49 research outputs found
Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation
Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Rα on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation
Distinct Roles of ComK1 and ComK2 in Gene Regulation in Bacillus cereus
The B. subtilis transcriptional factor ComK regulates a set of genes coding for DNA uptake from the environment and for its integration into the genome. In previous work we showed that Bacillus cereus expressing the B. subtilis ComK protein is able to take up DNA and integrate it into its own genome. To extend our knowledge on the effect of B. subtilis ComK overexpression in B. cereus we first determined which genes are significantly altered. Transcriptome analysis showed that only part of the competence gene cluster is significantly upregulated. Two ComK homologues can be identified in B. cereus that differ in their respective homologies to other ComK proteins. ComK1 is most similar, while ComK2 lacks the C-terminal region previously shown to be important for transcription activation by B. subtilis ComK. comK1 and comK2 overexpression and deletion studies using transcriptomics techniques showed that ComK1 enhances and ComK2 decreases expression of the comG operon, when B. subtilis ComK was overexpressed simultaneously
TESS Hunt for Young and Maturing Exoplanets (THYME). III. A Two-planet System in the 400 Myr Ursa Major Group
Exoplanets can evolve significantly between birth and maturity as their
atmospheres, orbits, and structures are shaped by their environment. Young
planets (1 Gyr) offer the opportunity to probe these sculpting processes.
However, most of the known young planets orbit prohibitively faint stars. We
present the discovery of two planets transiting HD 63433 (TOI 1726, TIC
130181866), a young Sun-like () star. Through kinematics,
lithium abundance, and rotation, we confirm that HD 63433 is a member of the
Ursa Major moving group ( Myr). Based on the TESS light curve
and updated stellar parameters, the planet radii are and
, the orbital periods are 7.11 and 20.55 days, and the
orbital eccentricities are lower than abut 0.2. Using HARPS-N velocities, we
measure the Rossiter-McLaughlin signal of the inner planet, demonstrating the
orbit is prograde. Since the host star is bright (V=6.9), both planets are
amenable to transmission spectroscopy, radial velocity measurements of their
masses, and more precise determination of the stellar obliquity. This system is
therefore poised to play an important role in our understanding of planetary
system evolution in the first billion years after formation
TOI-1634 b: An Ultra-short-period Keystone Planet Sitting inside the M-dwarf Radius Valley
Studies of close-in planets orbiting M dwarfs have suggested that the M dwarf
radius valley may be well-explained by distinct formation timescales between
enveloped terrestrials, and rocky planets that form at late times in a
gas-depleted environment. This scenario is at odds with the picture that
close-in rocky planets form with a primordial gaseous envelope that is
subsequently stripped away by some thermally-driven mass loss process. These
two physical scenarios make unique predictions of the rocky/enveloped
transition's dependence on orbital separation such that studying the
compositions of planets within the M dwarf radius valley may be able to
establish the dominant physics. Here, we present the discovery of one such
keystone planet: the ultra-short period planet TOI-1634 b ( days,
, ) orbiting a
nearby M2 dwarf (, , ) and
whose size and orbital period sit within the M dwarf radius valley. We confirm
the TESS-discovered planet candidate using extensive ground-based follow-up
campaigns, including a set of 32 precise radial velocity measurements from
HARPS-N. We measure a planetary mass of ,
which makes TOI-1634 b inconsistent with an Earth-like composition at
and thus requires either an extended gaseous envelope, a large
volatile-rich layer, or a rocky portion that is not dominated by iron and
silicates to explain its mass and radius. The discovery that the bulk
composition of TOI-1634 b is inconsistent with that of the Earth favors the
gas-depleted formation mechanism to explain the emergence of the radius valley
around M dwarfs with
Toi-1235 b: A keystone super-earth for testing radius valley emergence models around early m dwarfs
Small planets on close-in orbits tend to exhibit envelope mass fractions of
either effectively zero or up to a few percent depending on their size and
orbital period. Models of thermally-driven atmospheric mass loss and of
terrestrial planet formation in a gas-poor environment make distinct
predictions regarding the location of this rocky/non-rocky transition in
period-radius space. Here we present the confirmation of TOI-1235 b (
days, R), a planet whose size and
period are intermediate between the competing model predictions, thus making
the system an important test case for emergence models of the rocky/non-rocky
transition around early M dwarfs ( R,
M). We confirm the TESS planet discovery using
reconnaissance spectroscopy, ground-based photometry, high-resolution imaging,
and a set of 38 precise radial-velocities from HARPS-N and HIRES. We measure a
planet mass of M which implies an iron core
mass fraction of % in the absence of a gaseous envelope. The
bulk composition of TOI-1235 b is therefore consistent with being Earth-like
and we constrain a H/He envelope mass fraction to be % at 90% confidence.
Our results are consistent with model predictions from thermally-driven
atmospheric mass loss but not with gas-poor formation, which suggests that the
former class of processes remain efficient at sculpting close-in planets around
early M dwarfs. Our RV analysis also reveals a strong periodicity close to the
first harmonic of the photometrically-determined stellar rotation period that
we treat as stellar activity, despite other lines of evidence favoring a
planetary origin ( days,
M) that cannot be firmly ruled out by our data
Selective Reduction of Post-Selection CD8 Thymocyte Proliferation in IL-15Rα Deficient Mice
Peripheral CD8+ T cells are defective in both IL-15 and IL-15Rα knock-out (KO) mice; however, whether IL-15/IL-15Rα deficiency has a similar effect on CD8 single-positive (SP) thymocytes remains unclear. In this study, we investigated whether the absence of IL-15 transpresentation in IL-15Rα KO mice results in a defect in thymic CD8 single positive (SP) TCRhi thymocytes. Comparison of CD8SP TCRhi thymocytes from IL-15Rα KO mice with their wild type (WT) counterparts by flow cytometry showed a significant reduction in the percentage of CD69− CD8SP TCRhi thymocytes, which represent thymic premigrants. In addition, analysis of in vivo 5-bromo-2-deoxyuridine (BrdU) incorporation demonstrated that premigrant expansion of CD8SP TCRhi thymocytes was reduced in IL-15Rα KO mice. The presence of IL-15 transpresentation-dependent expansion in CD8SP TCRhi thymocytes was assessed by culturing total thymocytes in IL-15Rα-Fc fusion protein-pre-bound plates that were pre-incubated with IL-15 to mimic IL-15 transpresentation in vitro. The results demonstrated that CD8SP thymocytes selectively outgrew other thymic subsets. The contribution of the newly divided CD8SP thymocytes to the peripheral CD8+ T cell pool was examined using double labeling with intrathymically injected FITC and intravenously injected BrdU. A marked decrease in FITC+ BrdU+ CD8+ T cells was observed in the IL-15Rα KO lymph nodes. Through these experiments, we identified an IL-15 transpresentation-dependent proliferation process selective for the mature CD8SP premigrant subpopulation. Importantly, this process may contribute to the maintenance of the normal peripheral CD8+ T cell pool
Like mother, like child : investigating perinatal and maternal health stress in post-medieval London.
Post-Medieval London (sixteenth-nineteenth centuries) was a stressful environment for the poor. Overcrowded and squalid housing, physically demanding and risky working conditions, air and water pollution, inadequate diet and exposure to infectious diseases created high levels of morbidity and low life expectancy. All of these factors pressed with particular severity on the lowest members of the social strata, with burgeoning disparities in health between the richest and poorest. Foetal, perinatal and infant skeletal remains provide the most sensitive source of bioarchaeological information regarding past population health and in particular maternal well-being. This chapter examined the evidence for chronic growth and health disruption in 136 foetal, perinatal and infant skeletons from four low-status cemetery samples in post-medieval London. The aim of this study was to consider the impact of poverty on the maternal-infant nexus, through an analysis of evidence of growth disruption and pathological lesions. The results highlight the dire consequences of poverty in London during this period from the very earliest moments of life