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Metabolic rewiring underlies effective macrophages defense to respond disease microenvironment. However, the underlying mechanisms driving metabolic rewiring to enhance macrophage effector functions remain unclear. Here, we demonstrated that the metabolic reprogramming in inflammatory macrophages depended on the acetylation of CLYBL, a citramalyl-CoA lyase, at lysine 154 (K154), and blocking CLYBL-K154 acetylation restricted the release of pro-inflammatory factors. Mechanistically, we found a crucial AMPK-CLYBL acetylation positive feedback loop, triggered by toll-like receptors (TLRs), involving AMPK hypophosphorylation and CLYBL hyperacetylation. The deacetylase enzyme SIRT2 acted as the bridge between AMPK phosphorylation and CLYBL acetylation, thereby regulating macrophage polarization and the release of pro-inflammatory cytokines. Furthermore, CLYBL hypoacetylation decreased monocyte infiltration, thereby alleviating cardiac remodeling. These findings suggest that the AMPK-CLYBL acetylation positive feedback loop serves as a metabolic switch driving inflammatory response and inhibiting CLYBL-K154 acetylation may offer a promising therapeutic strategy for inflammatory response-related disorders., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: All procedures performed in this study involving animal experiments were in accordance with the relevant guidelines and regulations of The Animal Subjects Committee of China Medical University (license no. CMU20231452)., (© 2025. The Author(s).)

Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes and persistent inflammation. Although persistent activation of signal transducer and activator of transcription 3 (STAT3) is implicated in its pathogenesis, the mechanisms underlying the sustained STAT3 activation remain poorly understood. Here, we identify sphingosine-1-phosphate receptor 3 (S1PR3) as a critical regulator of STAT3 activation and psoriasis pathogenesis, orchestrating a self-amplifying circuit that sustains keratinocyte hyperproliferation and chronic inflammation. S1PR3 expression is markedly elevated in psoriatic lesions and correlates with disease severity. Using genetic and pharmacological approaches, we reveal a novel S1PR3-Src-STAT3 signaling axis that drives both early and prolonged STAT3 activation in keratinocytes. Mechanistically, S1PR3 operates through Gαi/PKA-mediated Src activation, enhancing STAT3 phosphorylation and subsequent transcriptional activity. Importantly, we reveal a previously unrecognized positive feedback loop wherein activated STAT3 directly upregulates S1PR3 expression, perpetuating inflammation and hyperproliferation. Genetic deletion of S1pr3 in mice or pharmacological inhibition of S1PR3 significantly attenuates psoriasis-like skin inflammation, decreasing epidermal hyperplasia, dermal angiogenesis, and inflammatory mediator production. These findings provide new insights into the molecular mechanisms underlying psoriasis and identify S1PR3 as a promising therapeutic target. Our study suggests that disrupting the S1PR3-STAT3 feedback loop may offer a novel strategy for treating psoriasis and potentially other chronic inflammatory diseases driven by persistent STAT3 activation., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and Consent to participate: The study was conducted in accordance with the principles of the Declaration of Helsinki. The animal experiment was approved by the Medical School of Nanjing University Ethics Committee. Human skin biopsy specimens were obtained with informed consent and were approved by the First Affiliated Hospital of Nanjing Medical University Clinical Research Ethics Committee., (© 2025. The Author(s).)

Background: A previous study found that MAF1 homolog, a negative regulator of RNA polymerase III (MAF1), protects the blood-brain barrier (BBB) in sepsis-associated encephalopathy (SAE); however, the related molecular mechanisms remain unclear., Subjects and Methods: In this study, a rat sepsis model was constructed using the cecum ligation and puncture (CLP) method. In vitro, rat brain microvascular endothelial cells and astrocytes were stimulated with serum from the sepsis model rats. The loss of MAF1 protein levels and the molecular mechanisms leading to cell damage were investigated., Results: It was shown in the SAE models that MAF1 was expressed at low levels. Knockdown of Cullin 2 (CUL2) stimulated the accumulation of MAF1 protein, attenuated the RNA sensor RIG-I/interferon regulatory factor 3 (IRF3) signaling pathway, and reduced cell apoptosis. Furthermore, it increased phosphatase and tensin homolog (PTEN) expression and inactivated the serine/threonine kinase (AKT)/mechanistic target of the rapamycin kinase (mTOR) signaling pathway. Interference with forkhead box O1 (FOXO1) inhibited MAF1 expression and activated the RIG-I/IRF3 signaling pathway, while MAF1 overexpression promoted PTEN expression, decreased cell apoptosis, and normalized autophagy., Conclusions: These findings demonstrate that CUL2 promoted MAF1 ubiquitination and caused BBB injury in SAE. Through the regulatory loop of PTEN/AKT/FOXO1/MAF1, CUL2 initiated the gradual downregulation of MAF1, which subsequently regulated polymerase III (Pol III)-dependent transcription and played essential roles in cell apoptosis in SAE., Clinical Trial Number: not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were carried out strictly in accordance with the Declaration of Helsinki and Basel Declaration. The experiments were approved by the Animal Care and Use Committee of Guangdong Provincial People’s Hospital (no. KY-Z-2022-2284-03; data 12/01/2022). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Emerging evidence shows that small nucleolar RNA (snoRNA), a type of highly conserved non-coding RNA, is involved in tumorigenesis and aggressiveness. However, the roles of snoRNAs in regulating alternative splicing crucial for cancer progression remain elusive., Methods: High-throughput RNA sequencing and comprehensive analysis were performed to identify crucial snoRNAs and downstream alternative splicing events. Biotin-labeled RNA pull-down, mass spectrometry, cross-linking RNA immunoprecipitation, and in vitro binding assays were applied to explore interaction of snoRNAs with protein partners. Alternative splicing and gene expression was observed by real-time quantitative RT-PCR and western blot assays. In vitro and in vivo studies were performed to investigate biological effects of snoRNAs and their protein partners in gastric cancer. Survival analysis was undertaken by using Kaplan-Meier method and log-rank test., Results: SNORA37 was identified as an up-regulated snoRNA essential for tumorigenesis and aggressiveness of gastric cancer. Gain- and loss-of-function studies indicated that SNORA37 promoted the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. Mechanistically, as an ELAV like RNA binding protein 1 (ELAVL1)-generated snoRNA, SNORA37 directly bound to cap methyltransferase 1 (CMTR1) to facilitate its interaction with ELAVL1, resulting in nuclear retention and activity of ELAVL1 in regulating alternative splicing of CD44. Rescue studies revealed that SNORA37 exerted oncogenic roles in gastric cancer progression via facilitating CMTR1-ELAVL1 interaction. In clinical gastric cancer cases, high levels of SNORA37, CMTR1, ELAVL1, or CD44 were associated with shorter survival and poor outcomes of patients., Conclusions: These results indicated that SNORA37/CMTR1/ELAVL1 feedback loop drives gastric cancer progression via facilitating CD44 alternative splicing., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were approved by Experimental Animal Ethics, Huazhong University of Science and Technology, and conducted in accordance with the guidelines established by National Institutes of Health's Guidelines for the Care and Use of Experimental Animals. The Institutional Review Board of Union Hospital, Tongji Medical College approved the human tissue study. All procedures were carried out in accordance with guidelines set forth by Declaration of Helsinki. Consent for publication: All authors have agreed to publish this manuscript. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

The fertile gonad includes cells of two distinct developmental origins: the somatic mesoderm and the germ line. How somatic and germ cells interact to develop and maintain fertility is not well understood. Here, using grafting experiments and transgenic reporter animals, we find that a specific part of the gonad-the germinal zone-acts as a sexual organizer to induce and maintain de novo germ cells and somatic gonads in the cnidarian Hydractinia symbiolongicarpus . Germ cells express a member of the transforming growth factor-β family, Gonadless ( Gls ), that induces gonad morphogenesis. Loss of Gls resulted in animals lacking gonads but having nonproliferative germ cells. We propose that primary germ cells drive gonad development though Gls secretion. The germinal zone in the newly formed gonad provides positive feedback to induce secondary germ cells by activating Tfap2 in resident pluripotent stem cells. The contribution of germ cell signaling to the patterning of somatic gonadal tissue may be a general animal feature.

