Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential effects of nerve growth factor and dexamethasone on herpes simplex virus type 1 oriL- and oriS-dependent DNA replication in PC12 cells

The herpes simplex virus type 1 (HSV-1) genome contains three origins of DNA replication, one copy of oriL and two copies of oriS. Although oriL and oriS are structurally different, they have extensive nucleotide sequence similarity and can substitute for each other to initiate viral DNA replication. A fundamental question that remains to be answered is why the HSV-1 genome contains two types of origin. We have recently identified a novel glucocorticoid response element (GRE) within oriL that is not present in oriS and have shown by gel mobility shift assays that purified glucocorticoid receptor (GR), as well as GR present in cellular extracts, can bind to the GRE in oriL. To determine whether glucocorticoids and the GRE affect the efficiency of oriL-dependent DNA replication, we performed transient DNA replication assays in the presence and absence of dexamethasone (DEX). Because HSV-1 is a neurotropic virus and establishes latency in cells of neural origin, these tests were conducted in PC12 cells, which assume the properties of sympathetic neurons when differentiated with nerve growth factor (NGF). In NGF-differentiated PC12 cells, oriL-dependent DNA replication was enhanced 5-fold by DEX, whereas in undifferentiated cells, DEX enhanced replication approximately 2-fold. Notably, the enhancement of oriL function by DEX was abolished when the GRE was mutated. NGF-induced differentiation alone had no effect. In contrast to oriL, oriS-dependent DNA replication was reduced approximately 5-fold in NGF-differentiated PC12 cells and an additional 4-fold in differentiated cells treated with DEX. In undifferentiated PC12 cells, DEX had only a minor inhibitory effect (approximately 2-fold) on oriS function. Although the cis-acting elements that mediate the NGF- and DEX-specific repression of oriS-dependent DNA replication are unknown, a functional GRE is critical for the DEX-induced enhancement of oriL function in NGF-differentiated PC12 cells. The enhancement of oriL-dependent DNA replication by DEX in differentiated PC12 cells suggests the possibility that glucocorticoids, agents long recognized to enhance reactivation of latent herpesvirus infections, act through the GRE in oriL to stimulate viral DNA replication and reactivation in terminally differentiated neurons in vivo.
Bayesian models for subgroup analysis in clinical trials

Background In a pharmaceutical drug development setting, possible interactions between the treatment and particular baseline clinical or demographic factors are often of interest. However, the subgroup analysis required to investigate such associations remains controversial. Concerns with classical hypothesis testing approaches to the problem include low power, multiple testing, and the possibility of data dredging. Purpose As an alternative to hypothesis testing, the use of shrinkage estimation techniques is investigated in the context of an exploratory post hoc subgroup analysis. A range of models that have been suggested in the literature are reviewed. Building on this, we explore a general modeling strategy, considering various options for shrinkage of effect estimates. This is applied to a case-study, in which evidence was available from seven-phase II–III clinical trials examining a novel therapy, and also to two artificial datasets with the same structure. Methods Emphasis is placed on hierarchical modeling techniques, adopted within a Bayesian framework using freely available software. A range of possible subgroup model structures are applied, each incorporating shrinkage estimation techniques. Results The investigation of the case-study showed little evidence of subgroup effects. Because inferences appeared to be consistent across a range of well-supported models, and model diagnostic checks showed no obvious problems, it seemed this conclusion was robust. It is reassuring that the structured shrinkage techniques appeared to work well in a situation where deeper inspection of the data suggested little evidence of subgroup effects. Limitations The post hoc examination of subgroups should be seen as an exploratory analysis, used to help make better informed decisions regarding potential future studies examining specific subgroups. To a certain extent, the degree of understanding provided by such assessments will be limited by the quality and quantity of available data. Conclusions In light of recent interest by health authorities into the use of subgroup analysis in the context of drug development, it appears that Bayesian approaches involving shrinkage techniques could play an important role in this area. Hopefully, the developments outlined here provide useful methodology for tackling such a problem, in-turn leading to better informed decisions regarding subgroups.
Management of fever in patients with central vein catheters

We have evaluated a standardized prospective system for managing episodes of fever in pediatric patients with indwelling central vein catheters being used primarily for delivery of parenteral nutrients. Over an 18-month period 72 such patients, accounting for 4347 “catheter days,” were followed. Thirty-two patients experienced a total of 88 episodes of fever. An infection unrelated to the presence of the catheter (e.g. otitis media, pneumonia, urinary tract infection) was found to be the cause of fever in 27 episodes (31.7%); in all the infection responded to appropriate antibiotic therapy. Ten of the episodes of fever (11.4%) lasted for less than 2 hours and were not evaluated further. Two episodes occurred in patients who no longer required the catheter; these resolved with elective catheter removal. The cause of the remaining 49 episodes of fever was assumed to be catheter-related sepsis; these were treated empirically with an intravenous antibiotic regimen of vancomycin (40 mg/kg/day) and gentamicin (7.5 mg/kg/day). In 16 of these cases blood cultures were negative and the antibiotic regimen was either stopped or continued for other indications. The remaining 33 episodes of fever were associated with positive blood cultures, i.e. documented episodes of catheter-related sepsis. In 10 of these the catheters were removed. The remaining 23 episodes of catheter-related sepsis were treated for 14 days with antibiotics given through the central vein catheter. In 5 of these episodes blood cultures remained positive after 48 hours of specific antibiotic therapy at which time the catheter was removed. The remaining 18 episodes (78.3%) resolved completely without catheter removal. On the basis of this experience we conclude that antibiotic therapy, administered as described here, without simultaneous catheter removal successfully eradicates catheter-related infections.
Glucose modulation induces reactive oxygen species and increases P‐glycoprotein‐mediated multidrug resistance to chemotherapeutics

Cancer cells develop resistance to stress induced by chemotherapy. In tumours, a considerable glucose gradient exists, resulting in stress. Notably, hypoxia‐inducible factor‐1 (HIF‐1) is a redox‐sensitive transcription factor that regulates P‐glycoprotein (Pgp), a crucial drug‐efflux transporter involved in multidrug resistance (MDR). Here, we investigated how glucose levels regulate Pgp‐mediated drug transport and resistance.
Constraints on arm position when pointing in three dimensions: Donders' law and the Fick gimbal strategy.

1. While making saccades between targets with the head stationary, eye positions are constrained to two of the possible three degrees of freedom. Classically this constraint has been described by Donders' and Listing's laws. The objective was to determine whether these laws also apply for the straight arm when pointing between different targets. Thus we determined whether the arm adopts only one angular position for every pointing direction (Donders' law) and whether these positions can be described by rotations from a reference position about axes that lie in a plane (Listing's law). 2. The angular positions (orientations) of the arm in three-dimensional space were studied as subjects pointed with a straight arm at different targets. Arm position was measured with the search coil technique by means of coils attached to the back of the hand. Pointing was studied over a range of +/- 45 degrees in all directions from a central target located 45 degrees to the right of the straight-ahead position. 3. The positions of the arm in space were described by quaternion vectors, i.e., a particular position was described in terms of the axis and amplitude of a rotation from a reference position to that position. Using this description, it was found that the straight arm adopted a similar orientation (standard deviations ranged from 2.8 to 4.8 degrees) when pointing at a particular target irrespective of which target from which it had moved. 4. The angular position vectors for arm positions associated with relatively small movements (e.g., less than +/- 30 degrees) lay in a flat surface with minimal torsion. At first sight, this surface appeared to be similar to Listing's plane of the eye. However, for positions associated with larger movements (e.g., +/- 45 degrees) it became apparent that, unlike the eye, the surface deviated from one obeying Listing's law, i.e., it was twisted and showed torsion like that produced by rotations around the horizontal and vertical axes of a Fick gimbal. (The characteristic of a Fick gimbal is that the vertical axis is fixed, whereas the horizontal axis moves with the gimbal.) 5. Although there were differences between subjects, all showed a twisted position vector surface. The twist was always in the same direction, and it was always less than that of a Fick gimbal. 6. This position vector surface had a similar shape whether the arm was stationary or was moving between targets, whether subjects pointed with or without vision, and whether the pointing arm had moved between targets or from a bent-elbow position on the lap. (ABSTRACT TRUNCATED AT 400 WORDS)
Effect of loading and fracture motions on diaphyseal tibial fractures

A computerized motion sensor was used to record the three‐dimensional components of interfragmentary motion during healing in three patients with closed, low‐energy fractures of the tibial diaphysis treated with functional braces. At the first measurement session, 2 weeks after fracture, the patients applied approximately 15 kg to the injured limb. Although this produced 1–4 mm of translation of the fragments, this was recovered when the load was removed. The maximum rotational and angulatory displacements often occurred as the patients rose from the chair with no weight applied to the limb and frequently were reduced as the 15 kg of load was applied. Under load, the maximum axial rotation was 3° and the maximum angular displacement was 1°. As with the translations, the initial rotational and angulatory positions of the fragments were recovered when the load was removed and the patient returned to the seated position. At 8 weeks, the patient applied full body weight, producing a maximum interfragmentary translation of 0.5 mm and maximum axial rotation or angulation of 0.5°. Abundant peripheral callus formed in all three fractures, and they healed by 15 weeks through typical gradual consolidation and mineralization of the callus, accompanied by a corresponding reduction in interfragmentary motions.
Fatal Injuries in Oklahoma: Descriptive Epidemiology Using Medical Examiner Data

To characterize mortality associated with injuries and other health problems in Oklahoma, we examined data from the Office of the Chief Medical Examiner of the State of Oklahoma for the years 1978 through 1984. Each year, approximately 1,500 and 800 deaths resulted from unintentional injury (UI) and intentional injury (ie, suicide and homicide), respectively. The medical examiner (ME) data differed substantially from the state's vital statistics (VS); over the seven years, the ME records showed 2,021 (16%) fewer UI deaths than did the VS, as well as 24 (1%) more cases of suicide and 499 (23%) more cases of homicide. Rates for UI and suicide were highest for young adults and for the elderly; in contrast, rates for homicide were highest for young adults, and then decreased with age. For each of the three categories of injury-related deaths, rates for male subjects were approximately three times those for female subjects; rates also varied by race-ethnic group. Deaths due to UI and homicide occurred more often in the summer and on weekends, though suicides did not vary by month and were slightly more common on weekdays. This study indicates that ME data represent an important source of epidemiologic information for the surveillance and study of injury-related mortality.
Noncompetitive inhibition of human CYP2C9 in vitro by a commercial Rhodiola rosea product

A commercial Rhodiola rosea (R. rosea) product has previously demonstrated CYP2C9 inhibition in humans. The purpose of this study was to provide in vitro inhibitory data for this particular interaction and to classify the mechanism of the interaction. Another aim was to examine the in vitro influence of ethanol on the CYP2C9 activity. Human CYP2C9 (wild type) isolated from a baculovirus‐infected cell system was incubated with 0.8 μmol/L losartan for 20 min. Sulfaphenazole was used as a positive control. The commercial R. rosea product “Arctic Root” was used as test inhibitor. Formation of the CYP2C9‐produced losartan metabolite EXP‐3174 was determined by validated LC‐MS/MS methodology. Possible mechanism‐based (irreversible) inhibition was evaluated using time‐ and NADPH‐dependent inhibition assays. Kinetic constants (Km, Vmax, and Ki) were calculated from a Lineweaver‐Burk plot. Mode of inhibition was determined. CYP2C9 was inhibited by “Arctic Root” with an IC50 (extract concentration yielding 50% reduction in enzyme activity) of 19.2 ± 2.7 μg/mL. Inhibitor concentrations of 20 μg/mL and 40 μg/mL yielded Ki values of 16.37 μg/mL and 5.59 μg/mL, respectively. The Lineweaver‐Burk plot showed noncompetitive inhibition mode. No time‐ or NADPH‐dependent inhibition was observed. The presence of ethanol inhibited CYP2C9 activity in a concentration‐dependent manner. In conclusion, the commercial R. rosea product “Arctic Root” demonstrated noncompetitive inhibition of CYP2C9 in vitro. Further work identifying the constituents responsible for this inhibition is needed.
The influence of time pressure and accountability on auditors' processing of nondiagnostic information

This paper extends Hackenbrack [1992] in examining the influence of nondiagnostic (i.e., irrelevant) information on auditor judgment. Hackenbrack found that auditors given a mix of diagnostic and nondiagnostic evidence made fraud-risk assessments that were less extreme (more regressive) than those based on diagnostic evidence only. This behavior is consistent with the nonnormative judgment tendency known as the dilution effect (Nisbett, Zukier, and Lemley [1981]). Using a different task and context than Hackenbrack, I replicate his results. I extend Hackenbrack's research by investigating, in a laboratory setting, whether auditors exhibit the dilution effect when faced with time pressure and
Mcl-1, Vascular Endothelial Growth Factor-R2, and 14-3-3σ Expression Might Predict Primary Response against Radiotherapy and Chemotherapy in Patients with Locally Advanced Squamous Cell Carcinomas of the Head and Neck

Purpose: This study was done to explore whether the expression of a selected set of proteins could predict primary response to radiotherapy or concomitant radiotherapy and chemotherapy in patients with advanced head and neck cancer. Experimental Design: Forty-three pretreatment tumor biopsies were taken during diagnostic panendoscopy and examined for Mcl-1, vascular endothelial growth factor (VEGF)-R2, CD9, and 14-3-3σ expression by immunohistochemistry. Forty-three patients underwent primary radiotherapy, of which, 29 patients received concomitant chemotherapy (low dose daily cisplatin, mitomycin C bolus). The primary end-point was locoregional tumor control 6 months after completion of radiotherapy. Mcl-1, VEGF-R2, CD9, and 14-3-3σ expression were correlated with patients' primary response to radiotherapy and chemotherapy and with established clinicopathologic variables. Results: Thirty complete and 13 partial responses were observed in our patient group. High expression levels of Mcl-1 (P = 0.021), VEGF-R2 (P = 0.032), and 14-3-3σ (P = 0.013), but not of CD9, in tumor biopsies was correlated with complete response. Overexpression of at least two of the three aforementioned proteins in pretreatment biopsies predicted—with a likelihood of 80%—whether a patient would achieve complete response to radiotherapy and chemotherapy. However, if only one of these proteins is overexpressed, there is a likelihood of 84.6% that this patient would not completely respond to therapy. Conclusion: Determining the expression levels of Mcl-1, VEGF-R2, and 14-3-3σ may be helpful in predicting the early clinical response in head and neck tumor patients receiving primary radiotherapy and chemotherapy and may further allow a pretherapeutic selection of patients.
The impact of the pcaob individual engagement inspection process-preliminary evidence

ABSTRACT This study investigates the impact on auditors' and clients' activities of Public Company Accounting Oversight Board (PCAOB) inspections of individual engagements. I find that both auditors and clients react to a Part I Finding, which identifies audit deficiencies on their inspected engagements. Audit firm effort increases on inspected engagements and non-inspected engagements of offices or partners that receive a Part I Finding, suggesting direct, as well as spillover, effects of the PCAOB inspections. The client is also more likely to switch auditors. However, auditor effort and financial reporting quality subsequently decline for inspected engagements that did not receive a Part I Finding. In these cases, clients are less likely to switch auditors. Additional analyses show that the auditor reaction depends on whether the auditor is an industry specialist, the client reaction depends on the size of the auditor, and effects on financial reporting quality depend on whether the deficiency is a fir.
The Effects of Audit Market Liberalisation and Auditor Type on Audit Opinions: The Iranian Experience

Audit services were provided exclusively by a state entity in Iran until late 2001, when the audit market was liberalised. The liberalisation of the audit market resulted in increased competition, as more private auditors became licensed to operate and provide audit services. The present study examines the effects of audit market liberalisation and auditor type (i.e., state and private auditors) on audit opinions. It is predicted that increased competition in the audit market may reduce the relative bargaining power of auditors, which can compromise auditors’ independence when issuing audit opinions. The present study also investigates whether the process of issuing audit opinions is influenced by the government, thus resulting in a lower rate of modified audit opinions issued by state auditors compared to those issued by private auditors. Importantly, this study develops an explanation based upon a bargaining power view of auditor independence in issuing audit opinions and upon the limitations of the explanation for the circumstances in which auditor and owner interests are aligned in the case of government entities. The present study analyses the data of firms listed on the Tehran Stock Exchange between 1999 and 2010. The findings, after controlling for auditor choice, reveal that modified audit opinions have decreased following the liberalisation of the audit market in Iran, and compared to private auditors, state auditors have issued fewer modified audit opinions. The findings suggest that increased competition in the audit market is more likely to decrease the relative bargaining power of auditors and that there is a significant concern regarding audit opinions when both auditee and auditor are state‐controlled entities.
Pay Inequity and Job Performance: An Insider-Econometrics Study

Using personnel data on back-office employees of an insurance company, we calculate three measures of pay inequity, “inequality,” “envy,” and “altruism,” for total pay as well as, separately, for three pay components, salary, commissions, and year-end bonuses. Job performance is measured by the value of commissions for new contracts which accrue to the sales agents who are serviced by the back-office employee. Quantile panel regressions show that inequity effects on performance distinctly differ over the performance distribution and across the different pay components. Further, results depend on the time structure of pay and, possibly also, on pay secrecy rules.
Attentional bias towards sleep‐related stimuli in insomnia disorder: a behavioural and ERP study

Many studies have used behavioural experiments to show an attentional bias towards sleep‐related stimuli in people with insomnia disorder. A measurement of event‐related potential is needed to investigate the cognitive processing mechanism of the attentional process. The present study used the emotional Stroop paradigm and event‐related potentials to measure attentional bias towards sleep‐negative, sleep‐positive and sleep‐unrelated neutral words. The study comprised 16 participants with insomnia disorder and 15 participants who were good sleepers. Behavioural data indicated that there was a significant interference effect of sleep‐positive words between the insomnia group and the good sleepers, and a marginally significant interference effect from sleep‐negative words between groups. In the insomnia group, event‐related potential data showed that sleep‐negative words elicited higher amplitudes of P1 and N1 components than did sleep‐positive and sleep‐unrelated words. Our results provide evidence for the early cognitive processing of sleep‐negative stimuli, which suggests that the psychological treatment of insomnia could benefit from addressing early hypervigilance towards these stimuli.