Miracle-dz/UniFAR-FTUs huggingface dataset:
Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis

Significance Tumor suppressor Pbx-regulating protein-1 (Prep1) and myeloid ecotropic viral integration site-1 (Meis1) oncogene are transcriptional regulators, which bind to the same partner, pre–B-cell leukemia homeobox-1 (Pbx1). Meis1 overexpression induces tumorigenesis in Prep1i/i mouse embryonic fibroblasts, which is counteracted by Prep1 reexpression. The mechanism is unique: by binding to Pbx1, Prep1 regulates the stability of Meis1 and Pbx1. Influencing Meis1 stability, Prep1 controls the transcriptional landscape of Meis1 and hence, its tumorigenic activity. We also identify two novel Meis1 binding proteins, Ddx3x and Ddx5 RNA helicases, that are essential for cell proliferation and tumorigenesis, and their interaction with Meis1 is impaired at low Meis1 level. Thus, the level and function of three proteins (Prep1, Meis1, and Pbx1) of the same family are regulated by their stability, which depends on their interaction. Pbx-regulating protein-1 (Prep1) is a tumor suppressor, whereas myeloid ecotropic viral integration site-1 (Meis1) is an oncogene. We show that, to perform these activities in mouse embryonic fibroblasts, both proteins competitively heterodimerize with pre–B-cell leukemia homeobox-1 (Pbx1). Meis1 alone transforms Prep1-deficient fibroblasts, whereas Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can, therefore, alternatively act as an oncogene or tumor suppressor. Prep1 posttranslationally controls the level of Meis1, decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth-promoting DNA binding landscape of Meis1 to the growth-controlling landscape of Prep1. Hence, the key feature of Prep1 tumor-inhibiting activity is the control of Meis1 stability.
5‐HTTLPR moderates the association between interdependence and brain responses to mortality threats

While behavioral research suggests an association between cultural worldview and decreased anxiety of death, the underlying neurobiological mechanisms remain unclear. Using functional MRI, we investigated whether and how the serotonin transporter promoter polymorphism (5‐HTTLPR), which has been associated with mental disorders such as anxiety and depression, moderates the associations between a cultural trait (i.e., interdependence) and self‐report of death anxiety/depression and between interdependence and brain responses to mortality threats. Long/long and short/short allele carriers of the 5‐HTTLPR were scanned using fMRI while they performed a one‐back task on death‐related, death‐unrelated negative, and neutral words. Participants’ interdependence and death anxiety/depression were assessed using questionnaires after scanning. We found that participants who assessed themselves with greater interdependence reported lower death anxiety/depression and showed decreased neural response to death‐related words in emotion‐related brain regions including the anterior cingulate, putamen, and thalamus. However, these results were evident in long/long allele carriers of the 5‐HTTLPR but not in short/short allele carriers who even showed positive associations between interdependence and neural activities in the anterior cingulate, putamen and thalamus in response to death‐related words. Our findings suggest candidate mechanisms for explaining the complex relationship between genotype, cultural traits, and mental/neural responses to mortality threats. Hum Brain Mapp 38:6157–6171, 2017. © 2017 Wiley Periodicals, Inc.
Customizing the Therapeutic Response of Signaling Networks to Promote Antitumor Responses by Drug Combinations

Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potential. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of combination therapies, and design methods to determine drug targets for combination regimens. Based on a joint systems analysis of cellular SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyze the targets of drug combinations. Our method explores mechanisms of sensitizing the SN through a combination of two drugs targeting vertical signaling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to customize the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the down-stream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects together with the capability of drug combinations to suppress resistance mechanisms before they become clinically manifest.
Prevalence of and Risk Factors for Trachoma in Oromia Regional State of Ethiopia: Results of 79 Population-Based Prevalence Surveys Conducted with the Global Trachoma Mapping Project

ABSTRACT Purpose: To complete the baseline trachoma map in Oromia, Ethiopia, by determining prevalences of trichiasis and trachomatous inflammation – follicular (TF) at evaluation unit (EU) level, covering all districts (woredas) without current prevalence data or active control programs, and to identify factors associated with disease. Methods: Using standardized methodologies and training developed for the Global Trachoma Mapping Project, we conducted cross-sectional community-based surveys from December 2012 to July 2014. Results: Teams visited 46,244 households in 2037 clusters from 252 woredas (79 EUs). A total of 127,357 individuals were examined. The overall age- and sex-adjusted prevalence of trichiasis in adults was 0.82% (95% confidence interval, CI, 0.70–0.94%), with 72 EUs covering 240 woredas having trichiasis prevalences above the elimination threshold of 0.2% in those aged ≥15 years. The overall age-adjusted TF prevalence in 1–9-year-olds was 23.4%, with 56 EUs covering 218 woredas shown to need implementation of the A, F and E components of the SAFE strategy (surgery, antibiotics, facial cleanliness and environmental improvement) for 3 years before impact surveys. Younger age, female sex, increased time to the main source of water for face-washing, household use of open defecation, low mean precipitation, low mean annual temperature, and lower altitude, were independently associated with TF in children. The 232 woredas in 64 EUs in which TF prevalence was ≥5% require implementation of the F and E components of the SAFE strategy. Conclusion: Both active trachoma and trichiasis are highly prevalent in much of Oromia, constituting a significant public health problem for the region.
A Dominant-negative Gα Mutant That Traps a Stable Rhodopsin-Gα-GTP-βγ Complex*

Residues comprising the guanine nucleotide-binding sites of the α subunits of heterotrimeric (large) G-proteins (Gα subunits), as well as the Ras-related (small) G-proteins, are highly conserved. This is especially the case for the phosphate-binding loop (P-loop) where both Gα subunits and Ras-related G-proteins have a conserved serine or threonine residue. Substitutions for this residue in Ras and related (small) G-proteins yield nucleotide-depleted, dominant-negative mutants. Here we have examined the consequences of changing the conserved serine residue in the P-loop to asparagine, within a chimeric Gα subunit (designated αT*) that is mainly comprised of the α subunit of the retinal G-protein transducin and a limited region from the α subunit of Gi1. The αT*(S43N) mutant exhibits a significantly higher rate of intrinsic GDP-GTP exchange compared with wild-type αT*, with light-activated rhodopsin (R*) causing only a moderate increase in the kinetics of nucleotide exchange on αT*(S43N). The αT*(S43N) mutant, when bound to either GDP or GTP, was able to significantly slow the rate of R*-catalyzed GDP-GTP exchange on wild-type αT*. Thus, GTP-bound αT*(S43N), as well as the GDP-bound mutant, is capable of forming a stable complex with R*. αT*(S43N) activated the cGMP phosphodiesterase (PDE) with a dose-response similar to wild-type αT*. Activation of the PDE by αT*(S43N) was unaffected if either R* or β1γ1 alone was present, whereas it was inhibited when R* and the β1γ1 subunit were added together. Overall, our studies suggest that the S43N substitution on αT* stabilizes an intermediate on the G-protein activation pathway consisting of an activated G-protein-coupled receptor, a GTP-bound Gα subunit, and the β1γ1 complex.
Effects of Atracurium Added to Local Anesthetics on Akinesia in Peribulbar Block

Background and Objectives Peribulbar anesthesia (PBA) is widely used in cataract surgery, but the onset time of akinesia is not as rapid as with retrobulbar block. The aim of this study was to evaluate whether addition of low-dose atracurium to the local anesthetic mixture has any effects on akinesia in PBA. Methods Sixty adults undergoing cataract surgery were randomly allocated to receive either 8 mL of a lidocaine-bupivacaine mixture, plus 0.5 mL 0.9% NaCl (group I) or 8 mL of the same local anesthetic mixture plus 0.5 mL (5 mg) atracurium (group II). The level of akinesia was graded by a observer unaware of group assignment. The onset time and duration of akinesia were also recorded by an observer, again unaware of group assignment. Results The onset time of complete akinesia in group II was significantly shorter than that in group I (P < .05). In group I, 86% of patients had an akinesia score of 0 (complete akinesia) in the first 10 minutes. The rate of complete akinesia was 93% in group II in the same period. This difference was not significant. The success rate of complete akinesia was 93% in group I and 100% in group II at the end of the measurement interval. None of the group II patients required supplementary block, while 2 patients in group I received additional injections for inadequate akinesia. Conclusion Atracurium added at a dose of 5 mg to a lidocaine-bupivacaine mixture for peribulbar block decreases the onset time of akinesia and provides better surgical conditions without obvious side-effects.
Lineage Structure of the Human Antibody Repertoire in Response to Influenza Vaccination

High-throughput sequencing suggests age-related differences in the changes in the human antibody repertoire after influenza vaccination. Antibodies Act Their Age One of the main advantages of the immune system in fighting infection is its ability to diversify—antibody and T cell receptor genes physically rearrange, creating a repertoire of potential responses that can be called upon and expanded if needed. However, the very diversity of this repertoire is what makes immune responses hard to study. Although we can know how any individual B cell or antibody responds to stimulation, getting the big picture is much more difficult. Adding in another variable, such as time, further complicates things. Now, Jiang et al. use high-throughput long read sequencing to characterize the human antibody response after influenza vaccination. People of age are thought to have altered immune systems compared to younger individuals. However, why exactly how the antibody repertoire changes with age remains unclear. By analyzing more than 5 million antibody heavy chain sequences, the authors were able to compare isotype diversity, lineage structure, and mutational activity in differently aged populations. They found that the elderly have fewer lineages, with reduced diversity, compared with younger subjects; however, the antibodies present before vaccination had higher levels of mutation. These same techniques can be used to study individual-specific immune responses and may aid in optimizing vaccination in the future. The human antibody repertoire is one of the most important defenses against infectious disease, and the development of vaccines has enabled the conferral of targeted protection to specific pathogens. However, there are many challenges to measuring and analyzing the immunoglobulin sequence repertoire, including that each B cell’s genome encodes a distinct antibody sequence, that the antibody repertoire changes over time, and the high similarity between antibody sequences. We have addressed these challenges by using high-throughput long read sequencing to perform immunogenomic characterization of expressed human antibody repertoires in the context of influenza vaccination. Informatic analysis of 5 million antibody heavy chain sequences from healthy individuals allowed us to perform global characterizations of isotype distributions, determine the lineage structure of the repertoire, and measure age- and antigen-related mutational activity. Our analysis of the clonal structure and mutational distribution of individuals’ repertoires shows that elderly subjects have a decreased number of lineages but an increased prevaccination mutation load in their repertoire and that some of these subjects have an oligoclonal character to their repertoire in which the diversity of the lineages is greatly reduced relative to younger subjects. We have thus shown that global analysis of the immune system’s clonal structure provides direct insight into the effects of vaccination and provides a detailed molecular portrait of age-related effects.
A multilevel study of socio-economic inequalities in food choice behaviour and dietary intake among the Dutch population: the GLOBE study

Abstract Objective To examine the influence of individual- and area-level socio-economic characteristics on food choice behaviour and dietary intake. Setting The city of Eindhoven in the south-east Netherlands. Design A total of 1339 men and women aged 25–79 years were sampled from 85 areas (mean number of participants per area = 18.4, range 2–49). Information on socio-economic position (SEP) and diet was collected by structured face-to-face interviews (response rate 80.9%). Individual-level SEP was measured by education and household income, and area-level deprivation was measured using a composite index that included residents' education, occupation and employment status. Diet was measured on the basis of (1) a grocery food index that captured compliance with dietary guidelines, (2) breakfast consumption and (3) intakes of fruit, total fat and saturated fat. Multilevel analyses were performed to examine the independent effects of individual- and area-level socio-economic characteristics on the dietary outcome variables. Results After adjusting for individual-level SEP, few trends or significant effects of area deprivation were found for the dietary outcomes. Significant associations were found between individual-level SEP and food choice, breakfast consumption and fruit intake, with participants from disadvantaged backgrounds being less likely to report food behaviours or nutrient intakes consistent with dietary recommendations. Conclusions The findings suggest that an individual's socio-economic characteristics play a more important role in shaping diet than the socio-economic characteristics of the area in which they live. In this Dutch study, no independent influence of area-level socio-economic characteristics on diet was detected, which contrasts with findings from the USA, the UK and Finland.
Effect of Imatinib Mesylate Combined with Granulocyte Colony-Stimulating Factor on Leukaemic Blast Cells Derived from Advanced-Stage Chronic Myelogenous Leukaemia Patients

Neutropenia is a severe adverse effect that can occur when treating patients with imatinib mesylate for advanced-stage chronic myelogenous leukaemia (CML). Therefore, we evaluated in vitro the combined effect of imatinib and granulocyte colony-stimulating factor (G-CSF) on proliferation and apoptosis of Bcr-Abl-expressing leukaemic cells to infer the safety of G-CSF administration. In KU812 and K562 cell lines, G-CSF neither stimulated their proliferation nor abolished the suppressive effect of imatinib. However, it stimulated the proliferation of blast cells in 2 out of the 5 cases with advanced-stage CML. These in vitro studies appear to provide data for the decision of G-CSF administration in combination with imatinib in the treatment of neutropenic patients with advanced-stage CML.
Gas-filled microbubbles – a novel susceptibility contrast agent for brain and liver MRI

Gas-filled microbubbles have the potential to become a unique intravascular MR contrast agent due to their magnetic susceptibility effect, biocompatibility and localized manipulation via ultrasound cavitation. However, in vivo demonstration of microbubble susceptibility effect is limited so far and microbubble susceptibility effect is relatively weak when compared with other intravascular MR susceptibility contrast agents. In this study, two types of microbubbles, custom-made albumin-coated microbubbles (AMBs) and a commercially available lipid-based clinical ultrasound contrast agent (SonoVue®), were investigated with in vivo dynamic brain and liver MRI in Sprague-Dawley rats at 7 Tesla. Transverse relaxation rate enhancements (ΔR2∗) maps were computed for brain and liver, yielding results similar to those obtained with a common MR blood pool contrast agent. These results indicate that gas-filled microbubbles can serve as an intravascular MR contrast agent at high field. Enhancement of microbubble susceptibility effect by entrapping monocrystalline iron oxide nanoparticles (MIONs) into microbubbles was also investigated at 7 T in vitro. This is the first experimental demonstration of microbubble susceptibility enhancement for MRI application. This study indicates that gas-filled microbubble susceptibility effect can be substantially increased using iron oxides nanoparticles. With such approach, microbubbles can potentially be visualized with higher sensitivity and lower concentrations by MRI. Such capability has the potential to lead to real-time MRI guidance in various microbubble-based drug delivery and therapeutic applications.
An Automated Social Graph De-anonymization Technique

We present a generic and automated approach to re-identifying nodes in anonymized social networks which enables novel anonymization techniques to be quickly evaluated. It uses machine learning (decision forests) to matching pairs of nodes in disparate anonymized sub-graphs. The technique uncovers artefacts and invariants of any black-box anonymization scheme from a small set of examples. Despite a high degree of automation, classification succeeds with significant true positive rates even when small false positive rates are sought. Our evaluation uses publicly available real world datasets to study the performance of our approach against real-world anonymization strategies, namely the schemes used to protect datasets of The Data for Development (D4D) Challenge. We show that the technique is effective even when only small numbers of samples are used for training. Further, since it detects weaknesses in the black-box anonymization scheme it can re-identify nodes in one social network when trained on another.
Social behavior shapes the chimpanzee pan-microbiome

Chimpanzee social activity is associated with diversity in the gut microbiome. Animal sociality facilitates the transmission of pathogenic microorganisms among hosts, but the extent to which sociality enables animals’ beneficial microbial associations is poorly understood. The question is critical because microbial communities, particularly those in the gut, are key regulators of host health. We show evidence that chimpanzee social interactions propagate microbial diversity in the gut microbiome both within and between host generations. Frequent social interaction promotes species richness within individual microbiomes as well as homogeneity among the gut community memberships of different chimpanzees. Sampling successive generations across multiple chimpanzee families suggests that infants inherited gut microorganisms primarily through social transmission. These results indicate that social behavior generates a pan-microbiome, preserving microbial diversity across evolutionary time scales and contributing to the evolution of host species–specific gut microbial communities.
Relationship between Spontaneous Aminoglycoside Resistance in Escherichia coli and a Decrease in Oligopeptide Binding Protein

ABSTRACT Changes in the amount of oligopeptide binding protein (OppA) in spontaneous kanamycin-resistant mutants of Escherichia coliwere investigated. Among 20 colonies obtained from 108cells cultured in the presence of 20 μg of kanamycin/ml, 1 colony had no detectable OppA and 7 colonies were mutants with reduced amounts of OppA. Sensitivity of wild-type cells to kanamycin increased slightly by transformation of the oppA gene, but the sensitivity of the mutants increased greatly by the transformation. A mutant with no OppA was found to be a nonsense mutant of the oppA gene at amino acid position 166. In a mutant having a reduced level of OppA, the reduction was due to the decrease in OppA synthesis at the translational level. These mutants were also resistant to other aminoglycoside antibiotics, including streptomycin, neomycin, and isepamicin. Isepamicin uptake activities decreased greatly in these two kinds of mutants. The results support the proposition that aminoglycoside antibiotics are transported into cells by the oligopeptide transport system, and that transport is an important factor for spontaneous resistance to aminoglycoside antibiotics.