Miracle-dz/UniFAR-FTUs huggingface dataset:
DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus

Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. Methods DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses. Results We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus. Conclusions Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.
MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15‐CD2 Isoform

Hereditary hearing loss (HL) is characterized by both allelic and locus genetic heterogeneity. Both recessive and dominant forms of HL may be caused by different mutations in the same deafness gene. In a family with post‐lingual progressive non‐syndromic deafness, whole‐exome sequencing of genomic DNA from five hearing‐impaired relatives revealed a single variant, p.Gly488Glu (rs145970949:G>A) in MYO3A, co‐segregating with HL as an autosomal dominant trait. This amino acid change, predicted to be pathogenic, alters a highly conserved residue in the motor domain of MYO3A. The mutation severely alters the ATPase activity and motility of the protein in vitro, and the mutant protein fails to accumulate in the filopodia tips in COS7 cells. However, the mutant MYO3A was able to reach the tips of organotypic inner ear culture hair cell stereocilia, raising the possibility of a local effect on positioning of the mechanoelectrical transduction (MET) complex at the stereocilia tips. To address this hypothesis, we investigated the interaction of MYO3A with the cytosolic tail of the integral tip‐link protein protocadherin 15 (PCDH15), a core component of MET complex. Interestingly, we uncovered a novel interaction between MYO3A and PCDH15 shedding new light on the function of myosin IIIA at stereocilia tips.
Joint Community and Structural Hole Spanner Detection via Harmonic Modularity

Detecting communities (or modular structures) and structural hole spanners, the nodes bridging different communities in a network, are two essential tasks in the realm of network analytics. Due to the topological nature of communities and structural hole spanners, these two tasks are naturally tangled with each other, while there has been little synergy between them. In this paper, we propose a novel harmonic modularity method to tackle both tasks simultaneously. Specifically, we apply a harmonic function to measure the smoothness of community structure and to obtain the community indicator. We then investigate the sparsity level of the interactions between communities, with particular emphasis on the nodes connecting to multiple communities, to discriminate the indicator of SH spanners and assist the community guidance. Extensive experiments on real-world networks demonstrate that our proposed method outperforms several state-of-the-art methods in the community detection task and also in the SH spanner identification task (even the methods that require the supervised community information). Furthermore, by removing the SH spanners spotted by our method, we show that the quality of other community detection methods can be further improved.
Platelet‐rich fibrin‐based matrices to improve angiogenesis in an in vitro co‐culture model for bone tissue engineering

In the context of prevascularization strategies for tissue‐engineering purposes, co‐culture systems consisting of outgrowth endothelial cells (OECs) and primary osteoblasts (pOBs) have been established as a promising in vitro tool to study regeneration mechanisms and to identify factors that might positively influence repair processes such as wound healing or angiogenesis. The development of autologous injectable platelet‐rich fibrin (PRF), which can be generated from peripheral blood in a minimal invasive procedure, fulfils several requirements for clinically applicable cell‐based tissue‐engineering strategies. During this study, the established co‐culture system of OECs and pOBs was mixed with injectable PRF and was cultivated in vitro for 24 h or 7 days. The aim of this study was to analyse whether PRF might have a positive effect on wound healing processes and angiogenic activation of OECs in the co‐culture with regard to proinflammatory factors, adhesion molecules and proangiogenic growth factor expression. Histological cell detection revealed the formation of lumina and microvessel‐like structures in the PRF/co‐culture complexes after 7 days of complex cultivation. Interestingly, the angiogenic activation of OECs was accompanied by an upregulation of wound healing‐associated factors, as well as by a higher expression of the proangiogenic factor vascular endothelial growth factor, which was evaluated both on the mRNA level as well as on the protein level. Thus, PRF might positively influence wound healing processes, in particular angiogenesis, in the in vitro co‐culture, making autologous PRF‐based matrices a beneficial therapeutic tool for tissue‐engineering purposes by simply profiting from the PRF, which contains blood plasma, platelets and leukocytes.
Specialty Training in Family Medicine in Montenegro – an Evaluation of The Programme By the First Generation of Trainees

Abstract Introduction One of the aims of health care reform in Montenegro is to strengthen primary care. An important step forward is the implementation of specialty training in family medicine (FM). The aim of this article is to evaluate the implementation of specialty training in family medicine in Montenegro, regarding the content, structure and methods, by the first generation of trainees and the coordinator of the training. Methods A questionnaire was sent by mail in July and August 2017 to all 26 eligible trainees who started specialty training in 2013. Twenty-two of the 26 trainees (84.6%) responded. The questionnaire consisted of closed and open-ended questions related to the evaluation of the training. A descriptive quantitative and qualitative analysis with predefined themes and a semi-structured interview with the coordinator were carried out. Results The process of training in FM was assessed positively by both trainees and the coordinator. The positive assessment included that the specialisation course offered modern design through modules and practice, and trainees both improved their existing knowledge and skills and acquired new ones necessary for everyday work. The coordinator emphasised the importance of the introduction of new teaching methods and formative assessment, the important role of mentors, and the involvement of Slovenian colleagues in the teaching process and supervision of the programme. Conclusions The implementation of speciality training in FM in Montenegro was successful. Several assessment methods were used that can be further developed in individual structured feedback, which could stimulate the continual improvement of trainees’ knowledge and competencies.
Modeling and simulation of the electro-chemical behavior of chemically stimulated polyelectrolyte hydrogel layer composites

Polyelectrolyte hydrogels are viscoelastic electroactive polymers which respond to external physical or chemical stimuli by a reversible volume phase transition. Novel fabrication methods allow the creation of hydrogel layer composites in which each layer shows a different sensitivity (e.g. to a different stimulus). This offers new opportunities, for example, in the design of new microsensors, microactuators and microfluidic devices as well as for high-selective membranes and target-specific drug delivery systems. Since only few research groups numerically investigated the transport mechanisms in hydrogel layer composites, a gap remains to describe the movement and transient distribution of ions inside the layer system. In this article, the multifield formulation is adopted to describe the transient distribution of ions in salt-sensitive hydrogel layer composites on the basis of a numerical simulation. For this, the Nernst-Planck and the Poisson equation are solved using one-dimensional finite elements for both anionic-anionic and anionic-cationic gel layer composites under chemical stimulation. Between adjacent gels, an additional interlayer is introduced to account for the physical and chemical bonding region between the gels. Adaptive mesh refinement provides a good resolution close to the interface between the adjacent gel layers. The obtained results are used to predict the osmotic pressure inside the gels and the dependent swelling of the gel layer composite. The excellent agreement of the obtained results with the Donnan equilibrium demonstrates the high potential of the method applied to predict the behavior of hydrogel layer composites.
Air Pollution and Deaths among Elderly Residents of São Paulo, Brazil: An Analysis of Mortality Displacement

Background: Evaluation of short-term mortality displacement is essential to accurately estimate the impact of short-term air pollution exposure on public health. Objectives: We quantified mortality displacement by estimating single-day lag effects and cumulative effects of air pollutants on mortality using distributed lag models. Methods: We performed a daily time series of nonaccidental and cause-specific mortality among elderly residents of São Paulo, Brazil, between 2000 and 2011. Effects of particulate matter smaller than 10 μm (PM10), nitrogen dioxide (NO2) and carbon monoxide (CO) were estimated in Poisson generalized additive models. Single-day lag effects of air pollutant exposure were estimated for 0-, 1- and 2-day lags. Distributed lag models with lags of 0–10, 0–20 and 0–30 days were used to assess mortality displacement and potential cumulative exposure effects. Results: PM10, NO2 and CO were significantly associated with nonaccidental and cause-specific deaths in both single-day lag and cumulative lag models. Cumulative effect estimates for 0–10 days were larger than estimates for single-day lags. Cumulative effect estimates for 0–30 days were essentially zero for nonaccidental and circulatory deaths but remained elevated for respiratory and cancer deaths. Conclusions: We found evidence of mortality displacement within 30 days for nonaccidental and circulatory deaths in elderly residents of São Paulo. We did not find evidence of mortality displacement within 30 days for respiratory or cancer deaths. Citation: Costa AF, Hoek G, Brunekreef B, Ponce de Leon AC. 2017. Air pollution and deaths among elderly residents of São Paulo, Brazil: an analysis of mortality displacement. Environ Health Perspect 125:349–354; http://dx.doi. org/10.1289/EHP98
Reasoning bias, working memory performance and a transdiagnostic phenotype of affective disturbances and psychotic experiences in the general population

