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1.  Maternal obesity is associated with the formation of small dense LDL and hypoadiponectinaemia in the third trimester 
Context
Maternal obesity is associated with high plasma triglyceride, poor vascular function and increased risk for pregnancy complications. In normal weight pregnant women, higher triglyceride is associated with increased small, dense LDL.
Hypothesis
In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of VLDL-1 particles and formation of small dense LDL via lipoprotein lipase.
Design
Women (n=55) of BMI 18-46 kg/m2 were sampled longitudinally at 12, 26 and 35 weeks’ gestation and 4 months post-natal.
Setting
Women were recruited at hospital antenatal appointments and study visits were in a clinical research suite.
Outcome measures
Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin and adiponectin were determined.
Results
Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum and then returned to higher post-natal levels than normal weight women. Estradiol response to pregnancy (trimester 1-3 incremental area under the curve) was positively associated with plasma triglyceride response (r2 adjusted 25%, P<0.001). In the third trimester, the proportion of small, dense LDL-III was 2 fold higher in obese women than normal weight women (mean [SD] 40.7[18.8] vs 21.9[10.9] %, P<0.005), and 35% of obese, 14% of overweight and none of the normal weight women displayed an atherogenic LDL subfraction phenotype. The LDL-III mass response to pregnancy was inversely associated with adiponectin response (17%, P=0.013).
Conclusions
Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome.
doi:10.1210/jc.2012-3481
PMCID: PMC3736085  PMID: 23337718
pregnancy; lipids; obesity
2.  A High-Dose Shiitake Mushroom Increases Hepatic Accumulation of Triacylglycerol in Rats Fed a High-Fat Diet: Underlying Mechanism 
Nutrients  2014;6(2):650-662.
Shiitake mushroom have been shown to have health benefits including lowering plasma lipids and preventing body weight gain. However, their underlying mechanisms are largely unknown. The study aim was to assess the potential underlying mechanism of Shiitake mushrooms in lowering plasma triacylglycerol (TAG) in rats fed a high fat diet (HFD). Forty Wistar rats were divided into control group were given HFD and treatment group were fed HFD, enriched with Shiitake mushroom powder at a low dose (LD-M): 0.7%, medium dose (MD-M): 2%, or high dose (HD-M): 6% (wt:wt) for six weeks. Diets were isocaloric containing ~50% energy from fat. After six weeks’ dietary intervention, the rats were sacrificed, and blood and tissue samples were collected. The HD-M group showed a significantly higher ratio of liver weight to 100 g body weight (p < 0.05), a more severe hepatic steatosis marker, such as hepatocyte ballooning (p < 0.0001), and more liver triacylglycerol content than LD-M and MD-M (p < 0.05). HD-M also showed a significantly decreased ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) compared to HFD (p < 0.05), however, there were no differences compared to HD-M and MD-M. Our results also showed a positive association between the dosage, liver TAG, and liver ballooning histology. A negative association was found between the mushroom dosage and the ratio of liver PC to PE. This study showed the mechanism of how high-dose Shiitake mushroom (HD-M) prevents obesity by increasing TAG accumulation in the liver, rather than adipose tissue.
doi:10.3390/nu6020650
PMCID: PMC3942724  PMID: 24566434
Shiitake mushroom; beta glucan; high fat diet (HFD); hepatic triacylglycerol
3.  The Large GTPase Dynamin Associates with the Spindle Midzone and Is Required for Cytokinesis 
Current biology : CB  2002;12(24):2111-2117.
Summary
Cytokinesis involves the concerted efforts of the microtubule and actin cytoskeletons as well as vesicle trafficking and membrane remodeling to form the cleavage furrow and complete daughter cell separation (for reviews, see [1–6]). The exact mechanisms that support membrane remodeling during cytokinesis remain largely undefined. In this study, we report that the large GTPase dynamin, a protein involved in membrane tubulation and vesiculation [7, 8], is essential for successful cytokinesis. Using biochemical and morphological methods, we demonstrate that dynamin localizes to the spindle midzone and the subsequent intercellular bridge in mammalian cells and is also enriched in spindle midbody extracts. In Caenorhabditis elegans, dynamin localized to newly formed cleavage furrow membranes and accumulated at the midbody of dividing embryos in a manner similar to dynamin localization in mammalian cells. Further, dynamin function appears necessary for cytokinesis, as C. elegans embryos from a dyn-1 ts strain [9], as well as dynamin RNAi-treated embryos, showed a marked defect in the late stages of cytokinesis. These findings indicate that, during mitosis, conventional dynamin is recruited to the spindle midzone and the subsequent intercellular bridge, where it plays an essential role in the final separation of dividing cells.
PMCID: PMC3690653  PMID: 12498685
4.  Condensin controls recruitment of RNA polymerase II to achieve nematode X-chromosome dosage compensation 
eLife  2013;2:e00808.
The X-chromosome gene regulatory process called dosage compensation ensures that males (1X) and females (2X) express equal levels of X-chromosome transcripts. The mechanism in Caenorhabditis elegans has been elusive due to improperly annotated transcription start sites (TSSs). Here we define TSSs and the distribution of transcriptionally engaged RNA polymerase II (Pol II) genome-wide in wild-type and dosage-compensation-defective animals to dissect this regulatory mechanism. Our TSS-mapping strategy integrates GRO-seq, which tracks nascent transcription, with a new derivative of this method, called GRO-cap, which recovers nascent RNAs with 5′ caps prior to their removal by co-transcriptional processing. Our analyses reveal that promoter-proximal pausing is rare, unlike in other metazoans, and promoters are unexpectedly far upstream from the 5′ ends of mature mRNAs. We find that C. elegans equalizes X-chromosome expression between the sexes, to a level equivalent to autosomes, by reducing Pol II recruitment to promoters of hermaphrodite X-linked genes using a chromosome-restructuring condensin complex.
DOI: http://dx.doi.org/10.7554/eLife.00808.001
eLife digest
In many species, including humans, females have two X chromosomes whereas males have only one. To ensure that females do not end up with a double dose of the proteins encoded by genes on the X chromosome, animals employ a strategy called dosage compensation to control the expression of X-linked genes.
The mechanisms underlying dosage compensation vary between species, but they typically involve a regulatory complex that binds to the X chromosomes of one sex to modify gene expression. In the nematode worm Caenorhabditis elegans—which consists of hermaphrodites (XX) and males (XO)—this regulatory complex, called the dosage compensation complex (DCC), binds to both X chromosomes of XX individuals, reducing gene expression from each by 50%. DCC shares many subunits with a protein complex called condensin, which regulates the structure of chromosomes to achieve proper chromosome segregation. However, it is unclear exactly how the DCC controls the expression of X-linked genes.
For a gene to be expressed, an enzyme called RNA polymerase II must bind to the gene’s promoter—a stretch of DNA upstream of the protein-coding part of the gene—so that it can begin transcribing the DNA into RNA. Promoters have been difficult to define in C. elegans, but Kruesi et al. devised a strategy to map transcription start sites, and hence promoters, throughout the worm genome. The strategy integrates the results of two methods: One measures the extent and orientation of each gene’s transcribed region, and the other locates the distinctive cap structures that mark the true 5′ ends of newly made RNAs.
Using this new promoter information, coupled with genome-wide measurements of the levels of newly synthesized transcripts from wild-type and dosage-compensation-defective animals, they showed that C. elegans achieves dosage compensation by reducing the recruitment of RNA polymerase II to the promoters of X-linked genes in XX individuals.
Kruesi et al. also identified a second regulatory mechanism that acts in both sexes to increase the level of transcription of genes on the X chromosome. This ensures that after dosage compensation, genes on the X chromosome are expressed at a similar level to those on the autosomes (all chromosomes other than X and Y).
As well as shedding light on the mechanism by which dosage compensation occurs in C. elegans, the study by Kruesi et al. provides a valuable data set on transcription start sites in the worm, and puts forward a general strategy that could be used to map these sites in other species.
DOI: http://dx.doi.org/10.7554/eLife.00808.002
doi:10.7554/eLife.00808
PMCID: PMC3687364  PMID: 23795297
dosage compensation; transcription; X-chromosome and autosome balance; transcription start site identification technology; X chromosome; C. elegans
5.  Dissection of the Mammalian Midbody Proteome Reveals Conserved Cytokinesis Mechanisms 
Science (New York, N.Y.)  2004;305(5680):61-66.
Cytokinesis is the essential process that partitions cellular contents into daughter cells. To identify and characterize cytokinesis proteins rapidly, we used a functional proteomic and comparative genomic strategy. Midbodies were isolated from mammalian cells, proteins were identified by multidimensional protein identification technology (MudPIT), and protein function was assessed in Caenorhabditis elegans. Of 172 homologs disrupted by RNA interference, 58% displayed defects in cleavage furrow formation or completion, or germline cytokinesis. Functional dissection of the midbody demonstrated the importance of lipid rafts and vesicle trafficking pathways in cytokinesis, and the utilization of common membrane cytoskeletal components in diverse morphogenetic events in the cleavage furrow, the germline, and neurons.
doi:10.1126/science.1097931
PMCID: PMC3679889  PMID: 15166316
6.  PREECLAMPSIA IS ASSOCIATED WITH COMPROMISED MATERNAL SYNTHESIS OF LONG CHAIN POLYUNSATURATED FATTY ACIDS LEADING TO OFFSPRING DEFICIENCY 
Hypertension  2012;60(4):1078-1085.
Obesity and excessive lipolysis are implicated in preeclampsia. Intrauterine growth restriction is associated with low maternal body mass index and decreased lipolysis. Our aim was to assess how maternal and offspring fatty acid metabolism is altered in mothers in the third trimester of pregnancy with preeclampsia (n=62) or intrauterine growth restriction (n=23) compared to healthy pregnancies (n=164). Markers of lipid metabolism and erythrocyte fatty acid concentrations were measured. Maternal adipose tissue fatty acid composition and mRNA expression of adipose tissue fatty acid metabolizing enzymes and placental fatty acid transporters were compared. Mothers with preeclampsia had higher plasma triglyceride (21%, p<0.001) and non-esterified fatty acid (50%, p<0.001) concentrations than Controls. Concentrations of major n-6 and n-3 long chain polyunsaturated fatty acids in erythrocytes were 23-60% lower (all p<0.005) in preeclampsia and intrauterine growth restriction mothers and offspring compared to Controls. Subcutaneous adipose tissue Δ-5 and Δ-6 desaturase and very long chain fatty acid elongase mRNA expression was lower in preeclampsia than Controls [Control 3.38(2.96) vs preeclampsia 1.83(1.91), p=0.030; 3.33(2.25) vs 1.03(0.96), p<0.001; 0.40 (0.81) vs 0.00 (0.00), p=0.038 (square root) expression relative to control gene respectively]. Low maternal and fetal long chain polyunsaturated fatty acid concentrations in preeclampsia may be the result of decreased maternal synthesis.
doi:10.1161/HYPERTENSIONAHA.112.197897
PMCID: PMC3604624  PMID: 22949531
fatty acid; pregnancy; pre-eclampsia; intrauterine growth restriction
7.  Expanding Awareness of Docosahexaenoic Acid during Pregnancy 
Nutrients  2013;5(4):1098-1109.
Pregnant women do not currently meet the consensus recommendation for docosahexaenoic acid (DHA) (≥200 mg/day). Pregnant women in Australia are not receiving information on the importance of DHA during pregnancy. DHA pregnancy education materials were developed using current scientific literature, and tested for readability and design aesthetics. The study aimed to evaluate their usefulness, the desire for pregnant women to receive these materials and whether a larger separate study (using a control group) is warranted to evaluate the influence the materials may have on increasing DHA consumption in pregnant women in Australia. Pregnant women (N = 118) were recruited at antenatal clinics at two NSW hospitals. Participants completed a 16-item questionnaire and DHA educational materials (pamphlet and shopping card) were provided. Participants were contacted via phone two weeks later and completed the second questionnaire (25-item, N = 74). Statistics were conducted in SPSS and qualitative data were analysed to identify common themes. Ninety three percent of women found the materials useful, with the main reason being it expanded their knowledge of DHA food sources. Only 34% of women had received prior information on DHA, yet 68% said they would like to receive information. Due to the small sample size and lack of a control group, this small study cannot provide a cause and effect relationship between the materials and nutrition related behaviours or knowledge, however the results indicate a potential positive influence towards increased fish consumption and awareness of DHA containing foods. This suggests a larger study, with a control group is warranted to identify the impact such materials could have on Australian pregnant women.
