Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals.

BACKGROUND: The isolation of human monoclonal antibodies (mAbs) that neutralize a broad spectrum of primary HIV-1 isolates and the characterization of the human neutralizing antibody B cell response to HIV-1 infection are important goals that are central to the design of an effective antibody-based vaccine. METHODS AND FINDINGS: We immortalized IgG(+) memory B cells from individuals infected with diverse clades of HIV-1 and selected on the basis of plasma neutralization profiles that were cross-clade and relatively potent. Culture supernatants were screened using various recombinant forms of the envelope glycoproteins (Env) in multiple parallel assays. We isolated 58 mAbs that were mapped to different Env surfaces, most of which showed neutralizing activity. One mAb in particular (HJ16) specific for a novel epitope proximal to the CD4 binding site on gp120 selectively neutralized a multi-clade panel of Tier-2 HIV-1 pseudoviruses, and demonstrated reactivity that was comparable in breadth, but distinct in neutralization specificity, to that of the other CD4 binding site-specific neutralizing mAb b12. A second mAb (HGN194) bound a conserved epitope in the V3 crown and neutralized all Tier-1 and a proportion of Tier-2 pseudoviruses tested, irrespective of clade. A third mAb (HK20) with broad neutralizing activity, particularly as a Fab fragment, recognized a highly conserved epitope in the HR-1 region of gp41, but showed striking assay-dependent selectivity in its activity. CONCLUSIONS: This study reveals that by using appropriate screening methods, a large proportion of memory B cells can be isolated that produce mAbs with HIV-1 neutralizing activity. Three of these mAbs show unusual breadth of neutralization and therefore add to the current panel of HIV-1 neutralizing antibodies with potential for passive protection and template-based vaccine design.

Dental topography and molar wear in Alouatta palliata from Costa Rica.

Paleoprimatologists depend on relationships between form and function of teeth to reconstruct the diets of fossil species. Most of this work has been limited to studies of unworn teeth. A new approach, dental topographic analysis, allows the characterization and comparison of worn primate teeth. Variably worn museum specimens have been used to construct species-specific wear sequences so that measurements can be compared by wear stage among taxa with known differences in diet. This assumes that individuals in a species tend to wear their molar teeth in similar ways, a supposition that has yet to be tested. Here we evaluate this assumption with a longitudinal study of changes in tooth form over time in primates. Fourteen individual mantled howling monkeys (Alouatta palliata) were captured and then recaptured after 2, 4, and 7 years when possible at Hacienda La Pacifica in Costa Rica between 1989-1999. Dental impressions were taken each time, and molar casts were produced and analyzed using dental topographic analysis. Results showed consistent decreases in crown slope and occlusal relief. In contrast, crown angularity, a measure of surface jaggedness, remained fairly constant except with extreme wear. There were no evident differences between specimens collected in different microhabitats. These results suggest that different individual mantled howling monkeys wear their teeth down in similar ways, evidently following a species-specific wear sequence. Dental topographic analysis may therefore be used to compare morphology among similarly worn individuals from different species.

An evaluation of remifentanil-sevoflurane response surface models in patients emerging from anesthesia: model improvement using effect-site sevoflurane concentrations.

