Mode of Action of Invasion-Inhibitory Antibodies Directed against Apical Membrane Antigen 1 of Plasmodium falciparum

Antibodies against apical membrane antigen 1 (AMA-1) of Plasmodium falciparum inhibit merozoite invasion into erythrocytes. Invasion-inhibitory polyclonal AMA-1 antibodies inhibit secondary proteolytic processing and surface redistribution of AMA-1 on merozoites. We present evidence supporting inhibition of processing and redistribution as probable causes of inhibition of invasion by polyclonal antibodies. Polyclonal anti-AMA-1 was much more inhibitory than monoclonal antibody (MAb) 4G2dc1 in an invasion assay. Although both polyclonal and monoclonal immunoglobulin G (IgG) inhibited secondary processing of the 66-kDa form of AMA-1, only polyclonal IgG caused its anomalous processing, inhibited its redistribution, and cross-linked soluble forms of AMA-1 on merozoites. Moreover, Fab fragments of polyclonal IgG that fail to cross-link did not show the enhancement of inhibitory effect over intact IgG, as observed in the case of Fab fragments of MAb 4G2dc1. We propose that although blocking of biologically important sites is a common direct mode of action of anti-AMA-1 antibodies, blocking of AMA-1 secondary processing and redistribution are additional indirect inhibitory mechanisms by which polyclonal IgG inhibits invasion. We also report a processing inhibition assay that uses a C-terminal AMA-1-specific MAb, 28G2dc1, to detect merozoite-bound remnants of processing (∼20 kDa from normal processing to 48 and 44 kDa and ∼10 kDa from anomalous processing to a 52-kDa soluble form of AMA-1). The ratio of intensity of 10-kDa bands to the sum of 10- and 20-kDa bands was positively correlated with inhibition of invasion by polyclonal antibodies. This assay may serve as an important immunochemical correlate for inhibition of invasion

Electron, photon, and ion beams from the relativistic interaction of Petawatt laser pulses with solid targets

In our Petawatt laser experiments several hundred joules of 1 {micro}m laser light in 0.5-5.0 ps pulses with intensities up to 3 x 10{sup 20}Wcm{sup -2} were incident on solid targets producing a strongly relativistic interaction. The energy content, spectra, and angular patterns of the photon, electron, and ion radiations were diagnosed in a number of ways, including several novel (to laser physics) nuclear activation techniques. From the beamed bremsstrahlung we infer that about 40-50% of the laser energy is converted to broadly beamed hot electrons. Their direction centroid varies from shot to shot, but the beam has a consistent width. Extraordinarily luminous ion beams almost precisely normal to the rear of various targets are seen--up to 3 x 10{sup 13} protons with kT{sub ion} {approx} several MeV representing {approx}6% of the laser energy. We observe ion energies up to at least 55 MeV. The ions appear to originate from the rear target surfaces. The edge of the ion beam is very sharp, and collimation increases with ion energy. At the highest energies, a narrow feature appears in the ion spectra, and the apparent size of the emitting spot is smaller than the full back surface area. Any ion emission from the front of the targets is much less than from the rear and is not sharply beamed. The hot electrons generate a Debye sheath with electrostatic fields of order MV per micron which apparently accelerate the ions

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu

Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts

OBJECTIVE To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody-positive relatives of people with type 1 diabetes. RESEARCH DESIGN AND METHODS We examined 2-h OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (mean ± SD age, 13.84 ± 9.53 years; BMI Z-score, 0.33 ± 1.07; 56.1% male) and 3,720 PTP participants (age, 16.01 ± 12.33 years; BMI Z-score, 0.66 ± 1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-score, HOMA-insulin resistance, and peak glucose/C-peptide levels, respectively) were performed. RESULTS In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (P < 0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: χ2 = 25.76 vs. χ2 = 8.62; PTP: χ2 = 149.19 vs. χ2 = 79.98; all P < 0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. CONCLUSIONS In two independent at-risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression