Miracle-dz/UniFAR-FTUs huggingface dataset:
Machine learning-based identification of SOX10 as an immune regulator of macrophage in gliomas

Gliomas, originating from the glial cells, are the most lethal type of primary tumors in the central nervous system. Standard treatments like surgery have not significantly improved the prognosis of glioblastoma patients. Recently, immune therapy has become a novel and effective option. As a conserved group of transcriptional regulators, the Sry-type HMG box (SOX) family has been proved to have a correlation with numerous diseases. Based on the large-scale machine learning, we found that the SOX family, with significant immune characteristics and genomic profiles, can be divided into two distinct clusters in gliomas, among which SOX10 was identified as an excellent immune regulator of macrophage in gliomas. The high expression of SOX10 is related to a shorter OS in LGG, HGG, and pan-cancer groups but benefited from the immunotherapy. It turned out in single-cell sequencing that SOX10 is high in neurons, M1 macrophages, and neural stem cells. Also, macrophages are found to be elevated in the SOX10 high-expression group. SOX10 has a positive correlation with macrophage cytokine production and negative regulation of macrophages’ chemotaxis and migration. In conclusion, our study demonstrates the outstanding cluster ability of the SOX family, indicating that SOX10 is an immune regulator of macrophage in gliomas, which can be an effective target for glioma immunotherapy.
Editorial: Towards genome interpretation: Computational methods to model the genotype-phenotype relationship

Genome Interpretation (GI) is an umbrella term for the scientific efforts oriented towards modelling and understanding the relationship between genotype and phenotype in living organisms (Daneshjou et al., 2017; Andreoletti et al., 2019; Raimondi et al., 2022a). Even temporarily setting epigenetic and environmental effects aside, untangling the complex relation between the complete set of genetic material of an individual organism (be it a human, other animals, plants, or microorganisms) and its observed phenotypes is an extremely ambitious and challenging endeavor, in particular for nonMendelian traits. Being able to reliably model this genotype-phenotype relationship could revolutionize many aspects of genetics, biology, and medicine (Daneshjou et al., 2017; Fröhlich et al., 2018). For example, it could warn us about late-onset genetic disorders, helping their prevention (Weedon et al., 2006; Morrison et al., 2007). It could also lead to the design of medications and treatments tailored to each patient’s genome, complementing environmental and medical-history data to improve patient prognosis (Fröhlich et al., 2018). Applied to cancer, it could bring a novel understanding of cancer development, helping devise highly specific cocktails of drugs and discover novel molecules to target each unique tumor (Li et al., 2019). Such personalized approaches to medicine, called Precision Medicine, are still largely out of our reach in many clinical settings (Daneshjou et al., 2017; Fröhlich et al., 2018). In the last decade, the avalanche of scientific results brought by Next Generation Sequencing (NGS) and big data technologies seemed almost unstoppable, and at times it seemed that finally cracking the genotype-phenotype problem was within reach. Ten years later, notwithstanding the vast amounts of data collected and numerous advances in genetics (Moreau and Tranchevent, 2012; Boycott et al., 2013; Erwin et al., 2014; Goodwin et al., 2016), including the discovery of the causative variants for many Mendelian OPEN ACCESS
The role of L1 in L2 speech production at different stages of L2 development: Evidence from L2 Chinese oral production of verb-phrase ellipsis by English and Korean speakers

The article reports on an empirical study investigating the role of L1 at the initial and developmental stages of L2 speech production. It examines two types of Chinese verb- phrase-ellipsis, ΣP-ellipsis licensed by the auxiliary shi ‘BE’ and vP-ellipsis licensed by the other auxiliaries, in 45 English and 45 Korean adult speakers’ L2 Chinese speech production. An elicited imitation task was administered to L2 learners at beginner, intermediate and advanced Chinese proficiency levels. L1 influence is not observed at beginner levels, but it appears at intermediate and advanced levels, L1 influence disappears at different time in English and Korean learners’ oral production of verb-ellipsis and ΣP-ellipsis. It is proposed that the absence of L1 influence at beginner levels is due to a breakdown of syntax-stylistics interface and beginners’ difficulty in implementing checking and deleting operations in their L2 oral production. The different timings of the disappearance of L1 influence in the two language groups at advanced levels is attributed to interactions between the persistence of L1 influence and the computational complexity involved in the target elliptical structures.
Cost-effectiveness of two screening strategies based on Chinese diabetes risk score for pre-diabetes in China

