193 research outputs found
Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD
Demonstration of a Novel Technique to Measure Two-Photon Exchange Effects in Elastic e±p Scattering
Background: The discrepancy between proton electromagnetic form factors extracted using unpolarized and polarized scattering data is believed to be a consequence of two-photon exchange (TPE) effects. However, the calculations of TPE corrections have significant model dependence, and there is limited direct experimental evidence for such corrections.
Purpose: The TPE contributions depend on the sign of the lepton charge in e±p scattering, but the luminosities of secondary positron beams limited past measurement at large scattering angles, where the TPE effects are believe to be most significant. We present the results of a new experimental technique for making direct e±p comparisons, which has the potential to make precise measurements over a broad range in Q2 and scattering angles.
Methods: We use the Jefferson Laboratory electron beam and the Hall B photon tagger to generate a clean but untagged photon beam. The photon beam impinges on a converter foil to generate a mixed beam of electrons, positrons, and photons. A chicane is used to separate and recombine the electron and positron beams while the photon beam is stopped by a photon blocker. This provides a combined electron and positron beam, with energies from 0.5 to 3.2 GeV, which impinges on a liquid hydrogen target. The large acceptance CLAS detector is used to identify and reconstruct elastic scattering events, determining both the initial lepton energy and the sign of the scattered lepton.
Results: The data were collected in two days with a primary electron beam energy of only 3.3 GeV, limiting the data from this run to smaller values of Q2 and scattering angle. Nonetheless, this measurement yields a data sample for e±p with statistics comparable to those of the best previous measurements. We have shown that we can cleanly identify elastic scattering events and correct for the difference in acceptance for electron and positron scattering. Because we ran with only one polarity for the chicane, we are unable to study the difference between the incoming electron and positron beams. This systematic effect leads to the largest uncertainty in the final ratio of positron to electron scattering: R=1.027±0.005±0.05 for ⟨Q2⟩=0.206 GeV2 and 0.830⩽ε⩽0.943.
Conclusions: We have demonstrated that the tertiary e± beam generated using this technique provides the opportunity for dramatically improved comparisons of e±p scattering, covering a significant range in both Q2 and scattering angle. Combining data with different chicane polarities will allow for detailed studies of the difference between the incoming e+ and e− beams
UBC-Nepal expedition: markedly lower cerebral blood flow in high-altitude Sherpa children compared with children residing at sea level
Developmental cerebral hemodynamic adaptations to chronic high-altitude exposure, such as in the Sherpa population, are largely unknown. To examine hemodynamic adaptations in the developing human brain, we assessed common carotid (CCA), internal carotid (ICA), and vertebral artery (VA) flow and middle cerebral artery (MCA) velocity in 25 (9.6 ± 1.0 yr old, 129 ± 9 cm, 27 ± 8 kg, 14 girls) Sherpa children (3,800 m, Nepal) and 25 (9.9 ± 0.7 yr old, 143 ± 7 cm, 34 ± 6 kg, 14 girls) age-matched sea level children (344 m, Canada) during supine rest. Resting gas exchange, blood pressure, oxygen saturation and heart rate were assessed. Despite comparable age, height and weight were lower (both P < 0.01) in Sherpa compared with sea level children. Mean arterial pressure, heart rate, and ventilation were similar, whereas oxygen saturation (95 ± 2 vs. 99 ± 1%, P < 0.01) and end-tidal Pco2 (24 ± 3 vs. 36 ± 3 Torr, P < 0.01) were lower in Sherpa children. Global cerebral blood flow was ∼30% lower in Sherpa compared with sea level children. This was reflected in a lower ICA flow (283 ± 108 vs. 333 ± 56 ml/min, P = 0.05), VA flow (78 ± 26 vs. 118 ± 35 ml/min, P < 0.05), and MCA velocity (72 ± 14 vs. 88 ± 14 cm/s, P < 0.01). CCA flow was similar between Sherpa and sea level children (425 ± 92 vs. 441 ± 81 ml/min, P = 0.52). Scaling flow and oxygen uptake for differences in vessel diameter and body size, respectively, led to the same findings. A lower cerebral blood flow in Sherpa children may reflect specific cerebral hemodynamic adaptations to chronic hypoxia
Electroexcitation of Nucleon Resonances from CLAS Data on Single Pion Electroproduction
We present results on the electroexcitation of the low mass resonances Δ(1232)P33 , N(1440)P11 , N(1520)D13 , and N(1535)S11 in a wide range of Q2. The results were obtained in the comprehensive analysis of data from the Continuous Electron Beam Accelerator Facility (CEBAF) large acceptance spectrometer (CLAS) detector at the Thomas Jefferson National Accelerator Facility (JLab) on differential cross sections, longitudinally polarized beam asymmetries, and longitudinal target and beam-target asymmetries for π electroproduction off the proton. The data were analyzed using two conceptually different approaches—fixed-t dispersion relations and a unitary isobar model—allowing us to draw conclusions on the model sensitivity of the obtained electrocoupling amplitudes. The amplitudes for the Δ(1232)P33 show the importance of a meson-cloud contribution to quantitatively explain the magnetic dipole strength, as well as the electric and scalar quadrupole transitions. They do not show any tendency of approaching the pQCD regime for Q2⩽6 GeV2 . For the Roper resonance, N(1440)P11, the data provide strong evidence that this state is a predominantly radial excitation of a three-quark (3q) ground state. Measured in pion electroproduction, the transverse helicity amplitude for the N(1535)S11 allowed us to obtain the branching ratios of this state to the πN and ηN channels via comparison with the results extracted from η electroproduction. The extensive CLAS data also enabled the extraction of the γ∗p → N(1520)D13 and N(1535)S11 longitudinal helicity amplitudes with good precision. For the N(1535)S11, these results became a challenge for quark models and may be indicative of large meson-cloud contributions or of representations of this state that differ from a 3q excitation. The transverse amplitudes for the N(1520)D13 clearly show the rapid changeover from helicity-3/2 dominance at the real photon point to helicity-1/2 dominance at Q2 \u3e1 GeV2, confirming a long-standing prediction of the constituent quark model
Functional and molecular profiling of hematopoietic stem cells during regeneration
Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. Although mouse HSCs have been well studied under homeostatic conditions, the mechanisms regulating HSC activation under stress remain unclear. Here, we analyzed the different phases of regeneration after transplantation. We isolated bone marrow from mice at 8 time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs, and progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function, demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence
Functional and molecular profiling of hematopoietic stem cells during regeneration
Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. Although mouse HSCs have been well studied under homeostatic conditions, the mechanisms regulating HSC activation under stress remain unclear. Here, we analyzed the different phases of regeneration after transplantation. We isolated bone marrow from mice at 8 time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs, and progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function, demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence.</p
Functional and molecular profiling of hematopoietic stem cells during regeneration
Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. Although mouse HSCs have been well studied under homeostatic conditions, the mechanisms regulating HSC activation under stress remain unclear. Here, we analyzed the different phases of regeneration after transplantation. We isolated bone marrow from mice at 8 time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs, and progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function, demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence.</p
Photodisintegration of \u3csup\u3e4\u3c/sup\u3eHE into \u3ci\u3ep\u3c/i\u3e+\u3ci\u3et\u3c/i\u3e
The two-body photodisintegration of 4He into a proton and a triton has been studied using the CEBAF Large-Acceptance Spectrometer (CLAS) at the Thomas Jefferson National Accelerator Facility. Real photons produced with the Hall-B bremsstrahlung-tagging system in the energy range from 0.35 to 1.55 GeV were incident on a liquid 4He target. This is the first measurement of the photodisintegration of 4He above 0.4 GeV. The differential cross sections for the γ 4He →pt reaction were measured as a function of photon-beam energy and proton-scattering angle and are compared with the latest model calculations by J.-M. Laget. At 0.6−1.2 GeV, our data are in good agreement only with the calculations that include three-body mechanisms, thus confirming their importance. These results reinforce the conclusion of our previous study of the three-body breakup of 3He that demonstrated the great importance of three-body mechanisms in the energy region 0.5−0.8 GeV
Measurement of Semi-Inclusive π+ Electroproduction Off the Proton
Semi-inclusive π+ electroproduction on protons has been measured with the CLAS detector at Jefferson Lab. The measurement was performed on a liquid-hydrogen target using a 5.75 GeV electron beam. The complete five-fold differential cross sections were measured over a wide kinematic range including the complete range of azimuthal angles between hadronic and leptonic planes, ϕ , enabling us to separate the ϕ-dependent terms. Our measurements of the ϕ -independent term of the cross section at low Bjorken x were found to be in fairly good agreement with pQCD calculations. Indeed, the conventional current fragmentation calculation can account for almost all of the observed cross section, even at small π+ momentum. The measured center-of-momentum spectra are in qualitative agreement with high-energy data, which suggests a surprising numerical similarity between the spectator diquark fragmentation in the present reaction and the antiquark fragmentation measured in e+e− collisions. We have observed that the two ϕ -dependent terms of the cross section are small. Within our precision the cos2ϕ term is compatible with zero, except for the low-z region, and the measured cos ϕ term is much smaller in magnitude than the sum of the Cahn and Berger effects
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