| 1. |
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| 2. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Feron, Romain, et al.
(författare)
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RADSex : A computational workflow to study sex determination using restriction site-associated DNA sequencing data
- 2021
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Ingår i: Molecular Ecology Resources. - : John Wiley & Sons. - 1755-098X .- 1755-0998. ; 21:5, s. 1715-1731
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Tidskriftsartikel (refereegranskat)abstract
- The study of sex determination and sex chromosome organization in nonmodel species has long been technically challenging, but new sequencing methodologies now enable precise and high-throughput identification of sex-specific genomic sequences. In particular, restriction site-associated DNA sequencing (RAD-Seq) is being extensively applied to explore sex determination systems in many plant and animal species. However, software specifically designed to search for and visualize sex-biased markers using RAD-Seq data is lacking. Here, we present RADSex, a computational analysis workflow designed to study the genetic basis of sex determination using RAD-Seq data. RADSex is simple to use, requires few computational resources, makes no prior assumptions about the type of sex-determination system or structure of the sex locus, and offers convenient visualization through a dedicated R package. To demonstrate the functionality of RADSex, we re-analysed a published data set of Japanese medaka, Oryzias latipes, where we uncovered a previously unknown Y chromosome polymorphism. We then used RADSex to analyse new RAD-Seq data sets from 15 fish species spanning multiple taxonomic orders. We identified the sex determination system and sex-specific markers in six of these species, five of which had no known sex-markers prior to this study. We show that RADSex greatly facilitates the study of sex determination systems in nonmodel species thanks to its speed of analyses, low resource usage, ease of application and visualization options. Furthermore, our analysis of new data sets from 15 species provides new insights on sex determination in fish.
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| 7. |
- Iyer, Nirmal, et al.
(författare)
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The design and performance of the XL-Calibur anticoincidence shield
- 2023
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 1048
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Tidskriftsartikel (refereegranskat)abstract
- The XL-Calibur balloon-borne hard X-ray polarimetry mission comprises a Compton-scattering polarimeter placed at the focal point of an X-ray mirror. The polarimeter is housed within a BGO anticoincidence shield, which is needed to mitigate the considerable background radiation present at the observation altitude of -40 km. This paper details the design, construction and testing of the anticoincidence shield, as well as the performance measured during the week-long maiden flight from Esrange Space Centre to the Canadian Northwest Territories in July 2022. The in-flight performance of the shield followed design expectations, with a veto threshold <100 keV and a measured background rate of -0.5 Hz (20-40 keV). This is compatible with the scientific goals of the mission, where %-level minimum detectable polarisation is sought for a Hz-level source rate.
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| 14. |
- Falstad, Niklas, 1987, et al.
(författare)
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CON-quest: Searching for the most obscured galaxy nuclei
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 649
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Tidskriftsartikel (refereegranskat)abstract
- Context. Some luminous and ultraluminous infrared galaxies (LIRGs and ULIRGs) host extremely compact (r < 100 pc) and dusty nuclei. The high extinction associated with large column densities of gas and dust toward these objects render them hard to detect at many wavelengths. The intense infrared radiation arising from warm dust in these sources can provide a significant fraction of the bolometric luminosity of the galaxy and is prone to excite vibrational levels of molecules such as HCN. This results in emission from the rotational transitions of vibrationally excited HCN (HCN-vib); the brightest emission is found in compact obscured nuclei (CONs; ςHCN-vib > 1 L⊙ pc-2 in the J = 3-2 transition). However, there have been no systematic searches for CONs, and it is unknown how common they