Objective Studies have shown that screening for pre-diabetes mellitus (pre-DM) is essential to prevent type 2 diabetes mellitus (T2DM). This study evaluates the cost-effectiveness of two screening strategies that apply the Chinese Diabetes Risk Score (CDRS) to screen for pre-DM in China. Methods A Markov microsimulation model was conducted from a social perspective, and the input parameters were obtained from published literature or publicly available data. Two screening strategies for pre-DM based on CDRS were built and compared with the control group to determine the cost-effective strategy. The screening strategy of the control group was screening for pre-DM by fasting plasma glucose (FPG) test in adults undergoing annual health examination and no screening in adults without an annual health examination (status quo). Two screening strategies were strategy 1: screening for pre-DM using CDRS in all adults (including with or without an annual health examination); and strategy 2: supplemental self-screening for pre-DM using CDRS in adults without an annual health examination, based on the status quo. We focus on the cumulative prevalence of T2DM and the incremental cost-effectiveness ratio which signifies the cost per case of T2DM prevented. We also evaluated the cost-effectiveness from the health system perspective. One-way and probabilistic sensitivity analyses were conducted to verify the robustness of the results. Results The costs a case of T2DM prevented for strategy 1 compared with the control group and strategy 2 were $299.67 (95% CI 298.88, 300.46) and $385.89 (95% CI 381.58, 390.20), respectively. In addition, compared with the control group, the cost of strategy 2 to prevent a case of T2DM was $272.23 (95% CI 271.50, 272.96). Conclusions Screening for pre-DM using CDRS in all adults was the most cost-effective health policy. We suggest that medical institutions replace FPG with CDRS for pre-DM screening; at the same time, self-screening for pre-DM using CDRS is widely promoted among adults without an annual health examination. There were still some disputes about how CDRS is included in the health examination projects, so strategy 2 should be considered as an alternative screening strategy. Findings provide a reference for the application of the CDRS in pre-DM screening and contribute to T2DM prevention.
Kaempferol attenuated diabetic nephropathy by reducing apoptosis and promoting autophagy through AMPK/mTOR pathways

Introduction Renal podocyte injury, apoptosis and autophagy are involved in the occurrence and development of diabetic nephropathy (DN). Kaempferol (KPF) has the promotion of autophagy and inhibition of apoptosis properties in the development of miscellaneous diseases, but these functions in DN have not yet been elucidated. Methods We used db/db mice to evaluate the protective role of KPF on DN. The anti-DN effect of KPF was evaluated by urine albumin-to-creatinine ratio and pathological changes of kidney tissue. Injury of podocytes was observed through Transmission electron microscopy. Immunofluorescence, Western blot, and Immunohistochemistry were used to detect the protein expression of podocyte-associated molecules, autophagy, and AMPK/mTOR pathway. Results We demonstrated that KPF treatment significantly attenuated diabetes-induced albuminuria and glycolipid metabolism dysfunction. In addition, KPF alleviated mesangial matrix expansion, glomerular basement membrane thickening and loss or fusion of podocytes. Mechanistically, KPF treatment regulated the expression of autophagic proteins (upregulated LC3II, Beclin-1, Atg7 and Atg 5, and downregulated p62/SQSTM1), accompanied by inhibited renal apoptosis (downregulated Caspase 3 and Bax, and upregulated Bcl-2). KPF could significantly regulate the AMPK/mTOR signaling pathways by increasing p-AMPK and decreasing p-mTOR expressions. Discussion In conclusion, KPF might have a protective effect on DN through reduced apoptosis and enhanced podocytes autophagy, which were correlated with regulating AMPK/mTOR pathways.
Vitamin D inhibits bone loss in mice with thyrotoxicosis by activating the OPG/RANKL and Wnt/β-catenin signaling pathways

Objective Vitamin D and thyroid hormones have crucial roles in bone metabolism. This study aims to explore the effects of vitamin D on bone metabolism in mice with thyrotoxicosis and its mechanisms. Methods 12-week-old mice were randomly divided into 6 groups (6 mice/group), the control (CON) group, vitamin D (VD) group, low-dose LT4 (Low LT4) group, low-dose LT4+VD (Low LT4+VD) group, high-dose LT4 (High LT4) group, high-dose LT4+VD (High LT4+VD) group, LT4 was provided every day and vitamin D3 every other day for 12 weeks. Thyroid function, 25-hydroxy vitamin D, type I collagen carboxy-terminal peptide (CTX), and type I procollagen amino-terminal peptide were determined. In addition, microcomputed tomography, bone histology and histomorphometry, a three-point bending test, and the mRNA expression of osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL) and β-catenin in bone were conducted. Results The BMD of lumbar vertebrae and femur decreased and the bone microstructure was destroyed significantly in thyrotoxicosis mice. Addition of vitamin D improved the BMD and bone microstructure only in the low LT4+VD group. Mice with thyrotoxicosis had a significantly higher level of CTX (P<0.05), which was decreased by treatment with vitamin D (P<0.05). The eroded surface per bone surface (Er. S/BS) of the cancellous bone and elongated surface/endocortical perimeter (Er. S/E Pm) of the cortical bone significantly increased in the Low LT4 and High LT4 groups (P<0.05). Treatment with vitamin D significantly decreased the Er. S/BS and Er. S/E Pm. But, treatment with vitamin D did not significantly improve the toughness and rigidity of bones. The ratio of OPG to RANKL and mRNA expression of β-catenin in the Low LT4+VD group were higher than that in the Low LT4 group (P<0.05). Conclusion In mice with thyrotoxicosis, treatment with vitamin D can inhibit bone resorption and improve the BMD and trabecular bone architecture by increasing the ratio of OPG to RANKL and upregulating the expression of Wnt/β-catenin.
Drug-induced liver injury in COVID-19 treatment: Incidence, mechanisms and clinical management

The COVID-19 outbreak triggered a serious and potentially lethal pandemic, resulting in massive health and economic losses worldwide. The most common clinical manifestations of COVID-19 patients are pneumonia and acute respiratory distress syndrome, with a variety of complications. Multiple organ failure and damage, ultimately leading to patient death, are possible as a result of medication combinations, and this is exemplified by DILI. We hope to summarize DILI caused by the antiviral drugs favipiravir, remdesivir, lopinavir/ritonavir, and hydroxychloroquine in COVID-19 patients in this review. The incidence of liver injury in the treatment of COVID-19 patients was searched on PubMed to investigate DILI cases. The cumulative prevalence of acute liver injury was 23.7% (16.1%–33.1%). We discuss the frequency of these events, potential mechanisms, and new insights into surveillance strategies. Furthermore, we also describe medication recommendations aimed at preserving DILI caused by treatment in COVID-19 patients.
Laryngeal extra-skeletal Ewing sarcoma treated with DC-CTL immunotherapy: A case report and review of the literature

Extra-skeletal Ewing sarcoma (EES) is a rare sarcoma composed primarily of small round cells, capable of metastasizing and relapsing. Few cases of EES originating from the larynx have been reported, and no publications regarding laryngeal EES treated with dendritic cells-cytotoxic T lymphocytes (DC-CTL) immunotherapy have been found. We described a 29-year-old woman with a mass found in the larynx. Diffuse small round cells with scanty cytoplasm shown by histology test and extremely positive staining of CD99 revealed by immunohistochemistry helped determine the diagnosis of laryngeal EES. The patient survived for seven years with no signs of recurrence or metastasis after six cycles of DC-CTL immunotherapy based on traditional treatments. This case indicates that DC-CTL immunotherapy could be considered a new option for treating EES.
Echocardiographic predictors of thrombus in left atrial appendage—The role of novel transthoracic parameters

Introduction The left atrium appendage thrombus (LAAT) formation is a complex process. A CHA2DS2-VASc scale is an established tool for determining the thromboembolic risk and initiation of anticoagulation treatment in patients with atrial fibrillation or flutter (AF/AFL). We aimed to identify whether any transthoracic echocardiography (TTE) parameters could have an additional impact on LAAT detection. Methods That is a sub-study of multicenter, prospective, observational study LATTEE (NCT03591627), which enrolled 3,109 consecutive patients with AF/AFL referred for transesophageal echocardiography (TEE) before cardioversion or ablation. Results LAAT was diagnosed in 8.0% of patients. The univariate logistic regression analysis [based on pre-specified in the receiver operating characteristic (ROC) analysis cut-off values with AUC ≥ 0.7] identified left ventricular ejection fraction (LVEF) ≤ 48% and novel TTE parameters i.e., the ratios of LVEF and left atrial diameter (LAD) ≤ 1.1 (AUC 0.75; OR 5.64; 95% CI 4.03–7.9; p < 0.001), LVEF to left atrial area (LAA) ≤ 1.7 (AUC 0.75; OR 5.64; 95% CI 4.02–7.9; p < 0.001), and LVEF to indexed left atrial volume (LAVI) ≤ 1.1 (AUC 0.75, OR 6.77; 95% CI 4.25–10.8; p < 0.001) as significant predictors of LAAT. In a multivariate logistic regression analysis, LVEF/LAVI and LVEF/LAA maintained statistical significance. Calculating the accuracy of the abovementioned ratios according to the CHA2DS2-VASc scale values revealed their highest predictive power for LAAT in a setting with low thromboembolic risk. Conclusion Novel TTE indices could help identify patients with increased probability of the LAAT, with particular applicability for patients at low thromboembolic risk.
A novel elicitor protein phosphopentomutase from Bacillus velezensis LJ02 enhances tomato resistance to Botrytis cinerea

