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Keratitis induced by Pseudomonas aeruginosa (P. aeruginosa) is an acute and serious corneal inflammation. As a family of gene regulators, miRNAs play a crucial role in modulating host response after microbial invasion. However, their functions in P. aeruginosa keratitis remain largely unclear. In the present study, we demonstrated that miR-155 expression was significantly increased in macrophages and corneal tissue after P. aeruginosa infection. In vivo studies demonstrated that mice with miR-155 knockdown displayed more resistance to P. aeruginosa keratitis, with a lower bacterial burden. In addition, in vitro and in vivo studies indicated that miR-155 enhanced apoptosis of macrophages after P. aeruginosa infection, and resulted in a susceptible phenotype of P. aeruginosa keratitis. Moreover, miR-155 induced apoptosis through reducing activation of PI3K-Akt signaling pathway. Our data provided evidence of miR-155 mediated apoptosis of macrophage in P. aeruginosa keratitis, which may be an underlying target for the therapy of P. aeruginosa keratitis and other infectious diseases.

Abstract Background Telomerase, by safeguarding damaged telomeres and bolstering DNA damage repair, has the capacity to heighten the radioresistance of tumour cells. Thus, in turn, can compromise the efficacy of radiotherapy (RT) and radioimmunotherapy. Our previous studies have revealed that the highly selective telomerase inhibitor, BIBR1532, possesses the potential to enhance the radiosensitivity of Non-small cell lung cancer (NSCLC). In this study, we delve further into the impact of BIBR1532 on the immune activation induced by RT and elucidate the underlying mechanisms. Methods Biological information analyses, immunofluorescence assays, western blot assays, flow cytometry analysis were conducted to elucidate the functions of the combination of BIBR1532 with radiotherapy in NSCLC. Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Both in vitro and in vivo studies were conducted to examine the antitumor effects. Results Our findings indicate that the confluence of BIBR1532 with RT significantly augments the activation of the cGAS-STING pathway in both in vivo and in vitro settings, thereby fostering an effective anti-tumoral immune response. The effects can be ascribed to two key processes. Firstly, ionizing radiation, in precipitating DNA double-strand breaks (DSBs), prompts the release of tumour-derived double-stranded DNA (dsDNA) into the cytoplasm. Subsequently, BIBR1532 amplifies the activation of antigen-presenting cells by dsDNA post-RT and instigates the cGAS-STING pathway. Secondly, BIBR1532 enhances the ferroptosis response in NSCLC following RT, thereby promoting unrestrained lipid peroxidation and elevated levels of reactive oxygen species (ROS) within tumour cells. This ultimately leads to mitochondrial stress and the release of endogenous mitochondrial DNA (mtDNA) into the cytoplasm, thus facilitating the activation of the STING pathway and the induction of a type I interferon (IFN)-linked adaptive immune response. Conclusion This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC.

Abstract Background We aimed to investigate the effects of PinX1 on non-small cell lung cancer(NSCLC) radiosensitivity and radiotherapy-associated tumor immune microenvironment and its mechanisms. Methods The effect of PinX1 silencing on radiosensitivity in NSCLC was assessed by colony formation and CCK8 assay, immunofluorescence detection of γ- H2AX and micronucleus assay. Western blot was used to assess the effect of PinX1 silencing on DNA damage repair pathway and cGAS-STING pathway. The nude mouse and Lewis lung cancer mouse model were used to assess the combined efficacy of PinX1 silencing and radiotherapy in vivo. Changes in the tumor immune microenvironment were assessed by flow cytometry for different treatment modalities in the Lewis luuse model. The interaction protein RBM10 was screened by immunoprecipitation-mass spectrometry. Results Silencing PinX1 enhanced radiosensitivity and activation of the cGAS-STING pathway while attenuating the DNA damage repair pathway. Silencing PinX1 further increases radiotherapy-stimulated CD8+ T cell infiltration and activation, enhances tumor control and improves survival in vivo; Moreover, PinX1 downregulation improves the anti-tumor efficacy of radioimmunotherapy, increases radioimmune-stimulated CD8+ T cell infiltration, and reprograms M2-type macrophages into M1-type macrophages in tumor tissues. The interaction of PinX1 and RBM10 may promote telomere maintenance by assisting telomerase localization to telomeres, thereby inhibiting the immunostimulatory effects of IR. Conclusions In NSCLC, silencing PinX1 significantly contributed to the radiosensitivity and promoted the efficacy of radioimmunotherapy. Mechanistically, PinX1 may regulate the transport of telomerase to telomeres through interacting with RBM10, which promotes telomere maintenance and DNA stabilization. Our findings reveal that PinX1 is a potential target to enhance the efficacy of radioimmunotherapy in NSCLC patients.

ABSTRACTBackground The salivary microbiome may interact with chemoradiotherapy through dynamic changes in microbial composition and systemic immunity. We aimed to explore the association between the salivary microbiome and response to chemoradiotherapy in initially inoperable patients with local advanced esophageal squamous cell carcinoma (LAESCC).Methods Salivary and peripheral blood samples were collected before and after chemoradiotherapy. The microbiome and metabolic pathways were analyzed by 16S ribosomal RNA sequencing and liquid chromatography tandem mass spectrometry/Mass spectrometry analyses.Results The salivary microbiome exhibited characteristic variations between patients and healthy controls. A significant correlation was found between Prevotella_salivae, Saccharibacteria_TM7_G3_bacterium_HMT_351, and Veillonellaceae_G1_bacterium_HMT_129 and pathological complete response (pCR) in initially inoperable patients who underwent surgery. The PICRUSt suggested that immune diseases and cell motility were different in tumor compared to normal groups. KEGG enrichment analysis showed enriched lipid metabolism, signal transduction, and membrane transport in the tumor group. CD3+CD8 T cells, IL6, IL10, and IFNγ exhibited an increasing trend during the treatment process of chemoradiotherapy.Conclusions Our study demonstrated that variations in specific saliva taxa associated with host immunomodulatory cells and cytokines could be promising for early efficacy prediction of chemoradiotherapy in initially inoperable patients with LAESCC.

Abstract The ideal mechanical properties and behaviors of materials without the influence of defects are of great fundamental and engineering significance but considered inaccessible. Here, we use single-atom-thin isotopically pure hexagonal boron nitride (hBN) to demonstrate that two-dimensional (2D) materials offer us close-to ideal experimental platforms to study intrinsic mechanical phenomena. The highly delicate isotope effect on the mechanical properties of monolayer hBN is directly measured by indentation: lighter 10B gives rise to higher elasticity and strength than heavier 11B. This anomalous isotope effect establishes that the intrinsic mechanical properties without the effect of defects could be measured, and the so-called ultrafine and normally neglected isotopic perturbation in nuclear charge distribution sometimes plays a more critical role than the isotopic mass effect in the mechanical and other physical properties of materials.

Abstract Background Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with high incidence in China. The molecular mechanisms of vasculogenic mimicry (VM) and angiogenesis are not fully elucidated in NPC. More specially, it has seldomly been reported that Epstein–Barr virus‐encoded miRNA can regulate VM and angiogenesis in NPC. The aim of this study was to investigate the function and molecular mechanism of a targeting exosome system (iRGD‐exo‐antagomiR) against VM and angiogenesis in NPC, and to provide new approaches for improving the comprehensive treatment of NPC. Methods Exosomes were isolated by differential ultracentrifugation. Dynamic light scattering, transmission electron microscopy and western blotting were performed to characterize the exosomes. The 3D‐Culture assay, tube formation assay, chicken chorioallantoic membrane assay, Matrigel plug assay, mouse xenograft tumor modeling and immunohistochemical staining were applied to evaluate the anti‐VM and anti‐angiogenic effects of the targeting exosome system in vitro and in vivo. Western blot was performed to detect the changes of downstream regulated networks following interference and recovery of the target gene. Results In vitro or in vivo treatment with iRGD‐tagged exosome containing antagomiR‐BART1‐5p specifically suppressed VM and angiogenesis in NPC. EBV‐miR‐BART1‐5p promoted VM and angiogenesis in vitro and in vivo by regulating VEGF, PI3K, Akt, mTOR and HIF1‐α in a Spry2‐dependent manner. Conclusions Our findings demonstrated that targeting exosomes enveloped EBV‐miR‐BART1‐5p‐antagomiRs in a Spry2‐dependent manner for NPC therapy through both anti‐VM and anti‐angiogenesis in vitro and in vivo.

The construction of “new liberal arts” and the advent of the era of artificial intelligence are forcing the traditional training mode of legal talents to change in the direction of interdisciplinary, high-quality composite talents who know how to govern society, among which, the legal evidence-based talents are the talents training direction adapted to the future needs and have a noble sense of social responsibility. At present, the cultivation of evidence-based talents is still in the exploratory stage, and in order to use the specific cultivation method, we need to cooperate with high-quality enterprises and practical departments. Practical exploration reveals that, on the one hand, utilizing the technical resources of enterprises can effectively enhance students’ ability to use evidence-based research methods. On the other hand, in cooperation with practical departments, conducting research on the rule of law around real issues and evaluating the implementation effect of policies can well exercise students’ practical ability and deepen their patriotic sentiment of helping people in the world. In addition, this paper also carries out the vectorized representation of legal text based on the N-Gram model, calculates the similarity of legal cases by combining with Word2Vec, and introduces the graph representation learning to establish a similar case law recommendation model, which helps students to find out the similar cases in the massive cases. It is conducive to students’ cultivation of systematic thinking in evidence-based jurisprudence and enhancement of their ability to discriminate similar cases. Through the practice of the course, the initial feasible experience of “five-stage parallel progress” and “three integration of science and reality” on the cultivation of evidence-based law talents has been formed, and the incentives and assessment mechanisms for the cultivation of industry-academia integration need to be further strengthened in the future.

BackgroundAlterations in gut microbiota composition and function have been linked to the development and progression of thyroid cancer (TC). However, the exact nature of the causal relationship between them remains uncertain.MethodsA bidirectional two-sample Mendelian randomization (TSMR) analysis was conducted to assess the causal connection between gut microbiota (18,340 individuals) and TC (6,699 cases combined with 1,613,655 controls) using data from a genome-wide association study (GWAS). The primary analysis used the inverse-variance weighted (IVW) method to estimate the causal effect, with supplementary approaches including the weighted median, weighted mode, simple mode, and MR-Egger. Heterogeneity and pleiotropy were assessed using the Cochrane Q test, MR-Egger intercept test, and MR-PRESSO global test. A reverse TSMR analysis was performed to explore reverse causality.ResultsThis study identified seven microbial taxa with significant associations with TC. Specifically, the genus Butyrivibrio (OR: 1.127, 95% CI: 1.008-1.260, p = 0.036), Fusicatenibacter (OR: 1.313, 95% CI: 1.066-1.618, p = 0.011), Oscillospira (OR: 1.240, 95% CI: 1.001-1.536, p = 0.049), Ruminococcus2 (OR: 1.408, 95% CI: 1.158-1.711, p < 0.001), Terrisporobacter (OR: 1.241, 95% CI: 1.018-1.513, p = 0.032) were identified as risk factors for TC, while The genus Olsenella (OR: 0.882, 95% CI: 0.787-0.989, p = 0.031) and Ruminococcaceae UCG004 (OR: 0.719, 95% CI: 0.566-0.914, p = 0.007) were associated with reduced TC risk. The reverse MR analysis found no evidence of reverse causality and suggested that TC may lead to increased levels of the genus Holdemanella (β: 0.053, 95% CI: 0.012~0.094, p = 0.011) and decreased levels of the order Bacillales (β: -0.075, 95% CI: -0.143~-0.006, p = 0.033). No significant bias, heterogeneity, or pleiotropy was detected in this study.ConclusionThis study suggests a potential causal relationship between gut microbiota and TC, providing new insights into the role of gut microbiota in TC. Further research is needed to explore the underlying biological mechanisms.

The atomic pathway in the photoinduced ultrafast structural phase transition of VO2 has been a controversial problem for a long time. Here the authors, using MeV ultrafast electron diffraction, show that the melting of V-V dimers and the transformation of crystal symmetry are two processes with different timescales.

Summary: Pollen tube integrity is required for achieving double fertilization in angiosperms. The rapid alkalinization factor4/19-ANXUR1/2-Buddha’s paper seal 1/2 (RALF4/19-ANX1/2-BUPS1/2)-complex-mediated signaling pathway is critical to maintain pollen tube integrity, but the underlying mechanisms regulating the polar localization and distribution of these complex members at the pollen tube tip remain unclear. Here, we find that COBRA-like protein 11 (COBL11) loss-of-function mutants display a low pollen germination ratio, premature pollen tube burst, and seed abortion in Arabidopsis. COBL11 could interact with RALF4/19, ANX1/2, and BUPS1/2, and COBL11 functional deficiency could result in the disrupted distribution of RALF4 and ANX1, altered cell wall composition, and decreased levels of reactive oxygen species in pollen tubes. In conclusion, COBL11 is a regulator of pollen tube integrity during polar growth, which is conducted by a direct interaction that ensures the correct localization and polar distribution of RALF4 and ANX1 at the pollen tube tip.

Abstract Radiation resistance and unsatisfactory efficacy of radioimmunotherapy are important barriers to non-small cell lung cancer (NSCLC) treatment. The impacts of anlotinib on radiation and tumor immune microenvironment (TIME) in NSCLC remain to be resolved. Here, we find anlotinib enhances radiosensitivity, and further increases radiotherapy-stimulated CD8+ T cell infiltration and activation via triggering cGAS/STING pathway. Moreover, anlotinib shows significant effects on radioimmunotherapy (radiotherapy plus anti-PD-L1). The addition of anlotinib alleviates CD8+ T cell exhaustion, promotes the cytotoxicity and proliferation of CD8+ T cells, and boosts immune memory activation. Our work reveals the crucial role of anlotinib in antitumor immunity, and provides preclinical evidence for the application of anlotinib combined with radioimmunotherapy in NSCLC treatment.

