RESUMO
Cancer, recognized as a primary cause of death worldwide, has profound health implications and incurs a substantial social burden. Numerous efforts have been made to develop cancer treatments, among which anticancer peptides (ACPs) are garnering recognition for their potential applications. While ACP screening is time-consuming and costly, in silico prediction tools provide a way to overcome these challenges. Herein, we present a deep learning model designed to screen ACPs using peptide sequences only. A contrastive learning technique was applied to enhance model performance, yielding better results than a model trained solely on binary classification loss. Furthermore, two independent encoders were employed as a replacement for data augmentation, a technique commonly used in contrastive learning. Our model achieved superior performance on five of six benchmark datasets against previous state-of-the-art models. As prediction tools advance, the potential in peptide-based cancer therapeutics increases, promising a brighter future for oncology research and patient care.
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Antineoplásicos , Aprendizado Profundo , Peptídeos , Peptídeos/química , Peptídeos/uso terapêutico , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Neoplasias/tratamento farmacológico , Biologia Computacional/métodos , Aprendizado de Máquina , AlgoritmosRESUMO
PURPOSE: Ischemia-reperfusion injury is inevitable during donor organ harvest and recipient allograft reperfusion in kidney transplantation, and affects graft outcomes. Dexmedetomidine, an α2-adrenoreceptor agonist, has renoprotective effects against ischemia-reperfusion injury. We investigated the effects of intraoperative dexmedetomidine infusion on renal function and the development of delayed graft function after elective living donor kidney transplantation in a randomized controlled trial. METHODS: A total of 104 patients were randomly assigned to receive either an intraoperative infusion of dexmedetomidine 0.4 µg·kg-1·hr-1 or 0.9% saline. The primary outcome was the serum creatinine level on postoperative day (POD) 7. Secondary outcomes were renal function and the degree of inflammation and included the following variables: serum creatinine level and estimated glomerular filtration rate up to six months; incidence of delayed graft function; and levels of serum cystatin C, plasma interleukin (IL)-1ß, and IL-18 during the perioperative period. RESULTS: The mean (standard deviation) serum creatinine level on POD 7 was comparable between the groups (dexmedetomidine vs control: 1.11 [0.87] mg·dL-1 vs 1.06 [0.73] mg·dL-1; mean difference, 0.05; 95% confidence interval, -0.27 to 0.36; P = 0.77). Delayed graft function occurred in one patient in each group (odds ratio, 1.020; P > 0.99). There were no significant differences in the secondary outcomes between the groups (all P > 0.05). CONCLUSIONS: Intraoperative dexmedetomidine infusion did not produce any beneficial effects on renal function or delayed graft function in patients undergoing elective living donor kidney transplantation. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT03327389); registered 31 October 2017.
RéSUMé: OBJECTIF: Les lésions d'ischémie-reperfusion sont inévitables lors du prélèvement d'organes du donneur et de la reperfusion de l'allogreffe chez le receveur pour une transplantation rénale, et affectent le devenir du greffon. La dexmédétomidine, un agoniste des adrénorécepteurs de type α2, a des effets néphroprotecteurs sur les lésions d'ischémie-reperfusion. Nous avons réalisé une étude randomisée contrôlée afin d'examiner les effets d'une perfusion peropératoire de dexmédétomidine sur la fonction rénale et l'apparition d'un retard de fonctionnement du greffon après une transplantation rénale élective issue de donneurs vivants. MéTHODE: Au total, 104 patients ont été aléatoirement répartis pour recevoir une perfusion peropératoire de 0,4 µg·kg-1·r-1 de dexmédétomidine ou une solution saline à 0,9 %. Le critère d'évaluation principal était la créatininémie au jour postopératoire (JPO) 7. Les critères d'évaluation secondaires étaient la fonction rénale et le degré d'inflammation et comprenaient les variables suivantes : créatininémie et infiltration glomérulaire estimée jusqu'à six mois; incidence de retard de fonctionnement du greffon; et taux sériques de cystatine C, d'interleukine plasmatique (IL)-1ß et d'IL-18 pendant la période périopératoire. RéSULTATS: Le taux moyen (écart type) de créatinine sérique au JPO 7 était comparable entre les groupes (dexmédétomidine vs témoin : 1,11 [0,87] mg·dL-1 vs 1,06 [0,73] mg·dL-1; différence moyenne, 0,05; intervalle de confiance à 95 %, -0,27 à 0,36; P = 0,77). Un patient de chaque groupe a subi un retard de fonctionnement du greffon (rapport de cotes, 1,020; P > 0.99). Aucune différence intergroupe significative n'a été observée en ce qui concerne les critères d'évaluation secondaires. CONCLUSION: La perfusion peropératoire de dexmédétomidine n'a produit aucun effet bénéfique sur la fonction rénale ou le retard de fonctionnement du greffon chez les patients bénéficiant d'une transplantation rénale élective issue de donneur vivant. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT03327389); enregistrée le 31 octobre 2017.
Assuntos
Dexmedetomidina , Transplante de Rim , Dexmedetomidina/farmacologia , Taxa de Filtração Glomerular , Humanos , Rim/fisiologia , Doadores VivosRESUMO
MOTIVATION: Feedback circuits are crucial network motifs, ubiquitously found in many intra- and inter-cellular regulatory networks, and also act as basic building blocks for inducing synchronized bursting behaviors in neural network dynamics. Therefore, the system-level identification of feedback circuits using time-series measurements is critical to understand the underlying regulatory mechanism of synchronized bursting behaviors. RESULTS: Multi-Step Granger Causality Method (MSGCM) was developed to identify feedback loops embedded in biological networks using time-series experimental measurements. Based on multivariate time-series analysis, MSGCM used a modified Wald test to infer the existence of multi-step Granger causality between a pair of network nodes. A significant bi-directional multi-step Granger causality between two nodes indicated the existence of a feedback loop. This new identification method resolved the drawback of the previous non-causal impulse response component method which was only applicable to networks containing no co-regulatory forward path. MSGCM also significantly improved the ratio of correct identification of feedback loops. In this study, the MSGCM was testified using synthetic pulsed neural network models and also in vitro cultured rat neural networks using multi-electrode array. As a result, we found a large number of feedback loops in the in vitro cultured neural networks with apparent synchronized oscillation, indicating a close relationship between synchronized oscillatory bursting behavior and underlying feedback loops. The MSGCM is an efficient method to investigate feedback loops embedded in in vitro cultured neural networks. The identified feedback loop motifs are considered as an important design principle responsible for the synchronized bursting behavior in neural networks.
Assuntos
Causalidade , Biologia Computacional/métodos , Retroalimentação , Redes Neurais de Computação , Algoritmos , Animais , Simulação por Computador , RatosRESUMO
Cancer is caused by the accumulation of genetic alterations and therefore has been historically considered to be irreversible. Intriguingly, several studies have reported that cancer cells can be reversed to be normal cells under certain circumstances. Despite these experimental observations, conceptual and theoretical frameworks that explain these phenomena and enable their exploration in a systematic way are lacking. In this review, we provide an overview of cancer reversion studies and describe recent advancements in systems biological approaches based on attractor landscape analysis. We suggest that the critical transition in tumorigenesis is an important clue for achieving cancer reversion. During tumorigenesis, a critical transition may occur at a tipping point, where cells undergo abrupt changes and reach a new equilibrium state that is determined by complex intracellular regulatory events. We introduce a conceptual framework based on attractor landscapes through which we can investigate the critical transition in tumorigenesis and induce its reversion by combining intracellular molecular perturbation and extracellular signaling controls. Finally, we present a cancer reversion therapy approach that may be a paradigm-changing alternative to current cancer cell-killing therapies.
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Carcinogênese , Neoplasias , Humanos , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Neoplasias/genética , Mutação , Transdução de SinaisRESUMO
PURPOSE: The estimated glomerular filtration rate (eGFR) at 6 months after donation (eGFR6m) is strongly associated with the risk of end-stage renal disease in living kidney donors. This study aimed to investigate the incidence of eGFR6m <60 mL/min/1.73 m² (eGFR6m <60) and identify the risk factors that can predict the occurrence of eGFR6m <60 in living kidney donors. MATERIALS AND METHODS: Living kidney donors who underwent nephrectomy at Severance Hospital between January 2009 and December 2019 were identified. We excluded 94 of 1233 donors whose creatinine values at 6 months after donation were missing. The risk factors for eGFR6m <60 were assessed using multivariate regression analysis. The optimal cutoff points for candidate risk factors for predicting eGFR6m <60 occurrence were determined using the Youden index. RESULTS: The eGFR6m <60 occurred in 17.3% of the participants. Older age (≥44 years), history of hypertension, lower preoperative eGFR (<101 mL/min/1.73 m²), and degree of increase in creatinine levels on postoperative day 2 compared to those before surgery (ΔCr2_pre) (≥0.39 mg/dL) increased the risk of eGFR6m <60. The addition of ΔCr2_pre to preoperative eGFR yielded a higher predictive accuracy for predicting eGFR6m <60 than that with preoperative eGFR alone {area under the receiver operating characteristic curve=0.886 [95% confidence interval (CI), 0.863-0.908] vs. 0.862 (95% CI, 0.838-0.887), p<0.001}. CONCLUSION: The incidence of eGFR6m <60 was 17.3%. Older age, lower preoperative eGFR, history of hypertension, and greater ΔCr2_pre were associated with the occurrence of eGFR6m <60 after living donor nephrectomy. The combination of preoperative eGFR and ΔCr2_pre showed the highest predictive power for eGFR6m <60.
Assuntos
Hipertensão , Transplante de Rim , Humanos , Taxa de Filtração Glomerular , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Doadores Vivos , Creatinina , Rim/cirurgia , Rim/fisiologia , Nefrectomia/efeitos adversosRESUMO
Objective:The main objective of this study was to induce and evaluate drug-dose-dependent outer retinal degeneration in cynomolgus monkeys by application of N-methyl-N-nitrosourea (MNU).Approach:Intravitreal temporary tamponade induced outer retinal degeneration with MNU solutions (2-3 mg ml-1) after vitrectomy in five cynomolgus monkeys. Optical coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinography (ffERG), and visual evoked potentials (VEP) were performed at baseline and weeks 2, 6, and 12 postoperatively. At week 12, OCT angiography, histology, and immunohistochemistry were performed.Main results:Outer retinal degeneration was observed in four monkeys, especially in the peripheral retina. Anatomical and functional changes occurred at week 2 and persisted until week 12. FAF images showed hypoautofluorescence dots, similar to AF patterns seen in human retinitis pigmentosa. Hyperautofluorescent lesions in the pericentral area were also observed, which corresponded to the loss of the ellipsoid zone on OCT images. OCT revealed thinning of the outer retinal layer adding to the loss of the ellipsoid zone outside the vascular arcade. Histological findings confirmed that the abovementioned changes resulted from a gradual loss of photoreceptors from the perifovea to the peripheral retina. In contrast, the inner retina, including ganglion cell layers, was preserved. Functionally, a decrease or extinction of scotopic ffERGs was observed, which indicated rod-dominant loss. Nevertheless, VEPs were relatively preserved.Significance:Therefore, we can conclude that temporary exposure to intravitreal MNU tamponade after vitrectomy induces rod-dominant outer retinal degeneration in cynomolgus monkeys, especially in the peripheral retina.
Assuntos
Degeneração Retiniana , Animais , Macaca fascicularis , Metilnitrosoureia/efeitos adversos , Potenciais Evocados Visuais , Retina/patologia , Primatas , Tomografia de Coerência Óptica/métodosRESUMO
Biological oscillations are found ubiquitously in cells and are widely variable, with periods varying from milliseconds to months, and scales involving subcellular components to large groups of organisms. Interestingly, independent oscillators from different cells often show synchronization that is not the consequence of an external regulator. What is the underlying design principle of such synchronized oscillations, and can modeling show that the complex consequences arise from simple molecular or other interactions between oscillators? When biological oscillators are coupled with each other, we found that synchronization is induced when they are connected together through a positive feedback loop. Increasing the coupling strength of two independent oscillators shows a threshold beyond which synchronization occurs within a few cycles, and a second threshold where oscillation stops. The positive feedback loop can be composed of either double-positive (PP) or double-negative (NN) interactions between a node of each of the two oscillating networks. The different coupling structures have contrasting characteristics. In particular, PP coupling is advantageous with respect to stability of period and amplitude, when local oscillators are coupled with a short time delay, whereas NN coupling is advantageous for a long time delay. In addition, PP coupling results in more robust synchronized oscillations with respect to amplitude excursions but not period, with applied noise disturbances compared to NN coupling. However, PP coupling can induce a large fluctuation in the amplitude and period of the resulting synchronized oscillation depending on the coupling strength, whereas NN coupling ensures almost constant amplitude and period irrespective of the coupling strength. Intriguingly, we have also observed that artificial evolution of random digital oscillator circuits also follows this design principle. We conclude that a different coupling strategy might have been selected according to different evolutionary requirements.
Assuntos
Relógios Biológicos/fisiologia , Modelos Biológicos , Animais , Engenharia Biomédica , Fenômenos Fisiológicos Celulares , HumanosRESUMO
Oxygen supplementation is crucial for awake tracheal intubation (ATI) using a flexible bronchoscope in patients with an anticipated difficult airway. However, the modality of optimal oxygen delivery remains unclear. This retrospective study compared high-flow nasal oxygen (HFNO) and conventional low-flow oxygen supply during ATI. We applied inverse probability of treatment weighting (IPTW) to account for biases due to clinical characteristic differences between the groups. The primary endpoint was the lowest oxygen saturation during ATI. The secondary endpoints were incidence of desaturation, multiple attempts, failure rate, and procedural duration. After IPTW adjustment, the lowest oxygen saturation in the HFNO group during ATI was significantly higher than that in the conventional oxygenation group (99.3 ± 0.2 vs. 97.5 ± 0.5, P < 0.001). Moreover, the HFNO group had fewer cases with multiple attempts than the conventional oxygenation group (3% vs. 16%, P = 0.007). There were no significant differences between the two groups in the incidence of desaturation, failure and procedural duration. Our findings suggest that HFNO was associated with improved lowest oxygen saturation and a lower rate of multiple attempts during ATI. Therefore, we recommend using HFNO for safer oxygen delivery and improved quality of procedure during ATI.
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Oxigênio , Vigília , Humanos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/métodos , Pontuação de Propensão , Estudos Retrospectivos , TraqueiaRESUMO
Freezing is a common process applied in the pharmaceutical industry to store and transport biotherapeutics. Herewith, multi-scale molecular dynamics simulations of Lactate dehydrogenase (LDH) protein in phosphate buffer with/without ice formation performed to uncover the still poorly understood mechanisms and molecular details of protein destabilization upon freezing. Both fast and slow ice growing conditions were simulated at 243 K from one or two-side of the simulation box, respectively. The rate of ice formation at all-atom simulations was crucial to LDH stability, as faster freezing rates resulted in enhanced structural stability maintained by a higher number of intramolecular hydrogen bonds, less flexible protein's residues, lower solvent accessibility and greater structural compactness. Further, protein aggregation investigated by coarse-grained simulations was verified to be initiated by extended protein structures and retained by electrostatic interactions of the salt bridges between charged residues and hydrogen bonds between polar residues of the protein. Lastly, the study of free energy of dissociation through steered molecular dynamics simulation revealed LDH was destabilized by the solvation of the hydrophobic core and the loss of hydrophobic interactions. For the first time, experimentally validated molecular simulations revealed the detailed mechanisms of LDH destabilization upon ice formation and cryoconcentration of solutes.
Assuntos
Simulação de Dinâmica Molecular , Proteínas , Congelamento , Ligação de Hidrogênio , Eletricidade EstáticaRESUMO
Purpose: To present normative data of optical coherence tomography (OCT) parameters, electrophysiological tests, and optical biometry conducted for cynomolgus monkeys. Methods: Multimodal examinations were performed for 11 adult cynomolgus monkeys (Macaca fascicularis, weighing 2.6-7.5 kg, aged 45-99 months). A-scan biometry was performed to measure ocular biometry. OCT images were obtained at 30° and 55°. After the pupils were fully dilated, electroretinogram (ERG) and visual evoked potentials (VEP) were recorded with a commercial system using a contact lens electrode. Results: All cynomolgus monkeys were males. The mean axial length was 17.92 ± 0.34 mm. The central total retinal layer (TRL) and subfoveal choroidal thicknesses were 286.27 ± 18.43 and 234.73 ± 53.93 µm, respectively. The TRL and nerve fiber layer thickness was greater in the nasal than in other quadrants in the Early Treatment Diabetic Retinopathy Study circle in the macula. Peripheral TRL and ganglion cell complex thickness on the temporal outside the vascular arcades were lower than on the other sides. The peak latency of a-wave and b-wave in scotopic and photopic 3.0 ERG was 14.78 ± 1.00 and 32.89 ± 1.81 ms, and 12.91 ± 1.03 and 31.79 ± 2.16 ms, respectively. The n2 wave peak latency of VEP was 15.21 ± 8.07 ms. The a-wave peak latency of ERG and the n2 wave peak latency of VEP negatively correlated with age. Conclusions: The normative ocular biometric, electrophysiological test, and OCT parametric data of cynomolgus monkeys could serve as reference values for further preclinical studies. Translational Relevance: We present normative data of cynomolgus monkeys' eyes, an adequate animal model for preclinical studies.
Assuntos
Potenciais Evocados Visuais , Tomografia de Coerência Óptica , Animais , Biometria , Eletrofisiologia , Macaca fascicularis , MasculinoRESUMO
Many clinical trials for cancer precision medicine have yielded unsatisfactory results due to challenges such as drug resistance and low efficacy. Drug resistance is often caused by the complex compensatory regulation within the biomolecular network in a cancer cell. Recently, systems biological studies have modeled and simulated such complex networks to unravel the hidden mechanisms of drug resistance and identify promising new drug targets or combinatorial or sequential treatments for overcoming resistance to anticancer drugs. However, many of the identified targets or treatments present major difficulties for drug development and clinical application. Nanocarriers represent a path forward for developing therapies with these "undruggable" targets or those that require precise combinatorial or sequential application, for which conventional drug delivery mechanisms are unsuitable. Conversely, a challenge in nanomedicine has been low efficacy due to heterogeneity of cancers in patients. This problem can also be resolved through systems biological approaches by identifying personalized targets for individual patients or promoting the drug responses. Therefore, integration of systems biology and nanomaterial engineering will enable the clinical application of cancer precision medicine to overcome both drug resistance of conventional treatments and low efficacy of nanomedicine due to patient heterogeneity.
Assuntos
Engenharia , Nanomedicina/métodos , Neoplasias , Medicina de Precisão/métodos , Biologia de Sistemas , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Integração de SistemasRESUMO
BACKGROUND: Adrenal insufficiency (AI) is associated with high morbidity and mortality. The aim of this systematic review was to enhance diagnostic approaches and summarize therapeutic strategies in the management of AI in patients with systematic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). METHODS: A literature search of PubMed and Medline databases was performed and 91 publications containing 105 cases were included for the final analysis. RESULTS: The following frequency of clinical signs and symptoms was noted: abdominal pain (39.04%) was the leading symptom, followed by fever (33.33%), vomiting (23.81%), and nausea (19.05%). APS was present in 73%, SLE in 17% of the patients, while 2% had a diagnosis of both, SLE and APS. ACTH stimulation test (ACTHst) was performed in 18% of cases and 76.6% of them were unresponsive towards stimulation. Variable treatment approaches were used: hydrocortisone was most commonly used (38.09%), followed by fludrocortisone (26.67%), prednisolone (20.00%) and volume replacement treatment (11.43%), respectively. CONCLUSIONS: This analysis highlights the importance of an early diagnosis and initiation of therapeutic management when AI is suspected. In line, signs and symptoms related to autoimmune diseases in patients with AI should be reviewed crtitically.
Assuntos
Insuficiência Adrenal/etiologia , Síndrome Antifosfolipídica/complicações , Lúpus Eritematoso Sistêmico/complicações , Adolescente , Insuficiência Adrenal/mortalidade , Insuficiência Adrenal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome Antifosfolipídica/imunologia , Criança , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
A key step in sensory information processing involves modulation and integration of neuronal oscillations in disparate frequency bands, a poorly understood process. Here, we investigate how top-down input causes frequency changes in slow oscillations during sensory processing and, in turn, how the slow oscillations are combined with fast oscillations (which encode sensory input). Using experimental connectivity patterns and strengths of interneurons, we develop a system-level model of a neuronal circuit controlling these oscillatory behaviors, allowing us to understand the mechanisms responsible for the observed oscillatory behaviors. Our analysis discovers a circuit capable of producing the observed oscillatory behaviors and finds that a detailed balance in the strength of synaptic connections is the critical determinant to produce such oscillatory behaviors. We not only uncover how disparate frequency bands are modulated and combined but also give insights into the causes of abnormal neuronal activities present in brain disorders.
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Retroalimentação , Neurônios/fisiologia , Sensação/fisiologia , Interneurônios/fisiologia , Modelos Neurológicos , Células Piramidais/fisiologia , Sinapses/fisiologiaRESUMO
Although fibroblasts are dormant in normal tissue, they exhibit explosive activation during wound healing and perpetual activation in pathologic fibrosis and cancer stroma. The key regulatory network controlling these fibroblast dynamics is still unknown. Here, we report that Twist1, a key regulator of cancer-associated fibroblasts, directly upregulates Prrx1, which, in turn, increases the expression of Tenascin-C (TNC). TNC also increases Twist1 expression, consequently forming a Twist1-Prrx1-TNC positive feedback loop (PFL). Systems biology studies reveal that the Twist1-Prrx1-TNC PFL can function as a bistable ON/OFF switch and regulates fibroblast activation. This PFL can be irreversibly activated under pathologic conditions, leading to perpetual fibroblast activation. Sustained activation of the Twist1-Prrx1-TNC PFL reproduces fibrotic nodules similar to idiopathic pulmonary fibrosis in vivo and is implicated in fibrotic disease and cancer stroma. Considering that this PFL is specific to activated fibroblasts, Twist1-Prrx1-TNC PFL may be a fibroblast-specific therapeutic target to deprogram perpetually activated fibroblasts.
Assuntos
Retroalimentação , Fibroblastos/metabolismo , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular , Fibrose , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/metabolismo , Biologia de Sistemas , Tenascina/metabolismo , Proteína 1 Relacionada a Twist/metabolismoRESUMO
BACKGROUND: Cancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history. However, no systematic analysis has been attempted so far. RESULTS: To investigate this from a systems biological perspective, we have constructed a logical network model of colorectal tumorigenesis by integrating key regulatory molecules and their interactions from previous experimental data. We identified molecular targets that can reverse cancerous cellular states to a normal state by systematically perturbing each molecular activity in the network and evaluating the resulting changes of the attractor landscape with respect to uncontrolled proliferation, EMT, and stemness. Intriguingly, many of the identified targets were well in accord with previous studies. We further revealed that the identified targets constitute stable network motifs that contribute to enhancing the robustness of attractors in cancerous cellular states against diverse regulatory signals. CONCLUSIONS: The proposed framework for systems analysis is applicable to the study of tumorigenesis and reversion of other types of cancer.
Assuntos
Carcinogênese , Neoplasias Colorretais/patologia , Espaço Intracelular/metabolismo , Biologia de Sistemas , Neoplasias Colorretais/genética , Modelos Biológicos , MutaçãoRESUMO
Cancer is caused by the accumulation of multiple genetic mutations, but their cooperative effects are poorly understood. Using a genome-wide analysis of all the somatic mutations in colorectal cancer patients in a large-scale molecular interaction network, here we find that a giant cluster of mutation-propagating modules in the network undergoes a percolation transition, a sudden critical transition from scattered small modules to a large connected cluster, during colorectal tumorigenesis. Such a large cluster ultimately results in a giant percolated cluster, which is accompanied by phenotypic changes corresponding to cancer hallmarks. Moreover, we find that the most commonly observed sequence of driver mutations in colorectal cancer has been optimized to maximize the giant percolated cluster. Our network-level percolation study shows that the cooperative effect rather than any single dominance of multiple somatic mutations is crucial in colorectal tumorigenesis.
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Carcinogênese/genética , Neoplasias Colorretais/genética , Mutação/genética , Mapas de Interação de Proteínas , Bases de Dados Genéticas , Epistasia Genética , Análise Fatorial , Humanos , TranscriptomaRESUMO
Most biological processes have been considered to be irreversible for a long time, but some recent studies have shown the possibility of their reversion at a cellular level. How can we then understand the reversion of such biological processes? We introduce a unified conceptual framework based on the attractor landscape, a molecular phase portrait describing the dynamics of a molecular regulatory network, and the phenotype landscape, a map of phenotypes determined by the steady states of particular output molecules in the attractor landscape. In this framework, irreversible processes involve reshaping of the phenotype landscape, and the landscape reshaping causes the irreversibility of processes. We suggest reverse control by network rewiring which changes network dynamics with constant perturbation, resulting in the restoration of the original phenotype landscape. The proposed framework provides a conceptual basis for the reverse control of irreversible biological processes through network rewiring. WIREs Syst Biol Med 2016, 8:366-377. doi: 10.1002/wsbm.1346 For further resources related to this article, please visit the WIREs website.
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Fenômenos Biológicos , Modelos Biológicos , Animais , Carcinogênese/genética , Diferenciação Celular , Senescência Celular , Redes Reguladoras de Genes , HumanosRESUMO
Prostaglandin E2 (PGE2) is known to have a key role in the development of colorectal cancer, but previous experiments showed its contrasting (i.e. tumor-promoting or tumor-suppressive) roles depending on experimental conditions. To elucidate the mechanisms underlying such contrasting roles of PGE2 in tumorigenesis, we investigated all the previous experiments and found a new signal transduction pathway mediated by retinoic acid receptor-related orphan receptor (ROR)α, in which PGE2/PKCα-dependent phosphorylation of RORα attenuates Wnt target gene expression in colon cancer cells. From mathematical simulations combined with biochemical experimentation, we revealed that RORα induces a biphasic response of Wnt target genes to PGE2 stimulation through a regulatory switch formed by an incoherent feedforward loop, which provides a mechanistic explanation on the contrasting roles of PGE2 observed in previous experiments. More interestingly, we found that RORα constitutes another regulatory switch formed by coupled positive and negative feedback loops, which regulates the hysteretic response of Wnt signaling and eventually converts a proliferative cellular state into an anti-proliferative state in a very delicate way. Our results indicate that RORα is the key regulator at the center of these hidden switches that critically regulate cancer cell proliferation and thereby being a promising anti-cancer therapeutic target.
Assuntos
Proliferação de Células , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteína Quinase C-alfa/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Western Blotting , Imunoprecipitação da Cromatina , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Dinoprostona/metabolismo , Retroalimentação Fisiológica , Humanos , Modelos Teóricos , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fosforilação , Proteína Quinase C-alfa/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Proteínas Wnt/genética , beta Catenina/genéticaRESUMO
The brain requires task-dependent interregional coherence of information flow in the anatomically connected neural network. However, it is still unclear how a neuronal group can flexibly select its communication target. In this study, we revealed a hidden routing mechanism on the basis of recurrent connections. Our simulation results based on the spike response model show that recurrent connections between excitatory and inhibitory neurons modulate the resonant frequency of a local neuronal group, and that this modulation enables a neuronal group to receive selective information by filtering a preferred frequency component. We also found that the recurrent connection facilitates the successful routing of any necessary information flow between neuronal groups through frequency-dependent resonance of synchronized oscillations. Taken together, these results suggest that recurrent connections act as a phase-locking neuronal tuner which determines the resonant frequency of a local group and thereby controls the preferential routing of incoming signals.
Assuntos
Potenciais de Ação/fisiologia , Encéfalo/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Simulação por Computador , Retroalimentação Fisiológica/fisiologia , HumanosRESUMO
BACKGROUND: Abnormal synchronization of brain oscillations is found to be associated with various core symptoms of schizophrenia. However, the underlying mechanism of this association remains yet to be elucidated. RESULTS: In this study, we found that coupled local and global feedback (CLGF) circuits in the cortical functional network are related to the abnormal synchronization and also correlated to the negative symptom of schizophrenia. Analysis of the magnetoencephalography data obtained from patients with chronic schizophrenia during rest revealed an increase in beta band synchronization and a reduction in gamma band power compared to healthy controls. Using a feedback identification method based on non-causal impulse responses, we constructed functional feedback networks and found that CLGF circuits were significantly reduced in schizophrenia. From computational analysis on the basis of the Wilson-Cowan model, we unraveled that the CLGF circuits are critically involved in the abnormal synchronization and the dynamical switching between beta and gamma bands power in schizophrenia. Moreover, we found that the abundance of CLGF circuits was negatively correlated with the development of negative symptoms of schizophrenia, suggesting that the negative symptom is closely related to the impairment of this circuit. CONCLUSIONS: Our study implicates that patients with schizophrenia might have the impaired coupling of inter- and intra-regional functional feedbacks and that the CLGF circuit might serve as a critical bridge between abnormal synchronization and the negative symptoms of schizophrenia.