Publications by authors named "Michael Little"

39 Publications

Adult liver transplant anesthesiology practice patterns and resource utilization in the United States: Survey results from the society for the advancement of transplant anesthesia.

Clin Transplant 2021 Oct 12:e14504. Epub 2021 Oct 12.

Department of Anesthesiology, University of Colorado, Aurora, CO.

Introduction: Liver transplant anesthesiology is an evolving and expanding subspecialty, and programs have, in the past, exhibited significant variations of practice at transplant centers across the United States. In order to explore current practice patterns, the Quality & Standards Committee from the Society for the Advancement of Transplant Anesthesia (SATA) undertook a survey of liver transplant anesthesiology program directors.

Methods: Program directors were invited to participate in an online questionnaire. A total of 110 program directors were identified from the 2018 Scientific Registry of Transplant Recipients (SRTR) database. Replies were received from 65 programs (response rate of 59%).

Results: Our results indicate an increase in transplant anesthesia fellowship training and advanced training in transesophageal echocardiography (TEE). We also find that the use of intraoperative TEE and viscoelastic testing is more common. However, there has been a reduction in the use of veno-venous bypass, routine placement of pulmonary artery catheters and the intraoperative use of anti-fibrinolytics when compared to prior surveys.

Conclusion: The results show considerable heterogeneity in practice patterns across the country that continues to evolve. However, there appears to be a movement towards the adoption of specific structural and clinical practices. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/ctr.14504DOI Listing
October 2021

Joseph L.A. Ghesquiere (Halle, Belgium, November 30, 1925 - Archennes, Belgium, January 26, 2021).

Ann Hum Biol 2021 Jun 7;48(4):369-370. Epub 2021 Jun 7.

University of Texas, Austin, TX, USA.

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http://dx.doi.org/10.1080/03014460.2021.1932666DOI Listing
June 2021

Spatiotemporal impacts of COVID-19 on air pollution in California, USA.

Sci Total Environ 2021 Jan 10;750:141592. Epub 2020 Aug 10.

NSF Spatiotemporal Innovation Center, George Mason Univ., Fairfax, VA 22030, USA; Department of Geography and GeoInformation Science, George Mason Univ., Fairfax, VA 22030, USA. Electronic address:

Various recent studies have shown that societal efforts to mitigate (e.g. "lockdown") the outbreak of the 2019 coronavirus disease (COVID-19) caused non-negligible impacts on the environment, especially air quality. To examine if interventional policies due to COVID-19 have had a similar impact in the US state of California, this paper investigates the spatiotemporal patterns and changes in air pollution before, during and after the lockdown of the state, comparing the air quality measurements in 2020 with historical averages from 2015 to 2019. Through time series analysis, a sudden drop and uptick of air pollution are found around the dates when shutdown and reopening were ordered, respectively. The spatial patterns of nitrogen dioxide (NO) tropospheric vertical column density (TVCD) show a decreasing trend over the locations of major powerplants and an increasing trend over residential areas near interactions of national highways. Ground-based observations around California show a 38%, 49%, and 31% drop in the concentration of NO, carbon monoxide (CO) and particulate matter 2.5 (PM) during the lockdown (March 19-May 7) compared to before (January 26-March 18) in 2020. These are 16%, 25% and 19% sharper than the means of the previous five years in the same periods, respectively. Our study offers evidence of the environmental impact introduced by COVID-19, and insight into related economic influences.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416771PMC
January 2021

Mutational analysis confirms the presence of distal inhibitor-selectivity determining residues in B. stearothermophilus dihydrofolate reductase.

Arch Biochem Biophys 2020 10 15;692:108545. Epub 2020 Aug 15.

Dept. of Chemistry & Biochemistry, Montclair State University, Montclair, NJ, 07043, USA. Electronic address:

Many antibacterial and antiparasitic drugs work by competitively inhibiting dihydrofolate reductase (DHFR), a vital enzyme in folate metabolism. The interactions between inhibitors and DHFR active site residues are known in many homologs but the contributions from distal residues are less understood. Identifying distal residues that aid in inhibitor binding can improve targeted drug development programs by accounting for distant influences that may be less conserved and subject to frequent resistance causing mutations. Previously, a novel, homology-based, computational approach that mines ligand inhibition data was used to predict residues involved in inhibitor selectivity in the DHFR family. Expectedly, some inhibitor selectivity determining residue positions were predicted to lie in the active site and coincide with experimentally known inhibitor selectivity determining positions. However, other residues that group spatially in clusters distal to the active site have not been previously investigated. In this study, the effect of introducing amino acid substitutions at one of these predicted clusters (His38-Ala39-Ile40) on the inhibitor selectivity profile in Bacillus stearothermophilus dihydrofolate reductase (Bs DHFR) was investigated. Mutations were introduced into these cluster positions to change sidechain chemistry and size. We determined k and K values and measured K values at equilibrium for two competitive DHFR inhibitors, trimethoprim (TMP) and pyrimethamine (PYR). Mutations in the His38-Ala39-Ile40 cluster significantly impacted inhibitor binding and TMP/PYR selectivity - seven out of nine mutations resulted in tighter binding to PYR when compared to TMP. These data suggest that the His38-Ala39-Ile40 cluster is a distal inhibitor selectivity determining region that favors PYR binding in Bs DHFR and, possibly, throughout the DHFR family.
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http://dx.doi.org/10.1016/j.abb.2020.108545DOI Listing
October 2020

Evolutionary Strategies for Body Size.

Authors:
Michael A Little

Front Endocrinol (Lausanne) 2020 10;11:107. Epub 2020 Mar 10.

Department of Anthropology, Binghamton University, State University of New York, Binghamton, NY, United States.

Humans show marked variation in body size around the world, both within and among populations. At present, the tallest people in the world are from the Netherlands and the Balkan countries, while the shortest populations are central African Pygmies. There are genetic, genetic plasticity, developmental, and environmental bases for size variation in from the recent past and the present. Early populations of species also have shown considerable size variation. Populations from the present and the past are also marked by sexual dimorphism, which, itself, shows group variation. There is abundant evidence for the effects of limited food and disease on human growth and resultant adult body size. This environmental influence has been reflected in "secular trends" (over a span of years) in growth and adult size from socioeconomic prosperity or poverty (availability of resources). Selective and evolutionary advantages of small or large body size also have been documented. Heritability for human height is relatively great with current genome-wide association studies (GWAS) identifying hundreds of genes leading to causes of growth and adult size variation. There are also endocrinological pathways limiting growth. An example is the reduced tissue sensitivity to human growth hormone (HGH) and insulin-like growth factor (IGF-1) in Philippine and African hunter-gatherer populations. In several short-statured hunter-gatherer populations (Asian, African, and South American), it has been hypothesized that short life expectancy has selected for early maturity and truncated growth to enhance fertility. Some island populations of humans and other mammals are thought to have been selected for small size because of limited resources, especially protein. The high-protein content of milk as a staple food may contribute to tall stature in East African pastoral peoples. These and other evolutionary questions linked to life history, male competition, reproduction, and mobility are explored in this paper.
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http://dx.doi.org/10.3389/fendo.2020.00107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075806PMC
February 2021

Mouse Gut Microbiome-Encoded β-Glucuronidases Identified Using Metagenome Analysis Guided by Protein Structure.

mSystems 2019 Aug 27;4(4). Epub 2019 Aug 27.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Gut microbial β-glucuronidase (GUS) enzymes play important roles in drug efficacy and toxicity, intestinal carcinogenesis, and mammalian-microbial symbiosis. Recently, the first catalog of human gut GUS proteins was provided for the Human Microbiome Project stool sample database and revealed 279 unique GUS enzymes organized into six categories based on active-site structural features. Because mice represent a model biomedical research organism, here we provide an analogous catalog of mouse intestinal microbial GUS proteins-a mouse gut GUSome. Using metagenome analysis guided by protein structure, we examined 2.5 million unique proteins from a comprehensive mouse gut metagenome created from several mouse strains, providers, housing conditions, and diets. We identified 444 unique GUS proteins and organized them into six categories based on active-site features, similarly to the human GUSome analysis. GUS enzymes were encoded by the major gut microbial phyla, including (60%) and (21%), and there were nearly 20% for which taxonomy could not be assigned. No differences in gut microbial gene composition were observed for mice based on sex. However, mice exhibited differences based on active-site features associated with provider, location, strain, and diet. Furthermore, diet yielded the largest differences in composition. Biochemical analysis of two low-fat-associated GUS enzymes revealed that they are variable with respect to their efficacy of processing both sulfated and nonsulfated heparan nonasaccharides containing terminal glucuronides. Mice are commonly employed as model organisms of mammalian disease; as such, our understanding of the compositions of their gut microbiomes is critical to appreciating how the mouse and human gastrointestinal tracts mirror one another. GUS enzymes, with importance in normal physiology and disease, are an attractive set of proteins to use for such analyses. Here we show that while the specific GUS enzymes differ at the sequence level, a core GUSome functionality appears conserved between mouse and human gastrointestinal bacteria. Mouse strain, provider, housing location, and diet exhibit distinct GUSomes and gene compositions, but sex seems not to affect the GUSome. These data provide a basis for understanding the gut microbial GUS enzymes present in commonly used laboratory mice. Further, they demonstrate the utility of metagenome analysis guided by protein structure to provide specific sets of functionally related proteins from whole-genome metagenome sequencing data.
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http://dx.doi.org/10.1128/mSystems.00452-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712278PMC
August 2019

Testing longitudinal associations between executive function and academic achievement.

Dev Psychol 2019 Apr 27;55(4):767-779. Epub 2018 Dec 27.

School of Education.

Children with higher levels of executive function (EF) skills consistently demonstrate higher levels of academic achievement. Despite the consistency of these associations, fundamental questions remain about whether efforts to improve an individual child's EF skills result in corresponding improvements in his or her academic performance. In the absence of experimental evidence, developmentalists have used repeated measures designs to test the nature, magnitude, and direction of the associations between EF skills and academic achievement. In contrast to previous studies, this study described how between- and within-person associations between EF and achievement address different questions. Using data from a subsample of participants ( = 6,040) from the Early Childhood Longitudinal Study-Kindergarten, 2010-2011 (ECLS-K:2011) cohort, we estimated a series of latent growth curve models with structured residuals to test the between and within-person associations between 2 dimensions of EF (working memory, cognitive flexibility) and 2 domains of academic achievement (math, reading). Whereas between-person associations between EF and achievement were large (φ = .55-.91), the within-person associations were small (βs = -.10-.25). Within-person effects of earlier reading achievement on later EF skills was the most consistent finding. Results were unchanged when analyses were repeated using the subset of children who were eligible for free and reduced-price lunch, a proxy for low socioeconomic households. Results are discussed with respect to interest in improving EF skills as a means for facilitating school outcomes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/dev0000664DOI Listing
April 2019

Coming to grips with economic development: Variation in adult hand grip strength during health transition in Vanuatu.

Am J Phys Anthropol 2018 12 27;167(4):760-776. Epub 2018 Sep 27.

Department of Anthropology, SUNY Binghamton, Binghamton, New York.

Objectives: To determine whether (1) maximal handgrip strength (HGS) is associated with inter-island level of economic development in Vanuatu, (2) how associations between island of residence and HGS are mediated by age, sex, body size/composition, and individual sociodeomographic variation, and (3) whether HGS is predictive of hypertension.

Material And Methods: HGS was collected from 833 adult (aged 18 and older) men and women on five islands representing a continuum of economic development in Vanuatu. HGS was measured using a handheld dynamometer. Participants were administered in an extensive sociobehavioral questionnaire and were also assessed for height, weight, percent body fat, forearm skinfold thickness, forearm circumference, and blood pressure.

Results: HGS was significantly greater in men than in women regardless of island of residence. HGS was also significantly positively associated with inter-island level of economic development. Grip strength-to-weight ratio was not different across islands except in older individuals, where age-related decline occurred primarily on islands with greater economic development. HGS significantly declined with age in both men and women.

Conclusion: HGS is positively associated with modernization in Vanuatu, but the relationship between HGS and modernization is largely due to an association of both variables with increased body size on more modernized islands. Further research on the role of individual variation in diet and physical activity are necessary to clarify the relationship between HGS and modernization.
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http://dx.doi.org/10.1002/ajpa.23704DOI Listing
December 2018

Active site flexibility revealed in crystal structures of Parabacteroides merdae β-glucuronidase from the human gut microbiome.

Protein Sci 2018 12 27;27(12):2010-2022. Epub 2018 Oct 27.

Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina, 27599-3290.

β-Glucuronidase (GUS) enzymes in the gastrointestinal tract are involved in maintaining mammalian-microbial symbiosis and can play key roles in drug efficacy and toxicity. Parabacteroides merdae GUS was identified as an abundant mini-Loop 2 (mL2) type GUS enzyme in the Human Microbiome Project gut metagenomic database. Here, we report the crystal structure of P. merdae GUS and highlight the differences between this enzyme and extant structures of gut microbial GUS proteins. We find that P. merdae GUS exhibits a distinct tetrameric quaternary structure and that the mL2 motif traces a unique path within the active site, which also includes two arginines distinctive to this GUS. We observe two states of the P. merdae GUS active site; a loop repositions itself by more than 50 Å to place a functionally-relevant residue into the enzyme's catalytic site. Finally, we find that P. merdae GUS is able to bind to homo and heteropolymers of the polysaccharide alginic acid. Together, these data broaden our understanding of the structural and functional diversity in the GUS family of enzymes present in the human gut microbiome and point to specialization as an important feature of microbial GUS orthologs.
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http://dx.doi.org/10.1002/pro.3507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237702PMC
December 2018

Total intravenous anesthesia vs inhaled anesthetic for intraoperative visualization during endoscopic sinus surgery: a double blind randomized controlled trial.

Int Forum Allergy Rhinol 2018 10 10;8(10):1123-1126. Epub 2018 Sep 10.

Department of Surgery, University of Alberta, Edmonton, AB, Canada.

Background: Bleeding during endoscopic sinus surgery (ESS) can impair visualization and delay surgical progress. The role that anesthetic technique may have on the quality of surgical field during ESS has been previously studied. However, meta-analyses have deemed the current literature inconclusive and lacking methodological consistency. This study was designed with these critiques in mind to assess the effect of total intravenous anesthesia (TIVA) vs inhaled anesthetic on the quality of the surgical field during ESS.

Methods: This study was a double-blind, randomized, controlled trial of 30 patients of American Society of Anesthesiologists (ASA) class 1 or 2 undergoing bilateral ESS for the primary diagnosis of chronic rhinosinusitis. In addition to standard techniques to minimize blood loss, study patients were randomized to maintenance anesthesia with intravenous propofol or inhaled desflurane. Anesthetic depth was standardized using bispectral index (BIS). The primary outcome measured was the Wormald grading scale to assess the endoscopic surgical field.

Results: The use of TIVA was associated with a statistically significant reduction in mean Wormald score compared to desflurane (4.21 vs 5.53, p = 0.024). Mean Boezaart score was also lower in the TIVA arm (2.18 vs 2.76, p = 0.034). Experimental groups were homogeneous in all compared baseline characteristics. Secondary outcomes including surgical duration, time to extubation, and estimated blood loss were not found to be statistically significant between experimental groups.

Conclusion: Even with all other factors implemented to optimize the surgical field, utilization of TIVA vs inhaled anesthetic still resulted in a statistically significant improvement in surgical field during ESS.
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http://dx.doi.org/10.1002/alr.22129DOI Listing
October 2018

Crystal structure of the mouse innate immunity factor bacterial permeability-increasing family member A1.

Acta Crystallogr F Struct Biol Commun 2018 05 16;74(Pt 5):268-276. Epub 2018 Apr 16.

Department of Chemistry, University of North Carolina, 4350 Genome Sciences Building, Chapel Hill, NC 27599-3290, USA.

Bacterial permeability-increasing family member A1 (BPIFA1) is an innate immunity factor and one of the most abundantly secreted proteins in the upper airways. BPIFA1 is multifunctional, with antimicrobial, surfactant and lipopolysaccharide-binding activities, as well as established roles in lung hydration. Here, the 2.5 Å resolution crystal structure of BPIFA1 from Mus musculus (mBPIFA1) is presented and compared with those of human BPIFA1 (hBPIFA1) and structural homologs. Structural distinctions between mBPIFA1 and hBPIFA1 suggest potential differences in biological function, including the regulation of a key pulmonary ion channel.
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http://dx.doi.org/10.1107/S2053230X18004600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931138PMC
May 2018

Physical anthropology in 1918 and the founding of the U.S. journal.

Authors:
Michael A Little

Am J Phys Anthropol 2018 04;165(4):626-637

Department of Anthropology, Binghamton University, State University of New York, Binghamton, New York.

In 1918, the first issue of the American Journal of Physical Anthropology was prepared and distributed by Aleš Hrdlička, the Curator of Physical Anthropology at the Smithsonian Institution. This was a singular act, both in the general and specific sense. It was the first journal of physical anthropology published in the United States, and it was a sole effort by Hrdlička, who was committed to promoting and recognizing physical anthropology as a new science in America. On this 100th anniversary of the founding of the journal, Hrdlička's efforts were successful: physical/biological anthropology is a strong and timely discipline that represents a major area of scientific research today.
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http://dx.doi.org/10.1002/ajpa.23394DOI Listing
April 2018

Structural basis for the regulation of β-glucuronidase expression by human gut Enterobacteriaceae.

Proc Natl Acad Sci U S A 2018 01 21;115(2):E152-E161. Epub 2017 Dec 21.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290;

The gut microbiota harbor diverse β-glucuronidase (GUS) enzymes that liberate glucuronic acid (GlcA) sugars from small-molecule conjugates and complex carbohydrates. However, only the Enterobacteriaceae family of human gut-associated Proteobacteria maintain a GUS operon under the transcriptional control of a glucuronide repressor, GusR. Despite its potential importance in , , , , and opportunistic pathogens, the structure of GusR has not been examined. Here, we explore the molecular basis for GusR-mediated regulation of GUS expression in response to small-molecule glucuronides. Presented are 2.1-Å-resolution crystal structures of GusRs from and in complexes with a glucuronide ligand. The GusR-specific DNA operator site in the regulatory region of the GUS operon is identified, and structure-guided GusR mutants pinpoint the residues essential for DNA binding and glucuronide recognition. Interestingly, the endobiotic estradiol-17-glucuronide and the xenobiotic indomethacin-acyl-glucuronide are found to exhibit markedly differential binding to these GusR orthologs. Using structure-guided mutations, we are able to transfer GusR's preferential DNA and glucuronide binding affinity to GusR. Structures of putative GusR orthologs from GUS-encoding Firmicutes species also reveal functionally unique features of the Enterobacteriaceae GusRs. Finally, dominant-negative GusR variants are validated in cell-based studies. These data provide a molecular framework toward understanding the control of glucuronide utilization by opportunistic pathogens in the human gut.
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http://dx.doi.org/10.1073/pnas.1716241115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777068PMC
January 2018

An Atlas of β-Glucuronidases in the Human Intestinal Microbiome.

Structure 2017 07 1;25(7):967-977.e5. Epub 2017 Jun 1.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Departments of Biochemistry, Microbiology, and Genomics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Microbiome-encoded β-glucuronidase (GUS) enzymes play important roles in human health by metabolizing drugs in the gastrointestinal (GI) tract. The numbers, types, and diversity of these proteins in the human GI microbiome, however, remain undefined. We present an atlas of GUS enzymes comprehensive for the Human Microbiome Project GI database. We identify 3,013 total and 279 unique microbiome-encoded GUS proteins clustered into six unique structural categories. We assign their taxonomy, assess cellular localization, reveal the inter-individual variability within the 139 individuals sampled, and discover 112 novel microbial GUS enzymes. A representative in vitro panel of the most common GUS proteins by read abundances highlights structural and functional variabilities within the family, including their differential processing of smaller glucuronides and larger carbohydrates. These data provide a sequencing-to-molecular roadmap for examining microbiome-encoded enzymes essential to human health.
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http://dx.doi.org/10.1016/j.str.2017.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533298PMC
July 2017

Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor.

Nat Commun 2017 02 6;8:14118. Epub 2017 Feb 6.

Cystic Fibrosis Center/Marsico Lung Institute, Marsico Hall, 125 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.

Asthma is a chronic airway disease characterized by inflammation, mucus hypersecretion and abnormal airway smooth muscle (ASM) contraction. Bacterial permeability family member A1, BPIFA1, is a secreted innate defence protein. Here we show that BPIFA1 levels are reduced in sputum samples from asthmatic patients and that BPIFA1 is secreted basolaterally from healthy, but not asthmatic human bronchial epithelial cultures (HBECs), where it suppresses ASM contractility by binding to and inhibiting the Ca influx channel Orai1. We have localized this effect to a specific, C-terminal α-helical region of BPIFA1. Furthermore, tracheas from Bpifa1 mice are hypercontractile, and this phenotype is reversed by the addition of recombinant BPIFA1. Our data suggest that BPIFA1 deficiency in asthmatic airways promotes Orai1 hyperactivity, increased ASM contraction and airway hyperresponsiveness. Strategies that target Orai1 or the BPIFA1 deficiency in asthma may lead to novel therapies to treat this disease.
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http://dx.doi.org/10.1038/ncomms14118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303822PMC
February 2017

Grip strength and body composition in Turkana pastoralist children and adolescents.

Authors:
Michael A Little

Am J Hum Biol 2017 Mar 17;29(2). Epub 2016 Sep 17.

Department of Anthropology, Binghamton University, State University of New York, Binghamton, NY, 13902.

Objectives: In an earlier study, age changes and sex differences in grip strength were documented for adult Turkana pastoralists of Kenya (Little and Johnson, 1986). The objective here is to characterize age changes and sex differences in grip strength of Turkana children and adolescents in the context of arm lean tissue composition, and in comparison with other African, African-American, and non-Western populations.

Methods: Anthropometric measurements, derived body composition values, and grip strength measures (maximum voluntary contraction) were taken on a sample of 232 nomadic Turkana pastoralist children (94 boys and 138 girls) aged 3 to 21 years. Relationships were tested between grip strength (in Newtons) and mid-upper arm (brachium) lean tissue cross-sectional areas. Comparisons were made among several different ethnic groups.

Results: Turkana children and adolescents had low arm muscle (derived lean tissue) and grip strength values when compared with U.S. NHANES percentile references. Girls' percentile rankings were greater than boys' percentile rankings for muscle and for grip strength. Both boys and girls were intermediate when compared with other non-Western populations and U.S. strength grip reference values. Correlations between grip strength and arm lean tissue areas were highly significant for both boys and girls.

Conclusions: The greater relative muscle size and grip strength values of late adolescent girls compared to boys is consistent with an earlier study of adults. The difference is likely to result from greater physical subsistence activity and greater access to food in girls than in boys. Several suggestions are given to explain why Turkana youths have relatively small muscle sizes.
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http://dx.doi.org/10.1002/ajhb.22922DOI Listing
March 2017

Structural Features Essential to the Antimicrobial Functions of Human SPLUNC1.

Biochemistry 2016 05 17;55(21):2979-91. Epub 2016 May 17.

Departments of Chemistry, Biochemistry, and Microbiology, University of North Carolina , 4350 Genome Sciences Building, Chapel Hill, North Carolina 27599-3290, United States.

SPLUNC1 is an abundantly secreted innate immune protein in the mammalian respiratory tract that exerts bacteriostatic and antibiofilm effects, binds to lipopolysaccharide (LPS), and acts as a fluid-spreading surfactant. Here, we unravel the structural elements essential for the surfactant and antimicrobial functions of human SPLUNC1 (short palate lung nasal epithelial clone 1). A unique α-helix (α4) that extends from the body of SPLUNC1 is required for the bacteriostatic, surfactant, and LPS binding activities of this protein. Indeed, we find that mutation of just four leucine residues within this helical motif to alanine is sufficient to significantly inhibit the fluid spreading abilities of SPLUNC1, as well as its bacteriostatic actions against Gram-negative pathogens Burkholderia cenocepacia and Pseudomonas aeruginosa. Conformational flexibility in the body of SPLUNC1 is also involved in the bacteriostatic, surfactant, and LPS binding functions of the protein as revealed by disulfide mutants introduced into SPLUNC1. In addition, SPLUNC1 exerts antibiofilm effects against Gram-negative bacteria, although α4 is not involved in this activity. Interestingly, though, the introduction of surface electrostatic mutations away from α4 based on the unique dolphin SPLUNC1 sequence, and confirmed by crystal structure, is shown to impart antibiofilm activity against Staphylococcus aureus, the first SPLUNC1-dependent effect against a Gram-positive bacterium reported to date. Together, these data pinpoint SPLUNC1 structural motifs required for the antimicrobial and surfactant actions of this protective human protein.
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http://dx.doi.org/10.1021/acs.biochem.6b00271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887393PMC
May 2016

Compound aggregation in drug discovery: implementing a practical NMR assay for medicinal chemists.

J Med Chem 2013 Jun 13;56(12):5142-50. Epub 2013 Jun 13.

Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec H7S2G5, Canada.

The pharmaceutical industry has recognized that many drug-like molecules can self-aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that can be performed on equipment prevalent in most synthetic chemistry departments. We show that (1)H NMR resonances are sensitive to large molecular-size entities and to smaller multimers and mixtures of species. Practical details are provided for sample preparation and for determining the concentrations of single molecule, aggregate entities, and precipitate. The critical concentrations above which aggregation begins can be found and were corroborated by comparisons with light scattering techniques. Disaggregation can also be monitored using detergents. This NMR assay should serve as a practical and readily available tool for medicinal chemists to better characterize how their compounds behave in aqueous media and influence drug design decisions.
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http://dx.doi.org/10.1021/jm400535bDOI Listing
June 2013

Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus.

Bioorg Med Chem Lett 2013 Jul 7;23(13):3841-7. Epub 2013 May 7.

Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5.

We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.
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http://dx.doi.org/10.1016/j.bmcl.2013.04.077DOI Listing
July 2013

Hepatic and renal Bcrp transporter expression in mice treated with perfluorooctanoic acid.

Toxicology 2013 Apr 19;306:108-13. Epub 2013 Feb 19.

Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA.

The breast cancer resistance protein (Bcrp) is an efflux transporter that participates in the biliary and renal excretion of drugs and environmental chemicals. Recent evidence suggests that pharmacological activation of the peroxisome proliferator activated receptor alpha (PPARα) can up-regulate the hepatic expression of Bcrp. The current study investigated the regulation of hepatic and renal Bcrp mRNA and protein in mice treated with the PPARα agonist perfluorooctanoic acid (PFOA) and the ability of PFOA to alter human BCRP function in vitro. Bcrp mRNA and protein expression were quantified in the livers and kidneys of male C57BL/6 mice treated with vehicle or PFOA (1 or 3mg/kg/day oral gavage) for 7 days. PFOA treatment increased liver weights as well as the hepatic mRNA and protein expression of the PPARα target gene, cytochrome P450 4a14. Compared to vehicle-treated control mice, PFOA increased hepatic Bcrp mRNA and protein between 1.5- and 3-fold. Immunofluorescent staining confirmed enhanced canalicular Bcrp staining in liver sections from PFOA-treated mice. The kidney expression of cytochrome P450 4a14 mRNA, but not Bcrp, was increased in mice treated with PFOA. Micromolar concentrations of PFOA decreased human BCRP ATPase activity and inhibited BCRP-mediated transport in inverted membrane vesicles. Together, these studies demonstrate that PFOA induces hepatic Bcrp expression in mice and may inhibit human BCRP transporter function at concentrations that exceed levels observed in humans.
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http://dx.doi.org/10.1016/j.tox.2013.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645321PMC
April 2013

A half century of high-altitude studies in anthropology: introduction to the plenary session.

Am J Hum Biol 2013 Mar-Apr;25(2):148-50. Epub 2013 Feb 5.

Department of Anthropology, Binghamton University, State University of New York, Binghamton, NY.

Until 50 years ago, high-altitude terrestrial research was conducted largely within the realm of environmental physiology, where interests were focused on physiological mechanisms and mountain exploration. Scientists from the United States, Europe, and Peru had developed sophisticated physiological models of adaptation and acclimatization to the hypoxia of high altitude, but very little research had been conducted on permanent residents, particularly natives of high altitude in the two major regions of the world-the Andes and the Himalayas. In 1962, Raul T. Baker initiated a project at the Pennsylvania State University to explore the responses of indigenous Peruvians to the major stresses at altitude: hypoxia and cold. Approaches to this early research were anthropological in perspective and centered on population-level studies with an evolutionary approach. Studies were conducted by applying a combination of physiological experimental methods, simulated field experiments, and extended anthropological field observations. Early hypotheses at this time were that heredity played a major role in the adaptive complexes in native high-altitude residents. These early hypotheses were later modified to incorporate or replace the genetic hypotheses with developmental adaptation models. A half century of research within anthropology and research in other fields has presented a vastly more complex and integrated picture of high-altitude adaptation in native residents. Recent studies incorporate physiology and oxygen transport, population and molecular genetics, reproduction, growth, and development. The history and current status of high-altitude research and its anthropological applications are treated in papers from this plenary symposium.
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http://dx.doi.org/10.1002/ajhb.22356DOI Listing
May 2014

Joseph S. Weiner and the foundation of post-WW II human biology in the United Kingdom.

Am J Phys Anthropol 2012 2;149 Suppl 55:114-31. Epub 2012 Nov 2.

Department of Anthropology, Binghamton University, State University of New York, Binghamton, NY, USA.

Both the United States and the United Kingdom experienced a transformation in the science of physical anthropology from the period before World War II until the post-war period. In the United States, Sherwood L. Washburn is credited with being a leading figure in this transformation. In the United Kingdom, two individuals were instrumental in bringing about a similar change in the profession. These were Joseph S. Weiner at the University of Oxford and Nigel Barnicot at the University of London, with Weiner playing the principal role as leader in what Washburn called the "New Physical Anthropology," that is, the application of evolutionary theory, the de-emphasis on race classification, and the application of the scientific method and experimental approaches to problem solving. Weiner's contributions to physical anthropology were broad-based--climatic and work physiology, paleoanthropology, and human variation--in what became known as human biology in the U.K. and human adaptability internationally. This biographical essay provides evidence for the significant influence of J.S. Weiner on the post-war development of human biology (biological or physical anthropology) inthe U.K.
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http://dx.doi.org/10.1002/ajpa.22164DOI Listing
February 2013

Human Biology Association archives at the Smithsonian Institution National Anthropological Archives.

Am J Hum Biol 2012 Mar-Apr;24(2):253-6. Epub 2012 Feb 3.

Binghamton University, USA.

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http://dx.doi.org/10.1002/ajhb.22242DOI Listing
April 2012

Reducing xerostomia after chemo-IMRT for head-and-neck cancer: beyond sparing the parotid glands.

Int J Radiat Oncol Biol Phys 2012 Jul 4;83(3):1007-14. Epub 2011 Nov 4.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.

Purpose: To assess whether, in addition to sparing the parotid glands (PGs), xerostomia after chemotherapy plus intensity-modulated radiotherapy (chemo-IMRT) for head-and-neck cancer is affected by reducing the dose to the other salivary glands.

Patients And Methods: In a prospective study, 78 patients with Stage III-IV oropharynx/nasopharynx cancer underwent chemo-IMRT, with the aim of sparing the parts of the bilateral PGs, oral cavity (OC) containing the minor salivary glands, and contralateral submandibular gland (SMG) outside the target (when contralateral level I was not a target). Before therapy and periodically for 24 months, validated patient-reported xerostomia questionnaire (XQ) scores and observer-graded xerostomia scores were recorded. Also, the stimulated and unstimulated saliva was measured selectively from each of the PGs and SMGs. The mean OC doses served as surrogates of minor salivary gland dysfunction. Regression models assessed the XQ and observer-graded xerostomia predictors.

Results: Statistically significant predictors of the XQ score on univariate analysis included the OC, PG, and SMG mean doses and the baseline XQ score, time since RT, and both stimulated and unstimulated PG saliva flow rates. Similar factors were statistically significant predictors of observer-graded xerostomia. The OC, PG, and SMG mean doses were moderately intercorrelated (r = 0.47-0.55). On multivariate analyses, after adjusting for the PG and SMG doses, the OC mean dose (p < .0001), interval from RT (p < .0001), and stimulated PG saliva (p < .0025) were significant predictors of the XQ scores and the OC mean dose and time for observer-graded xerostomia. Although scatter plots showed no thresholds, an OC mean dose of <40 Gy and contralateral SMG mean dose of <50 Gy were each associated with low patient-reported and observer-rated xerostomia at almost all post-therapy points.

Conclusion: The PG, SMG, and OC mean doses were significant predictors of both patient-reported and observer-rated xerostomia after chemo-IMRT, with OC doses remaining significant after adjusting for the PG and SMG doses. These results support efforts to spare all the salivary glands by IMRT, beyond the PGs alone.
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http://dx.doi.org/10.1016/j.ijrobp.2011.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288420PMC
July 2012

Priming the semantic neighbourhood during the attentional blink.

PLoS One 2010 Sep 14;5(9):e12645. Epub 2010 Sep 14.

School of Psychology, University of Sydney, Sydney, Australia.

Background: When two targets are presented in close temporal proximity amongst a rapid serial visual stream of distractors, a period of disrupted attention and attenuated awareness lasting 200-500 ms follows identification of the first target (T1). This phenomenon is known as the "attentional blink" (AB) and is generally attributed to a failure to consolidate information in visual short-term memory due to depleted or disrupted attentional resources. Previous research has shown that items presented during the AB that fail to reach conscious awareness are still processed to relatively high levels, including the level of meaning. For example, missed word stimuli have been shown to prime later targets that are closely associated words. Although these findings have been interpreted as evidence for semantic processing during the AB, closely associated words (e.g., day-night) may also rely on specific, well-worn, lexical associative links which enhance attention to the relevant target.

Methodology/principal Findings: We used a measure of semantic distance to create prime-target pairs that are conceptually close, but have low word associations (e.g., wagon and van) and investigated priming from a distractor stimulus presented during the AB to a subsequent target (T2). The stimuli were words (concrete nouns) in Experiment 1 and the corresponding pictures of objects in Experiment 2. In both experiments, report of T2 was facilitated when this item was preceded by a semantically-related distractor.

Conclusions/significance: This study is the first to show conclusively that conceptual information is extracted from distractor stimuli presented during a period of attenuated awareness and that this information spreads to neighbouring concepts within a semantic network.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012645PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939035PMC
September 2010

Raymond Pearl and the shaping of human biology.

Hum Biol 2010 Feb;82(1):77-102

Department of Anthropology, Binghamton University. Binghamton, NY, USA.

Raymond Pearl (1879-1940) was a significant figure in the field of biology. He founded the journal Human Biology and almost single-handedly promoted and established the scientific discipline of human biology. His scientific versatility was one of his most important features during the first four decades of the 20th century, and he played a major role in developing the fields of biodemography, human population biology, human life-cycle and life span approaches, fertility, growth, the biology of longevity and senescence, and mortality. He was one of the earliest biologists to combine biometric analyses and experimental studies to explore the dimensions of human biology. Pearl also was broadly educated in the arts, music, literature, history, the classics, and science. His writing was sophisticated and often witty, and his views were sometimes provocative and controversial. His network of colleagues and friends among the literary and science worlds was substantial. The following biographical memoir of Raymond Pearl is designed to commemorate the 80th anniversary of the founding of his journal Human Biology and is a tribute to this great scientist. Pearl's sudden death at age 61 truncated a scientific career that was one of the most productive of the 20th century.
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http://dx.doi.org/10.3378/027.082.0105DOI Listing
February 2010

Functional tricuspid regurgitation in a patient with endocarditis.