INTRODUCTION: We previously reported models that characterized the synergistic interaction between remifentanil and sevoflurane in blunting responses to verbal and painful stimuli. This preliminary study evaluated the ability of these models to predict a return of responsiveness during emergence from anesthesia and a response to tibial pressure when patients required analgesics in the recovery room. We hypothesized that model predictions would be consistent with observed responses. We also hypothesized that under non-steady-state conditions, accounting for the lag time between sevoflurane effect-site concentration (Ce) and end-tidal (ET) concentration would improve predictions. METHODS: Twenty patients received a sevoflurane, remifentanil, and fentanyl anesthetic. Two model predictions of responsiveness were recorded at emergence: an ET-based and a Ce-based prediction. Similarly, 2 predictions of a response to noxious stimuli were recorded when patients first required analgesics in the recovery room. Model predictions were compared with observations with graphical and temporal analyses. RESULTS: While patients were anesthetized, model predictions indicated a high likelihood that patients would be unresponsive (> or = 99%). However, after termination of the anesthetic, models exhibited a wide range of predictions at emergence (1%-97%). Although wide, the Ce-based predictions of responsiveness were better distributed over a percentage ranking of observations than the ET-based predictions. For the ET-based model, 45% of the patients awoke within 2 min of the 50% model predicted probability of unresponsiveness and 65% awoke within 4 min. For the Ce-based model, 45% of the patients awoke within 1 min of the 50% model predicted probability of unresponsiveness and 85% awoke within 3.2 min. Predictions of a response to a painful stimulus in the recovery room were similar for the Ce- and ET-based models. DISCUSSION: Results confirmed, in part, our study hypothesis; accounting for the lag time between Ce and ET sevoflurane concentrations improved model predictions of responsiveness but had no effect on predicting a response to a noxious stimulus in the recovery room. These models may be useful in predicting events of clinical interest but large-scale evaluations with numerous patients are needed to better characterize model performance.

Dietary inference from upper and lower molar morphology in platyrrhine primates.

The correlation between diet and dental topography is of importance to paleontologists seeking to diagnose ecological adaptations in extinct taxa. Although the subject is well represented in the literature, few studies directly compare methods or evaluate dietary signals conveyed by both upper and lower molars. Here, we address this gap in our knowledge by comparing the efficacy of three measures of functional morphology for classifying an ecologically diverse sample of thirteen medium- to large-bodied platyrrhines by diet category (e.g., folivore, frugivore, hard object feeder). We used Shearing Quotient (SQ), an index derived from linear measurements of molar cutting edges and two indices of crown surface topography, Occlusal Relief (OR) and Relief Index (RFI). Using SQ, OR, and RFI, individuals were then classified by dietary category using Discriminate Function Analysis. Both upper and lower molar variables produce high classification rates in assigning individuals to diet categories, but lower molars are consistently more successful. SQs yield the highest classification rates. RFI and OR generally perform above chance. Upper molar RFI has a success rate below the level of chance. Adding molar length enhances the discriminatory power for all variables. We conclude that upper molar SQs are useful for dietary reconstruction, especially when combined with body size information. Additionally, we find that among our sample of platyrrhines, SQ remains the strongest predictor of diet, while RFI is less useful at signaling dietary differences in absence of body size information. The study demonstrates new ways for inferring the diets of extinct platyrrhine primates when both upper and lower molars are available, or, for taxa known only from upper molars. The techniques are useful in reconstructing diet in stem representatives of anthropoid clade, who share key aspects of molar morphology with extant platyrrhines.

Biogeography in deep time - What do phylogenetics, geology, and paleoclimate tell us about early platyrrhine evolution?

Molecular data have converged on a consensus about the genus-level phylogeny of extant platyrrhine monkeys, but for most extinct taxa and certainly for those older than the Pleistocene we must rely upon morphological evidence from fossils. This raises the question as to how well anatomical data mirror molecular phylogenies and how best to deal with discrepancies between the molecular and morphological data as we seek to extend our phylogenies to the placement of fossil taxa. Here I present parsimony-based phylogenetic analyses of extant and fossil platyrrhines based on an anatomical dataset of 399 dental characters and osteological features of the cranium and postcranium. I sample 16 extant taxa (one from each platyrrhine genus) and 20 extinct taxa of platyrrhines. The tree structure is constrained with a "molecular scaffold" of extant species as implemented in maximum parsimony using PAUP with the molecular-based 'backbone' approach. The data set encompasses most of the known extinct species of platyrrhines, ranging in age from latest Oligocene (∼26 Ma) to the Recent. The tree is rooted with extant catarrhines, and Late Eocene and Early Oligocene African anthropoids. Among the more interesting patterns to emerge are: (1) known early platyrrhines from the Late Oligocene through Early Miocene (26-16.5Ma) represent only stem platyrrhine taxa; (2) representatives of the three living platyrrhine families first occur between 15.7 Ma and 13.5 Ma; and (3) recently extinct primates from the Greater Antilles (Cuba, Jamaica, Hispaniola) are sister to the clade of extant platyrrhines and may have diverged in the Early Miocene. It is probable that the crown platyrrhine clade did not originate before about 20-24 Ma, a conclusion consistent with the phylogenetic analysis of fossil taxa presented here and with recent molecular clock estimates. The following biogeographic scenario is consistent with the phylogenetic findings and climatic and geologic evidence: Tropical South America has been a center for platyrrhine diversification since platyrrhines arrived on the continent in the middle Cenozoic. Platyrrhines dispersed from tropical South America to Patagonia at ∼25-24 Ma via a "Paraná Portal" through eastern South America across a retreating Paranense Sea. Phylogenetic bracketing suggests Antillean primates arrived via a sweepstakes route or island chain from northern South America in the Early Miocene, not via a proposed land bridge or island chain (GAARlandia) in the Early Oligocene (∼34 Ma). Patagonian and Antillean platyrrhines went extinct without leaving living descendants, the former at the end of the Early Miocene and the latter within the past six thousand years. Molecular evidence suggests crown platyrrhines arrived in Central America by crossing an intermittent connection through the Isthmus of Panama at or after 3.5Ma. Any more ancient Central American primates, should they be discovered, are unlikely to have given rise to the extant Central American taxa in situ.

The Origin and Diversification of Birds.

Birds are one of the most recognizable and diverse groups of modern vertebrates. Over the past two decades, a wealth of new fossil discoveries and phylogenetic and macroevolutionary studies has transformed our understanding of how birds originated and became so successful. Birds evolved from theropod dinosaurs during the Jurassic (around 165-150 million years ago) and their classic small, lightweight, feathered, and winged body plan was pieced together gradually over tens of millions of years of evolution rather than in one burst of innovation. Early birds diversified throughout the Jurassic and Cretaceous, becoming capable fliers with supercharged growth rates, but were decimated at the end-Cretaceous extinction alongside their close dinosaurian relatives. After the mass extinction, modern birds (members of the avian crown group) explosively diversified, culminating in more than 10,000 species distributed worldwide today.

Podredumbre del cuello y del rizoma y marchitamiento de Iris germanica producidos por Fusarium oxysporum y Sclerotium rolfsii

p.15-17

La podredumbre del cuello y las raíces de la aralia (Fatsia japonica) por Fusarium solani

p.123-125

Guidance on interviewing child witnesses in Scotland

The guidance was commissioned from Dr Amina Memon and Lynn Hulse at Aberdeen University. Their work was overseen by a steering group with representatives from the Scottish Executive Justice Department, the Crown Office and Procurator Fiscal Service, NCH Scotland, the Association of Chief Police Officers in Scotland, the Association of Directors of Social Work, the Law Society for Scotland, the Scottish Association of Community Child Health and the Scottish Children’s Reporter Administration. A full list of those involved is given in the Appendix C. pt. 1. Guidance on interviewing child witnesses in Scotland -- pt. 2. Guidance on the questioning of children in court -- pt. 3. Lord Justice-General's memorandum on child witnesses: appendix to Guidance on the questioning of children in court -- pt. 4. Guidance on child witness court familiarisation visits -- pt. 5. Information about child, young and vulnerable adult witnesses to inform decision-making in the legal process: good practice guide -- pt. 6. Code of practice to facilitate the provision of therapeutic support to child witnesses in court proceedings -- pt. 7. Guidance on the conduct of identity parades with child witnesses.

Twentieth Century Society Spring lecture series: second lives for Twentieth Century masterpieces

The Twentieth Century Society’s Spring lecture series (six in total) looks at the restoration and refurbishment of key C20 buildings in Britain and the US. Buildings covered: BBC Broadcasting House in London (G Val Meyer 1930-32, MacCormac Jamieson Prichard 2000-09). Speaker: Mark Hines (Mark Hines Architects), was the project architect and is the author of The Story of Broadcasting House: Home of the BBC. 5 February 2009. Crown Hall, Chicago (Mies van der Rohe 1952), the Art and Architecture Building, Yale University, New Haven (Paul Rudolf 1961-63) and the former Wills head office in Bristol (SOM with YRM 1970-75). Speaker: Patrick Bellew (Atelier 10 Engineers), 12 February 2009. Center for British Art, Yale University, New Haven (Louis Kahn 1969-77). Speaker: Peter Inskip (Inskip and Jenkins Architects), 17 February 2009. Brunswick Centre London (Patrick Hodgkinson 1967-72; Levitt Bernstein with Patrick Hodgkinson 2006). Speaker: Stuart Tappin (Stand Consulting Engineers Ltd), 26 February 2009. De La Warr Pavilion, Bexhill-on-Sea (Mendelsohn and Chermayeff 1934-5, John McAslan and Partners 2000-05). Speaker: Mark Cannata (HOK Architects), 5 March 2009. Finsbury Health Centre London (Lubetkin & Tecton 1938, first phase of conservation work Avanti Architects 1995.). Speaker: John Allan of Avanti Architects, 12 March 2009.

Microwave mediated reduction of heterocycle and fluorine containing nitroaromatics with Mo(CO)(6) and DBU

Heterocycle containing nitroaromatics were reduced by Mo(CO)(6) and DBU in EtOH under microwave irradiation within 15 min. Under the same conditions, 4-fluoronitrobenzene was reduced to 4-fluoroaniline, whereas 2-chloro-1-fluoro-4-nitrobenzene afforded a mixture of 3-chloro-4-fluoroaniline and 3-chloro-4-ethoxyaniline. The extent of the competing SNAr/reduction process could be influenced by the nature of the solvent, with t-BuOH the inert solvent of choice. The latter was used as solvent for SNAr/reductions of 2-chloro-1-fluoro-4-nitrobenzene with S-nucleophiles to yield 3-chloro-4-mercaptoanilines. Crown Copyright (c) 2008 Published by Elsevier Ltd. All rights reserved.

Effects on zooplankton of a warmer ocean: Recent evidence from the Northeast Pacific

The consequences for pelagic communities of warming trends in mid and high latitude ocean regions could be substantial, but their magnitude and trajectory are not yet known. Environmental changes predicted by climate models (and beginning to be confirmed by observations) include warming and freshening of the upper ocean and reduction in the extent and duration of ice cover. One way to evaluate response scenarios is by comparing how "similar" zooplankton communities have differed among years and/or locations with differing temperature. The subarctic Pacific is a strong candidate for such comparisons, because the same mix of zooplankton species dominates over a wide range of temperature climatologies, and observations have spanned substantial temperature variability at interannual-to-decadal time scales. In this paper, we review and extend copepod abundance and phenology time series from net tow and Continuous Plankton Recorder surveys in the subarctic Northeast Pacific. The two strongest responses we have observed are latitudinal shifts in centers of abundance of many species (poleward under warm conditions), and changes in the life cycle timing of Neocalanus plumchrus in both oceanic and coastal regions (earlier by several weeks in warm years and at warmer locations). These zooplankton data, plus indices of higher trophic level responses such as reproduction, growth and survival of pelagic fish and seabirds, are all moderately-to-strongly intercorrelated (vertical bar r vertical bar = 0.25-0.8) with indices of local and basin-scale temperature anomalies. A principal components analysis of the normalized anomaly time series from 1979 to 2004 shows that a single "warm-and-low-productivity" vs. "cool-and-high-productivity" component axis accounts for over half of the variance/covariance. Prior to 1990, the scores for this component were negative ("cool" and "productive") or near zero except positive in the El Nino years 1983 and 1987. The scores were strongly and increasingly positive ("warm" and "low productivity") from 1992 to 1998; negative from 1999 to 2002; and again increasingly positive from 2003-present. We suggest that, in strongly seasonal environments, anomalously high temperature may provide misleading environmental cues that contribute to timing mismatch between life history events and the more-nearly-fixed seasonality of insolation, stratification, and food supply. Crown Copyright (c) 2007 Published by Elsevier Ltd. All rights reserved.

Evolution of the Diatoms: VIII. Re-Examination of the SSU-Rrna Gene Using Multiple Outgroups and a Cladistic Analysis of Valve Features.

The resolution of the SSU rRNA gene for phylogenetic analysis in the diatoms has been evaluated by Theriot et al. who claimed that the SSU rRNA gene could not be used to resolve the monophyly of the three diatoms classes described by Medlin and Kaczmarska. Although they used both only bolidomonads and heterokonts as outgroups, they did not explore outgroups further away than the heterokonts. In this study, the use of the multiple outgroups inside and outside the heterokonts with the rRNA gene for recovering the three monophyletic clades at the class level is evaluated. Trees with multiple outgroups ranging from only bolidophytes to Bacteria and Archea were analyzed with Bayesian and Maximum Likelihood analyses and two data sets were recovered with the classes being monophyletic. Other data sets were analyzed with non-weighted and weighted maximum parsimony. The latter reduced the number of clades and lengthened branch lengths between the clades. One data set using a weighted analysis recovered the three classes as monophyletic. Taking only bolidophytes as the only outgroup never produced monophyletic clades. Multiple outgroups including many heterokonts and certain members of the crown group radiation recovered monophyletic clades. The three classes can be defined by clear morphological differences primarily based on auxospore ontogeny and envelope structure, the presence or absence of a structure (tube process or sternum) associated with the annulus and the location of the cribrum in those genera with loculate areolae. A cladistic analysis of some of these features is presented and recovers the three classes.

Melancholy and the Early Modern University

Critics have observed that in early Stuart England, the broad, socially significant concept of melancholy was recoded as a specifically medical phenomenon—a disease rather than a fashion. This recoding made melancholy seem less a social attitude than a private ailment. However, I argue that at the Stuart universities, this recoded melancholy became a covert expression of the disillusionment, disappointment, and frustration produced by pressures there—the overcrowding and competition which left many men “disappointed” in preferment, alongside James I’s unprecedented royal involvement in the universities. My argument has implications for Jürgen Habermas’s account of the emergence of the public sphere, which he claims did not occur until the eighteenth-century. I argue that although the university was increasingly subordinated to the crown’s authority, a lingering sense of autonomy persisted there, a residue of the medieval university’s relative autonomy from the crown; politicized by the encroaching Stuart presence, an alienated community at the university formed a kind of public in private from authority within that authority’s midst. The audience for the printed book, a sphere apart from court or university, represented a forum in which the publicity at the universities could be consolidated, especially in seemingly “private” literary forms such as the treatise on melancholy. I argue that Robert Burton’s exaggerated performance of melancholy in The Anatomy of Melancholy, which gains him license to say almost anything, resembles the performed melancholy that the student-prince Hamlet uses to frustrate his uncle’s attempts to surveil him. After tracing melancholy’s evolving literary function through Hamlet, I go on to discuss James’s interventions into the universities. I conclude by considering two printed (and widely circulated) books by university men: the aforementioned The Anatomy of Melancholy by Burton, an Oxford cleric, and The Temple by George Herbert, who left a career as Cambridge’s public orator to become a country parson. I examine how each of these books uses the affective pattern of courtly-scholarly disappointment—transumed by Burton as melancholy, and by Herbert as holy affliction—to develop an empathic form of publicity among its readership which is in tacit opposition to the Stuart court.