Abstract Background The jumping to conclusions (JTC) reasoning bias and decreased working memory performance (WMP) are associated with psychosis, but associations with affective disturbances (i.e. depression, anxiety, mania) remain inconclusive. Recent findings also suggest a transdiagnostic phenotype of co-occurring affective disturbances and psychotic experiences (PEs). This study investigated whether JTC bias and decreased WMP are associated with co-occurring affective disturbances and PEs. Methods Data were derived from the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). Trained interviewers administered the Composite International Diagnostic Interview (CIDI) at three time points in a general population sample (N = 4618). The beads and digit-span task were completed to assess JTC bias and WMP, respectively. CIDI was used to measure affective disturbances and an add-on instrument to measure PEs. Results Compared to individuals with neither affective disturbances nor PEs, the JTC bias was more likely to occur in individuals with co-occurring affective disturbances and PEs [moderate psychosis (1–2 PEs): adjusted relative risk ratio (RRR) 1.17, 95% CI 0.98–1.41; and high psychosis (3 or more PEs or psychosis-related help-seeking behaviour): adjusted RRR 1.57, 95% CI 1.19–2.08], but not with affective disturbances and PEs alone, whereas decreased WMP was more likely in all groups. There was some evidence of a dose–response relationship, as JTC bias and decreased WMP were more likely in individuals with affective disturbances as the level of PEs increased or help-seeking behaviour was reported. Conclusion The findings suggest that JTC bias and decreased WMP may contribute to a transdiagnostic phenotype of co-occurring affective disturbances and PEs.
PCN: Part and Context Information for Pedestrian Detection with CNNs

Pedestrian detection has achieved great improvements in recent years, while complex occlusion handling is still one of the most important problems. To take advantage of the body parts and context information for pedestrian detection, we propose the part and context network (PCN) in this work. PCN specially utilizes two branches which detect the pedestrians through body parts semantic and context information, respectively. In the Part Branch, the semantic information of body parts can communicate with each other via recurrent neural networks. In the Context Branch, we adopt a local competition mechanism for adaptive context scale selection. By combining the outputs of all branches, we develop a strong complementary pedestrian detector with a lower miss rate and better localization accuracy, especially for occlusion pedestrian. Comprehensive evaluations on two challenging pedestrian detection datasets (i.e. Caltech and INRIA) well demonstrated the effectiveness of the proposed PCN.
Spontaneous Chloroplast Mutants Mostly Occur by Replication Slippage and Show a Biased Pattern in the Plastome of Oenothera[OPEN]

Spontaneous chloroplast mutants mostly occur by replication slippage and display a mutation spectrum very different from that in the eukaryotic nucleus and that of bacteria. Spontaneous plastome mutants have been used as a research tool since the beginning of genetics. However, technical restrictions have severely limited their contributions to research in physiology and molecular biology. Here, we used full plastome sequencing to systematically characterize a collection of 51 spontaneous chloroplast mutants in Oenothera (evening primrose). Most mutants carry only a single mutation. Unexpectedly, the vast majority of mutations do not represent single nucleotide polymorphisms but are insertions/deletions originating from DNA replication slippage events. Only very few mutations appear to be caused by imprecise double-strand break repair, nucleotide misincorporation during replication, or incorrect nucleotide excision repair following oxidative damage. U-turn inversions were not detected. Replication slippage is induced at repetitive sequences that can be very small and tend to have high A/T content. Interestingly, the mutations are not distributed randomly in the genome. The underrepresentation of mutations caused by faulty double-strand break repair might explain the high structural conservation of seed plant plastomes throughout evolution. In addition to providing a fully characterized mutant collection for future research on plastid genetics, gene expression, and photosynthesis, our work identified the spectrum of spontaneous mutations in plastids and reveals that this spectrum is very different from that in the nucleus.
Genome Analysis of Endomicrobium proavitum Suggests Loss and Gain of Relevant Functions during the Evolution of Intracellular Symbionts

ABSTRACT Bacterial endosymbionts of eukaryotes show progressive genome erosion, but detailed investigations of the evolutionary processes involved in the transition to an intracellular lifestyle are generally hampered by the lack of extant free-living lineages. Here, we characterize the genome of the recently isolated, free-living Endomicrobium proavitum, the second member of the Elusimicrobia phylum brought into pure culture, and compare it to the closely related “Candidatus Endomicrobium trichonymphae” strain Rs-D17, a previously described but uncultured endosymbiont of termite gut flagellates. A reconstruction of the metabolic pathways of Endomicrobium proavitum matched the fermentation products formed in pure culture and underscored its restriction to glucose as the substrate. However, several pathways present in the free-living strain, e.g., for the uptake and activation of glucose and its subsequent fermentation, ammonium assimilation, and outer membrane biogenesis, were absent or disrupted in the endosymbiont, probably lost during the massive genome rearrangements that occurred during symbiogenesis. While the majority of the genes in strain Rs-D17 have orthologs in Endomicrobium proavitum, the endosymbiont also possesses a number of functions that are absent from the free-living strain and may represent adaptations to the intracellular lifestyle. Phylogenetic analysis revealed that the genes encoding glucose 6-phosphate and amino acid transporters, acetaldehyde/alcohol dehydrogenase, and the pathways of glucuronic acid catabolism and thiamine pyrophosphate biosynthesis were either acquired by horizontal gene transfer or may represent ancestral traits that were lost in the free-living strain. The polyphyletic origin of Endomicrobia in different flagellate hosts makes them excellent models for future studies of convergent and parallel evolution during symbiogenesis. IMPORTANCE The isolation of a free-living relative of intracellular symbionts provides the rare opportunity to identify the evolutionary processes that occur in the course of symbiogenesis. Our study documents that the genome of “Candidatus Endomicrobium trichonymphae,” which represents a clade of endosymbionts that have coevolved with termite gut flagellates for more than 40 million years, is not simply a subset of the genes present in Endomicrobium proavitum, a member of the ancestral, free-living lineage. Rather, comparative genomics revealed that the endosymbionts possess several relevant functions that were either prerequisites for colonization of the intracellular habitat or might have served to compensate for genes losses that occurred during genome erosion. Some gene sets found only in the endosymbiont were apparently acquired by horizontal transfer from other gut bacteria, which suggests that the intracellular bacteria of flagellates are not entirely cut off from gene flow.
Human Cytomegalovirus pTRS1 and pIRS1 Antagonize Protein Kinase R To Facilitate Virus Replication

ABSTRACT Human cytomegalovirus (HCMV) counteracts host defenses that otherwise act to limit viral protein synthesis. One such defense is the antiviral kinase protein kinase R (PKR), which inactivates the eukaryotic initiation factor 2 (eIF2) translation initiation factor upon binding to viral double-stranded RNAs. Previously, the viral TRS1 and IRS1 proteins were found to antagonize the antiviral kinase PKR outside the context of HCMV infection, and the expression of either pTRS1 or pIRS1 was shown to be necessary for HCMV replication. In this study, we found that expression of either pTRS1 or pIRS1 is necessary to prevent PKR activation during HCMV infection and that antagonism of PKR is critical for efficient viral replication. Consistent with a previous study, we observed decreased overall levels of protein synthesis, reduced viral protein expression, and diminished virus replication in the absence of both pTRS1 and pIRS1. In addition, both PKR and eIF2α were phosphorylated during infection when pTRS1 and pIRS1 were absent. We also found that expression of pTRS1 was both necessary and sufficient to prevent stress granule formation in response to eIF2α phosphorylation. Depletion of PKR prevented eIF2α phosphorylation, rescued HCMV replication and protein synthesis, and reversed the accumulation of stress granules in infected cells. Infection with an HCMV mutant lacking the pTRS1 PKR binding domain resulted in PKR activation, suggesting that pTRS1 inhibits PKR through a direct interaction. Together our results show that antagonism of PKR by HCMV pTRS1 and pIRS1 is critical for viral protein expression and efficient HCMV replication. IMPORTANCE To successfully replicate, viruses must counteract host defenses that limit viral protein synthesis. We have identified inhibition of the antiviral kinase PKR by the viral proteins TRS1 and IRS1 and shown that this is a critical step in HCMV replication. Our results suggest that inhibiting pTRS1 and pIRS1 function or restoring PKR activity during infection may be a successful strategy to limit HCMV disease.
Performance, carcass characteristics and gain cost of feedlot cattle fed a high level of concentrate and different feed additives

The objective of this study was to evaluate the effects of feeding cattle with isoprotein and isoenergetic diets, with and without the addition of polyclonal antibody preparation (PAP), yeasts (YST) or monensin sodium (MON) on performance, carcass characteristics and gain cost in feedlot. Ninety-five 20-month old bullocks (323.3±21.8 kg) were distributed in 25 pens. The completely randomized experimental design had a 2 × 2 + 1 factorial arrangement and the treatments were replicated 5 times. There was no effect of MON for DMI throughout the feedlot period; however, MON reduced the dry matter intake (DMI) in g/kg of BW in the first 28 days when compared with the other treatments. The gain cost decreased with MON addition in relation to the other treatments. Inclusion of YST decreased average daily gain (ADG), final body weight, hot carcass weight, carcass weight, gain to feed ratio and DMI in g/kg body weight, worsening feed conversion and increasing the gain cost in the feeding periods. Inclusion of PAP increased ADG and decreased the gain cost, besides improving feed conversion. For MON and PAP, a difference was found for kidney-pelvic fat and kidney-pelvic fat per 100 kg of hot carcass weight. For MON and YST, there was a difference in ADG, feed conversion, gain cost and carcass yield and kidney-pelvic fat per 100 kg of hot carcass. Treatment YST worsened performance in relation to the non-supplemented treatments. Feeding PAP to animals did not influence performance and carcass characteristics of bullocks in feedlot negatively. Thus, PAP shows potential to substitute MON in cattle feeding using isoprotein and isoenergetic diets.