String Network Research Articles

Proteomic profiles of Leptospira borgpetersenii serovar Hardjo strains JB197 and HB203 cultured at different temperatures

Leptospirosis is a global zoonotic disease affecting humans, domestic, and wild animals. Leptospira are typically shed in the urine of reservoir hosts which persist in suitable environments where incidental host transmission occurs after direct contact with infected urine or contaminated environments. Interestingly, serologically identical L. borgpetersenii serovar Hardjo strains JB197 and HB203 show divergent disease severity in the hamster model; JB197 causes severe acute infection while HB203 causes persistent chronic infection. Historically, serovar Hardjo was limited to culture at 29 °C, but utilization of HAN media allows propagation from host tissues at 37 °C. Here, the proteome of strains JB197 and HB203 were characterized after culture from experimentally challenged hamsters at 29 °C and 37 °C. Comparative analyses of JB197 and HB203 samples cultured at 29 °C yielded 425 significantly differentially expressed (DE) proteins, while strains at 37 °C yielded 613 DE proteins including prominent outer membrane proteins and known virulence factors. In agreement, membrane protein GO terms were identified by STRING network analyses along with numerous metabolic KEGG pathways consistent with condition differences. Within strain, JB197 cultured at 29 °C vs 37 °C identified 529 DE proteins, while HB203 identified 524 DE proteins. Investigating differential protein profiles provide insights into strain specific behaviors with implications for better understanding host-pathogen interactions, disease transmission, and response to environmental conditions which can contribute to vaccine development, diagnostic improvement, and ultimately leptospirosis control. SignificanceLeptospirosis is a devastating zoonotic disease affecting humans, wild and domestic animals around the globe. Different species and serovars of Leptospira can affect various animal host species differently; for instance, a serovar that is asymptomatic in the rat may cause severe disease in a dog or human. These differences in host response are not only found at the species and serovar level for Leptospira, but also at the strain level. A prime example comes from strains JB197 and HB203, both species L. borgpetersenii, both serovar Hardjo. Interestingly, JB197 causes a severe acute infection in the hamster while HB203 causes an asymptomatic chronic infection. Understanding these unique relationships between pathogen and host species is important, especially in the context of prevention technologies such as vaccine design, where the strain of Leptospira used as a bacterin might have different efficiencies in different hosts. In this study, proteomic profiles of strains JB197 and HB203 were analyzed, and results revealed diverse protein expression profiles of outer membrane proteins, as well as proteins functioning in motility and growth.

Exploring Potentilla nepalensis Phytoconstituents: Integrated Strategies of Network Pharmacology, Molecular Docking, Dynamic Simulations, and MMGBSA Analysis for Cancer Therapeutic Targets Discovery.

Potentilla nepalensis belongs to the Rosaceae family and has numerous therapeutic applications as potent plant-based medicine. Forty phytoconstituents (PCs) from the root and stem through n-hexane (NR and NS) and methanolic (MR and MS) extracts were identified in earlier studies. However, the PCs affecting human genes and their roles in the body have not previously been disclosed. In this study, we employed network pharmacology, molecular docking, molecular dynamics simulations (MDSs), and MMGBSA methodologies. The SMILES format of PCs from the PubChem was used as input to DIGEP-Pred, with 764 identified as the inducing genes. Their enrichment studies have shown inducing genes' gene ontology descriptions, involved pathways, associated diseases, and drugs. PPI networks constructed in String DB and network topological analyzing parameters performed in Cytoscape v3.10 revealed three therapeutic targets: TP53 from MS-, NR-, and NS-induced genes; HSPCB and Nf-kB1 from MR-induced genes. From 40 PCs, two PCs, 1b (MR) and 2a (MS), showed better binding scores (kcal/mol) with p53 protein of -8.6 and -8.0, and three PCs, 3a, (NR) 4a, and 4c (NS), with HSP protein of -9.6, -8.7, and -8.2. MDS and MMGBSA revealed these complexes are stable without higher deviations with better free energy values. Therapeutic targets identified in this study have a prominent role in numerous cancers. Thus, further investigations such as in vivo and in vitro studies should be carried out to find the molecular functions and interlaying mechanism of the identified therapeutic targets on numerous cancer cell lines in considering the PCs of P. nepalensis.

