Decomposing Noise in Biochemical Signaling Systems Highlights the Role of Protein Degradation

AbstractStochasticity is an essential aspect of biochemical processes at the cellular level. We now know that living cells take advantage of stochasticity in some cases and counteract stochastic effects in others. Here we propose a method that allows us to calculate contributions of individual reactions to the total variability of a system’s output. We demonstrate that reactions differ significantly in their relative impact on the total noise and we illustrate the importance of protein degradation on the overall variability for a range of molecular processes and signaling systems. With our flexible and generally applicable noise decomposition method, we are able to shed new, to our knowledge, light on the sources and propagation of noise in biochemical reaction networks; in particular, we are able to show how regulated protein degradation can be employed to reduce the noise in biochemical systems

Scaling Properties of the Energy Density in SU(2) Lattice Gauge Theory

The lattice data for the energy density of $SU(2)$ gauge theory are calculated with \nop~derivatives of the coupling constants. These derivatives are obtained from two sources : i) a parametrization of the \nop~beta function in accord with the measured critical temperature and $\Delta\beta-$values and ii) a \nop~calculation of the presssure. We then perform a detailed finite size scaling analysis of the energy density near $T_c$. It is shown that at the critical temperature the energy density is scaling as a function of $VT^3$ with the corresponding $3d$ Ising model critical exponents. The value of $\epsilon(T_c)/T^4_c$ in the continuum limit is estimated to be 0.256(23). In the high temperature regime the energy density is approaching its weak coupling limit from below, at $T/T_c \approx 2$ it has reached only about $70\%$ of the limit.Comment: 15 pages + 9 figures, BI-TP 94/3

Thoracic and Lumbar Vertebral Bone Mineral Density Changes in a Natural Occurring Dog Model of Diffuse Idiopathic Skeletal Hyperostosis

Ankylosing spinal disorders can be associated with alterations in vertebral bone mineral density (BMD). There is however controversy about vertebral BMD in patients wuse idiopathic skeletal hyperostosis (DISH). DISH in Boxer dogs has been considered a natural occurring disease model for DISH in people. The purpose of this study was to compare vertebral BMD between Boxers with and without DISH. Fifty-nine Boxers with (n=30) or without (n=29) DISH that underwent computed tomography were included. Vertebral BMD was calculated for each thoracic and lumbar vertebra by using an earlier reported and validated protocol. For each vertebral body, a region of interest was drawn on the axial computed tomographic images at three separate locations: immediately inferior to the superior end plate, in the middle of the vertebral body, and superior to the inferior end plate. Values from the three axial slices were averaged to give a mean Hounsfield Unit value for each vertebral body. Univariate statistical analysis was performed to identify factors to be included in a multivariate model. The multivariate model including all dogs demonstrated that vertebral DISH status (Coefficient 24.63; 95% CI 16.07 to 33.19; p <0.001), lumbar vertebrae (Coefficient -17.25; 95% CI -23.42 to -11.09; p < 0.01), and to a lesser extent higher age (Coefficient -0.56; 95% CI -1.07 to -0.05; p = 0.03) were significant predictors for vertebral BMD. When the multivariate model was repeated using only dogs with DISH, vertebral DISH status (Coefficient 20.67; 95% CI, 10.98 to 30.37; p < 0.001) and lumbar anatomical region (Coefficient -38.24; 95% CI, -47.75 to -28.73; p < 0.001) were again predictors for vertebral BMD but age was not. The results of this study indicate that DISH can be associated with decreased vertebral BMD. Further studies are necessary to evaluate the clinical importance and pathophysiology of this finding

Collaborative Language Planning Project: Report from First Meeting

Report from the first meeting of the Collaborative Language Planning Project, held May 17, 2018 at the University of Montana\u27s Native American Center

Scaling and Asymptotic Scaling in the SU(2) Gauge Theory

We determine the critical couplings for the deconfinement phase transition in $SU(2)$ gauge theory on $N_\tau \times N_\sigma^3$ lattices with $N_\tau = 8$ and 16 and $N_\sigma$ varying between 16 and 48. A comparison with string tension data shows scaling of the ratio $T_c / \sqrt{\sigma}$ in the entire coupling regime $\beta =2.30-2.75$, while the individual quantities still exhibit large scaling violations. We find $T_c / \sqrt{\sigma}=0.69(2)$. We also discuss in detail the extrapolation of $T_c / Lambda_{\rm{\bar{M} \bar{S}}}$ and $\sqrt{\sigma} / Lambda_{\rm{\bar{M}\bar{S}}}$ to the continuum limit. Our result, which is consistent with the above ratio, is $T_c / Lambda_{\rm{\bar{M}\bar{S}}} = 1.23(11)$ and $\sqrt{\sigma} / Lambda_{\rm{\bar{M}\bar{S}}} = 1.79(12)$. We also comment upon corresponding results for $SU(3)$ gauge theory and four flavour QCD.Comment: 27 pages with 9 postscript figures included. Plain TeX file (needed macros are included). BI-TP 92-26, FSU-SCRI-92-103, HLRZ-92-39 (Quote of UKQCD string tension, and accordingly Figs. 5 and 7a, plus a few typo's corrected.

The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity

Different tissues contain diverse and dynamic cellular niches, providing distinct signals to tissue-resident or migratory infiltrating immune cells. Hedgehog (Hh) proteins are secreted inter-cellular signalling molecules, which are essential during development and are important in cancer, post-natal tissue homeostasis and repair. Hh signalling mediated by the Hh-responsive transcription factor Gli2 also has multiple roles in T-lymphocyte development and differentiation.Here, we investigate the function of Gli2 in T-cell signalling and activation. Gene transcription driven by the Gli2 transcriptional activator isoform (Gli2A) attenuated T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Expression of Gli2A in T-cells altered gene expression profiles, impaired the TCR-induced Ca2+ flux and nuclear expression of NFAT2, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of the AP-1 and NFκB complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFκB activity upon TCR ligation. These data are important for nderstanding the molecular mechanisms of immunomodulation, particularly in tissues where Hh proteins or other Gli-activating ligands such as TGFβ are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments

Intimate Partner Violence and Health Care-Seeking Patterns Among Female Users of Urban Adolescent Clinics

To assess the prevalence of intimate partner violence (IPV) and associations with health care-seeking patterns among female patients of adolescent clinics, and to examine screening for IPV and IPV disclosure patterns within these clinics. A self-administered, anonymous, computerized survey was administered to female clients ages 14–20 years (N = 448) seeking care in five urban adolescent clinics, inquiring about IPV history, reasons for seeking care, and IPV screening by and IPV disclosure to providers. Two in five (40%) female urban adolescent clinic patients had experienced IPV, with 32% reporting physical and 21% reporting sexual victimization. Among IPV survivors, 45% reported abuse in their current or most recent relationship. IPV prevalence was equally high among those visiting clinics for reproductive health concerns as among those seeking care for other reasons. IPV victimization was associated with both poor current health status (AOR 1.57, 95% CI 1.03–2.40) and having foregone care in the past year (AOR 2.59, 95% CI 1.20–5.58). Recent IPV victimization was associated only with past 12 month foregone care (AOR 2.02, 95% CI 1.18–3.46). A minority (30%) reported ever being screened for IPV in a clinical setting. IPV victimization is pervasive among female adolescent clinic attendees regardless of visit type, yet IPV screening by providers appears low. Patients reporting poor health status and foregone care are more likely to have experienced IPV. IPV screening and interventions tailored for female patients of adolescent clinics are needed

A novel class of microRNA-recognition elements that function only within open reading frames.

MicroRNAs (miRNAs) are well known to target 3' untranslated regions (3' UTRs) in mRNAs, thereby silencing gene expression at the post-transcriptional level. Multiple reports have also indicated the ability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function through similar mechanisms regardless of the locations of their sites of action. Here, we report a class of miRNA-recognition elements (MREs) that function exclusively in CDS regions. Through functional and mechanistic characterization of these 'unusual' MREs, we demonstrate that CDS-targeted miRNAs require extensive base-pairing at the 3' side rather than the 5' seed; cause gene silencing in an Argonaute-dependent but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences of miRNAs that target CDS versus the 3' UTR and suggest that CDS-targeted miRNAs may use a translational quality-control-related mechanism to regulate translation in mammalian cells

Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model

The alignment in flavour space of the Yukawa matrices of a general two-Higgs-doublet model results in the absence of tree-level flavour-changing neutral currents. In addition to the usual fermion masses and mixings, the aligned Yukawa structure only contains three complex parameters, which are potential new sources of CP violation. For particular values of these three parameters all known specific implementations of the model based on discrete Z_2 symmetries are recovered. One of the most distinctive features of the two-Higgs-doublet model is the presence of a charged scalar. In this work, we discuss its main phenomenological consequences in flavour-changing processes at low energies and derive the corresponding constraints on the parameters of the aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP. References added. Discussion slightly extended. Conclusions unchange

Covering one eye in fixation-disparity measurement causes slight movement of fellow eye

In the subjective measurement of fixation disparity (FD), the subject fuses contours presented in the peripheral macular areas of both eyes (fusion lock). The position of the eyes relative to each other is monitored by means of two haploscopically seen vertical lines presented in the central macular area, one above and one below a binocularly seen horizontal line. The subject is instructed to shift one of the vertical lines horizontally until the two are aligned, while fixating their intersection with the horizontal line. It has recently been questioned whether the foveolae really are pointed towards the perceived intersection. In this study, we monitored the position of one eye while intermittently covering the fellow eye, while the subject maintained fixation of the intersection of the remaining vertical line and the horizontal line. We found slight differences in position of the measured eye, depending on whether the other eye was covered or not, i.e. depending on the presence or absence of fusion in the macular periphery. These differences were more pronounced in the non-dominant eye