Miracle-dz/UniFAR-FTUs huggingface dataset:
Stepwise Regulated Chromatin Assembly of MCM2–7 Proteins*

Acquisition of the competence to replicate requires the assembly of the MCM2–7 (minichromosome maintenance) protein complex onto pre-replicative chromatin, a step of the licensing reaction. This step is thought to occur through binding of a heterohexameric MCM complex containing the six related MCM subunits. Here we show that assembly of the MCM complex onto pre-replicative chromatin occurs through sequential stabilization of specific MCM subunits. Inhibition of licensing with 6-dimethylaminopurine results in chromatin containing specifically bound MCM4 and MCM6. A similar result was obtained by interference of the assembly reaction with an MCM3 antibody. The presence of chromatin-bound MCM intermediates was confirmed by reconstitution experiments in vitro with purified proteins and by the observation of an ordered association of MCM subunits with chromatin. These results indicate that the assembly of the MCM complex onto pre-replicative chromatin is regulated at the level of distinct subunits, suggesting an additional regulatory step in the formation of pre-replication complexes.
Loss of anti-aggregatory effects of aortic valve tissue in patients with aortic stenosis.

BACKGROUND AND AIM OF THE STUDY Patients with aortic stenosis (AS) exhibit increased platelet aggregability, and thrombus formation has been documented on calcific and severely stenosed valves. Isolated porcine and canine aortic valves (AV) release nitric oxide (NO) and prostacyclin, which exert local antithrombotic effects; to date, this has not been studied in humans. In the present study the possible interaction of AV tissue with platelet aggregation was examined, using fragments of AV obtained from patients with AS and aortic regurgitation (AR). METHODS Fragments of AV tissue, excised from patients undergoing AV replacement, were co-incubated with blood samples obtained from normal subjects. The direct effects of valve tissue from patients with AS (n = 14) or with predominant AR (n = 13) on ADP-induced platelet aggregation and intraplatelet cGMP and cAMP content were compared. RESULTS In whole blood, non-calcified AV fragments from AR patients inhibited platelet aggregation by 57 +/- 6% (p < 0.01); in platelet-rich plasma results were analogous. In order to determine whether this anti-aggregatory effect could be attributed to the valvular release of NO or prostacyclin, intraplatelet cGMP and cAMP formation was assessed, respectively. While there were no significant changes in cGMP content, cAMP increased by 26 +/- 4% (p < 0.02). Both, anti-aggregatory and cAMP-stimulating effects were similar to those produced by 10 nM prostaglandin E1, a prostacyclin mimetic. Fragments from stenotic valves did not inhibit aggregation and did not affect cGMP or cAMP. Furthermore, fragments from heavily calcified regions potentiated aggregation and, in some cases, induced spontaneous aggregation. CONCLUSION Minimally calcified aortic valves (i.e., AR) and, therefore, presumably also normal valves, exert anti-aggregatory effects, most likely via prostacyclin release. AS is associated with a loss of this effect, thus potentially contributing to thrombotic risk.
Sinonasal Inverted Papilloma: Risk Factors for Local Recurrence After Surgical Resection

Objectives: Sinonasal inverted papillomas (SIP) present a potential for recurrence years after the surgery, but most studies report short-term follow-up, and risk factors for recurrence are still debated. Furthermore, several classifications are described, and no consensus exists regarding which one should be used. The aims of this study were to report our long-term results, investigate for potential risk factors for recurrence, and compare the existing 8 staging systems. Methods: Over a 28-year period, 110 patients with a diagnosis of SIP were enrolled. The median follow-up time was 55.6 months. Results: In multivariate Cox regression modeling, history of previous surgery was the only variable associated with recurrence (hazard ratio = 4.91, 95% CI, 1.80-13.39). Recurrences occurred up to 60 months after the surgery. Among the 8 staging systems, none proved to be associated with recurrence. Conclusion: The only factor associated with recurrence of SIP was prior surgery, probably corresponding to an incomplete initial resection. Due to late recurrences, an extended follow-up of at least 5 years is mandatory. In the absence of a classification predicting prognosis, Krouse’s staging system should be used to homogenize studies’ report since it is the most widely used.
The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia

While tobacco and alcohol are established risk factors for oesophageal squamous‐cell carcinoma, their roles in the aetiology of the increasingly common oesophageal adenocarcinoma remains uncertain. We tested the association between tobacco, snuff and alcohol use and the risk of oesophageal and cardia cancer in a nationwide, population‐based case‐control study in Sweden. Face‐to‐face interviews were conducted with 618 (81% of all eligible) patients (189 oesophageal adenocarcinoma, 262 cardia adenocarcinoma and 167 oesophageal squamous‐cell carcinoma) and 820 control subjects. Odds ratios (OR) were calculated by logistic regression with multivariate adjustments for potential confounding. The risk of oesophageal adenocarcinoma was not associated with snuff or alcohol use, and the association with smoking was weak or absent. Gastric cardia adenocarcinoma was dose‐dependently associated with smoking (OR=4.2, 95% CI=2.5–7.0 among heavy smokers compared with never‐smokers), but not with alcohol or snuff use. Oesophageal squamous‐cell carcinoma was strongly associated with tobacco, moderately with alcohol, but not with snuff use; combined use of tobacco and alcohol entailed a strongly increased risk (OR=23.1, 95% CI=9.6–56.0 among heavy users compared with never‐users). We conclude that tobacco smoking, a strong risk factor for oesophageal squamous‐cell carcinoma and cardia adenocarcinoma, does not play an important role in the aetiology of oesophageal adenocarcinoma. None of the studied exposures can explain the increasing incidence of oesophageal adenocarcinoma. Int. J. Cancer 85:340–346, 2000. ©2000 Wiley‐Liss, Inc.
Component-wise gradient boosting and false discovery control in survival analysis with high-dimensional covariates

MOTIVATION Technological advances that allow routine identification of high-dimensional risk factors have led to high demand for statistical techniques that enable full utilization of these rich sources of information for genetics studies. Variable selection for censored outcome data as well as control of false discoveries (i.e. inclusion of irrelevant variables) in the presence of high-dimensional predictors present serious challenges. This article develops a computationally feasible method based on boosting and stability selection. Specifically, we modified the component-wise gradient boosting to improve the computational feasibility and introduced random permutation in stability selection for controlling false discoveries. RESULTS We have proposed a high-dimensional variable selection method by incorporating stability selection to control false discovery. Comparisons between the proposed method and the commonly used univariate and Lasso approaches for variable selection reveal that the proposed method yields fewer false discoveries. The proposed method is applied to study the associations of 2339 common single-nucleotide polymorphisms (SNPs) with overall survival among cutaneous melanoma (CM) patients. The results have confirmed that BRCA2 pathway SNPs are likely to be associated with overall survival, as reported by previous literature. Moreover, we have identified several new Fanconi anemia (FA) pathway SNPs that are likely to modulate survival of CM patients. AVAILABILITY AND IMPLEMENTATION The related source code and documents are freely available at https://sites.google. com/site/bestumich/issues. CONTACT yili@umich.edu.
The effect of quantitative feed restriction on allometric growth in broilers

