Two <i>anti</i>-Prelog NAD-Dependent Alcohol Dehydrogenases with Broad Substrate Scope and Excellent Enantioselectivity

Enantiomerically pure alcohols are important to produce active pharmaceutical ingredients, agrochemicals and fine chemicals. Herein, we explored the substrate scope and chemo- and enantioselectivity of two NAD-dependent anti-Prelog alcohol dehydrogenases from Candida maris (Cm-ADH) and Pichia finlandica (Pf-ADH) in the asymmetric reduction of ketones. The ADHs were tested for the reduction of acetophenone with NADH that was recycled using a formate dehydrogenase and sodium formate. Cm-ADH and Pf-ADH performed best at 30 °C and at around pH 7 and pH 6, respectively. Pf-ADH operated well at 50 mM acetophenone concentration, while Cm-ADH was limited to 10 mM. Regarding the substrate scope, linear-chain alkyl ketones were efficiently reduced (up to 98 % conversion), while branched and cyclic ketones gave lower conversions (up to 60 %). Aryl-aliphatic ketones showed variable levels of conversion (&lt;1–79 %), while α,β-unsaturated and heteroaromatic ketones exhibited good to excellent conversions. In most of the cases, the enantiomeric excess was &gt;99 %. Aliphatic and aryl-aliphatic aldehydes were converted with up to &gt;99 % conversion. A scale-up experiment with Pf-ADH using acetophenone as substrate led to 73 % isolated yield and &gt;99 % ee (R). This work contributes to filling the gap in biocatalytic asymmetric synthesis of chiral alcohols by introducing two NAD-dependent ADHs with anti-Prelog selectivity

Cholesterol impairment contributes to neuroserpin aggregation

Intraneural accumulation of misfolded proteins is a common feature of several neurodegenerative pathologies including Alzheimer's and Parkinson's diseases, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is a rare disease due to a point mutation in neuroserpin which accelerates protein aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol depletion induced either by prolonged exposure to statins or by inhibiting the sterol regulatory binding-element protein (SREBP) pathway also enhances aggregation of neuroserpin proteins. These findings can be explained considering a computational model of protein aggregation under non-equilibrium conditions, where a decrease in the rate of protein clearance improves aggregation. Decreasing cholesterol in cell membranes affects their biophysical properties, including their ability to form the vesicles needed for protein clearance, as we illustrate by a simple mathematical model. Taken together, these results suggest that cholesterol reduction induces neuroserpin aggregation, even in absence of specific neuroserpin mutations. The new mechanism we uncover could be relevant also for other neurodegenerative diseases associated with protein aggregation.Comment: 7 figure

Nuove prospettive nel monitoraggio biologico degli elementi metallici: l'esempio del cromo esavalente

L’industria galvanica è un settore importante su tutto il territorio nazionale, poiché i processi che la caratterizzano riguardano un gran numero di fabbricazioni industriali ed artigianali. Nella cromatura galvanica esiste un rischio chimico specifico dovuto all’esposizione a composti contenenti Cromo esavalente [Cr(VI)]. Il condensato dell’aria espirata (CAE) è stato usato per studiare l’esposizione acuta e a lungo termine a Cr(VI) in lavoratori addetti alla cromatura a spessore. Cr-CAE correla con specifici biomarcatori di stress ossidativo ed è possibile misurarne anche la frazione non ancora ridotta a Cr(III). Il CAE è quindi un fluido biologico promettente per il monitoraggio della dose assorbita a livello dell’organo bersaglio, della cinetica di riduzione polmonare di Cr(VI) e più in generale dei suoi effetti locali pneumotossici nelle lavorazioni galvaniche, con la possibilità di affiancare la sua raccolta e la sua analisi alle misure tradizionalmente fatte durante il monitoraggio biologico

Bio-chemostratigraphy of the Barremian-Aptian shallow-water carbonates of the southern Apennines (Italy): pinpointing the OAE1a in a Tethyan carbonate platform

Low biostratigraphic resolution and lack of chronostratigraphic calibration hinder precise correlations between platform carbonates and coeval deep-water successions. These are the main obstacle when studying the record of Mesozoic oceanic anoxic events in carbonate platforms. In this paper carbon and strontium isotope stratigraphy areused to produce the first chronostratigraphic calibration of the Barremian-Aptian biostratigraphy of the Apenninic carbonate platform of southern Italy. According to this calibration, the segment of decreasing δ13C values, leading to the negative peak that is generally taken as the onset of the Selli event, starts a few metres above the last occurrence of Palorbitolina lenticularis and Voloshinoides murgensis. The following rise of δ13C values, corresponding to the interval of enhanced accumulation of organic matter in deep-water sections, ends just below the first acme of Salpingoporella dinarica, which roughly corresponds to the segment of peak δ13C values. The whole carbon isotope excursion associated with the oceanic anoxic event 1a is bracketed in the Apenninic carbonate platform between the last occurrence of Voloshinoides murgensis and the “Orbitolina level”, characterized by the association of Mesorbitolina parva and Mesorbitolina texana. Since these bioevents have been widely recognized beyond the Apenninic platform, the calibration presented in this paper can be used to pinpoint the interval corresponding to the Early Aptian oceanic anoxic event in other carbonate platforms of central and southern Tethys. This calibration will be particularly useful to interpret the record of the Selli event in carbonate platform sections for which a reliable carbon isotope stratigraphy is not available

Self-aerated bounded flows in special hydraulic structures. Part 1. A short review on design concepts and sizing procedures of aerators

Paper presented at the 6th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, South Africa, 30 June - 2 July, 2008.In a number of hydraulic structures, significant fluiddynamical differences may be observed between flows which are well aerated and flows which are not ([16]). These differences are not just a matter of scientific speculation. Effective or ineffective aeration may be in fact responsible for inducing a variety of flow regime transitions, some of which may result desirable in particular situations and undesirable in other cases ([16]). When flows are bounded the venting system actually rules the behaviour of the entire system. Despite the importance of aeration for the performance of many hydraulic structures, design methods and procedures, in force of the great complexity of the involved physical phenomena, may be still nowadays quite simplified and experimental tests on large scale physical models are to be considered unavoidable to properly size the air supply system ([15], [21]). In the first part of the paper, structural layout and flow patterns which may be observed in bottom outlets, chute spillways, baffled weirs and leaping weirs are described. Flow regime transitions occurring in these structures are shown to be ruled to a great extent from the sizing of the aerators, giving evidence that such elements are unavoidable whenever civil structures and mechanical equipment are prone to cavitation risk. Stemming from these premises, in the second part of the paper it is stressed that common design procedures of air vents are based upon the hypothesis that the flow of air through vents may be treated as that of an incompressible fluid. It is brought to light however that this procedure contrasts, not so infrequently, with many experimental results collected from various researchers over more than 50 years ([6], [15], [22]). A compressible flow formulation is therefore reckoned to be necessary to predict the main flow characteristics of air through ducts of variable size, length and roughness.vk201

The three-body recombination of a condensed Bose gas near a Feshbach resonance

In this paper, we study the three-body recombination rate of a homogeneous dilute Bose gas with a Feshbach resonance at zero temperature. The ground state and excitations of this system are obtained. The three-body recombination in the ground state is due to the break-up of an atom pair in the quantum depletion and the formation of a molecule by an atom from the broken pair and an atom from the condensate. The rate of this process is in good agreement with the experiment on $^{23}$Na in a wide range of magnetic fields.Comment: 10 pages, 2 figures, to be published in Phys. Rev.

A Glimpse in the Future of Malignant Mesothelioma Treatment

Malignant mesothelioma (MMe) is a rare neoplasm with few therapeutic options available. The landscape of effective therapy for this disease remained unchanged in the last two&nbsp;decades. Recently, however, the introduction of Immune Checkpoint Inhibitors (ICIs) led to small, but nevertheless, promising improvements. However, many efforts are still needed to radically improve the prognosis of MMe. In this review, we analyze all those therapeutic strategies for MMe that are still in a preclinical or early clinical phase of development. In particular, we focus on novel antiangiogenic drugs and their possible combination with immunotherapy. Furthermore, we describe also more complex strategies such as microRNA-loaded vectors, oncolytic viruses, and engineered lymphocytes

A Cretaceous carbonate delta drift in the Montagna della Maiella, Italy

The Upper Cretaceous (Campanian\u2013Maastrichtian) bioclastic wedge of the Orfento Formation in the Montagna della Maiella, Italy, is compared to newly discovered contourite drifts in the Maldives. Like the drift deposits in the Maldives, the Orfento Formation fills a channel and builds a Miocene delta-shaped and mounded sedimentary body in the basin that is similar in size to the approximately 350&nbsp;km 2 large coarse-grained bioclastic Miocene delta drifts in the Maldives. The composition of the bioclastic wedge of the Orfento Formation is also exclusively bioclastic debris sourced from the shallow-water areas and reworked clasts of the Orfento Formation itself. In the near mud-free succession, age-diagnostic fossils are sparse. The depositional textures vary from wackestone to float-rudstone and breccia/conglomerates, but rocks with grainstone and rudstone textures are the most common facies. In the channel, lensoid convex-upward breccias, cross-cutting channelized beds and thick grainstone lobes with abundant scours indicate alternating erosion and deposition from a high-energy current. In the basin, the mounded sedimentary body contains lobes with a divergent progradational geometry. The lobes are built by decametre thick composite megabeds consisting of sigmoidal clinoforms that typically have a channelized topset, a grainy foreset and a fine-grained bottomset with abundant irregular angular clasts. Up to 30&nbsp;m thick channels filled with intraformational breccias and coarse grainstones pinch out downslope between the megabeds. In the distal portion of the wedge, stacked grainstone beds with foresets and reworked intraclasts document continuous sediment reworking and migration. The bioclastic wedge of the Orfento Formation has been variously interpreted as a succession of sea-level controlled slope deposits, a shoaling shoreface complex, or a carbonate tidal delta. Current-controlled delta drifts in the Maldives, however, offer a new interpretation because of their similarity in architecture and composition. These similarities include: (i) a feeder channel opening into the basin; (ii) an excavation moat at the exit of the channel; (iii) an overall mounded geometry with an apex that is in shallower water depth than the source channel; (iv) progradation of stacked lobes; (v) channels that pinch out in a basinward direction; and (vi) smaller channelized intervals that are arranged in a radial pattern. As a result, the Upper Cretaceous (Campanian\u2013Maastrichtian) bioclastic wedge of the Orfento Formation in the Montagna della Maiella, Italy, is here interpreted as a carbonate delta drift

Multi-fluid stratified shear flows in pipes. Part 2. Critical conditions in the development of interfacial profiles

Paper presented at the 5th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, South Africa, 1-4 July, 2007.The focus of this paper is on mathematical formulation and computation of critical flow conditions in horizontal or nearly horizontal pipes. Continuity and momentum equations are derived considering an arbitrary number of fluids and then rearranged so as to yield a system of ordinary differential equations. It is shown that the matrix of the system needs to be invertible so as to compute interfacial profiles. Critical conditions are recognised as those for which the matrix becomes singular and the hypothesis of gradually varied flow fails. Some well known results of linear algebra are here used to define criteria capable of discerning between geometric and kinematic conditions of the flow which are certainly noncritical and others which may or may not be critical