Lung-specific supramolecular nanoparticles for efficient delivery of therapeutic proteins and genome editing nucleases.

Protein therapeutics play a critical role in treating a large variety of diseases, ranging from infections to genetic disorders. However, their delivery to target tissues beyond the liver, such as the lungs, remains a great challenge. Here, we report a universally applicable strategy for lung-targeted protein delivery by engineering Lung-Specific Supramolecular Nanoparticles (LSNPs). These nanoparticles are designed through the hierarchical self-assembly of metal-organic polyhedra (MOP), featuring a customized surface chemistry that enables protein encapsulation and specific lung affinity after intravenous administration. Our design of LSNPs not only addresses the hurdles of cell membrane impermeability of protein and nonspecific tissue distribution of protein delivery, but also shows exceptional versatility in delivering various proteins, including those vital for anti-inflammatory and CRISPR-based genome editing to the lung, and across multiple animal species, including mice, rabbits, and dogs. Notably, the delivery of antimicrobial proteins using LSNPs effectively alleviates acute bacterial pneumonia, demonstrating a significant therapeutic potential. Our strategy not only surmounts the obstacles of tissue-specific protein delivery but also paves the way for targeted treatments in genetic disorders and combating antibiotic resistance, offering a versatile solution for precision protein therapy.

Migration characteristics of microplastics in riparian soils and groundwater.

Investigations have revealed the presence of microplastics in both soil and groundwater, but the migration characteristics from soil to groundwater remain incompletely understood. In this study, two sampling sections consisting of soil-groundwater-river water were established near Lianxi Bridge and Xilin Bridge along the Jiuxi River in Xiamen. A total of 22 soil samples, 36 groundwater samples, and 18 river water samples were collected. Microplastics were detected in all samples with an abundance range of 392-836 n/kg in soil (mean, 655 ± 177 n/kg), 0.58-2.48 n/L groundwater (mean, 1.23 ± 0.42 n/L), and 0.38-1.80 n/L in river water (mean, 0.86 ± 0.41 n/L). Flakes predominantly constituted the shape of microplastics found in soil, while fibers dominated those present in water. Black, yellow, and red were the dominant color types. Polyamide (PA) and polyethylene (PE) were the main components of microplastics within soils, whereas polyethylene terephthalate (PET), polypropylene (PP), and PA prevailed within water. Microplastic particle sizes ranged from 39 to 2498 µm in soils, mainly from 29 to 3394 µm in water. The upstream section displayed higher abundances of microplastic compared to the downstream, revealing the soil particles having an intercepting effect on microplastics. The distribution and migration of microplastics in soil and groundwater are affected by many factors, including natural and anthropogenic factors, such as soil depth, soil properties, pore structure, hydrodynamics, hydraulic connections between groundwater and surface water, the extensive utilization and disposal of plastics, irrational exploitation of groundwater, and morphology and types of microplastics. These research findings contribute to a better understanding of the pathways, migration capacity, and influencing factors associated with microplastic entry into groundwater, thereby providing valuable technical support for the development of strategies aimed at controlling microplastic pollution.

Electrochromic windows with fast response and wide dynamic range for visible-light modulation without traditional electrodes.

Electrochromic (EC) devices represent an emerging energy-saving technology, exhibiting the capability to dynamically modulate light and heat transmittance. Despite their promising potential, the commercialization of EC devices faces substantial impediments such as high cost, intricate fabrication process, and low optical contrast inherent in conventional EC materials relying on the ion insertion/extraction mechanism. In this study, we introduce an innovative "electrode-free" electrochromic (EC) device, termed the EECD, which lacks an EC-layer on the electrodes during device assembling and in the bleached state. This device features a simplified fabrication process and delivers superior optical modulation. It achieves a high optical contrast ranging from 68-85% across the visible spectrum and boasts a rapid response time, reaching 90% coloring in just 17 seconds. In addition, EECD exhibits stable cycling for over 10,000 cycles without noticeable degradation and maintains functionality across a broad temperature range (0 °C to 50 °C). Furthermore, the fabricated large-area devices (40 cm × 40 cm) demonstrate excellent tinting uniformity, suggesting excellent scalability of this approach. Our study establishes a paradigmatic breakthrough for EC smart windows.