Poly(ADP-ribose) polymerase 1 (PARP1) plays a crucial role in DNA repair and genomic stability maintenance. However, the regulatory mechanisms governing PARP1 activity, particularly through deubiquitination, remain poorly elucidated. Using a deubiquitinase (DUB) library binding screen, we identified cylindromatosis (CYLD) as a bona fide DUB for PARP1 in breast cancer cells. Mechanistically, CYLD is recruited by PARP1 to DNA lesions upon genotoxic stress, where it cleaves K63-linked polyubiquitin chains on PARP1 at residues K748, K940, and K949, resulting in compromised PARP1 activation. In a reciprocal manner, PARP1 PARylates CYLD at sites E191, E231, E259, and E509, thereby enhancing its DUB activity. Consequently, depletion of CYLD leads to increased efficiency in base excision repair and confers breast cancer cells with resistance to alkylating agents. Conversely, overexpression of CYLD enhances sensitivity to PARP inhibitors (PARPi) even in homologous recombination-proficient breast cancer cells. These findings offer unique insights into the intricate interplay between CYLD and PARP1 in DNA repair, underscoring the pivotal role of targeting this regulatory axis for breast cancer chemotherapy., Competing Interests: Competing interests statement:The authors declare no competing interest.

One of the challenges that beset modelling complex biological networks is to relate networks to function to dynamics. A further challenge is deciphering the cellular function and dynamics that can change drastically when the network edge is tinkered with by adding or removing it. To illustrate this, the authors took a well-studied three-variable Goodwin oscillatory motif with only a negative feedback loop. To this motif, an edge was added that results in an emergent structure consisting of new feedforward and feedback loops while retaining Goodwin's original negative feedback loop. To relate emergent structure to oscillatory dynamics, the authors took all the combinations of edge signs in the interlocked motif. Bifurcation analysis reveals that all the structural combinations can be grouped into two categories based on their unique dynamics. These two groups also exhibit unique amplitude-frequency (amp-freq) plots. These two categories are attributed to the emergence of interlocked motifs with specific edge signs. To support the ideas, a well-studied plant circadian model of Arabidopsis thaliana was taken to illustrate the importance of interlocked motifs in fine-tuning amplitude and frequency in circadian oscillators. The authors briefly discuss its implications for central oscillators' adaptation to different environmental cues., (© 2025 The Author(s). IET Systems Biology published by John Wiley & Sons Ltd on behalf of The Institution of Engineering and Technology.)

Store-operated Ca 2+ entry is a mechanism controlled by the filling state of the intracellular Ca 2+ stores, predominantly the endoplasmic reticulum (ER), where ER-resident proteins STIM1 and STIM2 orchestrate the activation of Orai channels in the plasma membrane, and Orai1 playing a predominant role. Two forms of Orai1, Orai1α and Orai1β, have been identified, which arises the question whether they are equally regulated by STIM proteins. We demonstrate that STIM1 preferentially activates Orai1α over STIM2, yet both STIM proteins similarly activate Orai1β. Under resting conditions, there is a pronounced association between STIM2 and Orai1α. STIM1 and STIM2 are also shown to influence the protein levels of the Orai1 variants, independently of Ca 2+ influx, via lysosomal degradation. Interestingly, Orai1α and Orai1β appear to selectively regulate the protein level of STIM1, but not STIM2. These observations offer crucial insights into the regulatory dynamics between STIM proteins and Orai1 variants, enhancing our understanding of the intricate processes that fine-tune intracellular Ca 2+ signaling., (© 2025 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Background: Heterotopic ossification (HO) refers to the development of bone tissue in areas other than the skeletal system. The development and maturation of the skeletal system are significantly influenced by macrophage migration inhibitory factor (MIF). The objective of this study was to examine the impact of MIF on the in vitro osteogenic differentiation and mineralization of tendon-derived stem cells (TDSCs), mediated by a positive feedback loop involving ROS/HIF-1α/MIF., Methods: TDSCs were isolated and identified from the hind limbs of C57/BL6 mice. The functional and procedural roles of MIF in HO, focusing on the impact of MIF on the differentiation of TDSCs into bone-forming cells were investigated in vitro. Seventy-five mice were randomly assigned to five groups. Gene expression and histological analyses of MIF and its receptors, and determine the expression of osteogenic markers in vivo., Results: The results revealed a positive and concentration-dependent effect of MIF on the osteogenic differentiation of TDSCs. Furthermore, an ROS/HIF-1α/MIF positive loop was detected in the simulated early trauma hypoxic microenvironment, resulting in a 3 to 4 folds increase in MIF expression levels. MIF was also found to enhance double the expression levels of markers associated with bone and cartilage at the site of injury, consequently facilitating the development of HO, which was thought to be associated with the activation of the Wnt/β-catenin pathway., Conclusion: MIF, which mediates the ROS/HIF-1α/MIF positive feedback loop during the hypoxic phase of HO, triggers the Wnt/β-catenin signaling pathway to enhance the osteogenic differentiation and formation of HO in TDSCs., Competing Interests: Declaration of competing interest All authors state that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Natural communities are exposed to multiple environmental stressors, which simultaneously impact the population and trait dynamics of the species embedded within these communities. Given that certain traits, such as body size, are known to rapidly respond to environmental change, and given that they can strongly influence the density of populations, this raises the question of whether the strength of the eco-phenotypic feedback loop depends on the environment, and whether stressful environments would enhance or disrupt this feedback or causal linkage. We use two competing freshwater ciliates-Colpidium striatum and Paramecium aurelia-and expose their populations to a full-factorial design of increasing salinity and temperature conditions as well as interspecific competition. We found that salinity, temperature, and competition significantly affected the density and cell size dynamics of both species. Cell size dynamics strongly influenced density dynamics; however, the strength of this eco-phenotypic feedback loop weakened in stressful conditions and with interspecific competition. Our study highlights the importance of studying eco-phenotypic dynamics in different environments comprising stressful abiotic conditions and species interactions., (© 2024 The Author(s). Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Ovarian cancer (OC) is recognized as the most lethal type of gynecological malignancy, making treatment options challenging. Discovering novel therapeutic targets will benefit OC patients. This study aimed to reveal the mechanism by which SRSF9 regulates OC progression. Cell proliferation was determined via CCK-8 assays, whereas cell migration and invasion were monitored via Transwell assays. Western blotting and qPCR assays were used to detect protein and mRNA alterations. RNA pull-down, RNA immunoprecipitation (RIP), and actinomycin D experiments were performed to investigate the relationships between SRSF9 and USP22. Co-IP was used to validate the interaction between USP22 and ZEB1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to verify the regulatory effect of ZEB1 on the transcription of SRSF9. Subcutaneous xenograft models were established to evaluate the impact of SRSF9 on tumor development. Knockdown of SRSF9 significantly suppressed the proliferation, invasion, migration, tumorigenicity, and epithelial‒mesenchymal transition (EMT) of OC cells. SRSF9 can bind to USP22 mRNA, increasing its stability. Moreover, the overexpression of USP22 reversed the impact of SRSF9 silencing on malignant phenotypes. USP22 can mediate the deubiquitination of ZEB1, thereby enhancing the progression of OC. Furthermore, ZEB1 upregulated SRSF9 expression through transcriptional activation, thus establishing a positive feedback loop. SRSF9 enhanced the malignant characteristics of OC through a positive feedback loop of SRSF9/USP22/ZEB1. This functional circuit may help in the development of novel therapeutic approaches for treating OC.

Autophagy-dependent survival relies on a crucial oscillatory response during cellular stress. Although oscillatory behaviour is typically associated with processes like the cell cycle or circadian rhythm, emerging experimental and theoretical evidence suggests that such periodic dynamics may explain conflicting experimental results in autophagy research. In this study, we demonstrate that oscillatory behaviour in the regulation of the non-selective, stress-induced macroautophagy arises from a series of interlinked negative and positive feedback loops within the mTORC1-AMPK-ULK1 regulatory triangle. While many of these interactions have been known for decades, recent discoveries have revealed how mTORC1, AMPK, and ULK1 are truly interconnected. Although these new findings initially appeared contradictory to established models, additional experiments and our systems biology analysis clarify the updated regulatory structure. Through computational modelling of the autophagy oscillatory response, we show how this regulatory network governs autophagy induction. Our results not only reconcile previous conflicting experimental observations but also offer insights for refining autophagy regulation and advancing understanding of its mechanisms of action., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kapuy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rotenone remains an efficient pesticide used extensively in agriculture, leading to neurotoxicity and the increase of the prevalence of Parkinson's disease (PD). Previous studies indicated that Parkin, a neurohomeostasis regulatory factor, and NOD-like receptor protein 3 (NLRP3), a core factor driving the inflammatory response, interacted with each other, which affected neuroinflammation occurrence. However, whether rotenone accelerated PD progression via Parkin-NLRP3 loop and the specific mechanisms were still unclear. Here, a novel negative feedback mechanism of Parkin-NLRP3 that regulated PD caused by rotenone was certified. Rotenone treatment induced neurodegeneration in vitro- and vivo-models. The activation of NLRP3 inflammasome and Parkin was increased and decreased, respectively, and the expression of pyroptosis related proteins was up-regulated, because of the addition of rotenone. Notably, the overexpression of Parkin promoted NLRP3 ubiquitination, which down regulated pyroptosis mediated by NLRP3, protected mitochondrial function as well as preventing neurodegeneration. Additionally, the NLRP3 inhibitor MCC950 restored the activation of Parkin and down regulated pyroptosis mediated by NLRP3 in rotenone-induced PD. It was revealed that the Parkin-NLRP3 negative feedback loop participated in rotenone-induced PD by regulating pyroptosis, representing a new idea for the prevention and treatment of neurodegenerative diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Proteins become asymmetrically distributed in the one-cell Caenorhabditis elegans embryo thanks to reaction-diffusion mechanisms that are often entangled in complex feedback loops. Cortical polarity drives the enrichment of the RNA-binding proteins MEX-5 and MEX-6 in the anterior cytoplasm through concentration gradients. MEX-5 and MEX-6 promote the patterning of other cytoplasmic factors, including that of the anteriorly enriched mitotic polo-like kinase PLK-1, but also contribute to proper cortical polarity. The gradient of MEX-5 forms through a differential-diffusion mechanism. How MEX-6 establishes a gradient and how MEX-5 and MEX-6 regulate cortical polarity is not known. Here, we reveal that the two MEX proteins develop concentration asymmetries via similar mechanisms, but despite their strong sequence homology, they differ in terms of how their concentration gradients are regulated. We find that PLK-1 promotes the enrichment of MEX-5 and MEX-6 at the anterior through different circuits: PLK-1 influences the MEX-5 gradient indirectly by regulating cortical polarity while it modulates the formation of the gradient of MEX-6 through its physical interaction with the protein. We thus propose a model in which PLK-1 mediates protein circuitries between MEX-5, MEX-6, and cortical proteins to faithfully establish and maintain polarity., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: The Antarctic krill Euphausia superba is a keystone species in the Southern Ocean ecosystem. This crustacean has an ancestral clock whose main components have been identified and characterized in the past few years. However, the second feedback loop, modulating clock gene expression through two transcription factors, VRI and PDP1, has yet to be described. The presence of this second regulatory mechanism is suggested by the identification of its negative component, vrille, at the transcriptional level., Results: Here, we describe the second feedback loop of krill by identifying the positive component, pdp1, and functionally characterizing both pdp1 and vrille. Starting from the online transcriptome database KrillDB 2 , we identified and cloned three putative pdp1 sequences which were subsequently analyzed for tissue expression and functional activity using luciferase assays, individually and in combination with two vrille isoforms. Among the pdp1 isoforms, Espdp1_3 displayed higher expression levels in relevant circadian districts than the other two. Furthermore, EsPDP1_3 and EsVRI_2 exhibited the expected positive and negative regulation of the V/P-box in our in vitro system. Finally, Espdp1_3 and Esvrille also showed rhythmic expression in light-dark cycles, supporting their involvement in the regulation of the main circadian clock of the Antarctic krill., Conclusions: This study expands our knowledge about the molecular architecture of the Antarctic krill circadian clock by defining the components that take part in the modulation of clock expression, establishing a second feedback loop., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Competition among genes for limited transcriptional and translational resources impairs the functionality and modularity of synthetic gene circuits. Traditional control mechanisms, such as feedforward and negative feedback loops, have been proposed to alleviate these challenges, but they often focus on individual modules or inadvertently increase the burden on the system. In this study, we introduce three novel multimodule control strategies─local regulation, global regulation, and negatively competitive regulation (NCR)─that employ an antithetic regulatory mechanism to mitigate resource competition. Our systematic analysis reveals that while all three control mechanisms can alleviate resource competition to some extent, the NCR controller consistently outperforms both the global and local controllers. This superior performance stems from the unique architecture of the NCR controller, which is independent of specific parameter choices. Notably, the NCR controller not only facilitates the activation of less active modules through cross-activation mechanisms but also effectively utilizes the resource consumption within the controller itself. These findings emphasize the critical role of carefully designing the topology of multimodule controllers to ensure robust performance.

MicroRNAs post-transcriptionally regulate gene expression and contribute to numerous life processes, including circadian rhythms. However, whether miRNAs contribute to zebrafish circadian regulation has not yet been investigated. Here, we showed that mature miR-219-5p, and its three pre-miRNAs, mir-219-1, mir-219-2, and mir-219-3, are rhythmically expressed primarily in Tectum opticum (TeO), Corpus cerebelli (CCe), and Crista cerellaris (CC) of the zebrafish brain. While mir-219-1 and mir-219-2 are regulated by the circadian clock through the E-like box, mir-219-3 is regulated by light via the D-box. Deleting mir-219-1, mir-219-2, or mir-219-3 individually or knocking down miR-219-5p all results in a shortened period of locomotor rhythms and up-regulation of bmal1b. RIP assays with Ago2 and miRNA pull-down assays show that miR-219-5p binds to bmal1b in the RISC. Cell transfection and in Vivo assays show that miR219-5p inhibits bmal1b through binding to its 3'UTR. Further, transcriptome analysis of miR-219-5p knockdown zebrafish adult brain reveals possible roles of miR-219-5p in phototransduction and neuroactive ligand-receptor interaction. Together, our findings demonstrate that mir-219-1, mir-219-2, and mir-219-3 are controlled directly by the circadian clock; and in turn, miR-219-5p contributes to circadian regulation by targeting bmal1b, highlighting a miR-219-5p-bmal1b negative feedback loop in the zebrafish circadian circuit., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The Parkinson's disease (PD)-linked protein Leucine-Rich Repeat Kinase 2 (LRRK2) consists of seven domains, including a kinase and a Roc G domain. Despite the availability of several high-resolution structures, the dynamic regulation of its unique intramolecular domain stack is nevertheless still not well understood. By in-depth biochemical analysis, assessing the Michaelis-Menten kinetics of the Roc G domain, we have confirmed that LRRK2 has, similar to other Roco protein family members, a K M value of LRRK2 that lies within the range of the physiological GTP concentrations within the cell. Furthermore, the R1441G PD variant located within a mutational hotspot in the Roc domain showed an increased catalytic efficiency. In contrast, the most common PD variant G2019S, located in the kinase domain, showed an increased K M and reduced catalytic efficiency, suggesting a negative feedback mechanism from the kinase domain to the G domain. Autophosphorylation of the G1+2 residue (T1343) in the Roc P-loop motif is critical for this phosphoregulation of both the K M and the k cat values of the Roc-catalyzed GTP hydrolysis, most likely by changing the monomer-dimer equilibrium. The LRRK2 T1343A variant has a similar increased kinase activity in cells compared to G2019S and the double mutant T1343A/G2019S has no further increased activity, suggesting that T1343 is crucial for the negative feedback in the LRRK2 signaling cascade. Together, our data reveal a novel intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism. Interestingly, PD mutants differently change the kinetics of the GTPase cycle, which might in part explain the difference in penetrance of these mutations in PD patients., Competing Interests: BG, FH, BR, XZ, GG, AK, CG No competing interests declared, (© 2023, Gilsbach et al.)

The HPT complex, consisting of the hypothalamus, pituitary and thyroid, functions as a regulated system controlled by the respective hormones. This system maintains an intrinsic equilibrium, called the set point, which is unique to each individual. In order to optimize the treatment of thyroid patients and understand the dynamics of the system, a validated theoretical representation of this set point is required. Therefore, the research field of mathematical modeling of the HPT complex is significant as it provides insights into the interactions between hormones and the determination of this endogenous equilibrium. In literature, two mathematical approaches are presented for the theoretical determination of the set point in addition to a time-dependent model. The two approaches are based on the maximum curvature of the pituitary response function and the optimal gain factor in the representation of the HPT complex as a closed feedback system. This paper demonstrates that all hormone curves described by the model converge to the derived set point with increasing time. This result establishes a clear correlation between the physiological equilibrium described by the set point and the mathematical equilibrium with respect to autonomous systems of differential equations. It thus substantiates the validity of the theoretical set point approaches., Competing Interests: Declarations. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose. Ethics approval: The data exchange between the Medical University of Vienna (MUV) and the authors was approved by the Ethics Committee of the MUV., (© 2024. The Author(s).)

Inflammation-induced cholestasis is a common problem in septic patients and results from cytokine-mediated inhibition of bile acid export including impaired expression of the bile salt export pump (BSEP) with a consecutive increase in intracellular bile acids mediating cell damage. The present study focuses on the mechanisms by which interleukin 1 β (IL-1β), as a critical mediator of sepsis-induced cholestasis, controls the expression of BSEP in hepatocytes. Notably, the treatment of hepatocytes with IL-1β leads to the upregulation of a broad chemokine pattern. Thereby, the IL-1β -induced expression of in particular the CXCR2 ligands CXCL1 and 2 is further enhanced by bile acids, whereas the FXR-mediated upregulation of BSEP induced by bile acids is inhibited by IL-1β. In this context, it is interesting to note that inhibitor studies indicate that IL-1β mediates its inhibitory effects on bile acid-induced expression of BSEP indirectly via CXCR2 ligands. Consistently, inhibition of CXCR2 with the inhibitor SB225002 significantly attenuated of the inhibitory effect of IL-1β on BSEP expression. These data suggest that part of the cholestasis-inducing effect of IL-1β is mediated via a CXCR2-dependent feedback mechanism., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Angendohr et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Differential growth is central to eukaryotic morphogenesis. We showed using cellular imaging, simulations, and perturbations that light-induced differential growth in a curved organ, the Arabidopsis thaliana apical hook, emerges from the longitudinal expansion of subepidermal cells, acting in parallel with a differential in the material properties of epidermal cell walls that resist expansion. The greater expansion of inner hook cells that results in apical hook opening is gated by wall alkalinity and auxin, both of which are depleted upon illumination. We further identified mechanochemical feedback from wall mechanics to light stimulated auxin depletion, which may contribute to gating hook opening under mechanical restraint. These results highlight how plant cells coordinate growth among tissue layers by linking mechanics and hormonal gradients with the cell wall remodeling required for differential growth., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Coelimycin (CPK) producer Streptomyces coelicolor A3(2) is a well-established model for the genetic studies of bacteria from the genus Streptomyces, renowned for their ability to produce a plethora of antibiotics and other secondary metabolites. Expression regulation of natural product biosynthetic gene clusters (BGCs) is highly complex, involving not only regulatory proteins, like transcription factors, but also the products of the biosynthetic pathway that may act as ligands for some regulators and modulate their activity. Here, we present the evidence that intracellular CPK precursor(s) (preCPK) is involved in a negative feedback loop repressing the CPK BGC. Moreover, we provide a characterization of the cluster-encoded efflux pump CpkF. We show that CpkF is essential for the extracellular CPK production. In order to track down which CPK compounds - intra- or extracellular - are the ones responsible for the feedback signal, a luciferase-based reporter system was applied to compare the activity of 13 CPK gene promoters in the wild-type (WT) and two mutated strains. The first strain, lacking the CPK-specific exporter CpkF (ΔcpkF), was unable to produce the extracellular CPK. The second one did not produce any CPK at all, due to the disruption of the CpkC polyketide synthase subunit (ΔcpkC). All tested promoters were strongly upregulated in ΔcpkC strain, while in the ΔcpkF strain, promoter activity resembled the one of WT. These results lead to the conclusion that the CPK polyketide acts as a silencer of its own production. Supposedly this function is exerted via binding of the preCPK by an unidentified regulatory protein. KEY POINTS: •Intracellular coelimycin precursor takes part in a negative cpk cluster regulation •CpkF exporter is essential for the extracellular coelimycin production •Simple method for the analysis of coelimycin P2 production in agar medium., Competing Interests: Declarations. Ethical approval: This article does not contain any studies with human participants or animals performed by any of the authors. Competing interest: The authors declare no competing interests., (© 2024. The Author(s).)

GLABRA1 (GL1), which encodes an R2R3 MYB transcription factor, is a key regulator of trichome patterning in the aerial organs of Arabidopsis (Arabidopsis thaliana). Although it has been generally assumed that GL1 functions exclusively in shoots and is not expressed in roots, reverse transcription polymerase chain reaction (RT-PCR) analysis has revealed that GL1 is indeed expressed in roots. To investigate whether GL1 plays a role in root epidermal patterning, we analyzed the effects of gl1 mutations in sensitized genetic backgrounds. Our findings show that gl1 mutants enhance the root epidermal phenotype of a weak allele of the werewolf (wer) mutant and suppress the phenotype of the caprice (cpc) mutant. We also demonstrate that the GL1 promoter is active in N-position epidermal cells, and that the GFP-GL1 fusion protein is predominantly localized in the nucleus of N-position cells. Furthermore, we provide evidence that GL1 expression is positively regulated by WER, GLABRA3, ENHANCER OF GLABRA3, and TRANSPARENT TESTA GLABRA1, while negatively regulated by CPC, TRIPTYCHON, and GLABRA2 (GL2). Notably, GL2, which is positively regulated by GL1, moderately represses GL1 expression, and both GL1 and GL2 are positively regulated by WER in N-position cells. These findings suggest that a negative feedback regulation of GL1 expression via GL2 contributes to the fine-tuning of non-hair cell fate determination in Arabidopsis root epidermis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sepsis represents a primary cause of acute kidney injury (AKI), yet the underlying mechanisms of septic AKI remain poorly understood. Thus, there exists an urgent need for a deeper understanding of its underlying mechanisms and the development of effective therapeutic strategies. Our study reveals a notable induction in microRNA-202-5p (miR-202-5p) levels within renal tubular cells in septic AKI both in vivo and in vitro models. Treatment of renal tubular cells with LPS induced NF-κB activation, which was linked to the induction of miR-202-5p. ChIP assays confirmed NF-κB binding to the miR-202-5p gene promoter upon LPS stimulation. Functionally, miR-202-5p mimics attenuated tubular cell death, kidney injury, and intra-renal inflammatory cytokine production, whereas inhibition of miR-202-5p conferred injurious effects in septic AKI. Notably, miR-202-5p suppressed the expression of High Mobility Group Box 2 (HMGB2) in both in vitro and in vivo septic AKI models. Luciferase microRNA target assays further validated HMGB2 as a direct target of miR-202-5p. Knockdown of HMGB2 inhibits LPS-induced NF-κB activation in septic AKI, as evidenced by HMGB2 siRNA transfection significantly inhibited the nuclear translocation of NF-κB. Together, these findings elucidate the NF-κB/miR-202-5p/HMGB2 negative feedback loop which can attenuate kidney injury by inhibiting renal inflammation in septic AKI. Our findings open new avenues for developing targeted therapies to manage septic AKI effectively., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anthocyanins, a group of flavonoids, play diverse roles in plant growth and environmental adaptation. The biosynthesis and accumulation of anthocyanin are regulated by environmental cues, such as high light. However, the precise mechanism underlying anthocyanin biosynthesis under high light conditions remains largely unclear. Here, we report that the R3-MYB repressor MYB-LIKE 2 (MYBL2) negatively regulates high light-induced anthocyanin biosynthesis in Arabidopsis by repressing two R2R3-MYB activators, PRODUCTION OF ANTHOCYANIN PIGMENT 1 (PAP1) and PAP2, which are core components of the MYB-bHLH-WD40 (MBW) complex. We found that MYBL2 interacts with PAP1/2 and reduces their transcriptional activation activities, thus disrupting the expression of key genes involved in anthocyanin biosynthesis, such as DIHYDROFLAVONOL 4-REDUCTASE (DFR) and TRANSPARENT TESTA 19 (TT19). Additionally, MYBL2 attenuates the transcriptional activation of PAP1 and its own expression, but not that of PAP2. Conversely, PAP1 collaborates with TRANSPARENT TESTA 8 (TT8), a bHLH member of the MBW complex, to activate MYBL2 transcription when excessive anthocyanins are accumulated. Taken together, our findings reveal a negative feedback regulatory module composed of MYBL2 and PAP1 that fine-tunes high light-induced anthocyanin biosynthesis through modulating MBW complex assembly., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Mogk and den Brave discuss exciting results from a comprehensive screen of heat shock response components in yeast, published in this issue by Pincus and colleagues (https://doi.org/10.1083/jcb.202401082). Their work reveals modulatory regulatory loops that fine-tune the timing of the shutdown of this highly conserved pathway., (© 2024 Mogk and den Brave.)

Cells maintain homeostasis via dynamic regulation of stress response pathways. Stress pathways transiently induce response regulons via negative feedback loops, but the extent to which individual genes provide feedback has not been comprehensively measured for any pathway. Here, we disrupted the induction of each gene in the Saccharomyces cerevisiae heat shock response (HSR) and quantified cell growth and HSR dynamics following heat shock. The screen revealed a core feedback loop governing the expression of the chaperone Hsp70 reinforced by an auxiliary feedback loop controlling Hsp70 subcellular localization. Mathematical modeling and live imaging demonstrated that multiple HSR targets converge to promote Hsp70 nuclear localization via its release from cytosolic condensates. Following ethanol stress, a distinct set of factors similarly converged on Hsp70, suggesting that nonredundant subsets of the HSR regulon confer feedback under different conditions. Flexible spatiotemporal feedback loops may broadly organize stress response regulons and expand their adaptive capacity., (© 2024 Garde et al.)

Organisms detect temperature signals through peripheral neurons, which relay them to central circadian networks to drive adaptive behaviors. Despite recent advances in Drosophila research, how circadian circuits integrate temperature cues with circadian signals to regulate sleep/wake patterns remains unclear. In this study, we used the FlyWire brain electron microscopy connectome to map neuronal connections, identifying lateral posterior neurons LPNs as key nodes for integrating temperature information into the circadian network. LPNs receive input from both circadian and temperature-sensing neurons, promoting sleep behavior. Through connectome analysis, genetic manipulation, and behavioral assays, we demonstrated that LPNs, downstream of thermo-sensitive anterior cells (ACs), suppress activity-promoting lateral dorsal neurons LNds via the AstC pathway, inducing sleep Disrupting LPN-LNd communication through either AstCR1 RNAi in LNds or in an AstCR1 mutant significantly impairs the heat-induced reduction in the evening activity peak. Conversely, optogenetic calcium imaging and behavioral assays revealed that cold-activated LNds subsequently stimulate LPNs through NPF-NPFR signaling, establishing a negative feedback loop. This feedback mechanism limits LNd activation to appropriate levels, thereby fine-tuning the evening peak increase at lower temperatures. In conclusion, our study constructed a comprehensive connectome centered on LPNs and identified a novel peptidergic circadian feedback circuit that coordinates temperature and circadian signals, offering new insights into the regulation of sleep patterns in Drosophila., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yuan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neurovascular coupling (NVC) is the mechanism that drives the neurovascular response to neural activation, and NVC dysfunction has been implicated in various neurologic diseases. NVC is driven by (1) nonmetabolic feedforward mechanisms that are mediated by various signaling pathways and (2) metabolic feedback mechanisms that involve metabolic factors. However, the interplay between these feedback and feedforward mechanisms remains unresolved. We propose that feedforward mechanisms normally drive a swift, neural activation-induced regional cerebral blood flow (rCBF) overshoot, which floods the tissue beds, leading to local hypocapnia and hyperoxia. The feedback mechanisms are triggered by the resultant hypocapnia (not hyperoxia), which causes cerebral vasoconstriction in the neurovascular unit that counterbalances the rCBF overshoot and returns rCBF to a level that matches the metabolic activity. If feedforward mechanisms function improperly (eg, in a disease state), the rCBF overshoot, tissue-bed flooding, and local hypocapnia fail to occur or occur on a smaller scale. Consequently, the neural activation-related increase in metabolic activity results in local hypercapnia and hypoxia, both of which drive cerebral vasodilation and increase rCBF. Thus, feedback mechanisms ensure the brain milieu's stability when feedforward mechanisms are impaired. Our proposal integrates the feedforward and feedback mechanisms underlying NVC and suggests that these 2 mechanisms work like a fail-safe system, to a certain degree. We also discussed the difference between NVC and cerebral metabolic rate-CBF coupling and the clinical implications of our proposed framework., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 International Anesthesia Research Society.)

Introduction: Transcription of biological nitrogen fixation (nif) genes is activated by the NifA protein which recognizes specific activating sequences upstream of σ 54 -dependent nif promoters. The large quantities of nitrogenase which can make up 20% of the total proteins in the cell indicates high transcription activating efficiency of NifA and high transcription level of nifHDK nitrogenase genes., Objectives: Development of an efficient gene transcription activating strategy in bacteria based on positive transcription regulatory proteins and their regulating DNA sequences., Methods: We designed a highly efficient gene transcription activating strategy in which the nifA gene was placed directly downstream of its regulating sequences. The NifA protein binds its regulating sequences and stimulates transcription of itself and downstream genes. Overexpressed NifA causes transcription activation by positive reinforcement., Results: When this gene transcription activating strategy was used to overexpress NifA in Pseudomonas stutzeri DSM4166 containing the nif gene cluster, the nitrogenase activity was increased by 368 folds which was 16 times higher than that obtained by nifA driven by the strongest endogenous constitutive promoter. When this strategy was used to activate transcription of exogenous biosynthetic genes for the plant auxin indole-3-acetic acid and the antitumor alkaloid pigment prodigiosin in DSM4166, both of them resulted in better performance than the strongest endogenous constitutive promoter and the highest reported productions in heterologous hosts to date. Finally, we demonstrated the universality of this strategy using the positive transcriptional regulator of the psp operon, PspF, in E. coli and the pathway-specific positive transcription regulator of the polyene antibiotic salinomycin biosynthesis, SlnR, in Streptomyces albus., Conclusion: Many positive transcription regulatory proteins and their regulating DNA sequences have been identified in bacteria. The gene transcription activating strategy developed in this study will have broad applications in molecular biology and biotechnology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In the inflammatory microenvironment of atherosclerotic plaques, metabolic dysregulation of superoxide anion (O 2 - ) and hydrogen peroxide (H 2 O 2 ) leads to the activation of feedback mechanisms involving IL-1β, TNF-α, and MCP-1, which triggers inflammatory cascades between macrophages and vascular smooth muscle cells (VSMCs) in atherosclerosis (AS). To address this, a chondroitin sulfate (CS)-functionalized dual-targeted engineered nanozyme, CS-Lip/PB@Rap, was developed by encapsulating mesoporous Prussian blue nanoparticles (PBs) loaded with rapamycin (Rap) within CS-modified liposomes. CS functionalization endowed CS-Lip/PB@Rap with a specific targeting ability for CD44 receptors, thus enabling targeted delivery to inflammatory macrophages and VSMCs. Moreover, its enhanced multiple enzyme-like activities effectively modulated the imbalance of oxidative stress. The underlying mechanism of crosstalk regulation by these engineered nanozymes may inhibit the NF-κB pathway by restoring normal metabolism of O 2 - and H 2 O 2 , thereby blocking the TNF-α, IL-1β, and MCP-1 feedback loops between macrophages and VSMCs. This process reduced the production of inflammatory macrophages and inhibited the VSMC transformation from a contractile phenotype to a synthetic phenotype, preventing the formation of fibrous caps. Furthermore, the elimination of oxidative stress could decrease the production of oxygenized low-density lipoprotein (ox-LDL), which inhibited the formation of foam cells and alleviated the atherogenic progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

