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Introduction: Sepsis is defined as a multifactorial debilitating condition with high risks of death. The intense inflammatory response causes deleterious effects on the brain, a condition called sepsis-associated encephalopathy. Neuroinflammation or pathogen recognition are able to stress cells, resulting in ATP (Adenosine Triphosphate) release and P2X7 receptor activation, which is abundantly expressed in the brain. The P2X7 receptor contributes to chronic neurodegenerative and neuroinflammatory diseases; however, its function in long-term neurological impairment caused by sepsis remains unclear. Therefore, we sought to evaluate the effects of P2X7 receptor activation in neuroinflammatory and behavioral changes in sepsis-surviving mice.Methods: Sepsis was induced in wild-type (WT), P2X7−/−, and BBG (Brilliant Blue G)-treated mice by cecal ligation and perforation (CLP). On the thirteenth day after the surgery, the cognitive function of mice was assessed using the novel recognition object and Water T-maze tests. Acetylcholinesterase (AChE) activity, microglial and astrocytic activation markers, and cytokine production were also evaluated.Results: Initially, we observed that both WT and P2X7−/− sepsis-surviving mice showed memory impairment 13 days after surgery, once they did not differentiate between novel and familiar objects. Both groups of animals presented increased AChE activity in the hippocampus and cerebral cortex. However, the absence of P2X7 prevented partly this increase in the cerebral cortex. Likewise, P2X7 absence decreased ionized calcium-binding protein 1 (Iba−1) and glial fibrillary acidic protein (GFAP) upregulation in the cerebral cortex of sepsis-surviving animals. There was an increase in GFAP protein levels in the cerebral cortex but not in the hippocampus of both WT and P2X7−/− sepsis-surviving animals. Pharmacological inhibition or genetic deletion of P2X7 receptor attenuated the production of Interleukin-1β (IL-1β), Tumor necrosis factor-α (TNF-α), and Interleukin-10 (IL-10).Conclusion: The modulation of the P2X7 receptor in sepsis-surviving animals may reduce neuroinflammation and prevent cognitive impairment due to sepsis-associated encephalopathy, being considered an important therapeutic target.

Despite long-term sequelae of COVID-19 are emerging as a substantial public health concern, the mechanism underlying these processes still unclear. Evidence demonstrates that SARS-CoV-2 Spike protein can reach different brain regions, irrespective of viral brain replication resulting in activation of pattern recognition receptors (PRRs) and neuroinflammation. Considering that microglia dysfunction, which is regulated by a whole array of purinergic receptors, may be a central event in COVID-19 neuropathology, we investigated the impact of SARS-CoV-2 Spike protein on microglial purinergic signaling. Here, we demonstrate that cultured microglial cells (BV2 line) exposed to Spike protein induce ATP secretion and upregulation of P2Y6, P2Y12, NTPDase2 and NTPDase3 transcripts. Also, immunocytochemistry analysis shows that spike protein increases the expression of P2X7, P2Y1, P2Y6, and P2Y12 in BV2 cells. Additional, hippocampal tissue of Spike infused animals (6,5ug/site, i.c.v.) presents increased mRNA levels of P2X7, P2Y1, P2Y6, P2Y12, NTPDase1, and NTPDase2. Immunohistochemistry experiments confirmed high expression of the P2X7 receptor in microglial cells in CA3/DG hippocampal regions after spike infusion. These findings suggest that SARS-CoV-2 Spike protein modulates microglial purinergic signaling and opens new avenues for investigating the potential of purinergic receptors to mitigate COVID-19 consequences.

Polyamines are closely associated with environmental stresses and melatonin pretreatment enhances the resistance of fruit to chilling stress. However, a mechanism underlying melatonin-mediated chilling resistance remains to be answered. This research aimed to illuminate whether polyamines would be involved in melatonin-mediated chilling resistance. Therefore, in the experiment, the polyamines conjugated to the plasma membrane from the melatonin-pretreated apricot flesh cell were examined under chilling stress. Chilling resistance was judged by four parameters: fruit browning degree, plasma membrane permeability, malondialdehyde content and plasma membrane protein sulfhydryl level. Results showed melatonin pretreatment led to obvious rises in the levels of non-covalently conjugated spermine and spermidine, and covalently conjugated putrescine and spermidine in the plasma membrane. Methylglyoxyl-bis (guanylhydrazone) pretreatment could inhibit the melatonin-induced increases of non-covalently conjugated spermidine and spermine by inhibiting S-adenosylmethionine decarboxylase (SAMDC) activity and free spermidine and spermine contents in flesh, coupled with the decrease in chilling resistance. Similarly, phenanthroline pretreatment could inhibit the melatonin-induced increases in covalently conjugated putrescine and spermidine in the plasma membrane through inhibiting transglutaminase (TGase) activity and simultaneously could aggravate chilling damage. The results suggested melatonin pretreatment could enhance chilling resistance by increasing non-covalently conjugated spermidine and spermine, as well as covalently conjugated putrescine and spermidine in the plasma membrane of apricot fruit.

The effects of methylmercury (MeHg) on exposed populations are a public health problem. In contrast to widely studied neurological damage, few cardiovascular changes have been described. Our group evaluated the cardiotoxicity of a cumulative dose of 70 mg.kg−1 fractioned over a 14-day exposure period in mice (MeHg70 group). The effects of MeHg on proteins relevant to cardiac mitochondrial function were also investigated. The results obtained showed a reduction in oxygen consumption in the two settings. In cardiac tissue samples in oxygraphy studies, this reduction was related to a lower efficiency of complexes II and V, which belong to the oxidative phosphorylation system. In vivo, mice in the MeHg70 group presented lower oxygen consumption and running tolerance, as shown by ergometric analyses. Cardiac stress was evident in the MeHg70 group, as indicated by a marked increase in the level of the mRNA encoding atrial natriuretic peptide. Electrocardiogram studies revealed a lower heart rate at rest in the animals from the MeHg70 group, as well as prolonged left ventricular depolarisation and repolarisation. Through echocardiographic analysis, reductions in the left ventricular ejection fraction and left ventricular wall thickness of approximately 10% and 20%, respectively, were detected. These results indicate that the oral intake of MeHg can decrease cardiac function and oxidative metabolism. This finding highlights the importance of monitoring MeHg levels in humans and animals in contaminated areas, as well as periodically carrying out cardiac function tests. [ABSTRACT FROM AUTHOR]

The dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies, where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of a similar intensity and duration failed to induce pathology. The repetitive spOHT induced the rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, and Gasdermin D (GSDMD), and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinogram (PERG) amplitude and a significant loss of RGCs 7 days post-injury. The inactivation of inflammasome complexes in Nlrp1−/−, Casp1−/−, and GsdmD−/− knockout animals significantly suppressed the spOHT-induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

In the present study a relaxed eddy accumulation (REA) system for the quantification of vertical fluxes of nitrous acid (HONO) was developed and tested. The system is based on a three-channel long-path absorption photometer (LOPAP) instrument, for which two channels are used for the updrafts and downdrafts, respectively, and a third one for the correction of chemical interferences. The instrument is coupled to a REA gas inlet, for which an ultrasonic anemometer controls two fast magnetic valves to probe the two channels of the LOPAP instrument depending on the vertical wind direction. A software (PyREA) was developed, which controls the valves and measurement cycles, which regularly alternates between REA, zero and parallel ambient measurements. In addition, the assignment of the updrafts and downdrafts to the physical LOPAP channels is periodically alternated, to correct for differences in the interferences of the different air masses. During the study, only small differences of the interferences were identified for the updrafts and downdrafts excluding significant errors when using only one interference channel. In laboratory experiments, high precision of the two channels and the independence of the dilution-corrected HONO concentrations on the length of the valve switching periods were demonstrated. A field campaign was performed in order to test the new REA-LOPAP system at the TROPOS monitoring station in Melpitz, Germany. HONO fluxes in the range of -4×1013 molecules m−2 s−1 (deposition) to +1.0×1014 molecules m−2 s−1 (emission) were obtained. A typical diurnal variation of the HONO fluxes was observed with low, partly negative fluxes during night-time and higher positive fluxes around noon. After an intensive rain period the positive HONO emissions during daytime were continuously increasing, which was explained by the drying of the uppermost ground surfaces. Similar to other campaigns, the highest correlation of the HONO flux was observed with the product of the NO2 photolysis frequency and the NO2 concentration (J(NO2)⋅[NO2]), which implies a HONO formation by photosensitized conversion of NO2 on organic surfaces, such as humic acids. Other postulated HONO formation mechanisms are also discussed but are tentatively ranked being of minor importance for the present field campaign.

Deradicalisation refers to the process of distancing oneself from extremist ideologies. As a social challenge, it is usually addressed by specially qualified professionals. In this paper, based on 16 interviews with deradicalisation professionals, we comparatively examine deradicalisation practices in coercive environments in Germany and Pakistan. This cross-cultural comparison using “most dissimilar” cases allows us to distinguish between general and culture-specific approaches, while also allowing the strengths and weaknesses of the different approaches to emerge; this can be used to further develop deradicalisation efforts. Based on our evaluation of target groups, goals, professional understandings of radicalisation and its methods, this text elaborates the differences and similarities of deradicalisation practices; we also formulate consequences for deradicalisation practice and outline the need for further research.

Performance during instrumental learning is commonly believed to reflect the knowledge that has been acquired up to that point. However, recent work in rodents found that instrumental performance was enhanced during periods when reinforcement was withheld, relative to periods when reinforcement was provided. This suggests that reinforcement may mask acquired knowledge and lead to impaired performance. In the present study, we investigated whether such a beneficial effect of removing reinforcement translates to humans. Specifically, we tested whether performance during learning was improved during non-reinforced relative to reinforced task periods using signal detection theory and a computational modelling approach. To this end, 60 healthy volunteers performed a novel visual go/no-go learning task with deterministic reinforcement. To probe acquired knowledge in the absence of reinforcement, we interspersed blocks without feedback. In these non-reinforced task blocks, we found an increased d', indicative of enhanced instrumental performance. However, computational modelling showed that this improvement in performance was not due to an increased sensitivity of decision making to learnt values, but to a more cautious mode of responding, as evidenced by a reduction of a general response bias. Together with an initial tendency to act, this is sufficient to drive differential changes in hit and false alarm rates that jointly lead to an increased d'. To conclude, the improved instrumental performance in the absence of reinforcement observed in studies using asymmetrically reinforced go/no-go tasks may reflect a change in response bias rather than unmasking latent knowledge.