doi:10.3390/nu5041098
PMCID: PMC3705337  PMID: 23549329
docosahexaenoic acid; omega-3; pregnancy; fish; education
8.  Condensin and cohesin complexity: the expanding repertoire of functions 
Nature reviews. Genetics  2010;11(6):391-404.
Condensin and cohesin complexes act in diverse nuclear processes in addition to their widely known roles in chromosome compaction and sister chromatid cohesion. Recent work has elucidated the contribution of condensin and cohesin to interphase genome organization, control of gene expression, metazoan development and meiosis. Despite these wide-ranging functions, several themes have come to light: both complexes establish higher-order chromosome structure by inhibiting or promoting interactions between distant genomic regions, both complexes influence the chromosomal association of other proteins, and both complexes achieve functional specialization by swapping homologous subunits. Emerging data are expanding the range of processes in which condensin and cohesin are known to participate and are enhancing our knowledge of how chromosome architecture is regulated to influence numerous cellular functions.
doi:10.1038/nrg2794
PMCID: PMC3491780  PMID: 20442714
10.  C. elegans Anaplastic Lymphoma Kinase Ortholog SCD-2 Controls Dauer Formation by Modulating TGF-β Signaling 
Current biology : CB  2008;18(15):1101-1109.
Summary
Background
Different environmental stimuli, including exposure to dauer pheromone, food deprivation, and high temperature, can induce C. elegans larvae to enter the dauer stage, a developmentally arrested diapause state. Although molecular and cellular pathways responsible for detecting dauer pheromone and temperature have been defined in part, other sensory inputs are poorly understood, as are the mechanisms by which these diverse sensory inputs are integrated to achieve a consistent developmental outcome.
Results
In this paper, we analyze a wild C. elegans strain isolated from a desert oasis. Unlike wild-type laboratory strains, the desert strain fails to respond to dauer pheromone at 25°C, but it does respond at higher temperatures, suggesting a unique adaptation to the hot desert environment. We map this defect in dauer response to a mutation in the scd-2 gene, which, we show, encodes the nematode anaplastic lymphoma kinase (ALK) homolog, a proto-oncogene receptor tyrosine kinase. scd-2 acts in a genetic pathway shown here to include the HEN-1 ligand, the RTK adaptor SOC-1, and the MAP kinase SMA-5. The SCD-2 pathway modulates TGF-β signaling, which mediates the response to dauer pheromone, but SCD-2 might mediate a nonpheromone sensory input, such as food.
Conclusions
Our studies identify a new sensory pathway controlling dauer formation and shed light on ALK signaling, integration of signaling pathways, and adaptation to extreme environmental conditions.
doi:10.1016/j.cub.2008.06.060
PMCID: PMC3489285  PMID: 18674914
11.  Condensin restructures chromosomes in preparation for meiotic divisions 
The Journal of Cell Biology  2004;167(4):613-625.
The production of haploid gametes from diploid germ cells requires two rounds of meiotic chromosome segregation after one round of replication. Accurate meiotic chromosome segregation involves the remodeling of each pair of homologous chromosomes around the site of crossover into a highly condensed and ordered structure. We showed that condensin, the protein complex needed for mitotic chromosome compaction, restructures chromosomes during meiosis in Caenorhabditis elegans. In particular, condensin promotes both meiotic chromosome condensation after crossover recombination and the remodeling of sister chromatids. Condensin helps resolve cohesin-independent linkages between sister chromatids and alleviates recombination-independent linkages between homologues. The safeguarding of chromosome resolution by condensin permits chromosome segregation and is crucial for the formation of discrete, individualized bivalent chromosomes.
doi:10.1083/jcb.200408061
PMCID: PMC2172564  PMID: 15557118
12.  Targeting X Chromosomes for Repression 
Dosage compensation is a chromosome-wide regulatory process that balances X-chromosome gene expression between males and females in species whose sex-determining mechanisms require each sex to have a different complement of X chromosomes. Recent advances have clarified the molecular nature of the C. elegans sex-determination signal, which tallies X chromosome number relative to the ploidy and controls both the choice of sexual fate and the process of dosage compensation. Dissecting the sex signal has revealed molecular mechanisms by which small quantitative differences in intracellular signals are translated into dramatically different developmental fates. Recent experiments have also revealed fundamental principles by which C. elegans dosage compensation proteins recognize and bind X chromosomes of XX embryos to reduce gene expression. Dosage compensation proteins function not only in a condensin complex specialized for regulating X-chromosome gene expression, but also in distinct condensin complexes that control other chromosome-wide processes: chromosome segregation and meiotic crossover recombination. The reshuffling of interchangeable molecular parts creates independent machines with similar architecture but distinct biological functions.
doi:10.1016/j.gde.2010.03.008
PMCID: PMC2906122  PMID: 20381335
13.  Condensins Regulate Meiotic DNA Break Distribution, thus Crossover Frequency, by Controlling Chromosome Structure 
Cell  2009;139(1):73-86.
SUMMARY
Meiotic crossover (CO) recombination facilitates evolution and accurate chromosome segregation. CO distribution is tightly regulated: homolog pairs receive at least one CO, CO spacing is nonrandom, and COs occur preferentially in short genomic intervals called hotspots. We show that CO number and distribution are controlled on a chromosome-wide basis at the level of DNA double-strand break (DSB) formation by a condensin complex composed of subunits from two known condensins: the C. elegans dosage compensation complex and mitotic condensin II. Disruption of any subunit of the CO-controlling condensin dominantly changes DSB distribution, and thereby COs, and extends meiotic chromosome axes. These phenotypes are cosuppressed by disruption of a chromosome axis element. Our data implicate higher-order chromosome structure in the regulation of CO recombination, provide a model for the rapid evolution of CO hotspots, and show that reshuffling of interchangeable molecular parts can create independent machines with similar architectures but distinct biological functions.
doi:10.1016/j.cell.2009.07.035
PMCID: PMC2785808  PMID: 19781752
14.  Do Pregnant Women and Those at Risk of Developing Post-Natal Depression Consume Lower Amounts of Long Chain Omega-3 Polyunsaturated Fatty Acids? 
Nutrients  2010;2(2):198-213.
The aims were to compare intakes of long chain omega-3 polyunsaturated fatty acid (LC n-3 PUFA) in pregnant and non-pregnant women in Australia and to compare these intakes to the Australian National Nutrition Survey of 1995 (NNS95) [1] and to determine if the LC n-3 PUFA intakes differed in women who may be ‘at risk’ compared with women ‘not at risk’ of developing post-natal depression (PND). A validated LC n-3 PUFA food frequency questionnaire and pregnant women’s Edinburgh Postnatal Depression Scale (EPDS) scores were used. LC n-3 PUFA intakes were comparable to the NNS95 but did not differ due to pregnancy or whether or not a woman is at risk of developing PND.
doi:10.3390/nu2020198
PMCID: PMC3257633  PMID: 22254016
long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA); pregnant women; postnatal depression
15.  Sperm chromatin proteomics identifies evolutionarily conserved fertility factors 
Nature  2006;443(7107):101-105.
Male infertility is a long-standing enigma of significant medical concern. The integrity of sperm chromatin is a clinical indicator of male fertility and in vitro fertilization potential1: chromosome aneuploidy and DNA decondensation or damage are correlated with reproductive failure. Identifying conserved proteins important for sperm chromatin structure and packaging can reveal universal causes of infertility. Here we combine proteomics, cytology and functional analysis in Caenorhabditis elegans to identify spermatogenic chromatin-associated proteins that are important for fertility. Our strategy employed multiple steps: purification of chromatin from comparable meiotic cell types, namely those undergoing spermatogenesis or oogenesis; proteomic analysis by multidimensional protein identification technology (MudPIT) of factors that co-purify with chromatin; prioritization of sperm proteins based on abundance; and subtraction of common proteins to eliminate general chromatin and meiotic factors. Our approach reduced 1,099 proteins co-purified with spermatogenic chromatin, currently the most extensive catalogue, to 132 proteins for functional analysis. Reduction of gene function through RNA interference coupled with protein localization studies revealed conserved spermatogenesis-specific proteins vital for DNA compaction, chromosome segregation, and fertility. Unexpected roles in spermatogenesis were also detected for factors involved in other processes. Our strategy to find fertility factors conserved from C. elegans to mammals achieved its goal: of mouse gene knockouts corresponding to nematode proteins, 37% (7/19) cause male sterility. Our list therefore provides significant opportunity to identify causes of male infertility and targets for male contraceptives.
