Blazar spectral variability as explained by a twisted inhomogeneous jet.

Blazars are active galactic nuclei, which are powerful sources of radiation whose central engine is located in the core of the host galaxy. Blazar emission is dominated by non-thermal radiation from a jet that moves relativistically towards us, and therefore undergoes Doppler beaming. This beaming causes flux enhancement and contraction of the variability timescales, so that most blazars appear as luminous sources characterized by noticeable and fast changes in brightness at all frequencies. The mechanism that produces this unpredictable variability is under debate, but proposed mechanisms include injection, acceleration and cooling of particles, with possible intervention of shock waves or turbulence. Changes in the viewing angle of the observed emitting knots or jet regions have also been suggested as an explanation of flaring events and can also explain specific properties of blazar emission, such as intra-day variability, quasi-periodicity and the delay of radio flux variations relative to optical changes. Such a geometric interpretation, however, is not universally accepted because alternative explanations based on changes in physical conditions-such as the size and speed of the emitting zone, the magnetic field, the number of emitting particles and their energy distribution-can explain snapshots of the spectral behaviour of blazars in many cases. Here we report the results of optical-to-radio-wavelength monitoring of the blazar CTA 102 and show that the observed long-term trends of the flux and spectral variability are best explained by an inhomogeneous, curved jet that undergoes changes in orientation over time. We propose that magnetohydrodynamic instabilities or rotation of the twisted jet cause different jet regions to change their orientation and hence their relative Doppler factors. In particular, the extreme optical outburst of 2016-2017 (brightness increase of six magnitudes) occurred when the corresponding emitting region had a small viewing angle. The agreement between observations and theoretical predictions can be seen as further validation of the relativistic beaming theory.

Risk factors for community-associated Clostridioides difficile infection in young children.

The majority of paediatric Clostridioides difficile infections (CDI) are community-associated (CA), but few data exist regarding associated risk factors. We conducted a case-control study to evaluate CA-CDI risk factors in young children. Participants were enrolled from eight US sites during October 2014-February 2016. Case-patients were defined as children aged 1-5 years with a positive C. difficile specimen collected as an outpatient or ⩽3 days of hospital admission, who had no healthcare facility admission in the prior 12 weeks and no history of CDI. Each case-patient was matched to one control. Caregivers were interviewed regarding relevant exposures. Multivariable conditional logistic regression was performed. Of 68 pairs, 44.1% were female. More case-patients than controls had a comorbidity (33.3% vs. 12.1%; P = 0.01); recent higher-risk outpatient exposures (34.9% vs. 17.7%; P = 0.03); recent antibiotic use (54.4% vs. 19.4%; P < 0.0001); or recent exposure to a household member with diarrhoea (41.3% vs. 21.5%; P = 0.04). In multivariable analysis, antibiotic exposure in the preceding 12 weeks was significantly associated with CA-CDI (adjusted matched odds ratio, 6.25; 95% CI 2.18-17.96). Improved antibiotic prescribing might reduce CA-CDI in this population. Further evaluation of the potential role of outpatient healthcare and household exposures in C. difficile transmission is needed.

The International Mood Network (IMN) Nosology Project: differentiating borderline personality from bipolar illness.

OBJECTIVE: The differential diagnosis of bipolar illness vs. borderline personality is controversial. Both conditions manifest impulsive behavior, unstable interpersonal relationships, and mood symptoms. This study examines whether and which mood clinical features can differentiate between both conditions. METHOD: A total of 260 patients (mean ± standard deviation age 41 ± 13 years, 68% female) attending to a mood clinic were examined for diagnosis of bipolar illness and borderline personality disorder using SCID-I, SCID-II, and clinical mood criteria extracted from Mood Disorder Questionnaire (MDQ). They were analyzed using diagnoses as dependent variables. Predictors of bipolar and borderline diagnoses were identified by multivariable logistic regressions, and predictive validity of models was assessed using ROC curve analysis. RESULTS: Bipolar illness was strongly predicted by elevated mood (OR = 4.02, 95% CI: 1.80-9.15), increased goal-directed activities (OR = 3.90, 95% CI: 1.73-8.96), and episodicity of mood symptoms (OR = 3.48, 95% CI 1.49-8.39). This triad model predicted bipolar illness with 88.7% sensitivity, 81.4% specificity, and obtained an auROC of 0.91 (95% CI: 0.76-0.96) and a positive predictive value of 85.1%. For borderline personality disorder, only female gender was a statistically significant predictor (OR = 3.41, 95% CI: 1.29-13.7), and the predictive model obtained an auROC of 0.67 (95% CI: 0.53-0.74). CONCLUSION: In a mood disorder clinic setting, manic criteria and episodic mood course distinguished bipolar illness from borderline personality disorder.

Mercury Accumulation, Structural Damages, and Antioxidant and Immune Status Changes in the Gilthead Seabream (Sparus aurata L.) Exposed to Methylmercury.

In aquatic systems, mercury (Hg) is an environmental contaminant that causes acute and chronic damage to multiple organs. In fish, practically all of the organic Hg found is in the form of methylmercury (MeHg), which has been associated with animal and human health problems. This study evaluates the impact of waterborne-exposure to sublethal concentrations of MeHg (10 µg L(-1)) in gilthead seabream (Sparus aurata). Hg was seen to accumulate in liver and muscle, and histopathological damage to skin and liver was detected. Fish exposed to MeHg showed a decreased biological antioxidant potential and increased levels of the reactive oxygen molecules compared with the values found in control fish (nonexposed). Increased liver antioxidant enzyme activities (superoxide dismutase and catalase) were detected in 2 day-exposed fish with respect to the values of control fish. However, fish exposed to MeHg for 10 days showed liver antioxidant enzyme levels similar to those of the control fish but had increased hepato-somatic index and histopathological alterations in liver and skin. Serum complement levels were higher in fish exposed to MeHg for 30 days than in control fish. Moreover, head-kidney leukocyte activities increased, although only phagocytosis and peroxidase activities showed a significant increase after 10 and 30 days, respectively. The data show that 30 days of exposure to waterborne MeHg provokes more significant changes in fish than a short-term exposure of 2 or 10 days.

[Factors associated with compliance to the semi-recumbent position in the patient on mechanical ventilation: CAPCRI-Q questionnaire]. / Factores relacionados con el cumplimiento de la posición semiincorporada en el paciente con ventilación mecánica según los profesionales: cuestionario CAPCRI-Q.

AIM: To create a questionnaire (CAPCRI-Q) to determine the factors associated with the compliance of the semi-recumbent position in patients under mechanical ventilation. METHODS: A closed questionnaire was created using a literature review and clinical practice. The initial version consisted of 61 items placed into 5 categories: patient factors, team and professionals factors, activity, educational and training factors, and equipment and resources. A Delphi method was used to prepare the questionnaire. Comprehension, relevance and importance of each item were evaluated, as well as the recommendations of experts. A qualitative pilot test with 9 healthcare professionals was performed, followed by a quantitative pilot test with 67 nurses from 6 intensive care units to test the internal consistency of the instrument. RESULTS: Three rounds with 15 experts were required to reach a consensus. The final version of the questionnaire consisted of 36 items enclosed in the same categories as the initial version. The internal consistency analysis showed values greater than 0.800 for each independent item, each category, and for the global questionnaire (0.873; 95%CI: 0.825-0.913). The analysis of the nurses' responses emphasised the importance of the patient factors, as well as organisational and infra-structural factors, for the compliance of the recommendation. CONCLUSIONS: The questionnaire created is reliable and appears to have content validity. The most influential factors for compliance are those related to the patient and the internal organisation. The results of the questionnaire can be used to evaluate the factors influencing the compliance and to establish improvement strategies.

Role of main neuroendocrine pathways activated by swim stress on mast cell-dependent peritoneal TNF production after LPS administration in mice.

