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This paper proposes a deep learning-based method for mitosis detection in breast histopathology images. A main problem in mitosis detection is that most of the datasets only have weak labels, i.e., only the coordinates indicating the center of the mitosis region. This makes most of the existing powerful object detection methods hardly be used in mitosis detection. Aiming at solving this problem, this paper firstly applies a CNN-based algorithm to pixelwisely segment the mitosis regions, based on which bounding boxes of mitosis are generated as strong labels. Based on the generated bounding boxes, an object detection network is trained to accomplish mitosis detection. Experimental results show that the proposed method is effective in detecting mitosis, and the accuracies outperform state-of-the-art literatures. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic tumours present significant treatment challenges due to their resistance to chemotherapy and complex tumour microenvironment. Choosing the appropriate preclinical models and understanding how their characteristics affect drug delivery to the tumours is essential for designing clinically relevant experiments. This study investigates pancreatic tumours growing orthotopically or subcutaneously and presents the properties of their tumour microenvironments and their impacts on drug delivery. Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour models are needed to test potential treatments. This paper compared orthotopic and subcutaneous PDAC tumour models and their suitability for drug delivery studies. A novel aspect was the broad range of tumour properties that were studied, including tumour growth, histopathology, functional vasculature, perfusion, immune cell infiltration, biomechanical characteristics, and especially the extensive analysis of the structure and the orientation of the collagen fibres in the two tumour models. The study unveiled new insights into how these factors impact the uptake of a fluorescent model drug, the macromolecule called 800CW. While the orthotopic model offered a more clinically relevant microenvironment, the subcutaneous model offered advantages for drug delivery studies, primarily due to its reproducibility, and it was characterised by a more efficient drug uptake facilitated by its collagen organisation and well-perfused vasculature. The tumour uptake seemed to be influenced mainly by the structural organisation and the alignment of the collagen fibres and perfusion. Recognising the diverse characteristics of these models and their multifaceted impacts on drug delivery is crucial for designing clinically relevant experiments and improving our understanding of pancreatic cancer biology. [ABSTRACT FROM AUTHOR]

TAB182 participates in DNA damage repair and radio-/chemosensitivity regulation in various tumors, but its role in tumorigenesis and therapeutic resistance in breast cancer remains unclear. In the current paper, we observed that triple-negative Breast Cancer (TNBC), a highly aggressive type of breast cancer, exhibits a lower expression of TAB182. TAB182 knockdown stimulates the proliferation, migration, and invasion of TNBC cells. Our study first obtained RNA-seq data to explore the cellular functions mediated by TAB182 at the genome level in TNBC cells. A transcriptome analysis and in vitro experiments enabled us to identify that TAB182 downregulation drives the enhanced properties of cancer stem-like cells (CSCs) in TNBC cells. Furthermore, TAB182 deletion contributes to the resistance of cells to olaparib or cisplatin, which can be rescued by silencing GLI2, a gene downstream of cancer stemness-related signaling pathways. Our results reveal a novel function of TAB182 as a potential negative regulator of cancer stem-like properties and drug sensitivity in TNBC cells, suggesting that TAB182 may be a tumor suppressor gene and is associated with increased therapeutic benefits for TNBC patients. [ABSTRACT FROM AUTHOR]

The efficiency of antimony selenide (Sb2Se3) solar cells is still limited by significant interface and deep‐level defects, in addition to carrier recombination at the back contact surface. This paper investigates the use of lithium (Li) ions as dopant for Sb2Se3 films, using lithium hydroxide (LiOH) as a dopant medium. Surprisingly, the LiOH solution not only reacts at the back surface of the Sb2Se3 film but also penetrate inside the film along the (Sb4Se6)n molecular chain. First, the Li ions modify the grain boundary's carrier type and create an electric field between p‐type grain interiors and n‐type grain boundary. Second, a gradient band structure is formed along the vertical direction with the diffusion of Li ions. Third, carrier collection and transport are improved at the surface between Sb2Se3 and the Au layer due to the reaction between the film and alkaline solution. Additionally, the diffusion of Li ions increases the crystallinity, orientation, surface evenness, and optical electricity. Ultimately, the efficiency of Sb2Se3 solar cells is improved to 7.57% due to the enhanced carrier extraction, transport, and collection, as well as the reduction of carrier recombination and deep defect density. This efficiency is also a record for CdS/Sb2Se3 solar cells fabricated by rapid thermal evaporation. [ABSTRACT FROM AUTHOR]

The nuclear membrane serves a critical role in protecting the contents of the nucleus and facilitating material and signal exchange between the nucleus and cytoplasm. While extensive research has been dedicated to topics such as nuclear membrane assembly and disassembly during cell division, as well as interactions between nuclear transmembrane proteins and both nucleoskeletal and cytoskeletal components, there has been comparatively less emphasis on exploring the regulation of nuclear morphology through nuclear membrane integrity. In particular, the role of type II integral proteins, which also function as transcription factors, within the nuclear membrane remains an area of research that is yet to be fully explored. The integrity of the nuclear membrane is pivotal not only during cell division but also in the regulation of gene expression and the communication between the nucleus and cytoplasm. Importantly, it plays a significant role in the development of various diseases. This review paper seeks to illuminate the biomolecules responsible for maintaining the integrity of the nuclear membrane. It will delve into the mechanisms that influence nuclear membrane integrity and provide insights into the role of type II membrane protein transcription factors in this context. Understanding these aspects is of utmost importance, as it can offer valuable insights into the intricate processes governing nuclear membrane integrity. Such insights have broad-reaching implications for cellular function and our understanding of disease pathogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: Oncology is a rapidly advancing field in small-animal medicine, underscoring the importance of innovative therapeutic approaches. Tyrosine kinase inhibitors (TKIs) are drugs that block various important cellular functions and play an important role in treating cancer in people and dogs. However, their role in feline oncology is less established. This comprehensive review surveys the existing literature on tyrosine kinases (TKs) and the use of TKIs in cats, aiming to identify knowledge gaps, speculate on potential indications and lay the groundwork for future investigations. Diverse feline tissues have been examined for various TK expressions. However, although limited evidence exists on the use of TKIs in specific feline tumors, it trails behind progress in human and canine oncology. We believe additional research could identify new uses for these drugs and improve therapeutic options for cats with cancer in the future. Tyrosine kinase inhibitors (TKIs) have become invaluable in the treatment of human and canine malignancies, but their role in feline oncology is less defined. While toceranib phosphate and masitinib mesylate are licensed for use in dogs, no TKI is yet approved for cats. This review systematically maps the research conducted on the expression of tyrosine kinases in neoplastic and non-neoplastic domestic feline tissues, as well as the in vitro/in vivo use of TKIs in domestic cats. We identify and discuss knowledge gaps and speculate on the further research and potential indications for TKI use in cats. A comprehensive search of three electronic databases and relevant paper reference lists identified 139 studies meeting the inclusion criteria. The most commonly identified tumors were mast cell tumors (MCTs), mammary and squamous cell carcinomas and injection-site sarcomas. Based on the current literature, toceranib phosphate appears to be the most efficacious TKI in cats, especially against MCTs. Exploring the clinical use of TKIs in mammary carcinomas holds promise. Despite the progress, currently, the evidence falls short, underscoring the need for further research to discover new indications in feline oncology and to bridge the knowledge gaps between human and feline medicine. [ABSTRACT FROM AUTHOR]

Background and Objectives: Although there are many studies on the umami receptor and its signaling pathway, literature on the effect of umami taste acuity on dietary choices in healthy subjects is limited. The current study aims to clarify the relationship between umami taste acuity with sweet or bitter taste acuity, food preference and intake.Methods and Study Design: Forty-two healthy Japanese female university students were enrolled. The acuity for umami, sweet, and bitter tastes was evaluated using the filter-paper disc method. The study population was divided into 32 umami normal tasters and 10 hypo-tasters based on the taste acuity at the posterior part of the tongue using monosodium glutamate.Results: Umami hypo-tasters exhibited a significantly lower sensitivity to sweet tastes than normal tasters. However, the sensitivity to bitter taste was comparable between the two groups. Food preference was examined by the food preference checklist consisted of 81 food items. Among them, umami tasters preferred shellfish, tomato, carrot, milk, low fat milk, cheese, dried shiitake, and kombu significantly more than umami hypo-tasters did. A self-reported food frequency questionnaire revealed no significant differences in the intake of calories and three macronutrients between the two groups; however, umami tasters were found to eat more seaweeds and less sugar than umami hypo-tasters.Conclusions: These data together may indicate the possibility that umami taste acuity has an effect on a dietary life. Therefore, training umami taste acuity from early childhood is important for a healthy diet later in life. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor microenvironment (TME) is defined as the environment surrounding a tumor. There is a close, dynamic relation and interaction between the tumor and its neighboring microenvironment. There are some particularities of the thymus itself and of the TME of thymic epithelial tumors that hinder the routine use of targeted therapies, including immune checkpoint inhibitors. The understanding of the unique characteristics of the TME of thymic epithelial tumors could possibly result in the development of novel promising therapies. The tumor microenvironment (TME) is a complex and constantly changing entity. The TME consists of stromal cells, fibroblasts, endothelial cells, and innate and adaptive immune cells. Cancer development and progression occurs through this interplay between the tumor and the adjacent stroma. Cancer cells are capable of modifying their microenvironment by secreting various message-carrying molecules, such as cytokines, chemokines, and other factors. This action causes a reprogramming of the neighboring cells, which are enabled to play a crucial role in tumor survival and progression. The study of TME has many clinical implications in terms of cancer therapeutics because many new drugs, such as antibodies, kinase inhibitors, and liposome formulations that can encapsulate anti-cancer drugs, can be developed. Although chemotherapy is considered the standard of treatment for advanced disease, recent research has brought to light immunotherapy as a possible systemic alternative. However, the complex structure and function of the thymus hinders its routine use in clinical practice. The aim of this review paper is to discuss the recent advances in the investigation of the unique characteristics of the TME of thymic epithelial tumors that could possibly lead to the development of novel promising therapies. [ABSTRACT FROM AUTHOR]

Competent statistical analysis is essential to maintain rigor and reproducibility in physiological research. Unfortunately, the benefits offered by statistics are often negated by misuse or inadequate reporting of statistical methods. To address the need for improved quality of statistical analysis in papers, the American Physiological Society released guidelines for reporting statistics in journals published by the society. The guidelines reinforce high standards for the presentation of statistical data in physiology but focus on the conceptual challenges and, thus, may be of limited use to an unprepared reader. Experimental scientists working in the renal field may benefit from putting the existing guidelines in a practical context. This paper discusses the application of widespread hypothesis tests in a confirmatory study. We simulated pharmacological experiments assessing intracellular calcium in cultured renal cells and kidney function at the systemic level to review best practices for data analysis, graphical presentation, and reporting. Such experiments are ubiquitously used in renal physiology and could be easily translated to other practical applications to fit the reader's specific needs. We provide step-by-step guidelines for using the most common types of t tests and ANOVA and discuss typical mistakes associated with them. We also briefly consider normality tests, exclusion criteria, and identification of technical and experimental replicates. This review is supposed to help the reader analyze, illustrate, and report the findings correctly and will hopefully serve as a gauge for a level of design complexity when it might be time to consult a biostatistician. [ABSTRACT FROM AUTHOR]

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Yunnan-Myanmar and its surrounding areas are the areas directly affected by the collision of the Eurasian Plate and the Indian Plate. In view of the uneven distribution of GPS stations in Yunnan and Myanmar, this paper employs the method of regionally weighted interpolation. In areas with a high concentration of GPS stations, a combination of Voronoi cell weighting function and Gaussian function weighting is utilized, while in regions with sparse GPS coverage, a combination of Voronoi cell weighting function and quadratic function weighting is employed. Utilizing the rigid-body movement uniform strain model, we calculate the horizontal strain rates of the crust in Yunnan-Myanmar and adjacent areas, followed by an in-depth analysis of model performance and the activity of primary faults. The results show that: (1) We found that Yunnan Myanmar strain has obvious boundary characteristics. (2) Upon scrutinizing the model, it was ascertained that the model delineated in this study possesses an expansive search range, enabling it to yield more precise outcomes, particularly in regions characterized by the disparate distribution of GPS stations; (3) Through the analysis of the profiles of horizontal GPS velocity field and maximum shear strain rates of the main faults in the study area, we found that the direction of the maximum shear strain rate is consistent with the direction of the main faults in the study area, and that the slip and maximum shear strain rate of the major faults increase and decrease along the tectonic direction. [ABSTRACT FROM AUTHOR]

For precision cancer radiotherapy, high linear energy transfer (LET) particle irradiation offers a substantial advantage over photon-based irradiation. In contrast to the sparse deposition of low-density energy by χ- or γ-rays, particle irradiation causes focal DNA damage through high-density energy deposition along the particle tracks. This is characterized by the formation of multiple damage sites, comprising localized clustered patterns of DNA single- and double-strand breaks as well as base damage. These clustered DNA lesions are key determinants of the enhanced relative biological effectiveness (RBE) of energetic nuclei. However, the search for a fingerprint of particle exposure remains open, while the mechanisms underlying the induction of chromothripsis-like chromosomal rearrangements by high-LET radiation (resembling chromothripsis in tumors) await to be elucidated. In this work, we investigate the transformation of clustered DNA lesions into chromosome fragmentation, as indicated by the induction and post-irradiation repair of chromosomal damage under the dynamics of premature chromosome condensation in G0 human lymphocytes. Specifically, this study provides, for the first time, experimental evidence that particle irradiation induces localized shattering of targeted chromosome domains. Yields of chromosome fragments and shattered domains are compared with those generated by γ-rays; and the RBE values obtained are up to 28.6 for α-particles (92 keV/μm), 10.5 for C-ions (295 keV/μm), and 4.9 for protons (28.5 keV/μm). Furthermore, we test the hypothesis that particle radiation-induced persistent clustered DNA lesions and chromatin decompaction at damage sites evolve into localized chromosome shattering by subsequent chromatin condensation in a single catastrophic event—posing a critical risk for random rejoining, chromothripsis, and carcinogenesis. Consistent with this hypothesis, our results highlight the potential use of shattered chromosome domains as a fingerprint of high-LET exposure, while conforming to the new model we propose for the mechanistic origin of chromothripsis-like rearrangements. [ABSTRACT FROM AUTHOR]

Background: Protein-protein interactions (PPIs) are the core of protein function, which provide an effective means to understand the function at cell level. Identification of PPIs is the crucial foundation of predicting drug-target interactions. Although traditional biological experiments of identifying PPIs are becoming available, these experiments remain to be extremely time-consuming and expensive. Therefore, various computational models have been introduced to identify PPIs. In protein-protein interaction network (PPIN), Hub protein, as a highly connected node, can coordinate PPIs and play biological functions. Detecting hot regions on Hub protein interaction interfaces is an issue worthy of discussing.Methods: Two clustering methods, LCSD and RCNOIK are used to detect the hot regions on Hub protein interaction interfaces in this paper. In order to improve the efficiency of K-means clustering algorithm, the best k value is selected by calculating the distance square sum and the average silhouette coefficients. Then, the optimization of residue coordination number strategy is used to calculate the average coordination number. In addition, the pair potentials and relative ASA (PPRA) strategy is also used to optimize the predicted results.Results: DataHub dataset and PartyHub dataset were used to train two clustering models respectively. Experiments show that LCSD and RCNOIK have the same coverage with Hub protein datasets, and RCNOIK is slightly higher than LCSD in Precision. The predicted hot regions are closer to the standard hot regions.Conclusions: This paper optimizes two clustering methods based on PPRA strategy. Compared our methods for hot regions prediction against the well-known approaches, our improved methods have the higher reliability and are effective for predicting hot regions on Hub protein interaction interfaces. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is basically a tough condition on a patient's body where cell grows uncontrollably. Normal cells are affected, which destroys the health of the patient. The main problem in cancer is spreading from one part to another. Therefore, the mathematical modeling of cancerous tumors integrates to check overall stability. A novel approach is introduced such as Bernstein polynomial with combination of genetic algorithm, sliding mode controller, and synergetic control. The proposed solution has easily eliminated cancerous cells within five days using synergetic control. In addition, five cases are incorporated to evaluate error function. In addition, a brief comparative study is added to contrast the simulation results with theoretical modeling. Cancerous tumor cells divide uncontrollably, which results in either tumor or harm to the immune system of the body. Due to the destructive effects of chemotherapy, optimal medications are needed. Therefore, possible treatment methods should be controlled to maintain the constant/continuous dose for affecting the spreading of cancerous tumor cells. Rapid growth of cells is classified into primary and secondary types. In giving a proper response, the immune system plays an important role. This is considered a natural process while fighting against tumors. In recent days, achieving a better method to treat tumors is the prime focus of researchers. Mathematical modeling of tumors uses combined immune, vaccine, and chemotherapies to check performance stability. In this research paper, mathematical modeling is utilized with reference to cancerous tumor growth, the immune system, and normal cells, which are directly affected by the process of chemotherapy. This paper presents novel techniques, which include Bernstein polynomial (BSP) with genetic algorithm (GA), sliding mode controller (SMC), and synergetic control (SC), for giving a possible solution to the cancerous tumor cells (CCs) model. Through GA, random population is generated to evaluate fitness. SMC is used for the continuous exponential dose of chemotherapy to reduce CCs in about forty-five days. In addition, error function consists of five cases that include normal cells (NCs), immune cells (ICs), CCs, and chemotherapy. Furthermore, the drug control process is explained in all the cases. In simulation results, utilizing SC has completely eliminated CCs in nearly five days. The proposed approach reduces CCs as early as possible. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper, we present an artificial Intelligence (AI) based automatic detection of mitoses in Uterine Leiomyosarcoma. Mitotic count is one of the important biomarkers in the field of histopathology. A dataset is also made available to research community which consists of images having moitotically active region. These regions are labeled by a trained AI expert in coordination with a senior histopathologist. Preliminary results show AI as promising solution for detection of mitotically active regions mitotic region in Uterine leiomyosarcoma cases and can be used as a second opinion system. Uterine leiomyosarcoma (ULMS) is the most common sarcoma of the uterus, It is aggressive and has poor prognosis. Its diagnosis is sometimes challenging owing to its resemblance by benign smooth muscle neoplasms of the uterus. Pathologists diagnose and grade leiomyosarcoma based on three standard criteria (i.e., mitosis count, necrosis, and nuclear atypia). Among these, mitosis count is the most important and challenging biomarker. In general, pathologists use the traditional manual counting method for the detection and counting of mitosis. This procedure is very time-consuming, tedious, and subjective. To overcome these challenges, artificial intelligence (AI) based methods have been developed that automatically detect mitosis. In this paper, we propose a new ULMS dataset and an AI-based approach for mitosis detection. We collected our dataset from a local medical facility in collaboration with highly trained pathologists. Preprocessing and annotations are performed using standard procedures, and a deep learning-based method is applied to provide baseline accuracies. The experimental results showed 0.7462 precision, 0.8981 recall, and 0.8151 F1-score. For research and development, the code and dataset have been made publicly available. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer continuously evolves its ability to survive in time-varying microenvironment, which results, regarding the therapeutic context, in its therapeutic resistance. As it is accepted that the development of resistance is the direct consequence of intratumour heterogeneity, its evolutionary etiology is intensively studied. Models of carinogenesis are often assessed accordingly to how well they fit into the evolutionary scenario. In the paper, the relevant observations and concepts in cancer research, such as intratumour heterogeneity, cell plasticity, and Markov cell state dynamics, are reviewed and integrated into an evolutionary model. The possibility that the interaction between cancer cells can be interpreted as cooperation is proposed. The exploitation of the evolutionary modus operandi of cancer to steer its progression towards drug sensitive cancer cells is a challenging research topic. Integrating evolutionary principles into cancer therapy requires properly identified selection level, the relevant timescale, and the respective fitness of the principal selection unit on that timescale. Interpretation of some features of cancer progression, such as increased heterogeneity of isogenic cancer cells, is difficult from the most straightforward evolutionary view with the cancer cell as the principal selection unit. In the paper, the relation between the two levels of intratumour heterogeneity, genetic, due to genetic instability, and non-genetic, due to phenotypic plasticity, is reviewed and the evolutionary role of the latter is outlined. In analogy to the evolutionary optimization in a changing environment, the cell state dynamics in cancer clones are interpreted as the risk diversifying strategy bet hedging, optimizing the balance between the exploitation and exploration of the cell state space. [ABSTRACT FROM AUTHOR]

The ongoing rise in atmospheric pCO2 and the consequent increase in ocean acidification have direct effects on marine calcifying phytoplankton which potentially translates into altered carbon export. To date it remains unclear first, how nutrient ratio, in particular from coccolithophores preferred phosphate limitation, interacts with pCO2 on particulate carbon accumulation. Second, how direct physiological responses on the cellular level translate into a net population response. In this study cultures of Emiliania huxleyi were full-factorially exposed to two different N:P ratios (Redfield and high N:P) and three different pCO2 levels. Effects on net population particulate inorganic and organic carbon (PIC, POC) were measured after E. huxleyi cultures reached stationary phase. Thereby cell sizes and total cell abundance were taken into account. Corresponding to literature results show a significant negative cellular PIC and POC response which, however, was strongest under high N:P ratio. In contrast, net population PIC and POC accumulation was significantly attenuated under high N:P ratio. We suggest that less cellular nutrient accumulation allowed for higher cell abundances which compensated for the strong negative cellular PIC and POC response to pCO2 on the population level. Moreover, the design of this study also allowed following natural alteration of carbon chemistry through changing DIC and alkalinity. Our results suggest that at high initial pCO2 natural alteration of pCO2 during the experimental runtime was regulated by algal biomass. In contrast, at low initial pCO2 the PIC/POC ratio was responsible for changes in pCO2 . Our results point to the fact that the physiological (i.e. cellular) PIC and POC response to ocean acidification cannot be linearly extrapolated to total population response and thus carbon export. It is therefore recommended to consider effects of nutrient limitation on cell physiology and translate these to net population carbon accumulation when predicting the influence of coccolithophores on both, the atmospheric pCO2 feedback and their function in carbon export mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: IRS4 (insulin receptor substrate4) belongs to a family of intracellular proteins that include IRS1 and IRS2 and whose physiological function is to transmit the effects of insulin and IGF1 inside the cell. IRS4 is the least studied of this family, and its expression has recently been shown to be increased in many types of cancer. IRS4 serves to connect different signaling pathways, such as MAP kinases and PI3K/AKT. In addition, it has been observed that it is capable of activating several oncogenes, such as BRK (breast tumor kinase) and feline sarcoma-related protein (FER). Increased IRS4 expression in cancer cells may be due to changes in the regulatory region of the gene or increased chromosomal aberrations. Our objective has been to carry out a review to assess the possibility that IRS4 behaves as a meeting point for different oncogene signaling pathways, which we have called the oncogene platform. The IRS (insulin receptor substrate) family of scaffold proteins includes insulin receptor substrate-4 (IRS4), which is expressed only in a few cell lines, including human kidney, brain, liver, and thymus and some cell lines. Its N-terminus carries a phosphotyrosine-binding (PTB) domain and a pleckstrin homology domain (PH), which distinguishes it as a member of this family. In this paper, we collected data about the molecular mechanisms that explain the relevance of IRS4 in the development of cancer and identify IRS4 differences that distinguish it from IRS1 and IRS2. Search engines and different databases, such as PubMed, UniProt, ENSEMBL and SCANSITE 4.0, were used. We used the name of the protein that it encodes "(IRS-4 or IRS4)", or the combination of these terms with the word "(cancer)" or "(human)", for searches. Terms related to specific tumor pathologies ("breast", "ovary", "colon", "lung", "lymphoma", etc.) were also used. Despite the lack of knowledge on IRS4, it has been reported that some cancers and benign tumors are characterized by high levels of IRS-4 expression. Specifically, the role of IRS-4 in different types of digestive tract neoplasms, gynecological tumors, lung cancers, melanomas, hematological tumors, and other less common types of cancers has been shown. IRS4 differs from IRS1 and IRS2 in that can activate several oncogenes that regulate the PI3K/Akt cascade, such as BRK and FER, which are characterized by tyrosine kinase-like activity without regulation via extracellular ligands. In addition, IRS4 can activate the CRKL oncogene, which is an adapter protein that regulates the MAP kinase cascade. Knowledge of the role played by IRS4 in cancers at the molecular level, specifically as a platform for oncogenes, may enable the identification and validation of new therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Ceramide and associated enzymes play a substantial role in cell function such as in cell proliferation, differentiation, and apoptosis processes. Knowing the enzymatic pathway and targeting particular enzymes from that pathway can lead to a very successful therapeutic outcome. As such, this review is focused on the elaboration of the natural products and small inhibitor molecules that can target important enzymes such as ceramidase and ceramide synthase that participate in the central lipid ceramide pathway, as well as the outcome when those pathways are disturbed during disease progression. In addition, this paper also discusses cancer that is associated with the imbalance of ceramide enzymes. Molecular targeting strategies have been used for years in order to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping this in mind, it is essential to determine the role of each enzyme in a particular metabolic pathway. In this review, we provide in-depth information on various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase which are associated with various types of cancers. We also discuss the physicochemical properties of well-studied inhibitors with natural product origins and their related structures in terms of these enzymes. Targeting ceramide metabolism exhibited promising mono- and combination therapies at preclinical stages in preventing cancer progression and cemented the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide-metabolizing enzymes will help medicinal chemists design potent and selective small molecules for treating cancer progression at various levels. [ABSTRACT FROM AUTHOR]

