Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study.

One to two percent of couples suffer recurrent pregnancy loss and over 50% of the cases are unexplained. Whole genome sequencing (WGS) analysis has the potential to identify previously unrecognized causes of pregnancy loss, but few studies have been performed, and none have included DNA from families including parents, losses, and live births. We conducted a pilot WGS study in three families with unexplained recurrent pregnancy loss, including parents, healthy live births, and losses, which included an embryonic loss (<10 weeks' gestation), fetal deaths (10-20 weeks' gestation) and stillbirths (≥ 20 weeks' gestation). We used the Illumina platform for WGS and state-of-the-art protocols to identify single nucleotide variants (SNVs) following various modes of inheritance. We identified 87 SNVs involving 75 genes in embryonic loss (n = 1), 370 SNVs involving 228 genes in fetal death (n = 3), and 122 SNVs involving 122 genes in stillbirth (n = 2). Of these, 22 de novo, 6 inherited autosomal dominant and an X-linked recessive SNVs were pathogenic (probability of being loss-of-function intolerant >0.9), impacting known genes (e.g., DICER1, FBN2, FLT4, HERC1, and TAOK1) involved in embryonic/fetal development and congenital abnormalities. Further, we identified inherited missense compound heterozygous SNVs impacting genes (e.g., VWA5B2) in two fetal death samples. The variants were not identified as compound heterozygous SNVs in live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. In this pilot study, we provide evidence for de novo and inherited SNVs relevant to pregnancy loss. Our findings provide justification for conducting WGS using larger numbers of families and warrant validation by targeted sequencing to ascertain causal variants. Elucidating genes causing pregnancy loss may facilitate the development of risk stratification strategies and novel therapeutics.

Hot Isostatic Pressing for Fatigue Critical Additively Manufactured Ti-6Al-4V.

The efficacy of hot isostatic pressing (HIP) for enhancing fatigue performance is investigated for additively manufactured (AM) Ti-6Al-4V. The limitations of HIP are probed by varying the initial material state via the selection of AM system, powder chemical composition, and process parameters. We demonstrate that the fatigue performance of HIP'd AM Ti-6Al-4V depends on the as-built quality of the material. Differences in common material attributes, such as pre-HIP defect populations or post-HIP microstructure morphology, are shown to be insufficient to explain the observed discrepancies in performance. This implies that additional microstructure attributes or localized deviations from the expected structure control the failure of this material. Finally, HIP parameters outside ASTM recommendations were explored, where a reduced temperature and high-pressure treatment yielded significantly improved fatigue performance.

Atomic mechanism of near threshold fatigue crack growth in vacuum.

Structural failures resulting from prolonged low-amplitude loading are particularly problematic. Over the past century a succession of mechanisms have been hypothesized, as experimental validation has remained out of reach. Here we show by atomistic modeling that sustained fatigue crack growth in vacuum requires emitted dislocations to change slip planes prior to their reabsorption into the crack on the opposite side of the loading cycle. By harnessing a new implementation of a concurrent multiscale method we (1) assess the validity of long-hypothesized material separation mechanisms thought to control near-threshold fatigue crack growth in vacuum, and (2) reconcile reports of crack growth in atomistic simulations at loading amplitudes below experimental crack growth thresholds. Our results provide a mechanistic foundation to relate fatigue crack growth tendency to fundamental material properties, e.g. stacking fault energies and elastic moduli, opening the door for improved prognosis and the design of novel fatigue resistance alloys.

Dissolution at a Ductile Crack Tip.

The growth of cracks can be substantially influenced by the environment. Atomic modeling provides a means to isolate the action of individual mechanisms involved in such complex processes. Here, we utilize a newly implemented multiscale modeling approach to assess the role of material dissolution on long crack growth in a ductile material. While we find dissolution to be capable of freeing arrested fatigue cracks, the crack tip is always blunted under both static and cyclic loading, suggesting that dissolution has an overall crack arresting effect. Despite observations of plasticity-induced-dissolution and dissolution-induced-plasticity that are consistent with macroscale experiments, dissolution-induced-blunting is found to be independent of mechanical loading magnitude. This will simplify implementation of the dissolution-induced-blunting process into continuum crack growth models.

Performance assessment of DNA sequencing platforms in the ABRF Next-Generation Sequencing Study.

Assessing the reproducibility, accuracy and utility of massively parallel DNA sequencing platforms remains an ongoing challenge. Here the Association of Biomolecular Resource Facilities (ABRF) Next-Generation Sequencing Study benchmarks the performance of a set of sequencing instruments (HiSeq/NovaSeq/paired-end 2 × 250-bp chemistry, Ion S5/Proton, PacBio circular consensus sequencing (CCS), Oxford Nanopore Technologies PromethION/MinION, BGISEQ-500/MGISEQ-2000 and GS111) on human and bacterial reference DNA samples. Among short-read instruments, HiSeq 4000 and X10 provided the most consistent, highest genome coverage, while BGI/MGISEQ provided the lowest sequencing error rates. The long-read instrument PacBio CCS had the highest reference-based mapping rate and lowest non-mapping rate. The two long-read platforms PacBio CCS and PromethION/MinION showed the best sequence mapping in repeat-rich areas and across homopolymers. NovaSeq 6000 using 2 × 250-bp read chemistry was the most robust instrument for capturing known insertion/deletion events. This study serves as a benchmark for current genomics technologies, as well as a resource to inform experimental design and next-generation sequencing variant calling.

Characteristic and variability of five complete aphid mitochondrial genomes: Aphis fabae mordvilkoi, Aphis craccivora, Myzus persicae, Therioaphis tenera and Appendiseta robiniae (Hemiptera; Sternorrhyncha; Aphididae).

The complete mitochondrial genomes of aphids Aphis fabae mordvilkoi, A. craccivora, Myzus persicae from Aphidinae as well as Therioaphis tenera and Appendiseta robiniae from Calaphidinae were sequenced and compared with the genomes of other aphid species. A. fabae mordvilkoi, Th. tenera and A. robiniae mitogenomes were sequenced and analyzed for the first time. The annotation of A. craccivora and M. persicae were corrected compared to what was previously published. According to our data there is no translocation of tRNA-Tyr gene in A. craccivora mitogenome and this aphid species has an ancestral type of mitochondrial gene order. A + T content in all 5 mitogenomes was higher than 80%. A + T content in the Th. tenera CR was 59.5% which is untypically low. CRs of all 5 studied mitogenomes had 2 conserved motifs at their ends and extended G + C rich region. A. craccivora, M. persicae and Th. tenera had large tandem repeats inside the CRs. Detailed molecular analysis of all 5 aphid mitochondrial genomes showed the importance of a deep understanding of the molecular organization of all the functional regions of the mitochondrial DNA, which helps to avoid mistakes during genome annotation.

Assessment of Additive Manufacturing for Increasing Sustainability and Productivity of Smallholder Agriculture.

The System of Rice Intensification (SRI) seeks to increase both the sustainability and the productivity of smallholder rice farms, but the adoption of this methodology is constrained by local access to appropriate mechanical equipment. Valuable information about real difficulties in the adoption of SRI was collected through communications with five field partners. Two primary mechanization obstacles were identified, that is, the availability and performance of a roller component on a push seeder and a rotor component on a push weeder. The potential of additive manufacturing (AM), and especially material extrusion three-dimensional (3D) printing (ME3DP), to assist in overcoming the identified obstacles was assessed for two cases while considering both local prototyping and low-volume production. A simplified cost model was used to compare with the cost of manufacturing both in the United States and locally in the field. The acquired data suggests that in specific cases current ME3DP technology can more rapidly provide functional parts, accelerating the design cycle and lowering cost by about a factor of 10 relative to local fabrication routes. In the case where mechanical performance is critical and dimensional precision and surface finish are not, wire arc metal AM appears promising, but it is not as economical as fabrication by traditional means in the field.

On the debris-level origins of adhesive wear.

Every contacting surface inevitably experiences wear. Predicting the exact amount of material loss due to wear relies on empirical data and cannot be obtained from any physical model. Here, we analyze and quantify wear at the most fundamental level, i.e., wear debris particles. Our simulations show that the asperity junction size dictates the debris volume, revealing the origins of the long-standing hypothesized correlation between the wear volume and the real contact area. No correlation, however, is found between the debris volume and the normal applied force at the debris level. Alternatively, we show that the junction size controls the tangential force and sliding distance such that their product, i.e., the tangential work, is always proportional to the debris volume, with a proportionality constant of 1 over the junction shear strength. This study provides an estimation of the debris volume without any empirical factor, resulting in a wear coefficient of unity at the debris level. Discrepant microscopic and macroscopic wear observations and models are then contextualized on the basis of this understanding. This finding offers a way to characterize the wear volume in atomistic simulations and atomic force microscope wear experiments. It also provides a fundamental basis for predicting the wear coefficient for sliding rough contacts, given the statistics of junction clusters sizes.

Critical length scale controls adhesive wear mechanisms.

The adhesive wear process remains one of the least understood areas of mechanics. While it has long been established that adhesive wear is a direct result of contacting surface asperities, an agreed upon understanding of how contacting asperities lead to wear debris particle has remained elusive. This has restricted adhesive wear prediction to empirical models with limited transferability. Here we show that discrepant observations and predictions of two distinct adhesive wear mechanisms can be reconciled into a unified framework. Using atomistic simulations with model interatomic potentials, we reveal a transition in the asperity wear mechanism when contact junctions fall below a critical length scale. A simple analytic model is formulated to predict the transition in both the simulation results and experiments. This new understanding may help expand use of computer modelling to explore adhesive wear processes and to advance physics-based wear laws without empirical coefficients.

Two contemporaneous mitogenomes from terminal Pleistocene burials in eastern Beringia.

Pleistocene residential sites with multiple contemporaneous human burials are extremely rare in the Americas. We report mitochondrial genomic variation in the first multiple mitochondrial genomes from a single prehistoric population: two infant burials (USR1 and USR2) from a common interment at the Upward Sun River Site in central Alaska dating to ∼11,500 cal B.P. Using a targeted capture method and next-generation sequencing, we determined that the USR1 infant possessed variants that define mitochondrial lineage C1b, whereas the USR2 genome falls at the root of lineage B2, allowing us to refine younger coalescence age estimates for these two clades. C1b and B2 are rare to absent in modern populations of northern North America. Documentation of these lineages at this location in the Late Pleistocene provides evidence for the extent of mitochondrial diversity in early Beringian populations, which supports the expectations of the Beringian Standstill Model.