Investigation of the Oven Process in Indirect Metal Laser Sintering

This paper deals with the optimization of Indirect Metal Laser Sintering. Different experimental analyses have proven that the oven process is highly responsible for the part distortion. By means of polished micrograph sections and thermogravimetric and dilatometric investigations, the oven process has been divided into four main steps: polymer removal, solid-state sintering, infiltration and liquid-phase sintering. Further experiments were carried out at higher temperature phases of the oven process, using modified process parameters. The aim of this research is to improve the knowledge about the oven process. In another step, this process will be simulated by means of finite element analysis in order to minimize the part distortion.Mechanical Engineerin

Evolving a DSL implementation

Domain Specific Languages (DSLs) are small languages designed for use in a specific domain. DSLs typically evolve quite radically throughout their lifetime, but current DSL implementation approaches are often clumsy in the face of such evolution. In this paper I present a case study of an DSL evolving in its syntax, semantics, and robustness, implemented in the Converge language. This shows how real-world DSL implementations can evolve along with changing requirements

Four novel candidate causal variants for deficient homozygous haplotypes in Holstein cattle.

Mendelian variants can determine both insemination success and neonatal survival and thus influence fertility and rearing success of cattle. We present 24 deficient homozygous haplotype regions in the Holstein population of Switzerland and provide an overview of the previously identified haplotypes in the global Holstein breed. This study encompasses massive genotyping, whole-genome sequencing (WGS) and phenotype association analyses. We performed haplotype screenings on almost 53 thousand genotyped animals including 114 k SNP data with two different approaches. We revealed significant haplotype associations to several survival, birth and fertility traits. Within haplotype regions, we mined WGS data of hundreds of bovine genomes for candidate causal variants, which were subsequently evaluated by using a custom genotyping array in several thousand breeding animals. With this approach, we confirmed the known deleterious SMC2:p.Phe1135Ser missense variant associated with Holstein haplotype (HH) 3. For two previously reported deficient homozygous haplotypes that show negative associations to female fertility traits, we propose candidate causative loss-of-function variants: the HH13-related KIR2DS1:p.Gln159* nonsense variant and the HH21-related NOTCH3:p.Cys44del deletion. In addition, we propose the RIOX1:p.Ala133_Glu142del deletion as well as the PCDH15:p.Leu867Val missense variant to explain the unexpected low number of homozygous haplotype carriers for HH25 and HH35, respectively. In conclusion, we demonstrate that with mining massive SNP data in combination with WGS data, we can map several haplotype regions and unravel novel recessive protein-changing variants segregating at frequencies of 1 to 5%. Our findings both confirm previously identified loci and expand the spectrum of undesired alleles impairing reproduction success in Holstein cattle, the world's most important dairy breed

Mining massive genomic data of two Swiss Braunvieh cattle populations reveals six novel candidate variants that impair reproductive success

Background: This study was carried out on the two Braunvieh populations reared in Switzerland, the dairy Brown Swiss (BS) and the dual-purpose Original Braunvieh (OB). We performed a genome-wide analysis of array data of trios (sire, dam, and offspring) from the routine genomic selection to identify candidate regions showing missing homozygosity and phenotypic associations with five fertility, ten birth, and nine growth-related traits. In addition, genome-wide single SNP regression studies based on 114,890 single nucleotide polymorphisms (SNPs) for each of the two populations were performed. Furthermore, whole-genome sequencing data of 430 cattle including 70 putative haplotype carriers were mined to identify potential candidate variants that were validated by genotyping the current population using a custom array. Results: Using a trio-based approach, we identified 38 haplotype regions for BS and five for OB that segregated at low to moderate frequencies. For the BS population, we confirmed two known haplotypes, BH1 and BH2. Twenty-four variants that potentially explained the missing homozygosity and associated traits were detected, in addition to the previously reported TUBD1:p.His210Arg variant associated with BH2. For example, for BS we identified a stop-gain variant (p.Arg57*) in the MRPL55 gene in the haplotype region on chromosome 7. This region is associated with the ‘interval between first and last insemination’ trait in our data, and the MRPL55 gene is known to be associated with early pregnancy loss in mice. In addition, we discuss candidate missense variants in the CPT1C, MARS2, and ACSL5 genes for haplotypes mapped in BS. In OB, we highlight a haplotype region on chromosome 19, which is potentially caused by a frameshift variant (p.Lys828fs) in the LIG3 gene, which is reported to be associated with early embryonic lethality in mice. Furthermore, we propose another potential causal missense variant in the TUBGCP5 gene for a haplotype mapped in OB. Conclusions: We describe, for the first time, several haplotype regions that segregate at low to moderate frequencies and provide evidence of causality by trait associations in the two populations of Swiss Braunvieh. We propose a list of six protein-changing variants as potentially causing missing homozygosity. These variants need to be functionally validated and incorporated in the breeding program

Accuracy of 54K to HD gebotype imputation in Brown Swiss cattle

Imputation of genotypes can be used to reduce the implementation costs of genomic selection. In this study, we evaluated the accuracy of genotype imputation from Illumina 54k to Illumina High Density (HD) in Brown Swiss cattle. Genotype data comprised 6,106 54k and 880 HD genotyped bulls and cows of Brown Swiss and Original Braunvieh cattle. Genotype data was checked for parentage conflicts and SNP were excluded if MAF was below 0.5% and SNP call rate was lower than 90%. The final data set included 39,004 SNP for the 54k and 627,306 SNP for the HD chip. HD genotypes of animals born between 2004 and 2008 (n=365) were masked to mimic animals genotyped with the 54k chip. Methods used for imputation were FImpute and Findhap V2. Both programs use pedigree information for imputation. The accuracy of imputation was assessed by the correlation (r) between true and imputed genotypes, the percentage of correctly and incorrectly imputed genotypes. Both programs gave high imputation accuracy with FImpute outperforming Findhap. Accuracy of imputation increased with increasing relationship between the HD genotyped reference population and 54k genotyped imputation candidates. Average r for FImpute and Findhap were 0.992 and 0.988 when both parents of the 54k genotyped candidate were HD genotyped, respectively. Correlations were lower when no direct relatives were HD genotyped (0.971 and 0.918 for FImpute and Findhap, respectively). Accuracy of imputation highly depended on MAF of the imputed SNP. For FImpute, average r ranged between 0.89 (MAF <0.025) and 0.99 (MAF between 0.4 and 0.5)

A de novo variant in the bovine ADAMTSL4 gene in an Original Braunvieh calf with congenital cataract

Inherited forms of cataract are a heterogeneous group of eye disorders known in livestock species. Clinicopathological analysis of a single case of impaired vision in a newborn Original Braunvieh calf revealed nuclear cataract. Whole-genome sequencing of the parent-offspring trio revealed a de novo mutation of ADAMTSL4 in this case. The heterozygous p.Arg776His missense variant affects a conserved residue of the ADAMTSL4 gene that encodes a secreted glycoprotein expressed in the lens throughout embryonic development. In humans, ADAMTSL4 genetic variants cause recessively inherited forms of subluxation of the lens. Given that ADAMTSL4 is a functional candidate gene for inherited disorders of the lens, we suggest that heterozygosity for the identified missense variant may have caused the congenital cataract in the affected calf. Cattle populations should be monitored for unexplained cataract cases, with subsequent DNA sequencing a hypothesized pathogenic effect of heterozygous ADAMTSL4 variants could be confirmed

Is a heterozygous missense variant in SGSH the cause of a syndromic form of congenital amastia in an Original Braunvieh calf?

A 5-days-old female purebred Original Braunvieh female calf was referred owing to a congenital absence of teats and cleft palate. Gross pathology revealed the entire absence of the udder including teats, complete palatoschisis affecting both soft and hard palate, hepatomegaly, corneal opacity and an open vulva (Figure S1). Whole genome sequencing (WGS) was performed using genomic DNA obtained from ear tissue from the calf. Reads were mapped to the ARS-UCD1.2 assembly (Rosen et al., 2020), resulting in an average read depth of 14.7×. The WGS data were evaluated as previously described (Jacinto et al., 2021). Variant filtering did not reveal any private homozygous protein-changing variants present in the genome of the affected calf, making a possible recessive inheritance unlikely. Assuming that a spontaneous mutation affecting a protein-coding gene is the cause, filtering for private heterozygous coding variants present in the calf’s genome allowed the identification of six variants with a predicted moderate or high impact (Table S1). These variants were confirmed as true by visual inspection with the integrative genomes viewer software (Robinson et al., 2017). These variants were absent from a total of 5365 controls and a single variant affects SGSH, a putative candidate gene for the observed congenital anomaly. This heterozygous variant at chr19:52427490C&gt;T represents a missense variant in SGSH exon 4 (NM_001102189.2: c.425C&gt;T) (Figure S2). We suspected that the identified variant in SGSH either occurred post-zygotically in the developing embryo or was inherited from a mosaic parent. Unfortunately, no biological samples were available from the parents. The encoded amino acid of SGSH is predicted to be altered at codon 142 (NP_001095659.2: p.Thr142Met) located in the N-sulphoglucosamine sulphohydrolase domain. The substitution of threonine to methionine affects an amino acid that is highly conserved in all species (Figure S2) and has been predicted to be harmful using three different tools (Provean, −4.729; PhD-SNP, 50%; SIFT, 79%)

MYH3-associated non-syndromic palatoschisis (cleft palate, CP) in Limousine cattle.

We have successfully identified the most likely cause for a rare autosomal recessive disorder with only one case. Our clinicopathologic and genomic findings for the MYH3-related recessively inherited form of non-syndromic cleft palate are consistent with those recently reported by Vaiman et al. (2022) (OMIA002590-9913). Interestingly, the 2-year-old Limousine female in our study appears to be the oldest known animal with MYH3-associated non-syndromic palatoschisis. According to Vaiman et al. (2022), life expectancy is short, with most animals euthanized in the first month of life. In addition, the variant allele frequency was found to be lower in the current Swiss population compared with the French Limousine (2.4%)

WNT10B: A locus increasing risk of brachygnathia inferior in Brown Swiss cattle.

Shortening of the mandible (brachygnathia inferior) is a congenital, often inherited and variably expressed craniofacial anomaly in domestic animals including cattle. Brachygnathia inferior can lead to poorer animal health and welfare and reduced growth, which ultimately affects productivity. Within the course of the systematic conformation scoring, cases with a frequency of about 0.1% were observed in the Brown Swiss cattle population of Switzerland. In contrast, this anomaly is almost unknown in the Original Braunvieh population, representing the breed of origin. Because none of the individually examined 46 living offspring of our study cohort of 145 affected cows showed the trait, we can most likely exclude a monogenic-dominant mode of inheritance. We hypothesized that either a monogenic recessive or a complex mode of inheritance was underlying. Through a genome-wide association study of 145 cases and 509 controls with imputed 624k SNP data, we identified a 4.5 Mb genomic region on bovine chromosome 5 significantly associated with this anomaly. This locus was fine-mapped using whole-genome sequencing data. A run of homozygosity analysis revealed a critical interval of 430 kb. A breed specific frameshift duplication in WNT10B (rs525007739; c.910dupC; p.Arg304ProfsTer14) located in this genomic region was found to be associated with a 21.5-fold increased risk of brachygnathia inferior in homozygous carriers. Consequently, we present for the first time a genetic locus associated with this well-known anomaly in cattle, which allows DNA-based selection of Brown Swiss animals at decreased risk for mandibular shortening. In addition, this study represents the first large animal model of a WNT10B-related inherited developmental disorder in a mammalian species

Associated regions for multiple birth in Brown Swiss and Original Braunvieh cattle on chromosomes 15 and 11.

Twin and multiple births have negative effects on the performance and health of cows and calves. To decipher the genetic architecture of this trait in the two Swiss Brown Swiss cattle populations, we performed various association analyses based on de-regressed breeding values. Genome-wide association analyses were executed using ~600 K imputed SNPs for the maternal multiple birth trait in ~3500 Original Braunvieh and ~7800 Brown Swiss animals. Significantly associated QTL were observed on different chromosomes for both breeds. We have identified on chromosome 11 a QTL that explains ~6% of the total genetic variance of the maternal multiple birth trait in Original Braunvieh. For the Brown Swiss breed, we have discovered a QTL on chromosome 15 that accounts for ~4% of the total genetic variance. For Original Braunvieh, subsequent haplotype analysis revealed a 90-kb window on chromosome 11 at 88 Mb, where a likely regulatory region is located close to the ID2 gene. In Brown Swiss, a 130-kb window at 75 Mb on chromosome 15 was identified. Analysis of whole-genome sequence data using linkage-disequilibrium estimation revealed possible causal variants for the identified QTL. A presumably regulatory variant in the non-coding 5' region of the ID2 gene was strongly associated with the haplotype for Original Braunvieh. In Brown Swiss, an intron variant in PRDM11, one 3' UTR variant in SYT13 and three intergenic variants 5' upstream of SYT13 were identified as candidate variants for the trait multiple birth maternal. In this study, we report for the first time QTL for the trait of multiple births in Original Braunvieh and Brown Swiss cattle. Moreover, our findings are another step towards a better understanding of the complex genetic architecture of this polygenic trait