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Tumour-associated macrophages (TAMs) are abundant in glioblastoma (GBM) and play important roles in maintaining the suppressive tumour immune microenvironment (TIME). Strategies have been tried to deplete or transform the TAMs, but they face challenges to fundamentally reshape the TIME. Here, we report adoptively transferred macrophages as a new strategy to repolarize TAMs, modulate TIME and suppress GBM growth. We reveal adoptive macrophages primed to anti-inflammatory phenotype exhibit higher efficacy in traversing tumour vasculature and homing into GBM than those with pro-inflammatory phenotypes. Engineered anti-inflammatory macrophages, eM2-Mφs, are developed and show a unique characteristic of programmed phenotype repolarization. The adoptively transferred eM2-Mφs home to GBM efficiently post intravenous administration and their spontaneous transition into proinflammatory phenotype triggers reprogramming of endogenous TAMs. Moreover, low-dose irradiation (LDI) markedly enhances TAM infiltration and synergizes with adoptive eM2-Mφs to reverse the suppressive TIME. Combined treatment with LDI and eM2-Mφs followed by checkpoint inhibitor remarkably extends the survival of mouse models bearing intracranial GBM allografts. Collectively, this study provides an adoptive non-genetic engineered macrophage therapy to enhance immunotherapeutic response to GBM.

Objective The most serious complication of Kawasaki syndrome (KS) is coronary artery lesions (CAL). About 20%-25% of KS will develop into severe CAL without intervention. Machine learning (ML) is a branch of artificial intelligence (AI), which integrates complex data sets on a large scale and uses huge data to predict future events. Besides, computers can reveal new relationships that doctors may not easy to find. The present study presented a model to predict the risk of CAL in KS children by different algorithms to achieve the early diagnosis of CAL. Methods A total of 158 children were enrolled from Women and Children’s Hospital, Qingdao University and divided into 7 to 3 as the training sets and the test sets for modeling and validation studies. The clinical manifestations and auxiliary examinations were collected as input features in our models based on the latest 6th edition diagnostic guidelines. Prior to applying the algorithm to modeling, the principal component analysis (PCA) was used to achieve dimension reduction for eliminating the high correlation between features and the Synthetic Minority Oversampling Technique (SMOTE) for promoting accuracy. There are several classifiers are constructed for models including the Random Forest (RF), the Logical regression (LG), and the eXtreme Gradient Boosting (XGBoost). Results The sensitivity and specificity of RF were 0.8 and 0.906, and the area under the curve (AUC) was 0.972. For LG, the sensitivity and specificity were 0.6 and 0.976. The XGBoost were 0.2 and 0.953, respectively. Conclusion Models are established through three different algorithms to achieve the best sensitivity and specificity. The RF was superior to other methods, which provides a reference for the prevention of CAL.

Microcystin‑leucine arginine (MC‑LR) is an environmental toxin produced by cyanobacteria and is considered to be a potent carcinogen. However, to the best of our knowledge, the effect of MC‑LR on colorectal cancer (CRC) cell proliferation has never been studied. The aim of the present study was to investigate the effect of MC‑LR on CRC cell proliferation and the underlying mechanisms. Firstly, a Cell Counting Kit‑8 (CCK‑8) assay was conducted to determine cell viability at different concentrations, and 50 nM MC‑LR was chosen for further study. Subsequently, a longer CCK‑8 assay and a cell colony formation assay showed that MC‑LR promoted SW620 and HT29 cell proliferation. Furthermore, western blotting analysis showed that MC‑LR significantly upregulated protein expression of PI3K, p‑Akt (Ser473), p‑GSK3β (Ser9), β‑catenin, c‑myc and cyclin D1, suggesting that MC‑LR activated the PI3K/Akt and Wnt/β‑catenin pathways in SW620 and HT29 cells. Finally, the pathway inhibitors LY294002 and ICG001 were used to validate the role of the PI3K/Akt and Wnt/β‑catenin pathways in MC‑LR‑accelerated cell proliferation. The results revealed that MC‑LR activated Wnt/β‑catenin through the PI3K/Akt pathway to promote cell proliferation. Taken together, these data showed that MC‑LR promoted CRC cell proliferation by activating the PI3K/Akt/Wnt/β‑catenin pathway. The present study provided a novel insight into the toxicological mechanism of MC‑LR.

Metastatic melanoma patients carrying a BRAFV600mutation can be treated with BRAF inhibitors (BRAFi), in combination with MEK inhibitors (MEKi), but innate and acquired resistance invariably occurs. Resistance can involve transcriptional- and epigenetic-based phenotypic adaptations, as yet unpredictable. Predicting patient response to targeted therapies is crucial to guide clinical decision. We describe here the development of a highly efficient patient-derived xenograft model adapted to patient melanoma biopsies, using the avian embryo as a host (AVI-PDX™). In thisin vivoparadigm, we depict a fast and reproducible tumor engraftment of patient samples within the embryonic skin, preserving key molecular and phenotypic features. We show that sensitivity and resistance to BRAFi/MEKi targeted therapies can be reliably modeled in these AVI-PDX™, as well as synergies with other drugs, such as HDACi. We further provide proof-of-concept that the AVI-PDX™models the diversity of responses of melanoma patients to BRAFi/MEKi, within days, hence positioning it as a valuable tool for the design of personalized medicine assays and for the evaluation of novel combination strategies.

Background: It is reported that the adverse impact of nonpharmaceutical interventions (NPIs) on the mental health of children and adolescents may lead to psychologically related disorders during the coronavirus disease 2019 (COVID-19) period. Subject symptoms such as chest pain, chest tightness, and palpitation are closely related to increased stress and anxiety in children and adolescents. The present research aimed to determine the change in pediatric consult of the symptoms onset in children during the COVID-19 period compared with before and after the COVID-19 period.Methods: Children who visited Women and Children's Hospital, Qingdao University between January 23 to April 30, 2019 (pre-COVID-19 period), January 23 to April 30, 2020 (COVID-19 period), and January 23 to April 30, 2021 (post-COVID-19 period) presenting chest pain, chest tightness, and palpitation were recruited. Information to determine gender, ages, department for the initial visit, clinical manifestations, time from the latest onset to the visit, and diagnosis were recorded.Result: A total of 891 patients were enrolled in the present study (514 males; median age: 7.72). 123 patients presented during the pre-COVID-19 period while 130 during the COVID-19 period, nevertheless, the number substantially increased during the post-COVID-19 period (n=638). There was no significant difference among groups in the distribution of organic etiology. The median time from the latest onset to the visit during the pre-COVID-19 period was 7 days compared to 10 days during the COVID-19 period and 3 days during the post-COVID period. Conclusion: The pediatric consult of children with subject symptoms presented increased substantially during the post-COVID-19 period, with a less median time from the latest onset to the visit. The major etiology of subject symptoms was shown in favor of non-organic during the three periods.

Microcystin-LR (MC-LR) is an environmental toxin that is synthesized by cyanobacteria and considered a potential human carcinogen. However, the role of MC-LR in prostate cancer progression has not been elucidated. The purpose of this study was to investigate the effect of MC-LR on prostate cancer cell invasion and its underlying mechanisms. Transwell assay was performed, and the result showed that MC-LR increased DU145 cell invasion in a concentration-dependent manner. The result of Western blot showed that MC-LR promoted ERK phosphorylation, while enhancing VASP and ezrin phosphorylation. Moreover, PD0325901 was used to verify the role of the ERK/VASP/ezrin axis in MC-LR-promoted cell invasion. The results revealed that MC-LR promoted microfilament rearrangement and cell invasion by activating the ERK/VASP/ezrin pathway in DU145 cells. Finally, in vivo assay was performed, and the result suggested that MC-LR promoted p-ERK, p-VASP and p-ezrin expression and local invasion in nude mice model. Taken together, our data proved that MC-LR induced microfilament rearrangement and cell invasion by activating the ERK/VASP/ezrin pathway in DU145 cells.

This paper presents an optical fiber-based humidity sensor which has tunable sensitivity by using virtual Vernier effect. It is formed by splicing a short length of hollow core fiber (HCF) at the end of a single-mode fiber (SMF) and fabricating a membrane of Polyvinyl Alcohol (PVA)/Polyacrylic Acid (PAA) at the end of HCF for humidity sensing. The experimental data of the proposed sensor shows that the sensitivity of −140 pm/%RH is achieved. Then the virtual Vernier effect is applied for data processing of the humidity sensor and the sensitivity is amplified with an adjustable amplification factor up to 20. The maximum achieved sensitivity is −2.875 nm/%RH.