OBJECTIVE AND DESIGN: To characterize the effects of swim stress on the early mast cell (MC)-dependent peritoneal production of TNF in response to lipopolysaccharide (LPS) administration in mice, identifying the neuroendocrine mediators involved. SUBJECTS: Ten to twelve-week-old Swiss Webster, C57BL/6 J or c-Kit (Wsh/Wsh) mice were used. TREATMENT: Animals were intraperitoneally challenged with LPS at different times after forced swimming (FS) and peak TNF production was determined in peritoneal washes at optimal time after LPS administration. Selective blockage of main neuroendocrine pathways was performed before swim stress. METHODS: TNF concentrations were determined by ELISA. RESULTS: FS provoked an immediate and transient inhibition of LPS-elicited, MC-dependent TNF accumulation in peritoneum, which lasted around 30 min. Suppresive effects of FS were absent on MC-deficient c-Kit (Wsh/Wsh) mice but were recovered after reconstitution with MC. Adrenalectomy or DSP4 administration increased basal ip TNF levels and enhanced LPS-induced TNF release without any effect on stress-induced inhibitory effects, mifepristone did not produce any change on stress-induced inhibition, whereas mecamylamine administration increased basals and attenuated stress effects. CONCLUSIONS: Swim stress transiently inhibits the canonical MC-dependent response of TNF production in response to LPS in murine peritoneal cavity with the main participation of the cholinergic anti-inflammatory reflex.

[Quality of life of people with Parkinson's disease during confinement due to the covid-19 pandemic]. / Calidad de vida de las personas con enfermedad de Parkinson durante el confinamiento por la pandemia por covid-19.

INTRODUCTION: The study was aimed to explore the quality of life of people with Parkinson's disease during confinement due to the coronavirus infectious disease 2019 (covid-19) pandemic. MATERIAL AND METHODS: The study was quantitative, descriptive and correlational. The sample was 51 people with Parkinson's disease, from the region of Magallanes and Chilean Antarctica, and whose information was collected from the database of the Rehabilitation Corporation Club de Leones Cruz del Sur, to which they belong. RESULTS: The main results show that 51.6% of people with Parkinson's disease report a «good and very good¼ quality of life and that the main domains of the Parkinson's Disease Questionnaire (PDQ-39) affected are: body discomfort, mobility and emotional well-being. According to the analysis of the qualitative ranges of the PDQ-39, the dimensions that were most compromised during the confinement by the covid-19 pandemic were: communication, stigma and emotional well-being. In addition, women had a poorer quality of life than men. Finally, it was shown that the progression of symptoms affects the quality of life of people with Parkinson's disease. CONCLUSIONS: In conclusion, during the confinement due to the covid-19 pandemic people with Parkinson's disease increased symptoms and presented a lower quality of life, especially women.

Chronic Degradation of Seasonally Dry Tropical Forests Increases the Incidence of Genotoxicity in Birds.

Multiple studies have shown that exposure to pollutants can increase genotoxic damage in different taxa. However, to our knowledge, the effects of environmental stress have been explored little. In certain stressful ecosystems, such as seasonally dry tropical forests, the combined effects of anthropogenic activities and ongoing global changes can cause an increase in environmental stresses, in turn, may trigger physiological and genetic effects on biodiversity. The present aims to assess changes in the prevalence of genotoxic damage in birds within three states of forest degradation in the Tumbesian Region of Western Ecuador. We used blood samples from 50 bird species to determine the frequency of micronucleus and nuclear abnormalities in erythrocytes. Our results revealed a significant impact of forest degradation on the occurrence probability of micronucleus and nuclear abnormalities at the community level. Localities with higher levels of degradation exhibited higher levels of abnormalities. However, when analyzing the dominant species, we found contrasting responses. While Lepidocolaptes souleyetii showed a reduction in the proportion of nuclear abnormalities from the natural to shrub-dominated localities Troglodytes aedon and Polioptila plumbea showed an increase for semi-natural and shrub-dominated respectively. We concluded that the degradation process of these tropical forests increases the stress of bird community generating genotoxic damage. Bird responses seem to be species-specific, which could explain the differences in changes in bird composition reported in other studies.

Increased thin-spine density in frontal cortex pyramidal neurons in a genetic rat model of schizophrenia-relevant features.

The cellular mechanisms altered during brain wiring leading to cognitive disturbances in neurodevelopmental disorders remain unknown. We have previously reported altered cortical expression of neurodevelopmentally regulated synaptic markers in a genetic animal model of schizophrenia-relevant behavioral features, the Roman-High Avoidance rat strain (RHA-I). To further explore this phenotype, we looked at dendritic spines in cortical pyramidal neurons, as changes in spine density and morphology are one of the main processes taking place during adolescence. An HSV-viral vector carrying green fluorescent protein (GFP) was injected into the frontal cortex (FC) of a group of 11 RHA-I and 12 Roman-Low Avoidance (RLA-I) male rats. GFP labeled dendrites from pyramidal cells were 3D reconstructed and number and types of spines quantified. We observed an increased spine density in the RHA-I, corresponding to a larger fraction of immature thin spines, with no differences in stubby and mushroom spines. Glia cells, parvalbumin (PV) and somatostatin (SST) interneurons and surrounding perineuronal net (PNN) density are known to participate in FC and pyramidal neuron dendritic spine maturation. We determined by stereological-based quantification a significantly higher number of GFAP-positive astrocytes in the FC of the RHA-I strain, with no difference in microglia (Iba1-positive cells). The number of inhibitory PV, SST interneurons or PNN density, on the contrary, was unchanged. Results support our belief that the RHA-I strain presents a more immature FC, with some structural features like those observed during adolescence, adding construct validity to this strain as a genetic behavioral model of neurodevelopmental disorders.

Time-course of 5-HT(6) receptor mRNA expression during memory consolidation and amnesia.

Growing evidence indicates that antagonists of the 5-hydroxytryptamine (serotonin) receptor(6) (5-HT(6)) improve memory and reverse amnesia although the mechanisms involved are poorly understood. Hence, in this paper RT-PCR was used to evaluate changes in mRNA expression of 5-HT(6) receptor in trained and untrained rats treated with the 5-HT(6) receptor antagonist SB-399885 and amnesic drugs scopolamine or dizocilpine. Changes in mRNA expression of 5-HT(6) receptor were investigated at different times in prefrontal cortex, hippocampus and striatum. Data indicated that memory in the Pavlovian/instrumental autoshaping task was a progressive process associated to reduced mRNA expression of 5-HT(6) receptor in the three structures examined. SB-399885 improved long-term memory at 48h, while the muscarinic receptor antagonist scopolamine or the non-competitive NMDA receptor antagonist dizocilpine impaired it at 24h. Autoshaping training and treatment with SB-399885 increased 5-HT(6) receptor mRNA expression in (maximum increase) prefrontal cortex and striatum, 24 or 48h. The scopolamine-induced amnesia suppressed 5-HT(6) receptor mRNA expression while the dizocilpine-induced amnesia did not modify 5-HT(6) receptor mRNA expression. SB-399885 and scopolamine or dizocilpine were able to reestablish memory and 5-HT(6) receptor mRNA expression. These data confirmed previous memory evidence and of more interest is the observation that training, SB-399885 and amnesic drugs modulated 5-HT(6) receptor mRNA expression in prefrontal cortex, hippocampus and striatum. Further investigation in different memory tasks, times and amnesia models together with more complex control groups might provide further clues.

Hand perfusion following radial or ulnar forearm free flap harvest for oral cavity reconstruction: A prospective study.

The radial forearm free flap (RFFF) and ulnar forearm free flap (UFFF) are used in head and neck reconstruction because they provide a thin and pliable skin paddle as well as a long vascular pedicle. However, in spite of several studies showing the safety of the UFFF, the RFFF is more popular among reconstructive surgeons based on concerns about hand ischaemia. A prospective study was designed in which 10 UFFF and 11 RFFF surgeries were performed in 20 patients undergoing oral cavity reconstruction between January 2017 and July 2018. Hand vascular parameters were evaluated preoperatively and postoperatively using Doppler ultrasound and plethysmography. The preoperative and postoperative diameters of the radial and ulnar arteries, and the flow velocities through the remainder of the forearm artery were measured preoperatively and at 3 months postoperative. Additionally, a comparison was performed between the preoperative and postoperative fingertip perfusion values according to impedance plethysmography. The preoperative mean diameter of the radial artery (2.89±0.47mm) was significantly greater than that of the ulnar artery (2.35±0.48mm) at the level of the wrist; however, 3 months after the surgery, the mean diameters of the two arteries did not differ significantly. There were no differences in digital perfusion when a UFFF was used compared with an RFFF.

Neuroscience of the auditory-motor system: How does sound interact with movement?

Human musicality is a complex problem because it involves the coupling of multiple exogenous and endogenous signals with different physical properties. The synchronization of these signals translates into specific behaviors. The study of this synchronization, based on the physical properties of two oscillatory bodies, is the first step in understanding the behaviors associated with rhythmic auditory stimuli. In recent years, different neurorehabilitation therapies have emerged for motor pathologies involving music. However, the neurophysiological bases that describe the coupling phenomenon are not yet fully understood. In this article, two theories are addressed that attempt to explain the convergence of the auditory system and the motor system according to new neuroanatomical, neurophysiological and artificial neural network findings. It also reflects on the different approaches to a complex problem in cognitive neuroscience and the need for a study model for the different motor behaviors evoked by auditory stimuli.

Development of a calculator to establish indications to refer patients with lumbar degenerative disease for spinal surgery consultation. / Desarrollo de una calculadora para establecer indicación de derivación a consulta de cirugía del raquis en patología degenerativa lumbar.

BACKGROUND AND AIM: Low-back pain remains a common pathological entity in the Western population. We have found no data in the literature that assess whether, with correct physical examination and evaluation of simple x-rays of the spine, it is possible to diagnose patients who are highly likely to be candidates for lumbar spine surgery and thus reduce the care burden and resource consumption that this disorder entails. The aim of the study was to develop a user-friendly calculator that allows only patients who are strong candidates for surgical treatment to be referred for spinal surgery consultation. MATERIAL AND METHOD: An observational and retrospective study that included all adult patients from the healthcare area of Talavera de la Reina (Toledo, Spain) with a clinical and/or radiological diagnosis of degenerative lumbar spine disease referred by other specialists over one calendar year to the spinal surgery unit to assess whether surgery was indicated after unsuccessful conservative treatment. All the patients were assessed under the same protocol with a follow-up of 6years, at the end of which we performed a check of those who had undergone lumber spine surgery. RESULTS: A total of 201 patients were studied and at the end of the 6-year follow-up, a total of 77 patients had been operated. Concordance of 70% was found between the indication for surgical treatment and the treatment received at the end of the follow-up. Therefore a logistic regression was performed in an attempt to predict the patients that could be referred to the spinal surgery units and from that a calculator was generated, which included the plain x-ray variable as an essential item, and which showed as statistically significant (P<.05): age, Waddell's non-organic signs, Lasegue's sign and plain x-ray assessment. Once this tool had been obtained, the likelihood of undergoing surgery was calculated for all patients who were proposed surgical treatment, obtaining results above 62% as the cut-off point when using the calculator. CONCLUSIONS: The use of the calculator predicts the possibility of being a candidate for surgical treatment with 70% reliability. Therefore, patients with a result in the calculator of above 62% should be referred for spinal surgery consultation for assessment by a specialist.

Dissociation between schizophrenia-relevant behavioral profiles and volumetric brain measures after long-lasting social isolation in Roman rats.

Social isolation rearing of rodents is an environmental manipulation known to induce or potentiate psychotic-like symptoms and attentional and cognitive impairments relevant for schizophrenia. When subjected to a 28-week isolation rearing treatment, the Roman high-avoidance (RHA-I) rats display the common behavioral social isolation syndrome, with prepulse inhibition (PPI) deficits, hyperactivity, increased anxiety responses and learning/memory impairments when compared to their low-avoidance (RLA-I) counterparts. These results add face validity to the RHA-I rats as an animal model for schizophrenia-relevant behavioral and cognitive profiles and confirm previous results. The aim here was to further investigate the neuroanatomical effects of the isolation rearing, estimated through volume differences in medial prefrontal cortex (mPFC), dorsal striatum (dSt) and hippocampus (HPC). Results showed a global increase in volume in the mPFC in the isolated rats of both strains, as well as strain effects (RLA > RHA) in the three brain regions. These unexpected but robust results, might have unveiled some kind of compensatory mechanisms due to the particularly long-lasting isolation rearing period, much longer than those commonly used in the literature (which usually range from 4 to 12 weeks).

High-protein distillers dried grains with solubles produced using a novel front-end-back-end fractionation technology has greater nutritional value than conventional distillers dried grains with solubles when fed to growing pigs.

Two experiments were conducted to determine the standardized ileal digestibility (SID) of CP and AA, apparent total tract digestibility (ATTD) of GE, and DE and ME in conventional distillers dried grains with solubles (DDGS-CV) and in a novel source of high-protein distillers dried grains with solubles (DDGS-HP) produced by Lincolnway Energy (Nevada, IA). In Exp. 1, 18 barrows (initial BW: 72.47 ± 9.16 kg) that had a T-cannula installed in the distal ileum were allotted to a completely randomized design with 3 diets and 6 replicate pigs per diet. A nitrogen-free diet and 2 diets that contained cornstarch and DDGS-CV or DDGS-HPLincolnway as the sole source of CP and AA were formulated. Diets were fed to pigs for 7 d, and ileal digesta were collected on days 6 and 7 of each period. The SID for Leu, Lys, Met, Phe, and Glu was greater (P < 0.05) in DDGS-HPLincolnway than in DDGS-CV, and the SID of Ile, Val, and total indispensable AA, as well as the SID of Tyr, tended to be greater (P < 0.10) in DDGS-HPLincolnway than in DDGS-CV. No difference between DDGS-CV and DDGS-HPLincolnway was observed for the SID of CP and all other AA. In Exp. 2, 24 barrows (initial BW: 52.80 ± 2.55 kg) were housed individually in metabolism crates and randomly allotted to 1 of 3 diets. A corn-based basal diet (97.25% corn) and 2 diets that contained corn and DDGS-CV or corn and DDGS-HPLincolnway were formulated. Each diet was fed to 8 pigs. Feces and urine were collected using the marker to marker approach with 7-d adaptation and 5-d collection periods. The DE and ME in DDGS-CV and DDGS-HPLincolnway were calculated using the difference procedure. The DE and ME in DDGS-HPLincolnway on an as-fed basis were greater (P < 0.05) than in corn and DDGS-CV, but the ATTD of GE in DDGS-HPLincolnway and DDGS-CV was less (P < 0.01) than in corn. In conclusion, the SID of some AA and the DE and ME in DDGS-HPLincolnway were greater than in DDGS-CV.

Stimulation of nAchRα7 Receptor Inhibits TNF Synthesis and Secretion in Response to LPS Treatment of Mast Cells by Targeting ERK1/2 and TACE Activation.

The cholinergic anti-inflammatory pathway is recognized as one of the main mechanisms of neuromodulation of the immune system. Activation of the α7 nicotinic acetylcholine receptor (nAchRα7) suppresses cytokine synthesis in distinct immune cells but the molecular mechanisms behind this effect remain to be fully described. Mast cells (MCs) are essential players of allergic reactions and innate immunity responses related to chronic inflammation. Activation of TLR4 receptor in MCs leads to the rapid secretion of pre-synthesized TNF from intracellular pools and to the activation of NFκB, necessary for de novo synthesis of TNF and other cytokines. Here we report that the nAchRα7 receptor specific agonist GTS-21 inhibits TLR4-induced secretion of preformed TNF from MCs in vivo and in vitro. Utilizing bone marrow-derived mast cells (BMMCs) it was found that GTS-21 also diminished secretion of de novo synthesized TNF, TNF mRNA accumulation and IKK-dependent p65-NFκB phosphorylation in response to LPS. nAchRα7 triggering prevented TLR4-induced ERK1/2 phosphorylation, which resulted an essential step for TNF secretion due to the phosphorylation of the metallopeptidase responsible for TNF maturation (TACE). Main inhibitory actions of GTS-21 were prevented by AG490, an inhibitor of JAK-2 kinase. Our results show for the first time, that besides the prevention of NFκB-dependent transcription, inhibitory actions of nAchRα7 triggering include the blockade of pathways leading to exocytosis of granule-stored cytokines in MCs.

Impact of a shift work-like lighting schedule on the functioning of the circadian system in the short-lived fish Nothobranchius furzeri.