Terminal nucleotidyltransferases (TENTs) could generate a 'mixed tail' or 'U-rich tail' consisting of different nucleotides at the 3′ end of RNA by non-templated nucleotide addition to protect or degrade cellular messenger RNA. Recently, there has been increasing evidence that the decoration of virus RNA terminus with a mixed tail or U-rich tail is a critical way to affect viral RNA stability in virus-infected cells. This paper first briefly introduces the cellular function of the TENT family and non-canonical tails, then comprehensively reviews their roles in virus invasion and antiviral immunity, as well as the significance of the TENT family in antiviral therapy. This review will contribute to understanding the role and mechanism of non-canonical RNA tailing in survival competition between the virus and host. [ABSTRACT FROM AUTHOR]

Recent developments in stem cell technologies have made significant advancements in the field of in vitro gametogenesis. In vitro gametogenesis (IVG) is a promising technology where functional gametes (sperm or egg cells) can be generated from stem cells. Scientists have made continuous advancements in the field and successfully derived fully functional sperm from stem cells in mice. Two recent papers generated excitement in IVG by generating bi-maternal and bi-paternal mice from embryonic stem cells (ESCs) and pluripotent stem cells (PSCs). IVG is a promising technology with potential applications that include infertility treatment, fertility preservation, same-sex reproduction, bypassing oocyte depletion in women with advanced age, conservation biology, genetic disorder prevention, and research into human germ cell development. In vitro spermatogenesis (IVS) is the attempt to recreate the process of spermatogenesis in a culture system. Spermatogenesis is essential for male fertility and reproductive health, but it can be impaired by various factors such as genetic defects, environmental toxicants, infections, aging, or medical therapies. Spermatogenesis is a complex and highly regulated process involving multiple cell proliferation, differentiation, and maturation stages. The main challenges of IVS are to provide a suitable microenvironment that mimics the testis in vivo, to support the survival and development of all the cell types involved in spermatogenesis, and to achieve complete and functional spermatogenesis. Therefore, there is a great interest in developing methods to study spermatogenesis in vitro, both for basic research and clinical applications. This review covers recent developments in in vitro spermatogenesis in the past two years. Advances in tissue engineering and regenerative medicine have introduced techniques like ex vivo tissue culture and technologies such as bioreactors, microfluidic systems, and organoids. Bioreactors and microfluidic systems replicate physiological conditions for tissue and cell cultivation, while organoids model organ functionality. Meanwhile, scaffolds, made from various materials, provide essential structural support, guiding the growth and organization of cells into functional tissues. [ABSTRACT FROM AUTHOR]

Currently, women around the world are still suffering from various female common diseases with the high incidence, such as ovarian cancer, uterine fibroids and preeclampsia (PE), and some diseases are even with the high mortality rate. As a negative feedback regulator in G Protein-Coupled Receptor signaling (GPCR), the Regulator of G-protein Signaling (RGS) protein family participates in regulating kinds of cell biological functions by destabilizing the enzyme–substrate complex through the transformation of hydrolysis of G Guanosine Triphosphate (GTP). Recent work has indicated that, the Regulator of G-protein Signaling 2 (RGS2), a member belonging to the RGS protein family, is closely associated with the occurrence and development of certain female diseases, providing with the evidence that RGS2 functions in sustaining women's health. In this review paper, we summarize the current knowledge of RGS2 in female common diseases, and also tap and discuss its therapeutic potential by targeting multiple mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cells are dependent on normal cells for their survival and functionality because they can use nanoscale tubes to steal the mitochondria from immune cells. It also highlights the significance of mitochondria in the biology of cancer cells as the key organelles for cellular metabolism and energy generation. Recent research has shown that mitochondria are critical for cancer cell survival in the hostile tumor microenvironments, immune system evasion, acquisition of more aggressive characteristics, and treatment resistance. This article discusses the role of mitochondrial metabolism in cancer biology, customized cancer therapy, and how it affects cancer resistance to chemotherapy, immunotherapy, and radiation. For instance, by scavenging the produced reactive oxygen species, functioning mitochondria might enhance cancer resistance to radiation. According to this hypothesis, targeting mitochondria may improve oncological results. The tumors can respond completely to anticancer therapies or even experience malignant progression while receiving them. As a result, individualized cancer treatment is essential. Up until now, genetic analysis has been the foundation for customized cancer treatment. There is evidence that cancers with a high mitochondrial concentration are more difficult to cure. Evaluation of mitochondrial metabolism before therapy may supplement genetic data and enhance the personalization of oncological interventions. Energy is needed by cancer cells to stay alive and communicate with their surroundings. The primary organelles for cellular metabolism and energy synthesis are mitochondria. Researchers recently proved that cancer cells can steal immune cells' mitochondria using nanoscale tubes. This finding demonstrates the dependence of cancer cells on normal cells for their living and function. It also denotes the importance of mitochondria in cancer cells' biology. Emerging evidence has demonstrated how mitochondria are essential for cancer cells to survive in the harsh tumor microenvironments, evade the immune system, obtain more aggressive features, and resist treatments. For instance, functional mitochondria can improve cancer resistance against radiotherapy by scavenging the released reactive oxygen species. Therefore, targeting mitochondria can potentially enhance oncological outcomes, according to this notion. The tumors' responses to anticancer treatments vary, ranging from a complete response to even cancer progression during treatment. Therefore, personalized cancer treatment is of crucial importance. So far, personalized cancer treatment has been based on genomic analysis. Evidence shows that tumors with high mitochondrial content are more resistant to treatment. This paper illustrates how mitochondrial metabolism can participate in cancer resistance to chemotherapy, immunotherapy, and radiotherapy. Pretreatment evaluation of mitochondrial metabolism can provide additional information to genomic analysis and can help to improve personalized oncological treatments. This article outlines the importance of mitochondrial metabolism in cancer biology and personalized treatments. [ABSTRACT FROM AUTHOR]

