Differential Hox expression in murine embryonic stem cell models of normal and malignant hematopoiesis

The Hox family are master transcriptional regulators of developmental processes, including hematopoiesis. The Hox regulators, caudal homeobox factors (Cdx1-4), and Meis1, along with several individual Hox proteins, are implicated in stem cell expansion during embryonic development, with gene dosage playing a significant role in the overall function of the integrated Hox network. To investigate the role of this network in normal and aberrant, early hematopoiesis, we employed an in vitro embryonic stem cell differentiation system, which recapitulates mouse developmental hematopoiesis. Expression profiles of Hox, Pbx1, and Meis1 genes were quantified at distinct stages during the hematopoietic differentiation process and compared with the effects of expressing the leukemic oncogene Tel/PDGFR;2. During normal differentiation the Hoxa cluster, Pbx1 and Meis1 predominated, with a marked reduction in the majority of Hox genes (27/39) and Meis1 occurring during hematopoietic commitment. Only the posterior Hoxa cluster genes (a9, a10, a11, and a13) maintained or increased expression at the hematopoietic colony stage. Cdx4, Meis1, and a subset of Hox genes, including a7 and a9, were differentially expressed after short-term oncogenic (Tel/PDGFR;2) induction. Whereas Hoxa4-10, b1, b2, b4, and b9 were upregulated during oncogenic driven myelomonocytic differentiation. Heterodimers between Hoxa7/Hoxa9, Meis1, and Pbx have previously been implicated in regulating target genes involved in hematopoietic stem cell (HSC) expansion and leukemic progression. These results provide direct evidence that transcriptional flux through the Hox network occurs at very early stages during hematopoietic differentiation and validates embryonic stem cell models for gaining insights into the genetic regulation of normal and malignant hematopoiesis

Reconstructing the accumulation history of a saltmarsh sediment core: which age-depth model is best?

Saltmarsh-based reconstructions of relative sea-level (RSL) change play a central role in current efforts seeking to quantify the relationship between climate and sea-level rise. The development of an accurate chronology is pivotal, since errors in age-depth relationships will propagate to the final record as alterations in both the timing and magnitude of reconstructed change. A range of age-depth modelling packages are available but differences in their theoretical basis and practical operation mean contrasting accumulation histories can be produced from the same dataset. We compare the performance of five age-depth modelling programs (Bacon, Bchron, Bpeat, Clam and OxCal) when applied to the kinds of data used in high resolution, saltmarsh-based RSL reconstructions. We investigate their relative performance by comparing modelled accumulation curves against known age-depth relationships generated from simulated stratigraphic sequences. Bpeat is particularly sensitive to non-linearities which, whilst maximising the detection of small rate changes, has the potential to generate spurious variations, particularly in the last 400 years. Bacon generally replicates the pattern and magnitude of change but with notable offsets in timing. Bchron and OxCal successfully constrain the known accumulation history within their error envelopes although the best-fit solutions tend to underestimate the magnitude of change. The best-fit solutions of Clam generally replicate the timing and magnitude of changes well, but are sensitive to the underlying shape of the calibration curve, performing poorly where plateaus in atmospheric 14C concentration exist. We employ an ensemble of age-depth models to reconstruct a 1500 year accumulation history for a saltmarsh core recovered from Connecticut, USA based on a composite chronology comprising 26 AMS radiocarbon dates, 210Pb, 137Cs radionuclides and an historical pollen chronohorizon. The resulting record reveals non-linear accumulation during the late Holocene with a marked increase in rate around AD1800. With the exception of the interval between AD1500 and AD1800, all modelsproduce accumulation curves that agree to within ~10 cm at the century-scale. The accumulation rate increase around AD1800 is associated with the transition from a radiocarbon-based to a 210Pb dominated chronology. Whilst repeat analysis excluding the 210Pb data alters the precise timing and magnitude of this acceleration, a shift to faster accumulation compared to the long-term rate is a robust feature of the record and not simply an artefact of the switch in dating methods. Simulation indicates that a rise of similar magnitude to the post-AD1800 increase (detrended increase of ~16 cm) is theoretically constrained and detectable within the radiocarbon-dated portion of the record. The absence of such a signal suggests that the recent rate of accumulation is unprecedented in the last 1500 years. Our results indicate that reliable (sub)century-scale age-depth models can be developed from saltmarsh sequences, and that the vertical uncertainties associated with them translate to RSL reconstruction errors that are typically smaller than those associated with the most precise microfossil-based estimates of palaeomarsh-surface elevation

