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This paper summarizes the status and the recent measurements of the Pierre Auger Observatory. The energy spectrum is described and its features discussed. Searches for anisotropy of cosmic ray arrival directions on large scales and through correlation with catalogues of celestial objects are reported. The first measurement of the proton-air cross section around 1018 eV is discussed. The mass composition is addressed with measurements of the variation of the depth of shower maximum with energy and with muon density at the ground. An update on the searches for neutrinos and photons is also presented.

The study of ultra-high energy cosmic rays (UHECRs) has recently experienced a jump in statistics as well as improved instrumentation. This has allowed a better sensitivity in searching for anisotropies in the arrival directions of cosmic rays. In this written version of the presentation given by the inter-collaborative “Anisotropy Working Group” at the International Symposium on Future Directions in UHECR physics at CERN in February 2012, we report on the current status for anisotropy searches in the arrival directions of UHECRs.

We present measurements of microwave emission from an electron-beam induced air plasma performed at the 3 MeV electron Van de Graaff facility of the Argonne National Laboratory. Results include the emission spectrum between 1 and 15 GHz, the polarization of the microwave radiation and the scaling of the emitted power with respect to beam intensity. MAYBE measurements provide further insight on microwave emission from extensive air showers as a novel detection technique for Ultra-High Energy Cosmic Rays.

The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases., (© 2024. The Author(s).)

Background: The implementation of clinical practice guidelines (CPGs) is a cyclical process in which the evaluation stage can facilitate continuous improvement. Implementation science has utilized theoretical approaches, such as models and frameworks, to understand and address this process. This article aims to provide a comprehensive overview of the models and frameworks used to assess the implementation of CPGs., Methods: A systematic review was conducted following the Cochrane methodology, with adaptations to the "selection process" due to the unique nature of this review. The findings were reported following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines. Electronic databases were searched from their inception until May 15, 2023. A predetermined strategy and manual searches were conducted to identify relevant documents from health institutions worldwide. Eligible studies presented models and frameworks for assessing the implementation of CPGs. Information on the characteristics of the documents, the context in which the models were used (specific objectives, level of use, type of health service, target group), and the characteristics of each model or framework (name, domain evaluated, and model limitations) were extracted. The domains of the models were analyzed according to the key constructs: strategies, context, outcomes, fidelity, adaptation, sustainability, process, and intervention. A subgroup analysis was performed grouping models and frameworks according to their levels of use (clinical, organizational, and policy) and type of health service (community, ambulatorial, hospital, institutional). The JBI's critical appraisal tools were utilized by two independent researchers to assess the trustworthiness, relevance, and results of the included studies., Results: Database searches yielded 14,395 studies, of which 80 full texts were reviewed. Eight studies were included in the data analysis and four methodological guidelines were additionally included from the manual search. The risk of bias in the studies was considered non-critical for the results of this systematic review. A total of ten models/frameworks for assessing the implementation of CPGs were found. The level of use was mainly policy, the most common type of health service was institutional, and the major target group was professionals directly involved in clinical practice. The evaluated domains differed between the models and there were also differences in their conceptualization. All the models addressed the domain "Context", especially at the micro level (8/12), followed by the multilevel (7/12). The domains "Outcome" (9/12), "Intervention" (8/12), "Strategies" (7/12), and "Process" (5/12) were frequently addressed, while "Sustainability" was found only in one study, and "Fidelity/Adaptation" was not observed., Conclusions: The use of models and frameworks for assessing the implementation of CPGs is still incipient. This systematic review may help stakeholders choose or adapt the most appropriate model or framework to assess CPGs implementation based on their specific health context., Trial Registration: PROSPERO (International Prospective Register of Systematic Reviews) registration number: CRD42022335884. Registered on June 7, 2022., (© 2024. The Author(s).)

Lipid composition is conserved within sub-cellular compartments to maintain cell function. Lipidomic analyses of liver, muscle, white and brown adipose tissue (BAT) mitochondria revealed substantial differences in their glycerophospholipid (GPL) and free cholesterol (FC) contents. The GPL to FC ratio was 50-fold higher in brown than white adipose tissue mitochondria. Their purity was verified by comparison of proteomes with ER and mitochondria-associated membranes. A lipid signature containing PC and FC, calculated from the lipidomic profiles, allowed differentiation of mitochondria from BAT of mice housed at different temperatures. Elevating FC in BAT mitochondria prevented uncoupling protein (UCP) 1 function, whereas increasing GPL boosted it. Similarly, STARD3 overexpression facilitating mitochondrial FC import inhibited UCP1 function in primary brown adipocytes, whereas a knockdown promoted it. We conclude that the mitochondrial GPL/FC ratio is key for BAT function and propose that targeting it might be a promising strategy to promote UCP1 activity., (© 2024 Brunner et al.)

Aims: Nucleic acids, particularly antibiotic resistance genes, are commonly found on surfaces within healthcare environments, with levels not reducing following cleaning. Within the UK, there are no regulations for testing disinfectants against nucleic acids., Methods and Results: A series of commonplace in vitro methods were used to determine disinfectant-induced physical and functional damage to various nucleic acids; RNA (10 μg), genomic DNA (2 μg), and plasmids (1 μg). Using these methods, the optimal residence time (10 minutes) and working concentration (10%) were determined for a new disinfectant. Furthermore, comparison of disinfectants with different active ingredients including lactic acid (LA), sodium hydroxide (NaOH), chloroxylenol (PCMX), and quaternary ammonium compounds (QACs), were compared to controls. All disinfectants showed greater degradation by gel electrophoresis of genomic DNA and RNA than of purified plasmids. Functional analysis using quantitative polymerase chain reaction (qPCR) and polymerase chain reaction (PCR) demonstrated that no disinfectant tested (apart from control) could damage DNA to the level where PCR amplification was not possible, and only the NaOH reagent could achieve this for RNA., Conclusions: The set of methods described herein provides a platform for future standardization and potential regulation regarding monitoring cleaning solutions for their activity against nucleic acids., (© The Author(s) 2023. Published by Oxford University Press on behalf of Applied Microbiology International.)

Streptococcus agalactiae is considered the main bacterial pathogen in cultured Nile tilapia. Formaldehyde-inactivated vaccines are the most accepted method for prevention and control of the disease. However, alternative inactivation methods for S. agalactiae vaccines have not been fully explored. Recently, we developed a hydrogen peroxide-inactivated vaccine against S. agalactiae with moderate efficacy, with the possibility to improve vaccine efficacy by adding adjuvants. The current study compared the efficacy of aluminum hydroxide and Freund's incomplete adjuvant (FIA) incorporated into a novel hydrogen peroxide-inactivated intraperitoneal vaccine against S. agalactiae for Nile tilapia fingerlings. The relative percentage survival (RPS) for aluminum hydroxide-adjuvanted vaccine (59.3%), and FIA-adjuvanted vaccine (77.8%) were higher than the vaccine without adjuvant (40.7%). In addition, fish immunized with aluminum hydroxide-adjuvanted vaccine had significantly higher levels of specific antibodies than control fish at 4 weeks post vaccination (wpv). Blood lymphocytes counts showed a decrease in vaccinated groups when compared to control fish, suggesting white cells migration to the tissues where antigen presentation is ongoing. Fish that received FIA-adjuvanted vaccine exhibited persistence of adjuvant deposits on intraperitoneal surfaces for at least 4 wpv that may be related to its superior performance compared to aluminum hydroxide adjuvanted vaccine, which did not evidence any type of deposit at any sampling times. The results observed in this study demonstrate that hydrogen peroxide-inactivated vaccine administered with either aluminum hydroxide or FIA induce optimal levels of protection, with a superior performance for FIA vaccine, which could be a good alternative to conventional formaldehyde-inactivated vaccines against S. agalactiae, due to its shorter manufacture time, and less toxicity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Previous studies have demonstrated that targeting bradykinin receptors is a promising strategy to counteract the cognitive impairment related with aging and Alzheimer's disease (AD). The hippocampus is critical for cognition, and abnormalities in this brain region are linked to the decline in mental ability. Nevertheless, the impact of bradykinin signaling on hippocampal function is unknown. Therefore, we sought to determine the role of hippocampal bradykinin receptors B 1 R and B 2 R on the cognitive decline of middle-aged rats. Twelve-month-old rats exhibited impaired ability to acquire and retrieve spatial information in the Morris water maze task. A single intra-hippocampal injection of the selective B 1 R antagonist des-Arg 9 -[Leu 8 ]-bradykinin (DALBK, 3 nmol), but not the selective B 2 R antagonist D-Arg-[Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ]-BK (Hoe 140, 3 nmol), reversed the spatial learning and memory deficits on these animals. However, both drugs did not affect the cognitive function in 3-month-old rats, suggesting absence of nootropic properties. Molecular biology analysis revealed an up-regulation of B1R expression in the hippocampal CA1 sub-region and in the pre-frontal cortex of 12-month-old rats, whereas no changes in the B 2 R expression were observed in middle-aged rats. These findings provide new evidence that inappropriate hippocampal B 1 R expression and activation exert a critical role on the spatial learning and memory deficits in middle-aged rats. Therefore, selective B 1 R antagonists, especially orally active non-peptide antagonists, may represent drugs of potential interest to counteract the age-related cognitive decline., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Epilepsy is a brain function disorder characterized by unpredictable and recurrent seizures. The majority of patients with temporal lobe epilepsy (TLE), which is the most common type of epilepsy, have to live not only with seizures but also with behavioral alterations, including anxiety, psychosis, depression, and impaired cognitive functioning. The pilocarpine model has been recognized as an animal model of TLE. However, there are few studies addressing behavioral alterations in the maturation phase when evaluating the time course of the epileptogenic process after pilocarpine administration. Therefore, the present work was designed to analyze the neurobehavioral impairments of male adult Wistar rats during maturation and chronic phases in the pilocarpine model of epilepsy. Behavioral tests included: open-field tasks, olfactory discrimination, social recognition, elevated plus maze, and the forced swimming test. The main behavioral alterations observed in both maturation and chronic phases of the pilocarpine model were olfactory and short-term social memory deficits and decrease in the immobility time in the forced swimming test. Moreover, increased anxiety-like responses were only observed in the maturation phase. These findings indicate that early behavioral impairments can be observed in the pilocarpine model during the maturation phase, and these behavioral deficits also occur during the acquired epilepsy (chronic phase). Several of the neurobehavioral impairments that are associated with epilepsy in humans were observed in the pilocarpine-treated rats, thus, rendering this animal model a useful tool to study neuroprotective strategies as well as neurobiological and psychopathological mechanisms associated with epileptogenesis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The pilocarpine model in rodents reproduces the main features of mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) in humans. It has been demonstrated in this model that the phosphorylation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit is increased 1 h after pilocarpine treatment. Moreover, alterations in the levels of glutamate transporters have been associated with chronic epilepsy in humans. Despite these studies, the profile of these changes has not yet been addressed. We analyzed the protein content and phosphorylation profile of the AMPA receptor GluR1 subunit by western blotting. We also used quantitative real-time polymerase chain reaction to analyze the expression of glial glutamate transporters and the N-methyl-D-aspartate receptor NR1 subunit in the hippocampus (Hip) and cerebral cortex (Ctx) at different time points after pilocarpine-induced status epilepticus (Pilo-SE) in male adult Wistar rats. Biochemical analysis was performed in the Hip and Ctx at 1, 3, 12 h (acute period), 5 days (latent period), and 50 days (chronic period) after Pilo-SE. Key findings include an increase in the phosphorylation of GluR1-Ser(845) in the Ctx and GluR1-Ser(831) in the Hip at different times during the acute period, and a decrease in the total content of the GluR1 subunit in the Ctx in the latent period. There was a down-regulation of the mRNA expression and protein levels of EAAT1 and EAAT2, and a decrease of the NR1 mRNA expression, in the Ctx during the latent period. Notably, during the chronic period, the EAAT2 mRNA expression and protein levels decreased while the NR1 mRNA levels increased in the Hip. Taken together, our findings suggest a time- and structure-dependent imbalance of glutamatergic transmission in response to Pilo-SE, which might be associated with either epileptogenesis or the seizure threshold in MTLE-HS.

The epileptogenesis may involve a variety of signaling events that culminate with synaptic reorganization. Mitogen-activated protein kinases (MAPKs) and AKT may be activated by diverse stimulus including neurotransmitter, oxidative stress, growth factors and cytokines and are involved in synaptic plasticity in the hippocampus and cerebral cortex. The pilocarpine model in rodents reproduces the main features of mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) in humans. We analyze the phosphorylation profile of MAPKs (ERK1/2, p38(MAPK), JNK1/2/3) and AKT by western blotting in the hippocampus (Hip) and cortex (Ctx) of male adult wistar rats in different periods, after pilocarpine induced status epilepticus (Pilo-SE) and compared with control animals. Biochemical analysis were done in the Hip and Ctx at 1, 3, 12 h (acute period), 5 days (latent period) and 50 days (chronic period) after Pilo-SE onset. Hence, the main findings include increased phosphorylation of ERK1 and p38(MAPK) in the Hip and Ctx 1 and 12 h after the Pilo-SE onset. The JNK2/3 isoform (54 kDa) phosphorylation was decreased at 3 h after the Pilo-SE onset and in the chronic period in the Hip and Ctx. The AKT phosphorylation increased only in the Hip during the latent period. Our study demonstrates, in a systematic manner, the profile of MAPKs and AKT modulation in the hippocampus and cerebral cortex in response to pilocarpine. Based in the role of each signaling enzyme is possible that these changes may be related, at least partially, to modifications in the intrinsic neuronal physiology and epileptogenic synaptic network that appears in the MTLE-HS.

The glucose-dependent insulinotropic peptide receptor (GIPR) has been implicated with neuroplasticity and may be related to epilepsy. GIPR expression was analyzed by immunohistochemistry in the hippocampus (HIP) and neocortex (Cx) of rats undergoing pilocarpine induced status epilepticus (Pilo-SE), and in three young male patients with left mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) treated surgically. A combined GIPR immunohistochemistry and Fluoro-Jade staining was carried out to investigate the association between the GIPR expression and neuronal degeneration induced by Pilo-SE. GIPR was expressed in the cytoplasm of neurons from the HIP CA subfields, dentate gyrus (DG) and Cx of animals and human samples. The GIPR expression after the Pilo-SE induction increases significantly in the HIP after 1h and 5 days, but not after 12h or 50 days. In the Cx, the GIPR expression increases after 1h, 12h and 5 days, but not 50 days after the Pilo-SE. The expression of GIPR 12h after Pilo-SE was inversely proportional to the Fluoro-Jade staining intensity. In the human tissue, GIPR expression patterns were similar to those observed in chronic Pilo-SE animals. No Fluoro-Jade stained cells were observed in the human sample. GIPR is expressed in human HIP and Cx. There was a time and region dependent increase of GIPR expression in the HIP and Cx after Pilo-SE that was inversely associated to neuronal degeneration., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Previous studies have shown that cognitive deficits precede the classical motor symptoms seen in Parkinson's disease (PD) and that physical exercise may exert beneficial effects on PD. We have recently verified that the monoamine-depleting drug reserpine - at doses that do not modify motor function - impairs memory processes in rats. Here, we evaluated the potential of physical exercise to improve cognitive and motor deficits induced by reserpine. Adult Wistar rats were assigned to six groups: (1) untrained-vehicle; (2) untrained-reserpine; (3) running wheel (RW)-vehicle; (4) RW-reserpine; (5) treadmill-vehicle; and (6) treadmill-reserpine. Exercise groups were given free nocturnal access to RW or continuous treadmill exercise (20-25 min/day) for 5 days/week over 4 weeks. The animals were injected subcutaneously with reserpine (1.0 or 5.0mg/kg) or vehicle 48 h after the end of physical program, and 24h later they were tested in a battery of behavioral paradigms. RW and treadmill improved the motor deficits induced by a high reserpine dose (5.0mg/kg), as evaluated in the rotarod and open-field tests. Moreover, untrained rats treated with a low reserpine dose (1.0mg/kg) presented short-term social memory deficits (without motor or olfactory disturbance) that were selectively improved by the exercise training. Our results reinforce the potential of low to moderate physical exercise as a useful tool in the prevention of motor and cognitive impairments associated to CNS monoaminergic depletion.

