Bi-allelic
mutations cause Gaucher's disease (GD), the most common lysosomal storage disorder. Neuronopathic manifestations in GD include neurodegeneration, which can be severe and rapidly ...progressive.
mutations are also the most frequent genetic risk factors for Parkinson's disease. Dysfunction of the autophagy-lysosomal pathway represents a key pathogenic event in
-associated neurodegeneration. Using an induced pluripotent stem cell (iPSC) model of GD, we previously demonstrated that lysosomal alterations in GD neurons are linked to dysfunction of the transcription factor EB (TFEB). TFEB controls the coordinated expression of autophagy and lysosomal genes and is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1). To further investigate the mechanism of autophagy-lysosomal pathway dysfunction in neuronopathic GD, we examined mTORC1 kinase activity in GD iPSC neuronal progenitors and differentiated neurons. We found that mTORC1 is hyperactive in GD cells as evidenced by increased phosphorylation of its downstream protein substrates. We also found that pharmacological inhibition of glucosylceramide synthase enzyme reversed mTORC1 hyperactivation, suggesting that increased mTORC1 activity is mediated by the abnormal accumulation of glycosphingolipids in the mutant cells. Treatment with the mTOR inhibitor Torin1 upregulated lysosomal biogenesis and enhanced autophagic clearance in GD neurons, confirming that lysosomal dysfunction is mediated by mTOR hyperactivation. Further analysis demonstrated that increased TFEB phosphorylation by mTORC1 results in decreased TFEB stability in GD cells. Our study uncovers a new mechanism contributing to autophagy-lysosomal pathway dysfunction in GD, and identifies the mTOR complex as a potential therapeutic target for treatment of
-associated neurodegeneration.
Current methods for estimating heat vulnerability of young athletes use a heat index (HI) or a wet bulb globe thermometer (WBGT), neither of which fully include the environmental or physiological ...characteristics that can affect a person’s heat budget, particularly where activity occurs on a synthetic surface. This study analyzed and compared the standard methods, HI and WBGT, with a novel and more comprehensive method termed COMFA-Kid (CK) which is based on an energy budget model explicitly designed for youth. The COMFA model was presented at the same time to demonstrate the difference between a child and an adult during activity. Micrometeorological measurements were taken at a synthetic-surfaced football field during mid-day in hot environmental conditions. Standard methods (HI and WBGT) indicated that conditions on the field were relatively safe for youth to engage in activities related to football practice or games, whereas the CK method indicated that conditions were dangerously hot and could lead to exertional heat illness. Estimates using the CK method also indicated that coaches and staff standing on the sidelines, and parents sitting in the stands, would not only be safe from heat but would be thermally comfortable. The difference in thermal comfort experienced by coaches and staff off the field, versus that experienced by young players on the field, could affect decision making regarding the duration and intensity of practices and time in the game. The CK method, which is easy to use and available for modification for specific conditions, would lead to more accurate estimates of heat safety on outdoor synthetic surfaces in particular, and in sports with a high prevalence of heat illness such as football, and should be considered as a complementary or alternative preventive measure against heat.
We report the identification of compounds on Titan's surface by spatially resolved imaging spectroscopy methods through Titan's atmosphere, and set upper limits to other organic compounds. We present ...evidence for surface deposits of solid benzene (C6H6), solid and/or liquid ethane (C2H6), or methane (CH4), and clouds of hydrogen cyanide (HCN) aerosols using diagnostic spectral features in data from the Cassini Visual and Infrared Mapping Spectrometer (VIMS). Cyanoacetylene (2‐propynenitrile, IUPAC nomenclature, HC3N) is indicated in spectra of some bright regions, but the spectral resolution of VIMS is insufficient to make a unique identification although it is a closer match to the feature previously attributed to CO2. We identify benzene, an aromatic hydrocarbon, in larger abundances than expected by some models. Acetylene (C2H2), expected to be more abundant on Titan according to some models than benzene, is not detected. Solid acetonitrile (CH3CN) or other nitriles might be candidates for matching other spectral features in some Titan spectra. An as yet unidentified absorption at 5.01‐μm indicates that yet another compound exists on Titan's surface. We place upper limits for liquid methane and ethane in some locations on Titan and find local areas consistent with millimeter path lengths. Except for potential lakes in the southern and northern polar regions, most of Titan appears “dry.” Finally, we find there is little evidence for exposed water ice on the surface. Water ice, if present, must be covered with organic compounds to the depth probed by 1–5‐μm photons: a few millimeters to centimeters.
Competition between neurons is necessary for refining neural circuits during development and may be important for selecting the neurons that participate in encoding memories in the adult brain. To ...examine neuronal competition during memory formation, we conducted experiments with mice in which we manipulated the function of CREB (adenosine 3′,5′-monophosphate response element--binding protein) in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Our results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in a memory trace as a function of their relative CREB activity at the time of learning.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The aim of this study was to determine age-related differences in short-term (1-year) outcomes in patients with unruptured intracranial aneurysms (UIAs).
Four thousand fifty-nine patients ...prospectively enrolled in the International Study of Unruptured Intracranial Aneurysms were categorized into 3 groups by age at enrollment: < 50, 50-65, and > 65 years old. Outcomes assessed at 1 year included aneurysm rupture rates, combined morbidity and mortality from aneurysm procedure or hemorrhage, and all-cause mortality. Periprocedural morbidity, in-hospital morbidity, and poor neurological outcome on discharge (Rankin scale score of 3 or greater) were assessed in surgically and endovascularly treated groups. Univariate and multivariate associations of each outcome with age were tested.
The risk of aneurysmal hemorrhage did not increase significantly with age. Procedural and in-hospital morbidity and mortality increased with age in patients treated with surgery, but remained relatively constant with increasing age with endovascular treatment. Poor neurological outcome from aneurysm- or procedure-related morbidity and mortality did not differ between management groups for patients 65 years old and younger, but was significantly higher in the surgical group for patients older than 65 years: 19.0% (95% confidence interval CI 13.9%-24.4%), compared with 8.0% (95% CI 2.3%-13.6%) in the endovascular group and 4.2% (95% CI 2.3%-6.2%) in the observation group. All-cause mortality increased steadily with increasing age, but differed between treatment groups only in patients < 50 years of age, with the surgical group showing a survival advantage at 1 year.
Surgical treatment of UIAs appears to be safe, prevents 1-year hemorrhage, and may confer a survival benefit in patients < 50 years of age. However, surgery poses a significant risk of morbidity and death in patients > 65 years of age. Risk of endovascular treatment does not appear to increase with age. Risks and benefits of treatment in older patients should be carefully considered, and if treatment is deemed necessary for patients older than 65 years, endovascular treatment may be the best option.
Background
A number of school systems worldwide have proposed and implemented later school start times as a means of avoiding the potentially negative impacts that early morning schedules can have on ...adolescent students. Even mild sleep deprivation has been associated with significant health and educational concerns: increased risk for accidents and injuries, impaired learning, aggression, memory loss, poor self‐esteem, and changes in metabolism. Although researchers have begun to explore the effects of delayed school start time, no one has conducted a rigorous review of evidence to determine whether later school start times support adolescent health, education, and well‐being.
Objectives
We aimed to assess the effects of a later school start time for supporting health, education, and well‐being in high school students.
Secondary objectives were to explore possible differential effects of later school start times in student subgroups and in different types of schools; to identify implementation practices, contextual factors, and delivery modes associated with positive and negative effects of later start times; and to assess the effects of later school start times on the broader community (high school faculty and staff, neighborhood, and families).
Search methods
We conducted the main search for this review on 28 October 2014 and updated it on 8 February 2016. We searched CENTRAL as well as 17 key electronic databases (including MEDLINE, Embase, ERIC, PsycINFO, and Sociological s), current editions of relevant journals and organizational websites, trial registries, and Google Scholar.
Selection criteria
We included any randomized controlled trials, controlled before‐and‐after studies, and interrupted time series studies with sufficient data points that pertained to students aged 13 to 19 years and that compared different school start times. Studies that reported either primary outcomes of interest (academic outcomes, amount or quality of sleep, mental health indicators, attendance, or alertness) or secondary outcomes (health behaviors, health and safety indicators, social outcomes, family outcomes, school outcomes, or community outcomes) were eligible.
Data collection and analysis
At least two review authors independently determined inclusion and exclusion decisions through screening titles, s, and full‐text reports. Two review authors independently extracted data for all eligible studies. We presented findings through a narrative synthesis across all studies. When two or more study samples provided sufficient information to permit effect size calculations, we conducted random‐effects meta‐analyses to synthesize effects across studies.
