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Super-resolution imaging of cell metabolism is hindered by the incompatibility of small metabolites with fluorescent dyes and the limited resolution of imaging mass spectrometry. We present ultrasensitive reweighted visible stimulated Raman scattering (URV-SRS), a label-free vibrational imaging technique for multiplexed nanoscopy of intracellular metabolites. We developed a visible SRS microscope with extensive pulse chirping to improve the detection limit to ~4,000 molecules and introduced a self-supervised multi-agent denoiser to suppress non-independent noise in SRS by over 7.2 dB, resulting in a 50-fold sensitivity enhancement over near-infrared SRS. Leveraging the enhanced sensitivity, we employed Fourier reweighting to amplify sub-100-nm spatial frequencies that were previously overwhelmed by noise. Validated by Fourier ring correlation, we achieved a lateral resolution of 86 nm in cell imaging. We visualized the reprogramming of metabolic nanostructures associated with virus replication in host cells and subcellular fatty acid synthesis in engineered bacteria, demonstrating its capability towards nanoscopic spatial metabolomics., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Hepatocellular carcinoma (HCC) is a common cancer characterized by robustly proliferative and metastatic capabilities. Bromodomain-containing proteins are critical to the development of diverse diseases via regulating cell proliferation, differentiation, and death. However, the role of Bromodomain-containing protein 3 (BRD3) in HCC is elusive. Here, we found that BRD3 is notably upregulated in HCC samples and promotes the proliferation of HCC cells. Depletion of BRD3 notably inhibits the expression of c-MYC and Cyclin D1 and abrogates cell cycle progression in HCC cells. Co-IP and biomass spectrometry found that Ku70 interacts with BRD3 in the nucleus. The Ku70-BRD3 complex increases the expression of Cyclin D1 and c-MYC at transcriptional level in HCC. Additionally, depletion of Ku70/BRD3 ameliorates the growth of HCC xenografts established in mice. More importantly, the expression of Ku70 or BRD3 is positively correlated with the protein expression of c-MYC and Cyclin D1 in HCC samples. High expression of BRD3 or Ku70 is closely associated with poor prognosis in HCC patients. Overall, we reveal the important role of the Ku70-BRD3 complex in the onset and progression of HCC, suggesting that the Ku70-BRD3 complex is a promising target for clinical intervention in HCC., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Large-scale proteomics studies can refine our understanding of health and disease and enable precision medicine. Here, we provide a detailed atlas of 2,920 plasma proteins linking to diseases (406 prevalent and 660 incident) and 986 health-related traits in 53,026 individuals (median follow-up: 14.8 years) from the UK Biobank, representing the most comprehensive proteome profiles to date. This atlas revealed 168,100 protein-disease associations and 554,488 protein-trait associations. Over 650 proteins were shared among at least 50 diseases, and over 1,000 showed sex and age heterogeneity. Furthermore, proteins demonstrated promising potential in disease discrimination (area under the curve [AUC] > 0.80 in 183 diseases). Finally, integrating protein quantitative trait locus data determined 474 causal proteins, providing 37 drug-repurposing opportunities and 26 promising targets with favorable safety profiles. These results provide an open-access comprehensive proteome-phenome resource (https://proteome-phenome-atlas.com/) to help elucidate the biological mechanisms of diseases and accelerate the development of disease biomarkers, prediction models, and therapeutic targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Exploring the composition of regional soil organic carbon （SOC） components and identifying their influencing factors are of utmost importance to deeply understand the potential mechanisms of SOC change in cropland soil. Based on data from 871 soil sampling points, this study explored the characteristics of soil particulate and mineral-associated organic carbon （POC and MAOC） in the surface soil of cropland and the relationships with climate, terrain, soil texture, agricultural land-use type, and fertilization across the Sichuan basin using analysis of variance, correlation analysis, and a random forest model. The results showed that the average content of POC and MAOC in the surface soil of cropland was 5.01 g·kg -1 and 9.79 g·kg -1 , respectively, accounting for 32.5% and 67.5% of the total SOC； the proportion of POC increased with SOC. The two SOC fractions showed a similar spatial distribution pattern, with the content being higher in peripheral areas and lower in the middle of the basin, which were determined together by structural and random factors. The results of the random forest model showed that the relative importance of agricultural land-use type was much more important than other factors. NPP, mean annual temperature, and soil texture showed the largest correlations with the two SOC fractions in dryland； mean annual temperature and slope had larger correlations with POC and mean annual temperature and soil texture in the dryland-paddy rotation land； and soil texture was the most relevant factor to POC and MAOC in the paddy field. The above results suggested that MAOC was the main component of SOC, and agricultural land-use type was the dominant control and regulated the effects of other factors on the two SOC fractions.

Sine oculis homeobox homolog 1 (SIX1) is a new identified cancer driver in the development of prostate cancer (PC). However, the upstream regulatory mechanisms for SIX1 reactivation in cancer remains elusive. Here, we found that Ku70 robustly interacts with SIX1 in the nucleus of PC cells. The HD domain of SIX1 and the DBD domain of Ku70 are required for formation of Ku70-SIX1 complex. 20 groups of hydrogen bonds were identified in this complex by molecular dynamics simulation. Depletion of Ku70/SIX1 notably abrogates the proliferation and migration of PC. Further studies revealed that SIX1 is recruited to the promoter region on glutamate-pyruvate transaminase 2 (GPT2). Ku70 enhances the SIX1-mediated transcriptional activation on GPT2, thereby facilitating the generation of alpha-ketoglutarate (α-KG). In addition, formation of the Ku70-SIX1 complex promotes GPT2-dependent cell proliferation and migration in PC. Moreover, the expression of GPT2 is upregulated and strongly correlated with the expression of Ku70/SIX1 in PC tissues. In summary, our findings not only provide insight into the mechanistic interactions between Ku70 and SIX1, but also highlight the significance of the Ku70-SIX1-GPT2 axis for α-KG metabolism and PC carcinogenesis., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The authors confirm that all methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all the subjects. All animal experiments were approved by the institutional animal care and use committees of Guangzhou Medical University(GY2022-137). All human subjects were performed with the approval of the Medical Ethics Committee of the First People’s Hospital of Foshan (ethics approval number: L [2024] No. 3)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Deciphering the connectome, the ensemble of synaptic connections that underlie brain function, is a central goal of neuroscience research. Here we report the in vivo mapping of connections between presynaptic and postsynaptic partners in zebrafish, by adapting the trans-Tango genetic approach that was first developed for anterograde transsynaptic tracing in Drosophila. Neural connections were visualized between synaptic partners in larval retina, brain and spinal cord and followed over development. The specificity of labeling was corroborated by functional experiments in which optogenetic activation of presynaptic spinal cord interneurons elicited responses in known motor neuronal postsynaptic targets, as measured by trans-Tango-dependent expression of a genetically encoded calcium indicator or by electrophysiology. Transsynaptic signaling through trans-Tango reveals synaptic connections in the zebrafish nervous system, providing a valuable in vivo tool to monitor and interrogate neural circuits over time., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Adaptative desaturation in fatty acid (FA) is an emerging hallmark of cancer metabolic plasticity. Desaturases such as stearoyl-CoA desaturase (SCD) and fatty acid desaturase 2 (FADS2) have been implicated in multiple cancers, and their dominant and compensatory effects have recently been highlighted. However, how tumors initiate and sustain their self-sufficient FA desaturation to maintain phenotypic transition remains elusive. This study aimed to explore the molecular orchestration of SCD and FADS2 and their specific reprogramming mechanisms in response to cancer progression., Methods: The potential interactions between SCD and FADS2 were explored by bioinformatics analyses across multiple cancer cohorts, which guided subsequent functional and mechanistic investigations. The expression levels of desaturases were investigated with online datasets and validated in both cancer tissues and cell lines. Specific desaturation activities were characterized through various isomer-resolved lipidomics methods and sensitivity assays using desaturase inhibitors. In-situ lipid profiling was conducted using multiplex stimulated Raman scattering imaging. Functional assays were performed both in vitro and in vivo, with RNA-sequencing employed for the mechanism verification., Results: After integration of the RNA-protein-metabolite levels, the data revealed that a reprogramming from SCD-dependent to FADS2-dependent desaturation was linked to cancer epithelial-mesenchymal transition (EMT) and progression in both patients and cell lines. FADS2 overexpression and SCD suppression concurrently maintained EMT plasticity. A FADS2/β-catenin self-reinforcing feedback loop facilitated the degree of lipid unsaturation, membrane fluidity, metastatic potential and EMT signaling. Moreover, SCD inhibition triggered a lethal apoptosis but boosted survival plasticity by inducing EMT and enhancing FA uptake via adenosine monophosphate-activated protein kinase activation. Notably, this desaturation reprogramming increased transforming growth factor-β2, effectively sustaining aggressive phenotypes and metabolic plasticity during EMT., Conclusions: These findings revealed a metabolic reprogramming from SCD-dependent to FADS2-dependent desaturation during cancer EMT and progression, which concurrently supports EMT plasticity. Targeting desaturation reprogramming represents a potential vulnerability for cancer metabolic therapy., (© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center.)

Most molecules and dielectric materials have characteristic bond vibrations or phonon modes in the mid-infrared regime. However, infrared absorption spectroscopy lacks the sensitivity for detecting trace analytes due to the low quantum efficiency of infrared sensors. Here, we report mid-infrared photothermal plasmonic scattering (MIP-PS) spectroscopy to push the infrared detection limit toward nearly a hundred molecules in a plasmonic nanocavity. The plasmon scattering from a nanoparticle-on-film cavity has extremely high sensitivity to the spacing defined by the analyte molecules inside the nanogap. Meanwhile, a 1000-fold infrared light intensity enhancement at the bond vibration frequency further boosts the interaction between mid-IR photons and analyte molecules. MIP-PS spectroscopic detection of nitrile or nitro group in ~130 molecules was demonstrated. This method heralds potential in ultrasensitive bond-selective biosensing and bioimaging.

Guanine-rich oligonucleotides (GROs) can fold into G-quadruplex (G4) structures. The diverse roles of G4 structures, particularly as targets for drug design, anticancer agents, and drug delivery systems, highlight their critical significance in cancer research. However, the formation of G4 structures is highly dependent on the specific nucleotide sequences and the number of G-tracts within each GRO. In vitro studies using circular dichroism (CD), nuclear magnetic resonance (NMR), and polyacrylamide gel electrophoresis (PAGE) demonstrated that GROs with fewer than four G-tracts can form intermolecular G4 structures in K + solution at 37 °C. In fluorescence lifetime imaging microscopy study, intermolecular parallel G4 structures, formed by single-stranded GROs containing three G-tracts with three guanines each, were observed to be detectable in the lysosomes of live CL1-0 cancer cells. In contrast, a mutated sequence with only two G-tracts was rarely detected in the lysosomes of CL1-0 cancer cells, highlighting its incapability of forming intermolecular parallel G4s. Furthermore, polymorphic G4 formation in vitro and in-cell studies revealed a potential correlation. Our findings demonstrate that exogenous GROs can be introduced to explore the structural dynamics of G4 formation in live cancer cells, as well as their potential as anticancer agents and drug delivery carriers targeting lysosomes., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Raman-activated cell sorting isolates single cells in a nondestructive and label-free manner, but its throughput is limited by small spontaneous Raman scattering cross section. Coherent Raman scattering integrated with microfluidics enables high-throughput cell analysis, but faces challenges with small cells (<3 μm) and tissue sections. Here, we report stimulated Raman-activated cell ejection (S-RACE) that enables high-throughput single-cell sorting by integrating stimulated Raman imaging, in situ image decomposition, and laser-induced cell ejection. S-RACE allows ejection of live bacteria or fungi guided by their Raman signatures. Furthermore, S-RACE successfully sorted lipid-rich Rhodotorula glutinis cells from a cell mixture with a throughput of ~13 cells per second, and the sorting results were confirmed by downstream quantitative polymerase chain reaction. Beyond single cells, S-RACE shows high compatibility with tissue sections. Incorporating a closed-loop feedback control circuit further enables real-time SRS imaging-identification-ejection. In summary, S-RACE opens exciting opportunities for diverse single-cell sorting applications.

Background: Sentrin/SUMO-specific protease 3 (SENP3) is essential to regulate protein stability and function in normal and cancer cells. Nevertheless, its role and action mechanisms in prostate cancer (PCa) remain elusive. Thus, clarification of SENP3's involvement and the SUMOylation process in PCa is pivotal for discovering potential targets and understanding SUMOylation dynamics., Methods: Cell viability, EdU staining, live cell imaging, and cell cycle assays were used to determine proliferation of PCa cells. Transwell and wound-healing assays were used to detect migration of PCa cells. The interaction between SENP3 and SIX1 was determined by co-immunoprecipitation, western blotting, and immunofluorescence assays. Xenograft models established on NOD-SCID mice were used to evaluate in vivo effects post SENP3 knockdown. Immunohistochemistry was performed to investigate the expression of SENP3 in PCa tissues., Results: This study found that SENP3 is highly expressed in PCa cell lines and tissues from PCa patients. Overexpressed SENP3 is associated with metastatic malignancy in PCa. Various in vivo and in vitro experiments confirmed that SENP3 promotes the proliferation and migration of PCa. In addition, SENP3 interacts with the SD domain of SIX1 and mediates its deSUMOylation and protein stability. Lys154 (K154) is required for the SUMOylation of SIX1. More importantly, SENP3 promotes the malignancy of PCa through the regulation of SIX1., Conclusions: We unravel the significant role of SENP3 in regulating protein stability of SIX1 and progression of PCa, which may deepen our understanding of the SUMOylation modification and provide a promising target for management of metastatic PCa., Competing Interests: Declarations. Ethics approval and consent to participate: The survey adhered to the Declaration of Helsinki and both national and international ethical standards. The Ethics Committee of Guangzhou Medical University approved the use of clinical materials (2019-3-1). Animal research was carried out in alignment with the Basel Declaration and the National Research Council’s Guidelines for the Care and Use of Laboratory Animals. This research received approval from the Laboratory Animal Ethics Committee of Guangzhou Medical University (2019-199). Consent for publication: All authors give consent for the publication of the manuscript. Competing interests: The authors declare that they have no competing interests with the contents of this article., (© 2024. The Author(s).)

The abundance and activity of estrogen receptor alpha (ERα) are tightly regulated by ubiquitin-specific peptidase 22 (USP22) during the progression of breast cancer (BCa). However, the post-transcriptional modifications on the USP22-ERα axis remain elusive. N6-methyladenosine (m 6 A) is critical to modulate RNA status in eukaryotic cells. Here, we find that METTL14 positively regulates the mRNA expression of USP22 and ERα. Mechanistically, METTL14 potently binds to the USP22 and ERα mRNA, and thereby enhancing their stability through m 6 A modification. YTHDC1 and YTHDF1 function as readers for m 6 A-modified USP22 and ERα, respectively. Additionally, METTL14 promotes the growth and migration of ERα + BCa via the USP22-ERα-Cyclin D1 axis. Enforced expression of USP22/ERα significantly reverses the METTL14 depletion-induced growth and migration inhibition in BCa. Moreover, our analysis of clinical samples shows that the expression of METTL14, USP22, and ERα is upregulated and correlated in BCa tissues. Overall, our findings reveal the key role of the METTL14-USP22-ERα axis in BCa progression, which further provides a druggable target to treat BCa., Competing Interests: Declaration of Competing Interest The authors do not have competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, the mechanisms underlying these effects are not well known. Here we combined quantitative microbiome profiling, long-read metagenomics, stable isotope probing and single-cell chemical imaging to investigate the impact of two widely prescribed drugs on the gut microbiome. Physiologically relevant concentrations of entacapone, a treatment for Parkinson's disease, or loxapine succinate, used to treat schizophrenia, were incubated ex vivo with human faecal samples. Both drugs significantly impact microbial activity, more so than microbial abundance. Mechanistically, entacapone can complex and deplete available iron resulting in gut microbiome composition and function changes. Microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Further, entacapone-induced iron starvation selected for iron-scavenging gut microbiome members encoding antimicrobial resistance and virulence genes. These findings reveal the impact of two under-investigated drugs on whole microbiomes and identify metal sequestration as a mechanism of drug-induced microbiome disturbance., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Crown.)

Retinal degenerative diseases of photoreceptors are a leading cause of blindness with no effective treatment. Retinal prostheses aim to restore sight by stimulating remaining retinal cells. Here, we present a photoacoustic retinal stimulation technology. We designed a polydimethylsiloxane and carbon-based flexible film that converts near-infrared laser pulses into a localized acoustic field with 56-μm lateral resolution, aiming at high-precision acoustic stimulation of mechanosensitive retinal cells. This photoacoustic stimulation resulted in robust and localized modulation of retinal ganglion cell activity in both wild-type and degenerated ex vivo retinae. When a millimeter-sized photoacoustic film was implanted in the rat subretinal space, pulsed laser stimulation generated neural modulation in vivo along the visual pathway to the superior colliculus, as measured by functional ultrasound imaging. The biosafety of the film was confirmed by the absence of short-term adverse effects under optical coherence tomography retinal imaging, while local thermal increases were measured below 1 °C. These findings demonstrate the potential of photoacoustic stimulation for high-acuity visual restoration over a large field of view in blind patients., Competing Interests: Competing interest declaration This study was funded in part by the company Axorus SAS. J-DL and HM are major stakeholders in Axorus. CY and J-XC are minor stakeholders in Axorus.

Metabolism-disorder-induced liver diseases have become increasingly prevalent worldwide and are clinically linked to obesity and type 2 diabetes. In addition, a large number of previous literature studies have indicated that plasma miR-130b is a promising biomarker for the early diagnosis and treatment of obesity. However, whether miRNA-130b that was positively correlated with obesity resulted in hepatic inflammation needs to be further studied. Therefore, the study aims to determine the effect of microvesicle-shuttled miRNA-130b (miR-130b-MV) on the hepatic inflammation and its potential mechanism in high-fat diet-induced obese mice. Three-week-old C57BL/6 mice were fed a high-fat diet for eight weeks. Then, the obese mice received tail vein injections of MV-packaged scrambled control microRNA (miR-SC-MV) or miR-130b-MV every other day for 10 days. Compared with the control group, the miR-130b-MV injection significantly reduced the body weight while increasing the ratio of liver wet weight to total body weight. In addition, the miR-130b-MV injection significantly activated the hepatic inflammation by increasing the expression of proinflammatory genes, although the plasma concentrations of IL-6 and TNF-α were only slightly increased. Furthermore, the miR-130b-MV injection significantly increased the hepatic miR-130b expression while significantly suppressing the protein expression and phosphorylation of GR, a potential target of miR-130b. Moreover, the miR-130b overexpression results in a decrease in the expression of endogenous GR protein and a decrease in the activity of the luciferase reporter of GR 3'-UTR. In addition, the miR-130b-MV injection significantly upregulated NF-kB (p50) in both the cytoplasm and nucleus, showing enhanced proinflammation response. The above results demonstrated that miR-130b-MV activated the hepatic inflammation by inhibiting GR-mediated immunosuppression in high-fat diet-induced obese mice, suggesting a novel mechanism underlying the obesity-induced hepatic inflammation, and the inhibition of miR-130b may serve as a new molecular therapeutic target for the prevention and treatment of hepatic inflammation.

Over the past three decades, there has been increasing interest in miniaturized percutaneous nephrolithotomy (mPCNL) techniques featuring smaller tracts as they offer potential solutions to mitigate complications associated with standard PCNL (sPCNL). However, despite this growing acceptance and recognition of its benefits, unresolved controversies and acknowledged limitations continue to impede widespread adoption due to a lack of consensus on optimal perioperative management strategies and procedural tips and tricks. In response to these challenges, an international panel comprising experts from the International Alliance of Urolithiasis (IAU) took on the task of compiling an expert consensus document on mPCNL procedures aimed at providing urologists with a comprehensive clinical framework for practice. This endeavor involved conducting a systematic literature review to identify research gaps (RGs), which formed the foundation for developing a structured questionnaire survey. Subsequently, a two-round modified Delphi survey was implemented, culminating in a group meeting to generate final evidence-based comments. All 64 experts completed the second-round survey, resulting in a response rate of 100.0%. Fifty-eight key questions were raised focusing on mPCNLs within 4 main domains, including general information (13 questions), preoperative work-up (13 questions), procedural tips and tricks (19 questions), and postoperative evaluation and follow-up (13 questions). Additionally, 9 questions evaluated the experts' experience with PCNLs. Consensus was reached on 30 questions after the second-round survey, while professional statements for the remaining 28 key questions were provided after discussion in an online panel meeting. mPCNL, characterized by a tract smaller than 18 Fr and an innovative lithotripsy technique, has firmly established itself as a viable and effective approach for managing upper urinary tract stones in both adults and pediatrics. It offers several advantages over sPCNL including reduced bleeding, fewer requirements for nephrostomy tubes, decreased pain, and shorter hospital stays. The series of detailed techniques presented here serve as a comprehensive guide for urologists, aiming to improve their procedural understanding and optimize patient outcomes., (© 2024. The Author(s).)

