Behavioural immune landscapes of inflammation.

Transcriptional and proteomic profiling of individual cells have revolutionized interpretation of biological phenomena by providing cellular landscapes of healthy and diseased tissues1,2. These approaches, however, do not describe dynamic scenarios in which cells continuously change their biochemical properties and downstream 'behavioural' outputs3-5. Here we used 4D live imaging to record tens to hundreds of morpho-kinetic parameters describing the dynamics of individual leukocytes at sites of active inflammation. By analysing more than 100,000 reconstructions of cell shapes and tracks over time, we obtained behavioural descriptors of individual cells and used these high-dimensional datasets to build behavioural landscapes. These landscapes recognized leukocyte identities in the inflamed skin and trachea, and uncovered a continuum of neutrophil states inside blood vessels, including a large, sessile state that was embraced by the underlying endothelium and associated with pathogenic inflammation. Behavioural screening in 24 mouse mutants identified the kinase Fgr as a driver of this pathogenic state, and interference with Fgr protected mice from inflammatory injury. Thus, behavioural landscapes report distinct properties of dynamic environments at high cellular resolution.

The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin.

A cytosolic role for the histone methyltransferase Ezh2 in regulating lymphocyte activation has been suggested, but the molecular mechanisms underpinning this extranuclear function have remained unclear. Here we found that Ezh2 regulated the integrin signaling and adhesion dynamics of neutrophils and dendritic cells (DCs). Ezh2 deficiency impaired the integrin-dependent transendothelial migration of innate leukocytes and restricted disease progression in an animal model of multiple sclerosis. Direct methylation of talin, a key regulatory molecule in cell migration, by Ezh2 disrupted the binding of talin to F-actin and thereby promoted the turnover of adhesion structures. This regulatory effect was abolished by targeted disruption of the interactions of Ezh2 with the cytoskeletal-reorganization effector Vav1. Our studies reveal an unforeseen extranuclear function for Ezh2 in regulating adhesion dynamics, with implications for leukocyte migration, immune responses and potentially pathogenic processes.

Topical Clonidine Accelerates Cutaneous Wound Healing in Diabetic Rats by Regulating the Expression of Related Cytokine Signaling.

Based on the analgesic and anti-inflammatory effects of clonidine in previous studies, we hypothesized that clonidine could accelerate wound healing in rats by regulating the expression of related cytokines. In this study, the wound healing effect of clonidine was evaluated using an excision wound model in diabetic rats and a HaCaT cell model. The wounds were treated daily with topical clonidine. The results analyzed by ImageJ2 software show that the wounds of the rats that were treated with 15 ng/mL clonidine recovered faster, and the wound size was also significantly reduced compared to the control group. Western blot assays determined that clonidine induced an increase in the expression of vascular growth factors, namely, Ang-1, Ang-2, and VEGF. Moreover, clonidine demonstrated a rescuing effect on JAK2 within the JAK/STAT pathway by inhibiting SOCS3 expression, leading to decreased SOCS3 levels and increased expression of JAK2 and phospho-STAT3. Histopathological analysis revealed that clonidine promoted complete epithelial repair and minimized inflammation in skin tissue. Additionally, clonidine stimulated HaCaT cell proliferation in vitro and enhanced cellular energy levels in the presence of AGEs. In conclusion, clonidine promoted vascular growth and wound healing by stimulating the expression of cytokines that are beneficial for wound healing.

Prognostic and Predictive Significance of Ki67 in Primary Non-metastatic or Recurrent Acral Melanoma: Evidence from a Multicenter Retrospective Study.

