| 1. |
- Mullins, N., et al.
(författare)
-
Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
-
Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Abe, O, et al.
(författare)
-
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
-
Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
-
Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Guimond, S. E., et al.
(författare)
-
Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction
- 2022
-
Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 8:5, s. 527-545
-
Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.
|
|
| 11. |
|
|
| 12. |
- Coombes, R C, et al.
(författare)
-
Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.
- 2007
-
Ingår i: Lancet. - 1474-547X. ; 369:9561, s. 559-70
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. METHODS: 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. RESULTS: After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. CONCLUSIONS: Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.
|
|
| 13. |
- Coombes, Brandon J, et al.
(författare)
-
Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study.
- 2021
-
Ingår i: Complex psychiatry. - : S. Karger AG. - 2673-3005 .- 2673-298X. ; 7:3-4, s. 80-89
-
Tidskriftsartikel (refereegranskat)abstract
- Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.
|
|
| 14. |
|
|
| 15. |
- Coombes, D., et al.
(författare)
-
The basis for non-canonical ROK family function in the N-acetylmannosamine kinase from the pathogen Staphylococcus aureus
- 2020
-
Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 295:10, s. 3301-3315
-
Tidskriftsartikel (refereegranskat)abstract
- In environments where glucose is limited, some pathogenic bacteria metabolize host-derived sialic acid as a nutrient source. N-Acetylmannosamine kinase (NanK) is the second enzyme of the bacterial sialic acid import and degradation pathway and adds phosphate to N-acetylmannosamine using ATP to prime the molecule for future pathway reactions. Sequence alignments reveal that Gram-positive NanK enzymes belong to the Repressor, ORF, Kinase (ROK) family, but many lack the canonical Zn-binding motif expected for this function, and the sugar-binding EXGH motif is altered to EXGY. As a result, it is unclear how they perform this important reaction. Here, we study the Staphylococcus aureus NanK (SaNanK), which is the first characterization of a Gram-positive NanK. We report the kinetic activity of SaNanK along with the ligand?free, N-acetylmannosamine?bound and substrate analog GlcNAc?bound crystal structures (2.33, 2.20, and 2.20 ? resolution, respectively). These demonstrate, in combination with small-angle X-ray scattering, that SaNanK is a dimer that adopts a closed conformation upon substrate binding. Analysis of the EXGY motif reveals that the tyrosine binds to the N-acetyl group to select for the ?boat? conformation of N-acetylmannosamine. Moreover, SaNanK has a stacked arginine pair coordinated by negative residues critical for thermal stability and catalysis. These combined elements serve to constrain the active site and orient the substrate in lieu of Zn binding, representing a significant departure from canonical NanK binding. This characterization provides insight into differences in the ROK family and highlights a novel area for antimicrobial discovery to fight Gram-positive and S. aureus infections.
|
|
| 16. |
- Huang, X. F., et al.
(författare)
-
Genomewide Association Study of Acute Anterior Uveitis Identifies New Susceptibility Loci
- 2020
-
Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 61:6
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Acute anterior uveitis (AAU) is a common intraocular inflammatory disease. AAU occurs in 30% to 50% of patients with ankylosing spondylitis (AS), and both conditions are strongly associated with human leukocyte antigen (HLA)-B 27 , implying a shared etiology. This study aims to apply genomewide association study (GWAS) to characterize the genetic associations of AAU and their relationship to the genetics of AS. METHODS. We undertook the GWAS analyses in 2752 patients with AS with AAU (cases) and 3836 patients with AS without AAU (controls). There were 7,436,415 single-nucleotide polymorphisms (SNPs) available alter SNP microarray genotyping, imputation, and quality-control filtering. RESULTS. We identified one locus associated with AAU at genomewide significance: rs9378248 (P = 2.69 x 10(-8), odds ratio [OR] = 0.78), lying close to HLA-B. Suggestive association was observed at 11 additional loci, including previously reported AS loci ERAP1 (rs27529, P = 2.19 x 10(-7), OR = 1.22) and NOS2 (rs2274894, P = 8.22 x 10(-7), OR = 0.83). Multiple novel suggestive associations were also identified, including MERTK (rsl0171979, P = 2.56 x 10(-6), OR = 1.20), KIFAP3 (rs508063, P = 5.64 x 10(-7), OR = 1.20), CLCN7 (rs67412457, P = 1.33 x 10(-6), OR = 1.25), ACAA2 (rs9947182, P = 9.70 x 10(-7), OR = 1.37), and 5 intergenic loci. The SNP-based heritability is approximately 0.5 for AS alone, and is much higher (approximately 0.7) for AS with AAU. Consistent with the high heritability, a genomewide polygenic risk score shows strong power in identifying individuals at high risk of either AS with AAU or AS alone. CONCLUSIONS. We report here the first GWAS for AAU and identify new susceptibility loci. Our findings confirm the strong overlap in etiopathogenesis of AAU with AS, and also provide new insights into the genetic basis of AAU.
|
|
| 17. |
|
|
| 18. |
- Millischer, V., et al.
(författare)
-
Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden
- 2022
-
Ingår i: Lancet Psychiatry. - 2215-0374. ; 9:6, s. 447-457
-
Tidskriftsartikel (refereegranskat)abstract
- Background Lithium is the most effective treatment for bipolar disorder, resulting in strong suicide prevention effects. The therapeutic range of lithium, however, is narrow and treatment initiation requires individual titration to address inter-individual variability. We aimed to improve lithium dose prediction using clinical and genomic data. Methods We performed a population pharmacokinetic study followed by a genome-wide association study (GWAS), including two clinical Swedish cohorts. Participants in cohort 1 were from specialised outpatient clinics at Huddinge Hospital, in Stockholm, Sweden, and participants in cohort 2 were identified using the Swedish National Quality Registry for Bipolar disorder (BipolaR). Patients who received a lithium dose corresponding to at least one tablet of lithium sulphate (6 mmol) per day and had clinically relevant plasma concentrations of lithium were included in the study. Data on age, sex, bodyweight, height, creatinine concentration, estimated glomerular filtration rate (eGFR), lithium preparation, number of tablets of lithium per day, serum lithium concentration, and medications affecting kidney function (C09 antihypertensives, C03 [except C03D] sodium-retaining diuretics, and non-steroidal anti-inflammatory drugs) were obtained retrospectively for several timepoints when possible from electronic health records, BipolaR, and the Swedish prescription registry. The median time between timepoints was 1.07 years for cohort 1 and 1.09 years for cohort 2. The primary outcome of interest was the natural logarithm of total body clearance for lithium (CLLi) associated with the clinical variables. The residual effects after accounting for age and sex, representing the individual-level effects (CLLi,age/sex), were used as the dependent variable in a GWAS. Findings 2357 patients who were administered lithium (1423 women [60.4%] and 934 men [39.6%]; mean age 53.6 years [range 17-89], mainly of European descent) were included and 5627 data points were obtained. Age (variance explained [R-2]: R-cohort1(2)=0.41 and R-cohort2(2)=0.31; both p<0.0001), sex (R-cohort1(2)=0.0063 [p=0.045] and R-cohort2(2)=0.026 [p<0.0001]), eGFR (R-cohort1(2)=0.38 and R-cohort2(2)=0.0; both p<0.0001), comedication with diuretics (R-cohort1(2)=0.0058 [p=0.014] and R-cohort2(2)=0.0026 [p<0.0001]), and agents acting on the renin-aldosterone-angiotensin system (R-cohort1(2)=0.028 and R-cohort2(2)=0.015; both p<0.0001) were clinical predictors of CLLi. Notably, an association between CLLi and serum lithium was observed, with a lower CLLi being associated with higher serum lithium (R-cohort1(2)=0.13 and R-cohort2(2)=0.15; both p<0.0001). In a GWAS of CLLi,age/sex, one locus was associated with a change in CLLi (rs583503; beta=-0.053 [95% CI -0.071 to -0.034]; p<0.00000005). We also found enrichment of the associations with genes expressed in the medulla (p=0.0014, corrected FDR=0.04) and cortex of the kidney (p=0.0015, corrected FDR=0.04), as well as associations with polygenic risk scores for eGFR (p value threshold: 0.05, p=0.01), body-mass index (p value threshold: 0.05, p=0.00025), and blood urea nitrogen (p value threshold: 0.001, p=0.00043). The model based on six clinical predictors explained 61.4% of the variance in CLLi in cohort 1 and 49.8% in cohort 2. Adding genetic markers did not lead to major improvement of the models: within the subsample of genotyped individuals, the variance explained only increased from 59.32% to 59.36% in cohort 1 and from 49.21% to 50.03% in cohort 2 when including rs583503 and the four first principal components. Interpretation Our model predictors could be used clinically to better guide lithium dosage, shortening the time to reach therapeutic concentrations, thus improving care. Identification of the first genomic locus and PRS to be associated with CLLi introduces the opportunity of individualised medicine in lithium treatment. Copyright (C) 2022 Elsevier Ltd. All rights reserved.
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
- Sharma, Rohini, et al.
(författare)
-
Multicenter Reproducibility of F-18-Fluciclatide PET Imaging in Subjects with Solid Tumors
- 2015
-
Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 56:12, s. 1855-1861
-
Tidskriftsartikel (refereegranskat)abstract
- Integrins are upregulated on both tumor cells and associated vasculature, where they play an important role in angiogenesis and metastasis. Fluciclatide is an arginine-glycine-aspartic acid peptide with high affinity for alpha(v)beta(3)/alpha(v)beta(5) integrin, which can be radio-labeled for PET imaging of angiogenesis. Thus, F-18-fluciclatide is a potential biomarker of therapeutic response to antiangiogenic inhibitors. The aim of this study was to evaluate the reproducibility of F-18-fluciclatide in multiple solid-tumor types. Methods: Thirty-nine patients underwent PET/CT scanning at 40, 65, and 90 min after injection of F-18-fluciclatide (maximum, 370 MBq) on 2 separate days (2-9 d apart). Patients did not receive any therapy between PET/CT scans. F-18-fluciclatide images were reported and quantitative measures of uptake were extracted using the PERCIST methodology. Intrasubject reproducibility of PET uptake in all measurable lesions was evaluated by calculating relative differences in SUV between PET scans for each lesion during the 2 imaging sessions. Results: Thirty-nine measurable lesions were detected in 26 patients. Lesion uptake correlated strongly across imaging sessions (r = 0.92, P < 0.05, at 40 min; r = 0.94, P < 0.05, at 65 min; r = 0.94, P, 0.05, at 90 min) with a mean relative difference and SD of the relative difference of 0.006 +/- 0.18 at 40 min, 0.003 +/- 0.19 at 65 min, and 0.025 +/- 0.20 at 90 min. This reflects 95% limits of repeatability of 35%-39% for the difference between the 2 SUV measurements or a variability of 18%-20% in agreement from that observed in well-calibrated multicenter F-18-FDG studies. Conclusion: The test-retest reproducibility of F-18-fluciclatide across multiple tumor types has been measured and shown to be acceptable. This is an important step in the development of this in vivo biomarker to identify and quantify response to antiangiogenic therapy in cancer patients.
|
|
| 22. |
- Tran, DL, et al.
(författare)
-
Exercise Intolerance, Benefits, and Prescription for People Living With a Fontan Circulation: The Fontan Fitness Intervention Trial (F-FIT)-Rationale and Design
- 2022
-
Ingår i: Frontiers in pediatrics. - : Frontiers Media SA. - 2296-2360. ; 9, s. 799125-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Despite developments in surgical techniques and medical care, people with a Fontan circulation still experience long-term complications; non-invasive therapies to optimize the circulation have not been established. Exercise intolerance affects the majority of the population and is associated with worse prognosis. Historically, people living with a Fontan circulation were advised to avoid physical activity, but a small number of heterogenous, predominantly uncontrolled studies have shown that exercise training is safe—and for unique reasons, may even be of heightened importance in the setting of Fontan physiology. The mechanisms underlying improvements in aerobic exercise capacity and the effects of exercise training on circulatory and end-organ function remain incompletely understood. Furthermore, the optimal methods of exercise prescription are poorly characterized. This highlights the need for large, well-designed, multi-center, randomized, controlled trials.Aims and Methods: The Fontan Fitness Intervention Trial (F-FIT)—a phase III clinical trial—aims to optimize exercise prescription and delivery in people with a Fontan circulation. In this multi-center, randomized, controlled study, eligible Fontan participants will be randomized to either a 4-month supervised aerobic and resistance exercise training program of moderate-to-vigorous intensity followed by an 8-month maintenance phase; or usual care (control group). Adolescent and adult (≥16 years) Fontan participants will be randomized to either traditional face-to-face exercise training, telehealth exercise training, or usual care in a three-arm trial with an allocation of 2:2:1 (traditional:telehealth:control). Children (<16 years) will be randomized to either a physical activity and exercise program of moderate-to-vigorous intensity or usual care in a two-arm trial with a 1:1 allocation. The primary outcome is a change in aerobic exercise capacity (peak oxygen uptake) at 4-months. Secondary outcomes include safety, and changes in cardiopulmonary exercise testing measures, peripheral venous pressure, respiratory muscle and lung function, body composition, liver stiffness, neuropsychological and neurocognitive function, physical activity levels, dietary and nutritional status, vascular function, neurohormonal activation, metabolites, cardiac function, quality of life, musculoskeletal fitness, and health care utilization. Outcome measures will be assessed at baseline, 4-months, and 12-months. This manuscript will describe the pathophysiology of exercise intolerance in the Fontan circulation and the rationale and protocol for the F-FIT.
|
|
| 23. |
- Coombes, S., et al.
(författare)
-
Waves in Random Neural Media
- 2012
-
Ingår i: Discrete and Continuous Dynamical Systems. - : American Institute of Mathematical Sciences (AIMS). - 1078-0947 .- 1553-5231. ; 32:8, s. 2951-2970
-
Tidskriftsartikel (refereegranskat)abstract
- Translationally invariant integro-differential equations are a common choice of model in neuroscience for describing the coarse-grained dynamics of cortical tissue. Here we analyse the propagation of travelling wavefronts in models of neural media that incorporate some form of modulation or randomness such that translational invariance is broken. We begin with a study of neural architectures in which there is a periodic modulation of the neuronal connections. Recent techniques from two-scale convergence analysis are used to construct a homogenized model in the limit that the spatial modulation is rapid compared with the scale of the long range connections. For the special case that the neuronal firing rate is a Heaviside we calculate the speed of a travelling homogenized front exactly and find how the wave speed changes as a function of the amplitude of the modulation. For this special case we further show how to obtain more accurate results about wave speed and the conditions for propagation failure by using an interface dynamics approach that circumvents the requirement of fast modulation. Next we turn our attention to forms of disorder that arise via the variation of firing rate properties across the tissue. To model this we draw parameters of the firing rate function from a distribution with prescribed spatial correlations and analyse the corresponding fluctuations in the wave speed. Finally we consider generalisations of the model to incorporate adaptation and stochastic forcing and show how recent numerical techniques developed for stochastic partial differential equations can be used to determine the wave speed by minimising the L-2 norm of a travelling disordered activity profile against a fixed test function.
|
|
| 24. |
- Davids, Charlie J, et al.
(författare)
-
Acute cellular and molecular responses and chronic adaptations to low-load blood flow restriction and high-load resistance exercise in trained individuals.
- 2021
-
Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 131:6, s. 1731-1749
-
Tidskriftsartikel (refereegranskat)abstract
- Blood flow restriction (BFR) with low-load resistance exercise (RE) is often used as a surrogate to traditional high-load RE to stimulate muscular adaptations, such as hypertrophy and strength. However, it is not clear whether such adaptations are achieved through similar cellular and molecular processes. We compared changes in muscle function, morphology and signaling pathways between these differing training protocols. Twenty-one males and females (mean ± SD: 24.3 ± 3.1 years) experienced with resistance training (4.9 ± 2.6 years) performed nine weeks of resistance training (three times per week) with either high-loads (75-80% 1RM; HL-RT), or low-loads with BFR (30-40% 1RM; LL-BFR). Before and after the training intervention, resting muscle biopsies were collected, and quadricep cross-sectional area (CSA), muscular strength and power were measured. Approximately 5 days following the intervention, the same individuals performed an additional 'acute' exercise session under the same conditions, and serial muscle biopsies were collected to assess hypertrophic- and ribosomal-based signaling stimuli. Quadricep CSA increased with both LL-BFR (7.4±4.3%) and HL-RT (4.6±2.9%), with no significant differences between training groups (p=0.37). Muscular strength also increased in both training groups, but with superior gains in squat 1RM occurring with HL-RT (p<0.01). Acute phosphorylation of several key proteins involved in hypertrophy signaling pathways, and expression of ribosomal RNA transcription factors occurred to a similar degree with LL-BFR and HL-RT (all p>0.05 for between-group comparisons). Together, these findings validate low-load resistance training with continuous BFR as an effective alternative to traditional high-load resistance training for increasing muscle hypertrophy in trained individuals.
|
|
| 25. |
|
|
| 26. |
- Gilson, Nicholas D, et al.
(författare)
-
High intensity and sprint interval training, and work-related cognitive function in adults : A systematic review.
- 2023
-
Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : John Wiley & Sons. - 0905-7188 .- 1600-0838. ; 33:6, s. 814-833
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To assess evidence on the impact of acute and chronic high intensity interval training (HIIT) and sprint interval training (SIT) on work-related performance tests of cognitive function in adults.METHODS: The databases PubMed, CINAHL, Scopus, PsycINFO, Embase and the Cochrane Library were searched for relevant articles up to August 2022. Eligible studies assessed the effects of HIIT (70-100% VO2max ) and/or SIT (≥100% VO2max ) on cognitive function test scores in cognitively healthy adults, relative to a control or comparative exercise group/condition. Data on participant characteristics, exercise protocol, key outcomes and intervention setting were extracted. Study quality was assessed using a 9 (single session HIIT/SIT) and 14 (multiple session HIIT/SIT) item checklist.RESULTS: 36 studies (15 countries; n=11 to 945 participants) met inclusion criteria. Mean quality scores were 'fair-to-good' for acute (single session; mean=6.9 [SD 1.0]), and chronic (multiple session; mean=9.8 [SD 1.6]) training studies. Eighteen from 36 studies (12/20 [55%] acute and 6/16 [38%] chronic training studies) evidenced significant improvements in aspects of cognitive function related to work performance (i.e., attention, inhibition, memory, information processing speed, cognitive flexibility, intelligence, reaction time and learning). Only four studies tested the impact of HIIT/SIT on cognitive function in a work-based setting (e.g., the office or home).CONCLUSIONS: While there is promising evidence, particularly from acute training studies, to indicate that high intensity, short duration exercise benefits cognitive function in adults, there is very limited evidence of application in workplace contexts. To better understand the potential benefits to employee performance and safety, HIIT/SIT and cognitive function research needs to transition from laboratory to 'in-situ' occupational settings.
|
|
