CFP
Properdin precursor (Complement factor P) [PFC]
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Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼ 300 fM) and synuclein (∼ 300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.
MeSH Terms
- Aging
- Alzheimer Disease
- Animals
- Biomarkers
- Biosensing Techniques
- Cells, Cultured
- Disease Models, Animal
- Flow Cytometry
- Fluorescence Resonance Energy Transfer
- HEK293 Cells
- Humans
- Mice, Transgenic
- Mutant Proteins
- Protein Aggregation, Pathological
- Protein Binding
- Tauopathies
- tau Proteins
Keywords
- aging
- amyloid
- dementia
- neuropathology
IL-15 is a cytokine critical for development, maintenance, and response of T cells, natural killer (NK) cells, NK T cells, and dendritic cells. However, the identity and distribution of IL-15-expressing cells in lymphoid organs are not well understood. To address these questions, we established and analyzed IL-15-CFP knock-in mice. We found that IL-15 was highly expressed in thymic medulla, and medullary thymic epithelial cells with high MHC class II expression were the major source of IL-15. In bone marrow, IL-15 was detected primarily in VCAM-1( )PDGFRβ( )CD31(-)Sca-1(-) stromal cells, which corresponded to previously described CXCL12-abundant reticular cells. In lymph nodes, IL-15-expressing cells were mainly distributed in the T-cell zone and medulla. IL-15 was expressed in some fibroblastic reticular cells and gp38(-)CD31(-) double-negative stromal cells in the T-cell zone. Blood endothelial cells, including all high endothelial venules, also expressed high IL-15 levels in lymph nodes, whereas lymphatic endothelial cells (LECs) lacked IL-15 expression. In spleen, IL-15 was expressed in VCAM-1( ) stromal cells, where its expression increased as mice aged. Finally, IL-15 expression in blood and LECs of peripheral lymphoid organs significantly increased in LPS-induced inflammation. Overall, we have identified and characterized several IL-15-expressing cells in primary and secondary lymphoid organs, providing a unique perspective of IL-15 niche in immune microenvironment. This study also suggests that some stromal cells express IL-7 and IL-15 differentially and suggests a way to functionally classify different stromal cell subsets.
MeSH Terms
- Aging
- Animals
- Bone Marrow Cells
- Endothelial Cells
- Gene Knock-In Techniques
- Inflammation
- Interleukin-15
- Lipopolysaccharides
- Lymph Nodes
- Lymphoid Tissue
- Mesoderm
- Mice
- Mucous Membrane
- Spleen
- Stromal Cells
- T-Lymphocytes
- Thymus Gland
Keywords
- aging
- differentiation
- homeostasis
- thymus
The neural protein α-synuclein aggregates both in vivo and in vitro to form insoluble fibrils that are involved in Parkinson's disease pathogenesis. We have generated α-synuclein/fluorescent-protein fusion constructs overexpressed in muscle cells of the nematode, Caenorhabdtis elegans. Green Fluorescent Protein (GFP) variants, Cerulean (C) or Venus (V), were fused to the C-terminus of human α-synuclein (S); the resultant fusion genes were designated SV and SC, plus a CV fusion as well as S, C and V singly. The aggregation behavior of the purified fusion proteins (expressed in E. coli) will be described elsewhere. These constructs were fused to a C. elegans unc-54 myosin promoter, and integrated transgenic lines generated by microinjection, λ-irradiation, and outcrossing of fluorescent progeny. All transgenic lines expressing α- synuclein showed significant reductions (p <0.05) in lifespan, motility and pharyngeal pumping, as compared to wildtype worms or lines expressing CFP and/or YFP only. We showed that CFP and YFP labels colocalised in granular inclusions throughout the body wall in transgenic lines expressing both SC and SV fusions (SC SV), whereas SV C worms displayed YFP-labelled inclusions on a diffuse CFP background. These findings implied that the α-synuclein moieties of these fusion proteins still aggregated together in vivo, whereas CFP or YFP moieties alone did not. This in turn suggested that Foerster Resonanace Energy Transfer (FRET) between CFP and YFP labels in α-synuclein aggregates could allow the extent of aggregation to be quantified. Accordingly, we also showed that net FRET signals increased 2- fold between L4 and adult SC SV worms.
MeSH Terms
- Animals
- Animals, Genetically Modified
- Caenorhabditis elegans
- Fluorescence Resonance Energy Transfer
- Gene Expression Regulation
- Green Fluorescent Proteins
- Humans
- Longevity
- Luminescent Proteins
- Movement
- Survival Analysis
- alpha-Synuclein
Age-related macular degeneration (AMD) is the commonest cause of blindness in Western populations. Risk is influenced by age, genetic and environmental factors. Complement activation appears to be important in the pathogenesis and associations have been found between AMD and genetic variations in complement regulators such as complement factor H. We therefore investigated other complement regulators for association with AMD. We carried out a case-control study to test for association between AMD and single nucleotide polymorphisms (SNPs) spanning the genes encoding complement factor P (CFP, properdin), CD46 (membrane cofactor protein, MCP), CD55 (decay accelerating factor, DAF) and CD59 (protectin). All cases and controls were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. 20 SNPs were genotyped in 446 cases and 262 controls. For two SNPs with p-values approaching significance additional subjects were genotyped to increase the numbers to 622 cases and 359 controls. There was no evidence of association between AMD and any of the SNPs typed in CFP, CD46, CD55 or CD59. In a case-control sample that has shown the well established associations between AMD and variants in CFH, CFB and C3 there was absence of association with SNPs in CFP, CD46, CD55 and CD59. This suggests that these are not important susceptibility genes for AMD.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- CD55 Antigens
- CD59 Antigens
- Case-Control Studies
- Complement System Proteins
- Female
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genetic Variation
- Genotype
- Humans
- Macular Degeneration
- Male
- Membrane Cofactor Protein
- Polymorphism, Single Nucleotide
- Properdin
Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNgamma produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNgamma levels in HHCs correlate with tuberculosis development. A cohort of 2060 HHCs was followed for 2-3 years after exposure to a tuberculosis case. Besides TST, IFNgamma responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination. Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNgamma response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNgamma responders to CFP-10 (HR 1.82 95% CI 0.79-4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNgamma producers was observed (trend Log rank p = 0.007). CFP-10-induced IFNgamma production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprophylaxis to child contacts regardless of BCG vaccination.
MeSH Terms
- Adolescent
- Adult
- Aging
- Antigens, Bacterial
- Colombia
- Demography
- Family Characteristics
- Female
- Humans
- Incidence
- Interferon-gamma
- Male
- Middle Aged
- Mycobacterium tuberculosis
- Predictive Value of Tests
- Risk Factors
- Tuberculin Test
- Tuberculosis
- Young Adult
We established a method to evaluate postural control adaptability, applying it to 341 subjects, aged 18-29 years (young subjects) and 50-79 years, in order to investigate the influences of age and gender on adaptability. Subjects stood with eyes closed on a force plate fixed to a floor oscillator, which was sinusoidally oscillated in the anteroposterior direction with 0.5 Hz frequency and 2.5 cm amplitude. Five trials of 1-minute oscillation were conducted, with a short rest between trials. The mean speed of fluctuation of the center of foot pressure (CFP), as detected by the force plate, was calculated as an index of postural steadiness. Mean CFP speed decreased significantly in all age groups with trial repetition. The adaptability capability of elderly subjects was categorized as "good," "moderate," or "poor," as evaluated against a standard value, based on the variation of the regression of mean CFP speed between the 1st and 5th trials in young subjects. Results showed that the magnitude of reduction in the mean speed, with practice, was linearly related to the initial mean speed. We found a general decline in adaptability, and increase in initial mean speed, in subjects aged 60 years and older, with no gender difference detected in any age group. The proportion of subjects exhibiting moderate and poor adaptability increased gradually with age. In conclusion, age, but not gender, appears to affect adaptation of postural sway with short-term practice, although some elderly subjects maintain postural sway velocity and adaptability capabilities similar to those of young subjects.
MeSH Terms
- Accidental Falls
- Adaptation, Physiological
- Adolescent
- Adult
- Aged
- Aging
- Female
- Humans
- Male
- Middle Aged
- Postural Balance
- Posture
The phytohormone abscisic acid (ABA) regulates essential growth and developmental processes in plants. Recently, RNA-binding proteins have been described as components of ABA signaling during germination. We have identified ten ABA-regulated RNA-binding proteins in Arabidopsis seedlings. Among those genes, AtCSP41B and cpRNP29 are highly expressed in seedlings. Using promoter:reporter gene analyses, we showed that both AtCSP41B and cpRNP29 were in particular expressed in photosynthetically active organs like green cotyledons, leaves, and petioles. The analysis of CFP-fusion proteins demonstrates that cpRNP29 localized to chloroplasts and AtCSP41B to chloroplasts and stromules. Whereas RNA-binding of cpRNP29 has previously been shown, we demonstrated through in vitro RNA-binding assays that recombinant AtCSP41B binds to RNA, and that chloroplast petD RNA can serve as a target of AtCSP41B. Developmental or environmental stimuli affected the expression of AtCSP41B and cpRNP29 in seedlings. Both genes were repressed during senescence, but only AtCSP41B was significantly repressed upon water stress. In addition, AtCSP41B and cpRNP29 exhibited low expression in etiolated seedlings compared to green seedlings, and cpRNP29 was regulated during the day photoperiod. Homozygous T-DNA insertion lines were isolated, characterized on the molecular level, and monitored for phenotypic changes. Taken together, the data show that both proteins are regulated during processes that are known to involve ABA signaling. Their localization in chloroplasts and RNA-binding activity suggest a role in chloroplast RNA metabolism in Arabidopsis seedlings.
MeSH Terms
- Abscisic Acid
- Aging
- Arabidopsis
- Chloroplasts
- DNA, Bacterial
- DNA, Chloroplast
- Gene Expression Regulation, Plant
- Genes, Reporter
- Mutagenesis, Insertional
- Photoperiod
- Plants, Genetically Modified
- Promoter Regions, Genetic
- RNA, Chloroplast
- RNA-Binding Proteins
- Seedlings
- Water
In quail, activation of the hypothalamic-pituitary-adrenal axis has been linked to depression in the hypothalamic-pituitary-testicular axis, and cloacal gland development and foam production are known to be androgen dependent. Therefore, photoperiod manipulations that induce gonadal growth (long day) and involution (short day) were used to examine changes in cloacal gland physiology in male quail from lines selected for a reduced (low stress, LS) or exaggerated (high stress, HS) plasma corticosterone response to brief restraint. Line differences in cloacal gland area (CAREA) and volume (CVOL), the proportion of individuals that produced cloacal gland foam (PICF), and the intensity of cloacal gland foam production (CFP) were initially assessed in adult males maintained on stimulatory, long photoperiods of 14L:10D. Thereafter, these variables were re-examined weekly in the same males during their subsequent exposure to 3 wk of short days (6L:18D) followed by return to long d for 3 more wk. Line differences in testes weight relative to body weight (RTW) were also measured at the end of the study. CAREA and CVOL were markedly greater in LS than HS males grown under long days. As expected, these indices of cloacal gland size were greatly reduced upon exposure to short days in both lines. However, line differences (LS > HS) in CAREA and CVOL were maintained during the first 2 wk of exposure to short days. Line differences in the depressed cloacal gland size measures were no longer evident by the third week on short days as well as after the first week of relighting wherein there were no further depressions in gland size of either line. However, by the end of 2 wk of rephotostimulation and thereafter, marked line differences (LS > HS) in CAREA and CVOL re-emerged. Photoperiod-induced line effects on CFP generally mimicked those of CAREA and CVOL. The PICF was marginally different (P < 0.07) between the lines (LS > HS) only after 1 wk of light reduction. After 3 wk of rephotostimulation, RTW was nearly 25% greater in LS quail. The results suggest that selection for reduced adrenocortical responsiveness in Coturnix has resulted in certain reproductive advantages in middle-aged, adult males maintained on stimulatory photoperiods as well as in such adults subjected to photocastration and subsequent rephotostimulation.
MeSH Terms
- Adrenal Cortex
- Aging
- Animals
- Cloaca
- Corticosterone
- Coturnix
- Male
- Organ Size
- Photoperiod
- Restraint, Physical
- Selection, Genetic
- Stress, Physiological
- Testis
The time course of sexual development in male quail from lines selected for either a reduced (low stress, LS) or an exaggerated (high stress, HS) plasma corticosterone response to brief restraint was determined. Sexual development was assessed by examination of cloacal gland area (CAREA) and volume (CVOL), proportion of individuals that produced cloacal gland foam, and the intensity of cloacal gland foam production (CFP) at 4, 5, 6, 8, 10, 14, and 16 wk of age. These intervals encompass ages during which growing, photostimulated quail would be expected to evolve from being totally prepubescent to well into adulthood. Testes weight (TW) and the proportion of individuals that had achieved a combined TW of 500 mg (PI500) were also measured at 6 and 16 wk of age. Mean CAREA and CVOL were similar in LS and HS quail at 4 wk of age. Beginning at 5 wk of age and thereafter, CAREA was greater (P < 0.05) in LS than in HS quail. Similarly, beginning at 6 wk of age and thereafter, CVOL was greater (P < 0.05) in LS than in HS quail. More LS than HS birds also expressed foam at 4 (P < 0.05), 5 (P = 0.15), and 6 wk (P < 0.05) of age. From 8 wk on, all birds were in foam production. CFP results mimicked those found for CAREA and CVOL in that LS quail tended toward higher CFP values than HS quail at all intervals of measurement. TW were higher (P < 0.02) in LS than HS quail when data from the 2 ages at which testes were harvested were combined. At 6 wk of age, the LS and HS birds showed a PI500 line difference (P < 0.08) of 1.0 and 0.91, respectively; by 16 wk, all birds exhibited a maximum PI500. The results suggest that 1) selection for reduced adrenocortical responsiveness in Coturnix is accompanied by an accelerated onset of puberty in males, and 2) enhanced reproductive development in LS males remains extant throughout early to middle-age adulthood.
MeSH Terms
- Adrenal Cortex
- Aging
- Animals
- Cloaca
- Corticosterone
- Coturnix
- Male
- Organ Size
- Reproduction
- Restraint, Physical
- Selection, Genetic
- Sexual Maturation
- Stress, Physiological
- Testis
The purpose of this study was to evaluate the influence of fear of falling on balancing ability during abrupt deceleration in aged women. The subjects were 20 women aged between 67 and 75 years. They were classified into two groups, one having a fear of falling (group FF, n = 10) and another without this fear (group NFF, n = 10). The two groups had similar daily physical activities. Changes in the centre of foot pressure (CFP) were measured during postural sway following horizontal deceleration of the force platform on which they were standing, and the response time and CFP displacement were evaluated. In addition, the electromyogram (EMG) onset in the tibialis anterior muscle and medial gastrocnemius muscle during abrupt deceleration, and its difference between the two muscles were measured. and the relative level of co-contraction of antagonistic muscles (the co-contraction index, CCI) in the lower extremity muscle group was calculated. The response time and CFP displacement immediately after abrupt deceleration were significantly higher in group FF than in NFF (P < 0.05). The EMG onset in the two muscles did not significantly differ between the two groups. The difference in EMG onset between the two muscles was significantly lower in group FF than in NFF (P < 0.05). The CCI was significantly higher in group FF than in NFF (P < 0.05). These results suggest that there were negative effects of a fear of falling on the balancing ability immediately after abrupt deceleration. This may be because a fear of falling increases the co-contraction of antagonist muscles in the lower extremity muscle group.
MeSH Terms
- Aged
- Aging
- Deceleration
- Electromyography
- Fear
- Female
- Humans
- Muscle Contraction
- Muscle, Skeletal
- Physical Fitness
- Postural Balance
- Psychomotor Performance
- Reaction Time
Age-related differences in postural control in response to a relatively large deceleration resulting from postural disturbance were investigated in eight normal elderly men (age range 67-72 years) and eight young men as controls (age range 19-22 years) using a moving platform. Data were obtained for the hip, knee and ankle angles, position of the centre of foot pressure (CFP), head acceleration, and muscle activity of the leg muscles. The elderly subjects had slower and larger ankle and hip joint movements, and CFP displacement in response to the disturbance compared to the young controls. The elderly subjects also had a delayed occurrence, and greater magnitude of peak acceleration of head rotation than did the young subjects. For the elderly subjects, the CFP was closely related to angular changes in the hip joint movement, but not to those of the ankle and knee joint movements. For the young subjects, on the other hand, the CFP was significantly correlated with angular change in the ankle joint. Cocontraction of the tibialis anterior and gastrocnemius muscles was observed in the elderly subjects. The results indicated that a movement pattern for postural correction in the elderly adults was different from that of the young adults. The elderly relied more on hip movements while the young controls relied on ankle movements to control postural stability.
MeSH Terms
- Adult
- Aged
- Aging
- Ankle Joint
- Deceleration
- Foot
- Hip Joint
- Humans
- Knee Joint
- Male
- Physical Fitness
- Postural Balance
- Posture
- Pressure
- Random Allocation
One thousand two hundred posturographic tests have been performed since 1988 at the Laboratoire d'Exploration Fonctionnelle ORL, Centre Hospitalier Universitaire, Nancy-Brabois, using three complementary protocols (Toennis GmBh, G). Static tests [1] measure over 20 seconds periods the displacement of the center of foot pressure (CFP) on individual standing upright on the platform. Dynamic tests assess the mechanisms of balance control following measured platform movements, using surface EMG after a single sharp and unexpected tilt [2], or CFP displacements during longer regular oscillations of the platform [3]. The latter test enables an analysis of balance strategy adopted to maintain equilibrium. These three programs were applied to series of children, adults, elderly people, sportsmen, and patients suffering from ENT, neurological or traumatic disorders. They were confirmed to be complementary tests allowing a thorough investigation of all balance control mechanisms: visual afferences [1], somesthesy [2] and the combination of visual, somesthetic and vestibular afferences in the third test.
MeSH Terms
- Adolescent
- Adult
- Afferent Pathways
- Aged
- Aging
- Child
- Electromyography
- Female
- Humans
- Male
- Middle Aged
- Motor Activity
- Otorhinolaryngologic Diseases
- Postural Balance
- Posture
- Reference Values
- Reflex, Vestibulo-Ocular
- Reproducibility of Results
- Sensory Receptor Cells
- Sports
Body sway was studied at various body inclinations, voluntarily maintained for about 1 min, in young and elderly normals and in idiopathic parkinsonians. They stood on a dynamometric platform, whose output gave the instantaneous centre of foot pressure (CFP), its mean value and body sway area, with eyes open (EO) or closed (EC). Subjects held the normal upright stance, or the maximum possible inclined posture (body straight, rotated at the ankle joints) in forward or backward direction, or intermediate postures. EMG was recorded from tibialis anterior (TA), soleus (Sol), extensor digitorum brevis (EDB) and flexor digitorum brevis (FDB). The cross-correlation function between the profile of the EMG envelope and the profile of the shift of CFP along the sagittal plane was calculated. In young subjects standing with EO, the maximum extent of antero-posterior (A-P) displacement of CFP was about 60% of foot length. EC reduced this value to about 50%. In the elderly normals, the maximum A-P displacement was about 40% (EO) and 30% (EC). In both groups, sway area was minimal during normal stance with EO and increased progressively when the subjects leant forward or backward. With EC, sway area further increased during normal stance and the rate of increase in relation to inclination augmented markedly. Sol was tonically active during normal stance. Forward leaning increased Sol EMG and induced activity in FDB. TA and EDB were active during backward leaning. The peak of the cross-correlation function between Sol EMG and instantaneous CFP was higher during normal stance than forward inclination, while the reverse was true for FDB. This suggests a role of FDB in the fine-tuning of postural adjustment during forward leaning, and a weight-supporting role of Sol. During backward inclination, TA but not EDB was cross-correlated with CFP. In the parkinsonians, maximum A-P displacement of CFP was just about 30% of foot length (EO; about 20% with EC); its extent was inversely correlated with the severity of the disease. The relationship between sway area and A-P displacement was similar to the elderly, both with EO and EC, within the common range of inclination. In the patients affected by the long-term syndrome, A-P displacement was further reduced while sway area increase at the critical postures was often absent. In all patients, the relationship between muscle activity and body inclination was comparable to normal.(ABSTRACT TRUNCATED AT 400 WORDS)
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Electromyography
- Female
- Humans
- Male
- Middle Aged
- Muscles
- Parkinson Disease
- Postural Balance
- Posture
- Reference Values