BACKGROUND: Type I interferon (IFN-I, IFN-α/β), precisely controlled by multiple regulators, including suppressor of cytokine signaling 1 (SOCS1), is critical for host defense against pathogens. However, the impact of IFN-α/β on malaria parasite infections, beneficial or detrimental, remains controversial.
OBJECTIVE: The contradictory results are suspected to arise from differences in parasite species and host genetic backgrounds. To date, no prior study has employed a comparative approach utilizing two parasite models to investigate the underlying mechanisms of IFN-I response. Moreover, whether and how SOCS1 involves in the distinct IFN-α/β dynamics is still unclear.
METHODS: Here we perform single-cell RNA sequencing analyses (scRNA-seq) to dissect the dynamics of IFN-α/β responses against P. yoelii 17XL (17XL) and P. berghei ANKA (PbANKA) infections; conduct flow cytometry analysis and functional depletion to identify key cellular players induced by IFN-I; and establish mathematical models to explore the mechanisms underlying the differential IFN-I dynamics regulated by SOCS1.
RESULTS: 17XL stimulates an early protective but insufficient toll-like receptor 7 (TLR7)-interferon regulatory factor 7 (IRF7)-dependent IFN-α/β response, resulting in CD11ahiCD49dhiCD4+ T cell activation to enhance anti-malarial immunity. On the contrary, a late IFN-α/β induction through toll-like receptor 9 (TLR9)-IRF7/ stimulator of interferon genes (STING)- interferon regulatory factor 3 (IRF3) dependent pathways expands programmed cell death protein 1 (PD-1)+CD8+ T cells and impairs host immunity during PbANKA infection. Furthermore, functional assay and mathematical modeling show that SOCS1 significantly suppresses IFN-α/β production via negative feedback and incoherent feed-forward loops (I1-FFL). Additionally, differential activation patterns of various transcriptional factors (TFs) synergistically regulate the distinct IFN-I responses.
CONCLUSIONS: This study reveals the dual functions of IFN-I in anti-malarial immunity: Early IFN-α/β enhances immune responses against Plasmodium infection by promoting CD11ahiCD49dhiCD4+ T cell, while late IFN-α/β suppresses these response by expanding PD-1+CD8+ T cells. Moreover, both the SOCS1-related network motifs and TFs activation patterns contribute to determine distinct dynamics of IFN-I responses. Hence, our findings suggest therapies targeting SOCS1- or TFs-regulated IFN-I dynamics could be an efficacious approach for preventing malaria and enhancing vaccine efficacy.

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.

Dysregulation of the transforming growth factor-β (TGF-β) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-β receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-β-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-β receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-β signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-β signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-β signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-β signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-β signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

A thermodynamic model for memory formation is proposed. Key points include: 1) Any thought or consciousness corresponds to a thermodynamic system of nerve cells. 2) The system concept of nerve cells can only be described by thermodynamics of condensed matter. 3) The memory structure is logically associated with the system structure or the normal structure of biology. 4) The development of our thoughts is processed irreversibly, and numerous states or thoughts can be generated. 5) Memory formation results from the reorganization and change of cellular structures (or memory structures), which are related to nerve cell skeleton and membrane. Their alteration can change the excitability of nerve cells and the pathway of neural impulse conduction. 6) Amnesia results from the loss of thermodynamic stability of the memory structure, which can be achieved by different ways. Some related phenomena and facts are discussed. The analysis shows that thermodynamics can account for the basic properties of memory.

Two recent studies reinvestigated the phenomenon of photorespiration as a photoprotective mechanism. Smith et al. suggest alleviated negative feedback regulation of chloroplast ATP synthase as an alternative hypothesis. Von Bismarck et al. discuss how photorespiration-impaired mutants cope somewhat better with fluctuating light (FL) environments because of downregulated photosynthesis and complex metabolic re-routing.

Broussonetia papyrifera, a valuable feed resource, is known for its fast growth, wide adaptability, high protein content and strong selenium enrichment capacity. Selenomethionine (SeMet), the main selenium form in selenium fortification B. papyrifera, is safe for animals and this enhances its nutritional value as a feed resource. However, the molecular mechanisms underlying SeMet synthesis remain unclear. This study identified three homocysteine S-methyltransferase genes from the B. papyrifera genome. The phylogenetic tree demonstrated that BpHMTs were divided into two classes, and BpHMT2 in the Class 2-D subfamily evolved earlier and possesses more fundamental functions. On the basis of the correlation between gene expression levels and selenium content, BpHMT2 was identified as a key candidate gene associated with selenium tolerance. Subcellular localization experiments confirmed the targeting of BpHMT2 in nucleus, cell membrane and chloroplasts. Moreover, three BpHMT2 overexpression Arabidopsis thaliana lines were confirmed to enhance plant selenium tolerance and SeMet accumulation. Overall, our finding provides insights into the molecular mechanisms of selenium metabolism in B. papyrifera, highlighting the potential role of BpHMT2 in SeMet synthesis. This research contributes to our understanding of selenium-enriched feed resources, with increased SeMet content contributing to the improved nutritional value of B. papyrifera as a feed resource.

In black porgy (Acanthopagrus schlegelii), the brain-pituitary-testis (Gnrh-Gths-Dmrt1) axis plays a vital role in male fate determination and maintenance, and then inhibiting female development in further (puberty). However, the feedback of gonadal hormones on regulating brain signaling remains unclear. In this study, we conducted short-term sex steroid treatment and surgery of gonadectomy to evaluate the feedback regulation between the gonads and the brain. The qPCR results show that male phase had the highest gths transcripts; treatment with estradiol-17β (E2) or 17α-methyltestosterone (MT) resulted in the increased pituitary lhb transcripts. After surgery, apart from gnrh1, there is no difference in brain signaling genes between gonadectomy and sham fish. In the diencephalon/mesencephalon transcriptome, de novo assembly generated 283,528 unigenes; however, only 443 (0.16%) genes showed differentially expressed between sham and gonadectomy fish. In the present study, we found that exogenous sex steroids affect the gths transcription; this feedback control is related to the gonadal stage. Furthermore, gonadectomy may not affect gene expression of brain signaling (Gnrh-Gths axis). Our results support the communication between ovotestis and brain signaling (Gnrh-Gths-testicular Dmrt1) for the male fate.

The transcription factor FgHtf1 is important for conidiogenesis in Fusarium graminearum and it positively regulates the expression of the sporulation-related gene FgCON7. However, the regulatory mechanism underlying its functions is still unclear. The present study intends to uncover the functional mechanism of FgHtf1 in relation to FgCon7 in F. graminearum. We demonstrated that FgCON7 serves as a target gene for FgHtf1. Interestingly, FgCon7 also binds the promoter region of FgHTF1 to negatively regulate its expression, thus forming a negative-feedback loop. We demonstrated that FgHtf1 and FgCon7 have functional redundancy in fungal development. FgCon7 localizes in the nucleus and has transcriptional activation activity. Deletion of FgCON7 significantly reduces conidia production. 4444 genes were regulated by FgCon7 in ChIP-Seq, and RNA-Seq revealed 4430 differentially expressed genes in FgCON7 deletion mutant, with CCAAT serving as a consensus binding motif of FgCon7 to the target genes. FgCon7 directly binds the promoter regions of FgMSN2, FgABAA, FgVEA and FgSMT3 genes and regulates their expression. These genes were found to be important for conidiogenesis. To our knowledge, this is the first study that unveiled the mutual regulatory functions of FgCON7 and FgHTF1 to form a negative-feedback loop, and how the loop mediates sporulation in F. graminearum.

We construct a multi-stage cell lineage model for cell division, apoptosis and movement. Cells are assumed to secrete and respond to negative feedback molecules which act as a control on the stem cell divisions (including self-renewal, asymmetrical cell division (ACD) and differentiation). The densities of cells and molecules are described by coupled reaction-diffusion partial differential equations, and the plane wavefront propagation speeds can be obtained analytically and verified numerically. It is found that with ACD the population and propagation of stem cells can be promoted but the negative regulation on self-renewal and differentiation will work slowly. Regulatory inhibition on differentiation will inversely increase stem cells but not affect the population and wave propagation of the cell lineage. While negative regulation on self-renewal and ACD will decrease the population of stem cells and slow down the propagation, and even drive stem cells to extinction. Moreover we find that inhibition on self-renewal has a strength advantage while inhibition on ACD has a range advantage to kill stem cells. Possible relations to model cancer development and therapy are also discussed.

Plant secondary metabolites offer resistance to invasion by herbivorous organisms, and are also useful in the chemical, pharmaceutical, cosmetic, and fragrance industries. There are numerous approaches to enhancing secondary metabolite yields. However, a growing number of studies has indicated that feedback regulation may be critical in regulating secondary metabolite biosynthesis. Here, we review examples of feedback regulation in secondary metabolite biosynthesis pathways, phytohormone signal transduction, and complex deposition sites associated with secondary metabolite biosynthesis. We propose a new strategy to enhance secondary metabolite production based on plant feedback regulation. We also discuss challenges in feedback regulation that must be overcome before its application to enhancing secondary metabolite yields. This review discusses recent advances in the field and highlights a strategy to overcome feedback regulation-related obstacles and obtain high secondary metabolite yields.