BACKGROUND: The purpose of this work was to investigate the prognostic significance of Ki67 in acral melanoma (AM). PATIENTS AND METHODS: Ki67 values in primary lesions (pKi67) of 481 patients with primary non-metastatic AM (primary cohort) from three tertiary hospitals and in recurrent lesions (rKi67) of 97 patients (recurrent cohort) were recorded. The associations of p/rKi67 with clinicopathological features and prognosis were analyzed. RESULTS: In the primary cohort, high pKi67 group tended to have more ulceration, pT4, lymph node metastasis (LNM), nodal macrometastases, and recurrence (all P < 0.05). Logistic regression analysis revealed that pKi67 was significantly associated with pT4 and LNM (P = 0.004 and 0.027, respectively). Furthermore, both 5-year overall survival (OS) and recurrence-free survival (RFS) rates in high pKi67 group were significantly worse than those in moderate and low pKi67 groups (OS 47.8% versus 55.7 versus 76.8%, P = 0.002; RFS: 27.1 versus 42.8 versus 61.8%, P < 0.001). Similarly, in the recurrent cohort, the 5-year survival after recurrence (SAR) rates in high rKi67 group was significantly worse than those in moderate and low rKi67 groups (31.7 versus 47.4 versus 75%; P = 0.026). Stratified analysis also indicated a significant survival difference among pKi67 groups within various subgroups. Most importantly, multivariate Cox analysis demonstrated that pKi67 could be independently associated with OS and RFS, as well as rKi67 for SAR (all P < 0.05). CONCLUSIONS: A high Ki67 value was significantly associated with adverse pathological and prognostic features in both primary and recurrent AM cohorts. Ki67 should be routinely evaluated to guide risk stratification and prognostic prediction.

Visualising cancer in 3D: 3-Dimensional Tissue Imaging for management of cutaneous basal cell carcinoma.

Surgical management of basal cell carcinoma (BCC) typically involves surgical excision with post-operative margin assessment using the bread-loafing technique; or gold-standard Mohs micrographic surgery (MMS), where margins are iteratively examined for residual cancer after tumour removal, with additional excisions performed upon detecting residual tumour at margins. There is limited sampling of resection margins with bread loafing, with detection of positive margins 44% of the time using 2 mm intervals. To resolve this, we have developed three-dimensional (3D) Tissue Imaging for: (1) complete examination of cancer margins and (2) detection of tumour proximity to nerves and blood vessels. 3D Tissue optical clearing with a light sheet imaging protocol was developed for margin assessment in two datasets assessed by two independent evaluators: (1) 48 samples from 29 patients with varied BCC subtypes, sizes and pigmentation levels; (2) 32 samples with matching Mohs' surgeon reading of tumour margins using two-dimensional haematoxylin & eosin-stained sections. The 3D Tissue Imaging protocol permits a complete examination of deeper and peripheral margins. Two independent evaluators achieved negative predictive values of 92.3% and 88.24% with 3D Tissue Imaging. Images obtained from 3D Tissue Imaging recapitulates histological features of BCC, such as nuclear crowding, palisading and retraction clefting and provides a 3D context for recognising normal skin adnexal structures. Concurrent immunofluorescence labelling of nerves and blood vessels allows visualisation of structures closer to tumour-positive regions, which may have a higher risk for neural and vascular infiltration. Together, this method provides more information in a 3D spatial context, enabling better cancer management by clinicians.

Glycine-Modified Co-MOF Pervaporation Membrane to Enhance Water Transporting.

Cobalt-based metal-organic frameworks (Co-MOFs) with a two-dimensional layered morphology have received increasing attention for pervaporation due to their stability and hydrophilic properties. Using amino glycine (Gly) as a cross-linking agent, the Co-MOF ultrathin two-dimensional membrane doped with organic filler sodium alginate (SA) with the "brick-mixed-sand" structure was proposed. Polyacrylonitrile (PAN) was selected as the support layer of the hybrid membrane. The introduction of Gly efficiently solved the nanomaterial stacking problem and controllably adjusted the interlayer spacing between the nanosheets, which demonstrated good performance for ethanol dehydration. The results of this experimental research showed that the total flux of alcohol/water (9:1) separation by Gly-Co-MOF-SA/PAN hybrid membranes reached 1902 g m-2 h-1, which was 67% higher than that of the pure SA membranes. The "brick-mixed-sand" lamellar dense morphology of Gly-Co-MOF not only enhances membrane hydrophilicity but also provides effective channels for the rapid transport of water, which is expected to be used for the dehydration of organic solvents.

Viperin inhibits interferon-γ production to promote Mycobacterium tuberculosis survival by disrupting TBK1-IKKε-IRF3-axis and JAK-STAT signaling.

OBJECTIVES AND DESIGN: As an interferon-inducible protein, Viperin has broad-spectrum antiviral effects and regulation of host immune responses. We aim to investigate how Viperin regulates interferon-γ (IFN-γ) production in macrophages to control Mycobacterium tuberculosis (Mtb) infection. METHODS: We use Viperin deficient bone-marrow-derived macrophage (BMDM) to investigate the effects and machines of Viperin on Mtb infection. RESULTS: Viperin inhibited IFN-γ production in macrophages and in the lung of mice to promote Mtb survival. Further insight into the mechanisms of Viperin-mediated regulation of IFN-γ production revealed the role of TANK-binding kinase 1 (TBK1), the TAK1-dependent inhibition of NF-kappa B kinase-epsilon (IKKε), and interferon regulatory factor 3 (IRF3). Inhibition of the TBK1-IKKε-IRF3 axis restored IFN-γ production reduced by Viperin knockout in BMDM and suppressed intracellular Mtb survival. Moreover, Viperin deficiency activated the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, which promoted IFN-γ production and inhibited Mtb infection in BMDM. Additionally, a combination of the anti-TB drug INH treatment in the absence of Viperin resulted in further IFN-γ production and anti-TB effect. CONCLUSIONS: This study highlights the involvement of TBK1-IKKε-IRF3 axis and JAK-STAT signaling pathways in Viperin-suppressed IFN-γ production in Mtb infected macrophages, and identifies a novel mechanism of Viperin on negatively regulating host immune response to Mtb infection.

Engineering van der Waals Materials for Advanced Metaphotonics.

The outstanding chemical and physical properties of 2D materials, together with their atomically thin nature, make them ideal candidates for metaphotonic device integration and construction, which requires deep subwavelength light-matter interaction to achieve optical functionalities beyond conventional optical phenomena observed in naturally available materials. In addition to their intrinsic properties, the possibility to further manipulate the properties of 2D materials via chemical or physical engineering dramatically enhances their capability, evoking new science on light-matter interaction, leading to leaped performance of existing functional devices and giving birth to new metaphotonic devices that were unattainable previously. Comprehensive understanding of the intrinsic properties of 2D materials, approaches and capabilities for chemical and physical engineering methods, the resulting property modifications and novel functionalities, and applications of metaphotonic devices are provided in this review. Through reviewing the detailed progress in each aspect and the state-of-the-art achievement, insightful analyses of the outstanding challenges and future directions are elucidated in this cross-disciplinary comprehensive review with the aim to provide an overall development picture in the field of 2D material metaphotonics and promote rapid progress in this fast emerging and prosperous field.

Biomarkers for immune-related adverse events in cancer patients treated with immune checkpoint inhibitors.

Although immune checkpoint inhibitors have greatly improved cancer therapy, they also cause immune-related adverse events, including a wide range of inflammatory side effects resulting from excessive immune activation. Types of immune-related adverse events are diverse and can occur in almost any organ, with different frequencies and severities. Furthermore, immune-related adverse events may occur within the first few weeks after treatment or even several months after treatment discontinuation. Predictive biomarkers include blood cell counts and cell surface markers, serum proteins, autoantibodies, cytokines/chemokines, germline genetic variations and gene expression profiles, human leukocyte antigen genotype, microRNAs and the gut microbiome. Given the inconsistencies in research results and limited practical utility, there is to date no established biomarker that can be used in routine clinical practice, and additional investigations are essential to demonstrate efficacy and subsequently facilitate integration into routine clinical use.

Viperin deficiency promotes dendritic cell activation and function via NF-kappaB activation during Mycobacterium tuberculosis infection.

OBJECTIVES AND DESIGN: Dendritic cells (DCs) are one of the key immune cells in bridging innate and adaptive immune response against Mycobacterium tuberculosis (Mtb) infection. Interferons (IFNs) play important roles in regulating DC activation and function. Virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible (Viperin) is one of the important IFN-stimulated genes (ISGs), and elicits host defense against infection. METHODS: We investigated the effects and mechanisms of Viperin on DC activation and function using Viperin deficient bone marrow-derived dendritic cells (BMDCs) during Mtb infection. RESULTS: Viperin deficiency enhanced phagocytic activity and increased clearance of Mtb in DCs, produced higher abundance of NO, cytokine including interleukin-12 (IL-12), Tumor necrosis factor-α (TNF-α), IL-1ß, IL-6 and chemokine including CXCL1, CXCL2 and CXCL10, elevated MHC I, MHC II and co-stimulatory molecules expression, and enhanced CD4+ and CD8+ T cell responses. Mechanistically, Viperin deficiency promoted DC activation and function through NF-κB p65 activation. NF-κB p65 inhibitor prevented cytokine and chemokine production, and co-stimulatory molecules expression promoted by Viperin deficiency. CONCLUSIONS: These results suggest that Mtb induced Viperin expression could impair the activation of host defense function of DCs and DC-T cell cross talk during Mtb infection. This research may provide a potential target for future HDT in TB therapy.

The inflammatory-nutritional score and nomogram for R0 resected head and neck soft tissue sarcoma.

OBJECTIVES: To explore the predictive value of inflammatory-nutritional score (INS) and a nomogram for survivals in head and neck soft tissue sarcoma (HNSTS) patients with negative resection margins (R0). METHODS: Clinical characteristics and hematological features of 315 HNSTS patients underwent R0 surgery were analyzed. RESULTS: The 5-year overall survival (OS) rate, 3-year recurrence-free survival rate and disease-free survival (DFS) rate were 77.3%, 61.0% and 55.4%, respectively. High INS was associated with a deep tumor location (p < 0.001), high tumor grade (p < 0.001), and advanced AJCC stage (p < 0.001). The low-risk group (INS 0) exhibited a higher 5-year OS rate and 3-year DFS rate than others (87.6% vs. 81.3% vs. 53.3%, p < 0.001; 62.2% vs. 56.9% vs. 37.9%, p = 0.007). The INS (p = 0.023), tumor depth (p < 0.001), pT classification (p = 0.022), pN classification (p < 0.001) and tumor grade (p < 0.001) were independent survival predictors. Moreover, a novel nomogram for predicting OS was generated and assessed by the concordance index, exhibiting a better performance than the p7TNMG classification alone (p < 0.001). CONCLUSIONS: For R0 resected HNSTS patients, the oncological outcomes can be predicted using the INS system and a specific nomogram.

Assessing traffic-related air pollution-induced fiber-specific white matter degradation associated with motor performance declines in aged rats.

Fine particulate matter (PM2.5) is thought to exacerbate Parkinson's disease (PD) in the elderly, and early detection of PD progression may prevent further irreversible damage. Therefore, we used diffusion tensor imaging (DTI) for probing microstructural changes after late-life chronic traffic-related PM2.5 exposure. Herein, 1.5-year-old Fischer 344 rats were exposed to clean air (control), high-efficiency particulate air (HEPA)-filtered ambient air (HEPA group), and ambient traffic-related PM2.5 (PM2.5 group, 9.933 ± 1.021 µg/m3) for 3 months. Rotarod test, DTI tractographic analysis, and immunohistochemistry were performed in the end of study period. Aged rats exposed to PM2.5 exhibited motor impairment with decreased fractional anisotropy and tyrosine hydroxylase expression in olfactory and nigrostriatal circuits, indicating disrupted white matter integrity and dopaminergic (DA) neuronal loss. Additionally, increased radial diffusivity and lower expression of myelin basic protein in PM2.5 group suggested ageing progression of demyelination exacerbated by PM2.5 exposure. Significant production of tumor necrosis factor-α was also observed after PM2.5 exposure, revealing potential inflammation of injury to multiple fiber tracts of DA pathways. Microstructural changes demonstrated potential links between PM2.5-induced inflammatory white matter demyelination and behavioral performance, with indication of pre-manifestation of DTI-based biomarkers for early detection of PD progression in the elderly.

Porous PVA-g-SPA/PVA-SA Catalytic Composite Membrane via Lyophilization for Esterification Enhancement.

A catalytic composite membrane was developed for the enhancement of esterification by lyophilization for the first time. The catalytic composite membrane was composed of a poly(vinyl alcohol) (PVA)-sodium alginate (SA) separation layer and a spongy porous catalytic layer cross-linked by PVA and 4-sulfophthalic acid (SPA). Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS) results indicated the successful synthesis of the catalytic composite membrane. The membrane properties were evaluated by ethanol dehydration and esterification. The conversion rate of acetic acid reached 95.9% after 12 h. Compared with batch reactions, the conversion rate increased by 24.4%. After five cycles, the membrane still maintained outstanding catalytic activity. The resistance of mass transfer was analyzed, and the results showed that the porous structure reduced the catalytic layer resistance to total resistance from 70.27 to 32.88%. The composite membrane with a spongy porous catalytic layer exhibited superior dehydration and catalytic performance.

High-performance, self-powered flexible MoS2 photodetectors with asymmetric van der Waals gaps.

With an urgent demand for low-energy-consumption and wearable devices, it is desirable to find an easy, effective, and low-cost method to fabricate self-powered flexible photodetectors with simple configurations and high-performance. Self-powered photodetectors are normally fabricated based on either two different materials or the same material in contact with two different metal electrodes. Here, a flexible MoS2 photodetector with the same Au electrodes was fabricated on a polyethylene terephthalate (PET) substrate which exhibits self-powered properties. To our knowledge, its configuration is the simplest, and the fabrication process is easy to implement. At a bias of 0 V, the photodetector exhibits a high responsivity of 431 mA W-1, a short response/recovery time of 40 ms/40 ms, and excellent flexibility. Compared with those at a bias of 2 V, a dark current is sufficiently suppressed, and the response/recovery speed is significantly improved. It is found that the driving force of the self-powered photodetector is provided by the asymmetric Schottky barriers originating from the spontaneous generation of two van der Waals gaps with different widths. The asymmetric barriers exist stably at the interfaces between the 2D material and Au electrodes as further observed for ReS2 or GaSe flakes, which show the generality of asymmetric Schottky barriers between the 2D material and Au electrodes. The discovery here thus gives a new way to generate asymmetric Schottky barriers and develop high-performance self-powered photodetectors.

Impact of time to first relapse on long-term outcome in adult retroperitoneal sarcoma patients after radical resection.

BACKGROUND: Local recurrence of primary retroperitoneal sarcoma (RPS) is one of the major causes of treatment failure and death. We attempted to assess the effects of time to local recurrence (TLR) on the survival after recurrence (SAR) and overall survival (OS) of RPS. METHODS: Included in this study were 224 patients who underwent R0 resection for primary RPS at our institution between January 2000 and December 2020, 118 of whom had local recurrence. Based on the median TLR (19.8 months), patients were divided into two groups: early local recurrence (ELR < 20 months) and late local recurrence (LLR > 20 months). The Kaplan-Meier method was employed to calculate the local recurrence-free survival (LRFS), SAR and OS. Univariate and multivariate analyses were conducted to explore the prognostic value of TLR. RESULTS: The median follow-up time was 60.5 months for the entire cohort and 58.5 months for the recurrence cohort. There were 60 (50.8%) patients in the ELR group and 58 (49.2%) in the LLR group. The ELR group exhibited a worse SAR (29.2 months vs. 73.4 months, P < 0.001), OS (41.8 months vs. 120.9 months, P < 0.001), and a lower 5-year OS rate (35.9% vs. 73.2%, P = 0.004) than the LLR group. Furthermore, multivariate analysis indicated that TLR was an independent prognostic indicator for SAR (P = 0.014) and OS (P < 0.001). CONCLUSIONS: In patients with RPS, ELR after R0 resection presents adverse effects on OS and SAR than those with LLR, and TLR could serve as a promising predictor for OS and SAR.