A broad spectrum of electromagnetic waves has been explored for wireless neuromodulation. Transcranial magnetic stimulation, with long wavelengths, cannot provide submillimeter spatial resolution. Visible light, with its short wavelengths, suffers from strong scattering in the deep tissue. Microwaves have centimeter-scale penetration depth and have been shown to reversibly inhibit neuronal activity. Yet, microwaves alone do not provide sufficient spatial precision to modulate target neurons without affecting surrounding tissues. Here, we report a split-ring resonator (SRR) that generates an enhanced microwave field at its gap with submillimeter spatial precision. With the SRR, microwaves at dosages below the safe exposure limit are shown to inhibit the firing of neurons within 1 mm of the SRR gap site. The microwave SRR reduced seizure activity at a low dose in both in vitro and in vivo models of epilepsy. This microwave dosage is confirmed to be biosafe via histological and biochemical assessment of brain tissue.

Objective: To explore the effects of neutrophilic granule protein (NGP) on the expression of lipocalin 2 (LCN2) in inflammatory macrophages and its mechanism., Methods: NGP-high-expressed RAW264.7 cells (NGP/RAW cells) and negative control RAW264.7 cells (NC/RAW cells) were cultured in vitro. Primary peritoneal macrophages of NGP-high-expressed mice and wild-type C57BL/6 mice were extracted, then cultured in vitro. The cell inflammatory model was established by stimulating with 10 mg/L lipopolysaccharide (LPS, LPS group), and the phosphate buffer solution (PBS) control group was set up. Enzyme-linked immunosorbent assay (ELISA) was used to detect the level of LCN2 in different types of cells. The protein expression of phosphorylated signal transduction and activator of transcription 1 (p-STAT1) was detected with Western blotting. Other NGP/RAW cells and NC/RAW cells were treated with 10 mg/L LPS, 5 mg/L STAT1 pathway inhibitor (fludarabine)+10 mg/L LPS, respectively. The PBS control group was set up. ELISA was used to detect the level of LCN2., Results: In different types of cells, the levels of LCN2 were increased significantly after LPS stimulation in the LPS group as compared with those in the PBS control group, and peaked at 24 hours (μmol/L: 25.61±1.02 vs. 0.46±0.02 in NC/RAW cells, 74.51±2.14 vs. 0.25±0.04 in NGP/RAW cells, 10.13±0.22 vs. 0.01±0.01 in primary macrophages of wild-type C57BL/6 mice, 28.35±0.61 vs. 0.08±0.01 in primary macrophages of NGP-high-expressed mice, all P < 0.05), indicating that the expression of LCN2 in macrophages altered during inflammation reaction. The level of LCN2 in NGP/RAW cells was found significantly increased at different time points after LPS stimulation comparing with that in NC/RAW cells (μmol/L: 8.32±0.22 vs. 3.12±0.11 at 6 hours, 23.12±0.86 vs. 8.12±0.32 at 12 hours, 74.51±2.14 vs. 25.61±1.02 at 24 hours, all P < 0.05), along with the expression of p-STAT1 was significantly up-regulated. The level of LCN2 in the primary macrophages of NGP-high-expressed mice was also significantly increased at 24 hours after LPS stimulation comparing with that in the primary macrophages of wild-type C57BL/6 mice (μmol/L: 28.35±0.61 vs. 10.13±0.22, P < 0.05). However, after pretreated with STAT1 pathway inhibitors, the production of LCN2 in NGP/RAW cells was decreased significantly comparing with that in the LPS group (μmol/L: 6.81±0.19 vs. 22.54±0.58, P < 0.05). But the inhibitors had no significant effect on LCN2 production in NC/RAW cells showing no significant difference as compared with LPS group (μmol/L: 8.04±0.20 vs. 7.86±0.15, P > 0.05), indicating that NGP could up-regulate the expression of LCN2 in macrophages stimulated by LPS by promoting STAT1 activation., Conclusions: NGP could positively regulate LCN2 expression in inflammatory macrophages by activating STAT1 pathway.

Bacterial infection significantly hinders the wound healing process. Overuse of antibiotics has led to the rise of drug resistance in bacteria, making the development of smart medical dressings that promote wound healing without antibiotics, a critical need. In this study, Cu₂O-SnO₂-PDA (PCS) nanoenzymes with Fenton-like activity and high photothermal conversion efficiency were developed. These nanoenzymes were then incorporated into a hydrogel through cross-linking of acrylamide (AM) and N-[Tris-(hydroxymethyl)methyl] acrylamide (THMA), forming a tough, highly-adhesive, and self-healing composite hydrogel (AT/PCS) with antimicrobial properties. The AT/PCS hydrogel exhibits excellent mechanical strength and adhesion, facilitating increased oxygen levels and strong adherence to the wound site. Moreover, it effectively regulates the wound microenvironment by combining synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT) for antibacterial treatment. The AT/PCS hydrogel enhances collagen deposition and expedites wound healing in a rat model, largely due to its potent antibacterial properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Flavonoid natural products are emerging as a promising approach for treating Ulcerative Colitis (UC) due to their natural origin and minimal toxicity. This study investigates the effects of Neohesperidin (NEO), a natural flavonoid, on Dextran Sodium Sulfate (DSS)-induced UC in mice, focusing on the underlying molecular mechanisms. Early intervention with NEO (25 and 50 mg/kg) mitigated colon shortening, restored damaged barrier proteins, and significantly reduced the inflammatory cytokine levels. Moreover, NEO inhibited the MAPK/NF-κB signaling pathway and enhanced the levels of intestinal barrier proteins (Claudin-3 and ZO-1). Additionally, NEO increased beneficial intestinal probiotics ( S24-7 and Lactobacillaceae ) while reducing harmful bacteria ( Erysipelotrichi , Enterobacteriaceae ). Fecal microbial transplantation (FMT) results demonstrated that NEO (50 mg/kg) markedly improved UC symptoms. In conclusion, early NEO intervention may alleviate DSS-induced UC by inhibiting inflammatory responses, preserving intestinal barrier integrity and modulating gut microbiota.

Background: Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics., Objectives: To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study., Design: Meta-analysis., Data Sources and Methods: Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle-Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4., Results: Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality ( n  = 31). Regarding resectable cases ( n  = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32-1.85, p  < 0.00001). For HER2-positive patients with advanced gastric cancer ( n  = 10), HER2 overexpression was also an unfavorable survival indicator (HR 1.70, 95%CI 1.23-2.35, p  = 0.001). Potential heterogeneous studies had been eliminated while outcomes remained stable by sensitivity analysis. Subgroup analysis suggested HER2-positive patients had a poorer prognosis in both East Asian (resectable: HR 1.56; advanced: HR 1.32) and non-East Asian countries (HR 1.58; HR 3.27)., Conclusion: As a novel survival biomarker in gastric cancer, HER2 overexpression indicates unfavorable prognosis among both resectable and advanced patients, irrespective of East Asian or non-East Asian populations., Trial Registration: PROSPERO (CRD42020168051)., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Photoacoustic (PA) emitters are emerging ultrasound sources offering high spatial resolution and ease of miniaturization. Thus far, PA emitters rely on electronic transitions of absorbers embedded in an expansion matrix such as polydimethylsiloxane (PDMS). Here, it is shown that mid-infrared vibrational excitation of C─H bonds in a transparent PDMS film can lead to efficient mid-infrared photoacoustic conversion (MIPA). MIPA shows 37.5 times more efficient than the commonly used PA emitters based on carbon nanotubes embedded in PDMS. Successful neural stimulation through MIPA both in a wide field with a size up to a 100 µm radius and in single-cell precision is achieved. Owing to the low heat conductivity of PDMS, less than a 0.5 °C temperature increase is found on the surface of a PDMS film during successful neural stimulation, suggesting a non-thermal mechanism. MIPA emitters allow repetitive wide-field neural stimulation, opening up opportunities for high-throughput screening of mechano-sensitive ion channels and regulators., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

This tutorial reviews the rapidly growing field of optical photothermal infrared (O-PTIR) spectroscopy and chemical imaging. O-PTIR is an infrared super-resolution measurement technique where a shorter wavelength visible probe is used to measure and map infrared (IR) absorption with spatial resolution up to 30× better than conventional techniques such as Fourier transform infrared and direct IR laser imaging systems. This article reviews key limitations of conventional IR instruments, the O-PTIR technology breakthroughs, and their origins that have overcome the prior limitations. This article also discusses recent developments in expanding multi-modal O-PTIR approaches that enable complementary Raman spectroscopy and fluorescence microscopy imaging, including wide-field O-PTIR imaging with fluorescence-based detection of IR absorption. Various practical subjects are covered, including sample preparation techniques, optimal measurement configurations, use of IR tags/labels and techniques for data analysis, and visualization. Key O-PTIR applications are reviewed in many areas, including biological and biomedical sciences, environmental and microplastics research, (bio)pharmaceuticals, materials science, cultural heritage, forensics, photonics, and failure analysis., Competing Interests: C.B.P. and M.K. are employees and/or shareholders of Photothermal Spectroscopy Corp. (PSC), a company that manufactures and sells O-PTIR instruments. J.-X.C. is a consultant for PSC and has other financial benefits related to sale of O-PTIR instruments via equity and license agreements., (© 2024 Author(s).)

Background: More muscle-invasive bladder cancer (MIBC) patients are now eligible for bladder-preserving therapy (BPT), underscoring the need for precision medicine. This study aimed to identify prognostic predictors and construct a predictive model among MIBC patients who undergo BPT., Methods: Data relating to MIBC patients were obtained from the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2016. Eleven features were included to establish multiple models. The predictive effectiveness was assessed using receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) and clinical impact curve (CIC). SHapley Additive exPlanations (SHAP) were used to explain the impact of features on the predicted targets., Results: The ROC showed that Catboost and Random Forest (RF) obtained better predictive discrimination in both 3- and 5-year models [test set area under curves (AUC) =0.80 and 0.83, respectively]. Furthermore, Catboost showed better performance in calibration plots, DCA and CIC. SHAP analysis indicated that age, M stage, tumor size, chemotherapy, T stage and gender were the most important features in the model for predicting the 3-year cancer-specific survival (CSS). In contrast, M stage, age, tumor size and gender as well as the N and T stages were the most important features for predicting the 5-year CSS., Conclusions: The Catboost model exhibits the highest predictive performance and clinical utility, potentially aiding clinicians in making optimal individualized decisions for MIBC patients with BPT., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-561/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

We propose a continuous-variable measurement-device-independent quantum key distribution with multi-ring discrete modulation (MR-CV-MDI-QKD) protocol. In our scheme, coherent states are allocated across distinct rings (amplitudes) in the phase space, and each ring is subjected to traditional M-symbol phase shift keying (MPSK) modulation. The analysis and simulation are given to demonstrate the security of our scheme under collective attacks. The results show that, compared with the traditional discrete modulated (DM)-CV-MDI-QKD where only the MPSK is used for modulation with a fixed amplitude, MR-CV-MDI-QKD can decrease the upper bound of the information accessible to an eavesdropper, thereby facilitating an extended transmission distance and increasing the secret key rate, furthermore, it exhibits a higher tolerance to diminished reverse reconciliation efficiency. This work provides an effective way for the practical implementation of the CV-MDI-QKD protocol.

While protein aggregation is a hallmark of many neurodegenerative diseases, acquiring structural information on protein aggregates inside live cells remains challenging. Traditional microscopy does not provide structural information on protein systems. Routinely used fluorescent protein tags, such as Green Fluorescent Protein (GFP), might perturb native structures. Here, we report a counter-propagating mid-infrared photothermal imaging approach enabling mapping of secondary structure of protein aggregates in live cells modeling Huntington's disease. By comparing mid-infrared photothermal spectra of label-free and GFP-tagged huntingtin inclusions, we demonstrate that GFP fusions indeed perturb the secondary structure of aggregates. By implementing spectra with small spatial step for dissecting spectral features within sub-micrometer distances, we reveal that huntingtin inclusions partition into a β-sheet-rich core and a ɑ-helix-rich shell. We further demonstrate that this structural partition exists only in cells with the [RNQ + ] prion state, while [rnq - ] cells only carry smaller β-rich non-toxic aggregates. Collectively, our methodology has the potential to unveil detailed structural information on protein assemblies in live cells, enabling high-throughput structural screenings of macromolecular assemblies., (© 2024 Wiley-VCH GmbH.)

Real-time tracking of intracellular carbohydrates remains challenging. While click chemistry allows bio-orthogonal tagging with fluorescent probes, the reaction permanently alters the target molecule and only allows a single snapshot. Here, we demonstrate click-free mid-infrared photothermal (MIP) imaging of azide-tagged carbohydrates in live cells. Leveraging the micromolar detection sensitivity for 6-azido-trehalose (TreAz) and the 300-nm spatial resolution of MIP imaging, the trehalose recycling pathway in single mycobacteria, from cytoplasmic uptake to membrane localization, is directly visualized. A peak shift of azide in MIP spectrum further uncovers interactions between TreAz and intracellular protein. MIP mapping of unreacted azide after click reaction reveals click chemistry heterogeneity within a bacterium. Broader applications of azido photothermal probes to visualize the initial steps of the Leloir pathway in yeasts and the newly synthesized glycans in mammalian cells are demonstrated.

Adult zebrafish are able to heal large-sized cutaneous wounds in hours with little to no scarring. This rapid re-epithelialization is crucial for preventing infection and jumpstarting the subsequent regeneration of damaged tissues. Despite significant progress in understanding this process, it remains unclear how vast numbers of epithelial cells are orchestrated on an organismic scale to ensure the timely closure of millimeter-sized wounds. Here, we report an unexpected role of adult zebrafish appendages (fins) in accelerating the re-epithelialization process. Through whole-body monitoring of single-cell dynamics in live animals, we found that fin-resident epithelial cells (FECs) are highly mobile and migrate to cover wounds in nearby body regions. Upon injury, FECs readily undergo organ-level mobilization, allowing for coverage of body surfaces of up to 4.78 mm 2 in less than 8 h. Intriguingly, long-term fate-tracking experiments revealed that the migratory FECs are not short-lived at the wound site; instead, the cells can persist on the body surface for more than a year. Our experiments on "fin-less" and "fin-gaining" individuals demonstrated that the fin structures are not only capable of promoting rapid re-epithelialization but are also necessary for the process. We further found that fin-enriched extracellular matrix laminins promote the active migration of FECs by facilitating lamellipodia formation. These findings lead us to conclude that appendage structures in regenerative vertebrates, such as fins, may possess a previously unrecognized function beyond serving as locomotor organs. The appendages may also act as a massive reservoir of healing cells, which speed up wound closure and tissue repair., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Articular cartilage defects are a global challenge, causing substantial disability. Repairing large defects is problematic, often exceeding cartilage's self-healing capacity and damaging bone structures. To tackle this problem, a scaffold-mediated therapeutic ion delivery system is developed. These scaffolds are constructed from poly(ε-caprolactone) and strontium (Sr)-doped bioactive nanoglasses (SrBGn), creating a unique hierarchical structure featuring macropores from 3D printing, micropores, and nanotopologies due to SrBGn integration. The SrBGn-embedded scaffolds (SrBGn-µCh) release Sr, silicon (Si), and calcium (Ca) ions, which improve chondrocyte activation, adhesion, proliferation, and maturation-related gene expression. This multiple ion delivery significantly affects metabolic activity and maturation of chondrocytes. Importantly, Sr ions may play a role in chondrocyte regulation through the Notch signaling pathway. Notably, the scaffold's structure and topological cues expedite the recruitment, adhesion, spreading, and proliferation of chondrocytes and bone marrow-derived mesenchymal stem cells. Si and Ca ions accelerate osteogenic differentiation and blood vessel formation, while Sr ions enhance the polarization of M2 macrophages. The findings show that SrBGn-µCh scaffolds accelerate osteochondral defect repair by delivering multiple ions and providing structural/topological cues, ultimately supporting host cell functions and defect healing. This scaffold holds great promise for osteochondral repair applications., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Catalpol, a natural iridoid glycoside, has potential therapeutic benefits, including anti-inflammatory and neuroprotective effects. Investigating catalpol's role in angiogenesis is critical for understanding its potential therapeutic applications, particularly in diseases where modulating angiogenesis is beneficial. This study investigates catalpol's influence on angiogenesis and its mechanisms, combining network pharmacology and in vitro experiments. The target genes corresponding to the catalpol were analyzed by SwissTargetPrediction. Then angiogenesis-related targets were acquired from databases like GeneCards. Subsequently, the Database for Annotation, Visualization and Integrated Discovery was employed for Gene Ontology and pathway analysis, while Cytoscape visualized protein interactions. The effect of catalpol on viability and angiogenesis of HUVECs was further examined using Cell Counting Kit-8 and angiogenesis assays. RT-qPCR and western blot were applied to check the expression of angiogenesis-related proteins. Totally, 312 target genes of catalpol and 823 angiogenesis-related targets were obtained with 56 common targets leading to PPI network analysis, highlighting hub genes (AKT1, EGFR, STAT3, MAPK3, and CASP3). These hub genes were mainly enriched in lipid and atherosclerosis pathway and EGFR-related pathway. The in vitro experimental results showed that catalpol achieved a concentration-dependent increase in HUVECs viability. Catalpol also promoted the migration and angiogenesis of HUVECs and up-regulated the expression of EGFR. EGFR knockdown inhibited the effect of catalpol on HUVECs. Catalpol promotes angiogenesis in HUVECs by upregulating EGFR and angiogenesis-related proteins, indicating its potential therapeutic application in vascular-related diseases., (© 2024 John Wiley & Sons Ltd.)

Introduction: This study explored the association between psoriasis and the weight-adjusted waist index (WWI), a newly developed measure of adiposity. The research was conducted among adults in the United States., Methods: Utilizing survey data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2009 to 2014, the present study aimed to investigate the potential correlation between psoriasis and WWI within a sample of 15,920 adult participants. Employing multivariable logistic regression and nonlinear curve fitting techniques, we analyzed this plausible association. Additionally, a subgroup analysis was conducted to ascertain the consistency across diverse populations., Results: A significant positive association was discovered between psoriasis and WWI in the investigated sample of 15,920 adults. After conducting a comprehensive adjustment of the model, it was observed that each incremental unit of WWI was significantly associated with an 14% elevated likelihood of developing psoriasis (OR = 1.16, 95% CI 1.01-1.36). Moreover, individuals belonging to the highest quartile of WWI exhibited a 47% higher risk of psoriasis compared to those in the lowest quartile (OR = 1.44, 95% CI 1.01-2.06). This positive correlation remained consistent across various subgroups. The study also compared WWI with BMI and waist circumference, finding that WWI is a more stable metric of obesity., Conclusions: Our study suggested that in US adults, there is a positive association between WWI and psoriasis. It also indicated that WWI showed potential as a valuable index of psoriasis among the general population., Competing Interests: Declaration of Competing Interest We would like to declare that all authors have no conflicts of interest in relation to this research., (Copyright © 2024. Published by Elsevier Inc.)

Neuromodulation is a powerful tool for fundamental studies in neuroscience and potential treatments of neurological disorders. Both photoacoustic (PA) and photothermal (PT) effects are harnessed for non-genetic high-precision neural stimulation. Using a fiber-based device excitable by a nanosecond pulsed laser and a continuous wave laser for PA and PT stimulation, respectively, PA and PT neuromodulation is systematically investigated at the single neuron level. These results show that to achieve the same level of neuron activation recorded by Ca 2+ imaging, the laser energy needed for PA stimulation is 1/40 of that needed for PT stimulation. The threshold energy for PA stimulation is found to be further reduced in neurons overexpressing mechano-sensitive channels, indicating direct involvement of mechano-sensitive channels in PA stimulation. Electrophysiology study of single neurons upon PA and PT stimulation is performed by patch clamp recordings. Electrophysiological features induced by PA are distinct from those by PT, confirming that PA and PT stimulation operate through different mechanisms. These insights offer a foundation for the rational design of more efficient and safer non-genetic neural modulation approaches., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: The clinical role of claudin 8 ( CLDN8 ) in kidney renal clear cell carcinoma (KIRC) remains unclarified. Herein, the expression level and potential molecular mechanisms of CLDN8 underlying KIRC were determined., Methods: High-throughput datasets of KIRC were collected from GEO, ArrayExpress, SRA, and TCGA databases to determine the mRNA expression level of the CLDN8 . In-house tissue microarrays and immunochemistry were performed to examine CLDN8 protein expression. A summary receiver operating characteristic curve (SROC) and standardized mean difference (SMD) forest plot were generated using Stata v16.0. Single-cell analysis was conducted to further prove the expression level of CLDN8 . A clustered regularly interspaced short palindromic repeats knockout screen analysis was executed to assess the growth impact of CLDN8 . Functional enrichment analysis was conducted using the Metascape database. Additionally, single-sample gene set enrichment analysis was implied to explore immune cell infiltration in KIRC., Results: A total of 17 mRNA datasets comprising 1,060 KIRC samples and 452 non-cancerous control samples were included in this study. Additionally, 105 KIRC and 16 non-KIRC tissues were analyzed using in-house immunohistochemistry. The combined SMD was -5.25 (95% confidence interval (CI): -6.13 to -4.37), and CLDN8 downregulation yielded an SROC area under the curve (AUC) close to 1.00 (95% CI: 0.99 - 1.00). CLDN8 downregulation was also confirmed at the single-cell level. Knocking out CLDN8 stimulated KIRC cell proliferation. Lower CLDN8 expression was correlated with worse overall survival of KIRC patients (hazard ratio of CLDN8 downregulation = 1.69, 95% CI: 1.2 - 2.4). Functional pathways associated with CLDN8 co-expressed genes were centered on carbon metabolism obstruction, with key hub genes ACADM , ACO2 , NDUFS1 , PDHB , SDHD , SUCLA2 , SUCLG1 , and SUCLG2., Conclusions: CLDN8 is downregulated in KIRC and is considered a potential tumor suppressor. CLDN8 deficiency may promote the initiation and progression of KIRC, potentially in conjunction with metabolic dysfunction., Competing Interests: The authors declare no conflict of interest., (Copyright 2024, Ji et al.)

