Design of an Adaptable Tooling System for Part to Part Variation Processing

Today’s automotive manufacturing facilities use different robotic systems with the specifically designed end of arm tooling (EOAT). Regardless of how accurate these robotic systems may be, they are programmed to repeat the same task and move to the same position repeatedly. As convenient as this process may be, it does not allow robots to automatically readjust to different part variations without the human assistance. This situation is especially noticeable in the plastics manufacturing industry, e.g., fuel tank welding. This thesis describes the systematic design methodology of an adaptable tooling system for a part to part variations processing aimed at automotive plastic fuel tank manufacturing. By combining a 3D vision system with a PLC, and a Fanuc R-2000iB/165F 6 axis robot, the system provides the robot with the ability to automatically readjust the processing unit to different part variations. The design approach specifies programming and device correlation by using Siemens S7, Fanuc TP, and SICK AG software. A case study using a fuel tank sample was developed to check the system for functionality and performance. Results of the study indicate that the system is accurate within ±0.25 mm, which is well suited for fuel tank manufacturing. The study signifies a new approach to vision guided robotics (VGR). It utilizes existing equipment for applications where part variation may be present. Three patent applications were published during the course of this research. They each cover plastic fuel tank welding applications

Intrauterine programming of obesity and type 2 diabetes

Abstract: The type 2 diabetes epidemic and one of its predisposing factors, obesity, are major influences on global health and economic burden. It is accepted that genetics and the current environment contribute to this epidemic; however, in the last two decades, both human and animal studies have consolidated considerable evidence supporting the ‘developmental programming’ of these conditions, specifically by the intrauterine environment. Here, we review the various in utero exposures that are linked to offspring obesity and diabetes in later life, including epidemiological insights gained from natural historical events, such as the Dutch Hunger Winter, the Chinese famine and the more recent Quebec Ice Storm. We also describe the effects of gestational exposure to endocrine disruptors, maternal infection and smoking to the fetus in relation to metabolic programming. Causal evidence from animal studies, motivated by human observations, is also discussed, as well as some of the proposed underlying molecular mechanisms for developmental programming of obesity and type 2 diabetes, including epigenetics (e.g. DNA methylation and histone modifications) and microRNA interactions. Finally, we examine the effects of non-pharmacological interventions, such as improving maternal dietary habits and/or increasing physical activity, on the offspring epigenome and metabolic outcomes

Mitigating Load Imbalance in Distributed Data Serving with Rack-Scale Memory Pooling

To provide low-latency and high-throughput guarantees, most large key-value stores keep the data in the memory of many servers. Despite the natural parallelism across lookups, the load imbalance, introduced by heavy skew in the popularity distribution of keys, limits performance. To avoid violating tail latency service-level objectives, systems tend to keep server utilization low and organize the data in micro-shards, which provides units of migration and replication for the purpose of load balancing. These techniques reduce the skew but incur additional monitoring, data replication, and consistency maintenance overheads. In this work, we introduce RackOut, a memory pooling technique that leverages the one-sided remote read primitive of emerging rack-scale systems to mitigate load imbalance while respecting service-level objectives. In RackOut, the data are aggregated at rack-scale granularity, with all of the participating servers in the rack jointly servicing all of the rack’s micro-shards. We develop a queuing model to evaluate the impact of RackOut at the datacenter scale. In addition, we implement a RackOut proof-of-concept key value store, evaluate it on two experimental platforms based on RDMA and Scale-Out NUMA, and use these results to validate the model. We devise two distinct approaches to load balancing within a RackOut unit, one based on random selection of nodes—RackOut_static—and another one based on an adaptive load balancing mechanism— RackOut_adaptive. Our results show that RackOut_static increases throughput by up to 6× for RDMA and 8.6× for Scale-Out NUMA compared to a scale-out deployment, while respecting tight tail latency service-level objectives. RackOut_adaptive improves the throughput by 30% for workloads with 20% of writes over RackOut_static

An Analysis of Load Imbalance in Scale-out Data Serving

Despite the natural parallelism across lookups, performance of distributed key-value stores is often limited due to load imbalance induced by heavy skew in the popularity distribution of the dataset. To avoid violating service level objectives expressed in terms of tail latency, systems tend to keep server utilization low and organize the data in micro-shards, which in turn provides units of migration and replication for the purpose of load balancing. These techniques reduce the skew, but incur additional monitoring, data replication and consistency maintenance overheads. This work shows that the trend towards extreme scale-out will further exacerbate the skew-induced load imbalance, and hence the overhead of migration and replication

SABRes: Atomic Object Reads for In-Memory Rack-Scale Computing

Modern in-memory services rely on large distributed object stores to achieve the high scalability essential to service thousands of requests concurrently. The independent and unpredictable nature of incoming requests results in random accesses to the object store, triggering frequent remote memory accesses. State-of-the-art distributed memory frameworks leverage the one-sided operations offered by RDMA technology to mitigate the traditionally high cost of remote memory access. Unfortunately, the limited semantics of RDMA one-sided operations bound remote memory access atomicity to a single cache block; therefore, atomic remote object access relies on software mechanisms. Emerging highly integrated rack-scale systems that reduce the latency of one-sided operations to a small multiple of DRAM latency expose the overhead of these software mechanisms as a major latency contributor. This technology-triggered paradigm shift calls for new one-sided operations with stronger semantics. We take a step in that direction by proposing SABRes, a new one-sided operation that provides atomic remote object reads in hardware. We then present LightSABRes, a lightweight hardware accelerator for SABRes that removes all atomicity-associated software overheads. Compared to a state-of-the-art software atomicity mechanism, LightSABRes improve the throughput of a microbenchmark atomically accessing 128B-8KB objects from remote memory by 15-97%, and the throughput of a modern in-memory distributed object store by 30-60%

Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts

STUDY QUESTION: Is cord blood DNA methylation associated with having been conceived by medically assisted reproduction? SUMMARY ANSWER: This study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation. WHAT IS KNOWN ALREADY: Medically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes. STUDY DESIGN, SIZE, DURATION: We investigated the association of DNA methylation and medically assisted reproduction using a case-control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls). MAIN RESULTS AND THE ROLE OF CHANCE: The ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling. LIMITATIONS, REASONS FOR CAUTIONS: While insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction. WIDER IMPLICATIONS OF THE FINDINGS: Newborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health. STUDY FUNDING/COMPETING INTERESTS(S): This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union's Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A

Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface

Plasma concentrations of biologically active vitamin D (1,25- (OH)2D) are tightly controlled via feedback regulation of renal 1-hydroxylase (CYP27B1; positive) and 24-hydroxylase (CYP24A1; catabolic) enzymes. In pregnancy, this regulation is uncoupled, and 1,25-(OH)2D levels are significantly elevated, suggesting a role in pregnancy progression. Epigenetic regulation of CYP27B1 and CYP24A1 has previously been described in cell and animal models, and despite emerging evidence for a critical role of epigenetics in placentation generally, little is known about the regulation of enzymes modulating vitamin D homeostasis at the fetomaternal interface. In this study, we investigated the methylation status of genes regulating vitamin D bioavailability and activity in the placenta. No methylation of the VDR (vitamin D receptor) and CYP27B1 genes was found in any placental tissues. In contrast, the CYP24A1 gene is methylated in human placenta, purified cytotrophoblasts, and primary and cultured chorionic villus sampling tissue. No methylation was detected in any somatic human tissue tested. Methylation was also evident in marmoset and mouse placental tissue. All three genes were hypermethylated in choriocarcinoma cell lines, highlighting the role of vitaminDderegulation in this cancer. Gene expression analysis confirmed a reduced capacity for CYP24A1 induction with promoter methylation in primary cells and in vitro reporter analysis demonstrated that promoter methylation directly down-regulates basal promoter activity and abolishes vitamin D-mediated feedback activation. This study strongly suggests that epigenetic decoupling of vitamin D feedback catabolism plays an important role in maximizing active vitamin D bioavailability at the fetomaternal interface

Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome

Trained innate immunity, long-lasting epigenetic modulation, and skewed myelopoiesis by heme

Contains fulltext : 239997.pdf (Publisher’s version ) (Open Access

The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?

Background Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother–father–newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian ‘Clinical review of the Health of adults conceived following Assisted Reproductive Technologies’ (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies (‘XWASs’ hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset. Results In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. Conclusions Genes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.publishedVersio