are. Aims. We aim to establish how common CONs are in the local Universe (z < 0.08), and whether their prevalence depends on the luminosity or other properties of the host galaxy. Methods. We conducted an Atacama Large Millimeter/submillimeter Array survey of the rotational J = 3-2 transition of HCN-vib in a volume-limited sample of 46 far-infrared luminous galaxies. Results. Compact obscured nuclei are identified in 38-13+18% of the ULIRGs, 21-6+12% of the LIRGs, and 0-0+9% of the lower luminosity galaxies. We find no dependence on the inclination of the host galaxy, but strong evidence of lower IRAS 25 μm to 60 μm flux density ratios (f25/f60) in CONs (with the exception of one galaxy, NGC 4418) compared to the rest of the sample. Furthermore, we find that CONs have stronger silicate features (s9.7 μm), but similar polycyclic aromatic hydrocarbon equivalent widths (EQW6.2 μm) compared to other galaxies. Along with signatures of molecular inflows seen in the far-infrared in most CONs, submillimeter observations also reveal compact, often collimated, outflows. Conclusions. In the local Universe, CONs are primarily found in (U)LIRGs, in which they are remarkably common. As such systems are often highly disturbed, inclinations are difficult to estimate, and high-resolution continuum observations of the individual nuclei are required to determine if the CON phenomenon is related to the inclinations of the nuclear disks. Further studies of the in- A nd outflow properties of CONs should also be conducted to investigate how these are connected to each other and to the CON phenomenon. The lower f25/f60 ratios in CONs as well as the results for the mid-infrared diagnostics investigated (EQW6.2 μm and s9.7 μm) are consistent with the notion that large dust columns gradually shift the radiation from the hot nucleus to longer wavelengths, making the mid- A nd far-infrared "photospheres"significantly cooler than the interior regions. Finally, to assess the importance of CONs in the context of galaxy evolution, it is necessary to extend this study to higher redshifts where (U)LIRGs are more common.
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| 15. |
- Reimer, Paula J., et al.
(författare)
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The IntCal20 Northern Hemisphere Radiocarbon Age Calibration Curve (0-55 cal kBP)
- 2020
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Ingår i: Radiocarbon. - 0033-8222. ; 62:4, s. 725-757
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Tidskriftsartikel (refereegranskat)abstract
- Radiocarbon (C) ages cannot provide absolutely dated chronologies for archaeological or paleoenvironmental studies directly but must be converted to calendar age equivalents using a calibration curve compensating for fluctuations in atmospheric C concentration. Although calibration curves are constructed from independently dated archives, they invariably require revision as new data become available and our understanding of the Earth system improves. In this volume the international C calibration curves for both the Northern and Southern Hemispheres, as well as for the ocean surface layer, have been updated to include a wealth of new data and extended to 55,000 cal BP. Based on tree rings, IntCal20 now extends as a fully atmospheric record to ca. 13,900 cal BP. For the older part of the timescale, IntCal20 comprises statistically integrated evidence from floating tree-ring chronologies, lacustrine and marine sediments, speleothems, and corals. We utilized improved evaluation of the timescales and location variable C offsets from the atmosphere (reservoir age, dead carbon fraction) for each dataset. New statistical methods have refined the structure of the calibration curves while maintaining a robust treatment of uncertainties in the C ages, the calendar ages and other corrections. The inclusion of modeled marine reservoir ages derived from a three-dimensional ocean circulation model has allowed us to apply more appropriate reservoir corrections to the marine C data rather than the previous use of constant regional offsets from the atmosphere. Here we provide an overview of the new and revised datasets and the associated methods used for the construction of the IntCal20 curve and explore potential regional offsets for tree-ring data. We discuss the main differences with respect to the previous calibration curve, IntCal13, and some of the implications for archaeology and geosciences ranging from the recent past to the time of the extinction of the Neanderthals.
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| 16. |
- Aalto, Susanne, 1964, et al.
