combinatorial

BACKGROUND: The tumor microenvironment (TME) exerts a significant influence on the development, invasion, metastasis, and drug resistance of breast cancer. Therefore, this study sought to investigate potential prognostic factors and markers indicative of TME remodeling in breast cancer, utilizing data from the TCGA database. METHODS: In this study, transcriptome RNA-seq data from 1222 breast cancer samples were processed using CIBERSORT and ESTIMATE algorithms. We conducted a differential gene expression analysis utilizing COX regression analysis and constructed protein-protein interaction (PPI) networks for enhanced visualization...

Natural products are small molecules synthesized by fungi, bacteria and plants, which historically have had a profound effect on human health and quality of life. These natural products have evolved over millions of years resulting in specific biological functions that may be of interest for pharmaceutical, agricultural, or nutraceutical use. Often natural products need to be structurally modified to make them suitable for specific applications. Combinatorial biosynthesis is a method to alter the composition of enzymes needed to synthesize a specific natural product resulting in structurally diversified molecules...

Phase-encoded oscillating neural networks offer compelling advantages over metal-oxide-semiconductor-based technology for tackling complex optimization problems, with promising potential for ultralow power consumption and exceptionally rapid computational performance. In this work, we investigate the ability of these networks to solve optimization problems belonging to the nondeterministic polynomial time complexity class using nanoscale vanadium-dioxide-based oscillators integrated onto a Silicon platform...

Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukaemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose...

Globally, traffic accidents on the highway network contribute significantly to a high fatality rate, drawing considerable attention from health institutions. The efficiency of transportation plays a vital role in mitigating the severe consequences of these incidents. This study delves into the issues of emergency vehicles experiencing delays despite having priority. Therefore, we construct mixed-integer linear programming with semi-soft time windows (MIPSSTW) model for optimizing emergency vehicle routing in highway incidents...

A highly flexible, tunable morphology membrane with excellent thermal stability and ionic conductivity can endow lithium metal batteries with high power density and reduced dendrite growth. Herein, a porous Polyurethane (PU) membrane with an adjustable morphology was prepared by a simple nonsolvent-induced phase separation technique. The precise control of the final morphology of PU membranes can be achieved through appropriate selection of a nonsolvent, resulting a range of pore structures that vary from finger-like voids to sponge-like pores...

Calcified cartilage digested by chondroclasts provides an excellent scaffold to initiate bone formation. We analyzed bioactive proteins and microarchitecture of calcified cartilage either separately or in combination and evaluated biomimetic osteogenic culture conditions of surface-coated micropatterning. To do so, we prepared a crude extract from porcine femoral growth plates, which enhanced in vitro mineralization when coated on flat-bottom culture dishes, and identified four candidate proteins by fractionation and mass spectrometry...

Vitamin B12 is a complex compound synthesized by microorganisms. The industrial production of vitamin B12 relies on specific microbial fermentation processes. E. coli has been utilized as a host for the de novo biosynthesis of vitamin B12 , incorporating approximately 30 heterologous genes. However, a metabolic imbalance in the intricate pathway significantly limits vitamin B12 production. In this study, we employed multivariate modular metabolic engineering to enhance vitamin B12 production in E. coli by manipulating two modules comprising a total of 10 genes within the vitamin B12 biosynthetic pathway...

Grade IV glioma, formerly known as glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor, and its treatment remains challenging in part due to extensive interpatient heterogeneity in disease driving mechanisms and lack of prognostic and predictive biomarkers. Using mechanistic inference of node-edge relationship (MINER), we have analyzed multiomics profiles from 516 patients and constructed an atlas of causal and mechanistic drivers of interpatient heterogeneity in GBM (gbmMINER)...

BACKGROUND: Deciphering gene regulation is essential for understanding the underlying mechanisms of healthy and disease states. While the regulatory networks formed by transcription factors (TFs) and their target genes has been mostly studied with relation to cis effects such as in TF binding sites, we focused on trans effects of TFs on the expression of their transcribed genes and their potential mechanisms. RESULTS: We provide a comprehensive tissue-specific atlas, spanning 49 tissues of TF variations affecting gene expression through computational models considering two potential mechanisms, including combinatorial regulation by the expression of the TFs, and by genetic variants within the TF...

BACKGROUND: Tumor-targeted therapy causes impressive tumor regression, but the emergence of resistance limits long-term survival benefits in patients. Little information is available on the role of the myeloid cell network, especially dendritic cells (DC) during tumor-targeted therapy. METHODS: Here, we investigated therapy-mediated immunological alterations in the tumor microenvironment (TME) and tumor-draining lymph nodes (LN) in the D4M.3A preclinical melanoma mouse model (harboring the V-Raf murine sarcoma viral oncogene homolog B (BRAF)V600E mutation) by using high-dimensional multicolor flow cytometry in combination with multiplex immunohistochemistry...

In the article, the extreme problem of finding the optimal placement plan of 5G base stations at certain points within a linear area of finite length is set. A fundamental feature of the author's formulation of the extreme problem is that it takes into account not only the points of potential placement of base stations but also the possibility of selecting instances of stations to be placed at a specific point from a defined excess set, as well as the aspect of inseparable interaction of placed 5G base stations within the framework of SON...

In protein-RNA cross-linking mass spectrometry, UV or chemical cross-linking introduces stable bonds between amino acids and nucleic acids in protein-RNA complexes that are then analyzed and detected in mass spectra. This analytical tool delivers valuable information about RNA-protein interactions and RNA docking sites in proteins, both in vitro and in vivo. The identification of cross-linked peptides with oligonucleotides of different length leads to a combinatorial increase in search space. We demonstrate that the peptide retention time prediction tasks can be transferred to the task of cross-linked peptide retention time prediction using a simple amino acid composition encoding, yielding improved identification rates when the prediction error is included in rescoring...

Non-clustered protocadherins (ncPcdhs) are adhesive molecules with spatio-temporally regulated overlapping expression in the developing nervous system. Although their unique role in neurogenesis has been widely studied, their combinatorial role in brain physiology and pathology is poorly understood. Using probabilistic cell typing by in situ sequencing, we demonstrate combinatorial inter- and intra-familial expression of ncPcdhs in the developing mouse cortex and hippocampus, at single-cell resolution. We discovered the combinatorial expression of Protocadherin-19 ( Pcdh19 ), a protein involved in PCDH19-clustering epilepsy, with Pcdh1 , Pcdh9 or Cadherin 13 ( Cdh13 ) in excitatory neurons...

Although RAS was formerly considered undruggable, various agents that inhibit RAS or specific RAS oncoproteins have now been developed. Indeed, the importance of directly targeting RAS has recently been illustrated by the clinical success of mutant-selective KRAS inhibitors. Nevertheless, responses to these agents are typically incomplete and restricted to a subset of patients, highlighting the need to develop more effective treatments, which will likely require a combinatorial approach. Vertical strategies that target multiple nodes within the RAS pathway to achieve deeper suppression are being investigated and have precedence in other contexts...

Dynamic combinatorial chemistry (DCC) leverages a reversible reaction to generate compound libraries from constituting building blocks under thermodynamic control. The position of this equilibrium can be biased by addition of a target macromolecule towards enrichment of bound ligands. While DCC has been applied to select ligands for a single target protein, its application to identifying chimeric molecules inducing proximity between two proteins is unprecedented. In this proof-of-concept study, we develop a DCC approach to select bifunctional proteolysis targeting chimeras (PROTACs) based on their ability to stabilize the ternary complex...

Post-transcriptional mRNA regulation shapes gene expression, yet how cis-elements and mRNA translation interface to regulate mRNA stability is poorly understood. We find that the strength of translation initiation, upstream open reading frame (uORF) content, codon optimality, AU-rich elements, microRNA binding sites, and open reading frame (ORF) length function combinatorially to regulate mRNA stability. Machine-learning analysis identifies ORF length as the most important conserved feature regulating mRNA decay...

Industrialising economies today are characterised by a multi-level heterogeneity of customs, norms, guidelines, standards, regulations and other laws that provide the broad scaffolding and the technical context for industrial activity. This institutional variety (IV) leads to combinatorial challenges about which institutions are mixed and matched as technologies and sectors evolve. Gaps in evolutionary political economy and evolutionary institutional methods should explain when variety is 'better' for industrial development...

Built upon the shoulders of graph theory, the field of complex networks has become a central tool for studying real systems across various fields of research. Represented as graphs, different systems can be studied using the same analysis methods, which allows for their comparison. Here, we challenge the widespread idea that graph theory is a universal analysis tool, uniformly applicable to any kind of network data. Instead, we show that many classical graph metrics-including degree, clustering coefficient, and geodesic distance-arise from a common hidden propagation model: the discrete cascade...

Polygonum multiflorum Thunb. (PMT) has shown promise in exerting cerebrovascular protective effects, and its potential for treating ischemic stroke (IS) has garnered attention. However, the lack of clarity regarding its chemical constituents and mechanisms has significantly hindered its clinical application. In this study, we employed network pharmacology and molecular docking techniques for the first time to elucidate the potential compounds and targets of PMT in treating IS. The databases CTD, DrugBank, DisGeNET, GeneCards, OMIM, TTD, PGKB, NCBI, TCMIP, CNKI, PubMed, ZINC, STITCH, BATMAN, ETCM and Swiss provided information on targets related to IS and components of PMT, along with their associated targets...