Metabolic engineering of beta-oxidation in Penicillium chrysogenum for improved semi-synthetic cephalosporin biosynthesis

Industrial production of semi-synthetic cephalosporins by Penicillium chrysogenum requires supplementation of the growth media with the side-chain precursor adipic acid. In glucose-limited chemostat cultures of P. chrysogenum, up to 88% of the consumed adipic acid was not recovered in cephalosporinrelated products, but used as an additional carbon and energy source for growth. This low efficiency of side-chain precursor incorporation provides an economic incentive for studying and engineering the metabolism of adipic acid in P. cluysogenum. Chemostat-based transcriptome analysis in the presence and absence of adipic acid confirmed that adipic acid metabolism in this fungus occurs via beta-oxidation. A set of 52 adipate-responsive genes included six putative genes for acyl-CoA oxidases and dehydrogenases, enzymes responsible for the first step of beta-oxidation. Subcellular localization of the differentially expressed acyl-CoA oxidases and dehydrogenases revealed that the oxidases were exclusively targeted to peroxisomes, while the dehydrogenases were found either in peroxisomes or in mitochondria. Deletion of the genes encoding the peroxisomal acyl-CoA oxidase Pc20g01800 and the mitochondrial acyl-CoA dehydrogenase Pc20g07920 resulted in a 1.6- and 3.7-fold increase in the production of the semi-synthetic cephalosporin intermediate adipoyl-6-APA, respectively. The deletion strains also showed reduced adipate consumption compared to the reference strain, indicating that engineering of the first step of beta-oxidation successfully redirected a larger fraction of adipic acid towards cephalosporin biosynthesis. (C) 2012 Elsevier Inc. All rights reserved.

Impact of maternal mild hyperglycemia on maternal care and offspring development and behavior of Wistar rats

The aim of the present study was to evaluate the effect of maternal mild hyperglycemia on maternal behavior, as well as the development, behavior, reproductive function, and glucose tolerance of the offspring. At birth, litters were assigned either to Control (subcutaneous (sc)-citrate buffer) or STZ groups (streptozotocin (STZ)-100 mg/kg-sc.). On PND 90 both STZ-treated and Control female rats were mated. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed during pregnancy. Pregnancy duration, litter size and sex ratio were assessed. Newborns were classified according to birth weight as small (SPA), adequate (APA), or large for pregnancy age (LPA). Maternal behavior was analyzed on PND 5 and 10. Offspring body weight, length, and anogenital distance were measured and general activity was assessed in the open field. Sexual behavior was tested in both male and female offspring. Levels of reproductive hormones and estrous cycle duration were evaluated in female offspring. Female offspring were mated and both a GTT and ITT performed during pregnancy. Neonatal STZ administration caused mild hyperglycemia during pregnancy and changed some aspects of maternal care. The hyperglycemic intrauterine milieu impaired physical development and increased immobility in the open field in the offspring although the latter effect appeared at different ages for males (adulthood) and females (infancy). There was no impairment in the sexual behavior of either male or female offspring. As adults, female offspring of STZ-treated mothers did not show glucose intolerance during pregnancy. Thus, offspring of female rats that show mild hyperglycemia in pregnancy have fewer behavioral and developmental impairments than previously reported in the offspring of severely diabetic dams suggesting that the degree of impairment is directly related to the mother glycemic intensity. (C) 2012 Elsevier Inc. All rights reserved.

What percentage of people in the general population satisfies the current clinical at-risk criteria of psychosis?

The clinical validity of at-risk criteria of psychosis had been questioned based on epidemiological studies that have reported much higher prevalence and annual incidence rates of psychotic-like experiences (PLEs as assessed by either self rating questionnaires or layperson interviews) in the general population than of the clinical phenotype of psychotic disorders (van Os et al., 2009). Thus, it is unclear whether “current at-risk criteria reflect behaviors so common among adolescents and young adults that a valid distinction between ill and non-ill persons is difficult” (Carpenter, 2009). We therefore assessed the 3-month prevalence of at-risk criteria by means of telephone interviews in a randomly drawn general population sample from the at-risk age segment (age 16–35 years) in the Canton Bern, Switzerland. Eighty-five of 102 subjects had valid phone numbers, 21 of these subjects refused (although 6 of them signaled willingness to participate at a later time), 4 could not be contacted. Sixty subjects (71% of the enrollment fraction) participated. Two participants met exclusion criteria (one for being psychotic, one for lack of language skills). Twenty-two at-risk symptoms were assessed for their prevalence and severity within the 3 months prior to the interview by trained clinical raters using (i) the Structured Interview for Prodromal Syndromes (SIPS; Miller et al., 2002) for the evaluation of 5 attenuated psychotic and 3 brief limited intermittent psychotic symptoms (APS, BLIPS) as well as state-trait criteria of the ultra-high-risk (UHR) criteria and (ii) the Schizophrenia Proneness Instrument, Adult version (SPI-A; Schultze-Lutter et al., 2007) for the evaluation of the 14 basic symptoms included in COPER and COGDIS (Schultze-Lutter et al., 2008). Further, psychiatric axis I diagnoses were assessed by means of the Mini-International Neuropsychiatric Interview, M.I.N.I. (Sheehan et al., 1998), and psychosocial functioning by the Scale of Occupational and Functional Assessment (SOFAS; APA, 1994). All interviewees felt ‘rather’ or ‘very’ comfortable with the interview. Of the 58 included subjects, only 1 (2%) fulfilled APS criteria by reporting the attenuated, non-delusional idea of his mind being literally read by others at a frequency of 2–3 times a week that had newly occurred 6 weeks ago. BLIPS, COPER, COGDIS or state-trait UHR criteria were not reported. Yet, twelve subjects (21%) described sub-threshold at-risk symptoms: 7 (12%) reported APS relevant symptoms but did not meet time/frequency criteria of APS, and 9 (16%) reported COPER and/or COGDIS relevant basic symptoms but at an insufficient frequency or as a trait lacking increase in severity; 4 of these 12 subjects reported both sub-threshold APS and sub-threshold basic symptoms. Table 1 displays type and frequency of the sub-threshold at-risk symptoms.

The organization of memory for familiar songs

Investigated the organizing principles in memory for familiar songs in 2 experiments. It was hypothesized that individuals do not store and remember each song in isolation. Rather, there exists a rich system of relationships among tunes that can be revealed through similarity rating studies and memory tasks. One initial assumption was the division of relations among tunes into musical (e.g., tempo, rhythm) and nonmusical similarity. In Exp I, 20 undergraduates were asked to sort 60 familiar tunes into groups according to both musical and nonmusical criteria. Clustering analyses showed clear patterns of nonmusical similarity but few instances of musical similarity. Exp II, with 16 Ss, explored the psychological validity of the nonmusical relationships revealed in Exp I. A speeded verification task showed that songs similar to each other are confused more often than are distantly related songs. A free-recall task showed greater clustering for closely related songs than for distantly related ones. The relationship between these studies and studies of semantic memory is discussed. Also, the contribution of musical training and individual knowledge to the organization of the memory system is considered. (19 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)

Connectionism as metaphor: Towards an integrated, unified conception of self-system and individual difference

Comments on an article by Kashima et al. (see record 2007-10111-001). In their target article Kashima and colleagues try to show how a connectionist model conceptualization of the self is best suited to capture the self's temporal and socio-culturally contextualized nature. They propose a new model and to support this model, the authors conduct computer simulations of psychological phenomena whose importance for the self has long been clear, even if not formally modeled, such as imitation, and learning of sequence and narrative. As explicated when we advocated connectionist models as a metaphor for self in Mischel and Morf (2003), we fully endorse the utility of such a metaphor, as these models have some of the processing characteristics necessary for capturing key aspects and functions of a dynamic cognitive-affective self-system. As elaborated in that chapter, we see as their principal strength that connectionist models can take account of multiple simultaneous processes without invoking a single central control. All outputs reflect a distributed pattern of activation across a large number of simple processing units, the nature of which depends on (and changes with) the connection weights between the links and the satisfaction of mutual constraints across these links (Rummelhart & McClelland, 1986). This allows a simple account for why certain input features will at times predominate, while others take over on other occasions. (PsycINFO Database Record (c) 2008 APA, all rights reserved)