Adult Nothobranchius furzeri of the MZM-04/10 strain were individually kept and subjected to a "5 + 2" shifting lighting schedule (SHIFT) for 8 weeks in order to evaluate the desynchronizing effects of a simulated human-like shift-work schedule on the functioning of the circadian system (CS). With this aim, sixteen 21-week-old N. furzeri were placed into a Morning, Night and Evening schedule (lights on from 08:00 to 16:00, 00:00 to 08:00 and 16:00 to 00:00 h, respectively) and fed once a day in the middle of the corresponding photophase (12:00, 04:00 and 20:00 h, respectively). Then, in the weekends (2 days), fish were always returned to the Morning shift. As controls, 16 fish were maintained under a non-shifting LD cycle condition (CONTROL) throughout the whole experiment, with lights on from 08:00 to 16:00 h. Rest-activity rhythm (RAR) of fish subjected to SHIFT showed several symptoms of chronodisruption, such as a decrease in the percentage of diurnal activity and a reduction of the relative amplitude and the circadian function index with time. When a periodogram analysis was performed, RAR of N. furzeri under SHIFT conditions showed up to three separate circadian components: one longer than 24 h (26.5 h) that followed the weekly 8 h delays; a short-period component (~23 h) that was related to the weekend's phase advances, and finally, a 24 h component. The shifting LD schedule also affected fish CS at a molecular level, with several significant differences in the expression of core genes of the molecular clock (bmal1, clock, rorα, rev-erbα) between SHIFT and CONTROL animals. RAR impairment along with changes in clock gene expression could be associated with high stress and accelerated aging in these fish.

Jacareubin inhibits FcεRI-induced extracellular calcium entry and production of reactive oxygen species required for anaphylactic degranulation of mast cells.

Mast cells (MCs) are important effectors in allergic reactions since they produce a number of pre-formed and de novo synthesized pro-inflammatory compounds in response to the high affinity IgE receptor (FcεRI) crosslinking. IgE/Antigen-dependent degranulation and cytokine synthesis in MCs have been recognized as relevant pharmacological targets for the control of deleterious inflammatory reactions. Despite the relevance of allergic diseases worldwide, efficient pharmacological control of mast cell degranulation has been elusive. In this work, the xanthone jacareubin was isolated from the heartwood of the tropical tree Callophyllum brasilense, and its tridimensional structure was determined for the first time by X-ray diffraction. Also, its effects on the main activation parameters of bone marrow-derived mast cells (BMMCs) were evaluated. Jacareubin inhibited IgE/Ag-induced degranulation in a dose-response manner with an IC50 = 46 nM. It also blocked extracellular calcium influx triggered by IgE/Ag complexes and by the SERCA ATPase inhibitor thapsigargin (Thap). Inhibition of calcium entry correlated with a blockage on the reactive oxygen species (ROS) accumulation. Antioxidant capacity of jacareubin was higher than the showed by α-tocopherol and caffeic acid, but similar to trolox. Jacareubin shown inhibitory actions on xanthine oxidase, but not on NADPH oxidase (NOX) activities. In vivo, jacareubin inhibited passive anaphylactic reactions and TPA-induced edema in mice. Our data demonstrate that jacareubin is a potent natural compound able to inhibit anaphylactic degranualtion in mast cells by blunting FcεRI-induced calcium flux needed for secretion of granule content, and suggest that xanthones could be efficient anti-oxidant, antiallergic, and antiinflammatory molecules.

Vav1 regulates phospholipase cgamma activation and calcium responses in mast cells.

The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated following engagement of many receptors, including FcepsilonRI. Vav1-deficient mice contain normal numbers of mast cells but respond more weakly than their normal counterparts to a passive systemic anaphylaxis challenge. Vav1-deficient bone marrow-derived mast cells also exhibited reduced degranulation and cytokine production, although tyrosine phosphorylation of FcepsilonRI, Syk, and LAT (linker for activation of T cells) was normal. In contrast, tyrosine phosphorylation of phospholipase Cgamma1 (PLCgamma1) and PLCgamma2 and calcium mobilization were markedly inhibited. Reconstitution of deficient mast cells with Vav1 restored normal tyrosine phosphorylation of PLCgamma1 and PLCgamma2 and calcium responses. Thus, Vav1 is essential to FcepsilonRI-mediated activation of PLCgamma and calcium mobilization in mast cells. In addition to its known role as an activator of Rac1 GTPases, these findings demonstrate a novel function for Vav1 as a regulator of PLCgamma-activated calcium signals.