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1,4-Phenylenebis(methylene)selenocyanate (p-XSC) inhibits chemically induced tumors in several laboratory animal models. To understand its mode of action, we synthesized p-[14C]XSC, examined its excretion pattern in female CD rats and also the nature of its metabolites. p-[14]XSC was synthesized from α,α-dibromo-p[ring-14C]xylene in 80% yield. The excretion profile of p-[14C]XSC (15.8 mg/kg body wt, 200 mgr;Ci/rat, oral administration, in 1 ml corn oil) in vivo was monitored by measuring radioactivity and selenium content. On the basis of radioactivity, 20% of the dose was excreted in the urine and 68% in the feces over 3 days. The cumulative percentages of the dose excreted over 7 days were 24% in urine and 75% in feces, similar to excretion rates of selenium. According to selenium measurement, <1% of the dose was detected in exhaled air; radioactivity was not detected. Only 15% of the dose was extractable from the feces with EtOAc and was identified as tetraselenocyclophane (TSC). Most of the radioactivity remained tightly bound to the feces. Approximately 10% of this bound material converted to TSC on reduction with NaBH4. Organic soluble metabolites in urine did not exceed 2% of the dose; sulfate (9% of urinary metabolites) and glucuronic acid (19.5% of urinary metabolites) conjugates were observed but their structural identification is still underway. Co-chromatography with a synthetic standard led to the detection of terephthalic acid (1,4-benzenedicarboxylic acid) as a minor metabolite. The major urinary conjugates contained selenium. Despite the low levels of selenium in the exhaled air, the reductive metabolism of p-XSC to H2Se cannot be ruled out. Identification of TSC in vivo indicates that a selenol may be a key intermediate responsible for the chemopreventive action of p-XSC. [ABSTRACT FROM PUBLISHER]

The search for primordial black holes (PBHs) with masses M≪M&#95;{⊙} is motivated by natural early-Universe production mechanisms and that PBHs can be dark matter. For M≲10^{14}  kg, the PBH density is constrained by null searches for their expected Hawking emission (HE), the characteristics of which are, however, sensitive to new states beyond the standard model. If there exists a large number of spin-0 particles in nature, PBHs can, through HE, develop and maintain non-negligible spins, modifying the visible HE. Taking account of the string axiverse of spin-0 axions that are expected to be present in string theory, we study in detail the resulting PBH characteristics, finding that for 10^{8}≲M≲10^{12}  kg evaporation constraints on PBHs are somewhat weakened, and the spin distributions could potentially be measured by future gamma-ray observatories if the PBH abundance is not too small. This yields a unique probe of the total number of light scalars in the fundamental theory, independent of how weakly they interact with known matter. The present energy density of hot, MeV-TeV axions produced by HE can exceed ρ&#95;{CMB}.

Inoculation of Bothrops jararaca snake venom (BjV) induces thrombocytopenia in humans and various animal species. Although several BjV toxins acting on hemostasis have been well characterized in vitro, it is not known which one is responsible for inducing thrombocytopenia in vivo. In previous studies, we showed that BjV incubated with metalloproteinase or serine proteinase inhibitors and/or anti-botrocetin antibodies still induced thrombocytopenia in rats and mice. Thus, herein we identified and characterized BjV toxins responsible for inducing thrombocytopenia. Initially, by filtering BjV on ultrafiltration systems, proteins with molecular masses between 30 and 50 kDa were shown to induce thrombocytopenia in mice, but they were not associated with hemorrhagic or coagulating activities. The 50 kDa ultrafiltrate was chromatographed, and two proteins (named fraction D and fraction E) induced thrombocytopenia in mice. However, neither fraction D nor fraction E induced platelet aggregation in platelet-rich plasma or whole blood from humans or mice. By mass spectrometry analysis, fraction E was identified as jararaca glycoprotein Ib (GPIb)-binding protein. Injection of these fractions caused thrombocytopenia in control or Vwf -/- mice, showing that the axis platelet GPIb - von Willebrand factor is not involved in their biological action in vivo. New studies are necessary to understand how these proteins act in vivo., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum contains majority of brain cells, neither its heterogeneity nor selective vulnerability in disease are well understood. Here we describe molecular, cellular and functional heterogeneity in the context of healthy cerebellum as well as in cerebellar disease Spinocerebellar Ataxia Type 1 (SCA1). We first compared disease pathology in cerebellar vermis and hemispheres across anterior to posterior axis in a knock-in SCA1 mouse model. Using immunohistochemistry, we demonstrated earlier and more severe pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice. We also demonstrate heterogeneity of Bergmann glia in the unaffected, wild-type mice. Then, using RNA sequencing, we found both shared, as well as, posterior cerebellum-specific molecular mechanisms of pathogenesis that include exacerbated gene dysregulation, increased number of altered signaling pathways, and decreased pathway activity scores in the posterior cerebellum of SCA1 mice. We demonstrated unexpectedly large differences in the gene expression between posterior and anterior cerebellar vermis of wild-type mice, indicative of robust intraregional heterogeneity of gene expression in the healthy cerebellum. Additionally, we found that SCA1 disease profoundly reduces intracerebellar heterogeneity of gene expression. Further, using fiber photometry, we found that population level PC calcium activity was altered in the posterior lobules in SCA1 mice during walking. We also identified regional differences in the population level activity of Purkinje cells (PCs) in unrestrained wild-type mice that were diminished in SCA1 mice., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Snakebite envenomation is classified as a Neglected Tropical Disease. Bothrops jararaca venom induces kidney injury and coagulopathy. HF3, a hemorrhagic metalloproteinase of B. jararaca venom, participates in the envenomation pathogenesis. We evaluated the effects of HF3 in mouse kidney and blood plasma after injection in the thigh muscle, mimicking a snakebite. Transcriptomic analysis showed differential expression of 31 and 137 genes related to kidney pathology after 2 h and 6 h, respectively. However, only subtle changes were observed in kidney proteome, with differential abundance of 15 proteins after 6 h, including kidney injury markers. N-terminomic analysis of kidney proteins showed 420 proteinase-generated peptides compatible with meprin specificity, indicating activation of host proteinases. Plasma analysis revealed differential abundance of 90 and 219 proteins, respectively, after 2 h and 6 h, including coagulation-cascade and complement-system components, and creatine-kinase, whereas a semi-specific search of N-terminal peptides indicated activation of endogenous proteinases. HF3 promoted host reactions, altering the gene expression and the proteolytic profile of kidney tissue, and inducing plasma proteome imbalance driven by changes in abundance and proteolysis. The overall response of the mouse underscores the systemic action of a hemorrhagic toxin that transcends local tissue damage and is related to known venom-induced systemic effects., Competing Interests: Declaration of competing interest The authors have no financial or non-financial interests to disclose. The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tumor invasion is likely driven by the product of intrinsic and extrinsic stresses, reduced intercellular adhesion, and reciprocal interactions between the cancer cells and the extracellular matrix (ECM). The ECM is a dynamic material system that is continuously evolving with the tumor microenvironment. Although it is widely reported that cancer cells degrade the ECM to create paths for migration using membrane-bound and soluble enzymes, other nonenzymatic mechanisms of invasion are less studied and not clearly understood. To explore tumor invasion that is independent of enzymatic degradation, we have created an open three-dimensional (3D) microchannel network using a novel bioconjugated liquid-like solid (LLS) medium to mimic both the tortuosity and the permeability of a loose capillary-like network. The LLS is made from an ensemble of soft granular microgels, which provides an accessible platform to investigate the 3D invasion of glioblastoma (GBM) tumor spheroids using in situ scanning confocal microscopy. The surface conjugation of the LLS microgels with type 1 collagen (COL1-LLS) enables cell adhesion and migration. In this model, invasive fronts of the GBM microtumor protruded into the proximal interstitial space and may have locally reorganized the surrounding COL1-LLS. Characterization of the invasive paths revealed a super-diffusive behavior of these fronts. Numerical simulations suggest that the interstitial space guided tumor invasion by restricting available paths, and this physical restriction is responsible for the super-diffusive behavior. This study also presents evidence that cancer cells utilize anchorage-dependent migration to explore their surroundings, and geometrical cues guide 3D tumor invasion along the accessible paths independent of proteolytic ability.

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, dominantly inherited neurodegenerative disease caused by the expanded polyQ tract in the protein ATAXIN1 (ATXN1) and characterized by progressive motor and cognitive impairments. There are no disease-modifying treatments or cures for SCA1. Brain-derived neurotrophic factor (BDNF) plays important role in cerebellar physiology and has shown therapeutic potential for cerebellar pathology in the transgenic mouse model of SCA1, ATXN1[82Q] line that overexpress mutant ATXN1 under a cerebellar Purkinje-cell-specific promoter. Here we demonstrate decreased expression of brain derived neurotrophic factor (BDNF) in the cerebellum and medulla of patients with SCA1. Early stages of disease seem most amenable to therapy. Thus, we next quantified Bdnf expression in Atxn1 154Q/2Q mice, a knock-in mouse model of SCA1, during the early symptomatic disease stage in four clinically relevant brain regions: cerebellum, medulla, hippocampus and motor cortex. We found that during the early stages of disease, Bdnf mRNA expression is reduced in the hippocampus and cerebellum, while it is increased in the cortex and brainstem. Importantly, we observed that pharmacological delivery of recombinant BDNF improved motor and cognitive performance, and mitigated pathology in the cerebellum and hippocampus of Atxn1 154Q/2Q mice. Our findings demonstrate brain-region specific deficiency of BDNF in SCA1 and show that reversal of low BDNF levels offers the potential for meaningful treatment of motor and cognitive deficits in SCA1., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene Ataxin1 ( ATXN1 ). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex, of Atxn1 154Q/2Q mice, a knock-in mouse model of SCA1. We found brain region-specific changes in astrocyte density and GFAP expression and area, early in the disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain region-specific manner and correlated with neuronal activity, indicating that astrocytes may compensate or exacerbate neuronal dysfunction. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions, indicating loss of astrocyte functions. We observed no obvious correlation between spatiotemporal changes in microglia and spatiotemporal astrocyte alterations, indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain region and disease stage-specific manner.

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin1 (ATXN1) gene. SCA1 is characterized by motor deficits, cerebellar neurodegeneration, and gliosis and gene expression changes. Expression of brain-derived neurotrophic factor (BDNF), growth factor important for the survival and function of cerebellar neurons, is decreased in ATXN1[82Q] mice, the Purkinje neuron specific transgenic mouse model of SCA1. As this decrease in BDNF expression may contribute to cerebellar neurodegeneration, we tested whether delivery of extrinsic human BDNF via osmotic ALZET pumps has a beneficial effect on disease severity in this mouse model of SCA1. Additionally, to test the effects of BDNF on established and progressing cerebellar pathogenesis and motor deficits, we delivered BDNF post-symptomatically. We have found that post-symptomatic delivery of extrinsic BDNF ameliorated motor deficits and cerebellar pathology (i.e., dendritic atrophy of Purkinje cells, and astrogliosis) indicating therapeutic potential of BDNF even after the onset of symptoms in SCA1. However, BDNF did not alter Purkinje cell gene expression changes indicating that certain aspects of disease pathogenesis cannot be ameliorated/slowed down with BDNF and that combinational therapies may be needed.

