Abstract Recently, we have demonstrated a method to record the longitudinal phase-space distribution of a pulsed cryogenic buffer gas cooled beam of barium fluoride molecules with high resolution. In ...this paper, we use this method to determine the influence of various source parameters. Besides the expected dependence on temperature and pressure, the forward velocity of the molecules is strongly correlated with the time they exit the cell, revealing the dynamics of the gas inside the cell. Three observations are particularly noteworthy: (1) The velocity of the barium fluoride molecules increases rapidly as a function of time, reaches a maximum 50–200 µ s after the ablation pulse and then decreases exponentially. We attribute this to the buffer gas being heated up by the plume of hot atoms released from the target by the ablation pulse and subsequently being cooled down via conduction to the cell walls. (2) The time constant associated with the exponentially decreasing temperature increases when the source is used for a longer period of time, which we attribute to the formation of a layer of isolating dust on the walls of the cell. By thoroughly cleaning the cell, the time constant is reset to its initial value. (3) The velocity of the molecules at the trailing end of the molecular pulse depends on the length of the cell. For short cells, the velocity is significantly higher than expected from the sudden freeze model. We attribute this to the target remaining warm over the duration of the molecular pulse giving rise to a temperature gradient within the cell. Our observations will help to optimize the source parameters for producing the most intense molecular beam at the target velocity.
Regulation of cell and tissue homeostasis by programmed cell death is a fundamental process with wide physiological and pathological implications. The advent of scalable somatic cell genetic ...technologies creates the opportunity to functionally map such essential pathways, thereby identifying potential disease-relevant components. We investigated the genetic basis underlying necroptotic cell death by performing a complementary set of loss-of-function and gain-of-function genetic screens. To this end, we established FADD-deficient haploid human KBM7 cells, which specifically and efficiently undergo necroptosis after a single treatment with either TNFα or the SMAC mimetic compound birinapant. A series of unbiased gene-trap screens identified key signaling mediators, such as TNFR1, RIPK1, RIPK3, and MLKL. Among the novel components, we focused on the zinc transporter SLC39A7, whose knock-out led to necroptosis resistance by affecting TNF receptor surface levels. Orthogonal, solute carrier (SLC)-focused CRISPR/Cas9-based genetic screens revealed the exquisite specificity of SLC39A7, among ~400 SLC genes, for TNFR1-mediated and FAS-mediated but not TRAIL-R1-mediated responses. Mechanistically, we demonstrate that loss of SLC39A7 resulted in augmented ER stress and impaired receptor trafficking, thereby globally affecting downstream signaling. The newly established cellular model also allowed genome-wide gain-of-function screening for genes conferring resistance to necroptosis via the CRISPR/Cas9-based synergistic activation mediator approach. Among these, we found cIAP1 and cIAP2, and characterized the role of TNIP1, which prevented pathway activation in a ubiquitin-binding dependent manner. Altogether, the gain-of-function and loss-of-function screens described here provide a global genetic chart of the molecular factors involved in necroptosis and death receptor signaling, prompting further investigation of their individual contribution and potential role in pathological conditions.
Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium ...infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling. Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in NIK can cause multiple aberrations of lymphoid immunity.
We report on the electrostatic trapping of neutral SrF molecules. The molecules are captured from a cryogenic buffer-gas beam source into the moving traps of a 4.5-m-long traveling-wave Stark ...decelerator. The SrF molecules in X2Σ + ( v = 0 , N = 1 ) state are brought to rest as the velocity of the moving traps is gradually reduced from 190 m / s to zero. The molecules are held for up to 50 ms in multiple electric traps of the decelerator. The trapped packets have a volume (FWHM) of 1 mm3 and a velocity spread of 5 ( 1 ) m / s , which corresponds to a temperature of 60(20) mK. Our result demonstrates a factor 3 increase in the molecular mass that has been Stark decelerated and trapped. Heavy molecules ( mass > 100 amu ) offer a highly increased sensitivity to probe physics beyond the standard model. This work significantly extends the species of neutral molecules of which slow beams can be created for collision studies, precision measurement, and trapping experiments.
Abstract An electrostatic hexapole lens is used to manipulate the transverse properties of a beam of barium fluoride molecules from a cryogenic buffer gas source. The spatial distribution of the beam ...is measured by recording state-selective laser-induced fluorescence on an emccd camera, providing insight into the intensity and transverse position spread of the molecular beam. Although the high mass and unfavorable Stark shift of barium fluoride pose a considerable challenge, the number of molecules in the low-field seeking component of the N = 1 state that pass a 4 mm diameter aperture 712 mm behind the source is increased by a factor of 12. Furthermore, it is demonstrated that the molecular beam can be displaced by up to ±5 mm by moving the hexapole lens. Our measurements agree well with numerical trajectory simulations. We discuss how electrostatic lenses may be used to increase the sensitivity of beam experiments such as the search for the electric dipole moment of the electron.
Antibody diversification requires the DNA deaminase AID to induce DNA instability at immunoglobulin (Ig) loci upon B cell stimulation. For efficient cytosine deamination, AID requires single-stranded ...DNA and needs to gain access to Ig loci, with RNA pol II transcription possibly providing both aspects. To understand these mechanisms, we isolated and characterized endogenous AID-containing protein complexes from the chromatin of diversifying B cells. The majority of proteins associated with AID belonged to RNA polymerase II elongation and chromatin modification complexes. Besides the two core polymerase subunits, members of the PAF complex, SUPT5H, SUPT6H, and FACT complex associated with AID. We show that AID associates with RNA polymerase-associated factor 1 (PAF1) through its N-terminal domain, that depletion of PAF complex members inhibits AID-induced immune diversification, and that the PAF complex can serve as a binding platform for AID on chromatin. A model is emerging of how RNA polymerase II elongation and pausing induce and resolve AID lesions.
Electro-optic sensor for static fields Grasdijk, J. O.; Bai, X. F.; Engin, I. ...
Applied physics. B, Lasers and optics,
11/2019, Letnik:
125, Številka:
11
Journal Article
Recenzirano
Odprti dostop
A sensor has been developed for low frequency and DC electric fields
E
. The device is capable of measuring fields with
Δ
E
=
4
(1) V/cm resolution. It is based on a Y-cut Z-propagation lithium ...niobate electro-optic crystal. For a particular commercially available bare crystal, we achieved an in air time constant
τ
c
(
a
i
r
)
=
6.4
(
1.8
)
h for the decay of the electro-optic signal. This enables field monitoring for several hours. As an application, we demonstrated that a constant electric field
E
ext
=
640
V/cm applied via external electrodes to a particular spherical glass container holding an Xe/He gas mixture decays inside this cell with a time constant
τ
E
glass
=
2.5
(
5
)
h. This is sufficient for the needs of experiments searching for a permanent electric dipole moment in
129
Xe. An integrated electric field sensor has been constructed which is coupled to a light source and light detectors via optical fibers. The sensor head does not contain any electrically conducting material.
The article “Electro-optic sensor for static fields”, written by “J. O. Grasdijk, X. F. Bai, I. Engin, K. Jungmann, H. J. Krause, B. Niederländer, A. Off enhäuser, M. Repetto, L. Willmann, S. Zimmer
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