Requirement of Osr1 in second heart field (SHF) for proper outflow tract (OFT) alignment

Congenital heart disease (CHD) is current in 1/3 of all birth defects and has the prevalence of 1 in 1000 births.1 1/3 of all CHDs consist of cardiac outflow tract (OFT) defects.1 Despite its high prevalence, the genetic ontogeny of CHD has much to be studied. Knocking out Osr1, a gene encoding for a putative transcription factor containing four C2H2-type zinc finger motifs, is reported to cause heart defects including atrioventricular septal defects (AVSDs) in mice2-4 while its involvement in OFT development has yet to be studied. Osr1 is expressed in the second heart field (SHF), overlapping the expression of Gli1, an important modulator of sonic hedgehog (Shh) signaling pathway.4 Shh-signaling has been reported to contribute to the OFT development.5 Our preliminary study has shown that Osr1 deletion causes OFT defects including DORV and OA—suggesting its role in OFT alignment. We hypothesize that Osr1 is required in the SHF and Shh-signaling for proper OFT alignment. We will use a Cre-lox cell-specific KO technique to create embryos with Osr1 specific KO in SHF cells and Shh-receiving cells. We expect to observe high percentages of OFT misalignment including DORV and OA in embryos with Osr1 specific KO in SHF cells and Shh-receiving cells. This study will provide information which cell lineage is required for Osr1 in OFT development

Requirement of Osr1 in second heart field (SHF) for proper outflow tract (OFT) alignment

Congenital heart disease (CHD) is current in 1/3 of all birth defects and has the prevalence of 1 in 1000 births.1 1/3 of all CHDs consist of cardiac outflow tract (OFT) defects.1 Despite its high prevalence, the genetic ontogeny of CHD has much to be studied. Knocking out Osr1, a gene encoding for a putative transcription factor containing four C2H2-type zinc finger motifs, is reported to cause heart defects including atrioventricular septal defects (AVSDs) in mice2-4 while its involvement in OFT development has yet to be studied. Osr1 is expressed in the second heart field (SHF), overlapping the expression of Gli1, an important modulator of sonic hedgehog (Shh) signaling pathway.4 Shh-signaling has been reported to contribute to the OFT development.5 Our preliminary study has shown that Osr1 deletion causes OFT defects including DORV and OA—suggesting its role in OFT alignment. We hypothesize that Osr1 is required in the SHF and Shh-signaling for proper OFT alignment. We will use a Cre-lox cell-specific KO technique to create embryos with Osr1 specific KO in SHF cells and Shh-receiving cells. We expect to observe high percentages of OFT misalignment including DORV and OA in embryos with Osr1 specific KO in SHF cells and Shh-receiving cells. This study will provide information which cell lineage is required for Osr1 in OFT development

Inhibitory effects of megakaryocytic cells in prostate cancer skeletal metastasis

Prostate cancer cells commonly spread through the circulation, but few successfully generate metastatic foci in bone. Osteoclastic cellular activity has been proposed as an initiating event for skeletal metastasis. Megakaryocytes (MKs) inhibit osteoclastogenesis, which could have an impact on tumor establishment in bone. Given the location of mature MKs at vascular sinusoids, they may be the first cells to physically encounter cancer cells as they enter the bone marrow. Identification of the interaction between MKs and prostate cancer cells was the focus of this study. K562 (human MK precursors) and primary MKs derived from mouse bone marrow hematopoietic precursor cells potently suppressed prostate carcinoma PC-3 cells in coculture. The inhibitory effects were specific to prostate carcinoma cells and were enhanced by direct cell-cell contact. Flow cytometry for propidium iodide (PI) and annexin V supported a proapoptotic role for K562 cells in limiting PC-3 cells. Gene expression analysis revealed reduced mRNA levels for cyclin D1, whereas mRNA levels of apoptosis-associated specklike protein containing a CARD (ASC) and death-associated protein kinase 1 (DAPK1) were increased in PC-3 cells after coculture with K562 cells. Recombinant thrombopoietin (TPO) was used to expand MKs in the marrow and resulted in decreased skeletal lesion development after intracardiac tumor inoculation. These novel findings suggest a potent inhibitory role of MKs in prostate carcinoma cell growth in vitro and in vivo. This new finding, of an interaction of metastatic tumors and hematopoietic cells during tumor colonization in bone, ultimately will lead to improved therapeutic interventions for prostate cancer patients. © 2011 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78486/1/204_ftp.pd

Maternal Diet Intervention Before Pregnancy Primes Offspring Lipid Metabolism in Liver

Nonalcoholic fatty liver disease (NAFLD) has a developmental origin and is influenced in utero. We aimed to evaluate if maternal diet intervention before pregnancy would be beneficial to reduce the risk of offspring NAFLD. In our study, female mice were either on a normal-fat diet (NF group), or a high-fat diet for 12 weeks and continued on this diet throughout pregnancy and lactation (HF group), or switched from HF-to-NF diet 1 week (H1N group), or 9 weeks (H9N group) before pregnancy. Compared with the NF offspring, the H1N and HF, but not the H9N offspring, displayed more severe hepatic steatosis and glucose intolerance. More specifically, an abnormal blood lipid panel was seen in the H1N offspring and abnormal hepatic free fatty acid composition was present in both the HF and H1N offspring, while the H9N offspring displayed both at normal levels. These physiological changes were associated with desensitized hepatic insulin/AKT signaling, increased expression of genes and proteins for de novo lipogenesis and cholesterol synthesis, decreased expression of genes and proteins for fatty acid oxidation, increased Pcsk9 expression, and hypoactivation of 5' AMP-activated protein kinase (AMPK) signaling in the HF and H1N offspring. However, these effects were completely or partially rescued in the H9N offspring. In summary, we found that early maternal diet intervention is effective in reducing the risk of offspring NAFLD caused by maternal HF diet. These findings provide significant support to develop effective diet intervention strategies and policies for prevention of obesity and NAFLD to promote optimal health outcomes for mothers and children

Lawmakers\u27 Use of Scientific Evidence Can Be Improved

Core to the goal of scientific exploration is the opportunity to guide future decision-making. Yet, elected officials often miss opportunities to use science in their policymaking. This work reports on an experiment with the US Congress-evaluating the effects of a randomized, dual-population (i.e., researchers and congressional offices) outreach model for supporting legislative use of research evidence regarding child and family policy issues. In this experiment, we found that congressional offices randomized to the intervention reported greater value of research for understanding issues than the control group following implementation. More research use was also observed in legislation introduced by the intervention group. Further, we found that researchers randomized to the intervention advanced their own policy knowledge and engagement as well as reported benefits for their research following implementation

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Lawmakers' use of scientific evidence can be improved.

Core to the goal of scientific exploration is the opportunity to guide future decision-making. Yet, elected officials often miss opportunities to use science in their policymaking. This work reports on an experiment with the US Congress-evaluating the effects of a randomized, dual-population (i.e., researchers and congressional offices) outreach model for supporting legislative use of research evidence regarding child and family policy issues. In this experiment, we found that congressional offices randomized to the intervention reported greater value of research for understanding issues than the control group following implementation. More research use was also observed in legislation introduced by the intervention group. Further, we found that researchers randomized to the intervention advanced their own policy knowledge and engagement as well as reported benefits for their research following implementation

Estimates of nuclear DNA content in 98 species of brown algae (Phaeophyta)

Despite the fact that brown algae are critical components of marine ecosystems around the world only one species has had its genome sequenced. To facilitate genome studies in the class we report data for 12 of the 19 recognized orders

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p