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Association mapping is a powerful tool for the identification of quantitative trait loci through the exploitation of the differential decay of linkage disequilibrium (LD) between marker loci and genes of interest in natural and domesticated populations. Using a sample of 230 tetraploid wheat lines (Triticum turgidum ssp), which included naked and hulled accessions, we analysed the pattern of LD considering 26 simple sequence repeats and 970 mostly mapped diversity array technology loci. In addition, to validate the potential for association mapping in durum wheat, we evaluated the same genotypes for plant height, heading date, protein content, and thousand-kernel weight. Molecular and phenotypic data were used to: (i) investigate the genetic and phenotypic diversity; (ii) study the dynamics of LD across the durum wheat genome, by investigating the patterns of LD decay; and (iii) test the potential of our panel to identify marker–trait associations through the analysis of four quantitative traits of major agronomic importance. Moreover, we compared and validated the association mapping results with outlier detection analysis based on population divergence. Overall, in tetraploid wheat, the pattern of LD is extremely population dependent and is related to the domestication and breeding history of durum wheat. Comparing our data with several other studies in wheat, we confirm the position of many major genes and quantitative trait loci for the traits considered. Finally, the analysis of the selection signature represents a very useful complement to validate marker–trait associations. [ABSTRACT FROM AUTHOR]

Levels of genetic diversity and population genetic structure of a collection of 230 accessions of seven tetraploid Triticum turgidum L. subspecies were investigated using six morphological, nine seed storage protein loci, 26 SSRs and 970 DArT markers. The genetic diversity of the morphological traits and seed storage proteins was always lower in the durum wheat compared to the wild and domesticated emmer. Using Bayesian clustering (K = 2), both of the sets of molecular markers distinguished the durum wheat cultivars from the other tetraploid subspecies, and two distinct subgroups were detected within the durum wheat subspecies, which is in agreement with their origin and year of release. The genetic diversity of morphological traits and seed storage proteins was always lower in the improved durum cultivars registered after 1990, than in the intermediate and older ones. This marked effect on diversity was not observed for molecular markers, where there was only a weak reduction. At K >2, the SSR markers showed a greater degree of resolution than for DArT, with their identification of a greater number of groups within each subspecies. Analysis of DArT marker differentiation between the wheat subspecies indicated outlier loci that are potentially linked to genes controlling some important agronomic traits. Among the 211 loci identified under selection, 109 markers were recently mapped, and some of these markers were clustered into specific regions on chromosome arms 2BL, 3BS and 4AL, where several genes/quantitative trait loci (QTLs) are involved in the domestication of tetraploid wheats, such as the tenacious glumes (Tg) and brittle rachis (Br) characteristics. On the basis of these results, it can be assumed that the population structure of the tetraploid wheat collection partially reflects the evolutionary history of Triticum turgidum L. subspecies and the genetic potential of landraces and wild accessions for the detection of unexplored alleles. [ABSTRACT FROM AUTHOR]

Trauma complicated by hemorrhagic shock (T/HS) is the leading cause of morbidity and mortality in the United States for individuals under the age of 44 years. Initial survivors are susceptible to developing multiple organ failure (MOF), which is thought to be caused, at least in part, by excessive or maladaptive activation of inflammatory pathways. We previously demonstrated in rodents that T/HS results in liver injury that can be prevented by IL-6 administration at the start of resuscitation; however, the contribution of the severity of HS to the extent of liver injury, whether or not resuscitation is required, and the mechanism(s) for the IL-6 protective effect have not been reported. In the experiments described here, we demonstrated that the extent of liver inflammation induced by T/HS depends on the duration of hypotension and requires resuscitation. We established that IL-6 administration at the start of resuscitation is capable of completely reversing liver inflammation and is associated with increased Stat3 activation. Global assessment of the livers showed that the main effect of IL-6 was to normalize the T/HS-induced inflammation transcriptome. Pharmacological inhibition of Stat3 activity within the liver blocked the ability of IL-6 to prevent liver inflammation and to normalize the T/HS-induced liver inflammation transcriptome. Genetic deletion of a Stat3&bgr;, a naturally occurring, dominant-negative isoform of the Stat3, attenuated T/HSinduced liver inflammation, confirming a role for Stat3, especially Stat3&agr;, in preventing T/HS-mediated liver inflammation. Thus, T/HS-induced liver inflammation depends on the duration of hypotension and requires resuscitation; IL-6 administration at the start of resuscitation reverses T/HS-induced liver inflammation, through activation of Stat3a, which normalized the T/HS-induced liver inflammation transcriptome. [ABSTRACT FROM AUTHOR]

Genomic regions subjected to selection frequently show signatures such as within-population reduced nucleotide diversity and outlier values of differentiation among differentially selected populations. In this study, we analyzed 50K SNP genotype data of 373 animals belonging to 23 sheep breeds of different geographic origins using the Rsb (extended haplotype homozygosity) and FST statistical approaches, to identify loci associated with the fat-tail phenotype. We also checked if these putative selection signatures overlapped with regions of high-homozygosity (ROH). The analyses identified novel signals and confirmed the presence of selection signature in genomic regions that harbor candidate genes known to affect fat deposition. Several genomic regions that frequently appeared in ROH were also identified within each breed, but only two ROH islands overlapped with the putative selection signatures. The results reported herein provide the most complete genome-wide study of selection signatures for fat-tail in African and Eurasian sheep breeds; they also contribute insights into the genetic basis for the fat tail phenotype in sheep, and confirm the great complexity of the mechanisms that underlie quantitative traits, such as the fat-tail.

Copy number variation (CNV) is a major source of genomic structural variation. The aim of this study was to detect genomic CNV regions (CNVR) in Valle del Belice dairy sheep population and to identify those affecting milk production traits. The GO analysis identified possible candidate genes and pathways related to the selected traits. We identified CNVs in 416 individuals genotyped using the Illumina OvineSNP50 BeadChip array. The CNV association using a correlation-trend test model was examined with the Golden Helix SVS 8.7.0 tool. Significant CNVs were detected when their adjusted p-value was

BackgroundLengths of hospital stay (LoS) after childbirth that are too long have a number of health, social and economic drawbacks. For this reason, in several high-income countries LoS has been reduced over the past decades and early discharge (ED) is increasingly applied to low-risk mothers and newborns.MethodsWe conducted a population-based study investigating LoS after chilbirth across all 12 maternity centres of Friuli Venezia-Giulia (FVG), North-Eastern Italy, using a database capturing all registered births in the region from 2005 to 2015 (11 years). Adjusting for clinical factors (clinical conditions of the mother and the newborn), socio-demographic bakground and obstetric history with multivariable logistic regression, we ranked facility centres for LoS that were longer than our proposed ED benchmarks (defined as >2 days for spontaneous vaginal deliveries and >3 days for instrumental vaginal deliveries). The reference was hospital A, a national excellence centre for maternal and child health.ResultsThe total number of births examined in our database was 109,550, of which 109,257 occurred in hospitals. During these 11 years, the number of births significantly diminished over time, and the pooled mean LoS for spontaneous vaginal deliveries in the whole FVG was 2.9 days. There was a significantly decreasing trend in the proportion of women remaining admitted more than the respective ED cutoffs for both delivery modes. The percentage of women staying longer that the ED benchmarks varied extensively by facility centre, ranging from 32% to 97% for spontaneous vaginal deliveries and 15% to 64% for instrumental vaginal deliveries. All hospitals but G were by far more likely to surpass the ED cutoff for spontaneous deliveries. As compared with hospital A, the most significant adjusted ORs for LoS overcoming the ED thresholds for spontaneous vaginal deliveries were: 89.38 (78.49-101.78); 26.47 (22.35-31.36); 10.42 (9.49-11.44); 10.30 (9.45-11.21) and 8.40 (7.68-9.19) for centres B, D, I, K and E respectively. By contrast the OR was 0.77 (95%CI: 0.72-0.83) for centre G. Similar mitigated patterns were observed also for instrumental vaginal deliveiries.ConclusionsFor spontaneous vaginal deliveries the mean LoS in the whole FVG was shorter than 3.4 days, the average figure most recently reported for the whole of Italy, but higher than other countries' with health systems similar to Italy's. Since our results are controlled for the effect of all other factors, the between-hospital variability we found is likely attributable to the health care provider itself. It can be argued that some maternity centres of FVG may have had ecocomic interest in longer LoS after childbirth, although fear of medico-legal backlashes, internal organizational malfunctions of hospitals and scarce attention of ward staff on performance efficiency shall not be ruled out. It would be therefore important to ensure higher level of coordination between the various maternity services of FVG, which should follow standardized protocols to pursue efficiency of care and allow comparability of health outcomes and costs among them. Improving the performance of FVG and Italian hospitals requires investment in primary care services.

[This corrects the article DOI: 10.1371/journal.pone.0204919.].

[This corrects the article DOI: 10.1371/journal.pone.0210753.].

The availability of accurate techniques to discriminate between marked laboratory-reared flies and unmarked wild flies captured in monitoring traps is essential for programs that integrate the Sterile Insect Technique (SIT) to manage fruit flies. In this study, the feasibility of using a stable isotope marking technique for the South American fruit fly, Anastrepha fraterculus (Wiedemann), was assessed. Wild flies were collected from apple orchards, which are a target of a SIT project in southern Brazil. To verify if adult flies could be labelled by the stable isotopes from larval diets, larvae were reared on two different C4-based diets and fruits in laboratory. To evaluate the influence of the two most common attractants applied to capture A. fraterculus (grape juice and CeraTrapTM) and the most common preservation method in fruit fly collections (ethanol), laboratory-reared flies were immersed in McPhail traps containing the respective treatments for two periods of time. Samples were analyzed in an elemental analyzer coupled to a Continuous Flow Isotope Ratio Mass Spectrometer (CF-IRMS) at CENA/USP. The δ13C signatures of flies reared on artificial diets differed significantly from the δ13C of flies whose larvae were reared on fruits and from wild flies. In contrast, the δ15N values were less conclusive and the technique could not rely solely on them. In all cases considered, the δ13C and δ15N signatures from males did not differ from females. Despite the alterations caused by the attractants tested and ethanol, laboratory-flies could be distinguished from the wild ones based on δ13C signatures. This is the first comprehensive study to demonstrate that it is possible to distinguish wild A. fraterculus from flies reared on larval diets containing C4 sugar. The first experimentally derived trophic discrimination factors were also obtained for this species. Thus, intrinsic isotope labelling can serve as a backup to conventional dye marking.

The evaluation of genetic variability is a useful research tool for the correct management of selection and conservation strategies in dog breeds. In addition to pedigree genealogies, genomic data allow a deeper knowledge of the variability and genetic structure of populations. To date, many dog breeds, such as small regional breeds, still remain uncharacterized. Braque Français type Pyrénées (BRA) is a dog breed originating from a very old type of gun-dog used for pointing the location of game birds to hunters. Despite the ancient background, the knowledge about levels of genetic diversity, degree of inbreeding and population structure is scarce. This may raise concerns on the possibility that few inbred bloodlines may dominate the breed, and on its future health. The aim of this work was therefore to provide a high-resolution representation of the genome-wide diversity and population structure of BRA dogs, using the 170K genome-wide SNP array. Genome-wide polymorphisms in BRA were compared with those of other worldwide dog breeds. Between-dog relationships estimated from genomic data were very similar to pedigree relationships (Pearson correlation rg,a = 0.92). Results showed that BRA generally presents moderate levels of genetic diversity when compared with the major canine breeds. The estimated effective population size (recent Ne = 51) shows a similar declining pattern over generations as all other dog breeds, pointing at a common demographic history of modern canine breeds, clearly different from the demography of feral wolves. Multidimensional scaling (MDS), Bayesian clustering and Neighbor Joining tree were used to visualize and explore the genetic relationships among breeds, and revealed that BRA was highly differentiated and presented only low levels of admixture with other breeds. Brittany Spaniel, English Setter, Gordon Setter and Weimaraner dogs are the closest breeds to BRA. The exact reason for BRA being so divergent from other dog breeds, based on these results, is not yet clear. Further studies including additional ≪braccoid≫ breeds will be needed to refine the results presented here and to investigate the origin of the BRA breed. Nonetheless, the genome-wide characterization reported here provides a comprehensive insight into the genome diversity and population structure of the Braque Français, type Pyrénées breed.

The Sterile Insect Technique (SIT) is an autocidal control method that relies on inundative releases of sterilized mass-reared insects. This technology has been used in several area-wide programmes for the suppression/eradication of fruit fly populations. Choosing the optimum sterilizing dose and the sterile release density is an essential step of the SIT. Considering unsolved issues related to the application of this technique against Anastrepha fraterculus (Wiedemann), this study aimed to define accurately the central target dose for both sexes of this species and to verify the induction of sterility in fertile flies at different sterile:fertile ratios. The results from the regression analyses proved that the sterilization process for the A. fraterculus Brazilian-1 morphotype (the most common in southern Brazil and Argentina) could consist of irradiating pupae 72 h before adult emergence at 40 Gy, with no detrimental effects to standard quality control parameters. The ovarian development in irradiated females was characterized, demonstrating that doses equal to or higher than 25 Gy cause complete and irreversible ovarian atrophy. The laboratory and field cage tests showed that the sterility induction increased with the proportion of sterile flies, and a sterile:fertile ratio of 50:1 should be appropriate in SIT field trials. The sterile females apparently did not distract the sterile males, despite of the slightly higher reductions in pupal yield for all ratios in their absence. The data generated in this study have a great practical value and will help decision-makers in planning field trials to evaluate the efficacy of the SIT against A. fraterculus populations.

Increasing grain yield potential in wheat has been a major target of most breeding programs. Genetic advance has been frequently hindered by negative correlations among yield components that have been often observed in segregant populations and germplasm collections. A tetraploid wheat collection was evaluated in seven environments and genotyped with a 90K SNP assay to identify major and stable quantitative trait loci (QTL) for grain yield per spike (GYS), kernel number per spike (KNS) and thousand-kernel weight (TKW), and to analyse the genetic relationships between the yield components at QTL level. The genome-wide association analysis detected eight, eleven and ten QTL for KNS, TKW and GYS, respectively, significant in at least three environments or two environments and the mean across environments. Most of the QTL for TKW and KNS were found located in different marker intervals, indicating that they are genetically controlled independently by each other. Out of eight KNS QTL, three were associated to significant increases of GYS, while the increased grain number of five additional QTL was completely or partially compensated by decreases in grain weight, thus producing no or reduced effects on GYS. Similarly, four consistent and five suggestive TKW QTL resulted in visible increase of GYS, while seven additional QTL were associated to reduced effects in grain number and no effects on GYS. Our results showed that QTL analysis for detecting TKW or KNS alleles useful for improving grain yield potential should consider the pleiotropic effects of the QTL or the association to other QTLs.

Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes. Despite simultaneous screening of these genes being widely available, mutation detection still remains incomplete in a non-marginal portion of patients. Here, we applied whole-exome sequencing (WES) in 3 Italian families negative after candidate-gene analyses. In Family 1, we identified a novel heterozygous intronic variant (c.2245-40A>G) -outside the conventionally screened candidate region for diagnosis- potentially disrupting COL4A5 exon29 splicing. Using a minigene-based approach in HEK293 cells we demonstrated that this variant abolishes exon29 branch site, causing exon skipping. Moreover, skewed X-inactivation of the c.2245-40A>G allele correlated with disease severity in heterozygous females. In Family 2, WES highlighted a novel COL4A5 hemizygous missense mutation (p.Gly491Asp), which segregates with the phenotype and impacts on a highly-conserved residue. Finally, in Family 3, we detected a homozygous 24-bp in-frame deletion in COL4A3 exon1 (NM_000091.4:c.30_53del:p.Val11_Leu18del or c.40_63del24:p.Leu14_Leu21del), which is ambiguously annotated in databases, although it corresponds to a recurrent AS mutation. Functional analyses showed that this deletion disrupts COL4A3 signal peptide, possibly altering protein secretion. In conclusion, WES -together with functional studies- was fundamental for molecular diagnosis in 3 AS families, highlighting pathogenic variants that escaped previous screenings.

Adipose stem cells (ASCs) are an appealing source of cells for therapeutic intervention; however, the environment from which ASCs are isolated may impact their usefulness. Using a range of functional assays, we have evaluated whether ASCs isolated from an obese environment are comparable to cells from non-obese adipose tissue. Results showed that ASCs isolated from obese tissue have a reduced proliferative ability and a loss of viability together with changes in telomerase activity and DNA telomere length, suggesting a decreased self-renewal capacity. Metabolic analysis demonstrated that mitochondrial content and function was impaired in obese-derived ASCs resulting in changes in favored oxidative substrates. These findings highlight the impact of obesity on adult stem properties. Hence, caution should be exercised when considering the source of ASCs for cellular therapies since their therapeutic potential may be impaired.

DNA adducts are considered an integrate measure of carcinogen exposure and the initial step of carcinogenesis. Their levels in more accessible peripheral blood lymphocytes (PBLs) mirror that in the bladder tissue. In this study we explore whether the formation of PBL DNA adducts may be associated with bladder cancer (BC) risk, and how this relationship is modulated by genetic polymorphisms, environmental and occupational risk factors for BC. These complex interrelationships, including direct and indirect effects of each variable, were appraised using the structural equation modeling (SEM) analysis. Within the framework of a hospital-based case/control study, study population included 199 BC cases and 213 non-cancer controls, all Caucasian males. Data were collected on lifetime smoking, coffee drinking, dietary habits and lifetime occupation, with particular reference to exposure to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). No indirect paths were found, disproving hypothesis on association between PBL DNA adducts and BC risk. DNA adducts were instead positively associated with occupational cumulative exposure to AAs (p = 0.028), whereas XRCC1 Arg 399 (p

Association mapping is a powerful tool for the identification of quantitative trait loci through the exploitation of the differential decay of linkage disequilibrium (LD) between marker loci and genes of interest in natural and domesticated populations. Using a sample of 230 tetraploid wheat lines (Triticum turgidum ssp), which included naked and hulled accessions, we analysed the pattern of LD considering 26 simple sequence repeats and 970 mostly mapped diversity array technology loci. In addition, to validate the potential for association mapping in durum wheat, we evaluated the same genotypes for plant height, heading date, protein content, and thousand-kernel weight. Molecular and phenotypic data were used to: (i) investigate the genetic and phenotypic diversity; (ii) study the dynamics of LD across the durum wheat genome, by investigating the patterns of LD decay; and (iii) test the potential of our panel to identify marker-trait associations through the analysis of four quantitative traits of major agronomic importance. Moreover, we compared and validated the association mapping results with outlier detection analysis based on population divergence. Overall, in tetraploid wheat, the pattern of LD is extremely population dependent and is related to the domestication and breeding history of durum wheat. Comparing our data with several other studies in wheat, we confirm the position of many major genes and quantitative trait loci for the traits considered. Finally, the analysis of the selection signature represents a very useful complement to validate marker-trait associations.