Gravitational waves from metastable cosmic strings in the Pati-Salam model in light of new pulsar timing array data

A series of pulsar timing arrays (PTAs) recently observed gravitational waves at the nanohertz frequencies. Motivated by this remarkable result, we present a novel class of Pati-Salam models that give rise to a network of metastable cosmic strings, offering a plausible explanation for the observed PTA data. Additionally, we introduce a hybrid inflationary scenario to eliminate magnetic monopoles that arise during the subsequent phase transitions from the Pati-Salam symmetry to the Standard Model gauge group. The resulting scalar spectral index is compatible with Planck data, and the tensor-to-scalar ratio is anticipated to be extremely small. Moreover, we incorporate a nonthermal leptogenesis to generate the required baryon asymmetry in our framework. Finally, the gravitational wave spectra generated by the metastable cosmic strings not only correspond to signals observed in recent PTAs, including NANOGrav, but are also within the exploration capacity of both present and future ground- and space-based experiments. Published by the American Physical Society 2024

Comprehensive analysis of autophagy associated genes and immune infiltrates in cervical cancer.

Cervical cancer (CC) is the most common gynecological malignant tumor and the fourth leading cause of cancer-related death in women. The progression of CC is significantly affected by autophagy. Our objective was to use bioinformatics analysis to explore the expression, prognostic significance, and immune infiltration of autophagy-related genes in CC. We identified a set of autophagy-related differentially expressed genes (ARDEGs) from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. ARDEGs were further validated by The Human Protein Atlas (HPA), GSE52903, and GSE39001 dataset. Hub genes were found by the STRING network and Cytoscape. We performed Gene Set Enrichment Analysis (GSEA), Gene ontology analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and immune infiltration analysis to further understand the functions of the hub genes. Kaplan-Meier (K-M) and receiver operating characteristic (ROC) were used to check the hub genes. A total of 10 up-regulated (CXCR4, BAX, SPHK1, EIF2AK2, TBK1, TNFSF10, ITGB4, CDKN2A, IL24, and BIRC5) and 19 down-regulated (PINK1, ATG16L2, ATG4D, IKBKE, MLST8, MAPK3, ERBB2, ULK3, TP53INP2, MTMR14, BNIP3, FOS, CCL2, FAS, CAPNS1, HSPB8, PTK6, FKBP1B , and DNAJB1) ARDEGs were identified. The ARDEGs were enriched in cell growth, apoptosis, human papillomavirus infection, and cytokine-mediated. Then, we found that low expression of MAPK3 was associated with poor prognosis in CC patients and was significantly enriched in immune pathways. In addition, the expression of MAPK3 was significantly positively correlated with the infiltration levels of macrophages, B cells, mast cell activation, and cancer-associated fibroblasts. Furthermore, MAPK3 was positively correlated with LGALS9, and negatively correlated with CTLA4 and CD40. Our results show that MAPK3 can be used as a new prognostic biomarker to predict the prognosis of patients with CC.

Probing stochastic gravitational wave background from SU(5) × U(1)χ strings in light of NANOGrav 15-year data

A realistic model of SU(5) × U(1)χ, embedded in SO(10) supersymmetric grand unified theory, is investigated for the emergence of a metastable cosmic string network. This network eventually decays via the Schwinger production of monopole-antimonopole pairs, subsequently generating a stochastic gravitational wave background that is compatible with the NANOGrav 15-year data. In order to avoid the monopole problem in the breaking of both SO(10) and SU(5), a non-minimal Higgs inflation scenario is incorporated. The radiative breaking of the U(1)χ symmetry at a slightly lower scale plays a pivotal role in aligning the string tension parameter with the observable range. The resultant gravitational wave spectrum not only accounts for the signal observed in the most recent pulsar timing array (PTA) experiments but is also accessible to both current and future ground-based and space-based experiments.

Cosmic string gravitational waves from global U(1)B−L symmetry breaking as a probe of the type I seesaw scale

In type I seesaw models, the right-handed neutrinos are typically super-heavy, consistent with the generation of baryon asymmetry via standard leptogenesis. Primordial gravitational waves of cosmological origin provides a new window to probe such high scale physics, which would otherwise be inaccessible. By considering a global U(1)B−L extension of the type I seesaw model, we explore the connection between the heaviest right-handed neutrino mass and primordial gravitational waves arising from the dynamics of global cosmic string network. As a concrete example, we study a global U(1)B−L extension of the Littlest Seesaw model, and show that the inevitable GW signals, if detectable, probe the parameter space that can accommodate neutrino oscillation data and successful leptogenesis, while respecting theoretical constraints like perturbativity of the theory. Including CMB constraints from polarization and dark radiation leaves a large region of parameter space of the model, including the best fit regions, which can be probed by GW detectors like LISA and ET in the near future. In general, the GW detectors can test high scale type I seesaw models with the heaviest right-handed neutrino mass above 2.5 × 1014 GeV, assuming the perturbativity, and 7 × 1013 GeV assuming that the coupling between the heaviest right-handed neutrino and the U(1)B−L breaking scalar is less than unity.

Probing the gravitational wave background from cosmic strings with the alternative LISA-TAIJI network

As one of the detection targets of all gravitational wave detectors today, the stochastic gravitational wave background (SGWB) provides an important means of understanding the evolution of our universe. In this paper, we explore the feasibility of detecting the SGWB generated by the loops arising throughout the cosmological evolution of the cosmic string network, using both individual space detectors (LISA and TAIJI) and joint space detectors (LISA-TAIJI). For the joint detectors, we choose three different configurations of TAIJI, namely TAIJIm, TAIJIp, and TAIJIc, to form the LISA-TAIJI networks, and we investigate their ability to detect the SGWB. By comparing the power-law sensitivity (PLS) curves of individual space detectors and joint detectors with the energy density spectrum of SGWB, we find that LISA-TAIJIc has the best sensitivity for detecting the SGWB from cosmic string loops. It thus holds promise for further constraining the tension of cosmic strings Gμ=O(10-17)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$G\\mu =O(10^{-17})$$\\end{document}.

Metastable cosmic strings

Many symmetry breaking patterns in grand unified theories (GUTs) give rise to cosmic strings that eventually decay when pairs of GUT monopoles spontaneously nucleate along the string cores. These strings are known as metastable cosmic strings and have intriguing implications for particle physics and cosmology. In this article, we discuss the current status of metastable cosmic strings, with a focus on possible GUT embeddings and connections to inflation, neutrinos, and gravitational waves (GWs). The GW signal emitted by a network of metastable cosmic strings in the early universe differs, in particular, from the signal emitted by topologically stable strings by a suppression at low frequencies. Therefore, if the underlying symmetry breaking scale is close to the GUT scale, the resulting GW spectrum can be accessible at current ground-based interferometers as well as at future space-based interferometers, such as LISA, and at the same time account for the signal in the most recent pulsar timing data sets. Metastable cosmic strings thus nourish the hope that future GW observations might shed light on fundamental physics close to the GUT scale.

Exploring the material basis and mechanism of action of clinacanthus nutans in treating renal cell carcinoma based on metabolomics and network pharmacology.

Clinacanthus nutans (for abbreviation thereafter) is often used as medicine in the form of fresh juice in the folk to treat many kinds of cancers, including renal cell carcinoma (RCC). It is speculated that its active ingredient may have heat sensitivity, but there are currently no reports on this aspect. Therefore, based on the folk application for fresh juice of C nutans, this study used metabonomics and network pharmacology to explore the material basis and mechanism of action of C nutans against RCC. Firstly, untargeted metabolomics profiling was performed by Liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry to screen the metabolites down-regulated by heat in the extract of C nutans. Secondly, we collected the targets of metabolites in the Swiss Target Prediction platform. In addition, the targets of RCC were obtained in the GeneCards database. The "component-target-disease" network was established by Cytoscape3.9.0 software. Then we constructed a protein-protein interaction network in the STRING network platform to screen core targets. The gene ontology and kyoto encyclopedia of genes and genomes enrichment analysis of core targets were carried out to predict the relevant pathway of C nutans in the treatment of RCC. Finally, the molecular docking verification of the core targets were carried out. In this study, 35 potential active ingredients and 125 potential targets were obtained. And the core targets were Cellular tumor antigen p53, Signal transducer and activator of transcription 3, and so on. Then, 48 biological processes, 30 cell components, and 36 molecular functions were obtained by gene ontology enrichment analysis. Besides, 44 pathways were obtained by Kyoto encyclopedia of genes and genomes enrichment analysis, including Pathway in cancer, PI3K-Akt signal pathway, P53 signal pathway, and so on. The docking model between the core target and its corresponding components was stable. This research is based on the folk application of C nutans, showed its potential active ingredients by metabonomics, and predicted the potential mechanism of C nutans in the treatment of RCC by network pharmacology. It provides new references for follow-up research and new drug development.