Muscarinic receptor agonists have been suggested as potential drugs to counteract age-related cognitive decline since critical changes in cholinergic system occur with aging. Recently, we demonstrated that single administration of the non-selective muscarinic receptor agonist pilocarpine prevents age-related spatial learning impairments in rats. In addition, increasing evidence suggests that areas in the central nervous system processing olfactory information are affected at the early stages of age-related diseases, such as Alzheimer's disease, and that specific olfactory testing may represent an important tool in the diagnosis of these diseases. In the present study, olfactory discrimination and short-term social memory of 3 and 24 month-old rats were assessed with the olfactory discrimination and social recognition memory tasks, respectively. The actions of the repeated treatment with pilocarpine (30 mg/kg, i.p.; once per day for 21 days) in relation to age-related effects on olfactory and cognitive functions were also studied. The 24 month-old rats exhibited significantly impaired performance in both models, demonstrating deficits in their odour discrimination and in their ability to recognize a juvenile rat after a short period of time. The treatment with pilocarpine improved in a specific manner these age-related deficits in 24 month-old rats without altering their motor performance. The present results extend the notion of the participation of muscarinic receptors in control of olfactory functions and reinforce the potential of muscarinic receptor agonists for the treatment of age-related cognitive decline.

The cholinergic pathways are intimately involved in the learning and memory process and disruption of this system produces impairments in many learning and memory models. Converging lines of evidence support the idea that there is an age-related decline in learning and memory in animals and this decline is strikingly similar to memory changes that occur when the cholinergic system is compromised. The purpose of this work was to evaluate whether a single administration of the muscarinic receptor agonist Pilocarpine (Pilo) could prevent the age-related learning impairment in rats. Three groups of animals received Pilo (300 mg/kg, i.p.), at 3 months of age, and the animals that did not show Status epilepticus were submitted to the water maze task 1 or 21 months after or once a month from the 4th to 24th month of age. The results showed that Pilo did not interfere with learning abilities 1-month after treatment nor in animals that were submitted to the test once a month. In addition, the animals treated with Pilo and submitted to the task 21 month after performed as well as control young rats in the training and in the testing sessions, while a marked learning impairment was detected in control old rats. These results indicate that a single administration of Pilo might prevent the age-related learning impairments in rats on a spatial task in the water maze.

A phase III clinical study was carried out among 534 fertile Latin American women to evaluate cycle control, side effects, and contraceptive efficacy of a once-a-month combined injectable, Mesigyna, consisting of 50 mg norethisterone enanthate and 5 mg estradiol valerate. The pregnancy rate at 1 year was 0 per 100 woman-years for a total experience of 4688 woman-months. The overall discontinuation rate at one year was 17.9%. Discontinuation rate for bleeding problems was 5.1%. The Colombian women had a significant increase (p <0.001) in bleeding problems compared to other countries. The discontinuation rate for amenorrhea was 1.1%. There were no significant differences between the groups regarding discontinuation for other medical or non-medical reasons. Mean weight gain after one year of use was 1.02 kg. Mesigyna is an appropiate once-a-month injectable contraceptive for Latin American women since it is highly effective and its perception of normal menstrual bleeding is of importance in the Latin American population.

After the realization of control research that had in view the transmission of dengue virus, we started to monitor two kinds of entomological vigilance, Breteau Index and ovitrap. We intended to evaluate the necessary time elapsed before Aedes sp mosquitoes were again detected at the urban area of Catanduva s town (SP). The ovitraps showed positiveness for the Aedes aegypti two months after the control research, while the Breteau Index became positive only at the fourth month after the end of the referred research.

The city of Ribeirão Preto suffered a dengue 1 epidemic that began in November 1990 and ended in March 1991. A serologic survey designed to detect IgG antibodies to the four dengue serotypes and other flaviviruses was carried out in Ribeirão Preto during September and October of 1992. Dengue 1 antibodies were detected in 5.4% of the survey participants. Significantly higher seropositivity (9.3%) was found among subjects residing in the Northwest Sector of Ribeirão Preto than among those living in the city's other three sectors. The Northwest Sector also exhibited relatively high levels of breeding sites used by the Aedes aegypti vector, the highest number of reported dengue cases of any sector, and relatively poor socioeconomic conditions. The fact that the epidemic was limited mainly to the Northwest Sector probably resulted mainly from intense vector control and educational measures undertaken in response to the outbreak. As of the 1992 survey, most of the city's population remained vulnerable to dengue 1 infection; however, an estimated 23,000 with dengue 1 antibodies appeared to be at relatively high risk of developing dengue hemorrhagic fever/dengue shock syndrome in the event of infection with dengue 2. Both of these considerations indicate an ongoing need to maintain dengue education and vector control measures.