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Ferric iron is an essential nutrient for bacterial growth. Pathogenic bacteria synthesize iron-chelating entities known as siderophores to sequestrate ferric iron from host organisms in order to colonize and replicate. The development of antimicrobial peptides (AMPs) conjugated to iron chelators represents a promising strategy for reducing iron availability, inducing bacterial death, and enhancing simultaneously the efficacy of AMPs. Here we designed, synthesized, and characterized three hydroxamate-based peptides Pep-cyc1, Pep-cyc2, and Pep-cyc3, derived from a cyclic temporin L peptide (Pep-cyc) developed previously by some of us. The Fe3+ complex formation of each ligand was characterized by UVvisible spectroscopy, mass spectrometry, IR, and NMR spectroscopies. In addition, the effect of Fe3+ on the stabilization of -helix conformation of hydroxamate-based peptides and the cotton effect were examined by CD spectroscopy. Moreover, the antimicrobial results obtained in vitro on some Gram-negative strains (K. Pneumoniae and E. coli) showed the ability of each peptide to chelate efficaciously Fe3+ obtaining a reduction of MIC values in comparison to their parent peptide Pepcyc. Our results demonstrated that siderophore conjugation could increase the efficacy and selectivity of AMPs used for the treatment of infectious diseases caused by Gram-negative pathogens.

L'autore affronta le ragioni strutturali di una guerra, attraverso un'angolazione geopolitica. Un conflitto presenta evoluzioni belliche anche per l'attrattiva del mestiere delle armi. Tra conflitto e guerra sono comunque possibili vie pacifiche di risoluzione.

The interaction with proteins of metal-based drugs plays a crucial role in their transport, mechanism, and activity. For an active MLn complex, where L is the organic carrier, various binding modes (covalent and non-covalent, single or multiple) may occur and several metal moieties (M, ML, ML2, etc.) may interact with proteins. In this study, we have evaluated the interaction of [VIVO(malt)2] (bis(maltolato)oxidovanadium(IV) or BMOV, where malt = maltolato, i.e., the common name for 3-hydroxy-2-methyl-4H-pyran-4-onato) with the model protein hen egg white lysozyme (HEWL) by electrospray ionization mass spectrometry, electron paramagnetic resonance, and X-ray crystallography. The multiple binding of different V-containing isomers and enantiomers to different sites of HEWL is observed. The data indicate both non-covalent binding of cis-[VO(malt)2(H2O)] and [VO(malt)(H2O)3]+ and covalent binding of [VO(H2O)3-4]2+ and cis-[VO(malt)2] and other V-containing fragments to the side chains of Glu35, Asp48, Asn65, Asp87, and Asp119 and to the C-terminal carboxylate. Our results suggest that the multiple and variable interactions of potential VIVOL2 drugs with proteins can help to better understand their solution chemistry and contribute to define the molecular basis of the mechanism of action of these intriguing molecules.

Compounds with the general formula Ln3+(SeO3)(HSeO3)·2H2O, where Ln = Sm3+, Tb3+, Nd3+ and Lu3+, are characterized by orthorhombic symmetry with space group P212121 and unit-cell parameters in the ranges a ∼ 6.473–6.999, b ∼ 6.845–7.101, c ∼ 16.242–16.426 Å. Light-purple irregularly shaped crystals of a new monoclinic polytype of neodymium selenite Nd(SeO3)(HSeO3)·2H2O have been obtained during a mild-condition hydrothermal synthesis. The monoclinic unit-cell parameters are: a = 7.0815 (2), b = 6.6996 (2), c = 16.7734 (5) Å, β = 101.256 (1)°, V = 780.48 (6) Å3; space group P21/c. The crystal structures of Nd(SeO3)(HSeO3)·2H2O polymorphs show order–disorder (OD) character and can be described using the same OD groupoid family, more precisely a family of OD structures built up from two kinds of non-polar layers (category IV). The first monoclinic maximum degree order (MDO) structure (MDO1-polytype) with space group P21/c can be obtained when the inversion centre is active in the L 2n -type layers, while the second MDO structure (MDO2-polytype) is orthorhombic with space group P212121 and can be obtained when the [21--] operation is active in the L 2n -type layers. The structural complexity parameters and DFT calculations of both polytypes show that the polytype structures are extremely close energy-wise and almost equally viable from the point of total energy of the structure.