Background: Ulcerative colitis (UC) is a prolonged inflammatory disease of the gastrointestinal tract. Current therapeutic options remain limited, underscoring the imperative to explore novel therapeutic strategies. Narirutin (NR), a flavonoid naturally present in citrus fruits, exhibits excellent anti-inflammatory effects in vitro, yet its in vivo efficacy, especially in UC, remains underexplored., Objective: This work examined the effect of NR on dextrose sodium sulfate (DSS)-induced UC in mice in vivo, with a specific focus on the role of gut flora in it., Methods: The effects of NR (10, 20, and 40 mg/kg) on DSS-induced UC in mice were investigated by monitoring changes in body weight, disease activity index (DAI) scores, colon length, and histological damage. Colonic levels of pro-inflammatory mediators, tight junction (TJ) proteins, and inflammation-related signaling pathway proteins were analyzed via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. The role of gut microbiota in NR against colitis was analyzed through 16S rRNA sequencing, flora clearance assays, and fecal microbiota transplantation (FMT) assays., Results: NR administration suppressed DSS-induced colitis as reflected in a decrease in body weight loss, DAI score, colon length shortening, and histological score. Furthermore, NR administration preserved the integrity of the DSS-induced intestinal barrier by inhibiting the reduction of TJ proteins (claudin3, occludin, and zonula occludens-1). Moreover, NR administration markedly repressed the activation of the toll-like receptor 4-mitogen-activated protein kinase/nuclear factor-κB pathway and reduced the amount of pro-inflammatory mediators in the colon. Importantly, the results of 16S rRNA sequencing showed that the intestinal flora of mice with colitis exhibited richer microbial diversity following NR administration, with elevated abundance of Lactobacillaceae (Lactobacillus) and decreased abundance of Bacteroidaceae (Bacteroides) and Shigella. In addition, the anti-colitis effect of NR almost disappeared after gut flora clearance. Further FMT assay also validated this gut flora-dependent protective mechanism of NR., Conclusion: Our findings suggest that NR is a prospective natural compound for the management of UC by modulating intestinal flora., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Stigmasterol (ST), a phytosterol found in food, has various biological activities. However, the effect of ST on milk synthesis in dairy cows remains unclear. Therefore, bovine primary mammary epithelial cells (BMECs) were isolated, cultured, and treated with ST to determine the effect of ST on milk synthesis. The study revealed that 10 μM ST significantly increased milk synthesis in BMECs by activating the mammalian target of rapamycin (mTOR) signaling pathway. Further investigation revealed that this activation depends on the regulatory role of oxysterol binding protein 5 (ORP5). ST induces the translocation of ORP5 from the cytoplasm to the lysosome, interacts with the mTOR, recruits mTOR to target the lysosomal surface, and promotes the activation of the mTOR signaling pathway. Moreover, ST was found to increase ORP5 protein levels by inhibiting its degradation via the ubiquitin-proteasome pathway. Specifically, the E3 ubiquitin ligase membrane-associated cycle-CH-type finger 4 (MARCH4) promotes the ubiquitination and subsequent degradation of ORP5. ST mitigates the interaction between MARCH4 and ORP5, thereby enhancing the structural stability of ORP5 and reducing its ubiquitination. In summary, ST stabilizes ORP5 by inhibiting the interaction between MARCH4 and ORP5, thereby activating mTOR signaling pathway and enhancing milk synthesis.

Biomimetic stress-relaxing hydrogels with reversible crosslinks attract significant attention for stem cell tissue regeneration compared with elastic hydrogels. However, stress-relaxing hyaluronic acid (HA)-based hydrogels fabricated using conventional technologies lack stability, biocompatibility, and mechanical tunability. Here, it is aimed to address these challenges by incorporating calcium or phosphate components into the HA backbone, which allows reversible crosslinking of HA with alginate to form interpenetrating networks, offering stability and mechanical tunability for mimicking cartilage. Diverse stress-relaxing hydrogels (τ1/2; SR50, 60-2000 s) are successfully prepared at ≈3 kPa stiffness with self-healing and shear-thinning abilities, favoring hydrogel injection. In vitro cell experiments with RNA sequencing analysis demonstrate that hydrogels tune chondrogenesis in a biphasic manner (hyaline or calcified) depending on the stress-relaxation properties and phosphate components. In vivo studies confirm the potential for biphasic chondrogenesis. These results indicate that the proposed stress-relaxing HA-based hydrogel with biphasic chondrogenesis (hyaline or calcified) is a promising material for cartilage regeneration., (© 2024 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Photothermal microscopy is a highly sensitive pump-probe method for mapping nanostructures and molecules through the detection of local thermal gradients. While visible photothermal microscopy and mid-infrared photothermal microscopy techniques have been developed, they possess inherent limitations. These techniques either lack chemical specificity or encounter significant light attenuation caused by water absorption. Here, we present an overtone photothermal (OPT) microscopy technique that offers high chemical specificity, detection sensitivity, and spatial resolution by employing a visible probe for local heat detection in the C-H overtone region. We demonstrate its capability for high-fidelity chemical imaging of polymer nanostructures, depth-resolved intracellular chemical mapping of cancer cells, and imaging of multicellular C. elegans organisms and highly scattering brain tissues. By bridging the gap between visible and mid-infrared photothermal microscopy, OPT establishes a new modality for high-resolution and high-sensitivity chemical imaging. This advancement complements large-scale shortwave infrared imaging approaches, facilitating multiscale structural and chemical investigations of materials and biological metabolism., (© 2024. The Author(s).)

