| 1. |
- Abdollahpur, Mostafa, et al.
(author)
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A subspace projection approach to quantify respiratory variations in the f-wave frequency trend
- 2022
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 13
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Journal article (peer-reviewed)abstract
- Background: The autonomic nervous system (ANS) is known as a potent modulator of the initiation and perpetuation of atrial fibrillation (AF), hence information about ANS activity during AF may improve treatment strategy. Respiratory induced ANS variation in the f-waves of the ECG may provide such information. Objective: This paper proposes a novel approach for improved estimation of such respiratory induced variations and investigates the impact of deep breathing on the f-wave frequency in AF patients. Methods: A harmonic model is fitted to the f-wave signal to estimate a high-resolution f-wave frequency trend, and an orthogonal subspace projection approach is employed to quantify variations in the frequency trend that are linearly related to respiration using an ECG-derived respiration signal. The performance of the proposed approach is evaluated and compared to that of a previously proposed bandpass filtering approach using simulated f-wave signals. Further, the proposed approach is applied to analyze ECG data recorded for 5 min during baseline and 1 min deep breathing from 28 AF patients from the Swedish cardiopulmonary bioimage study (SCAPIS). Results: The simulation results show that the estimates of respiratory variations obtained using the proposed approach are more accurate than estimates obtained using the previous approach. Results from the analysis of SCAPIS data show no significant differences between baseline and deep breathing in heart rate (75.5 ± 22.9 vs. 74 ± 22.3) bpm, atrial fibrillation rate (6.93 ± 1.18 vs. 6.94 ± 0.66) Hz and respiratory f-wave frequency variations (0.130 ± 0.042 vs. 0.130 ± 0.034) Hz. However, individual variations are large with changes in heart rate and atrial fibrillatory rate in response to deep breathing ranging from -9% to +5% and -8% to +6%, respectively and there is a weak correlation between changes in heart rate and changes in atrial fibrillatory rate ( r = 0.38, p < 0.03). Conclusion: Respiratory induced f-wave frequency variations were observed at baseline and during deep breathing. No significant changes in the magnitude of these variations in response to deep breathing was observed in the present study population.
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| 2. |
- Abdollahpur, Mostafa, et al.
(author)
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Respiratory Induced Modulation in f-Wave Characteristics During Atrial Fibrillation
- 2021
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 12
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Journal article (peer-reviewed)abstract
- The autonomic nervous system (ANS) is an important factor in cardiac arrhythmia, and information about ANS activity during atrial fibrillation (AF) may contribute to personalized treatment. In this study we aim to quantify respiratory modulation in the f-wave frequency trend from resting ECG. First, an f-wave signal is extracted from the ECG by QRST cancelation. Second, an f-wave model is fitted to the f-wave signal to obtain a high resolution f-wave frequency trend and an index for signal quality control ((Formula presented.)). Third, respiratory modulation in the f-wave frequency trend is extracted by applying a narrow band-pass filter. The center frequency of the band-pass filter is determined by the respiration rate. Respiration rate is estimated from a surrogate respiration signal, obtained from the ECG using homomorphic filtering. Peak conditioned spectral averaging, where spectra of sufficient quality from different leads are averaged, is employed to obtain a robust estimate of the respiration rate. The envelope of the filtered f-wave frequency trend is used to quantify the magnitude of respiratory induced f-wave frequency modulation. The proposed methodology is evaluated using simulated f-wave signals obtained using a sinusoidal harmonic model. Results from simulated signals show that the magnitude of the respiratory modulation is accurately estimated, quantified by an error below 0.01 Hz, if the signal quality is sufficient ((Formula presented.)). The proposed method was applied to analyze ECG data from eight pacemaker patients with permanent AF recorded at baseline, during controlled respiration, and during controlled respiration after injection of atropine, respectively. The magnitude of the respiratory induce f-wave frequency modulation was 0.15 ± 0.01, 0.18 ± 0.02, and 0.17 ± 0.03 Hz during baseline, controlled respiration, and post-atropine, respectively. Our results suggest that parasympathetic regulation affects the magnitude of respiratory induced f-wave frequency modulation.
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| 3. |
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| 4. |
- Adiels, Martin, 1976, et al.
(author)
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Kinetic Studies to Elucidate Impaired Metabolism of Triglyceride-rich Lipoproteins in Humans.
- 2015
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 6:NOV, s. 342-
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Research review (peer-reviewed)abstract
- To develop novel strategies for prevention and treatment of dyslipidemia, it is essential to understand the pathophysiology of dyslipoproteinemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion, and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labeled with stable isotopes and mathematical modeling, provides us with a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering our understanding of the pathogenesis of dyslipoproteinemia.
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| 5. |
- Aggarwal, Tanya, et al.
(author)
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Knockdown of SLC38 Transporter Ortholog-CG13743 Reveals a Metabolic Relevance in Drosophila
- 2020
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In: Frontiers in Physiology. - : FRONTIERS MEDIA SA. - 1664-042X. ; 10
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Journal article (peer-reviewed)abstract
- Solute Carrier (SLC) is a cluster of families of membrane bound transporters, of which many members lack defined substrate profile, and many more are poorly characterized. Many play a vital role in regulating metabolic systems, protein synthesis, and post translational modifications. SLC38 is one of the families of SLCs, which are also known as sodium-coupled neutral amino acid transporters (SNATs). In mice, it has 11 members (SNAT1-11) but in Drosophila there are two homologs for the SLC38 family; CG13743 and CG30394. Here, we show characteristics of Drosophila CG13743 which closely resembles SLC38A11 in humans. SLC38A11 still remains an orphan member of the SLC38 family which has not been functionally well studied. We used the UAS-GAL4 system to investigate and control gene expression using RNAi lines for ubiquitous knockdown of the CG13743 gene. It was found to be expressed mainly in salivary gland and brain. Knockdown flies had reduced body weight and consumed less sugar compared with controls. The gene knockdown also affected stored energy pools (lipids and glycogen) and influenced feeding pattern and total activity. In all, this shows novel findings for the characterization of CG13743 in Drosophila and a possible role in maintaining general metabolic pathways and behavior of the fly.
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| 6. |
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| 7. |
- Alajbegovic, Azra, et al.
(author)
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Molecular regulation of arterial aneurysms : Role of actin dynamics and microRNAs in vascular smooth muscle
- 2017
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 8:AUG, s. 569-569
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Journal article (peer-reviewed)abstract
- Aortic aneurysms are defined as an irreversible increase in arterial diameter by morethan 50% relative to the normal vessel diameter. The incidence of aneurysm rupture isabout 10 in 100,000 persons per year and ruptured arterial aneurysms inevitably resultsin serious complications, which are fatal in about 40% of cases. There is also a hereditarycomponent of the disease and dilation of the ascending thoracic aorta is often associatedwith congenital heart disease such as bicuspid aortic valves (BAV). Furthermore, specificmutations that have been linked to aneurysm affect polymerization of actin filaments.Polymerization of actin is important to maintain a contractile phenotype of smooth musclecells enabling these cells to resist mechanical stress on the vascular wall caused by theblood pressure according to the law of Laplace. Interestingly, polymerization of actin alsopromotes smooth muscle specific gene expression via the transcriptional co-activatorMRTF, which is translocated to the nucleus when released from monomeric actin. Inaddition to genes encoding for proteins involved in the contractile machinery, recentstudies have revealed that several non-coding microRNAs (miRNAs) are regulated bythis mechanism. The importance of these miRNAs for aneurysm development is onlybeginning to be understood. This review will summarize our current understanding aboutthe influence of smooth muscle miRNAs and actin polymerization for the developmentof arterial aneurysms.
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| 8. |
- Anand-Ivell, Ravinder, et al.
(author)
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Amniotic fluid INSL3 measured during the critical time window in human pregnancy relates to cryptorchidism, hypospadias, and phthalate load : A large case-control study
- 2018
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9:APR
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Journal article (peer-reviewed)abstract
- The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by perfluorooctane sulfonate (PFOS) exposure, and by smoking, suggesting an adrenal stress response. In contrast, the testis specific biomarkers insulin-like peptide 3 (INSL3) and androstenedione are negatively impacted by the phthalate endocrine disruptors. Using a case-control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13-16, and some, though not all steroid biomarkers. Cases are also linked to a specifically increased variance in the Leydig cell biomarker INSL3 compared to controls, an effect exacerbated by maternal smoking. No influence of phthalate metabolites or PFOS was evident on the distribution of cases and controls. Considering that several animal and human studies have shown a negative impact of phthalate load on fetal and cord blood INSL3, respectively, the present results suggest that such endocrine disruptors may rather be altering the relative dynamics of testicular development and consequent hormone production, leading to a desynchronization of tissue organization during fetal development. Being born small for gestational age appears not to impact on the testicular biomarker INSL3 in second trimester amniotic fluid.
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| 9. |
- Andersson, Erik, 1984-, et al.
(author)
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A Comparison between Different Methods of Estimating Anaerobic Energy Production
- 2018
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9:FEB
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Journal article (peer-reviewed)abstract
- Purpose: The present study aimed to compare four methods of estimating anaerobic energy production during supramaximal exercise.Methods: Twenty-one junior cross-country skiers competing at a national and/or international level were tested on a treadmill during uphill (7°) diagonal-stride (DS) roller-skiing. After a 4-minute warm-up, a 4 × 4-min continuous submaximal protocol was performed followed by a 600-m time trial (TT). For the maximal accumulated O2 deficit (MAOD) method the V." role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V.V.O2-speed regression relationship was used to estimate the V." role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V.V.O2 demand during the TT, either including (4+Y, method 1) or excluding (4-Y, method 2) a fixed Y-intercept for baseline V." role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V.V.O2. The gross efficiency (GE) method (method 3) involved calculating metabolic rate during the TT by dividing power output by submaximal GE, which was then converted to a V." role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V.V.O2 demand. An alternative method based on submaximal energy cost (EC, method 4) was also used to estimate V." role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V.V.O2 demand during the TT.Results: The GE/EC remained constant across the submaximal stages and the supramaximal TT was performed in 185 ± 24 s. The GE and EC methods produced identical V." role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V.V.O2 demands and O2 deficits. The V." role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V.V.O2 demand was ~3% lower for the 4+Y method compared with the 4-Y and GE/EC methods, with corresponding O2 deficits of 56 ± 10, 62 ± 10, and 63 ± 10 mL·kg−1, respectively (P < 0.05 for 4+Y vs. 4-Y and GE/EC). The mean differences between the estimated O2 deficits were −6 ± 5 mL·kg−1 (4+Y vs. 4-Y, P < 0.05), −7 ± 1 mL·kg−1 (4+Y vs. GE/EC, P < 0.05) and −1 ± 5 mL·kg−1 (4-Y vs. GE/EC), with respective typical errors of 5.3, 1.9, and 6.0%. The mean difference between the O2 deficit estimated with GE/EC based on the average of four submaximal stages compared with the last stage was 1 ± 2 mL·kg−1, with a typical error of 3.2%.Conclusions: These findings demonstrate a disagreement in the O2 deficits estimated using current methods. In addition, the findings suggest that a valid estimate of the O2 deficit may be possible using data from only one submaximal stage in combination with the GE/EC method.
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| 10. |
- Andersson, Erik, 1984-, et al.
(author)
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Anaerobic Capacity in Running : The Effect of Computational Method
- 2021
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In: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 12:August, s. 1-13
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Journal article (peer-reviewed)abstract
- Introduction: To date, no study has compared anaerobic capacity (AnC) estimates computed with the maximal accumulated oxygen deficit (MAOD) method and the gross energy cost (GEC) method applied to treadmill running exercise.Purpose: Four different models for estimating anaerobic energy supply during treadmill running exercise were compared.Methods: Fifteen endurance-trained recreational athletes performed, after a 10-min warm-up, five 4-min stages at ∼55–80% of peak oxygen uptake, and a 4-min time trial (TT). Two linear speed-metabolic rate (MR) regression models were used to estimate the instantaneous required MR during the TT (MRTT_req), either including (5+YLIN) or excluding (5-YLIN) a measured Y-intercept. Also, the average GEC (GECAVG) based on all five submaximal stages, or the GEC based on the last submaximal stage (GECLAST), were used as models to estimate the instantaneous MRTT_req. The AnC was computed as the difference between the MRTT_req and the aerobic MR integrated over time.Results: The GEC remained constant at ∼4.39 ± 0.29 J⋅kg–1⋅m–1 across the five submaximal stages and the TT was performed at a speed of 4.7 ± 0.4 m⋅s–1. Compared with the 5-YLIN, GECAVG, and GECLAST models, the 5+YLIN model generated a MRTT_req that was ∼3.9% lower, with corresponding anaerobic capacities from the four models of 0.72 ± 0.20, 0.74 ± 0.16, 0.74 ± 0.15, and 0.54 ± 0.14 kJ⋅kg–1, respectively (F1.07,42 = 13.9, P = 0.002). The GEC values associated with the TT were 4.22 ± 0.27 and 4.37 ± 0.30 J⋅kg–1⋅m–1 for 5+YLIN and 5-YLIN, respectively (calculated from the regression equation), and 4.39 ± 0.28 and 4.38 ± 0.27 J⋅kg–1⋅m–1 for GECAVG and GECLAST, respectively (F1.08,42 = 14.6, P < 0.001). The absolute typical errors in AnC ranged between 0.03 and 0.16 kJ⋅kg–1 for the six pair-wise comparisons and the overall standard error of measurement (SEM) was 0.16 kJ⋅kg–1.Conclusion: These findings demonstrate a generally high disagreement in estimated anaerobic capacities between models and show that the inclusion of a measured Y-intercept in the linear regression (i.e., 5+YLIN) is likely to underestimate the MRTT_req and the GEC associated with the TT, and hence the AnC during maximal 4-min treadmill running.
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| 11. |
- Andersson, Erik, 1984-, et al.
(author)
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Sex differences in performance and pacing strategies during sprint skiing
- 2019
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
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Journal article (peer-reviewed)abstract
- Purpose: This study aimed to compare performance and pacing strategies between elite male and female cross-country skiers during a sprint competition on snow using the skating technique.Methods: Twenty male and 14 female skiers completed an individual time-trial prolog (TT) and three head-to-head races (quarter, semi, and final) on the same 1,572-m course, which was divided into flat, uphill and downhill sections. Section-specific speeds, choice of sub-technique (i.e., gear), cycle characteristics, heart rate and post-race blood lactate concentration were monitored. Power output was estimated for the different sections during the TT, while metabolic demand was estimated for two uphill camera sections and the final 50-m flat camera section.Results: Average speed during the four races was ∼12.5% faster for males than females (P < 0.001), while speeds on the flat, uphill and downhill sections were ∼11, 18, and 9% faster for the males than females (all P< 0.001 for terrain, sex, and interaction). Differences in uphill TT speed between the sexes were associated with different sub-technique preferences, with males using a higher gear more frequently than females (P < 0.05). The estimated metabolic demand relative to maximal oxygen uptake (V˙" role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V˙V˙O2max) was similar for both sexes during the two uphill camera sections (∼129% of V˙" role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V˙V˙O2max) and for the final 50-m flat section (∼153% of V˙" role="presentation" style="box-sizing: border-box; display: inline; line-height: normal; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px; margin: 0px; position: relative; outline: 0px !important;">V˙V˙O2max). Relative power output during the TT was 18% higher for males compared to females (P < 0.001) and was highly variable along the course for both sexes (coefficient of variation [CV] between sections 4–9 was 53%), while the same variation in heart rate was low (CV was ∼3%). The head-to-head races were ∼2.4% faster than the TT for both sexes and most race winners (61%) were positioned first already after 30 m of the race. No sex differences were observed during any of the races for heart rate or blood lactate concentration.Conclusion: The average sex difference in sprint skiing performance was ∼12.5%, with varying differences for terrain-specific speeds. Moreover, females skied relatively slower uphill (at a lower gear) and thereby elicited more variation in their speed profiles compared to the males.
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| 12. |
- Andonov, Sreten
(author)
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Cutting corners: The impact of storage and DNA extraction on quality and quantity of DNA in honeybee (Apis mellifera) spermatheca
- 2023
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 14
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Journal article (peer-reviewed)abstract
- The purpose of our study was to investigate methods of short-term storage that allow preservation, transport and retrieval of genetic information contained in honeybee queen's spermatheca. Genotyping of the honeybee colony requires well ahead planned sample collection, depending on the type of data to be acquired. Sampling and genotyping of spermatheca's content instead of individual offspring is timesaving, allowing answers to the questions related to patriline composition immediately after mating. Such procedure is also cheaper and less error prone. For preservation either Allprotect Tissue Reagent (Qiagen) or absolute ethanol were used. Conditions during transportation were simulated by keeping samples 6-8 days at room temperature. Six different storing conditions of spermathecas were tested, complemented with two DNA extraction methods. We have analysed the concentration of DNA, RNA, and proteins in DNA extracts. We also analysed how strongly the DNA is subjected to fragmentation (through amplification of genetic markers ANT2 and tRNA(leu)-COX2) and whether the quality of the extracted DNA is suitable for microsatellite (MS) analysis. Then, we tested the usage of spermatheca as a source of patriline composition in an experiment with three instrumentally inseminated virgin queens and performed MS analysis of the extracted DNA from each spermatheca, as well as queens' and drones' tissue. Our results show that median DNA concentration from spermathecas excised prior the storage, regardless of the storing condition and DNA extraction method, were generally lower than median DNA concentration obtained from spermathecas dissected from the whole queens after the storage. Despite the differences in DNA yield from the samples subjected to different storing conditions there was no significant effect of storage method or the DNA extraction method on the amplification success, although fewer samples stored in EtOH amplified successfully in comparison to ATR storing reagent. However, we recommend EtOH as a storing reagent due to its availability, low price, simplicity in usage in the field and in the laboratory, and capability of good preservation of the samples for DNA analysis during transport at room temperature.
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| 13. |
- Andreasen, Laura, et al.
