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Fibroblasts can be reprogrammed into cardiovascular progenitor cells (CPCs) using transgenic approaches, although the underlying mechanism remains unclear. We determined whether activation of endogenous genes such as Gata4, Nkx2.5, and Tbx5 can rapidly establish autoregulatory loops and initiate CPC generation in adult extracardiac fibroblasts using a CRISPR activation system. The induced fibroblasts (>80%) showed phenotypic changes as indicated by an Nkx2.5 cardiac enhancer reporter. The progenitor characteristics were confirmed by colony formation and expression of cardiovascular genes. Cardiac sphere induction segregated the early and late reprogrammed cells that can generate functional cardiomyocytes and vascular cells in vitro. Therefore, they were termed CRISPR-induced CPCs (ciCPCs). Transcriptomic analysis showed that cell cycle and heart development pathways were important to accelerate CPC formation during the early reprogramming stage. The CRISPR system opened the silenced chromatin locus, thereby allowing transcriptional factors to access their own promoters and eventually forming a positive feedback loop. The regenerative potential of ciCPCs was assessed after implantation in mouse myocardial infarction models. The engrafted ciCPCs differentiated into cardiovascular cells in vivo but also significantly improved contractile function and scar formation. In conclusion, multiplex gene activation was sufficient to drive CPC reprogramming, providing a new cell source for regenerative therapeutics.

In this work, an excitonic energy transfer (EET) based non-radical mechanism was proposed for the degradation of organic pharmaceuticals by graphitic carbon nitride (g-C

In this work, the different selectivity of SO

The efficiency and mechanism of heterogeneous catalytic O

A series of investigations have been carried out to study the decomposition of methylene blue (MB) by the VUV/UVC based AOPs. However, MB degradation by VUV/UVC direct photolysis has not been reported previously. For the first time, the degradation kinetics and mechanisms of methylene blue by a chemical-free technology VUV/UVC (185 nm/254 nm) irradiation were systematically investigated in bench scale. Firstly, we investigated the impact of reaction conditions (i.e., VUV power, temperature, initial pH, and initial MB concentration on the VUV/UVC irradiation process. We found that MB degradation by VUV/UVC irradiation is an endothermic reaction, and the apparent activation energy was calculated to be 14.72 kJ·mol-1, which is similar UVC/TiO2 and electrical discharge plasma system, while higher VUV power and lower initial MB concentration have enhancement effects. The degradation rate constant was a convex function of the solution pH and reached the optimal value at pH 9.19. Compared with VUV/UVC irradiation and UVC/H2O2 processes, hydroxyl radical (·OH) plays the dominated role in VUV/UVC irradiation system, while both ·OH and HO2· contribute to conventional UVC/H2O2 process. The degradation pathways were proposed including demethylation and chromophores oxidation, and the possible pathway was confirmed by combining the experimental observations with the density functional theory (DFT) calculation. In summary, this study provides the results that VUV/UVC is an effective and chemical-free technology for MB removal from water.

The high concentration of salt in industrial wastewater has a strong inhibitory effect on the removal of pollutants by free radicals. A method has been developed to effectively remove micro organic pollutants in industrial high-salinity wastewater. This study investigated the combination of ferrate(VI) (Fe

In this work, the role of Fe in the synergetic effect of persulfate/sulfite and Fe