Reducing Myofibroblast Arrhythmogeneicity by Pharmacological Targeting of Their Cytoskeleton

Introduction: Slow conduction and ectopic activity are key elements of cardiac arrhythmogenesis. Both anomalies can be caused by myofibroblasts (MFBs) following establishment of heterocellular gap junctional coupling with cardiomyocytes. Because MFBs are characterized by the expression of {alpha}-smooth muscle actin ({alpha}-SMA) containing stress fibers, we investigated whether pharmacological interference with stress fiber formation might affect myofibroblast arrhythmogenicity. Methods: Experiments were done with patterned growth strands of neonatal rat ventricular cardiomyocytes coated with cardiac MFBs. Impulse propagation characteristics were measured optically using voltage sensitive dyes. Electrophysiological characteristics of single MFBs were assessed using patch clamp techniques. Actin polymerization was inhibited by latrunculin B (LtB). Data are given as mean±S.D. (n=5 to 22). Results: As assessed by immunocytochemistry, exposure of MFBs to LtB (0.3–10 µmol/L) profoundly disrupted stress fiber formation. This led, within minutes, to a dramatic change in cell morphology with MFBs assuming an astrocyte-like shape. In pure cardiomyocyte preparations, LtB had negligible effects on impulse conduction velocity ({theta}) and maximal action potential upstroke velocities (dV/dtmax). In contrast, LtB applied to MFB coated cardiomyocyte strands substantially increased {theta} from 247±32 to 371±26 mm/s and dV/dtmax from 40±7 to 81±1 %APA/ms, i.e., to values similar to those of pure cardiomyocyte strands (342±13 mm/s; 82±1 %APA/ms). Moreover, LtB at 1 µmol/L completely abolished MFB induced ectopic activity. LtB induced normalization of electrophysiologic parameters can be explained by the finding that LtB hyperpolarized MFBs from –25 mV to –50 mV, thus limiting their depolarizing effect on cardiomyocytes which was shown before to cause slow conduction and ectopic activity. Conclusions: Pharmacological interference with the cytoskeleton of cardiac MFBs alters their electrophysiological phenotype to such an extent that detrimental effects on cardiomyocyte electrophysiology are completely abolished. This observation might form a basis for the development of therapeutic strategies aimed at limiting the arrhythmogenic potential of MFBs.

Modification of Actin Fibers Changes the Electrical Phenotype of Cardiac Myofibroblasts

Background: Slow conduction and ectopic activity are major determinants of cardiac arrhythmogenesis. Both of these conditions can be elicited by myofibroblasts (MFBs) following establishment of heterocellular gap junctional coupling with cardiomyocytes. MFBs appear during structural remodeling of the heart and are characterized by the expression of α-smooth muscle actin (α-SMA) containing stress fibers. In this study, we investigated whether pharmacological interference with the actin cytoskeleton affects myofibroblast arrhythmogeneicity. Methods: Experiments were performed with patterned growth strands of neonatal rat ventricular cardiomyocytes coated with cardiac MFBs. Impulse conduction velocity (θ) and maximal upstroke velocities of propagated action potentials (dV/dtmax), expressed as % action potential amplitude change (%APA) per ms, were measured optically using voltage sensitive dyes. Actin was destabilized by latrunculin B (LtB) and cytochalasin D and stabilized with jasplakinolide. Data are given as mean ± S.D. (n = 5-22). Single cell electrophysiology was assessed using standard patch-clamp techniques. Results: As revealed by immunocytochemistry, exposure of MFBs to LtB (0.01-10 μmol/L) profoundly disrupted stress fibers which led to drastic changes in cell morphology with MFBs assuming an astrocyte-like shape. In control cardiomyocyte strands (no MFB coat), LtB had negligible effects on θ and dV/dtmax. In contrast, LtB applied to MFB-coated strands increased θ dose-dependently from 197 ± 35 mm/s to 344 ± 26 mm/s and dV/dtmax from 38 ± 5 to 78 ± 3% APA/ms, i.e., to values virtually identical to those of cardiomyocyte control strands (339 ± 24 mm/s; 77 ± 3% APA/ms). Highly similar results were obtained when exposing the preparations to cytochalasin D. In contrast, stabilization of actin with increasing concentrations of jasplakinolide exerted no significant effects on impulse conduction characteristics in MFB-coated strands. Whole-cell patch-clamp experiments showed that LtB hyperpolarized MFBs from -25 mV to -50 mV, thus limiting their depolarizing effect on cardiomyocytes which was shown before to cause arrhythmogenic slow conduction and ectopic activity. Conclusion: Pharmacological interference with the actin cytoskeleton of cardiac MFBs affects their electrophysiological phenotype to such an extent that they loose their detrimental effects on cardiomyocyte electrophysiology. This result might form a basis for the development of therapeutic strategies aimed at limiting the arrhythmogenic potential of MFBs.

Prospective effects of emotion regulation on emotional adjustment

Deficits in emotion-regulation skills have widely been shown to be associated with poor emotional adjustment. However, it is still unclear whether these deficits are a cause or a consequence of poor adjustment. The purpose of the present research was to clarify the reciprocal effects between these 2 concepts. In 2 studies (Ns = 446 and 635), self-reports of emotion regulation and emotional adjustment were assessed twice with a 2-week interval. Cross-lagged regression analyses demonstrated that self-reports of emotion regulation predicted subsequent adjustment, over and above the effects of previous adjustment, whereas emotional adjustment did not predict subsequent emotion regulation. Thus, a focus on emotion-regulation skills may be important in the prevention and treatment of affect-related mental health problems.

Disentangling the effects of low self-esteem and stressful events on depression: Findings from three longitudinal studies

Diathesis-stress models of depression suggest that low self-esteem and stressful events jointly influence the development of depressive affect. More specifically, the self-esteem buffering hypothesis states that, in the face of challenging life circumstances, individuals with low self-esteem are prone to depression because they lack sufficient coping resources, whereas those with high self-esteem are able to cope effectively and consequently avoid spiraling downward into depression. The authors used data from 3 longitudinal studies of adolescents and young adults, who were assessed 4 times over a 3-year period (Study 1; N = 359), 3 times over a 6-week period (Study 2; N = 249), and 4 times over a 6-year period (Study 3; N = 2,403). In all 3 studies, low self-esteem and stressful events independently predicted subsequent depression but did not interact in the prediction. Thus, the results did not support the self-esteem buffering hypothesis but suggest that low self-esteem and stressful events operate as independent risk factors for depression. In addition, the authors found evidence in all 3 studies that depression, but not low self-esteem, is reciprocally related to stressful events, suggesting that individuals high in depression are more inclined to subsequently experience stressful events.

Gender as a moderator of the fair process effect

This paper examines gender as a moderator of the fair-process effect in an ultimatum game setting. Results from games with 112 German high-school students support the hypothesis that fair procedures can decrease rejection behavior in unfair human allocation decisions. Furthermore, procedural fairness results in a statistically significant difference for women in accepting an unfair distribution. In contrast, procedural fairness appears to have no significant impact on men’s rejection behavior. However, we found no significant gender differences in the perception of procedural fairness. We conclude that, although men perceive procedural fairness similarly to women, this aspect is less important for determining their subsequent behavior. (PsycINFO Database Record (c) 2013 APA, all rights reserved)

Is low self-esteem a risk factor for depression? Findings from a longitudinal study of Mexican-origin youth

We examined the relation between low self-esteem and depression using longitudinal data from a sample of 674 Mexican-origin early adolescents who were assessed at age 10 and 12 years. Results supported the vulnerability model, which states that low self-esteem is a prospective risk factor for depression. Moreover, results suggested that the vulnerability effect of low self-esteem is driven, for the most part, by general evaluations of worth (i.e., global self-esteem), rather than by domain-specific evaluations of academic competence, physical appearance, and competence in peer relationships. The only domain-specific self-evaluation that showed a prospective effect on depression was honesty-trustworthiness. The vulnerability effect of low self-esteem held for male and female adolescents, for adolescents born in the United States versus Mexico, and across different levels of pubertal status. Finally, the vulnerability effect held when we controlled for several theoretically relevant 3rd variables (i.e., social support, maternal depression, stressful events, and relational victimization) and for interactive effects between self-esteem and the 3rd variables. The present study contributes to an emerging understanding of the link between self-esteem and depression and provides much needed data on the antecedents of depression in ethnic minority populations

Does low self-esteem predict depression and anxiety? A meta-analysis of longitudinal studies

Low self-esteem and depression are strongly related, but there is not yet consistent evidence on the nature of the relation. Whereas the vulnerability model states that low self-esteem contributes to depression, the scar model states that depression erodes self-esteem. Furthermore, it is unknown whether the models are specific for depression or whether they are also valid for anxiety. We evaluated the vulnerability and scar models of low self-esteem and depression, and low self-esteem and anxiety, by meta-analyzing the available longitudinal data (covering 77 studies on depression and 18 studies on anxiety). The mean age of the samples ranged from childhood to old age. In the analyses, we used a random-effects model and examined prospective effects between the variables, controlling for prior levels of the predicted variables. For depression, the findings supported the vulnerability model: The effect of self-esteem on depression (β = -.16) was significantly stronger than the effect of depression on self-esteem (β = -.08). In contrast, the effects between low self-esteem and anxiety were relatively balanced: Self-esteem predicted anxiety with β = -.10, and anxiety predicted self-esteem with β = -.08. Moderator analyses were conducted for the effect of low self-esteem on depression; these suggested that the effect is not significantly influenced by gender, age, measures of self-esteem and depression, or time lag between assessments. If future research supports the hypothesized causality of the vulnerability effect of low self-esteem on depression, interventions aimed at increasing self-esteem might be useful in reducing the risk of depression.

Increase of Caffeine and Decrease of Corticosteroids for Extremely Low Birthweight Infants with Respiratory Failure from 1997 to 2011

AIM To compare treatment strategies for respiratory failure in extremely low birth weight (ELBW) infants in Germany in 1997 to Germany, Austria and Switzerland in 2011. METHODS A detailed questionnaire about treatment strategies for ELBW infants was sent to all German centres treating ELBW infants in 1997. A follow-up survey was conducted in 2011 in Germany, Austria and Switzerland. RESULTS In 1997 and 2011, 63.6% and 66.2% of the hospitals responded. In 2011 the response rate was higher in Switzerland than in Germany, and in university hospitals versus non-university hospitals. Treatment strategies did not differ between university and non-university hospitals as well as NICUs of different sizes in 2011. Differences between Germany, Austria and Switzerland were minimal. Administration of caffeine increased significantly, whereas theophylline and doxapram declined (all p<0.001). While the use of dexamethasone decreased and the use of hydrocortisone increased, the overall use of corticosteroids declined (all p<0.001). Between 1997 and 2011 therapy with inhalations and mucolytics decreased (both p<0.001) whereas the use application of diuretics did not change significantly. In mechanically ventilated infants the application of muscle relaxants and sedation declined significantly (p=0.009 and p<0.001), whereas analgesia use did not change. CONCLUSION Treatment strategies for respiratory failure in ELBW infants have changed significantly between 1997 and 2011. This article is protected by copyright. All rights reserved.