An Implementation of Trust Chain Framework with Hierarchical Content Identifier Mechanism by Using Blockchain Technology.

Advances in information technology (IT) and operation technology (OT) accelerate the development of manufacturing systems (MS) consisting of integrated circuits (ICs), modules, and systems, toward Industry 4.0. However, the existing MS does not support comprehensive identity forensics for the whole system, limiting its ability to adapt to equipment authentication difficulties. Furthermore, the development of trust imposed during their crosswise collaborations with suppliers and other manufacturers in the supply chain is poorly maintained. In this paper, a trust chain framework with a comprehensive identification mechanism is implemented for the designed MS system, which is based and created on the private blockchain in conjunction with decentralized database systems to boost the flexibility, traceability, and identification of the IC-module-system. Practical implementations are developed using a functional prototype. First, the decentralized application (DApp) and the smart contracts are proposed for constructing the new trust chain under the proposed comprehensive identification mechanism by using blockchain technology. In addition, the blockchain addresses of IC, module, and system are automatically registered to InterPlanetary File System (IPFS), individually. In addition, their corresponding hierarchical CID (content identifier) values are organized by using Merkle DAG (Directed Acyclic Graph), which is employed via the hierarchical content identifier mechanism (HCIDM) proposed in this paper. Based on insights obtained from this analysis, the trust chain based on HCIDM can be applied to any MS system, for example, this trust chain could be used to prevent the counterfeit modules and ICs employed in the monitoring system of a semiconductor factory environment. The evaluation results show that the proposed scheme could work in practice under the much lower costs, compared to the public blockchain, with a total cost of 0.002094 Ether. Finally, this research is developed an innovation trust chain mechanism that could be provided the system-level security for any MS toward Industrial 4.0 in order to meet the requirements of both manufacturing innovation and product innovation in Sustainable Development Goals (SDGs).

Full-Stokes Polarization Perfect Absorption with Diatomic Metasurfaces.

Metamaterial-based perfect absorbers provide efficient ways for selective absorption of light with both linear or circular polarizations. Perfect absorption for an arbitrary polarization requires the development of subwavelength structures absorbing efficiently elliptically polarized light, but they remain largely unexplored. Here, we design and realize experimentally novel plasmonic metasurfaces for full-Stokes polarization perfect absorption in the mid-infrared. The metasurface unit cell consists of coupled anisotropic meta-atoms forming a diatomic metamolecule. The designed plasmonic metastructures provide a strong field enhancement by at least 1 order of magnitude higher than conventional perfect absorbers. In experiment, our plasmonic metasurfaces demonstrate sharp differentiation of spectral responses for an arbitrary pair of orthogonal polarization states (linear, circular, or elliptical) providing perfect absorption for one polarization with strong reflection for its counterpart. Our results suggest a novel route for efficient control of light polarization in metasurfaces offering numerous potential applications ranging from thermal imaging to chiral molecule detection.

Hybrid anisotropic plasmonic metasurfaces with multiple resonances of focused light beams.

Plasmonic metasurfaces supporting collective lattice resonances have attracted increasing interest due to their exciting properties of strong spatial coherence and enhanced light-matter interaction. Although the focusing of light by high-numerical-aperture (NA) objectives provides an essential way to boost the field intensities, it remains challenging to excite high-quality resonances by using high-NA objectives due to strong angular dispersion. Here, we address this challenge by employing the physics of bound states in the continuum (BICs). We design a novel anisotropic plasmonic metasurface combining a two-dimensional lattice of high-aspect-ratio pillars with a one-dimensional plasmonic grating, fabricated by a two-photon polymerization technique and gold sputtering. We demonstrate experimentally multiple resonances with absorption amplitudes exceeding 80% at mid-IR using an NA = 0.4 reflective objective. This is enabled by the weak angular dispersion of quasi-BIC resonances in such hybrid plasmonic metasurfaces. Our results suggest novel strategies for designing photonic devices that manipulate focused light with a strong field concentration.