objective of the described research effort was to identify
a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with
improved norepinephrine transporter activity and acceptable metabolic
stability and exhibiting minimal drug–drug interaction. We
describe herein the discovery of a series of 3-substituted pyrrolidines,
exemplified by compound 1. Compound 1 is
a selective SNRI in vitro and in vivo, has favorable ADME properties,
and retains inhibitory activity in the formalin model of pain behavior.
Compound 1 thus represents a potential new probe to explore
utility of SNRIs in central nervous system disorders, including chronic
SERT; NET; dual; reuptake
inhibitor; SNRI; SERT RO; α-MMT; pain
Galantamine is an acetylcholinesterase inhibitor and an allosteric modulator of the α4β2 and α7 nicotinic receptors. There are several case reports describing the potential benefits of galantamine for negative symptoms associated with schizophrenia. This secondary analysis describes the effects of galantamine on psychopathology in people with schizophrenia.
Subjects with clinically stable chronic schizophrenia were randomized to adjunctive galantamine (24 mg/d) or placebo in a 12-week double-blind trial. Symptomatology was assessed with the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale. The Scale for the Assessment of Negative Symptoms (SANS) was used to measure negative symptoms.
Eighty-six patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia or schizoaffective disorder taking a stable dose of antipsychotic medications were randomized to adjunctive treatment with study drug (galantamine, n = 42; placebo, n = 44); 73 subjects completed the study (galantamine, n = 35; placebo, n = 38). No significant differences were found on BPRS total score (P = 0.585) or BPRS subfactor scores. Scale for the Assessment of Negative Symptoms total scores also did not decrease significantly (P = 0.106) in either group; however, galantamine treatment was associated with a greater benefit in the SANS subfactor, alogia (P = 0.007).
The lack of robust significant effects of galantamine on negative, and other symptom domains, may be due to the relatively low baseline level of these symptoms in the tested population. Galantamine may have some benefit on certain negative symptoms, particularly alogia. Studies specifically designed to address the issue of the efficacy of galantamine for negative symptoms are needed to confirm this observation.
schizophrenia; galantamine; randomized controlled trials; nicotine
Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.
The aims of this study were to use dynamic hepatocyte-specific contrast-enhanced MRI to evaluate liver volume and function in liver cirrhosis, correlate the results with standard scoring models and explore the inhomogeneous distribution of liver function in cirrhotic livers.
10 patients with liver cirrhosis and 20 healthy volunteers, serving as controls, were included. Hepatic extraction fraction (HEF), input relative blood flow and mean transit time were calculated on a voxel-by-voxel basis using deconvolutional analysis. Segmental and total liver volumes as well as segmental and total hepatic extraction capacity, expressed in HEFml, were calculated. An incongruence score (IS) was constructed to reflect the uneven distribution of liver function. The Mann–Whitney U-test was used for group comparison of the quantitative liver function parameters, liver volumes and ISs. Correlations between liver function parameters and clinical scores were assessed using Spearman rank correlation.
Patients had larger parenchymal liver volume, lower hepatocyte function and more inhomogeneous distribution of function compared with healthy controls.
The study demonstrates the non-homogeneous nature of liver cirrhosis and underlines the necessity of a liver function test able to compensate for the heterogeneous distribution of liver function in patients with diseased liver parenchyma.
Advances in knowledge:
The study describes a new way to quantitatively assess the hepatic uptake of gadoxetate or gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid in the liver as a whole as well as on a segmental level.
It has been suggested that a history of trauma exposure is associated with increased vulnerability to the physical health consequences of subsequent trauma exposure, and that posttraumatic stress symptoms (PTSS) may serve as a key pathway in this vulnerability. However, few studies have modeled these relationships using mediation, and most have failed to consider whether specific characteristics of the prior trauma exposure have a differential impact on physical and mental health outcomes.
The present study examined 180 victims of a serious motor vehicle accident (MVA) who reported prior exposure to traumatic events. PTSS were assessed by clinical interview 6 weeks post-MVA, and physical health was assessed 6 months post-MVA. Using structural equation modeling, the present study examined the extent to which event (age at first trauma, number and types of trauma) and response (perceptions of life threat, physical injury and distress) characteristics of prior trauma were related to physical health outcomes following a serious MVA, and whether these relationships were mediated by PTSS.
Results revealed that both event and response characteristics of prior trauma history were associated with poorer physical health, and that PTSS served as a mechanism through which response characteristics, but not event characteristics, led to poorer physical health.
These results highlight the enduring impact of trauma exposure on physical health outcomes, and underscore the importance of considering multiple mechanisms through which different aspects of prior trauma exposure may impact physical health.
trauma; PTSD/posttraumatic stress disorder; quality of life; life events/stress; depression
Child and adolescent posttraumatic stress disorder (PTSD) is associated with an increased risk for a number of deleterious mental and physical health outcomes that if untreated may persist throughout the life course. Efficacious interventions applied soon after trauma exposure have the potential to reduce or prevent the development of PTSD symptoms and their associated impact on behavior and physical health. We review extant research related to treatment-modifiable peritraumatic predictors of pediatric PTSD, which have informed an emerging field of pharmacologic secondary prevention (i.e., occurring shortly following trauma exposure) of PTSD. Challenges and opportunities for early posttrauma PTSD prevention are described. Finally, we offer new models for biologically informed integration of pharmacologic and psychosocial secondary prevention intervention strategies for children and adolescents.
Healthcare costs and service use for autism spectrum disorder (ASD) were compared between Medicaid and private insurance, using 2003 insurance claims data in 24 states. In terms of costs and service use per child with ASD, Medicaid had higher total healthcare costs ($22,653 vs. $5,254), higher ASD-specific costs ($7,438 vs. $928), higher psychotropic medication costs($1,468 vs. $875), more speech therapy visits (13.0 vs. 3.6 visits), more occupational/physical therapy visits (6.4 vs. 0.9 visits), and more behavior modification/social skills visits (3.8 vs. 1.1 visits) than private insurance (all p<0.0001). In multivariate analysis, being enrolled in Medicaid had the largest effect on costs, after controlling for other variables. The findings emphasize the need for continued efforts to improve private insurance coverage of autism.
Autism spectrum disorder; children; healthcare costs; service use; Medicaid; private insurance
Patients with heart failure and coronary artery disease often undergo coronary artery bypass grafting (CABG) but assessment of the risk of an adverse outcome in these patients is difficult. To evaluate the ability of biomarkers to contribute independent prognostic information in these patients, we measured levels in patients enrolled in the Biomarker Sub-studies of the Surgical Treatment for Ischemic Heart Failure (STICH) trials. Patients in STICH Hypothesis 1 were randomized to medical therapy or CABG whereas those in STICH Hypothesis 2 were randomized to CABG or CABG with left ventricular reconstruction.
Methods and Results
In sub-study patients assigned to STICH Hypothesis 1 (n=606), plasma levels of sTNFR-1 and BNP were highly predictive of the primary outcome variable of mortality by univariate analysis (BNP χ2=40.6; p<0.0001: sTNFR-1 χ2=38,9; p<0.0001). When considered in the context of multivariable analysis, both BNP and sTNFR-1 contributed independent prognostic information beyond the information provided by a large array of clinical factors independent of treatment assignment. Consistent results were seen when assessing the predictive value of BNP and sTNFR-1 in patients assigned to STICH Hypothesis 2 (n=626). Both plasma levels of BNP (χ2=30.3) and sTNFR-1 (χ2=45.5) were highly predictive in univariate analysis (p<0.0001) as well as in multivariable analysis for the primary endpoint of death or cardiac hospitalization. In multivariable analysis, the prognostic information contributed by BNP (χ2=6.0; p=0.049) and sTNFR-1 (χ2=8.8; p=0.003) remained statistically significant even after accounting for other clinical information. Although the biomarkers added little discriminatory improvement to the clinical factors (increase in c-index ≤ 0.1), Net Reclassification Improvement (NRI) for the primary endpoints was 0.29 for BNP and 0.21 for sTNFR-1in the Hypothesis 1 cohort, and 0.15 for BNP and 0.30 for sTNFR-1 in the Hypothesis 2 cohort, reflecting important predictive improvement.
Elevated levels of sTNFR-1 and BNP are strongly associated with outcomes, independent of therapy, in two large and independent studies, thus providing important cross-validation for the prognostic importance of these two biomarkers.
heart failure; cardiovascular disease; bypass graft
Tumor necrosis factor (TNF) superfamily ligands that provoke a dilated cardiac phenotype signal through a common scaffolding protein termed TNF receptor associated factor 2 (TRAF2); however, virtually nothing is known with regard to TRAF2 signaling in the adult mammalian heart.
Methods and Results
We generated multiple founder lines of mice with cardiac restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (MHC-TRAF2HC). MHC-TRAF2HC transgenic mice developed a time-dependent increase in cardiac hypertrophy, LV dilation and adverse LV remodeling, and a significant decrease in LV +dP/dt and −dP/dt when compared to littermate (LM) controls (p < 0.05 compared to LM). During the early phases of LV remodeling there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2HC mice aged, there was a significant decrease in total MMP activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in NF-κB activation at 4 – 12 weeks and JNK activation at 4 weeks in the MHCs TRAF2HC mice. Transciptional profiling revealed that > 95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2HC hearts contained κB elements in their promoters.
These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart.
tumor necrosis factor superfamily; dilated cardiomyopathy; inflammation; TNF receptor associated factor 2
Recent studies have suggested a potentially important role for a family of tiny regulatory RNAs, known as microRNAs (miRNAs or miRs), in the control of diverse aspects of cardiac function in health and disease. Although the field of miRNA biology is relatively new, there is emerging evidence that miRNAs may play an important role in the pathogenesis of heart failure through their ability to regulate the expression levels of genes that govern the process of adaptive and maladaptive cardiac remodeling. Here we review the biology of miRNAs in relation to their role in modulating various aspects of the process of cardiac remodeling, as well as discuss the potential application of miRNA biology to the field of heart failure.
heart failure; cardiac remodeling; microRNAs; neurohormonal activation; arrhythmia
African-Americans have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on blood pressure in African-Americans. During two winter periods from 2008–2010, 283 African-Americans (median age, 51 years) were randomized into a four-arm, double-blind trial for three months of placebo, 1,000, 2,000, or 4,000 international units of cholecalciferol per day. At baseline, three months, and six months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mmHg for those receiving placebo, −0.66 mmHg for 1,000 units/day, −3.4 mmHg for 2,000 units/day, and −4.0 mmHg for 4,000 units/day of cholecalciferol (−1.4 mmHg for each additional 1000 units/day of cholecalciferol; p=0.04). For each 1 ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2 mmHg reduction in systolic pressure (p = 0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (p=0.37). Within an unselected population of African-Americans, three months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among African-Americans, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension.
Blood pressure; Hypertension; African Americans; Randomized controlled trial; Vitamin D
Children with Down syndrome (DS) have a higher prevalence of obesity than other children. Whether this increased risk for obesity is due to a lower resting energy expenditure (REE) is controversial. Our study assessed whether 1) the REE of children with DS adjusted for fat free mass (FFM) was lower than that of sibling controls and 2) the changes in fat mass (FM) over three years were associated with FFM-adjusted baseline REE.
This study used cross-sectional and prospective cohort designs. Four annual measurement visits were conducted with 28 children with DS and 35 sibling controls aged 3–10y. REE and serum thyroxine (T4) were measured at baseline. Anthropometry, skinfold thicknesses measures, and, in a subsample, dual energy x-ray absorptiometry (DXA) were used at each visit to calculate FM.
Children with DS had significantly lower REE adjusted for FFM (−78 kcal/day, 95% CI: −133 to −27, p=0.003). The difference remained significant after adjustment for FM, sex, and African ancestry (−49 kcal/day, 95% CI: −94 to −4, p=0.03). In the longitudinal analysis, the baseline REE adjusted for baseline FFM was not predictive of FM accretion over time (p=0.8).
Children with DS have lower REE than sibling controls, but REE was not associated with changes in FM over time. The results suggest that the lower REE of children with DS does not explain their increased risk for obesity.
obesity; fat free mass; fat mass
To estimate sample sizes for pediatric multiple sclerosis (MS) trials using new T2 lesion count, annualized relapse rate (ARR), and time to first relapse (TTFR) endpoints.
Poisson and negative binomial models were fit to new T2 lesion and relapse count data, and negative binomial time-to-event and exponential models were fit to TTFR data of 42 children with MS enrolled in a national prospective cohort study. Simulations were performed by resampling from the best-fitting model of new T2 lesion count, number of relapses, or TTFR, under various assumptions of the effect size, trial duration, and model parameters.
Assuming a 50% reduction in new T2 lesions over 6 months, 90 patients/arm are required, whereas 165 patients/arm are required for a 40% treatment effect. Sample sizes for 2-year trials using relapse-related endpoints are lower than that for 1-year trials. For 2-year trials and a conservative assumption of overdispersion (ϑ), sample sizes range from 70 patients/arm (using ARR) to 105 patients/arm (TTFR) for a 50% reduction in relapses, and 230 patients/arm (ARR) to 365 patients/arm (TTFR) for a 30% relapse reduction. Assuming a less conservative ϑ, 2-year trials using ARR require 45 patients/arm (60 patients/arm for TTFR) for a 50% reduction in relapses and 145 patients/arm (200 patients/arm for TTFR) for a 30% reduction.
Six-month phase II trials using new T2 lesion count as an endpoint are feasible in the pediatric MS population; however, trials powered on ARR or TTFR will need to be 2 years in duration and will require multicentered collaboration.
We present a new method to quantify differences in myelinated nerve fibers. These differences range from morphologic characteristics of individual fibers to differences in macroscopic properties of collections of fibers. Our method uses statistical physics tools to improve on traditional measures, such as fiber size and packing density. As a case study, we analyze cross–sectional electron micrographs from the fornix of young and old rhesus monkeys using a semi-automatic detection algorithm to identify and characterize myelinated axons. We then apply a feature selection approach to identify the features that best distinguish between the young and old age groups, achieving a maximum accuracy of 94% when assigning samples to their age groups. This analysis shows that the best discrimination is obtained using the combination of two features: the fraction of occupied axon area and the effective local density. The latter is a modified calculation of axon density, which reflects how closely axons are packed. Our feature analysis approach can be applied to characterize differences that result from biological processes such as aging, damage from trauma or disease or developmental differences, as well as differences between anatomical regions such as the fornix and the cingulum bundle or corpus callosum.
Studies in experimental and human heart failure suggest that phosphodiesterase type-5 inhibitors may enhance cardiovascular function, and thus, exercise capacity in heart failure with preserved ejection fraction.
To determine the effect of the phosphodiesterase type-5 inhibitor, sildenafil, in comparison to placebo on exercise capacity and clinical status in heart failure with preserved ejection fraction.
Design, setting, and patients
Multicenter, double-blind, placebo-controlled, parallel design, randomized clinical trial of 216 stable outpatients with heart failure, ejection fraction ≥ 50%, elevated N-terminal pro-brain natriuretic peptide or elevated invasively-measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in the United States and Canada.
Sildenafil (n=113) or placebo (n=103) administered orally at 20 mg three times daily for 12 weeks followed by 60 mg three times daily for 12 weeks.
Main outcome measures
Primary endpoint was change in peak oxygen consumption after 24 weeks of therapy. Secondary endpoints included change in six-minute walk distance and a three tier hierarchical composite clinical status score where patients were ranked (range 1-N) based on time to death, time to cardiovascular or cardiorenal hospitalization and change in quality of life for participants alive without cardiovascular or cardiorenal hospitalization at 24 weeks.
Median age was 69 years and 48% of patients were female. At baseline, median peak oxygen consumption (11.7 ml/kg/min) and six-minute walk distance (308 meters) were reduced and median E/e′ (16), left atrial volume index (44 ml/m2) and pulmonary artery systolic pressure (41 mmHg) were consistent with chronically-elevated left ventricular filling pressures. At 24 weeks, median (interquartile range) changes in peak oxygen consumption (ml/kg/min) in patients who received placebo [−0.20 (−0.70, 1.00)] or sildenafil [−0.20 (−1.20, 1.10); p=0.90] were not significantly different. The mean clinical status rank score (higher value indicates better status; expected value with no treatment effect = 95) was not significantly different (p=0.85) at 24 weeks in patients who received placebo (95.8) or sildenafil (94.2). Changes in six-minute walk distance (meters) at 24 weeks in patients who received placebo [15.0 (−26.0, 45.0)] or sildenafil [5.0 (−37.0, 55.0); p=0.92] were also not significantly different. Adverse events occurred in 78 (76%) of patients who received placebo and 90 (80%) of patients who received sildenafil. Serious adverse events occurred in 16 (16%) of patients who received placebo and 25 (22%) of patients who received sildenafil.
Chronic phosphodiesterase type-5 inhibitor therapy with sildenafil for 24 weeks did not alter exercise capacity or clinical status compared to placebo in patients with heart failure and preserved ejection fraction.
clinicaltrials.gov number, NCT00763867
What is the relation between humans and non-human animals? From a biological perspective, we view humans as one species among many, but in the fables and films we create for children, we often offer an anthropocentric perspective, imbuing non-human animals with human-like characteristics. What are the consequences of these distinctly different perspectives on children’s reasoning about the natural world? Some have argued that children universally begin with an anthropocentric perspective and that acquiring a biological perspective requires a basic conceptual change (cf. Carey, 1985). But recent work reveals that this anthropocentric perspective, evidenced in urban 5-year-olds, is not evident in 3-year-olds (Herrmann etal., 2010). This indicates that the anthropocentric perspective is not an obligatory first step in children’s reasoning about biological phenomena. In the current paper, we introduced a priming manipulation to assess whether 5-year-olds’ reasoning about a novel biological property is influenced by the perspectives they encounter in children’s books. Just before participating in a reasoning task, each child read a book about bears with an experimenter. What varied was whether bears were depicted from an anthropomorphic (Berenstain Bears) or biological perspective (Animal Encyclopedia). The priming had a dramatic effect. Children reading the Berenstain Bears showed the standard anthropocentric reasoning pattern, but those reading the Animal Encyclopedia adopted a biological pattern. This offers evidence that urban 5-year-olds can adopt either a biological or a human-centered stance, depending upon the context. Thus, children’s books and other media are double-edged swords. Media may (inadvertently) support human-centered reasoning in young children, but may also be instrumental in redirecting children’s attention to a biological model.
cognitive development; biological reasoning; cultural priming; children’s books; anthropocentrism
Parents of seriously ill children participate in making difficult medical decisions for their child. In some cases, parents face situations where their initial goals, such as curing the condition, may have become exceedingly unlikely. While some parents continue to pursue these goals, others relinquish their initial goals and generate new goals such as maintaining the child’s quality of life. We call this process of transitioning from one set of goals to another regoaling.
Regoaling involves factors that either promote or inhibit the regoaling process, including disengagement from goals, reengagement in new goals, positive and negative affect, and hopeful thinking. We examine these factors in the context of parental decision making for a seriously ill child, presenting a dynamic conceptual model of regoaling. This model highlights four research questions that will be empirically tested in an ongoing longitudinal study of medical decision making among parents of children with serious illness. Additionally, we consider potential clinical implications of regoaling for the practice of pediatric palliative care.
The psychosocial model of regoaling by parents of children with a serious illness predicts that parents who experience both positive and negative affect and hopeful patterns of thought will be more likely to relinquish one set of goals and pursue a new set of goals. A greater understanding of how parents undergo this transition may enable clinicians to better support them through this difficult process.
Parental decision making; Pediatric palliative care; Goals; Disengagement; Reengagement; Regoaling; Positive affect; Negative affect; Hopeful thinking; Conceptual model
Introduction. When using the double interval slide technique for arthroscopic repair of chronic large or massive rotator cuff tears, the posterior interval release is directed toward the scapular spine until the fat pad that protects the suprascapular nerve is reached. Injury to the suprascapular nerve can occur due to the nerve's proximity to the operative field. This study aimed to identify safe margins for avoiding injury to the suprascapular nerve. Materials and Methods. For 20 shoulders in ten cadavers, the distance was measured from the suprascapular notch to the glenoid rim, the articular margin of the rotator cuff footprint, and the lateral border of the acromion. Results. From the suprascapular notch, the suprascapular nerve coursed an average of 3.42 cm to the glenoid rim, 5.34 cm to the articular margin of the rotator cuff footprint, and 6.09 cm to the lateral border of the acromion. Conclusions. The results of this study define a safe zone, using anatomic landmarks, to help surgeons avoid iatrogenic injury to the suprascapular nerve when employing the double interval slide technique in arthroscopic repair of the rotator cuff.
Individuals with alcohol problems frequently report receipt of pressure from a variety of formal and informal sources. While some studies have shown a positive association between receipt of pressure and treatment seeking, other studies have not found a clear association. The mix of findings may be due to several study design factors including sample limitations, lack of contextual alcohol measures as moderators, and failure to include assessment of internal beliefs that relate to help seeking.
Current drinkers from the National Alcohol Surveys (NAS) from 1984-2005 (N=16,183) were used to describe the association between pressure and help seeking using moderators that included frequent heavy drinking, alcohol related negative consequences, and beliefs about abstention or moderation of alcohol consumption.
The rate of help seeking in the past year was 1.6% across all NAS surveys with Alcoholics Anonymous being the predominant source of help sought followed by physical or mental health services. In 1984 and 1990 approximately 80% of those seeking help also received pressure. The percent declined to 57% in 1995 and leveled off at 64% in 2000 and 61% in 2005. Logistic regression models showed an association between past year receipt of pressure and help seeking. Frequent heavy drinking, alcohol related negative consequences, and strong beliefs about alcohol use were also associated with help seeking, however, they did not moderate the relationship between pressure and help seeking.
Pressure is associated with help seeking as are a variety of other factors, including heavy alcohol consumption, negative consequences, and strong beliefs about moderate alcohol use. However, the effect of these factors appears to be independent of pressure and not interactive. Future research needs to assess the types of pressure and impact on help seeking to inform public policy and treatment providers as to who receives what type of pressure, when it is helpful, and when it is counterproductive.
alcohol; pressure; help seeking; alcohol treatment; general population
Rodent 13C magnetic resonance spectroscopy studies show that glutamatergic signaling requires high oxidative energy in the awake resting state and allowed calibration of functional magnetic resonance imaging (fMRI) signal in terms of energy relative to the resting energy. Here, we derived energy used for glutamatergic signaling in the awake resting human. We analyzed human data of electroencephalography (EEG), positron emission tomography (PET) maps of oxygen (CMRO2) and glucose (CMRglc) utilization, and calibrated fMRI from a variety of experimental conditions. CMRglc and EEG in the visual cortex were tightly coupled over several conditions, showing that the oxidative demand for signaling was four times greater than the demand for nonsignaling events in the awake state. Variations of CMRO2 and CMRglc from gray-matter regions and networks were within ±10% of means, suggesting that most areas required similar energy for ubiquitously high resting activity. Human calibrated fMRI results suggest that changes of fMRI signal in cognitive studies contribute at most ±10% CMRO2 changes from rest. The PET data of sleep, vegetative state, and anesthesia show metabolic reductions from rest, uniformly >20% across, indicating no region is selectively reduced when consciousness is lost. Future clinical investigations will benefit from using quantitative metabolic measures.
astrocytes; baseline; field potentials; glutamate; multiunit activity; resting state
We describe an implementation of maximum likelihood classification for single particle electron cryo-microscopy that is based on the FREALIGN software. Particle alignment parameters are determined by maximizing a joint likelihood that can include hierarchical priors, while classification is performed by expectation maximization of a marginal likelihood. We test the FREALIGN implementation using a simulated dataset containing computer-generated projection images of three different 70S ribosome structures, as well as a publicly available dataset of 70S ribosomes. The results show that the mixed strategy of the new FREALIGN algorithm yields performance on par with other maximum likelihood implementations, while remaining computationally efficient.
Electron microscopy; maximum likelihood; classification; single particle; protein structure
Telomeres are nucleoprotein structures that cap the end of chromosomes and shorten with sequential cell divisions in normal aging. Short telomeres are also implicated in the incidence of many cancers, but the evidence is not conclusive for colorectal cancer (CRC). Therefore, the aim of this study was to assess the association of CRC and telomere length.
In this case–control study, we measured relative telomere length from peripheral blood leukocytes (PBLs) DNA with quantitative PCR in 598 CRC patients and 2,212 healthy controls.
Multivariate analysis indicated that telomere length was associated with risk for CRC, and this association varied in an age-related manner; younger individuals (≤50 years of age) with longer telomeres (80–99 percentiles) had a 2–6 times higher risk of CRC, while older individuals (>50 years of age) with shortened telomeres (1–10 percentiles) had 2–12 times the risk for CRC. The risk for CRC varies with extremes in telomere length in an age-associated manner.
Younger individuals with longer telomeres or older individuals with shorter telomeres are at higher risk for CRC. These findings indicate that the association of PBL telomere length varies according to the age of cancer onset and that CRC is likely associated with at minimum two different mechanisms of telomere dynamics.
Behavioral responses to temperature are critical for survival, and animals from insects to humans show strong preferences for specific temperatures1, 2. Preferred temperature selection promotes avoidance of adverse thermal environments in the short-term and maintenance of optimal body temperatures over the long-term1, 2, but its molecular and cellular basis is largely unknown. Recent studies have yielded conflicting views of thermal preference in Drosophila, attributing importance to either internal3 or peripheral4 warmth sensors. Here we reconcile these views by demonstrating that thermal preference is not a singular response, but involves multiple systems relevant in different contexts. We previously found that the Transient Receptor Potential (TRP) channel TRPA1 acts internally to control the slowly developing preference response of flies exposed to a shallow thermal gradient3. Here we find that the rapid response of flies exposed to a steep warmth gradient does not require TRPA1; rather, the Gustatory receptor (Gr) Gr28b(D) drives this behavior via peripheral thermosensors. Grs are a large gene family widely studied in insect gustation and olfaction and implicated in host-seeking by insect disease vectors5–7, but not previously implicated in thermosensation. At the molecular level, Gr28b(D) misexpression confers thermosensitivity upon diverse cell types, suggesting it is a warmth sensor. These data reveal a new type of thermosensory molecule and uncover a functional distinction between peripheral and internal warmth sensors in this tiny ectotherm reminiscent of thermoregulatory systems in larger, endothermic animals2. The use of multiple, distinct molecules to respond to a given temperature, as observed here, may facilitate independent tuning of an animal’s distinct thermosensory responses.
Gr28b; thermosensation; TRPA1; TRP; thermosensor; thermoreceptor