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine-encoding CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by progressive motor deficits, cognitive decline, and mood changes including anxiety and depression, with longer number of repeats correlating with worse disease outcomes. While mouse models have been very useful in understanding etiology of ataxia and cognitive decline, our understanding of mood symptoms in SCA1 has lagged. It remains unclear whether anxiety or depression stem from an underlying brain pathology or as a consequence of living with an untreatable and lethal disease. To increase our understanding of the etiology of SCA1 mood alterations, we used the elevated-plus maze, sucrose preference and forced swim tests to assess mood in four different mouse lines. We found that SCA1 knock-in mice exhibit increased anxiety that correlated with the length of CAG repeats, supporting the idea that underlying brain pathology contributes to SCA1-like anxiety. Additionally, our results support the concept that increased anxiety is caused by non-cerebellar pathology, as Purkinje cell specific SCA1 transgenic mice exhibit decreased anxiety-like behavior. Regarding the molecular mechanism, partial loss of ATXN1 may play a role in anxiety, based on our results for Atxn1 haploinsufficient and null mice.

Over the past decade, research has unveiled the intimate relationship between neuroinflammation and neurodegeneration. Microglia and astrocytes react to brain insult by setting up a multimodal inflammatory state and act as the primary defenders and executioners of neuroinflammatory structural and functional changes. Microglia and astrocytes also play critical roles in the maintenance of normal brain function. This intricate balance of homeostatic and neuroinflammatory functions can influence the onset and the course of neurodegenerative diseases. The emergent role of the microglial-astrocytic axis in neurodegenerative disease presents many druggable targets that may have broad therapeutic benefits across neurodegenerative disease. Here, we provide a brief review of the basal function of both microglia and astrocytes, how they are changed in disease states, the significant differences between mouse and human glia, and use of human induced pluripotent stem cells derived from patients to study cell autonomous changes in human astrocytes and microglia.

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1). Although motor and balance deficits are the core symptoms of SCA1, cognitive decline is also commonly observed in patients. While mutant ATXN1 is expressed throughout the brain, pathological findings reveal severe atrophy of cerebellar cortex in SCA1 patients. The cerebellum has recently been implicated in diverse cognitive functions, yet to what extent cerebellar neurodegeneration contributes to cognitive alterations in SCA1 remains poorly understood. Much of our understanding of the mechanisms underlying pathogenesis of motor symptoms in SCA1 comes from mouse models. Reasoning that mouse models could similarly offer important insights into the mechanisms of cognitive alterations in SCA1, we tested cognition in several mouse lines using Barnes maze and fear conditioning. We confirmed cognitive deficits in Atxn1154Q/2Q knock-in mice with brain-wide expression of mutant ATXN1 and in ATXN1 null mice. We found that shorter polyQ length and haploinsufficiency of ATXN1 do not cause significant cognitive deficits. Finally, ATXN1[82Q ] transgenic mice-with cerebellum limited expression of mutant ATXN1-demonstrated milder impairment in most aspects of cognition compared to Atxn1154Q/2Q mice, supporting the concept that cognitive deficits in SCA1 arise from a combination of cerebellar and extra-cerebellar dysfunctions., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Nitrates and perchlorates are present both on Earth and Mars. In the Martian environment perchlorates dominate over nitrates whereas on Earth is contrariwise. This implies that the mechanisms responsible for their formation are different for both planets. The chemical elements required for their formation are nitrogen and chlorine, which are present in the atmosphere and surface, respectively. Dust in the Martian atmosphere causes atmospheric perturbations that lead to the development of dust-devils and sandstorms. Dust devils contain both chemical elements simultaneously, and normally generate high electric fields that can trigger the formation of electric discharges. Here we present laboratory experiments of this phenomenon using laser ablation of a sodium chloride (NaCl) plate in two different simulated atmospheres: (1) 96% CO 2 , 2% N 2 and 2% Ar; and (2) 66% CO 2 , 33% N 2 and 1% Ar. The dust that condensed and accumulated on the walls of the reactor was analyzed by different analytical techniques that included Fourier transform infrared spectroscopy, visible spectroscopy using azo dyes, thermogravimetry/simultaneous thermal analyses coupled to mass spectrometry, powder X-ray diffraction, and ion chromatography. The main components of the ablated dust corresponded to NaCl ≥ 91.5%, sodium nitrate (NaNO 3  = 1.6-6.0%), and sodium perchlorate (NaClO 4  ∼ 0.2-0.3%). It is interesting to note that these salts formed in a dry process that is relevant to Mars today. A thermochemical model was used to understand the chemical steps that led to the formation of these salts in the gas phase. The NaNO 3 NaClO 4 (wt/wt) ratio of this process was estimated to vary from 5.0 to 30.0; this ratio is too high compared to that found on Mars (NO 3 - ClO 4 - (wt/wt)) from 0.004 to 0.13). This implies that gaseous NaCl was not efficiently oxidized to perchlorate by the electric discharge process. We propose instead that gaseous metal chlorides (e.g., MgCl 2 , NaCl, CaCl 2 , KCl) were supplied to the atmosphere by the volatilization of chloride minerals present in the dust by electric discharges generated in dust devils and were subsequently oxidized to perchlorate by photochemical processes. Further work is required to assess the relative contribution of this possible source., (Copyright © 2019 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the perception of schoolchildren between 7-10 years of a public school in Natal-RN about healthy eating., Method: Descriptive study, with quantitative and qualitative approach by focus group interviews with 29 students whose average age was 8.8 years. The analysis was aided by IRAMUTEQ software and supported the concept of perception of Merleau-Ponty., Results: Children's perception about healthy eating was associated with fresh foods and culinary preparations. We identified concepts acquired at school on the topic, as well as teachers criticizing the consumption of ultra-processed foods. There were reports of predilection for certain school meals and rejection of others. In addition, children have cited the presence of unhealthy foods served at school. Regarding the role of families, parents were cited in the role of guide for a healthy consumption at the same time they encouraged to consumption of processed foods at home or they provided money to buy them. Many children did not consume healthy foods, mainly fruits and vegetables because they consider unpalatable., Conclusion: The perception of children about healthy foods was influenced by school, family and media. Although they possessed sense of what would be a healthy feed, the pleasure in eating processed foods led to unhealthy practices. The findings show the need for a look magnified by the professionals involved in this role to stimulate and drive healthy practices.

We present a model where the inflaton can naturally account for all the dark matter in the Universe within the warm inflation paradigm. In particular, we show that the symmetries and particle content of the warm little inflaton scenario (i) avoid large thermal and radiative corrections to the scalar potential, (ii) allow for sufficiently strong dissipative effects to sustain a radiation bath during inflation that becomes dominant at the end of the slow-roll regime, and (iii) enable a stable inflaton remnant in the postinflationary epochs. The latter behaves as dark radiation during nucleosynthesis, leading to a non-negligible contribution to the effective number of relativistic degrees of freedom, and becomes the dominant cold dark matter component in the Universe shortly before matter-radiation equality for inflaton masses in the 10^{-4}-10^{-1}  eV range. Cold dark matter isocurvature perturbations, anticorrelated with the main adiabatic component, provide a smoking gun for this scenario that can be tested in the near future.

Microglia, the resident macrophages of the central nervous system, critically influence neural function during development and in adulthood. Microglia are also profoundly sensitive to insults to the brain to which they respond with process of activation that includes spectrum of changes in morphology, function, and gene expression. Ataxias are a class of neurodegenerative diseases characterized by motor discoordination and predominant cerebellar involvement. In case of inherited forms of ataxia, mutant proteins are expressed throughout the brain and it is unclear why cerebellum is particularly vulnerable. Recent studies demonstrated that cerebellar microglia have a uniquely hyper-vigilant immune phenotype compared to microglia from other brain regions. These findings may indicate that microglia actively contribute to cerebellar vulnerability in ataxias. Here we review current knowledge about cerebellar microglia, their activation, and their role in the pathogenesis of ataxias. In addition, we briefly review advantages and disadvantages of several experimental approaches available to study microglia., (Copyright © 2019. Published by Elsevier Ltd.)

Victims of Bothrops jararaca snakebites manifest bleedings, blood incoagulability, platelet dysfunction, and thrombocytopenia, and the latter has been directly implicated in the genesis of hemorrhagic diathesis. We addressed herein the direct effects of B. jararaca venom (BjV) on ex vivo platelet aggregation and granule secretion in washed human and mouse platelets. BjV directly aggregated platelets, but the extent of platelet aggregation was lower in human than mouse platelets. On the other hand, BjV (24.4 μg/mL) and thrombin (0.1 U/mL) induced a similar extent of ATP and platelet factor 4 (PF4) secretion in both species. BjV-induced platelet aggregation was independent of the platelet dense body content, as in pearl mouse (Ap3b1 -/- ) platelets, whose dense bodies are deficient in adenine nucleotides and serotonin, the extent of platelet aggregation was superior to that induced in BALB/c or C57BL/6 mice. BjV-induced β-hexosaminidase secretion in human platelets was less intense than that evoked by thrombin, and the contrary was observed in mouse platelets. Irreversible inactivation of platelet cyclooxygenase 1 by acetylsalicylic acid did not reduce BjV-induced platelet aggregation. BjV exerted no cytotoxic activity in human and mouse platelets, as evaluated by lactate dehydrogenase loss. Eptifibatide, which inhibits the binding of fibrinogen to platelet glycoprotein complex GPIIb-IIIa, differently blocked BjV-induced platelet aggregation in mice and humans. BjV-induced platelet aggregation did not depend on snake venom serine proteinases nor metalloproteinases in mice, whilst serine proteinases were rather important for platelet aggregation in humans. Our results show that BjV induces direct activation, aggregation, and secretion in human and mouse platelets, but it exerts diverse responses in them, which should be considered in comparative studies to understand pathophysiological events during Bothrops envenomation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This case illustrates the importance and potential of having TCD monitoring in intensive care. This easy-to-use, safe, low-cost, and bedside tool allows evaluation of the safety and feasibility of an alternative treatment of VSP in SCH and demonstrates the potential to avoid the use of angiography, a high cost, invasive procedure., Competing Interests: The authors declare that there is no conflict of interest.

Snakebites are a major Collective Health problem worldwide. In Brazil, Bothrops jararaca snake venom (BjV) evokes hemostatic disturbances, bleeding manifestations, and redox status imbalance. Specific antivenom therapy, although efficacious to revert most snakebite-induced manifestations, is incapable of treating secondary manifestations, such as oxidative/nitrosative stress. Searching for new complementary therapies that could attenuate physiological derangements triggered by envenomation, we elected to test quercetin-3-rutinoside (rutin) by its potential as both a potent antioxidant and a hemostasis modulatory compound. The activity of rutin was evaluated both on the biological activities of crude BjV in vitro, and in vivo by the ability of rutin (14.4 mg/kg b.w.) to modulate hematological, hemostatic and redox status markers altered by BjV injection (1.6 mg/kg b.w., s.c.) in mice. In vitro, rutin failed to inhibit BjV-induced platelet aggregation and biological activities of major BjV enzymes (metalloproteinases, phospholipases A2, serine proteases, and L-amino acid oxidases). On the other hand, rutin attenuated local hemorrhage, and the increase in reactive species, prevented the fall in RBC counts and fibrinogen levels, diminished tail bleeding and shortened prothrombin time (PT) evoked by envenomation. Furthermore, rutin reduced tissue factor (TF) activity and altered the protein expression of TF in liver, lungs, heart and skin. In conclusion, the disturbances in redox status and hemostatic system induced by B. jararaca envenomation were modulated by rutin, suggesting it has a great potential to be used as an ancillary therapeutic agent for snakebites., Competing Interests: The authors have declared that no competing interests exist.

Here we show that the novel object recognition test can discriminate between high (HRN, neophobic) and low (LRN, neophilic) novelty responders in zebrafish populations. Especially when we observe the latency to the first entry in the novel object zone, zebrafish did not maintain these behavioral phenotypes in sequential tests and only the HRN group returned to their initial responsive behavior when exposed to fluoxetine. Our results have important implications for behavioral data analysis since such behavioral differences can potentially increase individual response variability and interfere with the outcomes obtained from various behavioral tasks. Our data reinforce the validity of personality determination in zebrafish since we show clear differences in behavior in response to fluoxetine.

The superradiant instability can lead to the generation of extremely dense axion clouds around rotating black holes. We show that, despite the long lifetime of the QCD axion with respect to spontaneous decay into photon pairs, stimulated decay becomes significant above a minimum axion density and leads to extremely bright lasers. The lasing threshold can be attained for axion masses μ≳10^{-8}  eV, which implies superradiant instabilities around spinning primordial black holes with mass ≲0.01  M&#95;{⊙}. Although the latter are expected to be nonrotating at formation, a population of spinning black holes may result from subsequent mergers. We further show that lasing can be quenched by Schwinger pair production, which produces a critical electron-positron plasma within the axion cloud. Lasing can nevertheless restart once annihilation lowers the plasma density sufficiently, resulting in multiple laser bursts that repeat until the black hole spins down sufficiently to quench the superradiant instability. In particular, axions with a mass ∼10^{-5}  eV and primordial black holes with mass ∼10^{24}  kg, which may account for all the dark matter in the Universe, lead to millisecond bursts in the GHz radio-frequency range, with peak luminosities ∼10^{42}  erg/s, suggesting a possible link to the observed fast radio bursts.

Chemical communication relating to predation risk is a trait common among fish species. Prey fish under threat of predation can signal risk to conspecific fish, which then exhibit defensive responses. Fish also assess predation risk by visual cues and change their behavior accordingly. Here, we explored whether these behavioral changes act as visual alarm signals to conspecific fish that are not initially under risk. We show that shoals of zebrafish ( Danio rerio ) visually exposed to a predator display antipredator behaviors. In addition, these defensive maneuvers trigger antipredator reactions in conspecifics and, concomitantly, stimulate the hypothalamus-pituitary-interrenal axis, leading to cortisol increase. Thus, we conclude that zebrafish defensive behaviors act as visual alarm cues that induce antipredator and stress response in conspecific fish., Competing Interests: The authors declare there are no competing interests.

The glucocorticoid cortisol, the end product of hypothalamus-pituitary-interrenal axis in zebrafish (Danio rerio), is synthesized via steroidogenesis and promotes important physiological regulations in response to a stressor. The failure of this axis leads to inability to cope with environmental challenges preventing adaptive processes in order to restore homeostasis. Pesticides and agrichemicals are widely used, and may constitute an important class of environmental pollutants when reach aquatic ecosystems and nontarget species. These chemical compounds may disrupt hypothalamus-pituitary-interrenal axis by altering synthesis, structure or function of its constituents. We present evidence that organophosphorus exposure disrupts stress response by altering the expression of key genes of the neural steroidogenesis, causing downregulation of star, hsp70, and pomc genes. This appears to be mediated via muscarinic receptors, since the muscarinic antagonist scopolamine blocked these effects., (© 2017 Wiley Periodicals, Inc.)

Several studies have reported the presence of methylphenidate (MPH) in effluents; however, its impacts on aquatic life are not yet well understood. Here, we investigated the effects of acute exposure on endocrine and behavioral stress responses to environmentally relevant concentrations of MPH in zebrafish. We show that MPH blunts the response of cortisol to stress in zebrafish. On the other hand, MPH stresses fish per se. Additionally, MPH seems to modulate anxiety-like behaviors. We conclude that the presence of MPH in aquatic environments can alter neuroendocrine and behavior responses, which might considerably impact fish survival and welfare., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: This study aimed to identify predictors of early (7-day) mortality in patients with septic acute kidney injury (AKI) who required continuous renal replacement therapy (CRRT)., Methods: Prospective cohort of 186 septic AKI patients undergoing CRRT at a tertiary hospital, from October 2005 to November 2010., Results: After multivariate adjustment, five variables were associated to early mortality: norepinephrine utilization, liver failure, medical condition, lactate level, and pre-dialysis creatinine level. These variables were combined in a score, which demonstrated good discrimination, with a C-statistic of 0.82 (95% CI = 0.76-0.88), and good calibration (χ 2  = 4.3; p = 0.83). SAPS 3, APACHE II and SOFA scores demonstrated poor performance in this population., Conclusions: The HEpatic failure, LactatE, NorepInephrine, medical Condition, and Creatinine (HELENICC) score outperformed tested generic models. Future studies should further validate this score in different cohorts.

In this study, we show that an adaptation of the spinning test can be used as a model to study the exercise-exhaustion-recovery paradigm in fish. This forced swimming test promotes a wide range of changes in the hypothalamus-pituitary-interrenal axis functioning, intermediary metabolism, as well in fish behavior at both exercise and recovery periods. Our results pointed that this adapted spinning test can be considered a valuable tool for evaluating drugs and contaminant effects on exercised fish. This can be a suitable protocol both to environmental-to evaluate contaminants that act in fish energy mobilization and recovery after stressors-and translational perspectives-effects of drugs on exercised or stressed humans.

We suggest a structure for the vacuum comprised of a network of tightly knotted/linked flux tubes formed in a QCD-like cosmological phase transition and show that such a network can drive cosmological inflation. As the network can be topologically stable only in three space dimensions, this scenario provides a dynamical explanation for the existence of exactly three large spatial dimensions in our Universe., (© The Author(s) 2017.)

Here we provide, at least to our knowledge, the first evidence that aripiprazole (APPZ) in the water blunts the stress response of exposed fish in a concentration ten times lower than the concentration detected in the environment. Although the mechanism of APPZ in the neuroendocrine axis is not yet determined, our results highlight that the presence of APPZ residues in the environment may interfere with the stress responses in fish. Since an adequate stress response is crucial to restore fish homeostasis after stressors, fish with impaired stress response may have trouble to cope with natural and/or imposed stressors with consequences to their welfare and survival.

We show that inflation can naturally occur at a finite temperature T>H that is sustained by dissipative effects, when the inflaton field corresponds to a pseudo Nambu-Goldstone boson of a broken gauge symmetry. Similar to the Little Higgs scenarios for electroweak symmetry breaking, the flatness of the inflaton potential is protected against both quadratic divergences and the leading thermal corrections. We show that, nevertheless, nonlocal dissipative effects are naturally present and are able to sustain a nearly thermal bath of light particles despite the accelerated expansion of the Universe. As an example, we discuss the dynamics of chaotic warm inflation with a quartic potential and show that the associated observational predictions are in very good agreement with the latest Planck results. This model constitutes the first realization of warm inflation requiring only a small number of fields; in particular, the inflaton is directly coupled to just two light fields.

In agriculture intensive areas, fishponds and natural water bodies located in close proximity to these fields receive water with variable amounts of agrichemicals. Consequently, toxic compounds reach nontarget organisms. For instance, aquatic organisms can be exposed to tebuconazole-based fungicides (TBF), glyphosate-based herbicides (GBH), and atrazine-based herbicides (ABH) that are potentially dangerous, which motivates the following question: Are these agrichemicals attractant or aversive to fish? To answer this question, adult zebrafish were tested in a chamber that allows fish to escape from or seek a lane of contaminated water. This attraction and aversion paradigm was evaluated with zebrafish in the presence of an acute contamination with these compounds. We showed that only GBH was aversive to fish, whereas ABH and TBF caused neither attraction nor aversion for zebrafish. Thus, these chemicals do not impose an extra toxic risk by being an attractant for fish, although TBF and ABH can be more deleterious, because they induce no aversive response. Because the uptake and bioaccumulation of chemicals in fish seems to be time- and dose-dependent, a fish that remains longer in the presence of these substances tends to absorb higher concentrations than one that escapes from contaminated sites.

Background: Intensive care unit (ICU) admission triage is performed routinely and is often based solely on clinical judgment, which could mask biases. A computerized algorithm to aid ICU triage decisions was developed to classify patients into the Society of Critical Care Medicine's prioritization system. In this study, we sought to evaluate the reliability and validity of this algorithm., Methods: Nine senior physicians evaluated forty clinical vignettes based on real patients. The reference standard was defined as the priorities ascribed by two investigators with full access to patients' records. Agreement of algorithm-based priorities with the reference standard and with intuitive priorities provided by the physicians were evaluated. Correlations between algorithm prioritization and physicians' judgment of the appropriateness of ICU admissions in scarcity and nonscarcity settings were also evaluated. Validity was further assessed by retrospectively applying this algorithm to 603 patients with requests for ICU admission for association with clinical outcomes., Results: Agreement between algorithm-based priorities and the reference standard was substantial, with a median κ of 0.72 (interquartile range [IQR] 0.52-0.77). Algorithm-based priorities demonstrated higher interrater reliability (overall κ 0.61, 95% confidence interval [CI] 0.57-0.65; median percentage agreement 0.64, IQR 0.59-0.70) than physicians' intuitive prioritization (overall κ 0.51, 95% CI 0.47-0.55; median percentage agreement 0.49, IQR 0.44-0.56) (p = 0.001). Algorithm-based priorities were also associated with physicians' judgment of appropriateness of ICU admission (priorities 1, 2, 3, and 4 vignettes would be admitted to the last ICU bed in 83.7%, 61.2%, 45.2%, and 16.8% of the scenarios, respectively; p < 0.001) and with actual ICU admission, palliative care consultation, and hospital mortality in the retrospective cohort., Conclusions: This ICU admission triage algorithm demonstrated good reliability and validity. However, more studies are needed to evaluate a difference in benefit of ICU admission justifying the admission of one priority stratum over the others.

Psychotropic medications are widely used, and their prescription has increased worldwide, consequently increasing their presence in aquatic environments. Therefore, aquatic organisms can be exposed to psychotropic drugs that may be potentially dangerous, raising the question of whether these drugs are attractive or aversive to fish. To answer this question, adult zebrafish were tested in a chamber that allows the fish to escape or seek a lane of contaminated water. These attraction and aversion paradigms were evaluated by exposing the zebrafish to the presence of acute contamination with these compounds. The zebrafish were attracted by certain concentrations of diazepam, fluoxetine, risperidone and buspirone, which were most likely detected by olfaction, because this behavior was absent in anosmic fish. These findings suggest that despite their deleterious effects, certain psychoactive drugs attract fish., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Fish production ponds and natural water body areas located in close proximity to agricultural fields receive water with variable amounts of agrochemicals, and consequently, compounds that produce adverse effects may reach nontarget organisms. The aim of this study was to investigate whether waterborne methyl-parathion-based insecticide (MPBI) affected gene expression patterns of brain glucocorticoid receptor (GR), steroidogenic acute regulatory protein (StAR), and heat shock protein 70 (hsp70) in adult zebrafish (Danio rerio) exposed to this chemical for 96 h. Treated fish exposed to MPBI-contaminated water showed an inhibition of brain StAR and hsp70 gene expression. Data demonstrated that MPBI produced a decrease brain StAR and hsp70 gene expression.

The contamination of rivers and other natural water bodies, including underground waters, is a current reality. Human occupation and some economic activities generate a wide range of contaminated effluents that reach these water resources, including psychotropic drug residues. Here we show that fluoxetine, diazepam and risperidone affected the initial development of zebrafish. All drugs increased mortality rate and heart frequency and decreased larvae length. In addition, risperidone and fluoxetine decreased egg hatching. The overall results points to a strong potential of these drugs to cause a negative impact on zebrafish initial development and, since the larvae viability was reduced, promote adverse effects at the population level. We hypothesized that eggs and larvae absorbed the drugs that exert its effects in the central nervous system. These effects on early development may have significant environmental implications., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The presence of drugs and their metabolites in surface waters and municipal effluents has been reported in several studies, but its impacts on aquatic organisms are not yet well understood. This study investigated the effects of acute exposure to the antipsychotic risperidone on the stress and behavioral responses in zebrafish. It became clear that intermediate concentration of risperidone inhibited the hypothalamic-pituitary-interrenal axis and displayed anxiolytic-like effects in zebrafish. The data presented here suggest that the presence of this antipsychotic in aquatic environments can alter neuroendocrine and behavior profiles in zebrafish.

Here, we show that individually housed zebrafish presented a reduced cortisol response to an acute stressor (persecution with a pen net for 120 s) compared to zebrafish housed in groups of 10. We hypothesized that the cortisol response to stress was reduced in individually housed zebrafish because they depend solely on their own perceptions of the stressor, whereas among grouped zebrafish, the stress response might be augmented by chemical and/or behavioral cues from the other members of the shoal. This hypothesis was based on previous described chemical communication of stress in fish as well on individual variation in stressor perception and potential individual differences in fish personality., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We studied the stress response of Rhamdia quelen fingerlings at 45, 90, 135 and 180 d following acute exposure to agrichemicals. Herein, we report the novel observation that acute exposure of fingerling-aged fish to a methyl parathion-based insecticide (MPBI) and to a tebuconazole-based fungicide (TBF) induced chronic inhibition of the stress response. In contrast, fish exposed to an atrazine-simazine-based herbicide (ASBH) recovered the stress response on day 45, and fish exposed to a glyphosate-based herbicide (GBH) did not present stress response inhibition. Additionally, fish exposed to MPBI, GBH and ASBH showed lower survival rates and attained lower final weights. In the case of TBF, the presence of the stressful stimulus more strongly influenced the changes in the performance parameters than did the agrichemical exposure itself. An impairment of the cortisol response may seriously hamper the adaptive response and the ability to promote the necessary metabolic and ionic adjustments to respond to environmental stress., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The presence of pharmaceutical products in the aquatic environment has been reported in several studies. However, the impact of these drugs on living organisms is still uncharacterized. Here, we investigated the effects of acute exposure to either diazepam or fluoxetine on the stress response in Danio rerio. We showed that diazepam and fluoxetine inhibited the stress axis in zebrafish. Intermediate concentrations of diazepam suppressed the stress response as measured by cortisol levels, whereas fluoxetine inhibited cortisol increase at concentrations similar to those found in the environment. These data suggest that the presence of psychoactive drugs in aquatic ecosystems could cause neuroendocrine dysfunction in fish.

We investigated chemical cues among groups of zebrafish (Danio rerio) when communicating information about the risk of predation. We found that visual cues of the predator (tiger Oscar, Astronotus ocellatus) did not increase whole-body cortisol levels in groups of zebrafish but that water conditioned by these (donor) zebrafish stressed (target) conspecifics, thereby increasing whole-body cortisol. This finding was confirmed when these zebrafish groups were in different aquaria and communicated exclusively via water transfer. This result indicates that the stress induced in the target zebrafish does not depend on an increase in whole-body cortisol levels in the donor zebrafish. Because cortisol participation is rejected in this predation-risk communication, other chemicals from the stress systems should be investigated.

We investigated a group of Rhamdia quelen females during their entire first reproductive cycle and beginning of the 2nd cycle by evaluating the stress response at different phases of gonadal maturation. In mammals, including humans, pubertal development modulates stress response reactivity due to the maturation of the neuroendocrine stress axis. These shifts in the stress reactivity were also detected in salmonid fishes. This effect comes from changes in the sensitivity of the stress axis glands or in the capacity of the adrenal tissue to synthesise glucocorticoids. Here, for the first time, we show that similar to mammals and salmonid fishes, pre-pubertal female R. quelen exhibit a protracted stress response compared to adult fish, pointing to puberty as a key event on HPI axis modulation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The effects of ethanol exposure on Danio rerio have been studied from the perspectives of developmental biology and behavior. However, little is known about the effects of ethanol on the prey-predator relationship and chemical communication of predation risk. Here, we showed that visual contact with a predator triggers stress axis activation in zebrafish. We also observed a typical stress response in zebrafish receiving water from these conspecifics, indicating that these fish chemically communicate predation risk. Our work is the first to demonstrate how alcohol effects this prey-predator interaction. We showed for the first time that alcohol exposure completely blocks stress axis activation in both fish seeing the predator and in fish that come in indirect contact with a predator by receiving water from these conspecifics. Together with other research results and with the translational relevance of this fish species, our data points to zebrafish as a promising animal model to study human alcoholism.

In southern South America and other parts of the world, aquaculture is an activity that complements agriculture. Small amounts of agrichemicals can reach aquaculture ponds, which results in numerous problems caused by oxidative stress in non-target organisms. Substances that can prevent or reverse agrichemical-induced oxidative damage may be used to combat these effects. This study includes four experiments. In each experiment, 96 mixed-sex, 6-month-old Rhamdia quelen (118±15 g) were distributed into eight experimental groups: a control group that was not exposed to contaminated water, three groups that were exposed to various concentrations of bee products, three groups that were exposed to various concentrations of bee products plus tebuconazole (TEB; Folicur 200 CE™) and a group that was exposed to 0.88 mg L(-1) of TEB alone (corresponding to 16.6% of the 96-h LC50). We show that waterborne bee products, including royal jelly (RJ), honey (H), bee pollen (BP) and propolis (P), reversed the oxidative damage caused by exposure to TEB. These effects were likely caused by the high polyphenol contents of these bee-derived compounds. The most likely mechanism of action for the protective effects of bee products against tissue oxidation and the resultant damage is that the enzymatic activities of superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) are increased.

This study investigated the influence of neonatal handling on behavioral and biochemical consequences of chronic mild stress (CMS) in adulthood. Male rat pups were submitted to daily tactile stimulation (TS) or maternal separation (MS), from postnatal day 1 (PND1) to postnatal day 21 (PND21), for 10 min/day. In adulthood, half the number of animals were exposed to CMS for 3 weeks and submitted to behavioral testing, including sucrose preference (SP), elevated plus maze (EPM), and defensive burying tasks (DBTs), followed by biochemical assessments. CMS reduced SP, increased anxiety in EPM and DBT, and increased adrenal weight. In addition, CMS decreased plasma vitamin C (VIT C) levels and increased protein carbonyl (PC) levels, catalase (CAT) activity in hippocampus and cortex, and superoxide dismutase (SOD) levels in cortex. In contrast, both forms of neonatal handling were able to prevent reduction in SP, anxiety behavior in DBT, and CMS-induced adrenal weight increase. Furthermore, they were also able to prevent plasma VIT C reduction, hippocampal PC levels increase, CAT activity increase in hippocampus and cortex, and SOD levels increase in cortex following CMS. Only TS was able to prevent CMS-induced anxiety symptoms in EPM and PC levels in cortex. Taken together, these findings show the protective role of neonatal handling, especially TS, which may enhance ability to cope with stressful situations in adulthood.

In many vertebrate species, including humans, the developmental stage directly influences an organism's reactivity to stress. For instance, fishes appear to exhibit "stress insensitive" periods early in development, which contributes to important alterations in stress responses. This phenomenon raises the important question of whether size or age influences fish stress responses, as there may be large discrepancies in size at any stage of ontogeny. We therefore posed the following question: what key role does the age and/or weight/length of fish play in contributing to different stress levels? To address this question, we conducted 2 simple experiments to compare the cortisol response to stress in the fish Rhamdia quelen. In the first experiment, we compared the cortisol response of fish of 2 different age groups (3 vs. 12 months) with the same body size, whereas in the second experiment we compared 2 groups of the same age (3 months) but with different body sizes. The results showed a similar stress response in fish of the same age but different size, but a large difference in the stress response in fish of the same size but different age. Both tests indicate that age is the determining factor for the functioning of the hypothalamo-pituitary-interrenal (HPI) axis, and is probably related to the stage of maturation. This study makes a significant contribution to our knowledge of the stress, behavior, and welfare of fish of different age classes, primarily with respect to the timing of measurements and the accurate determination of fish age, regardless of size., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In this study we evaluated the influence of neonatal tactile stimulation (TS) on behavioral and biochemical effects related to a low dose of diazepam (DZP) in adult rats. Male pups of Wistar rats were handled (TS) daily from PND1 to PND21 for 10 min, while unhandled (UH) rats were not touched. In adulthood, half the animals of each group received a single administration of diazepam (0.25mg/kg body weight i.p.) or vehicle and then were submitted to behavioral and biochemical evaluations. In the TS group, DZP administration reduced anxiety-like symptoms in different behavioral paradigms (elevated plus maze, EPM; staircase and open-field and defensive burying) and increased exploratory behavior. These findings show that neonatal TS increased DZP pharmacological responses in adulthood compared to neonatally UH animals, as observed by reduced anxiety-like symptoms and lower levels of plasma cortisol. TS also changed plasma levels of antioxidant defenses such as vitamin C and glutathione peroxidase, whose increase may be involved in lower oxidative damages to proteins in cortex, subthalamic region and hippocampus of these animals. Here we are showing for the first time that neonatal TS is able to change responsiveness to benzodiazepine drugs in adulthood and provides better pharmacological responses in novel situations of stress., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This study investigated differences in the cortisol response of fish at different developmental stages after exposure to an acute stressor. Three experiments using 126 fish each were performed using 3 different age groups of jundiá (Rhamdia quelen): fingerlings at 60 days of age, juveniles at 180 days, and adults at 360 days. In each experiment, the fish in each group were randomly distributed into either a handled experimental group or a non-handled control group. The handled group was then exposed to an acute stressor for measurement of cortisol concentrations at 5, 15, 30, 60, and 240 min after exposure and subsequent comparison of cortisol concentrations with those of the non-handled groups at the 6 sampling times. Between the experimental and control groups, the results revealed that the handled fish in each of the 3 age groups had higher cortisol concentrations compared to the non-handled fish in the equivalent age group. Among the age groups of the handled fish, the results revealed that the fingerlings and juveniles attained peak cortisol concentrations within 5 to 30 min after stressor exposure whereas the adults attained peak concentrations 60 min after exposure. This finding has important implications for the design of research into stress and welfare among fish at different developmental stages., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Older adults have been facing usability problems every day, and with the increasing of life expectation those issues will be more and more frequent. The study of this group capacities and limitations could help designers to project systems more usable to everyone.

This present article describes a research on the development, under the approach of participatory design, a virtual teaching-learning of Histology in which students and teachers participated actively in all stages of development of the educational environment. We postulates that the development of virtual learning environment of Histology, through the Participatory Design approach, contributes to greater acceptance and use by students and that the adoption of virtual environment for teaching and learning by teachers is a determining factor of use by students.