Caffeine, the most widely consumed psychoactive drug, enhances attention/vigilance, stabilizes mood, and might also independently enhance cognitive performance. Notably, caffeine displays clearer and ...more robust beneficial effects on memory performance when memory is perturbed by stressful or noxious stimuli either in human or animal studies. Thus, caffeine restores memory performance in sleep-deprived or aged human individuals, a finding replicated in rodent animal models. Likewise, in animal models of Alzheimer's disease (AD), caffeine alleviates memory dysfunction, which is in accordance with the tentative inverse correlation between caffeine intake and the incidence of AD in different (but not all) cohorts. Caffeine also affords beneficial effects in animal models of conditions expected to impair memory performance such as Parkinson's disease, chronic stress, type 2 diabetes, attention deficit and hyperactivity disorder, early life convulsions, or alcohol-induced amnesia. Thus, caffeine should not be viewed as a cognitive enhancer but instead as a cognitive normalizer. Interestingly, these beneficial effects of caffeine on stress-induced memory disturbance are mimicked by antagonists of adenosine A2A receptors. This prominent role of A2A receptors in preventing memory deterioration is probably related to the synaptic localization of this receptor in limbic areas and its ability to control glutamatergic transmission, especially NMDA receptor-dependent plasticity, and to control apoptosis, brain metabolism, and the burden of neuroinflammation. This opens the real and exciting possibility that caffeine consumption might be a prophylactic strategy and A2A receptor antagonists may be a novel therapeutic option to manage memory dysfunction both in AD and in other chronic neurodegenerative disorders where memory deficits occur.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Background Adenosine A2A receptors (A2A R) modulate dopamine and glutamate signaling and thereby may influence some of the psychomotor and cognitive processes associated with schizophrenia. ...Because astroglial A2A R regulate the availability of glutamate, we hypothesized that they might play an unprecedented role in some of the processes leading to the development of schizophrenia, which we investigated using a mouse line with a selective deletion of A2A R in astrocytes (Gfa2-A2A R knockout KO mice. Methods We examined Gfa2-A2A R KO mice for behaviors thought to recapitulate some features of schizophrenia, namely enhanced MK-801 psychomotor response (positive symptoms) and decreased working memory (cognitive symptoms). In addition, we probed for neurochemical alterations in the glutamatergic circuitry, evaluating glutamate uptake and release and the levels of key proteins defining glutamatergic signaling (glutamate transporter-I GLT-I, N -methyl-D-aspartate receptors NMDA-R and α-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors AMPA-R) to provide a mechanistic understanding of the phenotype encountered. Results We show that Gfa2-A2A R KO mice exhibited enhanced MK-801 psychomotor response and decreased working memory; this was accompanied by a disruption of glutamate homeostasis characterized by aberrant GLT-I activity, increased presynaptic glutamate release, NMDA-R 2B subunit upregulation, and increased internalization of AMPA-R. Accordingly, selective GLT-I inhibition or blockade of GluR1/2 endocytosis prevented the psychomotor and cognitive phenotypes in Gfa2-A2A R KO mice, namely in the nucleus accumbens. Conclusions These results show that the dysfunction of astrocytic A2A R, by controlling GLT-I activity, triggers an astrocyte-to-neuron wave of communication resulting in disrupted glutamate homeostasis, thought to underlie several endophenotypes relevant to schizophrenia.
The health implications of acrylamide in food are a matter of concern based on toxicological studies in rodents, which showed that doses of acrylamide more than 100 times higher than those estimated ...to result from dietary exposure in humans are carcinogenic; however, the cancer types reported in rodents are species-specific, and whether these results can be extrapolated to humans is still in question. In fact, human epidemiological studies revealed a general lack of association between dietary acrylamide exposure and the incidence of different cancer types. Even occupational exposure to acrylamide, resulting in acrylamide exposure nearly 10 times higher than dietary exposure, did not increase tumor occurrence. Furthermore, the consumption of coffee, which is a main contributor of dietary acrylamide exposure, actually decreases the overall incidence of cancer in humans and afford global health benefits, increasing both lifespan and healthspan on ageing. This paradox clearly illustrates the risk of evaluating an individual molecule independently of its complete food matrix, which may have other components that completely override the effects of the considered molecule.
Adenosine acts in parallel as a neuromodulator and as a homeostatic modulator in the central nervous system. Its neuromodulatory role relies on a balanced activation of inhibitory A
1 receptors (A1R) ...and facilitatory A
2A receptors (A2AR), mostly controlling excitatory glutamatergic synapses: A1R impose a tonic brake on excitatory transmission, whereas A2AR are selectively engaged to promote synaptic plasticity phenomena. This neuromodulatory role of adenosine is strikingly similar to the role of adenosine in the control of brain disorders; thus, A1R mostly act as a hurdle that needs to be overcame to begin neurodegeneration and, accordingly, A1R only effectively control neurodegeneration if activated in the temporal vicinity of brain insults; in contrast, the blockade of A2AR alleviates the long-term burden of brain disorders in different neurodegenerative conditions such as ischemia, epilepsy, Parkinson's or Alzheimer's disease and also seem to afford benefits in some psychiatric conditions. In spite of this qualitative agreement between neuromodulation and neuroprotection by A1R and A2AR, it is still unclear if the role of A1R and A2AR in the control of neuroprotection is mostly due to the control of glutamatergic transmission, or if it is instead due to the different homeostatic roles of these receptors related with the control of metabolism, of neuron–glia communication, of neuroinflammation, of neurogenesis or of the control of action of growth factors. In spite of this current mechanistic uncertainty, it seems evident that targeting adenosine receptors might indeed constitute a novel strategy to control the demise of different neurological and psychiatric disorders. This article is part of a Special Issue entitled: “Adenosine Receptors”.
► Bolstering the effects of adenosine A1 receptors affords neuroprotection. ► Blocking the effects of adenosine A2A receptors affords neuroprotection. ► Chronic consumption of caffeine affords neuroprotection.
Aquaculture is one of the fastest growing sectors in the world, having a very important role in the economy. However, the losses associated with bacterial infections such as vibriosis, lead to huge ...economic costs. The regular use of antibiotics in aquaculture has resulted in the development of resistant strains, which have contributed to the inefficacy of antibiotics. To reduce the risk of the development and spreading of microbial resistance and to control the fish diseases in aquaculture, alternative strategies must be developed. Phage therapy can be an eco-friendly alternative to prevent and control pathogenic bacteria in aquaculture. However, phage bacterial resistance is already well documented but the use of phage cocktails can overcome this drawback. The aim of this study was to evaluate the efficiency of cocktails of two and three phages of Vibrio parahaemolyticus (VP-1, VP-2 and VP-3) to control Vibrio in aquaculture. All phages were effective against V. parahaemolyticus, however, the VP-3 phage was the most efficient one (additional reduction of more 2 log when compared with the other two phages). The use of cocktails with two and three phages was significantly more effective (reductions of 4 log after 2h) than the use of VP-1 and VP-2 phages alone (reductions of 0.8 log after 2h), however, the efficiency of VP-3 phage was similar for the phage alone and for the phage in the cocktails (reduction of 3.8 log and 4.2 log for VP-3 phage alone and in cocktails, respectively, after 8 and 6h). All phages remained viable for a long time (at least 5–7months) in marine water. The VP-3 phage presented a larger burst size and a shorter latent period (42 and 40min, respectively) than the other two phages (9 and 120min and 15 and 90min, respectively, for VP-1 and VP-2 phages). Overall, the use of phage cocktails of two or three phages increased the efficiency of phage therapy against Vibrio (more efficient and faster bacterial inactivation), delaying the development of resistance by the bacteria and the use of Vibrio phages with high burst sizes and short lytic cycles also increases the efficiency of phage therapy.
•Phage therapy can be an eco-friendly alternative to antibiotics in aquaculture•Phage cocktails overcome the phage bacterial resistance drawback•Phage cocktails increased the efficiency of phage therapy against Vibrio•Phages with high burst sizes and short cycles increase the efficiency of phage therapy
Franciscanas are the most endangered dolphins in the Southwestern Atlantic. Due to their coastal and estuarine habits, franciscanas suffer from extensive fisheries bycatch, as well as from habitat ...loss and degradation. Four Franciscana Management Areas (FMA), proposed based on biology, demography, morphology and genetic data, were incorporated into management planning and in the delineation of research efforts. We re-evaluated that proposal through the analysis of control region sequences from franciscanas throughout their distribution range (N = 162), including novel sequences from the northern limit of the species and two other previously unsampled localities in Brazil. A deep evolutionary break was observed between franciscanas from the northern and southern portions of the species distribution, indicating that they must be managed as two Evolutionarily Significant Units (ESU). Furthermore, additional FMAs should be recognised to accommodate the genetic differentiation found in each ESU. These results have immediate consequences for the conservation and management of this endangered species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Synaptic plasticity in the autoassociative network of recurrent connections among hippocampal CA3 pyramidal cells is thought to enable the storage of episodic memory. Impaired episodic memory is an ...early manifestation of cognitive deficits in Alzheimer's disease (AD). In the APP/PS1 mouse model of AD amyloidosis, we show that associative long-term synaptic potentiation (LTP) is abolished in CA3 pyramidal cells at an early stage. This is caused by activation of upregulated neuronal adenosine A2A receptors (A2AR) rather than by dysregulation of NMDAR signalling or altered dendritic spine morphology. Neutralization of A2AR by acute pharmacological inhibition, or downregulation driven by shRNA interference in a single postsynaptic neuron restore associative CA3 LTP. Accordingly, treatment with A2AR antagonists reverts one-trial memory deficits. These results provide mechanistic support to encourage testing the therapeutic efficacy of A2AR antagonists in early AD patients.
Approximately 57% of the Brazilian northeast region is recognized as semi-arid land and has been undergoing intense land use processes in the last decades, which have resulted in severe degradation ...of its natural assets. Therefore, the objective of this study is to identify the areas that are susceptible to desertification in this region based on the 11 influencing factors of desertification (pedology, geology, geomorphology, topography data, land use and land cover change, aridity index, livestock density, rural population density, fire hot spot density, human development index, conservation units) which were simulated for two different periods: 2000 and 2010. Each indicator were assigned weights ranging from 1 to 2 (representing the best and the worst conditions), representing classes indicating low, moderate and high susceptibility to desertification. The results indicate that 94% of the Brazilian northeast region is under moderate to high susceptibility to desertification. The areas that were susceptible to soil desertification increased by approximately 4.6% (83.4 km2) from 2000 to 2010. The implementation of the methodology provides the technical basis for decision-making that involves mitigating actions and the first comprehensive national assessment within the United Nations Convention to Combat Desertification framework.
Background
BRAF mutation is associated with a poor prognosis in patients with metastatic colorectal cancer. For patients with resectable colorectal liver metastases (CRLMs), the prognostic impact of ...BRAF mutation is unknown and the benefit of surgery debated. This nationwide intergroup (ACHBT, FRENCH, AGEO) study aimed to evaluate the oncological outcome of patients undergoing liver resection for BRAF‐mutated CRLMs.
Methods
The study included patients who underwent resection for BRAF‐mutated CRLMs in 24 centres between 2012 and 2016. A case‐matched comparison was made with 183 patients who underwent resection of CRLMs with wild‐type BRAF during the same interval.
Results
Sixty‐six patients who underwent resection for BRAF‐mutated CRLMs in 24 centres were compared with 183 patients with wild‐type BRAF. The 1‐ and 3‐year disease‐free survival (DFS) rates were 46 and 19 per cent for the BRAF‐mutated group, and 55·4 and 27·8 per cent for the group with wild‐type BRAF (P = 0·430). In multivariable analysis, BRAF mutation was not associated with worse DFS (hazard ratio 1·16, 95 per cent c.i. 0·72 to 1·85; P = 0·547). The 1‐ and 3‐year overall survival rates after surgery were 94 and 54 per cent respectively among patients with BRAF mutation, and 95·8 and 82·9 per cent in those with wild‐type BRAF (P = 0·004). Median survival after disease progression was 23·0 (95 per cent c.i. 11·0 to 35·0) months among patients with mutated BRAF and 44·3 (35·9 to 52·6) months in those with wild‐type BRAF (P = 0·050). Multisite disease progression was more common in the BRAF‐mutated group (48 versus 29·8 per cent; P = 0·034).
Conclusion
These results support surgical treatment for resectable BRAF‐mutated CRLM, as BRAF mutation by itself does not increase the risk of relapse after resection. BRAF mutation is associated with worse survival in patients whose disease relapses after resection of CRLM, as for non‐metastatic colorectal cancer.
For patients with resectable colorectal liver metastases, the prognostic impact of BRAF mutation is unknown and the benefit of surgery debated. This nationwide case–control study showed that BRAF mutation by itself does not increase the risk of relapse after surgery, but is associated with worse survival after relapse. wtBRAF, wild‐type BRAF; mutBRAF, mutated BRAF.
No effect on recurrence
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