Aurantiamide mitigates acute kidney injury by suppressing renal necroptosis and inflammation via GRPR-dependent mechanism.

Acute kidney injury (AKI) manifests as a clinical syndrome characterised by the rapid accumulation of metabolic wastes, such as blood creatinine and urea nitrogen, leading to a sudden decline in renal function. Currently, there is a lack of specific therapeutic drugs for AKI. Previously, we identified gastrin-releasing peptide receptor (GRPR) as a pathogenic factor in AKI. In this study, we investigated the therapeutic potential of a novel Chinese medicine monomer, aurantiamide (AA), which exhibits structural similarities to our previously reported GRPR antagonist, RH-1402. We compared the therapeutic efficacy of AA with RH-1402 both in vitro and in vivo using various AKI models. Our results demonstrated that, in vitro, AA attenuated injury, necroptosis, and inflammatory responses in human renal tubular epithelial cells subjected to repeated hypoxia/reoxygenation and lipopolysaccharide stimulation. In vivo, AA ameliorated renal tubular injury and inflammation in mouse models of ischemia/reperfusion and cecum ligation puncture-induced AKI, surpassing the efficacy of RH-1402. Furthermore, molecular docking and cellular thermal shift assay confirmed GRPR as a direct target of AA, which was further validated in primary cells. Notably, in GRPR-silenced HK-2 cells and GRPR systemic knockout mice, AA failed to mitigate renal inflammation and injury, underscoring the importance of GRPR in AA's mechanism of action. In conclusion, our study has demonstrated that AA serve as a novel antagonist of GRPR and a promising clinical candidate for AKI treatment.

Time-dependent analysis of erectile dysfunction in kidney transplant recipients: insights from four distinct time periods.

BACKGROUND AND INTENTION: Erectile dysfunction (ED) is an underappreciated clinical condition in men. This study aims to compare the dynamic changes in the distribution of ED among male kidney transplant recipients (mKTRs) in four epochs: end-stage renal disease period (ESRDp), early post-transplant period (EPTP), pre-COVID-19, and post-COVID-19. METHODS: General information was gathered through interviews, follow-ups, and medical records. The International Index of Erectile Function Questionnaire-5 was used to assess erectile function. The Mann-Whitney U test and chi-square test were used to analyze differences in ED strength. Univariate and logistic regression analyses were conducted to identify risk factors for ED. RESULTS: The database contains 230 mKTRs. In the ESRDp, 17.0% had normal erectile function, 53.5% had mild ED, 18.3% had moderate ED, and 11.3% had severe ED. In the EPTP, the distribution was 38.2% normal, 42.6% mild, 10.8% moderate, and 8.2% severe. In the pre-COVID-19 period, it was 34.3%, 47.3%, 10.4%, and 7.8%, and in the post-COVID-19 period, it was 23.0%, 45.6%, 21.3%, and 10.0%. Overall, erectile function improved after kidney transplant (KT). However, post-COVID-19, the proportion of erectile function significantly decreased compared to EPTP and pre-COVID-19 periods. Risk factors for post-pandemic ED included degree, Generalized Anxiexy Disorder-7, kidney donor type, postoperative time, hypertension and hemoglobin concentration. CONCLUSION: KT improves erectile function in mKTRs within 5 years, but post-SARS-CoV-2 viral infection, ED worsens due to altered risk factors. These findings inform future research for comprehensive ED prevention and management strategies in this population.

A Crystalline-Water Electrolyte Enabled High Depth-of-Discharge Anodes in Aqueous Zinc Metal Batteries.

Aqueous zinc metal batteries are regarded as a promising energy storage solution for a green and sustainable society in the future. However, the practical application of metallic zinc anode is plagued by the thermodynamic instability issue of water molecules in conventional electrolytes, which leads to severe dendrite growth and side reactions. In this work, an ultra-thin and high areal capacity metallic zinc anode is achieved by utilizing crystalline water with a stable stoichiometric ratio. Unlike conventional electrolytes, the designed electrolyte can effectively suppress the reactivity of water molecules and diminish the detrimental corrosion on the metallic zinc anode, while preserving the inherent advantages of water molecules, including great kinetic performance in electrolytes and H+ capacity contribution in cathodes. Based on the comprehensive performance of the designed electrolyte, the 10 µm Zn||10 µm Zn symmetric cell stably ran for 1000 h at the current density of 1 mA cm-2, and the areal capacity of 1 mAh cm-2, whose depth-of-discharge is over 17.1%. The electrochemical performance of the 10 µm Zn||9.3 mg cm-2 polyaniline (PANI) full-cell demonstrates the feasibility of the designed electrolyte. This work provides a crucial understanding of balancing activity of water molecules in aqueous zinc metal batteries.

A chemo-selective enrichment strategy to achieve in-depth coverage of methyllysine proteome.

Proteomics is a powerful method to comprehensively understand cellular posttranslational modifications (PTMs). Due to low abundance, tryptic peptides with PTMs are usually enriched for enhanced coverage by LC-MS/MS. Affinity chromatography for phosphoproteomes by metal-oxide and pan-specific antibodies for lysine acetylome allow identification of tens of thousands of modification sites. Lysine methylation is a significant PTM, however, only hundreds of methylation sites were identified from available approaches. Here we report an aryl diazonium-based chemoselective strategy that enables enrichment of monomethyllysine (Kme1) peptides via covalent bond with extraordinary sensitivity. We identified more than ten thousand Kme1 peptides from diverse cell lines and mouse tissues, that implied wide lysine methylation impact on cellular processes. In addition, we found a significant amount of methyl marks that were not S-adenosyl methionine (SAM)-dependent by isotope labeling experiments. And therefore, this method paves a way to broad application in lysine methylation research and new biology discovery.

Virtual-point-based deconvolution for optical-resolution photoacoustic microscopy.

Optical-resolution photoacoustic microscopy (OR-PAM) has been increasingly utilized for in vivo imaging of biological tissues, offering structural, functional, and molecular information. In OR-PAM, it is often necessary to make a trade-off between imaging depth, lateral resolution, field of view, and imaging speed. To improve the lateral resolution without sacrificing other performance metrics, we developed a virtual-point-based deconvolution algorithm for OR-PAM (VP-PAM). VP-PAM has achieved a resolution improvement ranging from 43% to 62.5% on a single-line target. In addition, it has outperformed Richardson-Lucy deconvolution with 15 iterations in both structural similarity index and peak signal-to-noise ratio on an OR-PAM image of mouse brain vasculature. When applied to an in vivo glass frog image obtained by a deep-penetrating OR-PAM system with compromised lateral resolution, VP-PAM yielded enhanced resolution and contrast with better-resolved microvessels.

The risk of Alzheimer's disease and cognitive impairment characteristics in eight mental disorders: A UK Biobank observational study and Mendelian randomization analysis.

INTRODUCTION: The cognitive impairment patterns and the association with Alzheimer's disease (AD) in mental disorders remain poorly understood. METHODS: We analyzed data from 486,297 UK Biobank participants, categorizing them by mental disorder history to identify the risk of AD and the cognitive impairment characteristics. Causation was further assessed using Mendelian randomization (MR). RESULTS: AD risk was higher in individuals with bipolar disorder (BD; hazard ratio [HR] = 2.37, P < 0.01) and major depressive disorder (MDD; HR = 1.63, P < 0.001). MR confirmed a causal link between BD and AD (ORIVW = 1.098), as well as obsessive-compulsive disorder (OCD) and AD (ORIVW = 1.050). Cognitive impairments varied, with BD and schizophrenia showing widespread deficits, and OCD affecting complex task performance. DISCUSSION: Observational study and MR provide consistent evidence that mental disorders are independent risk factors for AD. Mental disorders exhibit distinct cognitive impairment prior to dementia, indicating the potential different mechanisms in AD pathogenesis. Early detection of these impairments in mental disorders is crucial for AD prevention. HIGHLIGHTS: This is the most comprehensive study that investigates the risk and causal relationships between a history of mental disorders and the development of Alzheimer's disease (AD), alongside exploring the cognitive impairment characteristics associated with different mental disorders. Individuals with bipolar disorder (BD) exhibited the highest risk of developing AD (hazard ratio [HR] = 2.37, P < 0.01), followed by those with major depressive disorder (MDD; HR = 1.63, P < 0.001). Individuals with schizophrenia (SCZ) showed a borderline higher risk of AD (HR = 2.36, P = 0.056). Two-sample Mendelian randomization (MR) confirmed a causal association between BD and AD (ORIVW = 1.098, P < 0.05), as well as AD family history (proxy-AD, ORIVW = 1.098, P < 0.001), and kept significant after false discovery rate correction. MR also identified a nominal significant causal relationship between the obsessive-compulsive disorder (OCD) spectrum and AD (ORIVW = 1.050, P < 0.05). Individuals with SCZ, BD, and MDD exhibited impairments in multiple cognitive domains with distinct patterns, whereas those with OCD showed only slight declines in complex tasks.

A universal solvent-replacement strategy to convert alginate hydrogels into mechanically strong and transparent alginate eutectogels for sensitive strain sensors.

Eutectogels based on natural polymers have attracted significant attention as an alternative to easily dehydrated hydrogels and expensive ionogels in the development of flexible strain sensors. The feasibility of employing eutectogels derived from pure natural polymers could be greatly enhanced if their mechanical properties satisfy the requirements of applications. Herein, alginate eutectogels (AEs) with high mechanical properties (tensile strain 217 % and strength 2.26 MPa at fracture), and excellent transparency (over 90 %) are acquired via CaCl2 inducing ionic crosslinking and subsequent deep eutectic solvents (DESs, composed of glycerol and choline chloride) initiating physical crosslinking with a universal solvent- replacement strategy. Among them, sodium alginate, a natural polysaccharide polymer, is selected as representative supporting scaffolds and forms water-insoluble alginate hydrogels (AHs) in CaCl2 coagulation bath. The exchange of DESs with water of AHs not only restrengthens the polymer network by physical crosslinking, but also endows the obtained AEs with long-term solvent retention and high temperature resistance. In addition, the AEs not only have high reliability but also exhibit better linear sensitivity in a wide strain range (0-200 %). In particular, the AEs display multiple sensitivity to stretching, bending, and human motions, demonstrating feasibility as sensitive strain sensors.

CD147-K148me2-Driven Tumor Cell-Macrophage Crosstalk Provokes NSCLC Immunosuppression via the CCL5/CCR5 Axis.

Immunosuppression is a major hallmark of tumor progression in non-small cell lung cancer (NSCLC). Cluster of differentiation 147 (CD147), an important pro-tumorigenic factor, is closely linked to NSCLC immunosuppression. However, the role of CD147 di-methylation in the immunosuppressive tumor microenvironment (TME) remains unclear. Here, di-methylation of CD147 at Lys148 (CD147-K148me2) is identified as a common post-translational modification (PTM) in NSCLC that is significantly associated with unsatisfying survival outcomes among NSCLC sufferers, especially those in the advanced stages of the disease. The methyltransferase NSD2 catalyzes CD147 to generate CD147-K148me2. Further analysis demonstrates that CD147-K148me2 reestablishes the immunosuppressive TME and promotes NSCLC progression. Mechanistically, this modification promotes the interaction between cyclophilin A (CyPA) and CD147, and in turn, increases CCL5 gene transcription by activating p38-ZBTB32 signaling, leading to increased NSCLC cell-derived CCL5 secretion. Subsequently, CD147-K148me2-mediated CCL5 upregulation facilitates M2-like tumor-associated macrophage (TAM) infiltration in NSCLC tissues via CCL5/CCR5 axis-dependent intercellular crosstalk between tumor cells and macrophages, which is inhibited by blocking CD147-K148me2 with the targeted antibody 12C8. Overall, this study reveals the role of CD147-K148me2-driven intercellular crosstalk in the development of NSCLC immunosuppression, and provides a potential interventional strategy for PTM-targeted NSCLC therapy.

An agonist of the adenosine A2A receptor, CGS21680, promotes corneal epithelial wound healing via the YAP signalling pathway.

BACKGROUND AND PURPOSE: The adenosine A2A receptor (A2AR) is involved in various physiological and pathological processes in the eye; however, the role of the A2AR signalling in corneal epithelial wound healing is not known. Here, the expression, therapeutic effects and signalling mechanism of A2AR in corneal epithelial wound healing were investigated using the A2AR agonist CGS21680. EXPERIMENTAL APPROACH: A2AR localization and expression during wound healing in the murine cornea were determined by immunofluorescence staining, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. The effect of CGS21680 on corneal epithelial wound healing in the lesioned corneal and cultured human corneal epithelial cells (hCECs) by modulating cellular proliferation and migration was critically evaluated. The role of Hippo-YAP signalling in mediating the CGS21680 effect on wound healing by pharmacological inhibition of YAP signalling was explored. KEY RESULTS: A2AR expression was up-regulated after corneal epithelial injury. Topical administration of CGS21680 dose-dependently promoted corneal epithelial wound healing in the injured corneal epithelium by promoting cellular proliferation. Furthermore, CGS21680 accelerated the cellular proliferation and migration of hCECs in vitro. A2AR activation promoted early up-regulation and later down-regulation of YAP signalling molecules, and pharmacological inhibition of YAP signalling reverted CGS21680-mediated wound healing effect in vivo and in vitro. CONCLUSION AND IMPLICATIONS: A2AR activation promotes wound healing by enhancing cellular proliferation and migration through the YAP signalling pathway. A2ARs play an important role in the maintenance of corneal epithelium integrity and may represent a novel therapeutic target for facilitating corneal epithelial wound healing.

Catalytic Dual-Mode Immunotherapy: Anisotropic AuPt Heterostructure Decorated with Starry Pt Nanoclusters for Robust Cancer Photometalloimmunotherapy.

To overcome current limitations in photoimmunotherapy, such as insufficient tumor antigen generation and a subdued immune response, a novel photo-/metallo dual-mode immunotherapeutic agent (PMIA) is introduced for potent near-infrared (NIR) light-triggered cancer therapy. PMIA features a dumbbell-like AuPt heterostructure decorated with starry Pt nanoclusters, meticulously engineered for enhancing plasmonic catalysis through multi-dimensional regulation of Pt growth on Au nanorods. Under NIR laser exposure, end-tipped Pt nanoclusters induce efficient electron-hole spatial separation along the longitudinal axis, resulting in radial and axial electron distribution polarization, conferring unique anisotropic properties to PMIA. Additionally, starry Pt nanoclusters on the sides of Au nanorods augment the local electron enrichment field. Validated through finite-difference time-domain analysis and Raman scattering, this configuration fosters local electron enrichment, facilitating robust reactive oxygen species generation for potent photoimmunotherapy. Moreover, Pt nanoclusters facilitate Pt2+ ion release, instigating intranuclear DNA damage and inducing synergistic immunogenic cell death (ICD) for metalloimmunotherapy. Consequently, PMIA elicits abundant danger-associated molecular patterns, promotes T cell infiltration, and triggers systemic immune responses, effectively treating primary and distant tumors, inhibiting metastasis in vivo. This study unveils a pioneering dual-mode ICD amplification strategy driven by NIR light, synergistically integrating photoimmunotherapy and metalloimmunotherapy, culminating in potent cancer photometalloimmunotherapy.

Deep learning-assisted diagnosis of large vessel occlusion in acute ischemic stroke based on four-dimensional computed tomography angiography.

Purpose: To develop deep learning models based on four-dimensional computed tomography angiography (4D-CTA) images for automatic detection of large vessel occlusion (LVO) in the anterior circulation that cause acute ischemic stroke. Methods: This retrospective study included 104 LVO patients and 105 non-LVO patients for deep learning models development. Another 30 LVO patients and 31 non-LVO patients formed the time-independent validation set. Four phases of 4D-CTA (arterial phase P1, arterial-venous phase P2, venous phase P3 and late venous phase P4) were arranged and combined and two input methods was used: combined input and superimposed input. Totally 26 models were constructed using a modified HRNet network. Assessment metrics included the areas under the curve (AUC), accuracy, sensitivity, specificity and F1 score. Kappa analysis was performed to assess inter-rater agreement between the best model and radiologists of different seniority. Results: The P1 + P2 model (combined input) had the best diagnostic performance. In the internal validation set, the AUC was 0.975 (95%CI: 0.878-0.999), accuracy was 0.911, sensitivity was 0.889, specificity was 0.944, and the F1 score was 0.909. In the time-independent validation set, the model demonstrated consistently high performance with an AUC of 0.942 (95%CI: 0.851-0.986), accuracy of 0.902, sensitivity of 0.867, specificity of 0.935, and an F1 score of 0.901. The best model showed strong consistency with the diagnostic efficacy of three radiologists of different seniority (k = 0.84, 0.80, 0.70, respectively). Conclusion: The deep learning model, using combined arterial and arterial-venous phase, was highly effective in detecting LVO, alerting radiologists to speed up the diagnosis.

NKUT: Dataset and Benchmark for Pediatric Mandibular Wisdom Teeth Segmentation.

Germectomy is a common surgery in pediatric dentistry to prevent the potential dangers caused by impacted mandibular wisdom teeth. Segmentation of mandibular wisdom teeth is a crucial step in surgery planning. However, manually segmenting teeth and bones from 3D volumes is time-consuming and may cause delays in treatment. Deep learning based medical image segmentation methods have demonstrated the potential to reduce the burden of manual annotations, but they still require a lot of well-annotated data for training. In this paper, we initially curated a Cone Beam Computed Tomography (CBCT) dataset, NKUT, for the segmentation of pediatric mandibular wisdom teeth. This marks the first publicly available dataset in this domain. Second, we propose a semantic separation scale-specific feature fusion network named WTNet, which introduces two branches to address the teeth and bones segmentation tasks. In WTNet, We design a Input Enhancement (IE) block and a Teeth-Bones Feature Separation (TBFS) block to solve the feature confusions and semantic-blur problems in our task. Experimental results suggest that WTNet performs better on NKUT compared to previous state-of-the-art segmentation methods (such as TransUnet), with a maximum DSC lead of nearly 16%.

Polyphenol-Assisted Biomineralization of Metal-Organic Framework Nanoparticles for Precision Delivery of Therapeutic Proteins to Cancer Cells.

The delivery of proteins into the cytosol holds great promise for cell signaling manipulation and the development of precision medicine. However, this potency is challenged by achieving targeted and controlled delivery, specifically within diseased cells. In this study, we introduce a versatile and effective method for the precision delivery of therapeutic proteins to cancer cells by designing polyphenol-assisted biomineralization of zeolite imidazole framework-8 (ZIF-8). We demonstrate that by leveraging the strong noncovalent binding affinity of epigallocatechin gallate (EGCG) with both proteins and ZIF-8, our approach significantly enhances the biomineralization of ZIF-8, which in turn improves the efficiency of protein encapsulation and intracellular delivery. Moreover, the incorporation of EGCG within ZIF-8 enables controlled degradation of the nanoparticles and the selective release of the encapsulated proteins in cancer cells. This selective release is triggered by the oxidation of EGCG in response to the high levels of reactive oxygen species (ROS) found within cancer cells that destabilize the EGCG/ZIF-8 nanoparticles. We have further demonstrated the ability of EGCG/ZIF-8 to deliver a wide range of proteins into cancer cells, including bacterial virulence protein, to rewire cell signaling and prohibit tumor cell growth in a mouse xenograft model. Our strategy and findings underscore the potential of designing the EGCG/ZIF-8 interface for specific and controlled protein delivery for targeted cancer therapy.

Stable hydrogen evolution reaction at high current densities via designing the Ni single atoms and Ru nanoparticles linked by carbon bridges.

Continuous and effective hydrogen evolution under high current densities remains a challenge for water electrolysis owing to the rapid performance degradation under continuous large-current operation. In this study, theoretical calculations, operando Raman spectroscopy, and CO stripping experiments confirm that Ru nanocrystals have a high resistance against deactivation because of the synergistic adsorption of OH intermediates (OHad) on the Ru and single atoms. Based on this conceptual model, we design the Ni single atoms modifying ultra-small Ru nanoparticle with defect carbon bridging structure (UP-RuNiSAs/C) via a unique unipolar pulse electrodeposition (UPED) strategy. As a result, the UP-RuNiSAs/C is found capable of running steadily for 100 h at 3 A cm-2, and shows a low overpotential of 9 mV at a current density of 10 mA cm-2 under alkaline conditions. Moreover, the UP-RuNiSAs/C allows an anion exchange membrane (AEM) electrolyzer to operate stably at 1.95 Vcell for 250 h at 1 A cm-2.

Melanoma differentiation-associated protein 5 prevents cardiac hypertrophy via apoptosis signal-regulating kinase 1-c-Jun N-terminal kinase/p38 signaling.

Pathological cardiac hypertrophy (CH) is driven by maladaptive changes in myocardial cells in response to pressure overload or other stimuli. CH has been identified as a significant risk factor for the development of various cardiovascular diseases, ultimately resulting in heart failure. Melanoma differentiation-associated protein 5 (MDA5), encoded by interferon-induced with helicase C domain 1 (IFIH1), is a cytoplasmic sensor that primarily functions as a detector of double-stranded ribonucleic acid (dsRNA) viruses in innate immune responses; however, its role in CH pathogenesis remains unclear. Thus, the aim of this study was to examine the relationship between MDA5 and CH using cellular and animal models generated by stimulating neonatal rat cardiomyocytes with phenylephrine and by performing transverse aortic constriction on mice, respectively. MDA5 expression was upregulated in all models. MDA5 deficiency exacerbated myocardial pachynsis, fibrosis, and inflammation in vivo, whereas its overexpression hindered CH development in vitro. In terms of the underlying molecular mechanism, MDA5 inhibited CH development by promoting apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, thereby suppressing c-Jun N-terminal kinase/p38 signaling pathway activation. Rescue experiments using an ASK1 activation inhibitor confirmed that ASK1 phosphorylation was essential for MDA5-mediated cell death. Thus, MDA5 protects against CH and is a potential therapeutic target.

Testicular volume is a noninvasive predictor of sperm retrieval failure in idiopathic nonobstructive azoospermia.

We investigated the prognostic importance of noninvasive factors in predicting sperm retrieval failure in idiopathic nonobstructive azoospermia (iNOA). We studied 193 patients with nonobstructive azoospermia who underwent microsurgical testicular sperm extraction. The Chi-square test and Mann-Whitney U tests for clinical parameters and seminiferous tubule distribution were used for between-group comparisons. A logistic regression analysis was conducted to identify predictors of retrieval failure. Area under the receiver operating characteristic curve for each variable was evaluated, and the net clinical benefit was calculated using a clinical decision curve. Patients with iNOA had a lower sperm retrieval rate than those with known causes. Moreover, testicular volume was an independent factor affecting sperm extraction outcomes (odds ratio = 0.79, P < 0.05). The testicular volume cut-off value was 6.5 ml (area under the curve: 0.694). The patients with iNOA were categorized into two groups on the basis of the distribution of seminiferous tubules observed. The sperm retrieval rate and testicular volume were significantly different between the groups with a uniform or heterogeneous tubule distribution. There was also a significant association between a uniform tubule distribution and testicular volume. In conclusion, a testicular volume of more than 6.5 ml effectively predicts microsurgical testicular sperm extraction failure due to a uniform tubule distribution in patients with iNOA.

Ferritin-nanocaged aggregation-induced emission nanoaggregates for NIR-II fluorescence-guided noninvasive, controllable male contraception.

Controllable contraception in male animals was demonstrated through the utilization of gold nanorods' photothermal effect to accomplish mild testicular hyperthermia. However, the challenges arising from testicular administration and the non-biodegradability of nanoparticles hinder further clinical implementation. Therefore, a straightforward, non-invasive, and enhanced contraception approach is required. This study explores the utilization of human heavy chain ferritin (HFn) nanocarriers loaded with aggregation-induced emission luminogens (AIEgens) for noninvasive, controllable male contraception guided by Near-Infrared-II (NIR-II) fluorescence imaging. The HFn-caged AIEgens (HFn@BBT) are delivered via intravenous injection and activated by near-infrared irradiation. Lower hyperthermia treatment induces partial damage to the testes and seminiferous tubules, reducing fertility indices by approximately 100% on the 7th day, which gradually recovers to 80% on the 60th day. Conversely, implementation of elevated hyperthermia therapy causes total destruction of both testes and seminiferous tubules, leading to a complete loss of fertility on the 60th day. Additionally, the use of AIEgens in NIR-II imaging offers improved fluorescence efficiency and penetration depth. The findings of this study hold significant promise for the advancement of safe and effective male contraceptive methods, addressing the need for noninvasive and controllable approaches to reproductive health and population control.