Publications by authors named "Ronald Nelson"

30 Publications

  • Page 1 of 1

Understanding the Molecular Basis of 5-HT Receptor Partial Agonists through 3D-QSAR Studies.

Int J Mol Sci 2021 Mar 30;22(7). Epub 2021 Mar 30.

Departamento de Química, Facultad de Ciencias, Universidad Católica del Norte, Av. Angamos 0610, Antofagasta 1270709, Chile.

Alzheimer's disease (AD) is a neurodegenerative disorder whose prevalence has an incidence in senior citizens. Unfortunately, current pharmacotherapy only offers symptom relief for patients with side effects such as bradycardia, nausea, and vomiting. Therefore, there is a present need to provide other therapeutic alternatives for treatments for these disorders. The 5-HT receptor is an attractive therapeutic target since it has a potential role in central and peripheral nervous system disorders such as AD, irritable bowel syndrome, and gastroparesis. Quantitative structure-activity relationship analysis of a series of 62 active compounds in the 5-HT receptor was carried out in the present work. The structure-activity relationship was estimated using three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques based on these structures' field molecular (force and Gaussian field). The best force-field QSAR models achieve a value for the coefficient of determination of the training set of R = 0.821, and for the test set R = 0.667, while for Gaussian-field QSAR the training and the test were R = 0.898 and R = 0.695, respectively. The obtained results were validated using a coefficient of correlation of the leave-one-out cross-validation of Q = 0.804 and Q = 0.886 for force- and Gaussian-field QSAR, respectively. Based on these results, novel 5-HT partial agonists with potential biological activity (pEC 8.209-9.417 for force-field QSAR and 9.111-9.856 for Gaussian-field QSAR) were designed. In addition, for the new analogues, their absorption, distribution, metabolism, excretion, and toxicity properties were also analyzed. The results show that these new derivatives also have reasonable pharmacokinetics and drug-like properties. Our findings suggest novel routes for the design and development of new 5-HT partial agonists.
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http://dx.doi.org/10.3390/ijms22073602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036435PMC
March 2021

Skeletal diversity in Pt- and Au-catalyzed annulations of allenedienes: dissecting unconventional mechanistic pathways.

Chem Sci 2020 Mar 27;11(16):4209-4220. Epub 2020 Mar 27.

Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela 15782 Santiago de Compostela Spain

We describe the discovery of unprecedented annulation processes of 1,7-allenedienes, promoted by Pt or Au catalysts. These transformations revealed mechanistic pathways that had not been previously observed in reactions involving carbophilic catalysis. In particular, we have found that allenedienes bearing a silyl ether in the carbon tether connecting the diene and the allene divergently afford cyclopropane-embedded tricyclic derivatives, 6,6-fused bicarbocyclic products or 5,6-fused bicarbocyclic systems, depending on the type of Au or Pt catalyst used. We have carried out experimental and computational studies that shed light on the mechanistic reasons behind this rich and unusual skeletal divergence, and provide new lessons on the drastic influence of platinum ancillary ligands on the reaction outcome.
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http://dx.doi.org/10.1039/d0sc00650eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152626PMC
March 2020

Neurosensory and Sinus Evolution as Tyrannosauroid Dinosaurs Developed Giant Size: Insight from the Endocranial Anatomy of Bistahieversor sealeyi.

Anat Rec (Hoboken) 2020 04 22;303(4):1043-1059. Epub 2020 Jan 22.

Los Alamos National Laboratory, Los Alamos, New Mexico.

Tyrannosaurus rex and other tyrannosaurid dinosaurs were apex predators during the latest Cretaceous, which combined giant size and advanced neurosensory systems. Computed tomography (CT) data have shown that tyrannosaurids had a trademark system of a large brain, large olfactory bulbs, elongate cochlear ducts, and expansive endocranial sinuses surrounding the brain and sense organs. Older, smaller tyrannosauroid relatives of tyrannosaurids developed some, but not all, of these features, raising the hypothesis that tyrannosaurid-style brains evolved before the enlarged tyrannosaurid-style sinuses, which might have developed only with large body size. This has been difficult to test, however, because little is known about the brains and sinuses of the first large-bodied tyrannosauroids, which evolved prior to Tyrannosauridae. We here present the first CT data for one of these species, Bistahieversor sealeyi from New Mexico. Bistahieversor had a nearly identical brain and sinus system as tyrannosaurids like Tyrannosaurus, including a large brain, large olfactory bulbs, reduced cerebral hemispheres, and optic lobes, a small tab-like flocculus, long and straight cochlear ducts, and voluminous sinuses that include a supraocciptal recess, subcondyar sinus, and an anterior tympanic recess that exits the braincase via a prootic fossa. When characters are plotted onto tyrannosauroid phylogeny, there is a two-stage sequence in which features of the tyrannosaurid-style brain evolved first (in smaller, nontyrannosaurid species like Timurlengia), followed by features of the tyrannosaurid-style sinuses (in the first large-bodied nontyrannosaurid tyrannosauroids like Bistahieversor). This suggests that the signature tyrannosaurid sinus system evolved in concert with large size, whereas the brain did not. Anat Rec, 303:1043-1059, 2020. © 2020 American Association for Anatomy.
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http://dx.doi.org/10.1002/ar.24374DOI Listing
April 2020

The Gut Microbiota in Collagenous Colitis Shares Characteristics With Inflammatory Bowel Disease-Associated Dysbiosis.

Clin Transl Gastroenterol 2019 07;10(7):e00065

Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.

Introduction: In inflammatory bowel disease (IBD), an aberrant immune response to gut microbiota is important, but the role of the microbiota in collagenous colitis (CC) is largely unknown. We aimed to characterize the microbiota of patients with CC compared with that of healthy control and patients with IBD.

Methods: Fecal samples were collected from patients with CC (n = 29), age- and sex-matched healthy controls (n = 29), patients with Crohn's disease (n = 32), and patients with ulcerative colitis (n = 32). Sequence data were obtained by 454 sequencing of 16S rRNA gene amplicons, and the obtained sequences were subsequently taxonomically classified.

Results: Analysis of similarity statistics showed a segregation between patients with CC and healthy controls with increasing taxonomic resolution, becoming significant comparing operational taxonomic unit data (P = 0.006). CC had a lower abundance of 10 different taxa. Taxa-specific analyses revealed a consistent lower abundance of several operational taxonomic units belonging to the Ruminococcaceae family in patients with CC, q < 0.05 after false discovery rate correction. Loss of these taxa was seen in patients with CC with active disease and/or corticosteroid treatment only and resembled the findings in patients with IBD.

Discussion: CC is associated with a specific fecal microbiome seen primarily in patients with active disease or ongoing corticosteroid treatment, whereas the microbiome of CC patients in remission resembled that of healthy controls. Notably, the shift in key taxa, including the Ruminococcaceae family, was also observed in IBD. There may be common mechanisms in the pathogenesis of CC and IBD.
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http://dx.doi.org/10.14309/ctg.0000000000000065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708665PMC
July 2019

Amnion membrane hydrogel and amnion membrane powder accelerate wound healing in a full thickness porcine skin wound model.

Stem Cells Transl Med 2020 01 21;9(1):80-92. Epub 2019 Jul 21.

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina.

There is a need for effective wound treatments that retain the bioactivity of a cellular treatment, but without the high costs and complexities associated with manufacturing, storing, and applying living biological products. Previously, we developed an amnion membrane-derived hydrogel and evaluated its wound healing properties using a mouse wound model. In this study, we used a full thickness porcine skin wound model to evaluate the wound-healing efficacy of the amnion hydrogel and a less-processed amnion product comprising a lyophilized amnion membrane powder. These products were compared with commercially available amnion and nonamnion wound healing products. We found that the amnion hydrogel and amnion powder treatments demonstrated significant and rapid wound healing, driven primarily by new epithelialization versus closure by contraction. Histological analysis demonstrated that these treatments promote the formation of a mature epidermis and dermis with similar composition to healthy skin. The positive skin regenerative outcomes using amnion hydrogel and amnion powder treatments in a large animal model further demonstrate their potential translational value for human wound treatments.
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http://dx.doi.org/10.1002/sctm.19-0101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954699PMC
January 2020

Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines.

Molecules 2018 Jul 10;23(7). Epub 2018 Jul 10.

Department of Chemistry, Wake Forest University, P.O. Box 7486, Winston-Salem, NC 27109, USA.

A number of new substituted morpholinopyrimidines were prepared utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. One of the disubstituted pyrimidines was converted into two trisubstituted compounds which were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor ZSTK474, and were found to be 1.5⁻3-times more potent. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by prostate-specific antigen, and it did not prevent inhibition of AKT phosphorylation and hence the inhibition of PI3K by the modified inhibitor.
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http://dx.doi.org/10.3390/molecules23071675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100461PMC
July 2018

Synthesis and PI 3-Kinase Inhibition Activity of Some Novel 2,4,6-Trisubstituted 1,3,5-Triazines.

Molecules 2018 Jul 4;23(7). Epub 2018 Jul 4.

Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA.

A number of new trisubstituted triazine phosphatidylinositol 3-kinase (PI3K) inhibitors were prepared via a three-step procedure utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. All were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor, ZSTK474. The most active inhibitors prepared here were 2⁻4 times more potent than ZSTK474. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by a prostate-specific antigen, and it did not prevent inhibition of protein kinase B (Akt) phosphorylation, and hence, the inhibition of PI3K by the modified inhibitor.
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http://dx.doi.org/10.3390/molecules23071628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100378PMC
July 2018

Toward patient-centered outcomes for cognitive evaluations: the perspective of those affected by Parkinson's disease.

Clin Neuropsychol 2018 Aug - Oct;32(7):1303-1318. Epub 2017 Dec 20.

e Georgetown Area Parkinson's Support Group , Georgetown , TX , USA.

Objective: Patient-centered outcomes research is predicated on the idea that the opinions, attitudes, and preferences of patients should help inform study design and interpretation. To date, little is known about what defines patient-centered outcomes from cognitive evaluations. The current evaluation sought to explore this issue in persons with Parkinson's disease (PwPD) and their care partners (CP).

Method: Focus groups of 22 PwPD/CP dyads were conducted to identify potential consumer oriented endpoints from cognitive evaluations. These endpoints were utilized to create a Patient-Centered Cognitive Assessment Outcomes Scale, which was administered to a different group of 50 PwPD/CP dyads who rated the importance of each outcome and identified their top three priority outcomes.

Results: Three themes emerged from the focus groups: improved knowledge, advice, and planning. Both PwPD and CP rated items in all three domains as being very important outcomes. Priorities for outcomes in both groups favored treatment planning information slightly above knowledge based outcomes.

Conclusions: The PwPD and CP identified improved knowledge, advice for daily activities, and knowledge they could use to plan for future eventualities as very important. This information can be used as a framework for future studies aimed at demonstrating patient-centered outcomes from neuropsychological evaluations. Implications for future research are discussed.
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http://dx.doi.org/10.1080/13854046.2017.1414884DOI Listing
August 2019

Laser-plasmas in the relativistic-transparency regime: Science and applications.

Phys Plasmas 2017 May 30;24(5):056702. Epub 2017 May 30.

Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico 87545, USA.

Laser-plasma interactions in the novel regime of relativistically induced transparency (RIT) have been harnessed to generate intense ion beams efficiently with average energies exceeding 10 MeV/nucleon (>100 MeV for protons) at "table-top" scales in experiments at the LANL Trident Laser. By further optimization of the laser and target, the RIT regime has been extended into a self-organized plasma mode. This mode yields an ion beam with much narrower energy spread while maintaining high ion energy and conversion efficiency. This mode involves self-generation of persistent high magnetic fields (∼10 T, according to particle-in-cell simulations of the experiments) at the rear-side of the plasma. These magnetic fields trap the laser-heated multi-MeV electrons, which generate a high localized electrostatic field (∼0.1 T V/m). After the laser exits the plasma, this electric field acts on a highly structured ion-beam distribution in phase space to reduce the energy spread, thus separating acceleration and energy-spread reduction. Thus, ion beams with narrow energy peaks at up to 18 MeV/nucleon are generated reproducibly with high efficiency (≈5%). The experimental demonstration has been done with 0.12 PW, high-contrast, 0.6 ps Gaussian 1.053 m laser pulses irradiating planar foils up to 250 nm thick at 2-8 × 10 W/cm. These ion beams with co-propagating electrons have been used on Trident for uniform volumetric isochoric heating to generate and study warm-dense matter at high densities. These beam plasmas have been directed also at a thick Ta disk to generate a directed, intense point-like Bremsstrahlung source of photons peaked at ∼2 MeV and used it for point projection radiography of thick high density objects. In addition, prior work on the intense neutron beam driven by an intense deuterium beam generated in the RIT regime has been extended. Neutron spectral control by means of a flexible converter-disk design has been demonstrated, and the neutron beam has been used for point-projection imaging of thick objects. The plans and prospects for further improvements and applications are also discussed.
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http://dx.doi.org/10.1063/1.4983991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449275PMC
May 2017

Genomewide analysis of admixture and adaptation in the Africanized honeybee.

Mol Ecol 2017 Jul 24;26(14):3603-3617. Epub 2017 Apr 24.

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

Genetic exchange by hybridization or admixture can make an important contribution to evolution, and introgression of favourable alleles can facilitate adaptation to new environments. A small number of honeybees (Apis mellifera) with African ancestry were introduced to Brazil ~60 years ago, which dispersed and hybridized with existing managed populations of European origin, quickly spreading across much of the Americas in an example of a massive biological invasion. Here, we analyse whole-genome sequences of 32 Africanized honeybees sampled from throughout Brazil to study the effect of this process on genome diversity. By comparison with ancestral populations from Europe and Africa, we infer that these samples have 84% African ancestry, with the remainder from western European populations. However, this proportion varies across the genome and we identify signals of positive selection in regions with high European ancestry proportions. These observations are largely driven by one large gene-rich 1.4-Mbp segment on chromosome 11 where European haplotypes are present at a significantly elevated frequency and likely confer an adaptive advantage in the Africanized honeybee population. This region has previously been implicated in reproductive traits and foraging behaviour in worker bees. Finally, by analysing the distribution of ancestry tract lengths in the context of the known time of the admixture event, we are able to infer an average generation time of 2.0 years. Our analysis highlights the processes by which populations of mixed genetic ancestry form and adapt to new environments.
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http://dx.doi.org/10.1111/mec.14122DOI Listing
July 2017

Concise, Enantioselective, and Versatile Synthesis of (-)-Englerin A Based on a Platinum-Catalyzed [4C+3C] Cycloaddition of Allenedienes.

Angew Chem Int Ed Engl 2016 11 13;55(46):14359-14363. Epub 2016 Oct 13.

Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain.

A practical synthesis of (-)-englerin A was accomplished in 17 steps and 11 % global yield from commercially available achiral precursors. The key step consists of a platinum-catalyzed [4C+3C] allenediene cycloaddition that directly delivers the trans-fused guaiane skeleton with complete diastereoselectivity. The high enantioselectivity (99 % ee) stems from an asymmetric ruthenium-catalyzed transfer hydrogenation of a readily assembled diene-ynone. The synthesis also features a highly stereoselective oxygenation, and a late-stage cuprate alkylation that enables the preparation of previously inaccessible structural analogues.
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http://dx.doi.org/10.1002/anie.201607348DOI Listing
November 2016

Genetics of Interactive Behavior in Silver Foxes (Vulpes vulpes).

Behav Genet 2017 Jan 18;47(1):88-101. Epub 2016 Oct 18.

Animal Sciences Department, College of Agricultural, Consumer and Environmental Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.

Individuals involved in a social interaction exhibit different behavioral traits that, in combination, form the individual's behavioral responses. Selectively bred strains of silver foxes (Vulpes vulpes) demonstrate markedly different behaviors in their response to humans. To identify the genetic basis of these behavioral differences we constructed a large F population including 537 individuals by cross-breeding tame and aggressive fox strains. 98 fox behavioral traits were recorded during social interaction with a human experimenter in a standard four-step test. Patterns of fox behaviors during the test were evaluated using principal component (PC) analysis. Genetic mapping identified eight unique significant and suggestive QTL. Mapping results for the PC phenotypes from different test steps showed little overlap suggesting that different QTL are involved in regulation of behaviors exhibited in different behavioral contexts. Many individual behavioral traits mapped to the same genomic regions as PC phenotypes. This provides additional information about specific behaviors regulated by these loci. Further, three pairs of epistatic loci were also identified for PC phenotypes suggesting more complex genetic architecture of the behavioral differences between the two strains than what has previously been observed.
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http://dx.doi.org/10.1007/s10519-016-9815-1DOI Listing
January 2017

Synergistic gold and enamine catalysis: intermolecular α-alkylation of aldehydes with allenamides.

Chem Commun (Camb) 2016 Feb;52(14):2909-12

Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS) and Departamento de Química Orgánica, Universidad de Santiago de Compostela, C/Jenaro de la Fuente, s/n, 15782, Santiago de Compostela, Spain. and Instituto de Química Orgánica General (CSIC), Juan de la Cierva, 3, 28006, Madrid, Spain.

Aldehydes can be α-alkylated with allenamides by the combined action of an organocatalyst and a gold complex. The reaction requires the simultaneous generation of an enamine and a gold-activated allenamide. Importantly, by using a chiral amine as organocatalyst it is possible to obtain aldehyde products featuring all-carbon quaternary stereocenter at their α-position, with moderate to good levels of enantioselectivity.
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http://dx.doi.org/10.1039/c5cc09533fDOI Listing
February 2016

Work-Related Health Complaints and Injuries, and Health and Safety Perceptions of Latino Day Laborers.

Workplace Health Saf 2015 Aug;63(8):350-61

Department of Community Health Systems, University of California San Francisco School of Nursing.

This study describes socio-demographic, health, and work factors as well as health and safety perceptions of day laborers who reported work-related health complaints and injuries. The researchers completed a secondary data analysis of 217 interviews conducted in 2009 with day laborers in a large city. The participants reported 83 health complaints or injuries (38%) that had occurred during the prior 12 months, with 57 of these complaints or injuries resulting in lost work time. Pain and soreness of the back were the most prevalent health complaints or injuries; 66% of participants did not report their injuries, 62% reported no health and safety training, 96% reported they needed personal protective equipment (PPE), and 63% were provided with PPE. Latino day laborers reported a high 12-month prevalence of work-related health complaints and injuries. Ongoing policy work is needed to encourage injury reporting by day laborers and the provision of health and safety training and PPE to this group of workers.
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http://dx.doi.org/10.1177/2165079915592746DOI Listing
August 2015

Characterization of genetic diversity and gene mapping in two Swedish local chicken breeds.

Front Genet 2015 17;6:44. Epub 2015 Feb 17.

Department of Clinical Sciences, Swedish University of Agricultural Sciences Uppsala, Sweden.

The aim of this paper is to study genetic diversity in the two Swedish local chicken breeds Bohuslän-Dals svarthöna and Hedemorahöna. The now living birds of both of these breeds (about 500 for Bohuslän-Dals svarthöna and 2600 for Hedemorahöna) originate from small relicts of earlier larger populations. An additional aim was to make an attempt to map loci associated with a trait that are segregating in both these breeds. The 60k SNP chip was used to genotype 12 Bohuslän-Dals svarthöna and 22 Hedemorahöna. The mean inbreeding coefficient was considerably larger in the samples from Hedemorahöna than in the samples from Bohuslän-Dals svarthöna. Also the proportion of homozygous SNPs in individuals was larger in Hedemorahöna. In contrast, on the breed level, the number of segregating SNPs were much larger in Hedemorahöna than in Bohuslän-Dals svarthöna. A multidimensional scaling plot shows that the two breeds form clusters well-separated from each other. Both these breeds segregate for the dermal hyperpigmentation phenotype. In Bohuslän-Dals svarthöna most animals have dark skin, but some individuals with lighter skin exists (most easily detected by their red comb). An earlier study of the Fm locus showed that this breed has the same complex rearrangement involving the EDN3 gene as Silkie chicken and two other studied Asian breeds. In the breed Hedemorahöna, most individuals have normal skin pigmentation (and red comb), but there are some birds with darker skin and dark comb. In this study the involvement of the EDN3 gene is confirmed also in Hedemorahöna. In addition we identify a region on chromosome 21 that is significantly associated with the trait.
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http://dx.doi.org/10.3389/fgene.2015.00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330917PMC
March 2015

Degrees of separation as a statistical tool for evaluating candidate genes.

Comput Biol Med 2014 Dec 14;55:49-52. Epub 2014 Oct 14.

Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

Selection of candidate genes is an important step in the exploration of complex genetic architecture. The number of gene networks available is increasing and these can provide information to help with candidate gene selection. It is currently common to use the degree of connectedness in gene networks as validation in Genome Wide Association (GWA) and Quantitative Trait Locus (QTL) mapping studies. However, it can cause misleading results if not validated properly. Here we present a method and tool for validating the gene pairs from GWA studies given the context of the network they co-occur in. It ensures that proposed interactions and gene associations are not statistical artefacts inherent to the specific gene network architecture. The CandidateBacon package provides an easy and efficient method to calculate the average degree of separation (DoS) between pairs of genes to currently available gene networks. We show how these empirical estimates of average connectedness are used to validate candidate gene pairs. Validation of interacting genes by comparing their connectedness with the average connectedness in the gene network will provide support for said interactions by utilising the growing amount of gene network information available.
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http://dx.doi.org/10.1016/j.compbiomed.2014.10.004DOI Listing
December 2014

Impact of lifestyle on the gut microbiota of healthy infants and their mothers—the ALADDIN birth cohort.

