Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence.

Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Prevalence and clinical expression of germ line predisposition to myeloid neoplasms in adults with marrow hypocellularity.

Systematic studies of germ line genetic predisposition to myeloid neoplasms in adult patients are still limited. In this work, we performed germ line and somatic targeted sequencing in a cohort of adult patients with hypoplastic bone marrow (BM) to study germ line predisposition variants and their clinical correlates. The study population included 402 consecutive adult patients investigated for unexplained cytopenia and reduced age-adjusted BM cellularity. Germ line mutation analysis was performed using a panel of 60 genes, and variants were interpreted per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines; somatic mutation analysis was performed using a panel of 54 genes. Of the 402 patients, 27 (6.7%) carried germ line variants that caused a predisposition syndrome/disorder. The most frequent disorders were DDX41-associated predisposition, Fanconi anemia, GATA2-deficiency syndrome, severe congenital neutropenia, RASopathy, and Diamond-Blackfan anemia. Eighteen of 27 patients (67%) with causative germ line genotype were diagnosed with myeloid neoplasm, and the remaining with cytopenia of undetermined significance. Patients with a predisposition syndrome/disorder were younger than the remaining patients and had a higher risk of severe or multiple cytopenias and advanced myeloid malignancy. In patients with myeloid neoplasm, causative germ line mutations were associated with increased risk of progression into acute myeloid leukemia. Family or personal history of cancer did not show significant association with a predisposition syndrome/disorder. The findings of this study unveil the spectrum, clinical expressivity, and prevalence of germ line predisposition mutations in an unselected cohort of adult patients with cytopenia and hypoplastic BM.

Early transfusion patterns improve the Molecular International Prognostic Scoring System (IPSS-M) prediction in myelodysplastic syndromes.

BACKGROUND: The Molecular International Prognostic Scoring System (IPSS-M) is the new gold standard for diagnostic outcome prediction in patients with myelodysplastic syndromes (MDS). This study was designed to assess the additive prognostic impact of dynamic transfusion parameters during early follow-up. METHODS: We retrieved complete transfusion data from 677 adult Swedish MDS patients included in the IPSS-M cohort. Time-dependent erythrocyte transfusion dependency (E-TD) was added to IPSS-M features and analyzed regarding overall survival and leukemic transformation (acute myeloid leukemia). A multistate Markov model was applied to assess the prognostic value of early changes in transfusion patterns. RESULTS: Specific clinical and genetic features were predicted for diagnostic and time-dependent transfusion patterns. Importantly, transfusion state both at diagnosis and within the first year strongly predicts outcomes in both lower (LR) and higher-risk (HR) MDSs. In multivariable analysis, 8-month landmark E-TD predicted shorter survival independently of IPSS-M (p < 0.001). A predictive model based on IPSS-M and 8-month landmark E-TD performed significantly better than a model including only IPSS-M. Similar trends were observed in an independent validation cohort (n = 218). Early transfusion patterns impacted both future transfusion requirements and outcomes in a multistate Markov model. CONCLUSION: The transfusion requirement is a robust and available clinical parameter incorporating the effects of first-line management. In MDS, it provides dynamic risk information independently of diagnostic IPSS-M and, in particular, clinical guidance to LR MDS patients eligible for potentially curative therapeutic intervention.

Relationship between clone metrics and clinical outcome in clonal cytopenia.

Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.

MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma.

Despite the importance of the RAS-RAF-MAPK pathway in normal physiology and disease of numerous organs, its role during pituitary development and tumourigenesis remains largely unknown. Here, we show that the over-activation of the MAPK pathway, through conditional expression of the gain-of-function alleles BrafV600E and KrasG12D in the developing mouse pituitary, results in severe hyperplasia and abnormal morphogenesis of the gland by the end of gestation. Cell-lineage commitment and terminal differentiation are disrupted, leading to a significant reduction in numbers of most of the hormone-producing cells before birth, with the exception of corticotrophs. Of note, Sox2+ stem cells and clonogenic potential are drastically increased in the mutant pituitaries. Finally, we reveal that papillary craniopharyngioma (PCP), a benign human pituitary tumour harbouring BRAF p.V600E also contains Sox2+ cells with sustained proliferative capacity and disrupted pituitary differentiation. Together, our data demonstrate a crucial function of the MAPK pathway in controlling the balance between proliferation and differentiation of Sox2+ cells and suggest that persistent proliferative capacity of Sox2+ cells may underlie the pathogenesis of PCP.

Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans.

Aberrant embryonic development of the hypothalamus and/or pituitary gland in humans results in congenital hypopituitarism (CH). Transcription factor 7-like 1 (TCF7L1), an important regulator of the WNT/ß-catenin signaling pathway, is expressed in the developing forebrain and pituitary gland, but its role during hypothalamo-pituitary (HP) axis formation or involvement in human CH remains elusive. Using a conditional genetic approach in the mouse, we first demonstrate that TCF7L1 is required in the prospective hypothalamus to maintain normal expression of the hypothalamic signals involved in the induction and subsequent expansion of Rathke's pouch progenitors. Next, we reveal that the function of TCF7L1 during HP axis development depends exclusively on the repressing activity of TCF7L1 and does not require its interaction with ß-catenin. Finally, we report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects. We demonstrate that these variants exhibit reduced repressing activity in vitro and in vivo relative to wild-type TCF7L1. Together, our data provide support for a conserved molecular function of TCF7L1 as a transcriptional repressor during HP axis development in mammals and identify variants in this transcription factor that are likely to contribute to the etiology of CH.

Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion.

There is growing evidence that contact inhibition of locomotion (CIL) is essential for morphogenesis and its failure is thought to be responsible for cancer invasion; however, the molecular bases of this phenomenon are poorly understood. Here we investigate the role of the polarity protein Par3 in CIL during migration of the neural crest, a highly migratory mesenchymal cell type. In epithelial cells, Par3 is localised to the cell-cell adhesion complex and is important in the definition of apicobasal polarity, but the localisation and function of Par3 in mesenchymal cells are not well characterised. We show in Xenopus and zebrafish that Par3 is localised to the cell-cell contact in neural crest cells and is essential for CIL. We demonstrate that the dynamics of microtubules are different in different parts of the cell, with an increase in microtubule catastrophe at the collision site during CIL. Par3 loss-of-function affects neural crest migration by reducing microtubule catastrophe at the site of cell-cell contact and abrogating CIL. Furthermore, Par3 promotes microtubule catastrophe by inhibiting the Rac-GEF Trio, as double inhibition of Par3 and Trio restores microtubule catastrophe at the cell contact and rescues CIL and neural crest migration. Our results demonstrate a novel role of Par3 during neural crest migration, which is likely to be conserved in other processes that involve CIL such as cancer invasion or cell dispersion.

Real-time mixed reality display of dual particle radiation detector data.

Radiation source localization and characterization are challenging tasks that currently require complex analyses for interpretation. Mixed reality (MR) technologies are at the verge of wide scale adoption and can assist in the visualization of complex data. Herein, we demonstrate real-time visualization of gamma ray and neutron radiation detector data in MR using the Microsoft HoloLens 2 smart glasses, significantly reducing user interpretation burden. Radiation imaging systems typically use double-scatter events of gamma rays or fast neutrons to reconstruct the incidence directional information, thus enabling source localization. The calculated images and estimated 'hot spots' are then often displayed in 2D angular space projections on screens. By combining a state-of-the-art dual particle imaging system with HoloLens 2, we propose to display the data directly to the user via the head-mounted MR smart glasses, presenting the directional information as an overlay to the user's 3D visual experience. We describe an open source implementation using efficient data transfer, image calculation, and 3D engine. We thereby demonstrate for the first time a real-time user experience to display fast neutron or gamma ray images from various radioactive sources set around the detector. We also introduce an alternative source search mode for situations of low event rates using a neural network and simulation based training data to provide a fast estimation of the source's angular direction. Using MR for radiation detection provides a more intuitive perception of radioactivity and can be applied in routine radiation monitoring, education & training, emergency scenarios, or inspections.

A Haspin-ARHGAP11A axis regulates epithelial morphogenesis through Rho-ROCK dependent modulation of LIMK1-Cofilin.

Throughout mitosis, a plethora of processes must be efficiently concerted to ensure cell proliferation and tissue functionality. The mitotic spindle does not only mediate chromosome segregation, but also defines the axis of cellular division, thus determining tissue morphology. Functional spindle orientation relies on precise actin dynamics, shaped in mitosis by the LIMK1-Cofilin axis. The kinase Haspin acts as a guardian of faithful chromosome segregation that ensures amphitelic chromosome attachment and prevents unscheduled cohesin cleavage. Here, we report an unprecedented role for Haspin in the determination of spindle orientation in mitosis. We show that, during mitosis, Haspin regulates Rho-ROCK activity through ARHGAP11A, a poorly characterized GAP, and that ROCK is in turn responsible for the mitotic activation of LIMK1 and stabilization of the actin cytoskeleton, thus supporting a functional spindle orientation. By exploiting 3D cell cultures, we show that this pathway is pivotal for the establishment of a morphologically functional tissue.

Expansion of ventral foregut is linked to changes in the enhancer landscape for organ-specific differentiation.

Cell proliferation is fundamental for almost all stages of development and differentiation that require an increase in cell number. Although cell cycle phase has been associated with differentiation, the actual process of proliferation has not been considered as having a specific role. Here we exploit human embryonic stem cell-derived endodermal progenitors that we find are an in vitro model for the ventral foregut. These cells exhibit expansion-dependent increases in differentiation efficiency to pancreatic progenitors that are linked to organ-specific enhancer priming at the level of chromatin accessibility and the decommissioning of lineage-inappropriate enhancers. Our findings suggest that cell proliferation in embryonic development is about more than tissue expansion; it is required to ensure equilibration of gene regulatory networks allowing cells to become primed for future differentiation. Expansion of lineage-specific intermediates may therefore be an important step in achieving high-fidelity in vitro differentiation.

Transcriptional heterogeneity and cell cycle regulation as central determinants of Primitive Endoderm priming.

During embryonic development cells acquire identity as they proliferate, implying that an intrinsic facet of cell fate choice requires coupling lineage decisions to cell division. How is the cell cycle regulated to promote or suppress heterogeneity and differentiation? We explore this question combining time lapse imaging with single-cell RNA-seq in the contexts of self-renewal, priming, and differentiation of mouse embryonic stem cells (ESCs) towards the Primitive Endoderm (PrE) lineage. Since ESCs are derived from the inner cell mass (ICM) of the mammalian blastocyst, ESCs in standard culture conditions are transcriptionally heterogeneous containing dynamically interconverting subfractions primed for either of the two ICM lineages, Epiblast and PrE. Here, we find that differential regulation of cell cycle can tip the balance between these primed populations, such that naïve ESC culture promotes Epiblast-like expansion and PrE differentiation stimulates the selective survival and proliferation of PrE-primed cells. In endoderm differentiation, this change is accompanied by a counter-intuitive increase in G1 length, also observed in vivo. While fibroblast growth factor/extracellular signal-regulated kinase (FGF/ERK) signalling is a key regulator of ESC differentiation and PrE specification, we find it is not just responsible for ESCs heterogeneity, but also the inheritance of similar cell cycles between sisters and cousins. Taken together, our results indicate a tight relationship between transcriptional heterogeneity and cell cycle regulation in lineage specification, with primed cell populations providing a pool of flexible cell types that can be expanded in a lineage-specific fashion while allowing plasticity during early determination.

Application of radiochromic gel dosimetry to commissioning of a megavoltage research linear accelerator for small-field animal irradiation studies.

PURPOSE: To develop and implement an efficient and accurate commissioning procedure for small-field static beam animal irradiation studies on an MV research linear accelerator (Linatron-M9) using radiochromic gel dosimetry. MATERIALS: The research linear accelerator (Linatron-M9) is a 9 MV linac with a static fixed collimator opening of 5.08 cm diameter. Lead collimators were manually placed to create smaller fields of 2 × 2 cm2 , 1 × 1 cm2 , and 0.5 × 0.5 cm2 . Relative dosimetry measurements were performed, including profiles, percent depth dose (PDD) curves, beam divergence, and relative output factors using various dosimetry tools, including a small volume ionization chamber (A14), GAFCHROMIC™ EBT3 film, and Clearview gel dosimeters. The gel dosimeter was used to provide a 3D volumetric reference of the irradiated fields. The Linatron profiles and relative output factors were extracted at a reference depth of 2 cm with the output factor measured relative to the 2 × 2 cm2 reference field. Absolute dosimetry was performed using A14 ionization chamber measurements, which were verified using a national standards laboratory remote dosimetry service. RESULTS: Absolute dosimetry measurements were confirmed within 1.4% (k = 2, 95% confidence = 5%). The relative output factor of the small fields measured with films and gels agreed with a maximum relative percent error difference between the two methods of 1.1 % for the 1 × 1 cm2 field and 4.3 % for the 0.5 × 0.5 cm2 field. These relative errors were primarily due to the variability in the collimator positioning. The measured beam profiles demonstrated excellent agreement for beam size (measured as FWHM), within approximately 0.8 mm (or less). Film measurements were more accurate in the penumbra region due to the film's finer resolution compared with the gel dosimeter. Following the van Dyk criteria, the PDD values of the film and gel measurements agree within 11% in the buildup region starting from 0.5 cm depth and within 2.6 % beyond maximum dose and into the fall-off region for depths up to 5 cm. The 2D beam profile isodose lines agree within 0.5 mm in all regions for the 0.5 × 0.5 cm2 and the 1 × 1 cm2 fields and within 1 mm for the larger field of 2 × 2 cm2 . The 2D PDD curves agree within approximately 2% of the maximum in the typical therapy region (1-4 cm) for the 1 × 1 cm2 and 2 × 2 cm2 and within 5% for the 0.5 × 0.5 cm2 field. CONCLUSION: This work provides a commissioning process to measure the beam characteristics of a fixed beam MV accelerator with detailed dosimetric evaluation for its implementation in megavoltage small animal irradiation studies. Radiochromic gel dosimeters are efficient small-field relative dosimetry tools providing 3D dose measurements allowing for full representation of dose, dosimeter misalignment corrections and high reproducibility with low inter-dosimeter variability. Overall, radiochromic gels are valuable for fast, full relative dosimetry commissioning in comparison to films for application in high-energy small-field animal irradiation studies.

A simulation study of ionizing radiation acoustic imaging (iRAI) as a real-time dosimetric technique for ultra-high dose rate radiotherapy (UHDR-RT).

PURPOSE: Electron-based ultra-high dose rate radiation therapy (UHDR-RT), also known as Flash-RT, has shown the ability to improve the therapeutic index in comparison to conventional radiotherapy (CONV-RT) through increased sparing of normal tissue. However, the extremely high dose rates in UHDR-RT have raised the need for accurate real-time dosimetry tools. This work aims to demonstrate the potential of the emerging technology of Ionized Radiation Acoustic Imaging (iRAI) through simulation studies and investigate its characteristics as a promising relative in vivo dosimetric tool for UHDR-RT. METHODS: The detection of induced acoustic waves following a single UHDR pulse of a modified 6 MeV 21EX Varian Clinac in a uniform porcine gelatin phantom that is brain-tissue equivalent was simulated for an ideal ultrasound transducer. The full 3D dose distributions in the phantom for a 1 × 1 cm2 field were simulated using EGSnrc (BEAMnrc∖DOSXYZnrc) Monte Carlo (MC) codes. The relative dosimetry simulations were verified with dose experimental measurements using Gafchromic films. The spatial dose distribution was converted into an initial pressure source spatial distribution using the medium-dependent dose-pressure relation. The MATLAB-based toolbox k-Wave was then used to model the propagation of acoustic waves through the phantom and perform time-reversal (TR)-based imaging reconstruction. The effect of the various linear accelerator (linac) operating parameters, including linac pulse duration and pulse repetition rate (frequency), were investigated as well. RESULTS: The MC dose simulation results agreed with the film measurement results, specifically at the central beam region up to 80% dose within approximately 5% relative error for the central profile region and a local relative error of <6% for percentage dose depth. IRAI-based FWHM of the radiation beam was within approximately 3 mm relative to the MC-simulated beam FWHM at the beam entrance. The real-time pressure signal change agreed with the dose changes proving the capability of the iRAI for predicting the beam position. IRAI was tested through 3D simulations of its response to be based on the temporal changes in the linac operating parameters on a dose per pulse basis as expected theoretically from the pressure-dose proportionality. The pressure signal amplitude obtained through 2D simulations was proportional to the dose per pulse. The instantaneous pressure signal amplitude decreases as the linac pulse duration increases, as predicted from the pressure wave generation equations, such that the shorter the linac pulse the higher the signal and the better the temporal (spatial) resolutions of iRAI. The effect of the longer linac pulse duration on the spatial resolution of the 3D constructed iRAI images was corrected for linac pulse deconvolution. This correction has improved the passing rate of the 1%/1 mm gamma test criteria, between the pressure-constructed and dosimetric beam characteristics, to as high as 98%. CONCLUSIONS: A full simulation workflow was developed for testing the effectiveness of iRAI as a promising relative dosimetry tool for UHDR-RT radiation therapy. IRAI has shown the advantage of 3D dose mapping through the dose signal linearity and, hence, has the potential to be a useful dosimeter at depth dose measurement and beam localization and, hence, potentially for in vivo dosimetry in UHDR-RT.

A geno-clinical decision model for the diagnosis of myelodysplastic syndromes.

The differential diagnosis of myeloid malignancies is challenging and subject to interobserver variability. We used clinical and next-generation sequencing (NGS) data to develop a machine learning model for the diagnosis of myeloid malignancies independent of bone marrow biopsy data based on a 3-institution, international cohort of patients. The model achieves high performance, with model interpretations indicating that it relies on factors similar to those used by clinicians. In addition, we describe associations between NGS findings and clinically important phenotypes and introduce the use of machine learning algorithms to elucidate clinicogenomic relationships.

