Could the SNA Complete the SCOT Model? \\Computer development in the USA between 1931-1950: a case study approach

Analyzing the literature of computing history we can establish that computing stories of different epochs are concerned with an array of problem areas, thus the authors of the accounts posed various questions - from the misunderstood inventions and forgotten genius to the community revaluation role of the Internet in the post-modern society. J. V. Atanasoff, J. Mauchly, J. P. Eckert, H. Aiken, G. Stibitz and J. Neumann all played their parts in the history of computing between 1930 and 1950 in the USA. Bowing before their notability the authors of institute-specific accounts recognised all of them as founders of electrical-digital computing technology. In this study I will argue that any discussion about claims to priority is an outworn conception because the first electrical- digital computer in the USA came into being in a network of ``socio-technical ensembles´´. The argument is based on a social construction approach (SCOT) of the history of technology combined with social network analysis as during our investigation the SCOT model proved inadequate for studying the history of computers. Following the improvement of key concepts and methods applied by SCOT-ists in different case studies I endeavour to choose the best suitable framework which can be applied to a description of a technological artefact more complex than the bicycle

Genetic deletion of TRPA1 receptor attenuates amyloid beta- 1-42 (Aβ 1-42)-induced neurotoxicity in the mouse basal forebrain in vivo

Amyloid β 1-42 peptide (Aβ1-42) accumulates in Alzheimer's disease (AD) that is toxic to the basal forebrain cholinergic (BFC) neurons in substantia innominata-nucleus basalis magnocellularis complex (SI-NBM). Transient Receptor Potential Ankyrin1 (TRPA1) receptor is present in murine brain, however its role in neurotoxic processes is unclear. We investigated the Aβ1-42-induced neurotoxicity in TRPA1 wild-type (TRPA1+/+) and knockout (TRPA1-/-) mice. Expression and neuroanatomical localization of TRPA1 receptor were examined using RT qPCR. Cholinergic fibre loss was determined on acetylcholinesterase (AChE) stained brain slices, and choline acetyltransferase (ChAT) immunohistochemistry was used to assess the cholinergic cell loss. Novel object recognition (NOR), radial arm maze (RAM) and Y-maze tests were used to investigate memory loss. Aβ1-42-injected WT mice showed marked loss of cholinergic fibres and cell bodies, which was significantly attenuated in TRPA1-/- animals. According to the NOR and RAM tests, pronounced memory loss was detected in Aβ1-42-injected TRPA1+/+ mice, but not in TRPA1-/- group. Our findings demonstrate that TRPA1 KO animals show substantially reduced morphological damage and memory loss after Aβ1-42 injection in the SI-NBM. We conclude that TRPA1 receptors may play an important deteriorating role in the Aβ1-42-induced cholinergic neurotoxicity and the consequent memory loss in the murine brain

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 μM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives

A humán immundeficiencia vírus látens humán herpeszvírus 6-ot aktiváló és NK sejteket fertőző képességének vizsgálata = Studies on the ability of human immunodeficiency virus activate latent human herpesvirus-6 and to infect NK cells

A macrophagok mind a humán herpeszvírus 6 A (HHV-6A), mind a humán immundeficiencia vírus 1 (HIV-1) fontos célsejtjei, így jelentős szerepet játszanak e két vírus disszeminációjában, patogenezisében. Ám a két vírus kölcsönhatását ezekben a sejtekben még nem tanulmányozták részletesen. Munkánk során azt vizsgáltuk, hogy macrophagokban van-e a HHV-6A-nak hatása a HIV-1 CCR5 koreceptort használó R5 variánsának replikációjára. Eredményeink alapján a HHV-6A szignifikánsan szuppresszálja a HIV-1 ezen variánsainak replikációját a kettősen fertőzött macrophagokban. HHV-6A hatására jelentős mennyiségű interleukin-8 (IL 8) és RANTES szekréciót mértünk. A CCR5 természetes ligandja a RANTES, receptorához való kötődése a receptor foszforilációját, homológ deszenzitizációját, majd internalizációját eredményezi. Ugyanakkor a CCR5 receptor működését heterológ módon más kemokin receptorok (CXCR1), így azok ligandjai is (IL-8) befolyásolhatják. Kettősen fertőzött sejtjeinken a CCR5 receptor expressziója és érzékenysége, így az R5 variáns HIV-1 törzsekkel szembeni fogékonyság is jelentős mértékben lecsökkent. A CCR5 koreceptorok csökkent érzékenysége, száma jelentős mértékű szelekciós nyomás lehet a CXCR4 kemokin koreceptort használó X4 variánsok felé, melyek megjelenése általában a betegség rossz prognózisát jelenti. Így tehát a HIV-1-fertőzésben igen gyakran reaktiválódó HHV-6 a HIV-1 R5 variánsaival szembeni fogékonyság csökkentésével az AIDS progresszió igen fontos kofaktora lehet. | Human herpesvirus 6 (HHV-6) frequently reactivates in human immunodeficiency virus 1 (HIV-1) infected patients, and is thought to be a cofactor in AIDS progression. Macrophages are targets and reservoirs of HIV-1 and HHV-6; hence, they have an important role in dissemination and pathogenesis of these viruses. Our study examined the effects of HHV-6A variant on replication of R5 variants of HIV-1 in macrophages. For this purpose, HIV-1 replication was investigated in macrophages infected with HIV-1 alone or along with HHV-6A. Our results demonstrated that HHV-6A significantly suppressed HIV-1 replication in coinfected cultures. HHV-6A infection resulted in increased secretion of RANTES and IL-8. RANTES is able to induce desensitization and internalization of CCR5, the chemokine coreceptor of R5 variants. In addition, IL-8 receptor activation results in cross-desensitization and cross-internalization of CCR5. We found that CCR5 sensitivity and expression level is diminished in HHV-6A-infected macrophage cultures compared with uninfected cells. Taken together, our results indicate that HHV-6A infection decreases the susceptibility of macrophages to R5 variants of HIV-1 in which the HHV-6A induced RANTES and IL-8 may have importance

A növénytermesztési tér (talaj-növény) anyagforgalmának interaktív vizsgálata a minőségi búza előállítása céljából = Interactive study of material circulation in agronomy space (soil-plant) for the production of quality wheat

A tartamkísérleti eredményeink azt bizonyították, hogy a növénytermesztési tér (talaj-növény) anyagforgalma (tápanyag- és vízháztartása) jelentősen befolyásolta a földfeletti fitomassza tömeget, a LAI-t, ezeken keresztül pedig az őszi búza termésmennyiségét és minőségét. A nedves sikértartalmat és a valorigráfos értékszámot az évjárat, a fajta és a trágyázás jelentősen, a vetésváltás és növényvédelem mérsékelt mértékben befolyásolta. A búzafajták termésmennyiség szempontjából optimális műtrágya adagját (N60-90+PK) meghaladta a minőség szempontjából optimális műtrágya dózist (N120-150+PK). | The results of our long-term experiments proved, that the materials flows of crop husbandry site (soil-plant) deeply modified the surface dry matter production, the LAI, the yields and the baking quality parameters of winter wheat varieties. The wet gluten content and farinograph index were highly modified by cropyear, genotype and fertilization, and the effects of forecrops and crop protection technology on them were moderate. The optimum fertilizer doses for yields were moderated (N60-90+PK) comparing with the optimum doses for baking quality (N120-150+PK)

Novel Drug Developmental Strategies for Treatment-Resistant Depression

Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment‐resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I–III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu(5) receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S‐ketamine, but add‐on therapies with second‐generation antipsychotics, certain nutritive, anti‐inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large‐scale, high‐throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund’s Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca2+-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca2+-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities