Heterogeneous mass distribution of the rubble-pile asteroid (101955) Bennu.

The gravity field of a small body provides insight into its internal mass distribution. We used two approaches to measure the gravity field of the rubble-pile asteroid (101955) Bennu: (i) tracking and modeling the spacecraft in orbit about the asteroid and (ii) tracking and modeling pebble-sized particles naturally ejected from Bennu's surface into sustained orbits. These approaches yield statistically consistent results up to degree and order 3, with the particle-based field being statistically significant up to degree and order 9. Comparisons with a constant-density shape model show that Bennu has a heterogeneous mass distribution. These deviations can be modeled with lower densities at Bennu's equatorial bulge and center. The lower-density equator is consistent with recent migration and redistribution of material. The lower-density center is consistent with a past period of rapid rotation, either from a previous Yarkovsky-O'Keefe-Radzievskii-Paddack cycle or arising during Bennu's accretion following the disruption of its parent body.

Hemispherical differences in the shape and topography of asteroid (101955) Bennu.

We investigate the shape of near-Earth asteroid (101955) Bennu by constructing a high-resolution (20 cm) global digital terrain model from laser altimeter data. By modeling the northern and southern hemispheres separately, we find that longitudinal ridges previously identified in the north extend into the south but are obscured there by surface material. In the south, more numerous large boulders effectively retain surface materials and imply a higher average strength at depth to support them. The north has fewer large boulders and more evidence of boulder dynamics (toppling and downslope movement) and surface flow. These factors result in Bennu's southern hemisphere being rounder and smoother, whereas its northern hemisphere has higher slopes and a less regular shape. We infer an originally asymmetric distribution of large boulders followed by a partial disruption, leading to wedge formation in Bennu's history.

Initial Orbit Determination and Event Reconstruction From Estimation of Particle Trajectories About (101955) Bennu.

The OSIRIS-REx mission has observed multiple instances of particles being ejected from the surface of near-Earth asteroid (101955) Bennu. The ability to quickly identify the particle trajectories and origins is necessary following a particle ejection event. Using proven initial orbit determination techniques, we can rapidly estimate particle trajectories and ejection locations. We present current results pertaining to the identification of particle tracks, an evaluation of the estimated orbits and the excess velocity necessary to induce the particle ejection from the surface, and the uncertainty quantification of the ejection location. We estimate energies per particle ranging from 0.03 to 11.03 mJ for the largest analyzed events and velocities ranging from 5 to 90 cm/s, though we exclude the highest-velocity particles in this technique. We estimate ejection times for eight events and constrain six of the analyzed ejection events to have occurred between about 16:30 and 19:00 local solar time, with the largest events occurring between 16:30 and 18:05.

Episodes of particle ejection from the surface of the active asteroid (101955) Bennu.

Active asteroids are those that show evidence of ongoing mass loss. We report repeated instances of particle ejection from the surface of (101955) Bennu, demonstrating that it is an active asteroid. The ejection events were imaged by the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) spacecraft. For the three largest observed events, we estimated the ejected particle velocities and sizes, event times, source regions, and energies. We also determined the trajectories and photometric properties of several gravitationally bound particles that orbited temporarily in the Bennu environment. We consider multiple hypotheses for the mechanisms that lead to particle ejection for the largest events, including rotational disruption, electrostatic lofting, ice sublimation, phyllosilicate dehydration, meteoroid impacts, thermal stress fracturing, and secondary impacts.

The dynamic geophysical environment of (101955) Bennu based on OSIRIS-REx measurements.

The top-shape morphology of asteroid (101955) Bennu is commonly found among fast-spinning asteroids and binary asteroid primaries, and might have contributed significantly to binary asteroid formation. Yet a detailed geophysical analysis of this morphology for a fast-spinning asteroid has not been possible prior to the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission. Combining the measured Bennu mass and shape obtained during the Preliminary Survey phase of OSIRIS-REx, we find a significant transition in Bennu's surface slopes within its rotational Roche lobe, defined as the region where material is energetically trapped to the surface. As the intersection of the rotational Roche lobe with Bennu's surface has been most recently migrating towards its equator (given Bennu's increasing spin rate), we infer that Bennu's surface slopes have been changing across its surface within the last million years. We also find evidence for substantial density heterogeneity within this body, suggesting that its interior has a distribution of voids and boulders. The presence of such heterogeneity and Bennu's top-shape is consistent with spin-induced failure at some point in its past, although the manner of its failure cannot be determined yet. Future measurements by the OSIRIS-REx spacecraft will give additional insights and may resolve questions regarding the formation and evolution of Bennu's top-shape morphology and its link to the formation of binary asteroids.

A method to produce radiation hybrids for the D-genome chromosomes of wheat (Triticum aestivum L.).

Radiation hybrid (RH) mapping is based on radiation-induced chromosome breakage rather than meiotic recombination, as a means to induce marker segregation for mapping. To date, the implementation of this mapping approach in hexaploid (Triticum aestivum L.; 2n = 6x = 42; AABBDD) and tetraploid (T. turgidum L.; 2n = 4x = 28; AABB) wheat has concentrated on the production of mapping panels for individual chromosomes. In order to extend the usefulness of this approach, we have devised a method to produce panels for the simultaneous mapping of all chromosomes of the D subgenome of hexaploid wheat. In this approach, seeds of hexaploid wheat (AABBDD) are irradiated and the surviving plants are crossed to tetraploid wheat (AABB) to produce a mapping panel based on quasi-pentaploids (AABBD). Chromosome lesions in the A and B genomes are largely masked in the quasi-pentaploids due to the presence of A- and B-genome chromosomes from the tetraploid parent. On the other hand, the chromosomes from the D-genome are present in one copy (hemizygous) and allow radiation hybrid mapping of all D-genome chromosomes simultaneously. Our analyses showed that transmission of D-genome chromosomes was apparently normal and that radiation-induced chromosome breakage along D-genome chromosomes was homogeneous. Chromosome breakage levels between D-genome chromosomes were comparable except for chromosome 6D which suffered greater chromosome breakage. These results demonstrate the feasibility of constructing D-genome radiation hybrids (DGRHs) in wheat.

Temperature has a causal effect on avian timing of reproduction.

Many bird species reproduce earlier in years with high spring temperatures, but little is known about the causal effect of temperature. Temperature may have a direct effect on timing of reproduction but the correlation may also be indirect, for instance via food phenology. As climate change has led to substantial shifts in timing, it is essential to understand this causal relationship to predict future impacts of climate change. We tested the direct effect of temperature on laying dates in great tits (Parus major) using climatized aviaries in a 6-year experiment. We mimicked the temperature patterns from two specific years in which our wild population laid either early ('warm' treatment) or late ('cold' treatment). Laying dates were affected by temperature directly. As the relevant temperature period started three weeks prior to the mean laying date, with a range of just 4 degrees C between the warm and the cold treatments, and as the birds were fed ad libitum, it is likely that temperature acted as a cue rather than lifting an energetic constraint on the onset of egg production. We furthermore show a high correlation between the laying dates of individuals reproducing both in aviaries and in the wild, validating investigations of reproduction of wild birds in captivity. Our results demonstrate that temperature has a direct effect on timing of breeding, an important step towards assessing the implication of climate change on seasonal timing.

Shifts in caterpillar biomass phenology due to climate change and its impact on the breeding biology of an insectivorous bird.

Timing of reproduction has major fitness consequences, which can only be understood when the phenology of the food for the offspring is quantified. For insectivorous birds, like great tits (Parus major), synchronisation of their offspring needs and abundance of caterpillars is the main selection pressure. We measured caterpillar biomass over a 20-year period and showed that the annual peak date is correlated with temperatures from 8 March to 17 May. Laying dates also correlate with temperatures, but over an earlier period (16 March-20 April). However, as we would predict from a reliable cue used by birds to time their reproduction, also the food peak correlates with these temperatures. Moreover, the slopes of the phenology of the birds and caterpillar biomass, when regressed against the temperatures in this earlier period, do not differ. The major difference is that due to climate change, the relationship between the timing of the food peak and the temperatures over the 16 March-20 April period is changing, while this is not so for great tit laying dates. As a consequence, the synchrony between offspring needs and the caterpillar biomass has been disrupted in the recent warm decades. This may have severe consequences as we show that both the number of fledglings as well as their fledging weight is affected by this synchrony. We use the descriptive models for both the caterpillar biomass peak as for the great tit laying dates to predict shifts in caterpillar and bird phenology 2005-2100, using an IPCC climate scenario. The birds will start breeding earlier and this advancement is predicted to be at the same rate as the advancement of the food peak, and hence they will not reduce the amount of the current mistiming of about 10 days.

Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection.

The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.

Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects.

BACKGROUND: Intensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown. METHODS: Twenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities. RESULTS: Those taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL3 cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P < 0.01) in those taking ritonavir-compared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles. CONCLUSION: Treatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.

Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response.

The effects of 1 year of zidovudine, lamivudine, and ritonavir treatment on immune reconstitution were evaluated in 34 human immunodeficiency virus (HIV)-infected individuals. After 48 weeks of therapy, 20 (59%) subjects had <100 copies HIV RNA/mL. CD4+ T cells increased from a median of 192/mm3 at baseline to 362/mm3 at week 48. Lymphocyte proliferative responses to Candida normalized within 12 weeks, but responses to HIV and tetanus remained depressed throughout therapy. Alloantigen responses increased within 12 weeks and then declined to baseline levels. Recovery of delayed-type hypersensitivity responses occurred after 12 weeks for Candida and after 48 weeks for mumps. The magnitude of virologic suppression was correlated with numeric increases in CD4+ T cells, but not with measures of functional immune reconstitution. Plasma virus suppression <100 copies/mL was not significantly correlated with increases in CD4+ T cells or functional immune reconstitution.

A simple relationship between viral load and survival time in HIV-1 infection.

Despite important recent insights into the short-term dynamics of HIV-1 infection, our understanding of the long-term pathogenesis of AIDS remains unclear. Using an approach that places rapid progressors, typical progressors, and nonprogressors on a single clinical spectrum of disease progression, we quantitate the previously reported relationship between viral load and survival time. We introduce the concept of viral constant, present evidence that this quantity is conserved across patients, and explore the immunopathological implications of this finding. We conclude with a quantitative approach for assessing the benefits of a given regime of antiviral therapy.

Ritonavir and saquinavir combination therapy for the treatment of HIV infection.

OBJECTIVE: To evaluate the safety and antiretroviral activity of ritonavir (Norvir) and saquinavir (Invirase) combination therapy in patients with HIV infection. DESIGN: A multicenter, randomized, open-label clinical trial. SETTING: Seven HIV research units in the USA and Canada. PATIENTS: A group of 141 adults with HIV infection, CD4 T lymphocyte counts of 100-500 x 10(6) cells/l, whether treated previously or not with reverse transcriptase inhibitor therapy, but without previous HIV protease inhibitor drug therapy. INTERVENTIONS: After discontinuation of prior therapy for 2 weeks, group I patients were randomized to receive either combination (A) ritonavir 400 mg and saquinavir 400 mg twice daily or (B) ritonavir 600 mg and saquinavir 400 mg twice daily. After an initial safety assessment of group I patients, group II patients were randomized to receive either (C) ritonavir 400 mg and saquinavir 400 mg three times daily or (D) ritonavir 600 mg and saquinavir 600 mg twice daily. Investigators were allowed to add up to two reverse transcriptase inhibitors (including at least one with which the patient had not been previously treated) to a patient's regimen after week 12 for failure to achieve or maintain an HIV RNA level < or = 200 copies/ml documented on two consecutive occasions. MEASUREMENTS: Plasma HIV RNA levels and CD4+ T-lymphocyte counts were measured at baseline, every 2 weeks for 2 months, and monthly thereafter. Safety was assessed through the reporting of adverse events, physical examinations, and the monitoring of routine laboratory tests. RESULTS: The 48 weeks of study treatment was completed by 75% (106/141) of the patients. Over 80% of the patients on treatment at week 48 had an HIV RNA level < or = 200 copies/ml. In addition, intent-to-treat and on-treatment analyses revealed comparable results. Suppression of plasma HIV RNA levels was similar for all treatment arms (mean areas under the curve minus baseline through 48 weeks were-1.9, -2.0, -1.6, -1.8 log10 copies/ml in ritonavir-saquinavir 400-400 mg twice daily, 600-400 mg twice daily, 400-400 mg three times daily, and 600-600 mg twice daily, respectively). Median CD4 T-lymphocyte count rose by 128 x 10(6) cells/l from baseline, with an interquartile range (IQR) of 82-221 x 10(6) cells/l. The most common adverse events were diarrhea, circumoral paresthesia, asthenia, and nausea. Reversible elevation of serum transaminases (> 5 x upper limit of normal) occurred in 10% (14/141) of the patients enrolled in this study and was associated with baseline abnormalities in liver function tests, baseline hepatitis B surface antigen positivity, or hepatitis C antibody positivity (relative risk, 5.0; 95% confidence interval 1.5-16.9). Most moderate or severe elevations in liver function tests occurred in patients treated with ritonavir-saquinavir 600-600 mg twice daily. CONCLUSIONS: Ritonavir 400 mg combined with saquinavir 400 mg twice daily with the selective addition of reverse transcriptase inhibitors was the best-tolerated regimen of four dose-ranging regimens and was equally as active as the higher dose combinations in HIV-positive patients without previous protease inhibitor treatment.

Characterization of viral dynamics in human immunodeficiency virus type 1-infected patients treated with combination antiretroviral therapy: relationships to host factors, cellular restoration, and virologic end points.

Biphasic plasma viral decays were modeled in 48 patients treated with ritonavir, zidovudine, and lamivudine. Estimated first- and second-phase decay rates were d1 as 0.47/day and d2 as 0.04/day. Interpatient differences in both decay rates were significant. The d1 was directly correlated with baseline CD4+, CD4+CD28+, and CD8+CD28+ T lymphocyte counts (P<.05) and inversely correlated with baseline virus load (P=.044) and the magnitude of CD4+ and CD8+ T lymphocyte recovery (P<.01). The d2 was directly correlated with baseline percentage of CD8+ T lymphocytes (P=.023), the CD8+CD38+ cell number (P=.024), and the level of IgG that binds to human immunodeficiency virus (HIV) type 1 gp120 (P=.02). Viral decay rates were not predictive of treatment failure or durability of viral suppression. These exploratory findings are consistent with a model in which immunologic factors contribute to elimination of HIV-infected cells and suggest a dynamic interplay between regulation of HIV expression and lymphocyte activation and recovery.

The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses.

Twelve subjects were treated with zidovudine, lamivudine, and ritonavir within 90 days of onset of symptoms of acute infection to determine whether human immunodeficiency virus type 1 (HIV-1) infection could be eradicated from an infected host. In adherent subjects, with or without modifications due to intolerance, viral replication was suppressed during the 24-month treatment period. Durable suppression reduced levels of HIV-1-specific antibodies and cytotoxic T lymphocyte responses in selected subjects. Proviral DNA in mononuclear cells uniformly persisted. The persistence of HIV-1 RNA expression in lymphoid tissues and peripheral blood mononuclear cells suggests that elimination of this residual pool of virus should be achieved before considering adjustments in antiretroviral therapeutic regimens. In addition, given the reduction in levels of virus-specific immune responses, it would seem prudent to consider enhancing these responses using vaccine strategies prior to the withdrawal of antiviral therapy.

Effect of fluoxetine on pharmacokinetics of ritonavir.

