Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria.

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αß T and non-classic CD4+ αß TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.

The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death.

Pathogenic and other cytoplasmic DNAs activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to induce inflammation via transcriptional activation by IRF3 and nuclear factor κB (NF-κB), but the functional consequences of exposing cGAS to chromosomes upon mitotic nuclear envelope breakdown are unknown. Here, we show that nucleosomes competitively inhibit DNA-dependent cGAS activation and that the cGAS-STING pathway is not effectively activated during normal mitosis. However, during mitotic arrest, low level cGAS-dependent IRF3 phosphorylation slowly accumulates without triggering inflammation. Phosphorylated IRF3, independently of its DNA-binding domain, stimulates apoptosis through alleviating Bcl-xL-dependent suppression of mitochondrial outer membrane permeabilization. We propose that slow accumulation of phosphorylated IRF3, normally not sufficient for inducing inflammation, can trigger transcription-independent induction of apoptosis upon mitotic aberrations. Accordingly, expression of cGAS and IRF3 in cancer cells makes mouse xenograft tumors responsive to the anti-mitotic agent Taxol. The Cancer Genome Atlas (TCGA) datasets for non-small cell lung cancer patients also suggest an effect of cGAS expression on taxane response.

Selective deployment of transcription factor paralogs with submaximal strength facilitates gene regulation in the immune system.

In multicellular organisms, duplicated genes can diverge through tissue-specific gene expression patterns, as exemplified by highly regulated expression of RUNX transcription factor paralogs with apparent functional redundancy. Here we asked what cell-type-specific biologies might be supported by the selective expression of RUNX paralogs during Langerhans cell and inducible regulatory T cell differentiation. We uncovered functional nonequivalence between RUNX paralogs. Selective expression of native paralogs allowed integration of transcription factor activity with extrinsic signals, while non-native paralogs enforced differentiation even in the absence of exogenous inducers. DNA binding affinity was controlled by divergent amino acids within the otherwise highly conserved RUNT domain and evolutionary reconstruction suggested convergence of RUNT domain residues toward submaximal strength. Hence, the selective expression of gene duplicates in specialized cell types can synergize with the acquisition of functional differences to enable appropriate gene expression, lineage choice and differentiation in the mammalian immune system.

The pupal moulting fluid has evolved social functions in ants.

Insect societies are tightly integrated, complex biological systems in which group-level properties arise from the interactions between individuals1-4. However, these interactions have not been studied systematically and therefore remain incompletely known. Here, using a reverse engineering approach, we reveal that unlike solitary insects, ant pupae extrude a secretion derived from the moulting fluid that is rich in nutrients, hormones and neuroactive substances. This secretion elicits parental care behaviour and is rapidly removed and consumed by the adults. This behaviour is crucial for pupal survival; if the secretion is not removed, pupae develop fungal infections and die. Analogous to mammalian milk, the secretion is also an important source of early larval nutrition, and young larvae exhibit stunted growth and decreased survival without access to the fluid. We show that this derived social function of the moulting fluid generalizes across the ants. This secretion thus forms the basis of a central and hitherto overlooked interaction network in ant societies, and constitutes a rare example of how a conserved developmental process can be co-opted to provide the mechanistic basis of social interactions. These results implicate moulting fluids in having a major role in the evolution of ant eusociality.

Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

BMP signaling: at the gate between activated melanocyte stem cells and differentiation.

Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single-cell RNA sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics of McSCs through quiescence, activation, and melanocyte maturation. Unearthing converging signs of increased WNT and BMP signaling along this progression, we endeavored to understand how these pathways are integrated. Employing conditional lineage-specific genetic ablation studies in mice, we found that loss of BMP signaling in the lineage leads to hair graying due to a block in melanocyte maturation. We show that interestingly, BMP signaling functions downstream from activated McSCs and maintains WNT effector, transcription factor LEF1. Employing pseudotime analysis, genetics, and chromatin landscaping, we show that following WNT-mediated activation of McSCs, BMP and WNT pathways collaborate to trigger the commitment of proliferative progeny by fueling LEF1- and MITF-dependent differentiation. Our findings shed light upon the signaling interplay and timing of cues that orchestrate melanocyte lineage progression in the hair follicle and underscore a key role for BMP signaling in driving complete differentiation.

Stromal netrin 1 coordinates renal arteriogenesis and mural cell differentiation.

The kidney vasculature has a complex architecture that is essential for renal function. The molecular mechanisms that direct development of kidney blood vessels are poorly characterized. We identified a regionally restricted, stroma-derived signaling molecule, netrin 1 (Ntn1), as a regulator of renal vascular patterning in mice. Stromal progenitor (SP)-specific ablation of Ntn1 (Ntn1SPKO) resulted in smaller kidneys with fewer glomeruli, as well as profound defects of the renal artery and transient blood flow disruption. Notably, Ntn1 ablation resulted in loss of arterial vascular smooth muscle cell (vSMC) coverage and in ectopic SMC deposition at the kidney surface. This was accompanied by dramatic reduction of arterial tree branching that perdured postnatally. Transcriptomic analysis of Ntn1SPKO kidneys revealed dysregulation of vSMC differentiation, including downregulation of Klf4, which we find expressed in a subset of SPs. Stromal Klf4 deletion similarly resulted in decreased smooth muscle coverage and arterial branching without, however, the disruption of renal artery patterning and perfusion seen in Ntn1SPKO. These data suggest a stromal Ntn1-Klf4 axis that regulates stromal differentiation and reinforces stromal-derived smooth muscle as a key regulator of renal blood vessel formation.

Impaired cell fate through gain-of-function mutations in a chromatin reader.

Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by 'reader' proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatin-reader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.

Chemo-phosphoproteomic profiling with ATR inhibitors berzosertib and gartisertib uncovers new biomarkers and DNA damage response regulators.

The ATR kinase protects cells against DNA damage and replication stress and represents a promising anti-cancer drug target. The ATR inhibitors (ATRi) berzosertib and gartisertib are both in clinical trials for the treatment of advanced solid tumours as monotherapy or in combination with genotoxic agents. We carried out quantitative phospho-proteomic screening for ATR biomarkers that are highly sensitive to berzosertib and gartisertib, using an optimized mass spectrometry pipeline. Screening identified a range of novel ATR-dependent phosphorylation events, which were grouped into three broad classes: i) targets whose phosphorylation is highly sensitive to ATRi and which could be the next generation of ATR biomarkers; ii) proteins with known genome maintenance roles not previously known to be regulated by ATR; iii) novel targets whose cellular roles are unclear. Class iii targets represent candidate DNA damage response proteins and, with this in mind, proteins in this class were subjected to secondary screening for recruitment to DNA damage sites. We show that one of the proteins recruited, SCAF1, interacts with RNAPII in a phospho-dependent manner and recruitment requires PARP activity and interaction with RNAPII. We also show that SCAF1 deficiency partly rescues RAD51 loading in cells lacking the BRCA1 tumour suppressor. Taken together these data reveal potential new ATR biomarkers and new genome maintenance factors.

ATRX guards against aberrant differentiation in mesenchymal progenitor cells.

Alterations in the tumor suppressor ATRX are recurrently observed in mesenchymal neoplasms. ATRX has multiple epigenetic functions including heterochromatin formation and maintenance and regulation of transcription through modulation of chromatin accessibility. Here, we show in murine mesenchymal progenitor cells (MPCs) that Atrx deficiency aberrantly activated mesenchymal differentiation programs. This includes adipogenic pathways where ATRX loss induced expression of adipogenic transcription factors and enhanced adipogenic differentiation in response to differentiation stimuli. These changes are linked to loss of heterochromatin near mesenchymal lineage genes together with increased chromatin accessibility and gains of active chromatin marks. We additionally observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Finally, we demonstrated that loss of ATRX in a mesenchymal malignancy, undifferentiated pleomorphic sarcoma, results in similar epigenetic disruption and de-repression of transposable elements. Together, our results reveal a role for ATRX in maintaining epigenetic states and transcriptional repression in mesenchymal progenitors and tumor cells and in preventing aberrant differentiation in the progenitor context.

Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells.

Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels. Rather, analysis of Dis3l2-null nephron progenitor cells, a potential cell of origin of Wilms tumors, reveals up-regulation of Igf2, a growth-promoting gene strongly associated with Wilms tumorigenesis. These findings nominate a new potential mechanism underlying the pathology associated with DIS3L2 deficiency.

CDKL5 kinase controls transcription-coupled responses to DNA damage.

Mutations in the gene encoding the CDKL5 kinase are among the most common genetic causes of childhood epilepsy and can also give rise to the severe neurodevelopmental condition CDD (CDKL5 deficiency disorder). Despite its importance for human health, the phosphorylation targets and cellular roles of CDKL5 are poorly understood, especially in the cell nucleus. Here, we report that CDKL5 is recruited to sites of DNA damage in actively transcribed regions of the nucleus. A quantitative phosphoproteomic screen for nuclear CDKL5 substrates reveals a network of transcriptional regulators including Elongin A (ELOA), phosphorylated on a specific CDKL5 consensus motif. Recruitment of CDKL5 and ELOA to damaged DNA, and subsequent phosphorylation of ELOA, requires both active transcription and the synthesis of poly(ADP-ribose) (PAR), to which CDKL5 can bind. Critically, CDKL5 kinase activity is essential for the transcriptional silencing of genes induced by DNA double-strand breaks. Thus, CDKL5 is a DNA damage-sensing, PAR-controlled transcriptional modulator, a finding with implications for understanding the molecular basis of CDKL5-related diseases.

Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs.

The Hippo signaling pathway acts as a brake on regeneration in many tissues. This cascade of kinases culminates in the phosphorylation of the transcriptional cofactors Yap and Taz, whose concentration in the nucleus consequently remains low. Various types of cellular signals can reduce phosphorylation, however, resulting in the accumulation of Yap and Taz in the nucleus and subsequently in mitosis. We earlier identified a small molecule, TRULI, that blocks the final kinases in the pathway, Lats1 and Lats2, and thus elicits proliferation of several cell types that are ordinarily postmitotic and aids regeneration in mammals. In the present study, we present the results of chemical modification of the original compound and demonstrate that a derivative, TDI-011536, is an effective blocker of Lats kinases in vitro at nanomolar concentrations. The compound fosters extensive proliferation in retinal organoids derived from human induced pluripotent stem cells. Intraperitoneal administration of the substance to mice suppresses Yap phosphorylation for several hours and induces transcriptional activation of Yap target genes in the heart, liver, and skin. Moreover, the compound initiates the proliferation of cardiomyocytes in adult mice following cardiac cryolesions. After further chemical refinement, related compounds might prove useful in protective and regenerative therapies.

Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence.

Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates. Our data unveiled regulation of senescence as a novel way by which mechanistic target of rapamycin (mTOR) influences reprogramming. On one hand, mTOR inhibition blunts the induction of cyclin-dependent kinase (CDK) inhibitors (CDKIs), including p16INK4a, p21CIP1, and p15INK4b, preventing OSKM-induced senescence. On the other hand, inhibition of mTOR blunts the senescence-associated secretory phenotype (SASP), which itself favors reprogramming. These contrasting actions contribute to explain the complex effect that mTOR has on reprogramming. Overall, our study highlights the advantage of combining functional screens with scRNA-seq to accelerate the discovery of pathways controlling complex phenotypes.

N and OH-Immobilized Cu3 Clusters In Situ Reconstructed from Single-Metal Sites for Efficient CO2 Electromethanation in Bicontinuous Mesochannels.

Cu-based catalysts hold promise for electrifying CO2 to produce methane, an extensively used fuel. However, the activity and selectivity remain insufficient due to the lack of catalyst design principles to steer complex CO2 reduction pathways. Herein, we develop a concept to design carbon-supported Cu catalysts by regulating Cu active sites' atomic-scale structures and engineering the carbon support's mesoscale architecture. This aims to provide a favorable local reaction microenvironment for a selective CO2 reduction pathway to methane. In situ X-ray absorption and Raman spectroscopy analyses reveal the dynamic reconstruction of nitrogen and hydroxyl-immobilized Cu3 (N,OH-Cu3) clusters derived from atomically dispersed Cu-N3 sites under realistic CO2 reduction conditions. The N,OH-Cu3 sites possess moderate *CO adsorption affinity and a low barrier for *CO hydrogenation, enabling intrinsically selective CO2-to-CH4 reduction compared to the C-C coupling with a high energy barrier. Importantly, a block copolymer-derived carbon fiber support with interconnected mesopores is constructed. The unique long-range mesochannels offer an H2O-deficient microenvironment and prolong the transport path for the CO intermediate, which could suppress the hydrogen evolution reaction and favor deep CO2 reduction toward methane formation. Thus, the newly developed catalyst consisting of in situ constructed N,OH-Cu3 active sites embedded into bicontinuous carbon mesochannels achieved an unprecedented Faradaic efficiency of 74.2% for the CO2 reduction to methane at an industry-level current density of 300 mA cm-2. This work explores effective concepts for steering desirable reaction pathways in complex interfacial catalytic systems via modulating active site structures at the atomic level and engineering pore architectures of supports on the mesoscale to create favorable microenvironments.

ChatGPT-4 accuracy for patient education in laryngopharyngeal reflux.

INTRODUCTION: Chatbot Generative Pre-trained Transformer (ChatGPT) is an artificial intelligence-powered language model chatbot able to help otolaryngologists in practice and research. The ability of ChatGPT in generating patient-centered information related to laryngopharyngeal reflux disease (LPRD) was evaluated. METHODS: Twenty-five questions dedicated to definition, clinical presentation, diagnosis, and treatment of LPRD were developed from the Dubai definition and management of LPRD consensus and recent reviews. Questions about the four aforementioned categories were entered into ChatGPT-4. Four board-certified laryngologists evaluated the accuracy of ChatGPT-4 with a 5-point Likert scale. Interrater reliability was evaluated. RESULTS: The mean scores (SD) of ChatGPT-4 answers for definition, clinical presentation, additional examination, and treatments were 4.13 (0.52), 4.50 (0.72), 3.75 (0.61), and 4.18 (0.47), respectively. Experts reported high interrater reliability for sub-scores (ICC = 0.973). The lowest performances of ChatGPT-4 were on answers about the most prevalent LPR signs, the most reliable objective tool for the diagnosis (hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring (HEMII-pH)), and the criteria for the diagnosis of LPR using HEMII-pH. CONCLUSION: ChatGPT-4 may provide adequate information on the definition of LPR, differences compared to GERD (gastroesophageal reflux disease), and clinical presentation. Information provided upon extra-laryngeal manifestations and HEMII-pH may need further optimization. Regarding the recent trends identifying increasing patient use of internet sources for self-education, the findings of the present study may help draw attention to ChatGPT-4's accuracy on the topic of LPR.

Diagnosis of vocal cord dysfunction/inducible laryngeal obstruction: An International Delphi Consensus Study.

BACKGROUND: Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is characterized by breathing difficulties in association with excessive supraglottic or glottic laryngeal narrowing. The condition is common and can occur independently; however, it may also be comorbid with other disorders or mimic them. Presentations span multiple specialties and misdiagnosis or delayed diagnosis is commonplace. Group-consensus methods can efficiently generate internationally accepted diagnostic criteria and descriptions to increase clinical recognition, enhance clinical service availability, and catalyze research. OBJECTIVES: We sought to establish consensus-based diagnostic criteria and methods for VCD/ILO. METHODS: We performed a modified 2-round Delphi study between December 7, 2021, and March 14, 2022. The study was registered at ANZCTR (Australian New Zealand Clinical Trials Registry; ACTRN12621001520820p). In round 1, experts provided open-ended statements that were categorized, deduplicated, and amended for clarity. These were presented to experts for agreement ranking in round 2, with consensus defined as ≥70% agreement. RESULTS: Both rounds were completed by 47 international experts. In round 1, 1102 qualitative responses were received. Of the 200 statements presented to experts across 2 rounds, 130 (65%) reached consensus. Results were discussed at 2 international subject-specific conferences in June 2022. Experts agreed on a diagnostic definition for VCD/ILO and endorsed the concept of VCD/ILO phenotypes and clinical descriptions. The panel agreed that laryngoscopy with provocation is the gold standard for diagnosis and that ≥50% laryngeal closure on inspiration or Maat grade ≥2 define abnormal laryngeal closure indicative of VCD/ILO. CONCLUSIONS: This Delphi study reached consensus on multiple aspects of VCD/ILO diagnosis and can inform clinical practice and facilitate research.

SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer.

Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.

Designing and Engineering Atomically Dispersed Metal Catalysts for CO2 to CO Conversion: From Single to Dual Metal Sites.

The electrochemical CO2 reduction reaction (CO2 RR) is a promising approach to achieving sustainable electrical-to-chemical energy conversion and storage while decarbonizing the emission-heavy industry. The carbon-supported, nitrogen-coordinated, and atomically dispersed metal sites are effective catalysts for CO generation due to their high activity, selectivity, and earth abundance. Here, we discuss progress, challenges, and opportunities for designing and engineering atomic metal catalysts from single to dual metal sites. Engineering single metal sites using a nitrogen-doped carbon model was highlighted to exclusively study the effect of carbon particle sizes, metal contents, and M-N bond structures in the form of MN4 moieties on catalytic activity and selectivity. The structure-property correlation was analyzed by combining experimental results with theoretical calculations to uncover the CO2 to CO conversion mechanisms. Furthermore, dual-metal site catalysts, inheriting the merits of single-metal sites, have emerged as a new frontier due to their potentially enhanced catalytic properties. Designing optimal dual metal site catalysts could offer additional sites to alter the surface adsorption to CO2 and various intermediates, thus breaking the scaling relationship limitation and activity-stability trade-off. The CO2 RR electrolysis in flow reactors was discussed to provide insights into the electrolyzer design with improved CO2 utilization, reaction kinetics, and mass transport.

Stromal ß-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor.

Wilms' tumor (WT) morphologically resembles the embryonic kidney, consisting of blastema, epithelial and stromal components, suggesting tumors arise from the dysregulation of normal development. ß-Catenin activation is observed in a significant proportion of WTs; however, much remains to be understood about how it contributes to tumorigenesis. Although activating ß-catenin mutations are observed in both blastema and stromal components of WT, current models assume that activation in the blastemal lineage is causal. Paradoxically, studies performed in mice suggest that activation of ß-catenin in the nephrogenic lineage results in loss of nephron progenitor cell (NPC) renewal, a phenotype opposite to WT. Here, we show that activation of ß-catenin in the stromal lineage non-autonomously prevents the differentiation of NPCs. Comparisons of the transcriptomes of kidneys expressing an activated allele of ß-catenin in the stromal or nephron progenitor cells reveals that human WT more closely resembles the stromal-lineage mutants. These findings suggest that stromal ß-catenin activation results in histological and molecular features of human WT, providing insights into how alterations in the stromal microenvironment may play an active role in tumorigenesis.