String Network Research Articles

Search for germline gene variants in colorectal cancer families presenting with multiple primary colorectal cancers.

A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.

TWIST1/miR-199a axis promotes tumor aggressiveness through inhibiting oxidative phosphorylation in carcinomas

Background Metabolic reprogramming has emerged as a key hallmark of cancer progression, though its role in tumor aggressiveness is still evolving. Here, using a pan-cancer genome approach, we aimed to comprehensively assess the metabolic reprogramming involved in tumor aggressiveness in carcinomas and identify metabolic hubs which can be therapeutically targeted to treat aggressive tumors in the clinic. Methods In this study, we employed a stringent pan-cancer multi-omic metabolism-targeted differential expression approach to identify the metabolic hubs regulating tumor aggressiveness. mRNA, miRNA, DNA methylation and mutation profiling data of tumors representing 14 different types of carcinomas was downloaded from TCGA database. Cell line expression profiling and drug response data was downloaded from CCLE database. Pathway enrichment, GSEA, String protein-protein interaction, miRNA-mRNA prediction, network random-walk and CCLE drug response analyses were carried out. Results We identified downregulated expression of enzymes involved in oxidative phosphorylation as a key common factor across carcinomas, aligning with the Warburg effect. Additionally, we established that the decreased dependence on oxidative phosphorylation is driven by elevated expression of miR-199 family miRNAs that inhibit their expression at the post-transcriptional level. Furthermore, we identified the epithelial-to-mesenchymal transition-related transcription factor, TWIST1, as a master regulator of tumor aggressiveness by controlling miR-199a-3p and -5p expression. Random walk analysis of established miRNA-mRNA network identified NDUFA2, DLD, COX15, NDUFB5, and TIMM13 as crucial metabolic hubs downregulated as tumors become aggressive. Drug response analysis suggested that targeting PDGFR signaling may offer a novel therapeutic approach to counteract the aggressiveness driven by the loss of oxidative phosphorylation. Conclusion We identified TWIST1/miR-199a axis mediated suppression of oxidative phosphorylation as major metabolic contributor towards tumor aggressiveness in carcinomas. These insights underscore the critical interplay between metabolic reprogramming and tumor aggressiveness, opening avenues for potential metabolic therapies in clinical settings.

Investigating the Potential Effects of 6PPDQ on Prostate Cancer Through Network Toxicology and Molecular Docking

(1) Background: N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPDQ), as a newly discovered environmental toxin, has been found more frequently in our living conditions. The literature reports that damage to the reproductive and cardiovascular system is associated with exposure to 6PPDQ. However, the relationship between 6PPDQ and cancer still requires more investigation. This research aims to investigate the association between 6PPDQ and prostate cancer. (2) Methods and Results: Based on the data retrieved from the Pharmmapper, CTD, SEA, SwissTargetPrediction, GeneCard, and OMIM databases, we summarized 239 potential targets utilizing the Venn tool. Through the STRING network database and Cytoscape software, we constructed a PPI network and confirmed ten core targets, including IGF1R, PIK3R1, PTPN11, EGFR, SRC, GRB2, JAK2, SOS1, KDR, and IRS1. We identified the potential pathways through which 6PPDQ acts on these core targets using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Ultimately, through molecular docking methods, 6PPDQ binds closely with these ten core targets. These findings indicate that 6PPDQ may influence the proteins related to prostate cancer and may be linked to prostate cancer via several known signaling pathways. (3) Conclusions: This article employs innovative network toxicology to elucidate the prostate carcinogenic effects of 6PPDQ through its modulation of specific vital genes and signaling pathways, thereby establishing a foundational platform for future investigations into the impact of 6PPDQ on prostate cancer and potentially other tumors.

The STRING database in 2025: protein networks with directionality of regulation.

Proteins cooperate, regulate and bind each other to achieve their functions. Understanding the complex network of their interactions is essential for a systems-level description of cellular processes. The STRING database compiles, scores and integrates protein-protein association information drawn from experimental assays, computational predictions and prior knowledge. Its goal is to create comprehensive and objective global networks that encompass both physical and functional interactions. Additionally, STRING provides supplementary tools such as network clustering and pathway enrichment analysis. The latest version, STRING 12.5, introduces a new 'regulatory network', for which it gathers evidence on the type and directionality of interactions using curated pathway databases and a fine-tuned language model parsing the literature. This update enables users to visualize and access three distinct network types-functional, physical and regulatory-separately, each applicable to distinct research needs. In addition, the pathway enrichment detection functionality has been updated, with better false discovery rate corrections, redundancy filteringand improved visual displays. The resource now also offers improved annotations of clustered networks and provides users with downloadable network embeddings, which facilitate the use of STRING networks in machine learning and allow cross-species transfer of protein information. The STRING database is available online at https://string-db.org/.

On damping a control system with global aftereffect on quantum graphs: Stochastic interpretation

Quantum graphs model processes in complex systems represented as spatial networks in various fields of natural science and technology. An example is the oscillations of elastic string networks, the nodes of which, besides the continuity conditions, also obey the Kirchhoff conditions, expressing the balance of tensions. In this paper, we propose a new look at quantum graphs as temporal networks, which means that the variable parametrizing the edges of a graph is interpreted as time, while each internal vertex is a branching point giving several different scenarios for the further trajectory of a process. Then Kirchhoff‐type conditions may also arise. Namely, they will be satisfied by such a trajectory of the process that is optimal with account of all the scenarios simultaneously. By employing the recent concept of global delay, we extend the problem of damping a first‐order control system with aftereffect, considered earlier only on an interval, to an arbitrary tree graph. The first means that the delay, imposed starting from the initial moment of time, associated with the root of the tree, propagates through all internal vertices. Bringing the system into the equilibrium and minimizing the energy functional with account of the anticipated probability of each scenario, we come to a variational problem. Then, we establish its equivalence to a self‐adjoint boundary value problem on the tree for some second‐order equations involving both the global delay and the global advance. The unique solvability of both problems is proved. We also illustrate that the interval case when the coefficients of the equation are discrete stochastic processes in discrete time can be viewed as the extension to a tree.

Percolating cosmic string networks from kination

We describe a new mechanism, whose ingredients are realized in string compactifications, for the formation of cosmic (super)string networks. Oscillating string loops grow when their tension μ decreases with time. If 2H+μ˙/μ<0, where H is the Hubble parameter, loops grow faster than the scale factor and an initial population of isolated small loops (for example, produced by nucleation) can grow, percolate, and form a network. This condition is satisfied for fundamental strings in the background of a kinating volume modulus rolling toward the asymptotic large volume region of moduli space. Such long kination epochs are motivated in string cosmology by both the electroweak hierarchy problem and the need to solve the overshoot problem. The tension of such a network today is set by the final vacuum; for phenomenologically appealing large volume scenario vacua, this would lead to a fundamental string network with Gμ∼10−10. Published by the American Physical Society 2024

Explaining PTA results by metastable cosmic strings from SO(10) GUT

In a recent paper ( Phys. Rev. D 108 (2023) 095053), we have demonstrated that the 2023 PTA results, which hint at a stochastic gravitational wave (GW) background at nanohertz frequencies, point towards a promising model-building route for realizing SO(10) Grand Unification with embedded inflation. The proposed supersymmetric scenario solves the doublet-triplet splitting without fine-tuning, accounts for charged fermion and neutrino masses, avoids conflicts with current proton decay bounds, and includes only representations no larger than the adjoint. It features multi-step breaking of SO(10) to the Standard Model gauge symmetry, with inflation embedded such that metastable cosmic strings are produced at the end of inflation. This cosmic string network generates a stochastic GW background that can explain the PTA results. In this paper, we provide a detailed analysis of the singled out GUT model class, focusing on how the gauge coupling unification condition affects the scales of multi-step SO(10) breaking and the preferred GW spectra. The lowest breaking scale, linked to inflation, the generation of right-handed neutrino masses for the seesaw mechanism, and metastable cosmic string production, coincides with the range suggested by the PTA results.

Studies on the Anti-Inflammatory Effect of Xiaoyao Pills in The Treatment of Postmenopausal Osteoporosis in Mice.

Osteoporosis is a common metabolic disease of elderly and postmenopausal women, with no obvious symptoms during its early stages. In the latter stages of this condition, the patients are prone to fractures, and this can seriously affect their health and quality of life. The worldwide increase in life expectancy has made osteoporosis a global concern. The Xiaoyao pills were previously used in the treatment of depression. In addition, the drug appeared to have estrogen-like activity, which affected the expression of ALP, an early osteoblast-specific marker, and COL-1, a major component of bone extracellular matrix. Xiaoyao pills were assessed for their effects on postmenopausal osteoporosis (PMOM) in mice. The target information of each herbal component of Xiaoyao pills was accessed through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Information from GeneCards, OMIM, PharmGkb, TTD, DrugBank, and other websites was used to construct the regulatory network of the herbal complex through Cytoscape and String network to assess the protein interactions. Mice were ovariectomized, and treated with high and low doses of Xiaoyao pills and these were compared to controls. Their symptoms were assessed by immunocytochemistry of bone tissues. The results suggested that Xiaoyao pills had the ability to alleviate the symptoms of PMOM in ovariectomized mice through the IL-17 signaling pathway. This drug has the potential to become a novel therapeutic agent for the treatment of osteoporosis.

Scaling solutions for current-carrying cosmic string networks

Cosmic string networks are the best motivated relics of cosmological phase transitions, being unavoidable in many physically plausible extensions of the Standard Model. Most studies, including those providing constraints from and forecasts of their observational signals, rely on assumptions of featureless networks, neglecting the additional degrees of freedom on the string worldsheet, e.g., charges and currents, which are all but unavoidable in physically realistic models. An extension of the canonical velocity-dependent one-scale model, accounting for all such possible degrees of freedom, has been recently developed. Here we improve its physical interpretation by studying and classifying its possible asymptotic scaling solutions, and in particular how they are affected by the expansion of the Universe and the available energy loss or transfer mechanisms. We find three classes of solutions. For sufficiently fast expansion rates the charges and currents decay and one asymptotes to the Nambu-Goto case, while for slower expansion rates they can dominate the network dynamics. In between the two there is a third regime in which the network, including its charge and current, reaches full scaling. Under specific but plausible assumptions, this intermediate regime corresponds to the matter-dominated era. Our results agree with, and significantly extend, those of previous studies. Published by the American Physical Society 2024

Gravitational waves from cosmic superstrings and gauge strings

We perform a phenomenological comparison of the gravitational wave (GW) spectrum expected from cosmic gauge string networks and superstring networks comprised of multiple string types. We show how violations of scaling behavior and the evolution of the number of relativistic degrees of freedom in the early Universe affect the GW spectrum. We derive simple analytical expressions for the GW spectrum from superstrings and gauge strings that are valid for all frequencies relevant to pulsar timing arrays (PTAs) and laser interferometers. We analyze the latest data from PTAs and show that superstring networks are consistent with 32 nHz data from NANOGrav, but are excluded by 3.2 nHz data at 3σ unless the string coupling gs< 0.2 or the strings evolve in only about 10% of the volume of the higher-dimensional space. We also point out that while gauge string networks are excluded by NANOGrav-15 data at 3σ, they are completely compatible with EPTA and PPTA data. Finally, we study correlations between GW signals at PTAs and laser interferometers.

Axion dark matter from cosmic string network

We perform lattice simulations to estimate the axion dark matter abundance radiated from the global cosmic strings in the post-inflationary scenario. The independent numerical confirmation on the recently observed logarithmic growth in both the number of strings per Hubble patch and the spectral index of the power law scaling for the axion spectrum is reported. These logarithmic scalings are checked against two different prescriptions for generating initial random field configurations, namely fat-string type and thermal phase transition. We discuss a possible strong correlation between the axion spectrum and the string evolutions with different initial conditions to support the insensitivity of scaling behaviors against different initial data and we provide a qualitative understanding of it. The impact of various combinations of the power law of the axion spectrum, nonlinearities around the QCD scale, and average inter-string distances on the axion abundance are discussed. Additionally, we introduce a new novel string identification method, based on the tetrahedralization of the space, which guarantees the connectedness of the strings and provides a convenient way of assigning the core location. Finally we derive a lower bound on the axion mass.

ELANE is a promising prognostic biomarker that mediates pyroptosis in gastric cancer

BackgroundGastric cancer (GC) is a typical malignant tumor and the main cause of cancer-related deaths. Its pathogenesis involves multiple steps, including pyroptosis, although these steps are still uncertain. Pyroptosis, also known as gasdermin-mediated programmed necrosis, participates in various pathological processes in tumors, including GC. ELANE, which encodes neutrophil elastase, is closely associated with GC. Additionally, ELANE has been implicated in GC cell pyroptosis, but this has not been confirmed. Therefore, investigating the link between ELANE and pyroptosis in GC is warranted. This research uses bioinformatics and experiments to examine the relationship between ELANE, pyroptosis, and GC prognosis. MethodsThe GEO and TCGA databases, along with pyroptosis-related genes, were applied to identify pyroptosis-related differentially expressed genes (DEGs). ELANE was selected via primary screening. Using the median expression level of ELANE as the threshold, pyroptosis-related DEGs were divided into low- and high-ELANE groups. Based on the DEGs in these two groups, GO, KEGG and GSEA analyses were conducted to elucidate the mechanisms of ELANE in GC. Furthermore, we plotted ROC and Kaplan–Meier curves to analyze the clinical and pathological features of ELANE expression. The Nomograms tool was applied to calculate the predictive value of ELANE for the clinical outcomes of GC cases. Immunohistochemical analysis was performed to detect the level of ELANE in GC tissues and to validate whether ELANE was involved in pyroptosis in GC cells through cell experiments. Finally, the immune infiltration of ELANE was investigated, and interaction networks (proteins-ELANE, microRNA-ELANE, and small-molecule drug-ELANE) were constructed. ResultsWe aimed to investigate the expression of the ELANE gene in GC and study the relationship among ELANE, pyroptosis, and the prognosis of patients with GC. Differential expression analysis of gene-expression datasets from TCGA-STAD and GSE49051 revealed that the expression of the ELANE gene was significantly up-regulated in GC. Using STRING network analysis, we identified multiple proteins involved in the occurrence and development of GC, including interactions between ELANE and GSDMC, a member of the gasdermin protein family. Survival analysis showed that ELANE expression levels significantly affected overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) in patients with GC. Additionally, ROC analysis demonstrated that ELANE was effective in distinguishing GC patients from normal controls (AUC = 0.812). Immunohistochemical analysis showed that ELANE was highly expressed in gastric cancer tissues and was closely related to age, tumor grade, and stage. The cell experiments further confirmed that the high expression of ELANE in gastric cancer cells was associated with pyroptosis. Comprehensive analysis indicated that ELANE could be used as a potential prognostic marker for GC and plays an important role in pyroptosis. ConclusionHigh ELANE expression is related to poor survival and prognosis of patients with GC. It participates in pyroptosis and immune infiltration in GC. Therefore, ELANE is a promising prognostic biomarker for pyroptosis in GC.

Whole-exome Sequencing of Atypical Parathyroid Tumors Detects Novel and Common Genes Linked to Parathyroid Tumorigenesis

Abstract Context Atypical parathyroid tumor (APT) represents a neoplasm characterized by histological features typical of parathyroid carcinoma (PC) but lacking local infiltration and/or distant metastasis, leading to uncertainty regarding its malignant potential. Objective To characterize the molecular landscape and deregulated pathways in APT. Methods Whole-exome sequencing (WES) was conducted on 16 APTs. DNA from tumors and matched peripheral blood underwent WES using Illumina HiSeq3000. Results A total of 192 nonsynonymous variants were identified. The median number of protein-altering mutations was 9. The most frequently mutated genes included BCOR, CLMN, EZH1, JAM2, KRTAP13-3, MUC16, MUC19, and OR1S1. Seventeen mutated genes belong to the Cancer Gene Census list. The most consistent hub genes identified through STRING network analysis were ATM, COL4A5, EZH2, MED12, MEN1, MTOR, PI3, PIK3CA, PIK3CB, and UBR5. Deregulated pathways included the PI3 K/AKT/mTOR pathway, Wnt signaling, and extracellular matrix organization. Variants in genes such as MEN1, CDC73, EZH2, PIK3CA, and MTOR, previously reported as established or putative/candidate driver genes in benign adenoma (PA) and/or PC, were also identified in APT. Conclusion APT does not appear to have a specific molecular signature but shares genomic alterations with both PA and PC. The incidence of CDC73 mutations is low, and it remains unclear whether these mutations are associated with a higher risk of recurrence. Our study confirms that PI3 K/AKT/mTOR and Wnt signaling represents the pivotal pathways in parathyroid tumorigenesis and also revealed mutations in key epigenetic modifier genes (BCOR, KDM2A, MBD4, and EZH2) involved in chromatin remodeling, DNA, and histone methylation.

Evolution of current-carrying string networks

Cosmic string networks are expected to form in early Universe phase transitions via the Kibble mechanism and are unavoidable in several Beyond the Standard Model theories. While most predictions of observational signals of string networks assume featureless Abelian-Higgs or Nambu-Goto string networks, in many such extensions the networks can carry additional degrees of freedom, including charges and currents; these are often generically known as superconducting strings. All such degrees of freedom can impact the evolution of the networks and therefore their observational signatures. We report on the results of 20483 field theory simulations of the evolution of a current-carrying network of strings, highlighting the different scaling behaviours of the network in the radiation and matter eras. We also report the first numerical measurements of the coherence length scales for the charge and current and of the condensate equation of state, and show that the latter mainly depends on the expansion rate, with chirality occurring for the matter era. Qualitatively, the fact that the matter era is the optimal expansion rate for these networks to reach scaling is in agreement with recent analytic modelling.

Cosmic Strings from Thermal Inflation

Thermal inflation was proposed as a mechanism to dilute the density of cosmological moduli. Thermal inflation is driven by a complex scalar field possessing a large vacuum expectation value and a very flat potential, called a “flaton”. Such a model admits cosmic string solutions, and a network of such strings will inevitably form in the symmetry breaking phase transition at the end of the period of thermal inflation. We discuss the differences of these strings compared to the strings which form in the Abelian Higgs model. Specifically, we find that the upper bound on the symmetry breaking scale is parametrically lower than in the case of Abelian Higgs strings, and that the lower cutoff on the string loop distribution is determined by cusp annihilation rather than by gravitational radiation (for the value of the transition temperature proposed in the original work on thermal inflation).

Prediction and assessment of deleterious and disease causing nonsynonymous single nucleotide polymorphisms (nsSNPs) in human FOXP4 gene: An in-silico study

In humans, FOXP gene family is involved in embryonic development and cancer progression. The FOXP4 (Forkhead box protein P4) gene belongs to this FOXP gene family. FOXP4 gene plays a crucial role in oncogenesis. Single nucleotide polymorphisms are biological markers and common determinants of human diseases. Mutations can largely affect the function of the corresponding protein. Therefore, the molecular mechanism of nsSNPs in the FOXP4 gene needs to be elucidated. Initially, the SNPs of the FOXP4 gene were extracted from the dbSNP database and a total of 23124 SNPs was found, where 555 nonsynonymous, 20525 intronic, 1114 noncoding transcript, 334 synonymous were obtained and the rest were unspecified. Then, a series of bioinformatics tools (SIFT, PolyPhen2, SNAP2, PhD SNP, PANTHER, I-Mutant2.0, MUpro, GOR IV, ConSurf, NetSurfP 2.0, HOPE, DynaMut2, GeneMANIA, STRING and Schrodinger) were used to explore the effect of nsSNPs on FOXP4 protein function and structural stability. First, 555 nsSNPs were analyzed using SIFT, of which 57 were found as deleterious. Following, PolyPhen2, SNAP2, PhD SNP and PANTHER analyses, 10 nsSNPs (rs372762294, rs141899153, rs142575732, rs376938850, rs367607523, rs112517943, rs140387832, rs373949416, rs373949416 and rs376160648) were common and observed as deleterious, damaging and diseases associated. Following that, using I-Mutant2.0 and MUpro servers, 7 nsSNPs were found to be the most unstable. GOR IV predicted that these seven nsSNPs affect protein structure by altering the protein contents of alpha helixes, extended strands, and random coils. Following DynaMut2, 5 nsSNPs showed a decrease in the ΔΔG value compared with the wild-type and were found to be responsible for destabilizing the corresponding protein. GeneMANIA and STRING network revealed interaction of FOXP4 with other genes. Finally, molecular dynamics simulation analysis revealed consistent fluctuation in RMSD and RMSF values, Rg and hydrogen bonds in the mutant proteins compared with WT, which might alter the functional and structural stability of the corresponding protein. As a result, the aforementioned integrated comprehensive bioinformatic analyses provide insight into how various nsSNPs of the FOXP4 gene change the structural and functional properties of the corresponding protein, potentially proceeding with the pathophysiology of human diseases.

Ultrahigh frequency primordial gravitational waves beyond the kHz: The case of cosmic strings

We investigate gravitational-wave backgrounds (GWBs) of primordial origin that would manifest only at ultrahigh frequencies, from kilohertz to 100 gigahertz, and leave no signal at LIGO, the Einstein Telescope, the Cosmic Explorer, LISA, or pulsar-timing arrays. We focus on GWBs produced by cosmic strings and make predictions for the GW spectra scanning over high-energy scale (beyond 1010 GeV) particle physics parameters. Signals from local string networks can easily be as large as the big bang nucleosynthesis/cosmic microwave background bounds, with a characteristic strain as high as 10−26 in the 10 kHz band, offering prospects to probe grand unification physics in the 1014–1017 GeV energy range. In comparison, GWB from axionic strings is suppressed (with maximal characteristic strain ∼10−31) due to the early matter era induced by the associated heavy axions. We estimate the needed reach of hypothetical futuristic GW detectors to probe such GWB and, therefore, the corresponding high-energy physics processes. Beyond the information of the symmetry-breaking scale, the high-frequency spectrum encodes the microscopic structure of the strings through the position of the UV cutoffs associated with cusps and kinks, as well as potential information about friction forces on the string. The IR slope, on the other hand, reflects the physics responsible for the decay of the string network. We discuss possible strategies for reconstructing the scalar potential, particularly the scalar self-coupling, from the measurement of the UV cutoff of the GW spectrum. Published by the American Physical Society 2024

Percolating cosmic string loops from evaporating primordial black holes

The Pulsar timing data from NANOGrav Collaboration has regenerated interest in the possibility of observing stochastic gravitational wave background arising from cosmic strings. Standard theory of formation of cosmic strings is based on a spontaneous symmetry breaking (SSB) phase transition in the early universe, with a string network forming via the so called Kibble mechanism. This string network rapidly evolves and reaches a scaling solution with a given spectrum of string loops and long strings at any given time. This scenario necessarily requires that the entire observable Universe goes through the SSB phase transition. This would not be possible, e.g., in models of low energy inflation, where the reheat temperature is much lower than the energy scale of cosmic strings. We point out a very different possibility, where a network of even high energy scale cosmic strings can form when the temperature of the Universe is much lower. We consider local heating of plasma in the early universe by evaporating primordial black holes (PBHs). It is known that for suitable masses of PBHs, Hawking radiation of evaporating primordial black holes may re-heat the surrounding plasma to high temperatures, restoring certain symmetries locally which are broken at the ambient temperature of the Universe at that stage. Expansion of the hot plasma cools it so that the locally restored symmetry is spontaneously broken again. If this SSB supports formation of cosmic strings, then string loops will form in this region around the PBH. Further, resulting temperature gradients lead to large pressure gradients such that plasma will develop radial flow with the string loops getting stretched as they get dragged by the flow. For a finite density of PBHs of suitable masses, one will get local hot spots, each one contributing to expanding cosmic string loops. For suitable PBH density, the loops from different regions may intersect. If that happens, then intercommutation of strings can lead to percolation, leading to the possibility of formation of infinite string network, even when the entire universe never goes through the respective SSB phase transition.

Network pharmacology and molecular docking analysis on the mechanism of Tripterygium wilfordii Hook in the treatment of Sjögren syndrome.

Tripterygium wilfordii Hook. F (TWH) has significant anti-inflammatory and immunosuppressive effects, and is widely used in the inflammatory response mediated by autoimmune diseases. However, the multi-target mechanism of TWH action in Sjögren syndrome (SS) remains unclear. Therefore, the aim of this study was to explore the molecular mechanism of TWH in the treatment of SS using network pharmacology and molecular docking methods. TWH active components and target proteins were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. SS-related targets were obtained from the GeneCards database. After overlap, the therapeutic targets of TWH in the treatment of SS were screened. Protein-protein interaction and core target analysis were performed by STRING network platform and Cytoscape software. In addition, the affinity between TWH and the disease target was confirmed by molecular docking. Finally, the DAVID (visualization and integrated) database was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of overlapping targets. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database shows that TWH contains 30 active components for the treatment of SS. Protein-protein interaction and core target analysis suggested that TNF, MMP9, TGFB1, AKT1, and BCL2 were the key targets of TWH in the treatment of SS. In addition, the molecular docking method confirmed that the bioactive molecules of TWH had a high affinity with the target of SS. Enrichment analysis showed that TWH active components were involved in multiple signaling pathways. Pathways in cancer, Lipid and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications is the main pathway. It is associated with a variety of biological processes such as inflammation, apoptosis, immune injury, and cancer. Based on data mining network pharmacology, and molecular docking method validation, TWH is likely to be a promising candidate for the treatment of SS drug, but still need to be further verified experiment.

Abstract 5669: Rare germline variants on SI gene and the possibility of colorectal cancer development

Abstract Research on cancer and germline variants has been ongoing. The germline variant in CPGs has been linked to cancer development. BRCA 1/2 is a typical case and oncometabolite production due to germline variants of the FH gene can affect the cancer progression. Among the genes related to IEMs, SI (Sucrase-isomaltase) is an enzyme that converts sucrose into glucose and fructose to allow normal metabolism in the small intestine. In addition, SI is highly specifically expressed in the gastrointestinal tract (nTPM = 435.9). So, we focused on and hypothesized the biological traits of the SI gene and alteration caused by germline variants could affect colorectal cancer progression. We used the public cancer databases PCAWG and TCGA and the healthy cohorts 1000G. We confirmed carriers with SI germline variants are the top gene with a high prevalence of IEM-related genes. We also established the hypothesis the SI gene may match “Knudson’s Two-hit hypothesis”. Depending on whether germline variants in IEM-related genes or not, we performed regression and utilized LOH (Loss of heterozygosity) information for each cancer sample from the public database. In COAD and STAD which are in the gastrointestinal tract, SI was confirmed to have a high tendency for LOH according to germline prevalence. Next, we performed DEG analysis and found SI germline carriers had upregulated genes related to the IFIT (Interferon-induced proteins with tetratricopeptide repeats) family. STRING network analysis also showed significance in pathways associated with “Interferon alpha/beta signaling (FDR = 0.00058)”, “Antiviral defense (FDR = 0.0016)”, “Innate immunity (FDR = 0.0317)”, and “Tetratricopeptide repeats (FDR = 0.0413)”. The following GSEA revealed that “KEGG_CYTOSOLIC DNA-SENSING PATHWAY” and “HALLMARK_INTERFERON_ALPHA_RESPONSE” were enriched in the SI germline carriers. In summary, it can be suggested immune regulation caused by SI germline variants may lead to cancer progression. We executed a follow-up analysis using the genes with low expression levels to the SI germline carriers. Among the down-regulated genes in the DEG, REG4 (Regenerating Family Member 4) and RELMβ (Resistin-Like Molecule Beta) genes were confirmed to express and function specifically only in the gastrointestinal tract. RELMβ is essential for preserving energy balance and glucose metabolism. As a validation at the protein level, we conducted IHC (Immunohistochemistry) on tissues from Korean colorectal cancer patients and confirmed lower REG4 and RELMβ expression were associated with poor prognosis. Our results suggest that SI germline carriers may cause colorectal cancer by affecting the immune system due to decreased SI enzyme function. Additionally, the decreased REG4 and RELMβ expression levels are associated with the SI germline variant and may affect cancer progression. Further analyses and experimental validations are still required. Citation Format: Seokhyeon Kim, Jeong Mo Bae, Youngil Koh, Sung-Soo Yoon. Rare germline variants on SI gene and the possibility of colorectal cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5669.