-MOFs) and their derivatives have exhibited great advantages in activating persulfate for wastewater treatment. In this article, we provide a comprehensive review of recent research progress on the significant potential of Fe-MOFs for removing antibiotics, organic dyes, phenols, and other contaminants from aqueous environments. Firstly, multiple approaches for preparing Fe-MOFs, including the MIL and ZIF series were introduced. Subsequently, removal performance of pollutants such as antibiotics of sulfonamides and tetracyclines (TC), organic dyes of rhodamine B (RhB) and acid orange 7 (AO7), phenols of phenol and bisphenol A (BPA) by various Fe-MOFs was compared. Finally, different degradation mechanisms, encompassing free radical degradation pathways and non-free radical degradation pathways were elucidated. This review explores the synthesis methods of Fe-MOFs and their application in removing organic pollutants from water bodies, providing insights for further refining the preparation of Fe-MOFs.

Site-specific albumin tagging with NIR-II fluorogenic dye for high-performance and super-stable bioimaging.

Synthetic near-infrared-II (NIR-II) dyes are promising for deep tissue imaging, yet they are generally difficult to target a given biomolecule with high specificity. Furthermore, the interaction mechanism between albumin and cyanine molecules, which is usually regarded as uncertain "complexes" such as crosslinked nanoparticles, remains poorly understood. Methods: Here, we propose a new class of NIR-II fluorogenic dyes capable of site-specific albumin tagging for in situ albumin seeking/targeting or constructing high-performance cyanine@albumin probes. We further investigate the interaction mechanism between NIR-II fluorogenic dyes and albumin. Results: We identify CO-1080 as an optimal dye structure that produces a stable/bright NIR-II cyanine@albumin probe. CO-1080 exhibits maximum supramolecular binding affinity to albumin while catalyzing their covalent attachment. The probe shows exact binding sites located on Cys476 and Cys101, as identified by proteomic analysis and docking modeling. Conclusion: Our cyanine@albumin probe substantially improves the pharmacokinetics of its free dye counterpart, enabling high-performance NIR-II angiography and lymphography. Importantly, the site-specific labeling tags between NIR-II fluorogenic dyes and albumin occur under mild conditions, offering a specific and straightforward synthesis strategy for NIR-II fluorophores in the fields of targeting bioimaging and imaging-guided surgery.

Alterations in the brain functional network of abstinent male individuals with methamphetamine use disorder.

Methamphetamine is a highly addictive psychostimulant drug that is abused globally and is a serious threat to health worldwide. Unfortunately, the specific mechanism underlying addiction remains unclear. Thus, this study aimed to investigate the characteristics of functional connectivity in the brain network and the factors influencing methamphetamine use disorder in patients using magnetic resonance imaging. We included 96 abstinent male participants with methamphetamine use disorder and 46 age- and sex-matched healthy controls for magnetic resonance imaging. Compared with healthy controls, participants with methamphetamine use disorder had greater impulsivity, fewer small-world attributes of the resting-state network, more nodal topological attributes in the cerebellum, greater functional connectivity strength within the cerebellum and between the cerebellum and brain, and decreased frontoparietal functional connectivity strength. In addition, after controlling for covariates, the partial correlation analysis showed that small-world properties were significantly associated with methamphetamine use frequency, psychological craving, and impulsivity. Furthermore, we revealed that the small-word attribute significantly mediated the effect of methamphetamine use frequency on motor impulsivity in the methamphetamine use disorder group. These findings may further improve our understanding of the neural mechanism of impulse control dysfunction underlying methamphetamine addiction and assist in exploring the neuropathological mechanism underlying methamphetamine use disorder-related dysfunction and rehabilitation.

Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.

Trends and driving forces of agricultural carbon emissions: A case study of Anhui, China.

To facilitate accurate prediction and empirical research on regional agricultural carbon emissions, this paper uses the LLE-PSO-XGBoost carbon emission model, which combines the Local Linear Embedding (LLE), Particle Swarm Algorithm (PSO) and Extreme Gradient Boosting Algorithm (XGBoost), to forecast regional agricultural carbon emissions in Anhui Province under different scenarios. The results show that the regional agricultural carbon emissions in Anhui Province generally show an upward and then downward trend during 2000-2021, and the regional agricultural carbon emissions in Anhui Province in 2030 are expected to fluctuate between 11,342,100 tones and 14,445,700 tones under five different set scenarios. The projections of regional agricultural carbon emissions can play an important role in supporting the development of local regional agriculture, helping to guide the input and policy guidance of local rural low-carbon agriculture and promoting the development of rural areas towards a resource-saving and environment-friendly society.

GPNMB promotes peripheral nerve regeneration by activating the Erk1/2 and Akt pathways via binding Na+/K+-ATPase α1 in Schwann cells.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is ubiquitously expressed and has protective effects on the central nervous system. In particular, it is also expressed in the peripheral nervous system (PNS) and upregulated after peripheral nerve injury. However, the role and underlying mechanism of GPNMB in the PNS, especially in peripheral nerve regeneration (PNR), are still unknown and need to be further investigated. In this study, recombinant human GPNMB (rhGPNMB) was injected into a sciatic nerve injury model. It was found that rhGPNMB facilitated the regeneration and functional recovery of the injured sciatic nerve in vivo. Moreover, it was also confirmed that GPNMB activated the Erk1/2 and Akt pathways via binding with Na+/K + -ATPase α1 (NKA α1) and promoted the proliferation and migration of Schwann cells (SCs) and their expression and secretion of neurotrophic factors and neural adhesion molecules in vitro. Our findings demonstrate that GPNMB facilitates PNR through activation of the Erk1/2 and Akt pathways in SCs by binding with NKA α1 and may be a novel strategy for PNR.

Mediating role of anxiety and impulsivity in the association between child maltreatment and lifetime non-suicidal self-injury with and without suicidal self-injury.

BACKGROUND: Child maltreatment can increase the risk of lifetime non-suicidal self-injury (NSSI) and suicidal self-injury (SSI), but there is limited knowledge regarding the differences of potentially psychological mechanisms between NSSI with and without SSI. METHODS: Participants, 3918 community-based Chinese young men aged 18-34 years in Chengdu, were included in this study. We investigated the association between depression, anxiety, psychosis, child maltreatment, adulthood traumatic events, impulsivity, alcohol dependence, drug abuse, and lifetime of NSSI among participants with and without SSI. Parallel mediation analysis was utilized to explore the mediators for the relation between child maltreatment and NSSI. RESULTS: The prevalence of lifetime NSSI was 6.1 % (95 % CI: 5.4 %-6.9 %) among young men. Anxiety and impulsivity partially mediated the effect of child maltreatment on NSSI either with (indirect effect: 51.2 %) or without SSI (indirect effect: 34.3 %). Depression was independently and significantly associated with only NSSI but not with NSSI+SSI. Alcohol dependence and psychosis were independently and significantly associated with NSSI+SSI and mediated the effect of child maltreatment on NSSI+SSI. LIMITATIONS: The cross-sectional survey data limits the robustness of the proof to the causal relationships. CONCLUSIONS: Anxiety and impulsivity are associated with NSSI either with or without SSI and partially mediate the effect of child maltreatment on NSSI. Depression is associated with only NSSI, while alcohol dependence and psychosis are only associated with NSSI+SSI. It could be crucial to improve treatment and recovery of alcohol dependence and psychosis for preventing young men engaged in NSSI from attempting SSI.

3D reconstruction of bone CT scan images based on deformable convex hull.

Three-dimensional (3D) reconstruction of computed tomography (CT) and magnetic resonance imaging (MRI) images is an important diagnostic method, which is helpful for doctors to clearly recognize the 3D shape of the lesion and make the surgical plan. In the study of medical image reconstruction, most researchers use surface rendering or volume rendering method to construct 3D models from image sequences. The watertightness of the algorithm-reconstructed surface will be affected by the segmentation precision or the thickness of the CT layer. The articular surfaces at femoral ends are often used in biomechanical simulation experiments. The model may not conform to its original shape due to the manual repair of non-watertight surfaces. To solve this problem, a 3D reconstruction method of leg bones based on deep learning is proposed in this paper. By deforming the convex hull of the target, comparing with state-of-the-art methods, our method can stably generate a watertight model with higher reconstruction accuracy. In the situation of target transition structures getting fuzzy and the layer spacing increasing, the proposed method can maintain better reconstruction performance and appear higher robustness. Also, the chamfer loss is optimized based on the rotational shape of the leg bones, and the weight of the loss function can be assigned according to the geometric characteristics of the target. Experiment results show that the optimization method improves the accuracy of the model. Furthermore, our research provides a reference for the application of deep learning in medical image reconstruction.

Spatiotemporally controlled Pseudomonas exotoxin transgene system combined with multifunctional nanoparticles for breast cancer antimetastatic therapy.

The tumor microenvironment is a barrier to breast cancer therapy. Cancer-associated fibroblast cells (CAFs) can support tumor proliferation, metastasis, and drug resistance by secreting various cytokines and growth factors. Abnormal angiogenesis provides sufficient nutrients for tumor proliferation. Considering that CAFs express the sigma receptor (which recognizes anisamide, AA), we developed a CAFs and breast cancer cells dual-targeting nano drug delivery system to transport the LightOn gene express system, a spatiotemporal controlled gene expression consisting of a light-sensitive transcription factor and a specific minimal promoter. We adopted RGD (Arg-Gly-Asp) to selectively bind to the αvß3 integrin on activated vascular endothelial cells and tumor cells. After the LightOn system has reached the tumor site, LightOn gene express system can spatiotemporal controllably express toxic Pseudomonas exotoxin An under blue light irradiation. The LightOn gene express system, combined with multifunctional nanoparticles, achieved high targeting delivery efficiency both in vitro and in vivo. It also displayed strong tumor and CAFs inhibition, anti-angiogenesis ability and anti-metastasis ability, with good safety. Moreover, it improved survival rate, survival time, and lung metastasis rate in a mouse breast cancer model. This study proves the efficacy of combining the LightOn system with targeted multifunctional nanoparticles in tumor and anti-metastatic therapy and provides new insights into tumor microenvironment regulation.