High-precision neuromodulation plays a pivotal role in elucidating fundamental principles of neuroscience and treating specific neurological disorders. Optical neuromodulation, enabled by spatial resolution defined by the diffraction limit at the submicrometer scale, is a general strategy to achieve such precision. Optogenetics offers single-neuron spatial resolution with cellular specificity, whereas the requirement of genetic transfection hinders its clinical application. Direct photothermal modulation, an alternative nongenetic optical approach, often associates a large temperature increase with the risk of thermal damage to surrounding tissues.Photoacoustic (also called optoacoustic) neural stimulation is an emerging technology for neural stimulation with the following key features demonstrated. First, the photoacoustic approach demonstrated high efficacy without the need for genetic modification. The generated pulsed ultrasound upon ns laser pulses with energy ranging from a few μJ to tens of μJ is sufficient to activate wild-type neurons. Second, the photoacoustic approach provides sub-100-μm spatial precision. It overcomes the fundamental wave diffraction limit of ultrasound by harnessing the localized ultrasound field generated through light absorption. A spatial precision of 400 μm has been achieved in rodent brains using a fiber-based photoacoustic emitter. Single-cell stimulation in neuronal cultures in vitro and in brain slices ex vivo is achieved using tapered fiber-based photoacoustic emitters. This precision is 10 to 100 times better than that for piezo-based low-frequency ultrasound and is essential to pinpoint a specific region or cell population in a living brain. Third, compared to direct photothermal stimulation via temperature increase, photoacoustic stimulation requires 40 times less laser energy dose to evoke neuron activities and is associated with a minimal temperature increase of less than 1 °C, preventing potential thermal damage to neurons. Fourth, photoacoustics is a versatile approach and can be designed in various platforms aiming at specific applications. Our team has shown the design of fiber-based photoacoustic emitters, photoacoustic nanotransducers, soft biocompatible photoacoustic films, and soft photoacoustic lenses. Since they interact with neurons through ultrasound without the need for direct contact, photoacoustic enables noninvasive transcranial and dura-penetrating brain stimulation without compromising high precision.In this Account, we will first review the basic principles of photoacoustic and discuss the key design elements of PA transducers for neural modulation guided by the principle. We will also highlight how these design goals were achieved from a materials chemistry perspective. The design of different PA interfaces, their unique capability, and their applications in neural systems will be reviewed. In the end, we will discuss the remaining challenges and future perspectives for this technology.

The nucleus incertus (NI), a conserved hindbrain structure implicated in the stress response, arousal, and memory, is a major site for production of the neuropeptide relaxin-3. On the basis of goosecoid homeobox 2 ( gsc2 ) expression, we identified a neuronal cluster that lies adjacent to relaxin 3a ( rln3a ) neurons in the zebrafish analogue of the NI. To delineate the characteristics of the gsc2 and rln3a NI neurons, we used CRISPR/Cas9 targeted integration to drive gene expression specifically in each neuronal group, and found that they differ in their efferent and afferent connectivity, spontaneous activity, and functional properties. gsc2 and rln3a NI neurons have widely divergent projection patterns and innervate distinct subregions of the midbrain interpeduncular nucleus (IPN). Whereas gsc2 neurons are activated more robustly by electric shock, rln3a neurons exhibit spontaneous fluctuations in calcium signaling and regulate locomotor activity. Our findings define heterogeneous neurons in the NI and provide new tools to probe its diverse functions., Competing Interests: ES, JC, MM, AS, MH No competing interests declared, (© 2023, Spikol et al.)

A comprehensive understanding of the molecular mechanisms underlying microbial catabolism of dibutyl phthalate (DBP) is still lacking. Here, we newly isolated a bacterial strain identified as Pseudomonas aeruginosa PS1 with high efficiency of DBP degradation. The degradation ratios of DBP at 100-1000 mg/L by this strain reached 80-99 % within 72 h without a lag phase. A rare DBP-degradation pathway containing two monobutyl phthalate-catabolism steps was proposed based on intermediates identified by HPLC-TOF-MS/MS. In combination with genomic and transcriptomic analyses, we identified 66 key genes involved in DBP biodegradation and revealed the genetic basis for a new complete catabolic pathway from DBP to Succinyl-CoA or Acetyl-CoA in the genus Pseudomonas for the first time. Notably, we found that a series of homologous genes in Pht and Pca clusters were simultaneously activated under DBP exposure and some key intermediate degradation related gene clusters including Pht, Pca, Xyl, Ben, and Cat exhibited a favorable coexisting pattern, which contributed the high-efficient DBP degradation ability and strong adaptability to this strain. Overall, these results broaden the knowledge of the catabolic diversity of DBP in microorganisms and enhance our understanding of the molecular mechanism underlying DBP biodegradation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reports in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study aimed to explore the expression level and transcriptional regulation mechanism of Extra Spindle Pole Bodies Like 1 (ESPL1) in bladder cancer (BC)., Methods: A multicentre database of samples (n = 1391) was assayed for ESPL1 mRNA expression in BC and validated at the protein level by immunohistochemical (IHC) staining of in-house samples (n = 202). Single-cell sequencing (scRNA-seq) analysis and enrichment analysis explored ESPL1 distribution and their accompanying molecular mechanisms. ATAC-seq, ChIP-seq and Hi-C data from multiple platforms were used to investigate ESPL1 upstream transcription factors (TFs) and potential epigenetic regulatory mechanisms. Immune-related analysis, drug sensitivity and molecular docking of ESPL1 were also calculated. Furthermore, upstream microRNAs and the binding sites of ESPL1 were predicted. The expression level and early screening efficacy of miR-299-5p in blood (n = 6625) and tissues (n = 537) were examined., Results: ESPL1 was significantly overexpressed at the mRNA level (p < 0.05, SMD = 0.75; 95 % CI = 0.09, 1.40), and IHC staining of in-house samples verified this finding ( p  < 0.0001). ESPL1 was predominantly distributed in BC epithelial cells. Coexpressed genes of ESPL1 were enriched in cell cycle-related signalling pathways, and ESPL1 might be involved in the communication between epithelial and residual cells in the Hippo, ErbB, PI3K-Akt and Ras signalling pathways. Three TFs (H2AZ, IRF5 and HIF1A) were detected upstream of ESPL1 and presence of promoter-super enhancer and promoter-typical enhancer loops. ESPL1 expression was correlated with various immune cell infiltration levels. ESPL1 expression might promote BC growth and affect the sensitivity and therapeutic efficacy of paclitaxel and gemcitabine in BC patients. As an upstream regulator of ESPL1, miR-299-5p expression was downregulated in both the blood and tissues, possessing great potential for early screening., Conclusions: ESPL1 expression was upregulated in BC and was mainly distributed in epithelial cells. Elevated ESPL1 expression was associated with TFs at the upstream transcription start site (TSS) and distant chromatin loops of regulatory elements. ESPL1 might be an immune-related predictive and diagnostic marker for BC, and the overexpression of ESPL1 played a cancer-promoting role and affected BC patients' sensitivity to drug therapy. miR-299-5p was downregulated in BC blood and tissues and was also expected to be a novel marker for early screening., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

The surface topological features of bioimplants are among the key indicators for bone tissue replacement because they directly affect cell morphology, adhesion, proliferation, and differentiation. In this study, we investigated the physical, electrochemical, and biological responses of sandblasted titanium (SB-Ti) surfaces with pore geometries fabricated using a plasma electrolytic oxidation (PEO) process. The PEO treatment was conducted at an applied voltage of 280 V in a solution bath consisting of 0.15 mol L -1 calcium acetate monohydrate and 0.02 mol L -1 calcium glycerophosphate for 3 min. The surface chemistry, wettability, mechanical properties and corrosion behavior of PEO-treated sandblasted Ti implants using hydroxyapatite particles (PEO-SB-Ti) were improved with the distribution of calcium phosphorous porous oxide layers, and showed a homogeneous and hierarchically porous surface with clusters of nanopores in a bath containing calcium acetate monohydrate and calcium glycerophosphate. To demonstrate the efficacy of PEO-SB-Ti, we investigated whether the implant affects biological responses. The proposed PEO-SB-Ti were evaluated with the aim of obtaining a multifunctional bone replacement model that could efficiently induce osteogenic differentiation as well as antibacterial activities. These physical and biological responses suggest that the PEO-SB-Ti may have a great potential for use an artificial bone replacement compared to that of the controls., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.