Increased Thermal Challenges Differentially Modulate Neural Plasticity and Stress Responses in Post-Smolt Atlantic Salmon (Salmo salar)

The successful transfer of farmed post-smolt Atlantic salmon (Salmo salar) depends on proper stress responses and cognitive functions during the early seawater (SW) phase. However, with increasing summer oceanic temperatures, these processes may become a challenge, implicating allostasis and welfare. Therefore, we examined the effect of post-smolt transfer from 10°C SW to elevated temperatures (13°C, 16°C, and 18°C) on plasma cortisol and telencephalic genes modulating cognition (neurod, bdnf, pcna, and c-fos) and stress-axis regulation (crf, crfbp, mr, gr1, gr2, and hsd11b2). Fish were sampled at i) 1 day following transfer, ii) 45 days of acclimation, and iii) 45 days and 1 h after an acute challenge test (ACT) using confinement stress. Fish transferred to 13°C retained stress responses, elevating levels of cortisol, crf, mr, gr2, c-fos, and bdnf and maintaining levels of neurod and pcna. Contrastingly, although cortisol increased at 16°C, telencephalic genes reverted to an inhibition of stress responses, increasing crfbp and gr1 complemented with dampened bdnf, neurod, and c-fos responses. However, transferring post-smolts to 18°C showed the most adverse effects, having absent stress responses (cortisol and c-fos), elevated crfbp, and a suppression of hsd11b2 and neurod. The hsd11b2 downregulation implies low cortisol inhibition in line with absent modulations in corticosteroid receptors and stress responses. These results suggest that the transfer to 16°C and 18°C inhibits the normal reactive response of post-smolts. Following acclimation (45 days), cortisol levels were basal for all groups; however, post-smolts at 16°C and 18°C maintained a telencephalic inhibition of key regulatory genes (crf, mr, gr2, and hsd11b2), alongside a lower mr/gr1 ratio, an indicator of chronic allostatic load. Moreover, neural plasticity (neurod and pcna) was suppressed at 16°C and 18°C, suggesting impacts of elevated allostatic loads with potentially inferior cognitive capacities. Despite maintaining similar plasma cortisol responses to ACTs, post-smolts at 16°C and 18°C elevated neural activation (c-fos) to stress, implying greater challenges, with the 18°C group also elevating the level of bdnf. In summary, the telencephalon shows that post-smolts transferred to 16°C and 18°C continue to struggle with the thermal allostatic loads even after acclimation, which is not revealed by plasma cortisol levels, grounding the importance of telencephalic measures in identifying environmental thresholds and hidden challenges.publishedVersio

Exposure to cold temperatures differentially modulates neural plasticity and stress responses in post-smolt Atlantic salmon (Salmo salar)

The transfer success of farmed post-smolt Atlantic salmon (Salmo salar) to sea-cages rely on neural adaptions to promote stress resilience. As low temperatures impact physiology, this suggests that off-season transfer to cold waters may be challenging. To address this, post-smolts reared at 13 °C seawater were abruptly transferred to 10 °C, 7 °C, and 4 °C, then acclimated to these respective temperatures for 58-days followed by an acute challenge test (ACT) using confinement stress. Plasma and brain samples were collected after i) the abrupt temperature transfer at 1-h and 1-day, ii) 58-days of acclimation, and iii) 1-h post ACT. In tandem to measuring plasma cortisol levels, the expression of key genes involved in telencephalic regulation (crf, crfbp, mr, gr1, gr2 and hsd11b2) and neural plasticity (neurod, bdnf, pcna, and cfos) were analyzed. Post-smolts exposed to the 7 °C and 4 °C displayed the largest alteration in telencephalic functions, differentially regulating mr and gr1, to elevate the mr/g1 ratio for downregulating Gr1, proposing an elevated stress loads. After acclimation, these coincided with blunted stress responses capacities to ACTs for both cortisol and telencephalic neural activity (cfos), suggesting a continuation of challenges and reduced the capacity to mount a stress response. Concomitantly, these telencephalic alterations in CRs coincided with a differential modulation in neural plasticity, measured as elevated bdnf and neurod during the abrupt transfer period (acute) and after acclimation (prolonged), respectively, revealing neural responses are still robustly maintained to retain a degree of stress resilience. However, exposure of post-smolts to 4 °C clearly induced the most adverse and suppressive effects in telencephalic functions, cued by a suppression in pcna and stress response capacities, downregulation in the CRF system, and largest elevation in the mr/g1 ratio. Conversely, acclimating post-smolts to 7 °C elevated 11hsdb2 proposing a greater inhibition of cortisol action that may point to still adequate maintenance of CR and neural processes. Taken together, these findings show that cold temperatures alter key neural processes required for maintaining proper stress management, providing an alternative explanation for reductions in fish stress reactivity commonly observed with declining temperature. Therefore, exposing post-smolts at 13 °C to temperature reductions of 6 °C or greater should be avoided in aquaculture.publishedVersio

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Adipose tissue fatty acids suggest spatial and temporal dietary differences in great cormorants of the Baltic Sea area

Increased numbers of great cormorants (Phalacrocorax carbo) in the Baltic Sea may have local impacts on fisheries and salmonid hatcheries. We studied spatial and temporal variability in cormorant diet, and potential consumption of hatchery salmonids, by analysing knee subcutaneous adipose tissue fatty acids (FA) of specimens (N = 77) collected along Swedish and Finnish coasts in different seasons during 2013–2017. The FA profiles of the subspecies sinensis and carbo were similar, with large individual variation. The proportion of C18 polyunsaturated FAs (PUFAs) was the largest in the north, whereas the proportion of C20–22 monounsaturated FAs (MUFAs) increased towards the south, reflecting diminishing freshwater and increasing marine food web characteristics towards the south. As an exception, the C20–22 MUFA percentage was high in sinensis collected in June 2017 from the northern Baltic Sea. The source of C20–22 MUFAs was probably hatchery salmonids, raised on ocean fish hatchery feed and released 10 days before, near the cormorant capture site. The FA profiles of northern and southern cormorants differed from each other both in early and late summer samples, suggesting spatially different diets. The largest individual variation was found in 22:1n-11, characteristic of ocean zooplanktivorous fish, and likely originating from Atlantic wild or Baltic Sea hatchery-reared fish. This study shows that adipose tissue FA profiles can be used as proxies for seabird diet monitoring and indicators of predation on hatchery-reared fish. Obtaining quantitative estimates on the proportions of dietary fish species requires future feeding experiments, allowing calibration between the FA compositions and diet.Peer reviewe

Exposure to cold temperatures differentially modulates neural plasticity and stress responses in post-smolt Atlantic salmon (Salmo salar)

The transfer success of farmed post-smolt Atlantic salmon (Salmo salar) to sea-cages rely on neural adaptions to promote stress resilience. As low temperatures impact physiology, this suggests that off-season transfer to cold waters may be challenging. To address this, post-smolts reared at 13 °C seawater were abruptly transferred to 10 °C, 7 °C, and 4 °C, then acclimated to these respective temperatures for 58-days followed by an acute challenge test (ACT) using confinement stress. Plasma and brain samples were collected after i) the abrupt temperature transfer at 1-h and 1-day, ii) 58-days of acclimation, and iii) 1-h post ACT. In tandem to measuring plasma cortisol levels, the expression of key genes involved in telencephalic regulation (crf, crfbp, mr, gr1, gr2 and hsd11b2) and neural plasticity (neurod, bdnf, pcna, and cfos) were analyzed. Post-smolts exposed to the 7 °C and 4 °C displayed the largest alteration in telencephalic functions, differentially regulating mr and gr1, to elevate the mr/g1 ratio for downregulating Gr1, proposing an elevated stress loads. After acclimation, these coincided with blunted stress responses capacities to ACTs for both cortisol and telencephalic neural activity (cfos), suggesting a continuation of challenges and reduced the capacity to mount a stress response. Concomitantly, these telencephalic alterations in CRs coincided with a differential modulation in neural plasticity, measured as elevated bdnf and neurod during the abrupt transfer period (acute) and after acclimation (prolonged), respectively, revealing neural responses are still robustly maintained to retain a degree of stress resilience. However, exposure of post-smolts to 4 °C clearly induced the most adverse and suppressive effects in telencephalic functions, cued by a suppression in pcna and stress response capacities, downregulation in the CRF system, and largest elevation in the mr/g1 ratio. Conversely, acclimating post-smolts to 7 °C elevated 11hsdb2 proposing a greater inhibition of cortisol action that may point to still adequate maintenance of CR and neural processes. Taken together, these findings show that cold temperatures alter key neural processes required for maintaining proper stress management, providing an alternative explanation for reductions in fish stress reactivity commonly observed with declining temperature. Therefore, exposing post-smolts at 13 °C to temperature reductions of 6 °C or greater should be avoided in aquaculture

Exposure to cold temperatures differentially modulates neural plasticity and stress responses in post-smolt Atlantic salmon (Salmo salar)

The transfer success of farmed post-smolt Atlantic salmon (Salmo salar) to sea-cages rely on neural adaptions to promote stress resilience. As low temperatures impact physiology, this suggests that off-season transfer to cold waters may be challenging. To address this, post-smolts reared at 13 °C seawater were abruptly transferred to 10 °C, 7 °C, and 4 °C, then acclimated to these respective temperatures for 58-days followed by an acute challenge test (ACT) using confinement stress. Plasma and brain samples were collected after i) the abrupt temperature transfer at 1-h and 1-day, ii) 58-days of acclimation, and iii) 1-h post ACT. In tandem to measuring plasma cortisol levels, the expression of key genes involved in telencephalic regulation (crf, crfbp, mr, gr1, gr2 and hsd11b2) and neural plasticity (neurod, bdnf, pcna, and cfos) were analyzed. Post-smolts exposed to the 7 °C and 4 °C displayed the largest alteration in telencephalic functions, differentially regulating mr and gr1, to elevate the mr/g1 ratio for downregulating Gr1, proposing an elevated stress loads. After acclimation, these coincided with blunted stress responses capacities to ACTs for both cortisol and telencephalic neural activity (cfos), suggesting a continuation of challenges and reduced the capacity to mount a stress response. Concomitantly, these telencephalic alterations in CRs coincided with a differential modulation in neural plasticity, measured as elevated bdnf and neurod during the abrupt transfer period (acute) and after acclimation (prolonged), respectively, revealing neural responses are still robustly maintained to retain a degree of stress resilience. However, exposure of post-smolts to 4 °C clearly induced the most adverse and suppressive effects in telencephalic functions, cued by a suppression in pcna and stress response capacities, downregulation in the CRF system, and largest elevation in the mr/g1 ratio. Conversely, acclimating post-smolts to 7 °C elevated 11hsdb2 proposing a greater inhibition of cortisol action that may point to still adequate maintenance of CR and neural processes. Taken together, these findings show that cold temperatures alter key neural processes required for maintaining proper stress management, providing an alternative explanation for reductions in fish stress reactivity commonly observed with declining temperature. Therefore, exposing post-smolts at 13 °C to temperature reductions of 6 °C or greater should be avoided in aquaculture

Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits