Miracle-dz/UniFAR-FTUs huggingface dataset:
The emerging functions of the p53-miRNA network in stem cell biology

The p53 pathway plays an essential role in tumor suppression, regulating multiple cellular processes coordinately to maintain genome integrity in both somatic cells and stem cells. Despite decades of research dedicated to p53 function in differentiated somatic cells, we are just starting to understand the complexity of the p53 pathway in the biology of pluripotent stem cells and tissue stem cells. Recent studies have demonstrated that p53 suppresses proliferation, promotes differentiation of embryonic stem (ES) cells and constitutes an important barrier to somatic reprogramming. In addition, emerging evidence reveals the role of the p53 network in the self-renewal, proliferation and genomic integrity of adult stem cells. Interestingly, non-coding RNAs, and microRNAs in particular, are integral components of the p53 network, regulating multiple p53-controlled biological processes to modulate the self-renewal and differentiation potential of a variety of stem cells. Thus, elucidation of the p53-miRNA axis in stem cell biology may generate profound insights into the mechanistic overlap between malignant transformation and stem cell biology.
Importance of HCV genotype 1 subtypes for drug resistance and response to therapy

The treatment for patients infected with hepatitis C virus (HCV) genotype 1 has undergone major changes with the availability of direct‐acting antivirals. Triple therapy, containing telaprevir or boceprevir, first‐wave NS3 protease inhibitors, in combination with peginterferon and ribavirin, improved rates of sustained virologic response compared with peginterferon and ribavirin alone in patients with HCV genotype 1. However, the development of drug‐resistant variants is a concern. In patients treated with telaprevir or boceprevir, different patterns of resistance are observed for the two major HCV genotype 1 subtypes, 1a and 1b. Genotype 1b is associated with a lower rate of resistant variant selection and better response to triple therapy compared with genotype 1a. Similar subtype‐specific patterns have been observed for investigational direct‐acting antivirals, including second‐wave NS3 protease inhibitors, NS5A inhibitors and non‐nucleoside NS5B inhibitors. This review explores resistance to approved and investigational direct‐acting antivirals for the treatment of HCV, focusing on the differences between genotype 1a and genotype 1b. Finally, given the importance of HCV genotype 1 subtype on resistance and treatment outcomes, clinicians must also be aware of the tests currently available for genotype subtyping and their limitations.
Predicting the substrate specificity of a glycosyltransferase implicated in the production of phenolic volatiles in tomato fruit

The volatile compounds that constitute the fruit aroma of ripe tomato (Solanum lycopersicum) are often sequestered in glycosylated form. A homology‐based screen was used to identify the gene SlUGT5, which is a member of UDP‐glycosyltransferase 72 family and shows specificity towards a range of substrates, including flavonoid, flavanols, hydroquinone, xenobiotics and chlorinated pollutants. SlUGT5 was shown to be expressed primarily in ripening fruit and flowers, and mapped to chromosome I in a region containing a QTL that affected the content of guaiacol and eugenol in tomato crosses. Recombinant SlUGT5 protein demonstrated significant activity towards guaiacol and eugenol, as well as benzyl alcohol and methyl salicylate; however, the highest in vitro activity and affinity was shown for hydroquinone and salicyl alcohol. NMR analysis identified isosalicin as the only product of salicyl alcohol glycosylation. Protein modelling and substrate docking analysis were used to assess the basis for the substrate specificity of SlUGT5. The analysis correctly predicted the interactions with SlUGT5 substrates, and also indicated that increased hydrogen bonding, due to the presence of a second hydrophilic group in methyl salicylate, guaiacol and hydroquinone, appeared to more favourably anchor these acceptors within the glycosylation site, leading to increased stability, higher activities and higher substrate affinities.
Die Relevanz von Multisektor-Partnerschaften für den Privatsektor und Partnerschaftserfahrungen bei Holcim

Einfuhrung Eine der wichtigsten Botschaften vom Weltgipfel fur nachhaltige Entwicklung im September 2002 in Johannesburg war, dass die Welt mehr Zusammenarbeit zwischen verschiedenen Stakeholders (Anspruchsgruppen) brauche, um nachhaltige Entwicklung zu erreichen. Besonders seit jenem Zeitpunkt sind Partnerschaften fur diverse Gruppen zu einem Modewort geworden, unabhangig davon, ob es sich dabei um eine Partnerschaft zwischen mehreren Sektoren (cross-sector partnership), zwischen den drei Ha.
Tooth loss, periodontal disease, and cognitive decline in the Atherosclerosis Risk in Communities (ARIC) study.

OBJECTIVE The purpose of this prospective study was to investigate whether poor oral health predicted 8-year cognitive function change in predominantly late middle adults in the Atherosclerosis Risk in Communities (ARIC) study. METHODS Participants included a subset of ARIC participants aged 52-75 years at 1996-1998 from two study sites: Forsyth County NC and Jackson MS. All subjects completed cognitive function assessments both in 1996-1998 and 2004-2006, and the same subjects received a dental examination at the initial visit. Cognitive assessment consisted of delayed word recall (DWR), digit symbol substitution (DSS), and word fluency (WF) tests. In the analysis, cognitive function for 911 dentally screened participants was evaluated, and 558 of 785 dentate participants received comprehensive oral examinations, including periodontal probing. Measures of oral health included dental status, number of teeth, and periodontal disease classified by the biofilm-gingival interface (BGI) index. The generalized estimating equations (GEE) method was used to analyze repeated measures of cognitive scores with adjustment for socio-demographic characteristics and cardiovascular risk factors. RESULTS Of 911 study participants, 13.8% were edentulous. About 13% of dentally examined participants had periodontal pockets (≥ 4 mm) with severe bleeding. At the follow-up visit, DWR and WF scores were lower in edentulous compared to dentate people, whereas other oral health measures were not associated with cognitive function. Mean values declined over time for all three cognitive measures, although poor oral health conditions were not associated with greater degree of decline in cognitive function. CONCLUSIONS In these late middle-aged adults, complete tooth loss was significantly associated with lower cognitive performance. However, neither edentulism, number of teeth, nor periodontal disease predicted greater subsequent cognitive decline.
Object detection and tracking using statistical and stochastic techniques

This paper proposes a multilevel structure for object detection and tracking in simple and complex environments. The foreground object is obtained using self-adaptive Gaussian Mixture Model (GMM) for dealing with the illumination changes, repetitive motion of the targets and clutters in the scenario. To obtain the robust and flexible target tracking, synergizing combinations of the two random modeling techniques are used. One is the Pseudo-2D Hidden Markov Models (P2DHMMs) for modeling the outline of the object and detects the human. The other is the Kalman Filter which uses the P2DHMM output to track the detected human.
Law, Politics and the Rise and Fall of German Stock Market Development, 1870-1938

Law and politics had a significant impact on stock market development in Germany between 1870 and the beginning of World War II. IPOs can be a bellwether for stock market development and nearly 1100 were carried out on the Berlin Stock Exchange during this period. Regulatory changes occurring in the 1880s and 1890s contributed to a very high survival rate among those companies going public. The IPO market retained its vibrancy through the 1920s notwithstanding an infamous hyperinflation episode. Collapse followed, however, in the 1930s, at least partly due to regulatory changes inimical to the publicly quoted firm brought about by the ideological shifts under Nazi rule.
Type IV prepilin peptidase gene of Neisseria gonorrhoeae MS11: presence of a related gene in other piliated and nonpiliated Neisseria strains

The assembly of type IV pili in Neisseria gonorrhoeae is a complex process likely to require the products of many genes. One of these is the enzyme prepilin peptidase, which cleaves and then N methylates the precursor pilin subunits prior to their assembly into pili. We have used a PCR amplification strategy to clone the N. gonorrhoeae prepilin peptidase gene, pilDNg. A single copy of the gene is shown to be present in the chromosome. Its product promotes correct cleavage of the gonococcal prepillin in Escherichia coli cells carrying both the prepilin peptidase gene and the pilin structural gene. PilDNg also cleaves prePulG, a type IV pilin-like protein of Klebsiella oxytoca. Moreover, PilDNg complements a mutation in the gene coding for the prepilin peptidase-like protein of K. oxytoca, pulO, partially restoring PulG-PulO-dependent extracellular secretion of the enzyme pullulanase. Finally, we show that genes homologous to pilDNg are present and expressed in a variety of species in the genus Neisseria, including some commensal strains.
Rich-club organization of the newborn human brain

Significance To investigate the organizational principles of human brain development, we analyzed cerebral structural connectivity in the period leading up to the time of normal birth. We found that a “rich club” of interconnected cortical hubs previously reported in adults is present by 30 wk gestation. From mid to late gestation, connections between core hubs and the rest of the brain increased significantly. To determine the influence of environmental factors on network development, we also compared term-born infants to those born prematurely. Alterations in cortical–subcortical connectivity and short-distance connections outside the core network were associated with prematurity. Rich-club organization in the human brain precedes the emergence of complex neurological function, and alterations during this time may impact negatively on subsequent neurodevelopment. Combining diffusion magnetic resonance imaging and network analysis in the adult human brain has identified a set of highly connected cortical hubs that form a “rich club”—a high-cost, high-capacity backbone thought to enable efficient network communication. Rich-club architecture appears to be a persistent feature of the mature mammalian brain, but it is not known when this structure emerges during human development. In this longitudinal study we chart the emergence of structural organization in mid to late gestation. We demonstrate that a rich club of interconnected cortical hubs is already present by 30 wk gestation. Subsequently, until the time of normal birth, the principal development is a proliferation of connections between core hubs and the rest of the brain. We also consider the impact of environmental factors on early network development, and compare term-born neonates to preterm infants at term-equivalent age. Though rich-club organization remains intact following premature birth, we reveal significant disruptions in both in cortical–subcortical connectivity and short-distance corticocortical connections. Rich club organization is present well before the normal time of birth and may provide the fundamental structural architecture for the subsequent emergence of complex neurological functions. Premature exposure to the extrauterine environment is associated with altered network architecture and reduced network capacity, which may in part account for the high prevalence of cognitive problems in preterm infants.
Post–Glucose Load Plasma α-Dicarbonyl Concentrations Are Increased in Individuals With Impaired Glucose Metabolism and Type 2 Diabetes: The CODAM Study

OBJECTIVE There is increasing evidence that postprandial glucose excursions play an important role in the development of vascular complications. The underlying mechanism is unknown, but glucose-derived formation of reactive α-dicarbonyl compounds may explain why acute hyperglycemia leads to increased risk for diabetes complications. In the current study, we investigated whether α-dicarbonyls are increased after a glucose load in individuals without or with impaired glucose metabolism (IGM) and type 2 diabetes. RESEARCH DESIGN AND METHODS Cross-sectional, linear analyses were performed in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM [n = 574, 61% men, 60 years old]) study. Individuals with normal glucose metabolism (n = 279), IGM (n = 120), and type 2 diabetes (n = 92) who had complete data on an oral glucose tolerance test (OGTT) and were not on insulin treatment were included in the study population. Plasma α-dicarbonyl (methylglyoxal [MGO], glyoxal [GO], and 3-deoxyglucosone [3-DG]) levels were measured in the fasting state and in samples of the OGTT by ultra-performance liquid chromatography–tandem mass spectrometry. RESULTS The presence of both IGM and type 2 diabetes was significantly associated with higher α-dicarbonyl incremental areas under the curve (iAUCs), as calculated from the OGTT (for IGM, MGO β = 0.190 [95% CI 0.106–0.274], GO β = 0.287 [95% CI 0.172–0.401], and 3-DG β = 0.285 [95% CI 0.221–0.349]; for type 2 diabetes, MGO β = 0.293 [95% CI 0.180–0.405], GO β = 0.536 [95% CI 0.382–0.689], and 3-DG β = 0.542 [95% CI 0.456–0.628]). Adjustment for glucose iAUC attenuated these associations. iAUCs of the α-dicarbonyls correlated highly with glucose iAUC but not with fasting glucose levels or HbA1c. CONCLUSIONS The increased levels of α-dicarbonyls during an OGTT in individuals with IGM and type 2 diabetes underline the potential importance of α-dicarbonyl stress as a candidate to explain the increased risk of diabetes complications in individuals with postprandial hyperglycemia.
Risk of oesophageal cancer in Barrett’s oesophagus and gastro-oesophageal reflux

Background and aims: While patients with Barrett’s oesophagus develop oesophageal adenocarcinoma more frequently than the general population, it has controversially been suggested that gastro-oesophageal reflux (GORD) itself is a more important determinant of risk. In order to assess the validity of this suggestion, we examined the risk of oesophageal cancer in patients with Barrett’s and with GORD compared with the general population in a community based cohort study. Methods: Cohorts of patients with Barrett’s (n = 1677), oesophagitis (n = 6392), and simple reflux (n = 6328), and a reference cohort (n = 13416) were selected from the General Practice Research Database. The last three cohorts were matched to the Barrett’s cohort by general practitioner practice, age, and sex. Cox’s regression analysis was used to calculate relative risks for oesophageal cancer. Standardised incidence ratio methodology was used to estimate the relative risks for oesophageal adenocarcinoma. Results: A total of 137 oesophageal cancers were identified, of which 94 prevalent cases were excluded. The hazard ratios for oesophageal cancer were 10.6 (5.1–22.0), 2.2 (0.9–5.2), and 1.7 (0.7–4.5) in the Barrett’s, oesophagitis, and reflux cohorts compared with the reference cohort, respectively. The corresponding relative risks for oesophageal adenocarcinoma were 29.8 (9.6–106), 4.5 (1.04–19.6), and 3.1 (0.6–14.2). Conclusion: Barrett’s oesophagus increases the risk of oesophageal cancer approximately 10 times and oesophageal adenocarcinoma approximately 30 times compared with the general population. There is only a modestly increased risk of oesophageal cancer in patients with reflux who have no record of Barrett’s oesophagus. Our findings therefore do not support the suggestion that gastro-oesophageal reflux disease itself predisposes to cancer.
Factors that drive variation among gut microbial communities

Surveys of humans from around the world have revealed differences in gut microbiota composition among geographically separated populations. But because humans from the same regions often share common ancestry as well as dietary and cultural habits, most studies have not been able to differentiate among the effects of heritable factors and external factors on the composition of the gut microbiota. Here we discuss how the analysis of gut microbial communities of chimpanzees residing in Gombe Stream National Park has provided an unprecedented opportunity to measure the effects of external factors while controlling for heritable factors. The differences in gut microbiota composition between separated host populations of chimpanzees are due almost entirely to external factors, with the contribution of heritable factors to intraspecific variation in gut microbiota composition being too small to detect. The dominant influence of external factors in generating differences among the gut microbiota of our closest relatives lends promise to the possibility of manipulating the composition of the gut microbiome within human hosts. These results highlight the need for controlled studies that isolate the roles of specific external factors, such as diet, cultural practices and geography, in generating differences in the gut microbiota composition.
High‐throughput concentration–response analysis for omics datasets

Omics‐based methods are increasingly used in current ecotoxicology. Therefore, a large number of observations for various toxic substances and organisms are available and may be used for identifying modes of action, adverse outcome pathways, or novel biomarkers. For these purposes, good statistical analysis of toxicogenomic data is vital. In contrast to established ecotoxicological techniques, concentration–response modeling is rarely used for large datasets. Instead, statistical hypothesis testing is prevalent, which provides only a limited scope for inference. The present study therefore applied automated concentration–response modeling for 3 different ecotoxicotranscriptomic and ecotoxicometabolomic datasets. The modeling process was performed by simultaneously applying 9 different regression models, representing distinct mechanistic, toxicological, and statistical ideas that result in different curve shapes. The best‐fitting models were selected by using Akaike's information criterion. The linear and exponential models represented the best data description for more than 50% of responses. Models generating U‐shaped curves were frequently selected for transcriptomic signals (30%), and sigmoid models were identified as best fit for many metabolomic signals (21%). Thus, selecting the models from an array of different types seems appropriate, because concentration–response functions may vary because of the observed response type, and they also depend on the compound, the organism, and the investigated concentration and exposure duration range. The application of concentration–response models can help to further tap the potential of omics data and is a necessary step for quantitative mixture effect assessment at the molecular response level. Environ Toxicol Chem 2015;34:2167–2180. © 2015 SETAC
Identification of the Membrane-Active Regions of the Severe Acute Respiratory Syndrome Coronavirus Spike Membrane Glycoprotein Using a 16/18-Mer Peptide Scan: Implications for the Viral Fusion Mechanism

ABSTRACT We have identified the membrane-active regions of the severe acute respiratory syndrome coronavirus (SARS CoV) spike glycoprotein by determining the effect on model membrane integrity of a 16/18-mer SARS CoV spike glycoprotein peptide library. By monitoring the effect of this peptide library on membrane leakage in model membranes, we have identified three regions on the SARS CoV spike glycoprotein with membrane-interacting capabilities: region 1, located immediately upstream of heptad repeat 1 (HR1) and suggested to be the fusion peptide; region 2, located between HR1 and HR2, which would be analogous to the loop domain of human immunodeficiency virus type 1; and region 3, which would correspond to the pretransmembrane region. The identification of these membrane-active regions, which are capable of modifying the biophysical properties of phospholipid membranes, supports their direct role in SARS CoV-mediated membrane fusion, as well as facilitating the future development of SARS CoV entry inhibitors.
Enhancement of hemoglobin and F‐cell production by targeting growth inhibition and differentiation of K562 cells with ribonucleotide reductase inhibitors (didox and trimidox) in combination with streptozotocin

Upon appropriate drug treatment, the human erythroleukemic K562 cells have been shown to produce hemoglobin and F‐cells. Fetal hemoglobin (Hb F) inhibits the polymerization events of sickle hemoglobin (Hb S), thereby ameliorating the clinical symptoms of sickle cell disease. Ribonucleotide reductase inhibitors (RRIs) have been shown to inhibit the growth of myeloid leukemia cells leading to the production of Hb F upon differentiation. Of the RRIs currently in use, hydroxyurea is the most effective agent for Hb F induction. We have examined the capacity of two novel RRIs, didox (DI) and trimidox (TRI), in combination with streptozotocin (STZ), to induce hemoglobin and F‐cell production. The K562 cells were cultured with different concentrations of didox‐STZ or trimidox‐STZ at a fixed molar ratio of 3:1 and 1:5 for 96 hr, respectively. At pre‐determined time intervals, aliquots of cells were obtained and total hemoglobin (benzidine positive) levels, number of F‐cells, and Hb F were determined by the differential staining technique, fetal hemoglobin assay kit, and fluorescence cytometry respectively. The effect of combined drug treatment on the growth of K562 cells was examined by isobologram analysis. Our results indicate that a synergistic growth‐inhibitory differentiation effect occurred when didox or trimidox was used in combination with STZ on K562 cells. There was an increase in the number of both benzidine‐positive normoblasts and F‐cells, accompanied by morphologic appearances typical of erythroid maturation. On day 4, the number of benzidine‐positive cells showed a 6–9‐fold increase and the number of F‐cells was between 2.5‐ and 5.7‐fold higher than the respective controls. Based upon these results, treatment with a ribonucleotide reductase inhibitor, such as didox or trimidox, in combination with STZ, might offer an additional promising option in sickle cell disease therapy. Am. J. Hematol. 63:176–183, 2000. © 2000 Wiley‐Liss, Inc.
Role of protein phosphatase 2C from bovine adrenal chromaffin cells in the dephosphorylation of phospho‐serine 40 tyrosine hydroxylase

Tyrosine hydroxylase (TH) is the rate‐limiting enzyme in the synthesis of catecholamines. It is dephosphorylated by protein phosphatase (PP) 2A and PP2C. In this study we used a fixed amount of bacterially expressed rat TH (5 µm), phosphorylated only at serine 40 (pSer40TH), to determine the PP activities against this site that are present in extracts from the bovine adrenal cortex, adrenal medulla, adrenal chromaffin cells and rat striatum. We found that PP2C was the main TH phosphatase activity in extracts from the adrenal medulla and adrenal chromaffin cells. In adrenal cortex extracts PP2C and PP2A activities toward pSer40TH did not differ significantly. PP2A was the main TH phosphatase activity in extracts from rat striatum. Kinetic studies with extracts from adrenal chromaffin cells showed that when higher concentrations of pSer40TH (> 5 µm) were used the activity of PP2C increased more than the activity of PP2A. PP2C was maximally activated by 1.25 mm Mn2+ and by 5 mm Mg2+ but was inhibited by calcium. Our data suggest a more important role for PP2C than was previously suggested in the dephosphorylation of serine 40 on TH.