Sample size calculation for multi-arm parallel design with restricted mean survival time.

With the recent advances in oncology treatment, restricted mean survival time (RMST) is increasingly being used to replace the routine approach based on hazard ratios in randomized controlled trials for time-to-event outcomes. While RMST has been widely applied in single-arm and two-arm designs, challenges still exist in comparing RMST in multi-arm trials with three or more groups. In particular, it is unclear in the literature how to compare more than one intervention simultaneously or perform multiple testing based on RMST, and sample size determination is a major obstacle to its penetration to practice. In this paper, we propose a novel method of designing multi-arm clinical trials with right-censored survival endpoint based on RMST that can be applied in both phase II/III settings using a global χ2 test as well as a modeling-based multiple comparison procedure. The framework provides a closed-form sample size formula built upon a multi-arm global test and a sample size determination procedure based on multiple-comparison in the phase II dose-finding study. The proposed method enjoys strong robustness and flexibility as it requires less a priori set-up than conventional work, and obtains a smaller sample size while achieving the target power. In the assessment of sample size, we also incorporate practical considerations, including the presence of non-proportional hazards and staggered patient entry. We evaluate the validity of our method through simulation studies under various scenarios. Finally, we demonstrate the accuracy and stability of our method by implementing it in the design of two real clinical trial examples.

NIR-II Protein-Escaping Dyes Enable High-Contrast and Long-Term Prognosis Evaluation of Flap Transplantation.

Real-time vascular positioning, postoperative flap monitoring, and vascular reconstruction assessment are of great importance in flap transplantation. Cyanine dyes offer the advantage of high resolution in the Near-infrared-II (NIR-II) imaging window. However, the nonspecific binding of many cyanine dyes to endogenous albumin leads to high organ accumulation and skin absorption, resulting in low-quality imaging and poor reproducibility of contrast during long-term (e.g., 7 days) postoperative monitoring. Here, a novel strategy is proposed that can be widely applied to prevent protein binding for NIR-I/II Cl-containing cyanine dyes. This strategy produces protein-escaping dyes, ensuring high fluorescence enhancement in the blood with rapid clearance and no residual fluorescence, allowing for short-term repeatable injections for vascular imaging. This strategy in the perioperative monitoring of pedicle perforator flap models in mice and rats is successfully applied. Furthermore, leveraging the universality of this strategy, multiple nonoverlapping protein-escaping probes that achieve dual-excitation (808 and 1064 nm) interference-free imaging of nerve-vessel and tumor-vessel simultaneously are designed and synthesized. These protein-escaping dyes enable long-term repeatable dual-color imaging of tumor localization, resection, and tumor-vessel reconstruction at the wound site.

Fe(III)-Shikonin supramolecular nanomedicines as immunogenic cell death stimulants and multifunctional immunoadjuvants for tumor vaccination.

Immunoadjuvants, as an indispensable component of tumor vaccines, can observably enhance the magnitude, breadth, and durability of antitumor immunity. However, current immunoadjuvants suffer from different issues such as weak immunogenicity, inadequate cellular internalization, poor circulation time, and mono-functional bioactivity. Methods: Herein, we construct Fe3+-Shikonin metal-phenolic networks (FeShik) nanomedicines as immunogenic cell death (ICD) stimulants and multifunctional immunoadjuvants for tumor vaccination. The multifunctionality of FeShik nanomedicines is investigated by loading ovalbumin (OVA) as the model antigen to construct OVA@FeShik nanovaccines or 4T1 tumor cell fragment (TF) as homologous antigen to construct TF@FeShik nanovaccines. In vitro examinations including GSH responsive, •OH generation, colloid stability, cellular uptake, cytotoxicity mechanism of ferroptosis and necroptosis, ICD effect, the promotion of DC maturation and antigen cross-presentation were studied. In vivo observations including pharmacokinetics and biodistribution, antitumor effect, abscopal effect, immune memory effect, and biosafety were performed. Results: The presence of FeShik nanomedicines can significantly prolong the blood circulation time of antigens, increasing the bioavailability of antigens. Upon phagocytosis by tumor cells, FeShik nanomedicines can disassemble into Fe2+ and Shikonin in response to tumor microenvironments, leading to ICD of tumor cells via ferroptosis and necroptosis. Consequently, ICD-released autologous tumor cell lysates and pro-inflammatory cytokines not only stimulate DC maturation and antigen cross-presentation, but also promote macrophage repolarization and cytotoxic T lymphocyte infiltration, resulting in the activation of adaptive immune responses toward solid tumors. Conclusion: In a word, our FeShik supramolecular nanomedicines integrate bioactivities of ICD stimulants and immunoadjuvants, such as eradicating tumor cells, activating antitumor immune responses, modulating immunosuppressive tumor microenvironments, and biodegradation after immunotherapy. Encouraged by the diversity of polyphenols and metal ions, our research may provide a valuable paradigm to establish a large library for tumor vaccination.