&NA; Feed restriction in broilers is aimed at preventing metabolic disorders, increasing feed efficiency, or manipulating carcass conformation. The purpose of the current study was to investigate the effects of modest graded levels feed restriction during the second and third wk of life. Mixed‐sex chickens were raised in pens with 4 replications per treatment to 35 d of age. Chickens were fed ad libitum throughout the trial, or 90, 80, or 70% of expected ad libitum feed intake during the second wk of life, or 95, 90, 85, or 80% of expected ad libitum feed intake during the third wk of life. Feed intake, BW, ADG, and feed conversion ratio (FCR) were measured and weekly dissections were conducted to characterize allometric growth of the breast muscle, legs, abdominal fat pad, liver, gastro‐intestinal tract (GIT), and heart. Feeding 70% of ad libitum during wk 2 and 80% during wk 3 reduced ADG during the restriction period and reduced BW at the end of the restriction period, but chickens exhibited complete compensatory growth within one wk after the restriction period. No significant effects of restriction treatment were found on BW, FCR, fat pad, empty GIT, breast muscle, heart, legs, and liver weight at d 35, but allometric growth curve for breast muscle was lower in birds fed 80 and 85% of ad libitum during wk 3, and for birds fed 70% of ad libitum in wk 2. Allometric growth curves for all body parts were different between males and females, except for the liver. Females had higher relative fat pad, breast muscle, and liver weight and a lower GIT and heart and leg weight compared with males at d 35. Feed restriction could differentially affect males and females. This study showed that feeding 70% of ad libitum in wk 2 might be beneficial to reduce fat pad, but later feed restriction in wk 3 may reduce breast muscle weight at broiler processing age.
Regulation of the Interaction between Protein Kinase C-related Protein Kinase 2 (PRK2) and Its Upstream Kinase, 3-Phosphoinositide-dependent Protein Kinase 1 (PDK1)*

The members of the AGC kinase family frequently exhibit three conserved phosphorylation sites: the activation loop, the hydrophobic motif (HM), and the zipper (Z)/turn-motif (TM) phosphorylation site. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates the activation loop of numerous AGC kinases, including the protein kinase C-related protein kinases (PRKs). Here we studied the docking interaction between PDK1 and PRK2 and analyzed the mechanisms that regulate this interaction. In vivo labeling of recombinant PRK2 by 32Pi revealed phosphorylation at two sites, the activation loop and the Z/TM in the C-terminal extension. We provide evidence that phosphorylation of the Z/TM site of PRK2 inhibits its interaction with PDK1. Our studies further provide a mechanistic model to explain different steps in the docking interaction and regulation. Interestingly, we found that the mechanism that negatively regulates the docking interaction of PRK2 to the upstream kinase PDK1 is directly linked to the activation mechanism of PRK2 itself. Finally, our results indicate that the mechanisms underlying the regulation of the interaction between PRK2 and PDK1 are specific for PRK2 and do not apply for other AGC kinases.
Accumulation of natural SF6 in the sedimentary aquifers of the North China Plain as a restriction on groundwater dating

We employed environmental tracers (3H-3He, SF6) in a study investigating the groundwater recharge in the North China Plain (NCP), a sedimentary aquifer system consisting of fluvial and alluvial river deposits near the city of Shijiazhuang. The 3H-3He dating method revealed reasonable results for the young groundwater with ages covering the range of recent to ∼40 a. SF6 samples were taken in parallel for independent dating and to compare the applicability of both methods. However, the SF6-results are influenced and, in part, dominated by a systematic non-atmospheric component, revealing that the dating with SF6 is unreliable in this region. A correlation of non-atmospheric SF6 and 3H-3He ages suggests a continuous accumulation of natural SF6 in the groundwater of the NCP aquifers. Although terrigenic SF6 has previously been associated with crystalline or igneous rocks, our results indicate that it can also be accumulated in sandy aquifers on the timescale relevant for SF6 dating.
Effects of foveal ablation on emmetropization and form-deprivation myopia.

PURPOSE Because of the prominence of central vision in primates, it has generally been assumed that signals from the fovea dominate refractive development. To test this assumption, the authors determined whether an intact fovea was essential for either normal emmetropization or the vision-induced myopic errors produced by form deprivation. METHODS In 13 rhesus monkeys at 3 weeks of age, the fovea and most of the perifovea in one eye were ablated by laser photocoagulation. Five of these animals were subsequently allowed unrestricted vision. For the other eight monkeys with foveal ablations, a diffuser lens was secured in front of the treated eyes to produce form deprivation. Refractive development was assessed along the pupillary axis by retinoscopy, keratometry, and A-scan ultrasonography. Control data were obtained from 21 normal monkeys and three infants reared with plano lenses in front of both eyes. RESULTS Foveal ablations had no apparent effect on emmetropization. Refractive errors for both eyes of the treated infants allowed unrestricted vision were within the control range throughout the observation period, and there were no systematic interocular differences in refractive error or axial length. In addition, foveal ablation did not prevent form deprivation myopia; six of the eight infants that experienced monocular form deprivation developed myopic axial anisometropias outside the control range. CONCLUSIONS Visual signals from the fovea are not essential for normal refractive development or the vision-induced alterations in ocular growth produced by form deprivation. Conversely, the peripheral retina, in isolation, can regulate emmetropizing responses and produce anomalous refractive errors in response to abnormal visual experience. These results indicate that peripheral vision should be considered when assessing the effects of visual experience on refractive development.
NMR Structure of the N-terminal J Domain of Murine Polyomavirus T Antigens

