Sexual Dimorphisms in Habitat-Specific Morphology and Behavior in the Green Anole Lizard

Species that occur in variable environments often exhibit morphological and behavioral traits that are specific to local habitats. Because the ability to move effectively is closely associated with structural habitat, locomotor traits may be particularly sensitive to fine-scale habitat differences. Anolis lizards provide an excellent opportunity to study the relationship between locomotion and natural perch use in the field, as laboratory studies have demonstrated that lizards that use broader perches develop longer limbs and have higher sprint speeds. We examined Anolis carolinensis (the green anole) in three habitats in close proximity. Our goals were to determine whether habitat-specific differences in hindlimb and toe morphologies occurred in a population in which perch size was variable but not manipulated, whether locomotor behaviors were associated with these morphologies, and whether habitat-specific traits differed between the sexes. We found that while juveniles in the three habitats did not differ in limb or toe morphology, adult females using broader perches had relatively longer limbs than females using narrower perches. Females also differed in toe length across habitats, but not in relation to perch diameter. Males, in contrast, exhibited differing growth patterns (allometry) in these traits, and marginal differences in locomotor behavior. Together, these results suggest that sex-specific responses in morphology and behavior, consistent with experimental observations of phenotypic plasticity, provide a mechanism for refining local habitat use

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

The genome of the green anole lizard and a comparative analysis with birds and mammals

The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments. Among amniotes, genome sequences are available for mammals and birds, but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes. Also, A. carolinensis mobile elements are very young and diverse—more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds. We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.National Science Foundation (U.S.) (NSF grant DEB-0920892)National Science Foundation (U.S.) (NSF grant DEB-0844624)National Human Genome Research Institute (U.S.

Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors

Background: Intervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/Principal Findings: We have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-gamma, IL-2, TNF-alpha production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8+ T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.Conclusions: Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption

Hallucinogen-like actions of 2,5-dimethoxy-4-( n )-propylthiophenethylamine (2C-T-7) in mice and rats

Few studies have examined the effects of 2,5-dimethoxy-4-( n )-propylthiophenethylamine (2C-T-7) in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46369/1/213_2005_Article_9.pd

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.

The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Proceedings of the Fourth Caldwell Conference, St. Catherines Island, Georgia, March 27-29, 2009.

391 p. : ill. (chiefly col.), maps (chiefly col.) ; 26 cm. "Issued March 23, 2011."This edited volume addresses the geoarchaeology of St. Catherines Island (Georgia). The field of geoarchaeology has typically been defined as either geology pursued within an archaeological framework or (sometimes the reverse) as archaeology framed with the help of geological methodology. Either way, the formalized objectives of geoarchaeology define a broad range of pursuits, from placing archaeological sites into relative and absolute temporal context through the application of stratigraphic principles and absolute dating techniques, to understanding the natural processes of site formation, to reconstructing the landscapes that existed around a site or group of sites at the time of occupation. The editors of this volume have generally followed the lead of G.R. Rapp and C.L. Hill (2006, Geoarchaeology : the earth-science approach to archaeological interpretation) by stressing the importance of multiple viewpoints and methodologies in applying geoscience techniques to evaluate the archaeological record. In the broadest sense, then, Geoarchaeology of St. Catherines Island applies multiple earth science concepts, techniques, or knowledge bases to the known archaeological record and the processes that created that record. This volume consists of 16 papers presenting the newest research on the stratigraphic and geomorphological evolution of the St. Catherines Island landscape. Of particular interest are presentations addressing the relative timing and nature of sedimentation, paleobiology, sea level change, stream capture, hydrology, and erosional patterning evident on St. Catherines Island (and to some degree the rest of the Georgia Bight). These papers were initially presented at the Fourth Caldwell Conference, cosponsored by the American Museum of Natural History and the St. Catherines Island Foundation, held on St. Catherines Island (Georgia), March 27-29, 2009. Table of contents: Why this archaeologist cares about geoarchaeology : some pasts and futures of St. Catherines Island / David Hurst Thomas -- Evolution of late Pleistocene-Holocene climates and environments of St. Catherines Island and the Georgia Bight / Fredrick J. Rich, Anthony Vega, and Frank J. Vento -- Geoarchaeological research at St. Catherines Island : defining the geological foundation / Gale A. Bishop, Brian K. Meyer, R. Kelly Vance, and Fredrick J. Rich -- Development of a late Pleistocene-Holocene genetic stratigraphic framework for St. Catherines Island : archaeological implications / Frank J. Vento and Patty A. Stahlman -- Ichnological diagnosis of ancient storm-washover fans, Yellow Banks Bluff, St. Catherines Island / Anthony J. Martin and Andrew K. Rindsberg -- Quaternary vegetation and depositional history of St. Catherines Island / Fredrick J. Rich and Robert K. Booth -- Recent shoreline erosion and vertical accretion patterns, St. Catherines Island / Donald B. Potter Jr. -- Role of storm events in beach ridge formation, St. Catherines Island / Harold B. Rollins, Kathi Beratan, and James E. Pottinger -- Drainage changes at Ossabaw, St. Catherines, and Sapelo sounds and their influence on island morphology and spit building on St. Catherines Island / Timothy M. Chowns -- Vibracores and vibracore transects : constraining the geological and cultural history of St. Catherines Island / Gale A. Bishop, David Hurst Thomas, Matthew C. Sanger, Brian K. Meyer, R. Kelly Vance, Robert K. Booth, Fredrick J. Rich, Donald B. Potter, and Timothy Keith-Lucas -- Application of ground penetrating radar to investigations of the stratigraphy, structure, and hydrology of St. Catherines Island / R. Kelly Vance, Gale A. Bishop, Fredrick J. Rich, Brian K. Meyer, and Eleanor J. Camann -- Postsettlement dispersal and dynamic repopulation of estuarine habitats by adult Mercenaria mercenaria, St. Catherines Island / Robert S. Prezant, Harold B. Rollins, and Ronald B. Toll -- The foundation for sea turtle geoarchaeology and zooarchaeology : morphology of recent and ancient sea turtle nests, St. Catherines Island, Georgia, and Cretaceous Fox Hills Sandstone, Elbert County, Colorado / Gale A. Bishop, Fredric L. Pirkle, Brian K. Meyer, and William A. Pirkle -- Sea turtle habitat deterioration on St. Catherines Island : defining the modern transgression / Gale A. Bishop and Brian K. Meyer -- Modeling indigenous hunting and harvesting of sea turtles and their eggs on the Georgia Coast / Gale A. Bishop, David Hurst Thomas, and Brian K. Meyer -- Geomorphology, sea level, and marine resources : St. Catherines Island / Harold B. Rollins and David Hurst Thomas -- Appendix 1. Noncultural radiocarbon record from St. Catherines Island : a compendium -- Appendix 2. Vibracore record from St. Catherines Island : a compendium.Conference sponsored by the American Museum of Natural History and the St. Catherines Island Foundation