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Objective. Mesenchymal stromal/stem cells (MSCs) are an important part of the glioma microenvironment and are involved in the malignant progression of glioma. In our previous study, we showed that MSCs can be induced to a malignant phenotype (tMSCs) by glioma stem cells (GSCs) in the microenvironment. However, the potential mechanism by which tMSCs maintain their malignant phenotype after malignant transformation has not been fully clarified. Methods. The expression of HOTAIRM1, FUS, and E2F7 was detected by qRT-PCR. Clone formation, EdU, and Transwell assay were used to explore the role of HOTAIRM1, FUS, and E2F7 on the proliferation, migration, and invasion of tMSCs. Bioinformatics analysis and RNA immunoprecipitation were used to explore the relation among HOTAIRM1, FUS, and E2F7. Results. HOTAIRM1 was upregulated in tMSCs compared with MSCs. Loss- and gain-of-function assays showed that HOTAIRM1 promoted the proliferation, migration, and invasion of tMSCs. qRT-PCR and functional assays revealed that E2F7 might be the downstream target of HOTAIRM1. A further study of the mechanism showed that HOTAIRM1 could bind to FUS, an RNA-binding protein (RBP), and thus regulate E2F7, which could promote the malignant phenotype of tMSCs. Conclusion. Our study revealed that the HOTAIRM1/FUS/E2F7 axis is involved in the malignant progression of tMSCs transformed by GSCs in the glioma microenvironment and may function as a novel target for glioma therapy.

Chemo-resistance hinders the therapeutic efficacy of temozolomide (TMZ) in treating glioblastoma multiforme (GBM). Recurrence of GBM even after combination of maximal tumor resection, concurrent radio-chemotherapy, and systemic TMZ applocation is inevitable and attributed to the high therapeutic resistance of glioma stem cells (GSCs), which can survive, evolve, and initiate tumor tissue remodeling, the underlying mechanisms of GSCs chemo-resistance, have not been fully elucidated up-to-now. Emerging evidence showed that METTL3-mediated N6-methyladenosine (m6A) modification contributed to the self-renew and radio-resistance in GSCs, however, its role on maintenance of TMZ resistance of GSCs has not been clarified and need further investigations. We found that the cell viability and half-maximal inhibitory concentration (IC50) of GSCs against TMZ significantly decreased after GSCs underwent serum-induced differentiation to adherent growth of tumor cells. Besides, METTL3 expression and total m6A modification declined dramatically in consistence with GSCs differentiation. Knockdown of METTL3 weakened self-renew, proliferation and TMZ IC50 of GSCs, whereas enhanced TMZ induced γH2AX level, indicating upregulation of double-strand DNA damage. We also found that mRNA stability of two critical DNA repair genes (MGMT and APNG) was regulated by METTL3-mediated m6A modification. In conclusion, we speculated that METTL3-mediated m6A modification of MGMT and APNG mRNAs played crucial roles on suppression of TMZ sensitivity of GSCs, which suggest a potential new therapeutic target of METTL3 against GBM.

With the spread of the COVID-19 pandemic and the implementation of closure measures in 2020, population mobility and human activities have decreased, which has seriously impacted atmospheric quality. Huaibei City is an important coal and chemical production base in East China, which faces increasing environmental problems. The impact of anthropogenic activities on air quality in this area was investigated by comparing the COVID-19 lockdown in 2020 with the normal situation in 2021. Tropospheric NO2, HCHO and SO2 column densities were observed by ground-based multiple axis differential optical absorption spectroscopy (MAX-DOAS). In situ measurements for PM2.5, NO2, SO2 and O3 were also taken. The observation period was divided into four phases, the pre-lockdown period, phase 1 lockdown, phase 2 lockdown and the post-lockdown period. Ground-based MAX-DOAS results showed that tropospheric NO2, HCHO and SO2 column densities increased by 41, 14 and 14%, respectively, during phase 1 in 2021 vs. 2020. In situ results showed that NO2 and SO2 increased by 59 and 11%, respectively, during phase 1 in 2021 vs. 2020, but PM2.5 and O3 decreased by 15 and 17%, respectively. In the phase 2 period, due to the partial lifting of control measures, the concentration of pollutants did not significantly change. The weekly MAX-DOAS results showed that there was no obvious weekend effect of pollutants in the Huaibei area, and NO2, HCHO and SO2 had obvious diurnal variation characteristics. In addition, the relationship between the column densities and wind speed and direction in 2020 and 2021 was studied. The results showed that, in the absence of traffic control in 2021, elevated sources in the Eastern part of the city emitted large amounts of NO2. The observed ratios of HCHO to NO2 suggested that tropospheric ozone production involved NOX-limited scenarios. The correlation analysis between HCHO and different gases showed that HCHO mainly originated from primary emission sources related to SO2.