(författare)
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ALMA resolves the remarkable molecular jet and rotating wind in the extremely radio-quiet galaxy NGC 1377
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 640
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Tidskriftsartikel (refereegranskat)abstract
- Submillimetre and millimetre line and continuum observations are important in probing the morphology, column density, and dynamics of the molecular gas and dust around obscured active galactic nuclei (AGNs) and their mechanical feedback. With very high-resolution (0.'' 02x0.'' 03 (2x3 pc)) ALMA 345 GHz observations of CO 3-2, HCO+ 4-3, vibrationally excited HCN 4-3 nu (2)=1f, and continuum we have studied the remarkable, extremely radio-quiet, molecular jet and wind of the lenticular galaxy NGC 1377. The outflow structure is resolved, revealing a 150 pc long, clumpy, high-velocity (similar to 600 km s(-1)), collimated molecular jet where the molecular emission is emerging from the spine of the jet with an average diameter of 3-7 pc. The jet widens to 10-15 pc about 25 pc from the centre, which is possibly due to jet-wind interactions. A narrow-angle (50 degrees -70 degrees), misaligned and rotating molecular wind surrounds the jet, and both are enveloped by a larger-scale CO-emitting structure at near-systemic velocity. The jet and narrow wind have steep radial gas excitation gradients and appear turbulent with high gas dispersion (sigma> 40 km s(-1)). The jet shows velocity reversals that we propose are caused by precession, or more episodic directional changes. We discuss the mechanisms powering the outflow, and we find that an important process for the molecular jet and narrow wind is likely magneto-centrifugal driving. In contrast, the large-scale CO-envelope may be a slow wind, or cocoon that stems from jet-wind interactions. An asymmetric, nuclear r similar to 2 pc dust structure with a high inferred molecular column density N(H-2) similar or equal to 1.8x10(24) cm(-2) is detected in continuum and also shows compact emission from vibrationally excited HCN. The nuclear dust emission is hot (T-d> 180 K) and its luminosity is likely powered by a buried AGN. The lopsided structure appears to be a warped disk, which is responsible for a significant part of the nuclear obscuration and possibly formed as a result of uneven gas inflows. The dynamical mass inside r=1.4 pc is estimated to 9(-3)(+2) x 10(6)M(circle dot) 9 - 3 + 2 x 10 6 M circle dot , implying that the supermassive black hole (SMBH) has a high mass with respect to the stellar velocity dispersion of NGC 1377. We suggest that the SMBH of NGC 1377 is currently in a state of moderate growth, at the end of a more intense phase of accretion and also evolving from a state of more extreme nuclear obscuration. The nuclear growth may be fuelled by low-angular momentum gas inflowing from the gas ejected in the molecular jet and wind. Such a feedback-loop of cyclic outflows and central accretion could explain why there is still a significant reservoir of molecular gas in this ageing, lenticular galaxy. A feedback-loop would be an effective process in growing the nuclear SMBH and thus would constitute an important phase in the evolution of NGC 1377. This also invites new questions as to SMBH growth processes in obscured, dusty galaxies.
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| 17. |
- Awes, T., et al.
(författare)
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Design and performance of a silicon–tungsten calorimeter prototype module and the associated readout
- 2021
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Ingår i: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002. ; 988
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Tidskriftsartikel (refereegranskat)abstract
- We describe the details of a silicon–tungsten prototype electromagnetic calorimeter module and associated readout electronics. Detector performance for this prototype has been measured in test beam experiments at the CERN PS and SPS accelerator facilities in 2015/16. The results are compared to those in Monte Carlo Geant4 simulations. This is the first real-world demonstration of the performance of a custom ASIC designed for fast, lower-power, high-granularity applications.
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| 18. |
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| 19. |
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| 20. |
- Ghaznavi, C, et al.
(författare)
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Changes in marriage, divorce and births during the COVID-19 pandemic in Japan
- 2022
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Ingår i: BMJ global health. - : BMJ. - 2059-7908. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Marriage, divorce and fertility are declining in Japan. There is concern that the COVID-19 pandemic may have accelerated the decrease in marriages and births while increasing the number of divorces. Changes in partnership behaviours and fertility have significant implications for mental health, well-being and population demographics.MethodsJapanese vital statistical data were collected for December 2011–May 2021. We used the Farrington algorithm on the daily numbers of marriages, divorces and births (per month) in order to determine whether any given month between January 2017 and May 2021 had a significant excess or deficit. Analyses were conducted at the national and regional levels.ResultsDuring the pandemic, significant deficits in the national number of marriages were noted in January 2020, April 2020, May 2020, July 2020, September 2020 and April 2021. Regional marriage patterns reflected national trends. Divorces were noted to be in deficit during April 2020, May 2020 and May 2021 at the country level. Regional analyses mirrored national divorce trends with the exception of Shikoku, which showed no deficits during the pandemic. Significant deficits in the number of total births were noted in December 2020, January 2021 and February 2021. Regionally, birth deficits were concentrated in Chubu, Kansai and Kanto. After the start of the pandemic, no significant excesses in marriages, divorces or births were noted at the national or regional level.ConclusionsMarriages and divorces declined during the pandemic in Japan, especially during state of emergency declarations. There were decreased births between December 2020 and February 2021, approximately 8–10 months after the first state of emergency, suggesting that couples altered their pregnancy intention in response to the pandemic. Metropolitan regions were more affected by the pandemic than their less metropolitan counterparts.
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| 21. |
- Ghaznavi, C, et al.
(författare)
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Recent changes in the reporting of STIs in Japan during the COVID-19 pandemic
- 2023
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Ingår i: Sexually transmitted infections. - : BMJ. - 1472-3263 .- 1368-4973. ; 99:2, s. 124-127
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Tidskriftsartikel (refereegranskat)abstract
- The COVID-19 pandemic has had variable effects on the rates of STIs reported across the globe. This study sought to assess how the number of STI reports changed during the pandemic in Japan.MethodsWe used national infectious disease surveillance data from the National Institute of Infectious Diseases (Tokyo, Japan) for the period between January 2013 and December 2021. We compared reported rates of chlamydia, gonorrhoea, condyloma acuminata and genital herpes, as well as total notifications for HIV/AIDS and syphilis during the pandemic versus previous years in Japan. We used a quasi-Poisson regression to determine whether any given week or month between January 2018 and December 2021 had a significant excess or deficit of STIs. Notification values above or below the 95% upper and lower prediction thresholds were considered as statistically significant. The start of the pandemic was defined as January 2020.ResultsChlamydia generally remained within predicted range during the pandemic period. Reporting of gonorrhoea was significantly higher than expected throughout early-to-mid 2021 but otherwise generally remained within predicted range prior to 2021. Condyloma, herpes and HIV/AIDS reporting were transiently significantly lower than expected throughout the pandemic period, but no significant periods of higher-than-expected reporting were detected. Syphilis showed widespread evidence of significantly lower-than-predicted reporting throughout 2020 but eventually reversed, showing significantly higher-than-predicted reporting in mid-to-late 2021.ConclusionsThe COVID-19 pandemic was associated with variable changes in the reporting of STIs in Japan. Higher-than-predicted reporting was more likely to be observed in the later phases of the pandemic. These changes may have been attributable to pandemic-related changes in sexual behaviour and decreased STI clinic attendance and testing, but further research on the long-term impact of the pandemic on STIs is necessary.
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| 23. |
- Humire, Pedro, et al.
(författare)
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Methanol masers in NGC 253 with ALCHEMI
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 663
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Tidskriftsartikel (refereegranskat)abstract
- Context. Methanol masers of Class I (collisionally pumped) and Class II (radiatively pumped) have been studied in great detail in our Galaxy in a variety of astrophysical environments such as shocks and star-forming regions and are they are helpful to analyze the properties of the dense interstellar medium. However, the study of methanol masers in external galaxies is still in its infancy. Aims. Our main goal is to search for methanol masers in the central molecular zone (CMZ; inner 500 pc) of the nearby starburst galaxy NGC253. Methods. Covering a frequency range between 84 and 373 GHz (λ = 3.6-0.8 mm) at high angular (1."6 ∼ 27 pc) and spectral (∼8-9 km s-1) resolution with ALCHEMI (ALMA Comprehensive High-resolution Extragalactic Molecular Inventory), we have probed dierent regions across the CMZ of NGC253. In order to look for methanol maser candidates, we employed the rotation diagram method and a set of radiative transfer models. Results.We detect for the first time masers above 84 GHz in NGC253, covering an ample portion of the J-1 (J-1)0-E line series (at 84, 132, 229, and 278 GHz) and the J0 (J-1)1 A series (at 95, 146, and 198 GHz). This confirms the presence of the Class I maser line at 84 GHz, which was already reported, but now being detected in more than one location. For the J-1 (J-1)0-E line series, we observe a lack of Class I maser candidates in the central star-forming disk. Conclusions. The physical conditions for maser excitation in the J-1 (J-1)0-E line series can be weak shocks and cloud-cloud collisions as suggested by shock tracers (SiO and HNCO) in bi-symmetric shock regions located in the outskirts of the CMZ. On the other hand, the presence of photodissociation regions due to a high star-formation rate would be needed to explain the lack of Class I masers in the very central regions.