PLC-β is widely distributed in eukaryotic cells and is the key enzyme in phosphatidylinositol signal transduction pathway. The cellular functions regulated by its four subtypes (PLC-β1, PLC-β2, PLC-β3, PLC-β4) play an important role in maintaining homeostasis of organism. PLC-β and its related signals can promote or inhibit the occurrence and development of cancer by affecting the growth, differentiation and metastasis of cells, while targeted intervention of PLC-β1-PI3K-AKT, PLC-β2/CD133, CXCR2-NHERF1-PLC-β3, Gaq-PLC-β4-PKC-MAPK and so on can provide new strategies for the precise prevention and treatment of malignant tumors. This paper reviews the mechanism of PLC-β in various tumor cells from four aspects: proliferation and differentiation, invasion and metastasis, angiogenesis and protective measures. [ABSTRACT FROM AUTHOR]

Estrogen and progesterone, acting through their cognate receptors the estrogen receptor α (ERα) and the progesterone receptor (PR) respectively, regulate uterine biology. Using rapid immunoprecipitation and mass spectrometry (RIME) and co-immunoprecipitation, we identified TRIM28 (Tripartite motif containing 28) as a protein which complexes with ERα and PR in the regulation of uterine function. Impairment of TRIM28 expression results in the inability of the uterus to support early pregnancy through altered PR and ERα action in the uterine epithelium and stroma by suppressing PR and ERα chromatin binding. Furthermore, TRIM28 ablation in PR-expressing uterine cells results in the enrichment of a subset of TRIM28 positive and PR negative pericytes and epithelial cells with progenitor potential. In summary, our study reveals the important roles of TRIM28 in regulating endometrial cell composition and function in women, and also implies its critical functions in other hormone regulated systems. This paper identifies Tripartite motif-containing 28 (TRIM28) as a novel modulator of steroid hormone signaling. TRIM28 deficiency disrupts uterine cell functions and composition leading to fertility defects [ABSTRACT FROM AUTHOR]

Tissue phenotyping is a fundamental step in computational pathology for the analysis of tumor micro-environment in whole slide images (WSIs). Automatic tissue phenotyping in whole slide images (WSIs) of colorectal cancer (CRC) assists pathologists in better cancer grading and prognostication. In this paper, we propose a novel algorithm for the identification of distinct tissue components in colon cancer histology images by blending a comprehensive learning system with deep features extraction in the current work. Firstly, we extracted the features from the pre-trained VGG19 network which are then transformed into mapped features space for nodes enhancement generation. Utilizing both mapped features and enhancement nodes, the proposed algorithm classifies seven distinct tissue components including stroma, tumor, complex stroma, necrotic, normal benign, lymphocytes, and smooth muscle. To validate our proposed model, the experiments are performed on two publicly available colorectal cancer histology datasets. We showcase that our approach achieves a remarkable performance boost surpassing existing state-of-the-art methods by (1.3% AvTP, 2% F1) and (7% AvTP, 6% F1) on CRCD-1, and CRCD-2, respectively. [ABSTRACT FROM AUTHOR]

The RNA contained in exosomes plays a crucial role in information transfer between cells in various life activities. The accurate detection of low-abundance exosome RNA (exRNA) is of great significance for cell function studies and the early diagnosis of diseases. However, their intrinsic properties, such as their short length and high sequence homology, represent great challenges for exRNA detection. In this paper, we developed a dual-signal isothermal amplification method based on rolling circle amplification (RCA) coupled with DNAzyme (RCA–DNAzyme). The sensitive detection of low-abundance exRNA, the specific recognition of their targets and the amplification of the detection signal were studied and explored. By designing padlock probes to specifically bind to the target exRNA, while relying on the ligation reaction to enhance recognition, the precise targeting of exosome RNA was realized. The combination of RCA and DNAzyme could achieve a twice-as-large isothermal amplification of the signal compared to RCA alone. This RCA–DNAzyme assay could sensitively detect a target exRNA at a concentration as low as 527 fM and could effectively distinguish the target from other miRNA sequences. In addition, this technology was successfully proven to be effective for the quantitative detection of miR-21 by spike recovery, providing a new research approach for the accurate detection of low-abundance exRNA and the exploration of unknown exRNA functions. [ABSTRACT FROM AUTHOR]

Simple Summary: This narrative literature review delves into the role of EPH/ephrin signaling in liver cancer and its implications for tumor progression and potential therapeutic strategies. This review focuses on the relationship between hypoxia and HCC development, highlighting the upregulation of hypoxia-inducible factor 1-alpha (HIF-1α) in HCC cells under low oxygen conditions. It explores the significance of the EPH/ephrin axis in regulating the hypoxic tumor microenvironment (TME) of HCC. The review also highlights the new avenues for therapeutic interventions that open the targeting of the EPH/ephrin signaling pathway in liver cancer treatment by unraveling the significance of the EPH/ephrin signaling. Liver cancer is a complex and challenging disease with limited treatment options and dismal prognosis. Understanding the underlying molecular mechanisms driving liver cancer progression and metastasis is crucial for developing effective therapeutic strategies. The EPH/ephrin system, which comprises a family of cell surface receptors and their corresponding ligands, has been implicated in the pathogenesis of HCC. This review paper aims to provide an overview of the current understanding of the role of the EPH/ephrin system in HCC. Specifically, we discuss the dysregulation of EPH/ephrin signaling in HCC and its impact on various cellular processes, including cell proliferation, migration, and invasion. Overall, the EPH/ephrin signaling system emerges as a compelling and multifaceted player in liver cancer biology. Elucidating its precise mechanisms and understanding its implications in disease progression and therapeutic responses may pave the way for novel targeted therapies and personalized treatment approaches for liver cancer patients. Further research is warranted to unravel the full potential of the EPH/ephrin system in liver cancer and its clinical translation. [ABSTRACT FROM AUTHOR]

