TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity.

Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b+ F4/80+ TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity.

A practical risk stratification system based on ultrasonography and clinical characteristics for predicting the malignancy of soft tissue masses.

OBJECTIVE: To establish a practical risk stratification system (RSS) based on ultrasonography (US) and clinical characteristics for predicting soft tissue masses (STMs) malignancy. METHODS: This retrospective multicenter study included patients with STMs who underwent US and pathological examinations between April 2018 and April 2023. Chi-square tests and multivariable logistic regression analyses were performed to assess the association of US and clinical characteristics with the malignancy of STMs in the training set. The RSS was constructed based on the scores of risk factors and validated externally. RESULTS: The training and validation sets included 1027 STMs (mean age, 50.90 ± 16.64, 442 benign and 585 malignant) and 120 STMs (mean age, 51.93 ± 17.90, 69 benign and 51 malignant), respectively. The RSS was constructed based on three clinical characteristics (age, duration, and history of malignancy) and six US characteristics (size, shape, margin, echogenicity, bone invasion, and vascularity). STMs were assigned to six categories in the RSS, including no abnormal findings, benign, probably benign (fitted probabilities [FP] for malignancy: 0.001-0.008), low suspicion (FP: 0.008-0.365), moderate suspicion (FP: 0.189-0.911), and high suspicion (FP: 0.798-0.999) for malignancy. The RSS displayed good diagnostic performance in the training and validation sets with area under the receiver operating characteristic curve (AUC) values of 0.883 and 0.849, respectively. CONCLUSION: The practical RSS based on US and clinical characteristics could be useful for predicting STM malignancy, thereby providing the benefit of timely treatment strategy management to STM patients. CRITICAL RELEVANCE STATEMENT: With the help of the RSS, better communication between radiologists and clinicians can be realized, thus facilitating tumor management. KEY POINTS: There is no recognized grading system for STM management. A stratification system based on US and clinical features was built. The system realized great communication between radiologists and clinicians in tumor management.

Functional characterization of MiFTs implicated in early flowering and stress resistances of mango.

Phosphatidylethanolamine binding protein (PEBP) family plays important roles in multiple developmental processes in plants. In this study, a total of 11 PEBP gene family members were identified from the mango (Mangifera indica L.) genome, and these proteins were divided into three subfamilies based on their phylogenetic relationships: TERMINAL FLOWER 1 (TFL1)-like, MOTHER OF FT AND TFL (MFT)-like, and FLOWERING LOCUS T (FT)-like. Expression analysis revealed that MiFT1a, MiFT1b and MiFT2 were expressed mainly in leaves, whereas MiFT3 and MiFT4 were expressed mainly in embryos. The overexpression of MiFTs significantly promoted early flowering under both long- and short-day conditions. Interestingly, it still significantly promoted early flowering at 16 °C and 28 °C, with MiFT1a exhibiting the most significant, followed by MiFT1b and MiFT2. Additionally, the expression level of MiFT3 is related to the embryonic development of mango. Further studies revealed that overexpression of MiFT3 inhibited seed germination in transgenic Arabidopsis lines. In addition, the MiFT1a and MiFT1b transgenic lines did not respond to abiotic stress, while MiFT2, MiFT3 and MiFT4 enhanced resistance to salt or drought stress in Arabidopsis. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays revealed that MiFTs can interact with flower related and multiple stress proteins, such as bZIP protein (MiFD), 14-3-3 protein, zinc finger protein (MiZFP4), RING zinc-finger protein (MiRZFP34), and phosphatase 2C (MiPP2C25A and MiPP2C25B). These results indicate that FT subfamily not only regulates flowering but also participates in stress response, but there are differences in the function among these genes.

Photoredox Catalyzed Conia-Ene-Type Cyclization/Smiles Rearrangement Cascade Reactions to Access Substituted Methylenecarbocycles.

We report a novel visible-light-driven photoredox-catalyzed cascade reaction involving Conia-ene-type cyclization and Smiles rearrangement initiated from alkyne-tethered α-sulfonyl esters. This methodology not only facilitates the rapid synthesis of a broad spectrum of highly substituted methylenecarbocycles but also introduces a new mechanistic pathway with aryl group migration, surpassing the conventional 1,5-hydrogen shift typically observed in Conia-ene reactions.

Camrelizumab combined with chemotherapy for stage IV pulmonary sarcomatoid cancer with pancreatic metastases.

The pancreas is a rare metastatic site for lung cancer. We report the case of a 66-year-old male with pulmonary sarcomatoid carcinoma (PSC) with pancreatic and right posterior renal fascia metastases treated with immunotherapy and platinum-based chemotherapy. A pathological biopsy of the right posterior fascial mass showed lung invasive adenocarcinoma and sarcomatoid carcinoma metastasis. Immunohistochemistry staining showed that PD- L1 expression was high and next-generation sequencing revealed KRAS and TP53 mutations. Camrelizumab and chemotherapy were administered, and the metastasis disappeared. Immunotherapy combined with platinum-based chemotherapy is effective in treating PSC with pancreatic metastases.

Synthesis of α,α-Difluoromethylene Amines from Thioamides Using Silver Fluoride.

We developed a mild, rapid process employing AgF and thioamides to produce α,α-difluoromethylene amines efficiently. This method exhibited remarkable tolerance toward various functional groups present in N-sulfonylthioamides, thereby broadening the scope of difluoromethylene sulfonamides through a straightforward approach. Additionally, we applied this approach to synthesize various perfluoroalkyl amines, establishing practical synthetic routes for exploring these compounds in pharmaceutical chemistry and materials science.

Changed ventral striatum structural covariance and grey matter volume in depression during a one-year follow-up.

Empirical findings suggest reduced cortico-striatal structural connectivity in patients with major depressive disorder (MDD). However, the relationship between the abnormal structural covariance and one-year outcome of first-episode drug-naive patients has not been evaluated. This longitudinal study aimed to identify specific changes of ventral striatum-related brain structural covariance and grey matter volume in forty-two first-episode patients with major depression disorder compared with thirty-seven healthy controls at the baseline and the one-year follow-up conditions. At the baseline, patients showed decreased structural covariance between the left ventral striatum and the bilateral superior frontal gyrus (SFG), bilateral middle frontal gyrus (MFG), right supplementary motor area (SMA) and left precentral gyrus and increased grey matter volume at the left fusiform and left parahippocampus. At the one-year follow-up, patients showed decreased structural covariance between the left ventral striatum and the right SFG, right MFG, left precentral gyrus and left postcentral gyrus, and increased structural covariance between the right ventral striatum and the right amygdala, right hippocampus, right parahippocampus, right superior temporal pole, right insula and right olfactory bulb and decreased volume at the left SMA compared with controls. These findings suggest that specific ventral striatum connectivity changes contribute to the early brain development of the MDD.

Structural identification, rheological properties and immunological receptor of a complex galacturonoglucan from fruits of Schisandra chinensis (Turcz.) Baill.

A complex heteropolysaccharide SCP-2 named schisanan B (Mw = 1.005 × 105 g/mol) was obtained from water extracts of Schisandra chinensis fruits, and its planar structure was finally deduced as a galacturonoglucan by a combination of monosaccharide compositions, methylation analysis, partial acid hydrolysis, enzymatic hydrolysis and 1D/2D-nuclear magnetic resonance spectroscopy. The conformation of SCP-2 exhibited a globular shape with branching in ammonium formate aqueous solutions. The rheological properties of SCP-2 were investigated on concentrations, temperature, pH and salts. The in vitro immunomodulatory activity assay demonstrated that SCP-2 significantly enhanced the production of nitric oxide (NO) and stimulated the secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in macrophages. Through a combination of high-resolution live-cell imaging, surface plasmon resonance, and molecular docking techniques, SCP-2 exhibited a strong binding affinity with the Toll-like receptor 4 (TLR4). Moreover, western blot analysis revealed that SCP-2 effectively induced downstream signaling proteins associated with TLR4 activation, thereby promoting macrophage activation. The evidence strongly indicates that TLR4 functions as a membrane protein target in the activation of macrophages and immune regulation induced by SCP-2.

Innovative design to achieve a multi-band electromagnetic wave stealth.

Metamaterials have opened up a new field of electromagnetic wave stealth that can achieve cross-band electromagnetic wave stealth through high electromagnetic wave absorption and low infrared emission. However, traditional cross-band stealth metamaterials make covering the terahertz band challenging and have certain design flaws. This Letter introduces an innovative cross-band electromagnetic wave stealth metasurface design that can achieve cross-band stealth in the infrared, microwave, and THz bands. We use phase change materials and the gradient principle to achieve GHz and THz cross-band absorption. We also design surface height-covered low infrared emitting materials, which give them lower infrared emissivity. These functions give it enormous potential in military applications, and using phase change materials for cross-band absorption also provides new, to our knowledge, ideas for multifunctional stealth materials.

Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis.

Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage of gasdermin proteins B-E (GSDMB-GSDME) is well established as a trigger for pyroptosis, but the intracellular activation mechanism of GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced activation of GSDMA. Nutrient stresses stimulate GSDMA activation via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation of Ser353 on human GSDMA by ULK1 or the phospho-mimetic Ser353Asp mutant of GSDMA liberates GSDMA from auto-inhibition, facilitating its membrane targeting and initiation of pyroptosis. To further validate the significance of GSDMA phosphorylation, we generated a constitutively active mutant Ser354Asp of mouse Gsdma, which induced skin inflammation and hyperplasia in mice, reminiscent of phenotypes with activated Gsdma. This study uncovers phosphorylation of GSDMA as a mechanism underlying pyroptosis initiation and cellular response to nutrient stress.

Advances in small-molecule fluorescent probes for the study of apoptosis.

Apoptosis, as type I cell death, is an active death process strictly controlled by multiple genes, and plays a significant role in regulating various activities. Mounting research indicates that the unique modality of cell apoptosis is directly or indirectly related to different diseases including cancer, autoimmune diseases, viral diseases, neurodegenerative diseases, etc. However, the underlying mechanisms of cell apoptosis are complicated and not fully clarified yet, possibly due to the lack of effective chemical tools for the nondestructive and real-time visualization of apoptosis in complex biological systems. In the past 15 years, various small-molecule fluorescent probes (SMFPs) for imaging apoptosis in vitro and in vivo have attracted broad interest in related disease diagnostics and therapeutics. In this review, we aim to highlight the recent developments of SMFPs based on enzyme activity, plasma membranes, reactive oxygen species, reactive sulfur species, microenvironments and others during cell apoptosis. In particular, we generalize the mechanisms commonly used to design SMFPs for studying apoptosis. In addition, we discuss the limitations of reported probes, and emphasize the potential challenges and prospects in the future. We believe that this review will provide a comprehensive summary and challenging direction for the development of SMFPs in apoptosis related fields.

Enhancement of Bone Repair in Diabetic Rats with Metformin-Modified Silicified Collagen Scaffolds.

Regenerating bone defects in diabetic rats presents a significant challenge due to the detrimental effects of reactive oxygen species and impaired autophagy on bone healing. To address these issues, a metformin-modified biomimetic silicified collagen scaffold is developed utilizing the principles of biomimetic silicification. In vitro and in vivo experiments demonstrated that the scaffold enhanced bone tissue regeneration within the diabetic microenvironment through the release of dual bio-factors. Further analysis reveals a potential therapeutic mechanism whereby these dual bio-factors synergistically promoted osteogenesis in areas of diabetic bone defects by improving mitochondrial autophagy and maintaining redox balance. The present study provides critical insights into the advancement of tissue engineering strategies aimed at bone regeneration in diabetic patients. The study also sheds light on the underlying biological mechanisms.

Rise of Metal-Organic Frameworks: From Synthesis to E-Skin and Artificial Intelligence.

Metal-organic frameworks (MOFs) have attained broad research attention in the areas of sensors, resistive memories, and optoelectronic synapses on the merits of their intriguing physical and chemical properties. In this review, recent progress on the synthesis of MOFs and their electronic applications is introduced and discussed. Initially, the crystal structures and properties of MOFs encompassing optical, electrical, and chemical properties are discussed in brief. Subsequently, advanced synthesis methods for MOFs are introduced, categorized into hydrothermal approach, microwave synthesis, mechanochemical synthesis, and electrochemical deposition. After that, the various roles of MOFs in widespread applications, including sensing, information storage, optoelectronic synapses, machine learning, and artificial intelligence, are discussed, highlighting their versatility and the innovative solutions they provide to long-standing challenges. Finally, an outlook on remaining challenges and a future perspective for MOFs are proposed.

Visible Light-Promoted Aromatization-Driven Deconstructive Fluorination of Spiro Carbocycles.

A visible light-promoted aromatization-driven deconstructive fluorination of spiro carbocycles is presented. A series of spiro dihydroquinazolinones reacted efficiently with NFSI under visible light irradiation to afford the 2-(4-fluoroalkyl)quinazolin-4(3H)-ones in good yields with excellent functional group tolerance. A radical pathway involving C-C bond cleavage and F atom transfer is proposed for the reaction. In addition, the ring-opening chlorination of spiro dihydroquinazolinones with NCS was also applicable.

Copper-Catalyzed Aromatization-Driven Ring-Opening Amination and Oxygenation of Spiro Dihydroquinazolinones.

Mild and inexpensive copper-catalyzed aromatization-driven ring-opening amination and oxygenation of spiro dihydroquinazolinones are presented, respectively. These protocols provide facile and atom-economical access to the aminated and the carbonyl-containing quinazolin-4(3H)-ones in good yields with good functional group compatibility, which are difficult to obtain by conventional methods. Remarkably, a telescoped procedure involving the condensation and the ring-opening/functionalization for simple cycloalkanone was found to be accessible. Mechanistic studies suggest a radical pathway for this transformation.

Role of hsa_circ_0007482 in pterygium development: insights into proliferation, apoptosis, and clinical correlations.

AIM: To investigate the impact of hsa_circ_0007482 on the proliferation and apoptosis of human pterygium fibroblasts (HPFs) and its correlation with the severity grades of pterygium. METHODS: Pterygium and normal conjunctival tissues were collected from the superior area of the same patient's eye (n=33). The correlation between pterygium severity and hsa_circ_0007482 expression using quantitative reverse-transcription polymerase chain reaction (RT-qPCR) were analyzed. Three distinct siRNA sequences targeting hsa_circ_0007482, along with a negative control sequence, were transfected into HPFs. Cell proliferation was assessed using the cell counting kit-8. Expression levels of Ki67, proliferating cell nuclear antigen (PCNA), Cyclin D1, Bax, B-cell lymphoma-2 (Bcl-2), and Caspase-3 were measured via RT-qPCR. Immunofluorescence staining was employed to detect Ki67 and vimentin expressions. Apoptosis was evaluated using flow cytometry. RESULTS: Hsa_circ_0007482 expression was significantly higher in pterygium tissues compared to normal conjunctival tissues (P<0.001). Positive correlations were observed between hsa_circ_0007482 expression and pterygium severity, thickness, and vascular density. Knockdown of hsa_circ_0007482 inhibited cell proliferation, reducing the mRNA expression of Ki67, PCNA, and Cyclin D1 in HPFs. Hsa_circ_0007482 knockdown induced apoptosis, increasing mRNA expression levels of Bax and Caspase-3, while decreasing Bcl-2 expression in HPFs. Additionally, hsa_circ_0007482 knockdown attenuated vimentin expression in HPFs. CONCLUSION: The downregulation of hsa_circ_0007482 effectively hampers cell proliferation and triggers apoptosis in HPFs. There are discernible positive correlations detected between the expression of hsa_circ_0007482 and the severity of pterygium.

Oropharyngeal microbiome profiling and its association with age and heart failure in the elderly population from the northernmost province of China.

Respiratory tract infections are the most common triggers for heart failure in elderly people. The healthy respiratory commensal microbiota can prevent invasion by infectious pathogens and decrease the risk of respiratory tract infections. However, upper respiratory tract (URT) microbiome in the elderly is not well understood. To comprehend the profiles of URT microbiota in the elderly, and the link between the microbiome and heart failure, we investigated the oropharyngeal (OP) microbiome of these populations in Heilongjiang Province, located in the North-East of China, a high-latitude and cold area with a high prevalence of respiratory tract infection and heart failure. Taxonomy-based analysis showed that six dominant phyla were represented in the OP microbial profiles. Compared with young adults, the OP in the elderly exhibited a significantly different microbial community, mainly characterized by highly prevalent Streptococcus, unidentified_Saccharibacteria, Veillonella, unidentified_Pre votellaceae, and Neisseria. While unidentified_Prevotellaceae dominated in the young OP microbiome. There was competition for niche dominance between Streptococcus and member of Prevotellaceae in the OP. Correlation analysis revealed that the abundance of unidentified_Saccharibacteria was positive, while Streptococcus was negatively correlated to age among healthy elderly. The bacterial structure and abundance in the elderly with heart failure were much like healthy controls. Certain changes in microbial diversity indicated the potential OP microbial disorder in heart failure patients. These results presented here identify the respiratory tract core microbiota in high latitude and cold regions, and reveal the robustness of OP microbiome in the aged, supplying the basis for microbiome-targeted interventions.IMPORTANCETo date, we still lack available data on the oropharyngeal (OP) microbial communities in healthy populations, especially the elderly, in high latitude and cold regions. A better understanding of the significantly changed respiratory tract microbiota in aging can provide greater insight into characteristics of longevity and age-related diseases. In addition, determining the relationship between heart failure and OP microbiome may provide novel prevention and therapeutic strategies. Here, we compared OP microbiome in different age groups and elderly people with or without heart failure in northeastern China. We found that OP microbial communities are strongly linked to healthy aging. And the disease status of heart failure was not a powerful factor affecting OP microbiome. The findings may provide basic data to reveal respiratory bacterial signatures of individuals in a cold geographic region.

BSA-stabilized selenium nanoparticles ameliorate intracerebral hemorrhage's-like pathology by inhibiting ferroptosis-mediated neurotoxicology via Nrf2/GPX4 axis activation.

Intracerebral hemorrhage (ICH) is a prevalent hemorrhagic cerebrovascular emergency. Alleviating neurological damage in the early stages of ICH is critical for enhancing patient prognosis and survival rate. A novel form of cell death called ferroptosis is intimately linked to hemorrhage-induced brain tissue injury. Although studies have demonstrated the significant preventive impact of bovine serum albumin-stabilized selenium nanoparticles (BSA-SeNPs) against disorders connected to the neurological system, the neuroprotective effect on the hemorrhage stroke and the mechanism remain unknown. Therefore, based on the favorable biocompatibility of BSA-SeNPs, h-ICH (hippocampus-intracerebral hemorrhage) model was constructed to perform BSA-SeNPs therapy. As expected, these BSA-SeNPs could effectively improve the cognitive deficits and ameliorate the damage of hippocampal neuron. Furthermore, BSA-SeNPs reverse the morphology of mitochondria and enhanced the mitochondrial function, evidenced by mitochondrial respiration function (OCR) and mitochondrial membrane potential (MMP). Mechanistically, BSA-SeNPs could efficiently activate the Nrf2 to enhance the expression of antioxidant GPX4 at mRNA and protein levels, and further inhibit lipid peroxidation production in erastin-induced ferroptotic damages. Taken together, this study not only sheds light on the clinical application of BSA-SeNPs, but also provides its newly theoretical support for the strategy of the intervention and treatment of neurological impairment following ICH.

Successful treatment of severe hepatic impairment in erythropoietic protoporphyria: A case report and review of literature.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare genetic disorder stemming from ferrochelatase gene mutations, which leads to abnormal accumulation of protoporphyrin IX primarily in erythrocytes, skin, bone marrow and liver. Although porphyria-related severe liver damage is rare, its consequences can be severe with limited treatment options. CASE SUMMARY: This case study highlights a successful intervention for a 35-year-old male with EPP-related liver impairment, employing a combination of red blood cell (RBC) exchange and therapeutic plasma exchange (TPE). The patient experienced significant symptom relief and a decrease in bilirubin levels following multiple PE sessions and an RBC exchange. CONCLUSION: The findings suggest that this combined approach holds promise for managing severe hepatic impairment in EPP.

Photoredox-Catalyzed Sequential Decarboxylative/Defluorinative Aminoalkylation of CF3-Alkenes with N-Arylglycines.

A photoredox-catalyzed sequential decarboxylative/defluorinative aminoalkylation of CF3-alkenes with N-arylglycines is described. This metal-free and redox-neutral protocol provided efficient access to the monofluoroalkenyl-1,5-diamines in good yields with excellent functional group compatibility. Mechanistic studies revealed that the reaction proceeds via a radical pathway with the gem-difluoroalkenyl amine as an intermediate.