Obesity is a metabolic condition brought on by the interplay of hereditary and environmental factors, making it one of the most common diseases in the world. Insulin resistance (IR) and obesity have a close connection and can both be advantageous. One of the main methods of epigenetic regulation is DNA methylation modification. Studies have demonstrated over the past few years that DNA methylation is crucial to the emergence of obesity and DNA methylation can lead to IR. Adipose tissue participates in the physiopathological processes of obesity and IR and functions as an endocrine organ controlling the body's balanced metabolism, thus, adipose tissue-associated gene DNA methylation affects the development of obesity and IR by influencing the function of adipose tissue. Hence, an explanation of current research on DNA methylation, IR, and obesity, following the most recent developments, exploring changes in DNA methylation in different types of adipose tissue in insulin-resistant patients and obese patients may enable the identification of novel targets in clinical obesity prevention and treatment.The following electronic bibliographic databases will be searched from inception for peer-reviewed original research published: MEDLINE (through PubMed), Scopus, and EMBASE. Cochrane Library, Cochrane Clinical Trials Registry, the National Institutes for Health Clinical Trials Registry, and the WHO International Clinical Trials Registry Platform from inception to December 31, 2021 will be conducted. Systematic reviews will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. The development of search strategies will make use of medical issue phrases and keywords associated with DNA methylation, Adipose tissue DNA methylation, obesity, and IR. Identified citations will be independently reviewed by two authors to determine eligibility at the title and abstract level, and then at the full text and data extraction phases. Disagreements and conflicts will be resolved through discussion with a third author. Two authors will extract the necessary data from the included studies independently, and The Cochrane Risk of Bias Assessment Tool will be used to assess the bias of randomized controlled studies, and the Newcastle-Ottawa scale for nonrandomized controlled studies. If the interventions and outcomes evaluated are sufficiently homogeneous, results from subgroups of studies will be pooled together in a meta-analysis.

Color picker is a necessary interactive component in visualization system. Current color pickers are based on the WIMP paradigm and are mainly designed for mouse, touch and ray interactions. In the context of immersive and remote interaction, mid-air interaction is an important method. However, common solution of color selection using hands is simulating cursors or rays with fingers, which does not take full advantage of mid-air interaction—intuition, naturalness and remote interaction. This results in fatigue and long selection time. In this paper, we proposed a mid-air interaction metaphor for color selection which enabled users to select hue, saturation and lightness simultaneously using mutually independent and intuitive hand motions. We conducted a user study to evaluate the performance of the interaction technique. Results showed that the metaphor improved the efficiency of color selection with mid-air interaction. Questionnaire results showed that the metaphor enhanced users’ perception of color space; the semantics of hand motions were consistent with users’ intention of color selection; the metaphor was easy to learn and memorize.

Background: Cinnamon is a spice used in cooking and in large quantities as a medical complement with hypoglycemic and lipid-lowering properties. The potential pharmacological mechanisms underlying cinnamon’s anti-diabetic properties and its active ingredients have not been adequately determined. The current meta-analysis aims to systematically review the potential pharmacological mechanisms underlying the hypoglycemic and hypolipidemic efficacy of cinnamon administration and summarize clinical recommendations of cinnamon and its active ingredients.Method: Relevant randomized clinical trials (RCTs) were identified through a literature search that spanned the years January 2005 to April 2022. Retrieve electronic databases including Web of Science, PubMed, Embase, Medline, and the Cochrane Library. To obtain standardized mean differences (SMDs), continuous outcomes were pooled and 95 percent confidence intervals (CIs) were provided. Categorical outcomes were aggregated to calculate relative risks (RRs) and were accompanied by 95% CIs. Heterogeneity was measured using the Cochrane Q-test and I2 statistics, with a p < 0.05 considered as substantial heterogeneity. If I2 was less than 50%, a fixed effect model was employed; otherwise, a random effect model was used. Subgroup analyses and sensitivity analyses were performed to identify the origins of heterogeneity. Publication bias was retrieved by means of a funnel-plot analysis and Egger’s test. The data were analyzed using revman (V.5.3) and stata (V.15) software packages.Results: These 16 RCTs included a total of 1,020 patients who were followed for a duration ranging from 40 days to 4 months. According to the current meta-analysis results, glycolipid levels in diabetic individuals who received cinnamon were significantly improved as compared to those who got placebo (All p < 0.05). An adverse effect was only detected in one patient.Conclusion: These findings imply that cinnamon has a significant influence on lipid and glucose metabolism regulation. An even more pronounced effect was observed in patients with HbA1c of 8%. The results of this study suggested that cinnamon may be utilized as hypoglycemic and lipid-lowering supplement in clinical settings with a guaranteed safety profile.Systematic Review Registration: [PROSPERO], identifier [CRD42022322735].

The recent development of dendritic cell (DC)-based immunotherapy has resulted in advances in glioblastoma multiforme (GBM) treatment. However, the cell fate of DCs in the GBM microenvironment, especially in microenvironments in which glioma stem cell (GSC)-mediated remodeling has resulted in highly immuno-suppressive conditions, has not yet been fully investigated. The current study observed direct and active mutual interactions between GSCs and primary cultured DCs in a dual-color tracing model. Highly proliferative DCs could be monoclonal and continuously passaged, and these cells exhibited acquired tumorigenicity in vivo, indicating their malignant transformation. Transformed DCs (t-DCs) still expressed DC-specific surface markers, namely, CD80 and CD11c, and immune-related costimulatory molecules, namely, CD80, CD86, CD40, and ICAM-1. However, the expression levels of these molecules in t-DCs decreased moderately compared to those in naive DCs. Mechanistic studies revealed the upregulation of the proliferation-related gene pentraxin 3 (PTX3) in t-DCs. Stable overexpression of PTX3 further promoted the proliferation and migration of t-DCs in vitro, decreased the expression of costimulatory molecules, and increased the tumorigenicity of t-DCs in vivo. Bioinformatics prediction, qRT‒PCR verification, and luciferase reporter gene analysis indicated that the transcription factor zinc finger protein 148 (ZNF148) directly bound to the PTX3 promoter region and enhanced PTX3 expression. Downregulation of ZNF148 significantly decreased PTX3 expression and reduced the proliferation and migration of t-DCs. Overexpression of ZNF148 significantly increased PTX3 expression and promoted the proliferation and migration of t-DCs, achieving the same biological effects as PTX3 overexpression in t-DCs. Simultaneously, downregulation of ZNF148 partially reversed the effect of PTX3 overexpression in t-DCs. In conclusion, the ZNF148/PTX3 axis played an important role in regulating the malignant transformation of DCs after cross-talk with GSCs, and this axis may serve as a new target for sensitizing GBM to DC-based immunotherapy.

Glioma is the most common malignant tumor of the central nervous system, with high heterogeneity, strong invasiveness, high therapeutic resistance, and poor prognosis, comprehending a serious challenge in neuro-oncology. Until now, the mechanisms underlying glioma progression have not been fully elucidated.The expression of DExH-box helicase 9 (DHX9) in tissues and cells was detected by qRT-PCR and western blot. EdU and transwell assays were conducted to assess the effect of DHX9 on proliferation, migration and invasion of glioma cells. Cocultured model was used to evaluate the role of DHX9 on macrophages recruitment and polarization. Animal study was performed to explore the role of DHX9 on macrophages recruitment and polarization in vivo. Bioinformatics analysis, dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay was used to explore the relation between DHX9 and TCF12/CSF1.DHX9 was elevated in gliomas, especially in glioblastoma multiforme (GBM). Besides promoting the proliferation, migration, and invasion of glioma cells, DHX9 facilitated the infiltration of macrophages into glioma tissues and polarization to M2-like macrophages, known as tumor-associated macrophages (TAMs). DHX9 silencing decreased the expression of colony-stimulating factor 1 (CSF1), which partially restored the inhibitory effect on malignant progress of glioma and infiltration of TAMs caused by DHX9 knockdown by targeting the transcription factor 12 (TCF12). Moreover, TCF12 could directly bind to the promoter region of CSF1.DHX9/TCF12/CSF1 axis regulated the increases in the infiltration of TAMs to promote glioma progression and might be a novel potential target for future immune therapies against gliomas.

Glioblastoma has high recurrence, while the sensitivity of recurrent glioblastoma to chemotherapy is lower than that of primary glioblastoma. Moreover, there is no standardized treatment for recurrent glioblastoma. Unfortunately, the biological mechanism of recurrent glioblastoma is still unclear, and there are few related studies. We compared the phenotypes of clinical glioblastoma specimens, in-vitro cultured glioma stem-like cells (GSCs) and patient-derived xenograft tumor (PDX) models to explore the molecular genetic characteristics of primary and recurrent glioblastoma from the same patient. In vitro, SU5-2, GSCs derived from recurrent glioblastoma specimens, had stronger proliferative activity and self-renewal ability. Meanwhile, SU5-2 was more resistant to temozolomide and invasive than SU5-1, which derived from primary glioblastoma specimens. Further analysis of the expression of costimulatory molecules showed that the expression of B7-H1, B7-H2 and B7-H3 of SU5-2 were upregulated. In vivo, Kaplan-Meier survival curve analysis showed that the median survival of the recurrent PDX group was worse. The results of gene detection in vitro, PDX model and clinical samples were consistent. Our results showed that the GSCs based on glioblastoma specimens and the PDX models could replicate the main molecular genetic characteristics of original tumors, which provided a reliable experimental platform for both tumor translation kinds of research and screening of molecular therapeutic targets.

This study demonstrates a mobile passive differential optical absorption spectroscopy (DOAS) based remote sensing method for quantifying the emission fluxes of soot pollutants. First, the mobile DOAS system scans the plume emitted from urban sources. Then, the DOAS method retrieves the total columns of pollutant gases along the measurement path. Combining the longitude, latitude, and mobile speed recorded by vehicle GPS, the net emission fluxes of NO

Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.

We investigate in detail the spectral pulsation of evolving soliton molecules in an anomalous dispersion fiber laser by utilizing the dispersive Fourier transform technique. The spectral pulsations of an evolving soliton molecule with different properties were achieved in our experiments, such as single-period and double-period pulsation. This type pulsation is characterized by the fact that the soliton molecules periodically experience oscillation in spectral profile and peak power due to the periodic vibration evolution of the internal pulses. However, the continuous weak energy exchange between the two solitons inside the soliton molecules results in an almost invariable pulse energy. In addition, analytical fitting models are given to further reveal the spectral pulsation phenomenon of the evolving soliton molecules. These experimental findings can shed some light on the dynamics of soliton molecules in fiber lasers.

Direct-ink-writing (DIW)-based 3D-printing technology combined with the direct-foaming method provides a new strategy for the fabrication of porous materials. We herein report a novel method of preparing porous SiC ceramics using the DIW process and investigate their mechanical and wave absorption properties. We investigated the effects of nozzle diameter on the macroscopic shape and microstructure of the DIW SiC green bodies. Subsequently, the influences of the sintering temperature on the mechanical properties and electromagnetic (EM) wave absorption performance of the final porous SiC-sintered ceramics were also studied. The results showed that the nozzle diameter played an important role in maintaining the structure of the SiC green part. The printed products contained large amounts of closed pores with diameters of approximately 100–200 μm. As the sintering temperature increased, the porosity of porous SiC-sintered ceramics decreased while the compressive strength increased. The maximum open porosity and compressive strength were 65.4% and 7.9 MPa, respectively. The minimum reflection loss (RL) was −48.9 dB, and the maximum effective absorption bandwidth (EAB) value was 3.7 GHz. Notably, porous SiC ceramics after sintering at 1650 °C could meet the application requirements with a compressive strength of 7.9 MPa, a minimum RL of −27.1 dB, and an EAB value of 3.4 GHz. This study demonstrated the potential of direct foaming combined with DIW-based 3D printing to prepare porous SiC ceramics for high strength and excellent EM wave absorption applications.

Generation of chimeric antigen receptor (CAR) T cells from pluripotent stem cells (PSCs) will enable advances in cancer immunotherapy. Understanding how CARs affect T cell differentiation from PSCs is important for this effort. The recently described artificial thymic organoid (ATO) system supports in vitro differentiation of PSCs to T cells. Unexpectedly, PSCs transduced with a CD19-targeted CAR resulted in diversion of T cell differentiation to the innate lymphoid cell 2 (ILC2) lineage in ATOs. T cells and ILC2s are closely related lymphoid lineages with shared developmental and transcriptional programs. Mechanistically, we show that antigen-independent CAR signaling during lymphoid development enriched for ILC2-primed precursors at the expense of T cell precursors. We applied this understanding to modulate CAR signaling strength through expression level, structure, and presentation of cognate antigen to demonstrate that the T cell-versus-ILC lineage decision can be rationally controlled in either direction, providing a framework for achieving CAR-T cell development from PSCs.

Extraventricular neurocytoma (EVN) is a rare intracranial tumor. The most common locations of EVN were frontal lobe and cerebellum, followed by temporal lobe. Heterogeneous contrast enhancement, cystic changes, perilesional edema and calcification were a few distinct imaging characteristics. EVN is a primary tumor with either glial or neuronal differentiation or potential for atypical changes. The lack of characteristic manifestations in histopathology makes EVN difficult to distinguish from other low-grade neuronal and mixed neuronal-glial tumors. Herein, we describe a case of frontal extraventricular neurocytoma in a 37-year-old male presenting with dizzy and review the literature on this rare tumor. Pathological examination reveals that the tumor mainly composed of oligodendroglia-like cells, with expression of synaptophysin (SYN) and Olig2 (oligodendrocyte transcription factor 2), and microcalcifications. Methylation profile and t-SNE analysis show our sample cluster with the other two reference EVNs. Next-generation sequencing (NGS) shows FGFR1-TACC1 fusion. We report a case of EVN with expression of Olig2, FGFR1-TACC1 fusion, methylation of MGMT promoter, and discuss our experience along with a review of the published literature.

Citrinin (CIT)—an established public health threat—is a frequent component of red fermented rice (RFR). Although various quantitative techniques have been developed to detect citrinin in red fermen...

As one of the universal phenomena in diverse fields, pulsating solitons exhibit charming and complex transient behaviors. Herein, based on the dispersive Fourier transform technique, three typical types of dissipative soliton pulsations are unveiled in a net normal-dispersion mode-locked fiber laser. According to their different oscillation modes, they are divided into single-period soliton pulsation, double-period soliton pulsation and asynchronous soliton pulsation. In particular, for the double-period soliton pulsation, the pulse shape repeats itself after two pulsations. Moreover, for asynchronous soliton pulsation, the dual-soliton evolve at different rates during the pulsation process, leading to the appearance of asynchronous phenomena. The findings will provide new insights into the complex mechanisms of soliton pulsation in fiber lasers and nonlinear dissipative systems.

Colliding bodies optimization (CBO) is a recently proposed algorithm, and there are no algorithm-specific parameters that should be previously determined in updating equations of bodies. CBO has been used to solve various optimization problems because of its simple structure. However, CBO suffers from low convergence speed and premature convergence. To enhance CBO’s performance, a new variant named learning strategy based colliding bodies optimization (LSCBO), which is based on the learning strategy of the Teaching–learning-based optimization algorithm (TLBO), is proposed in this paper. In this method, a hybrid strategy combining the colliding process of CBO and the learning process of TLBO is proposed to generate new positions of the bodies. Compared with some other CBO variants, the guidance of the best individual is introduced to improve the convergence speed of CBO, and a random mutation method based on the historic information is designed to help bodies escape from local optima. Moreover, a new method for determining the mass of bodies is designed to avoid computation overflow. To evaluate the effectiveness of LSCBO, 47 benchmark functions and three real-world structural design problems are tested in the simulation experiments, and the results are compared with those of other well-known meta-heuristic algorithms. The statistical simulation results indicate that the performance of CBO is obviously improved by the developed method.

As a new evolutionary computation method, the structure of backtracking search optimization algorithm (BSA) is simple and the exploration capability of it is strong. However, the global performance of the BSA is significantly affected by mutation strategies and control parameters. Designing appropriate mutation strategies and control parameters is important to improve the global performance of the BSA. In this paper, an adaptive BSA with knowledge learning (KLBSA) is developed to improve the global performance of the BSA. In the method, an adaptive control parameter based on the global and local information of the swarms in the current iteration is designed to adjust the search step length of individuals, which helps to balance the exploration and exploitation abilities of the algorithm. Moreover, a new mutation strategy based on the guidance of different information is designed to improve the optimization ability of the algorithm. In addition, a multi-population strategy is implemented to thoroughly improve the searching ability of the algorithm for different searching areas. To this end, experiments on three groups of benchmark functions and three real-world problems are implemented to verify the performance of the proposed KLBSA algorithm. The results indicate that the proposed algorithm performs competitively and effectively when compared to some other evolutionary algorithms .

Recent progress in real-time measurement technology makes it possible to spectrally characterize multi-soliton complexes. Here, we report on real-time observation to the multi-pulse structures in a net-normal dispersion mode-locked fiber laser. With careful adjustment of cavity parameters, several kinds of multi-soliton complexes, such as the coexistence of soliton singlet and soliton molecule, as well as the coexistence of different types of soliton molecules, are realized in the experiment. Real-time spectral information of each pulse under multi-soliton states can be well resolved with the dispersive Fourier transformation technique, which is markedly different from the results measured by conventional measurement instruments. Note that this is the first reported the simultaneous generation of different types of soliton molecules in a fiber laser to our best knowledge. The findings help to understand the complicated dynamics of the coexisting pattern between different kinds of dissipative solitons.