PFOS-induced dyslipidemia and impaired cholinergic neurotransmission in developing zebrafish: Insight into its mechanisms

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant that has been widely detected in the environment and is known to accumulate in organisms, including humans. The study investigated dose-dependent mortality, hatching rates, malformations, lipid accumulation, lipid metabolism alterations, and impacts on cholinergic neurotransmission. Increasing PFOS concentration led to higher mortality, hindered hatching, and caused concentration-dependent malformations, indicating severe abnormalities in developing zebrafish. The results also demonstrated that PFOS exposure led to a significant increase in total lipids, triglycerides, total cholesterol, and LDL in a concentration-dependent manner, while HDL cholesterol levels were significantly decreased. Additionally, PFOS exposure led to a significant decrease in glucose levels. The study identified TGs, TCHO, and glucose as the most sensitive biomarkers in assessing lipid metabolism alterations. The study also revealed altered expression of genes involved in lipid metabolism, including upregulation of fasn, acaca, and hmgcr and downregulation of ldlr, pparα, and abca1, as well as decreased lipoprotein lipase (LPL) and increased fatty acid synthase (FAS) activity,suggesting an impact on fatty acid synthesis, cholesterol uptake, and lipid transport. Additionally, PFOS exposure led to impaired cholinergic neurotransmission, evidenced by a concentration-dependent inhibition of acetylcholinesterase activity, altered gene expressions related to neural development and function, and reduced Na+/K+-ATPase activity. STRING network analysis highlighted two distinct gene clusters related to lipid metabolism and cholinergic neurotransmission, with potential interactions through the pparα-creb1 pathway. Overall, this study provide important insights into the potential health risks associated with PFOS exposure, including dyslipidemia, cardiovascular disease, impaired glucose metabolism, and neurotoxicity. Further research is needed to fully elucidate the underlying mechanisms and potential long-term effects of PFOS exposure.

Multi-target mechanism of Solanum xanthocarpum for treatment of psoriasis based on network pharmacology and molecular docking

Solanum xanthocarpum (SX) has been used to treat a variety of diseases, including skin disorders like psoriasis (PSO). SX possesses many pharmacological activities of anti-inflammatory, anti-cancer, immunosuppressive, and healing qualities. However, the multi-target mechanism of SX on PSO still needs clarity. Materials and methods: The Indian Medicinal Plants, Phytochemicals and Therapeutics (IMPPAT) database and the Swiss Target Prediction online tool were used to find the active phytochemical components and their associated target proteins. OMIM and GeneCards databases were used to extract PSO-related targets. A Venn diagram analysis determined the common targets of SX against PSO. Subsequently, the protein–protein interaction (PPI) network and core PPI target analysis were carried out using the STRING network and Cytoscape software. Also, utilising the online Metascape and bioinformatics platform tool, a pathway enrichment analysis of common targets using the Kyoto Encyclopaedia of Genes and Genome (KEGG) and Gene Ontology (GO) databases was conducted to verify the role of targets in biological processes, cellular components and molecular functions with respect to KEGG pathways. Lastly, molecular docking simulations were performed to validate the strong affinity between components of SX and key target receptors. Results: According to the IMPPAT Database information, 8 active SX against PSO components were active. According to the PPI network and core targets study, the main targets against PSO were EGFR, SRC, STAT3, ERBB2, PTK2, SYK, EP300, CBL, TP53, and AR. Moreover, molecular docking simulations verified the binding interaction of phytochemical SX components with their PSO targets. Last but not least, enrichment analysis showed that SX is involved in several biological processes, including peptidyl-tyrosine phosphorylation, peptidyl-tyrosine modification, and peptidyl-serine modification. The relevant KEGG signalling pathways are the PI3K-AKT signalling pathway, the EGFR tyrosine kinase inhibitor resistance pathway, and the MAPK signalling pathway. Conclusion: The network pharmacology technique, which is based on data interpretation and molecular docking simulation techniques, has proven the multi-target function of SX phytoconstituents.

