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Background: Radioresistance and immune escape are crucial reasons for unsatisfactory therapeutic effects of glioblastoma (GBM). Although triggering receptor expressed on myeloid cells-2 (TREM2) involved in forming immunosuppressive microenvironment, but the underlying mechanism and its roles in mediating cancer radioresistance remain unclear, moreover, the efficient delivery of drugs targeting TREM2 to GBM encounters serious challenges. Hence, this study aimed to elucidate the effect and mechanisms of targeted TREM2 silencing on reversing the radioresistance and immune escape of GBM aided by a glutathione-responsive biomimetic nanoparticle (NP) platform. Methods: Radioresistant GBM cell lines and TREM2 stable knockdown GBM cell lines were firstly established. RNA sequencing, colony formation assay, western blot, enzyme-linked immunosorbent assay and co-immunoprecipitation assay were used to detect the molecular mechanisms of TREM2 in regulating the radioresistance and immune escape of GBM. The glutathione-responsive biomimetic NP, angiopep-2 (A2)- cell membrane (CM)-NP/siTREM2/spam1, was then constructed to triply and targeted inhibit TREM2 for in vivo study. Orthotopic GBM-bearing mouse models were established to evaluate the anti-GBM effect of TREM2 inhibition, multiplex immunofluorescence assay was conducted to detect the infiltration of immune cells. Results: TREM2 was a regulator in accelerating the radioresistance and immune escape of GBM through participating in DNA damage repair and forming a positive feedback loop with high mobility group box 1 (HMGB1) to cascade the activation of Toll-like receptor 4 (TLR4)/protein kinase B (Akt) signaling. A2-CM-NP/siTREM2/spam1 was successfully synthesized with excellent passive targeting, active targeting and homologous targeting, and the in vivo results exhibited its remarkable anti-GBM therapeutic effect through promoting the infiltration of type 1 helper T cells and CD8+T cells, reducing the infiltration of type 2 helper T cells and regulatory T cells, repolarizing macrophages to M1-type, and decreasing the secretion of pro-tumor and immunosuppressive cytokines. Conclusions: Targeting TREM2 therapy is a promising avenue for optimizing radiotherapy and immunotherapy to improve the prognosis of GBM patients. [ABSTRACT FROM AUTHOR]

Background: Recent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway's functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored. Methods: Bioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play. Results: XTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo. Conclusion: The results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM. [ABSTRACT FROM AUTHOR]

Epithelial mesenchymal transition (EMT) occurring in retinal pigment epithelial cells (RPE) is a crucial mechanism that contributes to the development of age-related macular degeneration (AMD), a pivotal factor leading to permanent vision impairment. Long non-coding RNAs (lncRNAs) have emerged as critical regulators orchestrating EMT in RPE cells. In this study, we explored the function of the lncRNA CYTOR (cytoskeleton regulator RNA) in EMT of RPE cells and its underlying mechanisms. Through weighted correlation network analysis, we identified CYTOR as an EMT-related lncRNA associated with AMD. Experimental validation revealed that CYTOR orchestrates TGF-β1-induced EMT, as well as proliferation and migration of ARPE-19 cells. Further investigation demonstrated the involvement of CYTOR in regulating the WNT5A/NFAT1 pathway and NFAT1 intranuclear translocation in the ARPE-19 cell EMT model. Mechanistically, CHIP, EMSA and dual luciferase reporter assays confirmed NFAT1's direct binding to CYTOR's promoter, promoting transcription. Reciprocally, CYTOR overexpression promoted NFAT1 expression, while NFAT1 overexpression increased CYTOR transcription. These findings highlight a mutual promotion between CYTOR and NFAT1, forming a positive feedback loop that triggers the EMT phenotype in ARPE-19 cells. These discoveries provide valuable insights into the molecular mechanisms of EMT and its association with AMD, offering potential avenues for targeted therapies in EMT-related conditions, including AMD. [ABSTRACT FROM AUTHOR]

In this paper, we employ computational analysis to investigate the long-term potentiation (LTP) and memory formation in synapses between neurons. We use a mathematical model describing the synaptic transmission as a signal transduction pathway with a positive feedback loop formed by diffusion of nitric oxide (NO) to the presynaptic site. We found that the model of synaptic transmission exhibits a hysteresis-like behavior, where the strength of synaptic transmission depends not just on instantaneous interstimulus intervals, but also on the history of activity. The switching between resting and memory states can be induced by physiologically relevant and moderate (less than 50%) changes in the duration of interstimulus intervals. [ABSTRACT FROM AUTHOR]

Abstract Background Radioresistance and immune escape are crucial reasons for unsatisfactory therapeutic effects of glioblastoma (GBM). Although triggering receptor expressed on myeloid cells-2 (TREM2) involved in forming immunosuppressive microenvironment, but the underlying mechanism and its roles in mediating cancer radioresistance remain unclear, moreover, the efficient delivery of drugs targeting TREM2 to GBM encounters serious challenges. Hence, this study aimed to elucidate the effect and mechanisms of targeted TREM2 silencing on reversing the radioresistance and immune escape of GBM aided by a glutathione-responsive biomimetic nanoparticle (NP) platform. Methods Radioresistant GBM cell lines and TREM2 stable knockdown GBM cell lines were firstly established. RNA sequencing, colony formation assay, western blot, enzyme-linked immunosorbent assay and co-immunoprecipitation assay were used to detect the molecular mechanisms of TREM2 in regulating the radioresistance and immune escape of GBM. The glutathione-responsive biomimetic NP, angiopep-2 (A2)- cell membrane (CM)-NP/siTREM2/spam1, was then constructed to triply and targeted inhibit TREM2 for in vivo study. Orthotopic GBM-bearing mouse models were established to evaluate the anti-GBM effect of TREM2 inhibition, multiplex immunofluorescence assay was conducted to detect the infiltration of immune cells. Results TREM2 was a regulator in accelerating the radioresistance and immune escape of GBM through participating in DNA damage repair and forming a positive feedback loop with high mobility group box 1 (HMGB1) to cascade the activation of Toll-like receptor 4 (TLR4)/protein kinase B (Akt) signaling. A2-CM-NP/siTREM2/spam1 was successfully synthesized with excellent passive targeting, active targeting and homologous targeting, and the in vivo results exhibited its remarkable anti-GBM therapeutic effect through promoting the infiltration of type 1 helper T cells and CD8+T cells, reducing the infiltration of type 2 helper T cells and regulatory T cells, repolarizing macrophages to M1-type, and decreasing the secretion of pro-tumor and immunosuppressive cytokines. Conclusions Targeting TREM2 therapy is a promising avenue for optimizing radiotherapy and immunotherapy to improve the prognosis of GBM patients.

Abstract Background Recent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway’s functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored. Methods Bioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play. Results XTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo. Conclusion The results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM.

In this study, we demonstrate the generation and storage of random voltage values using a ring oscillator consisting of feedback field-effect transistors (FBFETs). This innovative approach utilizes the logic-in-memory function of FBFETs to extract continuous output voltages from oscillatory cycles. The ring oscillator exhibited uniform probability distributions of 51.6% for logic 0 and 48.4% for logic 1. The generation of analog voltages provides binary random variables that are stored for over 5000 s. This demonstrates the potential of the ring oscillator in advanced physical functions and true random number generator technologies. [ABSTRACT FROM AUTHOR]

In this study, we examine the electrical characteristics of triple-gate feedback field-effect transistors (TG FBFETs) over a temperature range of −200 °C to 280 °C. With increasing temperature from 25 °C to 280 °C, the thermally generated charge carriers increase in the channel regions such that a positive feedback loop forms rapidly. Thus, the latch-up voltage shifts from −1.01 V (1.34 V) to −11.01 V (10.45 V) in the n-channel (p-channel) mode. In contrast, with decreasing temperature from 25 °C to −200 °C, the thermally generated charge carriers decrease, causing a shift in the latch-up voltage in the opposite direction to that of the increasing temperature case. Despite the shift in the latch-up voltage, the TG FBFETs exhibit ideal switching characteristics, with subthreshold swings of 6.6 mV/dec and 7.2 mV/dec for the n-channel and p-channel modes, respectively. Moreover, the memory window widens with increasing temperature. Specifically, at temperatures above 85 °C, the memory windows are wider than 3.05 V and 1.42 V for the n-channel and p-channel modes, respectively. [ABSTRACT FROM AUTHOR]

In this paper, we employ computational analysis to investigate the long-term potentiation (LTP) and memory formation in synapses between neurons. We use a mathematical model describing the synaptic transmission as a signal transduction pathway with a positive feedback loop formed by diffusion of nitric oxide (NO) to the presynaptic site. We found that the model of synaptic transmission exhibits a hysteresis-like behavior, where the strength of synaptic transmission depends not just on instantaneous interstimulus intervals, but also on the history of activity. The switching between resting and memory states can be induced by physiologically relevant and moderate (less than 50%) changes in the duration of interstimulus intervals.

Abstract Background Nuclear respiratory factor 1 (NRF1) is a transcription factor that participates in several kinds of tumor, but its role in hepatocellular carcinoma (HCC) remains elusive. This study aims to explore the role of NRF1 in HCC progression and investigate the underlying mechanisms. Results NRF1 was overexpressed and hyperactive in HCC tissue and cell lines and high expression of NRF1 indicated unfavorable prognosis of HCC patients. NRF1 promoted proliferation, migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NRF1 activated ERK1/2-CREB signaling pathway by transactivating lysophosphatidylcholine acyltransferase 1 (LPCAT1), thus promoting cell cycle progression and epithelial mesenchymal transition (EMT) of HCC cells. Meanwhile, LPCAT1 upregulated the expression of NRF1 by activating ERK1/2-CREB signaling pathway, forming a positive feedback loop. Conclusions NRF1 is overexpressed in HCC and promotes HCC progression by activating LPCAT1-ERK1/2-CREB axis. NRF1 is a promising therapeutic target for HCC patients.

Thyroid carcinoma (THCA) is the most common malignancy in the endocrine system. Long intergenic non‐coding RNA 2454 (LINC02454) exhibits an HMGA2‐like expression pattern, but their relationship and roles in THCA are largely unknown. The present purpose was to delineate the roles of LINC02454 in THCA progression and its molecular mechanisms. We collected THCA tissues from patients and monitored patient survival. THCA cell colony formation, migration, and invasion were evaluated. Metastasis was evaluated by examining EMT markers through Western blotting. Gene interaction was determined with ChIP, RIP, RNA pull‐down, and luciferase activity assays. A mouse model of a subcutaneous tumor was used to determine the activity of LINC02454 knockdown in vivo. We found that LINC02454 was highly expressed in THCA, and its upregulation was associated with poor survival. The knockdown of LINC02454 repressed colony formation, migration, and invasion. Moreover, loss of LINC02454 inhibited tumor growth and metastasis in mice. HMGA2 promoted LINC02454 transcription via binding to the LINC02454 promoter, and silencing of HMGA2 suppressed malignant behaviors through downregulation of LINC02454. HMGA2 was a novel functional target of LINC02454 in THCA cells, and knockdown of LINC02454‐mediated anti‐tumor effects was reversed by HMGA2 overexpression. Mechanically, LINC02454 promoted CREB1 phosphorylation and nuclear translocation, and CREB1 was subsequently bound to the HMGA2 promoter to facilitate its expression. LINC02454 cis‐regulates HMGA2 transcription via facilitating CREB1 phosphorylation and nuclear translocation, and, in turn, HMGA2 promotes LINC02454 expression, thus accelerating thyroid carcinoma progression. Our results support therapeutic targets of LINC02454 and HMGA2 for THCA.LINC02454 cis‐regulates HMGA2 transcription via facilitating CREB1 phosphorylation and nuclear translocation, and HMGA2 promotes LINC02454 expression by binding to its promoter, thus accelerating malignant behaviors in thyroid carcinoma. [ABSTRACT FROM AUTHOR]

Background: Nuclear respiratory factor 1 (NRF1) is a transcription factor that participates in several kinds of tumor, but its role in hepatocellular carcinoma (HCC) remains elusive. This study aims to explore the role of NRF1 in HCC progression and investigate the underlying mechanisms. Results: NRF1 was overexpressed and hyperactive in HCC tissue and cell lines and high expression of NRF1 indicated unfavorable prognosis of HCC patients. NRF1 promoted proliferation, migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NRF1 activated ERK1/2-CREB signaling pathway by transactivating lysophosphatidylcholine acyltransferase 1 (LPCAT1), thus promoting cell cycle progression and epithelial mesenchymal transition (EMT) of HCC cells. Meanwhile, LPCAT1 upregulated the expression of NRF1 by activating ERK1/2-CREB signaling pathway, forming a positive feedback loop. Conclusions: NRF1 is overexpressed in HCC and promotes HCC progression by activating LPCAT1-ERK1/2-CREB axis. NRF1 is a promising therapeutic target for HCC patients. [ABSTRACT FROM AUTHOR]

Abstract Background Circular RNAs (circRNAs) circularized by back-splicing of pre-mRNA are widely expressed and affected the proliferation, invasion and metastasis of bladder cancer (BCa). However, the mechanism underlying circRNA biogenesis in mediating the distant metastasis of BCa still unexplored. Methods RNA sequencing data between BCa and normal adjacent tissues was applied to identify the differentially expressed circRNAs. The functions of circNIPBL in BCa were investigated via a series of biochemical experiments. The Clinical significance of circNIPBL was examined in a cohort of larger BCa tissues. Results In the present study, we identified a novel circRNA (hsa_circ_0001472), circNIPBL, which was significantly upregulated and had great influence on the poor prognosis of patients with BCa. Functionally, circNIPBL promotes BCa metastasis in vitro and in vivo. Mechanistically, circNIPBL upregulate the expression of Wnt5a and activated the Wnt/β-catenin signaling pathway via directly sponged miR-16-2-3p, leading to the upregulation of ZEB1, which triggers the EMT of BCa. Moreover, we revealed that ZEB1 interacted with the flanking introns of exons 2–9 on NIPBL pre-mRNA to trigger circNIPBL biogenesis, thus forming a positive feedback loop. Importantly, circNIPBL overexpression significantly facilitated the distant metastasis of BCa in the orthotopic bladder cancer model, while silencing ZEB1 remarkably blocked the effects of metastasis induced by circNIPBL overexpression. Conclusions Our study highlights that circNIPBL-induced Wnt signaling pathway activation triggers ZEB1-mediated circNIPBL biogenesis, which forms a positive feedback loop via the circNIPBL/miR-16-2-3p/Wnt5a/ZEB1 axis, supporting circNIPBL as a novel therapeutic target and potential biomarker for BCa patients. Graphical Abstract

