Complex Network Of Proteins Research Articles

Abstract 875: Breast cancer bioinformatics: Untangling the roles of nucleolin and BRCA1 in dysregulated DNA repair

Abstract Proteins that enable cells to sense and repair DNA damage are essential for maintaining the stability of genomes across cell divisions; dysregulation of these processes is an established hallmark of tumorigenesis. Nucleolin (NCL), a major RNA binding protein (RBP) and a caretaker tumor suppressor protein BRCA1 (the breast & ovarian cancer susceptibility gene) colocalize in breast cancer. Both NCL and BRCA1 have defined roles in homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair pathways which are often dysregulated in breast cancer. BRCA1, along with a complex molecular network of signaling proteins gets recruited to damaged replication forks to initiate the HR pathway where NCL function is also implicated. However, how NCL collaborates with BRCA1 to orchestrate the complex mechanism of DNA repair under stress conditions remains unknown. To address this gap in knowledge, we have applied in silico approaches to uncover the key players which drive the molecular interactions of NCL and BRCA1 at the damaged sites. We utilized the NIH PPI, IntAct, STRING, BioGRID, GeneMania, PrePPI, and Mentha databases to derive an overlapping interactome. In this study we present a comprehensive interactome analysis and 47 proteins identified that interact with both NCL and BRCA1. As expected, majority of these common interactors participate in DNA damage damage response along with several that are implicated in regulating the gene expression via chromatin remodeling/RNA binding or controlling cell proliferation. We classified this interactome into 5 major categories based on their GO functional annotations: chromatin remodeling, DNA damage, DNA repair, RNA-binding proteins, and cell cycle. Previously, we have successfully used computational approaches to model the RNA-binding domains (RBD) of NCL and delineate the binding interfaces between NCL-RBD and a subset of miRNA that are specifically dysregulated in breast cancer. Using the same strategy, we have modeled the full length NCL to provide a complete structural representation of the protein. Our model fills the gap in missing NCL structural data, especially the unexplored N- and C - termini that may play important roles in NCL protein-protein interactions. Our results provide predicted interaction scenarios between NCL and the subset of the overlapping interactome of NCL and BRCA1, focused on DNA repair mechanisms. These in silico models are critical to understand the protein complexity at the interface of damaged DNA to identify candidates that can be targeted in breast carcinoma. Citation Format: Nitu Farhin, Andy Lam, Anjana D. Saxena, Shaneen Singh. Breast cancer bioinformatics: Untangling the roles of nucleolin and BRCA1 in dysregulated DNA repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 875.

Editorial Highlights

Every organism is a model organism for understanding development, evolution, disease, and regeneration, and we have only begun to scratch the surface of the interdisciplinary genetic, molecular, cellular, and developmental mechanisms that regulate these biological processes. These “Highlights” denote exciting advances recently reported in Developmental Dynamics that illustrate the complex dynamics of developmental biology. Ocular Development and Disease. “Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling” by Aman George, Jerry Lee, James Liu, Suzie Kim and Brian Brooks; DevDyn 252:4, pp. 495-509; https://doi.org/10.1002/dvdy.561. Mutations in the human RERE gene (ATROPHIN 2, OMIM *605226) are associated with a neuro-developmental disorder that includes ophthalmic, cardiac, genitourinary and hearing defects. This study demonstrates that rerea mutant (babyface) zebrafish recapitulate the optic fissure closure defects that result from loss of RERE function in humans. Interestingly, the RERE gene acts as a transcriptional corepressor in various nuclear receptor signaling pathways, and the optic fissure phenotype is associated with expansion of proximal retinal optic stalk in concert with deregulated shh signaling. Consistent with this model, inhibiting shh signaling can rescue the coloboma phenotype. Craniofacial Biology. “Frem1 activity is regulated by Sonic Hedgehog signaling in the cranial neural crest mesenchyme during midfacial morphogenesis” by Matthew McLaughlin, Miranda Sun, Tyler Beames, Austin Steward, Joshua Theisen, Hannah Chung, Joshua Everson, Ivan Moskowitz, Michael Sheets and Robert Lipinski; DevDyn 252:4, pp. 483-494; https://doi.org/10.1002/dvdy.555. The human face exhibits remarkable variation, and is also highly prone to developmental anomalies. The Frem/Fras family of extracellular matrix proteins has been implicated in regulating face shape variation as well as being mutated in the pathogenesis of disorders such as Manitoba-oculo-tricho-anal bifid nose with or without anorectal and renal anomalies, and Fraser syndromes. This study examined the activity of Frem1 during facial morphogenesis and identified Sonic Hedgehog (Shh) as an upstream regulator that promotes the proliferation of neural crest cells. Shh-Frem1 signaling is disrupted during the pathogenesis of midface hypoplasia, which provides deeper insights into the mechanisms underlying congenital craniofacial anomalies, and variation in midfacial morphogenesis. Organogenesis. “Foxd1 is required for 3D patterning of the kidney interstitial matrix by Sarah Lipp, Kathryn Jacobson, Andrew Schwaderer, David Hains and Sarah Calve; DevDyn 252:4, pp. 463-482; https://doi.org/10.1002/dvdy.545. The extracellular matrix (ECM) comprises a complex network of proteins and glycosaminoglycans that functions as a reservoir of growth factors, while also providing structural integrity and support during kidney development. This study combined 3D imaging and proteomics to investigate the role of Foxd1 in stromal cells, which are responsible for synthesizing the interstitial extracellular matrix, and document how the extracellular matrix dynamically changes during normal murine kidney development and in a model of kidney hypodysplasia. Changes in interstitial extracellular matrix corresponded to disruptions in stromal cell patterning, which helps to shed light on why human patients with connective tissue disorders have an increased incidence of kidney cysts and congenital anomalies of the kidney and urinary tract.

Oxylipins and Reactive Carbonyls as Regulators of the Plant Redox and Reactive Oxygen Species Network under Stress.

Reactive oxygen species (ROS), and in particular H2O2, serve as essential second messengers at low concentrations. However, excessive ROS accumulation leads to severe and irreversible cell damage. Hence, control of ROS levels is needed, especially under non-optimal growth conditions caused by abiotic or biotic stresses, which at least initially stimulate ROS synthesis. A complex network of thiol-sensitive proteins is instrumental in realizing tight ROS control; this is called the redox regulatory network. It consists of sensors, input elements, transmitters, and targets. Recent evidence revealed that the interplay of the redox network and oxylipins-molecules derived from oxygenation of polyunsaturated fatty acids, especially under high ROS levels-plays a decisive role in coupling ROS generation and subsequent stress defense signaling pathways in plants. This review aims to provide a broad overview of the current knowledge on the interaction of distinct oxylipins generated enzymatically (12-OPDA, 4-HNE, phytoprostanes) or non-enzymatically (MDA, acrolein) and components of the redox network. Further, recent findings on the contribution of oxylipins to environmental acclimatization will be discussed using flooding, herbivory, and establishment of thermotolerance as prime examples of relevant biotic and abiotic stresses.

Proteomic landscape of the extracellular matrix in the fibrotic kidney

The extracellular matrix (ECM) is a complex three-dimensional network of proteins surrounding cells, forming a niche that controls cell adhesion, proliferation, migration and differentiation. The ECM network provides an architectural scaffold for surrounding cells and undergoes dynamic changes in composition and contents during the evolution of chronic kidney disease (CKD). Here, we unveiled the proteomic landscape of the ECM by delineating proteome-wide and ECM-specific alterations in normal and fibrotic kidneys. Decellularized kidney tissue scaffolds were made and subjected to proteomic profiling by liquid chromatography with tandem mass spectrometry. A total of 172 differentially expressed proteins were identified in these scaffolds from mice with CKD. Through bioinformatics analysis and experimental validation, we identified a core set of nine signature proteins, which could play a role in establishing an oxidatively stressed, profibrotic, proinflammatory and antiangiogenetic microenvironment. Among these nine proteins, glutathione peroxidase 3 (GPX3) was the only protein with downregulated expression during CKD. Knockdown of GPX3 invivo augmented ECM expression and aggravated kidney fibrotic lesions after obstructive injury. Transcriptomic profiling revealed that GPX3 depletion resulted in an altered expression of the genes enriched in hypoxia pathway. Knockdown of GPX3 induced NADPH oxidase 2 expression, promoted kidney generation of reactive oxygen species and activated p38 mitogen-activated protein kinase. Conversely, overexpression of exogenous GPX3 alleviated kidney fibrosis, inhibited NADPH oxidase 2 and p38 mitogen-activated protein kinase. These findings suggest that oxidative stress is a pivotal element of the fibrogenic microenvironment. Thus, our studies represent a comprehensive proteomic characterization of the ECM in the fibrotic kidney and provide novel insights into molecular composition of the fibrogenic microenvironment.

How COVID-19 and other pathological conditions and medical treatments activate our intravascular innate immune system.

COVID-19 has been shown to have a multifaceted impact on the immune system. In a recently published article in Front Immunol, we show that the intravascular innate immune system (IIIS) is strongly activated in severe COVID-19 with ARDS and appears to be one of the causes leading to severe COVID-19. In this article, we describe the IIIS and its physiological function, but also the strong pro-inflammatory effects that are observed in COVID-19 and in various other pathological conditions and treatments such as during ischemia reperfusion injury and in treatments where biomaterials come in direct contact with blood in, e.g., extracorporeal and intravasal treatments. In the present article, we describe how the IIIS, a complex network of plasma proteins and blood cells, constitute the acute innate immune response of the blood and discuss the effects that the IIIS induces in pathological disorders and treatments in modern medicine.

Microscale mechanics of actin-vimentin composite networks.

Most eukaryotic cells contain a complex network of cytoskeletal proteins comprised of filamentous actin, microtubule, and intermediate filaments. The ability of cells to resist mechanical deformation, transport cargo, and change shape during movement depends on these cytoskeletal proteins. Several previous studies have mainly focused on exploring the mechanics of in vitro reconstituted networks consisting of only one of these components, which may not be able to predict the properties of composite networks. Thus, investigating the interplay between the components as a composite is central to understanding the underlying biophysical principles. Here, we couple optical tweezers microrheology with confocal imaging to measure the viscoelastic response and structural dynamics of in vitro reconstituted filamentous actin (F-actin) and vimentin intermediate filaments (VIFs) composite networks by varying the relative concentration of the proteins. Our measurements shed new light on how VIFs and F-actin work synergistically during the various cellular processes.

Lavender Essential Oil Modulates Hepatic Cholesterol Metabolism in HepG2 Cells.

Cholesterol is an essential lipid that guarantees several biological processes in eukaryotic cells. Its metabolism is regulated by a complex protein network that could be significantly influenced by numerous exogenous sources, such as essential oils (EOs). For instance, it has been speculated that monoterpenoid and sesquiterpenoid compounds contained in lavender essential oil (LEO) may exert important hypocholesterolemic activities. However, the molecular mechanisms by which LEO influences cholesterol homeostasis are not characterized. In this work, we evaluated the ability of LEO to regulate the protein network that controls cholesterol metabolism in the HepG2 cell line. The main findings indicate that LEO administration increases intracellular cholesterol content. Concurrently, LEO affects the expression of proteins involved in cholesterol uptake, biosynthesis, and trafficking. These effects are partially mediated by terpinene-4-ol, one of the most abundant compounds in LEO. These results demonstrate that LEO modulates cholesterol metabolism in hepatic cells.

Transcriptional regulatory mechanisms and signaling networks in cancer.

Cancer is a general term that refers to a wide range of illnesses that are characterized by the development of aberrant cells that have the capacity to divide uncontrollably, invade, and harm healthy tissue. It is caused by both genetic and epigenetic changes that suppress abnormal proliferation and prevent cells from surviving outside of their normal niches. Complex protein networks are responsible for the development of a suitable environment via multiple cells signaling pathways. The study of these pathways is essential for analysing network context and developing novel cancer therapies. Transcription factors (TFs) are actively involved in gene expression and maintain the combinatorial on-and-off states of the gene. In addition, the TFs regulate cell identity and state; these TFs cooperate to establish cell-type-specific gene expression. In this chapter, we describe the number of transcription factors and their role in the progression of cancer. The knowledge of transcriptional factors and their network is crucial for emphasizing the specific transcriptional addiction and for designing new anticancer therapies.

Harnessing abiotic organic chemistry in living systems for biomedical applications.

Living systems are composed of a complex network of bioactive small molecules, proteins, ions and electrons, which present a wealth of opportunities for researchers to explore. Recently, organic chemists have developed a keen interest to move chemical reactions from laboratory flasks into living systems. This offers a new avenue for addressing challenges in current organic chemistry, expands the range of chemical transformations accessible to living systems, and provides a versatile tool for understanding and manipulating living systems. In this tutorial review, we include both the fundamental mechanisms and specific examples of how chemical reactions that typically occur outside of the biological context can be adapted for use within living systems. We also highlight the use of the resulting functional organic materials for biomedical applications including but not limited to imaging, therapy, theranostics and organic electronics. Finally, we discuss current challenges and future perspectives in this exciting field. We envision this tutorial review will serve as a guide for designing new chemical reactions and pathways in living systems that can expand the range of biological processes and functions and will accelerate the development of new biomaterials, biocatalysts, and therapeutics for precision medicine and other social needs.

Complement C3 Regulates Inflammatory Response and Monocyte/Macrophage Phagocytosis of Streptococcus agalactiae in a Teleost Fish.

The complement system is composed of a complex protein network and is pivotal to innate immunity. Complement 3 (C3) is a critical protein in the complement cascade and participates in complement activation and immune defense. In this study, C3 from Nile tilapia (Oreochromis niloticus) was cloned and its function in resisting pathogen infection was characterized. The full length of OnC3 open reading frame is 4974 bp, encoding 1657 aa, and the predicted protein mass weight is 185.93 kDa. The OnC3 amino acid sequence contains macroglobulin domains. The expression pattern of OnC3 mRNA in the tissues of healthy fish was detected, with the highest in the liver and the lowest in the muscle. After challenged with Streptococcus agalactiae and Aeromonas hydrophila, the expression of OnC3 mRNA was significantly up-regulated in the liver, spleen, and head kidney. Further, the recombinant OnC3 protein alleviated the inflammatory response and pathological damage of tissues after infected with S. agalactiae. Moreover, the OnC3 promoted the phagocytosis of monocytes/macrophages to S. agalactiae. The data obtained in this study provide a theoretical reference for in-depth understanding of C3 in host defense against bacterial infection and the immunomodulatory roles in teleost fish.

SWATH-MS based quantitative proteomics analysis reveals novel proteins involved in PAMP triggered immunity against potato late blight pathogen Phytophthora infestans.

Potato is the most important non-grain food in the world, while late blight caused by Phytophthora infestans seriously threatens the production of potato. Since pathogen-associated molecular patterns (PAMPs) are relatively conserved, PAMP-triggered immunity (PTI) can provide durable resistance to late blight for potato. However, knowledge of the regulatory mechanisms of PTI against oomycete pathogens at protein levels remains limited due to the small number of identified proteins. In the present work, changes in the proteome profile of Nicotiana benthamiana leaves upon P. infestans PAMP induction were examined using the SWATH-MS (sequential windowed acquisition of all theoretical mass spectra) approach, which provides quantification of protein abundances and large-scale identification of PTI-related proteins. A total of 4401 proteins have been identified, of which 1429 proteins were differentially expressed at least at one time point of 8, 12, 24 and 48h after PAMP induction, compared with the expression at 0h when immediately after PAMP induction. They were further analyzed by expression clustering and gene ontology (GO) enrichment analysis. Through functional verification, six novel DEPs of 19 candidates were proved to be involved in PTI responses, including mitochondrial phosphate carrier protein (MPT) 3, vesicle-associated membrane protein (VAMP) 714, lysophospholipase (LysoPL) 2, ascorbate peroxidase (APX) 1, heat shock 70 kDa protein (HSP) 2 and peptidyl-prolyl cis-trans isomerase FKBP (FKBP) 15-1. Taken together, the time course approach and the resulting large-scale proteomic analyses have enlarged our understanding of PTI mechanisms and provided a valuable resource for the discovery of complex protein networks involved in the resistance response of potato to late blight.

The Factor H protein family: The switchers of the complement alternative pathway.

The factor H (FH) protein family is emerging as a complex network of proteins controlling the fate of the complement alternative pathway (AP) and dictating susceptibility to a wide range of diseases including infectious, inflammatory, autoimmune, and degenerative diseases and cancer. Composed, in man, of seven highly related proteins, FH, factor H-like 1, and 5 factor H-related proteins, some of the FH family proteins are devoted to down-regulating the AP, while others exert an opposite function by promoting AP activation. Recent findings have provided insights into the molecular mechanisms defining their biological roles and their pathogenicity, illustrating the relevance that the balance between the regulators and the activators within this protein family has in defining the outcome of complement activation on cell surfaces. In this review we will discuss the emerging roles of the factor H protein family, their impact in the complement cascade, and their involvement in the pathogenesis of complement-mediated diseases associated with the AP dysregulation.