During the maturation of pre-B cells, the recombination activating gene 1 and 2 (RAG1/2) endonuclease complex plays a crucial role in coordinating V(D)J recombination by introducing DNA breaks in immunoglobulin (Ig) loci. Dysregulation of RAG1/2 has been linked to the onset of B cell malignancies, yet the mechanisms controlling RAG1/2 in pre-B cells exposed to excessive DNA damage are not fully understood. In this study, we show that DNA damage-induced activation of p53 initiates a negative-feedback loop which rapidly downregulates RAG1 levels. This feedback loop involves ataxia telangiectasia mutated activation, subsequent stabilization of p53, and modulation of microRNA-34a (miR-34a) levels, which is one of the p53 targets. Notably, this loop incorporates transcription factor forkhead box P1 as a downstream effector. The absence of p53 resulted in an increased proportion of IgM + cells prompted to upregulate RAG1/2 and to undergo Ig light chain recombination. Similar results were obtained in primary pre-B cells with depleted levels of miR-34a. We propose that in pre-B cells undergoing Ig gene recombination, the DNA breaks activate a p53/miR-34a/forkhead box P1-mediated negative-feedback loop that contributes to the rapid downregulation of RAG. This regulation limits the RAG-dependent DNA damage, thereby protecting the stability of the genome during V(D)J rearrangement in developing B cells., Competing Interests: Conflict of interest The authors declare no conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Metabolic-associated fatty liver disease (MAFLD) encompasses various chronic liver conditions, yet lacks approved drugs. Hypoxia-inducible factor-1α (HIF-1α) is pivotal in MAFLD development. Our prior research highlighted the efficacy of the nano-designed carbon monoxide (CO) donor, targeting HIF-1α in a mouse hepatic steatosis model. Given heme oxygenase-1 (HO-1, a major downstream molecule of HIF-1α) as the primary source of intrinsic CO, we hypothesized that upregulation of HO-1/CO, responsive to HIF-1α, forms a negative feedback loop regulating MAFLD progression. In this study, we explored the potential negative feedback mechanism of CO on HIF-1α and its downstream effects on MAFLD advancement. HIF-1α emerges early in hepatic steatosis induced by a high-fat (HF) diet, triggering increased HO-1 and inflammation. SMA/CORM2 effectively suppresses HIF-1α and steatosis progression when administered within the initial week of HF diet initiation but loses impact later. In adipose tissues, concurrent metabolic dysfunction and inflammation with HIF-1α activation suggest adipose tissue expansion initiates HF-induced steatosis, triggering hypoxia and liver inflammation. Notably, in an in vitro study using mouse hepatocytes treated with fatty acids, downregulating HO-1 intensified HIF-1α induction at moderate fatty acid concentrations. However, this effect diminished at high concentrations. These results suggest the HIF-1α-HO-1-CO axis as a feedback loop under physiological and mild pathological conditions. Excessive HIF-1α upregulation in pathological conditions overwhelms the CO feedback loop. Additional CO application effectively suppresses HIF-1α and disease progression, indicating potential application for MAFLD control., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study investigated the mechanisms driving the induction and sustained presence of neutrophil extracellular traps (NETs) in the synovial microenvironment of rheumatoid arthritis (RA). Synovial tissue and fluid samples were collected from patients with RA and osteoarthritis (OA), and NET levels and cytokine concentrations were measured using a cytometric bead array and enzyme-linked immunosorbent assay (ELISA). The ability of interleukin-33 (IL-33) to induce NET formation was evaluated using quantitative assays, immunofluorescence staining, live-cell imaging, and electron microscopy. Coincubation experiments of NETs with fibroblast-like synovial cells (FLSs) were conducted, and a modified Transwell migration assay was designed to assess neutrophil migration. The role of IL-33 and NETs in RA progression was further investigated using a collagen antibody-induced arthritis (CAIA) mouse model. The results revealed an increase in NETs and IL-33 levels in the synovial fluid of RA patients, with a significant positive correlation between them. NET formation assays confirmed that IL-33 activates neutrophils to produce NETs and that neutrophils from RA patients exhibit increased responsiveness to IL-33 stimulation. Both in vitro and in vivo evidence has demonstrated that NETs stimulate FLSs to secrete IL-33 and the chemokine CXCL8 via Toll-like receptor 9, promoting further neutrophil recruitment and increasing NET production within the RA synovium. This study reveals a novel positive feedback loop involving NETs and FLSs that is mediated by IL-33 that increases NET accumulation in RA. Targeting IL-33 or NET formation and amplification may offer new therapeutic strategies for managing RA., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: The present study was approved by the Institutional Medical Ethics Review Board of Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (ethical batch number: AF/SC-11/04.0). The authors declare no violation of the Declaration of Helsinki on human experimentation. Verbal and written informed consent were obtained from all participants. All experiments involving animals were also approved by Tongren Hospital (ethical batch number: AF/SC-11/04.0), and all the experiments involving animals were performed according to the guidelines of the committee., (© 2024. The Author(s).)

Abnormal antioxidant capacity of cancer is closely related to tumor malignancy. Modulation of oxidative stress status is a novel anticancer therapeutic target. Nrf2 is a key regulator of various antioxidant enzymes, but the mechanism of its deubiquitination remains largely unclear. This study unveiled that Nrf2 received post-transcriptional regulation from a proteasome-associated deubiquitinating enzyme, USP11, in colorectal cancer (CRC). It was found that USP11 was overexpressed in CRC tissues acting as an oncogene by inhibiting mitochondrial apoptosis, and USP11 managed to maintain balance in the production and elimination of reactive oxygen species (ROS). Mechanistically, we identified a feedback loop between USP11 and Nrf2 maintaining the redox homeostasis. USP11 stabilized Nrf2 by deubiquitinating and protecting it from proteasome-mediated degradation. Interestingly, we also map that Nrf2 could bind to the antioxidant reaction element (ARE) in the USP11 promoter to promote its transcription. Hence, USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis of CRC cells by activating Nrf2/ARE signaling pathway, thus promoting CRC progression. Schematic diagram of the mechanism by which USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis in CRC cells. This study found that USP11 was highly expressed in colorectal cancer (CRC) tissue and was associated with poor prognosis. In CRC, the inhibition of USP11 expression could promote the ubiquitination degradation of Nrf2, thereby inhibiting the Nrf2/ARE signaling pathway. This led to an increase in reactive oxygen species in the cell, causing mitochondrial apoptosis. In addition, Nrf2 could bind to the promoter region of USP11 to promote its transcription, both of which formed positive feedback loop., Competing Interests: Competing interests: The authors declare no competing interests. Ethics: All procedures performed in this study involving human specimens were in accordance with the ethical standards of the Institute Research Ethics Committee at Zhongnan hospital of Wuhan University (2020110). For animal experiments, the protocol of this study was approved by the Zhongnan Hospital of Wuhan University Institutional Animal Care Animal Welfare Committee (ZN2022042)., (© 2024. The Author(s).)

In ant foraging, the manner of group-mass recruitment demonstrates remarkable adaptability between tandem running and mass recruitment. In contrast to tandem running, where a leader recruits only one worker, the first phase of group-mass recruitment is characterized by strong invitations from leaders that result in a large group of recruits leaving the nest together in a rush, thereby accelerating the process of recruiting towards discovered resources. Furthermore, unlike sole mass recruitment, the influence of leaders during this first phase enhances the accuracy of information about food qualities and ensures a more rational allocation of recruits compared to simply following a dominant pheromone trail. In this study, we propose a model that integrates the Kelly criterion for the first phase of group-mass recruitment, followed by a post-Kelly strategy incorporating a delayed Pólya urn with two stages for the second phase of group-mass recruitment. The analytical process and simulation demonstrate that the Kelly criterion aims to maximize recruitment intensity during the initial foraging phase, employing crowd tactics to capture all available food sources and enhance competitiveness with other food-exploiting species. On the other hand, the post-Kelly strategy elucidates how the crowding negative feedback mitigates congestion resulting from overexploitation and improves overall efficiency in food exploitation., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to the Society for Mathematical Biology.)

The close spatial and temporal connection between osteogenesis and angiogenesis around type H vasculature is referred as "osteogenesis-angiogenesis coupling", which is one of the basic mechanisms of osteogenesis. Endothelial cells (ECs), bone marrow mesenchymal stem cells (BMSCs), and their specific lineage constitute important cluster that participate in the regulation of osteogenesis and angiogenesis in bone microenvironment. However, the regulatory mechanism of osteogenesis-angiogenesis coupling under the condition of bone healing has not been unveiled. In this study, we demonstrated that the exosome derived from ECs (EC-exo) is an initiator of type H blood vessels formation, and EC-exo acts as a mediator in orchestrating osteogenesis-angiogenesis coupling by enhancing BMSC osteogenic differentiation and EC angiogenesis both in monolayer and stereoscopic co-culture system of primary human cells. The transcriptome array indicated that zinc finger and BTB domain containing 16 (ZBTB16) is a key gene in EC-exo-mediated osteogenesis, and ZBTB16 is indispensable in EC-exo-initiated osteogenesis-angiogenesis coupling. Mechanistically, EC-exo up-regulated the expression of ZBTB16 in BMSCs, thereby promoting osteoprogenitor phenotype transformation; the osteoprogenitors further promote ECs which constitute type H vessel (H-ECs) generation by activating HIF-1α pathway; and the H-ECs conversely promotes osteogenic differentiation of BMSCs. The crosstalk between BMSCs and ECs triggered by EC-exo constitutes a positive feedback loop that enhances osteogenesis-angiogenesis coupling. This study demonstrates that EC-exo can become an effective therapeutic tool to promote bone regeneration and repair., Competing Interests: Declarations Ethics approval and consent to participate Obtaining samples of hBMSCs was reviewed and approved by Ethics Committee of the First Hospital of Jilin University (No. 22K095-002). The animal experiment was reviewed and approved by the Animal Protection and Utilization Committee of Changchun Weishi Testing Technology Service (No. 20230109-01). Consent for publication All authors agree to be published. Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Context: Type 2 diabetes has been described to be associated with hypothyroidism but we recently found that a decrease in pituitary sensitivity to thyroid hormone is associated with diabetes, obesity, and metabolic syndrome., Objective: We aimed to assess the longitudinal nature of this association in the population-based Study of Health in Pomerania (SHIP) in Germany., Methods: Among a population-based sample of 4308 participants aged 20 to 79 years, 77% were followed for a period of 5 years. We studied 2542 participants without diabetes or thyroid medication at baseline and complete data in the variables of interest. Data of baseline free thyroxine (fT4) and thyrotropin (TSH) were used to calculate the Parametric Thyroid Feedback Quantile-based Index (PTFQI), which measures whether TSH remains elevated despite fT4 being high. It uses the average population response as reference. PTFQI association with incidence of type 2 diabetes over 5 years was estimated with Poisson regression models adjusted for age, sex, and body mass index (BMI)., Results: Compared with the first PTFQI quartile, incidence rate ratios for diabetes were 1.54 (95% CI, 0.97-2.46), 1.55 (0.94-2.57), and 1.97 (1.27-3.10) for the upper quartiles (P trend = .004) after adjusting for age and sex. The association remained statistically significant after additionally adjusting for BMI: 1.64 (1.05-2.59) for the fourth vs the first quartile (P trend = .043)., Conclusion: An elevation of the pituitary TSH-inhibition threshold is associated with incident type 2 diabetes independently of BMI. The PTFQI might have clinical potential for prognosis and metabolic status monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, we have identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to our understanding of gut renewal and repair., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lung adenocarcinoma (LUAD) is the major subtype of lung cancer. The poor prognosis of LUAD patients is attributed primarily to metastasis. ADAMTS16 is a crucial member of the ADAMTS family and is involved in tumor progression. However, its role and regulatory mechanism in LUAD remain unexplored. In this study, ADAMTS16 was identified as a crucial oncogene and survival predictor in LUAD via analyses of public datasets. Clinical specimens and tissue microarrays confirmed the differential expression and prognostic value of ADAMTS16 in LUAD patients. Transcriptome data and in vitro experiments demonstrated that ADAMTS16 was positively associated with epithelial-mesenchymal transition (EMT) and the migration abilities of LUAD cells. Knockdown of ADAMTS16 attenuated lung and pleural metastasis in an animal model. Mechanistically, the results of the enzyme-linked immunosorbent assay (ELISA) and western blot (WB) suggested that ADAMTS16 activated the TGF-β signaling pathway by facilitating the conversion of LAP-TGF-β1 to active TGF-β1. Co-Immunoprecipitation (co-IP) indicated an interaction between ADAMTS16 and LAP-TGF-β1. Inhibition of ADAMTS16 impaired EMT and aggressiveness of LUAD cells, while treatment with recombinant TGF-β1 reversed this inhibition. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays indicated that SOX4 acted as a transcriptional activator of ADAMTS16 and that TGF-β1 regulated the expression of ADAMTS16 by increasing the binding of SOX4 to the promoter of ADAMTS16. Suppressing the TGF-β signaling pathway inhibited ADAMTS16 expression, EMT, and lung metastasis, whereas overexpressing SOX4 reversed this inhibition. Therefore, ADAMTS16 forms a positive feedback loop with the TGF-β1/SOX4 axis to regulate EMT and metastasis, and disruption of this feedback loop inhibits tumor progression. These findings underscore the potential of ADAMTS16 as a prognostic biomarker and therapeutic target in LUAD and offer novel insight into the mechanism of EMT and metastasis., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate This study was approved by the medical ethics review board of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (TJ-IRB20210222) and was carried out in accordance with the Declaration of Helsinki. All the patients provided written informed consent. All animal experiments were performed with the approval of the Ethics Committee of the Institutional Animal Care and Use Committee of Tongji Medical College, Huazhong University of Science and Technology (3509)., (© 2024. The Author(s).)

Objectives: T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further clarified., Methods: The expression levels of PU.1 and IL-9 in patients with RA were determined by ELISA, western blotting (WB) and immunohistochemical staining. PU.1-T cell-conditional knockout (KO) mice, IL-9 KO and IL-9R KO mice were used to establish collagen antibody-induced arthritis (CAIA), respectively. The inhibitor of PU.1 and IL-9 blocking antibody was used in collagen-induced arthritis (CIA). In an in vitro study, the effects of IL-9 were investigated using siRNAs and IL-9 recombinant proteins. Finally, the underlying mechanisms were further investigated by luciferase reporter analysis, WB and Chip-qPCR., Results: The upregulation of IL-9 expression in patients with RA exhibited a positive correlation with clinical markers. Using CAIA and CIA model, we demonstrated that interventions targeting PU.1 and IL-9 substantially mitigated the inflammatory phenotype. Furthermore, in vitro assays provided the proinflammatory role of IL-9, particularly in the hyperactivation of macrophages and fibroblast-like synoviocytes. Mechanistically, we uncovered that PU.1 and IL-9 form a positive feedback loop in RA: (1) PU.1 directly binds to the IL-9 promoter, activating its transcription and (2) Th9-derived IL-9 induces PU.1 via the IL-9R-JAK1/STAT3 pathway., Conclusions: These results support that the PU.1-IL-9 axis forms a positive loop in Th9 dysregulation of RA. Targeting this signalling axis presents a potential target approach for treating RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

In a Science paper, Park et al. identified interleukin (IL)-1α as a key driver of positive feedback in inflammaging, linking aging-associated downregulation of DNMT3A to increased IL-1α production in lung myeloid cells. This triggers emergency myelopoiesis in the bone marrow, amplifying myeloid-mediated intratumoral immunosuppression for tumor progression in aged mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The anti-tumor immune response is greatly hindered by the protumor polarization of tumor-associated macrophages (TAMs). Cancer-related inflammation plays a central role in TAMs protumor polarization. Our study explored the unique positive feedback loop between inflammasome and complement in TAMs. The present study identified NOD-like receptors family pyrin domain containing 12 (NLRP12) formed positive feedback with C1qA and drove TAMs protumor polarization via the LILRB4/NF-κB pathway. In addition, NLRP12 was predominantly expressed in TAMs and was associated with poorer prognosis in lung adenocarcinoma (LUAD) patients. Knocking down LILRB4 inhibited TAMs protumor polarization. NLRP12-overexpressing TAMs promoted tumor cells' malignant progression and inhibited T cells' proliferation and cytotoxic function. Lastly, NLRP12 knockout (NLRP12 -/- ) reversed macrophage polarization, enhanced T-cell anti-tumor immunity, and suppressed tumor growth. Our findings highlighted the essential role of NLRP12/C1qA positive feedback loop and the LILRB4/NF-κB pathway in promoting TAMs protumor polarization. Inhibition of NLRP12 suppressed tumor development and promoted immune response. NLRP12 may be a promising target for LUAD immunotherapy., Competing Interests: Declarations Conflict of interest The authors declare no conflict of interests. Ethical approval All animal experiments were approved by the Committee of Animal Care and Use of Renmin Hospital of Wuhan University, under the consent number WDRM 20240405B, and were performed following the Guide for the Care and Use of Laboratory Animals. Consent to publish Not applicable., (© 2024. The Author(s).)

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly prevalent in China, exhibiting resistance to current treatments. ΔNP63α, the main isoform of p63, is frequently amplified in ESCC and contributes to therapeutic resistance, although the molecular mechanisms remain unknown. Here, we report that ΔNP63α is highly expressed in ESCC and is associated with radioresistance by reducing ROS level. Furthermore, ΔNP63α plays a critical role in radioresistance by directly transactivating the expression of PLEC. PLEC competitively interacts with KEAP1, resulting in the release of NRF2 from KEAP1 and its translocation from the cytosol to the nucleus, where it activates gene expression to facilitate ROS elimination. Additionally, radiotherapy-induced ROS also activates ΔNP63α expression via NRF2. Pharmacologic inhibition of NRF2 effectively improves radiosensitivity in nude mice. Collectively, our results strongly suggest that the ΔNp63α/PLEC/NRF2 axis plays a key role in radioresistance in ESCC, indicating that targeting NRF2 is a promising therapeutic approach for ESCC treatment., (© 2024. The Author(s).)

A wide range of cells respond to fibroblast growth factor 2 (FGF2) by proliferation via activation of the Ras/ERK1/2 pathway. In this study, the potential involvement of salt inducible kinase SIK2) in this cascade within retinal Müller glia is explored. It is found that SIK2 phosphorylation status and activity are modulated in an FGF2-dependent manner, possibly via ERK1/2. With SIK2 downregulation, enhanced ERK1/2 activation with delayed attenuation and increased cell proliferation is observed, while SIK2 overexpression hampers FGF2-dependent ERK1/2 activation. In vitro kinase and site-directed mutagenesis studies indicate that SIK2 targets the pathway element GRB2-associated-binding protein 1 (Gab1) on Ser266. This phosphorylation event weakens Gab1 interactions with its partners growth factor receptor-bound protein 2 (Grb2) and Src homology region 2 domain containing phosphatase 2 (Shp2). Collectively, these results suggest that during FGF2-dependent proliferation process ERK1/2-mediated activation of SIK2 targets Gab1, resulting in downregulation of the Ras/ERK1/2 cascade in a feedback loop., (© 2024 Wiley‐VCH GmbH.)

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer., Competing Interests: Declarations Ethics approval and consent to participate All animal experiments in this study were evaluated and approved by the Animal Ethics Committee of Putuo District Center Hospital, Shanghai (Putuo Hospital, Shanghai University of Traditional Chinese Medicine). Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The emergence of drug-resistant mycobacterium tuberculosis (MTB, or TB) strains has led to an increasing incidence of TB. Spinal tuberculosis is the most common extrapulmonary tuberculosis. In the present study, tollip, a negative feedback regulatory factor in TLR4 signaling pathway was chosen based on previous studies on osteoarticular tuberculosis. U937 cells were transfected with recombinant lentivirus containing shRNA (RNA interference, RNAi) or overexpression vector containing Tollip gene and tested in vitro. The expression levels of Tollip and TLR4 were detected by Real-time PCR and immunofluorescence techniques, and the cell morphology and infection effect were observed by DAPI staining. The results suggested that Tollip gene could negatively inhibit the expression of related factors in TLR4 signaling pathway, and thus is a potential biomarker for early diagnosis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Antibodies are able to up- or downregulate antibody responses to the antigen they bind. Two major mechanisms can be distinguished. Suppression is most likely caused by epitope masking and can be induced by all isotypes tested (IgG1, IgG2a, IgG2b, IgG3, IgM, and IgE). Enhancement is often caused by the redistribution of antigen in a favorable way, either for presentation to B cells via follicular dendritic cells (IgM and IgG3) or to CD4 + T cells via dendritic cells (IgE, IgG1, IgG2a, and IgG2b). IgM and IgG3 complexes activate complement and are transported from the marginal zone to follicles by marginal zone B cells expressing complement receptors. IgE-antigen complexes are captured by CD23 + B cells in the blood and transported to follicles, delivered to CD8α + conventional dendritic cells, and presented to CD4 + T cells. Enhancement of antibody responses by IgG1, IgG2a, and IgG2b in complex with proteins requires activating FcγRs. These immune complexes are captured by dendritic cells and presented to CD4 + T cells, subsequently helping cognate B cells. Endogenous feedback regulation influences the response to booster doses of vaccines and passive administration of anti-RhD antibodies is used to prevent alloimmunization of RhD-negative women carrying RhD-positive fetuses., (© 2024 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.)

Cyclophilin A (CypA) is a peptidyl-prolyl isomerase that participates in multiple cancer events, but the molecular mechanisms of abnormal expression and regulation of CypA in ovarian cancer (OC) have never been considered. This study identifies CypA as a key driver of epithelial-mesenchymal transition (EMT) in ovarian cancer and explores the mechanisms that underly this process. We show that CypA is upregulated in tissues and serum of ovarian cancer patients and that CypA overexpression correlates with poor prognosis. CypA facilitates tumor growth and metastasis in vivo in subcutaneous tumor xenograft and abdominal metastatic models, and in vitro studies suggest a mechanism, showing that CypA accelerates ovarian cancer cell epithelial-mesenchymal transition by activating a PI3K/AKT signaling pathway. Mechanistic studies showed that STAT5A binds pri-miR-514a-3p and inhibits its activity, whereas miR-514a-3p directly binds to the 3'-UTR of CypA to suppress its expression, resulting in STAT5A promoting the expression of CypA, forming the STAT5A/miR-514a-3p/CypA axis. Furthermore, immunoprecipitates and mass spectrometry analysis identifies a CypA interaction with TAF15 that stabilizes TAF15 by suppressing its proteasome degradation and promotes its entry into the nucleus. While STAT5A is positively regulated by TAF15. Our findings identify a novel feedback loop for CypA that drives EMT and ovarian tumor growth and metastasis via a TAF15/STAT5A/miR-514a-3p pathway in ovarian cancer and facilitates the release of CypA into the extracellular, which provides a promising therapeutic target for OC treatment and a diagnostic biomarker., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: The informed consent was obtained from patients and the study was approved by the Medical Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (XYFY2022-KL439-01). All the research was performed in accordance with government policies and the Helsinki declaration. The animal experiments were approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University (202005A009)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Cushing's syndrome is characterized by chronic glucocorticoid oversecretion and diverse clinical manifestations. Distinguishing between adrenocorticotropic hormone (ACTH)-independent and ACTH-dependent forms is crucial for determining treatment options. Plasma ACTH levels aid in the differential diagnosis, with undetectable or low levels suggesting ACTH-independent hypercortisolemia. ACTH is derived from pro-opiomelanocortin, and its processing involves prohormone convertase 1/3. High-molecular-weight ACTH is generally found in ACTH-producing pituitary tumors and ectopic ACTH syndrome. The mechanism of negative feedback and the process of high-molecular-weight ACTH alternation during ACTH-independent Cushing's syndrome remain unclear. A 40-year-old woman with hypertension and multiple fractures developed symptoms suggestive of Cushing's syndrome. Computed tomography revealed a left adrenocortical tumor along with atrophy of the right adrenal gland. ACTH levels were undetectable at the previous clinic, indicating ACTH-independent Cushing's syndrome. However, subsequent measurements at our hospital revealed non-suppressed ACTH (18.1 pg/mL), prompting further investigation. Gel exclusion chromatography confirmed the presence of high-molecular-weight ACTH. Metyrapone treatment decreased the cortisol levels. In this situation, in which ACTH levels should be elevated, a decrease in high-molecular-weight ACTH levels was observed. Histological findings revealed cortisol-producing adenoma without ACTH expression. This case highlights the importance of assay differences in evaluating ACTH concentrations and introduces a novel finding of circulating high-molecular-weight ACTH. The observed decline in high-molecular-weight ACTH levels suggests a potential time lag in the negative feedback within the hypothalamic-pituitary-adrenal axis exhibited by glucocorticoids. This temporal aspect of the regulation of ACTH-related molecules warrants further exploration to enhance our understanding of the hypothalamic-pituitary-adrenal axis feedback mechanism., (© 2024 British Society for Neuroendocrinology.)