Supine posture changes lung volumes and increases ventilation heterogeneity in cystic fibrosis

INTRODUCTION: Lung Clearance Index (LCI) is recognised as an early marker of cystic fibrosis (CF) lung disease. The effect of posture on LCI however is important when considering longitudinal measurements from infancy and when comparing LCI to imaging studies. METHODS: 35 children with CF and 28 healthy controls (HC) were assessed. Multiple breath washout (MBW) was performed both sitting and supine in triplicate and analysed for LCI, Scond, Sacin, and lung volumes. These values were also corrected for the Fowler dead-space to create 'alveolar' indices. RESULTS: From sitting to supine there was a significant increase in LCI and a significant decrease in FRC for both CF and HC (p<0.01). LCI, when adjusted to estimate 'alveolar' LCI (LCIalv), increased the magnitude of change with posture for both LCIalv and FRCalv in both groups, with a greater effect of change in lung volume in HC compared with children with CF. The % change in LCIalv for all subjects correlated significantly with lung volume % changes, most notably tidal volume/functional residual capacity (Vtalv/FRCalv (r = 0.54,p<0.001)). CONCLUSION: There is a significant increase in LCI from sitting to supine, which we believe to be in part due to changes in lung volume and also increasing ventilation heterogeneity related to posture. This may have implications in longitudinal measurements from infancy to older childhood and for studies comparing supine imaging methods to LCI

Hydroclimate changes in eastern Africa over the past 200,000 years may have influenced early human dispersal

Abstract: Reconstructions of climatic and environmental conditions can contribute to current debates about the factors that influenced early human dispersal within and beyond Africa. Here we analyse a 200,000-year multi-proxy paleoclimate record from Chew Bahir, a tectonic lake basin in the southern Ethiopian rift. Our record reveals two modes of climate change, both associated temporally and regionally with a specific type of human behavior. The first is a long-term trend towards greater aridity between 200,000 and 60,000 years ago, modulated by precession-driven wet-dry cycles. Here, more favorable wetter environmental conditions may have facilitated long-range human expansion into new territory, while less favorable dry periods may have led to spatial constriction and isolation of local human populations. The second mode of climate change observed since 60,000 years ago mimics millennial to centennial-scale Dansgaard-Oeschger cycles and Heinrich events. We hypothesize that human populations may have responded to these shorter climate fluctuations with local dispersal between montane and lowland habitats

TOI-1728b: The Habitable-zone Planet Finder confirms a warm super Neptune orbiting an M dwarf host

We confirm the planetary nature of TOI-1728b using a combination of ground-based photometry, near-infrared Doppler velocimetry and spectroscopy with the Habitable-zone Planet Finder.TOI-1728 is an old, inactive M0 star with \teff{} $= 3980^{+31}_{-32}$ K, which hosts a transiting super Neptune at an orbital period of $\sim$ 3.49 days. Joint fitting of the radial velocities and TESS and ground-based transits yields a planetary radius of $5.05_{-0.17}^{+0.16}$ R$_{\oplus}$, mass $26.78_{-5.13}^{+5.43}$ M$_{\oplus}$ and eccentricity $0.057_{-0.039}^{+0.054}$. We estimate the stellar properties, and perform a search for He 10830 \AA absorption during the transit of this planet and claim a null detection with an upper limit of 1.1$\%$ with 90\% confidence. A deeper level of He 10830 \AA ~ absorption has been detected in the planet atmosphere of GJ 3470b, a comparable gaseous planet. TOI-1728b is the largest super Neptune -- the intermediate subclass of planets between Neptune and the more massive gas-giant planets -- discovered around an M dwarf. With its relatively large mass and radius, TOI-1728 represents a valuable datapoint in the M-dwarf exoplanet mass-radius diagram, bridging the gap between the lighter Neptune-sized planets and the heavier Jovian planets known to orbit M-dwarfs. With a low bulk density of $1.14_{-0.24}^{+0.26}$ g/cm$^3$, and orbiting a bright host star (J $\sim 9.6$, V $\sim 12.4$), TOI-1728b is also a promising candidate for transmission spectroscopy both from the ground and from space, which can be used to constrain planet formation and evolutionary models.Comment: 21 pages, 12 figures, 4 tables: Accepted for publicatio

TOI-1728b: The Habitable-zone Planet Finder Confirms a Warm Super-Neptune Orbiting an M-dwarf Host

We confirm the planetary nature of TOI-1728b using a combination of ground-based photometry, near-infrared Doppler velocimetry and spectroscopy with the Habitable-zone Planet Finder. TOI-1728 is an old, inactive M0 star with T_(eff) = 3980⁺³¹₋₃₂ K, which hosts a transiting super-Neptune at an orbital period of ~3.49 days. Joint fitting of the radial velocities and TESS and ground-based transits yields a planetary radius of 5.05^(+0.16)_(-0.17) R_⊕, mass 26.78^(+5.43)_(-5.13) M_⊕, and eccentricity 0.057^(+0.054)_(-0.039). We estimate the stellar properties, and perform a search for He 10830 Å absorption during the transit of this planet and claim a null detection with an upper limit of 1.1% with 90% confidence. A deeper level of He 10830 Å absorption has been detected in the planet atmosphere of GJ 3470b, a comparable gaseous planet. TOI-1728b is the largest super-Neptune—the intermediate subclass of planets between Neptune and the more massive gas-giant planets—discovered around an M dwarf. With its relatively large mass and radius, TOI-1728 represents a valuable data point in the M-dwarf exoplanet mass–radius diagram, bridging the gap between the lighter Neptune-sized planets and the heavier Jovian planets known to orbit M dwarfs. With a low bulk density of 1.14^(+0.26)_(-0.24) g cm⁻³, and orbiting a bright host star (J ~ 9.6, V ~ 12.4), TOI-1728b is also a promising candidate for transmission spectroscopy both from the ground and from space, which can be used to constrain planet formation and evolutionary models

Early Last Interglacial ocean warming drove substantial ice mass loss from Antarctica

The future response of the Antarctic ice sheet to rising temperatures remains highly uncertain. A useful period for assessing the sensitivity of Antarctica to warming is the Last Interglacial (LIG) (129 to 116 ky), which experienced warmer polar temperatures and higher global mean sea level (GMSL) (+6 to 9 m) relative to present day. LIG sea level cannot be fully explained by Greenland Ice Sheet melt (∼2 m), ocean thermal expansion, and melting mountain glaciers (∼1 m), suggesting substantial Antarctic mass loss was initiated by warming of Southern Ocean waters, resulting from a weakening Atlantic meridional overturning circulation in response to North Atlantic surface freshening. Here, we report a blue-ice record of ice sheet and environmental change from the Weddell Sea Embayment at the periphery of the marine-based West Antarctic Ice Sheet (WAIS), which is underlain by major methane hydrate reserves. Constrained by a widespread volcanic horizon and supported by ancient microbial DNA analyses, we provide evidence for substantial mass loss across the Weddell Sea embayment during the LIG, most likely driven by ocean warming and associated with destabilization of subglacial hydrates. Ice sheet modeling supports this interpretation and suggests that millennial-scale warming of the Southern Ocean could have triggered a multimeter rise in global sea levels. Our data indicate that Antarctica is highly vulnerable to projected increases in ocean temperatures and may drive ice–climate feedbacks that further amplify warming