Сознание как менеджер когнитивных ресурсов. Эволюционная гипотеза о правильном функционировании сознания

For any biological trait, developing a good evolutionary explanation presents remarkable difficulties in relation to the adopted methodology, or definition of adaptation [1], and the frequent scarcity of empirical data [2; 3]. Furthermore, as far as mental phenomena are concerned, some philosophical theories such as Conscious Inessentialism [4], or the By-product Accident View [5] deny that the property of being conscious could have conferred any real selective advantage to organisms, making its evolutionary explanation even more arduous. Nonetheless, consciousness can reasonably be viewed as a useful tool that, from some point of phylogenesis onwards, contributed in some way to the fitness of its bearers. The main purpose of this paper, therefore, is to propose an evolutionary hypothesis about the proper function of consciousness. We will firstly define the notions of proper function and adaptive value. Then we will examine why having something like a conscious control core, no matter how basic or minimal, could be adaptively valuable, and we will do so through an analogy between this core and a digital resource manager (the operating system of advanced digital electronic devices). Finally, and in conclusion, we will formulate our hypothesis, which suggests that at some point of phylogenesis, cognitive unity emerged, and without it, no handling of complexity — and production of goal-directed behaviours — would appear to be possible.Для любого биологического признака разработка хорошего эволюционного объяснения представляет значительные трудности в связи с принятой методологией или определением адаптации [1] и частой нехваткой эмпирических данных [2; 3]. Кроме того, в том, что касается психических явлений, некоторые философские теории, такие как Сознательный несущественный подход [4] или Взгляд на случайность как побочный продукт [5], отрицают, что свойство быть сознательным могло дать организмам какое-либо реальное избирательное преимущество, что делает его эволюционное объяснение еще более затруднительным. Тем не менее, сознание можно разумно рассматривать как полезный инструмент, который с какого-то момента филогенеза и далее каким-то образом способствовал приспособленности его носителей. Таким образом, основная цель этой статьи состоит в том, чтобы предложить эволюционную гипотезу о правильной функции сознания. Сначала мы определим понятия надлежащей функции и адаптивной ценности. Затем мы рассмотрим, почему наличие чего-то вроде ядра сознательного управления, каким бы базовым или минимальным оно ни было, может быть адаптивно ценным, и мы сделаем это с помощью аналогии между этим ядром и менеджером цифровых ресурсов (операционная система современных цифровых электронных устройств). И наконец, в заключение, мы сформулируем нашу гипотезу, которая предполагает, что в какой-то момент филогенеза возникло когнитивное единство, а без него никакое управление сложностью, равно как и выработка целенаправленного поведения, были бы невозможны

Improved statistical learning abilities in adult bilinguals

Using multiple languages may confer distinct advantages in cognitive control, yet it is unclear whether bilingualism is associated with better implicit statistical learning, a core cognitive ability underlying language. We tested bilingual adults on a challenging task requiring simultaneous learning of two miniature grammars characterized by different statistics. We found that participants learned each grammar significantly better than chance and both grammars equally well. Crucially, a validated continuous measure of bilingual dominance predicted accuracy scores for both artificial grammars in a generalized linear model. The study thus demonstrates the first graded advantage in learning novel statistical relations in adult bilinguals

Is statistical learning trainable?

Statistical learning (SL) is the ability to implicitly extract regularities in the environment, and likely supports various higher-order behaviors, from language to music and vision. While specific patterns experience are likely to influence SL outcomes, this ability is tacitly conceptualized as a fixed construct, and few studies to date have investigated how experience may shape statistical learning. We report one experiment that directly tested whether SL can be modulated by previous experience. We used a prepost treatment design allowing us to pinpoint what specific aspects of \u201cprevious experience\u201d matter for SL. The results show that performance on an artificial grammar learning task at post-test depends on whether the grammar to be learned at post-test matches the underlying grammar structures learned during treatment. Our study is the first to adopt a pre-post test design to directly modulate the effects of learning on learning itself

Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide

A dual-action cyclooxygenase (COX)–fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX-inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (1), 2-(4-Isobutylphenyl)-N-(2-(3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (9) and N-(3-methylpyridin-2-yl)-2-(4′-isobutylphenyl)propionamide (2) inhibited FAAH with IC50 values of 134, 3.6 and 0.52 µM respectively. The corresponding values for COX-1 were ~29, ~50 and ~60 µM, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC50 values of ~6, ~10 and ~19 µM, respectively. Compound 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists. Read More: http://informahealthcare.com/doi/abs/10.3109/14756366.2011.64330

Antagonism of the prokineticin system prevents and reverses allodynia and inflammation in a mouse model of diabetes

Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro- and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease

Design and pharmacological evaluation of Ibuprofen amides derivatives as dual FAAH/COX inhibitors

Fatty acid amide hydrolase (FAAH) is a serine hydrolase enzyme responsible of the hydrolytic degradation of N-acylethanolamine endocannabinoids, such as the Arachidonoylethanolamide (anandamide, AEA), which it has been shown to alleviate pain and inflammation (1). In particular, the anti-nociceptive and anti-inflammatory effects of AEA could be enhanced by the simultaneous block of FAAH and COX enzymes (2). For this reason, several studies have been carried out in order to develop new FAAH/COX inhibitors (2). In 1997 it was reported that the NSAID ibuprofen inhibited FAAH, although with a modest potency (3), and successively the first dual inibhitor, the amide derivative of ibuprofen with a 2-amino-3-methylpyridine side chain (Ibu-AM5) was reported (4). -5). Benzylamides and piperazinoamides analogs of Ibuprofen have been also designed as less potent FAAH inhibitors than Ibu-AM5 (5). Here, I discuss the computational studies and the structure–activity relationships leading to the design, of novel Ibuprofen amide derivatives with a higher inhibition potency of FAAH and COX, which represent novel powerful anti-nociceptive agents

Critical role for prokineticin 2 in CNS autoimmunity

Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease. Methods: We investigated the expression of PK2 in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro. Results: Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demyelination, and decreased the production of interferon (IFN)-γ and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-γ and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen. Conclusion: These data suggest that PK2 is a critical immune regulator in CNS autoimmune demyelination and may represent a new target for therapy

Multidimensional Results and Reflections on CAR-T: The Italian Evidence

The present study aims at defining the economic and organizational impacts of the introduction of chimeric antigen receptor T-cell therapy (CAR-T) in Italy, for the management of diffuse large B-cell lymphoma (DLBCL) patients in third-line therapy, defining the overall level of sustainability for both hospitals and the National Healthcare System (NHS). The analysis focused on CAR-T and Best Salvage Care (in the following BSC), assuming the Italian hospital and NHS perspectives, over a 36-month time horizon. Process mapping and activity-based costing methodologies were applied to collect the hospital costs related to the BSC and CAR-T pathways, including adverse event management. Anonymous administrative data on services provided (diagnostic and laboratory examinations, hospitalizations, outpatient procedures, and therapies) to 47 third-line patients with lymphoma, as well as any organizational investments required, were collected, in two different Italian Hospitals. The economic results showed that the BSC clinical pathway required less resources in comparison with CAR-T (excluding the cost related to the therapy) (BSC: 29,558.41 vs. CAR-T: EUR 71,220.84, −58.5%). The budget impact analysis depicts that the introduction of CAR-T would generate an increase in costs ranging from 15% to 23%, without considering treatment costs. The assessment of the organizational impact reveals that the introduction of CAR-T therapy would require additional investments equal to a minimum of EUR 15,500 to a maximum of EUR 100,897.49, from the hospital perspective. Results show new economic evidence for healthcare decision makers, to optimize the appropriateness of resource allocation. The present analysis suggests the need to introduce a specific reimbursement tariff, both at the hospital and at NHS levels, since no consensus exists, at least in the Italian setting, concerning the proper remuneration for the hospitals who guarantee this innovative pathway, assuming high risks related to timely management of adverse events

The small GTPase Rab29 is a common regulator of immune synapse assembly and ciliogenesis

Acknowledgements We wish to thank Jorge Galán, Gregory Pazour, Derek Toomre, Giuliano Callaini, Joel Rosenbaum, Alessandra Boletta and Francesco Blasi for generously providing reagents and for productive discussions, and Sonia Grassini for technical assistance. The work was carried out with the financial support of Telethon (GGP11021) and AIRC.Peer reviewedPostprin

The endocannabinoid anandamide causes endothelium-dependent vasorelaxation in human mesenteric arteries

The endocannabinoid anandamide (AEA) causes vasorelaxation in animal studies. Although circulating AEA levels are increased in many pathologies, little is known about its vascular effects in humans. The aim of this work was to characterise the effects of AEA in human arteries. Ethical approval was granted to obtain mesenteric arteries from patients (n = 31) undergoing bowel resection. Wire myography was used to probe the effects and mechanisms of action of AEA. RT‐PCR was used to confirm the presence of receptor mRNA in human aortic endothelial cells (HAECs) and intracellular signalling proteins were measured using multiplex technology. AEA caused vasorelaxation of precontracted human mesenteric arteries with an Rmax of ∼30%. A synthetic CB1 agonist (CP55940) caused greater vasorelaxation (Rmax ∼60%) while a CB2 receptor agonist (HU308) had no effect on vascular tone. AEA-induced vasorelaxation was inhibited by removing the endothelium, inhibition of nitric oxide (NO) synthase, antagonising the CB1 receptor and antagonising the proposed novel endothelial cannabinoid receptor (CBe). AEA‐induced vasorelaxation was not affected by CB2 antagonism, by depleting sensory neurotransmitters, or inhibiting cyclooxygenase activity. RT‐PCR showed CB1 but not CB2 receptors were present in HAECs, and AEA and CP55940 had similar profiles in HAECs (increased phosphorylation of JNK, NFκB, ERK, Akt, p70s6K, STAT3 and STAT5). Post hoc analysis of the data set showed that overweight patients and those taking paracetamol had reduced vasorelaxant responses to AEA. These data show that AEA causes moderate endothelium-dependent, NO-dependent vasorelaxation in human mesenteric arteries via activation of CB1 receptors