Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of gender and menopausal status on the association of apolipoprotein E phenotype with plasma lipoprotein levels. Results from the Framingham Offspring Study.

Apolipoprotein (apo) E phenotype is an important genetic determinant of plasma low-density lipoprotein (LDL) cholesterol and apo B levels. We have determined apo E phenotype by isoelectric focusing and plasma lipid, lipoprotein cholesterol, apo A-I, apo B, and lipoprotein(a) levels, as well as LDL particle size, in 2258 men and women participating in the Framingham Offspring Study. Apo E phenotype (E2/2, E2/4, E3/2, E3/3, E3/4, and E4/4) was not associated with plasma lipoprotein(a) levels but was associated with plasma LDL cholesterol levels, apo B levels, and LDL size in men and with plasma total cholesterol, LDL cholesterol, and apo B levels in women. The average effect of the epsilon 2 allele was to lower plasma LDL cholesterol levels by 9.2 mg/dL in men and by 13.7 mg/dL in women, while the average effect of the epsilon 4 allele was to increase LDL cholesterol levels by 2.6 mg/dL in men and by 5.4 mg/dL in women. When men were divided into two groups according to their age (< 50 and > or = 50 years old), the average effect of the epsilon 2 allele was to lower plasma levels of LDL cholesterol by 10.2 mg/dL in younger men and by 7.5 mg/dL in older men. In premenopausal women, the average effect of the epsilon 2 allele was to lower LDL cholesterol by 8.2 mg/dL and, in postmenopausal women, by 20.4 mg/dL. An opposite effect of the epsilon 4 allele was observed: the epsilon 4 allele was associated with increases in plasma LDL cholesterol levels of 4.0 mg/dL in younger men and of 1.0 mg/dL in older men. (ABSTRACT TRUNCATED AT 250 WORDS)
Resource sharing of TCP connections with different round trip times

The performance of TCP connections sharing a common link and the resulting link usage depends on the various round trip times along the connections. Expressions exist for these values only in the homogenous case and heuristics for the general case give uncertain results. In this paper we first derive an exact expression (in the setting of fluid models) for the window evolution of TCP connections with different round trip delays. We next apply this result in a particular context to derive expressions for the maximum window sizes and the throughput of TCP connections as well the idle periods and the utilization of the shared link. We show that a bias in favor of connections with short round trip delays persists even for large buffer sizes. First- and second-order approximations in buffer size are given respectively for small and large buffers. These expressions show that for small buffers small round trip times predominate in global performance while the opposite is true for large buffers.
Strength training: importance of genetic factors.

PURPOSE This study focuses on the quantification of genetic and environmental factors in arm strength after high-resistance strength training. METHODS Male monozygotic (MZ, N = 25) and dizygotic (DZ, N = 16) twins (22.4 +/- 3.7 yr) participated in a 10-wk resistance training program for the elbow flexors. The evidence for genotype*training interaction, or association of interindividual differences in training effects with the genotype, was tested by a two-way ANOVA in the MZ twins and using a bivariate model-fitting approach on pre- and post-training phenotypes in MZ and DZ twins. One repetition maximum (1RM), isometric strength, and concentric and eccentric moments in 110 degree arm flexion at velocities of 30 degrees x s(-1), 60 degrees x s(-1), and 12 degrees x s(-1) were evaluated as well as arm muscle cross-sectional area (MCSA). RESULTS Results indicated significant positive training effects for all measures except for maximal eccentric moments. Evidence for genotype*training interaction was found for 1RM and isometric strength, with MZ intra-pair correlations of 0.46 and 0.30, respectively. Bivariate model-fitting indicated that about 20% of the variation in post-training 1RM, isometric strength, and concentric moment at 120 degrees x s(-1) was explained by training-specific genetic factors that were independent from genetic factors that explained variation in the pretraining phenotype (30-77%). CONCLUSIONS Genetic correlations between measures of pre- and post-training strength were indicative for high pleiotropic gene action and minor activation of training-specific genes during training.
An A-DNA structure with two independent duplexes in the asymmetric unit.

The crystal and molecular structure of the self-complementary A-DNA decamer sequence d(G4CGC4) was solved at 1.9 A resolution. The decamer crystallizes in space group P21 with two independent duplexes in the asymmetric unit. Duplex 1 has interactions which are distributed symmetrically about its length compared with duplex 2. The two end base pairs of duplex 1 have a similar NH.O hydrogen-bond pattern involving GGC segments of duplex 2 and a symmetry-related neighbour, while the end base pairs of duplex 2 interact with the GCC and GGG segments of its symmetry-related neighbours through NH.O and NH.N hydrogen bonds and a water-mediated hydrogen bond between the carboxyl groups of C40 and C8. In addition to the C4'-C5' torsion angle gamma assuming the trans conformation in certain steps, this angle also adopts the gauche- conformation at C37 as opposed to the preferred gauche+ conformation, with a concomitant change in phosphodiester P-O5' (alpha) in the opposite sense. This facilitates stacking between adjacent bases. The study suggests that the structural alterations in the two molecules in the asymmetric unit originate from an inherent propensity of the d(G4CGC4) base sequence for varied intermolecular interactions and malleability.
Characterization of a cellular protease that cleaves Pseudomonas exotoxin

Pseudomonas exotoxin (PE) is a 66-kDa bacterial toxin that is proteolytically cleaved by cells to produce an N-terminal fragment of 28 kDa and a C-terminal 37-kDa fragment which translocates to the cytosol and inhibits protein synthesis (M. Ogata, V.K. Chaudhary, I. Pastan, and D.J. FitzGerald, J. Biol. Chem. 265:20678-20685, 1990). When cells were broken by homogenization, the appropriate proteolytic activity was found associated with cellular membranes and not in a soluble fraction. Proteolysis of PE by crude membranes was stimulated by divalent cations, was ATP independent, and had a pH optimum of 5.5. When cells were disrupted by nitrogen cavitation and fractionated on Percoll gradients, proteolytic activity was present in fractions corresponding to the density of plasma membranes or endosomes but not in fractions containing lysosomes. Proteolytic activity was recovered in detergent extracts after crude membranes were treated with Nonidet P-40 or octylglucoside. Proteolysis of PE by either crude membranes or detergent extracts generated fragments of 28 and 37 kDa. The sizes of these fragments resembled those produced by intact cells. However, when the nontoxic mutant, PEgly276, which cannot be cleaved appropriately by intact cells, was incubated with membranes or extracts there was no production of the 28- and 37-kDa fragments.
Time-over-threshold for pulse shape discrimination in a time-of-flight phoswich PET detector

It is well known that a PET detector capable of measuring both photon time-of-flight (TOF) and depth-of-interaction (DOI) improves the image quality and accuracy. Phoswich designs have been realized in PET detectors to measure DOI for more than a decade. However, PET detectors based on phoswich designs put great demand on the readout circuits, which have to differentiate the pulse shape produced by different crystal layers. A simple pulse shape discrimination approach is required to realize the phoswich designs in a clinical PET scanner, which consists of thousands of scintillation crystal elements. In this work, we studied time-over-threshold (ToT) as a pulse shape parameter for DOI. The energy, timing and DOI performance were evaluated for a phoswich detector design comprising 3 mm×3 mm×10 mm LYSO:Ce crystal optically coupled to 3 mm×3 mm×10 mm calcium co-doped LSO:Ce,Ca(0.4%) crystal read out by a silicon photomultiplier (SiPM). A DOI accuracy of 97.2% has been achieved for photopeak events using the proposed time-over-threshold (ToT) processing. The energy resolution without correction for SiPM non-linearity was 9.7±0.2% and 11.3±0.2% FWHM at 511 keV for LYSO and LSO crystal layers, respectively. The coincidence time resolution for photopeak events ranges from 164.6 ps to 183.1 ps FWHM, depending on the layer combinations. The coincidence time resolution for inter-crystal scatter events ranges from 214.6 ps to 418.3 ps FWHM, depending on the energy windows applied. These results show great promises of using ToT for pulse shape discrimination in a TOF phoswich detector since a ToT measurement can be easily implemented in readout electronics.
Numerical Simulation of Two-Dimensional Dendritic Growth Using Phase-Field Model

In this article, we study the phase-field model of solidification for numerical simulation of dendritic crystal growth that occurs during the casting of metals and alloys. Phase-field model of solidification describes the physics of dendritic growth in any material during the process of under cooling. The numerical procedure in this work is based on finite difference scheme for space and the 4th-order Runge-Kutta method for time discretization. The effect of each physical parameter on the shape and growth of dendritic crystal is studied and visualized in detail.
Effect of electrochemical structuring of Ti6Al4V on osteoblast behaviour in vitro

Topography and surface chemistry have a profound effect on the way in which cells interact with an implant, which in turn impacts on clinical use and performance. In this paper we examine an electrochemical polishing approach in H2SO4/methanol that can be applied to the widely used orthopaedic/dentistry implant material, Ti6Al4V, to produce structured surfaces. The surface roughness, as characterized by Ra, was found to be dependent on the time of electropolishing but not on the voltage parameters used here. The surface chemistry, however, was dependent on the applied electrochemical potential. It was found that the chemical composition of the surface layer was modified during the electrochemical process, and at high potentials (9.0 V) a pure TiO2 layer of at least 10 nm was created on top of the bulk alloy. Characterization of these surfaces with rat cells from the osteoblast lineage provided further evidence of contact guidance by microscale topography with morphology analysis correlating with surface roughness (Ra 300–550 nm). Formation of a bone-like matrix after long-term culture on these surfaces was not strongly dependent upon Ra values but followed the voltage parameter. These findings suggest that the surfaces created by treatment at higher voltages (9.0 V) produced a nanoscale layer of pure TiO2 on the Ti6Al4V surface that influenced the programme of cellular differentiation culminating in osteogenesis.
Symmetric coupled composite right-/left-handed transmission line with dual-mode balanced filter characteristics

In this paper, a symmetric coupled composite right-/left-handed transmission line (CRLH-TL) with dual-mode balanced filter characteristics is proposed. Unlike the other symmetric structures, this configuration has the ability to operate under both common- and differential-mode excitation. This ability is achieved by providing a physical short circuit by means of ground vias at the center of each unit-cell along the symmetry plane of the structure. In this study, we implemented a dual-mode balanced filter on the basis of the fact that CRLH unit-cells can be operated under both common- and differential-mode excitation. To validate this ability, a five-cell four port symmetric coupled CRLH-TL is simulated, fabricated, and its performance is measured. The obtained results are in good agreement with the simulation results under both common- and differential-mode excitation.
Are You Being Served? Political Accountability and Quality of Government

How well any government functions hinges on how good citizens are at making their politicians accountable for their actions. Political control of public officials depends on two factors. First, free and regular elections allow citizens to discipline politicians--the credible threat of losing office in the next period compels policy makers to respond to the voters' interests. Second, and equally important, the degree of citizen information curbs the opportunities politicians may have to engage in political corruption and management. The presence of a well-informed electorate in a democratic setting explains between one-half and two-thirds of the variance in the levels of governmental performance and corruption. Copyright 2003, Oxford University Press.
Mapping of the Discontinuous Kininogen Binding Site of Prekallikrein

Prekallikrein, the precursor to the serine proteinase kallikrein, circulates in plasma in an equimolar complex with H-kininogen. The binding to H-kininogen is mediated by the kallikrein heavy chain consisting of four “apple” domains, A1-A4, which attaches to H-kininogen with high specificity and affinity (KD = 83 nM). At least two distinct portions of the kallikrein heavy chain form this H-kininogen binding site: a proximal segment located in the NH2-terminal fragment of the heavy chain encompassing A1, and distal segment(s) located in COOH-terminal fragment spanning domains A2-A4. The proximal binding segment has been located to amino acid positions 56-86 of A1. To precisely map the distal binding segment, we have identified monoclonal antibodies directed to the COOH-terminal fragment which interfere with the H-kininogen-prekallikrein complex formation. Monoclonal antibody 13G11 binds to recombinant apple domain A4 but not to domain A3 of the prekallikrein heavy chain. Deletion mutagenesis of domain A4 narrowed down the target epitope of 13G11 to the center portion of domain A4, positions 284-331. Direct binding studies of H-kininogen to various domain A4 constructs revealed that the distal H-kininogen binding portion is located on a segment of 48 residues, which overlaps the 13G11 epitope. Hence the tight interaction of H-kininogen and prekallikrein is mediated by at least two separate sequence segments located in domains A1 and A4, respectively, of the prekallikrein heavy chain. The isolated distal binding segment significantly prolongs the partial thromboplastin time of reconstituted Williams plasma thus stressing the critical role of the prekallikrein-H-kininogen complex formation in the initiation of the endogenous blood coagulation cascade.
Cyclin-dependent Kinase 9 Links RNA Polymerase II Transcription to Processing of Ribosomal RNA*

Background: Processing of ribosomal RNA is sensitive to Cdk inhibitors. Results: Inhibition of Cdk9 activity blocks 47 S rRNA processing and stabilizes a 3′ extended 47 S primary transcript. Defective 3′ processing negatively feeds back on RNAPI transcription. Conclusion: Cdk9 facilitates processing of 47 S rRNA by RNAPII-dependent synthesis of U8 snoRNA. Significance: Cdk9 may be a critical regulator of rRNA processing to harmonize RNAPII transcription activity with a ribosome biogenesis rate. Ribosome biogenesis is a process required for cellular growth and proliferation. Processing of ribosomal RNA (rRNA) is highly sensitive to flavopiridol, a specific inhibitor of cyclin-dependent kinase 9 (Cdk9). Cdk9 has been characterized as the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Here we studied the connection between RNAPII transcription and rRNA processing. We show that inhibition of RNAPII activity by α-amanitin specifically blocks processing of rRNA. The block is characterized by accumulation of 3′ extended unprocessed 47 S rRNAs and the entire inhibition of other 47 S rRNA-specific processing steps. The transcription rate of rRNA is moderately reduced after inhibition of Cdk9, suggesting that defective 3′ processing of rRNA negatively feeds back on RNAPI transcription. Knockdown of Cdk9 caused a strong reduction of the levels of RNAPII-transcribed U8 small nucleolar RNA, which is essential for 3′ rRNA processing in mammalian cells. Our data demonstrate a pivotal role of Cdk9 activity for coupling of RNAPII transcription with small nucleolar RNA production and rRNA processing.
Bullying and Ostracism Experiences in Children With Special Health Care Needs

Objective: Bullying experiences are becoming increasingly common in children and can have devastating consequences. Ostracism threatens a child's need for self-esteem, sense of belonging, sense of control, and meaningful existence. Recent literature suggests that children with special health care needs may be at risk for these negative events and consequences. This study compares bullying and ostracism experiences in children with and without various special health care needs. Methods: Participants aged 8 to 17 years completed questionnaires during a routine primary care or subspecialty clinic visit. Children with learning disabilities (N = 34), attention deficit or hyperactivity disorder (N = 100), autism spectrum disorders (N = 32), behavioral or mental health disorders (N = 33), and cystic fibrosis (CF, N = 22) were compared with 73 control children with no diagnosis on Reynolds' Bully-Victimization Scale scores and a 15-item pilot ostracism scale. Results: Compared with the control group, children in the learning disabilities, autism spectrum disorders, and attention deficit or hyperactivity disorder groups exhibited significant victimization scores on the Bully-Victimization Scale, whereas the behavioral or mental health disorders group had increased mean victimization scores. The learning disabilities group also reported clinically significant bullying. The CF group did not report involvement as bullies or victims. All children with special health care needs groups had increased mean frequency of threats to basic needs related to ostracism, and children with attention deficit or hyperactivity disorder and autism spectrum disorders were at higher risk for ostracism experiences. Conclusion: Children with special health care needs may be at higher risk for bullying, victimization, and ostracism. Further research is needed to explore this relationship, especially as it relates to child adjustment. Children with special health care needs should be asked about bullying and ostracism experiences and potential effects as part of mental health screening.
Age-related DNA methylation in normal breast tissue and its relationship with invasive breast tumor methylation

Age is a key risk factor for breast cancer and epigenetic alterations may contribute to age-related increases in breast cancer risk, though the relation of age-related methylation in normal breast tissues with altered methylation in breast tumors is unclear. We investigated the relation of age with DNA methylation in normal breast tissues genome-wide using two data sets from the Gene Expression Omnibus (GEO) database (GSE32393 and GSE31979). We validated our observations in an independent set of normal breast tissues, examined age-related methylation in normal breast for enrichment of genomic features, and compared age-related methylation in normal tissue with methylation alterations in breast tumors. Between the two array-based methylation data sets, there were 204 CpG loci with significant (P < 0.05) and consistent age-related methylation, 97% of which were increases in methylation. Our validation sets confirmed the direction of age-related DNA methylation changes in all measured regions. Among the 204 age-related CpG loci, we observed a significant enrichment for CpG islands (P = 8.7E-6) and polycomb group protein target genes (P = 0.03). In addition, 24 of the 204 CpGs with age-related methylation in normal breast were significantly differentially methylated between normal and breast tumor tissues. We identified consistent age-related methylation changes in normal breast tissue that are further altered in breast tumors and may represent early events contributing to breast carcinogenesis. This work identifies age-related methylation in normal breast tissue and begins to deconstruct the contribution of aging to epigenetic alterations present in breast tumors.
siRNA nanoparticles: the future of RNAi therapeutics for oncology?