T cell receptor (TCR)-engineered T cells are a promising approach to cell therapy for cancer. TCRs targeting public tumor associated antigens (TAAs) offer the widest potential coverage of patients within and across tumor types. TAA-specific TCRs, however, are rare in the blood and when detected are frequently of low affinity due to negative selection of high-affinity self-antigen reactive T cells in the thymus. Here, we present a TCR discovery platform based on in vitro generation of T cells from human pluripotent stem cells (PSCs) using the previously described artificial thymic organoid (ATO) system. We hypothesized that ATO-derived T cells offer several advantages for TCR discovery including a novel TCR repertoire and the absence of negative selection against TAAs during T cell development. Sequencing of the TCR repertoire of polyclonal CD8+ T cells generated from a HLA-A*02:01+ PSC line confirmed low junctional diversity at both the TCR beta and alpha loci, consistent with our previous finding of low TdT expression during T cell development from PSCs and an enrichment for germline-like TCRs. We then interrogated this novel TCR repertoire for reactivity against two well-described HLA-A2-restricted epitopes of NY-ESO-1 and WT1, reactivities to which are rare in the blood. Following co-culture with artificial APCs, a surprisingly high frequency of antigen-specific T cells was detected by MHC-tetramer staining. From these, high frequency TCR clonotypes were functionally validated by reconstitution in Jurkat TCR-reporter cells. Interestingly, from a single experimental run multiple antigen-specific TCRs were validated (5 out of 10 tested clonotypes for NY-ESO-1, and 2 out of 5 for WT1). This finding was reproducible across independent experimental runs, yielding further validated TCRs against these targets. To benchmark relative TCR affinities, we compared a panel of 5 ATO-derived NY-ESO-1 TCRs with 4 blood-derived TCRs with the same specificity, as well as the affinity-enhanced 1G4 TCR. ATO-derived TCRs showed not only superior performance to their blood derived counterparts in peptide dilution assays, but TCRs were identified with equivalent or superior cytotoxicity to 1G4, including against cell lines with endogenous NY-ESO-1 expression. Comparative in vivo anti-tumor efficacy studies are in process. A similarly high level of specificity and cytotoxicity was observed for ATO-derived WT1-specific TCRs. Finally, we demonstrate proof-of-concept identification of TCRs specific to a prostate-specific antigen for which high quality TCRs have remained elusive. In conclusion, the PSC ATO TCR-discovery platform efficiently identifies high-affinity TAA-specific TCRs, including against previously intractable targets. Considering the potential for MHC modularity of this in vitro system, this approach may theoretically enable rapid discovery of therapeutic TCRs based on any designated peptide/MHC-I combination. Citation Format: Chloe S. Wang, Suwen Li, Zhiyuan Mao, Olivia Zhou, Carlos Botero, William Satyadi, Patrick Chang, Sang Pil Yoo, Ho-Chung Chen, Shawn Lopez, Jami McLaughlin, Amélie Montel-Hagen, Owen N. Witte, Gay M. Crooks, Christopher S. Seet. PSC-derived T cells as a novel source of tumor antigen-specific T cell receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3604.

SUMMARY We report a serum-free, 3D murine artificial thymic organoid (M-ATO) system that mimics normal murine thymopoiesis with the production of all T cell stages, from early thymic progenitors to functional single-positive (CD8SP and CD4SP) TCRαβ and TCRγδ cells. RNA sequencing aligns M-ATO-derived populations with phenotypically identical primary thymocytes. M-ATOs initiated with Rag1−/− marrow produce the same differentiation block as seen in the endogenous thymus, and Notch signaling patterns in M-ATOs mirror primary thymopoiesis. M-ATOs initiated with defined hematopoietic stem cells (HSCs) and lymphoid progenitors from marrow and thymus generate each of the downstream differentiation stages, allowing the kinetics of T cell differentiation to be tracked. Remarkably, single HSCs deposited into each M-ATO generate the complete trajectory of T cell differentiation, producing diverse TCR repertoires across clones that largely match endogenous thymus. M-ATOs represent a highly reproducible and efficient experimental platform for the interrogation of clonal thymopoiesis from HSCs., In Brief Montel-Hagen et al. develop a murine artificial thymic organoid (M-ATO) system to reproduce thymopoiesis in vitro from bone marrow stem and progenitor cells (HSPCs). This method efficiently recapitulates the phenotypic and transcriptional features of normal murine T cell development even when initiated with a single HSC., Graphical Abstract

T cells and type 2 innate lymphoid cells (ILC2) are two closely related lymphoid lineages that share certain developmental and transcriptional programs, including a requirement for Notch and IL-7 signaling during differentiation. We recently developed an artificial thymic organoid (ATO) system that supports in vitro differentiation of human pluripotent stem cells (PSCs) to mature αβT cells. We show here that lentiviral introduction of a CD19-targeted chimeric antigen receptor (CAR) into PSCs surprisingly resulted in ILC2-biased lymphopoiesis from PSCs at the expense of T cell differentiation. PSC-derived ILC2s expressed the classical ILC2 markers CD25, CD200R, and CRTH2 as well GATA3, ID2, and TCF7, and responded to both cytokine stimuli and antigen-dependent CAR signaling by producing IL-5 and IL-13. To understand CAR-mediated lineage diversion from T to ILC2, we performed single cell RNAseq of PSC-derived hematopoietic progenitor cells before the phenotypic onset of either T or ILC2 differentiation. This revealed a gene signature of T cell receptor signaling, suggesting aberrant CAR activation at the earliest stages of lymphocyte development. We established that CAR signaling in ATOs was antigen-independent and thus likely driven by tonic signaling. We applied this finding to rationally modulate the T/ILC2 lineage decision by fine-tuning CAR signaling strength during lymphocyte development from PSCs, permitting restoration of conventional CAR-T cell differentiation or, conversely, directed differentiation of isogenic antigen-specific CAR-ILC2s. Taken together, our findings shed light on human ILC2 development and inform the applied differentiation of both ILC2s and conventional CAR-T cells from PSCs. Supported by Tobacco-Related Disease Research Program Predoctoral Award (SL), Broad Stem Cell Research Center UCLA Fellowship (SL, CSS), CIRM Bridges Program (CB), NIH T32 (ST), NIH K08CA235525 (CSS).

Obtaining the vertical distribution profile of trace gas is of great significance for studying the diffusion procedure of air pollution. In this article, a look-up table method based on multi-axis differential optical absorption spectroscopy (MAXDOAS) technology is established for retrieving the tropospheric NO2 vertical distribution profiles. This method retrieves the aerosol extinction profiles with minimum cost function. Then, the aerosol extinction profiles and the atmospheric radiation transfer model (RTM) are employed to establish the look-up table for retrieving the NO2 vertical column densities (VCDs) and profiles. The measured NO2 differential slant column densities (DSCDs) are compared with the NO2 DSCDs simulated by the atmospheric RTM, and the NO2 VCDs, the weight factor of NO2 in the boundary layer, and the boundary layer height are obtained by the minimization process. The look-up table is established to retrieve NO2 VCDs based on MAX-DOAS measurements in Huaibei area, and the results are compared with the data from Copernicus Atmospheric Monitoring Service(CAMS) model. It isfound that there are nearly consistent and the correlation coefficient R2 is morethan 0.86. The results show that this technology provides a more convenient and accurate retrieval method for the stereoscopic monitoring of atmospheric environment.

The cause of high contact resistance between carbon nanotube (CNT) filled vias and metal electrodes is studied. Contamination due to the chemical–mechanical polishing (CMP) process, which damages the sp2 bonds at the end of the CNTs, is found to be the main cause. An alternative oxygen plasma etching process is proposed to preserve the sp2 bonds at the CNT tips during the via planarization process. The improved properties of the CNT tips, with more sp2 bonds and fewer oxygen-containing groups, have been demonstrated using X-ray photoelectron spectroscopy (XPS). Based on the findings, a new CNT via integration process is designed, which includes selective CNT growth inside the via and O2 plasma planarization. A low contact resistance of 1.83 μΩ cm2 is demonstrated.

Multi-wavelength square pulses are generated in the dissipative soliton resonance (DSR) regime by a Yb-doped fiber laser (YDFL) with a long cavity configuration. The spectral filter effect provided by a passive fiber with low-stress birefringence facilitates the establishment of multi-wavelength operation. Through appropriate control of the cavity parameters, a multi-wavelength DSR pulse can be generated in single- and dual-waveband regions. When the multi-wavelength DSR works in the 1038 nm waveband, the pulse duration can broaden from 2 ns to 37.7 ns. The maximum intra-cavity pulse energy is 152.7 nJ. When the DSR works in the 1038 nm and 1080 nm wavebands, the pulse duration can be tuned from 2.3 ns to 10.5 ns with rising pump power. The emergence of the 1080 nm waveband is attributed to the stimulated Raman scattering (SRS) effect. Our work might help a deeper insight to be gained into DSR pulses in all-normal-dispersion YDFLs.

A backtracking search optimisation algorithm that uses historic population information for learning was proposed recently for solving optimisation problems. However, the learning ability and the robustness of this algorithm remain relatively poor. To improve the performance of the backtracking search algorithm (BSA), a modified backtracking search optimisation algorithm (MBSA), based on learning and niching strategies, is presented in this paper. Three main strategies, a learning strategy, a niching strategy, and a mutation strategy, are incorporated into the proposed MBSA algorithm. Learning the best individual in current generation and the best position achieved so far is used to improve the convergence speed. Niching and mutation strategies are used to improve the diversity of the MBSA. Finally, some benchmark functions and three chaotic time series prediction problems based on neural networks are simulated to test the effectiveness of MBSA, and the results are compared with those obtained using some other evolutionary algorithms (EAs). The simulation results indicate that the MBSA outperforms other EAs for most functions and chaotic time series.

Teaching–learning-based optimization (TLBO) algorithm is one of the recently proposed optimization algorithms. It has been successfully used for solving optimization problems in continuous spaces. To improve the optimization performance of the TLBO algorithm, a modified TLBO algorithm with differential and repulsion learning (DRLTLBO) is presented in this paper. In the proposed algorithm, the differential evolution (DE) operators are introduced into the teacher phase of DRLTLBO to increase the diversity of the new population. In the learner phase of DRLLBO, local learning method or repulsion learning method are adopted according to a certain probability to make learners search knowledge from different directions. In the local learning method, learners learn knowledge not only from the best learner but also from another random learner of their neighbors. In the repulsion learning method, learners learn knowledge from the best learner and keep away from the worst learner of their neighbors. Moreover, self-learning method is adopted to improve the exploitation ability of learners when they are not changed in some continuous generations. To decrease the blindness of random self-learning method, the history information of the corresponding learners in some continuous generations is used in self-learning phase. Furthermore, all learners are regrouped after a certain iterations to improve the local diversity of the learners. In the end, DRLTLBO is tested on 32 benchmark functions with different characteristics and two typical nonlinear modeling problems, and the comparison results show that the proposed DRLTLBO algorithm has shown interesting outcomes in some aspects.

A multilayer (Ni/Al/Ni) catalyst design is proposed to synthesize high-density carbon nanotubes (CNTs) on a conductive titanium silicide substrate. The Al intermediate layer immobilizes the Ni catalyst on the substrate during nanoparticle formation by interacting with the top and bottom Ni catalyst film, suppressing the diffusion of Ni into silicide and sintering of the Ni nanoparticles, as evidenced by secondary ion mass spectroscopy and atomic force microscopy analysis. Owing to the stable, high-density and evenly distributed nanoparticle catalysts with the multilayer catalyst design, we have synthesized vertically aligned CNTs with a density of 2.0 × 1010/cm2 and an average 50 walls per CNT. The CNT density using the Ni/Al/Ni catalyst is three times higher than that with the pure Ni catalyst. Furthermore, the proposed catalyst design enables CNT synthesis at a temperatures as low as 350 °C. The synthesized CNTs show Ohmic contact with Ti silicide, suggesting the catalyst design is promising for CNT applications on conductive substrates, especially for interconnect applications.

In order to improve the safety of underwater pipeline crawler in underwater operation and perfect its structural design, the stability of underwater pipeline crawler was studied. Firstly, the process of clamping the pipe with the clamping device of the crawler was divided into two stages: the clamping stage and the loading stage. Then the dynamic analysis was carried out, and the strength check of the V-shaped fixtures was accomplished. At last, the analysis results were summarized. The crawler mainly provides a platform for underwater pipeline operation equipment, which can be equipped with different equipment according to demand, providing convenience for underwater pipeline operation. Through simulation analysis and experimental verification have shown that the crawler meets the security requirements of underwater pipeline operations.

The poor utilization of visible light and the speedy recombination of photoexcited carriers limit the further development of carbon nitride polymer (CN) photocatalysts. It is a valid means for enhancing the photocatalytic ability to ameliorate the electronic and physicochemical properties via modifying the structure of CN. The sulfur- and chlorine-codoped graphite CN (S/Cl-CN) was successfully fabricated with low-cost ammonium chloride and thiourea as precursors. The introduction of Cl atoms will establish interlayer channels to promote interlayer charge migration and up-shifted conduction-band level. S atom is appropriate to be incorporated into the CN framework to replace N atom, which is beneficial to adjust the band gap. Then, inorganic-organic CdSe-diethylenetriamine (D) grown in situ are employed to fabricate a S/Cl-CN/CdSe-D heterojunction. S/Cl-CN/CdSe-D heterojunction exhibits greater hydrogen evolution activity compared to CN, S-CN, Cl-CN, S/Cl-CN, CdSe-D and CN/CdSe-D. Finally, Step-scheme (S-scheme) photocatalytic mechanism based on S/Cl-CN/CdSe-D heterostructure was proposed.