P02.08.B ROLE OF THE PROTEIN NETWORK OF THE PARACASPASE MALT1 IN SELF-RENEWAL PROPERTIES OF GLIOBLASTOMA CELLS

Abstract BACKGROUND Glioblastoma is the most common and most aggressive brain tumor in adults. Despite standard treatment combining surgery, radiotherapy and chemotherapy, relapse is inevitable, making this cancer a major public health issue. Within this tumor reside cells with a stem-like character, called GSCs for Glioblastoma Stem-like Cells, which maintain, initiate, and propagate the tumor, making them a potential target to hinder glioblastoma. These cells constitute a reservoir of heterogeneous cells capable of differentiating into neural lineage cell types. In this context, lysosomal homeostasis plays a key role in the maintenance of the GSC reservoir. Furthermore, previous studies demonstrated that the paracaspase MALT1 is a major regulator of lysosomal homeostasis: MALT1 is required for GSC viability as well as for the maintenance of stemness by modulating the abundance of lysosomal proteins. This current study addresses the issue of the balance between self-renewal and viability of GSCs. In addition, this project aims to identify and characterize an actor of self-renewal mechanisms that does not impact the survival-death balance of primary cells from patients. MATERIAL AND METHODS An initial analysis combining DepMap and String Network databases allowed us to select potential relays of the MALT1 activity in GSCs. A functional screening was then set up and performed in GSCs derived from patients to identify among 20 candidates those regulating cell expansion without impacting viability. RESULTS The strategy of functional screening allowed the selection of 14 genes with a global viability effect, while only 2 genes were affecting self-renewal while sparing viability in vitro. We next pursued with one of the identified targets, from the IKK family. The involvement of this serine/threonine protein kinase was then confirmed in multiple patient cells and in CRISPR-mediated knock-out. Future experiments will decipher the involvement of this kinase in the self-renewal properties of GSCs. CONCLUSION This study highlights a putative candidate specifically operating on the self-renewal of glioblastoma cells, that does not affect the life-death balance. Future investigations will permit to characterize and understand the underlying mechanisms.

Imprints of a supercooled phase transition in the gravitational wave spectrum from a cosmic string network

A network of cosmic strings (CS), if present, would continue emitting gravitational waves (GW) as it evolves throughout the history of the Universe. This results in a characteristic broad spectrum making it a perfect source to infer the expansion history. In particular, a short inflationary period caused by a supercooled phase transition would cause a drop in the spectrum at frequencies corresponding to that event. However, the impact on the spectrum is similar to the ones caused by an early matter-dominated era or from particle production, making it difficult to disentangle these different physical origins. We point out that, in the case of a short inflationary period, the GW spectrum receives an additional contribution from the phase transition itself. This leads to a characteristic imprint of a peak on top of a wide plateau both visible at future GW observatories.

Measures of non-Gaussianity in axion-string-induced CMB birefringence

The presence of axion strings in the Universe after recombination can leave an imprint on the polarization pattern of the cosmic microwave background radiation through the phenomenon of axion-string-induced birefringence via the hyperlight axion-like particle's coupling to electromagnetism. Across the sky, the polarization rotation angle is expected to display a patchwork of uniform regions with sharp boundaries that arise as the `shadow' of axion string loops. The statistics of such a birefringence sky map are therefore necessarily non-Gaussian. In this article we quantify the non-Gaussianity in axion-string-induced birefringence using two techniques, kurtosis and bispectrum, which correspond to 4- and 3-point correlation functions. If anisotropic birefringence were detected in the future, a measurement of its non-Gaussian properties would facilitate a discrimination across different new physics sources generally, and in the context of axion strings specifically, it would help to break degeneracies between the axion-photon coupling and properties of the string network.

Testing charge quantization with axion string-induced cosmic birefringence

We demonstrate that the Peccei-Quinn-electromagnetic anomaly coefficient 𝒜 can be directly measured from axion string-induced cosmic birefringence by applying scattering transform to the anisotropic polarization rotation of the cosmic microwave background. This breaks the degeneracy between 𝒜 and the effective number of string loops in traditional inference analyses that are solely based on the spatial power spectrum of polarization rotation. Carrying out likelihood-based parameter inference on mock rotation realizations generated according to phenomenological string network models, we show that scattering transform is able to extract enough non-Gaussian information to clearly distinguish a number of discrete 𝒜 values, for instance 𝒜=1/9, 1/3, 2/3, in the ideal case of noise-free rotation reconstruction, and, to a lesser but interesting degree at reconstruction noise levels comparable to that expected for the proposed CMB-HD concept. In the event of a statistical detection of cosmic birefringence by Stage III or IV CMB experiments, our technique can be applied to test the stringy nature of the birefringence pattern and extract fundamental information about the smallest unit of charge in theories beyond the Standard Model.