The loss of tomatoes caused by Botrytis cinerea (B. cinerea) is one of the crucial issues restricting the tomato yield. This study screened the elicitor protein phosphopentomutase from Bacillus velezensis LJ02 (BvEP) which improves the tomato resistance to B. cinerea. Phosphatemutase was reported to play a crucial role in the nucleoside synthesis of various microorganisms. However, there is no report on improving plant resistance by phosphopentomutase, and the related signaling pathway in the immune response has not been elucidated. High purity recombinant BvEP protein have no direct inhibitory effect on B. cinerea in vitro,and but induce the hypersensitivity response (HR) in Nicotiana tabacum. Tomato leaves overexpressing BvEP were found to be significantly more resistant to B. cinerea by Agrobacterium-mediated genetic transformation. Several defense genes, including WRKY28 and PTI5 of PAMP-triggered immunity (PTI), UDP and UDP1 of effector-triggered immunity (ETI), Hin1 and HSR203J of HR, PR1a of systemic acquired resistance (SAR) and the SAR related gene NPR1 were all up-regulated in transgenic tomato leaves overexpressing BvEP. In addition, it was found that transient overexpression of BvEP reduced the rotting rate and lesion diameter of tomato fruits caused by B. cinerea, and increased the expression of PTI, ETI, SAR-related genes, ROS content, SOD and POD activities in tomato fruits, while there was no significant effect on the weight loss and TSS, TA and Vc contents of tomato fruits. This study provides new insights into innovative breeding of tomato disease resistance and has great significance for loss reduction and income enhancement in the tomato industry.
Breakdown in Nonlinear Regression

Abstract The breakdown point is considered an important measure of the robustness of a linear regression estimator. This article addresses the concept of breakdown in nonlinear regression. Because it is not invariant to nonlinear reparameterization, the usual definition of the breakdown point in linear regression is inadequate for nonlinear regression. The original definition of breakdown due to Hampel is more suitable for nonlinear problems but may indicate breakdown when the fitted values change very little. We introduce breakdown functions, which measure breakdown of the fitted values. Using the breakdown functions, we introduce a new definition of the breakdown point. For the linear regression model, our definition of the breakdown point coincides with the usual definition for linear regression as well as with Hampel's definition. For most nonlinear regression functions, we show that the breakdown point of the least squares estimator is 1/n. We prove that for a large class of unbounded regression func.
Targeting glycolysis in non-small cell lung cancer: Promises and challenges

Metabolic disturbance, particularly of glucose metabolism, is a hallmark of tumors such as non-small cell lung cancer (NSCLC). Cancer cells tend to reprogram a majority of glucose metabolism reactions into glycolysis, even in oxygen-rich environments. Although glycolysis is not an efficient means of ATP production compared to oxidative phosphorylation, the inhibition of tumor glycolysis directly impedes cell survival and growth. This review focuses on research advances in glycolysis in NSCLC and systematically provides an overview of the key enzymes, biomarkers, non-coding RNAs, and signaling pathways that modulate the glycolysis process and, consequently, tumor growth and metastasis in NSCLC. Current medications, therapeutic approaches, and natural products that affect glycolysis in NSCLC are also summarized. We found that the identification of appropriate targets and biomarkers in glycolysis, specifically for NSCLC treatment, is still a challenge at present. However, LDHB, PDK1, MCT2, GLUT1, and PFKM might be promising targets in the treatment of NSCLC or its specific subtypes, and DPPA4, NQO1, GAPDH/MT-CO1, PGC-1α, OTUB2, ISLR, Barx2, OTUB2, and RFP180 might be prognostic predictors of NSCLC. In addition, natural products may serve as promising therapeutic approaches targeting multiple steps in glycolysis metabolism, since natural products always present multi-target properties. The development of metabolic intervention that targets glycolysis, alone or in combination with current therapy, is a potential therapeutic approach in NSCLC treatment. The aim of this review is to describe research patterns and interests concerning the metabolic treatment of NSCLC.
Analysis of the key ligand receptor CADM1_CADM1 in the regulation of thyroid cancer based on scRNA-seq and bulk RNA-seq data

Introduction Advanced papillary thyroid cancer (PTC) has a poor prognosis, 60~70% of which become radio iodine refractory (RAI-R), but the molecular markers that assess PTC progress to advanced PTC remain unclear. Meanwhile, current targeted therapies are badly effective due to drug resistance and adverse side effects. Ligand-receptor pairs (L/R pairs) play an important role in the interactions between tumor cells and other cells in the tumor microenvironment (TME). Nowadays, therapies targeting ligand-receptor pairs in the TME are advancing rapidly in the treatment of advanced cancers. However, therapies targeting L/R pairs applied to advanced PTC remains challenging because of limited knowledge about L/R pairs in PTC. Methods We screened the critical L/R pair: CADM1-CADM1 using 65311 single-cell RNA sequencing (scRNA-seq) samples from 7 patients in different stage of PTC and bulk RNA-seq datasets containing data from 487 tumor samples and 58 para-carcinoma samples. Moreover, the expression levels of CADM1-CADM1 was assessed by quantitative real time polymerase chain reaction (qRT-PCR) and the function was analyzed using Transwell immigration assay. Results We found that CADM1_CADM1 could be regarded as a biomarker representing a good prognosis of PTC. In addition, the high expression of CADM1_CADM1 can strongly increase the sensitivity of many targeted drugs, which can alleviate drug resistance. And the results of qRT-PCR showed us that the expression of CADM1_CADM1 in PTC was down-regulated and overexpression of CADM1 could suppresses tumor cell invasion migration. Conclusion Our study identified that CADM1_CADM1 played an essential role in the progression of PTC for the first time and our findings provide a new potential prognostic and therapeutic ligand-receptor pair for advanced PTC.
Voltage tunable polymer laser device

Since organic laser materials offer broad optical gain spectra they are predestined for the realization of widely tunable laser sources. Here we report on a compact organic laser device that allows for voltage controlled continuously wavelength tuning in the visible range of the spectrum by external deformation. The device consists of an elastomeric distributed feedback (DFB) laser and an electro-active elastomer actuator also known as artificial muscle. Second order DFB lasing is realized by a grating line structured elastomer substrate covered with a thin layer of dye doped polymer. To enable wavelength tuning the elastomer laser is placed at the center of the electro-active elastomer actuator. Chosen design of the actuator gives rise to homogeneous compression at this position. The voltage induced deformation of the artificial muscle is transferred to the elastomer laser and results in a decrease of grating period. This leads to an emission wavelength shift of the elastomer laser. The increase of actuation voltage to 3.25 kV decreased the emission wavelength from 604 nm to 557 nm, a change of 47 nm or 7.8%.
Factorization Homology as a Fully Extended Topological Field Theory

Given an En-algebra A we explicitly construct a fully extended n-dimensional topological field theory which is essentially given by factorization homology. Under the cobordism hypothesis, this is the fully extended n-TFT corresponding to the En-algebra A, considered as an object in a suitable Morita-p8, nq-category Algn. We first give a precise definition of a fully extended n-dimensional topological field theory using complete n-fold Segal spaces as a model for p8, nq-categories. This involves developing an n-fold Segal space Bordn of n-dimensional bordisms and endowing it with a symmetric monoidal structure. Exploiting the equivalence between En-algebras and locally constant factorization algebras proven by Lurie we use locally constant factorization algebras on stratified spaces to construct an p8, nq-category with En-algebras as objects, (pointed) bimodules as 1morphisms, (pointed) bimodules between bimodules as 2-morphisms, etc. and endow it with a symmetric monoidal structure. Finally, given an En-algebra we construct a morphism of n-fold Segal spaces from Bordn to Algn given by a suitable pushforward of the factorization algebra obtained by taking factorization homology. We show that this map respects the symmetric monoidal structure and thus is a fully extended n-TFT.