Abstract Background The outcome of patients with T4 esophageal squamous cell carcinoma (ESCC) is extremely poor. Two distinct therapeutic options are currently available for T4 esophageal cancers: neochemoradiotherapy followed by surgery (CRT-S) and definitive chemoradiotherapy (D-CRT). This study aimed to investigate the clinicopathologic characteristics of T4 ESCC in Chinese patients and compare the survival between the two therapeutic options. Methods We retrospectively analyzed 125 patients with clinically unresectable T4 ESCC in Tianjin Medical University Cancer Institute and Hospital from January 2010 to December 2020. Overall survival (OS), progression-free survival (PFS) and associated factors were analyzed. Results A total of 106 of 125 T4 ESCC patients were downstaged of the tumor by neoadjuvant CRT. Among 106 patients, 32 patients underwent CRT-S, and 74 patients underwent D-CRT. Patients in the CRT-S group had a higher OS (20.4 months vs. un-reached median OS, p = 0.037) and PFS (8.6 months vs. 21.0 months, p = 0.008) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor of PFS. After propensity score matching (PSM), 50 patients (CRT-S = 25; D-CRT = 25) were matched. Among these 50 patients, patients in the CRT-S group had a higher OS (15.6 months vs. un-reached median OS, p = 0.025) and PFS (7.2 months vs. 18.8 months, p = 0.026) than those in the D-CRT group. In multivariate analysis, treatment was an independent predictor for PFS. Conclusion We demonstrated that CRT-S was superior to D-CRT for T4 ESCC patients who were downstaged by neo-CRT with respect to longer OS and PFS. Randomized controlled trials involving large population samples are needed to define the standard treatment for T4 ESCC.

Design of a microfluidic manipulation system that can sense a liquid and control its flow is challenging. Here, the authors demonstrate fast torsional and tensile actuators using hollow fibres employing spiral nonlinear stress which can sense the fluid temperature and sort the fluid into the desired vessels.

The relationship between the charge density wave and excitonic correlations in a layered compound 1T-TiSe2 has remained controversial. Here, the authors observe a photo-induced dimensional crossover of the charge density wave and conclude that excitonic correlations are responsible for its out-of-plane phase coherence.

Abstract Resin uptake plays a critical role in the stiffness‐to‐weight ratio of wind turbine blades in which sandwich composites are used extensively. This work examines the flexural properties of nominally half‐inch thick sandwich composites made with polyvinyl chloride (PVC) foam cores (H60 and H80; PSC and GPC) at several resin uptakes. We found that the specific flexural strength and modulus for the H80 GPC sandwich composites increase from 82.04 to 90.70 kN · m/kg and 6.03 to 7.13 MN · m/kg, respectively, with 11.0% resin uptake reduction, which stands out among the four core sandwich composites. Considering reaching a high stiffness‐to‐weight ratio while preventing resin starvation, 32% to 38% and 40% to 45% resin uptakes are adequate ranges for the H80 PSC and GPC sandwich composites, respectively. The H60 GPC sandwich composites have lower debonding toughness than H60 PSC due to stress concentration in the smooth side skin‐core interphase region. The ailure mode of the sandwich composites depends on the core stiffness and surface texture. The H60 GPC sandwich composites exhibit core shearing and bottom skin‐core debonding failure, while the H80 GPC and PSC sandwich composites show top skin cracking and core crushing failure. The findings indicate that an appropriate range of resin uptake exists for each type of core sandwich composite, and that within the range, a low‐resin uptake leads to lighter blades and thus lower cyclic gravitational loads, beneficial for long blades.

Background: Patients with chronic constipation (CC) show altered gut microbial composition. Objectives: To compare the fecal microbiota with different constipation subtypes and to identify potential influencing factors. Design: This is a prospective cohort study. Methods: The stool samples of 53 individuals with CC and 31 healthy individuals were analyzed using 16S rRNA sequencing. The associations between microbiota composition and colorectal physiology, lifestyle factors, and psychological distress were analyzed. Results: In all, 31 patients with CC were classified as having slow-transit constipation, and 22 were classified under normal-transit constipation. The relative abundance of Bacteroidaceae was lower, and the relative abundance of Peptostreptococcaceae, Christensenellaceae, and Clostridiaceae was higher in slow-transit than in normal-transit group. In all, 28 and 25 patients with CC had dyssynergic defecation (DD) and non-DD, respectively. The relative abundance of Bacteroidaceae and Ruminococcaceae was higher in DD than in non-DD. Rectal defecation pressure was negatively correlated with the relative abundance of Prevotellaceae and Ruminococcaceae but positively correlated with that of Bifidobacteriaceae in CC patients. Multiple linear regression analysis suggested that depression was a positive predictor of Lachnospiraceae relative abundance, and sleep quality was an independent predictor of decreased relative abundance of Prevotellaceae. Conclusion: Patients with different CC subtypes showed different characteristics of dysbiosis. Depression and poor sleep were the main factors that affected the intestinal microbiota of patients with CC. Plain language summary Characteristics of fecal microbiota in different constipation subtypes and association with colon physiology, lifestyle factors, and psychological status Patients with chronic constipation (CC) show altered gut microbial composition. Previous studies in CC are limited by lacking of subtype stratification, which is reflected in the lack of agreement in findings across the large number of microbiome studies. We analyzed stool microbiome of 53 CC patients and 31 healthy individuals using 16S rRNA sequencing. We found that the relative abundance of Bacteroidaceae was lower, and the relative abundance of Peptostreptococcaceae, Christensenellaceae, and Clostridiaceae was higher in slow-transit than in normal-transit CC patients. The relative abundance of Bacteroidaceae and Ruminococcaceae was higher in dyssynergic defecation (DD) than in non-DD patients with CC. In addition, depression was a positive predictor of Lachnospiraceae relative abundance, and sleep quality was an independent predictor of decreased relative abundance of Prevotellaceae in all CC patients. This study emphasizes patients with different CC subtypes have different characteristics of dysbiosis. Depression and poor sleep may be the main factors that affect the intestinal microbiota of patients with CC.

Cell plates are transient structures formed by the fusion of vesicles at the center of the dividing plane; furthermore, these are precursors to new cell walls and are essential for cytokinesis. Cell plate formation requires a highly coordinated process of cytoskeletal rearrangement, vesicle accumulation and fusion, and membrane maturation. Tethering factors have been shown to interact with the Ras superfamily of small GTP binding proteins (Rab GTPases) and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), which are essential for cell plate formation during cytokinesis and are fundamental for maintaining normal plant growth and development. In Arabidopsis thaliana, members of the Rab GTPases, tethers, and SNAREs are localized in cell plates, and mutations in the genes encoding these proteins result in typical cytokinesis-defective phenotypes, such as the formation of abnormal cell plates, multinucleated cells, and incomplete cell walls. This review highlights recent findings on vesicle trafficking during cell plate formation mediated by Rab GTPases, tethers, and SNAREs.

Wilson’s disease (WD) is an inherited disorder of copper metabolism. Multimodal magnetic resonance imaging (MRI) has been reported to provide evidence of the extent and severity of brain lesions. However, there are few studies related to the diagnosis of WD with multimodal MRI. Here, we reported a WD patient who was subjected to Sanger sequencing, conventional MRI, and multimodal MRI examinations, including susceptibility-weighted imaging (SWI) and arterial spin labeling (ASL). Sanger sequencing demonstrated two pathogenic mutations in exon 8 of the ATP7B gene. Slit-lamp examination revealed the presence of Kayser–Fleischer rings in both eyes, as well as low serum ceruloplasmin and high 24-h urinary copper excretion on admission. Although the substantia nigra, red nucleus, and lenticular nucleus on T1-weighted imaging and T2-weighted imaging were normal, SWI and ASL showed hypointensities in these regions. Besides, decreased cerebral blood flow was found in the lenticular nucleus and the head of caudate nucleus. The patient recovered well after 1 year and 9 months of follow-up, with only a Unified Wilson Disease Rating Scale score of 1 for neurological symptom. Brain multimodal MRI provided a thorough insight into the WD, which might make up for the deficiency of conventional MRI.

Abstract Electrical transport of both longitudinal and transverse directions carries rich information. Mobility spectrum analysis (MSA) is capable of extracting charge information from conductivity tensor, including charge types, concentration and mobilities. Using a numerical method based on maximum entropy principle, i.e., maximum entropy mobility spectrum analysis (MEMSA), mobility spectrum for $$\beta $$ β -type PtBi $$_2$$ 2 is studied. Three hole-pockets and two electron-pockets were found, including a small hole pocket with very high mobility, which is very likely corresponding to Dirac Fermions. Benefiting from our high resolution result, we studied temperature dependence of carrier properties and explained the sign change phenomenon of Hall conductivity. We further compared the results with band structure obtained by our first principle calculation. The present results prove MEMSA is a useful tool of extracting carries’ information in recently discovered Iron-based superconductors, and topological materials.

Although the synergistic effect of traditional therapies combined with tumor targeting or immunotherapy can significantly reduce mortality, cancer remains the leading cause of disease related death to date. Limited clinical response rate, drug resistance and off-target effects, to a large extent, impede the ceilings of clinical efficiency. To get out from the dilemmas mentioned, bacterial therapy with a history of more than 150 years regained great concern in recent years. The rise of biological engineering and chemical modification strategies are able to optimize tumor bacterial therapy in highest measure, and meanwhile avoid its inherent drawbacks toward clinical application such as bacteriotoxic effects, weak controllability, and low security. Here, we give an overview of recent studies with regard to bacteria-mediated therapies combined with chemotherapy, radiotherapy, and immunotherapy. And more than that, we review the bacterial detoxification and targeting strategies via biological reprogramming or chemical modification, their applications, and clinical transformation prospects.

Brick-and-mortar composite structures found in nature are known for their superior mechanical performance. Here, computational approaches are used to understand the key design features that control mechanical behavior, providing guidance for the design of improved composites.

BackgroundWe aimed to analyze the first progression sites of first-line tyrosine kinase inhibitor (TKI) treatment for EGFR-mutant lung adenocarcinoma patients with systemic metastasis to recognize the potential candidates who might benefit from radiotherapy and establish a radiomic-based model to predict the first progression sites.Materials and MethodsWe retrospectively collected the clinical information and pre-treatment chest CT images of patients in Shanghai Chest Hospital from 2013 to 2017. All patients were diagnosed with stage IV EGFR-mutant lung adenocarcinoma and received TKI as first-line treatment. The first progression sites and survival were analyzed. The pre-treatment chest non-contrast CT images were utilized to establish a radiomic-based model to predict the first progression sites.ResultsWe totally collected 233 patients with systemic metastasis, among whom, there were 84 (36.1%) and 149 (63.9%) patients developing first progression in original lesions (OP) and new lesions (NP), respectively. The PFS and OS of patients with OP were longer than those with NP (PFS 11 months vs. 8 months, p = 0.03, OS 50 months vs. 35 months, p = 0.046). For 67.9% of the patients with OF, disease progressed within five sites (oligoprogression). The radiomic-based model could predict the progression sites with an AUC value of 0.736, a specificity of 0.60, and a sensitivity of 0.750 in the independent validation set.ConclusionAmong patients with systemic metastasis, there were 36.1% of patients developing OP at first progression who had a better prognosis than those developing NP. Patients with OP may be potential candidates who might benefit from radiotherapy. Radiomics is a useful method to distinguish patients developing OP and could provide some indications for radiotherapy.

Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

Different models are believed to be the reason for the superior mechanical properties of spider silk. Here, the authors prepare artificial spider silk by water-evaporation-induced self-assembly of a hydrogel fibre made from polyacrylic acid and silica nanoparticles.

Lung cancer is the most common cancer and the leading cause of cancer‐related death worldwide; hence, it is imperative that the mechanisms underlying the malignant properties of lung cancer be uncovered in order to efficiently treat this disease. Increasing evidence has shown that WT1‐interacting protein (WTIP) plays important roles both physiologically and pathologically in humans; however, the role of WTIP in cancer is unknown. Here, we investigated the role and mechanism of WTIP in cell proliferation and tumorigenesis of non‐small‐cell lung cancer (NSCLC). We report that WTIP is a tumor suppressor in human NSCLC. We found that WTIP expression was significantly reduced in both NSCLC cell lines and clinical specimens compared to that in normal controls; this reduction was largely attributed to promoter hypermethylation. Downregulation of WTIP significantly correlates with poor prognosis and predicts a shorter overall survival and progression‐free survival among NSCLC patients. Moreover, ectopic overexpression of WTIP dramatically inhibits cell proliferation and tumorigenesis in vitro and in vivo; conversely, depletion of WTIP expression shows the opposite effects. Mechanistically, WTIP impairs AKT phosphorylation and activation, leading to enhanced expression and transcriptional activity of FOXO1, which further increases p21Cip1 and p27Kip1, and decreases cyclin D1, which consequently results in cell cycle arrest. Collectively, the results of the current study indicate that WTIP is an important proliferation‐related gene and that WTIP expression may represent a novel prognostic biomarker for NSCLC.

The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. By performing mass spectrometry, we identified Lys231 and Lys421 as essential neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.

Low temperature is a major adverse environment that affects normal plant growth. Previous reports showed that the actin cytoskeleton plays an important role in the plant response to low-temperature stress, but the regulatory mechanism of the actin cytoskeleton in this process is not clear. C-repeat binding factors (CBFs) are the key molecular switches for plants to adapt to cold stress. However, whether CBFs are involved in the regulation of the actin cytoskeleton has not been reported. We found that Arabidopsis actin depolymerizing factor 5 (ADF5), an ADF that evolved F-actin bundling function, was up-regulated at low temperatures. We also demonstrated that CBFs bound to the ADF5 promoter directly in vivo and in vitro. The cold-induced expression of ADF5 was significantly inhibited in the cbfs triple mutant. The freezing resistance of the adf5 knockout mutant was weaker than that of wild type (WT) with or without cold acclimation. After low-temperature treatment, the actin cytoskeleton of WT was relatively stable, but the actin cytoskeletons of adf5, cbfs, and adf5 cbfs were disturbed to varying degrees. Compared to WT, the endocytosis rate of the amphiphilic styryl dye FM4-64 in adf5, cbfs, and adf5 cbfs at low temperature was significantly reduced. In conclusion, CBFs directly combine with the CRT/DRE DNA regulatory element of the ADF5 promoter after low-temperature stress to transcriptionally activate the expression of ADF5; ADF5 further regulates the actin cytoskeleton dynamics to participate in the regulation of plant adaptation to a low-temperature environment.

Kudoa (Myxosporea: Multivalvulida) parasites are critical pathogens in marine and freshwater fish associated with significant economic losses and reduced market prices caused by post-mortem myoliquefaction or numerous cysts on muscles. In the present study, large yellow croakers infected by Kudoa were found during fish disease surveillance in China in November 2020 and used for morphological observation and characterization using light DIC microscopy and electron microscopy. Numerous creamy-white oval plasmodia were observed in muscles and on the surface of brain cartilage, gill arches, and serosal surfaces. The spores were considerably longer and thicker than previously reported Kudoa, with protruding polar filaments (PFs) in the mature spores, fingertip-shaped apical projections (APs), and polar capsules. Phylogenetic analyses with SSU rDNA, LSU rDNA, and mitochondrial DNA showed that the Kudoa-infected sample (LcK-2020) had the highest similarity to Kudoa iwatai reported in Japan. Based on the morphological characterization and phylogenetic analysis, it could be concluded that the sample LcK-2020 was infected by Kudoa iwatai, which would be the first report of Kudoa iwatai infection in large yellow croaker in China.

A new type of surface state has recently been reported in ZrSiSe but its physical properties remain unclear. Here, Zhu, Chang, Huang, et al. report rotational symmetry breaking, healing effect and anomalous Umklapp scattering arising from the nonsymmorphic effect of the floating band state on ZrSiSe (001) surface.

Abstract Background Cisplatin-based chemotherapy with concurrent radiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma (ESCC). NS1-binding protein (NS1-BP), a member of the BTB-kelch protein family, has been shown to inhibit the proliferation of Hela cells by suppressing c-Myc. In the present study, we examined the potential function role of NS1-BP expression in ESCC, and particularly, the sensitivity of ESCC to radiotherapy. Methods NS1-BP expression was examined using immunohistochemistry in two cohorts (n = 98 for the training cohort; n = 46 for independent validation cohort) of ESCC patients receiving cisplatin-based chemotherapy and concurrent radiotherapy. Normal esophageal mucosal tissue blocks were used as a control. We also conducted a series of in vitro and in vivo experiments to examine the potential effects of over-expressing NS1-BP on ESCC cells, and particularly their sensitivity to ionizing irradiation. Results In the training cohort, NS1-BP downregulation was observed in 59% (85/144) of the ESCC specimens. NS1-BP downregulation was associated with chemoradiotherapeutic resistance and shorter disease-specific survival (DSS) in both the training and validation cohorts. Over-expressing NS1-BP in cultured ESCC cells substantially increased the cellular response to irradiation both in vitro and in vivo. NS1-BP also significantly enhanced IR-induced apoptosis, and abrogated IR-induced G2/M cell-cycle arrest and ATM/Chk1 phosphorylation. Immunoprecipitation assays indicated that NS1-BP could interact with c-Myc promoter regions to inhibit its transcription. In ESCC tissues, c-Myc expression was inversely correlated with NS1-BP levels, and was associated with a shorter DSS. Conclusions Our findings highlight the role and importance of NS1-BP in radiosensitivity of ESCC. Targeting the NS1-BP/c-Myc pathway may provide a novel therapeutic strategy for ESCC.

