Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

It has long been recognized that the T-cell compartment has more CD4 helper than CD8 cytotoxic T cells, and this is most evident looking at T-cell development in the thymus. However, it remains unknown how thymocyte development so favors CD4 lineage development. To identify the basis of this asymmetry, we analyzed development of synchronized cohorts of thymocytes in vivo and estimated rates of thymocyte death and differentiation throughout development, inferring lineage-specific efficiencies of selection. Our analysis suggested that roughly equal numbers of cells of each lineage enter selection and found that, overall, a remarkable ∼75% of cells that start selection fail to complete the process. Importantly it revealed that class I-restricted thymocytes are specifically susceptible to apoptosis at the earliest stage of selection. The importance of differential apoptosis was confirmed by placing thymocytes under apoptotic stress, resulting in preferential death of class I-restricted thymocytes. Thus, asymmetric death during selection is the key determinant of the CD4:CD8 ratio in which T cells are generated by thymopoiesis

Bogoliubov excitation spectrum of an elongated condensate from quasi-one-dimensional to three-dimensional transition

The quasiparticle excitation spectra of a Bose gas trapped in a highly anisotropic trap is studied with respect to varying total number of particles by numerically solving the effective one-dimensional (1D) Gross-Pitaevskii (GP) equation proposed recently by Mateo \textit{et al.}. We obtain the static properties and Bogoliubov spectra of the system in the high energy domain. This method is computationally efficient and highly accurate for a condensate system undergoing a 1D to three-dimensional (3D) cigar-shaped transition, as is shown through a comparison our results with both those calculated by the 3D-GP equation and analytical results obtained in limiting cases. We identify the applicable parameter space for the effective 1D-GP equation and find that this equation fails to describe a system with large number of atoms. We also identify that the description of the transition from 1D Bose-Einstein condensate (BEC) to 3D cigar-shaped BEC using this equation is not smooth, which highlights the fact that for a finite value of $a_\perp/a_s$ the junction between the 1D and 3D crossover is not perfect.Comment: 17 pages, 6 figure

History and the Boundaries of Legality: Historical Evidence at the ECCC

The Extraordinary Chambers in the Courts of Cambodia (ECCC) are marked by the amount of time that has elapsed between the fall of Democratic Kampuchea in 1979 and the creation of the tribunal. Does this passage of time matter? There are obvious practical reasons why it does: suspects die, witnesses die or have their memories fade, documents are lost and found, theories of accountability gain or lose currency within the broader public. And yet, formally, the mechanisms of criminal justice continue to operate despite the intervening years. The narrow jurisdiction limits the court’s attention to the events of 1975–1979, and potential evidence must meet legal requirements of relevance in order to be admissible. Beyond the immediate questions of the quality of the evidence, does history matter? Should it? One answer is that this history is largely irrelevant to the legal questions at issue. In this view, the events of Democratic Kampuchea from 1975–1979 can be tried without reference to the events of the intervening years. The facts relating to the crimes stand on their own, and the legal theories relate strictly to those facts and events. This approach would find nothing in particular to distinguish the operations of the ECCC from those of any other tribunal, save for the unfortunate problem of mortality and imperfect memory. Another possible (and plausible) answer is that the extralegal influence of history is comparable in kind to the extralegal influence of political interference — a matter of obvious and sustained concern at the ECCC. In this theory, advanced by several of the defense counsel, the evidence from 1975–1979 must be read in light of intervening events, which include the years of Vietnamese occupation, the collection of documentary evidence as part of an attempt to hold Khmer Rouge leaders accountable, and the stranglehold that the Heng Samrin–Hun Sen line of leadership has had over Cambodian political life. This historical gloss suggests the need for skepticism in reading evidence, and may even raise the question of what has been omitted (intentionally or unintentionally) from the documentary record. In this telling, the influence of history is effectively the accumulation of years of political interference, culminating in the well-known suspicions of interference on the Cambodian side of the court. I argue for a third understanding of the role of history, which neither reads it out through a single-minded focus on the face of the evidence, nor vests it with the power of thorough corruption. I argue instead that an understanding of the historical context of the court and of the evidence that is presented before it reframes the basic relationship between the court and Cambodian society. For, despite the differences between the two previous accountings of history, both insist on maintaining a strict boundary between the legal procedure of the court and the extralegal influences of society—the first version, in order to insist that the court can repel these influences; the second version, in order to insist that the court cannot. But this insistence on absolutism ignores the facts that the court is itself an actor in the drama of Cambodian history, a product of both domestic and international politics, and that just as attempts to determine accountability in civil society occur in the shadow of the law, so too are attempts to ground judicial fact-finding in robust historical accounts inevitably shaped by a wider historical discourse.Harvard Law School 2013 Student Writing Prize: Yong K. Kim '95 Memorial Priz

Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection

Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations; one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions; and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T and T are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable-sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T and T development

Computably enumerable Turing degrees and the meet property

Working in the Turing degree structure, we show that those degrees which contain computably enumerable sets all satisfy the meet property, i.e. if a is c.e. and b < a, then there exists non-zero m < a with b ^m = 0. In fact, more than this is true: m may always be chosen to be a minimal degree. This settles a conjecture of Cooper and Epstein from the 80s

Tracking and stress-testing U.S. household leverage

Borrowers' housing equity is an important component of their wealth and a critical determinant of their vulnerability to shocks. In this paper, we create a unique data set that allows us to provide a comprehensive look at the ratio of housing debt to housing values - what we refer to as household leverage - at the micro level. An advantage of our data is that we are able to study the evolution of household leverage over time and across locations in the United States. We find that leverage was at a very low point just prior to the large declines in house prices that began in 2006, but it rose very quickly thereafter, despite reductions in housing debt. As of late 2015, leverage statistics are approaching their pre-crisis levels, as house prices have risen over 30 percent nationally since 2012. We use our borrower-level leverage measures and another unique feature of our data - updated borrower credit scores - to conduct "stress tests": projecting leverage and defaults under various adverse house price scenarios. We find that while the riskiness of the household sector has declined significantly since 2012, it remains vulnerable to very severe declines in house prices

Transcranial direct current stimulation of the motor cortex in the treatment of chronic non-specific low back pain. A randomised, double-blind exploratory study

This exploratory study aimed to test the proof of principle that active anodal transcranial direct current stimulation (tDCS) applied to the motor cortex reduces pain significantly more than sham stimulation in a group of participants with chronic non-specific low back pain

The Absolute Magnitude of RRc Variables From Statistical Parallax

We present the first definitive measurement of the absolute magnitude of RR Lyrae c-type variable stars (RRc) determined purely from statistical parallax. We use a sample of 247 RRc selected from the All Sky Automated Survey (ASAS) for which high-quality light curves, photometry and proper motions are available. We obtain high-resolution echelle spectra for these objects to determine radial velocities and abundances as part of the Carnegie RR Lyrae Survey (CARRS). We find that M_(V,RRc) = 0.52 +/- 0.11 at a mean metallicity of [Fe/H] = -1.59. This is to be compared with previous estimates for RRab stars (M_(V,RRab) = 0.75 +/- 0.13 and the only direct measurement of an RRc absolute magnitude (RZ Cephei, M_(V, RRc) = 0.27 +/- 0.17). We find the bulk velocity of the halo to be (W_pi, W_theta, W_z) = (10.9,34.9,7.2) km/s in the radial, rotational and vertical directions with dispersions (sigma_(W_pi), sigma_(W_theta), sigma_(W_z)) = (154.7, 103.6, 93.8) km/s. For the disk, we find (W_pi, W_theta, W_z) = (8.5, 213.2, -22.1) km/s with dispersions (sigma_(W_pi), sigma_(W_theta), sigma_(W_z)) = (63.5, 49.6, 51.3) km/s. Finally, we suggest that UCAC2 proper motion errors may be overestimated by about 25%Comment: Submitted to ApJ. 11 pages including 6 figure