Central Regulator Research Articles

Distinct domain regions of NIN and NLP1 mediate symbiotic and nitrate signaling in Medicago truncatula.

Nodule Inception (NIN) and NIN-like protein 1 (NLP1), both belonging to the RWP-RK type transcription factors, play critical roles in plant development. Specifically, NIN is pivotal in facilitating root nodule symbiosis in nitrogen-starved conditions, while NLP1 coordinates nodulation in response to nitrate level. In this study, we conducted domain swapping experiments between NIN and NLP1 in Medicago truncatula to elucidate the functional significance of their respective domains. The findings reveal that the C-terminal regions, including the RWP-RK and PB1 domains of NIN, can substitute for those of NLP1, whereas reciprocal substitution do not yield equivalent outcomes. Moreover, our data emphasize the critical role of PB1-mediated interactions for NLP1's activity, a feature not essential for NIN. Additionally, the N-terminal segment, conserved in NLPs but containing deletions or mutations in NIN, is essential for the proper functioning of both NIN and NLP1. Collectively, our research suggests the evolutionary divergence of NIN from ancestral NLPs, indicating specific adaptations that have enabled NIN as a central regulator in root nodulation processes.

Invisible Threads: Emerging Water Governance in the Multi‐Actor Dynamics of the Mira‐Mataje Transboundary River Basin

ABSTRACTIn recent years, scholarly interest has surged in exploring the emergence of new governance regimes that redefine the self‐governing capacities of local communities in water management, navigating security challenges to ensure compliance to central government water laws and regulations. Embracing polycentric governance across various levels of political interaction provides insights into the factors driving the establishment of these regimes, particularly in regions with limited state presence, and where the threat of climate impact has become visible by climate extreme events as drought. This approach emphasizes the importance of decentralized, collaborative systems for effectively and sustainably managing water resources. Such systems promote equitable water use, regional stability, and resilience to drought through innovative, community‐driven solutions aimed at addressing water scarcity challenges. While the former, polycentric governance, involves multiple centers of authority making decisions collaboratively, the latter, decentralized governance, refers to communities independently managing their affairs. To understand evidence related to these dynamics, we focus on actors' interactions around the downstream area of the transboundary Mira River Basin, between Ecuador and Colombia. Employing mixed method approaches such as qualitative interviews, policy analysis, and participatory observation provides comprehensive insights into the complex interactions shaping transboundary water governance and community responses. These methods facilitate a thorough understanding of how institutional arrangements and governance structures evolve and adapt in diverse sociopolitical contexts, offering valuable lessons for sustainable water management strategies on (local) scale or on (cross‐border) collaboration. This is particularly crucial in addressing the challenges posed by drought scenarios, ensuring resilience and adaptability in water governance worldwide.

Identification of a central regulator of ginkgolide biosynthesis in Ginkgo biloba that integrates jasmonate and light signaling

Ginkgolides are secondary metabolites unique to Ginkgo biloba with the potential to prevent and treat cardiovascular and cerebrovascular diseases. Although the biosynthetic pathways of ginkgolides have been partly uncovered, the mechanism regulating their biosynthesis is still largely unknown. Here, using multiomic and genetic analyses, we report the identification of a transcription factor, named ETHYLENE RESPONSE FACTOR ASSOCIATED WITH GINKGOLIDE BIOSYNTHESIS (GbEAG), as a critical regulator of ginkgolide biosynthesis. GbEAG is highly expressed in the roots of G. biloba, and its expression is significantly induced by methyl jasmonate (MeJA). Ginkgolide content was significantly increased in roots by overexpressing GbEAG using a "cut-dip-regeneration" system. GbEAG positively regulates ginkgolide biosynthesis by directly binding to the GCC-boxes in the promoter regions of genes involved in the biosynthesis of ginkgolides, such as ISOPENTENYL DIPHOSPHATE ISOMERASE (GbIDI) and CYTOCHROME P450 7005C3 (GbCYP7005C3). GbEAG mediates the jasmonic acid (JA)-activated ginkgolide synthesis through its direct interaction with the JASMONATE ZINC-FINGER INFLORESCENCE MERISTEM DOMAIN 3 (GbJAZ3) repressor. Importantly, we also found that the central light-response regulator ELONGATED HYPOCOTYL 5 (GbHY5) mediates light induction of ginkgolide biosynthesis by binding to the G-box in the GbEAG promoter. Our findings provide mechanistic insights into the coordinated regulation of ginkgolide biosynthesis via JA and light signals, with GbEAG as a central regulator in G. biloba, and shed light on the potential to develop ginkgolide-rich varieties through molecular breeding and gene editing.

Transcription Factor Blimp-1: A Central Regulator of Oxidative Stress and Metabolic Reprogramming in Chronic Inflammatory Diseases

B-lymphocyte-induced maturation protein 1 (Blimp-1) is a transcription factor that, among other functions, modulates metabolism and helps to regulate antioxidant pathways, which is important in the context of chronic inflammatory diseases like diabetes, cardiovascular disease, and autoimmune disease. In immune cell function, Blimp-1 has a modulatory role in the orchestration of metabolic reprogramming and as a promoter of anti-inflammatory cytokines, including IL-10, responsible for modulating oxidative stress and immune homeostasis. Moreover, Blimp-1 also modulates key metabolic aspects, such as glycolysis and fatty acid oxidation, which regulate reactive oxygen species levels, as well as tissue protection. This review depicts Blimp-1 as an important regulator of antioxidant defenses and anti-inflammation and suggests that the protein could serve as a therapeutic target in chronic inflammatory and metabolic dysregulation conditions. The modulation of Blimp-1 in diseases such as diabetic coronary heart disease and atherosclerosis could alleviate oxidative stress, augment the protection of tissues, and improve disease outcomes. The therapeutic potential for the development of new treatments for these chronic conditions lies in the synergy between the regulation of Blimp-1 and antioxidant therapies, which are future directions that may be pursued. This review emphasizes Blimp-1’s emerging importance as a novel regulator in the pathogenesis of inflammatory diseases, providing new opportunities for therapeutic intervention.

Tonic ubiquitination of the central body weight regulator melanocortin receptor 4 (MC4R) promotes its constitutive exit from cilia.

The G protein-coupled receptor (GPCR) melanocortin receptor 4 (MC4R) is an essential regulator of body weight homeostasis. MC4R is unusual among GPCRs in that its activity is regulated by 2 opposing physiological ligands, the agonist ⍺-MSH and the antagonist/inverse agonist AgRP. Paradoxically, while MC4R localizes and functions at the cilium of hypothalamic neurons, the ciliary levels of MC4R are very low under unrestricted feeding conditions. Here, we find that the constitutive activity of MC4R is responsible for the continuous depletion of MC4R from cilia and that inhibition of MC4R's activity via AgRP leads to a robust accumulation of MC4R in cilia. Ciliary targeting of MC4R is mediated by its partner MRAP2 and the constitutive exit of MC4R from cilia relies on the sensor of activation β-arrestin, on ubiquitination, and on the BBSome ciliary trafficking complex. Thus, while MC4R exits cilia via conventional mechanisms, it only accumulates in cilia when its activity is suppressed by AgRP.

Early tolerance and late persistence as alternative drug responses in cancer

Bacteria withstand antibiotic treatment through three alternative mechanisms: resistance, persistence or tolerance. While resistance and persistence have been described, whether drug-induced tolerance exists in cancer cells remains largely unknown. Here, we show that human cancer cells elicit a tolerant response when exposed to commonly used chemotherapy regimens, propelled by the pervasive activation of autophagy, leading to the comprehensive activation of DNA damage repair pathways. After prolonged drug exposure, such tolerant responses morph into persistence, whereby the increased DNA damage repair is entirely reversed. The central regulator of mitophagy PINK1 drives this reduction in DNA repair via the cytoplasmic relocalization of the cell identity master HNF4A, thus hampering HNF4A transcriptional activation of DNA repair genes. We conclude that exposing cancer cells to relevant standard-of-care antitumour therapies induces a pervasive drug-induced tolerant response that might be broadly exploited to increase the impact of first-line, adjuvant treatments and debulking in advanced cancers.

Microenvironment regulation of asymmetric Fe coordination centers through designing p-n junction toward highly efficient oxygen reduction for rechargeable zinc-air batteries

Microenvironment regulation of asymmetric Fe coordination centers through designing p-n junction toward highly efficient oxygen reduction for rechargeable zinc-air batteries

Time- and Region-specific Effect of Vortioxetine on Central LPS-induced Transcriptional Regulation of NLRP3 Inflammasome.

Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) postchallenge. The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 μg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX's on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD. Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was discovered that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway. Thus, a novel VTX's molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.</p>.

Transcriptional signature of a hypersensitive glucocorticoid receptor variant in the neuroendocrine system suggests enhanced vulnerability to brain disorders.

The natural substitution Ala610Val in the porcine glucocorticoid receptor (GRAla610Val) leads to a profound compensatory downregulation of the hypothalamic-pituitary-adrenal (HPA) axis in early ontogeny. In this study, we leveraged this unique animal model to explore mechanisms of HPA axis regulation and consequences of its genetically-based persistent hypoactivity. To this end, we examined transcriptional signature of GRAla610Val in the hypothalamus, hippocampus, amygdala and adrenal gland in resting conditions (i.e. baseline glucocorticoid level) using mRNA sequencing. In addition, we studied transcriptome responses to two different doses of dexamethasone in the hypothalamus and hippocampus, depending on GRAla610Val. Across tissues, GRAla610Val consistently influenced the expression of several clustered protocadherins, particularly PCDHB7. Clustered protocadherins play an important role in neuronal connectivity and are implicated in different neurobiological disorders. Moreover, in line with our previous findings in blood immune cells, we found higher expression of pro-inflammatory genes, including canonical members of the TLR4 signaling pathway, in the brain of Val carriers. While the pro-inflammatory priming occurs already at resting conditions in the amygdala, in hypothalamus and hippocampus this seems to be associated with a stronger downregulation of several marker genes of homeostatic microglia, such as SALL1, by dexamethasone in Val carriers. Regarding the regulation of the HPA axis, GRAla610Val showed a dose-dependent effect on the central regulator of the axis, CRH, suggesting a dynamic adaptation to the glucocorticoid hypersensitivity of the Val variant. In the adrenal gland, GRAla610Val appears to downregulate cortisol production by impairing mitochondrial function. Overall, the transcriptional signature of GRAla610Val provides strong evidence that GR hypersensitivity leads to increased susceptibility to brain disorders.

Cellular senescence-associated gene IFI16 promotes HMOX1-dependent evasion of ferroptosis and radioresistance in glioblastoma

Glioblastoma multiforme (GBM) remains a therapeutic challenge due to its aggressive nature and recurrence. This study establishes a radioresistant GBM cell model through repeated irradiation and observes a cellular senescence-like phenotype in these cells. Comprehensive genomic and transcriptomic analyses identify IFI16 as a central regulator of this phenotype and contributes to radioresistance. IFI16 activates HMOX1 transcription thereby attenuating ferroptosis by reducing lipid peroxidation, ROS production, and intracellular Fe2+ content following irradiation. Furthermore, IFI16 interacts with the transcription factors JUND and SP1 through its pyrin domain, robustly facilitating HMOX1 expression, further inhibiting ferroptosis and enhancing radioresistance in GBM. Notably, glyburide, a sulfonylurea compound, effectively disrupts IFI16 function and enhances ferroptosis and radiosensitivity. By targeting the pyrin domain of IFI16, glyburide emerges as a potential therapeutic agent against GBM radioresistance. These findings underscore the central role of IFI16 in GBM radioresistance and offer promising avenues to improve GBM treatment.

Interaction of the Vagus Nerve and Serotonin in the Gut–Brain Axis

The gut–brain axis represents an important bidirectional communication network, with the vagus nerve acting as a central conduit for peripheral signals from the various gut organs to the central nervous system. Among the molecular mediators involved, serotonin (5-HT), synthesized predominantly by enterochromaffin cells in the gut, plays a pivotal role. Gut-derived serotonin activates vagal afferent fibers, transmitting signals to the nucleus tractus solitarius (NTS) and modulating serotonergic neurons in the dorsal raphe nucleus (DRN) as well as the norepinephrinergic neurons in the locus coeruleus (LC). This interaction influences emotional regulation, stress responses, and immune modulation. Emerging evidence also highlights the role of microbial metabolites, particularly short-chain fatty acids (SCFAs), in enhancing serotonin synthesis and vagal activity, thereby shaping gut–brain communication. This review synthesizes the current knowledge on serotonin signaling, vagal nerve pathways, and central autonomic regulation, with an emphasis on their implications for neuropsychiatric and gastrointestinal disorders. By elucidating these pathways, novel therapeutic strategies targeting the gut–brain axis may be developed to improve mental and physical health outcomes.

In Vitro and In Vivo Anticancer Activities of Water-Soluble Ru(II)(η6-p-cymene) Complexes via Activating Apoptosis Central Regulators and Possibilities of New Antitumor Strategies in Triple Negative Breast Cancers.

In this study, we synthesized 12 monofunctional tridentate ONS-donor salicylaldimine ligand (L)-based Ru(II) complexes with general formula [(Ru(L)(p-cymene)]+·Cl- (C1-C12), characterized by 1H NMR, 13C NMR, UV, FT-IR spectroscopy, HR-ESI mass spectrometry, and single-crystal X-ray analysis showing ligand's orientation around the Ru(II) center. All 12 of these 12 complexes were tested for their anticancer activities in multiple cancer cells. The superior antitumor efficacy of C2, C8, and C11 was demonstrated by reduced mitochondrial membrane potential, impaired proliferative capacity, and disrupted redox homeostasis, along with enhanced apoptosis through caspase-3 activation and downregulation of Bcl-2 expression. In the 4T1 breast cancer orthotopic mouse model, assessment of bioluminescence for metastatic spread, tumor burden, histopathological evaluation, immunohistochemistry (IHC), and hematological profiling and tissue Protein expression of caspase-3, cleaved caspase-3, TNF-α, and bcl-2 demonstrated that C8 treatment led to prolonged survival and suppressed tumor progression in triple negative breast cancer.

The dark side of fluorescent protein tagging - the impact of protein tags on biomolecular condensation.

Biomolecular condensation has emerged as an important mechanism to control various cellular processes through the formation of membraneless organelles. Fluorescent protein tags have been extensively used to study the formation and the properties of condensates in vitro and in vivo, but there is evidence that tags may perturb the condensation properties of proteins. In this study, we carefully assess the effects of protein tags on the yeast DEAD-box ATPase Dhh1, a central regulator of processing bodies (P-bodies), which are biomolecular condensates involved in mRNA metabolism. We show that fluorescent tags as well as a poly-histidine tag greatly affect Dhh1 condensation in vitro and lead to condensates with different dynamic properties. Tagging of Dhh1 with various fluorescent proteins in vivo alters the number of P-bodies upon glucose starvation and some tags even show constitutive P-bodies in non-stressed cells. These data raise concerns about the accuracy of tagged protein condensation experiments, highlighting the need for caution when interpreting the results.

The Impact of Traditional Chinese Medicines on Osteoclastogenesis through NF-κB Signaling Pathway: A Review

Osteoclasts are specialized cells responsible for bone resorption, which plays a crucial role in the dynamic processes of bone remodeling and maintenance. Osteolytic skeletal disorders, such as osteoporosis, arise from an imbalance between the activities of osteoclasts and osteoblasts. The regulatory mechanisms underlying osteoclast differentiation, known as osteoclastogenesis, are governed by the receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) signaling system. In this system, the RANK, a type 1 transmembrane protein, acts as a central regulator of osteoclastogenesis through various signaling pathways. This review seeks to explore the influence of Traditional Chinese Medicines (TCM) on osteoclastogenesis, focusing on the NF-κB signaling pathway. This study aims to offer valuable insights into potential therapeutic strategies for managing osteolytic skeletal disorders by investigating the interaction between TCM and the regulatory mechanisms that control osteoclast function. A comprehensive literature review was conducted, concentrating on studies that examine the effects of TCM on osteoclastogenesis and the NF-κB signaling pathway. Databases such as PubMed, Web of Science, and Google Scholar were searched for peer-reviewed articles, reviews, and clinical studies. The inclusion criteria focused on studies addressing the impact of TCM on osteoclast function and the associated molecular mechanisms, especially those involving the RANKL/RANK/OPG system and the NF-κB pathway. The review identified several TCM compounds with regulatory effects on osteoclastogenesis. These compounds were found to modulate the NF-κB pathway, influencing osteoclast differentiation and activity. Key findings highlighted the discovery of specific TCM herbs and their active ingredients that can inhibit osteoclast formation and function, promoting bone health. The mechanisms of action often involved suppressing RANKL-induced NF-κB activation, a crucial process for osteoclast differentiation and bone resorption. This review underscores the potential of TCMs as therapeutic agents for osteolytic skeletal disorders through their modulation of the NF-κB signaling pathway. The findings suggest that TCM may significantly regulate osteoclastogenesis, offering new avenues for developing treatments for conditions like osteoporosis. However, further research and clinical trials are necessary to fully elucidate the therapeutic potential of TCM and translate these findings into clinical practice.

Molecular Mechanisms of Vascular Tone in Exercising Pediatric Populations: A Comprehensive Overview on Endothelial, Antioxidative, Metabolic and Lipoprotein Signaling Molecules

Vasoactive molecules are central regulators of vascular tone, angiogenesis and inflammation. Key molecular agents include nitric oxide (NO), endothelin-1 (ET-1), prostacyclin, free triiodothyronine (fT3), leptin, low-density lipoprotein (LDL), high-density lipoprotein (HDL), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Dysregulation of these compounds can lead to endothelial dysfunction, an early predictor of atherosclerosis and cardiovascular diseases (CVD). Maintaining endothelial health is thus essential for vascular homeostasis and cardiovascular risk prevention. Regular exercise serves as a vital protective measure against CVD and the risk of cardiovascular conditions. However, young athletes often significantly exceed recommended levels of training load, engaging in highly intensive training that leads to substantial physiological adaptations. Despite this, research on the impact of exercise on vasoactive substances in children and adolescents, particularly young athletes, is limited and inconsistent. Most studies focus on those with pre-existing conditions, like obesity or diabetes mellitus. Existing findings suggest exercise may favorably affect vascular biomarkers in youth, but methodological variations hinder consistent conclusions. This literature review examines 68 studies on the effects of exercise on vascular molecules in children and adolescents, young athletes, and children and adolescents with pre-existing conditions, offering deeper insights into how exercise may influence vascular health at the molecular level.

Abscisic acid receptors functionally converge across 500 million years of land plant evolution.

Abscisic acid (ABA) functions as a central regulator of dehydration responses in land plants. As such, ABA signaling was pivotal in facilitating the colonization of terrestrial habitats. The conserved ABA signal transduction module consists of 2C-type protein phosphatases (PP2Cs) and their ABA-triggered inhibitors, PYRABACTIN RESISTANCE 1-like proteins (PYLs). Recent evidence indicates that ABA perception emerged from a latent signaling pathway involving a constitutively PP2C-inhibiting PYL homolog. Consequently, ancestral ABA receptors exerted high background signaling, limiting the dynamic range of ABA-dependent signaling. In angiosperms, ABA receptor families are characteristically large and diverse and include a clade-specific subgroup whose members form homodimers, thereby assuming strict ABA dependency. Here, we show that ABA receptors in mosses originate from an independent expansion, giving rise to three subfamilies. Yeast two-hybrid and invitro PP2C-inhibition assays indicate that moss PYLs feature low basal activities. However, size-exclusion chromatography and additional lines of evidence suggest that moss PYLs are predominantly monomeric. A combination of mutational analysis with biochemical and physiological assays reveals that the reduced basal activities of moss PYLs are achieved through unique sets of amino acid variations. Finally, introducing causal variations to dimeric receptors dramatically compromises their ABA responsiveness, suggesting that the two evolutionary trajectories are mutually exclusive. Hence, mosses appear to have evolved a parallel mechanism to mitigate the ancestrally high background signal of the core ABA perception apparatus. This convergence highlights the shared imperative of expanding the amplitude of a central, highly adaptive signaling pathway.

Calcineurin governs baseline and homeostatic regulations of non–rapid eye movement sleep in mice

Sleep need accumulates during waking and dissipates during sleep to maintain sleep homeostasis (process S). Besides the regulation of daily (baseline) sleep amount, homeostatic sleep regulation commonly refers to the universal phenomenon that sleep deprivation (SD) causes an increase of sleep need, hence, the amount and intensity of subsequent recovery sleep. The central regulators and signaling pathways that govern the baseline and homeostatic sleep regulations in mammals remain unclear. Here, we report that enhanced activity of calcineurin Aα (CNAα)-a catalytic subunit of calcineurin-in the mouse brain neurons sharply increases the amount (to ~17-h/d) and delta power-a measure of intensity-of non-rapid eye movement sleep (NREMS). Knockout of the regulatory (CnB1) or catalytic (CnAα and CnAβ) subunits of calcineurin diminishes the amount (to ~4-h/d) and delta power of baseline NREMS, but also nearly abrogates the homeostatic recovery NREMS following SD. Accordingly, mathematical modeling of process S reveals an inability to accumulate sleep need during spontaneous or forced wakefulness in calcineurin deficient mice. Moreover, calcineurin promotes baseline NREMS by antagonizing wake-promoting protein kinase A and, in part, by activating sleep-promoting kinase SIK3. Together, these results indicate that calcineurin is an important regulator of sleep need and governs both baseline and homeostatic regulations of NREMS in mice.

Rdh10-mediated Retinoic Acid Signaling Regulates the Neural Crest Cell Microenvironment During ENS Formation.

The enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate most of the neurons and glia that regulate gastrointestinal function. Defects in the migration or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an undetermined genetic diagnosis. Therefore, it's important to identify new genes, modifiers and environmental factors that regulate ENS development and disease. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, RA, and is therefore a central regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. We discovered that retinol dehydrogenase 10 ( Rdh10 ) loss-of-function mouse embryos exhibit intestinal aganglionosis, characteristic of HSCR. Vagal NCC form and migrate in Rdh10 mutant embryos but fail to invade the foregut. Rdh10 is highly expressed in the mesenchyme surrounding the entrance to the foregut and is essential between E7.5-E9.5 for NCC invasion into the gut. Comparative RNA-sequencing revealed downregulation of the Ret-Gdnf-Gfrα1 gene signaling network in Rdh10 mutants, which is critical for vagal NCC chemotaxis. Furthermore, the composition of the extracellular matrix through which NCC migrate is also altered, in part by increased collagen deposition. Collectively this restricts NCC entry into the gut, demonstrating that Rdh10 -mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of intestinal aganglionosis.

Autism-Associated Genes and Neighboring lncRNAs Converge on Key Gene Regulatory Networks.

The diversity of genes implicated in autism spectrum disorder (ASD) creates challenges for identifying core pathophysiological mechanisms. Aggregation of seven different classes of genetic variants implicated in ASD, in a database we call Consensus-ASD , reveals shared features across distinct types of ASD variants. Functional interrogation of 19 ASD genes and 9 neighboring long non-coding RNAs (lncRNAs) using CRISPR-Cas13 strikingly revealed differential gene expression profiles that were significantly enriched for other ASD genes. Furthermore, construction of a gene regulatory network (GRN) enabled the identification of central regulators that exhibit convergently altered activity upon ASD gene disruption. Thus, this study reveals how perturbing distinct ASD-associated genes can lead to shared, broad dysregulation of GRNs with critical relevance to ASD. This provides a crucial framework for understanding how diverse genes, including lncRNAs, can play convergent roles in key neurodevelopmental processes and ultimately contribute to ASD.

Creating Single Atomic Coordination for Hypoxia-Resistant Pyroptosis Nano-Inducer to Boost Anti-Tumor Immunotherapy.

General synthesis and mechanical understanding of type I nano-photosensitizers are of great importance for hypoxia-resistant pyroptosis inducers. Herein, a simple solvothermal treatment is developed to convert non-photosensitive small molecules (hemin) into uniform carbon nanodots (HNCDs) with strong type I photodynamic activity and red fluorescence emission. These HNCDs inherit the single atomic Fe-N4 center of hemin while creating sp2-hybridized carbon surroundings, which synergistically modulated the energy level and electron transfer for converting the type II photodynamic process to type I. After encapsulating HNCDs with bovine serum albumin (BSA)to facilitate in vivo applications, the resulting BSA nanoparticles (HB) can image tumors and significantly induce the pyroptosis of tumor cells even under an extremely hypoxic environment (2% O2). This evokes a strong antitumor immune response, effectively restraining tumor growth and lung metastasis in triple-negative breast cancer mice, with good biocompatibility. This work introduces an applicable pyroptosis nano-inducer to combat hypoxic tumors and highlights the regulation of Fe-N4 centers to develop hypoxia-resistant type I nano-photosensitizers for cancer treatment.