Fixed Monthly versus Less Frequent Ranibizumab Dosing and Predictors of Visual Response in Exudative Age-Related Macular Degeneration

Purpose. To examine temporal patterns of visual acuity (VA) response to pooled 0.3 mg/0.5 mg ranibizumab treatment in patients with age-related macular degeneration and identify potential baseline predictors of response. Design. Retrospective analysis. Methods. Results from 1824 ranibizumab-treated patients receiving fixed monthly, quarterly, or as-needed dosing after three monthly loading doses in four phase III/IIIb trials (ANCHOR, MARINA, PIER, and SAILOR) were analyzed. Results. At month 3, 14.9% to 29.4% of patients had gained ≥15 letters. Not all patients achieved peak gains at month 3; many continued to have VA increases throughout treatment. After three monthly loading doses, continued monthly dosing resulted in further gains, as there were more delayed 15-letter responders at month 12 (14.7–16.1%) than with less frequent dosing (5.0–6.0%). Monthly dosing also resulted in more patients maintaining VA gains at later time points. Early 15-letter responders had lower baseline mean VA than delayed 15-letter responders in ANCHOR and MARINA; no other differences in baseline characteristics were noted. Conclusions. Although some patients have rapid improvements in VA, others do not experience peak VA until later during treatment. Continued monthly dosing resulted in a greater percentage of patients gaining ≥15 letters than with switching to less frequent dosing regimens

Modeling Collisionless Matter in General Relativity: A New Numerical Technique

We propose a new numerical technique for following the evolution of a self-gravitating collisionless system in general relativity. Matter is modeled as a scalar field obeying the coupled Klein-Gordon and Einstein equations. A phase space distribution function, constructed using covariant coherent states, obeys the relativistic Vlasov equation provided the de Broglie wavelength for the field is very much smaller than the scales of interest. We illustrate the method by solving for the evolution of a system of particles in a static, plane-symmetric, background spacetime.Comment: 6 pages, 3 postscript figures, submitted to Physical Review

Band Calculations for Ce Compounds with AuCu3_{3}-type Crystal Structure on the basis of Dynamical Mean Field Theory I. CePd3_{3} and CeRh3_{3}

Band calculations for Ce compounds with the AuCu$_{3}$-type crystal structure were carried out on the basis of dynamical mean field theory (DMFT). The auxiliary impurity problem was solved by a method named NCA$f^{2}$vc (noncrossing approximation including the $f^{2}$ state as a vertex correction). The calculations take into account the crystal-field splitting, the spin-orbit interaction, and the correct exchange process of the $f^{1} \rightarrow f^{0},f^{2}$ virtual excitation. These are necessary features in the quantitative band theory for Ce compounds and in the calculation of their excitation spectra. The results of applying the calculation to CePd$_{3}$ and CeRh$_{3}$ are presented as the first in a series of papers. The experimental results of the photoemission spectrum (PES), the inverse PES, the angle-resolved PES, and the magnetic excitation spectra were reasonably reproduced by the first-principles DMFT band calculation. At low temperatures, the Fermi surface (FS) structure of CePd$_{3}$ is similar to that of the band obtained by the local density approximation. It gradually changes into a form that is similar to the FS of LaPd$_{3}$ as the temperature increases, since the $4f$ band shifts to the high-energy side and the lifetime broadening becomes large.}Comment: 12 pasges, 13 figure

Embodied cognitive ecosophy: the relationship of mind, body, meaning and ecology

The concept of embodied cognition has had a major impact in a number of disciplines. The extent of its consequences on general knowledge and epistemology are still being explored. Embodied cognition in human geography has its own traditions and discourses but these have become somewhat isolated in the discipline itself. This paper argues that findings in other disciplines are of value in reconceptualising embodied cognition in human geography and this is explored by reconsidering the concept of ecosophy. Criticisms of ecosophy as a theory are considered and recent work in embodied cognition is applied to consider how such criticisms might be addressed. An updated conceptualisation is proposed, the embodied cognitive ecosophy, and three characteristics arising from this criticism and synthesis are presented with a view to inform future discussions of ecosophy and emotional geography

Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8

Antibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, but samples from time-of-infection—often used to infer the B cell record—are unavailable. In this study, we used crystallography, next-generation sequencing (NGS), and functional assessments to infer the 10E8 developmental pathway from a single time point. Mutational analysis indicated somatic hypermutation of the 2nd-heavy chain-complementarity determining region (CDR H2) to be critical for neutralization, and structures of 10E8 variants with V-gene regions reverted to genomic origin for heavy-and-light chains or heavy chain-only showed structural differences >2 Å relative to mature 10E8 in the CDR H2 and H3. To understand these developmental changes, we used bioinformatic sieving, maximum likelihood, and parsimony analyses of immunoglobulin transcripts to identify 10E8-lineage members, to infer the 10E8-unmutated common ancestor (UCA), and to calculate 10E8-developmental intermediates. We were assisted in this analysis by the preservation of a critical D-gene segment, which was unmutated in most 10E8-lineage sequences. UCA and early intermediates weakly bound a 26-residue-MPER peptide, whereas HIV-1 neutralization and epitope recognition in liposomes were only observed with late intermediates. Antibody 10E8 thus develops from a UCA with weak MPER affinity and substantial differences in CDR H2 and H3 from the mature 10E8; only after extensive somatic hypermutation do 10E8-lineage members gain recognition in the context of membrane and HIV-1 neutralization

Sympatric Speciation: When Is It Possible in Bacteria?

This study investigated a potential auditory illusion in duration perception induced by rhythmic temporal contexts. Listeners with or without musical training performed a duration discrimination task for a silent period in a rhythmic auditory sequence. The critical temporal interval was presented either within a perceptual group or between two perceptual groups. We report the just-noticeable difference (difference limen, DL) for temporal intervals and the point of subjective equality (PSE) derived from individual psychometric functions based on performance of a two-alternative forced choice task. In musically untrained individuals, equal temporal intervals were perceived as significantly longer when presented between perceptual groups than within a perceptual group (109.25% versus 102.5% of the standard duration). Only the perceived duration of the between-group interval was significantly longer than its objective duration. Musically trained individuals did not show this effect. However, in both musically trained and untrained individuals, the relative difference limens for discriminating the comparison interval from the standard interval were larger in the between-groups condition than in the within-group condition (7.3% vs. 5.6% of the standard duration). Thus, rhythmic grouping affected sensitivity to duration changes in all listeners, with duration differences being harder to detect at boundaries of rhythm groups than within rhythm groups. Our results show for the first time that temporal Gestalt induces auditory duration illusions in typical listeners, but that musical experts are not susceptible to this effect of rhythmic grouping.Ellison Medical FoundationSwiss National Science Foundation (PA00P1_131448/1

Dispersal: an alternative mating tactic conditional on sex ratio and body size

Small male milkweed beetles are less successful at obtaining mates than are larger males. Larger males usually win fights and prevent smaller males from obtaining mates and from choosing larger more fecund females as mates. When sex ratios are male-biased, smaller males are particularly likely to experience these mating disadvantages. It follows that smaller males should be especially responsive to their local competitive environment and behave so as to minimize the mating disadvantages of their smaller size. This paper tests the hypothesis that smaller males disperse from host plant patches with male-biased sex ratios and remain in patches with female-biased sex ratios more readily than larger males.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46883/1/265_2004_Article_BF00299931.pd

Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization

The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1