siRNA clinical trials: state of the art With the emergence of siRNA-based nanomedicine as a powerful therapeutic strategy for cancers, seven of these therapeutics have now advanced to clinical trials. Carriers of siRNA therapeutics include transferrin-modified cyclodextrin (CALAA-01, Arrowhead Research Corporation, CA, USA), in vivo jetPEI (SNS01-T; Sevion Technologies, NJ, USA), cationic liposomes (ALN-VSP02, Alnylam Pharmaceuticals, MA, USA; TKM080301, Tekmira Pharmaceuticals, Burnaby, Canada; Atu027, Silence Therapeutics, London, UK; and DCRMYC, Dicerna Pharmaceuticals, Watertown, MA, USA) and neutral liposomes (siRNA–EphA2–1,2-dioleoyl-sn-glycero3-phosphocholine [DOPC], MD Anderson Cancer Center, TX, USA ). Among those in clinical trials, the cationic lipoplex targeting MYC1a (DCR-MYC) is the only nanoplex that requires the Dicer enzyme in order to obtain functional siRNA. In 2008, the transferrin-modified cyclodextrin polyplex (CALAA-01) was the first siRNA nanoparticle to be approved for cancer clinical trials. In a preclinical mouse study, a single dose of the cyclodextrin nanoplex targeting luciferase mRNA reduced its activity by 80% [1]. More importantly, melanoma patients receiving CALAA-01 in a Phase I clinical trial showed a 50–80% reduction in the RRM2 mRNA compared with mRNA from untreated tumor tissues [2]. Although this study showed promise, the development of CALAA-01 has been delayed and no results have been reported. SNS01-T is a polyethyleneimine (PEI)based (in vivo JetPEI) nanoparticle containing siRNAs targeting EIF5A and decoy plasmids expressing nonhypusinable eIF5A mutants for treatment of multiple myeloma and non-Hodgkin’s B-cell lymphoma [3]. Francis and colleagues have shown that SNS01-T enhances the antitumor efficacy of lenalidomide and bortezomib in a xenograft model [3]. An open-label, Phase I/II doseescalation study that includes 15 patients is currently underway. Sevion technologies, the manufacturer of SNS01-T, has reported no dose-limiting toxicities in four patients at a dose of 0.2 mg/kg of the nanoparticle. Cationic lipid nanoparticles (LNPs) have effectively downregulated oncogenes in malignant hepatomas (CDH16, PLK1, VEGF and MYC1a) and prostate tumors (PKN3) [4]. While LNPs have a circulation half-life that is longer than 18 h [5], most lipoplexes are ultimately internalized by the liver and spleen. Although the accumulation of lipoplexes may lead to tissue toxicity in these organs at higher dosages, they appear to be well-tolerated by humans at defined dosages. In Phase I clinical trials, the maximum tolerated doses were 0.336, 0.75 and 1.25 mg/kg for Atu027, TKM080301 and ALN-VSP02, respectively. As a result, LNPs targeting PKN3 (Atu027) and PLK1 (TKM080301) have been advanced to Phase II trials. Neutral DOPC liposomes have been used to target ovarian cancers (EPHA2, PTK2, and IL8) and melanoma (thrombin receptor) [6]. While siRNA–EphA2–DOPC inhibited tumor growth by approximately siRNA nanoparticles: the future of RNAi therapeutics for oncology?
Safety and efficacy of patient controlled epidural analgesia following pediatric spinal surgery

Background: Patient controlled epidural analgesia (PCEA) is uncommon in pediatric anesthesia. Because PCEA offers superior pain control compared with continuous epidural infusions in adults, we prospectively evaluated the analgesia efficacy and safety of PCEA in children and adolescents following extensive spinal surgery.