The potential interaction between fluoxetine, a known inhibitor of cytochrome P-450 isoform 2D6 (CYP2D6), and ritonavir, a human immunodeficiency virus type 1 protease inhibitor, was evaluated in this open-label study. Sixteen male and female subjects ranging in age from 18 to 40 years completed the study. Subjects received single doses of 600 mg of ritonavir on days 1 and 10. On study days 3 to 10, all subjects received 30 mg of fluoxetine every 12 h for a total of 16 consecutive doses. Serial blood samples for determination of ritonavir concentrations in plasma were collected after the administration of ritonavir on days 1 and 10. A limited number of blood samples for determination of fluoxetine and norfluoxetine concentrations were collected after administration of the morning dose on day 10. A statistically significant increase (19%) in the ritonavir area under the concentration-time curve (AUC) was observed with concomitant fluoxetine administration, with individual changes ranging from -12 to +56%. The change in the ritonavir AUC with concomitant fluoxetine administration was positively correlated with the norfluoxetine 24-h AUC (AUC24) (r2 = 0.42), the norfluoxetine/fluoxetine AUC24 ratio (r2 = 0.53), and the fluoxetine elimination rate constant (r2 = 0.65), with larger increases in the ritonavir AUC tending to occur with higher norfluoxetine concentrations and higher fluoxetine elimination rate constants. The effect of fluoxetine appeared to be larger in subjects with the CYP2D6 wt/wt genotype. There was little or no effect on the time to maximum drug concentration (Cmax) in serum, Cmax, and the elimination rate constant of ritonavir with concomitant fluoxetine administration. Considering the magnitude of the change observed, no ritonavir dose adjustment is recommended during concomitant fluoxetine administration.

ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease.

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, 50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

Pharmacokinetic interaction between ritonavir and clarithromycin.

BACKGROUND: Because ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, and clarithromycin, a macrolide antibiotic used in the treatment of disseminated infection caused by Mycobacterium avium complex, are likely to be administered concurrently for treatment of patients with HIV and acquired immunodeficiency syndrome (AIDS), the drug interaction potential of these 2 agents was evaluated. Both clarithromycin and ritonavir are metabolized to a significant extent through cytochrome P450-mediated biotransformation and are potential inhibitors of these enzymes. OBJECTIVE: To evaluate the pharmacokinetic effects of concomitant administration of multiple doses of ritonavir and clarithromycin. METHODS: This was an open-label, randomized, 3-period crossover study. Ritonavir alone (200 mg every 8 hours), clarithromycin alone (500 mg every 12 hours), and ritonavir and clarithromycin in combination were administered to 22 healthy volunteers. Blood samples were collected on day 4 for determination of ritonavir, clarithromycin, and its metabolite 14-(R)-hydroxyclarithromycin. RESULTS: Ritonavir practically completely inhibited the formation of 14-(R)-hydroxyclarithromycin. The mean area under the plasma concentration-time curve (AUC) for clarithromycin increased by 77% with concomitant ritonavir, and the harmonic mean terminal half-life increased from 5 hours to 14 hours. Statistically significant increases in peak plasma concentration (31%) and minimum plasma concentration (182%) were also observed. The effect of concomitant clarithromycin administration on ritonavir pharmacokinetics was statistically significant but small, with a 12.5% increase in mean AUC and a 15.3% increase in peak plasma concentration. The terminal half-life increased from 3.47 to 3.87 hours with concomitant clarithromycin. CONCLUSIONS: No adjustment of the ritonavir dose is necessary when administered with clarithromycin. In addition, no changes in clarithromycin dose are warranted in patients with normal renal function.

Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus.

The potency of therapeutic regimens containing human immunodeficiency virus (HIV) protease inhibitors is related to the ability to maintain concentrations of drug in the plasma of patients that are sufficient for blocking viral replication. The estimation of concentrations required for in vivo activity using in vitro assays is complicated by the fact that extensive binding of many protease inhibitors to serum proteins attenuates their antiviral potency. To provide insight into the relative in vivo potency of current protease inhibitors, we assayed their in vitro activity against wild-type and mutant HIV in the presence of human serum (HS). Using this assay, ABT-378, a new protease inhibitor with trough levels in humans far in excess of the EC50 in the presence of 50% HS, was identified. The antiviral activity of ABT-378 was only modestly attenuated by HS, in contrast to ritonavir, saquinavir, and nelfinavir. Examination of the effect of individual serum components suggested that the activity of ABT-378 is affected predominantly by binding to alpha1-acid glycoprotein (AGP) while the activity of ritonavir is modulated by both AGP and albumin. The method described here may provide insight into the in vivo potency of protease inhibitors and be useful for the preclinical evaluation and selection of new protease inhibitors for clinical studies.