Resveratrol-like Compounds as SIRT1 Activators

The sirtuin 1 (SIRT1) activator resveratrol has emerged as a promising candidate for the prevention of vascular oxidative stress, which is a trigger for endothelial dysfunction. However, its clinical use is limited by low oral bioavailability. In this work, we have applied a previously developed computational protocol to identify the most promising derivatives from our in-house chemical library of resveratrol derivatives. The most promising compounds in terms of SIRT1 activation and oral bioavailability, predicted in silico, were evaluated for their ability to activate the isolated SIRT1 enzyme. Then, we assessed the antioxidant effects of the most effective derivative, compound 3d, in human umbilical vein endothelial cells (HUVECs) injured with H₂O₂ 100 µM. The SIRT1 activator 3d significantly preserved cell viability and prevented an intracellular reactive oxygen species increase in HUVECs exposed to the oxidative stimulus. Such effects were partially reduced in the presence of a sirtuin inhibitor, sirtinol, confirming the potential role of sirtuins in the activity of resveratrol and its derivatives. Although 3d appeared less effective than resveratrol in activating the isolated enzyme, the effects exhibited by both compounds in HUVECs were almost superimposable, suggesting a higher ability of 3d to cross cell membranes and activate the intracellular target SIRT1.     

Stem Cell Therapy for Sequestration of Traumatic Brain Injury-Induced Inflammation

Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disabilities in the world. TBI is a signature disease for soldiers and veterans, but also affects civilians, including adults and children. Following TBI, the brain resident and immune cells turn into a “reactive” state, characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Other injuries to the brain, including radiation exposure, may trigger TBI-like pathology, characterized by inflammation. Currently there are no treatments to prevent or reverse the deleterious consequences of brain trauma. The recognition that TBI predisposes stem cell alterations suggests that stem cell-based therapies stand as a potential treatment for TBI. Here, we discuss the inflamed brain after TBI and radiation injury. We further review the status of stem cells in the inflamed brain and the applications of cell therapy in sequestering inflammation in TBI.     

Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches.     

Of Mouse and Man: Cross-Species Characterization of Hypertensive Cardiac Remodeling

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the disease. While the components of hypertensive remodelling are well established, the timeline and comparative quantification of pathological changes in hypertension have not been shown before. Here, we sought to identify the phasing of cardiac remodelling with hypertension using post-mortem tissue from SCD patients with early and advanced hypertensive heart disease (HHD). In order to study and quantify the progression of phenotypic changes, human specimens were contrasted to a well-described angiotensin-II-mediated hypertensive mouse model. While cardiomyocyte hypertrophy is an early adaptive response in the mouse that stabilises in established hypertension and declines as the disease progresses, this finding did not translate to the human setting. In contrast, optimising fibrosis quantification methods and applying them to each setting identified perivascular fibrosis as the prevailing possible cause for overall disease progression. Indeed, assessing myocardial inflammation highlights CD45+ inflammatory cell infiltration that precedes fibrosis and is an early-phase event in response to elevated arterial pressures that may underscore perivascular remodelling. Along with aetiology insight, we highlight cross-species comparison for quantification of cardiac remodelling in human hypertension. As such, this platform could assist with the development of therapies specific to the disease phase rather than targeting global components of hypertension, such as blood pressure lowering.     

Coordinated construction logistics: an innovation perspective

Coordinated construction logistics is an increasingly discussed topic in the Swedish construction industry. It is suggested as a means to increase efficiency in transportation, decrease material usage, coordinate health and safety on-site, etc. Much research on construction logistics has been done from a supply chain management perspective, often highlighting construction logistics as a necessary rational tool to improve efficiency in construction industry. However, could there be other ways to study this phenomenon? The purpose of this paper is to map empirically found coordinated construction logistics models and explore them as different types of innovation. The findings suggest that coordinated construction logistics models should be regarded as not being a fully embedded innovation as they have not yet changed the processes in the way they set out to do initially. Furthermore, differences are identified between company-based models, project-based models and system-based models, and suggest that differences in, for example, development, impact and objectives should be regarded both when conducting research on and when implementing coordinated construction logistics in practice. Finally, it is concluded that commitment, communication and cooperation are important when implementing coordinated construction logistics, which is in line with findings within the supply chain management literature.     

Carbon nanotube micropillars trigger guided growth of complex human neural stem cells networks

Nano Research - New strategies for spatially controlled growth of human neurons may provide viable solutions to treat and recover peripheral or spinal cord injuries. While topography cues are known...     

Who controls our data? The legal reasoning of the European Court of Justice in Wirtschaftsakademie Schleswig-Holstein and Tietosuojavaltuutettu v Jehovan todistajat

This paper analyses two judgments from the European Court of Justice. Both were delivered soon after the new Data Protection Regulation became applicable. The argumentation in the judgments provides timely clarification on certain key concepts in European data protection law. As the analysis will show, the ECJ continues its broad interpretation of the parties responsible for data processing. The judgments are generally compatible with the Court’s previous case law, which seeks to fill any potential gaps in the protection of individuals’ privacy rights. Hence, the aims of data protection rules are predominately interpreted by the Court within a fundamental rights framework. Even though the cases have certain significant differences, the conclusions to be drawn are similar: the argumentation of the Court is focused on data protection throughout. Moreover, the Court emphasises strong protection of personal data in all kinds of situations, even those where other rights could also be relevant.     

Tracking the Aquatic Impacts of a Historical Metal Mine Using Lacustrine Protists and Diatom Algae

Two lake sediment cores collected near a closed Cu–Au mine were analyzed for testate amoebas, diatoms, and geochemistry to compare their utility for assessment and monitoring of aquatic impacts of metal mines. Geochemical profiles displayed the mine history as increases in mineral matter-related elements during the mining period, and as post-mining metal peaks. Biotic assemblages co-varied with geochemical shifts, and the most notable ecological changes coincided with the peaks in metal concentrations. Additionally, nutrient enrichment caused a major shift in biotic assemblages. According to the results, the mine affected the lake environment over a relatively large area but the changes were transient. Major ecological effects occurred only after the actual mining period as the tailings weathered, which delayed the metal release. This suggests that mine impacts can be significantly reduced by careful design and after-care of the waste facilities.     

Astronomy and Etruscan Ritual: The Case of the Ara della Regina in Tarquinia

The ancient town of Tarquinia is the key place of the Etruscan system of beliefs, since its foundations were credited to Tarchon, descendant of the Greek hero Herakles, founder of the Etruscan League, and discloser of the sacred texts of the Etrusca Disciplina. These were said to come from the infant oracle Tages, who sprang out from the terrain in front of Tarchon while he was ploughing a field. In order to gain a better understanding of the relationship between the archaeological records and the Etruscan symbolic world we investigate here on different orientations and on their possible symbolic meaning at the Ara della Regina, the sanctuary of Tarquinia. The main base appears to be related to the sun rising a decades before the spring equinox, while the Archaic altar, probably representing Tarchon’s cenotaph, was orientated to the setting of the constellation Herakles.     

Functional Modification of Fibronectin by N‐Terminal FXIIIa‐Mediated Transamidation

A straightforward strategy is presented for the site‐specific incorporation of fluorophores or reactive probes into the extracellular matrix (ECM) protein fibronectin (Fn) by using the enzyme‐catalyzed transamidation by activated factor XIII. Characterization by SDS‐PAGE, western blotting, absorption measurements, mass spectrometry, and stepwise photobleaching for labeling quantification at the single‐molecule level showed that the labeling was efficient and restricted to the N‐terminal tails. The introduction of labels did not interfere with Fn fibrillogenesis, as verified by the incorporation of fluorescently labeled Fn into ECM and manually pulled Fn fibers. Site‐specific incorporation of an azide was used to create a template for bioorthogonal click chemistry reactions in a second bioconjugation step, thus offering versatile modification and application possibilities in the context of matrix biology and tissue engineering.