Counteracting the Common Shwachman–Diamond Syndrome-Causing SBDS c.258+2T>C Mutation by RNA Therapeutics and Base/Prime Editing

Shwachman-Diamond syndrome (SDS) represents one of the most common inherited bone marrow failure syndromes and is mainly caused by SBDS gene mutations. Only supportive treatments are available, with hematopoietic cell transplantation required when marrow failure occurs. Among all causative mutations, the SBDS c.258+2T>C variant at the 5 ' splice site (ss) of exon 2 is one of the most frequent. Here, we investigated the molecular mechanisms underlying aberrant SBDS splicing and showed that SBDS exon 2 is dense in splicing regulatory elements and cryptic splice sites, complicating proper 5 ' ss selection. Studies ex vivo and in vitro demonstrated that the mutation alters splicing, but it is also compatible with tiny amounts of correct transcripts, which would explain the survival of SDS patients. Moreover, for the first time for SDS, we explored a panel of correction approaches at the RNA and DNA levels and provided experimental evidence that the mutation effect can be partially counteracted by engineered U1snRNA, trans-splicing, and base/prime editors, ultimately leading to correctly spliced transcripts (from barely detectable to 2.5-5.5%). Among them, we propose DNA editors that, by stably reverting the mutation and potentially conferring positive selection to bone-marrow cells, could lead to the development of an innovative SDS therapy

The W43-MM1 mini-starburst ridge, a test for star formation efficiency models

Context: Star formation efficiency (SFE) theories are currently based on statistical distributions of turbulent cloud structures and a simple model of star formation from cores. They remain poorly tested, especially at the highest densities. Aims: We investigate the effects of gas density on the SFE through measurements of the core formation efficiency (CFE). With a total mass of $\sim2\times10^4$ M$_\odot$, the W43-MM1 ridge is one of the most convincing candidate precursor of starburst clusters and thus one of the best place to investigate star formation. Methods: We used high-angular resolution maps obtained at 3 mm and 1 mm within W43-MM1 with the IRAM Plateau de Bure Interferometer to reveal a cluster of 11 massive dense cores (MDCs), and, one of the most massive protostellar cores known. An Herschel column density image provided the mass distribution of the cloud gas. We then measured the 'instantaneous' CFE and estimated the SFE and the star formation rate (SFR) within subregions of the W43-MM1 ridge. Results: The high SFE found in the ridge ($\sim$6% enclosed in $\sim$8 pc$^3$) confirms its ability to form a starburst cluster. There is however a clear lack of dense cores in the northern part of the ridge, which may be currently assembling. The CFE and the SFE are observed to increase with volume gas density while the SFR steeply decreases with the virial parameter, $\alpha_{vir}$. Statistical models of the SFR may well describe the outskirts of the W43-MM1 ridge but struggle to reproduce its inner part, which corresponds to measurements at low $\alpha_{vir}$. It may be that ridges do not follow the log-normal density distribution, Larson relations, and stationary conditions forced in the statistical SFR models.Comment: 13 pages, 7 figures. Accepted by A&

Mapping the column density and dust temperature structure of IRDCs with Herschel

Infrared dark clouds (IRDCs) are cold and dense reservoirs of gas potentially available to form stars. Many of these clouds are likely to be pristine structures representing the initial conditions for star formation. The study presented here aims to construct and analyze accurate column density and dust temperature maps of IRDCs by using the first Herschel data from the Hi-GAL galactic plane survey. These fundamental quantities, are essential for understanding processes such as fragmentation in the early stages of the formation of stars in molecular clouds. We have developed a simple pixel-by-pixel SED fitting method, which accounts for the background emission. By fitting a grey-body function at each position, we recover the spatial variations in both the dust column density and temperature within the IRDCs. This method is applied to a sample of 22 IRDCs exhibiting a range of angular sizes and peak column densities. Our analysis shows that the dust temperature decreases significantly within IRDCs, from background temperatures of 20-30 K to minimum temperatures of 8-15 K within the clouds, showing that dense molecular clouds are not isothermal. Temperature gradients have most likely an important impact on the fragmentation of IRDCs. Local temperature minima are strongly correlated with column density peaks, which in a few cases reach NH2 = 1 x 10^{23} cm^{-2}, identifying these clouds as candidate massive prestellar cores. Applying this technique to the full Hi-GAL data set will provide important constraints on the fragmentation and thermal properties of IRDCs, and help identify hundreds of massive prestellar core candidates.Comment: Accepted for publication in A&A Herschel special issu

Preliminary Design and Numerical Analysis of a Scrap Tires Pyrolysis System

Abstract A plant prototype for whole scrap tires disposal and the consequent syngas production via pyrolysis has been developed. A numerical analysis on the innovative pyrolysis reactor, constituted by an autoclave closing device and an explosion-proof water system has been carried out. The aim of this analysis is to investigate the fluid-dynamics in the pyrolysis chamber and model the syngas production. The simulations, performed in the pre-realization system phase, have allowed to determine: i) the flow field of the fluid within the reactor, so as to optimize the geometry (e.g. size, vacuum system, water tank); ii) the temperature range, in order to determine the correct placement of thermocouples within reactor and prevent overheating that could compromise the safety of the system; iii) the pressure range, necessary to avoid the eventual flooding of the tires themselves. Thanks to these results, the test bench has been built at the CURTI S.p.A laboratory and experimental analysis has been performed. The experimental data are acquired and then elaborated, as shown in the paper

The Little-Hopfield model on a Random Graph

We study the Hopfield model on a random graph in scaling regimes where the average number of connections per neuron is a finite number and where the spin dynamics is governed by a synchronous execution of the microscopic update rule (Little-Hopfield model).We solve this model within replica symmetry and by using bifurcation analysis we prove that the spin-glass/paramagnetic and the retrieval/paramagnetictransition lines of our phase diagram are identical to those of sequential dynamics.The first-order retrieval/spin-glass transition line follows by direct evaluation of our observables using population dynamics. Within the accuracy of numerical precision and for sufficiently small values of the connectivity parameter we find that this line coincides with the corresponding sequential one. Comparison with simulation experiments shows excellent agreement.Comment: 14 pages, 4 figure

Statistical Mechanics of Soft Margin Classifiers

We study the typical learning properties of the recently introduced Soft Margin Classifiers (SMCs), learning realizable and unrealizable tasks, with the tools of Statistical Mechanics. We derive analytically the behaviour of the learning curves in the regime of very large training sets. We obtain exponential and power laws for the decay of the generalization error towards the asymptotic value, depending on the task and on general characteristics of the distribution of stabilities of the patterns to be learned. The optimal learning curves of the SMCs, which give the minimal generalization error, are obtained by tuning the coefficient controlling the trade-off between the error and the regularization terms in the cost function. If the task is realizable by the SMC, the optimal performance is better than that of a hard margin Support Vector Machine and is very close to that of a Bayesian classifier.Comment: 26 pages, 12 figures, submitted to Physical Review

An Optically Discovered Outburst from XTE J1859+226

Using the Zwicky Transient Facility, in 2021 February we identified the first known outburst of the black hole X-ray transient XTE J1859+226 since its discovery in 1999. The outburst was visible at X-ray, UV, and optical wavelengths for less than 20 days, substantially shorter than its full outburst of 320 days in 1999, and the observed peak luminosity was 2 orders of magnitude lower. Its peak bolometric luminosity was only 2 × 1035 erg s−1, implying an Eddington fraction of about 3 × 10−4. The source remained in the hard spectral state throughout the outburst. From optical spectroscopy measurements we estimate an outer disk radius of 1011 cm. The low observed X-ray luminosity is not sufficient to irradiate the entire disk, but we observe a surprising exponential decline in the X-ray light curve. These observations highlight the potential of optical and infrared synoptic surveys to discover low-luminosity activity from X-ray transients

cAMP response element-binding protein regulates differentiation and survival of newborn neurons in the olfactory bulb

The transcription factor cAMP response element-binding protein (CREB) is involved in multiple aspects of neuronal development and plasticity. Here, we demonstrate that CREB regulates specific phases of adult neurogenesis in the subventricular zone/olfactory bulb (SVZ/OB) system. Combining immunohistochemistry with bromodeoxyuridine treatments, cell tracer injections, cell transplants, and quantitative analyses, we show that although CREB is expressed by the SVZ neuroblasts throughout the neurogenic process, its phosphorylation is transient and parallels neuronal differentiation, increasing during the late phase of tangential migration and decreasing after dendrite elongation and spine formation. In vitro, inhibition of CREB function impairs morphological differentiation of SVZ-derived neuroblasts. Transgenic mice lacking CREB, in a null CREM genetic background, show reduced survival of newborn neurons in the OB. This finding is further supported by peripheral afferent denervation experiments resulting in downregulation of CREB phosphorylation in neuroblasts, the survival of which appears heavily impaired. Together, these findings provide evidence that CREB regulates differentiation and survival of newborn neurons in the OB