Senescence is accompanied by a reduced ability to respond to a variety of physical and behavioral stressors. A sizable literature has been devoted to the interplay between hypothalamic-pituitary-adrenocortical axis dysfunction and senescence; yet, the precise interactions remain an enigma. Adrenocorticotropic hormone (ACTH) is secreted in pulsatile bursts generating complex signals in the plasma compartment that must be “read” by adrenocortical cells in order to initiate appropriate secretory responses. We have previously demonstrated subtle differences between young and old rats in the pattern of fluctuations in plasma ACTH concentrations over time, despite no difference in mean levels. The present work addressed the physiological significance of these differences in the plasma ACTH signal by analyzing the corresponding plasma corticosterone concentration time series and the relationship between these two hormones over time. Time series of integrated 10-min ACTH and corticosterone concentrations were collected over 4 h at the time of diurnal activation and analyzed in the time and frequency domains. The time of onset of the diurnal surge occurred 20 min later in old rats, and the ratio of corticosterone to ACTH was less at the time of onset and peak of the diurnal surge. Corticosterone levels were lower in old rats and mean ACTH and corticosterone levels were correlated in young but not old rats, as were maximum levels of the two hormones. Cross-correlation of ACTH and corticosterone time series and comparison of spectra were consistent with smoother fluctuations in plasma corticosterone in old animals with less variability at time scales less than 55 min. We conclude that age may be associated with a delay in diurnal activation of the HPA axis, a loss of sensitivity of adrenal corticosterone secretion to plasma ACTH levels, and a relative loss of high frequency variability in the corticosterone signal, as seen in many physiological systems with age. 相似文献
Previous studies have suggested that ionizing radiation causes irreparable DNA double-strand breaks in mice and cell lines harboring mutations in any of the three subunits of DNA-dependent protein kinase (DNA-PK) (the catalytic subunit, DNA-PKcs, or one of the DNA-binding subunits, Ku70 or Ku86). In actuality, these mutants vary in their ability to resolve double-strand breaks generated during variable (diversity) joining [V(D)J] recombination. Mutant cell lines and mice with targeted deletions in Ku70 or Ku86 are severely compromised in their ability to form coding and signal joints, the products of V(D)J recombination. It is noteworthy, however, that severe combined immunodeficient (SCID) mice, which bear a nonnull mutation in DNA-PKcs, are substantially less impaired in forming signal joints than coding joints. The current view holds that the defective protein encoded by the murine SCID allele retains enough residual function to support signal joint formation. An alternative hypothesis proposes that DNA-PKcs and Ku perform different roles in V(D)J recombination, with DNA-PKcs required only for coding joint formation. To resolve this issue, we examined V(D)J recombination in DNA-PKcs-deficient (SLIP) mice. We found that the effects of this mutation on coding and signal joint formation are identical to the effects of the SCID mutation. Signal joints are formed at levels 10-fold lower than in wild type, and one-half of these joints are aberrant. These data are incompatible with the notion that signal joint formation in SCID mice results from residual DNA-PKcs function, and suggest a third possibility: that DNA-PKcs normally plays an important but nonessential role in signal joint formation. 相似文献
Objective: The maternal–fetal interface must modulate immune function to allow tolerance of fetal cells while still reacting to pathogens to suppress infection. Human leukocyte antigen-G (HLA-G) is a class Ib major histocompatibility complex protein involved in maternal–fetal tolerance. We posited that alterations in placental HLA-G expression predispose women to preterm birth. The aim of this study was to compare HLA-G expression in the maternal–fetal interface of term versus preterm human placentas.
Methods: We performed a cross-sectional study of specimens from the basal plate of the human placenta from women enrolled in a tissue specimen and clinical data consortium. Immunohistochemistry with digital microscopic analysis was used to quantify HLA-G protein expression in the basal plate from preterm and term placentas.
Results: Preterm birth <37 weeks occurred in 29.5% of 149 singleton pregnancies. HLA-G-positive cells occupied one-third of the basal plates, and the HLA-G-positive area was increased by 14% in placentas from preterm births than in those from term births (32.1% in term placentas versus 36.6% in preterm placentas).
Conclusion: Although HLA-G is required for maternal tolerance of the semi-allogeneic fetus, higher levels of HLA-G expression at the maternal–fetal interface is associated with preterm birth. 相似文献
Bioinformatics approaches to examine gene‐gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge‐driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty‐three SNP‐SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)–rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell‐to‐cell adhesion signaling, cell‐cell junction organization, and cell‐cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP‐SNP models, which included signal transduction and PI3K‐Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology‐driven method, applicable for any genome‐wide association study dataset. 相似文献
To develop self-reported short forms for the Life Impact Burn Recovery Evaluation (LIBRE) Profile.
Design
Short forms based on the item parameters of discrimination and average difficulty.
Setting
A support network for burn survivors, peer support networks, social media, and mailings.
Participants
Burn survivors (N=601) older than 18 years.
Interventions
Not applicable.
Main Outcome Measures
The LIBRE Profile.
Results
Ten-item short forms were developed to cover the 6 LIBRE Profile scales: Relationships with Family & Friends, Social Interactions, Social Activities, Work & Employment, Romantic Relationships, and Sexual Relationships. Ceiling effects were ≤15% for all scales; floor effects were <1% for all scales. The marginal reliability of the short forms ranged from .85 to .89.
Conclusions
The LIBRE Profile-Short Forms demonstrated credible psychometric properties. The short form version provides a viable alternative to administering the LIBRE Profile when resources do not allow computer or Internet access. The full item bank, computerized adaptive test, and short forms are all scored along the same metric, and therefore scores are comparable regardless of the mode of administration. 相似文献
AIDS and Behavior - This randomized controlled trial tested the efficacy of a multi-session, evidence-based, lay counselor-delivered transdiagnostic therapy, the Common Elements Treatment Approach... 相似文献