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Background: Previous magnetic resonance imaging (MRI) research suggests that, prior to the onset of psychosis, high risk youths already exhibit brain abnormalities similar to those present in patients with schizophrenia.
Objectives: The goal of the present study was to describe the functional organization of endogenous activation in young adolescents who report auditory verbal hallucinations (AVH) in view of the “distributed network” hypothesis of psychosis. We recruited 20 young people aged 13–16 years who reported AVHs and 20 healthy controls matched for age, gender and handedness from local schools.
Methods: Each participant underwent a semi-structured clinical interview and a resting state (RS) neuroimaging protocol. We explored functional connectivity (FC) involving three different networks: 1) default mode network (DMN) 2) salience network (SN) and 3) central executive network (CEN). In line with previous findings on the role of the auditory cortex in AVHs as reported by young adolescents, we also investigated FC anomalies involving both the primary and secondary auditory cortices (A1 and A2, respectively).
Further, we explored between-group inter-hemispheric FC differences (laterality) for both A1 and A2. Compared to the healthy control group, the AVH group exhibited FC differences in all three networks investigated. Moreover, FC anomalies were found in a neural network including both A1 and A2. The laterality analysis revealed no between-group, inter-hemispheric differences.
Conclusions: The present study suggests that young adolescents with subclinical psychotic symptoms exhibit functional connectivity anomalies directly and indirectly involving the DMN, SN, CEN and also a neural network including both primary and secondary auditory cortical regions.
Biogenesis of mitochondrial cytochrome c oxidase (COX) is a complex process involving the coordinate expression and assembly of numerous subunits (SU) of dual genetic origin. Moreover, several auxiliary factors are required to recruit and insert the redox-active metal compounds, which in most cases are buried in their protein scaffold deep inside the membrane. Here we used a combination of gel electrophoresis and pull-down assay techniques in conjunction with immunostaining as well as complexome profiling to identify and analyze the composition of assembly intermediates in solubilized membranes of the bacterium Paracoccus denitrificans. Our results show that the central SUI passes through at least three intermediate complexes with distinct subunit and cofactor composition before formation of the holoenzyme and its subsequent integration into supercomplexes. We propose a model for COX biogenesis in which maturation of newly translated COX SUI is initially assisted by CtaG, a chaperone implicated in CuB site metallation, followed by the interaction with the heme chaperone Surf1c to populate the redox-active metal-heme centers in SUI. Only then the remaining smaller subunits are recruited to form the mature enzyme which ultimately associates with respiratory complexes I and III into supercomplexes.
BACKGROUND: The analysis of microarray time series promises a deeper insight into the dynamics of the cellular response following stimulation. A common observation in this type of data is that some genes respond with quick, transient dynamics, while other genes change their expression slowly over time. The existing methods for detecting significant expression dynamics often fail when the expression dynamics show a large heterogeneity. Moreover, these methods often cannot cope with irregular and sparse measurements.
RESULTS: The method proposed here is specifically designed for the analysis of perturbation responses. It combines different scores to capture fast and transient dynamics as well as slow expression changes, and performs well in the presence of low replicate numbers and irregular sampling times. The results are given in the form of tables including links to figures showing the expression dynamics of the respective transcript. These allow to quickly recognise the relevance of detection, to identify possible false positives and to discriminate early and late changes in gene expression. An extension of the method allows the analysis of the expression dynamics of functional groups of genes, providing a quick overview of the cellular response. The performance of this package was tested on microarray data derived from lung cancer cells stimulated with epidermal growth factor (EGF).
CONCLUSION: Here we describe a new, efficient method for the analysis of sparse and heterogeneous time course data with high detection sensitivity and transparency. It is implemented as R package TTCA (transcript time course analysis) and can be installed from the Comprehensive R Archive Network, CRAN. The source code is provided with the Additional file 1.
In situ single particle analysis of ice particle residuals (IPRs) and out-of-cloud aerosol particles was conducted by means of laser ablation mass spectrometry during the intensive INUIT-JFJ/CLACE campaign at the high alpine research station Jungfraujoch (3580 m a.s.l.) in January–February 2013. During the 4-week campaign more than 70 000 out-of-cloud aerosol particles and 595 IPRs were analyzed covering a particle size diameter range from 100 nm to 3 µm. The IPRs were sampled during 273 h while the station was covered by mixed-phase clouds at ambient temperatures between −27 and −6 °C. The identification of particle types is based on laboratory studies of different types of biological, mineral and anthropogenic aerosol particles. The outcome of these laboratory studies was characteristic marker peaks for each investigated particle type. These marker peaks were applied to the field data. In the sampled IPRs we identified a larger number fraction of primary aerosol particles, like soil dust (13 ± 5 %) and minerals (11 ± 5 %), in comparison to out-of-cloud aerosol particles (2.4 ± 0.4 and 0.4 ± 0.1 %, respectively). Additionally, anthropogenic aerosol particles, such as particles from industrial emissions and lead-containing particles, were found to be more abundant in the IPRs than in the out-of-cloud aerosol. In the out-of-cloud aerosol we identified a large fraction of aged particles (31 ± 5 %), including organic material and secondary inorganics, whereas this particle type was much less abundant (2.7 ± 1.3 %) in the IPRs. In a selected subset of the data where a direct comparison between out-of-cloud aerosol particles and IPRs in air masses with similar origin was possible, a pronounced enhancement of biological particles was found in the IPRs.
