Multidrug resistance-associated protein 1 (ABCC1) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. Aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7-¹¹C-methylpurine (¹¹C-BMP), a prodrug radiotracer which is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-¹¹C-methylpurinyl))glutathione (¹¹C-MPG). Methods: Groups of Abcc1(-/-) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571 and wild-type control rats underwent dynamic PET scans after administration of ¹¹C-BMP intravenously (i.v.) or by intratracheal aerosolization (i.t.). In vitro transport experiments were performed with unlabeled BMP in the human distal lung epithelial cell line NCI-H441. Results: Pulmonary kinetics of radioactivity were significantly different between wild-type and Abcc1(-/-) rats, but differences were more pronounced after i.t. than after i.v. administration. After i.v. administration lung exposure (AUClung) was 77% higher and the elimination slope of radioactivity washout from the lungs (kE,lung) was 70% lower, whereas after i.t. administration AUClung was 352% higher and kE,lung was 86% lower in Abcc1(-/-) rats. Pretreatment with MK571 decreased kE,lung by 20% after i.t. radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in presence than in absence of MK571. Conclusion: PET with pulmonary administered ¹¹C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms or concomitant drug intake on pulmonary ABCC1 activity.

Chronic hyperglycemia is known to disrupt the proteolytic milieu, initiating compensatory and maladaptive pathways in the diabetic kidney. Such changes in intrarenal proteolysis are captured by the urinary peptidome. To elucidate the early kidney response to chronic hyperglycemia, we conducted a peptidomic investigation into urines from otherwise healthy youths with type 1 diabetes and their non-diabetic peers using unbiased and targeted mass spectrometry-based techniques. This cross-sectional study included two separate cohorts for the discovery (n = 30) and internal validation (n = 30) of differential peptide excretion. Peptide bioactivity was predicted using PeptideRanker and subsequently verified in vitro. Proteasix and the Nephroseq database were used to identify putative proteases responsible for peptide generation and examine their expression in diabetic nephropathy. A total of 6550 urinary peptides were identified in the discovery analysis. We further examined the subset of 162 peptides, which were quantified across all thirty samples. Of the 15 differentially excreted peptides (p < 0.05), seven derived from a C-terminal region (⁵⁸⁹SGSVIDQSRVLNLGPITRK⁶⁰⁷) of uromodulin, a kidney-specific protein. Increased excretion of five uromodulin peptides was replicated in the validation cohort using parallel reaction monitoring (p < 0.05). One of the validated peptides (SGSVIDQSRVLNLGPI) activated NFB and AP-1 signaling, stimulated cytokine release, and enhanced neutrophil migration in vitro. In silico analyses highlighted several potential proteases such as hepsin, meprin A, and cathepsin B to be responsible for generating these peptides. In summary, we identified a urinary signature of uromodulin peptides associated with early type 1 diabetes before clinical manifestations of kidney disease and discovered novel bioactivity of uromodulin peptides in vitro. Our present findings lay the groundwork for future studies to validate peptide excretion in larger and broader populations, to investigate the role of bioactive uromodulin peptides in high glucose conditions, and to examine proteases that cleave uromodulin.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here that suckling-weaning and fasting-refeeding transitions in rodents are associated with changes in AMPK activation and the cellular energy state in the liver. These nutritional transitions were characterized by a metabolic switch from lipid to glucose utilization, orchestrated by modifications in glucose levels and the glucagon/insulin ratio in the bloodstream. We therefore investigated the respective roles of glucose and pancreatic hormones on AMPK activation in mouse primary hepatocytes. We found that glucose starvation transiently activates AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK. Challenge of hepatocytes with metformin-induced metabolic stress strengthened both AMPK activation and cellular energy depletion under limited-glucose conditions, whereas neither glucagon nor insulin altered AMPK activation. Although both insulin and glucagon induced AMPKα phosphorylation at its Ser485/491 residue, they did not affect its activity. Finally, the decrease in cellular ATP levels in response to an energy stress was additionally exacerbated under fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic inflexibility and emphasizing the importance of AMPK for maintaining hepatic energy charge. Our results suggest that nutritional changes (i.e. glucose availability), rather than the related hormonal changes (i.e. the glucagon/insulin ratio), sensitize AMPK activation to the energetic stress induced by the dietary transition during fasting. This effect is critical for preserving the cellular energy state in the liver.

Jiachen Sun
Apr 27, 2020; 0:jlr.D120000794v1-jlr.D120000794
Methods

Jeroen van Smeden
Apr 7, 2020; 0:jlr.RA120000639v1-jlr.RA120000639
Research Articles

Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations.

Individuals with Netherton syndrome (NTS) have increased serine protease activity, which strongly impacts the barrier function of the skin epidermis and leads to skin inflammation. Here, we investigated how serine protease activity in NTS correlates with changes in the stratum corneum ceramides, which are crucial components of the skin barrier. We examined two key enzymes involved in epidermal ceramide biosynthesis, glucocerebrosidase (GBA) and acid-sphingomyelinase (ASM). We compared in situ expression levels and activities of GBA and ASM between NTS patients and controls and correlated the expression and activities with i) stratum corneum ceramide profiles, ii) in situ serine protease activity, and iii) clinical presentation of patients. Using activity-based probe labeling, we visualized and localized active, epidermal GBA, and a newly developed in situ zymography method enabled us to visualize and localize active ASM. Reduction in active GBA in NTS patients coincided with increased ASM activity, particularly in areas with increased serine protease activity. NTS patients with scaly erythroderma exhibited more pronounced anomalies in GBA and ASM activities than patients with ichthyosis linearis circumflexa. They also displayed a stronger increase in stratum corneum ceramides processed via ASM. We conclude that changes in the localization of active GBA and ASM correlate with i) altered stratum corneum ceramide composition in NTS patients, ii) local serine protease activity, and iii) the clinical manifestation of NTS. 

Lipid kinases and phosphatases play key roles in cell signaling and regulation, and are implicated in many human diseases, and are hence thus attractive targets for drug development. Currently, no direct in vitro activity assay is available for these important enzymes, which hampers mechanistic studies as well as high-throughput screening of small molecule modulators. Here we report a highly sensitive and quantitative assay employing a ratiometric fluorescence sensor that directly and specifically monitors the real-time concentration change of a single lipid species. Due Because of to its modular design, the assay system can be applied to a wide variety of lipid kinases and phosphatases, including Class I phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN). When applied to PI3K, the assay provided the newdetailed mechanistic information about the product inhibition and substrate acyl acyl-chain selectivity of PI3K and allowed enabled rapid evaluation of its small molecule inhibitors. We also used this assay to quantitatively determine the substrate specificity of PTEN, providing new insight into its physiological functionThe assay also quantitatively determined the substrate specificity of PTEN, thereby providing new insight into its physiological function. In summary, we have developed a fluorescence-based real-time assay for PI3K and PTEN that we anticipate could be adapted to measure the activities of other lipid kinases and phosphatases with high sensitivity and accuracy.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant defense were coordinately regulated in Stk25^–/– versus wild-type livers. We confirmed attenuated peroxisomal biogenesis and protection against oxidative and ER stress in STK25-deficient human liver cells, demonstrating the hepatocyte-autonomous manner of STK25’s action. In summary, our results suggest that regulation of peroxisomal function and metabolic stress response may be important molecular mechanisms by which STK25 controls the development and progression of NAFLD/NASH.

Sulfur is essential for biological processes such as amino acid biogenesis, iron–sulfur cluster formation, and redox homeostasis. To acquire sulfur-containing compounds from the environment, bacteria have evolved high-affinity uptake systems, predominant among which is the ABC transporter family. Theses membrane-embedded enzymes use the energy of ATP hydrolysis for transmembrane transport of a wide range of biomolecules against concentration gradients. Three distinct bacterial ABC import systems of sulfur-containing compounds have been identified, but the molecular details of their transport mechanism remain poorly characterized. Here we provide results from a biochemical analysis of the purified Escherichia coli YecSC-FliY cysteine/cystine import system. We found that the substrate-binding protein FliY binds l-cystine, l-cysteine, and d-cysteine with micromolar affinities. However, binding of the l- and d-enantiomers induced different conformational changes of FliY, where the l- enantiomer–substrate-binding protein complex interacted more efficiently with the YecSC transporter. YecSC had low basal ATPase activity that was moderately stimulated by apo FliY, more strongly by d-cysteine–bound FliY, and maximally by l-cysteine– or l-cystine–bound FliY. However, at high FliY concentrations, YecSC reached maximal ATPase rates independent of the presence or nature of the substrate. These results suggest that FliY exists in a conformational equilibrium between an open, unliganded form that does not bind to the YecSC transporter and closed, unliganded and closed, liganded forms that bind this transporter with variable affinities but equally stimulate its ATPase activity. These findings differ from previous observations for similar ABC transporters, highlighting the extent of mechanistic diversity in this large protein family.

Amylin, a pancreatic hormone and neuropeptide, acts principally in the hindbrain to decrease food intake and has been recently shown to act as a neurotrophic factor to control the development of AP->NTS and ARC->PVN axonal fiber outgrowth. Amylin is also able to activate ERK signaling specifically in POMC neurons independently of leptin. To investigate the physiological role of amylin signaling in POMC neurons, the core component of the amylin receptor, calcitonin receptor (CTR) was depleted from POMC neurons using an inducible mouse model. The loss of CTR in POMC neurons leads to increased body weight gain, increased adiposity, and glucose intolerance in male knockout mice, characterized by decreased energy expenditure (EE) and decreased expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). Furthermore, a decreased spontaneous locomotor activity and absent thermogenic reaction to the application of the amylin receptor agonist were observed in male and female mice. Together, these results show a significant physiological impact of amylin/calcitonin signaling in CTR-POMC neurons on energy metabolism and demonstrate the need for sex-specific approaches in obesity research and potentially treatment.

α-Klotho is a circulating factor with well-documented anti-aging properties; however, the central role of α-klotho in metabolism remains largely unexplored. The current study investigated the potential role of central α-klotho to modulate NPY/AgRP neurons, energy balance, and glucose homeostasis. Intracerebroventricular (ICV) administration of α-klotho suppressed food intake, improved glucose profiles, and reduced body weight in mouse models of Type I and II diabetes. Furthermore, central α-klotho inhibition via an anti-α-klotho antibody impaired glucose tolerance. Ex vivo patch clamp electrophysiology and immunohistochemical analysis revealed that α-klotho suppresses NPY/AgRP neuron activity, at least in part, by enhancing mIPSC’s. Experiments in hypothalamic GT1-7 cells observed α-klotho induces phosphorylation of AKT^ser473, ERK^{thr202/tyr204}, and FOXO1^ser256, as well as blunts AgRP gene transcription. Mechanistically, fibroblast growth factor 1 (FGFR1) inhibition abolished the downstream signaling of α-klotho, negated its ability to modulate NPY/AgRP neurons, and blunted its therapeutic effects. PI3 kinase inhibition also abolished α-klotho’s ability to suppress food intake and improve glucose clearance. These results indicate a prominent role of hypothalamic α-klotho/FGFR1/PI3K signaling in the modulation of NPY/AgRP neuron activity and maintenance of energy homeostasis, thus providing new insight into the pathophysiology of metabolic disease.

S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions.

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.

We know that exercise is good for you - the WHO recommends at least 150 minutes of moderate intensity or 75 minutes of vigorous intensity aerobic physical activity each week. That recommendation is built on evidence that relied on self reporting that may underestimate the amount of lower intensity exercise those people were doing, and at the...

OBJECTIVE

The objective of this study was to examine whether altered heart rate variability (HRV) could predict the risk of diabetes in Asians.

Rockville, Maryland : National Institute on Drug Abuse, 1987.

Yen-Chi Chen, Adrian Dobra.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 409--432.

Abstract:
Activity spaces are fundamental to the assessment of individuals’ dynamic exposure to social and environmental risk factors associated with multiple spatial contexts that are visited during activities of daily living. In this paper we survey existing approaches for measuring the geometry, size and structure of activity spaces, based on GPS data, and explain their limitations. We propose addressing these shortcomings through a nonparametric approach called density ranking and also through three summary curves: the mass-volume curve, the Betti number curve and the persistence curve. We introduce a novel mixture model for human activity spaces and study its asymptotic properties. We prove that the kernel density estimator, which at the present time, is one of the most widespread methods for measuring activity spaces, is not a stable estimator of their structure. We illustrate the practical value of our methods with a simulation study and with a recently collected GPS dataset that comprises the locations visited by 10 individuals over a six months period.

Jasper Akerboom
Oct 3, 2012; 32:13819-13840
Cellular

Benjamin Meyer
Jul 3, 2019; 39:5326-5335
Systems/Circuits

Jasper Akerboom
Oct 3, 2012; 32:13819-13840
Cellular

Gregor Thut
Sep 13, 2006; 26:9494-9502
BehavioralSystemsCognitive

Giving birth triggers a wide repertoire of physiological and behavioral changes in the mother to enable her to feed and care for her offspring. These changes require coordination and are often orchestrated from the CNS, through as of yet poorly understood mechanisms. A neuronal population with a central role in puerperal changes is the tuberoinfundibular dopamine (TIDA) neurons that control release of the pituitary hormone, prolactin, which triggers key maternal adaptations, including lactation and maternal care. Here, we used Ca²⁺ imaging on mice from both sexes and whole-cell recordings on female mouse TIDA neurons in vitro to examine whether they adapt their cellular and network activity according to reproductive state. In the high-prolactin state of lactation, TIDA neurons shift to faster membrane potential oscillations, a reconfiguration that reverses upon weaning. During the estrous cycle, however, which includes a brief, but pronounced, prolactin peak, oscillation frequency remains stable. An increase in the hyperpolarization-activated mixed cation current, I_h, possibly through unmasking as dopamine release drops during nursing, may partially explain the reconfiguration of TIDA rhythms. These findings identify a reversible plasticity in hypothalamic network activity that can serve to adapt the dam for motherhood.

SIGNIFICANCE STATEMENT Motherhood requires profound behavioral and physiological adaptations to enable caring for offspring, but the underlying CNS changes are poorly understood. Here, we show that, during lactation, neuroendocrine dopamine neurons, the "TIDA" cells that control prolactin secretion, reorganize their trademark oscillations to discharge in faster frequencies. Unlike previous studies, which typically have focused on structural and transcriptional changes during pregnancy and lactation, we demonstrate a functional switch in activity and one that, distinct from previously described puerperal modifications, reverses fully on weaning. We further provide evidence that a specific conductance (I_h) contributes to the altered network rhythm. These findings identify a new facet of maternal brain plasticity at the level of membrane properties and consequent ensemble activity.

Biases in sensory perception can arise from both experimental manipulations and personal trait-like features. These idiosyncratic biases and their neural underpinnings are often overlooked in studies on the physiology underlying perception. A potential candidate mechanism reflecting such idiosyncratic biases could be spontaneous alpha band activity, a prominent brain rhythm known to influence perceptual reports in general. Using a temporal order judgment task, we here tested the hypothesis that alpha power reflects the overcoming of an idiosyncratic bias. Importantly, to understand the interplay between idiosyncratic biases and contextual (temporary) biases induced by experimental manipulations, we quantified this relation before and after temporal recalibration. Using EEG recordings in human participants (male and female), we find that prestimulus frontal alpha power correlates with the tendency to respond relative to an own idiosyncratic bias, with stronger α leading to responses matching the bias. In contrast, alpha power does not predict response correctness. These results also hold after temporal recalibration and are specific to the alpha band, suggesting that alpha band activity reflects, directly or indirectly, processes that help to overcome an individual's momentary bias in perception. We propose that combined with established roles of parietal α in the encoding of sensory information frontal α reflects complementary mechanisms influencing perceptual decisions.

SIGNIFICANCE STATEMENT The brain is a biased organ, frequently generating systematically distorted percepts of the world, leading each of us to evolve in our own subjective reality. However, such biases are often overlooked or considered noise when studying the neural mechanisms underlying perception. We show that spontaneous alpha band activity predicts the degree of biasedness of human choices in a time perception task, suggesting that alpha activity indexes processes needed to overcome an individual's idiosyncratic bias. This result provides a window onto the neural underpinnings of subjective perception, and offers the possibility to quantify or manipulate such priors in future studies.

Autism spectrum disorder (ASD) is characterized partly by atypical attentional engagement, reflected in exaggerated and variable responses to sensory stimuli. Attentional engagement is known to be regulated by the locus ceruleus (LC). Moderate baseline LC activity globally dampens neural responsivity and is associated with adaptive deployment and narrowing of attention to task-relevant stimuli. In contrast, increased baseline LC activity enhances neural responsivity across cortex and widening of attention to environmental stimuli regardless of their task relevance. Given attentional atypicalities in ASD, this study is the first to evaluate whether, under different attentional task demands, individuals with ASD exhibit a different profile of LC activity compared with typically developing controls. Males and females with ASD and age- and gender-matched controls participated in a one-back letter detection test while task-evoked pupillary responses, an established correlate for LC activity, were recorded. Participants completed this task in two conditions, either in the absence or presence of distractor auditory tones. Compared with controls, individuals with ASD evinced atypical pupillary responses in the presence versus absence of distractors. Notably, this atypical pupillary profile was evident despite the fact that both groups exhibited equivalent task performance. Moreover, between-group differences in pupillary responses were observed specifically in response to task-relevant events, providing confirmation that the group differences most likely were specifically associated with distinctions in LC activity. These findings suggest that individuals with ASD show atypical modulation of LC activity with changes in attentional demands, offering a possible mechanistic and neurobiological account for attentional atypicalities in ASD.

SIGNIFICANCE STATEMENT Individuals with autism spectrum disorder (ASD) exhibit atypical attentional behaviors, including altered sensory responses and atypical fixedness, but the neural mechanism underlying these behaviors remains elusive. One candidate mechanism is atypical locus ceruleus (LC) activity, as the LC plays a critical role in attentional modulation. Specifically, LC activity is involved in regulating the trade-off between environmental exploration and focused attention. This study shows that, under tightly controlled conditions, task-evoked pupil responses, an LC activity proxy, are lower in individuals with ASD than in controls, but only in the presence of task-irrelevant stimuli. This suggests that individuals with ASD evince atypical modulation of LC activity in accordance with changes in attentional demands, offering a mechanistic account for attentional atypicalities in ASD.

It works like a very fine "molecular knob" able to modulate the electrical activity of the neurons of our cerebral cortex, crucial to the functioning of our brain.

Three-fourths of US preschool-age children are in child care; many are not achieving recommended levels of physical activity. Daily physical activity is essential for motor and socioemotional development and for the prevention of obesity. Little is known about physical-activity barriers in child care.

Injury and school-readiness concerns may inhibit children’s physical activity in child care. Fixed playground equipment that meets licensing codes is unchallenging and uninteresting to children. Centers may cut time and space for gross motor play to address concerns about school readiness. (Read the full article)

The social and emotional burdens of ostracism are well known, but few studies have tested whether ostracism adversely alters physical activity behaviors that may result in maintenance of childhood obesity.

This is the first study to experimentally assess the effect of simulated ostracism, or social exclusion, on physical activity behavior in children. Ostracism reduced accelerometer counts by 22% and increased time allocated to sedentary behaviors by 41%. (Read the full article)

Active video games can enable children under laboratory conditions to participate in moderate, and even vigorous, physical activity. There are inconsistencies in the literature, however, about whether active video games enable children to increase physical activity under more naturalistic circumstances.

This study tests whether children receiving a new active video game spontaneously engaged in more physical activity, and whether commercially available active video games have a public health benefit. No additional physical activity was detected, suggesting no public health benefit. (Read the full article)

New, effective approaches to obesity prevention are urgently needed. Social network interventions warrant our attention. Social networks play a significant role in adult and adolescent obesity. The role of social networks in pediatric obesity has not been examined.

Afterschool friendship ties play a critical role in setting physical activity patterns in children as young as 5 to 12 years. Children’s activity levels can be changed by the activity level of their social network during a 12-week afterschool program. (Read the full article)

There are limited cross-sectional data from observational studies of adolescents showing that regular participation in physical activity is associated with a higher quality of life status, whereas time spent in screen-based entertainment is associated with a poorer quality of life.

Adolescents who were physically active (particularly engaging in outdoor activity) over a 5-year period had higher quality of life than their less active peers. Conversely, high levels of screen-based entertainment over 5 years negatively affected quality of life status. (Read the full article)

Concerns persist about sexual disinhibition after human papillomavirus (HPV) vaccination of preteenage girls. Self-reported surveys have indicated few anticipated behavior changes after HPV vaccination. Little is known about sexual activity–related clinical outcomes after HPV vaccination.

Utilizing managed care organization electronic data, we evaluated the incidence of adverse outcomes of sexual activity among vaccinated preteenage girls and found little difference between those who received HPV vaccine and those who did not. (Read the full article)

Physical inactivity is one of the major modifiable factors contributing to the growing national epidemic of childhood obesity. There is lack of literature on pedometer-determined physical activity (PA) during the school day in US minority kindergarten and first-grade students.

This is the first study to assess school-day PA in US urban minority kindergarten and first-grade students. Higher grade level, participation in physical education class, and outdoor recess were found to be independent predictors of PA. (Read the full article)

Although previous studies indicate that perinatal factors are associated with altered neurodevelopment, data on the association between ischemic-hypoxic conditions and attention-deficit/hyperactivity disorder in children are sparse.

This study demonstrates that preeclampsia, birth asphyxia, and respiratory distress syndrome are independently associated with increased risk of attention-deficit/hyperactivity disorder in a large population-based study. (Read the full article)

Effective interventions are still elusive for the large numbers of children affected by overweight/obesity. The value of targeting physical activity (PA) remains unclear because its predictive relationship with improved BMI is still surprisingly poorly quantified.

In overweight and mildly obese children presenting to primary care, 3-year changes in PA (especially the moderate-vigorous component) predicted BMI outcomes. However, the effect was small, possibly explaining the disappointing BMI outcomes of brief primary care interventions targeting PA. (Read the full article)

The rise in type 2 diabetes in youth is a major public health concern thought to be partially due to decreasing activity levels and increasing obesity. The role of sedentary time as a possible contributor also needs to be examined.

Measured objectively, obese youth, with or without type 2 diabetes, spend little time in moderate to vigorous physical activity. Those with type 2 diabetes, however, were significantly more sedentary than their obese counterparts, identifying an important area for future intervention efforts. (Read the full article)

The prevalence of overweight and obesity in US adolescents has increased over the last century. However, recent evidence indicates a potential change in this trend. Parallel trends in adolescent behaviors that drive this epidemic have not been well studied.

Analyses of recent data indicate the prevalence of overweight and obesity may be stabilizing. Over the same period, adolescent physical activity, breakfast eating, and fruit and vegetable consumption increased and television viewing and consumption of sweets and sweetened beverages decreased. (Read the full article)

Physical activity (PA) levels in preschool children vary considerably between preschools, and are positively associated with the overall quality of the preschool. However, knowledge regarding specific characteristics of the preschool environment hypothesized to promote PA is inconsistent and lacking.

This study tested multiple potential correlates of preschool children’s objectively measured moderate and vigorous PA level during preschool attendance, identifying size of indoor area per child and location of preschool building on the playground as new potentially modifiable correlates. (Read the full article)

Several studies have shown that behavioral problems can be associated with defecation and voiding disorders, although few studies have looked directly at a link between a diagnosis of attention-deficit/hyperactivity disorder (ADHD) and constipation or fecal incontinence.

