EMD
Emerin [EDMD] [STA]
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Can RNA sequencing of human cumulus cells (CC) reveal molecular pathways involved in the physiology of reproductive aging? Senescent but not young CC activate gene pathways associated with hypoxia and oxidative stress. Shifts in socioeconomic norms are resulting in larger numbers of women postponing childbearing. The reproductive potential is sharply decreased with aging, and the reasons are poorly understood. Since CCs play an integral role in oocyte maturation and direct access to human oocytes is limited, we used whole transcriptome analysis of these somatic cells to gain insights into the molecular mechanisms playing a role in follicular senescence. Twenty CC samples (from a total of 15 patients) were obtained from oocytes of either male factor or egg donor patients. RNA sequencing and bioinformatic tools were used to identify differentially expressed genes between CCs from seven aged and eight young patients (<35 (years old) y.o. vs >40 y.o.). Quantitative-PCR and immunoflourescent staining were used for validation. RNA sequencing identified 11 572 genes expressed in CC of both age cohorts, 45 of which were differentially expressed. In CC collected from patients >40 y.o., genes involved in the hypoxia stress response (NOS2, RORA and NR4A3), vasculature development (NR2F2, PTHLH), glycolysis (RALGAPA2 and TBC1D4) and cAMP turnover (PDE4D) were significantly overexpressed when compared with CC of patients younger than 35 y.o. This study focused almost exclusively on assessing the genetic differences in CC transcriptome between young and older women. These genetic findings were not fully correlated with embryonic development and clinical outcome. Our data provide a new hypothesis-follicular hypoxia-as the main mechanism leading to ovarian follicular senescence and suggest a link between cumulus cell aging and oocyte quality decay. If specific molecular findings of hypoxia would be confirmed also in oocytes, genetic platforms could screen CC for hypoxic damage and identify healthier oocytes. Protocols of ovarian stimulation in older patients could also be adjusted to diminish oocyte exposure time to hypoxic follicles. GEO accession number: GSE81579 STUDY FUNDING AND COMPETING INTERESTS: Funded in part by EMD Serono Grant for Fertility Innovation (GFI).
MeSH Terms
- Adult
- Cell Hypoxia
- Cumulus Cells
- Female
- Gene Expression Profiling
- Humans
- Oocytes
- Ovarian Follicle
- Ovulation Induction
- Pregnancy
- Sequence Analysis, RNA
- Transcriptome
Keywords
- RNA sequencing
- WGCNA
- cumulus cells transcriptome
- oocyte senescence
The aim of this study was to investigate the effects of the ageing process in the electromechanical delay (EMD), rate of torque development (RTD) and peak torque (PT) of the knee extensor muscles. The volunteers were assigned to three groups: young group (YG - 23·44 ± 4·74 years, 78·14 ± 15·11 kg, 1·72 ± 0·05 m), middle-aged group (MAG - 49·56 ± 6·06 years, 72·01 ± 14·07 kg, 1·67 ± 0·06 m) and elderly group (EG - 68·67 ± 9·06 years, 67·96 ± 7·60 kg, 1·64 ± 0·07 m). The PT and RTD were assessed during maximal voluntary ballistic isometric contractions (MVBIC) in the isokinetic dynamometer. Muscle electrical activity was recorded (EMG) during MVBIC in the vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) muscles. The EMD was calculated during the MVBIC, through the time interval between the EMG onset and torque onset. The PT and RTD were higher in the YG than in the MAG (P = 0·02; P = 0·01, respectively) and in the EG (P = 0·002; P = 0·0004, respectively). There were no significant differences in EMD among the three age groups for the VL, VM and RF (P>0·05) muscles. We conclude that age affects the PT and RTD, but not EMD of the VL, VM and RF muscles.
MeSH Terms
- Adult
- Aged
- Aging
- Electromyography
- Excitation Contraction Coupling
- Female
- Humans
- Isometric Contraction
- Knee Joint
- Male
- Middle Aged
- Muscle, Skeletal
- Physical Endurance
- Reproducibility of Results
- Sensitivity and Specificity
- Torque
- Young Adult
Keywords
- ballistic
- elderly
- electromechanical delay
- peak torque
- rate of torque development
Human aging into senescence diminishes the capacity of the postural control system to adapt to the stressors of everyday life. Diminished adaptive capacity may be reflected by a loss of the fractal-like, multiscale complexity within the dynamics of standing postural sway (i.e., center-of-pressure, COP). We therefore studied the relationship between COP complexity and adaptive capacity in 22 older and 22 younger healthy adults. COP magnitude dynamics were assessed from raw data during quiet standing with eyes open and closed, and complexity was quantified with a new technique termed empirical mode decomposition embedded detrended fluctuation analysis (EMD-DFA). Adaptive capacity of the postural control system was assessed with the sharpened Romberg test. As compared to traditional DFA, EMD-DFA more accurately identified trends in COP data with intrinsic scales and produced short and long-term scaling exponents (i.e., α(Short), α(Long)) with greater reliability. The fractal-like properties of COP fluctuations were time-scale dependent and highly complex (i.e., α(Short) values were close to one) over relatively short time scales. As compared to younger adults, older adults demonstrated lower short-term COP complexity (i.e., greater α(Short) values) in both visual conditions (p>0.001). Closing the eyes decreased short-term COP complexity, yet this decrease was greater in older compared to younger adults (p<0.001). In older adults, those with higher short-term COP complexity exhibited better adaptive capacity as quantified by Romberg test performance (r(2) = 0.38, p<0.001). These results indicate that an age-related loss of COP complexity of magnitude series may reflect a clinically important reduction in postural control system functionality as a new biomarker.
MeSH Terms
- Adaptation, Physiological
- Adult
- Aged
- Aging
- Algorithms
- Female
- Humans
- Male
- Middle Aged
- Models, Biological
- Postural Balance
- Posture
- Young Adult
The aim of this study was to determine electromechanical delay (EMD) using supramaximal stimuli and to investigate its variation with gender, age, contraction level and fatigue. Fifteen male and 15 female healthy subjects (aged between 18 and 60) participated in our study. Electromyogram (EMG) recordings were taken from triceps surae muscle. While subjects contracted their muscles voluntarily at specified percentages of maximum voluntary contraction, 10 supramaximal stimuli were applied to the tibial nerve. The time lag between the onset of the EMG response (M-wave) and the onset of force generation was calculated as EMD. EMD was found to be 8.5 /-1.3 ms (at rest condition), which is much shorter than those reported in previous studies. Although EMD did not significantly vary with gender (P>0.05), it decreased significantly with escalating muscle contraction level (P<0.05) and increased significantly with advancing age and with fatigue (P<0.05). EMD was found to be considerably shorter than those reported in previous studies, and hence we discuss the possible reasons underlying this difference. We suggest that supramaximal nerve stimulation and high resolution EMG and force recording may have generated this difference. Current findings suggest that EMD is very sensitive to the method used to determine it. We discuss the reasons for the short EMD value that we have found in the present study.
MeSH Terms
- Adolescent
- Adult
- Aging
- Analysis of Variance
- Animals
- Biomechanical Phenomena
- Electric Stimulation
- Fatigue
- Female
- Humans
- Male
- Middle Aged
- Muscle Contraction
- Reaction Time
- Sex Characteristics
- Time Factors
- Young Adult
Ten prepubertal girls and 15 young women were tested for maximal torque, peak rate of torque development, electro-mechanical delay (EMD), and time to peak rate of torque development during isometric elbow flexion. Absolute peak torque (17.0 /- 7.7 vs. 40.5 /- 8.3 Nm) and peak rate of torque development (105.9 /- 58.6 vs. 297.2 /- 113.0 Nm s(-1)) were lower in the girls (p < .05). Normalized to muscle cross sectional area, torque was similar (8.27 /- 2.74 vs. 8.44 /- 1.65 Nm cm(-2)), as was peak rate of torque development, normalized to peak torque (6.21 /- 1.94 vs. 7.30 /- 2.26 Nm s(-1)/ Nm). Both, time to peak rate of torque development (123.8 /- 36.0 vs. 110.5 /- 52.6 ms) and EMD (73.2 /- 28.6 vs. 51.9 /- 25.6 ms), were longer in the girls, although EMD's difference only approached statistical significance (p = .06). Age-related isometric strength differences in females appear to be mainly muscle-size dependent. However, the time to peak torque and EMD findings suggest differential motor-unit activation which may functionally manifest itself in fast dynamic contractions.
MeSH Terms
- Aging
- Arm
- Child
- Electromyography
- Female
- Humans
- Isometric Contraction
- Muscle Strength
- Young Adult
The twitch of the triceps surae muscle (TS), which characterizes the contractile properties independently of volition, differs in amplitude, but not in time course, when evoked in pre or postpubertal children. The aim of the present study was to compare the TS twitch contractile properties in prepubertal children (7 to 11 y). M-wave and twitch were recorded at rest by supramaximal electrical stimulations of the posterior tibial nerve. Twitches were characterized by peak torque (Pt), contraction time (CT), half relaxation time (HRT), and rate of torque development (dPt/dt). Electromechanical delay (EMD) was quantified with regard to the TS M-wave onset. Pt values increased significantly with the age of the prepubertal children but remained lower than that for adult subjects. CT and HRT values did not change with age. Thus, dPt/dt increased significantly between the 7-year-old and the 11-year-old children but remained significantly lower than that for adults. Despite EMD values decreased with age, they remained significantly higher than those of adult subjects. These results confirmed the link between growth processes and the increase in twitch torque for prepubertal children within a limited range of age. However, the time-course characteristics were not affected by age. The increase in dPt/dt and the decrease in the EMD could be used as indirect indicators of changes in contractile kinetics and in musculo-tendinous stiffness with the age of the prepubertal children. The age-related relationships established by this study will serve as reference values for clinical testing of the TS performances in relation to muscle disease or disuse.
MeSH Terms
- Aging
- Analysis of Variance
- Child
- Electromyography
- Female
- Humans
- Male
- Muscle Contraction
- Muscle Relaxation
- Muscle, Skeletal
The superior cognitive effects of atypical neuroleptics over typical agents reported in the schizophrenia literature are often attributed to the more prominent antagonist activity of the atypical drugs at serotonin 5HT(2A) receptors. However, atypical neuroleptics also have activity at many additional neurotransmitter receptors and few studies have specifically (and prospectively) tested the hypothesis that 5HT(2A) antagonism alone results in enhanced cognitive function. The purpose of this study was to evaluate the selective 5-HT(2A) antagonist, 7-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) in young and aged monkeys in a test designed to assess working memory function. Four oral doses (0.1, 1.0, 3.0, and 10.0 mg/kg) of EMD 281014 were evaluated in six young adult (mean age=9.2 years) and eight aged rhesus macaques (mean age=24.9 years) trained to perform a computer-assisted delayed matching-to-sample (DMTS) task. Depending on dose, EMD 281014 improved DMTS accuracy in young and aged monkeys primarily at either the medium or long retention intervals. While the latencies associated with incorrect color selections (choices latencies) tended to be longer than those associated with correct selections (particularly in the aged subjects) under baseline conditions, there were no significant effects of EMD 281014 on either sample or choice latencies in either age group. In addition, no adverse effects were observed across the range of doses evaluated in either cohort of animals. These experiments, conducted in a non-human primate model, suggest that selective 5HT(2A) antagonists such as EMD 281014 could offer therapeutic benefit to younger and older psychiatric patients by improving working memory function.
MeSH Terms
- Aging
- Animals
- Body Weight
- Conditioning, Operant
- Dose-Response Relationship, Drug
- Female
- Indoles
- Macaca mulatta
- Male
- Memory, Short-Term
- Piperazines
- Psychomotor Performance
- Reaction Time
- Receptor, Serotonin, 5-HT2A
- Serotonin Antagonists
- Sex Characteristics
While there is general agreement on the age changes in non-rapid eye movement sleep, there is conflicting evidence on whether eye movement density (EMD) in rapid eye movement sleep is affected by aging. We therefore performed computer measurement of EMD in young and elderly normal subjects. Sleep electroencephalogram and electrooculogram were recorded in each subject on 4 nonconsecutive baseline nights. Eye movement density in the elderly subjects was compared to that in young adults. A sleep research laboratory with 4 separate bedrooms. Not applicable. Subjects were 19 young normal adults and 19 elderly normal adults. Digitized electrooculograms were analyzed with the extensively validated zero-cross period-amplitude module of PASS PLUS software. The EMD was measured as 0.3 to 2 Hz integrated amplitude per 20-second stage of rapid eye movement sleep. Eye-movement incidence was the number of half waves. Eye-movement amplitude was the sum of peak-trough excursions (curve length) in the average half wave. We also counted visually the number of 2-second epochs with eye movements for 1 baseline night in both groups. The EMD in the elderly subjects was substantially and significantly lower than in the young subjects. Visual scoring of EMD on 1 baseline night confirmed the statistically significant difference between age groups. Period-amplitude analysis revealed that a lower eye-movement incidence rather than reduced amplitude caused the lower EMD in the elderly. The EMD was significantly correlated within subjects across the nonconsecutive baseline nights in both groups; in both, subjects' EMD average across 2 nights provided a correlation greater than .90 with the 4-night mean. The incidence of eye movements during rapid eye movement sleep is substantially reduced in the elderly. We hypothesize that this reduction is due to degenerative (aging) rather than developmental brain changes. The correlation analysis indicates that EMD is a reasonably stable individual trait in both young and elderly adults. These results encourage normative studies of EMD over a wider age span and continued exploration of the relation of EMD to cognitive function in the elderly.
MeSH Terms
- Adult
- Aged
- Aging
- Electroencephalography
- Electrooculography
- Female
- Humans
- Male
- Sleep, REM
Myocardial mechanics in the male spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) at 18 months of age were studied. Left ventricular hypertrophy was documented in the SHR by an increase in left ventricle/body weight and left ventricle/tibial length ratios when compared to the WKY (P less than 0.001). Isolated left ventricular papillary muscles were studied at 28 degrees C while contracting 12 times/min at the apex of the length-tension curve. Active and passive length-tension relations were measured at relatively early (65 /- 3 min) and late (200 /- 5 min) times following sacrifice. No significant differences in passive length-tension relations between strains were observed. Between early and late measurements, a significant decrease in passive tension within the length spectrum 89-100% Lmax occurred in both SHR and WKY, accompanied by a significant increase in passive stiffness (P less than 0.01, SHR; P less than 0.001, WKY). Isometric performance was measured at relatively early (81 /- 3 min) and later (190 /- 5 min) times following sacrifice. Strain differences in active muscle performance were of a greater electromechanical delay time (EMD) (P less than 0.05, early: P less than 0.001, late) and time-to-peak tension (TPT) (P less than 0.001, late) in SHR compared to WKY. Between early and late measurements, decreases in EMD (P less than 0.01, SHR; P less than 0.001, WKY), TPT (P less than 0.001; P less than 0.001), the half-time of relaxation (P less than 0.001; P less than 0.001), and the resting tension (P less than 0.01; P less than 0.001) were observed, and the maximum rate of fall of tension increased (P less than 0.01; P less than 0.01). We conclude that studies must be precisely referenced from the time of sacrifice of the animal in order to accurately evaluate the effects of experimental hypertrophy on isolated muscle performance. No evidence for the depression of papillary muscle isometric performance was seen in the 18-month SHR when compared to the WKY, although prolonged EMD and TPT were observed.
MeSH Terms
- Aging
- Animals
- Body Weight
- Female
- Hypertension
- Isometric Contraction
- Male
- Myocardial Contraction
- Myocardium
- Organ Size
- Papillary Muscles
- Rats
- Rats, Inbred SHR
- Rats, Inbred Strains
- Rats, Inbred WKY
- Time Factors
The brains of 396 old albino rats of the breed Wistar-AF/Han-EMD were examined for spontaneous tumors of the CNS and the following tumors were diagnosed: 1 oligodendroglioma, 1 astrocytoma, 1 mixed glioma, 1 pleomorphic glioma, and 19 meningiomas. Thus the CNS tumor rate was 5.8%. In addition 6 micromeningiomas were found. Knowledge of the spontaneous tumor rate including the tumor incidence in the CNS of the animal strains used for these examinations is a necessary condition for the evaluation of the results of cancerogenicity tests. CNS tumors deserve particular attention because during recent years it was found that certain chemical compounds like for instance N-methyl-N-nitrosourea induce organ-specific tumors in the brain of rats. It is recommended, therefore, to always include the central nervous system in the autopsy and histologic examination of animals from cancerogenicity trials. For cerebral autopsy transversal sections through the different cerebral regions and histologic examination of transversal section surfaces of all tumors and suspected tumor areas are suggested.
MeSH Terms
- Animals
- Astrocytoma
- Body Weight
- Brain Neoplasms
- Glioma
- Longevity
- Meningioma
- Neoplasms, Nerve Tissue
- Oligodendroglioma
- Rats
- Rats, Inbred Strains
- Rodent Diseases