The DNA-dependent protein kinase (DNA-PK), which comprises the KU heterodimer and a catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor1. KU binds to DNA ends, initiates cNHEJ, and recruits and activates DNA-PKcs. KU also binds to RNA, but the relevance of this interaction in mammals is unclear. Here we use mouse models to show that DNA-PK has an unexpected role in the biogenesis of ribosomal RNA (rRNA) and in haematopoiesis. The expression of kinase-dead DNA-PKcs abrogates cNHEJ2. However, most mice that both expressed kinase-dead DNA-PKcs and lacked the tumour suppressor TP53 developed myeloid disease, whereas all other previously characterized mice deficient in both cNHEJ and TP53 expression succumbed to pro-B cell lymphoma3. DNA-PK autophosphorylates DNA-PKcs, which is its best characterized substrate. Blocking the phosphorylation of DNA-PKcs at the T2609 cluster, but not the S2056 cluster, led to KU-dependent defects in 18S rRNA processing, compromised global protein synthesis in haematopoietic cells and caused bone marrow failure in mice. KU drives the assembly of DNA-PKcs on a wide range of cellular RNAs, including the U3 small nucleolar RNA, which is essential for processing of 18S rRNA4. U3 activates purified DNA-PK and triggers phosphorylation of DNA-PKcs at T2609. DNA-PK, but not other cNHEJ factors, resides in nucleoli in an rRNA-dependent manner and is co-purified with the small subunit processome. Together our data show that DNA-PK has RNA-dependent, cNHEJ-independent functions during ribosome biogenesis that require the kinase activity of DNA-PKcs and its phosphorylation at the T2609 cluster.

In this study, a novel class of niobium (Nb) doped titanate nanoflakes (TNFs) are fabricated through a one-step hydrothermal method. Nb doping affects the curving of titanate nanosheet, leading to the formation of nanoflake structure. In addition, Nb5+ filled in the interlayers of [TiO6] alters the light adsorption property of pristine titanate. The band gap of Nb-TNFs is narrowed to 2.85 eV, while neat titanate nanotubes (TNTs) is 3.4 eV. The enhanced visible light adsorption significantly enhances the visible-light-driven activity of Nb-TNFs for ibuprofen (IBP) degradation. The pseudo-first order kinetics constant for Nb-TNFs is calculated to be 1.04 h−1, while no obvious removal is observed for TNTs. Photo-generated holes (h+) and hydroxyl radicals ( OH) are responsible for IBP degradation. The photocatalytic activity of Nb-TNFs depends on pH condition, and the optimal pH value is found to be 5. In addition, Nb-TNFs exhibited superior photo-stability during the reuse cycles. The results demonstrated Nb-TNFs are very promising in photocatalytic water purification.

CeO2-AgI, synthesized via depositing AgI nanoparticles onto CeO2 nanorods, was utilized for bacterial disinfection and organic contaminant degradation. Escherichia coli (E. coli) and Bisphenol A (BPA) were used as the model bacteria and emerging organic contaminant to test the photocatalytic activity of CeO2-AgI, respectively. Results showed that CeO2-AgI with the optimal AgI content exhibited superior photocatalytic activity over pure CeO2 or AgI for both inactivation of E. coli cells and BPA removal. However, the photocatalytic mechanisms for E. coli inactivation and BPA degradation were different. Specifically, the photo-generated holes (h+), photo-generated electrons (e−) and superoxide radicals ( O2−) were the dominated active species for E. coli inactivation, whereas, BPA degradation relied on the generation of O2− and e−. Cell membrane disruption was found to be the main disinfection mechanism. The decomposition of BPA was clarified by detecting the degradation intermediates by LC–MS and DFT calculation. The facile synthesized CeO2-AgI exhibited good photocatalytic stability in four reused cycles and thus could be potentially applied to purify water.

Fluoroquinolones in aquatic environments have caused worldwide concern due to the negative effects on human health and ecological environment. So far, the performance and mechanism for fluoroquinolones removal by the synergistic activation of peroxymonosulfate (PMS) via vacuum UV (VUV) irradiation and Fe2+ are still blank. Herein, compared with its sub-processes, VUV/Fe2+/PMS process significantly improved the degradation and mineralization efficiencies of three fluoroquinolones. Effect mechanisms of typical parameters (Fe2+ and PMS doses, initial pH) on norfloxacin (NOR) removal by VUV/Fe2+/PMS were elaborated and VUV/Fe2+/PMS showed excellent performance at wide initial pH (3−10). The results of fluorescence molecular probe and radical trapping experiments proved that hydroxyl radical, singlet oxygen, and sulfate radical were primary reactive oxygen species in VUV/Fe2+/PMS. The degradation pathways of NOR in VUV/Fe2+/PMS were mainly defluorination, piperazine ring transformation and quinolone group transformation, and its main inorganic by-products were F - , NO 3 − , and NH 4 + . Besides, the synergistic reaction pathways in integrated VUV/Fe2+/PMS process were elaborated. Furthermore, inorganic anions (such as Cl - , NO 3 - , SO 4 2 - , CO 3 2 - ) hardly affected NOR removal by VUV/Fe2+/PMS, while dissolved organic matter showed slight inhibition. Finally, well-pleasing results of fluoroquinolones removal by VUV/Fe2+/PMS in actual waters highlighted its superiority in the advanced treatment of secondary effluent.

Sulfite [S(IV)] is a promising alternative for sulfate radical-based advanced oxidation processes (SR-AOPs). Transition metal and photocatalysis are generally considered to have a synergetic effect for S(IV) activation. However, the study shows that the synergetic effect is target specific. Herein, an ultra-small Fe2O3 clusters deposited graphitic carbon nitride is synthesized and used for S(IV) activation. For carbamazepine (CBZ) degradation, photogenerated holes can transform S(IV) into sulfate radical and photogenerated electrons can accelerate Fe(II)/Fe(III) cycle, which account for the synergetic effect. In contrast, the degradation of diclofenac (DCF) depends on the excitation of DCF rather than photocatalyst. Instead of radical precursor, S(IV) acts as the electron transfer bridge between excited DCF and photocatalyst. Thus, the deposition of Fe2O3 negatively affects DCF degradation. Density Functional Theory calculation shows that the first excited state rather than the ground state of diclofenac is more suitable for reactive site prediction, which confirms the photosensitization-like degradation mechanism. Moreover, the effects of pH and coexisted anions varies for CBZ and DCF. The study shed light on the synergetic effect of transition metal and photocatalysis for S(IV) activation, and also open an avenue for the study of target specific mechanisms for AOPs.

This study reports the different degradation mechanisms of carbamazepine (CBZ) and diclofenac (DCF) by single-atom Barium (Ba) embedded g-C

Heart transplantation continues to be the gold standard clinical intervention to treat patients with end-stage heart failure. However, there are major complications associated with this surgical procedure that reduce the survival prognosis of heart transplant patients, including allograft rejection, malignancies, infections, and other complications that arise from the use of broad-spectrum immunosuppression drugs. Recent studies have demonstrated the use of mesenchymal stem cells (MSCs) against allotransplantation rejection in both in vitro and in vivo settings due to their immunomodulatory properties. Therefore, utilization of MSCs provides new and exciting strategies to improve heart transplantation and potentially reduce the use of broad-spectrum immunosuppression drugs while alleviating allograft rejection. In this review, we will discuss the current research on the mechanisms of cardiac allograft rejection, the physiological and immunological characteristics of MSCs, the effects of MSCs on the immune system, and immunomodulation of heart transplantation by MSCs.

Reactive oxygen species (ROS) have been implicated in mechanisms of heart development and regenerative therapies such as the use of pluripotent stem cells. The roles of ROS mediating cell fate are dependent on the intensity of stimuli, cellular context, and metabolic status. ROS mainly act through several targets (such as kinases and transcription factors) and have diverse roles in different stages of cardiac differentiation, proliferation, and maturation. Therefore, further detailed investigation and characterization of redox signaling will help the understanding of the molecular mechanisms of ROS during different cellular processes and enable the design of targeted strategies to foster cardiac regeneration and functional recovery. In this review, we focus on the roles of ROS in cardiac differentiation as well as transdifferentiation (direct reprogramming). The potential mechanisms are discussed in regard to ROS generation pathways and regulation of downstream targets. Further methodological optimization is required for translational research in order to robustly enhance the generation efficiency of cardiac myocytes through metabolic modulations. Additionally, we highlight the deleterious effect of the host’s ROS on graft (donor) cells in a paracrine manner during stem cell-based implantation. This knowledge is important for the development of antioxidant strategies to enhance cell survival and engraftment of tissue engineering-based technologies. Thus, proper timing and level of ROS generation after a myocardial injury need to be tailored to ensure the maximal efficacy of regenerative therapies and avoid undesired damage.

Background and Objective: CRISPR tools that allow for precise manipulation of individual loci have not been used in generation of i nduced c ardiac p rogenitor c ells ( iCPC s). This study was designed to determine the feasibility and effectiveness of reprogramming fibroblasts into iCPC using CRISPR activation (CRISPRa) system. Methods: Tail-tip fibroblasts (TTFs) were isolated from Nkx2-5 cardiac enhancer GFP reporter mice. A gRNA pool targeting 17 progenitor genes was synthesized and transduced with dCas9-VP64 lentivirus into TTFs ( Fig.1A ). The phenotype of iCPCs was then characterized by immunostaining and FACS of progenitor markers. Finally, the cardiac-lineage differentiation potential of iCPCs was determined by immunostaining and electrophysiological assay under defined induction mediums. Results: iCPCs with GFP expression were formed in TTFs after transduction of CRISPRa targeting Isl1, Gata4, Baf60c, Tbx5 and Nkx2-5 (Fig.1B), while GFP was not activated by control virus. Cardiac progenitor markers were activated in iCPCs as shown by immunostaining (Fig.1C). The generation efficiency of Flk1-postive iCPCs induced by CRISPRa was ~60% as showed by FACS. iCPCs can be differentiated into cardiomyocytes as identified by immunostaining of cardiac-specific markers (Fig.1D). The iCPC-derived cardiomyocytes displayed spontaneous beating and showed cardiac action potentials (Fig.1E). Conclusion: The CRISPRa system is an efficient and specific way to generate iCPCs, which could provide a novel source of cells for cardiac regenerative medicine. Conversion of fibroblasts into cardiac progenitors poses a novel therapeutic option for repair of myocardial infarction.

In this work, a series of long-term treatment trials were conducted to evaluate the remediation performance of amorphous iron pyrite (FeS2(am)) toward hexavalent chromium (Cr(VI)) in chromite ore processing residue (COPR). The effectiveness of FeS2(am) was assessed using alkaline digestion, the synthetic precipitation leaching procedure (SPLP) and the physiologically based extraction test (PBET). Reaction mechanisms were explored by monitoring the changes in the solid pH, redox potential (Eh), the chemical states of relevant elements as well as the crystal forms present in COPR. The results showed that, using a proper dosage, the total content of Cr and Cr(VI) in the leachate from treated COPR met the Chinese standard regulatory limits for the extraction toxicity of hazardous wastes (GB 5085.3–2007). In addition, the in vitro bioaccessibility of Cr(VI) in COPR was also significantly reduced. Moreover, the remediation effect was maintained for the subsequent six months. This long-term effect was attributed to the presence of reductive sulfur (S) species and Fe(II) that remained even after 180 days of treatment, which were identified using high-resolution X-ray photoelectron spectroscopy (HR-XPS) and X-ray diffraction (XRD). To maximize the effect of FeS2(am), 5% lime was employed as an additive to adjust the pH and thus contributed to Cr(VI) reduction and immobilization. To remediate COPR within 30 days, the use of 5% lime and a specific FeS2(am) dosage (FeS2(am):Cr(VI) = 1.25:1) is recommended based on the results. For rapid remediation (

Metal-free photocatalysts have attracted growing concern in recent years. In this work, a new class of carbon quantum dots (CQDs) modified porous graphitic carbon nitride (g-C3N4) is synthesized via a facile polymerization method. With the optimal CQDs loading, the CQDs modified g-C3N4 exhibits ∼15 times higher degradation kinetic towards diclofenac (DCF) than that of pure g-C3N4. The enhanced photocatalytic activity can be ascribed to the improved separation of charge carriers as well as the tuned band structure. Moreover, a photosensitation-like mechanism is proposed to elucidate the photo-generated electrons transfer and reactive radicals formation. CQDs are anchored to g-C3N4 surface via C-O bond, which provide channels for the preferential transfer of photo-excited electrons on DCF molecule to the conduction band of g-C3N4. Superoxide radical (·O2-) dominates the degradation of DCF, while holes (h+) show a negligible contribution. Density functional theory (DFT) calculation successfully predicts that the sites on DCF molecule with high Fukui index (f0) are preferable to be attacked by radicals. DCF degradation pathway mainly includes ring hydroxylation, ring closure and C-N bond cleavage processes. Acute toxicity estimation indicates the formation of less toxic intermediates/products compared to DCF after photocatalysis. Moreover, the hybrid photocatalysts exhibit good reusability in five consecutive cycles. This work not only proposes a deep insight into photosensitation-like mechanism in the photocatalysis system by using C3N4-based materials, but also develops new photocatalysts for potential application on removal of emerging organic pollutants from waters and wastewaters.

BiOI microspheres doped with different amounts of Ti were fabricated and used to remove diclofenac (DCF) from water under visible light irradiation. The fabricated photocatalysts were well characterized. Ti doped BiOI microspheres were found to exhibit higher photocatalytic activity towards DCF under visible light compared with BiOI. Ti doping broadened the band gap of BiOI, which leads to a more negative conduction band edge and a higher reducing activity of photo-generated electrons, thus facilitates ·O2− production during photocatalysis. Among all the fabricated Ti doped BiOI microspheres, TB450 exhibited the highest DCF photocatalytic removal efficiency. Specifically, 99.2% of DCF (C0 = 10 mg L−1) was removed by TB450 (250 mg L−1) at pH 5 within 90 min under visible light irradiation. Scavenger experiments indicated that active species including h+, ·O2− and H2O2 played important roles in the photocatalytic process. The degradation pathway of DCF was elucidated by theoretical density functional theory (DFT) and by-products identification through liquid chromatograph mass spectrometer (LC-MS) analysis. DCF degradation pathway mainly included hydroxylation and the cleavage of C N bond. DFT calculation can well interpret the degradation mechanism and the sites of DCF molecule with high radical-attack Fukui index (f0) exhibit high reactivity. Acidic condition was found to facilitate the DCF photocatalytic removal. Due to strong photo-stability, Ti doped BiOI microspheres contained good visible-light-driven (VLD) photocatalytic removal efficiency for DCF in the fourth consecutive reused cycle. Ti doped BiOI microspheres can be employed as a cost-effective and high-efficient material to efficiently degrade emerging contaminants (e.g., pharmaceutical) from wastewaters under visible light conditions.

Rural development, as one of the biggest challenges facing human beings recently, has attracted widely attention in the world, among which rural environment protection is essential for sustainable development. In response to the call to build “green livable villages”, the environmental monitoring and remediation in rural project (EMR-rural project) is launched. EMR-rural (2019 to 2022) is funded by the Ministry of Science and Technology of the People’s Republic of China (MOST). The project aims to develop key techniques and devices for contamination classification, risk assessment, pollution sources tracing and environmental remediation with regard to soil, underground and surface water quality in rural area. To this end, a new generation of physical, chemical and biological tools is integrated with intelligent management platform. The project follows a problem-oriented approach by in situ investigation, lab/pilot-scale mechanism exploration and field determination. EMR-rural takes advantage of the access to the applicable techniques and devices to investigate and to restore soil and water pollution in river network areas, mountainous areas as well as cold areas of China.

Carbamazepine (CBZ), a widely used antiepileptic drug, is refractory to biological wastewater treatment. Rapid removal of CBZ is possible using synthetic manganese oxide (δ-MnO2) but the removal mechanisms require further investigation. In this study, CBZ degradation by δ-MnO2 was carried out at different pH to further explore the degradation mechanisms. Results show that CBZ degradation by δ-MnO2 was highly pH dependent, and rapid degradation occurred when pH

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system. They are derived from differentiation of oligodendrocyte progenitors through a process requiring cell cycle exit and histone modifications. Here we identify the histone arginine methyl-transferase PRMT5, a molecule catalyzing symmetric methylation of histone H4R3, as critical for developmental myelination. PRMT5 pharmacological inhibition, CRISPR/cas9 targeting, or genetic ablation decrease p53-dependent survival and impair differentiation without affecting proliferation. Conditional ablation of Prmt5 in progenitors results in hypomyelination, reduced survival and differentiation. Decreased histone H4R3 symmetric methylation is followed by increased nuclear acetylation of H4K5, and is rescued by pharmacological inhibition of histone acetyltransferases. Data obtained using purified histones further validate the results obtained in mice and in cultured oligodendrocyte progenitors. Together, these results identify PRMT5 as critical for oligodendrocyte differentiation and developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation., Myelin-forming cells derive from oligodendrocyte progenitors. Here the authors identify histone arginine methyl-transferase PRMT5 as critical for developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation, to favor differentiation.

BiOBr-AgBr hybrid photocatalysts were synthesized via a facile precipitation and in-situ ion exchange method at room temperature. The as-synthesized photocatalysts were well characterized with different techniques. The disinfection activities of BiOBr-AgBr towards model bacterial strain Gram-negative Escherichia coli (E. coli) were tested under both dark and visible light irradiation conditions. 1 × 107 CFU/mL of E. coli cells could be completely inactivated by BiOBr-AgBr with the optimal silver amount (BiOBr-0.5AgBr) in 24 min under visible light irradiation, while 1.5 log CFU/mL decrease of viable cell density was achieved at the same experiment duration under dark condition. Obviously, with the visible light irradiation, the bactericidal efficiency BiOBr-0.5AgBr was significantly enhanced. The subsequent disinfection mechanism analysis showed that Ag+ released from BiOBr-0.5AgBr did not contribute to E. coli inactivation, while reactive oxygen species including h+, surfaced bounded OH, O2−, and H2O2 were found to play important roles in the disinfection process. The presence of dissolved O2 and the direct contact of cells with photocatalysts was found to be essential for the disinfection process. The reactive species induced the destruction of cell membrane, thus led to the death of bacteria. In addition, BiOBr-0.5AgBr exhibited good bactericidal activity within a wide pH range (5–9) and contained effective antibacterial activity even in fifth consecutive reuse cycles.

Magnetic Fe 3 O 4 @BiOI@AgI (FBA) spheres were synthesized through a multi-step process. The fabricated photocatalysts were characterized by different techniques. To testify the visible light driven photocatalytic activity of FBA, Rhodamine B and Bisphenol A were chosen as model common and emerging organic contaminants, respectively. While, gram-negative strain Escherichia coli was selected as model waterborne bacteria. The results showed that under visible light irradiation, FBA contained strong photocatalytic degradation capacity towards both RhB and BPA. Moreover, FBA was also found to exhibit excellent disinfection activity towards E. coli . The photocatalytic mechanisms for different pollutants by FBA were determined and found to vary for different pollutants. Specifically, scavenger experiments, degradation intermediates determination, as well as theoretical density functional theory (DFT) analysis showed that RhB and BPA were degraded via photosensitization (dominated by e - and ·O 2 − ) and direct photocatalytic oxidation (contributed by h + , e - and ·O 2 − ), respectively. Whereas, E. coli cells yet were found to be inactivated by the generation of e - and ·O 2 − rather than by the released Ag + . Since it contained superparamagnetic property, FBA could be easily separated from the reaction suspension after use. Due to the excellent photo stability, FBA exhibited strong photocatalytic activity in the fourth reused recycle. Therefore, FBA could serve as a promising alternative for water purification.

Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis1,2. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis3,4, the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis5, we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Taken together, our findings illustrate how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations.