Prokrusztész nélküli világ? Blokklánc és társadalmi makroevolúció

Bitcoin-őrület, a kriptovaluták burjánzása, új aranyláz – ha átengedjük magunkat a szalagcímek szóhangulatának, akkor könnyen tűnhet úgy, mintha újra a múlt század kilencvenes éveinek kipukkanással fenyegető dotcom-lufijának időszaka tért volna vissza. Ha azonban magát a blokkláncra (blockchain) keresztelt háttértechnológiát tesszük nagyító alá, kiderül, hogy a kétoldalú értékcserét intézményi (állami-pénzintézeti) kontroll nélkül is hitelessé és biztonságossá tévő megoldásegyüttesnek valójában rendkívüli jelentősége van: meghatározó szerepet játszhat egy olyan, páratlan horderejű társadalmi átalakulásban, amelyhez hasonlót eddig csak egyetlen egyszer tapasztaltunk a világtörténelemben, a városiasodás és a hierarchizált társadalmak kialakulásának időszakában, tíz-tizenkétezer éve. Az emiatt társadalmi makroevolúciós fogalmakkal értelmezhető átalakulás kirakós játékában még sok hiányzó elem van, de a blokklánccal egy újfajta társadalmi kontrollviszony alapvető infrastrukturális eleme született meg. Tanulmányunk a blokklánc-világ alapfogalmait, történetét, természetét és friss fejleményeit ennek a kontextusnak a fényében kívánja értelmezni.&#x0D; &#x0D; ---&#x0D; &#x0D; Blockchain and Social Macroevolution&#x0D; &#x0D; Bitcoin madness, the boom of the crypto economy, a new gold rush – if we let ourselves be influenced by the mood of these news headlines it might make us feel like we are in the early nineties with the dotcom boom repeating itself again along with the threat of a breaking bubble that finally happened. If we rather opt to examine the core blockchain technology that underlies these headlines, it might lead to something with real significance: the transaction system between two sides without an intermediary (state – financial institution) involved is set to change significantly as there is a technological solution that can guarantee cheaper transactions that are more secure and directly carried out between the parties. This may lead to a major change in society that is only comparable to urbanization and the evolution of hierarchical societies 10,000-12,000 years ago. According to our view, this aspect makes the real / possible social effects of blockchain open to interpretation by the theory, definitions and terms of social macroevolution. A large part of the puzzle is not yet finished, but a decentralized public blockchain may lead to a new era of social control over transactions. In this study, we revisit the basics of the Blockchain World, its history, recent developments and its social, political and historical context.</jats:p

Lokalna promjenljivost (nestalnost) mehaničkih svojstava tandemskih Ig/segmenata titina

The functionally elastic, I-band part of the myofibrillar protein titin (connectin) contains differentially expressed arrays of serially linked immunoglobulin (Ig)-like domains, the length and composition of which vary among the titin isoforms. The biological rationale of the differential expression as well as the contribution of the Ig domain mechanical characteristics to the overall mechanical behavior of titin are not exactly known. The paper briefly reviews the relevant works that have addressed the Ig-domain mechanics problems and presents the authors’ experimental approach to studying the mechanical behavior of Ig domains. The mechanics of an eight domain segment from the differentially expressed tandem Ig region of titin (I55-62) was studied with an atomic force microscope specially used for stretching single molecules, and the results were compared to known mechanical properties of other domains and segments.Funkcionalno elastična I-vrpca miofibrilarnoga proteina titina (konektina) sadrži razlicito izražene vrste serijski povezanih domena sličnih imunoglobulinu (Ig) čija se duljina i sastav razlikuju u pojedinim titinskim izoformama. Biološki razlozi diferencijalne ekspresije kao i doprinos mehaničkih svojstava domena koje su slične Ig ponašanju titina nisu u cjelosti poznati. U ovom su članku pregledno prikazani dosadašnji relevantni radovi koji se bave problemima mehaničkih svojstava Ig-domena te autorski eksperimentalni pristupi u istraživanju toga problema. U radu su također prikazani rezultati istraživanja mehaničkih svojstava diferencijalno eksprimiranoga tandemskoga Ig-područja titina (155-62), koji se sastoji od osam domena, pomoću mikroskopa atomske snage razlučivanja specijaliziranoga za rastezanje pojedinačne molekule. Ovim postupkom utvrđena mehanička svojstva ispitivanoga dijela titinske molekule uspoređena su s poznatim mehaničkim svojstvima drugih domena i segmenata

Peripheral blood derived gene panels predict response to infliximab in rheumatoid arthritis and Crohn’s disease

Background: Biological therapies have been introduced for the treatment of chronic inflammatory diseases including rheumatoid arthritis (RA) and Crohn's disease (CD). The efficacy of biologics differs from patient to patient. Moreover these therapies are rather expensive, therefore treatment of primary non-responders should be avoided. Method: We addressed this issue by combining gene expression profiling and biostatistical approaches. We performed peripheral blood global gene expression profiling in order to filter the genome for target genes in cohorts of 20 CD and 19 RA patients. Then RT-quantitative PCR validation was performed, followed by multivariate analyses of genes in independent cohorts of 20 CD and 15 RA patients, in order to identify sets ofinterrelated genes that can separate responders from non-responders to the humanized chimeric anti-TNFalpha antibody infliximab at baseline. Results: Gene panels separating responders from non-responders were identified using leave-one-out cross-validation test, and a pool of genes that should be tested on larger cohorts was created in both conditions. Conclusions: Our data show that peripheral blood gene expression profiles are suitable for determining gene panels with high discriminatory power to differentiate responders from non-responders in infliximab therapy at baseline in CD and RA, which could be cross-validated successfully. Biostatistical analysis of peripheral blood gene expression data leads to the identification of gene panels that can help predict responsiveness of therapy and support the clinical decision-making process

Deuterium Content of the Organic Compounds in Food Has an Impact on Tumor Growth in Mice

Research with deuterium-depleted water (DDW) in the last two decades proved that the deuterium/hydrogen ratio has a key role in cell cycle regulation and cellular metabolism. The present study aimed to investigate the possible effect of deuterium-depleted yolk (DDyolk) alone and in combination with DDW on cancer growth in two in vivo mouse models. To produce DDyolk, the drinking water of laying hens was replaced with DDW (25 ppm) for 6 weeks, resulting in a 60 ppm D level in dried egg yolk that was used as a deuterium-depleted food additive. In one model, 4T1, a cell line with a high metastatic capacity to the lung was inoculated in the mice’s mammary pad. After three weeks of treatment with DDW and/or DDyolk, the tumor volume in the lungs was smaller in all treated groups vs. controls with natural D levels. Tumor growth and survival in mice transplanted with an MCF-7 breast cancer cell line showed that the anticancer effect of DDW was enhanced by food containing the deuterium-depleted yolk. The study confirmed the importance of the D/H ratio in consumed water and in metabolic water produced by the mitochondria while oxidizing nutrient molecules. This is in line with the concept that the initiation of cell growth requires the cells to generate a higher D/H ratio, but DDW, DDyolk, or the naturally low-D lipids in a ketogenic diet, have a significant effect on tumor growth by preventing the cells from raising the D/H ratio to the threshold

Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model

BACKGROUND: Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and it has limited treatment options. RESULTS: In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro-phtalimide analogs, Ac-915 and Ac-2010. Both compounds bind lipid droplets and endoplasmic reticulum membrane, and interact with several proteins with chaperone functions (HSP60, HSP70, HSP90, and protein disulfide isomerase) as determined by affinity chromatography and resonant waveguide optical biosensor technology. Both compounds inhibited protein disulfide isomerase activity and induced cell death of different HCC cells at sub or low micromolar ranges detected by classical biochemical end-point assay as well as with real-time label-free measurements. Besides cell proliferation inhibiton, analogs also inhibited cell migration even at 250 nM. Relative biodistribution of the analogs was analysed in native tissue sections of different organs after administration of drugs, and by using fluorescent confocal microscopy based on the inherent blue fluorescence of the compounds. The analogs mainly accumulated in the liver. The effects of Ac-915 and Ac-2010 were also demonstrated on the advanced stages of hepatocarcinogenesis in a transgenic mouse model of N-nitrosodiethylamine (DEN)-induced HCC. Significantly less tumor development was found in the livers of the Ac-915- or Ac-2010-treated groups compared with control mice, characterized by less liver tumor incidence, fewer tumors and smaller tumor size. CONCLUSION: These results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids

Cellular Factor XIII, a Transglutaminase in Human Corneal Keratocytes

Cellular factor XIII (cFXIII, FXIII-A2), a transglutaminase, has been demonstrated in a few cell types. Its main function is to cross-link proteins by isopeptide bonds. Here, we investigated the presence of cFXIII in cells of human cornea. Tissue sections of the cornea were immunostained for FXIII-A in combination with staining for CD34 antigen or isopeptide cross-links. Isolated corneal keratocytes were also evaluated by immunofluorescent microscopy and flow cytometry. FXIII-A in the corneal stroma was quantified by Western blotting. FXIII-A mRNA was detected by RT-qPCR. The cornea of FXIII-A-deficient patients was evaluated by cornea topography. FXIII-A was detected in 68 ± 13% of CD34+ keratocytes. Their distribution in the corneal stroma was unequal; they were most abundant in the subepithelial tertile. cFXIII was of cytoplasmic localization. In the stroma, 3.64 ng cFXIII/mg protein was measured. The synthesis of cFXIII by keratocytes was confirmed by RT-qPCR. Isopeptide cross-links were detected above, but not within the corneal stroma. Slight abnormality of the cornea was detected in six out of nine FXIII-A-deficient patients. The presence of cFXIII in human keratocytes was established for the first time. cFXIII might be involved in maintaining the stability of the cornea and in the corneal wound healing process

The Anti-Inflammatory Role of Mannich Curcuminoids; Special Focus on Colitis

The incidence of inflammatory bowel disease (IBD) increases gradually in Western countries with high need for novel therapeutic interventions. Mannich curcuminoids, C142 or C150 synthetized in our laboratory, have been tested for anti-inflammatory activity in a rat model of TNBS (2,4,6-trinitrobenzenesulphonic acid) induced colitis. Treatment with C142 or C150 reduced leukocyte infiltration to the submucosa and muscular propria of the inflamed gut. C142 or C150 rescued the loss of body weight and C150 decreased the weight of standard colon preparations proportional with 20% less tissue oedema. Both C142 and C150 curcumin analogues caused 25% decrease in the severity of colonic inflammation and haemorrhagic lesion size. Colonic MPO (myeloperoxidase) enzyme activity as an indicator of intense neutrophil infiltration was 50% decreased either by C142 or C150 Mannich curcuminoids. Lipopolysaccharide (LPS) co-treatment with Mannich curcuminoids inhibited NF-&#954;B (nuclear factor kappa B) activity on a concentration-dependent manner in an NF-&#954;B-driven luciferase expressing reporter cell line. Co-treatment with LPS and curcuminoids, C142 or C150, resulted in NF-&#954;B inhibition with 3.57 &#956;M or 1.6 &#956;M half maximal effective concentration (EC50) values, respectively. C150 exerted a profound inhibition of the expression of inflammatory cytokines, tumor necrosis factor-&#945; (TNF-&#945;), interleukin-6 (IL-6), and interleukin-4 (IL-4) in human PBMCs (peripheral blood mononuclear cells) upon LPS stimulus. Mannich curcuminoids reported herein possess a powerful anti-inflammatory activity

Primary care obesity management in Hungary: evaluation of the knowledge, practice and attitudes of family physicians

BACKGROUND: Obesity, a threatening pandemic, has an important public health implication. Before proper medication is available, primary care providers will have a distinguished role in prevention and management. Their performance may be influenced by many factors but their personal motivation is still an under-researched area. METHOD: The knowledge, attitudes and practice were reviewed in this questionnaire study involving a representative sample of 10% of all Hungarian family physicians. In different settings, 521 practitioners (448 GPs and 73 residents/vocational trainees) were questioned using a validated questionnaire. RESULTS: The knowledge about multimorbidity, a main consequence of obesity, was balanced.Only 51% of the GPs were aware of the diagnostic threshold for obesity; awareness being higher in cities (60%) and the highest among residents (90%). They also considered obesity an illness rather than an aesthetic issue.There were wider differences regarding attitudes and practice, influenced by the the doctors' age, gender, known BMI, previous qualification, less by working location.GPs with qualification in family medicine alone considered obesity management as higher professional satisfaction, compared to physicians who had previously other board qualification (77%vs68%). They measured their patients' waist circumference and waist/hip ratio (72%vs62%) more frequently, provided the obese with dietary advice more often, while this service was less frequent among capital-based doctors who accepted the self-reported body weight dates by patients more frequently / commonly. Similar reduced activity and weight-measurement in outdoor clothing were more typical among older doctors.Diagnosis based on BMI alone was the highest in cities (85%). Consultations were significantly shorter in practices with a higher number of enrolled patients and were longer by female providers who consulted longer with patients about the suspected causes of developing obesity (65%vs44%) and offered dietary records for patients significantly more frequently (65%vs52%). Most of the younger doctors agreed that obesity management was a primary care issue.Doctors in the normal BMI range were unanimous that they should be a model for their patients (94%vs81%). CONCLUSION: More education of primary care physicians, available practical guidelines and higher community involvement are needed to improve the obesity management in Hungary

Agrin Binds BMP2, BMP4 and TGFβ1

The C-terminal 95 kDa fragment of some isoforms of vertebrate agrins is sufficient to induce clustering of acetylcholine receptors but despite two decades of intense agrin research very little is known about the function of the other isoforms and the function of the larger, N-terminal part of agrins that is common to all isoforms. Since the N-terminal part of agrins contains several follistatin-domains, a domain type that is frequently implicated in binding TGFβs, we have explored the interaction of the N-terminal part of rat agrin (Agrin-Nterm) with members of the TGFβ family using surface plasmon resonance spectroscopy and reporter assays. Here we show that agrin binds BMP2, BMP4 and TGFβ1 with relatively high affinity, the KD values of the interactions calculated from SPR experiments fall in the 10−8 M–10−7 M range. In reporter assays Agrin-Nterm inhibited the activities of BMP2 and BMP4, half maximal inhibition being achieved at ∼5×10−7 M. Paradoxically, in the case of TGFβ1 Agrin N-term caused a slight increase in activity in reporter assays. Our finding that agrin binds members of the TGFβ family may have important implications for the role of these growth factors in the regulation of synaptogenesis as well as for the role of agrin isoforms that are unable to induce clustering of acetylcholine receptors. We suggest that binding of these TGFβ family members to agrin may have a dual function: agrin may serve as a reservoir for these growth factors and may also inhibit their growth promoting activity. Based on analysis of the evolutionary history of agrin we suggest that agrin's growth factor binding function is more ancient than its involvement in acetylcholine receptor clustering

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

BACKGROUND: -Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: -We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensinconverting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-Btype natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: -Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255