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“IN SILICO ANALYSIS OF REGULATORY ELEMENTS OF ANTIBIOTIC
                                    PRODUCING GENES IN STREPTOMYCES SPECIES”
                                        by Pramod Katara*, Neha Sanghi,
                                            Vi

“IN SILICO ANALYSIS OF REGULATORY ELEMENTS OF ANTIBIOTIC PRODUCING GENES IN STREPTOMYCES SPECIES” by Pramod Katara*, Neha Sanghi, Vinay Sharma, India.

Clustering of co-expressed genes: Analysis of co- expressed genes performed by cluster using loose K-mean clustering, resulting cluster showed groups of co- expressed genes associated with our known antibiotic producing genes. We observed that lot of genes share similar expression pattern with antibiotic genes but their numbers are vary gene to gene and it ranged from 40- 210. It suggest that every antibiotic producing genes share similar gene expression pattern with different number of genes i.e genes like SCO5072, SCO5876, and SCO5881 show co-expression with more number of genes than compared to all other genes and some other genes like SCO5879 and SCO5890 shows co-expression with very low number of genes (Fig 1).
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Host cyclooxygenase 2 modulates carcinoma growth

Host cyclooxygenase 2 modulates carcinoma growth

expression of either COX-1 or COX-2 (Figure 3). To determine whether differential localization of COX-1 or COX-2 expression occurs within the tumors, in situ hybridization for COX-1 and COX-2 was performed on tumor sections. The COX-1 hybridization pattern was diffuse, with uniform accumulation throughout the tumor (data not shown). COX-2 mRNA hybridization, in contrast, was focal with punctate accumulation in carcinoma and stromal cells that surrounded areas of necrotic tissue (Figure 4). Immunolocalization of COX-2 protein showed a similar expression pattern (data not shown). Interestingly, the expression pattern for COX-2 and VEGF was similar, with high levels of expression in the stromal compartment, and a signif- icant reduction of VEGF expression in tumors grown in the COX-2 –/– mice (Figure 4). We also examined the
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Comparative Expression Pattern of Two Vestigial Like 2 Genes in Zebrafish

Comparative Expression Pattern of Two Vestigial Like 2 Genes in Zebrafish

Abstract The vestigial Vg gene, initially characterized in Drosophila, encodes a transcription co-factor which is crucial for wings development. Vg binds via its Sd interaction domain (SID) to the Scalloped (Sd) transcription factor and its vertebrate homolog Tef1. Previous studies identified several vertebrate genes sharing high homology with Drosophila Vg SID such as Vgl (for Vg-like), TONDU (also known as Vgl1) or Vito-1 (also known as Vgl2). In order to investigate the role of vestigial-like 2 (vgll2) in zebrafish muscle development, we managed to clone and characterize two zebrafishVgll2 homolog genes, Vgll2a and Vgll2b. Alignment data showed high sequence homology of Vgll2a to vertebrates Vgll2 sequences. In situ hybridization showed that the two investigated Vgll2 genes had a similar expression pattern: they were first detected in adaxial cells (11 hpf), than expanded laterally in somites and at the end of segmentation, both genes were expressed in additional structures including head muscles and fin buds. In addition, different expression patterns of the two genes were observed. Vgll2a was expressed in bronchial arches precursor streams, derived gill muscles and hypothalamic precursors. Vgll2b was expressed in notochord at 14 hpf and regressed following notochord maturation at 18hpf. Furthermore, the genetic regulation of vgll2 genes was analysed using smu mutants and data revealed that both genes are regulated via the Hedgehog signaling pathway.
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Subdivision of arthropod cap-n-collar expression domains is restricted to Mandibulata

Subdivision of arthropod cap-n-collar expression domains is restricted to Mandibulata

In all presently sampled branches of the mandibulate tree (hexapods, malacostracan crustaceans, and myriapods), part of cnc expression is restricted to within the Dfd expression domain. In hexapods, the expression domain of Dfd spans the mandibular and maxillary segments (Figure 5). cnc arises within the Dfd domain and progressively downregu- lates Dfd, with declining levels of Dfd expression signal in the mandibular segment over time [25]. Intriguingly, the temporal expression of Dfd follows the same pattern in the millipede G. marginata, with loss of expression in the distal mandible in older stages (Figure 4A-C of [39]). A similar expression pattern has been reported in the mandibular segment of the centipede Lithobius atkinsoni, namely the absence of Dfd expression in the distal mandible (note that the posterior boundary of Dfd is not the same in the two species; weak expression of Dfd is observed in the millipede trunk, but not in the centipede) (Figure 4C of [40]). These observations suggest conservation of the regulation of Dfd by cnc in the mandibular segment of non-hexapod mandibulates. Unfortunately, functional tools are currently lacking in myriapods, precluding a direct test of this genetic interaction in either centipedes or millipedes.
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Self similar pattern formation and continuous mechanics of self similar systems

Self similar pattern formation and continuous mechanics of self similar systems

Abstract. In many cases, the critical state of systems that reached the threshold is characterised by self-similar pat- tern formation. We produce an example of pattern forma- tion of this kind – formation of self-similar distribution of interacting fractures. Their formation starts with the crack growth due to the action of stress fluctuations. It is shown that even when the fluctuations have zero average the cracks generated by them could grow far beyond the scale of stress fluctuations. Further development of the fracture system is controlled by crack interaction leading to the emergence of self-similar crack distributions. As a result, the medium with fractures becomes discontinuous at any scale. We develop a continuum fractal mechanics to model its physical behaviour. We introduce a continuous sequence of continua of increas- ing scales covering this range of scales. The continuum of each scale is specified by the representative averaging vol- ume elements of the corresponding size. These elements de- termine the resolution of the continuum. Each continuum hides the cracks of scales smaller than the volume element size while larger fractures are modelled explicitly. Using the developed formalism we investigate the stability of self- similar crack distributions with respect to crack growth and show that while the self-similar distribution of isotropically oriented cracks is stable, the distribution of parallel cracks is not. For the isotropically oriented cracks scaling of perme- ability is determined. For permeable materials (rocks) with self-similar crack distributions permeability scales as cube of crack radius. This property could be used for detecting this specific mechanism of formation of self-similar crack distri- butions.
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Role of activins in embryo implantation and diagnosis of ectopic pregnancy: a review

Role of activins in embryo implantation and diagnosis of ectopic pregnancy: a review

Embryo implantation is a major prerequisite for the successful establishment of pregnancy. Ectopic implantation outside the intrauterine cavity and the development of ectopic pregnancy (EP) is a major cause of maternal morbidity and occasionally mortality during the first trimester. EP may be induced by failure of tubal transport and/or increased tubal receptivity. Activins, their type II receptors and follistatin have been localised in the human endometrial and tubal epithelium and they are major regulators of endometrial and tubal physiology during the menstrual cycle. Pathological expression of activins and their binding protein, follistatin, was observed in tissue and serum samples collected from EP. Several studies with different designs investigated the diagnostic value of a single measurement of serum activin-A in the differentiation between normal intrauterine and failing early pregnancy and the results are controversial. Nevertheless, the diagnostic value of activins in EP, including the other activin isoforms (activin-B and – AB) and follistatin, merits further research. This review appraises the data to date researching the role of activins in the establishment of normal pregnancy and, pathogenesis and diagnosis of tubal EP.
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The Epstein-Barr Virus SM Protein Is Functionally Similar to ICP27 from Herpes Simplex Virus in Viral Infections

The Epstein-Barr Virus SM Protein Is Functionally Similar to ICP27 from Herpes Simplex Virus in Viral Infections

Likewise, a chimeric protein consisting of the carboxy-ter- minal domain of the EHV homolog fused to the amino termi- nus of VP16 is a very weak transcriptional activator (27). Therefore, the EHV-1 protein does not follow the two-domain model of transcriptional activation established for VP16. Sim- ilarly, the functional overlap between ICP27 and SM may be achieved through the combined features of the individual pro- teins. Given the limited sequence similarity between these two proteins, it may be that functions conserved between ICP27 and SM require a complete three-dimensional protein struc- ture rather than smaller homologous domains. These proteins may have evolved to regulate gene expression through a com- mon mechanism despite unique overall protein arrangements. A number of ICP27 mutants have been generated and ana- lyzed in significant detail. With regard to this work, the phe- notype of mutant d1-2 (17, 68) is comparable to the phenotype of vSM/TK-⌬27. This mutant has four amino-terminal residues deleted that comprise part of the NES (75, 81). In transient- expression assays, a plasmid carrying the d1-2 mutant allele also complements the growth of an ICP27 null virus, but it is more effective at complementation than SM. Although the d1-2 mutant virus synthesized nearly wild-type levels of gC, reductions in the synthesis of other viral late proteins are comparable between d1-2 and vSM/TK-⌬27. Previous studies have demonstrated that disruptions in the ICP27 NES impair shuttling and viral replication (51, 75, 83). The similar pheno- types observed in d1-2 infections, where the NES is not fully functional (51), and in vSM/TK-⌬27 infections, where the NES may be suboptimal, strongly support a role for shuttling in the regulation of HSV late gene expression.
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Establishment and Maintenance of Kaposi's Sarcoma-Associated Herpesvirus Latency in B Cells

Establishment and Maintenance of Kaposi's Sarcoma-Associated Herpesvirus Latency in B Cells

KSHV clearly infects B cells in vivo, as demonstrated by the presence of virus in the peripheral blood mononuclear cells of KS patients and can cause B-cell-related diseases like PEL and multicentric Castleman’s disease (13, 15, 49). The question remains why the virus, which can infect many cell types in vitro, is unable to infect B cells in culture. To address this question, we attempted to infect BJAB cells in culture. We created a re- combinant virus that expresses both green fluorescent protein (GFP) and the puromycin resistance gene, which allows simple detection and powerful selection of recombinant infected cells. As observed with wild-type virus, we were unable to infect BJAB to any detectable extent. However, when naked viral DNA was in- troduced into BJAB cells, latency was established and could be maintained when kept under selection. The pattern of viral gene expression was similar to that in PEL cell lines. Virus can be successfully reactivated from the infected BJAB cells and pas- saged to endothelial cells. These studies indicate that BJAB cells are capable of establishing, maintaining, and reactivating from KSHV latency and thus provide a controlled system for examin- ing the effects of KSHV infection on B cells in culture.
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DjPum, a homologue of Drosophila Pumilio, is essential
to planarian stem cell maintenance

DjPum, a homologue of Drosophila Pumilio, is essential to planarian stem cell maintenance

clustering allows us to speculate that DjPum and the other proteins included in the Pumilio subfamily, can recognize related target sequences and play similar regulatory roles. The comparison between DjPum, mammalian and Drosophila PUF protein members shows that the eighth motif of the planarian protein contains some additional amino acids. This non- canonical structure could be of functional importance in determining the specificity of protein interactions. Mutational analysis in Drosophila indicates that Pumilio interacts with Brat, a member of the NHL family, via the outer face of repeats seven and eight, and the conserved C-terminal region (Goodwin, 2001). Moreover, the eighth repeat of Pumilio plays a key role in recruiting Nos to the Nos response element (NRE). The human relative, which bears an insertion of three amino acids within this motif, also binds the NRE, but is unable to recruit Nos (Sonoda and Wharton, 1999). Because the structural conservation of the eighth repeat appears essential to recruit Nos to target mRNAs, we suggest that DjPum cannot recruit a planarian Nos homologue. DjPum could have other regions, outside the repeats, able to recruit different proteins. It has been recently proposed that PUF proteins can function with alternative partners (Wickens et al., 2002). This suggests that a combinatorial mechanism involving RNA-protein and protein-protein interactions plays a key role to build a variety of PUF-containing complexes, that can regulate different developmental events (Asaoka-Taguchi et al., 1999; Deshpande et al., 1999; Gamberi et al., 2002; Moore et al., 2003; Nakahata et al., 2001; Sonoda and Wharton, 1999).
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Essential role of the cancer stem/progenitor cell marker nucleostemin for indole-3-carbinol anti-proliferative responsiveness in human breast cancer cells

Essential role of the cancer stem/progenitor cell marker nucleostemin for indole-3-carbinol anti-proliferative responsiveness in human breast cancer cells

We observed that 10AT-Her2 cells are highly sensitive to the anti-proliferative effects of I3C, a natural indole carbinol compound. I3C was shown to trigger a p53- dependent apoptotic response in 10AT-Her2 cells and can disrupt tumorsphere formation in cell suspension cultures as well as inhibit the in vivo growth of 10AT- Her2-derived tumor xenografts. Because the 10AT-Her2 cell population expresses relatively high levels of nucleoste- min, this system was used to determine whether this breast cancer stem/progenitor marker protein can be potentially targeted by and confer selective responsiveness to I3C. Nucleostemin is a multidomain nucleolus GTPase, which is associated with self-renewal of undifferentiated stem/ progenitor cells [60,61]. Co-immunoprecipitations revealed that I3C treatment of 10AT-Her2 cells strongly promoted nucleostemin binding to the MDM2 inhibitor of the p53 tumor suppressor, and thereby sequestered MDM2 into the nucleolus. Although I3C decreased the amount of p-MDM2, this natural indole carbinol compound appears to increase significantly the binding efficiency between phosphorylated MDM2 and nucleostemin. An important consequence of the induced nucleostemin–MDM2 inter- action is that I3C treatment prevented MDM2 binding to p53, which we propose allows the p53 tumor suppressor protein to escape the MDM2 inhibition and initiate its cellular apoptotic response (see Figure 9). We also ob- served the I3C-regulated nucleostemin–MDM2 as well as MDM2–p53 interactions occur in SKBR3 breast can- cer cells, but not in either MCF-7 or MDA-MB-231 cells even though all three of these human breast cancer cell lines are sensitive to the anti-proliferative effects of I3C. Conceivably, the attenuated stemness properties of MCF-7 and MDA-MB-231 cells may account for this difference in I3C-regulated protein–protein interaction properties. Consistent with this pathway mediating the anti-proliferative effects of I3C, expression of dominant negative p53 prevented the I3C apoptotic response in 10AT-Her2 cells, whereas knockdown of nucleostemin disrupted the I3C-induced localization of MDM2 into nuclear foci as well as strongly attenuated the apoptotic response. I3C did not alter the protein level of nucleoste- min, MDM2 or p53, implying that the key effects are on protein–protein interactions and subcellular localization (see Figure 9).
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Similar Document Retrieval using Pattern-Based Topic Modelling for Information Filtering

Similar Document Retrieval using Pattern-Based Topic Modelling for Information Filtering

ABSTRACT: Topic modelling is widely accepted in the areas of machine learning and text mining, etc. It was proposed to generate statistical models to classify multiple topics in a collection of documents. Where each topic is represented by a distribution of words. The word-based or term-based topic representations may not be able to semantically represent documents. Patterns are always more discriminative than single terms for representing documents. In this work, we propose to combine the statistical topic modelling with pattern mining techniques to generate pattern-based topic models with the purpose of enhancing the semantic representations of the traditional word- based topic models. Utilizing the proposed pattern-based topic model, users’ interests can be modelled with multiple topics and each of which is represented with semantically rich patterns. A novel information filtering model is proposed here. In information filtering model user information needs are created in terms of multiple topics where each topic is represented by patterns.
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Stem cell factor SALL4, a potential prognostic marker for myelodysplastic syndromes

Stem cell factor SALL4, a potential prognostic marker for myelodysplastic syndromes

During our over 2 years’ follow-up, 11 of 27 (40.74%) RAEB-1/RAEB-2 patients experience disease progres- sion. SALL4 expression of these cases (54.27±14.71, n=11) was significantly higher (p<0.01) than those with- out disease progression (30.47±10.89, n=16). 14 patients died of MDS or AML progressed from MDS. Since both IPSS and WHO have been used to guide clinical diag- nosis and management of MDS patients, we first con- ducted Kaplan-Meier survival analysis for MDS patients based on WHO subtypes and IPSS risk groups. Based on WHO subtypes, the RAEB-2 group that showed high SALL4 and Bmi-1 expression had a worse (p<0.01) sur- vival rate than other subtypes (Figure 4A). Based on IPSS risk groups, Int-2 and High risk patient groups whose SALL4 and Bmi-1 expression levels were higher than that from Int-1 and Low risk patient groups exhibited a worse (p<0.01) survival rate (Figure 4B). In- triguingly, we noted that among the Int-2 risk group, pa- tients who passed away during the follow up (53.42± 11.25, 4 of 12) had higher (p=0.0056) SALL4 expres- sion than those who were still alive at the end of the study (34.75±7.82, 8 of 12). This trend was also observed for Bmi-1 expression. Patients who passed away in the Table 1 Characteristics of patients with MDS, MDS-AML and MDS post-treatment
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The NuA4 Complex Promotes Translesion Synthesis (TLS)-Mediated DNA Damage Tolerance

The NuA4 Complex Promotes Translesion Synthesis (TLS)-Mediated DNA Damage Tolerance

We speculate that perhaps ssDNA gaps are similar to this structural pattern and that H2A.Z helps maintain these ge- nomic regions in a state conducive to the recruitment of error-prone/TLS factors. Expanding on potential function (s), ssDNA gaps are innately fragile and susceptible to double- stranded break (DSB) formation. The presence of H2A.Z at these regions would augment DSB repair (Adkins et al. 2013) or, if irreparable, aid in DNA break relocalization to the nuclear periphery (Horigome et al. 2014). We predicted there would be less chromatin associated H2A.Z in esa1- L254P cells upon MMS treatment; however, fractionation experiments showed no discernible change in H2A.Z levels in mutants compared to wild-type cells (Figure S8). Differ- ences could be below detection, as previous work monitor- ing the level of chromatin bound H2A.Z in cells lacking INO80, which catalyzes its eviction, suggest subtle H2A.Z redistribution at specific loci is not reflected by changes in H2A.Z levels in bulk chromatin (Papamichos-Chronakis et al. 2011).
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Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington's disease model system

Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington's disease model system

As shown in Fig. 1a for a galactose induction time of 1.5 hr, following a one-step Flag pull down and AU-FDS analysis, Htt-25Q complexes ranging from 30S to larger than 180S were detected. Extracts from a control strain lacking Htt-polyQ and subjected to a Flag pull down did not display any of these complexes (Fig. 1a). While the major peak at 1.5 hr had an S coefficient of 30S, larger discrete complexes were detected with S coefficients of 40S, 49S, 60S, 71S, 86S, and larger values (average of three replicas with Standard Error of the Means, S.E.M.s, less than 1.5% for each peak). Htt-103Q at 1.5 hr post induction displayed the same general pattern as that of Htt-25Q with complexes with S coefficients of 29S, 39S, 48S, 59S, 70S, and 82 S (average of four to six replicas with S.E.M.s of less than 5%) (Fig. 1a). The intermediate Htt-47Q form that also displays intermediate cytotoxicity (Table 1) showed the same pattern of soluble complexes at 1.5 hr (Fig. 1d). Hence, soon after induction, both the non-toxic and toxic soluble aggregates of Htt-polyQ looked very similar. All of these Htt forms, prior to galactose induction, contained only limited material in complexes sized at 29S or larger (see Fig. 1b to 1d), indicating that the Htt com- plexes formed principally upon induction of expression with galactose. Both Htt-25Q and Htt-103Q displayed similar growth rates in liquid medium following induction with galactose: a 1.4-fold increase in cell numbers was observed at 1.5 hr, a 2.5-fold increase was observed at 6 hr, and about a 3-fold increase was observed by 24 hr.
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miR-29 regulates Tet1 expression and contributes to early differentiation of mouse ESCs

miR-29 regulates Tet1 expression and contributes to early differentiation of mouse ESCs

shown to be abundant in embryonic stem cells (ESCs) and non-cancerous tissues. Tet1 protein and 5hmC are present in high levels in mouse ESCs and adult brain, suggesting a role in epigenetic control of these cells and tissues [12–15]. Indeed, Tet1 has an important role in mouse ESCs maintenance and functions to regulate the lineage differentiation potential of ESCs [16, 17]. Acute depletion of Tet1 impairs LIF/Stat3 signaling and results in loss of ESC identity [18]. Genome-wide analyses of Tet1 and 5hmC distribution by high-throughput sequencing (ChIP-seq) found that Tet1 has dual functions in transcriptional regulation in mouse ESCs, it can bind to both actively transcribed H3K4me3-only genes and PRC- repressed CpG-rich genes, thus can associate with either activated or repressed transcriptional states [19– 21]. In adult brain, Tet1 promotes 5mC hydroxylation, activates DNA demethylation, and is critical for neuronal activity- regulated gene expression and memory formation [22– 24]. Tet1 deficient mice exhibit impaired hippocampal neurogenesis accompanied by poor spatial learning and memory [25]. Consistently, 5hmC exists at high levels in
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How similar is similar enough?

How similar is similar enough?

We judge ( 3 ) false, which means that in selecting counterfactual worlds in which the weather is fine that are otherwise maximally similar to the actual world, we disregard the fact that Jones is wearing his hat. Lewis 1979 ’s list of priorities according to which similarity of laws trumps similarity of particular facts seems equipped to account for the judgment in ( 3 ): assuming determinism, the worlds we select are those worlds that shared the same history as the actual world up to the divergence time, i.e., the time when (thanks to a “miracle”) the deterministic chain of events broke and these worlds took different paths following the actual laws. That is, when selecting the most similar worlds, we need to select those worlds that are just like the actual world up until they diverge from the actual world, but that follow their own course afterwards. Applied to Tichý’s example, these worlds are going to be worlds that are just like the actual world up to the time when some miracle breaks the deterministic chain of events and the weather turns out to be fine but which, after that, follow undisturbed the actual laws. We should not try to make these worlds converge again just for the sake of maximizing the number of particular facts in common with the actual world since this would involve more “miracles” or inexplicable violations of the actual laws. Thus, since the actual laws say that if the weather is fine Jones might or might not wear his hat, the conditional in ( 3 ) comes out false.
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Immune Status in Very Preterm Neonates

Immune Status in Very Preterm Neonates

RESULTS: Prematurity (preterm labor and preterm premature rupture of membranes cohorts), neonatal sepsis, and histologic chorioamnio- nitis were associated with signi fi cant reduction in monocyte MHC class II expression. Neonates who had evidence of subsequent protracted sepsis had low levels of MHC class II expression at birth. Serial mono- cyte MHC class II expression revealed a fall by day 2, in all preterm neonates, with the degree being in fl uenced by both prematurity and sepsis, and incomplete recovery by day 7, suggesting immunopar- alysis in preterm premature rupture of membranes and preterm labor cohorts. Whole blood lipopolysaccharide stimulation assay showed sig- ni fi cantly lower tumor necrosis factor a , values in preterm neonates who subsequently developed sepsis indicating a degree of immuno- paralysis.
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Identification of gene co-regulatory modules and associated cis-elements involved in degenerative heart disease

Identification of gene co-regulatory modules and associated cis-elements involved in degenerative heart disease

It is well established in yeast [10] and cultured human cells [11] that genes involved in a common physiological function tend to be regulated as groups. In such a group, often called a co-regulatory module [12], genes undergo similar changes in expression that act to roughly preserve their expression ratio over different physiological condi- tions and intrinsic genetic cues. Our goal is to identify such modules in human cardiomyopathies, under the assumption that these modules can provide information about the regulatory factors that control expression. Our analysis uses publicly available microarray data for human ventricular tissue remodeling due to a variety of cardiac disease states. To identify likely regulatory mod- ules in this data, we applied a hierarchical clustering algo- rithm to the Pearson correlation between gene expression levels across the different cardiomyopathies. Resulting clusters were visualized and characterized based on Gene Ontology annotations for function. With this analysis, we identified 35 modules, the largest of which are enriched in genes whose primary function is related to energy genera- tion or protein translation.
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Evidence for the temporal regulation of insect segmentation by a conserved sequence of transcription factors

Evidence for the temporal regulation of insect segmentation by a conserved sequence of transcription factors

Long-germ insects, such as the fruit fly Drosophila melanogaster, pattern their segments simultaneously, whereas short-germ insects, such as the beetle Tribolium castaneum, pattern their segments sequentially, from anterior to posterior. Although the two modes of segmentation at first appear quite distinct, much of this difference might simply reflect developmental heterochrony. We now show here that, in both Drosophila and Tribolium, segment patterning occurs within a common framework of sequential Caudal, Dichaete and Odd- paired expression. In Drosophila, these transcription factors are expressed like simple timers within the blastoderm, whereas in Tribolium they form wavefronts that sweep from anterior to posterior across the germband. In Drosophila, all three are known to regulate pair-rule gene expression and influence the temporal progression of segmentation. We propose that these regulatory roles are conserved in short-germ embryos, and that therefore the changing expression profiles of these genes across insects provide a mechanistic explanation for observed differences in the timing of segmentation. In support of this hypothesis, we demonstrate that Odd-paired is essential for segmentation in Tribolium, contrary to previous reports.
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Siglec-8 antibody reduces eosinophils and mast cells in a transgenic mouse model of eosinophilic gastroenteritis

Siglec-8 antibody reduces eosinophils and mast cells in a transgenic mouse model of eosinophilic gastroenteritis

Siglec-8–transgenic mice express Siglec-8 on eosinophils, mast cells, and basophils. Based on the data above demonstrating elevation and activation of eosinophils and mast cells in EG patient tissue, we set out to eval- uate the activity of an anti–Siglec-8 mAb in a murine disease model of EG and EGE. Like other members of the CD33-related Siglecs, Siglec-8 appears to have evolved recently, with close homologs found only in some primate species (11, 22). Therefore, to examine the in vivo activity of anti–Siglec-8 mAb, we generated a human Siglec-8–expressing transgenic mouse, distinct from previously generated mice (e.g., ROSA26-Si- glec-8–knockin mice) (23, 24). Instead, Siglec-8–transgenic founder mice were generated via the pronuclear microinjection of DNA (Supplemental Figure 3A) as described in Methods. Transmission of the Siglec-8 transgene was successful in 2 of the chimeric founders’ progeny (lines 335 and 307), and the transgenic mouse line selected (line 335) contained a single-copy insertion of the Siglec-8 gene (Supplemental Figure 3, B–D). Siglec-8–transgenic mice did not display differences between males or females compared to wild-type (WT) littermates in body weight, weights of major organs, absolute or relative percentages of blood cell types, blood chemistries, or coagulation (Supplemental Figure 3E). Examination of peripheral blood leukocytes (PBLs) and peritoneal lavage (PL) cells from these mice showed high levels of Siglec-8 on the cell surface of mast cells, eosinophils, and basophils in PBLs and PL (Supplemental Figure 4, A–C), consistent with the selec- tive expression of Siglec-8 on human immune cells (8, 11, 25). Siglec-8 was also found on eosinophils and mast cells in other tissues, including GI, lung, and skin (data not shown), demonstrating expression on both connective tissue and mucosal mast cells. In contrast, Siglec-8 was not detected on lymphocyte, neutrophil, monocyte, or macrophage cell populations (Supplemental Figure 4, A–C).
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