Thymulin inhibits monocrotaline-induced pulmonary hypertension modulating interleukin-6 expression and suppressing p38 pathway

The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zinc-dependent thymic hormone, has important immunobiological effects by inhibiting various proinflammatory cytokines and chemokines. We investigated morphological and hemodynamic effects of thymulin administration in a rat model of monocrotaline (MCT)-induced PH, as well as the pattern of proinflammatory cytokine gene expression and the intracellular pathways involved. Adult Wistar rats received an injection of MCT (60 mg/kg, sc) or an equal volume of saline. One day after, the animals randomly received during 3 wk an injection of saline, vehicle (zinc plus carboxymethyl cellulose), or thymulin (100 ng/kg, sc, daily). At d 23-25, the animals were anesthetized for hemodynamic recordings, whereas heart and lungs were collected for morphometric and molecular analysis. Thymulin prevented morphological, hemodynamic, and inflammatory cardiopulmonary profile characteristic of MCT-induced PH, whereas part of these effects were also observed in MCT-treated animals injected with the thymulin's vehicle containing zinc. The pulmonary thymulin effect was likely mediated through suppression of p38 pathway.Portuguese Foundation for Science and Technology (No. POCI/SAVFCF/60803/2004; POCTI/SAV-MMO/61547/2004 and PTDC/SAV-FCF/65793/2006) through Cardiovascular R&D Unit (FCT No. 51/94). R.S.M. was supported by Fundação para a Ciência e a Tecnologia (reference SFRH/BPD/15408/2005

Blockchain-Based Multi-UAV Surveillance System

This paper describes a framework for a Multi-UAV surveillance system based on a blockchain allowing to coordinate the UAVs and to manage financial exchanges between the different users. The objective of the system is to allow a set of Points-Of-Interest (POI) to be surveyed by a set of autonomous UAVs which cooperate to minimize the time between successive visits while having an unpredictable behavior to prevent external agents from learning their movements. The system can be seen as a marketplace where the UAVs are the service providers and the POIs are the service seekers. It is based on a blockchain embedded on the UAVs and on some nodes on the ground which has two main functionalities. The first one is to organize the routes of each UAV through an efficient Game Theoretical decision algorithm implemented in a smart contract. The second one is to allow financial transactions between the system and its users: the POIs subscribe to surveillance services by buying tokens and the UAVs are paid in tokens for the provided services. The first implementation tests show that the IOTA blockchain could be a good blockchain candidate to be integrated in the multi-UAV surveillance system already developed in our lab

Structural Basis for Xyloglucan Specificity and α‑d‑Xyl<i>p</i>(1 → 6)‑d‑Glc<i>p</i> Recognition at the −1 Subsite within the GH5 Family

GH5 is one of the largest glycoside hydrolase families, comprising at least 20 distinct activities within a common structural scaffold. However, the molecular basis for the functional differentiation among GH5 members is still not fully understood, principally for xyloglucan specificity. In this work, we elucidated the crystal structures of two novel GH5 xyloglucanases (XEGs) retrieved from a rumen microflora metagenomic library, in the native state and in complex with xyloglucan-derived oligosaccharides. These results provided insights into the structural determinants that differentiate GH5 XEGs from parental cellulases and a new mode of action within the GH5 family related to structural adaptations in the −1 subsite. The oligosaccharide found in the XEG5A complex, permitted the mapping, for the first time, of the positive subsites of a GH5 XEG, revealing the importance of the pocket-like topology of the +1 subsite in conferring the ability of some GH5 enzymes to attack xyloglucan. Complementarily, the XEG5B complex covered the negative subsites, completing the subsite mapping of GH5 XEGs at high resolution. Interestingly, XEG5B is, to date, the only GH5 member able to cleave XXXG into XX and XG, and in the light of these results, we propose that a modification in the −1 subsite enables the accommodation of a xylosyl side chain at this position. The stereochemical compatibility of the −1 subsite with a xylosyl moiety was also reported for other structurally nonrelated XEGs belonging to the GH74 family, indicating it to be an essential attribute for this mode of action

Dinuclear Zinc(II) Macrocyclic Complex as Receptor for Selective Fluorescence Sensing of Pyrophosphate

A new diethylenetriamine-derived macrocycle known as L, bearing 2-methylquinoline arms and containing <i>m</i>-xylyl spacers, was prepared in good yield by a one-pot [2 + 2] Schiff base condensation procedure, followed by reduction with sodium borohydride. Up to now this is the first hexaazamacrocycle with appended fluorophore units. Single-crystal X-ray diffraction determination of the dinuclear zinc­(II) complex of L showed that metal centers are located at about 7.20(2) Å from one another. This complex exhibits only weak fluorescence in aqueous solution, but the addition of 1 equiv of pyrophosphate (PPi) caused a 21-fold enhancement of the fluorescence intensity. The sensor response is linear up to a value of 10 μM HPPi^3– and has a detection limit of 300 nM. The receptor behaves as a highly selective sensor for pyrophosphate as other anions, including phosphate, phenylphosphate (PhP), adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP), failed to induce any fluorescence change and practically do not affect the fluorescence intensity of the sensor in the presence of HPPi^3–. Competition titrations carried out in aqueous solution at pH 7.4 [in 20 mM 3-(<i>N</i>-morpholino)­propanesulfonic acid (MOPS) buffer] by spectrofluorometry revealed a high association constant value of 6.22 log units for binding of PPi by the dinuclear zinc­(II) receptor, one of the highest reported values for colorimetric/fluorometric sensors able to work under real aqueous physiological conditions, while association constant values for binding of the other phosphorylated substrates are in the 5.51–4.03 log unit range

Synthesis of Novel Periodic Mesoporous Organosilicas Containing 1,4,5,8-Naphthalenediimides within the Pore Walls and Their Reduction To Generate Wall-Embedded Free Radicals

Novel periodic mesoporous organosilicas (PMOs) containing 1,4,5,8-Naphthalenediimide (NDI) chromophores as an integral part of the pore walls were synthesized in acidic conditions, in the presence of inorganic tetraethyl orthosilicate, using triblock copolymer surfactant Pluronic P-123 as a template. The NDI precursor, the bridged silsesquioxane <i>N</i>,<i>N</i>′-bis­(3-triethoxysilylpropyl)-1,4,5,8-naphthalenediimide, was synthesized by reaction of 1,4,5,8-naphthalenetetracarboxylic dianhydride with excess 3-aminopropyltriethoxysilane. A series of samples containing up to 19% (weight %) of NDI were prepared (the materials were labeled PMONDIs). ¹³C and ²⁹Si solid-state nuclear magnetic resonance revealed that the NDI moiety was intact in the PMONDIs and efficiently grafted to the silica network. Samples with up to 16% NDI load presented an ordered two-dimensional-hexagonal mesoscopic structure, according to small-angle X-ray scattering, transmission electron microscopy, and nitrogen adsorption isotherms. Fluorescence spectra of the PMONDIs showed excimer formation upon excitation, suggesting high flexibility of the organic moieties. Reduction of PMONDIs with aqueous sodium dithionite led to the formation of wall-embedded NDI anion radicals, as observed by the appearance of new visible/near-infrared absorption bands. The PMONDIs were also shown to be efficient photocatalysts in the degradation of sulfadiazine, an antibiotic selected here as a model pollutant, which is usually present in water bodies and wastewater

[1-8-NαC]-Zanriorb A1, a Proapoptotic Orbitide from Leaves of <i>Zanthoxylum riedelianum</i>

A new orbitide named [1-8-NαC]-zanriorb A1 (<b>1</b>) was isolated and characterized from the leaves of <i>Zanthoxylum riedelianum</i> using NMR and mass spectrometry. The absolute configuration of the amino acids was determined using Marfey’s method on the acid hydrolysates. Compound <b>1</b> induced cell death by apoptosis in Jurkat leukemia T cells (IC₅₀ 218 nM)

Multitask Imidazolium Salt Additives for Innovative Poly(l‑lactide) Biomaterials: Morphology Control, Candida spp. Biofilm Inhibition, Human Mesenchymal Stem Cell Biocompatibility, and Skin Tolerance

Candida species have great ability to colonize and form biofilms on medical devices, causing infections in human hosts. In this study, poly­(l-lactide) films with different imidazolium salt (1-<i>n</i>-hexadecyl-3-methylimidazolium chloride (<b>C</b>_<b>16</b><b>MImCl</b>) and 1-<i>n</i>-hexadecyl-3-methylimidazolium methanesulfonate (<b>C</b>_<b>16</b><b>MImMeS</b>)) contents were prepared, using the solvent casting process. Poly­(l-lactide)-imidazolium salt films were obtained with different surface morphologies (spherical and directional), and the presence of the imidazolium salt in the surface was confirmed. These films with different concentrations of the imidazolium salts <b>C</b>_<b>16</b><b>MImCl</b> and <b>C</b>_<b>16</b><b>MImMeS</b> presented antibiofilm activity against isolates of Candida tropicalis, Candida parapsilosis, and Candida albicans. The minor antibiofilm concentration assay enabled one to determine that an increasing imidazolium salt content promoted, in general, an increase in the inhibition percentage of biofilm formation. Scanning electron microscopy micrographs confirmed the effective prevention of biofilm formation on the imidazolium salt containing biomaterials. Lower concentrations of the imidazolium salts showed no cytotoxicity, and the poly­(l-lactide)-imidazolium salt films presented good cell adhesion and proliferation percentages with human mesenchymal stem cells. Furthermore, no acute microscopic lesions were identified in the histopathological evaluation after contact between the films and pig ear skin. In combination with the good morphological, physicochemical, and mechanical properties, these poly­(l-lactide)-based materials with imidazolium salt additives can be considered as promising biomaterials for use in the manufacturing of medical devices

Longevity in Untreated Congenital Growth Hormone Deficiency Due to a Homozygous Mutation in the GHRH Receptor Gene

Context: Reduced longevity observed in hypopituitarism has been attributed to GH deficiency (GHD). It is, however, unclear whether GHD or other confounding factors cause this early mortality

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially