Stable Isotope Analysis of Lake Sediments from Laguna Santa Elena and Laguna Azul, Costa Rica

Lake sediments are increasingly important archives of human-environment interactions and paleoclimate in the neotropics. In Costa Rica, Anchukaitis and Horn (Palaeogeography, Palaeoclimatology, Palaeoecology 221: 35–54, 2005) established a land-use history for Laguna Santa Elena (8.9306 N, 82.9275 W, 1055 m elevation), a small lake in the Diquís archaeological region, based on pollen and charcoal analyses of a 7-meter sediment core. I carried out stable carbon and nitrogen isotope and loss-on-ignition analyses at higher resolution to extend the existing 2000-year record. The new geochemical data parallel major trends in botanical proxies but also reveal aspects of human and environmental dynamics not apparent in the prior analysis. Inferred changes in land use in the watershed are consistent with archaeological evidence. Geochemical trends strongly suggest a population collapse at the site around the time of the Terminal Classic Drought of the Mayan region. The generally close correspondence between microfossil assemblages and geochemistry in the Santa Elena core demonstrates the usefulness of stable isotope analysis as a first line of investigation in paleoenvironmental research. Sediment samples for carbon isotope analysis need to be acidified to remove carbonates that can affect isotope measurements, and debate exists over whether nitrogen isotope analysis can use these acidified samples or require non-acidified samples. My thesis research tested the effects of pre-analysis acidification of sediment and soil samples from Laguna Santa Elena and a second lake in Costa Rica, Laguna Azul (9.9558 N, 83.6519 W, 630 m elevation) in the Central Highlands-Atlantic Watershed archaeological region. Results show that acidification may cause statistically significant differences in nitrogen isotope values. These differences appear to be random and unpredictable, and can manifest as either positive or negative shifts that have the potential to alter or even reverse relative trends in nitrogen isotope signals in lake sediment profiles. More tests are needed, but the results of this analysis suggest that researchers should avoid dual-mode analysis, in which data for both stable carbon and nitrogen isotopes are obtained from a single acidified sample, and should continue analyzing an additional non-acidified sample to obtain nitrogen isotope values

Holocene Precipitation Variability, Prehistoric Agriculture, and Natural and Human-Set Fires in Costa Rica

This dissertation presents the results of compound-specific stable hydrogen isotope analysis of n-alkanes from terrestrial leaf waxes preserved in sediment cores from three lakes in Costa Rica to reconstruct variations in paleohydrology during the Holocene. Results were compared with pollen and charcoal data from the same cores to examine relationships between paleohydrology, vegetation change, prehistoric agriculture, and fire, and with archaeological evidence in the watersheds of two lakes to better understand prehistoric human-environment interactions. Lago de las Morrenas 1 (9.4925 °N, 83.4848 °W, 3480 m) is in the Chirripó páramo of Costa Rica, which was never permanently occupied by prehistoric people. The analyses demonstrate 10,000 years of millennial-scale variations in hydroclimate at Morrenas 1, which was dry during the Early Holocene, mesic during the Middle Holocene, and dry over the Late Holocene. The Morrenas sediments record local manifestations of the 8200 BP event, the 5200 BP event, the Terminal Classic Drought (TCD), and the Little Ice Age (LIA). Laguna Bonillita (9.9921 °N, 83.6114 °W, 450 m), in the Caribbean lowlands of central Costa Rica, has a 2700-year history of continuous maize agriculture. The alkane data show variations in paleohydrology over the Late Holocene and local manifestations of the TCD and the LIA that match patterns throughout the circum-Caribbean. The Bonillita watershed was intensively farmed across the entire history of the lake. Changes in prehistoric culture and maize farming are temporally linked to climate change at Bonillita. The data indicate that maize agriculture benefitted from episodes of drier climate in this lowland rainforest environment. Laguna Santa Elena (8.9290 °N, 82.9257 °W, 1055 m), in the Diquís archaeological subregion of southern Pacific Costa Rica, has a 2000-year history of maize agriculture. The analyses document variations in Late Holocene paleohydrology, including local manifestations of the TCD and the LIA, that had important consequences for prehistoric people. Santa Elena may have experienced a decrease in rainfall during the TCD, but unlike the Caribbean side of the Isthmus, the amplitude of this drought event does not appear abnormal on centennial to millennial timescales. Two population collapses inferred to take place during dry periods instead happened during wet intervals at Santa Elena

The History of Flow Chemistry at Eli Lilly and Company

Flow chemistry was initially used for speed to early phase material delivery in the development laboratories, scaling up chemical transformations that we would not or could not scale up batch for safety reasons. Some early examples included a Newman Kwart Rearrangement, Claisen rearrangement, hydroformylation, and thermal imidazole cyclization. Next, flow chemistry was used to enable safe scale up of hazardous chemistries to manufacturing plants. Examples included high pressure hydrogenation, aerobic oxidation, and Grignard formation reactions. More recently, flow chemistry was used in Small Volume Continuous (SVC) processes, where highly potent oncolytic molecules were produced by fully continuous processes at about 10 kg/day including reaction, extraction, distillation, and crystallization, using disposable equipment contained in fume hoods

Simplified novel muraymycin analogues ; using a serine template strategy for linking key pharmacophores

The present status of antibiotic research requires the urgent invention of novel agents that act on multidrug-resistant bacteria. The World Health Organization has classified antibiotic-resistant bacteria into critical, high and medium priority according to the urgency of need for new antibiotics. Naturally occurring uridine-derived "nucleoside antibiotics" have shown promising activity against numerous priority resistant organisms by inhibiting the transmembrane protein MraY (translocase I), which is yet to be explored in a clinical context. The catalytic activity of MraY is an essential process for bacterial cell viability and growth including that of priority organisms. Muraymycins are one subclass of naturally occurring MraY inhibitors. Despite having potent antibiotic properties, the structural complexity of muraymycins advocates for simplified analogues as potential lead structures. Herein, we report a systematic structure-activity relationship (SAR) study of serine template-linked, simplified muraymycin-type analogues. This preliminary SAR lead study of serine template analogues successfully revealed that the complex structure of naturally occurring muraymycins could be easily simplified to afford bioactive scaffolds against resistant priority organisms. This study will pave the way for the development of novel antibacterial lead compounds based on a simplified serine template. [Abstract copyright: © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genome-wide association study of dental caries in the Hispanic Communities Health Study/Study of Latinos (HCHS/SOL)

Dental caries is the most common chronic disease worldwide, and exhibits profound disparities in the USA with racial and ethnic minorities experiencing disproportionate disease burden. Though heritable, the specific genes influencing risk of dental caries remain largely unknown. Therefore, we performed genome-wide association scans (GWASs) for dental caries in a population-based cohort of 12 000 Hispanic/Latino participants aged 18–74 years from the HCHS/SOL. Intra-oral examinations were used to generate two common indices of dental caries experience which were tested for association with 27.7 M genotyped or imputed single-nucleotide polymorphisms separately in the six ancestry groups. A mixed-models approach was used, which adjusted for age, sex, recruitment site, five principal components of ancestry and additional features of the sampling design. Meta-analyses were used to combine GWAS results across ancestry groups. Heritability estimates ranged from 20–53% in the six ancestry groups. The most significant association observed via meta-analysis for both phenotypes was in the region of the NAMPT gene (rs190395159; P-value = 6 × 10−10), which is involved in many biological processes including periodontal healing. Another significant association was observed for rs72626594 (P-value = 3 × 10−8) downstream of BMP7, a tooth development gene. Other associations were observed in genes lacking known or plausible roles in dental caries. In conclusion, this was the largest GWAS of dental caries, to date and was the first to target Hispanic/Latino populations. Understanding the factors influencing dental caries susceptibility may lead to improvements in prediction, prevention and disease management, which may ultimately reduce the disparities in oral health across racial, ethnic and socioeconomic strata

Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft—A preclinical study

From Wiley via Jisc Publications RouterHistory: received 2021-05-17, rev-recd 2021-09-16, accepted 2021-09-24, pub-electronic 2021-11-26Article version: VoRPublication status: PublishedAbstract: Introduction: Recent experimental evidence suggests normothermic machine perfusion of the vascularized composite allograft results in improved preservation compared to static cold storage, with less reperfusion injury in the immediate post‐operative period. However, metabolic acidosis is a common feature of vascularized composite allograft perfusion, primarily due to the inability to process metabolic by‐products. We evaluated the impact of combined limb‐kidney perfusion on markers of metabolic acidosis and inflammation in a porcine model. Methods: Ten paired pig forelimbs were used for this study, grouped as either limb‐only (LO, n = 5) perfusion, or limb‐kidney (LK, n = 5) perfusion. Infrared thermal imaging was used to determine homogeneity of perfusion. Lactate, bicarbonate, base, pH, and electrolytes, along with an inflammatory profile generated via the quantification of cytokines and cell‐free DNA in the perfusate were recorded. Results: The addition of a kidney to a limb perfusion circuit resulted in the rapid stabilization of lactate, bicarbonate, base, and pH. Conversely, the LO circuit became progressively acidotic, correlating in a significant increase in pro‐inflammatory cytokines. Global perfusion across the limb was more homogenous with LK compared to LO. Conclusion: The addition of a kidney during limb perfusion results in significant improvements in perfusate biochemistry, with no evidence of metabolic acidosis

Pattern Recognition Receptor Polymorphisms as Predictors of Oxaliplatin Benefit in Colorectal Cancer

Background Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification. Methods We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided. Results Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40). Conclusion In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers

Genome-wide Association Study of Platelet Count Identifies Ancestry-Specific Loci in Hispanic/Latino Americans

Platelets play an essential role in hemostasis and thrombosis. We performed a genome-wide association study of platelet count in 12,491 participants of the Hispanic Community Health Study/Study of Latinos by using a mixed-model method that accounts for admixture and family relationships. We discovered and replicated associations with five genes (ACTN1, ETV7, GABBR1-MOG, MEF2C, and ZBTB9-BAK1). Our strongest association was with Amerindian-specific variant rs117672662 (p value = 1.16 × 10−28) in ACTN1, a gene implicated in congenital macrothrombocytopenia. rs117672662 exhibited allelic differences in transcriptional activity and protein binding in hematopoietic cells. Our results underscore the value of diverse populations to extend insights into the allelic architecture of complex traits

Genetic epidemiology of motor neuron disease-associated variants in the Scottish population

Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population