Tryptophan mutations in G3BP1 tune the stability of a cellular signaling hub by weakening transient interactions with Caprin1 and USP10

Intrinsically disordered proteins (IDPs) often coordinate transient interactions with multiple proteins to mediate complex signals within large protein networks. Among these, the IDP hub protein G3BP1 can form complexes with cytoplasmic phosphoprotein Caprin1 and ubiquitin peptidase USP10; the resulting control of USP10 activity contributes to a pathogenic virulence system that targets endocytic recycling of the ion channel CFTR. However, while the identities of protein interactors are known for many IDP hub proteins, the relationship between pairwise affinities and the extent of protein recruitment and activity is not well understood. Here, we describe invitro analysis of these G3BP1 affinities and show tryptophan substitutions of specific G3BP1 residues reduce its affinity for both USP10 and Caprin1. We show that these same mutations reduce the stability of complexes between the full-length proteins, suggesting that copurification can serve as a surrogate measure of interaction strength. The crystal structure of G3BP1 TripleW (F15W/F33W/F124W) mutant reveals a clear reorientation of the side chain of W33, creating a steric clash with USP10 and Caprin1. Furthermore, an amino-acid scan of USP10 and Caprin1 peptides reveals similarities and differences in the ability to substitute residues in the core motifs as well as specific substitutions with the potential to create higher affinity peptides. Taken together, these data show that small changes in component binding affinities can have significant effects on the composition of cellular interaction hubs. These specific protein mutations can be harnessed to manipulate complex protein networks, informing future investigations into roles of these networks in cellular processes.

A Self-Assembly ICG Nanoparticle Potentiating Targeted Photothermal and Photodynamic Therapy in NSCLC.

In nonsmall cell lung cancers (NSCLC), near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has proven to be an efficient approach for locating pulmonary nodules and pulmonary sentinel lymph nodes. However, due to a lack of tumor selectivity, ICG's use as a photosensitizer for photothermal therapy (PTT) and photodynamic therapy (PDT) is restricted. In the current study, we aimed to develop a type of high-performance NIR nanoparticle formulated with ICG to enhance its targeted efficacy and tumor specificity on NSCLC. An ICG-osimertinib nanoparticle (ICG-Osi) was self-assembled through π-π stacking, with a size of 276 nm and a surface charge of -7.4 mV. The NIR visibility and epidermal growth factor receptor (EGFR) targetability of the ICG-Osi was confirmed by its binding efficiency to EGFR-expressing NSCLC cells in vitro and in vivo, regardless of EGFR mutation status. The targeted effect was further confirmed in mouse xenograft models and showed an extended tumor retention time (>96 h). We demonstrated a significantly enhanced hyperthermia effect and a retained reactive oxygen species (ROS) generating ability of ICG-Osi, resulting in a 2-fold higher cell death rate than ICG alone. The ICG-Osi down-regulated GPX4 and p62 expression while up-regulating caspase-3 and beclin1 expression in NSCLC cells, indicating a complex network of cell death-related proteins. Considering the merits of simple assembly, EGFR binding efficacy, improved hyperthermia effect, and efficient cancer cell suppression, the ICG-Osi exhibits great potential for clinical application in EGFR-expressing NSCLC therapy.

Potential application of TurboID-based proximity labeling in studying the protein interaction network in plant response to abiotic stress.

Abiotic stresses are major environmental conditions that reduce plant growth, productivity and quality. Protein-protein interaction (PPI) approaches can be used to screen stress-responsive proteins and reveal the mechanisms of protein response to various abiotic stresses. Biotin-based proximity labeling (PL) is a recently developed technique to label proximal proteins of a target protein. TurboID, a biotin ligase produced by directed evolution, has the advantages of non-toxicity, time-saving and high catalytic efficiency compared to other classic protein-labeling enzymes. TurboID-based PL has been successfully applied in animal, microorganism and plant systems, particularly to screen transient or weak protein interactions, and detect spatially or temporally restricted local proteomes in living cells. This review concludes classic PPI approaches in plant response to abiotic stresses and their limitations for identifying complex network of regulatory proteins of plant abiotic stresses, and introduces the working mechanism of TurboID-based PL, as well as its feasibility and advantages in plant abiotic stress research. We hope the information summarized in this article can serve as technical references for further understanding the regulation of plant adaptation to abiotic stress at the protein level.

Functional characterization of nutraceuticals using spectral clustering: Centrality of caveolae-mediated endocytosis for management of nitric oxide and vitamin D deficiencies and atherosclerosis.

It is well recognized that redox imbalance, nitric oxide (NO), and vitamin D deficiencies increase risk of cardiovascular, metabolic, and infectious diseases. However, clinical studies assessing efficacy of NO and vitamin D supplementation have failed to produce unambiguous efficacy outcomes suggesting that the understanding of the pharmacologies involved is incomplete. This raises the need for using systems pharmacology tools to better understand cause-effect relationships at biological systems levels. We describe the use of spectral clustering methodology to analyze protein network interactions affected by a complex nutraceutical, Cardio Miracle (CM), that contains arginine, citrulline, vitamin D, and antioxidants. This examination revealed that interactions between protein networks affected by these substances modulate functions of a network of protein complexes regulating caveolae-mediated endocytosis (CME), TGF beta activity, vitamin D efficacy and host defense systems. Identification of this regulatory scheme and the working of embedded reciprocal feedback loops has significant implications for treatment of vitamin D deficiencies, atherosclerosis, metabolic and infectious diseases such as COVID-19.

Comparative Genomics of the Waterfowl Innate Immune System.

Animal species differ considerably in their ability to fight off infections. Finding the genetic basis of these differences is not easy, as the immune response is comprised of a complex network of proteins that interact with one another to defend the body against infection. Here, we used population- and comparative genomics to study the evolutionary forces acting on the innate immune system in natural hosts of the avian influenza virus (AIV). For this purpose, we used a combination of hybrid capture, next- generation sequencing and published genomes to examine genetic diversity, divergence, and signatures of selection in 127 innate immune genes at a micro- and macroevolutionary time scale in 26 species of waterfowl. We show across multiple immune pathways (AIV-, toll-like-, and RIG-I -like receptors signalling pathways) that genes involved genes in pathogen detection (i.e., toll-like receptors) and direct pathogen inhibition (i.e., antimicrobial peptides and interferon-stimulated genes), as well as host proteins targeted by viral antagonist proteins (i.e., mitochondrial antiviral-signaling protein, [MAVS]) are more likely to be polymorphic, genetically divergent, and under positive selection than other innate immune genes. Our results demonstrate that selective forces vary across innate immune signaling signalling pathways in waterfowl, and we present candidate genes that may contribute to differences in susceptibility and resistance to infectious diseases in wild birds, and that may be manipulated by viruses. Our findings improve our understanding of the interplay between host genetics and pathogens, and offer the opportunity for new insights into pathogenesis and potential drug targets.

Using NMR to Dissect the Chemical Space and O-Sulfation Effects within the O- and S-Glycoside Analogues of Heparan Sulfate.

Heparan sulfate (HS), a sulfated linear carbohydrate that decorates the cell surface and extracellular matrix, is ubiquitously distributed throughout the animal kingdom and represents a key regulator of biological processes and a largely untapped reservoir of potential therapeutic targets. The temporal and spatial variations in the HS structure underpin the concept of “heparanome” and a complex network of HS binding proteins. However, despite its widespread biological roles, the determination of direct structure-to-function correlations is impaired by HS chemical heterogeneity. Attempts to correlate substitution patterns (mostly at the level of sulfation) with a given biological activity have been made. Nonetheless, these do not generally consider higher-level conformational effects at the carbohydrate level. Here, the use of NMR chemical shift analysis, NOEs, and spin–spin coupling constants sheds new light on how different sulfation patterns affect the polysaccharide backbone geometry. Furthermore, the substitution of native O-glycosidic linkages to hydrolytically more stable S-glycosidic forms leads to observable conformational changes in model saccharides, suggesting that alternative chemical spaces can be accessed and explored using such mimetics. Employing a series of systematically modified heparin oligosaccharides (as a proxy for HS) and chemically synthesized O- and S-glycoside analogues, the chemical space occupied by such compounds is explored and described.

Resistance to DNA repair inhibitors in cancer.

The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polθ (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.

A Key Protein Recognition Algorithm Based on High-order Complex Protein Network

Although the existing protein recognition methods have improved the recognition accuracy of key proteins to a certain extent, they have ignored the biological features of the proteins. In view of this shortcoming, this paper constructed a high-order dynamic complex protein network for key protein recognition. At first, this paper presented a method for feature selection and candidate set evaluation of complex protein network; a weighted network was constructed based on the obtained topological features of the complex protein network and the semantic similarity of protein gene ontology annotations. Then, this paper proposed an algorithm for recognizing key proteins in high-order dynamic protein network based on a Fruit fly optimization algorithm. At last, the effectiveness of the proposed model was verified by experimental results.