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PubMed2000

Corticolimbic interactions associated with performance on a short-term memory task are modified by age.

Aging has been associated with a decline in memory abilities dependent on hippocampal processing. We investigated whether the functional interactions between the hippocampus and related cortical areas were modified by age. Young and old subjects' brain activity was measured using positron emission tomography (PET) while they performed a short-term memory task (delayed visual discrimination) in which they determined which of two successively presented sine-wave gratings had the highest spatial frequency. Behavioral performance was equal for the two groups. Partial least squares (PLS) analysis of PET images identified a hippocampal voxel whose activity was similarly correlated with performance across groups. Using this voxel as a seed, a second PLS analysis identified cortical regions functionally connected to the hippocampus. Quantification of the neural interactions with structural equation modeling suggested that a different hippocampal network supported performance in the elderly. Unlike the neural network engaged by the young, which included prefrontal cortex Brodmann's area (BA) 10, fusiform gyrus, and posterior cingulate gyrus, the network recruited by the old included more anterior areas, i.e., dorsolateral prefrontal cortex (BA 9/46), middle cingulate gyrus, and caudate nucleus. Recruitment of a distinct corticolimbic network for visual memory in the elderly suggests that age-related neurobiological deterioration not only results in focal changes but also in the modification of large-scale network operations.

Adult↗

PubMed2006

The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism.

Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of beta-amyloid (Abeta) peptides, particularly Abeta42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of Abeta have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance Abeta42 production, they typically reduce Abeta40 generation and impair other PS-dependent activities. Third, gamma-secretase inhibitors can enhance the production of Abeta42 while blocking other gamma-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that Abeta42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of gamma-secretase.

Alzheimer Disease↗

PubMed2002

Haldane's rule by sexual transformation in Caenorhabditis.

Haldane's rule in C. briggsae x C. remanei broods was caused by sexual transformation; XX and XO hybrids were female. C. briggsae and C. remanei variants that partially suppress hybrid sexual transformation were identified. Effects of variant strains were cumulative. Hence, aberrant sex determination is a reproductive isolation mechanism in Caenorhabditis.

Animals↗

PubMedDate not supplied

MR detection of intracranial calcification: a phantom study.

To make a comparative analysis of calcium detection between MR and CT, anhydrous, insoluble calcium carbonate spheres varying in size from 1.5-7.0 mm were embedded in three physiologic tissue phantoms: low-protein gelatin (3 gm%), high-protein gelatin (6 gm%), and heavy mineral oil. The calcium-containing phantoms were scanned by CT and MR, using both T1- and T2-weighted sequences, with a slice thickness varying from 5-7 mm. Partial volume artifacts were determined by abutting phantoms with and without calcium and by varying the slice position to include different proportions of the calcium- and noncalcium-containing phantoms. Contrast-detail curves, expressed as a ratio of contrast to noise, were determined for varying sizes of calcification and degrees of partial voluming. As expected, the CT conspicuity of calcification (positive contrast) markedly surpasses that of MR (negative contrast). The difference was two orders of magnitude. When the calcification filled more than half the slice on MR, the conspicuity depended on the contrast of the matrix material; i.e., increased matrix intensity caused increased conspicuity. However, as the size of the calcification decreased, partial volume effects increased; i.e., increased matrix intensity caused decreased conspicuity. Conspicuity of small calcifications is independent of matrix material, since contrast and partial volume effects balance. We conclude that CT is clearly the method of choice for identifying small foci of calcification.

Brain↗

PubMed1993

Immunological responses critical to the therapeutic effects of adriamycin plus interleukin 2 in C57BL/6 mice bearing syngeneic EL4 lymphoma.