Main results
Our search located 17 eligible records reporting on 11 unique studies with 297,994 participants; the studies examined academic outcomes, amount and quality of sleep, mental health indicators, attendance, and student alertness. Overall, the quality of the body of evidence was very low, as we rated most studies as being at high or unclear risk of bias with respect to allocation, attrition, absence of randomization, and the collection of baseline data. Therefore, we cannot be confident about the effects of later school start times.
Preliminary evidence from the included studies indicated a potential association between later school start times and academic and psychosocial outcomes, but quality and comparability of these data were low and often precluded quantitative synthesis. Four studies examined the association between later school start times and academic outcomes, reporting mixed results. Six studies examined effects on total amount of sleep and reported significant, positive relationships between later school start times and amount of sleep. One study provided information concerning mental health outcomes, reporting an association between decreased depressive symptoms and later school start times. There were mixed results for the association between later school start times and absenteeism. Three studies reported mixed results concerning the association between later school start times and student alertness. There was limited indication of potential adverse effects on logistics, as the qualitative portions of one study reported less interaction between parents and children, and another reported staffing and scheduling difficulties. Because of the insufficient evidence, we cannot draw firm conclusions concerning adverse effects at this time.
It is important to note the limitations of this evidence, especially as randomized controlled trials and high‐quality primary studies are difficult to conduct; school systems are often unwilling or unable to allow researchers the necessary control over scheduling and data collection. Moreover, this evidence does not speak to the process of implementing later school starts, as the included studies focused on reporting the effects rather than exploring the process.
Authors' conclusions
This systematic review on later school start times suggests several potential benefits for this intervention and points to the need for higher quality primary studies. However, as a result of the limited evidence base, we could not determine the effects of later school start times with any confidence.
At present, there is no available method to study the in vivo microstructures of the airway wall (epithelium, smooth muscle, adventitia, basement membrane, glands, cartilage). Currently, we rely on ...ex vivo histologic evaluation of airway biopsies. To overcome this obstacle, we have developed an endoscopic ultrahigh-resolution diffractive optical coherence tomography (OCT) system, operating at a wavelength of 800 nm, to non-invasively study the in vivo microstructures of the airway wall. Prior to human study, validation of diffractive OCT's ability to quantitate airway microstructural components is required.
To validate and demonstrate the accuracy of this OCT system, we used an ovine model to image small airways (∼ 2 mm in diameter). Histologic samples and correlated OCT images were matched. The cross-sectional area of the airway wall, lumen, and other microstructures were measured and compared.
A total of 27 sheep were studied from which we identified 39 paired OCT-histology airway images. We found strong correlations between the OCT and the histology measurements of the airway wall area and the microstructural area measurements of the epithelium, basement membrane, airway smooth muscle, glands, cartilage, and adventitia. The correlations ranged from r=0.61 (p<0.001) for the epithelium to r=0.86 (p<0.001) for the adventitia with the correlation between the OCT and the histology measurements for the entire airway wall of r=0.76 (p<0.001).
Given the high degree of correlation, these data validate the ability to acquire and quantify in vivo microscopic level imaging with this newly developed 800nm ultra-high resolution diffractive OCT system.
Cities inadvertently create warmer and drier urban climate conditions than their surrounding areas through urbanization that replaces natural surfaces with impervious materials. These changes cause ...heat-related health problems and many studies suggest microclimatic urban design (MUD) as an approach to address these problems. In MUD-related research, although terrestrial radiation plays an important role in human thermal comfort and previous studies use thermal comfort models to identify human heat stress, few studies have addressed the effect of terrestrial radiation. This study develops the ground ratio factor (GRF) model to estimate the different terrestrial radiation according to different ground conditions. Three types of ground materials (asphalt, concrete, and grass) were considered in the model, and field studies were conducted in humid subtropical climate (Cfa) zone during the hot season (13 July to 19 September 2020). The model was validated by comparing the predicated terrestrial radiation (PTR) from the model with the actual terrestrial radiation (ATR). The results showed that there is a statistically significant strong correlation between PTR and ATR. The model can contribute to MUD strategies by updating existing human energy budget models, which can lead to the measurement of more accurate human thermal comfort for mitigating thermal environments.
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