Association of RAD51, XRCC1, XRCC2, and XRCC3 Polymorphisms with Risk of Breast Cancer.

Background: DNA repair genes are among the low-penetrance genes implicated in breast cancer. However variants of DNA repair genes may alter their protein function thus leading to carcinogenesis. Breast cancer is the most common cancer among women in India. The aim of the present study was to identify association, if any, of single nucleotide polymorphisms (SNP's) in four genes involved in DNA repair pathways including, RAD51 rs1801320, XRCC1 rs25487, XRCC2 rs3218536, and XRCC3 rs861539 with the risk of breast cancer. Materials and Methods: In this case-control study 611 female subjects (311 breast cancer patients and 300 healthy controls) were screened for four SNPs using polymerase chain reaction-restriction fragment length polymorphism analyses. Multifactor dimensionality reduction (MDR) analysis was performed to estimate the gene-gene interaction. Protein-protein interaction network analysis were studied using the STRING database. Results: The GC genotype (p = 0.018) and the combined GC+CC (p = 0.03) genotypes of RAD51 rs1801320 were significantly associated with reduced risk of breast cancer. The CT genotype (p = 0.0001), the combined CT+TT genotypes (p = 0.0002), and the T allele (p = 0.0019) of XRCC3 rs861539 polymorphism were associated with reduced risk of the breast cancer. No association of XRCC1 rs25487 and XRCC2 rs3218536 polymorphisms with breast cancer was observed. MDR analysis indicated a positive interaction between XRCC3 and XRCC2. String network analysis showed that the RAD51, XRCC1, XRCC2, and XRCC3 proteins are in strong interaction with each other and other breast cancer-related proteins such as BRCA2. Conclusion: RAD51 rs1801320 and XRCC3 rs861539 polymorphisms were associated with reduced risk of breast cancer. There is evidence of positive interactions among XRCC1, XRCC2, XRCC3, and RAD51.

CD73/adenosine pathway-related gene signature for intratumor heterogeneity and immune infiltration in prognosis of lung adenocarcinoma.

e20524 Background: Adenosine is an immunosuppressive molecule that can inhibit the activity of immune cells, particularly T cells, and promote tumor growth. CD73, also known as ecto-5'-nucleotidase, is a cell-surface enzyme that plays a role in the adenosine pathway can catalyzes the conversion of AMP to adenosine. Establish and evaluate a prognosis model based on CD73/ Adenosine pathway will help to understanding of the biological mechanisms in lung adenocarcinoma (LUAD) and providing more accurate predictions for patients' treatment. Methods: The RNA sequencing (RNA-seq), whole exome sequencing (WES) and clinical data were obtained from LUAD cohorts of the Cancer Genome Atlas (TCGA). CD73/ Adenosine pathway-related genes were identified by screening for genes that were in both the CD73 STRING network (confidence = 0.9, 1st shell ≤50 interactors) and the KEGG purine metabolism pathway gene list(map00230). Least absolute shrinkage and selection operator (LASSO) regression was conducted to develop a CD73/ Adenosine pathway-related risk score (CD73RS). Time-dependent ROC curve and survival analysis were conducted in LUAD-TCGA cohort to verify the predictive performance of CD73RS. The MATH (Mutant-Allele Tumor Heterogeneity) ITH scores were calculated to evaluate intratumor heterogeneity (ITH) in LUAD-TCGA WES "maf" files using the R package "maftools" and the "math.score" function. TIMER 2.0 database(http://timer.cistrome.org/) was conducted to estimation of tumor microenvironment to further understand the molecular features of CD73RS. An independent cohort (GSE72094) was used to verify the prognostic effect of CD73RS. Results: A prognosis prediction model based on 21 CD73/ Adenosine pathway-related genes was established using LASSO regression. Kaplan-Meier survival analysis of the risk model from LUAD-TCGA cohort showed that the high-risk group had a significantly worse prognosis (HR = 3.298, P = 1.26e-08). The area under the curve (AUC) in time-dependent ROC curve at 1, 3 and 5 years were turn out to be 0.794, 0.722 and 0.686, respectively. The validation set also showed worse prognosis in high-risk group(HR = 1.473,p = 0.0403). In the high-risk group, there was a higher ITH score compared to the low-risk group (p = 0.0094), along with lower infiltration levels of B cells(p = 7.23e-15), CD4+ T cells(p = 0.003), macrophage cells(p = 0.016), and myeloid dendritic cells(p = 0.037). Conclusions: We established and validated a CD73/ Adenosine pathway risk model that exhibits a robust predictive performance for the outcome of patients with LUAD. The CD73/Adenosine pathway has been shown to play a role in both self-driven genomic changes, such as intra-tumor heterogeneity (ITH), as well as non-autonomous processes, such as immune microenvironment adaptation, which contribute to tumor plasticity and development.

