Effetti della chiralità su librerie covalenti dinamiche di peptidi

I peptidi sono una classe di biomolecole in grado di attrarre molto interesse in diversi campi scientifici, grazie alla loro biocompatibilità e alla possibilità di assemblare in superstrutture in acqua. In particolare, i ciclopeptidi composti da α-amino acidi sono stati intensivamente studiati per la loro abilità di assemblare in nanotubi supramolecolari, i quali sono tenuti assieme da interazioni di legame idrogeno. L’intensiva ricerca in questa area ha elucidato le regole del design del loro auto-assemblaggio in termini di stereoconfigurazione e composizione amino-acidica. Tuttavia, uno studio estensivo di questa classe di composti richiede uno sforzo sintetico non banale. La chimica dinamica covalente offre quindi un’alternativa interessante alla classica sintesi consentendo di produrre ciclopeptidi da mattoncini lineari molto più semplici da sintetizzare. In questo modo, i reagenti si combinano in una libreria dinamica covalente. Inoltre, la formazione di legami covalenti sotto equilibrio termodinamico in concomitanza all’autoassemblaggio possono essere usati come possibile strada per scoprire nuove suprastrutture, grazie all’effetto di autoreplicazione. Un set di stereoisomeri tripeptidici Cys-Phe-Cys sono stati sintetizzati per studiare la loro abilità di reagire covalentemente in acqua alcalina attraverso lo scambio tiolo/disolfuro. Lo stereoisomerismo ha influito sulla chimica dinamica portando alla formazione di diversi oligomeri ciclici e ha permesso di fare luce sulle differenze chiave tra la libreria omochirale e quelle eterochirali. Gli oligomeri ciclici sono stati purificati con la cromatografia ad alta prestazione a fase inversa e caratterizzati da RMN e diffrazione a raggi X. Una particolare stereoconfigurazione ha permesso alla libreria di auto assemblarsi in un idrogel composto da un solo macrociclo all’equilibrio termodinamico. L’analisi del materiale supramolecolare da reologia, dicroismo circolare e microscopia a trasmissione elettronica ha rivelato la presenza di una struttura anisotropica allungata compatibile con la presenza di nanotubi, i quali il diametro potrebbe corrispondere alla taglia del mattoncino macrociclico. Questo composto ha conformazioni simili a diversi pH ma è in grado di auto assemblarsi solo quando si trova in forma zwitterionica. Riassumendo, questo studio dimostra come una scelta appropriata della stereoconfigurazione degli amino acidi su semplici tripeptidi può essere strategica nel progettare diverse strutture cicliche e in casi specifici, ottenere librerie in grado di convergere verso un gel composto da un unico prodotto. Questa ricerca pone quindi le basi per accedere facilmente ad una nuova classe di ciclopeptidi auto assemblanti che possono trovare varie applicazioni nella scienza di materiali e oltre.Peptides are a class of biomolecules that has attracted a lot of interest in different scientific fields, thanks to their biocompatibility and potential to self-assemble into supramolecular structures in water. In particular, cyclopeptides composed of α-amino acids have been intensively studied for their ability to stack into supramolecular nanotubes, which are held together by intermolecular hydrogen bonding. The intense research efforts in this area have unravelled the design rules for self-assembly in terms of stereoconfiguration, and amino-acidic composition. However, an extensive investigation on this class of compounds requires a synthetic effort that is not trivial. Dynamic covalent chemistry (DCC) thus offers an appealing alternative to classical chemical synthesis, to yield cyclopeptides from linear building blocks that are simpler to synthesise. In this way, the reagents can combine into a dynamic covalent library (DCL). Furthermore, the formation of covalent bonds under thermodynamic equilibrium can be used together with the self-assembly process, as a possible route to discover new suprastructures, thanks to the self-templating effect. A set of Cys-Phe-Cys tripeptide stereoisomers was synthesised to study their ability to undergo DCC in alkaline water, through thiol/disulfide exchange. The stereoisomerism impacted the DCC leading to the formation of diverse cyclic oligomers, and it allowed to shed light on key differences between the homochiral, and the heterochiral DCLs. Cyclic oligomers were purified by reverse-phase HPLC, and characterised by NMR and single-crystal XRD. A particular stereoconfiguration enabled the DCL to self-assemble into a hydrogel composed of only one macrocycle at the thermodynamic equilibrium. The analysis on the supramolecular material by rheology, circular dichroism, and transmission electron microscopy revealed the presence of an anisotropic and elongated supramolecular structure, compatible with the presence of nanotubes whose diameter could correspond to the size of its macrocyclic building block. This compound had a similar conformation in solution at different pH values, but it was able to self-assemble into hydrogels only in the zwitterionic form. Overall, this study demonstrated how an appropriate choice of amino acid stereoconfiguration on simple tripeptides can be a strategic design tool towards diverse cyclic structures and, in specific cases, to yield DCLs that eventually converge into a main gelator product. This research work thus laid the basis to easily access a new class of self-assembling cyclopeptides that could find various applications in materials science, and beyond

Immediate sequential bilateral cataract surgery: Prevalence, attitudes and concerns Among Italian ophthalmologists

Purpose: to investigate the existing practice patterns of immediate sequential bilateral cataract surgery (ISBCS) in Italy and to assess ophthalmologists' attitudes towards performing ISBCS in the future for cataract treatment. Methods: It is a multicenter cross-sectional study. From February,1st 2023 to March, 1st 2023 the Members of the Italian Society of Cataract and Refractive Surgery (AICCER) as well as the attendees of its annual national congress were invited to anonymously complete an electronic 7-item questionnaire on their current ICBCS practice. Questions included the average number of procedures per month, the main indications for ICBCS, and the main reasons for performing and not performing ISBCS. Data were analyzed using descriptive statistics. Results: of the 2300 recipients, 246 (10.7%) completed the survey. Of the respondents, 156 (63.4%) replied to perform ISBCS, most of them (82%) occasionally (1 to 5 procedures per month). Fifty-three percent (130 ophthalmologists) considered adopting ISBCS as routine practice in the near future. The conditions most considered for ISBCS were age-related cataract surgery under general and topical anesthesia and congenital cataract surgery. The availability of separate instruments for the two eyes as well as patient and hospital advantages were the most important reasons for performing ISBCS. The risk of bilateral endophthalmitis and medicolegal issues were the main reasons for not performing ISBCS. Conclusions: ISBCS remains controversial among Italian surgeons, despite growing evidence of its safety and efficacy. The risk of potentially blinding complications such as bilateral endophthalmitis, together with medicolegal concerns are the principal barriers to ISBCS implementation in routine practice

TinyML models for SoH estimation of lithium-ion batteries based on Electrochemical Impedance Spectroscopy

As battery systems become more widespread, the need for accurate and fast estimation of State of Health (SoH) in lithium-ion cells is increasingly critical. This study analyzes two data-driven model methods that leverage Electrochemical Impedance Spectroscopy (EIS) measurements to capture the internal electrochemical dynamics underlying battery degradation and estimate the cell’s current SoH. The first approach, Method A, utilizes an Equivalent Circuit Model (ECM) from EIS data and uses it to train various state-of-the-art Deep Learning (DL) models, including LSTM, GRU, CNN-LSTM, and CNN-GRU. In contrast, Method B directly employs raw EIS data to train the same set of DL models, bypassing the need for ECM development. Both methods demonstrated strong performance, with the CNN-GRU model from Method B yielding the best results, achieving a Mean Absolute Error (MAE) of only 0.87% and a Root Mean Square Error (RMSE) of 1.20%. Additionally, both methods included an analysis of various input features, such as State of Charge (SoC), to evaluate their impact on model performance. Finally, the models of Method B were optimized for size and computational efficiency, making them suitable for deployment on low-power edge devices and applications requiring TinyML capabilities. The average latency and size reduction of the models were 99.61% and 88.61%, respectively

The source of mafic post-collisional magmatism in the Southern Variscan domain: Insights from the Permian dyke swarms of northern Sardinia

Early Permian post-collisional magmatism is widely spread in southern Europe and it is represented by both felsic and mafic occurrences. One of the best places to observe such magmatism is northern Sardinia, where felsic Late Carboniferous-Early Permian batholiths are intruded by a large number of mafic dyke swarms. This study focuses on several dykes of mafic and intermediate composition from the Gallura region (northern Sardinia, Italy) that were emplaced during the extensional event(s) related to the collapse of the Variscan orogen. Based on textural, chemical and isotopic data the dikes are divided in three groups. Group 1 and Group 3 generally show calcalkaline affinity, moderate to high enrichment in LREE over HREE, respectively, strong enrichments in LILE, Nb and Ta negative anomaly. Group 1 samples show more radiogenic Nd and less radiogenic Sr isotopic values compared to Group 3, while the two groups show similar Pb isotopic values. Group 2 shows depleted LREE and depleted Srsingle bondNd isotopic composition, relatively close to those of MORBs. Nonetheless, the negative Nb anomaly and Pb isotopic composition clearly distinct from those of MORBs highlight the subduction signature also in dykes from this group. Our modelling suggest that the distinctive geochemical features of the three groups are not related to closed-system fractional crystallization or to crustal assimilation, but they are the result of melting of a heterogeneous mantle source. Group 1 and 2 could have formed by melting of a peridotite at the transition of the spinel and garnet stability, with Group 1 possibly requiring a more enriched mantle composition and generally lower melting temperature. By contrast, a peridotite-pyroxenite mixture or an amphibole peridotite is the most likely source of Group 3 dykes. The widespread coeval Early Permian mafic dykes and intrusive bodies from Southern Europe show geochemical features that are quite similar to those of northern Sardinia dykes. The comparison shows that the most common magma-types are similar to Group 1 and subordinately to Group 3 from Sardinia, suggesting that most of the mafic Early Permian post Variscan magmatism was formed by melting a mantle that was enriched during the Variscan orogeny. On the contrary, Group 2-like magmatism is very scarce in southern Europe and its more depleted compositions are probably the result of decompression melting of asthenospheric mantle with a subtle subduction signature

Single-dose (10 mg) psilocybin reduces symptoms in adults with obsessive-compulsive disorder: A pharmacological challenge study

Background Obsessive-compulsive disorder (OCD) is a common and disabling condition. A large proportion of patients fail to respond to first-line treatment with serotonin reuptake inhibitors either selective serotonin reuptake inhibitors (SSRIs) or clomipramine. Preliminary evidence suggests psilocybin, a serotonin receptor agonist, might be efficacious. We conducted a pharmacological challenge study to investigate the efficacy and mechanisms of effect of psilocybin in OCD. This analysis reports the clinical outcomes only. Methods Participants with a diagnosis of OCD of at least moderate severity, received two single doses of oral psilocybin, 1 mg followed by 10 mg, administered in fixed order separated by 4 weeks. On the day of dosing, they were treated in a day-care facility in the presence of clinicians experienced in the use of psychedelics for treating mental disorders. Psychological support was provided before, during and after dosing. Participants and raters were blinded to the order of treatment. They were assessed on the day before each dose (baseline 1, 2), on the day of dosing and at intervals over a 4-week period afterward using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (primary clinical outcome) and secondary clinical outcomes including the Montgomery-Åsberg Depression Rating Scale (MADRS). Adverse effects were also recorded. Results Nineteen adult participants (aged 20–60) entered the study and 18 completed all assessments. Clinical outcomes following 1 mg and 10 mg psilocybin were compared using a linear mixed-effects model and ANOVA. A significant between-dosage effect favouring 10 mg psilocybin was found one-week after dosing on the Y-BOCS (Cohen's d = 0.82, p = 0.002). In particular, the effect one-week after dosing was statistically significant on the compulsion subscale of the Y-BOCS (Cohen's d: 0.74, p = 0.003), compared to obsession (Cohen's d: 0.50, p = 0.06). The effect diminished over the subsequent 3 weeks. No effect of psilocybin was detected on the MADRS. Psilocybin was well tolerated, with few adverse events reported at both dosages and no serious adverse events. Conclusions In this study, which was limited by a small sample size and the absence of randomisation, a 10 mg dose of oral psilocybin was found to be well-tolerated and potentially efficacious in patients with OCD. Psilocybin produced a rapid-onset, moderate to large effect on compulsive symptoms, which lasted up to one week after dosing. Future randomised placebo-controlled clinical trials investigating a longer course of multiple weekly doses of 10 mg psilocybin are indicated in OCD and in other obsessive-compulsive and related disorders characterised by compulsions

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The essay traces the stages of philosophical reflection on time identifying their progressive sedimentation. Despite the variety, even conflicting, of solutions, the perception that time is ultimately a form of relationship emerges as a common background. Time is the way in which this relationship is articulated. But if time is primarily inherent to finiteness, as modernity has shown us through the successive passages of the inescapability of the subject and of secularization, it follows that the relationship essentially constitutes the finite. At a metaphysical level, we could also read the relationship between essence and existence as a form of temporalization, as the way in which the eternal and temporal dimensions become part of a declination. That is, it invests the very nature of the thing and regulates the way it appears. All this suggests to us to conceive time as a form of articulation of the intemporal

Titin-related familial dilated cardiomyopathy: factors associated with disease onset

Background and aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80-30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06-5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27-3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35-9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08-.23). Conclusions: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention

Measurement of top-quark pair production in association with charm quarks in proton–proton collisions at s=13 TeV with the ATLAS detector

Inclusive cross-sections for top-quark pair production in association with charm quarks are measured with proton–proton collision data at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 140 fb−1, collected with the ATLAS experiment at the LHC between 2015 and 2018. The measurements are performed by requiring one or two charged leptons (electrons and muons), two b-tagged jets, and at least one additional jet in the final state. A custom flavor-tagging algorithm is employed for the simultaneous identification of b-jets and c-jets. In a fiducial phase space that replicates the acceptance of the ATLAS detector, the cross-sections for tt ̄+≥2c and tt ̄+1c production are measured to be 1.28−0.24+0.27pb and 6.4−0.9+1.0pb, respectively. The measurements are primarily limited by uncertainties in the modeling of inclusive tt ̄ and tt ̄+bb ̄ production, in the calibration of the flavor-tagging algorithm, and by data statistics. Cross-section predictions from various tt ̄ simulations are largely consistent with the measured cross-section values, though all underpredict the observed values by 0.5 to 2.0 standard deviations. In a phase-space volume without requirements on the tt ̄ decay products and the jet multiplicity, the cross-section ratios of tt ̄+≥2c and tt ̄+1c to total tt ̄+jets production are determined to be (1.23±0.25)% and (8.8±1.3)%

Navigating Complex Environments with Finite-State Controllers

Organisms relying on chemical cues for navigation face significant challenges due to complexity in the environment. For instance, atmospheric turbulence dilutes and mixes odor signals with other scents and clean air, providing only weak, intermittent cues for insects like moths to navigate. Despite these challenges, many species develop effective strategies to locate distant targets in complex environments. This raises a key question: how are the sporadic chemical signals utilized to implement efficient source-localization strategies? The searcher’s memory of previously detected signals plays a vital role in this process. Current algorithms typically require continuous memory spaces with high dimensionality, which may impede optimization and complicate interpretation. In this research, we demonstrate through a computational modeling of the source localization problem that finite-state controllers, simple algorithmic devices with minimal memory requirements, are rich enough to explain various behavioral patterns observed in nature, first in the context of olfactory search. The controller’s memory states emerged to encode dual information streams: temporal data functioning as a clock, and spatial data serving as a map. In the microscale level, we developed a finite-state controller for E. coli chemotaxis that achieves precise adaptation and exhibits positive responses to increasing stimuli. Lastly, we extend the olfactory search problem to analyze sourcetracking in an alternative context: a porous medium characterized by chaotic flow patterns, where agents must simultaneously learn to circumvent obstacles while localizing a chemical signal source. Our findings demonstrate that finite-state controllers are simple yet powerful tools for understanding behavioral patterns in diverse navigation scenarios

Skin biocompatibility of hexagonal boron nitride: An in vitro study on HaCaT keratinocytes and 3D reconstructed human epidermis

Hexagonal boron nitride (hBN) is a promising two-dimensional (2D) material of interest to the scientific community and industry due to its revolutionary physico-chemical features. Skin contact is one of the most feasible exposure routes both for workers, producing hBN, and consumers, using hBN-enabled nanotechnologies. Hence, the toxic potential of hBN at the cutaneous level was evaluated following an in vitro approach with different degree of complexity, using a simplified cell model (HaCaT keratinocytes), and a more predictive and complete skin tissue (a 3D model of human epidermis). Despite its significant uptake by keratinocytes, hBN exerted only weak adverse effects, such as slight alterations of cells parameters indices of cytotoxicity (cell viability, cell mass and plasma membrane integrity) and mitochondrial-related dysfunctions (mitochondrial depolarization, ATP depletion and reactive oxygen species production), detectable only at high concentrations (>25 μg/mL) and mainly after a long exposure (72 h). In addition, adoption of the OECD TG 431 and 439 on the 3D reconstructed human epidermis model demonstrated hBN as a non-corrosive and non-irritant material, with an extremely low pro-inflammatory potential. These results denote a good biocompatibility of hBN at the skin level