An acoustic sensor based on Fiber Bragg grating and Fabry Perot (FBG-FP) cavity is introduced in this paper. In the low frequency (20 Hz) field, the sensitivity reaches 0.43 V/Pa. In the intermediate frequency range of 700 Hz-2 kHz, it has relatively flat frequency response characteristics, and the sensitivity is 28.2 mV/Pa. The signal-to-noise can reach 53.1 dB (100 Hz), and the minimum detection sound pressure is 2.52 mPa/Hz1/2.

Plant immunity frequently incurs growth penalties, which known as the trade-off between immunity and growth. Heterosis, the phenotypic superiority of a hybrid over its parents, has been demonstrated for many traits but rarely for disease resistance. Here, we report that the central circadian oscillator, CCA1, confers heterosis for bacterial defense in hybrids without growth vigor costs, and it even significantly enhances the growth heterosis of hybrids under pathogen infection. The genetic perturbation of CCA1 abrogated heterosis for both defense and growth in hybrids. Upon pathogen attack, the expression of CCA1 in F1 hybrids is precisely modulated at different time points during the day by its rhythmic histone modifications. Before dawn of the first infection day, epigenetic activation of CCA1 promotes an elevation of salicylic acid accumulation in hybrids, enabling heterosis for defense. During the middle of every infection day, diurnal epigenetic repression of CCA1 leads to rhythmically increased chlorophyll synthesis and starch metabolism in hybrids, effectively eliminating the immunity-growth heterosis trade-offs in hybrids., There is frequently a trade-off between plant immunity and growth. Here the authors show that the epigenetic control of CCA1, encoding a core component of the circadian oscillator, simultaneously promotes heterosis for both defense and growth in hybrids under pathogen invasion.

We report a miniature optical fiber fluid-pressure sensor based on a Fabry-Perot interferometer with extended air cavity and enhanced sensitivity. A sample with 830 μm air cavity length exhibit pressure sensitivity of about 3920 nm/kPa.

A wide-range pH sensor based on a coated long-period fiber grating is proposed. The pH responsive PVA/PAA hydrogel coating on the surface of the long period grating (LPG) swells/ deswells in response to change the local pH. The experimental results demonstrate a wide range for the PVA/PAA coated sensor in acid solution (from pH range 1.916 to 7.252). Moreover the sensor also shows a high repeatability and stability.

We developed a novel auto-nucleation suppressed mechanism (ANSM) for direct synthesis of EM-visible gold nanoparticles (AuNPs) on cysteine-rich tags (e.g., metallothionein) in cells for single-molecule detection with electron microscopy (it accompanies our Nature Method manuscript, Jiang et al. 2020 [1]). Both tagged-fusion proteins expressed in cells (e.g.bacteria, yeast and mammalian cells) and antigens stained with antibody-tag fusion proteins can be visualized by this protocol. Here we describe the typical protocols (both the chemical fixation and the high pressure freezing cases) developed for ANSM-based AuNP synthesis in HeLa cells expressing metallothionein (MTn) tags (Figure 1). This approach should be widely applicable to many systems for EM visualization of single-molecule in mammalian cells.

We developed a novel auto-nucleation suppressed mechanism (ANSM) for direct synthesis of EM-visible gold nanoparticles (AuNPs) on cysteine-rich tags (e.g., metallothionein) in cells for single-molecule detection with electron microscopy (it accompanies our Nature Method manuscript, Jiang et al. 2020 [1]). Both tagged-fusion proteins expressed in cells (e.g.bacteria, yeast and mammalian cells) and antigens stained with antibody-tag fusion proteins can be visualized by this protocol. Here we describe the typical protocols (both the chemical fixation and the high pressure freezing cases) developed for ANSM-based AuNP synthesis in yeast cells expressing metallothionein (MTn) tags (Figure 1). This approach should be useful for EM visualization of single-molecule in yeast cells, and easier adapted for bacterial cells.

Transcription factors, extensively described for their role in epithelial–mesenchymal transition (EMT-TFs) in epithelial cells, also display essential functions in the melanocyte lineage. Recent evidence has shown specific expression patterns and functions of these EMT-TFs in neural crest-derived melanoma compared to carcinoma. Herein, we present an update of the specific roles of EMT-TFs in melanocyte differentiation and melanoma progression. As major regulators of phenotype switching between differentiated/proliferative and neural crest stem cell-like/invasive states, these factors appear as major drivers of intra-tumor heterogeneity and resistance to treatment in melanoma, which opens new avenues in terms of therapeutic targeting.

Genetically encoded tags for single-molecule imaging in electron microscopy (EM) are long-awaited. Here, we report an approach for directly synthesizing EM-visible gold nanoparticles (AuNPs) on cysteine-rich tags for single-molecule visualization in cells. We first uncovered an auto-nucleation suppression mechanism that allows specific synthesis of AuNPs on isolated tags. Next, we exploited this mechanism to develop approaches for single-molecule detection of proteins in prokaryotic cells and achieved an unprecedented labeling efficiency. We then expanded it to more complicated eukaryotic cells and successfully detected the proteins targeted to various organelles, including the membranes of endoplasmic reticulum (ER) and nuclear envelope, ER lumen, nuclear pores, spindle pole bodies and mitochondrial matrices. We further implemented cysteine-rich tag-antibody fusion proteins as new immuno-EM probes. Thus, our approaches should allow biologists to address a wide range of biological questions at the single-molecule level in cellular ultrastructural contexts.

Single-molecule visualization in cells with genetically encoded tags for electron microscopy (EM) has been a long-awaited but unimplemented tool for cell biologists. Here, we report an approach for directly synthesizing EM-visible gold nanoparticles (AuNPs) on cysteine-rich tags for single-molecule visualization in cells. We first uncovered an auto-nucleation suppression mechanism that allows specific synthesis of AuNPs on isolated cysteine-rich tags. We next exploited this mechanism to develop an approach for single-molecule detection of proteins in prokaryotic cells and achieved an unprecedented labeling efficiency. We then expanded it to more complicated eukaryotic cells and successfully detected the proteins targeted to various organelles, including the membranes of endoplasmic reticulum (ER) and nuclear envelope, ER lumen, nuclear pores, spindle pole bodies, and mitochondrial matrix. Thus, our implementation of genetically encoded tags for EM should allow cell biologists to address an enormous range of biological questions at single-molecule level in diverse cellular ultrastructural contexts without using antibodies.

Genome-wide association studies (GWAS) have identified greater than 30 variants associated with ovarian cancer, but most of these variants were investigated in European populations. Here, we integrated GWAS and subsequent functional analyses to identify the genetic variants with potential regulatory effects. We conducted GWAS for ovarian cancer using 681 Japanese cases and 17,492 controls and found that rs137672 on 22q13.1 exhibited a strong association with a P-value of 1.05 × 10(-7) and an odds ratio of 0.573 with a 95% confidence interval of 0.466-0.703. In addition, three previously reported SNPs, i.e., rs10088218, rs9870207 and rs1400482, were validated in the Japanese population (P < 0.05) with the same risk allele as noted in previous studies. Functional studies including regulatory feature analysis and electrophoretic mobility shift assay (EMSA) revealed two regulatory SNPs in 22q13.1, rs2072872 and rs6509, that affect the binding affinity to some nuclear proteins in ovarian cancer cells. The plausible regulatory proteins whose motifs could be affected by the allele changes of these two SNPs were also proposed. Moreover, the protective G allele of rs6509 was associated with a decreased SYNGR1 expression level in normal ovarian tissues. Our findings elucidated the regulatory variants in 22q13.1 that are associated with ovarian cancer risk.

All-polymer solar cells based on blends of the low band gap polymers poly{[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b′]dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl]} (PTB7) and poly{[N,N-9-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,59-(2,29-bithiophene)} (P(NDI2OD-T2)) are demonstrated. The use of the donor polymer PTB7 instead of poly(3-hexylthiophene) results in a higher open-circuit voltage and an overall spectral response better matched to the solar spectrum. A power conversion efficiency of 1.1% is reported with a peak external quantum efficiency of 18% at a wavelength of 680 nm. The microstructure of PTB7:P(NDI2OD-T2) blends is also investigated using a combination of grazing-incidence wide-angle X-ray scattering (GIWAXS), near-edge X-ray fine-structure (NEXAFS) spectroscopy, atomic force microscopy (AFM), and scanning transmission X-ray microscopy (STXM). GIWAXS measurements show that PTB7:P(NDI2OD-T2) blends contain P(NDI2OD-T2) crystallites with a (100) thickness of 9.5 nm dispersed in an amorphous PTB7 matrix. STXM measurements indicate a lack of mesoscale phase separation, with AFM and NEXAFS measurements revealing a P(NDI2OD-T2)-rich top surface with fibrillar morphology. These results indicate that the pairing of low band gap polymers as both donor and acceptor polymers in all-polymer solar cells may be an effective strategy for realizing high-efficiency all-polymer solar cells. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2013