Miracle-dz/UniFAR-FTUs huggingface dataset:
The human poly(ADP‐ribose) polymerase nuclear localization signal is a bipartite element functionally separate from DNA binding and catalytic activity.

Poly(ADP‐ribose) polymerase (PARP, EC 2.4.2.30) is a zinc finger DNA‐binding protein involved in DNA repair processes in eukaryotes. By deletion and extensive site‐directed mutagenesis, its DNA‐binding domain fused to the N‐terminus of beta‐galactosidase was shown to contain a nuclear localization signal (NLS) of the form KRK‐X(11)‐KKKSKK (residues 207–226). In vitro, both the DNA‐binding capacity and the polymerizing activity of PARP are independent of the nuclear location function. Each basic cluster is essential but not sufficient on its own for this function, while both motifs together are. Crucial basic amino acids (K207, R208 and K222) in each of these two motifs are required for nuclear homing. The results presented here support the concept that the human PARP NLS is an autonomous functional element and belongs to the class of bipartite NLSs. We show that the linear distance between the two basic clusters is not crucial. Insertional mutation analysis leading to a partial reversion of the cytoplasmic phenotype displayed by the mutant K222I highlights the crucial positioning of this lysine. The structure‐function relationship of the second cluster of basic residues is discussed.
Normative pediatric brain data for spatial normalization and segmentation differs from standard adult data

Spatial normalization and morphological studies of pediatric brain imaging data based on adult reference data may not be appropriate due to the developmental differences between the two populations. In this study, we set out to create pediatric templates and a priori brain tissue data from a large collection of normal, healthy children to compare it to standard adult data available within a widely used imaging software solution (SPM99, WDOCN, London, UK). Employing four different processing strategies, we found considerable differences between our pediatric data and the adult data. We conclude that caution should be used when analyzing pediatric brain data using adult a priori information. To assess the effects of using pediatric a priori brain information, the data obtained in this study is available to the scientific community from our website (www.irc.cchmc.org). Magn Reson Med 50:749–757, 2003. © 2003 Wiley‐Liss, Inc.
Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy.

PURPOSE The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2)-overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population. PATIENTS AND METHODS This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy. RESULTS With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%). CONCLUSION T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.
Retinal origins of the temperature effect on absolute visual sensitivity in frogs.

1. The absolute sensitivity of vision was studied as a function of temperature in two species of frog (Rana temporaria, 9‐21 degrees C, and Rana pipiens, 13‐28 degrees C). 2. Log behavioural threshold (measured as the lowest light intensity by which frogs trying to escape from a dark box were able to direct their jumping) rose near‐linearly with warming with a regression coefficient of 1.26 +/‐ 0.03 log units per 10 degrees C (Q10 = 18). Threshold retinal illumination corresponded to 0.011 photoisomerizations per rod per second (Rh* s‐1) at 16.5 degrees C. 3. The effect of dim backgrounds on jumping thresholds suggested ‘dark lights’ of 0.011 Rh* s‐1 at 16.5 degrees C and 0.080 Rh* s‐1 at 23.5 degrees C, corresponding to Q10 = 17. 4. Response thresholds of retinal ganglion cells were extracellularly recorded in the isolated eyecup of R. temporaria. The thresholds of the most sensitive cells when stimulated with large‐field steps of light were similar to the behavioural threshold and changed with temperature in a similar manner. 5. The decrease in ganglion cell 'step’ sensitivity with warming consisted of a decrease in summation time (by a factor of 2‐3 between 10 and 20 degrees C) and an increase in the threshold number of photoisomerizations (a decrease in ‘flash’ sensitivity, by a factor of 2‐5 over the same interval). No effect of temperature changes on spatial summation was found. 6. Frequency‐of‐response functions of ganglion cells indicated an 11‐fold increase in noise‐equivalent dark light between 10 and 20 degrees C (mean values in four cells 0.009 vs. 0.10 Rh* s‐1). 7. The temperature dependence of ganglion cell flash sensitivity could be strongly decreased with dim background illumination. 8. It is concluded that the desensitization of dark‐adapted vision with rising temperature is a retinal effect composed of shortened summation time and lowered flash sensitivity (increased numbers of photons required for a threshold response) in ganglion cells. The desensitization bears no simple relation to the apparent retinal noise increase.
Psychological and Endocrine Responses to Psychosocial Stress and Dexamethasone/ Corticotropin-Releasing Hormone in Healthy Postmenopausal Women and Young Controls: The Impact of Age and a Two-Week Estradiol Treatment

In this placebo-controlled double-blind study, psychological and endocrine stress responses were investigated in healthy postmenopausal placebo-treated women (n = 15; 60–75 years; placebo via transdermal patches), healthy postmenopausal estradiol-treated women (n = 13; 60–79 years; 0.1 mg 17β-estradiol daily via transdermal patches) and young controls (n = 15; 20–31 years; untreated). The aged subjects received estradiol or placebo treatment for 14 days. All subjects were then exposed to the ‘Trier Social Stress Test’ (TSST) and the dexamethasone (Dex)-human corticotropin-releasing hormone (hCRH) test (100 µg hCRH after premedication with 1.5 mg Dex). Psychological parameters including perceived stressfulness, mood and subjective well-being were measured by visual analog scales, a mood questionnaire and a mood diary, respectively. Results show that the TSST induced significant increases in adrenocorticotropin (ACTH), free salivary cortisol, total plasma cortisol and heart rates (all p < 0.0001). Regardless of age, comparable hormonal response patterns were observed in the TSST as indicated by similar peak levels and recovery phases. Visual analog scales confirmed that the same amount of stress was experienced by young and elderly subjects. In both age groups, hCRH injection after Dex premedication provoked significant increases in ACTH, free salivary cortisol and total plasma cortisol (all p < 0.0001). In contrast to the psychosocial stressor, elderly women were found to respond with a markedly enhanced cortisol response compared to young controls in the Dex-CRH test (p < 0.025). Additional investigation of morning cortisol profiles could not reveal any age-related differences in basal hypothalamus-pituitary-adrenal (HPA) axis activity. Following estradiol treatment, estradiol levels significantly increased only in substituted postmenopausal women (p < 0.001) reaching concentrations typically found in younger women during the follicular phase of the menstrual cycle. Corticosteroid-binding globulin levels did not differ significantly between groups. When confronted with the TSST, no response differences emerged between the three groups. However, estradiol treatment appeared to blunt the total plasma cortisol response in the Dex-CRH test, resulting in smaller increases in untreated premenopausal women and estradiol-treated postmenopausal women compared to placebo-treated postmenopausal women (p < 0.02). In sum, no response differences were observed after confrontation with a psychosocial stress test in our sample of healthy elderly subjects. As shown with the Dex-CRH test, our data suggest that the negative feedback of the HPA axis in elderly women is altered. Moreover, the current data suggest that estradiol replacement may modulate HPA feedback sensitivity in humans.
Common and rare variants of DAOA in bipolar disorder

The D‐amino acid oxidase activator (DAOA, previously known as G72) gene, mapped on 13q33, has been reported to be genetically associated with bipolar disorder (BP) in several populations. The consistency of associated variants is unclear and rare variants in exons of the DAOA gene have not been investigated in psychiatric diseases. We employed a conditional linkage method—STatistical Explanation for Positional Cloning (STEPC) to evaluate whether any associated single nucleotide polymorphisms (SNPs) account for the evidence of linkage in a pedigree series that previously has been linked to marker D13S779 at 13q33. We also performed an association study in a sample of 376 Caucasian BP parent‐proband trios by genotyping 38 common SNPs in the gene region. Besides, we resequenced coding regions and flanking intronic sequences of DAOA in 555 Caucasian unrelated BP patients and 564 mentally healthy controls, to identify putative functional rare variants that may contribute to disease. One SNP rs1935058 could “explain” the linkage signal in the family sample set (P = 0.055) using STEPC analysis. No significant allelic association was detected in an association study by genotyping 38 common SNPs in 376 Caucasian BP trios. Resequencing identified 53 SNPs, of which 46 were novel SNPs. There was no significant excess of rare variants in cases relative to controls. Our results suggest that DAOA does not have a major effect on BP susceptibility. However, DAOA may contribute to bipolar susceptibility in some specific families as evidenced by the STEPC analysis. © 2009 Wiley‐Liss, Inc.
Trunk dental tissue evolved independently from underlying dermal bony plates but is associated with surface bones in living odontode-bearing catfish

Although oral dental tissue is a vertebrate attribute, trunk dental tissue evolved in several extinct vertebrate lineages but is rare among living species. The question of which processes trigger dental-tissue formation in the trunk remains open, and would shed light on odontogenesis evolution. Extra-oral dental structures (odontodes) in the trunk are associated with underlying dermal bony plates, leading us to ask whether the formation of trunk bony plates is necessary for trunk odontodes to emerge. To address this question, we focus on Loricarioidei: an extant, highly diverse group of catfish whose species all have odontodes. We examined the location and cover of odontodes and trunk dermal bony plates for all six loricarioid families and 17 non-loricarioid catfish families for comparison. We inferred the phylogeny of Loricarioidei using a new 10-gene dataset, eight time-calibration points, and noise-reduction techniques. Based on this phylogeny, we reconstructed the ancestral states of odontode and bony plate cover, and find that trunk odontodes emerged before dermal bony plates in Loricarioidei. Yet we discovered that when bony plates are absent, other surface bones are always associated with odontodes, suggesting a link between osteogenic and odontogenic developmental pathways, and indicating a remarkable trunk odontogenic potential in Loricarioidei.
Dolichol in Human Brain: Regional and Developmental Aspects

Abstract: Distinct regional differences in dolichol content were defined in human brain from 15 to 76 years of age. Concerning the regional distribution of dolichol, levels were: (1) higher in cortical gray matter than in subcortical white matter, (2) highest among cortical regions in temporal gray matter, (3) highest among all brain regions in thalamus, and (4) lowest among all brain regions in lower brain stem and spinal cord. The developmental changes in the contents of dolichol were found to be different among brain regions. For example, among regions with the highest levels of dolichol, in thalamus there was a six to sevenfold increase, but in parietal gray matter, only a 2.5‐fold increase. Regional and developmental changes in the proportions of the individual molecular species (isoprenologues) of dolichol were also observed. The findings indicate that the metabolism of dolichol is not uniform among regions of developing and aging human brain and may have implications for the role of dolichol in normal and diseased human brain.
Improving Web Usability Through Visualization

One reason for poor Web site usability is researchers' lack of understanding about how users surf for information. Predictive Web usage visualizations can help analysts uncover traffic patterns and usability problems. The author describes some of the techniques those in the User Interface Research Group at PARC have developed to visualize content changes, linkage structures, site usage, and so on. He explores how these techniques can be used to identify specific usability problems at large Web sites. As part of his work, he have created a predictive visualization model called Information Scent, in which simulated users help uncover patterns and deficiencies in information accessibility. He demonstrates these techniques using a prototype system called ScentViz to illustrate how Web usage analysis can be enhanced using visualization methods.
Cell-Free Massive MIMO systems

Cell-Free Massive MIMO systems comprise a large number of distributed, low cost, and low power access point antennas, connected to a network controller. The number of antennas is significantly larger than the number of users. The system is not partitioned into cells and each user is served by all access point antennas simultaneously. In this paper, we define cell-free systems and analyze algorithms for power optimization and linear pre-coding. Compared with the conventional small-cell scheme, Cell-Free Massive MIMO can yield more than ten-fold improvement in terms of 5%-outage rate.
Nosocomial transmission of tuberculosis infection in pediatrics wards

Analysis of restriction fragment length polymorphisms is a well‐established method of “DNA fingerprinting” that has been used to trace the transmission of particular strains of Mycobacterium tuberculosis during investigations of outbreaks. This report describe the use of restriction fragment length polymorphisms and arbitrarily primed polymerase chain reaction analysis to investigate two outbreaks of tuberculosis that affected six children who attended two pediatric wards in our hospital. In both outbreaks a history of household exposure to an adult with M. tuberculosis was obtained and suspected tuberculous contacts were identified. We have demonstrated unequivocally the strain relationship among the isolates in all the cases by restriction fragment length polymorphisms and arbitrarily primed polymerase chain reaction analysis. These techniques are very useful for performing epidemiologic studies of tuberculosis in children where natural history of tuberculosis infection is different from that in adults in that it is almost always primary infection rather than reactivation.
Alfentanil reduces the febrile response to interleukin‐2 in humans

Objective: Manifestation of intraoperative fever is impaired by volatile anesthetics and muscle relaxants. Opioids are common anesthetic adjuvants and remain the dominant treatment for postoperative surgical pain and sedation of critically ill patients. The effect of opioids on normal thermoregulatory control is well established. However, the extent to which these drugs might inhibit fever remains unknown. Accordingly, we tested the hypothesis that relatively low plasma concentrations of the μ‐receptor agonist alfentanil reduce fever magnitude. Design: Prospective, randomized, crossover study. Setting: Outcomes Research Laboratory, at the Department of Anesthesia and Perioperative Care, University of California, San Francisco. Patients: Eight healthy male volunteers, aged 25‐31 yrs, each studied on three separate days. Intervention: Each volunteer was given an intravenous injection of 30 IU/g interleukin (IL)‐2, followed 2 hrs later by 70 IU/g. One hour after the second dose, the volunteers were randomly assigned to three doses of alfentanil: a) none (control); b) a target plasma concentration of 100 ng/mL; and c) a target concentration of 200 ng/mL. Opioid administration continued for 5 hrs. Methods and Main Results: Alfentanil significantly reduced the febrile response to pyrogen, decreasing integrated tympanic membrane temperatures from 7.5 ± 2.2°C·hr on the control day, to 4.9 ± 1.5°C·hr with 100 ng/mL alfentanil, and to 5.1 ± 1.7°C·hr with 200 ng/mL alfentanil (p = .011). Peak temperatures were also significantly reduced from 38.5 ± 0.4°C on the control day, to 38.0 ± 0.4°C on the 100 ng/mL‐alfentanil day and 38.0 ± 0.6°C on the 200‐ng/mL day (p = .019). Plasma cytokine concentrations increased after IL‐2 administration, roughly in proportion to the elevation in core temperature. However, cytokine concentrations did not differ significantly among the treatment groups. Conclusion: Alfentanil significantly reduced the febrile response to IL‐2 administration. However, the reduction was comparable at plasma concentrations near 100 and 200 ng/mL. These data indicate that concentrations of opioids commonly observed in critical care patients significantly inhibit the manifestation of fever.
Integrating model-based and heuristic features in a real-time expert system

The Intelligent Alarm Processor, an alarm expert system integrated in a remote monitoring and control facility for a 22-kV network of more than 1350 substations, is described. With the Intelligent Alarm Processor, operators can locate network faults, analyze fault types, and detect malfunctions in the protection system. The system filters alarms based on their importance and independence, and suppresses repetitive alarms. Since the Intelligent Alarm Processor uses a model of the protection system, it can also validate its correct operation. To achieve these functions in a reasonable response time, the expert system has been designed with several hierarchic diagnosis levels that use heuristic rules as well as compiled qualitative models. <<ETX>>
Regular wavelets: a discrete-time approach

Regularity is a new filter property, brought by wavelet theory, for perfect reconstruction octave-band filter banks. Tools for investigating its role in coding applications are provided. First, discrete-time interpretations and optimal estimates of regularity are reviewed. Then, a simple design procedure for paraunitary FIR filter banks with optimal trade-off between frequency selectivity and regularity is given. Finally, the obtained filters are used to measure the effect of regularity versus frequency selectivity in a still image compression scheme with optimized rate-distortion. In this case, regularity is shown to be more relevant than frequency selectivity, especially for short filters. >
Solution Structure of the State 1 Conformer of GTP-bound H-Ras Protein and Distinct Dynamic Properties between the State 1 and State 2 Conformers*

Ras small GTPases undergo dynamic equilibrium of two interconverting conformations, state 1 and state 2, in the GTP-bound forms, where state 2 is recognized by effectors, whereas physiological functions of state 1 have been unknown. Limited information, such as static crystal structures and 31P NMR spectra, was available for the study of the conformational dynamics. Here we determine the solution structure and dynamics of state 1 by multidimensional heteronuclear NMR analysis of an H-RasT35S mutant in complex with guanosine 5′-(β, γ-imido)triphosphate (GppNHp). The state 1 structure shows that the switch I loop fluctuates extensively compared with that in state 2 or H-Ras-GDP. Also, backbone 1H,15N signals for state 2 are identified, and their dynamics are studied by utilizing a complex with c-Raf-1. Furthermore, the signals for almost all the residues of H-Ras·GppNHp are identified by measurement at low temperature, and the signals for multiple residues are found split into two peaks corresponding to the signals for state 1 and state 2. Intriguingly, these residues are located not only in the switch regions and their neighbors but also in the rigidly structured regions, suggesting that global structural rearrangements occur during the state interconversion. The backbone dynamics of each state show that the switch loops in state 1 are dynamically mobile on the picosecond to nanosecond time scale, and these mobilities are significantly reduced in state 2. These results suggest that multiconformations existing in state 1 are mostly deselected upon the transition toward state 2 induced by the effector binding.
The effect of two publicly funded insurance programs on use of dental services for young children.

OBJECTIVE The purpose of this study is to compare the use of dental services for preschool aged children enrolled in North Carolina Medicaid, a traditional program based on a fee-for-service schedule, and North Carolina Health Choice (NCHC), an State Children's Health Insurance Program (S-CHIP) dental insurance program structured similarly to private insurance. STUDY POPULATION All children (165,858) 1-5 years of age enrolled in Medicaid and S-CHIP (NCHC) at some time during one study year (October 1, 1999-September 30, 2000). DATA SOURCES/EXTRACTION METHODS: Medicaid and NCHC enrollment and dental claims files were obtained for individual children. STUDY DESIGN An observational study with a retrospective cohort design. Use of dental services for each child was measured as having at least one dental claim during the outcome period (October 1, 1999-September 30, 2000). Multivariable logistic regression models were developed to compare the effect of two differently administered insurance programs on the use of dental services, controlling for demographic, enrollment, and county characteristics. PRINCIPLE FINDINGS Children enrolled solely in S-CHIP (NCHC) were 1.6 times more likely (95 percent confidence intervals (CI)=1.50-1.79) to have a dental visit than those enrolled solely in Medicaid. Prediction models for children enrolled for 12 months indicated that those enrolled in S-CHIP (NCHC) had a significantly higher probability of having a dental visit (50 percent) than those enrolled in both plans (44 percent) or Medicaid only (39 percent), a trend found in all age groups. CONCLUSIONS The S-CHIP (NCHC) program appears to provide children with increased access to dental care compared to children in the Medicaid program.