We identified an increased risk for both constipation and fecal incontinence in children with ADHD. In patients with concomitant ADHD and defecation disorders, more aggressive medical and behavioral treatment of the constipation or fecal incontinence may be warranted. (Read the full article)

Levels of daily physical activity in children are decreasing worldwide. This implies risk factors for cardiovascular and metabolic diseases.

Strength training makes children not only stronger but significantly increases their daily spontaneous physical activity outside the training intervention. (Read the full article)

Prenatal and postnatal organophosphate (cholinesterase inhibitor) pesticide exposure has been associated with delays in attention, memory, intelligence, and inhibitory control. Two recent studies reported decreased attention and working memory with greater exposure to organophosphates in boys but not in girls.

This is the first study to report associations between decreased acetylcholinesterase activity, a stable marker of cholinesterase inhibitor pesticide exposure, and lower overall neurodevelopment, attention, inhibitory control, and memory. These associations were present in boys but not in girls. (Read the full article)

Attention-deficit/hyperactivity disorder (ADHD) is the most common mental health condition diagnosed in childhood, is highly heritable, and more common in boys. Although studies have identified perinatal risk factors, no one has investigated perinatal risk factors separately in boys and girls.

Contrary to other studies, low birth weight, postterm pregnancy, low Apgar scores, and fetal distress were not risk factors for ADHD irrespective of gender. Early term deliveries increased the risk of ADHD, and oxytocin augmentation in girls may be protective. (Read the full article)

Cognitive rest is recommended for the management of sport-related concussions. There are limited data to support this recommendation.

This study adds empirical data supporting the recommendation for cognitive rest after a sport-related concussion. (Read the full article)

The effects of previous school-based physical activity promotion interventions have been modest, and none have demonstrated significant or meaningful increases in children’s physical activity outside of school, a period characterized by disproportionally low levels of physical activity in youth.

This study adds to the evidence-base for the effectiveness of comprehensive school health programs by demonstrating that such novel interventions lead to statistically significant, meaningful increases in the amount of physical activity children achieved on weekends and after school hours. (Read the full article)

Individuals living in Mediterranean countries have historically had a lower risk of cardiovascular disease. Important changes in diet and lifestyle have taken place in these countries in recent years, and it is unknown how these changes might influence current cardiovascular health.

Fitness and fatness levels indicate that urban adolescents from southern Europe are less healthy than those from central northern Europe. The extent to which these differences might be explained by physical activity, diet, and genetics is analyzed and discussed in this article. (Read the full article)

Approximately 50% of children diagnosed with attention-deficit/hyperactivity disorder (ADHD) at <7 years of age in the community do not meet criteria for ADHD over time. There is a need to examine predictors of diagnostic stability in young children with ADHD.

Predictors of diagnostic stability from early to middle childhood include child’s baseline externalizing and internalizing symptoms, parental history of psychopathology, and socioeconomic status. These predictors may guide treatment planning at the time of ADHD diagnosis. (Read the full article)

Although expert consensus and previous literature document the importance of early feeding and activity behaviors and practices in preventing obesity and the risks of early rapid weight gain, few studies have rigorously assessed obesity-related behaviors by caregivers of infants.

This study demonstrates the high prevalence of behaviors thought to increase risk for obesity in a diverse, large sample of parent/2-month-old dyads and finds that many behaviors vary by race and ethnicity, suggesting the potential for culturally tailored interventions. (Read the full article)

Physical activity is beneficial to health. Parents are crucial in shaping children’s behaviors, with active mothers appearing to have active children. Little is known about this association in preschool-aged children, or about factors influencing activity in mothers of young children.

Mother-child physical activity levels were positively associated and influenced by temporal and demographic factors. Maternal activity levels were low, and influences differ by activity intensity. Health promotion efforts to increase activity in mothers may also benefit their young children. (Read the full article)