(author)
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Brugada syndrome-associated genetic loci are associated with J-point elevation and an increased risk of cardiac arrest
- 2018
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 9:JUL
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Journal article (peer-reviewed)abstract
- Introduction: A previous genome-wide association study found three genetic loci, rs9388451, rs10428132, and rs11708996, to increase the risk of Brugada Syndrome (BrS). Since the effect of these loci in the general population is unknown, we aimed to investigate the effect on electrocardiogram (ECG) parameters and outcomes in the general population. Materials and Methods: A cohort of 6,161 individuals (median age 45 [interquartile range (IQR) 40-50] years, 49% males), with available digital ECGs, was genotyped and subsequently followed for a median period of 13 [IQR 12.6-13.4] years. Data on outcomes were collected from Danish administrative healthcare registries. Furthermore, ~400,000 persons from UK Biobank were investigated for associations between the three loci and cardiac arrest/ventricular fibrillation (VF). Results: Homozygote carriers of the C allele in rs6800541 intronic to SCN10A had a significantly larger J-point elevation (JPE) compared with wildtype carriers (11 vs. 6 μV, P < 0.001). There was an additive effect of carrying multiple BrS-associated risk alleles with an increased JPE in lead V1. None of the BrS-associated genetic loci predisposed to syncope, atrial fibrillation, or total mortality in the general Danish population. The rs9388451 genetic locus adjacent to the HEY2 gene was associated with cardiac arrest/VF in an analysis using the UK Biobank study (odds ratio = 1.13 (95% confidence interval: 1.08-1.18), P = 0.006). Conclusions: BrS-associated risk alleles increase the JPE in lead V1 in an additive manner, but was not associated with increased mortality or syncope in the general population of Denmark. However, the HEY2 risk allele increased the risk of cardiac arrest/VF in the larger population study of UK Biobank indicating an important role of this common genetic locus.
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| 14. |
- Aoki, Y, et al.
(author)
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Fine Tuning of Phosphorothioate Inclusion in 2'-O-Methyl Oligonucleotides Contributes to Specific Cell Targeting for Splice-Switching Modulation
- 2021
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In: Frontiers in physiology. - : Frontiers Media SA. - 1664-042X. ; 12, s. 689179-
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Journal article (peer-reviewed)abstract
- Splice-switching antisense oligonucleotide- (SSO-) mediated correction of framedisrupting mutation-containing premessenger RNA (mRNA) transcripts using exon skipping is a highly promising treatment method for muscular diseases such as Duchenne muscular dystrophy (DMD). Phosphorothioate (PS) chemistry, a commonly used oligonucleotide modification, has been shown to increase the stability of and improve the pharmacokinetics of SSOs. However, the effect of PS inclusion in 2′-O-methyl SSOs (2OMe) on cellular uptake and splice switching is less well-understood. At present, we demonstrate that the modification of PS facilitates the uptake of 2OMe in H2k-mdx myoblasts. Furthermore, we found a dependency of SSO nuclear accumulation and high splice-switching activity on PS inclusion in 2OMe (2OMePS), as tested in various reporter cell lines carrying pLuc/705. Increased exon-inclusion activity was observed in muscle, neuronal, liver, and bone cell lineages via both the gymnotic uptake and lipofection of 2OMePS. Using the photoactivatable ribonucleoside-enhanced crosslinking and a subsequent proteomic approach, we identified several 2OMePS-binding proteins, which are likely to play a role in the trafficking of 2OMePS to the nucleus. Ablation of one of them, Ncl by small-interfering RNA (siRNA) enhanced 2OMePS uptake in C2C12 myoblasts and upregulated luciferase RNA splicing in the HeLa Luc/705 reporter cell line. Overall, we demonstrate that PS inclusion increases nuclear delivery and splice switching in muscle, neuronal, liver, and bone cell lineages and that the modulation of 2OMePS-binding partners may improve SSO delivery.
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| 15. |
- Appenroth, Daniel, et al.
(author)
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Body Temperature and Activity Rhythms Under Different Photoperiods in High Arctic Svalbard ptarmigan (Lagopus muta hyperborea)
- 2021
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 12
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Journal article (peer-reviewed)abstract
- Organisms use circadian rhythms to anticipate and exploit daily environmental oscillations. While circadian rhythms are of clear importance for inhabitants of tropic and temperate latitudes, its role for permanent residents of the polar regions is less well understood. The high Arctic Svalbard ptarmigan shows behavioral rhythmicity in presence of light-dark cycles but is arrhythmic during the polar day and polar night. This has been suggested to be an adaptation to the unique light environment of the Arctic. In this study, we examined regulatory aspects of the circadian control system in the Svalbard ptarmigan by recording core body temperature (Tb) alongside locomotor activity in captive birds under different photoperiods. We show that Tb and activity are rhythmic with a 24-h period under short (SP; L:D 6:18) and long photoperiod (LP; L:D 16:8). Under constant light and constant darkness, rhythmicity in Tb attenuates and activity shows signs of ultradian rhythmicity. Birds under SP also showed a rise in Tb preceding the light-on signal and any rise in activity, which proves that the light-on signal can be anticipated, most likely by a circadian system.
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| 16. |
- Ardalan, Maryam, 1979, et al.
(author)
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Dysmaturation of Somatostatin Interneurons Following Umbilical Cord Occlusion in Preterm Fetal Sheep
- 2019
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
-
Journal article (peer-reviewed)abstract
- Introduction: Cerebral white matter injury is the most common neuropathology observed in preterm infants. However, there is increasing evidence that gray matter development also contributes to neurodevelopmental abnormalities. Fetal cerebral ischemia can lead to both neuronal and non-neuronal structural-functional abnormalities, but less is known about the specific effects on interneurons. Objective: In this study we used a well-established animal model of fetal asphyxia in preterm fetal sheep to study neuropathological outcome. We used comprehensive stereological methods to investigate the total number of oligodendrocytes, neurons and somatostatin (STT) positive interneurons as well as 3D morphological analysis of STT cells 14 days following umbilical cord occlusion (UCO) in fetal sheep. Materials and Methods: Induction of asphyxia was performed by 25 min of complete UCO in five preterm fetal sheep (98-100 days gestational age). Seven, non-occluded twins served as controls. Quantification of the number of neurons (NeuN), STT interneurons and oligodendrocytes (Olig2, CNPase) was performed on fetal brain regions by applying optical fractionator method. A 3D morphological analysis of STT interneurons was performed using IMARIS software. Results: The number of Olig2, NeuN, and STT positive cells were reduced in IGWM, caudate and putamen in UCO animals compared to controls. There were also fewer STT interneurons in the ventral part of the hippocampus, the subiculum and the entorhinal cortex in UCO group, while other parts of cortex were virtually unaffected (p > 0.05). Morphologically, STT positive interneurons showed a markedly immature structure, with shorter dendritic length and fewer dendritic branches in cortex, caudate, putamen, and subiculum in the UCO group compared with control group (p < 0.05). Conclusion: The significant reduction in the total number of neurons and oligodendrocytes in several brain regions confirm previous studies showing susceptibility of both neuronal and non-neuronal cells following fetal asphyxia. However, in the cerebral cortex significant dysmaturation of STT positive neurons occurred in the absence of cell loss. This suggests an abnormal maturation pattern of GABAergic interneurons in the cerebral cortex, which might contribute to neurodevelopmental impairment in preterm infants and could implicate a novel target for neuroprotective therapies.
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| 17. |
- Arnardottir, H, et al.
(author)
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Stimulating the Resolution of Inflammation Through Omega-3 Polyunsaturated Fatty Acids in COVID-19: Rationale for the COVID-Omega-F Trial
- 2021
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In: Frontiers in physiology. - : Frontiers Media SA. - 1664-042X. ; 11, s. 624657-
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Journal article (peer-reviewed)abstract
- Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 triggers an immune response with local inflammation in the lung, which may extend to a systemic hyperinflammatory reaction. Excessive inflammation has been reported in severe cases with respiratory failure and cardiovascular complications. In addition to the release of cytokines, referred to as cytokine release syndrome or “cytokine storm,” increased pro-inflammatory lipid mediators derived from the omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid may cause an “eicosanoid storm,” which contributes to the uncontrolled systemic inflammation. Specialized pro-resolving mediators, which are derived from omega-3 PUFA, limit inflammatory reactions by an active process called resolution of inflammation. Here, the rationale for omega-3 PUFA supplementation in COVID-19 patients is presented along with a brief overview of the study protocol for the trial “Resolving Inflammatory Storm in COVID-19 Patients by Omega-3 Polyunsaturated Fatty Acids - A single-blind, randomized, placebo-controlled feasibility study” (COVID-Omega-F). EudraCT: 2020-002293-28; clinicaltrials.gov: NCT04647604.
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| 18. |
- Arnemo, Jon, et al.
(author)
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Lipidomics Reveals Seasonal Shifts in a Large-Bodied Hibernator, the Brown Bear
- 2019
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 10
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Journal article (peer-reviewed)abstract
- Prior to winter, heterotherms retain polyunsaturated fatty acids ("PUFA"), resulting in enhanced energy savings during hibernation, through deeper and longer torpor bouts. Hibernating bears exhibit a less dramatic reduction (2-5 degrees C) in body temperature, but lower their metabolism to a degree close to that of small hibernators. We determined the lipid composition, via lipidomics, in skeletal muscle and white adipose tissues ("WAT"), to assess lipid retention, and in blood plasma, to reflect lipid trafficking, of winter hibernating and summer active wild Scandinavian brown bears (Ursus arctos). We found that the proportion of monounsaturated fatty acids in muscle of bears was significantly higher during winter. During hibernation, omega-3 PUFAs were retained in WAT and short-length fatty acids were released into the plasma. The analysis of individual lipid moieties indicated significant changes of specific fatty acids, which are in line with the observed seasonal shift in the major lipid categories and can be involved in specific regulations of metabolisms. These results strongly suggest that the shift in lipid composition is well conserved among hibernators, independent of body mass and of the animals' body temperature.
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| 19. |
- Arnemo, Jon
(author)
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Seasonality in Biological Rhythms in Scandinavian brown Bears
- 2022
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 13
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Journal article (peer-reviewed)abstract
- Biological rhythms, such as rhythms in activity and body temperature, are usually highly synchronized and entrained by environmental conditions, such as photoperiod. However, how the expression of these rhythms changes during hibernation, when the perception of environmental cues is limited, has not yet been fully understood for all hibernators, especially in the wild. The brown bear (Ursus arctos) in Scandinavia lives in a highly seasonal environment and adapts to harsh winter conditions by exhibiting hibernation, characterized by reduced metabolism and activity. In this study, we aimed to explore the expression of biological rhythms in activity, body temperature and heart rate of free-ranging brown bears over the annual cycle, including active, hibernation and the transition states around den entry and exit. We found that rhythms in physiology and activity are mostly synchronized and entrained by the light-dark cycle during the bears' active state with predominantly diel and ultradian rhythms for body temperature, activity and heart rate. However, during hibernation, rhythms in body temperature and heart rate were considerably slowed down to infradian rhythms, influenced by the amount of snow in the denning area, whereas rhythms in activity remained diel. Rhythms in the transition states when bears prepared for entering or coming out of hibernation state displayed a combination of infradian and diel rhythms, indicating the preparation of the body for the change in environmental conditions. These results reveal that brown bears adjust their biological rhythms to the seasonal environment they inhabit. Rhythms in physiology and activity show simultaneity during the active state but are partly disconnected from each other during hibernation, when bears are most sheltered from the environment.
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| 20. |
- Aronsson, Patrik, 1983, et al.
(author)
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Soluble guanylate cyclase mediates the relaxation of healthy and inflamed bladder smooth muscle by aqueous nitric oxide.
- 2023
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In: Frontiers in physiology. - 1664-042X. ; 14
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Journal article (peer-reviewed)abstract
- Introduction: Due to its chemical properties, functional responses to nitric oxide (NO) are often difficult to examine. In the present study, we established a method to produce NO in an aqueous solution and validated its capacity to evoke functional responses in isolated rat bladders. Furthermore, we compared the NO responses to the commonly used NO donor sodium nitroprusside (SNP). We also investigated the impact of ongoing inflammation on the involvement of soluble guanylate cyclase (sGC) dependent signaling in NO relaxation. Methods: A setup to produce an aqueous NO solution was established, allowing the production of an aqueous solution containing a calculated NO concentration of 2mM. Sixty male Sprague-Dawley rats received either no treatment (controls) or cyclophosphamide (CYP; 100mg*kg-1 i.p., 60h prior to the experiment) to induce experimental cystitis. Bladder strip preparations were mounted in organ baths and studied at basal tension or pre-contracted with methacholine (3μM). Aqueous NO solution (40-400μL; 2mM corresponding to 4-40μM) or SNP (1-1,000μM) was added cumulatively in increasing concentrations. Relaxation to aqueous NO was also studied in the presence of the sGC inhibitor ODQ (0.25-25μM). The expression of sGC was investigated by immunohistochemical analysis. Results: The NO solution caused functional relaxations in both controls and inflamed bladder preparations. NO-induced relaxations were significantly greater in inflamed bladder strips at basal tension, whereas no differences were seen in methacholine pre-contracted strips. In the presence of the sGC inhibitor ODQ in a high concentration, the NO-evoked relaxations were abolished in both control and inflamed preparations. At a lower concentration of ODQ, only NO relaxations in inflamed preparations were attenuated. Immunohistochemical analysis showed that sGC was expressed in the detrusor and mucosa, with a significantly lower expression in the inflamed detrusor. Conclusion: In the present study, we found that aqueous NO solution induces relaxation of the rat detrusor by activating soluble guanylate cyclase in both control and inflamed bladder strips. Induction of inflammation conceivably leads to decreased sGC expression in the detrusor, which may explain the different susceptibility towards inhibition of sGC in inflamed versus control tissue. The use of an aqueous NO solution should be further considered as a valuable complement to the pharmacological tools currently used.
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| 21. |
- Baburamani, Ana A, et al.
(author)
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Vulnerability of the developing brain to hypoxic-ischemic damage: Contribution of the cerebral vasculature to injury and repair?
- 2012
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 3
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Journal article (peer-reviewed)abstract
- As clinicians attempt to understand the underlying reasons for the vulnerability of different regions of the developing brain to injury, it is apparent that little is known as to how hypoxia-ischemia may affect the cerebrovasculature in the developing infant. Most of the research investigating the pathogenesis of perinatal brain injury following hypoxia-ischemia has focused on excitotoxicity, oxidative stress and an inflammatory response, with the response of the developing cerebrovasculature receiving less attention. This is surprising as the presentation of devastating and permanent injury such as germinal matrix-intraventricular haemorrhage (GM-IVH) and perinatal stroke are of vascular origin, and the origin of periventricular leukomalacia (PVL) may also arise from poor perfusion of the white matter. This highlights that cerebrovasculature injury following hypoxia could primarily be responsible for the injury seen in the brain of many infants diagnosed with hypoxic-ischemic encephalopathy (HIE). Interestingly the highly dynamic nature of the cerebral blood vessels in the fetus, and the fluctuations of cerebral blood flow and metabolic demand that occur following hypoxia suggest that the response of blood vessels could explain both regional protection and vulnerability in the developing brain. However, research into how blood vessels respond following hypoxia-ischemia have mostly been conducted in adult models of ischemia or stroke, further highlighting the need to investigate how the developing cerebrovasculature responds and the possible contribution to perinatal brain injury following hypoxia. This review discusses the current concepts on the pathogenesis of perinatal brain injury, the development of the fetal cerebrovasculature and the blood brain barrier (BBB), and key mediators involved with the response of cerebral blood vessels to hypoxia. © 2012 Baburamani, Ek, Walker and Castillo-Melendez.
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| 22. |
- Bachmann, K. F., et al.
(author)
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Interactions between extracorporeal support and the cardiopulmonary system
- 2023
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In: Frontiers in Physiology. - 1664-042X. ; 14
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Journal article (peer-reviewed)abstract
- This review describes the intricate physiological interactions involved in the application of extracorporeal therapy, with specific focus on cardiopulmonary relationships. Extracorporeal therapy significantly influences cardiovascular and pulmonary physiology, highlighting the necessity for clinicians to understand these interactions for improved patient care. Veno-arterial extracorporeal membrane oxygenation (veno-arterial ECMO) unloads the right ventricle and increases left ventricular (LV) afterload, potentially exacerbating LV failure and pulmonary edema. Veno-venous (VV) ECMO presents different challenges, where optimal device and ventilator settings remain unknown. Influences on right heart function and native gas exchange as well as end-expiratory lung volumes are important concepts that should be incorporated into daily practice. Future studies should not be limited to large clinical trials focused on mortality but rather address physiological questions to advance the understanding of extracorporeal therapies. This includes exploring optimal device and ventilator settings in VV ECMO, standardizing cardiopulmonary function monitoring strategies, and developing better strategies for device management throughout their use. In this regard, small human or animal studies and computational physiological modeling may contribute valuable insights into optimizing the management of extracorporeal therapies.
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| 23. |
- Baird, Emily, et al.
(author)
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Flight control and landing precision in the nocturnal bee Megalopta is robust to large changes in light intensity.
- 2015
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 6
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Journal article (peer-reviewed)abstract
- Like their diurnal relatives, Megalopta genalis use visual information to control flight. Unlike their diurnal relatives, however, they do this at extremely low light intensities. Although Megalopta has developed optical specializations to increase visual sensitivity, theoretical studies suggest that this enhanced sensitivity does not enable them to capture enough light to use visual information to reliably control flight in the rainforest at night. It has been proposed that Megalopta gain extra sensitivity by summing visual information over time. While enhancing the reliability of vision, this strategy would decrease the accuracy with which they can detect image motion-a crucial cue for flight control. Here, we test this temporal summation hypothesis by investigating how Megalopta's flight control and landing precision is affected by light intensity and compare our findings with the results of similar experiments performed on the diurnal bumblebee Bombus terrestris, to explore the extent to which Megalopta's adaptations to dim light affect their precision. We find that, unlike Bombus, light intensity does not affect flight and landing precision in Megalopta. Overall, we find little evidence that Megalopta uses a temporal summation strategy in dim light, while we find strong support for the use of this strategy in Bombus.
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| 24. |
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| 25. |
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