Identifying the Neurodevelopmental Differences of Opioid Withdrawal

Cellular and Molecular Neurobiology - Stopping opioid medications can result in a debilitating withdrawal syndrome in chronic users. Opioid withdrawal can occur at all ages, but...     

Executive Function and IQ Predict Mathematical and Attention Problems in Very Preterm Children

Objective of this study was to examine the impact of executive function (EF) on mathematical and attention problems in very preterm (gestational age ≤ 30 weeks) children. Participants were 200 very preterm (mean age 8.2 ± 2.5 years) and 230 term children (mean age 8.3 ± 2.3 years) without severe disabilities, born between 1996 and 2004. EFs assessed included verbal fluency, verbal working memory, visuospatial span, planning, and impulse control. Mathematics was assessed with the Dutch Pupil Monitoring System and parents and teachers rated attention problems using standardized behavior questionnaires. The impact of EF was calculated over and above processing speed indices and IQ. Interactions with group (very preterm versus term birth status) were examined. Analyses were conducted separately for two subsamples: children in preschool and children in primary school. Very preterm children performed poorer on tests for mathematics and had more parent and teacher rated attention problems than term controls (ß_s>.11, P_s<.01). IQ contributed unique variance to mathematics in preschool and in primary school (ß_s>.16, P_s<.007). A significant interaction of group with IQ (ß = −. 24, P = .02) showed that IQ contributed unique variance to attention problems as rated by teachers, but that effects were stronger for very preterm than for term infants. Over and above IQ, EF contributed unique variance to mathematics in primary school (ß = .13, P<.001), to parent rated inattention in preschool and in primary school (ß_s>−.16, P_s<.04), and to teacher rated inattention in primary school (ß = −.19; ß = .19, P_s<.009). In conclusion, impaired EF is, over and above impaired IQ, an important predictor for poor mathematics and attention problems following very preterm birth.     

Comparing Cognitive and Somatic Symptoms of Depression in Myocardial Infarction Patients and Depressed Patients in Primary and Mental Health Care

Depression in myocardial infarction patients is often a first episode with a late age of onset. Two studies that compared depressed myocardial infarction patients to psychiatric patients found similar levels of somatic symptoms, and one study reported lower levels of cognitive/affective symptoms in myocardial infarction patients. We hypothesized that myocardial infarction patients with first depression onset at a late age would experience fewer cognitive/affective symptoms than depressed patients without cardiovascular disease. Combined data from two large multicenter depression studies resulted in a sample of 734 depressed individuals (194 myocardial infarction, 214 primary care, and 326 mental health care patients). A structured clinical interview provided information about depression diagnosis. Summed cognitive/affective and somatic symptom levels were compared between groups using analysis of covariance, with and without adjusting for the effects of recurrence and age of onset. Depressed myocardial infarction and primary care patients reported significantly lower cognitive/affective symptom levels than mental health care patients (F (2,682) = 6.043, p = 0.003). Additional analyses showed that the difference between myocardial infarction and mental health care patients disappeared after adjusting for age of onset but not recurrence of depression. These group differences were also supported by data-driven latent class analyses. There were no significant group differences in somatic symptom levels. Depression after myocardial infarction appears to have a different phenomenology than depression observed in mental health care. Future studies should investigate the etiological factors predictive of symptom dimensions in myocardial infarction and late-onset depression patients.     

Regional heterogeneities in the production of uric acid from adenosine in the bivascularly perfused rat liver

The heterogeneity of the liver parenchyma in relation to uric acid production from adenosine was investigated using the bivascularly perfused rat liver in the anterograde and retrograde modes. Adenosine was infused in livers from fed rats during 20 min at four different concentrations (20, 50, 100 and 200 M) according to four experimental protocols as follows: (A) anterograde perfusion, with adenosine infusion into the portal vein; (B) anterograde perfusion, with adenosine in the hepatic artery, (C) retrograde perfusion, with adenosine in the hepatic vein; (D) retrograde perfusion, with adenosine in the hepatic artery. With protocols A, B, and D uric acid production from adenosine was always characterized by initial bursts followed by progressive decreases toward smaller steady-states. With protocol C the initial burst was present only when 200 M adenosine was infused. The initial bursts in uric acid production were accompanied by simultaneous increases in the ratio of uric acid production/adenosine uptake rate. These initial bursts are thus representing increments in the production of uric acid that are not corresponded by similar increments in the metabolic uptake rates of adenosine. Global analysis of uric acid production revealed that the final steady-state rates were approximately equal for all infusion rates with protocols A, B and C, but smaller with protocol D. This difference, however, can be explained in terms of the differences in accessible cellular spaces, which are much smaller when protocol D is employed. When the analysis was performed in terms of the extra amounts of uric acid produced during the infusion of adenosine, where the initial bursts are also taken into account, different dose-response curves were found for each experimental protocol. These differences cannot be explained in terms of the accessible cell spaces and they are likely to reflect regional heterogeneities. From the various dose-response curves and from the known characteristics of the microcirculation of the rat liver it can be concluded that the initial bursts in uric acid production are generated in periportal hepatocytes. The reason for this heterogeneity could be related to the metabolic effects of adenosine, especially to oxygen uptake inhibition, which is likely to produce changes in the ATP/AMP ratios.     

A mitogen-activated protein kinase gene (MGV1) in Fusarium graminearum is required for female fertility,heterokaryon formation,and plant infection

Fusarium graminearum is an important pathogen of small grains and maize in many areas of the world. Infected grains are often contaminated with mycotoxins harmful to humans and animals. During the past decade, F. graminearum has caused several severe epidemics of head scab in wheat and barley. In order to understand molecular mechanisms regulating fungal development and pathogenicity in this pathogen, we isolated and characterized a MAP kinase gene, MGV1, which is highly homologous to the MPS1 gene in Magnaporthe grisea. The MGV1 gene was dispensable for conidiation in F. graminearum but essential for female fertility during sexual reproduction. Vegetative growth of mgv1 deletion mutants was normal in liquid media but reduced on solid media. Mycelia of the mgv1 mutants had weak cell walls and were hypersensitive to cell wall degrading enzymes. Interestingly, the mgv1 mutants were self-incompatible when tested for heterokaryon formation, and their virulence was substantially reduced. The ability of the mutants to accumulate trichothecene mycotoxins on inoculated wheat was also greatly reduced. Our data suggest that MGV1 in F. graminearum is involved in multiple developmental processes related to sexual reproduction, plant infection, and cell wall integrity.     

The role of the amygdala in signaling prospective outcome of choice

Can brain activity reveal a covert choice? Making a choice often evokes distinct emotions that accompany decision processes. Amygdala has been implicated in choice behavior that is guided by a prospective negative outcome. However, its specific involvement in emotional versus cognitive processing of choice behavior has been a subject of controversy. In this study, the human amygdala was monitored by functional magnetic resonance imaging (fMRI) while subjects were playing in a naturalistic choice paradigm against the experimenter. In order to win, players had to occasionally choose to bluff their opponent, risk "getting caught," and suffer a loss. A critical period, when choice has been made but outcome was still unknown, activated the amygdala preferentially following the choice that entailed risk of loss. Thus, the response of the amygdala differentiated between subject's covert choice of either playing fair or foul. These results support a role of the amygdala in choice behavior, both in the appraisal of inherent value of choice and the signaling of prospective negative outcomes.     

HS5 of the human beta-globin locus control region: a developmental stage-specific border in erythroid cells

Elements with insulator/border activity have been characterized most extensively in Drosophila melanogaster. In vertebrates, the first example of such an element was provided by a hypersensitive site of the chicken beta-globin locus, cHS4. It has been proposed that the homologous site in humans, HS5, functions as a border of the human beta-globin locus. Here, we have characterized HS5 of the human beta-globin locus control region. We have examined its tissue-specificity and assessed its insulating properties in transgenic mice using a lacZ reporter assay. Most importantly, we have tested its enhancer blocking activity in the context of the full beta-globin locus. Our results show that HS5 is erythroid-specific rather than ubiquitous in human tissues. Furthermore, HS5 does not fulfil the criteria of a general in vivo insulator in the transgene protection assay. Finally, a HS5 conditional deletion from the complete locus demonstrates that HS5 has no discernable activity in adult erythroid cells. Surprisingly, HS5 functions as an enhancer blocker in embryonic erythroid cells. We conclude that HS5 is a developmental stage-specific border in erythroid cells.     

Torsional sensing of small-molecule binding using magnetic tweezers

DNA-binding small molecules are widespread in the cell and heavily used in biological applications. Here, we use magnetic tweezers, which control the force and torque applied to single DNAs, to study three small molecules: ethidium bromide (EtBr), a well-known intercalator; netropsin, a minor-groove binding anti-microbial drug; and topotecan, a clinically used anti-tumor drug. In the low-force limit in which biologically relevant torques can be accessed (<10 pN), we show that ethidium intercalation lengthens DNA ∼1.5-fold and decreases the persistence length, from which we extract binding constants. Using our control of supercoiling, we measure the decrease in DNA twist per intercalation to be 27.3 ± 1° and demonstrate that ethidium binding delays the accumulation of torsional stress in DNA, likely via direct reduction of the torsional modulus and torque-dependent binding. Furthermore, we observe that EtBr stabilizes the DNA duplex in regimes where bare DNA undergoes structural transitions. In contrast, minor groove binding by netropsin affects neither the contour nor persistence length significantly, yet increases the twist per base of DNA. Finally, we show that topotecan binding has consequences similar to those of EtBr, providing evidence for an intercalative binding mode. These insights into the torsional consequences of ligand binding can help elucidate the effects of small-molecule drugs in the cellular environment.     

Synthesis and evaluation of a bimodal CXCR4 antagonistic peptide

The antagonistic Ac-TZ14011 peptide, which binds to the chemokine receptor 4, has been labeled with a multifunctional single attachment point reagent that contains a DTPA chelate and a fluorescent dye with Cy5.5 spectral properties. Flow cytometry and confocal microscopy showed that the bimodal labeled peptide gave a specific receptor binding that is similar to monofunctionalized peptide derivatives. Therefore, the newly developed bimodal peptide derivative can be used in multimodal imaging applications.