Dual-field-of-view high-spectral-resolution lidar: Simultaneous profiling of aerosol and water cloud to study aerosol-cloud interaction.

SignificanceAerosol-cloud interaction affects the cooling of Earth's climate, mostly by activation of aerosols as cloud condensation nuclei that can increase the amount of sunlight reflected back to space. But the controlling physical processes remain uncertain in current climate models. We present a lidar-based technique as a unique remote-sensing tool without thermodynamic assumptions for simultaneously profiling diurnal aerosol and water cloud properties with high resolution. Direct lateral observations of cloud properties show that the vertical structure of low-level water clouds can be far from being perfectly adiabatic. Furthermore, our analysis reveals that, instead of an increase of liquid water path (LWP) as proposed by most general circulation models, elevated aerosol loading can cause a net decrease in LWP.

RcLS2F - A Novel Fungal Class 1 KDAC Co-repressor Complex in Aspergillus nidulans.

The fungal class 1 lysine deacetylase (KDAC) RpdA is a promising target for prevention and treatment of invasive fungal infection. RpdA is essential for survival of the most common air-borne mold pathogen Aspergillus fumigatus and the model organism Aspergillus nidulans. In A. nidulans, RpdA depletion induced production of previously unknown small bioactive substances. As known from yeasts and mammals, class 1 KDACs act as components of multimeric protein complexes, which previously was indicated also for A. nidulans. Composition of these complexes, however, remained obscure. In this study, we used tandem affinity purification to characterize different RpdA complexes and their composition in A. nidulans. In addition to known class 1 KDAC interactors, we identified a novel RpdA complex, which was termed RcLS2F. It contains ScrC, previously described as suppressor of the transcription factor CrzA, as well as the uncharacterized protein FscA. We show that recruitment of FscA depends on ScrC and we provide clear evidence that ΔcrzA suppression by ScrC depletion is due to a lack of transcriptional repression caused by loss of the novel RcLS2F complex. Moreover, RcLS2F is essential for sexual development and engaged in an autoregulatory feed-back loop.

A multicentre randomized controlled trial on trans-generational attention deficit/hyperactivity disorder (ADHD) in mothers and children (AIMAC): an exploratory analysis of predictors and moderators of treatment outcome.

OBJECTIVE: We examined predictors and moderators of treatment outcome in mothers and children diagnosed with ADHD in a large multicentre RCT. METHOD: In total, 144 mother-child dyads with ADHD were randomly assigned to either a maternal ADHD treatment (group psychotherapy and open methylphenidate medication, TG) or to a control treatment (individual counselling without psycho- or pharmacotherapy, CG). After maternal ADHD treatment, parent-child training (PCT) for all mother-child dyads was added. The final analysis set was based on 123 dyads with completed primary outcome assessments (TG: n = 67, CG: n = 56). The primary outcome was the change in each child's externalizing symptoms. Multiple linear regression analyses were performed. RESULTS: The severity of the child's externalizing problem behaviour in the family at baseline predicted more externalizing symptoms in the child after PCT, independent of maternal treatment. When mothers had a comorbid depression, TG children showed more externalizing symptoms after PCT than CG children of depressive mothers. No differences between the treatment arms were seen in the mothers without comorbid depression. CONCLUSIONS: Severely impaired mothers with ADHD and depressive disorder are likely to need additional disorder-specific treatment for their comorbid psychiatric disorders to effectively transfer the contents of the PCT to the home situation (CCTISRCTN73911400).

EUREC4A: A Field Campaign to Elucidate the Couplings Between Clouds, Convection and Circulation.

Trade-wind cumuli constitute the cloud type with the highest frequency of occurrence on Earth, and it has been shown that their sensitivity to changing environmental conditions will critically influence the magnitude and pace of future global warming. Research over the last decade has pointed out the importance of the interplay between clouds, convection and circulation in controling this sensitivity. Numerical models represent this interplay in diverse ways, which translates into different responses of trade-cumuli to climate perturbations. Climate models predict that the area covered by shallow cumuli at cloud base is very sensitive to changes in environmental conditions, while process models suggest the opposite. To understand and resolve this contradiction, we propose to organize a field campaign aimed at quantifying the physical properties of trade-cumuli (e.g., cloud fraction and water content) as a function of the large-scale environment. Beyond a better understanding of clouds-circulation coupling processes, the campaign will provide a reference data set that may be used as a benchmark for advancing the modelling and the satellite remote sensing of clouds and circulation. It will also be an opportunity for complementary investigations such as evaluating model convective parameterizations or studying the role of ocean mesoscale eddies in air-sea interactions and convective organization.