FEMS Microbiol Ecol 2014 Dec 3;90(3):791-801. Epub 2014 Nov 3.

Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden; Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.

An anthroposophic lifestyle, which has been associated with reduced allergy risk in children, has several characteristics that could influence gut microbiota. This study aimed to investigate the impact of anthroposophic lifestyle as well as specific early life exposures on the gut microbiota. In total, 665 stool samples from 128 mother-infant pairs from the ALADDIN birth cohort study were included. Samples collected from infants at ages 6 days, 3 weeks, 2 months and 6 months, and from their mothers before and after delivery, respectively, were analyzed using 454-pyrosequencing. Information regarding lifestyle exposures was collected prospectively through interviews and questionnaires. Six-month-old infants in anthroposophic families had a significantly higher abundance of Bifidobacterium and lower abundances of Bacteroides and Veillonella. Caesarean section and breastfeeding had a significant impact on the microbiota: caesarean section was primarily associated with delayed colonization of Bifidobacterium and Bacteroides, whereas breastfed children had a higher relative abundance of Bifidobacterium and a lower abundance of Clostridiales. However, despite large differences in lifestyle exposures, we determined no significant differences in the gut microbiota between the anthroposophic and non-anthroposophic mothers or their infants' before 6 months of age.
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http://dx.doi.org/10.1111/1574-6941.12434DOI Listing
December 2014

Genetic influences on brain gene expression in rats selected for tameness and aggression.

Genetics 2014 Nov 3;198(3):1277-90. Epub 2014 Sep 3.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany Department of Human Genetics, Gonda Center, University of California, Los Angeles, California 90095

Interindividual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F2 intercross of two outbred lines of rats selected for tame and aggressive behavior toward humans for >64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40, and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals.
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http://dx.doi.org/10.1534/genetics.114.168948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224166PMC
November 2014

Variance heterogeneity in Saccharomyces cerevisiae expression data: trans-regulation and epistasis.

PLoS One 2013 4;8(11):e79507. Epub 2013 Nov 4.

Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

Here, we describe the results from the first variance heterogeneity Genome Wide Association Study (VGWAS) on yeast expression data. Using this forward genetics approach, we show that the genetic regulation of gene-expression in the budding yeast, Saccharomyces cerevisiae, includes mechanisms that can lead to variance heterogeneity in the expression between genotypes. Additionally, we performed a mean effect association study (GWAS). Comparing the mean and variance heterogeneity analyses, we find that the mean expression level is under genetic regulation from a larger absolute number of loci but that a higher proportion of the variance controlling loci were trans-regulated. Both mean and variance regulating loci cluster in regulatory hotspots that affect a large number of phenotypes; a single variance-controlling locus, mapping close to DIA2, was found to be involved in more than 10% of the significant associations. It has been suggested in the literature that variance-heterogeneity between the genotypes might be due to genetic interactions. We therefore screened the multi-locus genotype-phenotype maps for several traits where multiple associations were found, for indications of epistasis. Several examples of two and three locus genetic interactions were found to involve variance-controlling loci, with reports from the literature corroborating the functional connections between the loci. By using a new analytical approach to re-analyze a powerful existing dataset, we are thus able to both provide novel insights to the genetic mechanisms involved in the regulation of gene-expression in budding yeast and experimentally validate epistasis as an important mechanism underlying genetic variance-heterogeneity between genotypes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079507PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817098PMC
August 2014

A century after Fisher: time for a new paradigm in quantitative genetics.

Trends Genet 2013 Dec 23;29(12):669-76. Epub 2013 Oct 23.

Swedish University of Agricultural Sciences, Department of Clinical Sciences, Division of Computational Genetics, Box 7078, SE-750 07 Uppsala, Sweden. Electronic address:

Quantitative genetics traces its roots back through more than a century of theory, largely formed in the absence of directly observable genotype data, and has remained essentially unchanged for decades. By contrast, molecular genetics arose from direct observations and is currently undergoing rapid changes, making the amount of available data ever greater. Thus, the two disciplines are disparate both in their origins and their current states, yet they address the same fundamental question: how does the genotype affect the phenotype? The rapidly accumulating genomic data necessitate sophisticated analysis, but many of the current tools are adaptations of methods designed during the early days of quantitative genetics. We argue here that the present analysis paradigm in quantitative genetics is at its limits in regards to unraveling complex traits and it is necessary to re-evaluate the direction that genetic research is taking for the field to realize its full potential.
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http://dx.doi.org/10.1016/j.tig.2013.09.006DOI Listing
December 2013

MAPfastR: quantitative trait loci mapping in outbred line crosses.

G3 (Bethesda) 2013 Dec 9;3(12):2147-9. Epub 2013 Dec 9.

Department of Clinical Sciences, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden.

MAPfastR is a software package developed to analyze quantitative trait loci data from inbred and outbred line-crosses. The package includes a number of modules for fast and accurate quantitative trait loci analyses. It has been developed in the R language for fast and comprehensive analyses of large datasets. MAPfastR is freely available at: http://www.computationalgenetics.se/?page_id=7.
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http://dx.doi.org/10.1534/g3.113.008623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852377PMC
December 2013

Higher order interactions: detection of epistasis using machine learning and evolutionary computation.

Methods Mol Biol 2013 ;1019:499-518

Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

Higher order interactions are known to affect many different phenotypic traits. The advent of large-scale genotyping has, however, shown that finding interactions is not a trivial task. Classical genome-wide association studies (GWAS) are a useful starting point for unraveling the genetic architecture of a phenotypic trait. However, to move beyond the additive model we need new analysis tools specifically developed to deal with high-dimensional genotypic data. Here we show that evolutionary algorithms are a useful tool in high-dimensional analyses designed to identify gene-gene interactions in current large-scale genotypic data.
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http://dx.doi.org/10.1007/978-1-62703-447-0_24DOI Listing
December 2013

Selection on variance-controlling genes: adaptability or stability.

Evolution 2012 Dec 24;66(12):3945-9. Epub 2012 Aug 24.

Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.

Simulations on a model system where a variance-controlling master locus scales the effects of a set of effector loci show that selection affects the variance-controlling locus more strongly than the effector loci, and that the direction of selection is dependent on the frequency of environmental changes.
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http://dx.doi.org/10.1111/j.1558-5646.2012.01753.xDOI Listing
December 2012

The Wnt/β-catenin/T-cell factor 4 pathway up-regulates high-mobility group A1 expression in colon cancer.

Cell Biochem Funct 2013 Apr 7;31(3):228-36. Epub 2012 Sep 7.

Department of Chemistry, Physics, and Geology, Winthrop University, Rock Hill, SC 29733, USA.

High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/β-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestinal tumours when compared with normal intestinal mucosa. Conversely, restoration of Wnt signalling by the zinc induction of wild-type APC resulted in HMGA1 down-regulation in HT-29 cells. Because APC mutations are associated with mobilization of the β-catenin/TCF-4 transcriptional complex and subsequent activation of downstream oncogenic targets, we analyzed the 5'-flanking sequence of HMGA1 for putative TCF-4 binding elements. We identified two regions that specifically bind the β-catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the β-catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/β-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/β-catenin/TCF-4 signalling.
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http://dx.doi.org/10.1002/cbf.2876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616152PMC
April 2013

Sociodemographic characteristics, health, and success at obtaining work among Latino urban day laborers.

J Health Care Poor Underserved 2012 May;23(2):797-810

University of California, San Francisco School of Nursing, Department of Community Health Systems, San Francisco, CA 94143-0608, USA.

Background: The purpose of this study was to examine the health and social circumstances, knowledge of and access to health and social services, and success at getting work among urban day laborers.

Methods: We conducted an interview survey of 217 men waiting for work at several sites in San Francisco.

Results: Day laborers were generally unsuccessful at obtaining work and had less than optimal housing, but supported a number of family members. Over half reported fair or poor health, associated with longer time as a day laborer, poor English proficiency, and financially supporting three or more other people. Awareness of health and social services available to them was low.

Discussion: The stress of seeking work daily, separation from family, inadequate housing and lack of health care puts this population at increased risk for disease conditions associated with poor physical and mental health.
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http://dx.doi.org/10.1353/hpu.2012.0041DOI Listing
May 2012

Sex ratio dependent dispersal when sex ratios vary between patches.

J Theor Biol 2011 Dec 27;290:81-7. Epub 2011 Aug 27.

Department of Genetics, University of Pretoria, Pretoria, South Africa.

