Observation of a Near-Threshold Proton Resonance in

A near-threshold proton resonance in ^{11}B at E_{ex}=11.44±0.04 MeV is observed via the reaction ^{10}Be(d,n)^{11}Be→^{10}Be+p in inverse kinematics, measured with a beam of the radioactive isotope ^{10}Be. The resonance energy at E_{res}=211(40) keV is consistent with a proton signal observed by Ayyad et al. in the ß-delayed proton decay of ^{11}Be. By comparison to a distorted wave Born approximation calculation, a 0.27(6) spectroscopic factor is extracted and a tentative (ℓ=0) character is assigned for this resonance. The significant cross section in the proton-transfer (d,n) reaction, as well as the observation of its proton-decay signal, point to the threshold-resonance character of this state. The position of this state, its structure, and strong coupling to the s-wave continuum represent an ideal case to study quantum near-threshold many-body dynamics of unstable states. The presence of this state is an important step toward understanding the excessively large beta-delayed proton-decay branch of ^{11}Be.

Measurement of d+

The cross sections of nuclear reactions between the radioisotope ^{7}Be and deuterium, a possible mechanism of reducing the production of mass-7 nuclides in big-bang nucleosynthesis, were measured at center-of-mass energies between 0.2 and 1.5 MeV. The measured cross sections are dominated by the (d,α) reaction channel, towards which prior experiments were mostly insensitive. A new resonance at 0.36(5) MeV with a strength of ωγ=1.7(5) keV was observed inside the relevant Gamow window. Calculations of nucleosynthesis outcomes based on the experimental cross section show that the resonance reduces the predicted abundance of primordial ^{7}Li, but not sufficiently to solve the primordial lithium problem.

Erratum: Measurement of d+

This corrects the article DOI: 10.1103/PhysRevLett.122.182701.

Is the Structure of

A more detailed test of the implementation of nuclear forces that drive shell evolution in the pivotal nucleus ^{42}Si-going beyond earlier comparisons of excited-state energies-is important. The two leading shell-model effective interactions, SDPF-MU and SDPF-U-Si, both of which reproduce the low-lying ^{42}Si(2_{1}^{+}) energy, but whose predictions for other observables differ significantly, are interrogated by the population of states in neutron-rich ^{42}Si with a one-proton removal reaction from ^{43}P projectiles at 81 MeV/nucleon. The measured cross sections to the individual ^{42}Si final states are compared to calculations that combine eikonal reaction dynamics with these shell-model nuclear structure overlaps. The differences in the two shell-model descriptions are examined and linked to predicted low-lying excited 0^{+} states and shape coexistence. Based on the present data, which are in better agreement with the SDPF-MU calculations, the state observed at 2150(13) keV in ^{42}Si is proposed to be the (0_{2}^{+}) level.

Detection and assessment of copy number variation using PacBio long-read and Illumina sequencing in New Zealand dairy cattle.

Single nucleotide polymorphisms have been the DNA variant of choice for genomic prediction, largely because of the ease of single nucleotide polymorphism genotype collection. In contrast, structural variants (SV), which include copy number variants (CNV), translocations, insertions, and inversions, have eluded easy detection and characterization, particularly in nonhuman species. However, evidence increasingly shows that SV not only contribute a substantial proportion of genetic variation but also have significant influence on phenotypes. Here we present the discovery of CNV in a prominent New Zealand dairy bull using long-read PacBio (Pacific Biosciences, Menlo Park, CA) sequencing technology and the Sniffles SV discovery tool (version 0.0.1; https://github.com/fritzsedlazeck/Sniffles). The CNV identified from long reads were compared with CNV discovered in the same bull from Illumina sequencing using CNVnator (read depth-based tool; Illumina Inc., San Diego, CA) as a means of validation. Subsequently, further validation was undertaken using whole-genome Illumina sequencing of 556 cattle representing the wider New Zealand dairy cattle population. Very limited overlap was observed in CNV discovered from the 2 sequencing platforms, in part because of the differences in size of CNV detected. Only a few CNV were therefore able to be validated using this approach. However, the ability to use CNVnator to genotype the 557 cattle for copy number across all regions identified as putative CNV allowed a genome-wide assessment of transmission level of copy number based on pedigree. The more highly transmissible a putative CNV region was observed to be, the more likely the distribution of copy number was multimodal across the 557 sequenced animals. Furthermore, visual assessment of highly transmissible CNV regions provided evidence supporting the presence of CNV across the sequenced animals. This transmission-based approach was able to confirm a subset of CNV that segregates in the New Zealand dairy cattle population. Genome-wide identification and validation of CNV is an important step toward their inclusion in genomic selection strategies.

Exploiting biological priors and sequence variants enhances QTL discovery and genomic prediction of complex traits.

BACKGROUND: Dense SNP genotypes are often combined with complex trait phenotypes to map causal variants, study genetic architecture and provide genomic predictions for individuals with genotypes but no phenotype. A single method of analysis that jointly fits all genotypes in a Bayesian mixture model (BayesR) has been shown to competitively address all 3 purposes simultaneously. However, BayesR and other similar methods ignore prior biological knowledge and assume all genotypes are equally likely to affect the trait. While this assumption is reasonable for SNP array genotypes, it is less sensible if genotypes are whole-genome sequence variants which should include causal variants. RESULTS: We introduce a new method (BayesRC) based on BayesR that incorporates prior biological information in the analysis by defining classes of variants likely to be enriched for causal mutations. The information can be derived from a range of sources, including variant annotation, candidate gene lists and known causal variants. This information is then incorporated objectively in the analysis based on evidence of enrichment in the data. We demonstrate the increased power of BayesRC compared to BayesR using real dairy cattle genotypes with simulated phenotypes. The genotypes were imputed whole-genome sequence variants in coding regions combined with dense SNP markers. BayesRC increased the power to detect causal variants and increased the accuracy of genomic prediction. The relative improvement for genomic prediction was most apparent in validation populations that were not closely related to the reference population. We also applied BayesRC to real milk production phenotypes in dairy cattle using independent biological priors from gene expression analyses. Although current biological knowledge of which genes and variants affect milk production is still very incomplete, our results suggest that the new BayesRC method was equal to or more powerful than BayesR for detecting candidate causal variants and for genomic prediction of milk traits. CONCLUSIONS: BayesRC provides a novel and flexible approach to simultaneously improving the accuracy of QTL discovery and genomic prediction by taking advantage of prior biological knowledge. Approaches such as BayesRC will become increasing useful as biological knowledge accumulates regarding functional regions of the genome for a range of traits and species.

Leveraging genetically simple traits to identify small-effect variants for complex phenotypes.

BACKGROUND: Polymorphisms underlying complex traits often explain a small part (less than 1 %) of the phenotypic variance (σ2P). This makes identification of mutations underling complex traits difficult and usually only a subset of large-effect loci are identified. One approach to identify more loci is to increase sample size of experiments but here we propose an alternative. The aim of this paper is to use secondary phenotypes for genetically simple traits during the QTL discovery phase for complex traits. We demonstrate this approach in a dairy cattle data set where the complex traits were milk production phenotypes (fat, milk and protein yield; fat and protein percentage in milk) measured on thousands of individuals while secondary (potentially genetically simpler) traits are detailed milk composition traits (measurements of individual protein abundance, mineral and sugar concentrations; and gene expression). RESULTS: Quantitative trait loci (QTL) were identified using 11,527 Holstein cattle with milk production records and up to 444 cows with milk composition traits. There were eight regions that contained QTL for both milk production and a composition trait, including four novel regions. One region on BTAU1 affected both milk yield and phosphorous concentration in milk. The QTL interval included the gene SLC37A1, a phosphorous antiporter. The most significant imputed sequence variants in this region explained 0.001 σ2P for milk yield, and 0.11 σ2P for phosphorus concentration. Since the polymorphisms were non-coding, association mapping for SLC37A1 gene expression was performed using high depth mammary RNAseq data from a separate group of 371 lactating cows. This confirmed a strong eQTL for SLC37A1, with peak association at the same imputed sequence variants that were most significant for phosphorus concentration. Fitting any of these variants as covariables in the association analysis removed the QTL signal for milk production traits. Plausible causative mutations in the casein complex region were also identified using a similar strategy. CONCLUSIONS: Milk production traits in dairy cows are typical complex traits where polymorphisms explain only a small portion of the phenotypic variance. However, here we show that these mutations can have larger effects on secondary traits, such as concentrations of minerals, proteins and sugars in the milk, and expression levels of genes in mammary tissue. These larger effects were used to successfully map variants for milk production traits. Genetically simple traits also provide a direct biological link between possible causal mutations and the effect of these mutations on milk production.

Genetics of complex traits: prediction of phenotype, identification of causal polymorphisms and genetic architecture.

Complex or quantitative traits are important in medicine, agriculture and evolution, yet, until recently, few of the polymorphisms that cause variation in these traits were known. Genome-wide association studies (GWAS), based on the ability to assay thousands of single nucleotide polymorphisms (SNPs), have revolutionized our understanding of the genetics of complex traits. We advocate the analysis of GWAS data by a statistical method that fits all SNP effects simultaneously, assuming that these effects are drawn from a prior distribution. We illustrate how this method can be used to predict future phenotypes, to map and identify the causal mutations, and to study the genetic architecture of complex traits. The genetic architecture of complex traits is even more complex than previously thought: in almost every trait studied there are thousands of polymorphisms that explain genetic variation. Methods of predicting future phenotypes, collectively known as genomic selection or genomic prediction, have been widely adopted in livestock and crop breeding, leading to increased rates of genetic improvement.

Constraining the 6.05 MeV 0+ and 6.13 MeV 3- cascade transitions in the 12C(α,γ)16O reaction using the asymptotic normalization coefficients.

The 12C(α,γ)^16O reaction plays a fundamental role in astrophysics and needs to be known with accuracy better than 10%. Cascade γ transitions through the excited states of 16 O are contributing to the uncertainty. We constrained the contribution of the 0+ (6.05 MeV) and 3- (6.13 MeV) cascade transitions by measuring the asymptotic normalization coefficients for these states using the α-transfer reaction 6 Li(12C,d)^16O at sub-Coulomb energy. The contribution of the 0+ and 3- cascade transitions at 300 keV is found to be 1.96 ± 0.3 and 0.12 ± 0.04 keV b for destructive interference of the direct and resonance capture and 4.36 ± 0.45 and 1.44 ± 0.12 keV b for constructive interference, respectively. The combined contribution of the 0+ and 3- cascade transitions to the 12C(α,γ)16O reaction cross section at 300 keV does not exceed 4%. Significant uncertainties have been dramatically reduced.

How old are quantitative trait loci and how widely do they segregate?

The mutations that cause genetic variation in quantitative traits could be old and segregate across many breeds or they could be young and segregate only within one breed. This has implications for our understanding of the evolution of quantitative traits and for genomic prediction to improve livestock. We investigated the age of quantitative trait loci (QTL) for milk production traits identified as segregating in Holstein dairy cattle. We use a multitrait method and found that six of 11 QTL also segregate in Jerseys. Variants identified as Holstein-only QTL were fixed or rare [minor allele frequency (MAF) < 0.05] in Jersey. The age of the QTL mutations appears to vary from perhaps 2000 to 50,000 generations old. The older QTL tend to have high derived allele frequencies and often segregate across both breeds. Holstein-only QTL were often embedded within longer haplotypes, supporting the conclusion that they are typically younger mutations that have occurred more recently than QTL that segregate in both breeds. A reference population for genomic prediction using both Holsteins and Jersey cattle incorrectly predicted a QTL in Jersey cattle when the QTL only segregates in Holsteins. Overcoming this error should help to make genomic prediction more accurate in smaller breeds.

Evidence for pleiotropism and recent selection in the PLAG1 region in Australian Beef cattle.

A putative functional mutation (rs109231213) near PLAG1 (BTA14) associated with stature was studied in beef cattle. Data from 8199 Bos taurus, Bos indicus and Tropical Composite cattle were used to test the associations between rs109231213 and various phenotypes. Further, 23 496 SNPs located on BTA14 were tested for association with these phenotypes, both independently and fitted together with rs109231213. The C allele of rs109231213 significantly increased hip height, weight, net food intake, age at puberty in males and females and decreased IGF-I concentration in blood and fat depth. When rs109231213 was fitted as a fixed effect in the model, there was an overall reduction in associations between other SNPs and these traits but some SNPs remained associated (P < 10(-4) ). Frequency of the mutant C allele of rs109231213 differed among B. indicus (0.52), B. taurus (0.96) and Tropical Composite (0.68). Most chromosomes carrying the C allele had the same surrounding 10 SNP haplotype, probably because the C allele was introgressed into Brahman from B. taurus cattle. A region of reduced heterozygosity surrounds the C allele; this is small in B. taurus but 20 Mb long in Brahmans, indicating recent and strong selection for the mutant allele. Thus, the C allele appears to mark a mutation that has been selected almost to fixation in the B. taurus breeds studied here and introduced into Brahman cattle during grading up and selected to a frequency of 0.52 despite its negative effects on fertility.

Long-term selection strategies for complex traits using high-density genetic markers.

Selection of animals for breeding ranked on estimated breeding value maximizes genetic gain in the next generation but does not necessarily maximize long-term response. An alternative method, as practiced by plant breeders, is to build a desired genotype by selection on specific loci. Maximal long-term response in animal breeding requires selection on estimated breeding values with constraints on coancestry. In this paper, we compared long-term genetic response using either a genotype building or a genomic estimated breeding value (GEBV) strategy for the Australian Selection Index (ASI), a measure of profit. First, we used real marker effects from the Australian Dairy Herd Improvement Scheme to estimate breeding values for chromosome segments (approximately 25 cM long) for 2,650 Holstein bulls. Second, we selected 16 animals to be founders for a simulated breeding program where, between them, founders contain the best possible combination of 2 segments from 2 animals at each position in the genome. Third, we mated founder animals and their descendants over 30 generations with 2 breeding objectives: (1) to create a population with the "ideal genotype," where the best 2 segments from the founders segregate at each position, or (2) obtain the highest possible response in ASI with coancestry lower than that achieved under breeding objective 1. Results show that genotype building achieved the ideal genotype for breeding objective 1 and obtained a large gain in ASI over the current population (+A$864.99). However, selection on overall GEBV had greater short-term response and almost as much long-term gain (+A$820.42). When coancestry was lowered under breeding objective 2, selection on overall GEBV achieved a higher response in ASI than the genotype building strategy. Selection on overall GEBV seems more flexible in its selection decisions and was therefore better able to precisely control coancestry while maximizing ASI. We conclude that selection on overall GEBV while minimizing average coancestry is the more practical strategy for dairy cattle where selection is for highly polygenic traits, the reproductive rate is relatively low, and there is low tolerance of coancestry. The outcome may be different for traits controlled by few loci of relatively large effects or for different species. In contrast to other simulations, our results indicate that response to selection on overall GEBV may continue for several generations. This is because long-term genetic change in complex traits requires favorable changes to allele frequencies for many loci located throughout the genome.

'Magic' nucleus 42Si.

Nuclear shell structures--the distribution of the quantum states of individual protons and neutrons--provide one of our most important guides for understanding the stability of atomic nuclei. Nuclei with 'magic numbers' of protons and/or neutrons (corresponding to closed shells of strongly bound nucleons) are particularly stable. Whether the major shell closures and magic numbers change in very neutron-rich nuclei (potentially causing shape deformations) is a fundamental, and at present open, question. A unique opportunity to study these shell effects is offered by the 42Si nucleus, which has 28 neutrons--a magic number in stable nuclei--and 14 protons. This nucleus has a 12-neutron excess over the heaviest stable silicon nuclide, and has only one neutron fewer than the heaviest silicon nuclide observed so far. Here we report measurements of 42Si and two neighbouring nuclei using a technique involving one- and two-nucleon knockout from beams of exotic nuclei. We present strong evidence for a well-developed proton subshell closure at Z = 14 (14 protons), the near degeneracy of two different (s(1/2) and d(3/2)) proton orbits in the vicinity of 42Si, and a nearly spherical shape for 42Si.

Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity.

Colon carcinoma is one of the leading causes of death from cancer and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, it was reported that a population of undifferentiated cells from a primary tumor, so-called cancer stem cells (CSC), can reconstitute the original tumor on xenotransplantation. Here, we show that spheroid cultures of these colon CSCs contain expression of CD133, CD166, CD44, CD29, CD24, Lgr5, and nuclear beta-catenin, which have all been suggested to mark the (cancer) stem cell population. More importantly, by using these spheroid cultures or freshly isolated tumor cells from multiple colon carcinomas, we now provide compelling evidence to indicate that the capacity to propagate a tumor with all differentiated progeny resides in a single CSC. Single-cell-cloned CSCs can form an adenocarcinoma on xenotransplantation but do not generate the stroma within these tumors. Moreover, they can self-renew and are capable of multilineage differentiation. Further analysis indicated that the lineage decision is dictated by phosphoinositide 3-kinase (PI3K) signaling in CSCs. These data support the hypothesis that tumor hierarchy can be traced back to a single CSC that contains multilineage differentiation capacity, and provides clues to the regulation of differentiation in colon cancers in vivo.

Cancer stem cells--old concepts, new insights.

Cancer has long been viewed as an exclusively genetic disorder. The model of carcinogenesis, postulated by Nowell and Vogelstein, describes the formation of a tumor by the sequential accumulation of mutations in oncogenes and tumor suppressor genes. In this model, tumors are thought to consist of a heterogeneous population of cells that continue to acquire new mutations, resulting in a highly dynamic process, with clones that out compete others due to increased proliferative or survival capacity. However, novel insights in cancer stem cell research suggest another layer of complexity in the process of malignant transformation and preservation. It has been reported that only a small fraction of the cancer cells in a malignancy have the capacity to propagate the tumor upon transplantation into immuno-compromised mice. Those cells are termed 'cancer stem cells' (CSC) and can be selected based on the expression of cell surface markers associated with immature cell types. In this review, we will critically discuss these novel insights in CSC-related research. Where possible we integrate these results within the genetic model of cancer and illustrate that the CSC model can be considered an extension of the classic genetic model rather than a contradictory theory. Finally, we discuss some of the most controversial issues in this field.

Depressive disorders in relatives of anorexia nervosa patients with and without a current episode of nonbipolar major depression.

The first-degree relatives of anorexia nervosa patients with current nonbipolar major depression had a higher rate of depression than the relatives of anorexic patients without current depression, whose rate was similar to that for relatives of normal control subjects.

Anorexia nervosa and affective disorders: a controlled family history study.

Analysis of family history information from a prospectively studied group of 40 young female patients with anorexia nervosa and 23 normal control female subjects of similar age showed more depression and substance use disorders in first- and second-degree relatives of anorexia nervosa patients. Further, the pedigrees of the patients differed significantly from those of the control subjects in the higher frequency of depression and substance use disorders in consecutive generations and in the family "loading" of these disorders. These findings, consistent with previous reports, add to the growing evidence of an association between anorexia nervosa and familial risk for affective and related disorders.

Self-administered questionnaire for structured psychosocial screening in pediatrics.

Screening for psychosocial risk factors has been limited by lack of a structured approach. The purpose of this study was to assess the utility of a self-administered questionnaire compared with routine history as recorded in the medical record in screening for risk factors for dysfunctional parenting in an urban pediatric clinic. English-speaking parents were offered questionnaires in the waiting room. In addition to routine demographic and medical questions, the questionnaires contained standard screening instruments for substance abuse, depression, self-esteem, and social support, as well as questions about domestic violence, homelessness, and parental history of abuse as a child. Medical records were reviewed separately. Of the 114 mothers who returned questionnaires, the response rate for sensitive questions such as income was greater than or equal to 85%. Compared with the medical record, the questionnaire identified significantly more mothers with possible substance abuse, depression, low self-esteem, and/or history of abuse as a child (P less than .01 for each). Compared with what is usually recorded in the medical record, self-administered questionnaires yield substantial additional information regarding psychosocial risk factors for dysfunctional parenting. Such questionnaires should be considered for routine psychosocial screening in clinics serving high-risk populations.

Parents in jail.

OBJECTIVE: To determine the number of children in the United States with parents incarcerated in jail and to describe the characteristics of these parents and their criminal histories. SETTING: Inmates of local jails accounting for 36.5% of the incarcerated population of the US in 1989. PARTICIPANTS: Personal interviews with 5675 inmates randomly selected from 393,553 inmates of 3312 local jails in 1989. RESULTS: 44,263 (36%) inmates had children younger than the age of 15. Fathers outnumbered mothers 10-fold; the majority were in their 20s or 30s, unmarried, and poorly educated. The vast majority of parents had a record of prior offenses, and substance abuse accounted for one third of the incarcerations. Substance abuse was reported by 84% of inmates and 95% had sought prior treatment for alcohol, drug, or other mental health problems. CONCLUSIONS: Nearly 1 of 50 children in the US has a parent in jail. Parental imprisonment is not rare, is often chronic, and is strongly associated with other psychosocial and health problems in the family. Screening for parental imprisonment potentially should be included as part of a comprehensive biopsychosocial assessment.

Jaundice, terminating breast-feeding, and the vulnerable child.

Jaundice is the most commonly treated condition of otherwise well newborns. Although recommended treatments are thought to be safe and effective, the impact of jaundice and therapy on maternal attitudes and behavior is unknown. It was hypothesized that, in contrast to comparison mothers, mothers of jaundiced infants would be more likely to stop breast-feeding in the first month of life, have more separation difficulties with their infant, and be greater users of health care. Both groups of mothers were surveyed in the hospital and 1 month after discharge. Mothers were eligible if their infants were born at Yale-New Haven Hospital after February 1987 and were in the regular nursery. Jaundiced infants had a total serum bilirubin concentration greater than or equal to 205 mmol/L (12 mg/dL); control infants were not jaundiced. Of those who agreed to participate, 84% (85/101) of mothers of jaundiced infants and 80% (124/155) of control mothers completed the 1-month questionnaire. There were no substantial differences between the control and jaundiced groups, respectively, with regard to maternal age (29.1 years vs 29 years) education (66% vs 60% some college), or race (86% vs 82% white). Breast-feeding was more common in the jaundiced group (61% vs 79%, P less than .05). By 1 month, more mothers of jaundiced infants had completely stopped breast-feeding (19% vs 42%, P less than .01). They were more likely to have never left the baby with anyone else (including the father) or left the baby at most one time for less than 1 hour (15% vs 31%, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)