bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stretching Single Titin Molecules from Failing Human Hearts at Cardiac Cycle Reveals Titin's Role in Cardiac Kinetic Reserve
Authors: Chen Mei‐pian , Kiduko Salome A. , Saad Nancy S. , Canan Benjamin D. , Kilic Ahmet , Mohler Peter J. , Janssen Paul M.L. 
Published: June 2021

Diastolic dysfunction occurs not only in diastolic heart failure, but also ubiquitously in systolic heart failure. A main determinant of diastolic passive tension, the elastic sarcomeric protein titin, has been shown to be associated with heart failure, with unresolved mechanisms. Heart failure patients commonly experience symptoms only during physical activities or stress. To determine whether titin is playing a role in the mechanisms of heart failure in terms of its known impaired property of frequency‐dependent acceleration of relaxation (FDAR), we studied the FDAR responses in live left ventricular cardiomyocytes and single‐molecule force spectroscopy (SMFS) of titin elastic domains (PEVK‐distal Ig, distal Ig) from failing (n=11) and non‐failing (n=7) human hearts. To access SMFS on native titin, we developed a novel approach using atomic force microscopy to detect titin passive tension (TPT) based on frequency‐modulated cardiac cycle. Mean TPT was shown to be reduced upon an increased heart rate, which was significantly blunted in failing human hearts. The results from titin distal Ig domain were significantly correlated with the frequency‐dependent relaxation kinetics of human cardiomyocytes from the corresponding hearts, which was shown to be impaired in failing hearts. Correlation studies suggested that the higher the TPT, the faster the cardiomyocytes relaxed, but lower the potential of myocytes to speed up relaxation at a higher heart rate; such poorer FDAR response was also associated with a less reduction or a bigger increase in TPT upon a raised heart rate. Our study established a novel approach in detecting tension physiologically on native titin domains. The data from human hearts suggested that the regulation of kinetic reserve in cardiac relaxation and its pathological changes are associated with the intensity and dynamic changes of passive tension on titin.Support or Funding InformationThis project is supported by RO1HL113084 to Janssen PML, and T32NS779844 to Chen MPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chronic high fat diet disrupts renal molecular clock
Authors: Zhang Dingguo , Speed Joshua S. , Colson Jackson C. , Bailey Shannon M. , Young Martin E. , Gamble Karen L. , Pollock Jennifer S. , Pollock David M. 
Published: June 2021

Kidney function follows a strong circadian rhythm that is tightly regulated by clock genes. We previously reported that high salt diet induced dyssynchrony in renal clock gene expression in the cortex and medulla. However, whether changes in other dietary factors pose threats to renal circadian rhythms remain largely unknown. The current study was designed to test the hypothesis that high fat diet disrupts renal clock gene expression with 2 mouse models. First, C57Bl/6J male mice (8 weeks old, n=3) were fed normal fat (NF) or high fat (HF) diet for 20 weeks. During the last 2 weeks of the protocol, mice underwent either time restricted feeding, where food access was allowed only during lights‐off, active period (7 pm–7 am), or sham feeding procedure. Restricted feeding did not cause significant changes in body weight or food consumption. Renal cortex was collected in 4‐hour increments throughout a 24‐hour period and clock gene expression measured by qPCR. We found that Per2 expression has a robust circadian rhythm with a peak expression at zeitgeber time (ZT) 13. We did not observe any significant differences among groups. Second, Period2Luciferase (Per2Luc) mouse model was utilized to monitor real‐time molecular clock rhythm. Male and female Per2Luc mice (n=4) were fed NF or HF diet with sham or time restricted feeding. Kidneys were dissected into three parts (cortex, outer and inner medulla) at the end of study and cultured for 3 days to measure bioluminescent rhythms. We found that HF diet lengthened the period of luciferase rhythm by 2 hours (NF: 23.98 hours vs. HF: 26.17 hours, p=0.02) in the cortex. No significant differences were observed in the groups in renal outer medulla or inner medulla. Restricted feeding did not cause any significant changes in any groups. These data suggest that clock gene expression in the kidney follows a circadian rhythm that can be disrupted by chronic high fat diet.Support or Funding InformationP01 HL136267 Integrating novel mechanisms controlling sodium excretion and blood pressure UAB School of Medicine AMC21 Circadian Disruption and Susceptibility to Target Organ DamageThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hypertension Precedes Metabolic Syndrome in the ALMS1 (Alstrom Syndrome 1) Knockout Rat
Authors: King‐Medina Keyona N. , Ortiz Pablo A. 
Published: June 2021

We previously found that Alstrom syndrome 1 protein (ALMS1) is expressed in the kidney where it regulates thick ascending limb (TAL) NaCl reabsorption by controlling NKCC2 endocytosis. In humans, inactivating mutations in the ALMS1 gene causes obesity, insulin resistance and hypertension (metabolic syndrome). We found that deletion of ALMS1 in (Dahl salt‐sensitive) rats induced hypertension (measured by radio‐telemetry and tail‐cuff plethysmography). Moreover, the ALMS1 Knockout (ALMS1 KO) rats are hyperphagic and develop progressive obesity over time. Obesity is a risk factor for hypertension and insulin resistance. However, it is unclear whether the increase in blood pressure (BP) occurs prior to or after the development of metabolic alterations (obesity and insulin resistance) in the ALMS1 KO rats. We hypothesize that hypertension in the ALMS1 KO rats is primarily caused by a renal defect and not secondary to the metabolic syndrome. In order to study this we obtained young (shortly after weaning) ALMS1 KO and wild‐type (WT) rats (age range: 5–7 weeks old) and measured body weight, baseline blood glucose, glucose tolerance (IP injection of 2 kg/g of BW glucose) and systolic blood pressure (SBP) by tail‐cuff over time. ALMS1 KO (n=6) and WT (n=6) rats were given 30 g per day of regular chow (0.4% Na) with free access to water. At 5–7 weeks of age ALMS1 KO rats had similar body weights (ALMS1 KO: 209±13 g vs. WT: 182±15 g, N.S.). Baseline glucose was similar (ALMS1 KO: 88±3 vs. WT: 75±7 mg/dL, N.S.) and glucose tolerance test produced similar peaks and area under the curve. Importantly, the SBP was higher in ALMS1 KO rats (ALMS1 KO: 156±5 vs. WT: 143+3 mmHg, p<0.05). Four weeks later (9–11 weeks old), body weight began to diverge between strains (ALMS1 KO: 326±10 g vs. WT: 282±17 g, p<0.05). Baseline glucose was higher in ALMS1 KO (ALMS1 KO: 84±2 vs. WT: 71±3 mg/dL, p<0.05) and glucose tolerance test produced a higher peak in ALMS1 KO (ALMS1 KO: 376±27 vs. WT: 305±17 mg/dL, p<0.05), as well as a larger area under the curve (ALMS1 KO: 11915±1349 vs. WT: 9176±916 mg*min/dL). Lastly, the SBP continued to be elevated in the ALMS1 KO rats (ALMS1 KO: 160±3 vs. WT: 144±3 mmHg, p<0.05). Therefore, our data show that the genetic deletion of ALMS1 causes hypertension in rats and that the increase in blood pressure precedes the development of obesity and insulin resistance in this model. This is a new rat model of metabolic syndrome with established hypertension that does not require a high salt diet. Ongoing experiments will test whether caloric restriction prevents or decrease the hypertension and metabolic syndrome in this rat strain.Support or Funding InformationNIH F31 Diversity Grant: 5F31HL123285 (King‐Medina)and NIH‐NIDDK Grant: 5R01DK107263 (Ortiz)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Do senescent cells drive the ageing phenotype of skeletal muscle in vivo?
Authors: Shigdar Shahjahan , Staunton Caroline , Vasilaki Aphrodite , McArdle Anne 
Published: June 2021

Loss of skeletal muscle mass and function are critical factors in the development of frailty. The number of senescent cells increases with age in rodents (Krishnamurthy et al., 2004) and primates (Kreiling et al., 2011). We hypothesise that these cells trigger a local and/or systemic chronic inflammatory status in old mice with the production of senescence associated secretory phenotype molecules (SASPs) and we further hypothesise that this leads to the activation of NF‐kB mediated inflammatory pathway seen in skeletal muscle of old mice (Vasilaki et al, 2006), potentially by the so‐called bystander effect (Nelson et al, 2017).Initial studies have investigated whether key senescence associated molecules (such as p16, p21, and p53) are increased in the muscle bulk of old (24 months old) compared with young (3 months old) C57BL6 Wild Type (WT) mice in vivo. Whole quadriceps muscles from young and old mice were subjected to western blot analysis for senescence associated cyclin‐dependent kinase inhibitors, including p16, p21 and p53.Western blot analysis demonstrated that muscle from old mice showed a significantly increased content of p16, p21, and p53 compared with muscles of young mice (p<0.05) and analyses are underway to characterise the nature of cells expressing these senescent proteins within the muscle bulk. Further studies will determine the potential production of a SASP by these cells and the effect on chronic activation of NF‐kB in muscle fibres of old mice.Support or Funding InformationWork generously funded by the British Society for Research into Ageing and the Rosetrees Trust.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Novel intravital assessment of muscle cytosol H202 content supports a key role for motor unit remodelling in sarcopenia.
Authors: Staunton Caroline Amy , Vasilaki Aphrodite , Barrett‐Jolley Richard , McArdle Anne , Jackson Malcolm J. 
Published: June 2021

Sarcopenia; the age‐related loss of muscle mass and function, significantly affects quality of life in the ageing population and has been linked to remodelling and loss of motor units. Reactive oxygen species (ROS) generation, inflammation and FOXO‐dependant muscle atrophy are three key pathways associated with muscle dysfunction and this study focusses on the role of H202 in skeletal muscle ageing.The aim was to determine whether increases in H202 concentration occur in skeletal muscle fibres from adult (6–8 months) and old (26 months) mice and whether this was confined to denervated fibres, or additionally to healthy muscle fibres.The role of hydrogen peroxide (H202) in motor unit remodelling was examined using AAV‐mediated transfection of cyto‐Hyper2 (a highly specific H202 probe), into muscle of a transgenic Thy‐1 CFP mice. AAV6‐Hyper2 (5×1010 vg/ml) was directly injected into the anterior tibialis (TA) muscles of mice at 28 days prior to surgical crush of the common peroneal nerve or sham control mice and the TA muscles of these mice were imaged using intravital fluorescence microscopy at 3, 7 and 21 days post‐crush. Electrophysiological approaches are also being utilised to examine the structure and function of fibres and how this changes with ageing.Data from the sequential intravital images from adult mice showed that that the TA muscle fibres following nerve crush had an elevated H202 content that was statistically significant (p<0.001) by 3 days post nerve crush which coincided with the time at which neuromuscular junction (NMJ) breakdown occurred at the presynaptic terminus. Complete loss of pre‐synaptic structure of the NMJ was seen by 7 days post‐crush when H202 levels remained elevated and when skeletal muscle fibre atrophy was apparent. At 21 days post‐injury, full reinnervation of the muscle had occurred with both pre and post‐synaptic structures intact although there remained some faint AChR clustering. At this time point the muscle fibre H202 levels had returned to baseline values.In light of these unique data, current work is examining aged Thy‐1 CFP mice (26 months old) to determine the fibre H202 content following nerve injury and the regenerative capacity of the nerves. Potential therapeutic targets are also being examined using RNA‐seq approaches to identify novel sprouting factors and proteins of interest that could be driving these processes.Support or Funding InformationThis work was funded by the MRC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Muscle metaboreflex activity after an acute session of exercise under hypoxia
Authors: Crisafulli Antonio , Sainas Gianmarco , Magnani Sara , Roberto Silvana , Mannoni Mauro Ottavio , Pinna Virginia , Tocco Filippo , Doneddu Azzurra , Mulliri Gabriele 
Published: June 2021

In healthy subjects, when the muscle metaboreflex (MM) is activated, mean blood pressure (MBP) increases because of a sympathetic‐induced increase in both systemic vascular resistance (SVR) and cardiac output (CO)1. Acute hypoxia vasodilation has been often reported despite the increased sympathetic tone2. We hypothesized that a single session of exercise under normobaric hypoxia (ENH) resulted in an attenuation of the MBP increment during the muscle metaboreflex activated immediately after the ENH session. 10 well trained healthy male subjects (age 34.2±11.7 yrs) participated in this study. In separate days they underwent, randomly assigned, three exercise sessions consisting of 10 min pedaling at a workload corresponding to 80% of anaerobic threshold previously assessed. In one session (TEST21%) subjects breathed normoxic air (O2 21%), in the other two tests they breathed hypoxic air with O2 concentration of 16% (TEST16%) or 13% (TEST13%) respectively. Immediately after each exercise session they underwent randomly assigned the following protocol: 1) muscle metaboreflex activation obtained by the post‐exercise muscle ischemia (PEMI) method, and 2) control exercise recovery (CER) test. Response to the metaboreflex for each cardiovascular parameter was assessed as PEMI minus CER level. Hemodynamic parameters were evaluated by impedance cardiography. Results show that SVR response was reduced during the MM after the TST13% with respect to the other two tests (−46.5±394.2 vs. +108.9±256.3 and +213.6±228.8 dynes•s‐1•cm‐5 respectively, p<0.05). However, the MBP response was similar between conditions. This because of an increased CO response which occurred during TEST13% in comparison with TEST21% and TEST16% (+421.3±545 vs. +63.2±322.9 and +128.3±238.6 ml respectively, p<0.05). It was concluded that an acute session of exercise under hypoxia is able to reduce the capacity to vasoconstrict the vascular bed during the metaboreflex activation obtained by PEMI. However, mechanisms controlling cardiovascular responses successfully defended MBP response by increasing CO which compensated for the reduced SVR increment.Support or Funding InformationThis study was supported by the University of Cagliari and the Italian Ministry of Scientific Research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Virtual Unreality – Promise vs. Performance of Technology in Anatomy Education
Authors: Wainman Bruce , Pukas Giancarlo , Wolak Liliana , Zheng Eric , Norman Geoffrey 
Published: June 2021

A number of studies have shown that computer generated, interactive, 3D projections (a type of virtual reality or VR) of human anatomy have serious handicaps when compared to ordinary physical models. The mechanism underlying the deficiency is not clear. In the present study we replicated the finding of a large benefit for physical models over equivalent VR; amounting to an effect size of 1.38. We then showed, with a series of experiments, that the advantage is not a consequence of haptic (touch) feedback, or “transfer appropriate processing” (Learning in 3D is more effective when tested in 3D). Instead, it appears that the advantage of the physical model is entirely a result of binocular vision; restricting viewing to one eye extinguishes the advantage. Additional testing with the Microsoft HoloLens, using an exact duplicate of the physical model rendered as a mixed reality (MR) object, showed performance equal to the 3D projection and equal to the physical model when learned and tested with monocular vision and much worse than the physical model. The 10–20 fold cost of using VR and MR learning objects over the physical models does not appear to be justified given the cost and inferior performance in increasing anatomic knowledge.Support or Funding InformationPaul R. MacPherson Institute for Leadership, Innovation and Excellence in Teaching and the Faculty of Health Sciences, McMaster University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Time course of changes in arterial and venous function during normal and hypertensive pregnancies in humans
Authors: Yoo Jeung‐Ki , Badrov Mark B. , Syed Owais , Parker Rosemary S. , Stickford Abigail S. , Okada Yoshiyuki , Best Stuart A. , Levine Benjamin D. , Fu Qi 
Published: June 2021

Gestational hypertensive disorders (GHD) affect about 10% of pregnant women in the United States, and the most severe form (pre)eclampsia is the leading cause of maternal and fetal death and morbidity. The underlying mechanisms remain uncertain; however, impaired adaptation in maternal vascular function may be one contributing factor. We evaluated the time course of change in arterial and venous function before, early, late, and after pregnancy in women without a history of GHD (controls; n=26), women with a history of GHD (GHD history group; n=16), and women who developed GHD during the study (developed GHD group; n=7). Vascular and hemodynamic measurements were longitudinally performed prior to pregnancy (mid‐luteal phase), during early pregnancy (4–8 weeks of gestation), late pregnancy (32–36 weeks), and postpartum (6–10 weeks after delivery). A repeated‐measures analysis using linear mixed models was used for data analysis. At pre‐pregnancy, there was no difference in age, supine blood pressure, and heart rate among groups. Brachial artery endothelium‐dependent flow‐mediated dilation (FMD) showed significant differences among groups (group time interaction; P=0.03, Time; P=0.03, Group; P=0.01). Specifically, women who developed GHD in the study had lower FMD during early and late pregnancy (mean±SE; pre: 4.60±1.11%, early: 4.96±0.98%, late: 4.69±1.04%, and post: 5.64±0.97%) compared to controls (4.85±0.62%, 7.40±0.51%, 9.44±0.52%, and 6.91±0.53%) and the GHD history group (4.88±0.83%, 6.69±0.69%, 7.09±0.71%, and 5.25±0.79%). There were no significant interactions in forearm vascular resistance (FVR) or calf venous compliance (plethysmography; group time interaction P=0.9 and 0.6, respectively) among groups, while FVR decreased during pregnancy in all subjects. Our findings suggest that impaired endothelial functional adaptation during pregnancy, rather than regional (limb) vascular resistance and venous compliance is associated with the occurance of GHD in humans.Support or Funding InformationThis study was funded by the National Institutes of Health grant (R21HL088184), the American Heart Association Grant‐in‐Aid (13GRNT16990064), the Harry S. Moss Heart Trust, and the Texas Health Resources Research & Education Institute AwardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ELP‐VEGF Treatment Improves the Maternal Syndrome of Preeclampsia in the Dahl Salt Sensitive (S) Rat
Authors: Ross Courtney A. , Maeda Kenji J. , Logue Omar C. , Bidwell Gene L. , Garrett Michael R. , Sasser Jennifer 
Published: June 2021

Preeclampsia, a hypertensive disorder of pregnancy, is detrimental to both mother and fetus; however, there is currently no effective treatment for preeclampsia. The anti‐angiogenic protein sFlt‐1 has been implicated in the pathogenesis of preeclampsia through both clinical and experimental studies, leading us and others to propose that antagonism of sFlt‐1 via administration of vascular endothelial growth factor (VEGF) will reduce the maternal symptoms of hypertension and proteinuria in preeclamptic pregnancy. In this study, we tested the hypothesis that VEGF fused to the synthetic carrier elastin like polypeptide (ELP) will improve the maternal syndrome in the Dahl S rat model of superimposed preeclampsia. Female Dahl S rats (16–18 weeks of age) were placed in metabolic cages for 24‐hour urine collection, mated with Dahl S male rats, and randomly divided into control and ELP‐VEGF treated groups. ELP‐VEGF was administered via osmotic pump (5 mg/kg/day, Alzet 2ML1) beginning on day 10 of pregnancy, and pumps were replaced on day 17 of pregnancy. Urine was collected again on day 19, and blood and tissues were harvested on day 20. Urinary protein excretion (Bradford assay) did not differ between groups at baseline (87±11 vs 99±21 mg/d), but was significantly lower during late pregnancy in the ELP‐VEGF treated rats (* p=0.004, table). A subset of ELP‐VEGF‐treated rats (n=4) was implanted with telemetry transmitters (DSI) before mating. While previous studies have shown that blood pressure increases during pregnancy in the Dahl S rat, ELP‐VEGF treatment resulted in a fall in mean arterial pressure of 27±5 mmHg from day 9 to day 18 of pregnancy. No significant differences in fetal growth or litter size were observed following treatment. These data suggest that ELP‐VEGF treatment improves the maternal syndrome of preeclampsia without impairing fetal outcomes.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.