Imaging Special Nuclear Material using a Handheld Dual Particle Imager.

A compact radiation imaging system capable of detecting, localizing, and characterizing special nuclear material (e.g. highly-enriched uranium, plutonium…) would be useful for national security missions involving inspection, emergency response, or war-fighters. Previously-designed radiation imaging systems have been large and bulky with significant portions of volume occupied by photomultiplier tubes (PMTs). The prototype imaging system presented here uses silicon photomultipliers (SiPMs) in place of PMTs because SiPMs are much more compact and operate at low power and voltage. The SiPMs are coupled to the ends of eight stilbene organic scintillators, which have an overall volume of 5.74 × 5.74 × 7.11 cm3. The prototype dual-particle imager's capabilities were evaluated by performing measurements with a 252Cf source, a sphere of 4.5 kg of alpha-phase weapons-grade plutonium known as the BeRP ball, a 6 kg sphere of neptunium, and a canister of 3.4 kg of plutonium oxide (7% 240Pu and 93% 239Pu). These measurements demonstrate neutron spectroscopic capabilities, a neutron image resolution for a Watt spectrum of 9.65 ± 0.94° in the azimuthal direction and 22.59 ± 5.81° in the altitude direction, imaging of gamma rays using organic scintillators, and imaging of multiple sources in the same field of view.

Expectation-propagation for weak radionuclide identification at radiation portal monitors.

We propose a sparsity-promoting Bayesian algorithm capable of identifying radionuclide signatures from weak sources in the presence of a high radiation background. The proposed method is relevant to radiation identification for security applications. In such scenarios, the background typically consists of terrestrial, cosmic, and cosmogenic radiation that may cause false positive responses. We evaluate the new Bayesian approach using gamma-ray data and are able to identify weapons-grade plutonium, masked by naturally-occurring radioactive material (NORM), in a measurement time of a few seconds. We demonstrate this identification capability using organic scintillators (stilbene crystals and EJ-309 liquid scintillators), which do not provide direct, high-resolution, source spectroscopic information. Compared to the EJ-309 detector, the stilbene-based detector exhibits a lower identification error, on average, owing to its better energy resolution. Organic scintillators are used within radiation portal monitors to detect gamma rays emitted from conveyances crossing ports of entry. The described method is therefore applicable to radiation portal monitors deployed in the field and could improve their threat discrimination capability by minimizing "nuisance" alarms produced either by NORM-bearing materials found in shipped cargoes, such as ceramics and fertilizers, or radionuclides in recently treated nuclear medicine patients.

Review of Sterilization Techniques for Medical and Personal Protective Equipment Contaminated With SARS-CoV-2.

The outbreak of the novel coronavirus disease, COVID-19 turned into a global pandemic in March 2020. During these unprecedented times, there is an increased demand in medical and personal protective equipment (PPE). Since the supplies may take a long time to meet the global demand, reusing PPEs will help health care workers in their response to the COVID-19 pandemic. To ensure the safety and well-being of the medical first responders, PPE needs to be sterilized before reuse. In this review, we examine various sterilization techniques that can be used to sterilize PPEs and point out its limitations. The objective is to provide a foundation of knowledge incorporating different sterilization techniques that allow hospitals and clinics to pick the most suitable technique for sterilization of a particular PPE.

Genetic Deletion of Hesx1 Promotes Exit from the Pluripotent State and Impairs Developmental Diapause.

The role of the homeobox transcriptional repressor HESX1 in embryonic stem cells (ESCs) remains mostly unknown. Here, we show that Hesx1 is expressed in the preimplantation mouse embryo, where it is required during developmental diapause. Absence of Hesx1 leads to reduced expression of epiblast and primitive endoderm determinants and failure of diapaused embryos to resume embryonic development after implantation. Genetic deletion of Hesx1 impairs self-renewal and promotes differentiation toward epiblast by reducing the expression of pluripotency factors and decreasing the activity of LIF/STAT3 signaling. We reveal that Hesx1-deficient ESCs show elevated ERK pathway activation, resulting in accelerated differentiation toward primitive endoderm, which can be prevented by overexpression of Hesx1. Together, our data provide evidence for a novel role of Hesx1 in the control of self-renewal and maintenance of the undifferentiated state in ESCs and mouse embryos.

Author Correction: Active neutron and gamma-ray imaging of highly enriched uranium for treaty verification.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Author Correction: P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development.

The original version of this article contained an error in the spelling of Juan Pedro Martinez-Barbera, which was incorrectly given as Juan Pedro Martinez Barbera. This error has now been corrected in both the PDF and HTML versions of the Article.