A Class 1 Histone Deacetylase with Potential as an Antifungal Target.

Histone deacetylases (HDACs) remove acetyl moieties from lysine residues at histone tails and nuclear regulatory proteins and thus significantly impact chromatin remodeling and transcriptional regulation in eukaryotes. In recent years, HDACs of filamentous fungi were found to be decisive regulators of genes involved in pathogenicity and the production of important fungal metabolites such as antibiotics and toxins. Here we present proof that one of these enzymes, the class 1 type HDAC RpdA, is of vital importance for the opportunistic human pathogen Aspergillus fumigatus Recombinant expression of inactivated RpdA shows that loss of catalytic activity is responsible for the lethal phenotype of Aspergillus RpdA null mutants. Furthermore, we demonstrate that a fungus-specific C-terminal region of only a few acidic amino acids is required for both the nuclear localization and catalytic activity of the enzyme in the model organism Aspergillus nidulans Since strains with single or multiple deletions of other classical HDACs revealed no or only moderate growth deficiencies, it is highly probable that the significant delay of germination and the growth defects observed in strains growing under the HDAC inhibitor trichostatin A are caused primarily by inhibition of catalytic RpdA activity. Indeed, even at low nanomolar concentrations of the inhibitor, the catalytic activity of purified RpdA is considerably diminished. Considering these results, RpdA with its fungus-specific motif represents a promising target for novel HDAC inhibitors that, in addition to their increasing impact as anticancer drugs, might gain in importance as antifungals against life-threatening invasive infections, apart from or in combination with classical antifungal therapy regimes. IMPORTANCE: This paper reports on the fungal histone deacetylase RpdA and its importance for the viability of the fungal pathogen Aspergillus fumigatus and other filamentous fungi, a finding that is without precedent in other eukaryotic pathogens. Our data clearly indicate that loss of RpdA activity, as well as depletion of the enzyme in the nucleus, results in lethality of the corresponding Aspergillus mutants. Interestingly, both catalytic activity and proper cellular localization depend on the presence of an acidic motif within the C terminus of RpdA-type enzymes of filamentous fungi that is missing from the homologous proteins of yeasts and higher eukaryotes. The pivotal role, together with the fungus-specific features, turns RpdA into a promising antifungal target of histone deacetylase inhibitors, a class of molecules that is successfully used for the treatment of certain types of cancer. Indeed, some of these inhibitors significantly delay the germination and growth of different filamentous fungi via inhibition of RpdA. Upcoming analyses of clinically approved and novel inhibitors will elucidate their therapeutic potential as new agents for the therapy of invasive fungal infections-an interesting aspect in light of the rising resistance of fungal pathogens to conventional therapies.

Sex- and Subtype-Related Differences in the Comorbidity of Adult ADHDs.

OBJECTIVE: Comorbidity in adult ADHD (aADHD) has been investigated in a large number of studies using varying research approaches with divergent results. In contrast, there is limited information about sex- or subtype-related differences from studies with small sample size. METHOD: A large sample of 910 individuals (458 males, 452 females) affected with aADHD was recruited at a tertiary referral center. All probands underwent a four-step procedure for diagnosing aADHD, including the Structured Clinical Interview of Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) Axis I disorders to assess comorbidity. This study will provide additional information regarding the co-morbidity of Axis I disorders in the currently largest clinical referral sample. However, the main objective of this study is to gain information about sex- or subtype-related differences. RESULTS: Affected females show higher rates of mood (61% vs. 49%), anxiety (32% vs. 22%), and eating disorders (16% vs. 1%) than affected males, while substance use disorders were more frequent in affected males (45% vs. 29%), which mirrors sex differences in prevalence in the general population. There were hardly any relevant differences in comorbidities between subtypes, with the exception of the inattentive subtype having an especially low prevalence of panic disorder. Comorbidity in general and substance use disorders in particular, but not sex or subtype, were highly predictive of lower psychosocial status. CONCLUSION: Sex-related differences in the comorbidity of aADHD are more pronounced than subtype-related differences.

Effects of Group Psychotherapy, Individual Counseling, Methylphenidate, and Placebo in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.

IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high prevalence in adulthood. There is a recognized need to assess the efficacy of psychotherapy in adult ADHD. OBJECTIVE: To evaluate the efficacy of cognitive behavioral group psychotherapy (GPT) compared with individual clinical management (CM) and that of methylphenidate hydrochloride compared with placebo. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, randomized clinical trial of 18- to 58-year-old outpatients with ADHD from 7 German study centers. Patients were recruited between January 2007 and August 2010, treatment was finalized in August 2011, and final follow-up assessments occurred in March 2013. INTERVENTIONS: Sessions of GPT and CM were held weekly for the first 12 weeks and monthly thereafter (9 months). Patients received either methylphenidate or placebo for 1 year. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in the ADHD Index of the Conners Adult ADHD Rating Scale from baseline to the end of the 3-month intensive treatment (blinded observer ratings). Secondary outcomes included ADHD ratings after 1 year, blinded observer ratings using the Clinical Global Impression Scale, and self-ratings of depression. RESULTS: Among 1480 prescreened patients, 518 were assessed for eligibility, 433 were centrally randomized, and 419 were analyzed as randomized. After 3 months, the ADHD Index all-group baseline mean of 20.6 improved to adjusted means of 17.6 for GPT and 16.5 for CM, with no significant difference between groups. Methylphenidate (adjusted mean, 16.2) was superior to placebo (adjusted mean, 17.9) (difference, -1.7; 97.5% CI, -3.0 to -0.4; P = .003). After 1 year, treatment effects remained essentially stable. Descriptive analyses showed that methylphenidate was superior to placebo in patients assigned to GPT (difference, -1.7; 95% CI, -3.2 to -0.1; P = .04) or CM (difference, -1.7; 95% CI, -3.3 to -0.2; P = .03). Regarding depression, no significant differences were found. In contrast, GPT was superior to CM for all visits in the Clinical Global Impression global assessment of effectiveness. CONCLUSION AND RELEVANCE: Highly structured group intervention did not outperform individual CM with regard to the primary outcome. Psychological interventions resulted in better outcomes during a 1-year period when combined with methylphenidate as compared with placebo. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54096201.

Does intensive multimodal treatment for maternal ADHD improve the efficacy of parent training for children with ADHD? A randomized controlled multicenter trial.

BACKGROUND: This is the first randomized controlled multicenter trial to evaluate the effect of two treatments of maternal attention-deficit hyperactivity disorder (ADHD) on response to parent-child training targeting children's external psychopathology. METHODS: Mother-child dyads (n = 144; ADHD according to DSM-IV; children: 73.5% males, mean age 9.4 years) from five specialized university outpatient units in Germany were centrally randomized to multimodal maternal ADHD treatment [group psychotherapy plus open methylphenidate medication; treatment group (TG): n = 77] or to clinical management [supportive counseling without psychotherapy or psychopharmacotherapy; control group (CG): n = 67]. After 12 weeks, the maternal ADHD treatment was supplemented by individual parent-child training for all dyads. The primary outcome was a change in the children's externalizing symptom scores (investigator blinded to the treatment assignment) from baseline to the end of the parent-child training 6 months later. Maintenance therapy continued for another 6 months. An intention-to-treat analysis was performed within a linear regression model, controlling for baseline and center after multiple imputations of missing values. RESULTS: Exactly, 206 dyads were assessed for eligibility, 144 were randomized, and 143 were analyzed (TG: n = 77; CG: n = 66). After 6 months, no significant between-group differences were found in change scores for children's externalizing symptoms (adjusted mean TG-mean CG=1.1, 95% confidence interval -0.5-2.7; p = .1854), although maternal psychopathology improved more in the TG. Children's externalizing symptom scores improved from a mean of 14.8 at baseline to 11.4 (TG) and 10.3 (CG) after 6 months and to 10.8 (TG) and 10.1 (CG) after 1 year. No severe harms related to study treatments were found, but adverse events were more frequent in TG mothers than in CG mothers. CONCLUSIONS: The response in children's externalizing psychopathology did not differ between maternal treatment groups. However, multimodal treatment was associated with more improvement in maternal ADHD. Child and maternal treatment gains were stable (CCT-ISRCTN73911400).

A randomized controlled multicenter trial on the multimodal treatment of adult attention-deficit hyperactivity disorder: enrollment and characteristics of the study sample.

Adult ADHD is a frequent psychiatric disorder affecting relevant aspects of an individual's life. The aim of our study group was to carry out the first randomized controlled multicenter study to evaluate the effects of psychotherapy compared to clinical management in combination with psychopharmacological treatment with methylphenidate (MPH) or placebo (Plac) in a factorial four-arm design. Here, we present the enrollment procedure and description of adult ADHD patients recruited for the trial. Four hundred and thirty-three adult patients with ADHD were randomized at seven study sites in Germany to four treatment conditions: manualized dialectical-behavioral-therapy-based group psychotherapy (GPT) plus MPH or Plac, or clinical management (CM) including supportive counseling plus MPH or Plac with weekly sessions in the first 12 weeks and monthly sessions thereafter. Assessment for eligibility included standardized scales and instruments. After prescreening of 1,480 patients, 518 were evaluated for trial participation and 433 were randomized. The main reasons for prescreening failure were lack of interest in participating (n = 205), difficulties in meeting the time and effort requirements for participation (n = 186), and contraindications for psychopharmacological treatment with MPH (n = 194). The full analysis set (FAS) comprised 419 adult ADHD patients (mean age 35.2 years, males/females 1:1). Fifty-seven percent of the patients suffered from the combined ADHD subtype. Prevalence of at least one current or lifetime axis-I comorbidity was 66 %. Axis-II comorbidity rates was 18 % (patients with comorbid borderline and antisocial personality disorders were excluded). Our network was able to recruit an adult ADHD sample essentially comparable to community samples. A selection bias was created by excluding patients unable or unwilling to participate, or who had somatic and psychiatric contraindications for stimulant treatment (Current Controlled Trials ISRCTN54096201, FUNDING: Federal Ministry of Education and Research 01GV0606).

KCNIP4 as a candidate gene for personality disorders and adult ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children with striking persistence into adulthood and a high co-morbidity with other psychiatric disorders, including personality disorders (PD). The 4p15.31 region was shown to be associated with ADHD in several genome wide association studies (GWAS). In the present study we also report association of the 4p15.31 locus with Cluster B and Cluster C PD as identified by a pooled genome-wide association study in 400 individuals suffering from PD. The gene coding for the Kv channel-interacting protein 4 (KCNIP4) is located in this region. KCNIP4 is an interaction partner of presenilin and plays a role in a negative feedback loop in the Wnt/ß-catenin pathway. Thus, we reasoned it to be a promising candidate gene for ADHD as well as for PD. To clarify the role of KCNIP4 in those disorders, we conducted candidate gene based association studies in 594 patients suffering from adult ADHD and 630 PD patients as compared to 974 healthy control individuals. In the adult ADHD sample, six single markers and one haplotype block revealed to be associated with disease (p values from 0.0079 to 0.049). Seven markers within the KCNIP4 gene showed an association with PD (p values from 0.0043 to 0.0437). The results of these studies suggest a role of KCNIP4 in the etiology of ADHD, PD and other co-morbid disorders.

PPP2R2C as a candidate gene of a temperament and character trait-based endophenotype of ADHD.

There are several lines of evidence that the 4p16 region is a candidate locus of both attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder. None of the harbored candidate genes of this region were hitherto shown to be associated with ADHD despite promising functionality. One of the most promising candidate genes in this region is protein phosphatase 2, regulatory subunit B, gamma (PPP2R2C), which, however, thus far has not been assessed for a potential association with ADHD. A total of 513 in- and outpatients affected with adult ADHD and 536 controls as well as 170 nuclear families with 249 children affected with ADHD were genotyped for 35 SNPs, which tagged the promoter region, the 5' and 3' UTRs, and the exons of the PPP2R2C. Two independent samples provided evidence that the major G allele of rs16838844 increases risk toward ADHD. Allelic variations of PPP2R2C rs16838698 on the other hand might be associated with a variety of personality traits. There is evidence that allelic variation in PPP2R2C may be associated with a variety of personality traits and ADHD per se. Nevertheless, as all those conditions are comorbid, PPP2R2C might reflect a common underlying neurobiological risk factor.

Cross-talk towards the response regulator NtrC controlling nitrogen metabolism in Rhodobacter capsulatus.

Rhodobacter capsulatus NtrB/NtrC two-component regulatory system controls expression of genes involved in nitrogen metabolism including urease and nitrogen fixation genes. The ntrY-ntrX genes, which are located immediately downstream of the nifR3-ntrB-ntrC operon, code for a two-component system of unknown function. Transcription of ntrY starts within the ntrC-ntrY intergenic region as shown by primer extension analysis, but maximal transcription requires, in addition, the promoter of the nifR3-ntrB-ntrC operon. While ntrB and ntrY single mutant strains were able to grow with either urea or N2 as sole nitrogen source, a ntrB/ntrY double mutant (like a ntrC-deficient strain) was no longer able to use urea or N2. These findings suggest that the histidine kinases NtrB and NtrY can substitute for each other as phosphodonors towards the response regulator NtrC.

Role of GlnB and GlnK in ammonium control of both nitrogenase systems in the phototrophic bacterium Rhodobacter capsulatus.

In most bacteria, nitrogen metabolism is tightly regulated and P(II) proteins play a pivotal role in the regulatory processes. Rhodobacter capsulatus possesses two genes (glnB and glnK) encoding P(II)-like proteins. The glnB gene forms part of a glnB-glnA operon and the glnK gene is located immediately upstream of amtB, encoding a (methyl-) ammonium transporter. Expression of glnK is activated by NtrC under nitrogen-limiting conditions. The synthesis and activity of the molybdenum and iron nitrogenases of R. capsulatus are regulated by ammonium on at least three levels, including the transcriptional activation of nifA1, nifA2 and anfA by NtrC, the regulation of NifA and AnfA activity by two different NtrC-independent mechanisms, and the post-translational control of the activity of both nitrogenases by reversible ADP-ribosylation of NifH and AnfH as well as by ADP-ribosylation independent switch-off. Mutational analysis revealed that both P(II)-like proteins are involved in the ammonium regulation of the two nitrogenase systems. A mutation in glnB results in the constitutive expression of nifA and anfA. In addition, the post-translational ammonium inhibition of NifA activity is completely abolished in a glnB-glnK double mutant. However, AnfA activity was still suppressed by ammonium in the glnB-glnK double mutant. Furthermore, the P(II)-like proteins are involved in ammonium control of nitrogenase activity via ADP-ribosylation and the switch-off response. Remarkably, in the glnB-glnK double mutant, all three levels of the ammonium regulation of the molybdenum (but not of the alternative) nitrogenase are completely circumvented, resulting in the synthesis of active molybdenum nitrogenase even in the presence of high concentrations of ammonium.

Yeast two-hybrid studies on interaction of proteins involved in regulation of nitrogen fixation in the phototrophic bacterium Rhodobacter capsulatus.

Rhodobacter capsulatus contains two PII-like proteins, GlnB and GlnK, which play central roles in controlling the synthesis and activity of nitrogenase in response to ammonium availability. Here we used the yeast two-hybrid system to probe interactions between these PII-like proteins and proteins known to be involved in regulating nitrogen fixation. Analysis of defined protein pairs demonstrated the following interactions: GlnB-NtrB, GlnB-NifA1, GlnB-NifA2, GlnB-DraT, GlnK-NifA1, GlnK-NifA2, and GlnK-DraT. These results corroborate earlier genetic data and in addition show that PII-dependent ammonium regulation of nitrogen fixation in R. capsulatus does not require additional proteins, like NifL in Klebsiella pneumoniae. In addition, we found interactions for the protein pairs GlnB-GlnB, GlnB-GlnK, NifA1-NifA1, NifA2-NifA2, and NifA1-NifA2, suggesting that fine tuning of the nitrogen fixation process in R. capsulatus may involve the formation of GlnB-GlnK heterotrimers as well as NifA1-NifA2 heterodimers. In order to identify new proteins that interact with GlnB and GlnK, we constructed an R. capsulatus genomic library for use in yeast two-hybrid studies. Screening of this library identified the ATP-dependent helicase PcrA as a new putative protein that interacts with GlnB and the Ras-like protein Era as a new protein that interacts with GlnK.

Regulation of nitrogen fixation in the phototrophic purple bacterium Rhodobacter capsulatus.

In R. capsulatus synthesis and activity of the molybdenum and the alternative nitrogenase is controlled at three levels by the environmental factors ammonium, molybdenum, light, and oxygen. At the first level, transcription of the nifA1, nifA2, and anfA genes--which encode the transcriptional activators of all other nif and anf genes, respectively--is controlled by the Ntr system in dependence on ammonium availability. Mutations in ginB (coding for the signal transduction protein PII) result in significant expression of nifA and anfA in the presence of ammonium. In contrast to GlnB, the PII-paralogue GlnK is not involved in the Ntr signal transduction mechanism. In addition to ammonium control, transcription of anfA is inhibited by traces of molybdenum via the molybdate-dependent repressor proteins MopA and MopB. At the second level of regulation, activity of NifA1, NifA2, and AnfA is inhibited by ammonium in an NtrC-independent manner. This post-translational ammonium control of NifA activity is partially released in the absence of GlnK, and completely abolished in a glnB/glnK double mutant. In contrast, AnfA activity is still inhibited by ammonium in the glnB/glnK mutant background. At the third level of regulation, both GlnB and GlnK as well as the (methyl)-ammonium transporter AmtB are involved in ammonium control of the DraT/DraG system, which mediates reversible ADP-ribosylation of both nitrogenase reductases (NifH and AnfH) in response to changes in ammonium availability or light intensity. Most remarkably, in a glnB/glnK double mutant ammonium control of the molybdenum (but not of the alternative) nitrogenase is completely relieved, leading to synthesis of active nitrogenase in the presence of high concentrations of ammonium.