The Evolution of Agrarian Landscapes in the Tropical Andes.

Changes in land-use practices have been a central element of human adaptation to Holocene climate change. Many practices that result in the short-term stabilization of socio-natural systems, however, have longer-term, unanticipated consequences that present cascading challenges for human subsistence strategies and opportunities for subsequent adaptations. Investigating complex sequences of interaction between climate change and human land-use in the past-rather than short-term causes and effects-is therefore essential for understanding processes of adaptation and change, but this approach has been stymied by a lack of suitably-scaled paleoecological data. Through a high-resolution paleoecological analysis, we provide a 7000-year history of changing climate and land management around Lake Acopia in the Andes of southern Peru. We identify evidence of the onset of pastoralism, maize cultivation, and possibly cultivation of quinoa and potatoes to form a complex agrarian landscape by c. 4300 years ago. Cumulative interactive climate-cultivation effects resulting in erosion ended abruptly c. 2300 years ago. After this time, reduced sedimentation rates are attributed to the construction and use of agricultural terraces within the catchment of the lake. These results provide new insights into the role of humans in the manufacture of Andean landscapes and the incremental, adaptive processes through which land-use practices take shape.

2,100 years of human adaptation to climate change in the High Andes.

Humid montane forests are challenging environments for human habitation. We used high-resolution fossil pollen, charcoal, diatom and sediment chemistry data from the iconic archaeological setting of Laguna de los Condores, Peru to reconstruct changing land uses and climates in a forested Andean valley. Forest clearance and maize cultivation were initiated during periods of drought, with periods of forest recovery occurring during wetter conditions. Between AD 800 and 1000 forest regrowth was evident, but this trend was reversed between AD 1000 and 1200 as drier conditions coincided with renewed land clearance, the establishment of a permanent village and the use of cliffs overlooking the lake as a burial site. By AD 1230 forests had regrown in the valley and maize cultivation was greatly reduced. An elevational transect investigating regional patterns showed a parallel, but earlier, history of reduced maize cultivation and forest regeneration at mid-elevation. However, a lowland site showed continuous maize agriculture until European conquest but very little subsequent change in forest cover. Divergent, climate-sensitive landscape histories do not support categorical assessments that forest regrowth and peak carbon sequestration coincided with European arrival.

Paleoenvironmental history of the West Baray, Angkor (Cambodia).

Angkor (Cambodia) was the seat of the Khmer Empire from the 9th to 15th century AD. The site is noted for its monumental architecture and complex hydro-engineering systems, comprised of canals, moats, embankments, and large reservoirs, known as barays. We infer a 1,000-y, (14)C-dated paleoenvironmental record from study of an approximately 2-m sediment core taken in the largest Khmer reservoir, the West Baray. The baray was utilized and managed from the time of construction in the early 11th century, through the 13th century. During that time, the West Baray received relatively high rates of detrital input. In the 14th century, linear sedimentation rates diminished by an order of magnitude, yielding a condensed section that correlates temporally with episodes of regional monsoon failure during the late 14th and early 15th century, recorded in tree ring records from Vietnam. Our results demonstrate that changes in the water management system were associated with the decline of the Angkorian kingdom during that period. By the 17th century, the West Baray again functioned as a limnetic system. Ecologic and sedimentologic changes over the last millennium, detected in the baray deposits, are attributed to shifts in regional-scale Khmer water management, evolving land use practices in the catchment, and regional climate change.

2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy.

The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.

2-(4-carbonylphenyl)benzoxazole inhibitors of CETP: scaffold design and advancement in HDLc-raising efficacy.

The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Initial efforts aimed at engineering replacements for the aniline substructures in the benchmark molecule. Reversing the connectivity of the central aniline lead to a new class of 2-(4-carbonylphenyl)benzoxazoles. Structure-activity studies at the C-7 and terminal pyridine ring allowed for the optimization of potency and HDLc-raising efficacy in this new class of inhibitors. These efforts lead to the discovery of benzoxazole 11v, which raised HDLc by 24 mg/dl in our transgenic mouse PD model.

Identification and validation of genes affecting aortic lesions in mice.

Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli-hood-based model selection method to infer gene-disease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genome-wide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosis-related pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of causality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.

How effective leaders achieve success in critical change initiatives part 4: emergent leadership--an example with doctors.

Engaging family doctors in clinical practice innovations has often been seen to be a difficult challenge. It is happening in some creative ways with the Hamilton Family Health Team. This article illustrates how Ontario's Ministry of Health and Long-Term Care, some of the original leaders in the Hamilton Team, and CEO Terry McCarthy have created an environment that fosters emergent leadership. Their approach has accelerated the delivery of both increased access and improved patient care.

How effective leaders achieve success in critical change initiatives, Part 3: Command and let go of control.

This article is the third in a series outlining recent research into how effective leaders achieve success in critical change initiatives. This article focuses on the finding that successful leaders were able to "command" and "let go of control" at the same time.

How effective leaders achieve success in critical change initiatives, Part 2: why change leadership must transcend project management for complex initiatives to be successful.

This article is the second in a series outlining how effective leaders achieve success in critical change initiatives. This article focuses on why change leadership must transcend project management for complex initiatives to be successful.

How effective leaders achieve success in critical change initiatives. Part 1: building and sustaining momentum.

The first in a series of articles presenting the results of a research project focused on leaders who achieved proven success in large-scale change management initiatives. The overriding objective of the study was to discover what leadership behaviours and strategies were instrumental in achieving both short- and long-term success. This first piece outlines strategies to build and sustain momentum.

Influence of the intertropical convergence zone on the East Asian monsoon.

The Asian-Australian monsoon is an important component of the Earth's climate system that influences the societal and economic activity of roughly half the world's population. The past strength of the rain-bearing East Asian summer monsoon can be reconstructed with archives such as cave deposits, but the winter monsoon has no such signature in the hydrological cycle and has thus proved difficult to reconstruct. Here we present high-resolution records of the magnetic properties and the titanium content of the sediments of Lake Huguang Maar in coastal southeast China over the past 16,000 years, which we use as proxies for the strength of the winter monsoon winds. We find evidence for stronger winter monsoon winds before the Bølling-Allerød warming, during the Younger Dryas episode and during the middle and late Holocene, when cave stalagmites suggest weaker summer monsoons. We conclude that this anticorrelation is best explained by migrations in the intertropical convergence zone. Similar migrations of the intertropical convergence zone have been observed in Central America for the period ad 700 to 900 (refs 4-6), suggesting global climatic changes at that time. From the coincidence in timing, we suggest that these migrations in the tropical rain belt could have contributed to the declines of both the Tang dynasty in China and the Classic Maya in Central America.

Genetic suppressors of the Lotus japonicus har1-1 hypernodulation phenotype.

Lotus japonicus har1 mutants respond to inoculation with Mesorhizobium loti by forming an excessive number of nodules due to genetic lesions in the HAR1 autoregulatory receptor kinase gene. In order to expand the repertoire of mutants available for the genetic dissection of the root nodule symbiosis (RNS), a screen for suppressors of the L. japonicus har1-1 hypernodulation phenotype was performed. Of 150,000 M2 plants analyzed, 61 stable L. japonicus double-mutant lines were isolated. In the context of the har1-1 mutation, 26 mutant lines were unable to form RNS, whereas the remaining 35 mutant lines carried more subtle symbiotic phenotypes, either forming white ineffective nodules or showing reduced nodulation capacity. When challenged with Glomus intraradices, 18 of the 61 suppressor lines were unable to establish a symbiosis with this arbuscular mycorrhiza fungus. Using a combined approach of genetic mapping, targeting induced local lesions in genomics, and sequencing, all non-nodulating mutant lines were characterized and shown to represent new alleles of at least nine independent symbiotic loci. The class of mutants with reduced nodulation capacity was of particular interest because some of them may specify novel plant functions that regulate nodule development in L. japonicus. To facilitate mapping of the latter class of mutants, an introgression line, in which the har1-1 allele was introduced into a polymorphic background of L. japonicus ecotype MG20, was constructed.

SAR studies: designing potent and selective LXR agonists.

Counterscreening compounds from a Merck PPAR program discovered lead 1, as a nanomolar LXR/PPAR dual agonist. SAR optimization developed a series of heterocyclic LXR agonists having excellent selectivity over all PPAR isoforms and possessing high LXR affinity and strong in vivo potency.

Single preoperative dose versus long-term prophylactic antibiotic regimens in dental implant surgery.

PURPOSE: The purpose of this prospective study was to compare the efficacy of prophylactic antibiotic regimens commonly used in dental implant surgery. Preoperative single-dose and long-term prophylactic antibiotic regimens were compared. MATERIALS AND METHODS: This was a 2-center prospective study in which 215 patients underwent ambulatory endosseous implant placement. In the first group, 445 dental implants were placed in 125 patients after the administration of a single preoperative dose of prophylactic antibiotic with no postoperative antibiotics. In the second group, 302 dental implants were placed in 90 patients who received a preoperative dose of antibiotics and were instructed to take antibiotics postoperatively for 7 days. In both groups, 0.12% chlorhexidine pre- and postoperative mouth rinses were used. Patients returned for postoperative evaluation at 1 week, 2 weeks, and just prior to surgical uncovering. The surgical sites were assessed for pain, swelling, erythema, and purulence. RESULTS: In the first group, 3 patients developed wound dehiscence at 5 implant sites and 1 developed a minor inflammatory response. None of the patients in this group received further antibiotics. In the second group, 3 patients developed wound dehiscence, 2 developed an inflammatory response, and 1 was diagnosed with infection, for which another course of antibiotics was required. There was no statistical difference between the 2 groups according to the Fisher 2 x 4 exact test (P = .56). DISCUSSION: Indiscriminate use of antibiotics is unacceptable in clinical practice today. Surgeons must adhere to basic principles to gain the most benefit from the use of prophylactic antibiotics. CONCLUSION: Long-term prophylactic antibiotic use in implant surgery was of no advantage or benefit over a single-dose preoperative antibiotic regimen in this patient population.

Synchroneity of tropical and high-latitude Atlantic temperatures over the last glacial termination.

A high-resolution western tropical Atlantic sea surface temperature (SST) record from the Cariaco Basin on the northern Venezuelan shelf, based on Mg/Ca values in surface-dwelling planktonic foraminifera, reveals that changes in SST over the last glacial termination are synchronous, within +/-30 to +/-90 years, with the Greenland Ice Sheet Project 2 air temperature proxy record and atmospheric methane record. The most prominent deglacial event in the Cariaco record occurred during the Younger Dryas time interval, when SSTs dropped by 3 degrees to 4 degrees C. A rapid southward shift in the atmospheric intertropical convergence zone could account for the synchroneity of tropical temperature, atmospheric methane, and high-latitude changes during the Younger Dryas.

Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2.

Mice lacking the chemokine receptor chemotactic cytokine receptor 2 (CCR2) have a marked attenuation of monocyte recruitment in response to various inflammatory stimuli and a reduction of inflammatory lesions in models of demyelinating disease. In the present study, we compared nociceptive responses in inflammatory and neuropathic models of pain in CCR2 knockout and wild-type mice. In acute pain tests, responses were equivalent in CCR2 knockout and wild-type mice. In models of inflammatory pain, CCR2 knockout mice showed a 70% reduction in phase 2 of the intraplantar formalin-evoked pain response but only a modest (20-30%) and nonsignificant reduction of mechanical allodynia after intraplantar Freund's adjuvant (CFA). In a model of neuropathic pain, the development of mechanical allodynia was totally abrogated in CCR2 knockout mice. CFA administration induced marked up-regulation of CCR2 mRNA in the skin and a moderate increase in the sciatic nerve and dorsal root ganglia (DRG). In response to nerve ligation, persistent and marked up-regulation of CCR2 mRNA was evident in the nerve and DRG. Disruption of Schwann cells in response to nerve lesion resulted in infiltration of CCR2-positive monocytes/macrophages not only to the neuroma but also to the DRG. Chronic pain also resulted in the appearance of activated CCR2-positive microglia in the spinal cord. Collectively, these data suggest that the recruitment and activation of macrophages and microglia peripherally and in neural tissue may contribute to both inflammatory and neuropathic pain states. Accordingly, blockade of the CCR2 receptor may provide a novel therapeutic modality for the treatment of chronic pain.

Prospective study of 429 hydroxyapatite-coated cylindric omniloc implants placed in 121 patients.

PURPOSE: Controversy over the long-term clinical effectiveness of hydroxyapatite (HA)-coated dental implants still persists, despite numerous clinical studies documenting high survival rates. The Ohio State University College of Dentistry undertook a 5-year prospective study of 429 HA-coated cylindric implants placed into 121 patients to determine the long-term clinical performance of the implants. MATERIALS AND METHODS: All study subjects were patients screened and evaluated in the university's dental clinic by one of the principal investigators and one member of the surgical team. A total of 429 HA-coated implants were placed in 121 patients. The Ohio State University Human Subjects Committee approved and reviewed this study. RESULTS: At the time of this report, 375 implants had completed 5 years of clinical follow-up. Beyond the 5-year limit of the study, 282 implants had completed 6 years and 114 implants had completed 7 years of clinical monitoring. The cumulative survival rate was 96% at 5 years and 95% at 7 years of follow-up. Mean combined mesial/distal bone loss was 1.2 mm in the mandible and 1.4 mm in the maxilla after 5 years of functional loading. Implant failures were most commonly associated with short implants or angled abutments. DISCUSSION: Prospective clinical data are extremely valuable for clinicians evaluating the reliability of dental implant systems. In the present study, the implants achieved 100% osseointegration with minimal marginal bone loss, and 96% of the implants remained in function at 5 years. CONCLUSION: The HA-coated cylindric implants in this study provided a predictable means of oral rehabilitation.

Climate and the collapse of Maya civilization.

In the anoxic Cariaco Basin of the southern Caribbean, the bulk titanium content of undisturbed sediment reflects variations in riverine input and the hydrological cycle over northern tropical South America. A seasonally resolved record of titanium shows that the collapse of Maya civilization in the Terminal Classic Period occurred during an extended regional dry period, punctuated by more intense multiyear droughts centered at approximately 810, 860, and 910 A.D. These new data suggest that a century-scale decline in rainfall put a general strain on resources in the region, which was then exacerbated by abrupt drought events, contributing to the social stresses that led to the Maya demise.