Second-Generation Light-Fueled Supramolecular Pump

open7noFinancial support from the European Research Council (H2020 Advanced Grant 692981 to A.C.)We describe the modular design of a pseudorotaxane-based supramolecular pump and its photochemically driven autonomous nonequilibrium operation in a dissipative regime. These properties derive from careful engineering of the energy maxima and minima along the threading coordinate and their light-triggered modulation. Unlike its precursor, this second-generation system is amenable to functionalization for integration into more complex devices.openCanton, Martina; Groppi, Jessica; Casimiro, Lorenzo; Corra, Stefano; Baroncini, Massimo; Silvi, Serena; Credi, AlbertoCanton, Martina; Groppi, Jessica; Casimiro, Lorenzo; Corra, Stefano; Baroncini, Massimo; Silvi, Serena; Credi, Albert

Precision molecular threading/dethreading

Abstract: The general principles guiding the design of molecular machines based on interlocked structures are well known. Nonetheless, the identification of suitable molecular components for a precise tuning of the energetic parameters that determine the mechanical link is still challenging. Indeed, what are the reasons of the \u201call-or-nothing\u201d effect, which turns a molecular \u201cspeed-bump\u201d into a stopper in pseudorotaxane-based architectures? Here we investigate the threading and dethreading processes for a representative class of molecular components, based on symmetric dibenzylammonium axles and dibenzo[24]crown-8 ether, with a joint experimental-computational strategy. From the analysis of quantitative data and an atomistic insight, we derive simple rules correlating the kinetic behaviour with the substitution pattern, and provide rational guidelines for the design of modules to be integrated in molecular switches and motors with sophisticated dynamic feature

Improving Fatigue Resistance of Dihydropyrene by Encapsulation within a Coordination Cage

Photochromic molecules undergo reversible isomerization upon irradiation with light at different wavelengths, a process that can alter their physical and chemical properties. For instance, dihydropyrene (DHP) is a deep-colored compound that isomerizes to light-brown cyclophanediene (CPD) upon irradiation with visible light. CPD can then isomerize back to DHP upon irradiation with UV light or thermally in the dark. Conversion between DHP and CPD is thought to proceed via a biradical intermediate; bimolecular events involving this unstable intermediate thus result in rapid decomposition and poor cycling performance. Here, we show that the reversible isomerization of DHP can be stabilized upon confinement within a (PdIIL4)-L-6 coordination cage. By protecting this reactive intermediate using the cage, each isomerization reaction proceeds to higher yield, which significantly decreases the fatigue experienced by the system upon repeated photocycling. Although molecular confinement is known to help stabilize reactive species, this effect is not typically employed to protect reactive intermediates and thus improve reaction yields. We envisage that performing reactions under confinement will not only improve the cyclic performance of photochromic molecules, but may also increase the amount of product obtainable from traditionally low-yielding organic reactions

Impact of Polychlorinated Biphenyls Contamination on Estrogenic Activity in Human Male Serum

Polychlorinated biphenyls (PCBs) are thought to cause numerous adverse health effects, but their impact on estrogen signaling is still not fully understood. In the present study, we used the ER-CALUX bioassay to determine estrogenic/antiestrogenic activities of the prevalent PCB congeners and PCB mixtures isolated from human male serum. The samples were collected from residents of an area with an extensive environmental contamination from a former PCB production site as well as from a neighboring background region in eastern Slovakia. We found that the lower-chlorinated PCBs were estrogenic, whereas the prevalent higher-chlorinated PCB congeners 138, 153, 170, 180, 187, 194, 199, and 203, as well as major PCB metabolites, behaved as anti-estrogens. Coplanar PCBs had no direct effect on estrogen receptor (ER) activation in this in vitro model. In human male serum samples, high levels of PCBs were associated with a decreased ER-mediated activity and an increased dioxin-like activity, as determined by the DR-CALUX assay. 17β-Estradiol (E(2)) was responsible for a major part of estrogenic activity identified in total serum extracts. Significant negative correlations were found between dioxin-like activity, as well as mRNA levels of cytochromes P450 1A1 and 1B1 in lymphocytes, and total estrogenic activity. For sample fractions containing only persistent organic pollutants (POPs), the increased frequency of anti-estrogenic samples was associated with a higher sum of PCBs. This suggests that the prevalent non-dioxin-like PCBs were responsible for the weak antiestrogenic activity of some POPs fractions. Our data also suggest that it might be important to pay attention to direct effects of PCBs on steroid hormone levels in heavily exposed subjects

The J2-Immortalized Murine Macrophage Cell Line Displays Phenotypical and Metabolic Features of Primary BMDMs in Their M1 and M2 Polarization State

Macrophages are immune cells that are important for the development of the defensive front line of the innate immune system. Following signal recognition, macrophages undergo activation toward specific functional states, consisting not only in the acquisition of specific features but also of peculiar metabolic programs associated with each function. For these reasons, macrophages are often isolated from mice to perform cellular assays to study the mechanisms mediating immune cell activation. This requires expensive and time-consuming breeding and housing of mice strains. To overcome this issue, we analyzed an in-house J2-generated immortalized macrophage cell line from BMDMs, both from a functional and metabolic point of view. By assaying the intracellular and extracellular metabolism coupled with the phenotypic features of immortalized versus primary BMDMs, we concluded that classically and alternatively immortalized macrophages display similar phenotypical, metabolic and functional features compared to primary cells polarized in the same way. Our study validates the use of this immortalized cell line as a suitable model with which to evaluate in vitro how perturbations can influence the phenotypical and functional features of murine macrophages

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A directed search for gravitational waves from Scorpius X-1 with initial LIGO

19 pages, 8 figuresInternational audienceWe present results of a search for continuously-emitted gravitational radiation, directed at the brightest low-mass X-ray binary, Scorpius X-1. Our semi-coherent analysis covers 10 days of LIGO S5 data ranging from 50-550 Hz, and performs an incoherent sum of coherent $\mathcal{F}$-statistic power distributed amongst frequency-modulated orbital sidebands. All candidates not removed at the veto stage were found to be consistent with noise at a 1% false alarm rate. We present Bayesian 95% confidence upper limits on gravitational-wave strain amplitude using two different prior distributions: a standard one, with no a priori assumptions about the orientation of Scorpius X-1; and an angle-restricted one, using a prior derived from electromagnetic observations. Median strain upper limits of 1.3e-24 and 8e-25 are reported at 150 Hz for the standard and angle-restricted searches respectively. This proof of principle analysis was limited to a short observation time by unknown effects of accretion on the intrinsic spin frequency of the neutron star, but improves upon previous upper limits by factors of ~1.4 for the standard, and 2.3 for the angle-restricted search at the sensitive region of the detector

Inhibition of lactate export and cystine import to shutter metabolic fueling of antioxidant defence in chemoresistant medulloblastoma cells: a new strategy to overcome chemotherapy resistance

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Using light to study and operate supramolecular systems and motors

In Chapter 1 an introduction and significant examples from literature concerning the topics described in the following chapters are included. Successively, examples of molecular cages and containers are illustrated and the possible advantages of reactivity under confinement are described. Finally, the topic of molecular machines is discussed. In Chapter 2 a light-activated molecular pump is illustrated. In the first part of the chapter the description of the properties and the operation of this motor is reported. Secondly, different optimization approaches are introduced, among them the substitution of the pseudostopper unit have been investigated.In Chapter 3 a novel rotaxane (15) is described. Interestingly, this assembly presents both a point chiral element, due to the presence of an oxazoline moiety, and a mechanical one, intrinsic effect of the mechanical bond. Interestingly, this assembly presents both a point chiral element, due to the presence of an oxazoline moiety, and a mechanical one, intrinsic effect of the mechanical bond. Furthermore, the aim of this project is to exploit this structure as a switchable and possibly asymmetric catalyst, by using a pH-driven and a coordination-driven approach.In Chapter 4 the encapsulation of the photochromic DHP unit within a coordination molecular cage is reported. Initially, the formation and characterization of the complex are reported. The data showed a significant difference in the fatigue experienced by the encapsulated guest with the respect to the free DHP dissolved in organic solvents. Therefore, the improving contribution of the encapsulation was successfully proven

3D in vitro Models of Pathological Skeletal Muscle: Which Cells and Scaffolds to Elect?

Skeletal muscle is a fundamental tissue of the human body with great plasticity and adaptation to diseases and injuries. Recreating this tissue in vitro helps not only to deepen its functionality, but also to simulate pathophysiological processes. In this review we discuss the generation of human skeletal muscle three-dimensional (3D) models obtained through tissue engineering approaches. First, we present an overview of the most severe myopathies and the two key players involved: the variety of cells composing skeletal muscle tissue and the different components of its extracellular matrix. Then, we discuss the peculiar characteristics among diverse in vitro models with a specific focus on cell sources, scaffold composition and formulations, and fabrication techniques. To conclude, we highlight the efficacy of 3D models in mimicking patient-specific myopathies, deepening muscle disease mechanisms or investigating possible therapeutic effects