BACKGROUND: Despite its impact on female health worldwide, no efforts have been made to depict the global architecture of ovarian cancer research and to understand the trends in the related literature. Hence, it was the objective of this study to assess the global scientific performance chronologically, geographically and in regards to economic benchmarks using bibliometric tools and density equalizing map projections.
METHODS: The NewQIS platform was employed to identify all ovarian cancer related articles published in the Web of Science since 1900. The items were analyzed regarding quantitative aspects (e.g. publication date, country of origin) and parameters describing the recognition of the work by the scientific community (e.g. citation rates).
RESULTS: 23,378 articles on ovarian cancer were analyzed. The USA had the highest activity of ovarian cancer research with a total of n = 9312 ovarian cancer-specific publications, followed by the UK (n = 1900), China (n = 1813), Germany (n = 1717) and Japan (n = 1673). Ovarian cancer-specific country h-index also showed a leading position of the USA with an h-index (HI) of 207, followed by the UK (HI = 122), Canada (HI = 99), Italy (HI = 97), Germany (HI = 84), and Japan (HI = 81). In the socio-economic analysis, the USA were ranked first with an average of 175.6 ovarian cancer-related publications per GDP per capita in 1000 US-$, followed by Italy with an index level of 46.85, the UK with 45.48, and Japan with 43.3. Overall, the USA and Western European nations, China and Japan constituted the scientific power players publishing the majority of highly cited ovarian cancer-related articles and dominated international collaborative efforts. African, Asian and South American countries played almost no visible role in the scientific community.
CONCLUSIONS: The quantity and scientific recognition of publications related to ovarian cancer are continuously increasing. The research endeavors in the field are concentrated in high-income countries with no involvement of lower-resource nations. Hence, worldwide collaborative efforts with the aim to exchange epidemiologic data, resources and knowledge have to be strengthened in the future to successfully alleviate the global burden related to ovarian cancer.
It is long known that Kasugamycin inhibits translation of canonical transcripts containing a 5’-UTR with a Shine Dalgarno (SD) motif, but not that of leaderless transcripts. To gain a global overview of the influence of Kasugamycin on translation efficiencies, the changes of the translatome of Escherichia coli induced by a 10 minutes Kasugamycin treatment were quantified. The effect of Kasugamycin differed widely, 102 transcripts were at least twofold more sensitive to Kasugamycin than average, and 137 transcripts were at least twofold more resistant, and there was a more than 100-fold difference between the most resistant and the most sensitive transcript. The 5’-ends of 19 transcripts were determined from treated and untreated cultures, but Kasugamycin resistance did neither correlate with the presence or absence of a SD motif, nor with differences in 5’-UTR lengths or GC content. RNA Structure Logos were generated for the 102 Kasugamycin-sensitive and for the 137 resistant transcripts. For both groups a short Shine Dalgarno (SD) motif was retrieved, but no specific motifs associated with resistance or sensitivity could be found. Notably, this was also true for the region -3 to -1 upstream of the start codon and the presence of an extended SD motif, which had been proposed to result in Kasugamycin resistance. Comparison of the translatome results with the database RegulonDB showed that the transcript with the highest resistance was leaderless, but no further leaderless transcripts were among the resistant transcripts. Unexpectedly, it was found that translational coupling might be a novel feature that is associated with Kasugamycin resistance. Taken together, Kasugamycin has a profound effect on translational efficiencies of E. coli transcripts, but the mechanism of action is different than previously described.
Pulmonary hypertension (PH) is characterized by the increase of the mean pulmonary arterial pressure in the lung circulation. Despite the large number of experimental and clinical studies conducted on pulmonary hypertension, there is no comprehensive work that analyzed the global research activity on PH so far. We retrieved the bibliometric data of the publications on pulmonary hypertension for two periods from the Web of science database. Here, we set the first investigation period from 1900 to 2007 (t1) due to the cited half life of articles and the relating difficulties to interpret the citation parameters. The second evaluation period (t2) covers the time interval from 2008 onwards including the year 2015. The data were analyzed and processed to density-equalizing maps using the NewQIS platform. A total number of 18,986 publications were identified in t1 that come from 85 countries. The US published the highest number of publications (n = 7,290), followed by the UK, Germany, Japan and France. In t2 19,676 items could be found worked out by 130 countries. The raking started just the same with the USA as most publishing nation with 7,127 publications on PH, followed by the UK and Germany. Japan fell back on 6th place, whereas China came into view on the 5th position. Analyzing the average citation rate as a parameter for research quality, Mexico reached the highest value in t1 and Ireland in t2. While, the country specific h-index underlined the leading position of the US research in both evaluation periods again. The average number of international collaboration items was expanding from none in 1978 to 530 items in 2015 with the USA as the country with the highest number of collaboration articles. The present study is the first large scale density-equalizing mapping and scientometric analysis of global PH research activity. Our data draw a sketch of the global research architecture in this field, indicating a need for specific research programs in countries with a lower human development index.
Differentiated neurons can be rapidly acquired, within days, by inducing stem cells to express neurogenic transcription factors. We developed a protocol to maintain long-term cultures of human neurons, called iNGNs, which are obtained by inducing Neurogenin-1 and Neurogenin-2 expression in induced pluripotent stem cells. We followed the functional development of iNGNs over months and they showed many hallmark properties for neuronal maturation, including robust electrical and synaptic activity. Using iNGNs expressing a variant of channelrhodopsin-2, called CatCh, we could control iNGN activity with blue light stimulation. In combination with optogenetic tools, iNGNs offer opportunities for studies that require precise spatial and temporal resolution. iNGNs developed spontaneous network activity, and these networks had excitatory glutamatergic synapses, which we characterized with single-cell synaptic recordings. AMPA glutamatergic receptor activity was especially dominant in postsynaptic recordings, whereas NMDA glutamatergic receptor activity was absent from postsynaptic recordings but present in extrasynaptic recordings. Our results on long-term cultures of iNGNs could help in future studies elucidating mechanisms of human synaptogenesis and neurotransmission, along with the ability to scale-up the size of the cultures.
Background: HCV GT4 accounts for up to 20% of HCV infections worldwide. Simeprevir, given for 12 weeks as part of a 24- or 48-week combination regimen with PR is approved for the treatment of chronic HCV GT4 infection. Primary study objectives were assessment of efficacy and safety of simeprevir plus PR in treatment-naïve patients with HCV GT4 treated for 12 weeks. Primary efficacy outcome was sustained virologic response 12 weeks post-treatment (SVR12). Additional objectives included investigation of potential associations of rapid virologic response and baseline factors with SVR12.
Methods: This multicentre, open-label, single-arm study (NCT01846832) evaluated efficacy and safety of simeprevir plus PR in 67 patients with HCV GT4 infection. Patients were treatment-naïve, aged 18–70 years with METAVIR F0–F2 fibrosis. Patients with early virologic response (HCV RNA <25 IU/mL [detectable/undetectable in IL28B CC patients or undetectable in IL28B CT/TT patients] at Week 2 and undetectable at Weeks 4 and 8) were eligible to stop all treatment at the end of Week 12, otherwise PR therapy was continued to Week 24.
Results: Of 67 patients treated, 34 (51%) qualified for 12-week treatment including all but one patient with IL28B CC genotype (14/15). All patients in the 12-week group had undetectable HCV RNA at end of treatment, and 97% (33/34) achieved SVR12. No new safety signals with simeprevir plus PR were identified. The proportion of patients experiencing Grade 3–4 adverse events was lower in the 12-week group than in the 24-week group.
Conclusions: Our findings on simeprevir plus PR therapy shortened to 12 weeks in patients with HCV GT4 infection with favourable baseline characteristics and displaying early on-treatment virologic response are encouraging. No new safety signals were associated with simeprevir plus PR in this study.
The oncogene B-cell lymphoma 6 (BCL6) is associated with lymphomagenesis. Intriguingly, its expression is increased in preeclamptic placentas. Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity. Preeclamptic placentas are characterized by various defects like deregulated differentiation and impaired fusion of trophoblasts. Its pathogenesis is however not totally understood. We show here that BCL6 is present throughout the cell fusion process in the fusogenic trophoblastic cell line BeWo. Suppression of BCL6 promotes trophoblast fusion, indicated by enhanced levels of fusion-related β-hCG, syncytin 1 and syncytin 2. Increased mRNA levels of these genes could also be observed in primary term cytotrophoblasts depleted of BCL6. Conversely, stable overexpression of BCL6 reduces the fusion capacity of BeWo cells. These data suggest that an accurately regulated expression of BCL6 is important for proper differentiation and successful syncytialization of trophoblasts. While deregulated BCL6 is linked to lymphomagenesis by blocking lymphocyte terminal differentiation, increased BCL6 in the placenta contributes to the development of preeclampsia by impairing trophoblast differentiation and fusion.