Spatial organization of bacterial transcription and translation

In bacteria such as $\textit{Escherichia coli}$, DNA is compacted into a nucleoid near the cell center, while ribosomes$-$molecular complexes that translate messenger RNAs (mRNAs) into proteins$-$are mainly localized at the poles. We study the impact of this spatial organization using a minimal reaction-diffusion model for the cellular transcriptional-translational machinery. Our model predicts that $\sim 90\%$ of mRNAs are segregated to the poles and reveals a "circulation" of ribosomes driven by the flux of mRNAs, from synthesis in the nucleoid to degradation at the poles. To address the existence of non-specific, transient interactions between ribosomes and mRNAs, we developed a novel method to efficiently incorporate such transient interactions into reaction-diffusion equations, which allowed us to quantify the biological implications of such non-specific interactions, e.g. for ribosome efficiency

Application of adaptive multilevel splitting to high-dimensional dynamical systems

Stochastic nonlinear dynamical systems can undergo rapid transitions relative to the change in their forcing, for example due to the occurrence of multiple equilibrium solutions for a specific interval of parameters. In this paper, we modify one of the methods developed to compute probabilities of such transitions, Trajectory-Adaptive Multilevel Sampling (TAMS), to be able to apply it to high-dimensional systems. The key innovation is a projected time-stepping approach, which leads to a strong reduction in computational costs, in particular memory usage. The performance of this new implementation of TAMS is studied through an example of the collapse of the Atlantic Ocean Circulation

Shelf slope convection: A note for antarctic regions

Some basic processes associated with buoyancy-driven convection in the presence of coastal upwellingcurren ts were investigated in a 2.5D framework near the Adelie Coast of Antarctica. The surface buoyancy forcingw as derived from coolingand brine deposition due to ice formation, and was specified over a persistent off-shore polynya maintained by the off-shore katabatic winds. Rotational effects and the formation of a turbulent surface mixed layer were included in the model. The representation of topography was done via the VBM (virtual Boundary Method) that utilizes equivalent body forces in the momentum equation, thus enabling the use of very efficient Poisson solvers for the pressure, based on FFTs. The simulations were carried out near longitude 143E, between latitude 68S and 65S, over the nearshore shelf region. The hydrography was initialized with the 1/4 deg Levitus annual climatology. Two cases of idealized meteorological forcing were considered: constant winds blowingalong -shore and off-shore. The resultant motions in each case were characterized by interaction between the wind-driven upwellingmotions and the downward movingdense convection plumes, but with marked differences: a) the formation of a strongfron t under the open sea edge of the polynya only by off-shore winds; b) the periodic suppression of the surface off-shore currents and of the coastal upwelling only by the along-shore winds; c) the formation of deep upwelling currents along the slope between 400 and 200 meters only for along-shore winds, and d) the rapid filling of the surface layers (depths < 100m) with high salinities under the whole polynya by the off-shore forcing, vs. the delayed fillingof a narrow region near the downwellingplume with intermediate salinity values by the along-shore forcing

Association of a homozygous GCK missense mutation with mild diabetes

Background: Homozygous inactivating GCK mutations have been repeatedly reported to cause severe hyperglycemia, presenting as permanent neonatal diabetes mellitus (PNDM). Conversely, only two cases of GCK homozygous mutations causing mild hyperglycemia have been so far described. We here report a novel GCK mutation (c.1116G&gt;C, p.E372D), in a family with one homozygous member showing mild hyperglycemia. Methods: GCK mutational screening was carried out by Sanger sequencing. Computational analyses to investigate pathogenicity and molecular dynamics (MD) were performed for GCK-E372D and for previously described homozygous mutations associated with mild (n&nbsp;=&nbsp;2) or severe (n&nbsp;=&nbsp;1) hyperglycemia, used as references. Results: Of four mildly hyperglycemic family-members, three were heterozygous and one, diagnosed in the adulthood, was homozygous for GCK-E372D. Two nondiabetic family members carried no mutations. Fasting glucose (p&nbsp;=&nbsp;0.016) and HbA1c (p&nbsp;=&nbsp;0.035) correlated with the number of mutated alleles (0–2). In-silico predicted pathogenicity was not correlated with the four mutations’ severity. At MD, GCK-E372D conferred protein structure flexibility intermediate between mild and severe GCK mutations. Conclusions: We present the third case of homozygous GCK mutations associated with mild hyperglycemia, rather than PNDM. Our in-silico analyses support previous evidences suggesting that protein stability plays a role in determining clinical severity of GCK mutations

Spaces with Noetherian cohomology

Is the cohomology of the classifying space of a p-compact group, with Noetherian twisted coefficients, a Noetherian module? In this paper we provide, over the ring of p-adic integers, such a generalization to p-compact groups of the Evens-Venkov Theorem. We consider the cohomology of a space with coefficients in a module, and we compare Noetherianity over the field with p elements with Noetherianity over the p-adic integers, in the case when the fundamental group is a finite p-grou

A family history of type 2 diabetes as a predictor of fatty liver disease in diabetes-free individuals with excessive body weight

Comprehensive screening for non-alcoholic fatty liver disease (NAFLD) may help prompt clinical management of fatty liver disease. A family history, especially of diabetes, has been little studied as a predictor for NAFLD. We characterized the cross-sectional relationship between a family history of type 2 diabetes (FHT2D) and NAFLD probability in 1185 diabetes-free Apulian (Southern-Italy) subjects aged &gt; 20&nbsp;years with overweight or obesity not receiving any drug or supplementation. Clinical data and routine biochemistry were analysed. NAFLD probability was defined using the fatty liver index (FLI). A first-degree FHT2D was assessed by interviewing subjects and assigning a score of 0, 1, or 2 if none, only one, or both parents were affected by type 2 diabetes mellitus (T2DM). Our study population featured most females (70.9%, N = 840), and 48.4% (N = 574) of the sample had first-degree FHT2D. After dividing the sample by a FHT2D, we found a higher BMI, Waist Circumference (WC), and diastolic blood pressure shared by FHT2D subjects; they also showed altered key markers of glucose homeostasis, higher triglyceride levels, and worse liver function. FLI scores were significantly lower in subjects without a first-degree FHT2D. After running logistic regression models, a FHT2D was significantly associated with the NAFLD probability, even adjusting for major confounders and stratifying by age (under and over 40&nbsp;years of age). A FHT2D led to an almost twofold higher probability of NAFLD, regardless of confounding factors (OR 2.17, 95% CI 1.63 to 2.89). A first-degree FHT2D acts as an independent determinant of NAFLD in excess weight phenotypes, regardless of the age group (younger or older than 40&nbsp;years). A NAFLD risk assessment within multidimensional screening might be useful in excess weight subjects reporting FHT2D even in the absence of diabetes

Role of the Tracy-Widom distribution in the finite-size fluctuations of the critical temperature of the Sherrington-Kirkpatrick spin glass

We investigate the finite-size fluctuations due to quenched disorder of the critical temperature of the Sherrington-Kirkpatrick spin glass. In order to accomplish this task, we perform a finite-size analysis of the spectrum of the susceptibility matrix obtained via the Plefka expansion. By exploiting results from random matrix theory, we obtain that the fluctuations of the critical temperature are described by the Tracy-Widom distribution with a non-trivial scaling exponent 2/3

Efficacy and safety of GLP-1 receptor agonists as add-on to SGLT2 inhibitors in type 2 diabetes mellitus: A meta-analysis

GLP-1 receptor agonists (GLP-1RA) and SGLT2 inhibitors (SGLT2i) have been associated with improved glycemic control, body weight loss and favorable changes in cardiovascular risk factors and outcomes. We conducted a systematic review and meta-analysis to evaluate the effects of the addition of GLP-1RA to SGLT2i in patients with type 2 diabetes mellitus and inadequate glycemic control. Six databases were searched until March 2019. Randomized controlled trials (RCT) with a follow-up of at least 24 weeks reporting on HbA1c, body weight, systolic blood pressure, lipids, achievement of HbA1c &lt; 7%, requirement of rescue therapy due to hyperglycemia and hypoglycemic events were selected. Four RCTs were included. Compared to SGLT2i, the GLP-1RA/SGLT2i combination was associated with greater reduction in HbA1c (−0.74%), body weight (−1.61 kg), and systolic blood pressure (−3.32 mmHg). A higher number of patients achieved HbA1c &lt; 7% (RR = 2.15), with a lower requirement of rescue therapy (RR = 0.37) and similar incidence of hypoglycemia. Reductions in total and LDL cholesterol were found. The present review supports treatment intensification with GLP-1RA in uncontrolled type 2 diabetes on SGLT2i. This drug regimen could provide improved HbA1c control, together with enhanced weight loss and blood pressure and lipids control

Skin acrometastases in squamous cell carcinoma of the tongue.

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