doi:10.1038/nature05050
PMCID: PMC2731558  PMID: 16943775
16.  Clustered DNA motifs mark X chromosomes for repression by a dosage compensation complex 
Nature  2006;444(7119):614-618.
Gene expression in metazoans is regulated not only at the level of individual genes but also in a coordinated manner across large chromosomal domains (for example centromeres, telomeres and imprinted gene clusters1-3) and along entire chromosomes (for example X-chromosome dosage compensation4-6). The primary DNA sequence usually specifies the regulation of individual genes, but the nature of cis-acting information that controls genes over large regions has been elusive: higher-order DNA structure, specific histone modifications, subnuclear compartmentalization and primary DNA sequence are possibilities. One paradigm of chromosome-wide gene regulation is Caenorhabditis elegans dosage compensation in which a large dosage compensation complex (DCC) is targeted to both X chromosomes of hermaphrodites to repress transcript levels by half6. This essential process equalizes X-linked gene expression between the sexes (XO males and XX hermaphrodites). Here we report the discovery and dissection of cis-acting sites that mark nematode X chromosomes as targets for gene repression by the DCC. These rex (recruitment element on X) sites are widely dispersed along X and reside in promoters, exons and intergenic regions. rex sites share at least two distinct motifs that act in combination to recruit the DCC. Mutating these motifs severely reduces or abolishes DCC binding in vivo, demonstrating the importance of primary DNA sequence in chromosome-wide regulation. Unexpectedly, the motifs are not enriched on X, but altering motif numbers within rex sites demonstrates that motif co-occurrence in unusually high densities is essential for optimal DCC recruitment. Thus, X-specific repression is established through sequences not specific to X. The distribution of common motifs provides the foundation for repression along an entire chromosome.
doi:10.1038/nature05338
PMCID: PMC2693371  PMID: 17122774
17.  Three Distinct Condensin Complexes Control C. elegans Chromosome Dynamics 
Current biology : CB  2009;19(1):9-19.
Summary
Background
Condensin complexes organize chromosome structure and facilitate chromosome segregation. Higher eukaryotes have two complexes, condensin I and condensin II, each essential for chromosome segregation. The nematode Caenorhabditis elegans was considered an exception, because it has a mitotic condensin II complex but appeared to lack mitotic condensin I. Instead, its condensin I-like complex (here called condensin IDC) dampens gene expression along hermaphrodite X chromosomes during dosage compensation.
Results
Here we report the discovery of a third condensin complex, condensin I, in C. elegans. We identify new condensin subunits and show that each complex has a conserved five-subunit composition. Condensin I differs from condensin IDC by only a single subunit. Yet condensin I binds to autosomes and X chromosomes in both sexes to promote chromosome segregation, whereas condensin IDC binds specifically to X chromosomes in hermaphrodites to regulate transcript levels. Both condensin I and II promote chromosome segregation, but associate with different chromosomal regions during mitosis and meiosis. Unexpectedly, condensin I also localizes to regions of cohesion between meiotic chromosomes before their segregation.
Conclusions
We demonstrate that condensin subunits in C. elegans form three complexes, one that functions in dosage compensation and two that function in mitosis and meiosis. These results highlight how the duplication and divergence of condensin subunits during evolution may facilitate their adaptation to specialized chromosomal roles and illustrate the versatility of condensins to function in both gene regulation and chromosome segregation.
doi:10.1016/j.cub.2008.12.006
PMCID: PMC2682549  PMID: 19119011
18.  The T-Box Transcription Factor SEA-1 Is an Autosomal Element of the X 
Developmental cell  2005;9(3):339-349.
Summary
Sex is determined in C. elegans by a chromosome-counting mechanism that tallies X chromosome dose relative to the sets of autosomes, the X:A ratio. A group of genes on X called X signal elements (XSEs) communicates X chromosome number by repressing the activity of the master sex-determination switch gene xol-1 in a dose-dependent manner. xol-1 is repressed by transcriptional and posttranscriptional mechanisms and is inactive in XX animals (hermaphrodite) but active in XO animals (male). Prior to our work, the nature of the autosomal signal and its target(s) were unknown. Here we show the signal includes discrete, trans-acting autosomal signal elements (ASEs) that counter XSEs to coordinately control both sex determination and dosage compensation. sea-1, the first autosomal signal element, encodes a T-box transcription factor that opposes XSEs by activating transcription of xol-1. Hence, xol-1 integrates both X and autosomal signals to determine sexual fate.
doi:10.1016/j.devcel.2005.06.009
PMCID: PMC2649673  PMID: 16139225
19.  Him-10 Is Required for Kinetochore Structure and Function on Caenorhabditis elegans Holocentric Chromosomes 
The Journal of Cell Biology  2001;153(6):1227-1238.
Macromolecular structures called kinetochores attach and move chromosomes within the spindle during chromosome segregation. Using electron microscopy, we identified a structure on the holocentric mitotic and meiotic chromosomes of Caenorhabditis elegans that resembles the mammalian kinetochore. This structure faces the poles on mitotic chromosomes but encircles meiotic chromosomes. Worm kinetochores require the evolutionarily conserved HIM-10 protein for their structure and function. HIM-10 localizes to the kinetochores and mediates attachment of chromosomes to the spindle. Depletion of HIM-10 disrupts kinetochore structure, causes a failure of bipolar spindle attachment, and results in chromosome nondisjunction. HIM-10 is related to the Nuf2 kinetochore proteins conserved from yeast to humans. Thus, the extended kinetochores characteristic of C. elegans holocentric chromosomes provide a guide to the structure, molecular architecture, and function of conventional kinetochores.
PMCID: PMC2192032  PMID: 11402066
kinetochore; holocentric chromosomes; mitosis; meiosis; Caenorhabditis elegans
20.  Accumulation of Terminally Deleted RNAs May Play a Role in Seoul Virus Persistence 
Journal of Virology  2000;74(3):1321-1331.
Two independent, long-term infections were analyzed to determine whether changes in viral replication could contribute to the establishment and/or maintenance of persistent Seoul virus infections. Infected cell cultures initially contained high levels of infectious virus and intracellular viral RNA that peaked between approximately 7 to 16 days postinfection and then gradually declined until day 26. After day 26, the viral titers and the levels of the small (S), medium (M), and large (L) viral RNAs varied cyclically until the end of the studies. The changes in the concentrations of the RNAs and titer were similar in pattern and appeared to result from changes in the regulation of replication. Neither internal deletions nor an accumulation of nucleotide changes were found in the RNAs. However, fine mapping and sequence analysis revealed short deletions in some of the RNAs in the conserved complementary terminal sequences believed to contain the signals for initiation of replication and transcription. Deletions at the 3′ termini of S, M, and L virus-sense RNAs (vRNAs) accumulated during the acute phase of infection just before the time that the viral titer and the concentration of vRNAs and virus complementary-sense RNAs (cRNAs) began to decline. The absence of deletions at the 5′ termini of the S, M, and L cRNAs suggests that the 3′-deleted vRNAs may not be replication competent. Thus, as the percentage of 3′-deleted vRNAs increase in the population, they could potentially compete with standard virus and downregulate viral replication. Deletions at the 3′ L cRNA and 5′ L vRNA termini were also observed, and the proportion of these deleted RNAs varied cyclically during the infections. We propose a model in which terminal nucleotide deletions arise by nuclease activity of the viral polymerase. In addition, we speculate that cleaved terminal fragments might be used as primers during replication, resulting in the repair of some of the deleted RNAs.
PMCID: PMC111467  PMID: 10627543

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