Zebrafish her3 knockout impacts developmental and cancer-related gene signatures.

HES3 is a basic helix-loop-helix transcription factor that regulates neural stem cell renewal during development. HES3 overexpression is predictive of reduced overall survival in patients with fusion-positive rhabdomyosarcoma, a pediatric cancer that resembles immature and undifferentiated skeletal muscle. However, the mechanisms of HES3 cooperation in fusion-positive rhabdomyosarcoma are unclear and are likely related to her3/HES3's role in neurogenesis. To investigate HES3's function during development, we generated a zebrafish CRISPR/Cas9 null mutation of her3, the zebrafish ortholog of HES3. Loss of her3 is not embryonic lethal and adults exhibit expected Mendelian ratios. Embryonic her3 zebrafish mutants exhibit dysregulated neurog1 expression, a her3 target gene, and the mutant her3 fails to bind the neurog1 promoter sequence. Further, her3 mutants are significantly smaller than wildtype and a subset present with lens defects as adults. Transcriptomic analysis of her3 mutant embryos indicates that genes involved in organ development, such as pctp and grinab, are significantly downregulated. Further, differentially expressed genes in her3 null mutant embryos are enriched for Hox and Sox10 motifs. Several cancer-related gene pathways are impacted, including the inhibition of matrix metalloproteinases. Altogether, this new model is a powerful system to study her3/HES3-mediated neural development and its misappropriation in cancer contexts.

Video Laryngoscopy versus Direct Laryngoscopy for Orotracheal Intubation in the Out-of-Hospital Environment: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the effect of video and direct laryngoscopy on first-pass success rates for out-of-hospital orotracheal intubation. METHODS: MEDLINE, Embase, and Cochrane databases were searched from inception to January 2023. Out-of-hospital studies comparing video and direct laryngoscopy on either first-pass or overall intubation success were included. A random effects meta-analysis was performed with a primary outcome of first-pass success stratified by clinician type and laryngoscope blade geometry. The secondary outcomes were overall intubation success stratified by clinician type, and intubation time. All hypotheses and subgroup analyses were determined a priori. RESULTS: Twenty-five studies involving 35,489 intubations met inclusion criteria. Substantial heterogeneity (>75%) precluded reporting point estimates for nearly all analyses. For our primary outcome, video laryngoscopy was associated with improved first-pass success in 3/5 physician studies, 4/6 critical care paramedic/registered nurse studies, and 7/10 paramedic studies. Video laryngoscope devices with Macintosh blade geometry were associated with improved first-pass success in 7/10 studies, while devices with hyperangulated geometry were associated with improved first-pass success in 3/7 studies. Overall intubation success was greater with video laryngoscopy in 2/6 studies in the physician subgroup and 9/10 studies in the paramedic subgroup. Video laryngoscopy was not associated with overall intubation success among critical care paramedics/nurses (OR = 1.89, 0.96 to 3.72, I2 = 34%). Lastly, 4/5 studies found video laryngoscopy to be associated with longer intubation times. CONCLUSIONS: We found substantial heterogeneity among out-of-hospital studies comparing video laryngoscopy to direct laryngoscopy on first-pass success, overall success, or intubation time. This heterogeneity was not explained with stratification by study design, clinician type, video laryngoscope blade geometry, or leave-one-out meta-analysis. A majority of studies showed that video laryngoscopy was associated with improved first pass success in all subgroups, but only for paramedics and not physicians when looking at overall success. This improvement was more common in studies that used Macintosh blades than those that used hyperangulated blades. Future research should explore the heterogeneity identified in our analysis with an emphasis on differences in training, clinical milieu, and specific video laryngoscope devices.

The comparison of functional bracing of humeral shaft fractures: thermoplastic custom against preprepared commercial braces.

BACKGROUND: Functional humeral bracing of midshaft humeral fractures has been widely accepted as a gold standard for nonoperative treatment. Despite reported high union rates, there is no proven superiority of any orthosis. Here we aim to compare the outcomes after the use of custom-made thermoplastic vs. commercial humeral brace with regard to time to union, nonunion rates, types of nonunion, and conversion to surgery. METHODS: Patients with humeral fractures treated between 2018 and 2021 were identified retrospectively by electronic records. Only diaphyseal humerus fractures (AO 12) were included in the study. Proximal (AO 11) or distal (AO 13) fractures, open fractures, pathologic fractures, bilateral fractures, multiple fractures, and patients lost to follow-up were excluded. Patients attending one center received a custom-made thermoplastic splint, whereas those at the other center had an off-the-shelf humeral brace applied. Radiologic union was defined as healing of at least 3 of 4 cortices determined from follow-up radiographs. Data calculations were performed using the χ2 test. RESULTS: A total of 53 patients treated with a thermoplastic brace and 43 with a commercial brace were identified. A total of 52 men were included, and the cohort's mean age was 60.1 years (standard deviation: 16.1 years). Both groups had similar gender and age distributions. More patients achieved union with a thermoplastic brace (79.2%) than those with a commercial brace (76.7%), which was statistically significant (χ2, P = .04). Although time to union was similar both clinically and radiologically, patients with a commercial brace converted to surgical treatment more frequently (11 vs. 14 cases). CONCLUSION: Thermoplastic custom-made braces provide better fracture stability, allowing for statistically significantly higher rates of fracture union during a similar treatment period to commercially available splints. Patients wearing a commercial splint were significantly more likely to develop hypertrophic nonunion requiring surgery.

Genome assembly, structural variants, and genetic differentiation between lake whitefish young species pairs (Coregonus sp.) with long and short reads.

Nascent pairs of ecologically differentiated species offer an opportunity to get a better glimpse at the genetic architecture of speciation. Of particular interest is our recent ability to consider a wider range of genomic variants, not only single-nucleotide polymorphisms (SNPs), thanks to long-read sequencing technology. We can now identify structural variants (SVs) such as insertions, deletions and other rearrangements, allowing further insights into the genetic architecture of speciation and how different types of variants are involved in species differentiation. Here, we investigated genomic patterns of differentiation between sympatric species pairs (Dwarf and Normal) belonging to the lake whitefish (Coregonus clupeaformis) species complex. We assembled the first reference genomes for both C. clupeaformis sp. Normal and C. clupeaformis sp. Dwarf, annotated the transposable elements and analysed the genomes in the light of related coregonid species. Next, we used a combination of long- and short-read sequencing to characterize SVs and genotype them at the population scale using genome-graph approaches, showing that SVs cover five times more of the genome than SNPs. We then integrated both SNPs and SVs to investigate the genetic architecture of species differentiation in two different lakes and highlighted an excess of shared outliers of differentiation. In particular, a large fraction of SVs differentiating the two species correspond to insertions or deletions of transposable elements (TEs), suggesting that TE accumulation may represent a key component of genetic divergence between the Dwarf and Normal species. Together, our results suggest that SVs may play an important role in speciation and that, by combining second- and third-generation sequencing, we now have the ability to integrate SVs into speciation genomics.

Real-world adjuvant chemotherapy patterns and outcomes among elderly patients with resected early non-small-cell lung cancer in the USA.

Background: This study investigated real-world treatment patterns and overall survival (OS) in early non-small-cell lung cancer patients and the association between OS and time-to-adjuvant-treatment. Materials & methods: This retrospective study using Surveillance, Epidemiology and End Results data linked with Medicare claims included resected early non-small-cell lung cancer patients between 2010 and 2015. Unadjusted OS analyses used Kaplan-Meier curves; adjusted OS analyses used extended Cox proportional hazards models. Results: Only 54-71% of stage II-IIIA patients received any adjuvant treatment. Adjusted risk of death was higher when starting treatment outside 6-8 weeks after surgery (p < 0.05). Conclusion: Improved systemic therapy in the adjuvant chemotherapy setting is needed.

Lung cancer is one of the deadliest cancers in the USA. Most lung cancers are a type called non-small-cell lung cancer (NSCLC). Patients with NSCLC that has not spread to other parts of the body generally have surgery and may receive treatment before surgery, after surgery or both to help fight the cancer. It is not clear how often people receive treatment before or after surgery. It is important to know how patients are being treated because it helps clinicians decide how to use the new treatments that are becoming available. This study used a large database of more than 7000 people aged 65 years and older with lung cancer in the USA to understand how they are treated. More than a third of patients had stage IA NSCLC (39%), followed by stage IB (24%), stage II (20%), stage IIIA (15%) and stage IIIB (2%). Most people had surgery (64%) and some received another treatment after surgery (27%). That treatment was most often about 2 months of chemotherapy, on average. The study also tried to understand how the timing of treatment may have been important for their survival. People who received treatment after surgery lived the longest if they received that treatment about 6­8 weeks after the surgery. Overall, the study showed that a substantial proportion of people do not receive treatment for their NSCLC after surgery, even though treatment after surgery is recommended by medical guidelines. There is a need for more effective treatments for these patients, and when those treatments are given may be important for their survival.

Environmentally associated chromosomal structural variation influences fine-scale population structure of Atlantic Salmon (Salmo salar).

Chromosomal rearrangements (e.g., inversions, fusions, and translocations) have long been associated with environmental variation in wild populations. New genomic tools provide the opportunity to examine the role of these structural variants in shaping adaptive differences within and among wild populations of non-model organisms. In Atlantic Salmon (Salmo salar), variations in chromosomal rearrangements exist across the species natural range, yet the role and importance of these structural variants in maintaining adaptive differences among wild populations remains poorly understood. We genotyped Atlantic Salmon (n = 1429) from 26 populations within a highly genetically structured region of southern Newfoundland, Canada with a 220K SNP array. Multivariate analysis, across two independent years, consistently identified variation in a structural variant (translocation between chromosomes Ssa01 and Ssa23), previously associated with evidence of trans-Atlantic secondary contact, as the dominant factor influencing population structure in the region. Redundancy analysis suggested that variation in the Ssa01/Ssa23 chromosomal translocation is strongly correlated with temperature. Our analyses suggest environmentally mediated selection acting on standing genetic variation in genomic architecture introduced through secondary contact may underpin fine-scale local adaptation in Placentia Bay, Newfoundland, Canada, a large and deep embayment, highlighting the importance of chromosomal structural variation as a driver of contemporary adaptive divergence.

Dissecting the loci underlying maturation timing in Atlantic salmon using haplotype and multi-SNP based association methods.

Characterizing the role of different mutational effect sizes in the evolution of fitness-related traits has been a major goal in evolutionary biology for a century. Such characterization in a diversity of systems, both model and non-model, will help to understand the genetic processes underlying fitness variation. However, well-characterized genetic architectures of such traits in wild populations remain uncommon. In this study, we used haplotype-based and multi-SNP Bayesian association methods with sequencing data for 313 individuals from wild populations to test the mutational composition of known candidate regions for sea age at maturation in Atlantic salmon (Salmo salar). We detected an association at five loci out of 116 candidates previously identified in an aquaculture strain with maturation timing in wild Atlantic salmon. We found that at four of these five loci, variation explained by the locus was predominantly driven by a single SNP suggesting the genetic architecture of this trait includes multiple loci with simple, non-clustered alleles and a locus with potentially more complex alleles. This highlights the diversity of genetic architectures that can exist for fitness-related traits. Furthermore, this study provides a useful multi-SNP framework for future work using sequencing data to characterize genetic variation underlying phenotypes in wild populations.

Associations Between Medicaid Insurance, Biomarker Testing, and Outcomes in Patients With Advanced NSCLC.

BACKGROUND: Evidence suggests that patients with Medicaid experience lower-quality cancer care than those with commercial insurance. Whether this trend persists in the era of personalized medicine is unclear. This study examined the associations between Medicaid (vs commercial) insurance and receipt of biomarker testing, targeted therapy, and overall survival in patients with advanced non-small cell lung cancer (aNSCLC). METHODS: We conducted a retrospective study of patients who received an aNSCLC diagnosis from January 2011 to September 2019 using a nationwide US healthcare database. Eligible patients were aged 18 to 64 years with Medicaid or commercial insurance at diagnosis. Receipt of biomarker testing (ALK, EGFR, ROS1, BRAF, and PD-L1) was assessed. The likelihood of testing, biomarker-driven therapy (cancer immunotherapy or tyrosine kinase inhibitor treatment), and mortality were compared by insurance type using adjusted Cox regression. RESULTS: Our sample included 6,145 commercially insured and 865 Medicaid beneficiaries. Medicaid beneficiaries were more likely to be Black or African American (20% vs 9.3%; P <.001) and were less likely to have undergone biomarker testing (57% vs 71%; P <.001). In the adjusted analysis, Medicaid beneficiaries were less likely to have evidence of testing (hazard ratio [HR], 0.81; P <.001), any first-line treatment (HR, 0.72; P <.001), and first-line biomarker-driven therapy (HR, 0.70; P <.001). Medicaid beneficiaries with evidence of biomarker testing had a lower risk of death compared with those without evidence of biomarker testing (HR, 1.27 [95% CI, 1.06-1.52]; P =.010). Higher risk of death was observed in patients with Medicaid versus commercially insured patients (HR, 1.23; P <.001); this result remained unchanged after adjusting for biomarker testing (HR, 1.22; P < .001) but was partially ameliorated after adjustment for testing and treatment type (HR, 1.12; P =.010). CONCLUSIONS: Medicaid beneficiaries with aNSCLC were less likely to receive biomarker testing and biomarker-driven therapies, which may in part contribute to a higher observed risk of mortality compared with commercially insured patients.

Genetic variants associated with two major bovine milk fatty acids offer opportunities to breed for altered milk fat composition.

BACKGROUND: Although bovine milk is regarded as healthy and nutritious, its high content of saturated fatty acids (FA) may be harmful to cardiovascular health. Palmitic acid (C16:0) is the predominant saturated FA in milk with adverse health effects that could be countered by substituting it with higher levels of unsaturated FA, such as oleic acid (C18:1cis-9). In this work, we performed genome-wide association analyses for milk fatty acids predicted from FTIR spectroscopy data using 1811 Norwegian Red cattle genotyped and imputed to a high-density 777k single nucleotide polymorphism (SNP)-array. In a follow-up analysis, we used imputed whole-genome sequence data to detect genetic variants that are involved in FTIR-predicted levels of C16:0 and C18:1cis-9 and explore the transcript profile and protein level of candidate genes. RESULTS: Genome-wise significant associations were detected for C16:0 on Bos taurus (BTA) autosomes 11, 16 and 27, and for C18:1cis-9 on BTA5, 13 and 19. Closer examination of a significant locus on BTA11 identified the PAEP gene, which encodes the milk protein ß-lactoglobulin, as a particularly attractive positional candidate gene. At this locus, we discovered a tightly linked cluster of genetic variants in coding and regulatory sequences that have opposing effects on the levels of C16:0 and C18:1cis-9. The favourable haplotype, linked to reduced levels of C16:0 and increased levels of C18:1cis-9 was also associated with a marked reduction in PAEP expression and ß-lactoglobulin protein levels. ß-lactoglobulin is the most abundant whey protein in milk and lower levels are associated with important dairy production parameters such as improved cheese yield. CONCLUSIONS: The genetic variants detected in this study may be used in breeding to produce milk with an improved FA health-profile and enhanced cheese-making properties.

The Atlantic salmon genome provides insights into rediploidization.

The whole-genome duplication 80 million years ago of the common ancestor of salmonids (salmonid-specific fourth vertebrate whole-genome duplication, Ss4R) provides unique opportunities to learn about the evolutionary fate of a duplicated vertebrate genome in 70 extant lineages. Here we present a high-quality genome assembly for Atlantic salmon (Salmo salar), and show that large genomic reorganizations, coinciding with bursts of transposon-mediated repeat expansions, were crucial for the post-Ss4R rediploidization process. Comparisons of duplicate gene expression patterns across a wide range of tissues with orthologous genes from a pre-Ss4R outgroup unexpectedly demonstrate far more instances of neofunctionalization than subfunctionalization. Surprisingly, we find that genes that were retained as duplicates after the teleost-specific whole-genome duplication 320 million years ago were not more likely to be retained after the Ss4R, and that the duplicate retention was not influenced to a great extent by the nature of the predicted protein interactions of the gene products. Finally, we demonstrate that the Atlantic salmon assembly can serve as a reference sequence for the study of other salmonids for a range of purposes.

Insertion of an endogenous Jaagsiekte sheep retrovirus element into the BCO2 - gene abolishes its function and leads to yellow discoloration of adipose tissue in Norwegian Spælsau (Ovis aries).

BACKGROUND: The accumulation of carotenoids in adipose tissue leading to yellow fat is, in sheep, a heritable recessive trait that can be attributed to a nonsense mutation in the beta-carotene oxygenase 2 (BCO2) gene. However, not all sheep breeds suffering from yellow fat have this nonsense mutation, meaning that other functional mechanisms must exist. We investigated one such breed, the Norwegian spælsau. RESULTS: In spælsau we detected an aberration in BCO2 mRNA. Nanopore sequencing of genomic DNA revealed the insertion of a 7.9 kb endogenous Jaagsiekte Sheep Retrovirus (enJSRV) sequence in the first intron of the BCO2 gene. Close examination of its cDNA revealed that the BCO2 genes first exon was spliced together with enJSRV-sequence immediately downstream of a potential -AG splice acceptor site at enJSRV position 415. The hybrid protein product consists of 29 amino acids coded by the BCO2 exon 1, one amino acid coded by the junction sequence, followed by 28 amino acids arbitrary coded for by the enJSRV-sequence, before a translation stop codon is reached. CONCLUSIONS: Considering that the functional BCO2 protein consists of 575 amino acids, it is unlikely that the 58 amino acid BCO2/enJSRV hybrid protein can display any enzymatic function. The existence of this novel BCO2 allele represents an alternative functional mechanism accounting for BCO2 inactivation and is a perfect example of the potential benefits for searching for structural variants using long-read sequencing data.

Sex-dependent dominance at a single locus maintains variation in age at maturity in salmon.

Males and females share many traits that have a common genetic basis; however, selection on these traits often differs between the sexes, leading to sexual conflict. Under such sexual antagonism, theory predicts the evolution of genetic architectures that resolve this sexual conflict. Yet, despite intense theoretical and empirical interest, the specific loci underlying sexually antagonistic phenotypes have rarely been identified, limiting our understanding of how sexual conflict impacts genome evolution and the maintenance of genetic diversity. Here we identify a large effect locus controlling age at maturity in Atlantic salmon (Salmo salar), an important fitness trait in which selection favours earlier maturation in males than females, and show it is a clear example of sex-dependent dominance that reduces intralocus sexual conflict and maintains adaptive variation in wild populations. Using high-density single nucleotide polymorphism data across 57 wild populations and whole genome re-sequencing, we find that the vestigial-like family member 3 gene (VGLL3) exhibits sex-dependent dominance in salmon, promoting earlier and later maturation in males and females, respectively. VGLL3, an adiposity regulator associated with size and age at maturity in humans, explained 39% of phenotypic variation, an unexpectedly large proportion for what is usually considered a highly polygenic trait. Such large effects are predicted under balancing selection from either sexually antagonistic or spatially varying selection. Our results provide the first empirical example of dominance reversal allowing greater optimization of phenotypes within each sex, contributing to the resolution of sexual conflict in a major and widespread evolutionary trade-off between age and size at maturity. They also provide key empirical evidence for how variation in reproductive strategies can be maintained over large geographical scales. We anticipate these findings will have a substantial impact on population management in a range of harvested species where trends towards earlier maturation have been observed.

Induction of a proliferative response in the zebrafish retina by injection of extracellular vesicles.

Ongoing research using cell transplantation and viral-mediated gene therapy has been making progress to restore vision by retinal repair, but targeted delivery and complete cellular integration remain challenging. An alternative approach is to induce endogenous Müller glia (MG) to regenerate lost neurons and photoreceptors, as occurs spontaneously in teleost fish and amphibians. Extracellular vesicles (EVs) can transfer protein and RNA cargo between cells serving as a novel means of cell-cell communication. We conducted an in vivo screen in zebrafish to identify sources of EVs that could induce MG to dedifferentiate and generate proliferating progenitor cells after intravitreal injection into otherwise undamaged zebrafish eyes. Small EVs (sEVs) from C6 glioma cells were the most consistent at inducing MG-derived proliferating cells. Ascl1a expression increased after intravitreal injection of C6 sEVs and knockdown of ascl1a inhibited the induction of proliferation. Proteomic and RNAseq analyses of EV cargo content were performed to begin to identify key factors that might target EVs to MG and initiate retina regeneration.

Prevention of Perioperative Hypothermia: A Prospective, Randomized, Controlled Trial of Bair Hugger Versus Inditherm in Patients Undergoing Elective Arthroscopic Shoulder Surgery.

PURPOSE: To determine if a clinically significant difference in the core body temperature (CBT) exists between the Bair Hugger (BH) and Inditherm (IT) warming devices in patients undergoing arthroscopic shoulder surgery. METHODS: This was a parallel, 2-treatment, prospective, randomized, controlled trial conducted in patients undergoing elective arthroscopic shoulder surgery in the beach-chair position using room-temperature irrigation fluid. The BH was used as the indicative forced-air warming device, whereas the IT served as the indicative resistive heating system. By use of a minimal clinically significant difference of 0.6°C and standard deviation of 0.6°C, a power analysis showed that a sample size of 90 patients (45 per group) would be required. Patients fulfilling the inclusion criteria were recruited from the clinics of the senior authors. Anesthetic and surgical protocols were standardized. The intraoperative CBT was recorded every 5 minutes using a nasopharyngeal thermistor probe. Demographic data as well as the volume of irrigation fluid used were also noted. RESULTS: A steady decline in the CBT was observed in both groups up to 30 minutes after induction of anesthesia. Beyond 30 minutes, the BH group showed a gradual increase in temperature whereas it continued to decline in the IT group. A statistically significant difference in the CBT was observed from 60 minutes onward (P = .025). This difference continued to increase up to 90 minutes (P < .001). At no time was a rise in the CBT observed in the IT group. At completion of the study and surgical procedure, 13 of 47 patients in the BH group and 32 of 44 patients in the IT group had hypothermia (P = .0002). CONCLUSIONS: The CBT was statistically significantly better with the use of the BH compared with the IT mattress. However, the differences in the CBT did not reach the level of clinical significance of 0.6°C. Far fewer patients in the BH group had hypothermia at the end of surgery. Therefore, this study supports the use of the BH in elective arthroscopic shoulder surgery for the prevention of hypothermia. LEVEL OF EVIDENCE: Level I.

Symptom Presentation After Concussion and Pre-existing Anxiety Among Youth Athletes.

Our purpose was to evaluate the effect of self-reported pre-injury anxiety diagnosis on persistent symptom development, vestibular symptom severity, and balance control among youth who sustained a concussion. We performed a retrospective study of patients seen at a specialty pediatric concussion clinic. Patients were 18 years of age or younger, examined within 10 days of concussion, and received care until full recovery. A questionnaire was used to assess pre-existing medical and psychiatric conditions, including anxiety. Our main outcomes were prolonged symptom recovery defined as persistent symptoms for > 28 days after concussion) and severity of vestibular symptoms. Patients who reported pre-injury anxiety (n=43; median age=14.9 years; 37% female) were more likely to experience symptoms>28 days post-injury (76 vs. 54%; p=0.04) than those without pre-existing anxiety (n=241; median age=14.9 years; 53% female). After adjusting for sex, history of migraine, depression and ADHD, however, there was no independent association between pre-existing anxiety and prolonged symptom duration (adjusted odds ratio=2.34; 95% CI=0.083-6.63; p=0.11). Pre-existing anxiety was independently associated with self-reported nausea/vomiting severity (ß coefficient=0.59, 95% CI=0.07-1.11). A pre-existing anxiety diagnosis does not appear to be associated with persistent symptoms after concussion, although it may be associated with post-injury nausea.

Identification of genomic regions regulating sex determination in Atlantic salmon using high density SNP data.

BACKGROUND: A complete understanding of the genetic basis for sexual determination and differentiation is necessary in order to implement efficient breeding schemes at early stages of development. Atlantic salmon belongs to the family Salmonidae of fishes and represents a species of great commercial value. Although the species is assumed to be male heterogametic with XY sex determination, the precise genetic basis of sexual development remains unclear. The complexity is likely associated to the relatively recent salmonid specific whole genome duplication that may be responsible for certain genome instability. This instability together with the capacity of the sex-determining gene to move across the genome as reported by previous studies, may explain that sexual development genes are not circumscribed to the same chromosomes in all members of the species. In this study, we have used a 220 K SNP panel developed for Atlantic salmon to identify the chromosomes explaining the highest proportion of the genetic variance for sex as well as candidate regions and genes associated to sexual development in this species. RESULTS: Results from regional heritability analysis showed that the chromosomes explaining the highest proportion of variance in these populations were Ssa02 (heritability = 0.42, SE = 0.12) and Ssa21 (heritability = 0.26, SE = 0.11). After pruning by linkage disequilibrium, genome-wide association analyses revealed 114 SNPs that were significantly associated with sex, being Ssa02 the chromosome containing a greatest number of regions. Close examination of the candidate regions evidenced important genes related to sex in other species of Class Actinopterygii, including SDY, genes from family SOX, RSPO1, ESR1, U2AF2A, LMO7, GNRH-R, DND and FIGLA. CONCLUSIONS: The combined results from regional heritability analysis and genome-wide association have provided new advances in the knowledge of the genetic regulation of sex determination in Atlantic salmon, supporting that Ssa02 is the candidate chromosome for sex in this species and suggesting an alternative population lineage in Spanish wild populations according to the results from Ssa21.

A genetic linkage map for the salmon louse (Lepeophtheirus salmonis): evidence for high male:female and inter-familial recombination rate differences.

A salmon louse (Lepeophtheirus salmonis salmonis) genetic linkage map was constructed to serve as a genomic resource for future investigations into the biology of this important marine parasitic copepod species, and to provide insights into the inheritance patterns of genetic markers in this species. SNP genotyping of 8 families confirmed the presence of 15 linkage groups based upon the assignment of 93,773 markers. Progeny sample size weight adjusted map sizes in males (with the exception of SL12 and SL15) ranged in size from 96.50 cM (SL11) to 134.61 cM (SL06), and total combined map steps or bins ranged from 143 (SL09) to 203 (SL13). The SL12 male map was the smallest linkage group with a weight-averaged size of 3.05 cM with 6 recombination bins. Male:female specific recombination rate differences are 10.49:1 and represent one of the largest reported sex-specific differences for any animal species. Recombination ratio differences (M:F) ranged from 1.0 (SL12) to 29:1 (SL15). The number of markers exhibiting normal Mendelian segregation within the sex linkage group SL15 was extremely low (N = 80) in comparison to other linkage groups genotyped [range: 1459 (SL12)-10206 markers (SL05)]. Re-evaluation of Mendelian inheritance patterns of markers unassigned to any mapping parent according to hemizygous segregation patterns (models presented) identified matches for many of these markers to hemizygous patterns. The greatest proportion of these markers assigned to SL15 (N increased to 574). Inclusion of the hemizygous markers revised SL15 sex-specific recombination rate differences to 28:1. Recombination hot- and coldspots were identified across all linkage groups with all linkage groups possessing multiple peaks. Nine of 13 linkage groups evaluated possessed adjacent domains with hot-coldspot transitional zones. The most common pattern was for one end of the linkage to show elevated recombination in addition to internal regions. For SL01 and SL06, however, a terminal region with high recombination was not evident while a central domain possessing extremely high-recombination levels was present. High levels of recombination were weakly coupled to higher levels of SNP variation within domains, but this association was very strong for the central domains of SL01 and SL06. From the pooled paternal half-sib lots (several virgin females placed with 1 male), only 1 or two surviving family lots were obtained. Surviving families possessed parents where both the male and female possessed either inherently low or high recombination rates. This study provides insight into the organization of the sea louse genome, and describes large differences in recombination rate that exist among individuals of the same sex, and between the sexes. These differences in recombination rate may be coupled to the capabilities of this species to adapt to environmental and pharmaceutical treatments, given that family survivorship appears to be enhanced when parents have similar recombination levels.

Ancient chromosomal rearrangement associated with local adaptation of a postglacially colonized population of Atlantic Cod in the northwest Atlantic.

Intraspecific diversity is central to the management and conservation of exploited species, yet knowledge of how this diversity is distributed and maintained in the genome of many marine species is lacking. Recent advances in genomic analyses allow for genome-wide surveys of intraspecific diversity and offer new opportunities for exploring genomic patterns of divergence. Here, we analysed genome-wide polymorphisms to measure genetic differentiation between an offshore migratory and a nonmigratory population and to define conservation units of Atlantic Cod (Gadus morhua) in coastal Labrador. A total of 141 individuals, collected from offshore sites and from a coastal site within Gilbert Bay, Labrador, were genotyped using an ~11k single nucleotide polymorphism array. Analyses of population structure revealed strong genetic differentiation between migratory offshore cod and nonmigratory Gilbert Bay cod. Genetic differentiation was elevated for loci within a chromosomal rearrangement found on linkage group 1 (LG1) that coincides with a previously found double inversion associated with migratory and nonmigratory ecotype divergence of cod in the northeast Atlantic. This inverted region includes several genes potentially associated with adaptation to differences in salinity and temperature, as well as influencing migratory behaviour. Our work provides evidence that a chromosomal rearrangement on LG1 is associated with parallel patterns of divergence between migratory and nonmigratory ecotypes on both sides of the Atlantic Ocean.

Keeping them interested: a national study of factors that change medical student interest in working rurally.

INTRODUCTION: In most countries it remains a challenge to sustain the rural medical workforce. Based on evidence that medical students with rural backgrounds are more likely than their urban peers to enter rural practice, medical schools may have rural entry pathways. It is less well established what happens to career intentions during medical school. This study assessed how rural intentions persist or change during medical school and sought factors associated with either persistence or change in rural intention. METHODS: Students who participate in the Medical Schools Outcomes Database and Longitudinal Tracking project complete surveys at entry to and exit from medical school. They are asked about demographics, career intentions and influencing factors. This study used data from students at both of New Zealand's medical schools from 2006 to 2016. Participants were placed into one of four groups: rural intention at entry and rural intention at exit (R-R), urban at entry and rural at exit (U-R), rural at entry and urban at exit (R-U) or urban at entry and urban at exit (U-U). 'Rural' was defined as an area with a population of 100 000 or fewer. Differences among the groups in demographics and influencing factors were analysed. RESULTS: Overall, 4368 students completed an entry survey (response rate 85.9%), and 2243 students completed an exit survey (response rate 66.4%). A third intended to work in a rural area; of these, 49% had a rural background and 51% an urban background. From the linked entry and exit data (n=1114), there were 239 (21.4%), 188 (16.8%), 135 (12.1%) and 552 (49.5%) students in the R-R, U-R, R-U and U-U groups respectively (p<0.001). Most students had a stable geographical career intention. Of those who changed, more moved towards a rural intention than away from it. Medical students with a persistent rural pattern had characteristics of a rural background (70%), being female (68%), New Zealand European (76%) or having involvement with a rural club for at least 1 year (45%). These students were also more likely to express a GP career intention as their first choice (25%). There were small differences in age, but otherwise no particular demographic factors were associated with students who changed intention. Similarly there were only small differences in perceived career influencing factors among groups. CONCLUSION: This large national study shows a stability of career location intention for the majority of students. It confirms earlier findings of the importance of rural background in rural career preference, but shows that women may have a higher propensity for a persisting rural interest. Apart from providing quality experience in rural areas for all students, and facilitating rural clubs, the study did not reveal any other strategies that might be used by medical schools to either increase or prevent the loss of rural interest.

Genome-wide association study confirm major QTL for backfat fatty acid composition on SSC14 in Duroc pigs.

BACKGROUND: Fatty acid composition contributes importantly to meat quality and is essential to the nutritional value of the meat. Identification of genetic factors underlying levels of fatty acids can be used to breed for pigs with healthier meat. The aim of this study was to conduct genome-wide association studies (GWAS) to identify QTL regions affecting fatty acid composition in backfat from the pig breeds Duroc and Landrace. RESULTS: Using data from the Axiom porcine 660 K array, we performed GWAS on 454 Duroc and 659 Landrace boars for fatty acid phenotypes measured by near-infrared spectroscopy (NIRS) technology (C16:0, C16:1n-7, C18:0, C18:1n-9, C18:2n-6, C18:3n-3, total saturated fatty acids, monounsaturated fatty acids and polyunsaturated fatty acids). Two QTL regions on SSC4 and SSC14 were identified in Duroc for the de novo synthesized fatty acids traits, whereas one QTL on SSC8 was detected in Landrace for C16:1n-7. The QTL region on SSC14 has been reported in previous studies and a putative causative mutation has been suggested in the promoter region of the SCD gene. Whole genome re-sequencing data was used for genotype imputation and to fine map the SSC14 QTL region in Norwegian Duroc. This effort confirms the location of the QTL on this chromosome as well as suggesting other putative candidate genes in the region. The most significant single nucleotide polymorphisms (SNPs) located on SSC14 explain between 55 and 76% of the genetic variance and between 27 and 54% of the phenotypic variance for the de novo synthesized fatty acid traits in Norwegian Duroc. For the QTL region on SSC8 in Landrace, the most significant SNP explained 19% of the genetic variance and 5% of the phenotypic variance for C16:1n-7. CONCLUSIONS: This study confirms a major QTL affecting fatty acid composition on SSC14 in Duroc, which can be used in genetic selection to increase the level of fatty acid desaturation. The SSC14 QTL was not segregating in the Landrace population, but another QTL on SSC8 affecting C16:1n-7 was identified and might be used to increase the level of desaturation in meat products from this breed.