Miracle-dz/UniFAR-FTUs huggingface dataset:
CAK—Cyclin-Dependent Activating Kinase: A Key Kinase in Cell Cycle Control and a Target for Drugs?

The Cyclin-dependent kinase (CDK) Activating Kinase (CAK) is responsible for the activating phosphorylation of CDK1, CDK2, CDK4 and CDK6 and regulation of the cell cycle. The kinase is composed of three subunits: CDK7, Cyclin H and MAT1 (ménage a trois). Together with six other subunits, CAK is also part of the general transcription factor TFIIH where it is involved in promoter clearance and progression of transcription from the pre-initiation to the initiation stage. CAK is required for cell cycle progression, which suggests that CDK7 could be a target for cancer therapy. However its role in transcription and its ubiquitous presence raise sensible concerns about possible toxicity of its inhibitors. The recently determined structure of CDK7 allows the design of inhibitors with differential specificity for the different CDKs. We review the role of CAK in different biological processes and evaluate the biological evidence for CDK7 as a possible pharmacological target.
Medicaid Spending in the 1980s: The Access-Cost Containment Trade-off Revisited

Assesses the trends since 1984 in total Medicaid spending, access to services, and types of services covered, to document the current state of Medicaid in light of recent federal and state legislative and regulatory changes. Also reviews those policy changes to better understand the changing patterns of different covered services and groups. The study is based on detailed state-level Health Care Financing Administration records on Medicaid recipients and expenditures, by service and eligibility group.
Too late to back out? Options for breech presentation management

The decline of vaginal breech delivery (VBD) over the past two decades reflects very real concerns that VBD can unexpectedly go wrong, with the worst imaginable neonatal outcomes.1 In this context, caesarean delivery (CD) is now viewed as a safer option for the neonate; CD is performed for 85% of women with term breech presentation.2 This management paradigm for breech presentation reflects a significant shift during the last century. During the last two decades, planned CD has been considered by some to be superior to VBD for complicated breech presentation.3 Unfortunately, this ‘safer’ option is the reason for almost one-fifth of all primary CDs, despite breech presentation comprising only 4% of term deliveries.2 ,4 Once primary CD is performed for breech presentation, subsequent deliveries are almost always by CD.5 Repeat CD is associated with increased risks for haemorrhage and adherent placentation, and6 maternal morbidity is higher with CD than with uncomplicated vaginal delivery. Therefore a management option that minimises maternal morbidity while ensuring neonatal beneficence, is urgently required. In this commentary, we review the history of obstetric care for breech presentation, and present current management options. Breech presentation is associated with insufficient intrauterine space available for fetal movements, or other exogenous maternal and medical factors.7 Maternal constitutional factors include nulliparity, grand multiparity, contracted pelvis, high maternal age and uterine anomalies including fibroma. Pregnancy complications associated with breech presentation include fetal malformations, fetal growth retardation, hydramnios, oligohydramnios, placenta previa and short umbilical cord.7 ,8 There are different types of breech presentation such as complete, frank, footling or kneeling breech. ### Timeline of breech presentation management Women with term breech presentation in the period 1930–1960 had the option to attempt a VBD, or undergo a CD or external cephalic version (ECV). VBD was associated with a 5% risk …
Role of protons in activation of cardiac sympathetic C‐fibre afferents during ischaemia in cats

1 Chest pain caused by myocardial ischaemia is mediated by cardiac sympathetic afferents. The mechanisms of activation of cardiac afferents during ischaemia remain poorly understood. Increased lactic acid production is associated closely with myocardial ischaemia. The present study examined the role of protons generated during ischaemia in activation of cardiac sympathetic C‐fibre afferents. 2 Single‐unit activity of cardiac afferents innervating both ventricles was recorded from the left sympathetic chain in anaesthetized cats. Epicardial tissue pH was measured within 1‐1.5 mm of the surface by a pH‐sensitive needle electrode. Responses of cardiac afferents to myocardial ischaemia, lactic acid, sodium lactate, acidic phosphate buffer and hypercapnia were determined. 3 Occlusion of the coronary artery for 5 min decreased epicardial tissue pH from 7.35 ± 0.21 to 6.98 ± 0.22 (P < 0.05). Epicardial placement of isotonic neutral phosphate buffer, but not saline, prevented the ischaemia‐induced decrease in epicardial pH. This manoeuvre significantly attenuated the response of 16 afferents to 5 min of ischaemia (1.56 ± 0.23 pre‐treatment vs. 0.67 ± 0.18 impulses s−1). Topical application of 10‐100 μg ml−1 of lactic acid, but not sodium lactate, concentration‐dependently stimulated 18 cardiac afferents. Inhalation with high‐CO2 gas failed to activate 12 separate cardiac afferents. Furthermore, lactic acid stimulated cardiac afferents to a greater extent than acidic phosphate buffer solution, applied at a similar pH to the same afferents. 4 Collectively, this study provides important in vivo evidence that protons contribute to activation/sensitization of cardiac sympathetic C‐fibre afferents during myocardial ischaemia.
Feasibility of centre-based incident reporting in primary healthcare: the SPIEGEL study

Objective To evaluate the feasibility of a locally implemented incident-reporting procedure (IRP) in primary healthcare centres after 1 year. Setting and participants Five primary healthcare centres caring for more than 43 000 patients in The Netherlands. GPs, medical nurses, physiotherapists, pharmacists, pharmacist assistants and trainees reported incidents (a total of 117 employees). Methods An IRP was implemented in which participants were encouraged to report all incidents. In addition, dedicated ‘reporting weeks’ were introduced that emphasised reporting of minor incidents and near misses. In every centre, an IRP committee analysed the reported incidents in order to initiate improvements when necessary. Outcome measures Frequency and nature of reported incidents, number of incidents analysed by the IRP committees and number of improvements implemented. In addition, the authors studied the actual implementation of the IRP and the acceptability as experienced by participants. Results A total of 476 incidents were reported during a 9-month reporting period. Of all incidents, 62% were reported in a reporting week, and most were process-related. Possible harm for patients was none or small in 87% of the reported incidents. IRP committees analysed 84 incidents and found 230 root causes. All participating centres had initiated improvement projects as a result of reported incidents. Most interviewees considered the IRP feasible, but several practical, professional and personal barriers to implementation of the IRP were identified. Conclusion The implementation of a centre-based IRP in primary care is feasible. Reporting weeks enhance the willingness to report.
What is the evidence in humans that DNA methylation changes link events in utero and later life disease?

Development in utero is now recognized as crucial to determining later life disease susceptibility. Whilst mechanisms are poorly understood, there has been considerable interest in the potential role of epigenetic processes in intra‐uterine programming of disease. Epigenetic modifications include various mechanisms that influence chromatin structure and gene expression. Here, we review emerging data from human studies that altered DNA methylation links intra‐uterine events with later life disease. Further research in this field is needed to determine whether altered DNA methylation in target tissues can be used as a biomarker for the early identification of and intervention in individuals most at risk of later life disease.
2 Gastroesophageal Reflux Disease : Molecular Predictors in Neoplastic Progression of Barrett ’ s Esophagus

Barrett’s esophagus (BE) represents a metaplastic change from squamous epithelium to intestinal epithelium as a result of chronic gastroesophagheal reflux. Since the development of esophageal adenocarcinoma (EAC) is not universal among patients with BE, it is important to understand and to gauge the factors that influence risk of progression to dysplasia and cancer. While heartburn symptoms have been reported to be associated with BE (Eisen et al., 1997; Lagergren et al., 1999a), the severity of gastroesophageal reflux symptoms is not a reliable indicator for the presence of BE (Eloubeidi and Provenzale, 2001). There is a vital need to explore factors other than symptoms that not only may elucidate the pathophysiology of BE development but also that may be predictive of progression to EAC. Significant advances have been made along key areas such as cell cycle abnormalities, growth factors, adiposity, and the gut microbiome. This chapter aims to review some of these elements as well as the prognostic value of biomarkers for progression from BE to EAC. The importance of fulfilling the promise that these biomarkers hold is underscored by the notable increase in the risk of progression to cancer from 0.5% per year in non-dysplastic BE, to 13% in the setting of low-grade dysplasia, and to 40% in high-grade dysplasia (Curvers et al., 2010; Wani et al., 2009).
Creating a Culture Where Employees Own Safety

Safety is not something management does to or for employees. Management commitment to safety is necessary, but true safety excellence requires engagement from personnel throughout the organization, especially the hourly employees. Such engagement in safety benefits the employees as well as the organization. In fact, studies recognize that by focusing organizational effort to cultivate a culture of involvement and participation, zero injuries is achievable. However, safety must become a cooperative process where everyone participates to make the workplace safer. Every worker has something meaningful to contribute, and people will contribute if the climate is right.
Construction of Soft-Error-Tolerant FF with Wide Error Pulse Detecting Capability

In the recent high-density and low-power VLSIs, the occurrence of soft errors has become a significant problem. Recently, soft errors frequently occur on not only memory system but also logic circuits. Based on this standpoint, some constructions of soft-error-tolerant FFs were proposed. A conventional FF consists of some master and slave latches and C-elements. In the FF, soft error pulses occurring on combinational parts of logic circuits are corrected as long as the width of the pulses is narrow, that is within a specified width. However, error pulses with wide width are neither detected nor corrected in the FF. This paper presents a construction of soft-error-tolerant FFs by modifying the conventional soft-error-tolerant FF. The proposed FFs have the capability to detect error pulses having wide width as well as the capability to correct those having narrow width. The proposed FFs are also capable of detecting hard errors. The evaluation shows the soft-error-tolerant capability, AC characteristics, area overhead and power consumption of the FFs.
Coactivator recruitment: A new role for PAS domains in transcriptional regulation by the bHLH‐PAS family

Transcriptional regulation is dependent on layers of interactions between transcription factors and coactivators, controlling the specificity, temporal regulation, and extent to which transcriptional programs are executed. A key issue in the field of transcriptional regulation is to identify structural mechanisms by which transcription factors and coactivators build hierarchical protein assemblies. The basic helix‐loop‐helix Per‐ARNT‐Sim domain (bHLH‐PAS) family of transcriptional regulators comprises both transcription factors and coactivators, which have different functions despite conserved domain architecture. Within this family, the tandem PAS domains typically mediate dimerization of the transcription factors, while C‐terminal transactivation domains facilitate the dynamic interplay between transcription factors and coactivators. However, recent studies have shown that the modular PAS domains play an important role in regulating coactivator recruitment and oligomerization status. In this study, we provide a brief overview of the structural and functional studies that have identified a novel protein interaction interface on PAS domains utilized by both transcription factors and coactivators within the bHLH‐PAS family. J. Cell. Physiol. 223:553–557, 2010. © 2010 Wiley‐Liss, Inc.
Electric Mobility: On the Road to Energy Transition: A technical and actor assessment of social costs of electric mobility

Several Dutch municipalities stimulate electric mobility by deploying a charging infrastructure. Electric mobility is however expected to impact the electricity grid, thereby requiring the grid to be reinforced. Costs for network reinforcements are social costs and it is in society’s benefit to limit those costs. Municipalities have no real incentive to limit grid impact in their charging infrastructure deployment strategies. Network operators have the incentives, but have limited means to minimise the impact. System analysis, network impact analysis and institutional analysis are done to come to technical and institutional options to limit the grid impact of electric mobility and deal with the skewed incentive structure. It is concluded that network operators should create a grid impact guideline for charging station deployment which indicates the grid capacity to deal with high power charging stations. This guideline can be used to create a municipal strategic charging station deployment map.
Corporate Reporting Awards and Financial Reporting Quality

Choosing to participate in corporate reporting awards may be an efficient way for companies to signal their earnings quality or other positive reporting qualities such as transparency. This study investigates the link between corporate reporting awards (CRA) and financial reporting quality. We explore whether financial performance and earnings quality (i.e. accrual quality) predict the choice to participate in CRA and whether earnings quality predicts winning versus losing firms. We find that firms with stronger financial performance are more likely to participate in CRA. Further firms with higher earnings quality, who arguably are more likely to transparently report earnings, are significantly more likely to participate in CRA. However, we find no evidence that firms with higher earnings quality are more likely to win an award than other participants. This suggests that the qualitative criteria applied by the judges to distinguish winners from participants are not a substitute for measures of accruals quality and users of reporting award results should not view winning the awards as a reliable signal of earnings quality.
Analysis of -675 4 g/5 G SERPINE1 and C-159T CD14 polymorphisms in house dust mite-allergic asthma patients.

BACKGROUND Experimental studies indicate that endogenous plasminogen activator inhibitor-1 (PAI-1, encoded by the gene SERPINE1) modulates the immune response to lipopolysaccharide (LPS). On the other hand, LPS induces PAI-1 secretion. Activation of individual cells by LPS is facilitated by CD14. The single nucleotide polymorphisms -675 4G/5G in SERPINE1 and C-159T in CD14 are major determinants of PAI-1 and CD14 expression, respectively. OBJECTIVE To evaluate the frequency of the -675 4G/5G SERPINE1 and C-159T CD14 polymorphisms in house dust mite (HDM) allergic asthma patients. METHODS The polymorphisms were evaluated in unrelated inhabitants of northeastern Poland, including 372 HDM-allergic asthmatic patients and 160 healthy nonatopic control subjects using polymerase chain reaction. RESULTS Both the C allele of CD14 and the 4G allele of SERPINE1 were more frequently encountered in HDM-allergic asthmatic patients than in healthy control individuals. When the 5G/5G-TT/CT genotype was considered as a nonrisk genotype, all other genotypes were associated with asthma. The odds ratios ranged from 3.96 (95% confidence interval, 1.56-10.1) for the 5G/5G-CC genotype to 10.7 (95% confidence interval, 5.1-24.9) for the 4G/4G-CC genotype. Bronchial reactivity to histamine and total serum immunoglobulin (Ig) E levels were predominantly associated with the 4G/5G SERPINE1 variants, while bronchial reactivity to Dermatophagoides pteronyssinus and serum concentrations of specific IgE against D pteronyssinus were predominantly associated with the C/T CD14 variants. Patients with 4G/4G-CC genotype had the lowest forced expiratory volume in 1 second and the highest bronchial reactivity. CONCLUSION The SERPINE1 and CD14 polymorphisms studied here are associated with different aspects of bronchial reactivity and IgE response. Our results indicate that PAl-1 and CD14 may interact to affect susceptibility to allergic asthma.
HOW DRIVERS LOCATE UNFAMILIAR ADDRESSES - AN EXPERIMENT IN ROUTE FINDING

DRIVERS' PERFORMANCES IN WAY-FINDING WAS STUDIED BY OBSERVING 20 DRIVERS AS THEY DROVE TO TWO UNFAMILIAR ADDRESSESS, 11 AND 14 MILES FROM A STARTING POINT. THE DISTANCE TRAVELED, SPEED, AND TIME SPENT WERE COMPARED WITH THE PERFORMANCE OF A CONTROL GROUP, IN WHICH THE DRIVERS RECEIVED ON-ROUTE GUIDANCE INFORMATION. THE PERFORMANCE OF THE OBSERVED GROUP WAS NOT EFFICIENT. TO GET TO THE SAME DESTINATION, DRIVERS TRAVELED ALMOST HALF AGAIN AS FAR AS THE CONTROL GROUP, ACHIEVED LESS THAN TWO-THIRDS THE SPEED, AND TOOK MORE THAN TWICE AS LONG TO COMPLETE THEIR TRAVEL. THE EVIDENCE INDICATES THAT MOST TIME IS LOST IN THE AREA OF THE LOCAL ADDRESS. ALMOST ALL DRIVERS ADOPTED THE STRATEGY OF GOING TO THE LOCAL AREA AND ASKING SERVICE ATTENDANTS THERE FOR DETAILED ROUTING INFORMATION. SIX OF THE 20 DRIVERS STARTED OUT WITHOUT OBTAINING ANY ADVANCE INFORMATION AT ALL. /AUTHOR/
Appropriateness of antibiotic prescription for targeted therapy of infections caused by multidrug-resistant bacteria: assessment of the most common improper uses in a tertiary hospital in southern Italy.

A huge proportion of antibiotic therapies for infections caused by multidrug-resistant bacteria (MDR) are inappropriate. In this study, we described the most common causes of inappropriateness of definitive antibiotic regimes in a large university hospital in southern Italy and we evaluated the impact on microbial eradication, length of stay, 30-day readmission and mortality. We retrospectively assessed 45 patients who received a definitive antibiotic therapy after isolation of multidrug-resistant Staphylococcus aureus, Enterococcus spp. , Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. strains between 2014 and 2015. From the literature, we set a series of criteria to retrospectively determine the appropriateness of the therapy. In all, 61% of the prescribed antibiotic regimes were found to be inappropriate, especially due to incorrect drug dosage. It emerged that meropenem was the antibiotic most frequently inappropriately used. In 46% of infections caused by MDR but not extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenems were inappropriately administered. Microbial eradication was achieved in 87% of the appropriate therapy group compared to 31% of the inappropriate therapy group (chi-square=6.750, p<0.027). No statistically significant association was found between inappropriate therapy and the length of stay (chi-square=3.084, p=0.101) and 30-day readmission (p=0.103). Definitive antibiotic therapy in infections caused by multidrug-resistant bacteria in a large university hospital is often inappropriate, especially due to the drug dosing regimen, particularly in the case of meropenem and colistin. This inappropriateness has a significant impact on post-treatment microbial eradication in specimens collected after antibiotic therapy.
Eomesodermin promotes interferon‐γ expression and binds to multiple conserved noncoding sequences across the Ifng locus in mouse thymoma cell lines

The T‐box transcription factors T‐bet and eomesodermin (Eomes) have been shown to regulate the lineage‐specific expression of interferon‐γ (IFN‐γ). However, in contrast to T‐bet, the role of Eomes in the expression of IFN‐γ remains unclear. In this study, we investigated the Eomes‐dependent expression of IFN‐γ in the mouse thymoma BW5147 and EL4 cells, which do not express T‐bet or Eomes. The ectopic expression of Eomes induced BW5147 and EL4 cells to produce IFN‐γ in response to phorbol 12‐myristate 13‐acetate (PMA) and ionomycin (IM). In BW5147 cells, Eomes augmented luciferase activity driven by the Ifng promoter encoding from –2500 to +113 bp; however, it was not increased by a stimulation with PMA and IM. A chromatin immunoprecipitation assay showed that Eomes bound to the Ifng promoter and conserved noncoding sequence (CNS) –22 kb across the Ifng locus with high efficacy in BW5147 cells. Moreover, Eomes increased permissive histone modifications in the Ifng promoter and multiple CNSs. The stimulation with PMA and IM greatly augmented Eomes binding to CNS–54, CNS–34, CNS+19 and CNS+30, which was inhibited by FK506. These results indicated that Eomes bound to the Ifng promoter and multiple CNSs in stimulation‐dependent and stimulation‐independent manners.
Changes in joint position sense after surgically treated chronic lateral ankle instability

Background: A search of the literature shows that the effect of surgery on ankle proprioception has been hardly investigated. Objective: To examine the effect of anatomical reconstruction of the anterolateral capsuloligamentous complex on ankle joint position sense. Methods: A prospective study using the “slope box” test. Ten consecutive patients were included in the study, and 10 healthy athletes represented the control group. Results: Similar test-retest reliability rates (overall reliability 0.92; p = 0.0013) were obtained to those of the original designers of the method. There were no significant differences with respect to side dominance (p = 0.9216). Investigation of the characteristics of mean absolute estimate errors showed that the controls tested became error prone in the range of slope altitudes 7.5–25° in every direction, compared with the range 0–5° (range of p values 0.00003–0.00072). The results of the intervention group showed that, for the two main directions of interest (anterior and lateral), preoperative differences in mean absolute estimate errors between injured (anterior 3.91 (2.81)°; lateral 4.06 (2.85)°) and healthy (anterior 2.94 (2.21)°, lateral 3.19 (2.64)°) sides (anterior, p = 0.0124; lateral, p = 0.0250) had disappeared (postoperative differences: anterior, p = 0.6906; lateral, p = 0.4491). The afflicted ankle had improved significantly after surgery in both important directions (anterior, p<0.0001; lateral, p = 0.0023). Conclusions: The study shows that differences in joint position sense between healthy and injured ankles disappeared as the result of surgery. Preoperative data show that proprioceptive malfunction is a cause of functional instability. If treatment is by means of surgery, the retensioning of the original anterolateral structures is inevitable, even if other grafting or surgical techniques are used.
The contracting organization : a strategic guide to outsourcing

PART I: ORGANIZATIONS AND MARKETS 1. Why make when you can buy? 2. The shifting boundaries of organizations PART II: BENEFITS AND COSTS 3. The benefits of contracting 4. The costs of contracting PART III: CONTRACTING STRATEGIES 5. Specialization 6. Value capture 7. Control and flexibility 8. Organizational change PART IV: STRUCTURAL CHANGE 9. Public sector contracting 10. Contracting and the service economy 11. The future of contracting 12. Conclusions Glossary 100 key business concepts associated with contracting, outsourcing, and strategy