The NMR structure of the N-terminal, DnaJ-like domain of murine polyomavirus tumor antigens (PyJ) has been determined to high precision, with root mean square deviations to the mean structure of 0.38 Å for backbone atoms and 0.94 Å for all heavy atoms of ordered residues 5–41 and 50–69. PyJ possesses a three-helix fold, in which anti-parallel helices II and III are bridged by helix I, similar to the four-helix fold of the J domains of DnaJ and human DnaJ-1. PyJ differs significantly in the lengths of N terminus, helix I, and helix III. The universally conserved HPD motif appears to form a His-Pro C-cap of helix II. Helix I features a stabilizing Schellman C-cap that is probably conserved universally among J domains. On the helix II surface where positive charges of other J domains have been implicated in binding of hsp70s, PyJ contains glutamine residues. Nonetheless, chimeras that replace the J domain of DnaJ with PyJ function like wild-type DnaJ in promoting growth of Escherichia coli. This activity can be modulated by mutations of at least one of these glutamines. T antigen mutations reported to impair cellular transformation by the virus, presumably via interactions with PP2A, cluster in the hydrophobic folding core and at the extreme N terminus, remote from the HPD loop.
Direct inhibition of interleukin‐2 receptor α‐mediated signaling pathway induces G1 arrest and apoptosis in human head‐and‐neck cancer cells

Overexpression of the interleukin‐2 receptor (IL‐2R) α chain in tumor cells is associated with tumor progression and a poor patient prognosis. IL‐2Rα is responsible for the high affinity binding of the receptor to IL‐2, leading to activation of several proliferative and anti‐apoptotic intracellular signaling pathways. We have previously shown that human squamous cell carcinoma of a head‐and‐neck line (PCI‐13) genetically engineered to overexpress IL‐2Rα exhibit increased transforming activity, proliferation, and drug resistance, compared to the vector control cells (J Cell Biochem 2003;89:824–836). In this study, we report that IL‐2Rα+ cells express high levels of total and phosphorylated Jak3 protein and are more resistant to apoptosis induced by a Jak3 inhibitor than the control LacZ cells. Furthermore, we used daclizumab, a monoclonal antibody specific to IL‐2Rα, and determined the effects of IL‐2Rα inhibition on cell cycle and apoptosis as well as the involvement of potential cell cycle and apoptosis regulatory proteins. We found that daclizumab induces G1 arrest, associated with down‐regulation of cyclin A protein, preferentially in IL‐2Rα+ cells, but not in LacZ cells. In addition, daclizumab activates apoptotic death program via Bcl‐2 down‐regulation preferentially in IL‐2Rα+ cells. Finally, daclizumab also sensitizes IL‐2Rα+ cells to other apoptotic stimuli, although the effect is moderate. These results indicate that daclizumab inhibits the proliferative potential of IL‐2Rα+ cells via inhibition of cell cycle progression and induction of apoptosis. © 2005 Wiley‐Liss, Inc.
A framework for e-government implementation at a national level