Background The function of long non-coding RNA (lncRNA) MALAT1 in regulating triple-negative breast cancer (TNBC) stemness and tumorigenesis was investigated. Methods Sphere formation and colony formation assays coupled with flow cytometry were employed to evaluate the percentage of CD44high/CD44low cells, and ALDH+ cells were performed to evaluate the stemness. Bisulfite sequencing PCR (BSP) was employed to detect the methylation level of MALAT1. Tumor xenograft experiment was performed to evaluate tumorigenesis in vivo. Finally, dual-luciferase reporter and RIP assays were employed to verify the binding relationship between MALAT1 and miR-137. Results Our results revealed that MALAT1 and BCL11A were highly expressed in TNBC, while miR-137 and DNMT1 were lowly expressed. Our results proved that MALAT1 positively regulated BCL11A expression through targeting miR-137. Functional experiments revealed that MALAT1 inhibited DNMT1 expression through acting on the miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis. We also found that high MALAT1 expression in TNBC was related to the DNMT1-mediated hypomethylation of MALAT1. As expected, DNMT1 overexpression could remarkably inhibit TNBC stemness and tumorigenesis, which was eliminated by MALAT1 overexpression. Conclusion MALAT1 downregulated DNMT1 by miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis; meanwhile, DNMT1/MALAT1 formed a positive feedback loop to continuously promote TNBC malignant behaviors.

• A reaction-diffusion system with positive feedback in gene regulation is established. • The long-term dynamics of the system solution is completely analyzed. • The parameter sets of existence and non-existence of nonconstant steady state solution are obtained. • The influence of diffusivity on the region of attraction of equilibrium solution is explained. Developing appropriate spatiotemporal models can help us understand at the molecular level how organisms function, when and where certain genes are expressed, and to what extent. In this paper, we establish a reaction-diffusion model with positive feedback loop in the process of gene expression, which describes the expression of genes according to probability and random diffusion. We focus on the long-term behavior of the system, including the determination of invariant regions and the global stability of equilibria. In particular, in the absence of a globally stable equilibrium, we derive some results on the existence and nonexistence of nonconstant steady state solutions, and clarify the dependence of the existence of nonconstant solutions on the diffusion rate of reactants and the size of the reaction environment. These results contribute to understanding the heterogeneity of cell characterization. We also carry out numerical simulations to support our theoretical results. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) circularized by back-splicing of pre-mRNA are widely expressed and affected the proliferation, invasion and metastasis of bladder cancer (BCa). However, the mechanism underlying circRNA biogenesis in mediating the distant metastasis of BCa still unexplored. Methods: RNA sequencing data between BCa and normal adjacent tissues was applied to identify the differentially expressed circRNAs. The functions of circNIPBL in BCa were investigated via a series of biochemical experiments. The Clinical significance of circNIPBL was examined in a cohort of larger BCa tissues. Results: In the present study, we identified a novel circRNA (hsa_circ_0001472), circNIPBL, which was significantly upregulated and had great influence on the poor prognosis of patients with BCa. Functionally, circNIPBL promotes BCa metastasis in vitro and in vivo. Mechanistically, circNIPBL upregulate the expression of Wnt5a and activated the Wnt/β-catenin signaling pathway via directly sponged miR-16-2-3p, leading to the upregulation of ZEB1, which triggers the EMT of BCa. Moreover, we revealed that ZEB1 interacted with the flanking introns of exons 2–9 on NIPBL pre-mRNA to trigger circNIPBL biogenesis, thus forming a positive feedback loop. Importantly, circNIPBL overexpression significantly facilitated the distant metastasis of BCa in the orthotopic bladder cancer model, while silencing ZEB1 remarkably blocked the effects of metastasis induced by circNIPBL overexpression. Conclusions: Our study highlights that circNIPBL-induced Wnt signaling pathway activation triggers ZEB1-mediated circNIPBL biogenesis, which forms a positive feedback loop via the circNIPBL/miR-16-2-3p/Wnt5a/ZEB1 axis, supporting circNIPBL as a novel therapeutic target and potential biomarker for BCa patients. [ABSTRACT FROM AUTHOR]

• Positive feedback loops between fibroblasts and the mechanical environment drive the pathological progression of dermal fibrosis. • The stiffened matrix is derived from activated fibroblasts through increased collagen deposition, impaired collagen degradation, and intensified collagen crosslinking. • Elevated physical cues can activate fibroblasts through mechanical transduction involving mechanosensors, mechanotransduction, and mechanosensitive transcription factors. • Mechanically induced profibrotic biochemical factors are also involved in feedback loops. • Multipronged therapeutic strategies are required to break the vicious cycle in dermal fibrosis. Dermal fibrosis is characterized by excessive deposition of extracellular matrix in the dermis and affects millions of people worldwide and causes limited movement, disfigurement and psychological distress in patients. Fibroblast dysfunction of plays a central role in the pathogenesis of dermal fibrosis and is controlled by distinct factors. Recent studies support the hypothesis that fibroblasts can drive matrix deposition and stiffening, which in turn can exacerbate the functional dysregulation of fibroblasts. Ultimately, through a positive feedback loop, uncontrolled pathological fibrosis develops. This review aims to summarize the phenomenon and mechanism of the positive feedback loop in dermal fibrosis, and discuss potential therapeutic targets to help further elucidate the pathogenesis of dermal fibrosis and develop therapeutic strategies. In this review, fibroblast-derived compositional and structural changes in the ECM that lead to altered mechanical properties are briefly discussed. We focus on the mechanisms by which mechanical cues participate in dermal fibrosis progression. The mechanosensors discussed in the review include integrins, DDRs, proteoglycans, and mechanosensitive ion channels. The FAK, ERK, Akt, and Rho pathways, as well as transcription factors, including MRTF and YAP/TAZ, are also discussed. In addition, we describe stiffness-induced biological changes in the ECM on fibroblasts that contribute to the formation of a positive feedback loop. Finally, we discuss therapeutic strategies to treat the vicious cycle and present important suggestions for researchers conducting in-depth research. [ABSTRACT FROM AUTHOR]

The Alzheimer's disease (AD) is a neurodegenerative disease, which is caused by the aggregation of beta-amyloid peptide ( A β ) in the patient's brain and the disorder of Ca 2 + homeostasis in neurons. Caluwé and Dupont (Theor Biol 331:12–18, 2013) proposed a deterministic AD model to explore the effect of Ca 2 + on AD. They demonstrated the positive feedback loop between A β and Ca 2 + : and the occurrence of bistability. Based on their results, we further discuss the bistable behaviors. We present two periodically feasible drug strategies to alleviate the AD and screen out more effective one. In this paper, we also formulate a stochastic AD model, analyze the existence and uniqueness of global positive solutions and establish sufficient conditions for the existence of ergodic stationary distribution. Furthermore, the confidence ellipses describing the configurational arrangement of stochastic coexistence equilibria are constructed by stochastic sensitivity function technique, and tipping threshold is estimated as well. Noise-induced stochastic switching between two coexistence equilibria is observed in bistability region. Our results provide a new idea to control noise to alleviate AD through physical therapy. [ABSTRACT FROM AUTHOR]

Intensive glycemic control is insufficient for reducing the risk of heart failure among patients with diabetes mellitus (DM). While the “hyperglycemic memory” phenomenon is well documented, little is known about its underlying mechanisms. In this study, a type 1 DM model was established in C57BL/6 mice using streptozotocin (STZ). Leptin receptor-deficient (db/db) mice were used as a model of type 2 DM. A type 9 adeno-associated virus was used to overexpress or knock down miR-320 in vivo. Diastolic dysfunction was observed in the type 1 DM mice with elevated miR-320 expression. However, glycemic control using insulin failed to reverse diastolic dysfunction. miR-320 knockdown protected against STZ-induced diastolic dysfunction. Similar results were observed in the type 2 DM mice. In vitro, we found that miR-320 promoted CD36 expression, which in turn induced further miR-320 expression. CD36 was rapidly induced by hyperglycemia at protein level compared with the much slower induction of miR-320, suggesting a positive feedback loop of CD36/miR-320 with CD36 protein induction as the initial triggering event. In conclusion, in DM-induced cardiac injury, miR-320 and CD36 mutually enhance each other’s expression, leading to a positive feedback loop and a sustained hyperlipidemic state in the heart.

In this study, we demonstrate the generation and storage of random voltage values using a ring oscillator consisting of feedback field-effect transistors (FBFETs). This innovative approach utilizes the logic-in-memory function of FBFETs to extract continuous output voltages from oscillatory cycles. The ring oscillator exhibited uniform probability distributions of 51.6% for logic 0 and 48.4% for logic 1. The generation of analog voltages provides binary random variables that are stored for over 5000 s. This demonstrates the potential of the ring oscillator in advanced physical functions and true random number generator technologies.

In this study, we examine the electrical characteristics of triple-gate feedback field-effect transistors (TG FBFETs) over a temperature range of −200 °C to 280 °C. With increasing temperature from 25 °C to 280 °C, the thermally generated charge carriers increase in the channel regions such that a positive feedback loop forms rapidly. Thus, the latch-up voltage shifts from −1.01 V (1.34 V) to −11.01 V (10.45 V) in the n-channel (p-channel) mode. In contrast, with decreasing temperature from 25 °C to −200 °C, the thermally generated charge carriers decrease, causing a shift in the latch-up voltage in the opposite direction to that of the increasing temperature case. Despite the shift in the latch-up voltage, the TG FBFETs exhibit ideal switching characteristics, with subthreshold swings of 6.6 mV/dec and 7.2 mV/dec for the n-channel and p-channel modes, respectively. Moreover, the memory window widens with increasing temperature. Specifically, at temperatures above 85 °C, the memory windows are wider than 3.05 V and 1.42 V for the n-channel and p-channel modes, respectively.

Myocardial ischemia/reperfusion injury (MIRI) is a major cause of heart failure after myocardial infarction. It has been reported that miR‐322 is involved in MIRI progression, while the molecular mechanism of miR‐322 in regulating MIRI progression needs to be further probed. MIRI cell model was established by oxygen‐glucose deprivation/reoxygenation (OGD/R). Cell viability was assessed using MTS assay. Flow cytometry and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling staining were employed to analyze cell apoptosis. In addition, the interactions between miR‐322, Smad7/Smurf2, hypoxia‐inducible factor alpha (HIF‐1α), and β‐catenin were verified by dual‐luciferase reporter gene assay. Our results displayed that miR‐322 was significantly downregulated in OGD/R‐treated H9c2 cells, and its overexpression resulted in increased cell viability and reduced the apoptosis. Smurf2 and Smad7 were identified as the direct targets of miR‐322. Smad7 knockdown or Smurf2 knockdown increased OGD/R‐treated H9c2 cell viability and suppressed the apoptosis. Meanwhile, miR‐322 mimics abolished the mitigating effect of Smad7 or Smurf2 overexpression on MIRI. In addition, the Smad3/β‐catenin pathway was identified as the downstream pathway of Smurf2/Smad7. Moreover, it was found that HIF‐1α interacted with the miR‐322 promoter, and β‐catenin interacted with the HIF‐1α promoter to form a loop. HIF‐1α‐induced upregulated miR‐322 activated the Smad3/β‐catenin pathway by targeting Smurf2 and Smad7 to improve MIRI; meanwhile, β‐catenin/HIF‐1α formed a positive feedback loop to continuously improve MIRI. [ABSTRACT FROM AUTHOR]

How to achieve efficient drug accumulation in the tumor with low vascular density is a great challenge but the key to push the limit of anti-vascular therapeutic efficacy. Herein, we report a charge-reversible nanoparticles of gambogenic acid (CRNP-GNA) that would induce the positive feedback loop between increased tumor vascular permeability and improved drug accumulation. This positive feedback loop would remarkably improve tumor vascular permeability for efficient drug accumulation through few residue vessels. As compared to its charge-irreversible analogue in the latter injections, the accumulation in tumor and vascular permeability and retention indexes (VPRI) in CRNP-GNA group respectively boosted from nearly equal to 8.32 and 60 times, while its tumorous microvessel density decreased from nearly equal to only 7%. The self-augmented accumulation consequently amplified the antitumor efficacy via multiple pathways of anti-angiogenesis, vascular disruption and pro-apoptosis, where 5 out of 6 tumors in animal models were completely cured by CRNP-GNA. This work confirms that the underlying positive feedback loop for anti-vascular therapy could be induced by charge-reversible drug delivery nanosystem to achieve efficient and self-augmented drug accumulation even in the tumor with few vessels. It provides a novel strategy to conquer the dilemma between anti-vascular efficacy and drug accumulation. [Display omitted] • Tumor vasculature impacts the accumulation anti-vascular nanoagents, and vice versa. • GNA simultaneously exerts vascular disruption, anti-angiogenesis and pro-apoptosis. • CRNP-GNA damages tumor vasculature but sharply increases vascular permeability. • CRNP-GNA induces positive feedback loop for self-augmented accumulation in tumor. • Five out of six tumors in mice model were cured by multiple injections of CRNP-GNA. [ABSTRACT FROM AUTHOR]

In this study, the logic‐in‐memory operations are demonstrated of ternary NAND and NOR logic gates consisting of double‐gated feedback field‐effect transistors. The component transistors reconfigure their operation modes into n‐ or p‐channel modes by adjusting the gate biases. The highly symmetrical operation between these operation modes with an excellent on‐current ratio of 1.03 enables three distinguishable and stable logic levels in the ternary logic gates. Moreover, the ternary logic gates maintain the three logic states for several tens to hundreds of seconds under zero‐bias condition. This study demonstrates that the ternary logic gates are promising candidates for next‐generation low‐power computing systems. [ABSTRACT FROM AUTHOR]

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis, high lymph node metastasis and early recurrence. However, the molecular events regulating HNSCC tumorigenesis remain poorly understood. Therefore, uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC. In this study, we aimed to explore the role of pleckstrin‐2 (PLEK2) in regulating HNSCC tumorigenesis. Methods The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort. In vitro and in vivo experiments, including cell proliferation, colony formation, Matrigel invasion, tumor sphere formation, ALDEFLUOR, Western blotting assays and xenograft mouse models, were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells. The underlying molecular mechanisms for the tumor‐promoting role of PLEK2 were elucidated using co‐immunoprecipitation, cycloheximide chase analysis, ubiquitination assays, chromatin immunoprecipitation‐quantitative polymerase chain reaction, luciferase reporter assays and rescue experiments. Results The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues, and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance. Additionally, PLEK2 was important for maintaining the proliferation, invasion, epithelial‐mesenchymal transition, cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells. Mechanistically, PLEK2 interacted with c‐Myc and reduced the association of F‐box and WD repeat domain containing 7 (FBXW7) with c‐Myc, thereby avoiding ubiquitination and subsequent proteasome‐mediated degradation of c‐Myc. Moreover, the c‐Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells. c‐Myc also directly bounded to the PLEK2 promoter and activated its transcription, forming a positive feedback loop. Conclusions Collectively, these findings uncover a previously unknown molecular basis of PLEK2‐enhanced c‐Myc signaling in HNSCC, suggesting that PLEK2 may represent a promising therapeutic target for treating HNSCC.

Abstract Background Ectopic ACTH-dependent Cushing syndrome is rarely caused by pheochromocytoma (PCC). Glucocorticoid-regulated positive feedback loops in ACTH and catecholamines were proposed in some similar cases. Case presentation We present here an 80-year-old man who had previously undergone surgery for a left adrenal PCC and newly developed severe hypertension, hypokalemia, and typical Cushingoid manifestations. Investigations revealed hyperglycemia, hypokalemia, and extremely high catecholamines and their metabolites, ACTH and cortisol. Imaging modalities showed a recurrent large left adrenal mass positively visualized with 123I-metaiodobenzylguanidine as well as somatostatin receptor scintigraphy. Surgical interventions were not indicated; thus, metyrapone, phentolamine, and doxazocin were initiated, which successfully controlled his symptoms and biochemical conditions. With the evidence that metyrapone administration decreased ACTH and catecholamine levels, the existence of positive feedback loops was speculated. During the terminal stages of the disease, additional metyrosine treatment successfully stabilized his physiological and biochemical conditions. Upon the patient’s death, pathological autopsy was performed. Immunohistochemical analysis indicated that the tumor appeared to be co-positive with tyrosine hydroxylase (TH) as well as ACTH in most tumor cells in both PCC and liver metastasis. Most cells were clearly positive for somatostatin receptor 2 staining in the membrane compartment. The dense immunostaining of ACTH, TH, dopamine-β-hydroxylase and the large tumor size with positive feedback loops may be correlated with high levels of ACTH and catecholamines in the circulation. Conclusions We experienced a case of severe ectopic ACTH producing the largest reported recurrent malignant left PCC with liver metastases that presented positive feedback loops in the ACTH/cortisol and catecholamine/cortisol axes. Clinicians should be aware of the paradoxical response of ACTH on metyrapone treatment and possible steroid-induced catecholamine crisis.

Background: Rearranged during transfection (RET) tyrosine kinase signaling has been previously implicated in endocrine resistant breast cancer, however the mechanism by which this signaling cascade promotes resistance is currently not well described. We recently reported that glial cell-derived neurotrophic factor (GDNF)-RET signaling appears to promote a positive feedback loop with the transcription factor early growth response 1 (EGR1). Here we investigate the mechanism behind this feedback loop and test the hypothesis that GDNF-RET signaling forms a regulatory loop with EGR1 to upregulate cyclin D1 (CCND1) transcription, leading to cell cycle progression and tamoxifen resistance. Methods: To gain a better understanding of the GDNF-RET-EGR1 resistance mechanism, we studied the GDNF-EGR1 positive feedback loop and the role of GDNF and EGR1 in endocrine resistance by modulating their transcription levels using CRISPR-dCAS9 in tamoxifen sensitive (TamS) and tamoxifen resistant (TamR) MCF-7 cells. Additionally, we performed kinetic studies using recombinant GDNF (rGDNF) treatment of TamS cells. Finally, we performed cell proliferation assays using rGDNF, tamoxifen (TAM), and Palbociclib treatments in TamS cells. Statistical significance for qPCR and chromatin immunoprecipitation (ChIP)-qPCR experiments were determined using a student's paired t-test and statistical significance for the cell viability assay was a one-way ANOVA. Results: GDNF-RET signaling formed a positive feedback loop with EGR1 and also downregulated estrogen receptor 1 (ESR1) transcription. Upregulation of GDNF and EGR1 promoted tamoxifen resistance in TamS cells and downregulation of GDNF promoted tamoxifen sensitivity in TamR cells. Additionally, we show that rGDNF treatment activated GDNF-RET signaling in TamS cells, leading to recruitment of phospho-ELK-1 to the EGR1 promoter, upregulation of EGR1 mRNA and protein, binding of EGR1 to the GDNF and CCND1 promoters, increased GDNF protein expression, and subsequent upregulation of CCND1 mRNA levels. We also show that inhibition of cyclin D1 with Palbociclib, in the presence of rGDNF, decreases cell proliferation and resensitizes cells to TAM. Conclusion: Outcomes from these studies support the hypotheses that GDNF-RET signaling forms a positive feedback loop with the transcription factor EGR1, and that GDNF-RET-EGR1 signaling promotes endocrine resistance via signaling to cyclin D1. Inhibition of components of this signaling pathway could lead to therapeutic insights into the treatment of endocrine resistant breast cancer. [ABSTRACT FROM AUTHOR]

Abstract In this study, the logic‐in‐memory operations are demonstrated of ternary NAND and NOR logic gates consisting of double‐gated feedback field‐effect transistors. The component transistors reconfigure their operation modes into n‐ or p‐channel modes by adjusting the gate biases. The highly symmetrical operation between these operation modes with an excellent on‐current ratio of 1.03 enables three distinguishable and stable logic levels in the ternary logic gates. Moreover, the ternary logic gates maintain the three logic states for several tens to hundreds of seconds under zero‐bias condition. This study demonstrates that the ternary logic gates are promising candidates for next‐generation low‐power computing systems.

Abstract Background Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood. Methods Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Flow Cytometers was applied to identify the source of cytokines. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites. The corresponding functions were verified in the complementation test and in vivo animal experiment. Results Our results revealed that hypoxia triggered macrophage secreted CXCL8, which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages and continued to increase the expression and secretion of CXCL8. It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient’s pessimistic outcome. Conclusion Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.

The start of the consumer society in Norway is examined by studying the increased imports of colorants and their constituents during the 18th century. Based on historical customs records, 82 imported pigments and dyes, 27 binders and additives and nine mordants and auxiliaries are presented. Imports increased significantly in the middle and at end of the century, representing two chromatic "revolutions". This was especially evident for lead white and indigo; being the only particularly white and blue pigments used for painting and dyeing, respectively. Red dyes at different prices and properties (brazilwood, madder and cochineal) met the demands for red textile coloring in different social groups. The study presents a comprehensive overview of colorant imports and provides new insights in the development of consumption in Norway. Colorant imports were probably initiated by a supply-driven positive feed-back loop as a result of increased export trade. This was followed by a demand-driven loop, involving increased domestic trade, product preferences, "fashionability", consumer culture, economic conditions and enlightenment. A model is presented that can contribute to a further understanding of the start of the consumer society in the second half of the 18th century in Norway. [ABSTRACT FROM AUTHOR]

Understanding the dynamical hallmarks of network motifs is one of the fundamental aspects of systems biology. Positive feedback loops constituting one or two nodes – self-activation, toggle switch, and double activation loops – are the commonly observed motifs in regulatory networks underlying cell-fate decision systems. Their individual dynamics are well studied; they are capable of exhibiting bistability. However, studies across various biological systems suggest that such positive feedback loops are interconnected with one another, and design principles of coupled bistable motifs remain unclear. What happens to the bistability or multistability traits and the phenotypic space (collection of phenotypes exhibited by a system) due to the couplings? In this study, we explore a set of such interactions using discrete and continuous simulation methods. Our results suggest that the most frequent states in coupled networks follow the ‘rules’ within a motif (double activation, toggle switch) and those across the two motifs in terms of how the two motifs have been coupled. Moreover, ‘hybrid’ states can be observed, too, where one of the above-mentioned ‘rules’ can be compromised, leading to a more diverse phenotypic repertoire. Furthermore, adding direct and indirect self-activations to these coupled networks can increase the frequency of multistability. Thus, our observations revealed specific dynamical traits exhibited by various coupled bistable motifs. [ABSTRACT FROM AUTHOR]

Herein, aPD-L1-PolyMet/BPN nanocomposite (NC) was minimally fabricated through self-assembling black phosphorus nanosheet (BPN), Polymetformin (PolyMet), and anti-PD-L1 antibody (aPD-L1) in one platform for antitumor therapy. After further irradiated by near-infrared laser, the designed NC could achieve effective tumor eradication and metastasis inhibition through positive feedback-based multimodal therapy with active tumor targetability. [Display omitted] Combining immune checkpoint blockade therapy (ICBT) with other treatment modalities through nanotechnology offers an opportunity to further boost immunity for effective cancer treatment. Herein three-in-one programmed death-ligand 1 (PD-L1)-targeted nanocomposite (NC) was minimally fabricated through self-assembling photothermal agent black phosphorus nanosheet (BPN), chemotherapeutic agent Polymetformin (PolyMet), and immune checkpoint inhibitor anti-PD-L1 antibody (aPD-L1), avoiding the easy degradability of BPN through bridging the electrostatic interaction between PolyMet and BPN. The prepared aPD-L1-PolyMet/BPN NC could precisely target primary tumor through the interaction between aPD-L1 and PD-L1 based on ICBT, and the targeting efficacy was gradually reinforced due to the PD-L1 upregulation in tumor sites after photothermal therapy (PTT), ensuring positive feedback-mediated multimodal antitumor effect during continuous treatment loops. Moreover, the combinational therapy composed of photothermal immunotherapy (PIT), chemotherapy and ICBT strengthened the antitumor efficacy owing to their synergistic mechanism. Meanwhile, the generated positive feedback property during treatment displayed powerful antitumor effect, which not only inhibited primary and abscopal tumor progression, but also prevented tumor metastasis and promoted long-term tumor immune memory establishment. Therefore, this antitumor NC provided a prospective insight into the field of multimodal cancer therapy through rational and minimal design. [ABSTRACT FROM AUTHOR]

Abstract Background Recent data indicated that macrophages may mutually interact with cancer cells to promote tumor progression and chemoresistance, but the interaction in cholangiocarcinoma (CCA) is obscure. Methods 10x Genomics single-cell sequencing technology was used to identified the role of macrophages in CCA. Then, we measured the expression and prognostic role of macrophage markers and aPKCɩ in 70 human CCA tissues. Moreover, we constructed monocyte-derived macrophages (MDMs) generated from peripheral blood monocytes (PBMCs) and polarized them into M1/M2 macrophages. A co-culture assay of the human CCA cell lines (TFK-1, EGI-1) and differentiated PBMCs-macrophages was established, and functional studies in vitro and in vivo was performed to explore the interaction between cancer cells and M2 macrophages. Furthermore, we established the cationic liposome-mediated co-delivery of gemcitabine and aPKCɩ-siRNA and detect the antitumor effects in CCA. Results M2 macrophage showed tumor-promoting properties in CCA. High levels of aPKCɩ expression and M2 macrophage infiltration were associated with metastasis and poor prognosis in CCA patients. Moreover, CCA patients with low M2 macrophages infiltration or low aPKCɩ expression benefited from postoperative gemcitabine-based chemotherapy. Further studies showed that M2 macrophages-derived TGFβ1 induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance in CCA cells through aPKCɩ-mediated NF-κB signaling pathway. Reciprocally, CCL5 was secreted more by CCA cells undergoing aPKCɩ-induced EMT and consequently modulated macrophage recruitment and polarization. Furthermore, the cationic liposome-mediated co-delivery of GEM and aPKCɩ-siRNA significantly inhibited macrophages infiltration and CCA progression. Conclusion our study demonstrates the role of Macrophages-aPKCɩ-CCL5 Feedback Loop in CCA, and proposes a novel therapeutic strategy of aPKCɩ-siRNA and GEM co-delivered by liposomes for CCA.

In this study, the temperature-dependent electrical characteristics of p-channel mode feedback field-effect transistors (FBFETs) were examined at temperatures ranging from 250 to 425 K. Their steep subthreshold swings of less than 1 mV/dec were maintained even at temperatures up to 400 K. As the temperature increased to 400 K, the latch-up voltage shifted from −0.951 to −0.613 V, which was caused by a reduction in the potential barriers in the channels of the FBFETs. High $I_{\mathrm {on}}/I_{\mathrm {off}}$ ratios above 108 were maintained in the temperature range of 250 to 400 K. However, at temperatures over 400 K, the FBFETs were turned on regardless of the gate voltages owing to the generation of a thermally induced positive feedback loop.

Cancer stem cells (CSCs) characterized by self-renewal, invasiveness, tumorigenicity and resistance to treatment are regarded as the thorniest issues in refractory tumors. We develop a targeted and hierarchical controlled release nano-therapeutic platform (SEED-NPs) that self-identifies and responds to CSC and non-CSC micro-niches of tumors. In non-CSC micro-niche, reactive oxygen species (ROS) trigger the burst release of the chemotherapeutic drug and photosensitizer to kill tumor cells and reduce tumor volume by combining chemotherapy and photodynamic therapy (PDT). In CSC micro-niche, the preferentially released differentiation drug induces CSC differentiation and transforms CSCs into chemotherapy-sensitive cells. SEED-NPs exhibit an extraordinary capacity for downregulating the stemness of CD44+/CD24- SP (side population) cell population both in vitro and in vivo , and reveal a 4-fold increase of tumor-targeted accumulation. Also, PDT-generated ROS promote the formation of tunneling nanotubes and facilitate the divergent network transport of drugs in deep tumors. Moreover, ROS in turn promotes CSC differentiation and drug release. This positive-feedback-loop strategy enhances the elimination of refractory CSCs. As a result, SEED-NPs achieve excellent therapeutic effects in both 4T1 SP tumor-bearing mice and regular 4T1 tumor-bearing mice without obvious toxicities and eradicate half of mice tumors. SEED-NPs integrate differentiation, chemotherapy and PDT, which proved feasible and valuable, indicating that active targeting and hierarchical release are necessary to enhance antitumor efficacy. These findings provide promising prospects for overcoming barriers in the treatment of CSCs. Synergetic mechanism of the designed hierarchical targeted and self-recognizing and responding engineered enhanced differentiation nanoparticles (SEED-NPs) in malignant tumors. [Display omitted] • Hierarchical delivery and release with positive feedback loop for tumor therapy. • Tackle spatiotemporal relationship of CSC and non-CSC and benefit of ROS. • Formation of TNT promote divergence and deep penetration of drugs. • Triple-mode combined therapy achieve synergistic effect. [ABSTRACT FROM AUTHOR]

Second-generation or lignocellulosic biofuels are a tangible source of renewable energy, which is critical to combat climate change by reducing the carbon footprint. Filamentous fungi secrete cellulose-degrading enzymes called cellulases, which are used for production of lignocellulosic biofuels. However, inefficient production of cellulases is a major obstacle for industrial-scale production of second-generation biofuels. We used computational simulations to design and implement synthetic positive feedback loops to increase gene expression of a key transcription factor, CLR-2, that activates a large number of cellulases in a filamentous fungus, Neurospora crassa. Overexpression of CLR-2 reveals previously unappreciated roles of CLR-2 in lignocellulosic gene network, which enabled simultaneous induction of approximately 50% of 78 lignocellulosic degradation-related genes in our engineered Neurospora strains. This engineering results in dramatically increased cellulase activity due to cooperative orchestration of multiple enzymes involved in the cellulose degradation pathway. Our work provides a proof of principle in utilizing mathematical modeling and synthetic biology to improve the efficiency of cellulase synthesis for second-generation biofuel production.

Keratin 17 (K17) is a multifaceted cytoskeletal protein that is not commonly expressed in the epidermis under normal physiological conditions. However, in psoriasis, K17 is overexpressed in the suprabasal layer of the epidermis and plays an important role in the pathogenesis of the disease. In this review, we have summarized our findings and those reported in other studies concerning the pathogenic functions of K17, as well as the mechanisms underlying the increase in K17 expression in psoriasis. K17 exerts both pro-proliferative and pro-inflammatory effects on keratinocytes. Moreover, K17 peptides trigger autoreactive T cells and promote psoriasis-related cytokine production. In turn, these cytokines modulate the expression, stability, and protein–protein interactions of K17 through transcriptional and translational regulation and post-translational modification of K17 in keratinocytes. Thus, a K17/T-cell/cytokine autoimmune loop is implicated in the pathogenesis of psoriasis, which is supported by the fact that therapies targeting K17 have achieved good outcomes in psoriasis-like mouse models. Future perspectives of K17 in psoriasis have also been discussed to provide potential directions for further studies. • K17 exerts pro-proliferative and proinflammatory effects on keratinocytes. • A K17/T cell/cytokine autoimmune loop is implicated in psoriasis pathogenesis. • K17 can potentially serve as a therapeutic target in psoriasis treatment. [ABSTRACT FROM AUTHOR]

Background: Ectopic ACTH-dependent Cushing syndrome is rarely caused by pheochromocytoma (PCC). Glucocorticoid-regulated positive feedback loops in ACTH and catecholamines were proposed in some similar cases. Case presentation: We present here an 80-year-old man who had previously undergone surgery for a left adrenal PCC and newly developed severe hypertension, hypokalemia, and typical Cushingoid manifestations. Investigations revealed hyperglycemia, hypokalemia, and extremely high catecholamines and their metabolites, ACTH and cortisol. Imaging modalities showed a recurrent large left adrenal mass positively visualized with 123I-metaiodobenzylguanidine as well as somatostatin receptor scintigraphy. Surgical interventions were not indicated; thus, metyrapone, phentolamine, and doxazocin were initiated, which successfully controlled his symptoms and biochemical conditions. With the evidence that metyrapone administration decreased ACTH and catecholamine levels, the existence of positive feedback loops was speculated. During the terminal stages of the disease, additional metyrosine treatment successfully stabilized his physiological and biochemical conditions. Upon the patient's death, pathological autopsy was performed. Immunohistochemical analysis indicated that the tumor appeared to be co-positive with tyrosine hydroxylase (TH) as well as ACTH in most tumor cells in both PCC and liver metastasis. Most cells were clearly positive for somatostatin receptor 2 staining in the membrane compartment. The dense immunostaining of ACTH, TH, dopamine-β-hydroxylase and the large tumor size with positive feedback loops may be correlated with high levels of ACTH and catecholamines in the circulation. Conclusions: We experienced a case of severe ectopic ACTH producing the largest reported recurrent malignant left PCC with liver metastases that presented positive feedback loops in the ACTH/cortisol and catecholamine/cortisol axes. Clinicians should be aware of the paradoxical response of ACTH on metyrapone treatment and possible steroid-induced catecholamine crisis. [ABSTRACT FROM AUTHOR]

In this paper, a chopper capacitively-coupled instrumentation amplifier (CCIA) with high input impedance and low input-referred noise is presented for closed-loop neural recording. A recycling folded-cascode amplifier with an inherent common-mode feedback (CMFB) circuit is proposed as the first stage to tolerate large common-mode and differential in-band artifacts without any extra circuit since this structure has a large input common-mode range. Also, this structure can improve the noise efficiency factor (NEF) due to the smaller current consumption with the same gain and bandwidth than the conventional folded-cascode amplifier. The fully-differential common-source amplifier is used as the second stage for achieving a large output signal swing. Hence, the proposed chopper CCIA has a small total harmonic distortion (THD). The proposed pseudo resistor has a large amount and enough THD with less sensitivity to the PVT variations. It has made the small low cut-off frequency in the proposed chopper CCIA by using small capacitors in the DC servo-loop. Therefore, the total value of the on-chip capacitors is reduced. By reducing the low cut-off frequency in chopper CCIA, the positive feedback loop increases the input impedance at a low frequency more than the previous works using the positive feedback loop, despite the presence of DC servo-loop in the chopper CCIA. The proposed neural recording amplifier has been simulated with Cadence using TSMC 180 nm CMOS process with a 1.8 V power supply. [ABSTRACT FROM AUTHOR]

Peptide-based drugs hold great potential for cancer treatment, and their effectiveness is driven by mechanisms on how peptides target cancer cells and escape from potential lysosomal entrapment post-endocytosis. Yet, the mechanisms remain elusive, which hinder the design of peptide-based drugs. Here hendeca-arginine peptides (R11) are synthesized for targeted delivery in bladder carcinoma (BC), investigated the targeting efficiency and elucidated the mechanism of peptide-based delivery, with the aim of refining the design and efficacy of peptide-based therapeutics. It is demonstrated that the over-activated Piezo1/integrin β1 (ITGB1) signaling axis significantly facilitates tumor-targeted delivery of R11 peptides via macropinocytosis. Furthermore, R11 peptides formed hydrogen bonds with integrin β1, facilitating targeting and penetration into tumor cells. Additionally, R11 peptides protected integrin β1 from lysosome degradation, promoting its recycling from cytoplasm to membrane. Moreover, this findings establish a positive feedback loop wherein R11 peptides activate Piezo1 by increasing membrane fusion, promoting Ca 2+ releasing and resulting in enhanced integrin β1-mediated endocytosis in both orthotopic models and clinical tissues, demonstrating effective tumor-targeted delivery. Eventually, the Piezo1/integrin β1 signaling axis promoted cellular uptake and transport of peptides, establishing a positive feedback loop, promoting mechanical delivery to cancer and offering possibilities for drug modification in cancer therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The tendency for cell fate to be robust to most perturbations, yet sensitive to certain perturbations raises intriguing questions about the existence of a key path within the underlying molecular network that critically determines distinct cell fates. Reprogramming and trans-differentiation clearly show examples of cell fate change by regulating only a few or even a single molecular switch. However, it is still unknown how to identify such a switch, called a master regulator, and how cell fate is determined by its regulation. Here, we present CAESAR, a computational framework that can systematically identify master regulators and unravel the resulting canalizing kernel, a key substructure of interconnected feedbacks that is critical for cell fate determination. We demonstrate that CAESAR can successfully predict reprogramming factors for de-differentiation into mouse embryonic stem cells and trans-differentiation of hematopoietic stem cells, while unveiling the underlying essential mechanism through the canalizing kernel. CAESAR provides a system-level understanding of how complex molecular networks determine cell fates., (© The Author(s) 2024. Published by Oxford University Press.)

Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Abstract Ulcerative colitis (UC) has closely been associated with an increased risk of colorectal cancer. However, the exact mechanisms underlying colitis-associated cancer (CAC) development remain unclear. As a classic pattern-recognition receptor, Toll like receptor (TLR)4 is a canonical receptor for lipopolysaccharide of Gram-negative bacteria (including two CAC-associated pathogens Fusobacterium nucleatum and Salmonella), and functions as a key bridge molecule linking oncogenic infection to colonic inflammatory and malignant processes. Accumulating studies verified the overexpression of TLR4 in colitis and CAC, and the over-expressed TLR4 might promote colitis-associated tumorigenesis via facilitating cell proliferation, protecting malignant cells against apoptosis, accelerating invasion and metastasis, as well as contributing to the creation of tumor-favouring cellular microenvironment. In recent years, considerable attention has been focused on the regulation of TLR4 signaling in the context of colitis-associated tumorigenesis. MicroRNA (miR)-155 and TLR4 exhibited a similar dynamic expression change during CAC development and shared similar CAC-promoting properties. The available data demonstrated an interplay between TLR4 and miR-155 in the context of different disorders or cell lines. miR-155 could augment TLR4 signaling through targeting negative regulators SOCS1 and SHIP1; and TLR4 activation would induce miR-155 expression via transcriptional and post-transcriptional mechanisms. This possible TLR4-miR-155 positive feedback loop might result in the synergistic accelerating effect of TLR4 and miR-155 on CAC development. Video abstract

Background: Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood. Methods: Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Flow Cytometers was applied to identify the source of cytokines. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites. The corresponding functions were verified in the complementation test and in vivo animal experiment. Results: Our results revealed that hypoxia triggered macrophage secreted CXCL8, which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages and continued to increase the expression and secretion of CXCL8. It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient's pessimistic outcome. Conclusion: Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome. [ABSTRACT FROM AUTHOR]

In this paper, we propose a logic-in-memory (LIM) inverter comprising a silicon nanowire (SiNW) n-channel feedback field-effect transistor (n-FBFET) and a SiNW p-channel metal oxide semiconductor field-effect transistor (p-MOSFET). The hybrid logic and memory operations of the LIM inverter were investigated by mixed-mode technology computer-aided design simulations. Our LIM inverter exhibited a high voltage gain of 296.8 (V/V) when transitioning from logic '1' to '0' and 7.9 (V/V) when transitioning from logic '0' to '1', while holding calculated logic at zero input voltage. The energy band diagrams of the n-FBFET structure demonstrated that the holding operation of the inverter was implemented by controlling the positive feedback loop. Moreover, the output logic can remain constant without any supply voltage, resulting in zero static power consumption. [ABSTRACT FROM AUTHOR]

Abstract Background Liver cancer stem cells (LCSCs) play key roles in the metastasis, recurrence, and chemotherapeutic resistance of hepatocellular carcinoma (HCC). Our previous research showed that the POSTN gene is closely related to the malignant progression and poor prognosis of HCC. This study aimed to elucidate the role of POSTN in generating LCSCs and maintaining their stemness as well as the underlying mechanisms. Methods Human HCC tissues and matched adjacent normal tissues were obtained from 110 patients. Immunohistochemistry, western blotting (WB), and RT-PCR were performed to detect the expression of POSTN and stemness factors. The roles of transforming growth factor (TGF)-β1 and AP-2α in the POSTN-induced stemness transformation of HCC cells were explored in vitro and in vivo using LCSCs obtained by CD133+ cell sorting. Results The high expression of POSTN was correlated with the expression of various stemness factors, particularly CD133, in our HCC patient cohort and in TCGA and ICGC datasets. Knockdown of POSTN expression decreased the abilities of HCC cell lines to form tumours in xenograft mouse models. Knockdown of POSTN expression also suppressed cell viability and clone formation, invasion, and sphere formation abilities in vitro. Knockdown of AP-2α attenuated the generation of CD133+ LCSCs and their malignant behaviours, indicating that AP-2α was a critical factor that mediated the POSTN-induced stemness transformation and maintenance of HCC cells. The role of AP-2α was verified by using a specific αvβ3 antagonist, cilengitide, in vitro and in vivo. Activation of POSTN could release TGFβ1 from the extracellular matrix and initiated POSTN/TGFβ1 positive feedback signalling. Furthermore, we found that the combined use of cilengitide and lenvatinib suppressed the growth of HCC cells with high POSTN expression more effectively than the use of lenvatinib alone in the patient-derived xenograft (PDX) mouse model. Conclusions The POSTN/TGFβ1 positive feedback pathway regulates the expression of stemness factors and the malignant progression of HCC cells by regulating the transcriptional activation of AP-2α. This pathway may serve as a new target for targeted gene therapy in HCC.

In this study, we examined electrical stability of the p-channel feedback field-effect transistors (FBFETs) under negative bias stress (NBS) and positive bias stress (PBS). The intact FBFETs have a subthreshold swing (SS) of 0.12 mV/dec, an on-current of $\sim 10^{-4}$ A, and a threshold voltage ( $V_{\mathrm {TH}}$ ) of −0.76 V. There is a negligible change in the on-current and SS when the FBFETs are stressed by a gate-bias voltage corresponding to an electric field of 5.4 MV/cm across the gate oxide. On the other hand, as the duration of the stress increases to 1000 s, the $V_{\mathrm {TH}}$ shifts to −0.89 V and −0.67 V for NBS and PBS, respectively. The $V_{\mathrm {TH}}$ was recovered to over 83% at a recovery bias voltage of ±5 V. The electrical stabilities of FBFETs under NBS and PBS are discussed in this study.