The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons ...mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH
) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH
neurons project more profusely than ventral tegmental area TH
neurons to the hippocampus, optogenetic activation of locus coeruleus TH
neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH
photoactivation are sensitive to hippocampal D
/D
receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, locus coeruleus TH
neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus.
Objectives To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha ( PIK3CA ) mutations would be found in patients with more common disorders ...including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS). Study design We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children's Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Children's Hospital. Results Most individuals from Boston Children's Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼80% of cases. Seventy-four percent of patients with LM from Seattle Children's Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells. Conclusions Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low.
New conceptual models that highlight the importance of environmental, rather than molecular, controls on soil organic matter affect interpretations of organic matter (OM) persistence across ...terrestrial and aquatic boundaries. We propose that changing paradigms in our thinking about OM decomposition explain some of the uncertainties surrounding the fate of land-derived carbon (C) in marine environments. Terrestrial OM, which historically has been thought to be chemically recalcitrant to decay in soil and aquatic environments, dominates inputs to rivers yet is found in trace amounts in the ocean. We discuss three major transformations in our understanding of OM persistence that influence interpretations of the fate of aquatic OM: (1) a shift away from an emphasis on chemical recalcitrance as a primary predictor of turnover; (2) new interpretations of radiocarbon ages, which affect predictions of reactivity; and (3) the recognition that most OM leaving soils in dissolved form has been microbially processed. The first two explain rapid turnover for terrigenous OM in aquatic ecosystems once it leaves the soil matrix. The third suggests that the presence of terrestrial OM in aquatic ecosystems may be underestimated by the use of plant biomarkers. Whether these mechanisms occur in isolation of each other or in combination, they provide insight into the missing terrestrial C signature in the ocean. Spatially and temporally varying transformations of OM along land–water networks require that common terrestrial source indicators be interpreted within specific environmental contexts. We identify areas of research where collaborations between aquatic and terrestrial scientists will enhance quantification of C transfer from soils to inland water bodies, the ocean, and the atmosphere. Accurate estimates of OM processing are essential for improving predictions of the response of vulnerable C pools at the interface of soil and water to changes in climate and land use.
Epithelial fusion is a crucial process in embryonic development, and its failure underlies several clinically important birth defects. For example, failure of neural fold fusion during neurulation ...leads to open neural tube defects including spina bifida. Using mouse embryos, we show that cell protrusions emanating from the apposed neural fold tips, at the interface between the neuroepithelium and the surface ectoderm, are required for completion of neural tube closure. By genetically ablating the cytoskeletal regulators Rac1 or Cdc42 in the dorsal neuroepithelium, or in the surface ectoderm, we show that these protrusions originate from surface ectodermal cells and that Rac1 is necessary for the formation of membrane ruffles which typify late closure stages, whereas Cdc42 is required for the predominance of filopodia in early neurulation. This study provides evidence for the essential role and molecular regulation of membrane protrusions prior to fusion of a key organ primordium in mammalian development.
Glutamine is an essential nutrient for cancer cell proliferation, especially in the context of citric acid cycle anaplerosis. In this manuscript we present results that collectively demonstrate that, ...of the three major mammalian glutaminases identified to date, the lesser studied splice variant of the gene gls, known as Glutaminase C (GAC), is important for tumor metabolism. We show that, although levels of both the kidney-type isoforms are elevated in tumor vs. normal tissues, GAC is distinctly mitochondrial. GAC is also most responsive to the activator inorganic phosphate, the content of which is supposedly higher in mitochondria subject to hypoxia. Analysis of X-ray crystal structures of GAC in different bound states suggests a mechanism that introduces the tetramerization-induced lifting of a "gating loop" as essential for the phosphate-dependent activation process. Surprisingly, phosphate binds inside the catalytic pocket rather than at the oligomerization interface. Phosphate also mediates substrate entry by competing with glutamate. A greater tendency to oligomerize differentiates GAC from its alternatively spliced isoform and the cycling of phosphate in and out of the active site distinguishes it from the liver-type isozyme, which is known to be less dependent on this ion.
The overall purpose of this study was to investigate the role of personal relevance in conceptual change. First, we used an experimental design to investigate the role of augmented activation-which ...directly implicated teachers' personal prior beliefs about mathematics learning and instruction-and refutational text manipulations on short and long-term conceptual change in preservice and inservice teachers' constructivist beliefs about mathematics to test for a mechanism of change. Second, we examined the relationships among affect, cognitive processing, and conceptual change to clarify our understanding of the mechanisms of the conceptual change process and to empirically test key hypotheses in the Cognitive-Affective Model of Conceptual Change (CAMCC). Our results indicated that messages that heighten the personal relevance and challenge to prior beliefs with contrary evidence (i.e., augmented activation) produced conceptual change in preservice and inservice teachers' mathematics beliefs, whereas there was no consistent effect of refutational text. We also found support for several key pathways in the CAMCC, with implications for conceptual change theory and teacher education.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Visit-to-visit blood pressure variability (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with ...outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO study). We used the coefficient of variation (CV) and the average real variability in systolic blood pressure (SBP) as metrics of VTV-BPV. In all, 1844 out of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range 1.3-4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9 ± 4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.
Background
The need for dental rehabilitation under general anesthesia is increasing, with varying needs between patients. Mortality has been found to be a rare event in these patients; however other ...perioperative events can and do occur. Previous studies have established increased incidence of perioperative events with younger, sicker children, and longer anesthetics, however, no studies to date have evaluated if the incidence of perioperative events is more closely associated with one long anesthetic or multiple anesthetics per patient.
Aims
To evaluate the association of perioperative events related to single anesthetic duration or number of anesthetics per patient for dental rehabilitation.
Methods
After Children's Wisconsin Human Research Protection Program determined this quality activity did not meet the definition of human subjects research, we performed an epidemiologic observational evaluation by extracting all dental related cases (dental alone or with oral surgeon vs. dental with other specialties) with an associated general anesthesia encounter from Children's Wisconsin electronic data warehouse from June 1, 2015 to December 31, 2021. These cases occurred at a free‐standing children's hospital or associated pediatric‐only ambulatory surgery center. The risk of perioperative safety events was analyzed for previously identified risk groups such as American Society of Anesthesiologists Physical Status (ASA‐PS), patient age, anesthesia case time with the addition of number of dental cases per patient.
Results
In this study, 8468 procedures were performed on 8082 patients. Of this cohort, 7765 patients underwent one procedure for dental care while 317 patients underwent a total of 703 dental‐related procedures, ranging from two to five procedures per patient. Multivariable logistic regression identified increased risk of perioperative events in patients with ASA‐PS 3 (n = 1459, rate 1.78%, p value .001, OR 5.7, CI 2.1–15.5) and ASA‐PS 4 (n = 86, rate 5.8%, p < .001, OR 17.2, CI 4.4–67.3), anesthesia duration (p < .001, OR 1.46, CI 1.21–1.76), but no increased risk with number of anesthetics per patient (p value .54, OR 0.81, CI 0.4–1.61).
Conclusions
Limiting dental care under general anesthesia to multiple short cases may decrease the risk of perioperative events when compared to completing all treatment in one long operative session.
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