Abstract Positive cofactor 4 (PC4) participates in DNA damage repair and involved in nonhomologous end joining (NHEJ). Our previous results demonstrated that knockdown of PC4 downregulated the expression of XRCC4‐like factor (XLF) in esophageal squamous cell carcinoma. However, the mechanism how PC4 regulates the expression of XLF remains unclear. Here, we found that knockdown of PC4 increased radiosensitivity of non‐small cell lung cancer (NSCLC) both in vivo and in vitro. Furthermore, we found that PC4 knockdown downregulated the expression of XLF, whereas recovering XLF expression restored radioresistance in the PC4‐knockdown NSCLC cells. In addition, PC4 knockdown inhibited XLF expression by transcriptionally suppressing of XLF. Moreover, PC4 expression correlated with radiosensitivity and was an independent prognostic factor of progression‐free survival (PFS) in patients with NSCLC. These findings suggest that PC4 could be used as a promising therapeutic target for NSCLC.

Abstract Background False kelpfish (Sebastiscus marmoratus) is one of the target species in artificial breeding in China, and is susceptible to infection by Cryptocaryon irritans, which is an obligate parasitic ciliate that lives in the epithelium of the fish gills, skin and fins. Here, we sought to understand the mechanisms of molecular immunity of S. marmoratus against C. irritans infection. Methods We carried out an extensive analysis of the transcriptome of S. marmoratus immune-related tissues. A paired-end library was constructed from the cDNA synthesized using a Genomic Sample Prep Kit. Five normalized cDNA libraries were constructed using RNA from the control group and the four groups of C. irritans-infected fish. The libraries were sequenced on an Illumina Mi-Seq platform, and functional annotation of the transcriptome was performed using bioinformatics software. Results The data produced a total of 149,983,397 clean reads from five cDNA libraries constructed from S. marmoratus immune-related tissues. A total of 33,291 unigenes were assembled with an average length of 1768 bp. In eggNOG (Evolutionary Genealogy of Genes: non-supervised orthologous groups) categories, 333 unigenes (0.94%) were assigned to defense mechanisms. In the immune system process sub-categories of gene ontology (GO) enrichment analysis, with the passage of time post-infection, the number of differentially expressed genes (DEGs) was reduced from 24 h to 48 h but then increased from 72 h to 96 h. Specifically, the immune-related differentially expressed genes (IRDEGs), which belong to the KEGG (Kyoto encyclopedia of genes and genomes) pathways, such as the complement and coagulation cascades, chemokine signalling pathways and toll-like receptor signalling pathways were mainly observed at 24 h post-infection. Conclusions Infection with C. irritans resulted in a large number of DEGs in the immune-related tissues of S. marmoratus. The rapid and significant response of the S. marmoratus immune signalling pathways following C. irritans infection may be associated with their involvement in the immune process.

Atomically thin boron nitride remains undercharacterized in terms of their mechanical properties. Here authors test high-quality mono- and few-layer BN and show it to be one of the strongest electrically insulating materials and dramatically better in interlayer integrity than graphene under indentation.

Purpose and Objectives: Chemoradiotherapy (CRT) is an important component of treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Recent research findings support the role of CRT in activating an anti-tumor immune response. However, predictors of CRT efficacy are not fully understood. The aim of this study was to measure CRT-induced changes to lymphocyte subpopulations and to evaluate the prognostic value of lymphocyte alterations for patients with ESCC.Materials and Methods: In total, this pilot study enrolled 64 patients with ESCC who received neo-adjuvant CRT or definitive CRT. Peripheral blood samples were collected before and during treatment and were analyzed by flow cytometry for CD19, CD3, CD4, CD8, CD56, and CD16. Relationships between lymphocyte subset alterations and overall survival (OS) and progression-free survival (PFS) were evaluated using the log-rank test and a Cox regression model.Results: The median follow-up period was 11.8 months (range, 4.0–20.2 months). Compared to pre-treatment specimens, post-treatment blood samples had decreased proportions of CD19+ B-cells and increased proportions of CD3+ and CD8+ T-cells (all P < 0.05). Univariate and multivariate analysis showed that increased CD4+ T-cell ratios after CRT independently predicted superior PFS (hazard ratio [HR] = 0.383; 95% confidence interval [CI] = 0.173–0.848, P = 0.017) and that increased CD8+ T-cell ratios predicted improved OS (HR = 0.258; 95% CI = 0.083–0.802, P = 0.019). Patients with both increased CD4+ and CD8+ ratios had a superior PFS and OS, compared to patients with an increased CD4+ ratio only or CD8+ ratio only or neither (1-year PFS rate 63 vs. 25%, 1-year OS rate 80 vs. 62%, P = 0.005 and 0.025, respectively).Conclusions: CRT-induced increases in CD4+ and CD8+ T-cell ratios are reliable biomarker predictors of survival in patients with ESCC.