The inflammasome is hypothesized to be a key mediator of the response to physiological and psychological stressors, and its dysregulation may be implicated in major depressive disorder. Inflammasome ...activation causes the maturation of caspase-1 and activation of interleukin (IL)-1β and IL-18, two proinflammatory cytokines involved in neuroimmunomodulation, neuroinflammation and neurodegeneration. In this study, C57BL/6 mice with genetic deficiency or pharmacological inhibition of caspase-1 were screened for anxiety- and depressive-like behaviors, and locomotion at baseline and after chronic stress. We found that genetic deficiency of caspase-1 decreased depressive- and anxiety-like behaviors, and conversely increased locomotor activity and skills. Caspase-1 deficiency also prevented the exacerbation of depressive-like behaviors following chronic stress. Furthermore, pharmacological caspase-1 antagonism with minocycline ameliorated stress-induced depressive-like behavior in wild-type mice. Interestingly, chronic stress or pharmacological inhibition of caspase-1 per se altered the fecal microbiome in a very similar manner. When stressed mice were treated with minocycline, the observed gut microbiota changes included increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation and rebalance of gut microbiota, respectively, and the increment in Lachnospiracea abundance was consistent with microbiota changes of caspase-1 deficiency. Our results suggest that the protective effect of caspase-1 inhibition involves the modulation of the relationship between stress and gut microbiota composition, and establishes the basis for a gut microbiota-inflammasome-brain axis, whereby the gut microbiota via inflammasome signaling modulate pathways that will alter brain function, and affect depressive- and anxiety-like behaviors. Our data also suggest that further elucidation of the gut microbiota-inflammasome-brain axis may offer novel therapeutic targets for psychiatric disorders.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IMPORTANCE: The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. OBJECTIVE: To assess the ...association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women’s Health Initiative clinical trials. DESIGN, SETTING, AND PARTICIPANTS: Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017. INTERVENTIONS: In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years’ median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years’ median intervention duration. MAIN OUTCOMES AND MEASURES: The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer. RESULTS: Among 27 347 postmenopausal women who were randomized in both trials (baseline mean SD age, 63.4 years 7.2 years), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio HR, 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11). CONCLUSIONS AND RELEVANCE: In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.
The opportunity to participate in and contribute to emerging fields is increasingly prevalent in science. However, simply thinking about stepping outside of your academic silo can leave many students ...reeling from the uncertainty. Here, we describe 10 simple rules to successfully train yourself in an emerging field, based on our experience as students in the emerging field of ecological forecasting. Our advice begins with setting and revisiting specific goals to achieve your academic and career objectives and includes several useful rules for engaging with and contributing to an emerging field.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid ...tic disorders.
Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks.
Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (-5.5 +/- 6.9 vs -3.0 +/- 8.7, p = 0.063) and Tic Symptom Self-Report total score (-4.7 +/- 6.5 vs -2.9 +/- 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (-0.7 +/- 1.2 vs -0.1 +/- 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (-10.9 +/- 10.9 vs -4.9 +/- 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (-0.8 +/- 1.1 vs -0.3 +/- 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures.
Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.
We report the results of a search for 12.2-GHz methanol maser emission, targeted towards 113 known 6.7-GHz methanol masers associated with 1.2-mm dust continuum emission. Observations were carried ...out with the Australia Telescope National Facility (ATNF) Parkes 64-m radio telescope in the period 2008 June 20–25. We detect 68 12.2-GHz methanol masers with flux densities in excess of our 5σ detection limit of 0.55 Jy, 30 of which are new discoveries. This equates to a detection rate of 60 per cent, similar to previous searches of comparable sensitivity. We have made a statistical investigation of the properties of the 1.2-mm dust clumps with and without associated 6.7-GHz methanol maser and find that 6.7-GHz methanol masers are associated with 1.2-mm dust clumps with high-flux densities, masses and radii. We additionally find that 6.7-GHz methanol masers with higher peak luminosities are associated with less dense 1.2-mm dust clumps than those 6.7-GHz methanol masers with lower luminosities. We suggest that this indicates that more luminous 6.7-GHz methanol masers are generally associated with a later evolutionary phase of massive star formation than less luminous 6.7-GHz methanol maser sources. Analysis of the 6.7-GHz associated 1.2-mm dust clumps with and without associated 12.2-GHz methanol maser emission shows that clumps associated with both class II methanol maser transitions are less dense than those with no associated 12.2-GHz methanol maser emission. Furthermore, 12.2-GHz methanol masers are preferentially detected towards 6.7-GHz methanol masers with associated OH masers, suggesting that 12.2-GHz methanol masers are associated with a later evolutionary phase of massive star formation. We have compared the colours of the Spitzer Galactic Legacy Infrared Mid-Plane Survey Extraordinaire (GLIMPSE) point sources associated with the maser sources in the following two subgroups: 6.7-GHz methanol masers with and without associated 12.2-GHz methanol masers; and 6.7-GHz methanol masers with high- and those with low-peak luminosities. There is little difference in the nature of the associated GLIMPSE point sources in any of these subgroups, and we propose that the masers themselves are probably much more sensitive than mid-infrared data to evolutionary changes in the massive star formation regions that they are associated with. We present an evolutionary sequence for masers in high-mass star formation regions, placing quantitative estimates on the relative lifetimes for the first time.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
All-optical approaches to particle acceleration are currently attracting a significant research effort internationally. Although characterized by exceptional transverse and longitudinal emittance, ...laser-driven ion beams currently have limitations in terms of peak ion energy, bandwidth of the energy spectrum and beam divergence. Here we introduce the concept of a versatile, miniature linear accelerating module, which, by employing laser-excited electromagnetic pulses directed along a helical path surrounding the laser-accelerated ion beams, addresses these shortcomings simultaneously. In a proof-of-principle experiment on a university-scale system, we demonstrate post-acceleration of laser-driven protons from a flat foil at a rate of 0.5 GeV m(-1), already beyond what can be sustained by conventional accelerator technologies, with dynamic beam collimation and energy selection. These results open up new opportunities for the development of extremely compact and cost-effective ion accelerators for both established and innovative applications.
We present a GIS method to interpret qualitatively expressed socio-economic scenarios in quantitative map-based terms. (i) We built scenarios using local stakeholders and experts to define how major ...land cover classes may change under different sets of drivers; (ii) we formalised these as spatially explicit rules, for example agriculture can only occur on certain soil types; (iii) we created a future land cover map which can then be used to model ecosystem services. We illustrate this for carbon storage in the Eastern Arc Mountains of Tanzania using two scenarios: the first based on sustainable development, the second based on ‘business as usual’ with continued forest–woodland degradation and poor protection of existing forest reserves. Between 2000 and 2025 4% of carbon stocks were lost under the first scenario compared to a loss of 41% of carbon stocks under the second scenario. Quantifying the impacts of differing future scenarios using the method we document here will be important if payments for ecosystem services are to be used to change policy in order to maintain critical ecosystem services.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent mesial temporal sclerosis and temporal lobe epilepsy. However, little is known about the semiology of FSE.
...A prospective, multicenter study of the consequences of FSE included children, aged 1 month through 5 years, presenting with a febrile seizure lasting 30 minutes or more. Procedures included neurologic history and examination and an MRI and EEG within 72 hours. All information related to seizure semiology was reviewed by three epileptologists blinded to MRI and EEG results and to subsequent outcome. Inter-rater reliability was assessed by the kappa statistic.
Among 119 children, the median age was 1.3 years, the mean peak temperature was 103.2 degrees F, and seizures lasted a median of 68.0 minutes. Seizure duration followed a Weibull distribution with a shape parameter of 1.68. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. In one third of cases, FSE was unrecognized in the emergency department. Of the 119 children, 86% had normal development, 24% had prior febrile seizures, and family history of febrile seizures in a first-degree relative was present in 25%.
Febrile status epilepticus is usually focal and often not well recognized. It occurs in very young children and is usually the first febrile seizure. Seizures are typically very prolonged and the distribution of seizure durations suggests that the longer a seizure continues, the less likely it is to spontaneously stop.
The concentration of dissolved oxygen (DO) is an important attribute of aquatic ecosystems, influencing habitat, drinking water quality, biodiversity, nutrient biogeochemistry, and greenhouse gas ...emissions. While average summer DO concentrations are declining in lakes across the temperate zone, much remains unknown about seasonal factors contributing to deepwater DO losses. It is unclear whether declines are related to increasing rates of seasonal DO depletion or changes in seasonal stratification that limit re‐oxygenation of deep waters. Furthermore, despite the presence of important biological and ecological DO thresholds, there has been no large‐scale assessment of changes in the amount of habitat crossing these thresholds, limiting the ability to understand the consequences of observed DO losses. We used a dataset from >400 widely distributed lakes to identify the drivers of DO losses and quantify the frequency and volume of lake water crossing biologically and ecologically important threshold concentrations ranging from 5 to 0.5 mg/L. Our results show that while there were no consistent changes over time in seasonal DO depletion rates, over three‐quarters of lakes exhibited an increase in the duration of stratification, providing more time for seasonal deepwater DO depletion to occur. As a result, most lakes have experienced summertime increases in the amount of water below all examined thresholds in deepwater DO concentration, with increases in the proportion of the water column below thresholds ranging between 0.9% and 1.7% per decade. In the 30‐day period preceding the end of stratification, increases were greater at >2.2% per decade and >70% of analyzed lakes experienced increases in the amount of oxygen‐depleted water. These results indicate ongoing climate‐induced increases in the duration of stratification have already contributed to reduction of habitat for many species, likely increased internal nutrient loading, and otherwise altered lake chemistry. Future warming is likely to exacerbate these trends.
A study of more than 400 lakes revealed climatic warming contributed to an increase in stratification duration along with greater volumes of oxygen‐depleted water during the summer. This will likely reduce habitat availability, increase internal nutrient loading, and otherwise alter lake chemistry. Further warming will exacerbate these trends.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Humanity will soon define a new era for nature-one that seeks to transform decades of underwhelming responses to the global biodiversity crisis. Area-based conservation efforts, which include both ...protected areas and other effective area-based conservation measures, are likely to extend and diversify. However, persistent shortfalls in ecological representation and management effectiveness diminish the potential role of area-based conservation in stemming biodiversity loss. Here we show how the expansion of protected areas by national governments since 2010 has had limited success in increasing the coverage across different elements of biodiversity (ecoregions, 12,056 threatened species, 'Key Biodiversity Areas' and wilderness areas) and ecosystem services (productive fisheries, and carbon services on land and sea). To be more successful after 2020, area-based conservation must contribute more effectively to meeting global biodiversity goals-ranging from preventing extinctions to retaining the most-intact ecosystems-and must better collaborate with the many Indigenous peoples, community groups and private initiatives that are central to the successful conservation of biodiversity. The long-term success of area-based conservation requires parties to the Convention on Biological Diversity to secure adequate financing, plan for climate change and make biodiversity conservation a far stronger part of land, water and sea management policies.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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