Atrazine (AT), a widely utilized chemical herbicide, causes widespread contamination of agricultural water bodies. Recently, exposure to AT has been linked to the development of age-related neurodegenerative diseases (NDs), suggesting its neurotoxicity potential. As an endocrine disruptor, AT targets the hypothalamus, a crucial part of the neuroendocrine system. However, the toxicological mechanism of AT exposure to the hypothalamus and its correlation with ND development remain unexplored. Our results indicated that AT exposure caused significant morphological and structural damage to the hypothalamus, leading to the loss of mature and intact neurons and microglial activation. Furthermore, hypothalamic neural stem cells (HtNSCs) were recruited to areas of neuronal damage caused by AT. Through in vivo and in vitro experiments, we clarified the outcomes of AT-induced HtNSC recruitment alongside the loss of mature/intact neurons. Mechanistically, AT induces senescence in these recruited HtNSCs by activating integrated stress response signaling. This consequently hinders the repair of damaged neurons by inhibiting HtNSC proliferation and differentiation. Overall, our findings underscore the pivotal role of the integrated stress response pathway in AT-induced HtNSC senescence and hypothalamic damage. Additionally, the present study offers novel perspectives to understand the mechanisms of AT-induced neurotoxicity and provides preliminary evidence linking AT contamination to the development of NDs.

Metamaterials hold great potential to enhance the imaging performance of magnetic resonance imaging (MRI) as auxiliary devices, due to their unique ability to confine and enhance electromagnetic fields. Despite their promise, the current implementation of metamaterials faces obstacles for practical clinical adoption due to several notable limitations, including their bulky and rigid structures, deviations from optimal resonance frequency, and inevitable interference with the radiofrequency (RF) transmission field in MRI. Herein, we address these restrictions by introducing a flexible and smart metamaterial that enhances sensitivity by conforming to patient anatomies while ensuring comfort during MRI procedures. The proposed metamaterial selectively amplifies the magnetic field during the RF reception phase by passively sensing the excitation signal strength, remaining “off” during the RF transmission phase. Additionally, the metamaterial can be readily tuned to achieve a precise frequency match with the MRI system through a controlling circuit. The metamaterial presented here paves the way for the widespread utilization of metamaterials in clinical MRI, thereby translating this promising technology to the MRI bedside.

The NLRP3 inflammasome plays a critical role in various inflammatory conditions. However, despite extensive research in targeted drug development for NLRP3, including MCC950, clinical success remains elusive. Here, we discovered that the activated NLRP3 inflammasome complex (disc-NLRP3) and the activating mutation L351P exhibited resistance to MCC950. Through investigations using the small-molecule compound polydatin, HSP90α was found to stabilize both the resting (cage-NLRP3) and activated state (disc-NLRP3) of NLRP3 complexes, sustaining its activation. Our mechanistic studies revealed that polydatin specifically targets HSP90α, binding to it directly and subsequently interfering with the HSP90α-NLRP3 interaction. This disruption leads to the dissipation of cage-NLRP3, disc-NLRP3 complexes and NLRP3 L351P. Importantly, genetic and pharmacological inactivation of HSP90α effectively reduced NLRP3 inflammasome activation and alleviated cerulein-induced acute pancreatitis. These therapeutic effects highlight the clinical potential of HSP90α inhibition. Our findings demonstrate that HSP90α is crucial for the stability of both the resting and activated states of the NLRP3 inflammasome during its sustained activation, and targeting HSP90α represents a promising therapeutic strategy for diseases driven by the NLRP3 inflammasome.

Spermatogenesis is a sophisticated biological process by which spermatogonial stem cells (SSCs) undergo self-renewal and differentiation into spermatozoa. Molecular mechanisms underlying fate determinations of human SSCs by key genes and signaling pathways remain elusive. Here, we report for the first time that Yes1-associated transcriptional regulator (YAP1) is required for fate determinations of SSCs and male fertility by interacting with RAD21 and targeting NEDD4 in humans and mice. YAP1 was mainly located at cell nuclei of human SSCs. YAP1 silencing resulted in the decreases in proliferation and DNA synthesis as well as an enhancement in apoptosis of human SSCs both in vivo and in vitro. RNA sequencing and real-time polymerase chain reaction assays identified NEDD4 as a target of YAP1, and NEDD4 knockdown inhibited the proliferation of human SSCs and increased their apoptosis. Furthermore, YAP1 interacted with RAD21 to regulate NEDD4 transcription in human SSCs. Importantly, YAP1 abnormalities were found to be associated with non-obstructive azoospermia (NOA) as manifested as lower expression level of YAP1 in testicular tissues of NOA patients and YAP1 single-nucleotide variants (SNVs) in 777 NOA patients. Finally, Yap1 germline conditional knockout (cKO) mice assumed mitotic arrest, low sperm count, and motility. Collectively, these results highlight a critical role of YAP1 in determining the fate determinations of human SSCs and male infertility through the YAP1/RAD21/NEDD4 pathway. This study provides new insights into the genetic regulatory mechanisms underlying human spermatogenesis and the pathogenesis of NOA, and it offers new targets for gene therapy of male infertility.

Breast cancer (BC) often spreads to bones, leading to bone metastasis (BM). Current targeted therapies have limited effectiveness in the treatment of this condition. Osteoclasts, which contribute to bone destruction, are crucial in supporting tumor cell growth in the bones. Breast cancer bone metastasis (BCBM) treatments have limited efficacy and can cause adverse effects. Ononin exhibits anticancer properties against various cancers. The study examined the impact of ononin on the BCBM and the signaling pathways involved. Our study utilized a variety of experimental techniques, including cell viability assays, colony formation assays, wound-healing assays, Transwell migration assays, Western blot analysis, and tartrate-resistant acid phosphatase (TRAP) staining. We examined the effects of ononin on osteoclastogenesis induced in MDA-MB-231 conditioned medium- and RANKL-treated RAW 264.7 cells. In a mouse model of BCBM, ononin reduced tumor-induced bone destruction. Ononin treatment effectively inhibited proliferation and colony formation and reduced the metastatic capabilities of MDA-MB-231 cells by suppressing cell adhesion, invasiveness, and motility and reversing epithelial–mesenchymal transition (EMT) markers. Ononin markedly suppressed osteoclast formation and osteolysis-associated factors in MDA-MB-231 cells, as well as blocked the activation of the mitogen-activated protein kinase (MAPK) pathway in RAW 264.7 cells. Ononin treatment down-regulated the phosphorylation of MAPK signaling pathways, as confirmed using MAPK agonists or inhibitors. Ononin treatment had no adverse effects on the organ function. Our findings suggest that ononin has therapeutic potential as a BCBM treatment by targeting the MAPK pathway.

MXenes, a class of 2-dimensional transition metal carbides and nitrides, have garnered important attention due to their remarkable electrical and thermal conductivity, high photothermal conversion efficiency, and multifunctionality. This review explores the potential of MXene materials in various thermal applications, including thermal energy storage, heat dissipation in electronic devices, and the mitigation of electromagnetic interference in wearable technologies. Recent advancements in MXene composites, such as MXene/bacterial cellulose aerogel films and MXene/polymer composites, have demonstrated enhanced performance in phase change thermal storage and electromagnetic interference shielding, underscoring their versatility and effectiveness. Although notable progress has been made, challenges remain, including the need for a deeper understanding of photothermal conversion mechanisms, improvements in mechanical properties, exploration of diverse MXene types, and the development of sustainable synthesis methods. This paper discusses these aspects and outlines future research directions, emphasizing the growing importance of MXenes in addressing energy efficiency, health, and safety concerns in modern applications.

Radiative cooling has witnessed substantial progress while its performance is constrained by the thermal reciprocal Kirchhoff's law. Violating Kirchhoff's law to pursue nonreciprocal radiative cooling seems promising; however, the energy conservation requirement and radiant flux integrated over the entire hemisphere make the nonreciprocal benefit insignificant. This commentary discusses the practical limits of nonreciprocal radiative cooling and points toward the future direction of directional radiative cooling.

The vast potential of medical big data to enhance healthcare outcomes remains underutilized due to privacy concerns, which restrict cross-center data sharing and the construction of diverse, large-scale datasets. To address this challenge, we developed a deep generative model aimed at synthesizing medical data to overcome data sharing barriers, with a focus on breast ultrasound (US) image synthesis. Specifically, we introduce CoLDiT, a conditional latent diffusion model with a transformer backbone, to generate US images of breast lesions across various Breast Imaging Reporting and Data System (BI-RADS) categories. Using a training dataset of 9,705 US images from 5,243 patients across 202 hospitals with diverse US systems, CoLDiT generated breast US images without duplicating private information, as confirmed through nearest-neighbor analysis. Blinded reader studies further validated the realism of these images, with area under the receiver operating characteristic curve (AUC) scores ranging from 0.53 to 0.77. Additionally, synthetic breast US images effectively augmented the training dataset for BI-RADS classification, achieving performance comparable to that using an equal-sized training set comprising solely real images (P = 0.81 for AUC). Our findings suggest that synthetic data, such as CoLDiT-generated images, offer a viable, privacy-preserving solution to facilitate secure medical data sharing and advance the utilization of medical big data.

Disease-associated microglia (DAM) are observed in neurodegenerative diseases, demyelinating disorders, and aging. However, the spatiotemporal dynamics and evolutionary trajectory of DAM during the progression of amyotrophic lateral sclerosis (ALS) remain unclear. Using a mouse model of ALS that expresses a human SOD1 gene mutation, we found that the microglia subtype DAM begins to appear following motor neuron degeneration, primarily in the brain stem and spinal cord. Using reverse transcription quantitative polymerase chain reaction, RNAscope in situ hybridization, and flow cytometry, we found that DAM increased in number as the disease progressed, reaching their peak in the late disease stage. DAM responded to disease progression in both SOD1^G93A mice and sporadic ALS and C9orf72-mutated patients. Motor neuron loss in SOD1^G93A mice exhibited 2 accelerated phases: P90 to P110 (early stage) and P130 to P150 (late stage). Some markers were synchronized with the accelerated phase of motor neuron loss, suggesting that these proteins may be particularly responsive to disease progression. Through pseudotime trajectory analysis, we tracked the dynamic transition of homeostatic microglia into DAM and cluster 6 microglia. Interestingly, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia in SOD1^G93A mice and observed that DAM survival is independent of CSF1R. An in vitro phagocytosis assay directly confirmed that DAM could phagocytose more beads than other microglia subtypes. These findings reveal that the induction of the DAM phenotype is a shared cross-species and cross-subtype characteristic in ALS. Inducing the DAM phenotype and enhancing its function during the early phase of disease progression, or the time window between P130 and P150 where motor neuron loss slows, could serve as a neuroprotective strategy for ALS.

Cryopreservation is a promising technique for the long-term storage of skin. However, the formation of ice crystals during cryopreservation unavoidably damages skin structure and functionality. Currently, the lack of thorough and systematic investigation into the internal mechanisms of skin cryoinjury obstructs the advancement of cryopreservation technology. In this study, we identified 3 primary contributors to skin cryoinjury: interfacial ice nucleation, stress accumulation, and thermal stress escalation. We emphasized the paramount role of interfacial ice nucleation in provoking ice growth within the skin during the cooling process. This progress subsequently leads to stress accumulation within the skin. During the rewarming process, the brittleness of skin, previously subjected to freezing, experienced a marked increase in thermal stress due to ice recrystallization. Based on these insights, we developed a novel zwitterionic betaine-based solution formulation designed for cryopreservation skin. This cryoprotective agent formulation exhibited superior capability in lowering ice nucleation temperatures and inhibiting ice formation at interfaces, while also facilitating the growth of smooth and rounded ice crystals compared to sharp-edged and cornered crystals formed in aqueous solutions. As a result, we successfully achieved prolonged cryopreservation of the skin for at least 6 months, while preserving 98.7% of structural integrity and 94.7% of Young's modulus. This work provides valuable insights into the mechanisms of ice crystal damage during organ cryopreservation and profoundly impacts the field of organ transplantation and regenerative medicine.