Important roles of multiple Sp1 binding sites and epigenetic modifications in the regulation of the methionine sulfoxide reductase B1 (MsrB1) promoter

<p>Abstract</p> <p>Background</p> <p>Methionine sulfoxide reductases (Msrs) are enzymes that catalyze the reduction of oxidized methionine residues. Most organisms that were genetically modified to lack the <it>MsrA </it>gene have shown shortening of their life span. Methionine sulfoxide reductases B (MsrB) proteins codified by three separate genes, named <it>MsrB1</it>, <it>MsrB2</it>, and <it>MsrB3</it>, are included in the Msrs system. To date, the mechanisms responsible for the transcriptional regulation of <it>MsrB </it>genes have not been reported. The aim of this study was to investigate the regulation of MsrB1 selenoprotein levels through transcriptional regulation of the <it>MsrB1 </it>gene in MDA-MB231 and MCF-7 breast carcinoma cell lines.</p> <p>Results</p> <p>A <it>MsrB1 </it>gene promoter is located 169 base pairs upstream from the transcription start site. It contains three Sp1 binding sites which are sufficient for maximal promoter activity in transient transfection experiments.</p> <p>High levels of MsrB1 transcript, protein and promoter activity were detected in low metastatic MCF7 human breast cancer cells. On the contrary, very low levels of both MsrB1 transcript and promoter activity were detected in the highly metastatic counterpart MDA-MB231 cells.</p> <p>A pivotal role for Sp1 in the constitutive expression of the <it>MsrB1 </it>gene was demonstrated through transient expression of mutant <it>MsrB1 </it>promoter-reporter gene constructs and chromatin immunoprecipitation experiments.</p> <p>Since Sp1 is ubiquitously expressed, these sites, while necessary, are not sufficient to explain the patterns of gene expression of <it>MsrB1 </it>in various human breast cancer cells. MDA-MB231 cells can be induced to express MsrB1 by treatment with 5-Aza-2'-deoxycytidine, a demethylating agent. Therefore, the <it>MsrB1 </it>promoter is controlled by epigenetic modifications.</p> <p>Conclusion</p> <p>The results of this study provide the first insights into the transcriptional regulation of the human <it>MsrB1 </it>gene, including the discovery that the Sp1 transcription factor may play a central role in its expression. We also demonstrated that the <it>MsrB1 </it>promoter activity appears to be controlled by epigenetic modifications such as methylation.</p

CMB 3-point functions generated by non-linearities at recombination

We study the 3-point functions generated at recombination in the squeezed triangle limit, when one mode has a wavelength much larger than the other two and is outside the horizon. The presence of the long wavelength mode cannot change the physics inside the horizon but modifies how a late time observer sees the anisotropies. The effect of the long wavelength mode can be divided into a redefinition of time and spatial scales, a Shapiro time delay and gravitational lensing. The separation is gauge dependent but helps develop intuition. We show that the resulting 3-point function corresponds to an f_NL < 1 and that its shape is different from that created by the f_NL (or local) model.Comment: 16 pages, 4 figures. Expanded introduction of sec.2. Published versio

Galilean symmetry in the effective theory of inflation: new shapes of non-Gaussianity

We study the consequences of imposing an approximate Galilean symmetry on the Effective Theory of Inflation, the theory of small perturbations around the inflationary background. This approach allows us to study the effect of operators with two derivatives on each field, which can be the leading interactions due to non-renormalization properties of the Galilean Lagrangian. In this case cubic non-Gaussianities are given by three independent operators, containing up to six derivatives, two with a shape close to equilateral and one peaking on flattened isosceles triangles. The four-point function is larger than in models with small speed of sound and potentially observable with the Planck satellite.Comment: 23 pages, 6 figures. v2: minor changes to match JCAP published versio

A multi-state analysis of disease trajectories and mental health transitions in patients with type 2 diabetes: A population-based retrospective cohort study utilizing health administrative data

Aims: To investigate the risk of major depression and dementia in patients with type 2 diabetes, including dementia resulting from depression, and their impact on diabetes-related complications and mortality. Methods: We conducted a population-based retrospective cohort study including 11,441 incident cases of diabetes in 2015-2017, with follow-up until 2022. A multi-state survival analysis was performed on a seven-state model with 15 transitions to capture disease progression and onset of mental disorders. Results: Eight-year probabilities of depression, dementia, diabetes-related complications, and death were 9.7% (95% CI 8.7-10.7), 0.9% (95% CI 0.5-1.3), 10.4% (95% CI 9.5-11.4), and 14.8% (95% CI 13.9-15.7), respectively. Depression increased the risk of dementia up to 3.7% (95% CI 2.0-5.4), and up to 10.3% (95% CI 0.3-20.4) if coupled with diabetes complications. Eight-year mortality was 37.5% (95% CI 33.1-42.0) after depression, 74.1% (95% CI 63.7-84.5) after depression plus complications, 76.4% (95% CI 68.8-83.9) after dementia, and 98.6% (95% CI 96.1-100.0) after dementia plus complications. Conclusions: The interconnections observed across depression, dementia, complications, and mortality underscore the necessity for comprehensive and integrated approaches in managing diabetes. Early screening for depression, followed by timely and targeted interventions, may mitigate the risk of dementia and improve diabetes prognosis

Multi-disciplinary Consensus Statement Document Vaccinal prevention in adult patients with diabetes mellitus

open8noopenIcardi G.; Francia F.; Di Bartolo P.; Mannino D.; Alti E.; Purrello F.; Sesti G.; Sessa A.Icardi, G.; Francia, F.; Di Bartolo, P.; Mannino, D.; Alti, E.; Purrello, F.; Sesti, G.; Sessa, A

The CMB bispectrum in the squeezed limit

The CMB bispectrum generated by second-order effects at recombination can be calculated analytically when one of the three modes has a wavelength much longer than the other two and is outside the horizon at recombination. This was pointed out in \cite{Creminelli:2004pv} and here we correct their results. We derive a simple formula for the bispectrum, $f_{NL}^{loc} = - (1/6+ \cos 2 \theta) \cdot (1- 1/2 \cdot d \ln (l_S^2 C_{S})/d \ln l_S)$, where $C_S$ is the short scale spectrum and $\theta$ the relative orientation between the long and the short modes. This formula is exact and takes into account all effects at recombination, including recombination-lensing, but neglects all late-time effects such as ISW-lensing. The induced bispectrum in the squeezed limit is small and will negligibly contaminate the Planck search for a local primordial signal: this will be biased only by $f_{NL}^{loc}\approx-0.4$. The above analytic formula includes the primordial non-Gaussianity of any single-field model. It also represents a consistency check for second-order Boltzmann codes: we find substantial agreement with the CMBquick code.Comment: 20 pages, 4 figures, corrected typos to match published version on JCA

Synthesis of Imidazolidin-2-ones and Imidazol-2-ones via Base-Catalyzed Intramolecular Hydroamidation of Propargylic Ureas under Ambient Conditions

The first organo-catalyzed synthesis of imidazolidin-2-ones and imidazol-2-ones via intramolecular hydroamidation of propargylic ureas is reported. The phosphazene base BEMP turned out to be the most active organo-catalyst compared with guanidine and amidine bases. Excellent chemo- and regioselectivities to five-membered cyclic ureas have been achieved under ambient conditions, with a wide substrate scope and exceptionally short reaction times (down to 1 min). A base-mediated isomerization step to an allenamide intermediate is the most feasible reaction pathway to give imidazol-2-ones, as suggested by DFT studies

The role of late adolescents' emotion regulation in the experience of COVID-19 lockdown: A longitudinal study

The COVID-19 pandemic may be considered a unique mass-trauma experience. This study examined the relations between Italian late adolescents' emotion regulation strategies, their anxiety states, and their experience of the lockdown (in terms of discomfort related to restrictions, capacities to create new functional daily routines, and to find positive changes in one's own life) during the first wave of this pandemic. We analysed how participants' reports of cognitive reappraisal and expressive suppression were associated with anxiety states during the 2020 Italian COVID-19 lockdown (large scale physical distancing and movement restrictions) and one month after the lockdown restrictions had been removed. We also examined how cognitive reappraisal, expressive suppression, and anxiety states were linked to late adolescents' experience of lockdown. The participants were 497 Italian adolescents, aged from 17 to 24&nbsp;years (Mage &nbsp;=&nbsp;21.11, SD&nbsp;=&nbsp;1.83). A longitudinal structural equation modelling showed that emotion regulation strategies and anxiety states were not associated across time. Cognitive reappraisal was positively associated with routine reorganization and positive changes. In contrast, participants' expressive suppression was negatively related to their discomfort related to restrictions, ability to functionally reorganise their daily routine, and ability to find positive changes related to the COVID-19 emergency. Anxiety was positively linked to discomfort related to restrictions. The findings are discussed in light of the current literature related to emotion regulation and anxiety. Limitations and implications for practice are presented

Estimators for local non-Gaussianities

We study the Likelihood function of data given f_NL for the so-called local type of non-Gaussianity. In this case the curvature perturbation is a non-linear function, local in real space, of a Gaussian random field. We compute the Cramer-Rao bound for f_NL and show that for small values of f_NL the 3-point function estimator saturates the bound and is equivalent to calculating the full Likelihood of the data. However, for sufficiently large f_NL, the naive 3-point function estimator has a much larger variance than previously thought. In the limit in which the departure from Gaussianity is detected with high confidence, error bars on f_NL only decrease as 1/ln Npix rather than Npix^-1/2 as the size of the data set increases. We identify the physical origin of this behavior and explain why it only affects the local type of non-Gaussianity, where the contribution of the first multipoles is always relevant. We find a simple improvement to the 3-point function estimator that makes the square root of its variance decrease as Npix^-1/2 even for large f_NL, asymptotically approaching the Cramer-Rao bound. We show that using the modified estimator is practically equivalent to computing the full Likelihood of f_NL given the data. Thus other statistics of the data, such as the 4-point function and Minkowski functionals, contain no additional information on f_NL. In particular, we explicitly show that the recent claims about the relevance of the 4-point function are not correct. By direct inspection of the Likelihood, we show that the data do not contain enough information for any statistic to be able to constrain higher order terms in the relation between the Gaussian field and the curvature perturbation, unless these are orders of magnitude larger than the size suggested by the current limits on f_NL.Comment: 26 pages. v2: added comments about the approximations used, published JCAP versio

Action approach to cosmological perturbations: the 2nd order metric in matter dominance

We study nonlinear cosmological perturbations during the post-inflationary evolution, using the equivalence between a perfect barotropic fluid and a derivatively coupled scalar field with Lagrangian [-(\partial \phi)^2]^[(1+w)/2w]. Since this Lagrangian is just a special case of k-inflation, this approach is analogous to the one employed in the study of non-Gaussianities from inflation. We use this method to derive the second order metric during matter dominance in the comoving gauge directly as function of the primordial inflationary perturbation \zeta. Going to Poisson gauge, we recover the metric previously derived in the literature.Comment: 16 pages. New version, typo fixed in eq. (91