Complement system and alcoholic liver disease

Alcoholic liver disease (ALD) is a well recognized and growing health problem worldwide. ALD advances from fatty liver to inflammation, necrosis, fibrosis and cirrhosis. There is accumulating evidence that the innate immune system is involved in alcoholic liver injury. Within the innate and acquired immune systems, the complement system participates in inflammatory reactions and in the elimination of invading foreign, as well as endogenous apoptotic or injured cells. The present study aimed at evaluating the role of the complement system in the development of alcoholic liver injury. First, in order to study the effects of chronic ethanol intake on the complement system, the deposition of complement components in liver and the expression of liver genes associated with complement in animals with alcohol-induced liver injury were examined. It was demonstrated that chronic alcohol exposure leads to hepatic deposition of the complement components C1, C3, C8 and C9 in the livers of rats. Liver gene expression analysis showed that ethanol up-regulated the expression of transcripts for complement factors B, C1qA, C2, C3 and clusterin. In contrast, ethanol down-regulated the expression of the complement regulators factor H, C4bp and factor D and the terminal complement components C6, C8α and C9. Secondly, the role of the terminal complement pathway in the development of ALD was evaluated by using rats genetically deficient in the complement component C6 (C6-/-). It was found that chronic ethanol feeding induced more liver pathology (steatosis and inflammatory changes) in C6-/- rats than in wild type rats. The hepatic triacylglyceride content and plasma alanine aminotransferase activity increased in C6-/- rats, supporting the histopathological findings and elevation of the plasma pro-/anti-inflammatory TNF-/IL-10 ratio was also more marked in C6-/- rats. Third, the role of the alternative pathway in the development of alcoholic liver steatosis was characterized by using C3-/- mice. In C3-/- mice ethanol feeding tended to reduce steatosis and had no further effect on liver triacylglyceride, liver/body weight ratio nor on liver malondialdehyde level and serum alanine aminotransferase activity. In C3-/- mice alcohol-induced liver steatosis was reduced also after an acute alcohol challenge. In both wild type and C3-/- mice ethanol markedly reduced serum cholesterol and ApoA-I levels, phospholipid transfer protein activity and hepatic mRNA levels of fatty acid binding proteins and fatty acid -oxidation enzymes. In contrast, exclusively in C3-/- mice, ethanol treatment increased serum and liver adiponectin levels but down-regulated the expression of transcripts of lipogenic enzymes, adiponectin receptor 2 and adipose differentiation-related protein and up-regulated phospholipase D1. In conclusion, this study has demonstrated that the complement system is involved in the development of alcohol-induced liver injury. Chronic alcohol exposure causes local complement activation and induction of mRNA expression of classical and alternative pathway components in the liver. In contrast expression of the terminal pathway components and soluble regulators were decreased. A deficient terminal complement pathway predisposes to alcoholic liver damage and promotes a pro-inflammatory cytokine response. Complement component C3 contributes to the development of alcohol-induced fatty liver and its consequences by affecting regulatory and specific transcription factors of lipid homeostasis.Alkoholin aiheuttamat sairaudet ovat tämänhetkisen terveydenhuollon keskeisimpiä ongelmia ja voimakkaasti lisääntymässä sekä Suomessa että muualla maailmassa. Alkoholimaksavaurio alkaa maksan rasvoittumisesta ja etenee maksakirroosiin. Rasvamaksa voi kehittyä myös ilman alkoholia ylipainoisilla, joiden osuus väestössä on kasvussa. Maksa rasvoittuu jo yhden viikonlopun rajun ryypiskelyn seurauksena, mutta tila on palautuva jollei alkoholin käyttöä jatketa. Maksakirroosi sen sijaan on palautumaton vaurio, johon kuitenkin vain 15-25% alkoholisteista sairastuu. Alkoholin lisäksi täytyy siis olla muita yksilöllisiä tekijöitä, jotka laukaisevat vaurion kehittymisen. Suurin osa näistä tekijöistä on tuntemattomia. Tämän tutkimuksen lähtökohtana oli oletus, että kehon puolustus- ja puhtaanpitojärjestelmien tehokkuus vaikuttaa alttiuteen saada alkoholin aiheuttama maksasairaus. Kehon komplementtijärjestelmä on keskeinen immuunijärjestelmän osa. Komplementin tehtäviin kuuluu yhdessä tulehdussolujen kanssa poistaa kehosta haitallisia rakenteita, kuten mikrobeja ja vaurioituneita kudosrakenteita, sekä aikaansaada tulehdusreaktio. Tutkimustyössä tutkittiin synnynnäisten komplementtipuutosten vaikutusta alkoholimaksavaurion kehittymiseen eläinmalleissa. Rotille, joilla oli komplementtitekijän C6 puutos, kehittyi vaikeampi maksasairaus ja enemmän tulehdusmuutoksia kuin kontrollirotille kuuden viikon alkoholialtistuksen ja rasvapitoisen ruoan jälkeen. Tämä viittaa siihen, että komplementin lopputien toiminta suojaa maksaa alkoholin aiheuttamilta kudosvaurioilta. Tämä voi liittyä siihen, että komplementin solutuhokompleksi mahdollisesti estää alkoholin vaurioittamasta suolesta päässeitä mikrobeja aiheuttamasta kudostuhoa. Komplementtijärjestelmällä ja rasva-ainemetabolialla on havaittu olevan yhteyksiä keskenään. Alkoholi aiheuttaa rasvapitoista ruokaa syöville hiirille rasvamaksavaurion ja sitä seuraavan tulehdusreaktion. Mikäli hiiriltä puuttui komplementin tekijä C3 ei maksaan kertynyt rasvaa eikä tulehdusmuutoksiakaan kehittynyt. Tämä merkittävä tulos osoittaa, että komplementti ja erityisesti sen tekijä C3 osallistuu alkoholin aiheuttaman tulehduksellisen maksavaurion kehittymiseen. C3-puutoksen vaikutus on näin eri suuntainen kuin tekijän C6 puutos. C3 tekijä ja sen aktivaatiotuotteet vaikuttavat rasvametaboliaan lisäten triglyseridien kertymistä kudoksiin ja aiheuttaen tulehdusreaktioita. Hiirimallitutkimus osoitti selvästi ja ensimmäistä kertaa maailmassa, että C3 on olennainen tekijä alkoholivälitteisen maksavaurion kehittymisessä. C3-puutoksen vaikutusta maksavaurioon ja rasva-aineenvaihduntaan tutkittiin laajemmin selvittämällä alkoholin aiheuttamia geeniluennan muutoksia C3-puutteisilla ja normaaleilla hiirillä. C3 tekijän todettiin lisäävän hiirillä rasva-aineenvaihdunnan entsyymien ja adiponektiinireseptori 2:n määriä maksassa, mutta vähentävän suojaavan adiponektiinin määrää sekä maksassa että seerumissa. Komplementtijärjestelmällä ja rasva-aineenvaihdunnalla on näin ollen merkittäviä vuorovaikutuksia keskenään. Etanoli vaikutti suoraan myös komplementtijärjestelmän toimintaan. Se lisäsi komplementin aktivaatioon tarvittavien klassisen ja oikotin aktivaatioreittien tekijöiden geeniluentaa, mutta vähensi säätelijämolekyylien ja loppupään tekijöiden geenien luentaa. Yhteisvaikutus on näin ollen tulehdusta voimistava. Geenianalyyseissä voitiin myös todeta etanolin lisäävän kahden proteiinin, SPARCin ja lipokaliini-2:n tuottoa. Tämä antaa aiheen tutkia näiden molekyylien käyttöä varhaisina merkkiaineina alkoholin aiheuttaman maksavaurion toteamisessa. Tehdyt tutkimukset ovat paljastaneet komplementtijärjestelmän osallistuvan keskeisesti alkoholimaksavaurion kehittymiseen. Muita päätuloksia ovat yhteyden toteaminen rasvametabolian ja komplementin välillä sekä mahdollisten uusien merkkiaineiden löytäminen alkoholivälitteisen maksavaurion toteamiseen

CRIMINAL LAW—GIVE ME FREEDOM!: HOW AMBIGUOUS FEDERAL SUPERVISED RELEASE CONDITIONS UNDERMINE THE PURPOSE OF THE SENTENCING REFORM ACT

Vagueness, as the word suggests, is inherently uncertain. This Note addresses the issues of vagueness presented by unclear supervised release conditions, as well as discusses the split of authority pertaining thereto. Specifically, the condition discussed throughout the Note prohibits defendants from frequenting places where controlled substances are illegally present. Because federal appellate courts differ as to the condition’s meaning and its application, the existing circuit split will be thoroughly discussed. The main issues with the condition demonstrate a lack of attentiveness and forethought of the sentencing judges that ultimately impose undue hardships onto the defendants wishing to enter back into society. Furthermore, due to the lack of clarity of the proscribed terms, defendants may be uncertain as to what behavior is permitted and what act may result in re-incarceration. Since the proscribed terms are subject to varying interpretations, the defendants subject to this condition may find it difficult to obey. This Note will argue that the imposition of vague supervised release conditions is contradictory to the rehabilitative purpose of supervised release, and will urge the sentencing courts to exercise greater caution when imposing terms of federal supervision. This will ensure that defendants are not subject to unclear terms that may be unintentionally violated

Reformation and transformation of charity work at the beginning of the new time

This article is aimed at studying the transformation of Christian charity at the beginning of the New Time and the analysis of changes ongoing in this sphere. The authors of this research start with the analysis of the situation that had been formed in the economy, culture and activity of the Roman Catholic Church in the late Middle Ages. Such a preliminary excursion into the historical domain is not coincidental. It assists understanding the reasons for the Reformation and later events. However, “in the beginning was the Word”, therefore, the text analyzes the ideas of such founding fathers of Protestantism as Martin Luther, John Calvin, Huldrych Zwingli. The new ideology along with the sociocultural and socioeconomic factors promoted the formation of a radically different and more creative social system, also including the charity sphere that became more rational, practical and rough

Linking hopping conductivity to giant dielectric permittivity in oxides

With the promise of electronics breakthrough, giant dielectric permittivity materials are under deep investigations. In most of the oxides where such behavior was observed, charged defects at interfaces are quoted for such giant behavior to occur but the underlying conduction and localization mechanisms are not well known. Comparing macroscopic dielectric relaxation to microscopic dynamics of charged defects resulting from electron paramagnetic resonance investigations we identify the actual charged defects in the case of BaTiO3 ceramics and composites. This link between the thermal activation at these two complementary scales may be extended to the numerous oxides were giant dielectric behavior was found

Author Correction:Mutual interaction of red blood cells influenced by nanoparticles (Scientific Reports, (2019), 9, 1, (5147), 10.1038/s41598-019-41643-x)

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper

The status of world outlook and environmental competencies in aerospace engineering training: the general and special

The article is devoted to the study of the status of philosophical and environmental competences for engineering education programs in the field of space exploration. The authors prove that the specialists who will work in the space field in the XXI century face the most important problems, the solution of which is vital for humanity. It is stated that the quality of future decisions will be determined by the development of the philosophical and environmental ideas. It is demonstrated that these idea should necessarily have futurological character. It is suggested that the special courses aimed at the formation of futurological philosophical and environmental concepts can present as a possible solution to this problem (e.g. Creativity training for engineers, etc.)

Mutual interaction of red blood cells influenced by nanoparticles

Despite extensive studies on different types of nanoparticles as potential drug carriers, the application of red blood cells (RBCs) as natural transport agents for systemic drug delivery is considered a new paradigm in modern medicine and possesses great potential. There is a lack of studies on the influence of drug carriers of different compositions on RBCs, especially regarding their potential impact on human health. Here, we apply conventional microscopy to observe the formation of RBC aggregates and optical tweezers to quantitatively assess the mutual interaction of RBCs incubated with inorganic and polymeric nanoparticles. Scanning electron microscopy is utilized for direct observation of nanoparticle localization on RBC membranes. The experiments are performed in a platelet-free blood plasma mimicking the RBC natural environment. We show that nanodiamonds influence mutual RBC interactions more antagonistically than other nanoparticles, resulting in higher aggregation forces and the formation of larger cell aggregates. In contrast, polymeric particles do not cause anomalous RBC aggregation. The results emphasize the application of optical tweezers for the direct quantitative assessment of the mutual interaction of RBCs influenced by nanomaterials

Role of scattering and birefringence in phase retardation revealed by locus of Stokes vector on Poincaré sphere

SIGNIFICANCE: Biological tissues are typically characterized by high anisotropic scattering and may also exhibit linear form birefringence. Both scattering and birefringence bias the phase shift between transverse electric field components of polarized light. These phase alterations are associated with particular structural malformations in the tissue. In fact, the majority of polarization-based techniques are unable to distinguish the nature of the phase shift induced by birefringence or scattering of light. AIM: We explore the distinct contributions of scattering and birefringence in the phase retardation of circularly polarized light propagated in turbid tissue-like scattering medium. APPROACH: The circularly polarized light in frame of Stokes polarimetry approach is used for the screening of biotissue phantoms and chicken skin samples. The change of optical properties in chicken skin is accomplished by optical clearing, which reduces scattering, and mechanical stretch, which induces birefringence. The change of optical properties of skin tissue is confirmed by spectrophotometric measurements and second-harmonic generation imaging. RESULTS: The contributions of scattering and birefringence in the phase retardation of circularly polarized light propagated in biological tissues are distinguished by the locus of the Stokes vector mapped on the Poincaré sphere. The phase retardation of circularly polarized light due to scattering alterations is assessed. The value of birefringence in chicken skin is estimated as 0.3  ×  10  -  3, which agrees with alternative studies. The change of birefringence of skin tissue due to mechanical stretch in the order of 10  -  6 is detected. CONCLUSIONS: While the polarimetric parameters on their own do not allow distinguishing the contributions of scattering and birefringence, the resultant Stokes vector trajectory on the Poincaré sphere reveals the role of scattering and birefringence in the total phase retardation. The described approach, applied independently or in combination with Mueller polarimetry, can be beneficial for the advanced characterization of various types of malformations within biological tissues.</p

Inverse pressure-induced Mott transition in TiPO4_4

TiPO$_4$ shows interesting structural and magnetic properties as temperature and pressure are varied, such as a spin-Peierls phase transition and the development of incommensurate modulations of the lattice. Recently, high pressure experiments for TiPO$_4$ reported two new structural phases appearing at high pressures, the so-called phases IV and V [M. Bykov et al., Angew. Chem. Int. Ed. 55, 15053]. The latter was shown to include the first example of 5-fold O-coordinated P-atoms in an inorganic phosphate compound. In this work we characterize the electronic structure and other physical properties of these new phases by means of ab-initio calculations, and investigate the structural transition. We find that the appearance of phases IV and V coincides with a collapse of the Mott insulating gap and quenching of magnetism in phase III as pressure is applied. Remarkably, our calculations show that in the high pressure phase V, these features reappear, leading to an antiferromagnetic Mott insulating phase, with robust local moments