Enzyme-armed nanocleaner provides superior detoxification against organophosphorus compounds via a dual-action mechanism.

By inhibiting acetylcholinesterase (AChE) activity, organophosphate compounds (OPs) can quickly cause severe injury to the nervous system and death, making it extremely difficult to rescue victims after OP exposure. However, it is quite challenging to construct scavengers that neutralize and eliminate these harmful chemical agents promptly in the blood circulation system. Herein, we report an enzyme-armed biomimetic nanoparticle that enables a 'targeted binding and catalytic degradation' action mechanism designed for highly efficient in vivo detoxification (denoted as 'Nanocleaner'). Specifically, the resulting Nanocleaner is fabricated with polymeric cores camouflaged with a modified red blood cell membrane (RBC membrane) that is inserted with the organophosphorus hydrolase (OPH) enzyme. In such a subtle construct, Nanocleaner inherits abundant acetylcholinesterase (AChE) on the surface of the RBC membrane, which can specifically lure and neutralize OPs through biological binding. The OPH enzyme on the membrane surface breaks down toxicants catalytically. The in vitro protective effects of Nanocleaner against methyl paraoxon (MPO)-induced inhibition of AChE activity were validated using both preincubation and competitive regimens. Furthermore, we selected the PC12 neuroendocrine cell line as an experimental model and confirmed the cytoprotective effects of Nanocleaner against MPO. In mice challenged with a lethal dose of MPO, Nanocleaner significantly reduces clinical signs of intoxication, rescues AChE activity and promotes the survival rate of mice challenged with lethal MPO. Overall, these results suggest considerable promise of enzyme-armed Nanocleaner for the highly efficient removal of OPs for clinical treatment.

"Comparative study of adipose-derived stem cells from localized scleroderma patients and healthy donors in treating skin fibrosis".

BACKGROUND: Localized scleroderma (LoS) is an autoimmune disease characterized by fibrosis of the skin and atrophy of the subcutaneous fat tissue. Adipose-derived mesenchymal stem cells (ASCs) is a promising treatment approach for LoS. However, ASCs from scleroderma patients (LoS-ASCs) have been shown to exhibit altered characteristics compared to ASCs from healthy donors (healthy-ASCs). This study aimed to compare the abilities of LoS-ASCs and healthy-ASCs in treating skin fibrosis. METHODS: The paracrine ability of ASCs was tested with cytokine array. Bleomycin-challenged mice models received subcutaneous injection of LoS-ASCs and healthy-ASCs. Pathological staining and western blotting of COL1, α-SMA was performed. Fibroblasts derived from LoS lesions (LoS-FB) was co-cultured with ASCs, and subjected to RNA sequencing to further explore the similarities and differences in the treatment mechanism. RESULTS: In vivo comparison revealed that healthy ASCs had a stronger proliferation ability and secreted higher levels of growth factors and cytokines, including VEGFA, PDGFB, and IL-10. Pathological staining of the skin in mice models treated with ASCs demonstrated that healthy ASCs were more effective in reducing dermal thickness and collagen deposition, while increasing microvessel density and the proportion of M2 macrophages. Co-culture with both healthy-ASCs and LoS-ASCs reduced the proliferation and migration abilities of LoS-FB, as well as the protein expression of α-SMA and COL1. RNA sequencing and validation revealed potential difference in the canonical Wnt pathway. CONCLUSIONS: Healthy-ASCs exhibited stronger proliferation, paracrine, anti-fibrosis, pro-angiogenesis, and immunomodulation abilities in treating skin fibrosis in scleroderma mouse models. CLINICAL RELEVANCE STATEMENT: Allogenic ASCs obtained from healthy donors are more efficient in treating skin fibrosis, and could serve as a potential alternative for patients who are not suitable candidates for liposuction surgery in the future.

PTPRT loss enhances anti-PD-1 therapy efficacy by regulation of STING pathway in non-small cell lung cancer.

With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti-PD-1/PD-L1 axis therapy. Anti-PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-ß, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti-PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti-PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti-PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.

Phloretin alleviates sleep deprivation-induced cognitive impairment by reducing inflammation through PPARγ/NF-κB signaling pathway.

Sleep loss leads to significant pathophysiological consequences, including cognitive impairment. The neuroinflammation are pivotal factors in the pathogenesis of cognitive impairment induced by sleep loss. The phloretin (PHL), derived from peel of juicy fruits, has demonstrated potent anti-inflammatory properties. However, the precise influence of PHL on the cognitive impairment triggered by sleep loss and its underlying mechanism remain uncertain. In the present study, mice were subjected to sleep deprivation (SD) paradigm. Cognitive impairment induced by SD were significantly relieved by administration of PHL in a dose-dependent manner. Furthermore, PHL not only mitigated the synaptic losses but also enhanced dendritic spine density and neuronal activity within mice hippocampus following exposure to SD. Moreover, PHL treatment decreased the microglial numbers and altered microglial morphology in the hippocampus to restore the M1/M2 balances; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in SD-exposed mice. Additionally, in vivo and in vitro studies showed PHL might attenuate the inflammation through the PPARγ/NF-κB pathway. Our findings suggest that PHL exerts inhibitory effects on microglia-mediated neuroinflammation, thereby providing protection against cognitive impairment induced by SD through a PPAR-γ dependent mechanism. The results indicate PHL is expected to provide a valuable candidate for new drug development for SD-induced cognitive impairment in the future.

Research on Move-to-Escape Enhanced Dung Beetle Optimization and Its Applications.

The dung beetle optimization (DBO) algorithm is acknowledged for its robust optimization capabilities and rapid convergence as an efficient swarm intelligence optimization technique. Nevertheless, DBO, similar to other swarm intelligence algorithms, often gets trapped in local optima during the later stages of optimization. To mitigate this challenge, we propose the Move-to-Escape dung beetle optimization (MEDBO) algorithm in this paper. MEDBO utilizes a good point set strategy for initializing the swarm's initial population, ensuring a more uniform distribution and diminishing the risk of local optima entrapment. Moreover, it incorporates convergence factors and dynamically balances the number of offspring and foraging individuals, prioritizing global exploration initially and local exploration subsequently. This dynamic adjustment not only enhances the search speed but also prevents local optima stagnation. The algorithm's performance was assessed using the CEC2017 benchmark suite, which confirmed MEDBO's significant improvements. Additionally, we applied MEDBO to three engineering problems: pressure vessel design, three-bar truss design, and spring design. MEDBO exhibited an excellent performance in these applications, demonstrating its practicality and efficacy in real-world problem-solving contexts.

Development of Reliable Male-Specific Molecular Markers for Genetic Sex Identification in Sea Cucumber Apostichopus japonicus.

Apostichopus japonicus is an important marine aquaculture species in China, with high nutritional and economic value. In A. japonicus, there is no obvious sexual dimorphism in external appearance, and sex differentiation primarily relies on the observation of mature gonads after dissection, which leads to difficulties in sex identification. The confusion in sex identification greatly reduces breeding efficiency in the sea cucumber industry. Therefore, developing a reliable sex-specific marker is crucial. In this study, we identified 586 male-specific sequences through whole-genome assembly and sequence alignment, but did not identify any female-specific sequences, inferring an XY-type sex determination system in sea cucumbers. We developed a set of male-specific molecular markers to establish an accurate, stable, and widely adaptable genetic sex identification technique for A. japonicus. The male-specific molecular markers were validated with 100% accuracy in sea cucumber populations from six different geographical regions in China. In conclusion, this study provides further evidence for the XY-type sex determination system in A. japonicus and establishes an effective genetic sex identification method for multi-geographic populations, which benefits future study on reproductive biology and has significant implications in sea cucumber aquaculture industry.

Pathological complete response to neoadjuvant lorlatinib in a patient with stage IIIA ALK-positive non-small cell lung cancer: a case report.

Background: Given the promising efficacy of targeted therapies in patients with advanced non-small cell lung cancer (NSCLC) harboring oncogenic drivers, its use in adjuvant and even neoadjuvant therapy is increasing. Lorlatinib is a potent brain-penetrating third-generation anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) tyrosine kinase inhibitors (TKIs) with broad ALK mutation coverage. Currently, there is a limited evidence regarding the efficacy of lorlatinib as neoadjuvant therapy in locally advanced NSCLC in the presence of ALK rearrangements. The aim of this case report is to describe a rare case of pathological complete response (pCR) to neoadjuvant lorlatinib in a patient with stage IIIA ALK-positive NSCLC, providing evidence for neoadjuvant targeted therapy. Case Description: A 35-year-old male was pathologically diagnosed with locally advanced stage IIIA (cT2bN2M0) ALK-positive NSCLC. Clinically, the patient had pulmonary nodules in the left inferior lobe, which were enlarged progressively with follow-up, with the largest measuring approximately 4.6 cm × 2.8 cm by computed tomography (CT) scan and we found that the lymph nodes (stations 4L, 7, and 8) were invaded by metastasis. Following a 3-month neoadjuvant treatment with lorlatinib at 100 mg daily, his CT scan demonstrated a partial response (PR). This patient then underwent a left inferior lobectomy with mediastinal lymph node dissection (MLD) and mediastinal cyst resection via video-assisted thoracoscopic surgery (VATS). Postoperative pathology revealed a pCR. This patient continued to receive lorlatinib and remained disease free at his 10-month follow-up. Conclusions: Herein we reported the case of a pCR in stage IIIA ALK-positive NSCLC patient treated with neoadjuvant lorlatinib. Our findings underscore the potential of lorlatinib as a neoadjuvant treatment for resectable ALK-positive NSCLC.

Astrocytes in the Ventral Hippocampus Bidirectionally Regulate Innate and Stress-Induced Anxiety-Like Behaviors in Male Mice.

The mechanisms of anxiety disorders, the most common mental illness, remain incompletely characterized. The ventral hippocampus (vHPC) is critical for the expression of anxiety. However, current studies primarily focus on vHPC neurons, leaving the role for vHPC astrocytes in anxiety largely unexplored. Here, genetically encoded Ca2+ indicator GCaMP6m and in vivo fiber photometry calcium imaging are used to label vHPC astrocytes and monitor their activity, respectively, genetic and chemogenetic approaches to inhibit and activate vHPC astrocytes, respectively, patch-clamp recordings to measure glutamate currents, and behavioral assays to assess anxiety-like behaviors. It is found that vHPC astrocytic activity is increased in anxiogenic environments and by 3-d subacute restraint stress (SRS), a well-validated mouse model of anxiety disorders. Genetic inhibition of vHPC astrocytes exerts anxiolytic effects on both innate and SRS-induced anxiety-related behaviors, whereas hM3Dq-mediated chemogenetic or SRS-induced activation of vHPC astrocytes enhances anxiety-like behaviors, which are reversed by intra-vHPC application of the ionotropic glutamate N-methyl-d-aspartate receptor antagonists. Furthermore, intra-vHPC or systemic application of the N-methyl-d-aspartate receptor antagonist memantine, a U.S. FDA-approved drug for Alzheimer's disease, fully rescues SRS-induced anxiety-like behaviors. The findings highlight vHPC astrocytes as critical regulators of stress and anxiety and as potential therapeutic targets for anxiety and anxiety-related disorders.

Functional poly(e-caprolactone)/SerMA hybrid dressings with dimethyloxalylglycine-releasing property improve cutaneous wound healing.

Medical dressings with multifunctional properties, including potent regeneration capability and good biocompatibility, are increasingly needed in clinical practice. In this study, we reported a novel hybrid wound dressing (PCL/SerMA/DMOG) that combines electrospun PCL membranes with DMOG-loaded methacrylated sericin (SerMA) hydrogel. In such a design, DMOG molecules are released from the hybrid dressing in a sustained mannerin vitro. A series ofin vitroassays demonstrated that DMOG-loaded hybrid dressing has multiple biological functions, including promotion of human umbilical vein endothelial cells proliferation and migration,in vitrovascularization, and the generation of intracellular NO. When applied to the cutaneous wound, the PCL/SerMA/DMOG dressing significantly accelerated wound closure and tissue regeneration by promoting angiogenesis in the wound area, collagen deposition, and cell proliferation within the wound bed. These results highlight the potential clinical application of PCL/SerMA/DMOG hybrid dressings as promising alternatives for accelerating wound healing via improved biocompatibility and angiogenesis amelioration.