Stabilization of TGF-ß Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-ß Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance.

Dysregulation of the transforming growth factor-ß (TGF-ß) 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-ß receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-ß-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-ß receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-ß 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-ß signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-ß signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-ß 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-ß signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

Thermodynamic model for memory.

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.

Liver transcriptome and physiological analyses preliminarily revealed the adaptation mechanisms of Amur grayling (Thymallus arcticus grubei, Dybowski, 1869) fry for dietary lipid nutrition.

The Amur grayling (Thymallus arcticus grubei Dybowski, 1869), a species of potentially economic and research value, is renowned for its tender meat, exquisite flavor, and high nutritional contents. This study was conducted to investigate the physiological adaptation mechanisms to dietary lipids in Amur grayling fry (with average initial weight 4.64±0.03 g). This study involved a 56-day feeding trial with diets containing varying lipid levels (9.07%, 12.17%, 15.26%, 18.09%, 21.16%, and 24.07%, designated as GL1 through GL6, respectively) to explore the impact of dietary lipids on growth performance, intestinal digestion, liver antioxidative function, and transcriptomic profiles. Results showed that The group receiving 18% dietary lipid exhibited a markedly higher weight gain rate (WGR) and specific growth rate compared to other groups, alongside a reduced feed conversion ratio (FCR), except in comparison to the 15% lipid group. Activities of lipase in pancreatic secretion and amylase in stomach mucosa peaked in the 18% lipid treatment group, indicating enhanced digestive efficiency. The liver of fish in this group also showed increased activities of antioxidative enzymes and higher levels of glutathione and total antioxidative capacity, along with reduced malondialdehyde content compared to the 9% and 24% lipid treatments. Additionally, serum high-density lipoprotein cholesterol levels were highest in the 18% group. Transcriptomic analysis revealed four significant metabolic pathways affected: Cholesterol metabolism, Fat digestion and absorption, PPAR signaling, and Fatty acid degradation, involving key genes such as Lipase, Lipoprotein lipase, Fatty acid-binding protein, and Carnitine palmitoyltransferase I. These findings suggest that the liver of Amur grayling employs adaptive mechanisms to manage excessive dietary lipids. Quadratic regression analysis determined the optimal dietary lipid levels to be 16.62% and 16.52%, based on WGR and FCR, respectively. The optimal dietary lipid level for juvenile Amur grayling appears to be around 18%, as evidenced by improved growth performance, digestive function, balanced serum lipid profile, and enhanced liver antioxidative capacity. Exceeding this lipid threshold triggers both adaptive and potentially detrimental liver responses.

Photorespiration - emerging insights into photoprotection mechanisms.

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.

BcABF1 Plays a Role in the Feedback Regulation of Abscisic Acid Signaling via the Direct Activation of BcPYL4 Expression in Pakchoi.

Abscisic acid-responsive element-binding factor 1 (ABF1), a key transcription factor in the ABA signal transduction process, regulates the expression of downstream ABA-responsive genes and is involved in modulating plant responses to abiotic stress and developmental processes. However, there is currently limited research on the feedback regulation of ABF1 in ABA signaling. This study delves into the function of BcABF1 in Pakchoi. We observed a marked increase in BcABF1 expression in leaves upon ABA induction. The overexpression of BcABF1 not only spurred Arabidopsis growth but also augmented the levels of endogenous IAA. Furthermore, BcABF1 overexpression in Arabidopsis significantly decreased leaf water loss and enhanced the expression of genes associated with drought tolerance in the ABA pathway. Intriguingly, we found that BcABF1 can directly activate BcPYL4 expression, a critical receptor in the ABA pathway. Similar to BcABF1, the overexpression of BcPYL4 in Arabidopsis also reduces leaf water loss and promotes the expression of drought and other ABA-responsive genes. Finally, our findings suggested a novel feedback regulation mechanism within the ABA signaling pathway, wherein BcABF1 positively amplifies the ABA signal by directly binding to and activating the BcPYL4 promoter.

The effect of gonadal hormones on the gene expression of brain-pituitary in protandrous black porgy, Acanthopagrus schlegelii.

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-17ß (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.

Genome-wide identification of HMT gene family explores BpHMT2 enhancing selenium accumulation and tolerance in Broussonetia papyrifera.

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.

A feedback regulation of FgHtf1-FgCon7 loop in conidiogenesis and development of Fusarium graminearum.

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.

Building Feedback-Regulation System Through Atomic Design for Highly Active SO2 Sensing.

Reasonably constructing an atomic interface is pronouncedly essential for surface-related gas-sensing reaction. Herein, we present an ingenious feedback-regulation system by changing the interactional mode between single Pt atoms and adjacent S species for high-efficiency SO2 sensing. We found that the single Pt sites on the MoS2 surface can induce easier volatilization of adjacent S species to activate the whole inert S plane. Reversely, the activated S species can provide a feedback role in tailoring the antibonding-orbital electronic occupancy state of Pt atoms, thus creating a combined system involving S vacancy-assisted single Pt sites (Pt-Vs) to synergistically improve the adsorption ability of SO2 gas molecules. Furthermore, in situ Raman, ex situ X-ray photoelectron spectroscopy testing and density functional theory analysis demonstrate the intact feedback-regulation system can expand the electron transfer path from single Pt sites to whole Pt-MoS2 supports in SO2 gas atmosphere. Equipped with wireless-sensing modules, the final Pt1-MoS2-def sensors array can further realize real-time monitoring of SO2 levels and cloud-data storage for plant growth. Such a fundamental understanding of the intrinsic link between atomic interface and sensing mechanism is thus expected to broaden the rational design of highly effective gas sensors.

A model about regulation on three division modes of stem cell.

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.

Feedback regulation of plant secondary metabolism: Applications and challenges.

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.

The Interplay Between HIF-1α and EZH2 in Lung Cancer and Dual-Targeted Drug Therapy.

Interactions between oncogenic proteins contribute to the phenotype and drug resistance. Here, EZH2 (enhancer of zest homolog 2) is identified as a crucial factor that mediates HIF-1 (hypoxia-inducible factor) inhibitor resistance. Mechanistically, targeting HIF-1 enhanced the activity of EZH2 through transcription activation of SUZ12 (suppressor of zest 12 protein homolog). Conversely, inhibiting EZH2 increased HIF-1α transcription, but not the transcription of other HIF family members. Additionally, the negative feedback regulation between EZH2 and HIF-1α is confirmed in lung cancer patient tissues and a database of cell lines. Moreover, molecular prediction showed that a newly screened dual-target compound, DYB-03, forms multiple hydrogen bonds with HIF-1α and EZH2 to effectively inhibit the activity of both targets. Subsequent studies revealed that DYB-03 could better inhibit migration, invasion, and angiogenesis of lung cancer cells and HUVECs in vitro and in vivo compared to single agent. DYB-03 showed promising antitumor activity in a xenograft tumor model by promoting apoptosis and inhibiting angiogenesis, which could be almost abolished by the deletion of HIF-1α and EZH2. Notably, DYB-03 could reverse 2-ME2 and GSK126-resistance in lung cancer. These findings clarified the molecular mechanism of cross-regulation of HIF-1α and EZH2, and the potential of DYB-03 for clinical combination target therapy.

Mediation of the JNC/ILC2 pathway in DBP-exacerbated allergic asthma: A molecular toxicological study on neuroimmune positive feedback mechanism.

BACKGROUND: Dibutyl phthalate (DBP), a commonly used plasticizer, has been found to be strongly linked to a consistently high prevalence of allergic diseases, particularly allergic asthma. Previous animal experiments have demonstrated that exposure to DBP can worsen asthma by triggering the production of calcitonin gene-related peptide (CGRP), a neuropeptide in the lung tissue. However, the precise neuroimmune mechanism and pathophysiology of DBP-exacerbated allergic asthma with the assistance of CGRP remain unclear. OBJECTIVE: The present study was to investigate the potential pathophysiological mechanism in DBP-exacerbated asthma from the perspective of neural-immune interactions. METHODS AND RESULTS: C57BL/6 mice were orally exposed to different concentrations (0.4, 4, 40 mg/kg) of DBP for 28 days. They were then sensitized with OVA and nebulized with OVA for 7 consecutive excitations. To investigate whether DBP exacerbates allergic asthma in OVA induced mice, we analyzed airway hyperresponsiveness and lung histopathology. To investigate the activation of JNC and TRPV1 neurons and the release of CGRP by JNC cells, we measured the levels of TRPV1 channels, calcium inward flow, and downstream neuropeptide CGRP. Results showed that TRPV1 expression, inward calcium flux, and CGRP levels were significantly elevated in the lung tissues of the 40DBP + OVA group, suggesting the release of CGRP by JNC cells. To counteract the detrimental effects of DBP mediated by CGRP, we employed olcegepant (also known as BIBN-4096), a CGRP receptor specific antagonist. Results revealed that 40DBP + OVA + olcegepant led to notable decreases in TRPV1, calcium inward flow, and CGRP expression in lung tissues compare with 40DBP + OVA, further supporting the efficacy of olcegepant. Additionally, we also conducted ILC2 flow sorting and observed that neuropeptide CGRP-activated ILC2 cells have a crucial role as key effector cells in DBP-induced neuroimmune positive feedback regulation. Finally, we examined the protein expression of CGRP, GATA3 and P-GATA3, and found that significant upregulations of CGRP and P-GATA3 in the 40DBP + OVA group, suggest that GATA3 acted as a key regulator of CGRP-activated ILC2. CONCLUSION: The aforementioned studies indicate that exposure to DBP can exacerbate allergic asthma, leading to airway inflammation. This exacerbation occurs through the activation of TRPV1 in JNC, resulting in the release of CGRP. The excessive release of CGRP further promotes the release of Th2 cytokines by inducing the activation of ILC2 through GATA phosphorylation. Consequently, this process contributes to the development of airway inflammation and allergic asthma. The increased production of Th2 cytokines also triggers the production of IgE, which interacts with FcεRI on JNC neurons, thereby mediating neuro-immune positive feedback regulation.

Conformal Fabrication of Thick Film Platinum Strain Gauge Via Error Regulation Strategies for In Situ High-Temperature Strain Detection.

Monitoring high-temperature strain on curved components in harsh environments is a challenge for a wide range of applications, including in aircraft engines, gas turbines, and hypersonic vehicles. Although there are significant improvements in the preparation of high-temperature piezoresistive film on planar surfaces using 3D printing methods, there are still difficulties with poor surface compatibility and high-temperature strain testing on curved surfaces. Herein, a conformal direct ink writing (CDIW) system coupled with an error feedback regulation strategy was used to fabricate high-precision, thick films on curved surfaces. This strategy enabled the maximum amount of error in the distance between the needle and the substrate on a curved surface to be regulated from 155 to 4 µm. A conformal Pt thick-film strain gauge (CPTFSG) with a room-temperature strain coefficient of 1.7 was created on a curved metallic substrate for the first time. The resistance drift rate at 800 °C for 1 h was 1.1%, which demonstrated the excellent stability and oxidation resistance of the CPTFSG. High-temperature dynamic strain tests up to 769 °C revealed that the sensor had excellent high-temperature strain test performance. Furthermore, the CPTFSG was conformally deposited on an aero-engine turbine blade to perform in situ tensile and compressive strain testing at room temperature. High-temperature strain tests were conducted at 100 and 200 °C for 600 and 580 µÎµ, respectively, demonstrating a high steady-state response consistent with the commercial high-temperature strain transducer. In addition, steady-state strain tests at high temperatures up to 496 °C were tested. The CDIW error modulation strategy provides a highly promising approach for the high-precision fabrication of Pt thick films on complex surfaces and driving in situ sensing of high-temperature parameters on curved components toward practical applications.

Dynamic context-dependent regulation of auxin feedback signaling in synthetic gene circuits.

Phytohormone auxin plays a key role in regulating plant organogenesis. However, understanding the complex feedback signaling network that involves at least 29 proteins in Arabidopsis in the dynamic context remains a significant challenge. To address this, we transplanted an auxin-responsive feedback circuit responsible for plant organogenesis into yeast. By generating dynamic microfluidic conditions controlling gene expression, protein degradation, and binding affinity of auxin response factors to DNA, we illuminate feedback signal processing principles in hormone-driven gene expression. In particular, we recorded the regulatory mode shift between stimuli counting and rapid signal integration that is context-dependent. Overall, our study offers mechanistic insights into dynamic auxin response interplay trackable by synthetic gene circuits, thereby offering instructions for engineering plant architecture.

Feedback regulation of ubiquitination and phase separation of HECT E3 ligases.

Lipid homeostasis is essential for normal cellular functions and dysregulation of lipid metabolism is highly correlated with human diseases including neurodegenerative diseases. In the ubiquitin-dependent autophagic degradation pathway, Troyer syndrome-related protein Spartin activates and recruits HECT-type E3 Itch to lipid droplets (LDs) to regulate their turnover. In this study, we find that Spartin promotes the formation of Itch condensates independent of LDs. Spartin activates Itch through its multiple PPAY-motif platform generated by self-oligomerization, which targets the WW12 domains of Itch and releases the autoinhibition of the ligase. Spartin-induced activation and subsequent autoubiquitination of Itch lead to liquid-liquid phase separation (LLPS) of the poly-, but not oligo-, ubiquitinated Itch together with Spartin and E2 both in vitro and in living cells. LLPS-mediated condensation of the reaction components further accelerates the generation of polyubiquitin chains, thus forming a positive feedback loop. Such Itch-Spartin condensates actively promote the autophagy-dependent turnover of LDs. Moreover, we show that the catalytic HECT domain of Itch is sufficient to interact and phase separate with poly-, but not oligo-ubiquitin chains. HECT domains from other HECT E3 ligases also exhibit LLPS-mediated the promotion of ligase activity. Therefore, LLPS and ubiquitination are mutually interdependent and LLPS promotes the ligase activity of the HECT family E3 ligases.

DNA-Binding One Finger Transcription Factor PhDof28 Regulates Petal Size in Petunia.

Petal size is a key indicator of the ornamental value of plants, such as Petunia hybrida L., which is a popular ornamental species worldwide. Our previous study identified a flower-specific expression pattern of a DNA-binding one finger (Dof)-type transcription factor (TF) PhDof28, in the semi-flowering and full-flowering stages of petunia. In this study, subcellular localization and activation assays showed that PhDof28 was localized in the cell nucleus and could undergo in vitro self-activation. The expression levels of PhDof28 tended to be significantly up-regulated at the top parts of petals during petunia flower opening. Transgenic petunia 'W115' and tobacco plants overexpressing PhDof28 showed similar larger petal phenotypes. The cell sizes at the middle and top parts of transgenic petunia petals were significantly increased, along with higher levels of endogenous indole-3-acetic acid (IAA) hormone. Interestingly, the expression levels of two TFs, PhNAC100 and PhBPEp, which were reported as negative regulators for flower development, were dramatically increased, while the accumulation of jasmonic acid (JA), which induces PhBPEp expression, was also significantly enhanced in the transgenic petals. These results indicated that PhDof28 overexpression could increase petal size by enhancing the synthesis of endogenous IAA in petunias. Moreover, a JA-related feedback regulation mechanism was potentially activated to prevent overgrowth of petals in transgenic plants. This study will not only enhance our knowledge of the Dof TF family, but also provide crucial genetic resources for future improvements of plant ornamental traits.

B-Box proteins BBX28 and BBX29 interplay with PSEUDO-RESPONSE REGULATORS to fine-tune circadian clock in Arabidopsis.

As an endogenous time-keeping mechanism, the circadian clock benefits plant fitness and adaptation to the rhythmically changed diel environments. The key components within the core oscillator of plant circadian clock have been extensively characterised, however, the fine-tuning circadian regulators are still less identified. Here, we demonstrated that BBX28 and BBX29, the two B-Box V subfamily members lacking DNA-binding motifs, are involved in the regulation of Arabidopsis circadian clock. Over-expressing either BBX28 or BBX29 significantly lengthened circadian period, whereas loss-of-function of BBX28 rather than BBX29 displayed a modestly long period in free-running condition. Mechanistically, BBX28 and BBX29 interacted with core clock components PRR5, PRR7 and PRR9 in nucleus to augment their transcriptional repressive activities. RNA-sequencing analysis further revealed that BBX28 and BBX29 shared 686 common differentially expressed genes (DEGs) including a subset of known direct transcriptional targets of PRR proteins within core oscillator, including CCA1, LHY, LNKs and RVE8 etc. Intriguingly, PRR proteins can feedback repress BBX28 and BBX29 transcription by associating with their promoters. Together, our findings unmasked an exquisite mechanism in which BBX28 and BBX29 interplay with PRR proteins to fine-tune the circadian pace.

Precise Regulation of the TAA1/TAR-YUCCA Auxin Biosynthesis Pathway in Plants.

The indole-3-pyruvic acid (IPA) pathway is the main auxin biosynthesis pathway in the plant kingdom. Local control of auxin biosynthesis through this pathway regulates plant growth and development and the responses to biotic and abiotic stresses. During the past decades, genetic, physiological, biochemical, and molecular studies have greatly advanced our understanding of tryptophan-dependent auxin biosynthesis. The IPA pathway includes two steps: Trp is converted to IPA by TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS/TRYPTOPHAN AMINOTRANSFERASE RELATED PROTEINs (TAA1/TARs), and then IPA is converted to IAA by the flavin monooxygenases (YUCCAs). The IPA pathway is regulated at multiple levels, including transcriptional and post-transcriptional regulation, protein modification, and feedback regulation, resulting in changes in gene transcription, enzyme activity and protein localization. Ongoing research indicates that tissue-specific DNA methylation and miRNA-directed regulation of transcription factors may also play key roles in the precise regulation of IPA-dependent auxin biosynthesis in plants. This review will mainly summarize the regulatory mechanisms of the IPA pathway and address the many unresolved questions regarding this auxin biosynthesis pathway in plants.

Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein.

Diverse extracellular proteins negatively regulate WNT signaling. One such regulator is adenomatosis polyposis coli down-regulated 1 (APCDD1), a conserved single-span transmembrane protein. In response to WNT signaling in a variety of tissues, APCDD1 transcripts are highly up-regulated. We have determined the three-dimensional structure of the extracellular domain of APCDD1, and this structure reveals an unusual architecture consisting of two closely apposed ß-barrel domains (ABD1 and ABD2). ABD2, but not ABD1, has a large hydrophobic pocket that accommodates a bound lipid. The APCDD1 ECD can also bind to WNT7A, presumably via its covalently bound palmitoleate, a modification that is common to all WNTs and is essential for signaling. This work suggests that APCDD1 functions as a negative feedback regulator by titrating WNT ligands at the surface of responding cells.