A Smart Factory exploits information and communication technologies (ICT) to improve the production process and the working environment, usually addressing safety concerns. To this concern, factory-grade fire protection systems are governed by several procedures and standards whose application often becomes definitely challenging when the factory premises are dispersed across multiple administrative domains. In such contexts, the Smart Factory approach can prove very effective in the management and coordination of the factory-level fire protection system. However, a catastrophic event may compromise the ICT infrastructure, affecting communication among factory domains and therefore its smart services. A strategy to cope with the latter may be the introduction of mechanisms to handle data analysis on-site for a prompt response while enabling seamless data distribution and processing among neighbouring (federated) ICT infrastructures and emergency operators. In this work, a novel software-defined approach for the adaptive management of a Smart Factory infrastructure is proposed, centered around business logic rewiring and reconfiguration at run-time across different factory domains. Thereby, even in the case of catastrophic (e.g., potentially disruptive) events, working devices of the emergency system can go on with their operations, including transferring data to rescuers and others emergency control systems. To demonstrate the effectiveness of the proposed Software Defined Factory approach, a Federated Fire Protection System operating in an industrial setting is implemented as a case study, able to promptly react and adapt to infrastructure-critical fires and their consequences by leveraging all information and computing facilities pooled over Cloud/Fog/Edge devices spanning the premises.

This research analyzed the assortment size and depth, marketing characteristics, price policies and communication strategies in large-retail chains and online distributions for homogenized baby food. Comparisons of the assortment composition were made considering defined product categories based on the composition formula, specialty product, claims, product origin and packaging material. Prices differences were also assessed comparing the different retailer formats (supermarket, hypermarket, convenience store and discount). The main findings highlighted significant differences in the assortment planning decisions. In particular, direct sales seem to be more oriented towards providing a wide range of products together with more information on products healthiness and origin; online sales, on the other hand, focus its assortment planning decision on supplying products with high added value in composition and price: in fact, the extra communication of additional information regarding the product nutritional characteristics and certifications, as well as expert advice, characterized the majority of the explored websites. About the promotion, in the physical stores, more convenience packs have been used, while more discounts were applied directly to the online sale price. This research provides concrete tools to marketing managers to improve the planning and communication strategies of infant formula of homogenized products for a differentiated and successful sales policy. At the same time, producers can make a more informed and dynamic choice on the distribution chain that can best match the company's offer.

Purpose Dysregulation of the PI3K pathway is one of the most common events in breast cancer. Here we investigate the activity of the PI3K inhibitor MEN1611 at both molecular and phenotypic levels by dissecting and comparing its profile and efficacy in HER2 + breast cancer models with other PI3K inhibitors. Methods Models with different genetic backgrounds were used to investigate the pharmacological profile of MEN1611 against other PI3K inhibitors. In vitro studies evaluated cell viability, PI3K signaling, and cell death upon treatment with MEN1611. In vivo efficacy of the compound was investigated in cell line- and patient-derived xenografts models. Results Consistent with its biochemical selectivity, MEN1611 demonstrated lower cytotoxic activity in a p110δ-driven cellular model when compared to taselisib, and higher cytotoxic activity in the p110β-driven cellular model when compared to alpelisib. Moreover, MEN1611 selectively decreased the p110α protein levels in PIK3CA mutated breast cancer cells in a concentration- and proteasome-dependent manner. In vivo, MEN1611 monotherapy showed significant and durable antitumor activity in several trastuzumab-resistant PIK3CA-mutant HER2 + PDX models. The combination of trastuzumab and MEN1611 significantly improved the efficacy compared to single agent treatment. Conclusions The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335).

El Síndrome de Intestino Irritable (SII) es un trastorno gastrointestinal funcional crónico que representa un problema en salud pública debido al impacto que produce en la calidad de vida. Los tratamientos recomendados incluyen a la terapia cognitivo-conductual para el abordaje de aquellos factores psicológicos que exacerban los síntomas. El uso de la tecnología y particularmente de aplicaciones móviles ha crecido de manera significativa durante los últimos años. En Argentina no se han desarrollado aplicaciones para SII. Digestivamente es una aplicación móvil, basada en la terapia cognitivo-conductual desarrollada en este país. Tiene por objetivo el registro de los factores psicológicos de los pacientes con SII en el contexto de un tratamiento psicoterapéutico. En el presente trabajo se describe la aplicación y sus funcionalidades. Se espera que la utilización de la aplicación permita mayor adherencia al tratamiento y una mejoría en la sintomatología de estos pacientes.

A new mineral paratobermorite with the ideal crystal-chemical formula Ca4(Al0.5Si0.5)2Si4O16 (OH)·2H2O·(Ca·3H2O) is a member of the tobermorite group within the tobermorite supergroup. It was found at the Bazhenovskoe chrysotile asbestos deposit, Central Urals, Russia, in cavities of grossular rodingite in association with prehnite, pectolite, thomsonite-Ca, and calcite. Paratobermorite occurs as well-shaped prismatic to acicular crystals up to 1 × 1.5 × 8 mm3 typically assembled in spray- or bush-like radial clusters or open-work aggregates up to 1.5 cm across, which form interrupted crusts up to 3 × 5 cm2. Paratobermorite is transparent, colorless, pale yellowish, pale beige, or pinkish, with a vitreous luster. The mineral is brittle, with the (001) perfect cleavage. The Mohs hardness is ca. 3½. Dmeas = 2.51 (2) and Dcalc = 2.533 g/cm3. Paratobermorite is optically biaxial (+), α = 1.565 (2), β = 1.566 (2), γ = 1.578 (2), 2 Vmeas = 25 (10)° and 2 Vcalc = 32° (589 nm). Optical orientation is: X = c, Y = b, Z = a. The chemical composition of paratobermorite (electron microprobe, H2O by selective sorption from gaseous products of heating) is Na2O 0.40, K2O 0.28, CaO 36.60, MnO 0.04, BaO 0.07, Al2O3 6.46, SiO2 42.32, H2O 14.10, total 100.27 wt%. The empirical formula calculated on the basis of 22 O atoms per formula unit and (O,OH)17·5H2O is Na0.09K0.04Ca4.72Al0.92Si5.09O15.69(OH)1.31·5H2O. Like other members of the tobermorite supergroup, paratobermorite displays OD character, with two MDO (maximum degree of order) structures: one (MDO1), with non-standard space group F2/d11 and the second (MDO2), just corresponding to the structure-type of the new mineral, with non-standard space group C1121/m; its unit-cell parameters obtained from single-crystal X-ray diffraction data are: a = 11.2220(4), b = 7.3777(2), c = 22.9425(8) Å, γ = 89.990(3)°, V = 1899.46(10) Å3, and Z = 4; polytype 2M. The structure of paratobermorite is solved on a single crystal, R = 8.36%. Like structures of other “tobermorites 11 Å,” it is based on the complex layer built of a sheet of sevenfold Ca-centered polyhedra with wollastonite-type chains of T tetrahedra attached to the Ca-sheet from both sides. The tetrahedral (T) sites T1 and T2 are fully occupied by Si, while alternating T3 and T4 sites are filled by Al and Si in the ratio 1:1. The chains of tetrahedra belonging to neighboring complex layers share common oxygen vertices of the bridging T3,4 tetrahedra to form xonotlite-type ribbons [Si6O17]∞. The heteropolyhedral Ca-T-O scaffolding appears as a microporous quasi-framework with wide channels, which contain additional Ca atoms and H2O molecules. The complex Ca-T-O layers in paratobermorite (so-called “complex modules of type A”) significantly differ in topology (mutual arrangement of T tetrahedra and Ca polyhedra) from the complex Ca-T-O layers in tobermorite (“complex modules of type B”). IR spectrum confirms the presence of nonequivalent H2O molecules and nonequivalent T-O-T angles involving T atoms of two neighboring wollastonite-type chains. Due to the original topological type of the structure and the presence of significant amount of Al, which substitutes Si, paratobermorite can be considered as a novel microporous material, a perspective cation-exchanger.

With the significant impact of Internet services and the evolution in the hardware and software fields, the Internet size and usage scope are continuously covering smaller and resource-constrained devices. Such devices, commonly called IoT devices, with sensing/actuation capabilities, are now capable of managing the complexity of communications over the Internet. However, considering the current IoT ecosystem, this field is still fragmented with respect to the communication technologies, protocols, and data formats used by the different providers. This heterogeneity makes IoT devices/systems unable to communicate seamlessly, leading to limited cooperation and tightly coupled deployments. To overwhelm the interoperability barriers in IoT, we propose, in this paper, a Cloud-based approach with a Dynamic Domain Name System (DDNS) mechanism enabling the IoT devices to communicate using the REST model. An approach that follows the Web of things (WoT) paradigm. In particular, the system enables the IoT devices' hosted resources (e.g., sensors and actuators) to be steered using globally resolvable (over the Internet) Uniform Resource Locators (URLs) even when deployed behind Network Address Translators (i.e., NATs). Besides, the solution considers security aspects related to data transmission by leveraging the use of HTTPS with a Dynamic machnism managing Domain Validation (DV) certificates.

Il contributo riguarda l’autonomia della Provincia di Bolzano. Questa ha nel secondo Statuto di autonomia del 1972 la sua fonte giuridica principale, che però poggia su fondamentali presupposti giuridici, storici e filosofici. Non è un caso che nel 1947 il Segretario generale del Partito popolare sudtirolese Otto Guggenberg scriveva alla Costituente ricordando la storia autonomista del Tirolo come argomento principale per il riconoscimento dell’autonomia nel solco della sovranità popolare che si andava costituendo. Del resto, sovranità e autonomia erano stati dichiarati dalla Costituente concetti relazionali nell’art. 5, che condensava la lezione di pensatori come Montesquieu e Tocqueville. Lo sguardo giuridico, storico e filosofico sui presupposti dell’autonomia è una ricerca sulle sue origini, che guarda al passato per immaginare il futuro, Diritto Pubblico Europeo - Rassegna online, V. 20 N. 2 (2023): Diritto pubblico europeo Rassegna on line

Neurodegenerative diseases are often caused by uncontrolled amyloid aggregation. Hence, many drug discovery processes are oriented to evaluate new compounds that are able to modulate self-recognition mechanisms. Herein, two related glycoconjugate pentacoordinate Pt(II) complexes were analyzed in their capacity to affect the self-aggregation processes of two amyloidogenic fragments, Aβ21-40 and Aβ25-35, of the C-terminal region of the β-amyloid (Aβ) peptide, the major component of Alzheimerʼs disease (AD) neuronal plaques. The most water-soluble complex, 1Ptdep, is able to bind both fragments and to deeply influence the morphology of peptide aggregates. Thioflavin T (ThT) binding assays, electrospray ionization mass spectrometry (ESI-MS), and ultraviolet-visible (UV-vis) absorption spectroscopy indicated that 1Ptdep shows different kinetics and mechanisms of inhibition toward the two sequences and demonstrated that the peptide aggregation inhibition is associated with a direct coordinative bond of the compound metal center to the peptides. These data support the in vitro ability of pentacoordinate Pt(II) complexes to inhibit the formation of amyloid aggregates and pave the way for the application of this class of compounds as potential neurotherapeutics.

Here, the interaction between N,N-dimethyl-selenobenzoamide PhC(=Se)NMe2 (1) and various Lewis acids of different strengths, namely IC6F13(I), B(C6F5)(3) (B) and Met, has been analysed by a combined experimental and theoretical approach. In all cases, an increase of the C-NMe2 rotational barrier has been evidenced and quantified by H-1-variable temperature-exchange NMR spectroscopy (VT-EXSY) in the cases of 1-I and 1-B. For B(C6F5)(3), the structure of the adduct has been elucidated by single crystal X-ray diffraction, allowing the lengthening of the Se-C bond (186 pm) and the consequent double characteristic of the C-NMe2 bond (131 pm) to be measured. Computational studies (mainly natural bond orbitals and natural orbital for chemical valence analyses) gave precious insight into the effect of various Lewis acids on the electronic structure of 1. The advantages and the limitations of this new method to characterize chemical interactions are discussed.

New neutral carbene complexes of gold(I) [Au(Im-Me)X] (X = Cl, Au1; X = Br, Au2; X = I, Au3) have been synthesized and fully characterized by different techniques, including NMR and UV-vis absorption spectroscopy and single crystal X-ray diffraction. The carbene ligand Im-Me is decorated with a glucoside fragment via a triazole linker, obtainable through a click chemistry reaction. The compounds retain the Au-NHC fragment in aqueous solvents, and an equilibrium between the neutral halo- and the cationic di-carbene form [Au(Im-Me)2]+ is observed, whose extent follows the trend Au1 < Au2 < Au3. Cytotoxicity studies on two cancer and two non-tumorigenic cell lines reflect the solution behavior, as a certain difference among the complexes was disclosed, with the iodo complex Au3 being more active and selective. The compounds interact with both DNA and protein model systems. The X-ray structure of the adduct formed upon the reaction of Au1 with bovine pancreatic ribonuclease (RNase A) reveals Au binding at the side chain of His105 of both protein molecules A and B of the asymmetric unit. The binding of gold atoms at both the nitrogen atoms of the imidazole ring of His15 and at the N-terminal tail has been found in the adduct formed with hen egg white lysozyme.

This paper analyzes the way speech-language therapists instruct and correct aphasic speakers regarding the pronunciation of linguistic items and model pronunciation through auditory, verbal, visual, and tactile resources, thus configuring it as an embodied, multi- sensory experience. The data analysis shows that correction of a patient's productions is first initiated by therapists audibly, through repetition of the target item with specific prosodic features, such as loudness and length. When this type of cue proves to be inef- fective, therapists perform instructions and corrective demonstrations through visual and haptic cues: By using their body as an “instructional tool,” they represent, with gestures and facial expressions, features of the target sound. They can also touch a patient's face to help them to correctly realize specific articulatory movements. This paper focuses on the hierarchy of embodied resources that are mobilized by therapists, in an ordered and in- cremental way, to model pronunciation. Moreover, it highlights the methods used to enhance patients' visual attention toward embodied resources and solve issues of bodily coordination. More broadly, this paper highlights the complex embodied nature of speaking and, by focusing on a pathological situation and a therapeutic setting, shows what participants treat as relevant for producing speech sounds in interaction.

This study describes new platinum(II) cationic five-coordinate complexes (1-R,R’) of the formula [PtR(NHC)(dmphen)(ethene)]CF3SO3 (dmphen = 2,9-dimethyl-1,10-phenanthroline), containing in their axial positions an alkyl group R (methyl or octyl) and an imidazole-based NHC-carbene ligand with a substituent R’ of variable length (methyl or octyl) on one nitrogen atom. The Pt–carbene bond is stable both in DMSO and in aqueous solvents. In DMSO, a gradual substitution of dmphen and ethene is observed, with the formation of a square planar solvated species. Octanol/water partitioning studies have revealed the order of hydrophobicity of the complexes (1-Oct,Me > 1-Oct,Oct > 1-Me,Oct > 1-Me,Me). Their biological activity was investigated against two pairs of cancer and non-cancer cell lines. The tested drugs were internalized in cancer cells and able to activate the apoptotic pathway. The reactivity of 1-Me,Me with DNA and protein model systems was also studied using UV–vis absorption spectroscopy, fluorescence, and X-ray crystallography. The compound binds DNA and interacts in various ways with the model protein lysozyme. Remarkably, structural data revealed that the complex can bind lysozyme via non-covalent interactions, retaining its five-coordinate geometry.

Herein, we developed an innovative and easily accessible solid-phase synthetic protocol for Peptide Nucleic Acid (PNA) oligomers by systematically investigating the ultrasonication effects in all steps of the PNA synthesis (US-PNAS). When compared with standard protocols, the application of the so-obtained US-PNAS approach succeeded in improving the crude product purities and the isolated yields of different PNA, including small or medium-sized oligomers (5-mer and 9-mer), complex purine-rich sequences (like a 5-mer Guanine homoligomer and the telomeric sequence TEL-13) and longer oligomers (such as the 18-mer anti-IVS2-654 PNA and the 23-mer anti-mRNA 155 PNA). Noteworthy, our ultrasound-assisted strategy is compatible with the commercially available PNA monomers and well-established coupling reagents and only requires the use of an ultrasonic bath, which is a simple equipment generally available in most synthetic laboratories.

The paddlewheel [Ru2Cl(O2CCH3)4] complex was previously reported to react with the model protein hen egg white lysozyme (HEWL), forming adducts with two diruthenium moieties bound to Asp101 and Asp119 side chains upon the release of one acetate. To study the effect of the equatorial ligands on the reactivity with proteins of diruthenium compounds, X-ray structures of the adducts formed when HEWL reacts with [Ru2Cl(D-p-FPhF)(O2CCH3)3] [D-p-FPhF = N,N'-bis(4-fluorophenyl)formamidinate] under different conditions were solved. [Ru2Cl(D-p-FPhF)(O2CCH3)3] is bonded through their equatorial positions to the Asp side chains. Protein binding occurs cis or trans to D-p-FPhF. Lys or Arg side chains or even main-chain carbonyl groups can coordinate to the diruthenium core at the axial site. Data help to understand the reactivity of paddlewheel diruthenium complexes with proteins, providing useful information for the design of new artificial diruthenium-containing metalloenzymes with potential applications in the fields of catalysis, biomedicine, and biotechnology.

In this contribution, we analyze the specific turn-taking system of translation activity and we propose a praxeological and emic approach to translation units, which traditionally are defined in terms of equivalence between target and source languages. To this end, video-recorded and transcribed excerpts of interaction will be analyzed in their linguistic and multimodal components. Data are drawn from a large corpus of multilingual interactions, in which translation activity is performed by professional interpreters and by bilingual speakers. The theoretical and methodological approach underpinning the study is that of interactional linguistics, a field of research that developed in the 1990s from Conversation Analysis and from an interest for the study of language and grammatical structures in their locus of occurrence – interaction – and with reference to interactional purposes and uses (such as turn-taking).

For their easy and high-yield recombinant production, their high stability in a wide range of physico-chemical conditions and their characteristic hollow structure, ferritins (Fts) are considered useful scaffolds to encapsulate bioactive molecules. Notably, for the absence of immunogenicity and the selective interaction with tumor cells, the nanocages constituted by the heavy chain of the human variant of ferritin (hHFt) are optimal candidates for the delivery of anti-cancer drugs. hHFt nanocages can be disassembled and reassembled in vitro to allow the loading of cargo molecules, however the currently available protocols present some relevant drawbacks. Indeed, protein disassembly is achieved by exposure to extreme pH (either acidic or alkaline), followed by incubation at neutral pH to allow reassembly, but the final protein recovery and homogeneity are not satisfactory. Moreover, the exposure to extreme pH may affect the structure of the molecule to be loaded. In this paper, we report an alternative, efficient and reproducible procedure to reversibly disassemble hHFt under mild pH conditions. We demonstrate that a small amount of sodium dodecyl sulfate (SDS) is sufficient to disassemble the nanocage, which quantitatively reassembles upon SDS removal. Electron microscopy and X-ray crystallography show that the reassembled protein is identical to the untreated one. The newly developed procedure was used to encapsulate two small molecules. When compared to the existing disassembly/reassembly procedures, our approach can be applied in a wide range of pH values and temperatures, is compatible with a larger number of cargos and allows a higher protein recovery.

The increasing resistance of fungi to conventional antifungal drugs has prompted worldwide the search for new compounds. In this work, we investigated the antifungal properties of acylated Temporin L derivatives, Pent-1B and Dec-1B, against Candida albicans, including the multidrug-resistant strains. Acylated peptides resulted to be active both on reference and clinical strains with MIC values ranging from 6.5 to 26 µM, and they did not show cytotoxicity on human keratinocytes. In addition, we also observed a synergistic or additive effect with voriconazole for peptides Dec-1B and Pent-1B through the checkerboard assay on voriconazole-resistant Candida strains. Moreover, fluorescence-based assays, NMR spectroscopy, and confocal microscopy elucidated a potential membrane-active mechanism, consisting of an initial electrostatic interaction of acylated peptides with fungal membrane, followed by aggregation and insertion into the lipid bilayer and causing membrane perturbation probably through a carpeting effect.

Background: Urotensin-II receptor- (UTR) related pathway exerts a key-role in promoting inflammation. The aim was to assess the relationship between UTR expression and clinical, endoscopic and biochemical severity of ulcerative colitis (UC), exploring its predictivity of intravenous (iv) steroid administration therapeutic outcome. Methods: One-hundred patients with first diagnosis of UC and 44 healthy subjects were enrolled. UTR expression was assessed by qPCR, Western Blot (WB) and immunohistochemistry (IHC). Clinical, endoscopic and histological activity of UC were evaluated by using Truelove and Witts (T&W) severity index, Mayo Endoscopic Score (MES), and Truelove and Richards Index (TRI). The partial and full Mayo scores (PMS and FMS) were assessed to stage the disease. Results: The UTR expression, resulted higher in the lesioned mucosa of UC patients in comparison to healthy subjects (p

The most actual environmental problems in the XXI century are the following: global warming due to greenhouse gas emissions, energy production at coal, oil and power plants, air pollution, water pollution and waste recycling. Other environmental problems can be added to this short list, but the authors solve a specific task of promoting the idea of a promising “green” energy that will help humanity in conservation and development. European Union (EU) countries are planning to solve the main environmental challenges for the transition to low-carbon electricity by 2050. In many countries in the world every year there are more and more supporters of reducing emissions of carbon dioxide CO2, nitrogen oxides NO and NO2 and other greenhouse gases into the atmosphere. In recent years, EU has been consistently pursuing its own policy in the field of environmental protection, carrying out large-scale environmental measures. In Germany, United Kingdom (UK) and other European countries, a number of environmental initiatives are already gaining the status of state policy, which is being formalized in laws and regulations. Russian Federation acts on the world market as a leading country that produces and supplies significant energy resources not only to Europe, but also to many countries in the Asia-Pacific region. It is clear that the competitive stability of Russian energy companies significantly depends on the situation on the world energy market, but with the right strategy, Russia can actively influence the state of the entire energy market. With a confident leadership position, provided with significant natural, technological and human resources, Russian Federation has undeniable advantages over other energy-producing countries. It is Russia that can become the main supplier of clean energy for all other countries of the world, where tougher environmental requirements for energy generation are being cultivated. The authors of the study are considering the possibility of producing environmentally friendly hydrogen in Russia based on renewable energy sources (RES). The performed analysis shows the undeniable advantages of Russia in the export of hydrogen to other European countries.

Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes.

Onconase (ONC) is a monomeric amphibian "pancreatic-type" RNase endowed with remarkable anticancer activity. ONC spontaneously forms traces of a dimer (ONC-D) in solution, while larger amounts can be formed when ONC is lyophilized from mildly acidic solutions. Here, we report the crystal structure of ONC-D and analyze its catalytic and antitumor activities in comparison to ONC. ONC-D forms via the three-dimensional swapping of the N-terminal α-helix between two monomers, but it displays a significantly different quaternary structure from that previously modeled [Fagagnini A et al., 2017, Biochem J 474, 3767-81], and based on the crystal structure of the RNase A N-terminal swapped dimer. ONC-D presents a variable quaternary assembly deriving from a variable open interface, while it retains a catalytic activity that is similar to that of ONC. Notably, ONC-D displays antitumor activity against two human melanoma cell lines, although it exerts a slightly lower cytostatic effect than the monomer. The inhibition of melanoma cell proliferation by ONC or ONC-D is associated with the reduction of the expression of the anti-apoptotic B cell lymphoma 2 (Bcl2), as well as of the total expression and phosphorylation of the Signal Transducer and Activator of Transcription (STAT)-3. Phosphorylation is inhibited in both STAT3 Tyr705 and Ser727 key-residues, as well as in its upstream tyrosine-kinase Src. Consequently, both ONC species should exert their anti-cancer action by inhibiting the pro-tumor pleiotropic STAT3 effects deriving either by its phospho-tyrosine activation or by its non-canonical signaling pathways. Both ONC species, indeed, increase the portion of A375 cells undergoing apoptotic cell death. This study expands the variety of RNase domain-swapped dimeric structures, underlining the unpredictability of the open interface arrangement upon domain swapping. Structural data also offer valuable insights to analyze the differences in the measured ONC or ONC-D biological activities.

International audience; Grain storage proteins (GSPs) quantity and composition determine the end-use value of wheat flour. GSPs consists of low-molecular-weight glutenins (LMW-GS), high-molecular-weight glutenins (HMW-GS) and gliadins. GSP gene expression is controlled by a complex network of DNA-protein and protein-protein interactions, which coordinate the tissue-specific protein expression during grain development. The regulatory network has been most extensively studied in barley, particularly the two transcription factors (TFs) of the DNA binding with One Finger (DOF) family, barley Prolamin-box Binding Factor (BPBF) and Scutellum and Aleurone-expressed DOF (SAD). They activate hordein synthesis by binding to the Prolamin box, a motif in the hordein promoter. The BPBF ortholog previously identified in wheat, WPBF, has a transcriptional activity in expression of some GSP genes. Here, the wheat ortholog of SAD, named TaSAD, was identified. The binding of TaSAD to GSP gene promoter sequences in vitro and its transcriptional activity in vivo were investigated. In electrophoretic mobility shift assays, recombinant TaSAD and WPBF proteins bound to cis-motifs like those located on HMW-GS and LMW-GS gene promoters known to bind DOF TFs. We showed by transient expression assays in wheat endosperms that TaSAD and WPBF activate GSP gene expression. Moreover, co-bombardment of Storage Protein Activator (SPA) with WPBF or TaSAD had an additive effect on the expression of GSP genes, possibly through conserved cooperative protein-protein interactions.

Nummular headache is an unusual facial pain disorder with no evidence-based therapy recommendations. The ketogenic diet is an alternative therapy that demonstrated to be effective in migraineurs, but it was never used in the setting of nummular headache. We describe a 58-years old female patient with nummular headache successfully treated with a 6-months ketogenic diet and botulinum toxin type A injections. Ketogenic diet could be an effective alternative/complementary therapy in nummular headache patients although more studies are needed to confirm our results.

IntroductionMechanical thrombectomy (MT) is the first line treatment in acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Approximately half of patients treated with MT does not have a favorable outcome 3 months after stroke. The aim of this study was to identify predictors of futile recanalization (FR) in patients with LVO treated with MT.MethodsA retrospective analysis of consecutive patients with acute ischemic stroke due to anterior circulation LVO who underwent MT. Patients with a TICI score of 2b or 3 were included. We distinguished two groups, FR and meaningful recanalization (MR), according to patients' disability three months after stroke (FR: mRS score > 2; MR: mRS score < 2).ResultsWe enrolled 238 patients (FR, n = 129, 54.2%; MR, n = 109, 45.8%). Age (OR 1.05, 95% CI 1.01–1.09, p = 0.012), female sex (OR 2.43, 95% CI 1.12–5.30, p = 0.025), stress hyperglycemia, as measured by the GAR index, (OR 1.17, 95% CI 1.06–1.29, p = 0.002), NIHSS at admission (OR 1.15, 95% CI 1.07–1.25, p = 0.001) and time from symptoms onset to MT (OR 1.01, 95% CI 1.00–1.01, p = 0.020) were independent predictors of FR. The AUC for the model combining age, female sex, GAR index, NIHSS at admission and time from symptoms onset to MT was 0.81 (95% CI 0.76–0.87; p < 0.001). The optimal GAR index cut-off score to predict FR was 17.9.DiscussionFR is common after MT. We recognized older age, female sex and baseline NIHSS as non-modifiable predictors of FR. On the other hand, time from symptoms onset to MT and stress hyperglycemia were modifiable pre- and post-MT factors, respectively. Any effort should be encouraged to reduce the impact of these modifiable predictors.

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

IntroductionThe geological isolation, lack of freshwater inputs and specific internal water circulations make the Red Sea one of the most extreme—and unique—oceans on the planet. Its high temperature, salinity and oligotrophy, along with the consistent input of hydrocarbons due to its geology (e.g., deep-sea vents) and high oil tankers traffic, create the conditions that can drive and influence the assembly of unique marine (micro)biomes that evolved to cope with these multiple stressors. We hypothesize that mangrove sediments, as a model-specific marine environment of the Red Sea, act as microbial hotspots/reservoirs of such diversity not yet explored and described.MethodsTo test our hypothesis, we combined oligotrophic media to mimic the Red Sea conditions and hydrocarbons as C-source (i.e., crude oil) with long incubation time to allow the cultivation of slow-growing environmentally (rare or uncommon) relevant bacteria.Results and discussionThis approach reveals the vast diversity of taxonomically novel microbial hydrocarbon degraders within a collection of a few hundred isolates. Among these isolates, we characterized a novel species, Nitratireductor thuwali sp. nov., namely, Nit1536T. It is an aerobic, heterotrophic, Gram-stain-negative bacterium with optimum growth at 37°C, 8 pH and 4% NaCl, whose genome and physiological analysis confirmed the adaptation to extreme and oligotrophic conditions of the Red Sea mangrove sediments. For instance, Nit1536T metabolizes different carbon substrates, including straight-chain alkanes and organic acids, and synthesizes compatible solutes to survive in salty mangrove sediments. Our results showed that the Red Sea represent a source of yet unknown novel hydrocarbon degraders adapted to extreme marine conditions, and their discovery and characterization deserve further effort to unlock their biotechnological potential.

This research analysed the size and depth of assortment and the marketing strategies of communications around plant-based beverages (PBBs) on the Italian market. Sales of PBBs have increased over the last year due to their use as a substitute for cow’s milk and also thanks to their popularity in online distribution. This study compares the characteristics of the PBB assortment sold across 65 large-scale retail stores and on 74 websites. The comparison was made considering 15 product categories defined by main ingredient, packaging type, specialty, and claims found on labels. An ordered logit regression analysis was performed to understand how key product features positively or negatively influence the selling price. The results showed that online sales focus on describing plant-based beverages with characteristics that are closer to new consumer preferences (with labels such as “free from” products, “naturalness” of the product, and “health” characteristics). In both distribution channels, there were few products with packaging information related to nutritional characteristics, health benefits, and environmental sustainability, in contrast to the needs expressed by baby food purchasers. Additionally, the price analysis showed unexpected results: in fact, some products for which, according to the literature, consumers would be willing to pay a premium price, instead showed a lower retail price than the average price. These results could represent a concrete tool to improve the efficiency of promotional campaigns and communication strategies for baby food, optimising communication according to consumer needs.

BACKGROUND MXPyV, like MWPyV, was identified in stool samples from children suffering diarrhea in Mexico. In this study, we used a home-made real time PCR to investigate the presence of this novel viruses in stool specimen collected from under-Five- Year-Old Children with gastroenteritis. METHODS A total of 192 fecal specimens previously screened for RV, ADV, NoV, HPeV and SaV, were tested for MWPyV with Taqman real time PCR. RESULTS The most commonly detected virus was NoV GII (33.8%), followed by RV (21.3%), SaV (10.9%), HPeV(8%), NoV GI (6.7%) and AdV (1%). Real time PCR detected MWPyV in 1/192 (0.5%) patients. CONCLUSIONS We detected MWPyV in 0.5% of fecal specimens collected from pediatric patients suffering gastroenteritis which is smaller than the previously reported in literature (4.4% in Australia and 12% Mexico).

ImportanceAcute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk.ObjectiveTo compare mortality and risk of epilepsy following different types of acute symptomatic seizures.Design, Setting, and ParticipantsThis cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022.ExposuresType of acute symptomatic seizure.Main Outcomes and MeasuresAll-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke).ResultsA total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy.Conclusions and RelevanceIn this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up.

Intratumoral heterogeneity (ITH) can promote cancer progression and treatment failure, but the complexity of the regulatory programs and contextual factors involved complicates its study. To understand the specific contribution of ITH to immune checkpoint blockade (ICB) response, we generated single cell-derived clonal sublines from an ICB-sensitive and genetically and phenotypically heterogeneous mouse melanoma model, M4. Genomic and single cell transcriptomic analyses uncovered the diversity of the sublines and evidenced their plasticity. Moreover, a wide range of tumor growth kinetics were observedin vivo, in part associated with mutational profiles and dependent on T cell-response. Further inquiry into melanoma differentiation states and tumor microenvironment (TME) subtypes of untreated tumors from the clonal sublines demonstrated correlations between highly inflamed and differentiated phenotypes with the response to anti-CTLA-4 treatment. Our results demonstrate that M4 sublines generate intratumoral heterogeneity at both levels of intrinsic differentiation status and extrinsic TME profiles, thereby impacting tumor evolution during therapeutic treatment. These clonal sublines proved to be a valuable resource to study the complex determinants of response to ICB, and specifically the role of melanoma plasticity in immune evasion mechanisms.

Supplementary Figure Legends and Figures

Supplementary Table S1. Commercial tumor TMAs representing different solid tumor types. Supplementary Table S2. Summary of CD205 expression in human solid tumor types.