This study attempts to explore and investigate empirically how an e-government system can be implemented at a national level; the key issues that might restrict its implementation; and how these issues could be treated in practice. Following a comprehensive review of the relevant literature, an initial conceptual framework for e-government implementation is formulated The framework is then applied in a real world case study to support further data collection and to establish an exhaustive view of the e-government implementation process at a national level. The case study examines the development of an e-government implementation in Qatar and involved 26 semi-structured interviews, 10 observations, 10 electronic reports, analysis of around 50 documents, and numerous newspaper articles and press releases. The interviewees included senior officials from the e-government steering committee, the e-government project team and various government ministries. The documentations included all the key documents relating the e-government project. Based on the data collected the initial framework is then revised by using the interpretive case study approach, which depends on an iterative research cycle where triangulated data are extracted The study then combined the evidence from the literature with the case study data to narrow the gap between e-government implementation theory and practice. As a result, a comprehensive framework including detailed measurements to differentiate four development stages is created. This framework classifies the key issues that might restrict e-government implementation into two main categories, organisational and technological issues, and uses other issues as the development measurements. The framework can be used as a tool to determine the road ahead for implementing an e-government system at a national level and to identify the main practices, processes, possible goals, progress indicators and key conditions to move from one stage to another. It can be claimed that this study has made a novel contribution to the area of e-government and has expanded the boundaries of knowledge, especially for governments that are seeking to implement an egovernment system at a national level.
Adaptive Active Capacitor Converter for Improving Stability of Cascaded DC Power Supply System

Connecting converters in cascade is a basic configuration of dc distributed power systems (DPS). The impedance interaction between individually designed converters may make the cascaded system unstable. The previous presented approaches of stabilizing the cascaded systems need to modify the source and/or load converter's internal structure such as the topology and control circuit that are contradictory to the modularization characteristic of dc DPS. In this paper, an adaptive active capacitor converter (AACC) is introduced to stabilize the cascaded system. The AACC is connected in parallel with the cascaded system's intermediate bus and only needs to detect the bus voltage without any change of the existing subsystems. Hence, it can be designed as a standard module for dc DPS. The AACC serves as an equivalent bus capacitor to reduce the output impedance of the source converter, thus avoiding the intersection with the load converter's input impedance, and as a result, the cascaded system becomes stable. The equivalent bus capacitor emulated by the AACC is adaptive according to the output power of the cascaded system, and thus, the power loss of AACC is minimized and the dynamic response of the system is better than that of the system using a passive capacitor. Furthermore, since no electrolytic capacitor is needed in the AACC, the cascaded system's lifetime is prolonged. The operation principle, control, and design consideration of the AACC are discussed in this paper, and a 480 W cascaded system comprising two phase-shifted full-bridge converters has been built and evaluated. The experimental results verify the validity of the proposed AACC.
Prescribing pattern of psychotropic drugs in nursing home residents with dementia

ABSTRACT Background: The goal of this study is to determine patterns of psychotropic drug use (PDU), the association with neuropsychiatric symptoms (NPS), and the variability across dementia types in nursing home residents with dementia. In addition, PDU was analyzed across multiple indications. Methods: This was a prospective cohort study over a two-year period from 2006 to 2008, which involved 14 dementia special care units in nine nursing homes. A total of 117 residents with dementia participated in the study, of whom 35% had Alzheimer's dementia (AD) and 11% vascular dementia (VaD). PDU was classified according to anatomical therapeutic chemical-classification as either “present” or “absent”. Results: The majority of residents had moderately severe to severe dementia. At all successive assessments, almost two-thirds of residents received any psychotropic drug (PD) and almost one-third continued to receive any PD. Of all PDs, antipsychotics (APs) were prescribed most frequently. Fewer residents started with antidepressants, but continued to receive antidepressants at higher percentages. Anxiolytics showed an intermittent course, but a subgroup of 9% showed two-year continuation. Once started on PDs at baseline, residents continued to use PDs at high percentages: three-quarters continued to receive APs for at least six months. Half of residents received at least one PD; one-fifth received at least two PDs simultaneously. Residents with AD received more hypnotics and antidementia drugs; residents with VaD received more antipsychotics, antidepressants, anxiolytics and anticonvulsants. Conclusions: PDs have different utilization patterns, but overall, consistently high continuation rates were found. These results warrant scrutiny of continuous PDU.