Potent piperazine hydroxyethylamine HIV protease inhibitors containing novel P3 ligands

The 2-isopropyl thiazolyl group is a highly optimized P3 ligand for C2 symmetry-based HIV protease inhibitors, as exemplified in the drug ritonavir. Here we report that incorporation of this P3 ligand into a piperazine hydroxyethylamine series also yielded novel, highly potent inhibitors. In tissue culture assays, the presence of human serum was less deleterious to the activity of these inhibitors than to that of ritonavir. Furthermore, potent activity against ritonavir resistant HIV was observed.     

Hormonal secretion during nighttime sleep indicating stress of daytime exercise

We tested the hypothesis that long-duration exercise (LDE) of moderate intensity, but not LDE of low intensity, during the daytime changes the typical temporal patterns of hormone release during subsequent nocturnal sleep. Ten trained healthy men participated in a balanced crossover study including three conditions: 1) no exercise, 2) LDE of low intensity (biking 40 km; 1800-2030), and 3) LDE of moderate intensity (biking 120-150 km; 1600-2030). During the subsequent night (2300-0700), somnopolygraphic sleep recordings were obtained, and concentrations of cortisol, growth hormone (GH), and testosterone were measured every 15 min. During the no exercise nights, the typical secretory patterns were present with peak concentrations of GH but nadir concentrations of cortisol during the first half of sleep but increased cortisol levels and minimum GH levels during the second part of sleep. Testosterone concentrations increased during the second half of sleep. LDE of moderate intensity reduced rapid-eye-movement sleep [13.9 vs. 16.9% (no exercise); P < 0.01]. Levels of testosterone decreased with increasing intensity of daytime exercise (P < 0.05). Moderate-, but not low-intensity, LDE decreased GH levels in the first half (P < 0.05) and increased GH levels in the second half (P < 0.005) of sleep. Also, LDE of moderate intensity but not LDE of low intensity increased cortisol levels during the first half (P < 0.005) and decreased cortisol secretion during the second half (P < 0.05) of sleep. Results suggest that nocturnal profiles of GH and cortisol concentrations may serve to indicate the disturbance of normal anabolic functions of sleep due to daytime exercise.     

Studies of the neutralizing activity and avidity of anti-human immunodeficiency virus type 1 Env antibody elicited by DNA priming and protein boosting

DNA vaccination is an effective means of eliciting strong antibody responses to a number of viral antigens. However, DNA immunization alone has not generated persistent, high-titer antibody and neutralizing antibody responses to human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env). We have previously reported that DNA-primed anti-Env antibody responses can be augmented by boosting with Env-expressing recombinant vaccinia viruses. We report here that recombinant Env protein provides a more effective boost of DNA-initiated antibody responses. In rabbits primed with Env-expressing plasmids, protein boosting increased titer, persistence, neutralizing activity, and avidity of anti-Env responses. While titers increased rapidly after boosting, avidity and neutralizing activity matured more slowly over a 6-month period following protein boosting. DNA priming and protein immunization with HIV-1 HXB-2 Env elicited neutralizing antibody for T cell line-adapted, but not primary isolate, viruses. The most effective neutralizing antibody responses were observed after priming with plasmids which expressed noninfectious virus-like particles. In contrast to immunizations with HIV-1 Env, DNA immunizations with the influenza virus hemagglutinin glycoprotein did not require a protein boost to achieve high-titer antibody with good avidity and persistence.     

Effect of physical aging on the fracture behavior of crosslinked epoxies

The effect of physical aging on the fracture behavior, crack opening displacement, and plastic deformation zone of unmodified and rubber-modified epoxies was determined at two aging temperatures and different displacement rates. The strain energy release rate decreases to between 40 and 50% (for rubber modified and unmodified samples, respectively) of the unaged values after 35 days aging. Systematic dependence of the decrease in fracture toughness by aging on the rubber content is not apparent. The increased yield stress after physical aging is the main factor contributing to the reduction in fracture toughness, crack opening displacement, and plastic deformation zone. Physical aging suppresses the crack blunting mechanisms in epoxies.     

Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects

CONTEXT: Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population. OBJECTIVE: To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors"). DESIGN: Convenience sample. SUBJECTS: Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. SETTING: University-based medical centers and affiliated hospitals. MAIN OUTCOME MEASURES: Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences. RESULTS: The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas. CONCLUSIONS: Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.     

Quantal release at visualized terminals of a crayfish motor axon: intraterminal and regional differences

Synaptic transmission was measured at visualized terminal varicosities of the motor axon providing the sole excitatory innervation of the "opener" muscle in walking legs of crayfish (Procambarus clarkii Girard). Two questions were addressed: 1) How uniform is quantal emission at different locations along terminals innervating a single muscle fiber, and 2) can differences in quantal emission account for the different excitatory postsynaptic potential (EPSP) amplitudes generated by terminals localized in defined regions of the muscle? Extracellular "macropatch" electrodes were placed over individual varicosities, viewed after brief exposure to a fluorescent dye, and synaptic currents were recorded to determine quantal content of transmission. Along terminals supplying a single muscle fiber, nonuniform release was found: Varicosities closer to the point of origin of the terminal branch released more transmitter than those located more distally. Quantal content was higher for varicosities of the muscle's proximal region (where large EPSPs occur) than for varicosities of the central region (where small EPSPs occur). The probability of transmitter release per synapse is estimated to be greater for the proximal varicosities. At low frequencies of stimulation, quantal content per muscle fiber is two to four times larger in the proximal region. Taken in conjunction with a twofold higher mean input resistance for the proximal muscle fibers, the difference in quantal content can account for a four- to eightfold difference in EPSP amplitude. The observed mean EPSP amplitude is at least eight times larger in the proximal region. We discuss factors contributing to differences in EPSP amplitudes.     

Illness and injury in family day care: a seasonal survey

Many mothers with children under age 6 are employed and it is not usually feasible for a parent to stay home with a child who is mildly ill. Such ill children likely remain in child day care programs. The extent to which this occurs and the management of these children in family day care was studied. Over the course of a year, 1 to 3 visits were made to 714 family day care homes in order to survey providers. With enrollments ranging between 0 and 18 children per day care home at the time of each visit, information on 3,630 "child enrollment days" was collected. The median age of children in care was 2 years. An average of 16% of all children were ill on any one day (with seasonal variation); 1% were injured. Of ill children, 82% attended day care that day, 49% had contacted a physician about that illness, and 28% were administered a medication at the day care setting. Twenty-one percent of children receiving medication in day care had no contact with a physician for that illness. These data show that mild childhood illnesses are routinely managed by child day care providers. Physicians who traditionally limit their illness-management education to parents need to recognize the health education and consultation needs of day care providers.     

Modeling Groups of Plausible Virtual Pedestrians

In a proposed methodology for modeling dynamic crowd scenarios, a video corpus informs the modeling process, after which the resultant animations undergo perception-based evaluation. The aim is to improve the crowd's visual plausibility rather than the simulation's correctness. A real-life crowd animation system demonstrates the methodology's practical application.     

Accounting for no difference/preference responses or ties in choice experiments

The analysis of choice data in which no difference/preference responses, or ties, occur is considered in this paper. A key issue addressed in the paper is the need for “identicality norms” for difference and preference tests. These norms reflect the researcher’s expectation for the number of ties that would have occurred in the experiment had the products tested been putatively identical. Without these norms, the issue of how to account for ties can never be fully resolved. After this idea is developed, some methods from the statistics literature to account for ties are reviewed and the Thurstonian 2-AC (2-Alternative Choice) model is discussed. Common practices of equal or proportional redistribution of ties are noted to be either conservative or liberal, respectively, when the binomial distribution is used to evaluate results. In particular, the exact probability function for the equal allocation method is given as a particular type of mixing distribution, known as a convolution, of binomial probability functions. Regardless of which statistical method is used to test tied data, however, none of the current methods of analysis can account for segmentation or the effect of heterogeneity in individual assessors. To study the possible effect of heterogeneity, the data could first be tested against an identicality norm. Thus, this research clarifies the assumptions that are made when conducting tests on paired comparison data with ties and provides guidance on the choice of analytic method.