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PubMed1998

Covert visual attention modulates face-specific activity in the human fusiform gyrus: fMRI study.

Several lines of evidence demonstrate that faces undergo specialized processing within the primate visual system. It has been claimed that dedicated modules for such biologically significant stimuli operate in a mandatory fashion whenever their triggering input is presented. However, the possible role of covert attention to the activating stimulus has never been examined for such cases. We used functional magnetic resonance imaging to test whether face-specific activity in the human fusiform face area (FFA) is modulated by covert attention. The FFA was first identified individually in each subject as the ventral occipitotemporal region that responded more strongly to visually presented faces than to other visual objects under passive central viewing. This then served as the region of interest within which attentional modulation was tested independently, using active tasks and a very different stimulus set. Subjects viewed brief displays each comprising two peripheral faces and two peripheral houses (all presented simultaneously). They performed a matching task on either the two faces or the two houses, while maintaining central fixation to equate retinal stimulation across tasks. Signal intensity was reliably stronger during face-matching than house matching in both right- and left-hemisphere predefined FFAs. These results show that face-specific fusiform activity is reduced when stimuli appear outside (vs. inside) the focus of attention. Despite the modular nature of the FFA (i.e., its functional specificity and anatomic localization), face processing in this region nonetheless depends on voluntary attention.

Adolescent↗

PubMed2002

Seeing your own touched hands in a mirror modulates cross-modal interactions.

In mirror reflections, visual stimuli in near peripersonal space (e.g., an object in the hand) can project the retinal image of far, extrapersonal stimuli "beyond" the mirror. We studied the interaction of such visual reflections with tactile stimuli in a cross-modal congruency task. We found that visual distractors produce stronger interference on tactile judgments when placed close to the stimulated hand, but observed indirectly as distant mirror reflections, than when directly observed in equivalently distant far space, even when in contact with a dummy hand or someone else's hand in the far location. The stronger visual-tactile interference for the mirror condition implies that near stimuli seen as distant reflections in a mirror view of one's own hands can activate neural networks coding peripersonal space, because these visual stimuli are coded as having a true source near to the body.

Adult↗

PubMed2000

Reactive oxygen species expose cryptic epitopes associated with autoimmune goodpasture syndrome.

Goodpasture syndrome is an autoimmune disease of the kidneys and lungs mediated by antibodies and T-cells directed to cryptic epitopes hidden within basement membrane hexamers rich in alpha3 non-collagenous globular (NC1) domains of type IV collagen. These epitopes are normally invisible to the immune system, but this privilege can be obviated by chemical modification. Endogenous drivers of immune activation consequent to the loss of privilege have long been suspected. We have examined the ability of reactive oxygen species (ROS) to expose Goodpasture epitopes buried within NC1 hexamers obtained from renal glomeruli abundant in alpha3(IV) NC1 domains. For some hexameric epitopes, like the Goodpasture epitopes, exposure to ROS specifically enhanced recognition by Goodpasture antibodies in a sequential and time-dependent fashion; control binding of epitopes to alpha3(IV) alloantibodies from renal transplant recipients with Alport syndrome was decreased, whereas epitope binding to heterologous antibodies recognizing all alpha3 NC1 epitopes remained the same. Inhibitors of hydrogen peroxide and hydroxyl radical scavengers were capable of attenuating the effects of ROS in cells and kidney by 30-50%, respectively, thereby keeping the Goodpasture epitopes largely concealed when compared with a 70% maximum inhibition by iron chelators. Hydrogen peroxide administration to rodents was sufficient to expose Goodpasture epitope in vivo and initiate autoantibody production. Our findings collectively suggest that ROS can alter the hexameric structure of type IV collagen to expose or destroy selectively immunologic epitopes embedded in basement membrane. The reasons for autoimmunity in Goodpasture syndrome may lie in an age-dependent deterioration in inhibitor function modulating oxidative damage to structural molecules. ROS therefore may play an important role in shaping post-translational epitope diversity or neoantigen formation in organ tissues.

Animals↗

PubMed1995

Spatial repetition blindness is modulated by selective attention to color or shape.

Subjects reported either the colors or shapes of two simultaneous masked letters. Our first study found that they were less accurate when the reported features were identical ("repetition blindness," or RB), while repetition along the unreported dimension had no effect. Three follow-up studies confirmed that when the same dimension was judged (overtly or covertly) for both stimuli, performance was only affected by repetition along that dimension. However, when different dimensions were judged for the two stimuli, performance was affected by repetition on both dimensions. These findings support new conclusions about both RB and visual attention. First, RB depends critically on visual attention, rather than simply on the stimulus presented or the overt response required. Second, while attention can be restricted to a single visual dimension, this is efficient only when the same dimension is selected for both objects. Selecting the color of one object and the shape of another simultaneous object results in both dimensions being accessed for both objects.

Adult↗

PubMed2026

ZUP1 as a Novel Potential Oncogenic Driver and Prognostic Biomarker in Breast Cancer.

INTRODUCTION: Breast cancer is one of the main causes of cancer death in women globally. Identifying new predictive markers and therapeutic targets is important for improving patient outcomes. Zinc finger-containing U-rich RNA-binding protein 1 (ZUP1) is an RNA-binding protein containing a zinc finger structure that has not been systematically analyzed in breast cancer research. MATERIALS AND METHODS: The study used data from 1,231 samples from the Cancer Genome Atlas (TCGA) database. The ZUP1 expression in tumor tissues and normal tissues was compared. Its predictive value was assessed using survival analysis and regression models. Its biological role was explored through gene functional analysis. The immune cell analysis method was used to study the tumor immune environment, and the drug susceptibility database was used to predict drug responses. Predictive models were also built and validated. RESULTS: ZUP1 expression was significantly higher in breast cancer tissues than in normal tissues. High expression of ZUP1 is related to advanced tumor stage and is an independent indicator of poor survival prognosis in univariate and multivariate analyses. Functional enrichment revealed that ZUP1 is closely linked to cell cycle progression, DNA replication, and the Fanconi anemia (FA) pathway. Immune infiltration analysis demonstrated a significant negative link between ZUP1 levels and the abundance of resting mast cells and activated NK cells. Furthermore, high ZUP1 expression was associated with increased sensitivity to several targeted therapies, including Nutlin-3a and PD-0325901. A clinically applicable nomogram combining ZUP1 expression with key clinical factors (age, stage, T, N, M) was developed to predict 3- and 5-year OS with good calibration and discrimination. DISCUSSION: Our study identifies ZUP1 as a potential oncogenic factor and a robust independent prognostic biomarker in breast cancer. Its involvement in critical cellular processes and modulation of the tumor immune microenvironment highlights its potential as a novel therapeutic target. Functional experiments, including immunohistochemical staining and CCK8 proliferation assays, further supported the oncogenic role of ZUP1. The established nomogram provides a valuable tool for personalized risk assessment and clinical decision-making. CONCLUSION: Our findings suggest that ZUP1 is a novel multifaceted biomarker with significant implications for personalized treatment strategies in breast cancer.

ZUP1↗

PubMed2001

Perceptual awareness and its loss in unilateral neglect and extinction.

We review recent evidence from studies of patients with unilateral neglect and/or extinction, who suffer from a loss of awareness for stimuli towards the affected side of space. We contrast their deficit with the effects of damage to primary sensory areas, noting that such areas can remain structurally intact in neglect, with lesions typically centred on the right inferior parietal lobe. In keeping with preservation of initial sensory pathways, many recent studies have shown that considerable residual processing can still take place for neglected or extinguished stimuli, yet without reaching the patient's awareness. This ranges from preserved visual grouping processes through to activation of identity, semantics and emotional significance. Similarly to 'preattentive' processing in normals, such residual processing can modulate what will enter the patient's awareness. Recent studies have used measures such as ERPs and fMRI to determine the neural correlates of conscious versus unconscious perception in the patients, which in turn can be related to the anatomy of their lesions. We relate the patient findings to neurophysiological data from areas in the monkey parietal lobe, which indicate that these serve as cross-modal and sensorimotor interfaces highlighting currently relevant locations as targets for intentional action. We speculate on the special role such brain regions may play in perceptual awareness, seeking to explain how damage to a system which appears primarily to code space could eliminate awareness even for non-spatial stimulus properties at affected locations. This may relate to the extreme nature of 'winner-takes-all' functions within the parietal lobe, and their correspondingly strong influence on other brain areas.

Awareness↗

PubMed2026

Inflammatory Cytokines Impair Glucagon Expression and Secretion in Pancreatic α-Cells.

AIMS: Insulin resistance and obesity-associated inflammation are key drivers in the pathogenesis of Type 2 diabetes mellitus (T2DM). Whilst inflammatory cytokines are well known to impair β-cell function, their impact on pancreatic α-cells and glucagon (GCG) regulation remains poorly understood. In this study, we investigated the effects of the pro-inflammatory cytokines interleukin (IL)-1β, tumour necrosis factor (TNF)-α and interferon (IFN)-γ on GCG expression and secretion. MATERIALS AND METHODS: The viability and endocrine function of α-cell line αTC1 and isolated islets were investigated by WST-1 assay, LDH assay, qRT-PCR, Western blot analysis and ELISA. The transcriptional activity of the GCG promoter was analysed by reporter gene assays. The cellular composition of isolated islets was assessed by immunohistochemistry. RESULTS: We found that exposure of the α-cell line αTC1 to a mix of these cytokines activates cellular stress responses characterised by induction of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Moreover, cytokine treatment markedly reduced GCG gene expression and secretion through repression of GCG promoter activity. Mechanistically, this was associated with a disrupted transcriptional network. These findings were confirmed in isolated mouse islets, where cytokine exposure significantly reduced GCG expression and secretion in islets of both male and female donors. CONCLUSIONS: Taken together, these findings indicate that inflammatory cytokines are potent modulators of α-cell function as well as GCG secretion and provide novel insights into inflammation-driven dysregulation of the endocrine function of pancreatic islets.

Glucagon-Secreting Cells↗

PubMed2025

Mapping Species Birth Across the Recombination Landscapes of Marine Snails.

Understanding the drivers of heterogeneous genomic divergence is essential for uncovering the mechanisms that generate and constrain biodiversity. The extent to which adaptation and speciation are facilitated by reorganisation of the recombination landscape remains untested in many systems. Marine ecosystems, with their dynamic and fluid habitats, offer a compelling context to investigate genomic divergence. In this study, we mapped genomic divergence and selection across recombination landscapes of parapatric marine snail sister species that we show have recently undergone secondary contact. Regions of reduced recombination were enriched for genes exhibiting signatures of negative selection, whereas regions of high recombination were associated with genes under putative positive selection. Notably, the recombination landscape of the population in parapatry of one species (Scurria viridula) differs markedly from that of the other population within this same species, highlighting the role of introgression in reshaping recombination landscapes. In the other species (Scurria zebrina), conservation of the recombination landscape and divergent selection among populations suggest trapping of beneficial allele combinations in regions of low recombination maintains the identity of this species. Among species, signals of divergence with gene flow consistently cluster within specific genomic regions characterised by high recombination rate variation among the populations of S. viridula. These results challenge traditional theoretical expectations of recombination evolution by showing that the causes of genomic divergence can be population-specific. This study demonstrates that recombination landscapes are key modulators of genomic divergence, with contemporary evolutionary shifts that could enable populations to adapt to distinct environments. Our findings provide new insights into the interplay between recombination, selection, and gene flow during speciation, underscoring the complexity of evolutionary trajectories in marine systems.

Genetic Introgression↗

PubMed2026

Repair and regeneration across the lifespan: an ontogenetic perspective.

The capacity for tissue repair and regeneration undergoes a profound and progressive decline across the human lifespan, representing a fundamental driver of aging and chronic disease. This review establishes a comprehensive ontogenetic framework by mapping the continuous biological transition from the flawless, scarless regenerative plasticity of embryonic development to the irreversible fibrotic scarring and organ failure characteristic of senescence. We synthesize the hierarchical collapse of reparative networks across multiple biological scales. Importantly, this ontogenetic decline should not be interpreted as a purely degenerative trajectory but rather as a dynamic systems-level reprogramming in which evolutionary trade-offs prioritize tumor suppression, immune surveillance, and reproductive fitness over long-term regenerative fidelity. Recognizing this adaptive reallocation of biological resources reframes aging not simply as failure but as a predictable recalibration of repair hierarchies. At the molecular and cellular levels, the accumulation of genomic instability, unresolvable DNA damage, and mitochondrial dysfunction gradually overwhelms intracellular quality-control mechanisms. Concurrently, epigenetic drift and chronic, low-grade systemic inflammation ("inflammaging") dismantle the stem cell niche, driving adult stem cell exhaustion and shifting wound healing away from functional tissue replacement toward maladaptive fibrosis. Furthermore, we examine divergent, organ-specific repair trajectories. By contrasting the severe regenerative restrictions of the adult central nervous system and myocardium with the persistent, yet exhaustible, resilience of the liver, we elucidate the unique intrinsic and microenvironmental barriers that impede structural and functional recovery. Finally, we evaluate the clinical paradigm shift from passive management of age-related degeneration to active restoration of tissue integrity. By integrating systemic geroscience-which addresses the global hallmarks of aging-with targeted bioengineering and in vivo epigenetic modulation, contemporary regenerative medicine seeks to recreate permissive, youthful microenvironments. Ultimately, mastering these ontogenetic principles holds unprecedented potential to reactivate endogenous repair pathways, mitigate multi-organ collapse, and significantly extend human functional healthspan.

DNA repair↗

PubMed2005

Enhanced protein kinase B/Akt signalling in pituitary tumours.

Pituitary tumours have previously been shown to harbour several abnormalities that cause deregulation of the cell cycle, particularly down-regulation of expression of the cyclin-dependent kinase inhibitor p27. However, it has been unclear whether these are the primary initiating events, or are secondary to other more proximate alterations in signalling pathways. In other cellular systems the Akt signalling pathway has been associated with downstream modulation of cell-cycle control. The aim of the present study was to test the hypothesis that Akt signalling is enhanced in pituitary tumours, and to see if changes in Akt expression are related to previous findings on low expression levels of the nuclear cell-cycle inhibitor p27 in pituitary tumours. We examined normal and adenomatous human pituitary tissue for mRNA and protein expression of Akt1, Akt2 and p27, and the activation of Akt, as well the phosphatase involved in the inactivation of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). In pituitary adenomas Akt1 and Akt2 mRNA were found to be over-expressed compared with normal pituitary, while PTEN transcripts showed similar levels between the two tissue types. Immunohistochemical expression of phospho-Akt was found to be higher in the tumours than normal pituitaries, while the protein expression of nuclear p27 and PTEN was lower in the adenomas. However, the expression of p27 and Akt were not directly correlated. PTEN sequencing revealed no mutation in the coding region of the gene in pituitary adenomas, and thus we did not locate a cause for the increased phosphorylation of Akt. In summary, we have shown over-expression and activation of the Akt pathway in pituitary tumours, and we speculate that cell-cycle changes observed in such tumours are secondary to these more proximate alterations. Since Akt is a major downstream signalling molecule of growth factor-liganded tyrosine kinase receptors, our data are most compatible with an abnormality at this level as the primary driver of pituitary tumorigenesis.

Cell Cycle Proteins↗

PubMed2006

Environmental and biological monitoring of benzene exposure in a cohort of Italian taxi drivers.

