Miracle-dz/UniFAR-FTUs huggingface dataset:
Hexokinase 2 is a transcriptional target and a positive modulator of AHR signalling

Abstract The aryl hydrocarbon receptor (AHR) regulates the expression of numerous genes in response to activation by agonists including xenobiotics. Although it is well appreciated that environmental signals and cell intrinsic features may modulate this transcriptional response, how it is mechanistically achieved remains poorly understood. We show that hexokinase 2 (HK2) a metabolic enzyme fuelling cancer cell growth, is a transcriptional target of AHR as well as a modulator of its activity. Expression of HK2 is positively regulated by AHR upon exposure to agonists both in human cells and in mice lung tissues. Conversely, over-expression of HK2 regulates the abundance of many proteins involved in the regulation of AHR signalling and these changes are linked with altered AHR expression levels and transcriptional activity. HK2 expression also shows a negative correlation with AHR promoter methylation in tumours, and these tumours with high HK2 expression and low AHR methylation are associated with a worse overall survival in patients. In sum, our study provides novel insights into how AHR signalling is regulated which may help our understanding of the context-specific effects of this pathway and may have implications in cancer.
Comments on COVID-19 Vaccination and Exacerbation of Idiopathic Pulmonary Fibrosis

We read with great interest the research article by Sgalla and colleagues (1) regarding the coronavirus disease (COVID-19) vaccine and acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). We appreciate the authors’ valuable contribution to understanding that COVID-19 vaccination may act as a potential trigger of AE-IPF. However, there are still concerns worth further discussion. First, this study involved a total of 26 patients diagnosed with IPF. However, the small number of cases in this study may lead to a series of biases and not be able to reveal the influence of the COVID-19 vaccine on patients with IPF. Hence, more patients are suggested to be involved to have a solid research result. Second, this study categorized the patients into two groups: “triggered” and “idiopathic” AE-IPF. However, according to the protocol, the two groups of cases were not well matched. For example, patients with idiopathic AE-IPF had a higher CRP (C-reactive protein). The higher use of long-term oxygen therapy rate may be associated with an increased mortality rate. Therefore, the two groups of cases should be matched to reduce bias. Third, previous studies showed that patients with interstitial lung disease had a higher prevalence of other autoimmune diseases, such as rheumatoid arthritis and progressive systemic sclerosis (2–4). However, they also had similar phenotypes of usual interstitial pneumonia. Glucocorticoids are best suited for the initial management or treatment of acute exacerbations while transitioning to other therapies with more favorable long-term safety profiles. It is possible that vaccine-associated acute exacerbation is characterized by better steroid responsiveness, and some patients might have both IPF and subclinical autoimmune diseases. Before we generalize the results of this trial to all patients with IPF, we recommend a post hoc analysis of baseline immune profiles, such as RF (rheumatoid factor), ACPA (anti-cyclic citrullinated peptide antibodies), ANA (antinuclear antibody), and ENA (extractable nuclear antigen antibody). Above all, this study contributes to understanding that COVID-19 vaccination may act as a potential trigger of AE-IPF. Further studies are suggested to involve more patients in the study, match the study groups, and conduct a post hoc analysis. Author disclosures are available with the text of this letter at www.atsjournals. org.
The tomato cytochrome P450 CYP712G1 catalyses the double oxidation of orobanchol en route to the rhizosphere signalling strigolactone, solanacol

Summary Strigolactones (SLs) are rhizosphere signalling molecules and phytohormones. The biosynthetic pathway of SLs in tomato has been partially elucidated, but the structural diversity in tomato SLs predicts that additional biosynthetic steps are required. Here, root RNA‐seq data and co‐expression analysis were used for SL biosynthetic gene discovery. This strategy resulted in a candidate gene list containing several cytochrome P450s. Heterologous expression in Nicotiana benthamiana and yeast showed that one of these, CYP712G1, can catalyse the double oxidation of orobanchol, resulting in the formation of three didehydro‐orobanchol (DDH) isomers. Virus‐induced gene silencing and heterologous expression in yeast showed that one of these DDH isomers is converted to solanacol, one of the most abundant SLs in tomato root exudate. Protein modelling and substrate docking analysis suggest that hydroxy‐orbanchol is the likely intermediate in the conversion from orobanchol to the DDH isomers. Phylogenetic analysis demonstrated the occurrence of CYP712G1 homologues in the Eudicots only, which fits with the reports on DDH isomers in that clade. Protein modelling and orobanchol docking of the putative tobacco CYP712G1 homologue suggest that it can convert orobanchol to similar DDH isomers as tomato.
Deletion of Tgfβ signal in activated microglia prolongs hypoxia‐induced retinal neovascularization enhancing Igf1 expression and retinal leukostasis

Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it is known that retinal microglia contribute to both physiological and pathological angiogenesis, the molecular mechanisms by which these glia regulate pathological NV have not been fully elucidated. In this study, we utilized a retinal microglia‐specific Transforming Growth Factor‐β (Tgfβ) receptor knock out mouse model and human iPSC‐derived microglia to examine the role of Tgfβ signaling in activated microglia during retinal NV. Using a tamoxifen‐inducible, microglia‐specific Tgfβ receptor type 2 (Tgfβr2) knockout mouse [Tgfβr2 KO (ΔMG)] we show that Tgfβ signaling in microglia actively represses leukostasis in retinal vessels. Furthermore, we show that Tgfβ signaling represses expression of the pro‐angiogenic factor, Insulin‐like growth factor 1 (Igf1), independent of Vegf regulation. Using the mouse model of oxygen‐induced retinopathy (OIR) we show that Tgfβ signaling in activated microglia plays a role in hypoxia‐induced NV where a loss in Tgfβ signaling microglia exacerbates and prolongs retinal NV in OIR. Using human iPSC‐derived microglia cells in an in vitro assay, we validate the role of Transforming Growth Factor‐β1 (Tgfβ1) in regulating Igf1 expression in hypoxic conditions. Finally, we show that Tgfβ signaling in microglia is essential for microglial homeostasis and that the disruption of Tgfβ signaling in microglia exacerbates retinal NV in OIR by promoting leukostasis and Igf1 expression.
Fertility outcomes after treatment with intraperitoneal chemotherapy

Abstract Intraperitoneal chemotherapy (IPC) administration has been added to the therapeutic protocols of cancers, confined to the abdominal cavity. Since, a survival benefit in patients treated with adjuvant IPC has been demonstrated, fertility questions are raised in these patients. A comprehensive search of the English literature of PubMed/MEDLINE, EmBase and Google Scholar databases was conducted, from their inception until April 2021, following the MOOSE guidelines. Twelve out of 473 studies were included in the final review and analysis. After treatment with IPC for peritoneal carcinomatosis, 19 women, who underwent fertility-sparing surgery, with 20 successful pregnancies were reported. The mean interval time between IPC and pregnancy was 38.4 months (range 9–168 months). In 16 cases, conception was spontaneous, three required in vitro fertilisation, whereas one pregnancy was achieved through intrauterine insemination. Mean disease-free survival was 76 months (range 24–177 months). Childbearing is a feasible approach in selected patients, after treatment with IPC. When future pregnancy is desirable, a multidisciplinary team of surgeons, gynaecologists, oncologists and reproductive specialists is required, to inform the patient thoroughly about the fertility preservation alternatives, without endangering patient’s survival.
Diabetes regulated anti-inflammatory lncRNA is overexpressed in triple-negative breast cancer and predicts chemoresistance and tumor recurrence

ABSTRACT Diabetes regulated anti-inflammatory lncRNA (DRAIR) has been characterized as a critical player in type 2 diabetes mellitus. However, its role in other human diseases is unclear. Our preliminary sequencing analysis revealed an altered DRAIR level in triple-negative breast cancer (TNBC). We then explored the involvement of DRAIR in TNBC. In this study, plasma was collected from healthy controls (n = 60) and TNBC patients (n = 60). Non-tumor tissues and paired TNBC were also collected from TNBC patients. All TNBC patients received surgical resection of the primary tumors and chemotherapy. The 60 TNBC patients were divided into high and low plasma DRAIR level groups with median plasma DRAIR level as the cutoff value, and the occurrence of chemoresistance after treatment and tumor recurrence during a 5-year follow-up was monitored. Cell proliferation and viability were analyzed with BrdU assay and MTT assay, respectively. We found that plasma DRAIR levels were higher in TNBC patients than in controls. In addition, DRAIR expression in TNBC tissues was also significantly increased in TNBC tissues compared to the paired non-tumor tissues. Plasma DRAIR was positively and significantly related to DRAIR levels in TNBC tissues but not in non-tumor tissues. Patients in the high plasma DRAIR level group showed a significantly higher rate of chemoresistance after treatment and tumor recurrence during the follow-up. DRAIR promoted tumor cell proliferation and increased cell viability under doxorubicin treatment. Therefore, DRAIR is overexpressed in TNBC and predicts chemoresistance and tumor recurrence. Graphical abstract
Mapping Korean National Health Insurance Pharmaceutical Claim Codes to SNOMED CT

The objective of this study was to map pharmaceutical claim codes to SNOMED CT and thereby facilitate multicenter collaborative research and improve semantic interoperability. The claim codes were mapped to SNOMED CT using rule-based automated and manual methods. The maps were internally validated by terminologists and a pharmacist. Finally, 80% of all claim codes were mapped to the concepts of Pharmaceutical/biologic product hierarchy in SNOMED CT. Of them, 50.6% of the codes were exactly mapped to one clinical drug branch concept.
Improved PSO Algorithm based Optimal Operation in Power Systems Integrating Solar and Wind Energy Sources

This paper proposes an improved particle swarm optimization (PSO) algorithm for optimal operation of a power system including the solar and wind energy sources. The algorithm is to minimize operating costs of the hybrid power system. The proposed PSO algorithm is one of the standard PSO algorithm variants, which modifies the acceleration coefficients of the cognitive and social components in the velocity update equation of the PSO algorithm as linear time-varying parameters. The acceleration coefficients are varied during the evolution process of the PSO algorithm to improve the global search capability of particles in the early stage of the optimization process and direct the global optima at the end stage. Additionally, the inertia weight which is considered as a trade-off factor for the local and global search abilities of the PSO algorithm is also linearly decreased instead of a fixed constant value to improve its performance. The improved PSO algorithm based optimal operation of the hybrid power system with and without solar and wind powers is considered on a standard IEEE 30-bus 6-generator 41transmission line test power system. The numerical results demonstrate the capabilities of the proposed algorithm to generate optimal solutions of a hybrid power system considering the solar and wind energy resources. The comparison with the standard PSO algorithm demonstrates the superiority of the proposed algorithm and confirms its potential to optimize the operating costs of the hybrid power system.
BAY-885, a mitogen-activated protein kinase kinase 5 inhibitor, induces apoptosis by regulating the endoplasmic reticulum stress/Mcl-1/Bim pathway in breast cancer cells

ABSTRACT The mitogen-activated protein kinase kinase 5 (MEK5)/extracellular signal-regulated kinase 5 (ERK5) axis has been reported to promote tumorigenesis in breast cancer (BC). Therefore, targeting the MEK5/ERK5 axis is a potential strategy against BC. BAY-885 is a novel inhibitor of ERK5; however, to date, its anti-tumor effects in BC have not been investigated. This study aimed to assess the anti-tumor effects of BAY-885 in BC and identify its underlying mechanisms of action. Unlike other ERK5 inhibitors, which frequently failed to mimic ERK5 genetic ablation phenotypes, the BAY-885 treatment effectively recapitulated ERK5 depletion effects in BC cells. Results revealed that BAY-885 affected the viability and induced apoptosis in BC cells. Moreover, the BAY-885-mediated downregulation of myeloid cell leukemia-1 (Mcl-1) and upregulation of Bim were dependent on ERK5 inhibition. Furthermore, BAY-885 triggered activation of endoplasmic reticulum (ER) stress, which further led to the upregulation of Bim and downregulation of Mcl-1. ER stress was induced in an ERK5 inhibition-dependent manner. These findings suggested that BAY-885 induced apoptosis in BC cells via ER stress/Mcl-1/Bim axis, suggesting that BAY-885 may serve as a therapeutic agent for BC. GRAPHICAL ABSTRACT
OrthoQuantum: visualizing evolutionary repertoire of eukaryotic proteins

Abstract Extensive amounts of data from next-generation sequencing and omics studies have led to the accumulation of information that provides insight into the evolutionary landscape of related proteins. Here, we present OrthoQuantum, a web server that allows for time-efficient analysis and visualization of phylogenetic profiles of any set of eukaryotic proteins. It is a simple-to-use tool capable of searching large input sets of proteins. Using data from open source databases of orthologous sequences in a wide range of taxonomic groups, it enables users to assess coupled evolutionary patterns and helps define lineage-specific innovations. The web interface allows to perform queries with gene names and UniProt identifiers in different phylogenetic clades and supplement presence with an additional BLAST search. The conservation patterns of proteins are coded as binary vectors, i.e., strings that encode the presence or absence of orthologous proteins in other genomes. These strings are used to calculate top-scoring correlation pairs needed for finding co-inherited proteins which are simultaneously present or simultaneously absent in specific lineages. Profiles are visualized in combination with phylogenetic trees in a JavaScript-based interface. The OrthoQuantum v1.0 web server is freely available at http://orthoq.bioinf. fbb.msu. ru along with documentation and tutorial.
Contribution of Biological Age–Predictive Biomarkers to Nutrition Research: A Systematic Review of the Current Evidence and Implications for Future Research and Clinical Practice

ABSTRACT The global population is living longer; however, not everyone ages at the same rate with regard to their physical and cognitive abilities and their vulnerability to certain diseases and death. This review aimed to synthesize the contribution of biological age–predictive biomarkers to nutrition research and highlight the implications for future research and clinical practice. MEDLINE, CINAHL, and Cochrane CENTRAL were systematically searched on 30 September 2021 for randomized controlled trials and cross-sectional studies examining the association between nutrition and biological age in older adults reporting on genetic, clinical, or molecular biomarkers of biological aging. Cochrane's ROB 2 and ROBINS-I were used to assess the quality of included studies. Synthesis was undertaken narratively. Of 1245 records identified from the search, 13 studies from 8 countries and territories, involving 5043 participants, were included. Seven studies assessed associations between nutrient food intake and telomere attrition, reporting protective effects for branched-chain amino acids, calcium and vitamin D, and a diet of a lower inflammatory index; whereas they found shorter telomeres in people consuming more processed foods and arachidonic acid and other proinflammatory compounds. Five studies examined the associations between plasma nutrition biomarkers and cognitive function, and found a protective effect for HDL cholesterol, lycopene, carotenoids, ω-3 and ω-6 fatty acids, and vitamins B, C, D, and E; whereas trans fatty acids and fibrinogen correlated with a decline in cognitive function. One study used Horvath's clock and reported the epigenetic rejuvenation effect of a Mediterranean diet. In conclusion, biological aging was negatively associated with an anti-inflammatory diet. However, a few studies did not control for the confounding effect of other lifestyle factors. Future research should address this and also assess the synergistic effect of different nutrients, their combinations, and evaluate their dose–response relations. Nutrition practice can incorporate updated screening procedures for older people that include relevant biological aging nutrition markers, leading to anti-aging precision nutrition therapy. The methodology of this systematic review was registered in PROSPERO (CRD42021288122).
Research on the Harmonic in High-speed Railway Traction Power Supply System and Its Transmission Characteristic

With the development towards high-speed,high-capacity,high-density cyberization of high-speed railway,harmonics amplification and resonance problems of traction network caused by high-speed locomotive are getting more serious.In order to study the harmonic transmission characteristic of the traction network,Matlab/Simulink software was used to build the united model of electric multiple unit(EMU) locomotive and traction network.The correctness of this model was verified by the simulation of various power in different conditions.Based on this model,this paper analyzed the transmission characteristic of the harmonic currents under three conditions which include fixed locomotive position,different locomotive positions and different lengths of traction lines.Simulation results show that this united model is more practical than consist current model and consist power model.The research sheds light on reducing and avoiding the harm of traction resonance.
Using measures of reading time regularity (RTR) to quantify eye movement dynamics, and how they are shaped by linguistic information

In this article, we present the concept of reading time regularity (RTR) as a measure to capture reading process dynamics. The first study is concerned with examining one of the assumptions of RTR, namely, that process measures of reading, such as eye movement fluctuations and fixation durations, exhibit higher regularity when contingent on sequentially structured information, such as texts. To test this, eye movements of 26 German native speakers were recorded during reading-unrelated and reading-related tasks. To analyze the data, we used recurrence quantification analysis and sample entropy analysis to quantify the degree of temporal structure in time series of gaze steps and fixation durations. The results showed that eye movements become more regular in reading compared to nonreading conditions. These effects were most prominent when calculated on the basis of gaze step data. In a second study, eye movements of 27 native speakers of German were recorded for five conditions with increasing linguistic information. The results replicate the findings of the first study, verifying that these effects are not due to mere differences in task instructions between conditions. Implications for the concept of RTR and for future studies using these metrics in reading research are discussed.
Hyperuricemia Associated with Low Skeletal Muscle in the Middle-Aged and Elderly Population in China.

BACKGROUND Previous studies have presented inconsistent results on the relationship between serum uric acid and skeletal muscle mass (SMM). We aimed to explore whether a higher serum uric acid level was associated with low SMM in the Chinese population. METHODS We performed a cross-sectional analysis of 6595 subjects aged 45 years or older. They were tested for fasting blood glucose, total cholesterol, triglycerides, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, uric acid, blood urea nitrogen, creatinine, and estimated glomerular filtration rate. SMM was accessed by dual-energy x-ray absorptiometry using two approaches: weight-adjusted appendicular skeletal muscle mass (ASM)% and ASM/BMI (body mass index (kg/m2)). Low SMM was defined as a cut-off point of ASM/BMI<0.789 for men and<0.512 for women. RESULTS Compared with their normal group, patients with hyperuricemia had lower ASM% (29.33±2.33 vs 30.03±2.34 for males and 24.71±1.99 vs 25.19±2.07 for females, P<0.01) and ASM/BMI (0.83±0.10 vs 0.85±0.10 for male and 0.60±0.07 vs 0.62±0.07 for female), with a higher prevalence of the associated low SMM in both sexes (35.2 vs 26.5% for male and 10.5 vs 5.9% for female, P<0.01). Pearson analysis showed that ASM% and ASM/BMI were negatively correlated with SUA (male: ASM/BMI, r=-0.097, ASM%, r=-0.146; female: ASM/BMI, r=-0.151, ASM%, r=-0.157; all P<0.001). Logistic regression analysis showed a positive association of hyperuricemia with adjusted risk of low SMM association. CONCLUSIONS In a middle-aged and elderly Chinese population, hyperuricemia is independently and positively associated with low SMM and can vary by age and gender.
CB-Dock2: improved protein–ligand blind docking by integrating cavity detection, docking and homologous template fitting

Abstract Protein-ligand blind docking is a powerful method for exploring the binding sites of receptors and the corresponding binding poses of ligands. It has seen wide applications in pharmaceutical and biological researches. Previously, we proposed a blind docking server, CB-Dock, which has been under heavy use (over 200 submissions per day) by researchers worldwide since 2019. Here, we substantially improved the docking method by combining CB-Dock with our template-based docking engine to enhance the accuracy in binding site identification and binding pose prediction. In the benchmark tests, it yielded the success rate of ∼85% for binding pose prediction (RMSD < 2.0 Å), which outperformed original CB-Dock and most popular blind docking tools. This updated docking server, named CB-Dock2, reconfigured the input and output web interfaces, together with a highly automatic docking pipeline, making it a particularly efficient and easy-to-use tool for the bioinformatics and cheminformatics communities. The web server is freely available at https://cadd.labshare. cn/cb-dock2/.