Constitutive expression of ftsZ overrides the whi developmental genes to initiate sporulation of Streptomyces coelicolor

The filamentous soil bacteria Streptomyces undergo a highly complex developmental programme. Before streptomycetes commit themselves to sporulation, distinct morphological checkpoints are passed in the aerial hyphae that are subject to multi-level control by the whi sporulation genes. Here we show that whi-independent expression of FtsZ restores sporulation to the early sporulation mutants whiA, whiB, whiG, whiH, whiI and whiJ. Viability, stress resistance and high-resolution electron microscopy underlined that viable spores were formed. However, spores from sporulation-restored whiA and whiG mutants showed defects in DNA segregation/condensation, while spores from the complemented whiB mutant had increased stress sensitivity, perhaps as a result of changes in the spore sheath. In contrast to the whi mutants, normal sporulation of ssgB null mutants—which fail to properly localise FtsZ—could not be restored by enhancing FtsZ protein levels, forming spore-like bodies that lack spore walls. Our data strongly suggest that the whi genes control a decisive event towards sporulation of streptomycetes, namely the correct timing of developmental ftsZ transcription. The biological significance may be to ensure that sporulation-specific cell division will only start once sufficient aerial mycelium biomass has been generated. Our data shed new light on the longstanding question as to how whi genes control sporulation, which has intrigued scientists for four decades

The effects of integrative reminiscence on depressive symptomatology and mastery of older adults.

A quasi-experimental (non-randomized) study was conducted to study the effects of a new intervention The story of your life that combines integrative reminiscence with narrative therapy. The program consists of seven sessions of two hours and one follow-up session after 8 weeks. It is directed at community-dwelling people of 55 years and older with mild to moderate depressive symptoms. After the intervention the participants showed significantly less depressive symptoms and higher mastery, also in comparison with a waiting-list control group. Demographic factors and initial levels of depressive symptomatology and mastery were not found to moderate the effects. The effects were maintained at 3 months after completion of the intervention. Although the new program was positively evaluated by the majority of the participants there is room for improvement. Adaptations should be made, and evaluated in a randomised controlled trial

Nicotinic Acetylcholine Receptor Variants Are Related to Smoking Habits, but Not Directly to COPD

Genome-wide association studies identified single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine receptors (nAChRs) cluster as a risk factor for nicotine dependency and COPD. We investigated whether SNPs in the nAChR cluster are associated with smoking habits and lung function decline, and if these potential associations are independent of each other. The SNPs rs569207, rs1051730 and rs8034191 in the nAChR cluster were analyzed in the Vlagtwedde-Vlaardingen cohort (n = 1,390) that was followed for 25 years. We used GEE and LME models to analyze the associations of the SNPs with quitting or restarting smoking and with the annual FEV1 decline respectively. Individuals homozygote (CC) for rs569207 were more likely to quit smoking (OR (95%CI) = 1.58 (1.05–2.38)) compared to wild-type (TT) individuals. Individuals homozygote (TT) for rs1051730 were less likely to quit smoking (0.64 (0.42; 0.97)) compared to wild-type (CC) individuals. None of the SNPs was significantly associated with the annual FEV1 decline in smokers and ex-smokers. We show that SNPs in the nAChR region are associated with smoking habits such as quitting smoking, but have no significant effect on the annual FEV1 decline in smokers and ex-smokers, suggesting a potential role of these SNPs in COPD development via smoking habits rather than via direct effects on lung function

Altered effector function of peripheral cytotoxic cells in COPD

<p>Abstract</p> <p>Background</p> <p>There is mounting evidence that perforin and granzymes are important mediators in the lung destruction seen in COPD. We investigated the characteristics of the three main perforin and granzyme containing peripheral cells, namely CD8⁺T lymphocytes, natural killer (NK; CD56⁺CD3^-) cells and NKT-like (CD56⁺CD3⁺) cells.</p> <p>Methods</p> <p>Peripheral blood mononuclear cells (PBMCs) were isolated and cell numbers and intracellular granzyme B and perforin were analysed by flow cytometry. Immunomagnetically selected CD8+ T lymphocytes, NK (CD56⁺CD3^-) and NKT-like (CD56⁺CD3⁺) cells were used in an LDH release assay to determine cytotoxicity and cytotoxic mechanisms were investigated by blocking perforin and granzyme B with relevant antibodies.</p> <p>Results</p> <p>The proportion of peripheral blood NKT-like (CD56⁺CD3⁺) cells in smokers with COPD (COPD subjects) was significantly lower (0.6%) than in healthy smokers (smokers) (2.8%, p < 0.001) and non-smoking healthy participants (HNS) (3.3%, p < 0.001). NK (CD56⁺CD3^-) cells from COPD subjects were significantly less cytotoxic than in smokers (16.8% vs 51.9% specific lysis, p < 0.001) as were NKT-like (CD56⁺CD3⁺) cells (16.7% vs 52.4% specific lysis, p < 0.001). Both cell types had lower proportions expressing both perforin and granzyme B. Blocking the action of perforin and granzyme B reduced the cytotoxic activity of NK (CD56⁺CD3^-) and NKT-like (CD56⁺CD3⁺) cells from smokers and HNS.</p> <p>Conclusion</p> <p>In this study, we show that the relative numbers of peripheral blood NK (CD56⁺CD3^-) and NKT-like (CD56⁺CD3⁺) cells in COPD subjects are reduced and that their cytotoxic effector function is defective.</p

Synergids and filiform apparatus in the sexual and apomictic dandelions from section Palustria (Taraxacum, Asteraceae)

An evolutionary trend to reduce “unnecessary costs” associated with the sexual reproduction of their amphimictic ancestors, which may result in greater reproductive success, has been observed among the obligatory apomicts. However, in the case of the female gametophyte, knowledge about this trend in apomicts is not sufficient because most of the ultrastructural studies of the female gametophyte have dealt with amphimictic angiosperms. In this paper, we tested the hypothesis that, in contrast to amphimictic plants, synergids in apomictic embryo sacs do not form a filiform apparatus. We compared the synergid structure in two dandelions from sect. Palustria: the amphimictic diploid Taraxacum tenuifolium and the apomictic tetraploid, male-sterile Taraxacum brandenburgicum. Synergids in both species possessed a filiform apparatus. In T. brandenburgicum, both synergids persisted for a long time without any degeneration, in spite of the presence of an embryo and endosperm. We propose that the persistent synergids in apomicts may play a role in the transport of nutrients to the embryo

Response time variability and response inhibition predict affective problems in adolescent girls, not in boys: the TRAILS study

The present study examines the relationship between neurocognitive functioning and affective problems through adolescence, in a cross-sectional and longitudinal perspective. Baseline response speed, response speed variability, response inhibition, attentional flexibility and working memory were assessed in a cohort of 2,179 adolescents (age 10–12 years) from the TRacking Adolescents’ Individual Lives Survey (TRAILS). Affective problems were measured with the DSM-oriented Affective Problems scale of the Youth Self Report at wave 1 (baseline assessment), wave 2 (after 2.5 years) and wave 3 (after 5 years). Cross-sectionally, baseline response speed, response time variability, response inhibition and working memory were associated with baseline affective problems in girls, but not in boys. Longitudinally, enhanced response time variability predicted affective problems after 2.5 and 5 years in girls, but not in boys. Decreased response inhibition predicted affective problems after 5 years follow-up in girls, and again not in boys. The results are discussed in light of recent insights in gender differences in adolescence and state–trait issues in depression

Overview of data-synthesis in systematic reviews of studies on outcome prediction models

Background: Many prognostic models have been developed. Different types of models, i.e. prognostic factor and outcome prediction studies, serve different purposes, which should be reflected in how the results are summarized in reviews. Therefore we set out to investigate how authors of reviews synthesize and report the results of primary outcome prediction studies. Methods: Outcome prediction reviews published in MEDLINE between October 2005 and March 2011 were eligible and 127 Systematic reviews with the aim to summarize outcome prediction studies written in English were identified for inclusion. Characteristics of the reviews and the primary studies that were included were independently assessed by 2 review authors, using standardized forms. Results: After consensus meetings a total of 50 systematic reviews that met the inclusion criteria were included. The type of primary studies included (prognostic factor or outcome prediction) was unclear in two-thirds of the reviews. A minority of the reviews reported univariable or multivariable point estimates and measures of dispersion from the primary studies. Moreover, the variables considered for outcome prediction model development were often not reported, or were unclear. In most reviews there was no information about model performance. Quantitative analysis was performed in 10 reviews, and 49 reviews assessed the primary studies qualitatively. In both analyses types a range of different methods was used to present the results of the outcome prediction studies. Conclusions: Different methods are applied to synthesize primary study results but quantitative analysis is rarely performed. The description of its objectives and of the primary studies is suboptimal and performance parameters of the outcome prediction models are rarely mentioned. The poor reporting and the wide variety of data synthesis strategies are prone to influence the conclusions of outcome prediction reviews. Therefore, there is much room for improvement in reviews of outcome prediction studies. (aut.ref.

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (TALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy

Prevalence of abnormal Alzheimer’s disease biomarkers in patients with subjective cognitive decline: cross-sectional comparison of three European memory clinic samples

Introduction: Subjective cognitive decline (SCD) in cognitively unimpaired older individuals has been recognized as an early clinical at-risk state for Alzheimer's disease (AD) dementia and as a target population for future dementia prevention trials. Currently, however, SCD is heterogeneously defined across studies, potentially leading to variations in the prevalence of AD pathology. Here, we compared the prevalence and identified common determinants of abnormal AD biomarkers in SCD across three European memory clinics participating in the European initiative on harmonization of SCD in preclinical AD (Euro-SCD). Methods: We included three memory clinic SCD samples with available cerebrospinal fluid (CSF) biomaterial (IDIBAPS, Barcelona, Spain, n = 44; Amsterdam Dementia Cohort (ADC), The Netherlands, n = 50; DELCODE multicenter study, Germany, n = 42). CSF biomarkers (amyloid beta (Aβ)42, tau, and phosphorylated tau (ptau181)) were centrally analyzed in Amsterdam using prespecified cutoffs to define prevalence of pathological biomarker concentrations. We used logistic regression analysis in the combined sample across the three centers to investigate center effects with regard to likelihood of biomarker abnormality while taking potential common predictors (e.g., age, sex, apolipoprotein E (APOE) status, subtle cognitive deficits, depressive symptoms) into account. Results: The prevalence of abnormal Aβ42, but not tau or ptau181, levels was different across centers (64% DELCODE, 57% IDIBAPS, 22% ADC; p < 0.001). Logistic regression analysis revealed that the likelihood of abnormal Aβ42 (and also abnormal tau or ptau181) levels was predicted by age and APOE status. For Aβ42 abnormality, we additionally observed a center effect, indicating between-center heterogeneity not explained by age, APOE, or the other included covariates. Conclusions: While heterogeneous frequency of abnormal Aβ42 was partly explained by between-sample differences in age range and APOE status, the additional observation of center effects indicates between-center heterogeneity that may be attributed to different recruitment procedures. These findings highlight the need for the development of harmonized recruitment protocols for SCD case definition in multinational studies to achieve similar enrichment rates of preclinical AD

The Min System and Nucleoid Occlusion Are Not Required for Identifying the Division Site in Bacillus subtilis but Ensure Its Efficient Utilization

Precise temporal and spatial control of cell division is essential for progeny survival. The current general view is that precise positioning of the division site at midcell in rod-shaped bacteria is a result of the combined action of the Min system and nucleoid (chromosome) occlusion. Both systems prevent assembly of the cytokinetic Z ring at inappropriate places in the cell, restricting Z rings to the correct site at midcell. Here we show that in the bacterium Bacillus subtilis Z rings are positioned precisely at midcell in the complete absence of both these systems, revealing the existence of a mechanism independent of Min and nucleoid occlusion that identifies midcell in this organism. We further show that Z ring assembly at midcell is delayed in the absence of Min and Noc proteins, while at the same time FtsZ accumulates at other potential division sites. This suggests that a major role for Min and Noc is to ensure efficient utilization of the midcell division site by preventing Z ring assembly at potential division sites, including the cell poles. Our data lead us to propose a model in which spatial regulation of division in B. subtilis involves identification of the division site at midcell that requires Min and nucleoid occlusion to ensure efficient Z ring assembly there and only there, at the right time in the cell cycle