Anesth Analg 2009 Oct;109(4):1032-4

Department of Anesthesiology, University of Texas Health Science Center, San Antonio, Texas, USA.

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http://dx.doi.org/10.1213/ANE.0b013e3181b544afDOI Listing
October 2009

Blood pressure and lifestyle on Saba, Netherlands Antilles.

Am J Hum Biol 2009 May-Jun;21(3):319-25

Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.

During the 20th century, infectious disease morbidity and mortality generally waned whereas chronic degenerative diseases posed a growing burden at the global level. The population on Saba, Netherlands Antilles has recently experienced such an epidemiologic transition, and hypertension was reported to be extraordinarily high, although no prevalences have been reported and relationships with lifestyle factors associated with rapid modernization have not been explored. In this study, a medical and demographic questionnaires, as well as body composition and blood pressure measures were collected from 278 Saban men and women aged 18-91 years. When age and sex adjusted, 48% of the population was hypertensive. Age, BMI, and Afro-Caribbean descent were all associated with higher blood pressures. In a second phase, 124 individuals of the 278 were invited to receive a longer questionnaire on individual exposure to modernizing influences such as travel and education. Higher blood pressure was associated with having lived in fewer different places in the past; those who stayed only on Saba or Statia had higher blood pressures than those who had also lived in more modernized areas. However, this was no longer statistically significant after adjustment for age and BMI. Lifestyle incongruity was positively associated with higher blood pressure in that those with more discord between material wealth and income were more likely to be hypertensive, and this remained statistically significant after adjustment for age and adiposity. In summary, hypertension is highly prevalent on Saba and tended to be associated with greater age, adiposity, Afro-Caribbean ancestry, and lifestyle incongruity.
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http://dx.doi.org/10.1002/ajhb.20862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910626PMC
June 2009

Comparison of three strategies to delineate the bowel for whole pelvis IMRT of prostate cancer.

Radiother Oncol 2008 Jul 11;88(1):95-101. Epub 2008 Feb 11.

Department of Radiation Oncology, University of Texas Medical Branch, Galveston, USA.

Purpose: To compare three different contouring approaches of the bowel before and during whole pelvis IMRT of localized prostate cancer.

Materials: Nine patients were randomly selected among those treated for localized prostate cancer at UTMB from March 2004 to August 2006. On the planning CT, besides the usual organs at risk (OAR), for each patient we contoured the bowel according to three different definitions: each bowel segment ('BS'); 'BS+1', BS uniformly expanded by 1cm; intestinal cavity ('IC') or the 'container' of the bowel loops up to the pelvic/abdominal walls. For each patient we generated three rival plans each considering a different bowel definition, otherwise identical. Provided that the same target coverage and other OAR spare had been achieved, plans were compared for their ability to minimize bowel dose at planning. Furthermore, after co-registering 6 weekly CT to the initial planning CT for each patient, we investigated which of the three definitions would allow the best bowel protection also during treatment.

Results: All definitions provided a very similar average bowel DVH at planning. During treatment BS allowed an average approximately 20 cc more of bowel to receive at least 45 Gy over BS+1 and IC (p=0.008 and 0.029, respectively); on the contrary bowel V45 between IC and BS+1 were not significantly different (p=0.65).

Conclusion: A definition that takes into account internal organ motion is warranted to maximize bowel protection during treatment.
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http://dx.doi.org/10.1016/j.radonc.2008.01.015DOI Listing
July 2008

Acute toxicity of whole-pelvis IMRT in 87 patients with localized prostate cancer.

Acta Oncol 2008 ;47(2):301-10

Department of Radiation Oncology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.

Purpose: To assess the acute toxicity profile of whole pelvis IMRT (WP-IMRT) for localized prostate cancer.

Materials: Eighty seven patients treated with definitive WP-IMRT at UTMB from May 2002 to November 2006 were retrospectively reviewed. Treatment consisted of two sequential phases, WP-IMRT to 54 Gy at 1.8 Gy per fraction to the pelvic nodes and seminal vesicles and 60 Gy at 2 Gy to the prostate, and a separate external beam boost, 3DCRT or IMRT, to bring the dose to the prostate to 76 Gy. Acute toxicity was prospectively scored weekly during treatment and at 3 month follow-up according to CTC v2.0 for 10 genitourinary (GU) and gastrointestinal (GI) domains. The proportion of patients experiencing a given level of peak acute toxicity at a given point is reported.

Results: Treatment was feasible with delivered doses to PTVs not significantly lower than planned ones and with only two patients experiencing treatment gaps longer than 5 days. About 2/3 and 1/10 of the patients experienced peak grade 2 and grade 3 reactions at least once during RT, respectively. Frequency/urgency (Grade 2+: 37.9%) and diarrhea (36.7%) were the most prevalent symptoms followed by proctitis (21.8%) and dysuria (16.1%). GI reactions were generally shorter lasting compared to GU ones which accumulated progressively during treatment. At 3 months, almost half of the patients were asymptomatic and most of observed reactions (89.2%) were mild, with GI ones more likely to be fully resolved (92.5%) than GU ones (68.7%, chi(2), p=0.001).

Conclusion: Our approach is dosimetrically and clinically feasible with intense, but transient, acute toxicity.
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http://dx.doi.org/10.1080/02841860701558849DOI Listing
May 2008
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