Female biased sex ratios reduce competition between brothers when mating takes place within local patches. Male dispersal prior to mating is another strategy that reduces competition between brothers. One may thus expect these two traits to co-evolve and this is partially met in that sex ratios becomes less female biased as dispersal increases. However, the evolutionary stable degree of dispersal is unaffected by the sex ratio. The analytical models developed to reach these conclusions ignored variance in sex ratios, since this increases the structural complexity of models. For similar reasons finite clutch sizes are also routinely ignored. To overcome these shortfalls, we developed individual based simulations that allowed us to incorporate realistic clutch sizes and binomial variance in sex ratios between patches. We show that under variable sex ratios, males evolve to more readily disperse away from patches with higher sex ratios than lower sex ratios. We show that, while the dispersal rate is insensitive to the sex ratio when sex ratios are precise, it is affected by the number of males with dispersal decreasing as the number of males decreases.
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http://dx.doi.org/10.1016/j.jtbi.2011.08.030DOI Listing
December 2011

qtl.outbred: Interfacing outbred line cross data with the R/qtl mapping software.

BMC Res Notes 2011 May 26;4:154. Epub 2011 May 26.

Department of Breeding and Genetics, Swedish University of Agricultural Sciences, Box 7023, SE-75007 Uppsala, Sweden.

Background: qtl.outbred is an extendible interface in the statistical environment, R, for combining quantitative trait loci (QTL) mapping tools. It is built as an umbrella package that enables outbred genotype probabilities to be calculated and/or imported into the software package R/qtl.

Findings: Using qtl.outbred, the genotype probabilities from outbred line cross data can be calculated by interfacing with a new and efficient algorithm developed for analyzing arbitrarily large datasets (included in the package) or imported from other sources such as the web-based tool, GridQTL.

Conclusion: qtl.outbred will improve the speed for calculating probabilities and the ability to analyse large future datasets. This package enables the user to analyse outbred line cross data accurately, but with similar effort than inbred line cross data.
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http://dx.doi.org/10.1186/1756-0500-4-154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117720PMC
May 2011

1-(4-Meth-oxy-phen-yl)-2-(1H-1,2,4-triazol-1-yl)ethanone.

Acta Crystallogr Sect E Struct Rep Online 2010 Jul 10;66(Pt 8):o1978. Epub 2010 Jul 10.

In the title compound, C(11)H(11)N(3)O(2), the dihedral angle between the central ethanone fragment and the 4-meth-oxy-phenyl group is 2.9 (2)°, while that between the ethanone fragment and the triazole ring is 83.4 (2)°. The dihedral angle between the planes of the triazole and benzene rings is 81.7 (1)°. The 4-meth-oxy-phenyl group is cis with respect to the ethanone fragment O atom across the exocyclic C-C bond. In the crystal, mol-ecules are linked by C-H⋯N inter-actions into C(9) chains along [001].
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http://dx.doi.org/10.1107/S160053681002653XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3007452PMC
July 2010

Penile and scrotal elephantiasis caused by indolent Chlamydia trachomatis infection.

Urology 2003 Jan;61(1):224

Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center, Nashville Veterans Affairs Medical Center, Nashville, Tennessee 37232, USA.

Isolated penile and scrotal elephantiasis presents a diagnostic and therapeutic challenge. We report a case of chronic penile and scrotal elephantiasis caused by indolent Chlamydia trachomatis infection. The patient improved modestly with long-term doxycycline.
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http://dx.doi.org/10.1016/s0090-4295(02)02078-2DOI Listing
January 2003

Development of a standardized animal model for the study of alkali ingestion.

Vet Hum Toxicol 2002 Feb;44(1):45-7

Department of Emergency Medicine, Scott & White Clinic and Memorial Hospital, Texas A&M University Health Science Center, College of Medicine, Temple 76508, USA.

The purpose of this study was to develop an animal model that would grade in-vivo therapeutic modality testing for caustic ingestion. Caustic substances are found in many household items (eg detergents, bleaches, pipe cleaners) and pose a serious threat to health if ingested accidentally or intentionally with resulting injuries including immediate death or chronic debilitating morbidity. This study used 5, 3.8 or 1.8% sodium hydroxide (NaOH) to determine macro/microscopic injury at 10, 30, or 60 minutes. Macroscopic grading was based on gross evaluation of denudation of mucosa, edema, hyperemia, hemorrhage, ulcerations and necrosis. Microscopic grading was based on epithelial viability, cornified epithelial cell differentiation, granular cell differentiation, epithelial cell nuclei, muscle cell viability and muscle cell nuclei. Product concentration was shown a more significant predictor of injury than time of exposure. The grading system presented should provide a reliable method of producing and grading alkaline ingestions for future treatment hypothesis testing.
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February 2002
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