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1.  ILDR2: An Endoplasmic Reticulum Resident Molecule Mediating Hepatic Lipid Homeostasis 
PLoS ONE  2013;8(6):e67234.
Ildr2, a modifier of diabetes susceptibility in obese mice, is expressed in most organs, including islets and hypothalamus, with reduced levels in livers of diabetes-susceptible B6.DBA mice congenic for a 1.8 Mb interval of Chromosome 1. In hepatoma and neuronal cells, ILDR2 is primarily located in the endoplasmic reticulum membrane. We used adenovirus vectors that express shRNA or are driven by the CMV promoter, respectively, to knockdown or overexpress Ildr2 in livers of wild type and ob/ob mice. Livers in knockdown mice were steatotic, with increased hepatic and circulating triglycerides and total cholesterol. Increased circulating VLDL, without reduction in triglyceride clearance suggests an effect of reduced hepatic ILDR2 on hepatic cholesterol clearance. In animals that overexpress Ildr2, hepatic triglyceride and total cholesterol levels were reduced, and strikingly so in ob/ob mice. There were no significant changes in body weight, energy expenditure or glucose/insulin homeostasis in knockdown or overexpressing mice. Knockdown mice showed reduced expression of genes mediating synthesis and oxidation of hepatic lipids, suggesting secondary suppression in response to increased hepatic lipid content. In Ildr2-overexpressing ob/ob mice, in association with reduced liver fat content, levels of transcripts related to neutral lipid synthesis and cholesterol were increased, suggesting “relief” of the secondary suppression imposed by lipid accumulation. Considering the fixed location of ILDR2 in the endoplasmic reticulum, we investigated the possible participation of ILDR2 in ER stress responses. In general, Ildr2 overexpression was associated with increases, and knockdown with decreases in levels of expression of molecular components of canonical ER stress pathways. We conclude that manipulation of Ildr2 expression in liver affects both lipid homeostasis and ER stress pathways. Given these reciprocal interactions, and the relatively extended time-course over which these studies were conducted, we cannot assign causal primacy to either the effects on hepatic lipid homeostasis or ER stress responses.
doi:10.1371/journal.pone.0067234
PMCID: PMC3691114  PMID: 23826244
4.  Human Y chromosome haplogroup R-V88: a paternal genetic record of early mid Holocene trans-Saharan connections and the spread of Chadic languages 
Although human Y chromosomes belonging to haplogroup R1b are quite rare in Africa, being found mainly in Asia and Europe, a group of chromosomes within the paragroup R-P25* are found concentrated in the central-western part of the African continent, where they can be detected at frequencies as high as 95%. Phylogenetic evidence and coalescence time estimates suggest that R-P25* chromosomes (or their phylogenetic ancestor) may have been carried to Africa by an Asia-to-Africa back migration in prehistoric times. Here, we describe six new mutations that define the relationships among the African R-P25* Y chromosomes and between these African chromosomes and earlier reported R-P25 Eurasian sub-lineages. The incorporation of these new mutations into a phylogeny of the R1b haplogroup led to the identification of a new clade (R1b1a or R-V88) encompassing all the African R-P25* and about half of the few European/west Asian R-P25* chromosomes. A worldwide phylogeographic analysis of the R1b haplogroup provided strong support to the Asia-to-Africa back-migration hypothesis. The analysis of the distribution of the R-V88 haplogroup in >1800 males from 69 African populations revealed a striking genetic contiguity between the Chadic-speaking peoples from the central Sahel and several other Afroasiatic-speaking groups from North Africa. The R-V88 coalescence time was estimated at 9200–5600 kya, in the early mid Holocene. We suggest that R-V88 is a paternal genetic record of the proposed mid-Holocene migration of proto-Chadic Afroasiatic speakers through the Central Sahara into the Lake Chad Basin, and geomorphological evidence is consistent with this view.
doi:10.1038/ejhg.2009.231
PMCID: PMC2987365  PMID: 20051990
Y chromosome haplogroups; human migrations; Holocene; Africa; Chadic-speaking populations
5.  Regulation of Fto/Ftm gene expression in mice and humans 
Two recent, large GWAS in European populations have associated a ∼47 Kb region that contains part of the FTO gene with high BMI. The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to under/over feeding, and to 4 °C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the Ay, Lepob, Leprdb, Cpefat or tub mutations and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be co-regulated. The putative overlapping regulatory region contains at least 2 canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 – associated with lower body mass than the C allele – preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65 %, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed “ciliopathy”. FTM has recently been shown to be a ciliary basal body protein.
doi:10.1152/ajpregu.00839.2007
PMCID: PMC2808712  PMID: 18256137
obesity; hypothalamus; adipose tissue; CUTL1
6.  Analysis of knockout mice suggests a role for VGF in the control of fat storage and energy expenditure 
BMC Physiology  2009;9:19.
Background
Previous studies of mixed background mice have demonstrated that targeted deletion of Vgf produces a lean, hypermetabolic mouse that is resistant to diet-, lesion-, and genetically-induced obesity. To investigate potential mechanism(s) and site(s) of action of VGF, a neuronal and endocrine secreted protein and neuropeptide precursor, we further analyzed the metabolic phenotypes of two independent VGF knockout lines on C57Bl6 backgrounds.
Results
Unlike hyperactive VGF knockout mice on a mixed C57Bl6-129/SvJ background, homozygous mutant mice on a C57Bl6 background were hypermetabolic with similar locomotor activity levels to Vgf+/Vgf+ mice, during day and night cycles, indicating that mechanism(s) other than hyperactivity were responsible for their increased energy expenditure. In Vgf-/Vgf- knockout mice, morphological analysis of brown and white adipose tissues (BAT and WAT) indicated decreased fat storage in both tissues, and decreased adipocyte perimeter and area in WAT. Changes in gene expression measured by real-time RT-PCR were consistent with increased fatty acid oxidation and uptake in BAT, and increased lipolysis, decreased lipogenesis, and brown adipocyte differentiation in WAT, suggesting that increased sympathetic nervous system activity in Vgf-/Vgf- mice may be associated with or responsible for alterations in energy expenditure and fat storage. In addition, uncoupling protein 1 (UCP1) and UCP2 protein levels, mitochondrial number, and mitochondrial cristae density were upregulated in Vgf-/Vgf- BAT. Using immunohistochemical and histochemical techniques, we detected VGF in nerve fibers innervating BAT and Vgf promoter-driven reporter expression in cervical and thoracic spinal ganglia that project to and innervate the chest wall and tissues including BAT. Moreover, VGF peptide levels were quantified by radioimmunoassay in BAT, and were found to be down-regulated by a high fat diet. Lastly, despite being hypermetabolic, VGF knockout mice were cold intolerant.
Conclusion
We propose that VGF and/or VGF-derived peptides modulate sympathetic outflow pathways to regulate fat storage and energy expenditure.
doi:10.1186/1472-6793-9-19
PMCID: PMC2774661  PMID: 19863797
7.  Genome-wide association study identifies novel breast cancer susceptibility loci 
Easton, Douglas F. | Pooley, Karen A. | Dunning, Alison M. | Pharoah, Paul D. P. | Thompson, Deborah | Ballinger, Dennis G. | Struewing, Jeffery P. | Morrison, Jonathan | Field, Helen | Luben, Robert | Wareham, Nicholas | Ahmed, Shahana | Healey, Catherine S. | Bowman, Richard | Meyer, Kerstin B. | Haiman, Christopher A. | Kolonel, Laurence K. | Henderson, Brian E. | Marchand, Loic Le | Brennan, Paul | Sangrajrang, Suleeporn | Gaborieau, Valerie | Odefrey, Fabrice | Shen, Chen-Yang | Wu, Pei-Ei | Wang, Hui-Chun | Eccles, Diana | Evans, D. Gareth | Peto, Julian | Fletcher, Olivia | Johnson, Nichola | Seal, Sheila | Stratton, Michael R. | Rahman, Nazneen | Chenevix-Trench, Georgia | Bojesen, Stig E. | Nordestgaard, Børge G. | Axelsson, Christen K. | Garcia-Closas, Montserrat | Brinton, Louise | Chanock, Stephen | Lissowska, Jolanta | Peplonska, Beata | Nevanlinna, Heli | Fagerholm, Rainer | Eerola, Hannaleena | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Cox, David G. | Hall, Per | Wedren, Sara | Liu, Jianjun | Low, Yen-Ling | Bogdanova, Natalia | Schürmann, Peter | Dörk, Thilo | Tollenaar, Rob A. E. M. | Jacobi, Catharina E. | Devilee, Peter | Klijn, Jan G. M. | Sigurdson, Alice J. | Doody, Michele M. | Alexander, Bruce H. | Zhang, Jinghui | Cox, Angela | Brock, Ian W. | MacPherson, Gordon | Reed, Malcolm W. R. | Couch, Fergus J. | Goode, Ellen L. | Olson, Janet E. | Meijers-Heijboer, Hanne | van den Ouweland, Ans | Uitterlinden, André | Rivadeneira, Fernando | Milne, Roger L. | Ribas, Gloria | Gonzalez-Neira, Anna | Benitez, Javier | Hopper, John L. | McCredie, Margaret | Southey, Melissa | Giles, Graham G. | Schroen, Chris | Justenhoven, Christina | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana | Day, Nicholas E. | Cox, David R. | Ponder, Bruce A. J. | Luccarini, Craig | Conroy, Don | Shah, Mitul | Munday, Hannah | Jordan, Clare | Perkins, Barbara | West, Judy | Redman, Karen | Driver, Kristy | Aghmesheh, Morteza | Amor, David | Andrews, Lesley | Antill, Yoland | Armes, Jane | Armitage, Shane | Arnold, Leanne | Balleine, Rosemary | Begley, Glenn | Beilby, John | Bennett, Ian | Bennett, Barbara | Berry, Geoffrey | Blackburn, Anneke | Brennan, Meagan | Brown, Melissa | Buckley, Michael | Burke, Jo | Butow, Phyllis | Byron, Keith | Callen, David | Campbell, Ian | Chenevix-Trench, Georgia | Clarke, Christine | Colley, Alison | Cotton, Dick | Cui, Jisheng | Culling, Bronwyn | Cummings, Margaret | Dawson, Sarah-Jane | Dixon, Joanne | Dobrovic, Alexander | Dudding, Tracy | Edkins, Ted | Eisenbruch, Maurice | Farshid, Gelareh | Fawcett, Susan | Field, Michael | Firgaira, Frank | Fleming, Jean | Forbes, John | Friedlander, Michael | Gaff, Clara | Gardner, Mac | Gattas, Mike | George, Peter | Giles, Graham | Gill, Grantley | Goldblatt, Jack | Greening, Sian | Grist, Scott | Haan, Eric | Harris, Marion | Hart, Stewart | Hayward, Nick | Hopper, John | Humphrey, Evelyn | Jenkins, Mark | Jones, Alison | Kefford, Rick | Kirk, Judy | Kollias, James | Kovalenko, Sergey | Lakhani, Sunil | Leary, Jennifer | Lim, Jacqueline | Lindeman, Geoff | Lipton, Lara | Lobb, Liz | Maclurcan, Mariette | Mann, Graham | Marsh, Deborah | McCredie, Margaret | McKay, Michael | McLachlan, Sue Anne | Meiser, Bettina | Milne, Roger | Mitchell, Gillian | Newman, Beth | O'Loughlin, Imelda | Osborne, Richard | Peters, Lester | Phillips, Kelly | Price, Melanie | Reeve, Jeanne | Reeve, Tony | Richards, Robert | Rinehart, Gina | Robinson, Bridget | Rudzki, Barney | Salisbury, Elizabeth | Sambrook, Joe | Saunders, Christobel | Scott, Clare | Scott, Elizabeth | Scott, Rodney | Seshadri, Ram | Shelling, Andrew | Southey, Melissa | Spurdle, Amanda | Suthers, Graeme | Taylor, Donna | Tennant, Christopher | Thorne, Heather | Townshend, Sharron | Tucker, Kathy | Tyler, Janet | Venter, Deon | Visvader, Jane | Walpole, Ian | Ward, Robin | Waring, Paul | Warner, Bev | Warren, Graham | Watson, Elizabeth | Williams, Rachael | Wilson, Judy | Winship, Ingrid | Young, Mary Ann | Bowtell, David | Green, Adele | deFazio, Anna | Chenevix-Trench, Georgia | Gertig, Dorota | Webb, Penny
Nature  2007;447(7148):1087-1093.
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
doi:10.1038/nature05887
PMCID: PMC2714974  PMID: 17529967
8.  Positional Cloning of “Lisch-like”, a Candidate Modifier of Susceptibility to Type 2 Diabetes in Mice 
PLoS Genetics  2008;4(7):e1000137.
In 404 Lepob/ob F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lepob. The phenotypes of B6.DBA congenic mice include reduced β-cell replication rates accompanied by reduced β-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated “Lisch-like” (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646–amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes.
Author Summary
Type 2 diabetes (T2D) accounts for over 90% of instances of diabetes and is a leading cause of medical morbidity and mortality. Twin studies indicate a strong polygenic contribution to susceptibility within the context of obesity. Although approximately ten genes making important contributions to individual risk have been identified, it is clear that others remain to be identified. In this study, we intercrossed obese, diabetes-resistant and diabetes-prone mouse strains to implicate a genetic interval on mouse Chr1 associated with reduced β-cell numbers and elevated blood glucose. We narrowed the region using molecular genetics and computational approaches to identify a novel gene we designated “Lisch-like” (Ll). The orthologous human genetic interval has been repeatedly implicated in T2D. Mice with an induced mutation that reduces Ll expression are impaired in both β-cell development and glucose metabolism, and reduced expression of the homologous gene in zebrafish disrupts islet development. Ll is expressed in organs implicated in the pathophysiology of T2D (hypothalamus, islets, liver, and skeletal muscle) and is predicted to encode a transmembrane protein that could mediate cholesterol transport and/or convey signals related to cell division. Either mechanism could mediate effects on β-cell mass that would predispose to T2D.
doi:10.1371/journal.pgen.1000137
PMCID: PMC2464733  PMID: 18654634
10.  THE PRODUCTION OF INFECTION WITH PNEUMOCOCCI IN RABBITS BY INTRADERMAL INOCULATION OF TYPE III PNEUMOCOCCI, THE TREATMENT WITH SPECIFIC ANTISERUM, AND A COMPARISON WITH TYPE I INFECTIONS 
Intradermal lesions and subsequent bacteremia were produced in rabbits by the intradermal inoculation of Type III strains freshly isolated from pneumonia cases. Slight intradermal lesions were produced but no bacteremia was found in rabbits inoculated with an old stock Type III strain. The intradermal lesions and the bacteremia produced by the inoculation of Type III cultures in rabbits were usually less severe than those produced by the inoculation of Type I culture. The bacteremia in rabbits was checked and the rabbits protected by suitable amounts of Type III concentrated antiserum given intravenously 24 hours after the infecting dose. The amount of Type III antiserum necessary to protect rabbits inoculated intradermally with virulent Type III cultures was not appreciably greater than the amount of Type I antiserum required to protect against Type I.
PMCID: PMC2131915  PMID: 19869808

Results 1-10 (10)