Meso-inflationary QCD axion

We study the possibility that the axion Peccei-Quinn symmetry is spontaneously broken after the beginning of inflation. This scenario interpolates between preinflationary and postinflationary axion cosmology with significant phenomenological differences from both. Since the axion is not present at the early stages of inflation large inflationary fluctuations are produced only at scales not constrained by cosmic microwave background (CMB), avoiding the strongest isocurvature constraints. The energy density in isocurvature perturbations at short scales however can be comparable with the adiabatic contribution from misalignment. These large overdensities can lead to the formation of axion miniclusters and also to constraints from Lyman-$\ensuremath{\alpha}$ forest and future CMB spectral distortion measurements. If Peccei-Quinn symmetry is broken during the first O(25) $e$-foldings of inflation no axions are produced from the string network but contributions from the annihilation of domain walls can further boost the abundance. This scenario is minimally realized if the Hubble scale during inflation drops below the Peccei-Quinn symmetry breaking scale but other realizations are possible.

Candidate genes identification and RNA-seq based pathway analysis associated with primary angle-closure glaucoma with cataract

BackgroundCataract is commonly observed in patients with primary angle-closure glaucoma; however, its underlying pathological mechanisms remain unclear. This study aimed to improve our knowledge on the pathological processes involved in primary angle-closure glaucoma (PACG) by identifying potential prognostic genes associated with cataract progression.MethodsThirty anterior capsular membrane samples were collected from PACG patients with cataracts and age-related cataracts. Differentially expressed genes (DEGs) between these two cohorts were analyzed using high-throughput sequencing. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to screen the DEGs, and potential prognostic markers and their coexpression network were then predicted by bioinformatic analyses. The DEGs were further validated by reverse transcription-quantitative polymerase chain reaction.ResultsA total of 399 DEGs were found to be specifically associated with cataracts development in PACG patients, among which 177 and 221 DEGs were upregulated and downregulated, respectively. STRING and Cytoscape network analyses revealed seven genes—CTGF, FOS, CAV1, CYR61, ICAM1, EGR1, and NR4A1—that were remarkably enriched and mainly involved in the MAPK, PI3K/Akt, Toll-like receptor, and TNF signaling pathways. RT-qPCR-based validation further confirmed that the sequencing results were accurate and reliable.ConclusionsHerein, we identified seven genes and their signaling pathways that may contribute to cataract progression in patients with high intraocular pressure. Taken together, our findings highlight new molecular mechanisms that may explain the high incidence of cataracts in PACG patients. In addition, the genes identified herein may represent new foundations for the development of therapeutic strategies for PACG with cataract.

Probing minimal grand unification through gravitational waves, proton decay, and fermion masses

Motivated by the direct discovery of gravitational waves (GWs) from black holes and neutron stars, there is a growing interest in investigating GWs from other sources. Among them, GWs from cosmic strings are particularly fascinating since they naturally appear in a large class of grand unified theories (GUTs). Remarkably, a series of pulsar-timing arrays (PTAs) might have already observed GWs in the nHz regime, hinting towards forming a cosmic string network in the early universe, which could originate from phase transition associated with the seesaw scale emerging from GUT. In this work, we show that if these observations from PTAs are confirmed, GWs from cosmic strings, when combined with fermion masses, gauge coupling unification, and proton decay constraints, the parameter space of the minimal SO(10) GUT becomes exceedingly restrictive. The proposed minimal model is highly predictive and will be fully tested in a number of upcoming gravitational wave observatories.