1,279 research outputs found
The Rules of Human T Cell Fate in vivo.
The processes governing lymphocyte fate (division, differentiation, and death), are typically assumed to be independent of cell age. This assumption has been challenged by a series of elegant studies which clearly show that, for murine cells in vitro, lymphocyte fate is age-dependent and that younger cells (i.e., cells which have recently divided) are less likely to divide or die. Here we investigate whether the same rules determine human T cell fate in vivo. We combined data from in vivo stable isotope labeling in healthy humans with stochastic, agent-based mathematical modeling. We show firstly that the choice of model paradigm has a large impact on parameter estimates obtained using stable isotope labeling i.e., different models fitted to the same data can yield very different estimates of T cell lifespan. Secondly, we found no evidence in humans in vivo to support the model in which younger T cells are less likely to divide or die. This age-dependent model never provided the best description of isotope labeling; this was true for naĂŻve and memory, CD4+ and CD8+ T cells. Furthermore, this age-dependent model also failed to predict an independent data set in which the link between division and death was explored using Annexin V and deuterated glucose. In contrast, the age-independent model provided the best description of both naĂŻve and memory T cell dynamics and was also able to predict the independent dataset
Contemporary medical television and crisis in the NHS
This article maps the terrain of contemporary UK medical television, paying particular attention to Call the Midwife as its centrepiece, and situating it in contextual relation to the current crisis in the NHS. It provides a historical overview of UK and US medical television, illustrating how medical television today has been shaped by noteworthy antecedents. It argues that crisis rhetoric surrounding healthcare leading up to the passing of the Health and Social Care Act 2012 has been accompanied by a renaissance in medical television. And that issues, strands and clusters have emerged in forms, registers and modes with noticeable regularity, especially around the value of affective labour, the cultural politics of nostalgia and the neoliberalisation of healthcare
On the multiphoton ionisation photoelectron spectra of phenol
The phenol molecule is a prototype for non-adiabatic dynamics and the excited-state photochemistry of biomolecules. In this article, we report a joint theoretical and experimental investigation on the resonance enhanced multiphoton ionisation photoelectron (REMPI) spectra of the two lowest ionisation bands of phenol. The focus is on the theoretical interpretation of the measured spectra using quantum dynamics simulations. These were performed by numerically solving the time-dependent Schrödinger equation using the multi-layer variant of the multiconfiguration time-dependent Hartree algorithm together with a vibronic coupling Hamiltonian model. The ionising laser pulse is modelled explicitly within the ionisation continuum model to simulate experimental femtosecond 1+1 REMPI photoelectron spectra. These measured spectra are sensitive to very short lived electronically excited states, providing a rigorous benchmark for our theoretical methods. The match between experiment and theory allows for an interpretation of the features of the spectra at different wavelengths and shows that there are features due to both 'direct' and 'indirect' ionisation, resulting from non-resonant and resonant excitation by the pump pulse
Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia
Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab substantially reduce lowâdensity lipoprotein cholesterol (LDLâC) when added to statin therapy in patients who need additional LDLâC reduction.
Methods and Results: We conducted a systematic review and network metaâanalysis of randomized trials of lipidâlowering therapies from database inception through August 2016 (45 058 records retrieved). We found 69 trials of lipidâlowering therapies that enrolled patients requiring further LDLâC reduction while on maximally tolerated mediumâ or highâintensity statin, of which 15 could be relevant for inclusion in LDLâC reduction networks with evolocumab, alirocumab, ezetimibe, and placebo as treatment arms. PCSK9 inhibitors significantly reduced LDLâC by 54% to 74% versus placebo and 26% to 46% versus ezetimibe. There were significant treatment differences for evolocumab 140 mg every 2 weeks at the mean of weeks 10 and 12 versus placebo (â74.1%; 95% credible interval â79.81% to â68.58%), alirocumab 75 mg (â20.03%; 95% credible interval â27.32% to â12.96%), and alirocumab 150 mg (â13.63%; 95% credible interval â22.43% to â5.33%) at â„12 weeks. Treatment differences were similar in direction and magnitude for PCSK9 inhibitor monthly dosing. Adverse events were similar between PCSK9 inhibitors and control. Rates of adverse events were similar between PCSK9 inhibitors versus placebo or ezetimibe.
Conclusions: PCSK9 inhibitors added to mediumâ to highâintensity statin therapy significantly reduce LDLâC in patients requiring further LDLâC reduction. The network metaâanalysis showed a significant treatment difference in LDLâC reduction for evolocumab versus alirocumab
Multi-electron giant dipole resonances of atoms in crossed electric and magnetic fields
Multi-electron giant dipole resonances of atoms in crossed electric and
magnetic fields are investigated. Stationary configurations corresponding to a
highly symmetric arrangement of the electrons on a decentered circle are
derived, and a normal-mode stability analysis is performed. A classification of
the various modes, which are dominated either by the magnetic or Coulomb
interactions, is provided. A six-dimensional wave-packet dynamical study, based
on the MCTDH approach, is accomplished for the two-electron resonances,
yielding in particular lifetimes of more than 0.1 s for strong electric
fields.Comment: 7 pages, 3 figure
How electronic superpositions drive nuclear motion following the creation of a localized hole in the glycine radical cation
In this work we have studied the nuclear and electron dynamics in the glycine cation starting from localized hole states, using the Quantum Ehrenfest (QuEh) method. The nuclear dynamics is controlled both by the initial gradient and by the instantaneous gradient that results from the oscillatory electron dynamics (charge migration). We have used the Fourier transform (FT) of the spin densities to identify the normal modes of the electron dynamics. We observe an isomorphic relationship between the electron dynamics normal modes (ED-NM) and the nuclear dynamics, seen in the vibrational normal modes (Vib-NM). The FT spectra obtained this way show bands that are characteristic of the energy differences between the adiabatic hole states. These bands contain individual peaks that are in one-to-one correspondence with atom pair (+ âą) â(âą +) resonances (APR), which in turn stimulate nuclear motion involving the atom pair. With such understanding we anticipate 'designer' coherent superpositions that can drive nuclear motion in a particular direction
Effect of stem cell source on long-term chimerism and event-free survival in children with primary immunodeficiency disorders after fludarabine and melphalan conditioning regimen
BACKGROUND: Reduced-intensity conditioning (RIC) regimens are increasingly being used in the transplantation of patients with primary immunodeficiency disorders (PIDs), but there are no large studies looking at long-term lineage-specific chimerism.
OBJECTIVES: We sought to analyze long-term chimerism and event-free survival in children undergoing transplantation for PIDs using RIC with fludarabine and melphalan (Flu/Melph) and to study the effect of donor type and stem cell source.
METHODS: One hundred forty-two children underwent transplantation with RIC by using Flu/Melph and for PIDs by using bone marrow (n = 93) or peripheral blood stem cells (PBSCs; n = 49). Donors were matched unrelated donors (n = 72), mismatched unrelated donors (n = 37), matched sibling donors (n = 14), matched family donors (n = 12), and mismatched family donors (n = 7).
RESULTS: Overall survival at a median follow-up of 7.5 years was 78%, irrespective of stem cell source or donor type. When bone marrow was used as the stem cell source, 26% of patients ended up with very low levels of donor chimerism (50% donor chimerism) in all lineages.
CONCLUSIONS: On the basis of our experience, we would suggest that PBSCs should be the stem cell source of choice in children with PIDs undergoing transplantation with Flu/Melph RIC from a matched donor source. This is most likely to ensure sustained high-level donor chimerism
Threshold Photoelectron Spectrum of Cyclobutadiene: Comparison with Time-Dependent Wavepacket Simulations
The C4H4 isomer cyclobutadiene (CBD) is the prime model for antiaromaticity and thus a molecule of considerable interest in chemistry. Because it is highly reactive, it can only be studied under isolated conditions. Its electronic structure is characterized by a pseudo-JahnâTeller effect in the neutral and a E â ÎČ JahnâTeller effect in the cation. As a result, recording photoelectron spectra as well as describing them theoretically has been challenging. Here we present the photoion mass-selected threshold photoelectron spectrum of cyclobutadiene together with a simulation based on time-dependent wavepacket dynamics that includes vibronic coupling in the ion, taking into account eight vibrational modes in the cation. Excellent agreement between theory and experiment is found, and the ionization energy is revised to 8.06 ± 0.02 eV
Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience
Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency with an HLA-matched sibling donor (MSD) or family donor (MFD). Improved overall survival (OS) has been reported compared to the use of unrelated donors, and previous studies have demonstrated that adequate cellular and humoral immune recovery can be achieved even in the absence of conditioning. Detailed insight of the long-term outcome is still limited. We aim to address this by studying a large single-center cohort of 28 adenosine deaminase-deficient patients who underwent a total of 31 HSCT procedures, of which more than half were unconditioned. We report an OS of 85.7% and event-free survival of 71% for the entire cohort, with no statistically significant differences after procedures using related or unrelated HLA-matched donors. We find that donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which typically use a MSD or MFD. This is associated with poor metabolic correction and more frequent failure to discontinue immunoglobulin replacement therapy. Approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced intensity conditioning (RIC) prior to allogeneic transplantation improves the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction. Further longitudinal studies are needed to optimize future management and guidelines, but our findings support a potential role for the routine use of RIC in most ADA-deficient patients receiving an HLA-identical hematopoietic stem cell transplant, even when a MSD or MFD is available
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