The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism

Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo11C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13C high-resolution magic-angle-spinning that 13C acetate from fermentation of 13C-labelled carbohydrate in the colon increases hypothalamic 13C acetate above baseline levels. Hypothalamic 13C acetate regionally increases the 13C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation

Acute Regulation of Cardiac Metabolism by the Hexosamine Biosynthesis Pathway and Protein O-GlcNAcylation

OBJECTIVE: The hexosamine biosynthesis pathway (HBP) flux and protein O-linked N-acetyl-glucosamine (O-GlcNAc) levels have been implicated in mediating the adverse effects of diabetes in the cardiovascular system. Activation of these pathways with glucosamine has been shown to mimic some of the diabetes-induced functional and structural changes in the heart; however, the effect on cardiac metabolism is not known. Therefore, the primary goal of this study was to determine the effects of glucosamine on cardiac substrate utilization. METHODS: Isolated rat hearts were perfused with glucosamine (0-10 mM) to increase HBP flux under normoxic conditions. Metabolic fluxes were determined by (13)C-NMR isotopomer analysis; UDP-GlcNAc a precursor of O-GlcNAc synthesis was assessed by HPLC and immunoblot analysis was used to determine O-GlcNAc levels, phospho- and total levels of AMPK and ACC, and membrane levels of FAT/CD36. RESULTS: Glucosamine caused a dose dependent increase in both UDP-GlcNAc and O-GlcNAc levels, which was associated with a significant increase in palmitate oxidation with a concomitant decrease in lactate and pyruvate oxidation. There was no effect of glucosamine on AMPK or ACC phosphorylation; however, membrane levels of the fatty acid transport protein FAT/CD36 were increased and preliminary studies suggest that FAT/CD36 is a potential target for O-GlcNAcylation. CONCLUSION/INTERPRETATION: These data demonstrate that acute modulation of HBP and protein O-GlcNAcylation in the heart stimulates fatty acid oxidation, possibly by increasing plasma membrane levels of FAT/CD36, raising the intriguing possibility that the HBP and O-GlcNAc turnover represent a novel, glucose dependent mechanism for regulating cardiac metabolism

Developing adaptive control:Age-related differences in task choices and awareness of proactive and reactive control demands

Developmental changes in executive function are often explained in terms of core cognitive processes and associated neural substrates. For example, younger children tend to engage control reactively in the moment as needed, whereas older children increasingly engage control proactively, in anticipation of needing it. Such developments may reflect increasing capacities for active maintenance dependent upon dorsolateral prefrontal cortex. However, younger children will engage proactive control when reactive control is made more difficult, suggesting that developmental changes may also reflect decisions about whether to engage control, and how. We tested awareness of temporal control demands and associated task choices in 5-year-olds and 10-year-olds and adults using a demand selection task. Participants chose between one task that enabled proactive control and another task that enabled reactive control. Adults reported awareness of these different control demands and preferentially played the proactive task option. Ten-year-olds reported awareness of control demands but selected task options at chance. Five-year-olds showed neither awareness nor task preference, but a subsample who exhibited awareness of control demands preferentially played the reactive task option, mirroring their typical control mode. Thus, developmental improvements in executive function may in part reflect better awareness of cognitive demands and adaptive behavior, which may in turn reflect changes in dorsal anterior cingulate in signaling task demands to lateral prefrontal cortex

Pupillary Stroop effects

We recorded the pupil diameters of participants performing the words’ color-naming Stroop task (i.e., naming the color of a word that names a color). Non-color words were used as baseline to firmly establish the effects of semantic relatedness induced by color word distractors. We replicated the classic Stroop effects of color congruency and color incongruency with pupillary diameter recordings: relative to non-color words, pupil diameters increased for color distractors that differed from color responses, while they reduced for color distractors that were identical to color responses. Analyses of the time courses of pupil responses revealed further differences between color-congruent and color-incongruent distractors, with the latter inducing a steep increase of pupil size and the former a relatively lower increase. Consistent with previous findings that have demonstrated that pupil size increases as task demands rise, the present results indicate that pupillometry is a robust measure of Stroop interference, and it represents a valuable addition to the cognitive scientist’s toolbox

Cognitive Control in Adolescence: Neural Underpinnings and Relation to Self-Report Behaviors

Adolescence is commonly characterized by impulsivity, poor decision-making, and lack of foresight. However, the developmental neural underpinnings of these characteristics are not well established.To test the hypothesis that these adolescent behaviors are linked to under-developed proactive control mechanisms, the present study employed a hybrid block/event-related functional Magnetic Resonance Imaging (fMRI) Stroop paradigm combined with self-report questionnaires in a large sample of adolescents and adults, ranging in age from 14 to 25. Compared to adults, adolescents under-activated a set of brain regions implicated in proactive top-down control across task blocks comprised of difficult and easy trials. Moreover, the magnitude of lateral prefrontal activity in adolescents predicted self-report measures of impulse control, foresight, and resistance to peer pressure. Consistent with reactive compensatory mechanisms to reduced proactive control, older adolescents exhibited elevated transient activity in regions implicated in response-related interference resolution.Collectively, these results suggest that maturation of cognitive control may be partly mediated by earlier development of neural systems supporting reactive control and delayed development of systems supporting proactive control. Importantly, the development of these mechanisms is associated with cognitive control in real-life behaviors

Inspiration for the Future: The Role of Inspiratory Muscle Training in Cystic Fibrosis

Cystic fibrosis (CF) is an inherited, multi-system, life-limiting disease characterized by a progressive decline in lung function, which accounts for the majority of CF-related morbidity and mortality. Inspiratory muscle training (IMT) has been proposed as a rehabilitative strategy to treat respiratory impairments associated with CF. However, despite evidence of therapeutic benefits in healthy and other clinical populations, the routine application of IMT in CF can neither be supported nor refuted due to the paucity of methodologically rigorous research. Specifically, the interpretation of available studies regarding the efficacy of IMT in CF is hampered by methodological threats to internal and external validity. As such, it is important to highlight the inherent risk of bias that differences in patient characteristics, IMT protocols, and outcome measurements present when synthesizing this literature prior to making final clinical judgments. Future studies are required to identify the characteristics of individuals who may respond to IMT and determine whether the controlled application of IMT can elicit meaningful improvements in physiological and patient-centered clinical outcomes. Given the equivocal evidence regarding its efficacy, IMT should be utilized on a case-by-case basis with sound clinical reasoning, rather than simply dismissed, until a rigorous evidence-based consensus has been reached

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Wave and Surge Conditions after Proposed Expansion of Monterey Harbor, Monterey, California: Hydraulic Model Investigation

Source: https://erdc-library.erdc.dren.mil/jspui/A 1:120- scale model of Monterey Harbor, California, and sufficient offshore area to permit generation of the required test waves was used to investigate the arrangement and design of certain proposed harbor improvements with respect to wave and surge action and to determine current conditions in the navigation entrances to the harbor and its basins. The proposed harbor improvements consisted of (A.) enlarging the present harbor by construction of a detached north breakwater, approximately 3350 ft in length, and a companion east breakwater connected to shore and extending approximately 1100 ft seaward, and (B.) development of the inner-harbor area by constructing moles to form two additional basins for the anchorage of small pleasure craft. A 56-ft-long wave machine and electrical wave height measuring and recording apparatus were utilized in model operation. Base tests were conducted with existing prototype conditions installed in the model. Results of tests involving the various improvement plans were compared with base test results to determine the relative effectiveness of the various plans. It was concluded from the test results that (A.) either the single-entrance or the double-entrance plan will provide an improvement over existing conditions with respect to long-period surge in the harbor; (B.) although the harbor basins respond to several of the wave periods tested, no serious cases of resonance were noted; and (C.) either the single-entrance or the double-entrance plan will provide sufficient protection to the inner basins from short-period (5 to 20 sec) waves, except in a portion of the east basin. An analytical study of long-period sea-energy oscillations in the vicinity of Monterey Bay with respect to the possibility of related response in Monterey Harbor was conducted, and the results of that study are presented in Appendix A