Highly precise micromanipulation tools that can manipulate and interrogate cell organelles and components must be developed to support the rapid development of new cell-based medical therapies, thereby facilitating in-depth understanding of cell dynamics, cell component functions, and disease mechanisms. This paper presents a literature review on micro/nanomanipulation tools and their control methods for single-cell surgery. Micromanipulation methods specifically based on laser, microneedle, and untethered micro/nanotools are presented in detail. The limitations of these techniques are also discussed. The biological significance and clinical applications of single-cell surgery are also addressed in this paper. [ABSTRACT FROM AUTHOR]

Aims and Objectives: The aim of this work was to study the application of Modified Millipore technique (MMT) as a liquid-based tool to have multiple monolayer cellular smears for the routine cytology and Immunocytochemistry. Materials and Methods: In this study, we included 32 effusion fluid samples and 30 fine-needle aspiration cytology (FNAC) samples. From each of the samples, at first routine conventional smear was prepared. The residual samples were processed by MMT to make multiple smear preparation. Both the conventional and MMT of the monolayer cells were evaluated. The various cytomorphological features including the cellularity, background information, nuclear morphology, and cytoplasmic preservation were compared in these two techniques. Result: There were a total of 15 cases of fluid samples and 27 cases of FNAC. Statistical analysis of Mann–Whitney U test showed that the monolayer preparation by MMT and liquid-based cytology of fluid and FNAC smears are of same quality (P > 0.01). Conclusion: Monolayer preparation by MMT is cheap and effective. This technique can be used in routine laboratory for multiple monolayer cell preparations. [ABSTRACT FROM AUTHOR]

In the fractional frequency reuse (FFR) system, the bandwidth is partitioned into orthogonal subbands such that users in the cell-center region use the subbands of a frequency reuse factor (FR factor) equal to 1, whereas users in the cell-edge region exploit the subbands of an FR factor larger than 1. The distance threshold, which is used to distinguish the cell-edge region from the cell-center region, is an important factor in FFR system performance. In this paper, we study the optimal distance threshold to maximize system throughput in the downlink cellular networks, including aerial base stations. Subject to the constraint that a given target outage probability is satisfied, the optimal distance threshold is analyzed as a function of the cell size. It is proven that when the sizes of all cells in the network are scaled at the same rate, the optimal distance threshold normalized by the cell size is nondecreasing in the cell size. The analytical results in this paper provide a system design guideline for initial planning of FFR cellular networks of different sizes, including macro, pico, and femto systems. In particular, for size-scalable aerial networks comprising base stations in the sky, such as balloons or unmanned aerial vehicles, our analysis offers insight into the design of the distance threshold with regard to the cell size. [ABSTRACT FROM AUTHOR]

This paper provides a simple unified analysis of optimal interval division problems. My primitive is a cell function that assigns a value to each subinterval (cell). Submodular cell functions conveniently imply the property of decreasing marginal returns. Also, for coarse decision problems, optimal cutoffs commonly increase as prior belief shifts upward. Its implications on language and efficient menus are discussed. [ABSTRACT FROM AUTHOR]

Cell shape plays a fundamental role in many biological processes, including adhesion, migration, division and development, but it is not clear which shape model best predicts three-dimensional cell shape in structured environments. Here, we compare different modelling approaches with experimental data. The shapes of single mesenchymal cells cultured in custom-made 3D scaffolds were compared by a Fourier method with surfaces that minimize area under the given adhesion and volume constraints. For the minimized surface model, we found marked differences to the experimentally observed cell shapes, which necessitated the use of more advanced shape models. We used different variants of the cellular Potts model, which effectively includes both surface and bulk contributions. The simulations revealed that the Hamiltonian with linear area energy outperformed the elastic area constraint in accurately modelling the 3D shapes of cells in structured environments. Explicit modelling the nucleus did not improve the accuracy of the simulated cell shapes. Overall, our work identifies effective methods for accurately modelling cellular shapes in complex environments. Author summary: Cell shape and forces have emerged as important determinants of cell function and thus their prediction is essential to describe and control the behaviour of cells in complex environments. While there exist well-established models for the two-dimensional shape of cells on flat substrates, it is less clear how cell shape should be modeled in three dimensions. Different from the philosophy of the vertex model often used for epithelial sheets, we find that models based only on cortical tension as a constant geometrical surface tension are not sufficient to describe the shape of single cells in 3D. Therefore, we employ different variants of the cellular Potts model, where either a target area is prescribed by an elastic constraint or the area energy is described with a linear surface tension. By comparing the simulated shapes to experimental images of cells in 3D scaffolds, we can identify parameters that accurately model 3D cell shape. [ABSTRACT FROM AUTHOR]

INTRODUCTION This study aimed to investigate the effects of nicotine on the activation of pancreatic stellate cells (PSCs) and pancreatic fibrosis in chronic pancreatitis (CP), along with its underlying molecular mechanisms. METHODS This was an in vivo and in vitro study. In vitro, PSCs were cultured to study the effects of nicotine on their activation and oxidative stress. Transcriptome sequencing was performed to identify potential signaling pathways involved in nicotine action. And the impact of nicotine on mitochondrial Ca2+ levels and Ca2+ transport-related proteins in PSCs was analyzed. The changes in nicotine effects were observed after the knockdown of the mitochondrial calcium uniporter (MCU) in PSCs. In vivo experiments were conducted using a mouse model of CP to assess the effects of nicotine on pancreatic fibrosis and oxidative stress in mice. The alterations in nicotine effects were observed after treatment with the MCU inhibitor Ru360. RESULTS In vitro experiments demonstrated that nicotine promoted PSCs activation, characterized by increased cell proliferation, elevated α-SMA and collagen expression. Nicotine also increased the production of reactive oxygen species (ROS) and cellular malondialdehyde (MDA), exacerbating oxidative stress damage. Transcriptome sequencing revealed that nicotine may exert its effects through the calcium signaling pathway, and it was verified that nicotine elevated mitochondrial Ca2+ levels and upregulated MCU expression. Knockdown of MCU reversed the effects of nicotine on mitochondrial calcium homeostasis, improved mitochondrial oxidative stress damage and structural dysfunction, thereby alleviating the activation of PSCs. In vivo validation experiments showed that nicotine significantly aggravated pancreatic fibrosis in CP mice, promoted PSCs activation, exacerbated pancreatic tissue oxidative stress, and increased MCU expression. However, treatment with Ru360 significantly mitigated these effects. CONCLUSIONS This study confirms that nicotine upregulates the expression of MCU, leading to mitochondrial calcium overload and exacerbating oxidative stress in PSCs, and ultimately promoting PSCs activation and exacerbating pancreatic fibrosis in CP. [ABSTRACT FROM AUTHOR]

This document is an editorial introducing a special issue of the journal Pharmaceuticals on the topic of small molecules targeting protein-protein interactions (PPIs) for the development of new drugs. PPIs play a crucial role in cellular functions and the dysregulation of these interactions is associated with various diseases. The special issue focuses on the use of small molecules as modulators of PPIs, which offer advantages over larger protein-based therapeutics. The document provides a summary of the highlighted papers in the special issue, which cover topics such as the inhibition of oxidative stress in alcoholic liver disease, the design of small molecules targeting specific protein interactions, and the discovery of inhibitors for COVID-19 and cancer immunotherapy. The document concludes by emphasizing the importance of small molecules in modulating PPIs and their potential for effective therapeutic interventions. [Extracted from the article]

Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to function under low oxygen tension and metabolic stress. While Hypoxia-Inducible Factor (HIF)-1α has been shown to be essential for the inflammatory response of myeloid cells by regulating the metabolic switch to glycolysis, less is known about how HIF1α is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1α (IRE1α/XBP1) axis in order to initiate HIF1α-dependent production of cytokines such as IL1β, IL6 and VEGF-A. Knockout of either HIF1α or IRE1α in myeloid cells ameliorates vascular phenotypes in a model of retinal pathological angiogenesis driven by sterile inflammation. Thus, pathways associated with ER stress, in partnership with HIF1α, may co-regulate immune adaptation to low oxygen. [ABSTRACT FROM AUTHOR]

Simple Summary: As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, extracellular matrix (ECM), and soluble molecules forming the widely recognized tumor microenvironment. The main components of the tumor microenvironment include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), ECM, and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). The tumor microenvironment has been suggested to play a central role in tumor progression and treatment resistance. Accumulated evidence indicates that tumor maintenance, progression, and treatment resistance are determined by components of the microenvironment. Thus, targeting the components of the tumor microenvironment may have a therapeutic impact on melanoma treatment. The main topic of this paper deals with the main components of the tumor microenvironment and their impact as therapeutic targets in melanoma treatment. The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: If a perfume is released into a room, the occupants will immediately smell it; however, after a few minutes, they will become desensitized to the odor, although it is still in the room, as would be attested by newcomers to the gathering. Such behavior is called 'adaptation.' In response to a stepwise increase in an incoming signal (perfume), a sensory cell (the olfactory cell in the nose) sends an output signal (nerve impulses) to an organ (the brain) that responds appropriately (attraction or repulsion, say); however, in the continued presence of the input signal, the sensory cell ceases to respond and reverts to its 'resting' state. There are many examples of such near-perfect adaptive responses in the physiology of living cells, and it is natural to inquire as to the underlying molecular bases of such behavior. Using an evolutionary search procedure, this paper examines a wide class of molecular interaction networks for their potential to exhibit near-perfect adaptation. Adaptive networks that are stable to evolutionary fluctuations are characterized by a simple motif with two paths: (i) an incoming signal activates a receptor molecule, which activates an output signal, and simultaneously (ii) the receptor activates a modulator component that inhibits the output. Large-scale protein regulatory networks, such as signal transduction systems, contain small-scale modules ('motifs') that carry out specific dynamical functions. Systematic characterization of the properties of small network motifs is therefore of great interest to molecular systems biologists. We simulate a generic model of three-node motifs in search of near-perfect adaptation, the property that a system responds transiently to a change in an environmental signal and then returns near-perfectly to its pre-signal state (even in the continued presence of the signal). Using an evolutionary algorithm, we search the parameter space of these generic motifs for network topologies that score well on a pre-defined measure of near-perfect adaptation. We find many high-scoring parameter sets across a variety of three-node topologies. Of all possibilities, the highest scoring topologies contain incoherent feed-forward loops (IFFLs), and these topologies are evolutionarily stable in the sense that, under 'macro-mutations' that alter the topology of a network, the IFFL motif is consistently maintained. Topologies that rely on negative feedback loops with buffering (NFLBs) are also high-scoring; however, they are not evolutionarily stable in the sense that, under macro-mutations, they tend to evolve an IFFL motif and may—or may not—lose the NFLB motif. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is one of the life‐threatening diseases of the digestive system. MicroRNA has been asserted to be a regulator of AP. This paper explored the miR‐374a‐5p expression in AP patients and investigated the efficacy of AR42J cells. In this study, 60 healthy people, 58 MAP patients and 58 SAP patients were included, and the serum miR‐374a‐5p levels of the subjects were detected by RT‐qPCR technology. The pancreatitis cell model was structured by stimulating AR42J cells with cerulein. Next, cell viability and apoptosis were detected by CCK‐8 assay and flow cytometry. ELISA was used to measure the concentration of cytokines, such as TNF‐α, IL‐6, and IL‐1β. The data showed that miR‐374a‐5p was downregulated in samples from AP patients, while showing discriminative power for AP populations. Attenuated miR‐374a‐5p were negatively bound up with patients' Ranson score and APACHE II score. Besides, miR‐374a‐5p was declined in cerulein‐treated AR42J cells and forced elevation of miR‐374a‐5p was beneficial to increase cell viability, and inhibit cell apoptosis and inflammation. The present study found that miR‐374a‐5p was reduced in AP serum samples, and up‐regulated expression level of miR‐374a‐5p in cell models had a protective effect on cerulein‐induced inhibition of cell function and inflammatory response. [ABSTRACT FROM AUTHOR]