Pediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 ...(monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling, and functional validation, we show that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.
An annually resolved and absolutely dated ring-width chronology spanning 4,500 y has been constructed using subfossil, archaeological, and living-tree juniper samples from the northeastern Tibetan ...Plateau. The chronology represents changing mean annual precipitation and is most reliable after 1500 B.C. Reconstructed precipitation for this period displays a trend toward more moist conditions: the last 10-, 25-, and 50-y periods all appear to be the wettest in at least three and a half millennia. Notable historical dry periods occurred in the 4th century BCE and in the second half of the 15th century CE. The driest individual year reconstructed (since 1500 B.C.) is 1048 B.C., whereas the wettest is 2010. Precipitation variability in this region appears not to be associated with inferred changes in Asian monsoon intensity during recent millennia. The chronology displays a statistical association with the multidecadal and longer-term variability of reconstructed mean Northern Hemisphere temperatures over the last two millennia. This suggests that any further large-scale warming might be associated with even greater moisture supply in this region.
To meet the challenges posed by future generations of massively parallel supercomputers, a reformulation of the dynamical core for the Met Office's weather and climate model is presented. This new ...dynamical core uses explicit finite‐volume type discretizations for the transport of scalar fields coupled with an iterated‐implicit, mixed finite‐element discretization for all other terms. The target model aims to maintain the accuracy, stability and mimetic properties of the existing Met Office model independent of the chosen mesh while improving the conservation properties of the model. This paper details that proposed formulation and, as a first step towards complete testing, demonstrates its performance for a number of test cases in (the context of) a Cartesian domain. The new model is shown to produce similar results to both the existing semi‐implicit semi‐Lagrangian model used at the Met Office and other models in the literature on a range of bubble tests and orographically forced flows in two and three dimensions.
A simulation of a cold bubble of air as it falls to the ground, propagates along the surface and forms roll vortices. The flow is simulated using a new mixed finite‐element, finite‐volume semi‐implicit model that evolved from the GungHo project and is being developed as a replacement dynamical core for the Met Office's Unified Model.
SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a ...greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death. Here, we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. Using a range of in vivo and ex vivo assays, we showed that cells with heterozygous Samd9l mutations have impaired stemness relative to wild-type counterparts, which was exacerbated by inflammatory stimuli, and ultimately led to bone marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-beta as a potential targetable pathway. Further, we observed nonrandom genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking chromosome 7 deletions observed in patients. Collectively, our study has enhanced our understanding of mutant Samd9l hematopoietic phenotypes, emphasized the synergistic role of inflammation in exaggerating the associated hematopoietic defects, and provided insights into potential therapeutic options for patients.
We combine satellite and ground observations during 1950–2011 to study the long‐term links between multiple climate (air temperature and cryospheric dynamics) and vegetation (greenness and ...atmospheric CO2 concentrations) indicators of the growing season of northern ecosystems (>45°N) and their connection with the carbon cycle. During the last three decades, the thermal potential growing season has lengthened by about 10.5 days (P < 0.01, 1982–2011), which is unprecedented in the context of the past 60 years. The overall lengthening has been stronger and more significant in Eurasia (12.6 days, P < 0.01) than North America (6.2 days, P > 0.05). The photosynthetic growing season has closely tracked the pace of warming and extension of the potential growing season in spring, but not in autumn when factors such as light and moisture limitation may constrain photosynthesis. The autumnal extension of the photosynthetic growing season since 1982 appears to be about half that of the thermal potential growing season, yielding a smaller lengthening of the photosynthetic growing season (6.7 days at the circumpolar scale, P < 0.01). Nevertheless, when integrated over the growing season, photosynthetic activity has closely followed the interannual variations and warming trend in cumulative growing season temperatures. This lengthening and intensification of the photosynthetic growing season, manifested principally over Eurasia rather than North America, is associated with a long‐term increase (22.2% since 1972, P < 0.01) in the amplitude of the CO2 annual cycle at northern latitudes. The springtime extension of the photosynthetic and potential growing seasons has apparently stimulated earlier and stronger net CO2 uptake by northern ecosystems, while the autumnal extension is associated with an earlier net release of CO2 to the atmosphere. These contrasting responses may be critical in determining the impact of continued warming on northern terrestrial ecosystems and the carbon cycle.
•UBTF tandem duplications and KMT2A/menin complex co-occupy genomic targets dysregulated in UBTF-TD acute myeloid leukemias.•UBTF-TD acute myeloid leukemias are sensitive to menin inhibition.
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UBTF tandem duplications (UBTF-TDs) have recently emerged as a recurrent alteration in pediatric and adult acute myeloid leukemia (AML). UBTF-TD leukemias are characterized by a poor response to conventional chemotherapy and a transcriptional signature that mirrors NUP98-rearranged and NPM1-mutant AMLs, including HOX-gene dysregulation. However, the mechanism by which UBTF-TD drives leukemogenesis remains unknown. In this study, we investigated the genomic occupancy of UBTF-TD in transformed cord blood CD34+ cells and patient-derived xenograft models. We found that UBTF-TD protein maintained genomic occupancy at ribosomal DNA loci while also occupying genomic targets commonly dysregulated in UBTF-TD myeloid malignancies, such as the HOXA/HOXB gene clusters and MEIS1. These data suggest that UBTF-TD is a gain-of-function alteration that results in mislocalization to genomic loci dysregulated in UBTF-TD leukemias. UBTF-TD also co-occupies key genomic loci with KMT2A and menin, which are known to be key partners involved in HOX-dysregulated leukemias. Using a protein degradation system, we showed that stemness, proliferation, and transcriptional signatures are dependent on sustained UBTF-TD localization to chromatin. Finally, we demonstrate that primary cells from UBTF-TD leukemias are sensitive to the menin inhibitor SNDX-5613, resulting in markedly reduced in vitro and in vivo tumor growth, myeloid differentiation, and abrogation of the UBTF-TD leukemic expression signature. These findings provide a viable therapeutic strategy for patients with this high-risk AML subtype.
Upstream binding transcription factor tandem duplications (UBTF-TDs) are a recurrent finding in acute myeloid leukemia (AML) that confer a poor response to chemotherapy. Barajas and colleagues examined transcriptional targets of UBTF-TD in transformed CD34+ cells and patient-derived xenografts. Wild-type UBTF binds to ribosomal DNA loci, and UBTF-TD maintains that binding. However, UBTF-TD also binds to gene loci dysregulated in UBTF-TD AML, including HOXA/HOXB and MEIS1. Like other HOXA overexpressing AML cells, they are sensitive to menin inhibitors, offering a potential therapy for this high-risk AML.
Following previous work on an inherently mass‐conserving semi‐implicit (SI) semi‐Lagrangian (SL) discretization of the two‐dimensional (2D) shallow‐water equations and 2D vertical slice equations, ...that approach is here extended to the 3D deep‐atmosphere, non‐hydrostatic global equations. As with the reduced‐dimension versions of this model, an advantage of the approach is that it preserves the same basic structure as a standard, non‐mass‐conserving, SISL version of the model. Additionally, the model is simply switchable to hydrostatic and/or shallow‐atmosphere forms. It is also designed to allow simple switching between various geometries (Cartesian, spherical, spheroidal). The resulting mass‐conserving model is applied to a standard set of test problems for such models in spherical geometry and compared with results from the standard SISL version of the model.
Caspase-3 activation and function have been well-defined during programmed cell death, but caspase activity, at low levels, is also required for developmental processes such as lymphoid proliferation ...and erythroid differentiation. Post-translational modification of caspase-3 is one method used by cells to fine-tune activity below the threshold required for apoptosis, but the allosteric mechanism that reduces activity is unknown. Phosphorylation of caspase-3 at a conserved allosteric site by p38-MAPK (mitogen-activated protein kinase) promotes survival in human neutrophils, and the modification of the loop is thought to be a key regulator in many developmental processes. We utilized phylogenetic, structural, and biophysical studies to define the interaction networks that facilitate the allosteric mechanism in caspase-3. We show that, within the modified loop, Ser150 evolved with the apoptotic caspases, whereas Thr152 is a more recent evolutionary event in mammalian caspase-3. Substitutions at Ser150 result in a pH-dependent decrease in dimer stability, and localized changes in the modified loop propagate to the active site of the same protomer through a connecting surface helix. Likewise, a cluster of hydrophobic amino acids connects the conserved loop to the active site of the second protomer. The presence of Thr152 in the conserved loop introduces a “kill switch” in mammalian caspase-3, whereas the more ancient Ser150 reduces without abolishing enzyme activity. These data reveal how evolutionary changes in a conserved allosteric site result in a common pathway for lowering activity during development or a more recent cluster-specific switch to abolish activity.
Tree rings are commonly used proxy data for past climate variability. Probably the simplest practical solution for transforming raw tree-ring data into proxy estimates and retaining information on ...low-frequency tree-growth forcing is the regional curve standardization (RCS). This paper reviews the RCS concept and the development of this standardization method over the past 25 years. Tree-ring based estimation of low-frequency climate variability is illuminated with a growing diversification of the original concept. The RCS-type methods are seen to remain as essential tools in palaeoclimate research while the RCS chronologies of tree-ring and other incremental proxy data remain the only source for calendar year dated short-to-long timescale climate variations.
It is generally hypothesized that tree growth at the upper treeline is normally controlled by temperature while that at the lower treeline is precipitation limited. However, uniform patterns of ...inter-annual ring-width variations along altitudinal gradients are also observed in some situations. How changing elevation influences tree growth in the cold and arid Qilian Mountains, on the northeastern Tibetan Plateau, is of considerable interest because of the sensitivity of the region's local climate to different atmospheric circulation patterns. Here, a network of four Qilian juniper (Sabina przewalskii Kom.) ring-width chronologies was developed from trees distributed on a typical mountain slope at elevations ranging from 3000 to 3520 m above sea level (a.s.l.). The statistical characteristics of the four tree-ring chronologies show no significant correlation with increasing elevation. All the sampled tree growth was controlled by a common climatic signal (local precipitation) across the investigated altitudinal gradient (520 m). During the common reliable period, covering the past 450 years, the four chronologies have exhibited coherent growth patterns in both the high- and low-frequency domains. These results contradict the notion of contrasting climate growth controls at higher and lower elevations, and specifically the assumption that inter-annual tree-growth variability is controlled by temperature at the upper treeline. It should be stressed that these results relate to the relatively arid conditions at the sampling sites in the Qilian Mountains.
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