A safe and effective therapeutic combination of moderate doses of Adriamycin (doxorubicin, 4 mg/kg, IV, Days 1 and 8 or only Day 8) plus prolonged administration of moderate doses of interleukin 2 (2 micrograms, b.i.d., Days 9-40) was developed in the syngeneic EL4 (5 x 10(4) cells, IP, Day 0) lymphoma--C57B1/6 mouse model and has been reported in the companion paper. The studies described herein demonstrate that the effectiveness of this combination treatment against EL4 lymphoma growing intraperitoneally in C57B1/6 mice was dependent upon the presence of CD8+ cells. Thus, the induction of long-term survivors (60-80%) by Adriamycin plus interleukin 2 was completely ablated by pretreatment of mice with anti-CD8 monoclonal antibody (MAb), whereas pretreatment with anti-CD4 MAb only partially inhibited the therapeutic effects and anti-NK1.1 MAb had no effect. A close association between survival, an increase in phenotypically identified CD8+ cells, and an increase in specific anti-EL4 cytolytic activity was demonstrated with cells from the tumor site (peritoneum) but not consistently with cells from the spleen. No association was observed between survival and modulations in natural killer (NK), lymphokine-activated killer (LAK), or tumoricidal macrophage activity of spleen or peritoneal cells. Taken together the results indicate that, in this model, the most relevant correlate of a therapeutically effective host antitumor response is the level of specific EL4 tumor killing by cells present at the tumor site. Based on the findings reported herein, it can be predicted that weakly immunogenic tumors may be eradicated by immunologic mechanisms elicited in conjunction with properly designed therapeutic regimens.

Adjuvants, Immunologic↗

PubMed1975

X-ray crystallographic study of boronic acid adducts with subtilisin BPN' (Novo). A model for the catalytic transition state.

We have studied the structures of adducts formed between subtilisin BPN' and both benzeneboronic acid and 2-phenylethaneboronic acid by x-ray diffraction techniques. Electron density and difference maps at 2.5 A resolution were computed with phases calculated from a partially refined structure of the native enzyme (R = 0.23 at 2.0 A). Both adducts contain a covalent bond between Ogamma of the catalytic Ser-221 and the inhibitor boron atom. The boron atom is coordinated tetrahedrally, with one of the two additional boronic acid oxygen atoms lying in the "oxyanion hole" and the other at the leaving group site identified in previous studies (ROBERTUS, J.D., Kraut, J. ALDEN, R.A., and BIRKTOFT, J.J. (1972) Biochemistry 11, 4293-4303). Moreover, the previously postulated structure of the tetrahedral intermediate for substrate hydrolysis is isosteric with these boronic acid adducts, which can therefore be considered good models for the transition state complex (KOEHLER, K.K., and LIENHARD, G.E. (1972) Biochemistry 10, 2477-2483). These observations further support the suggestion that an important contribution to stabilization of this transition state complex, relative to both the Michaelis complex and the acyl intermediate, occurs as a consequence of hydrogen bond donation to the substrate carbonyl oxygen atom from the side chain amido group of Asn-155 and from the backbone amido group of Ser-221.

Binding Sites↗

PubMed2003

Overlapping subdeletions within a 348-bp in the 5' exon of the LAT region that facilitates epinephrine-induced reactivation of HSV-1 in the rabbit ocular model do not further define a functional element.

A previous study identified a 348-bp region at the 5' end of the 8.5-kb latency-associated transcript (LAT) of HSV-1 strain 17Syn+ that is necessary for maximum adrenergically induced reactivation following transcorneal iontophoresis of epinephrine (D.C. Bloom et al., 1996, J. Virol. 70, 2449-2459). In that study, the construct with complete deletion of the 348-bp region, 17delta348, failed to achieve the high reactivation frequency demonstrated by the parent (17Syn+) and rescued (17delta348R) viruses. To further characterize the function of the 348-bp region, we analyzed two genetic constructs with partial deletions in the same 348-bp region, 17delta201 and 17delta207, in the rabbit model. Both constructs exhibited the same high reactivation frequencies demonstrated by the parent 17Syn+ and the rescued 17delta348R viruses. These results suggest that the control of reactivation is distributed over a large portion of the 348-bp region, rather than being confined within a smaller, more discrete region. To assess whether the low reactivation phenotype of the 17delta348 construct was caused by a requirement for proper spacing of elements outside the 348-bp region, we constructed a virus (17delta348St) that contained a 360-bp stuffer fragment of heterologous DNA (lacZ) to maintain the proper spacing. The 17delta348St construct also displayed a low reactivation phenotype, similar to that of 17delta348, suggesting that the effect of deleting this segment of the 5' exon of LAT is obtained through a mechanism other than the disruption of spacing.

Animals↗

PubMed2004

Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older.

OBJECTIVES: To examine the impact of various treatment modalities on survival among patients with bladder cancer who were 80 years old or older compared with younger patients. A compendium of evidence suggests that bladder cancer surgery is safe among octogenarians; however, the benefit of such treatment in a population with limited life expectancy has not been well documented. METHODS: Subjects with the primary diagnosis of bladder cancer were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registry between 1988 and 1999. Of the 13,796 patients diagnosed with bladder cancer, 24% were older than 80 years of age. Proportional hazards regression modeling was performed to determine the independent association of treatment strategy on overall and bladder cancer survival while adjusting for multiple covariates. RESULTS: Of patients 80 years old or older, bladder cancer management included watchful waiting (7%), radiotherapy alone (1%), full or partial cystectomy (12%), and transurethral resection (79%). Patients 80 years old or older were less likely to be treated with extirpative surgery than their younger counterparts (P <0.0001). Cox proportional hazards models demonstrated that, among patients 80 years old or older, radical cystectomy/partial cystectomy had the greatest risk reduction in death from bladder cancer (hazard ratio 0.3) and death from any cause (hazard ratio 0.4) among the primary treatment modalities (both P <0.0001). CONCLUSIONS: Disparities in practice patterns between younger and geriatric patients with bladder cancer exist. We provide compelling evidence that aggressive surgical management of bladder cancer in these patients may improve survival. Risk adjustment tools should be used to identify patients (young and old) who would be better served by less aggressive management.

Age Factors↗

PubMed1991

Script generation as an indicator of knowledge representation in patients with Alzheimer's disease.

We examined script and lexical retrieval in patients with probable Dementia-Alzheimer's Type (DAT), Depressed patients, and normal controls. DAT patient breakdown in script production was structurally similar to their impaired lexical retrieval such that script events of low frequency and low centrality value were lost first. DAT patients also produced more events that fell outside the script boundary as well as more event-order errors. Four cases with DAT were identified on the basis of Z scores whose script production was at least 2 SDs greater than their lexical production or vice versa. This finding suggests that it may be possible to dissociate script and lexical knowledge and production processes. The findings lend partial support for a model of knowledge representation that includes parallel and partially redundant memory networks that are distinctly distributed in the brain.

Aged↗

PubMed2005

Mutations in connexin43 (GJA1) perturb bone growth in zebrafish fins.

Mechanisms that regulate the size and shape of bony structures are largely unknown. The molecular identification of the fin length mutant short fin (sof), which causes defects in the length of bony fin ray segments, may provide insights regarding the regulation of bone growth. In this report, we demonstrate that the sof phenotype is caused by mutations in the connexin43 (cx43) gene. This conclusion is supported by genetic mapping, reduced expression of cx43 in the original sof allele (sofb123), identification of missense mutations in three ENU-induced alleles, and by demonstration of partially abrogated cx43 function in sofb123 embryos. Expression of cx43 was identified in cells flanking the germinal region of newly growing segments as well as in the osteoblasts at segment boundaries. This pattern of cx43 expression in cells lateral to new segment growth is consistent with a model where cx43-expressing cells represent a biological ruler that measures segment size. This report identifies the first gene identification for a fin length mutation (sof) as well as the first connexin mutations in zebrafish, and therefore reveals a critical role for local cell-cell communication in the regulation of bone size and growth.

Alleles↗

PubMed1999

Two mutations identified in the androgen receptor of the new human prostate cancer cell line MDA PCa 2a.

PURPOSE: We have characterized the androgen receptor (AR) in a new human prostate cancer cell line, MDA PCa 2a, that has recently been established from a bone metastasis of a patient whose cancer exhibited androgen-independent growth. MATERIALS AND METHODS: Androgen responsiveness of these cells was assessed by measuring the effect of DHT and R1881 on cell growth and PSA secretion. Scatchard analysis was used to characterize the affinity and abundance of AR protein. Using a PCR based strategy, genomic DNA of the entire coding region of AR gene was sequenced to identify possible mutations. RESULTS: These cells express abundant AR (Nmax = 685 +/- 149 fmol./mg. protein), but the AR binding affinity (Kd) for DHT is only 25 nM, approximately 50-fold lower affinity than the mutated AR in LNCaP prostate cancer cells (Kd = 0.5 nM) or the wildtype AR in MCF-7 breast cancer cells (Kd = 0.4 nM). Two mutations, L701H and T877A, were identified in the ligand binding domain of the AR gene. Compared with LNCaP cells, the new cell line is significantly less responsive to DHT and R1881 as well as to other androgens such as testosterone, androstenedione, and DHEA. Similar to LNCaP cells, the ligand specificity of the AR in MDA PCa 2a cells appears to be relaxed and non-androgens such as progesterone and estradiol act as agonists although with less potency than in LNCaP cells. Interestingly, in the absence of androgens, the new cell line expresses 15-fold higher baseline levels of PSA than LNCaP. CONCLUSIONS: Two mutations were identified in the AR gene of the MDA PCa 2a cell line that are likely responsible for the decreased androgen sensitivity and altered ligand specificity observed in these cells. Thus, this new cell line with partial androgen responsiveness and PSA expression can serve as a functionally relevant model system of bone metastatic prostate cancer, and can be used to investigate the role of AR mutations in prostate cancer and its progression to androgen independence.

Cell Division↗

PubMed1999

Short-range vernier acuity: interactions of temporal frequency, temporal phase, and stimulus polarity.

We examined how vernier thresholds for flickering bars depend on the temporal frequency and relative temporal phase of the bars. The largest effect of relative phase (up to a fivefold increase in displacement thresholds) was seen at 2 Hz, and for most subjects, relative phase had little effect at 16 Hz and above. The effect of relative phase was essentially independent of contrast and trial duration. Thresholds were elevated by the greatest amount when bars were presented in antiphase, but at 1 and 4 Hz, quadrature phase offsets also led to substantial elevations in displacement thresholds. An experiment designed to examine the interaction of the vernier judgment with apparent motion failed to identify a role for mechanisms sensitive to apparent motion in threshold elevation. Another experiment in which the bars were modulated with sawtooth waveforms indicated that temporal correlation between the bars, rather than the ON versus OFF distinction, underlies the phase sensitivity. A simple dynamical model that posits partial rectification prior to a cross-correlation-like interaction accounts for the observed results.

Adolescent↗

PubMedDate not supplied

Identification of an E3 ubiquitin-protein ligase in the softshell clam (Mya arenaria).

Softshell clams (Mya arenaria) were exposed to dioxin in controlled laboratory experiments in order to study their molecular response to dioxin exposure. A complementary DNA (cDNA) fragment with sequence similarity to E3 ubiquitin-protein ligase appeared to be upregulated in dioxin-exposed clams compared to controls. E3 covalently ligates ubiquitin onto a protein, targeting it for degradation. Our findings suggest that the ubiquitin-mediated proteolytic pathway in the softshell clam may be activated by dioxin exposure. Because the clam E3-predicted amino acid sequence is most similar to a specific vertebrate E3 protein (E6-AP), we hypothesize that dioxin may stimulate ubiquitin-mediated degradation of cell-cycle regulatory proteins, such as the tumor suppressor p53, which promotes cell proliferation. This pathway has been observed in human cervical cancer. Partial cDNA sequence of the clam E3 has been identified using the differential display polymerase chain reaction (ddPCR) and RACE (Rapid Amplification of cDNA Ends) PCR; the full-length sequence is currently being determined. Discovering the molecular mechanism(s) stimulated by dioxin exposure in this invertebrate model may contribute to a better understanding of the effects of dioxin on marine organisms.

Amino Acid Sequence↗

PubMed2001

Migration pathways of human glioblastoma cells xenografted into the immunosuppressed rat brain.

Diffuse invasion of the brain by tumor cells is a hallmark of human glioblastomas and a major cause for the poor prognosis of these tumors. This phenomenon is only partially reproduced by rodent models of gliomas that display a very high rate of proliferation and limited cell migration. We have analyzed the development of human glioblastoma cells (GL15) xenografted into the brain of immunosuppressed rats, in order to define the characteristics of tumor cell invasion. As identified by the specific immunolabeling of the tumor cells for the human HLA-ABC antigen, GL15 tumors reproduced the three types of intraparenchymal invasion observed in patients. First, a majority of multipolar tumor cells intermingled rapidly and profusely with host neural cells in the margin of the injection site. This progressively enlarging area was principally responsible for the tumor growth over time. Second, in the gray matter, columns of thin bipolar tumor cells aligned along capillary walls. Third, in the white matter, elongated bipolar isolated tumor cells were observed scattered between axonal fibers. The maximum migration distances along white matter fibers remained significantly higher than the maximum migration distances along blood vessels, up to two months after injection. Development of the tumor was associated with a significant increase of vascularization in the area of tumor spread. Xenografting of human GL15 glioblastoma cells into the immunosuppressed rat brain allowed to differentiate between the three classical types of invasion identified in the clinic, to quantify precisely the distances of migration, and to evaluate cell morphology for each of these routes. The present results support the existence of host/tumor cells interactions with specific characteristics for each type of invasion.

Animals↗

PubMed2004

GAPSCORE: finding gene and protein names one word at a time.

MOTIVATION: New high-throughput technologies have accelerated the accumulation of knowledge about genes and proteins. However, much knowledge is still stored as written natural language text. Therefore, we have developed a new method, GAPSCORE, to identify gene and protein names in text. GAPSCORE scores words based on a statistical model of gene names that quantifies their appearance, morphology and context. RESULTS: We evaluated GAPSCORE against the Yapex data set and achieved an F-score of 82.5% (83.3% recall, 81.5% precision) for partial matches and 57.6% (58.5% recall, 56.7% precision) for exact matches. Since the method is statistical, users can choose score cutoffs that adjust the performance according to their needs. AVAILABILITY: GAPSCORE is available at http://bionlp.stanford.edu/gapscore/

Abstracting and Indexing↗

PubMed2006

Molecular mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKCzeta redistribution resulting in tight junction and epithelial barrier repair.

The probiotic Escherichia coli strain Nissle 1917 (EcN) has been used for decades in human medicine in Central Europe for the treatment and prevention of intestinal disorders and diseases. However, the molecular mechanisms underlying its beneficial effects are only partially understood. To identify molecular responses induced by EcN that might contribute to its probiotic properties polarized T84 cells were investigated employing DNA microarrays, quantitative RT-PCR, Western blotting, immunofluorescence and specific protein kinase C (PKC) inhibitors. Polarized T84 epithelial cell monolayers were used as a model to monitor barrier disruption by infection with the enteropathogenic E. coli (EPEC) strain E2348/69. Co-incubation of EPEC with EcN or addition of EcN following EPEC infection abolished barrier disruption and, moreover, restored barrier integrity as monitored by transepithelial resistance. DNA-microarray analysis of T84 cells incubated with EcN identified 300+ genes exhibiting altered expression. EcN altered the expression, distribution of zonula occludens-2 (ZO-2) protein and of distinct PKC isotypes. ZO-2 expression was enhanced in parallel to its redistribution towards the cell boundaries. This study provides evidence that EcN induces an overriding signalling effect leading to restoration of a disrupted epithelial barrier. This is transmitted via silencing of PKCzeta and the redistribution of ZO-2. We suggest that these properties contribute to the reported efficacy in the treatment of inflammatory bowel diseases and in part rationalize the probiotic nature of EcN.

Blotting, Western↗

PubMed2003

Searching for genes involved in arteriosclerosis: proteomic analysis of cultured human umbilical vein endothelial cells undergoing replicative senescence.

It is known that replicative senescence of endothelium in vivo contributes at least partially to age-related vascular disorders such as arteriosclerosis. However, the genes involved in this process remain to be identified. In this study, we employed a proteomics-based approach to identify candidate genes using in vitro cultured human umbilical vein endothelial cells (HUVECs) as an experimental model for replicative senescence. By comparing protein spots from young and senescent HUVECs using two-dimensional electrophoresis, we identified three up-regulated proteins and five down-regulated proteins in senescent HUVECs as compared to young HUVECs, whose alteration was not observed during replicative senescence of primary human fibroblasts. Consistent results were obtained in Western blotting analysis using specific antibodies raised against some of these proteins, whereas there were no significant changes in the mRNA levels of these genes during senescence of HUVECs. Among them, cathepsin B, a protease participating in both intracellular proteolysis and extracellular matrix remodeling was observed to be dramatically up-regulated in senescent HUVECs and whose activity is known to be up-regulated in atherosclerotic lesions with senescence-associated phenotypes in vivo. Additional proteins, including cytoskeletal proteins and proteins involved in the processes of synthesis, turnover and modification of protein, were identified, whose function in endothelium was previously unsuspected. These proteins identified by a proteomics-based approach using cultured HUVECs may be involved not only in replicative senescence but also in functional alterations in vascular endothelial cells with senescence-associated phenotypes and may serve as molecular markers for these processes.

Arteriosclerosis↗

PubMed1997

The associations of suicide attempts in adolescents.

OBJECTIVE: Suicide completion has increased in the United States among 15- to 24-year-olds from 4.5 per 100 000 (1950) to 13.2 per 100 000 (1990). Suicide attempts have been found to be associated with depression, substance use, overall number of life stressors, gender, and impulsive behaviors. We hypothesized that suicide attempt is associated with many other health risk behaviors. DESIGN: To evaluate this hypothesis, we analyzed the data from the 1993 Massachusetts Youth Risk Behavior Survey from a representative sample of students in grades 9 through 12 in public and private high schools. We examined the relationships between ever attempting suicide and engaging in other health risk or problem behaviors (eg, sexual activity, substance use, violence, and seat belt nonuse). RESULTS: The 3054 students were distributed among the 9th to 12th grades; 50.7% were female, 77.7% white, 6.7% black, 5.9% Hispanic, 4. 6% Asian, .8% Native American, and 4.4% other; and the mean age was 16 +/- 1.2 years. Based on logistic regression analysis, ever attempting suicide was associated with physical fights in the past 12 months (odds ratio [OR] = 1.3[95% confidence interval (CI), 1. 22-1.44]), regular cigarette use in the past 30 days (2.0[1.41-2. 97]), female gender (3.2[2.21-4.71]), lack of seat belt use (1.3[1. 21-1.34]), gun carrying in the past 30 days (1.4[1.12-1.70]), substance use before last sexual activity (1.4[1.09-1.84]), Native American or other (2.4[1.21-4.71]), and lifetime use of other drugs (1.2[1.04-1.40]). The full model correctly assigned 92% of the youth. There were small differences in models for males, females, and sexually active youth. Same gender sexual experiences for sexually active youth did not significantly improve the model (partial r = .0, OR = .87 [95% CI, .33-2.30]) and fewer (88%) of the youth were correctly assigned by the model. CONCLUSIONS: Ever attempting suicide is associated with other problem behaviors. This research proposes an empirical model of the relationship between suicide attempts and other health risk behaviors. Identifying which adolescents are at risk for suicide attempts from the presence of accompanying risk behaviors will help clinicians to evaluate suicide risk when other problem behaviors are identified, thus enabling the design of possible prevention strategies.

Adolescent↗