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| 24. |
- Martin, S., et al.
(författare)
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ALCHEMI, an ALMA Comprehensive High-resolution Extragalactic Molecular Inventory: Survey presentation and first results from the ACA array
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 656
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Tidskriftsartikel (refereegranskat)abstract
- Context. The interstellar medium is the locus of physical processes affecting the evolution of galaxies which drive or are the result of star formation activity, supermassive black hole growth, and feedback. The resulting physical conditions determine the observable chemical abundances that can be explored through molecular emission observations at millimeter and submillimeter wavelengths. Aims. Our goal is to unveiling the molecular richness of the central region of the prototypical nearby starburst galaxy NGC 253 at an unprecedented combination of sensitivity, spatial resolution, and frequency coverage. Methods. We used the Atacama Large Millimeter/submillimeter Array (ALMA), covering a nearly contiguous 289 GHz frequency range between 84.2 and 373.2 GHz, to image the continuum and spectral line emission at 1.6″(∼28 pc) resolution down to a sensitivity of 30 - 50 mK. This article describes the ALMA Comprehensive High-resolution Extragalactic Molecular Inventory (ALCHEMI) large program. We focus on the analysis of the spectra extracted from the 15″ (∼255 pc) resolution ALMA Compact Array data. Results. We modeled the molecular emission assuming local thermodynamic equilibrium with 78 species being detected. Additionally, multiple hydrogen and helium recombination lines are identified. Spectral lines contribute 5 to 36% of the total emission in frequency bins of 50 GHz. We report the first extragalactic detections of C2H5OH, HOCN, HC3HO, and several rare isotopologues. Isotopic ratios of carbon, oxygen, sulfur, nitrogen, and silicon were measured with multiple species. Concluison. Infrared pumped vibrationaly excited HCN, HNC, and HC3N emission, originating in massive star formation locations, is clearly detected at low resolution, while we do not detect it for HCO+. We suggest high temperature conditions in these regions driving a seemingly "carbon-rich"chemistry which may also explain the observed high abundance of organic species close to those in Galactic hot cores. The Lvib/LIR ratio was used as a proxy to estimate a 3% contribution from the proto super star cluster to the global infrared emission. Measured isotopic ratios with high dipole moment species agree with those within the central kiloparsec of the Galaxy, while those derived from 13C/18O are a factor of five larger, confirming the existence of multiple interstellar medium components within NGC 253 with different degrees of nucleosynthesis enrichment. The ALCHEMI data set provides a unique template for studies of star-forming galaxies in the early Universe.
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| 27. |
- Shrestha, R, et al.
(författare)
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Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status
- 2020
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Ingår i: Blood advances. - : American Society of Hematology. - 2473-9537 .- 2473-9529. ; 4:5, s. 845-854
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Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of ∼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency.
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| 28. |
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| 29. |
- Wilkes, Mark C., et al.
(författare)
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Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a
- 2020
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Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X. ; 91, s. 65-77
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Tidskriftsartikel (refereegranskat)abstract
- Diamond–Blackfan anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity and suppression of NLK expression both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data indicate that the effects of metformin on erythroid proliferation and differentiation are mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3′ untranslated region (3′UTR) to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treatment of DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.
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| 30. |
- Wilkes, MC, et al.
(författare)
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Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 3344-
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Tidskriftsartikel (refereegranskat)abstract
- Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.
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