An integrated approach based on ambient and biological monitoring, the latter including both biomarkers of exposure and susceptibility, was applied to characterize benzene exposure in a group of 37 taxi drivers of the city of Parma (Italy). Airborne benzene concentrations were assessed by 24 h personal sampling and work-shift sampling inside the taxicab using passive samplers (Radiello). Benzene metabolites, trans,trans-muconic acid (t,t-MA) and S-phenylmercapturic acid (S-PMA), and urinary cotinine as biomarker of smoking habits were measured by isotopic dilution liquid chromatography tandem mass spectrometry in both pre-shift (PS) and end-of-shift (EOS) samples. Urinary benzene (U-B) levels were determined by solid-phase microextraction gas chromatography-mass spectrometry in EOS samples. Relevant polymorphisms of microsomal epoxide hydrolase, NAD(P)H:quinone oxidoreductase, glutathione S-transferases M1-1 (GSTM1), T1-1, and A1 were characterized by PCR-based methods. Mean airborne benzene concentration was 5.85 +/- 1.65 microg/m3, as assessed by 24 h personal sampling integrating for work-shift, indoor or general environment activities. Significantly, higher benzene concentrations were detected in the taxicab during the work-shift (7.71 +/- 1.95 microg/m3, p < 0.005). Smokers eliminated significantly higher concentrations of U-B and S-PMA than non-smokers in EOS samples [geometric mean (geometric S.D.): 2.58 (4.23) versus 0.44 (1.79) microg/l for U-B; 3.79 (1.50) versus 2.14 (1.87) microg/gcreat. for S-PMA, p < 0.002]. Within smokers, S-PMA concentrations significantly increased at the end of the work-shift compared to pre-shift values (p < 0.05). t,t-MA showed a similar behaviour, although differences were not significant. In the narrow range examined, no correlation was observed between air benzene concentration and urinary biomarkers. All benzene biomarkers but EOS t,t-MA were correlated with U-cotinine (p < 0.05). GSTM1 polymorphism significantly modulated S-PMA excretion, as subjects bearing the GSTM1pos genotype [3.61 (1.15) microg/gcreat.] excreted significantly higher S-PMA concentrations than GSTM1null subjects [2.19 (1.18) microg/gcreat., p < 0.05].

Acetylcysteine↗

PubMed1976

Alcohol and highway crashes. Closing the gap between epidemiology and experimentation.

It is frequently observed that alcohol-impaired drivers involved in certain types of crashes apparently 'couldn't stop in time'. However accurate this observation, it is simply a description and is not an adequate explanation. Therein lies the basis for the gap between epidemiology and experimentation. If alcohol actually does degrade a motorist's performance and increase the probability of his being responsible for a fatal crash, then alcohol-induced changes in driving behavior should be manifest and should be measurable. However, no controlled study has previously been conducted to obtain systematic but unobtrusive data on the actual influences of alcohol upon real-world driving behavior in its natural environment. One recently completed field study is reported which was designed to provide such data by means of unobtrusive electronic measures of nocturnal driving performance. In the present paper, to illustrate one approach to closing the gap between epidemiology and experimentation, one combination variable was selected which lends itself readily to comparison across the full spectrum of alcohol investigation: reaction time and braking performance. A review of the literature concerning this interrelated variable examined alcohol influences upon reaction time as investigated in laboratory, simulator, and instrumented car experiments, as well as alcohol influences upon braking performance in instrumented car experiments and in our recent field study involving unobtrusive electronic measures. The reviewed experiments were interpreted in terms of a conceptualization of the information-processing sequence which leads up to brake use. On the basis of the reviewed results, it was concluded that alcohol increases reaction time (both simple and choice) appreciably more in driving situations than in laboratory experiments. It was also concluded that a consistent alcohol impairment of the qualitative aspects of braking performance is manifest in driving situations, for example, as reflected by changes in brake-pressure modulation. More specifically, the braking performance of motorists and subjects at high BACs is abrupt, unsmooth, and less controlled than that of sober motorists or the same subjects with no alcohol. It was concluded that at least in terms of quality, alcohol impairs response implementation of the final stage of the information-processing sequence. It was hypothesized that the abrupt, lower quality braking performance observed at high BACs results--at least in part--from less time remaining available for stopping because the information-processing time has been increased by alcohol at some previous stage--apparently the response-selection stage. At the most general level, it was suggested that high BACs both increase the time necessary to begin applying the brakes, as well as reduce the degree of control in the actual use of the brakes during the course of stopping. These two factors in combination probably account for a large part of the alcohol contribution to highway crashes.

Accidents, Traffic↗

PubMed1999

Oscillations of insulin secretion can be triggered by imposed oscillations of cytoplasmic Ca2+ or metabolism in normal mouse islets.

Glucose-induced insulin secretion depends on an acceleration of glucose metabolism, requires a rise in the cytoplasmic free Ca2+ concentration ([Ca2+]i), and is modulated by activation of protein kinases in beta-cells. Normal mouse islets were used to determine whether oscillations of these three signals are able and necessary to trigger oscillations of insulin secretion. The approach was to minimize or abolish spontaneous oscillations and to compare the impact of forced oscillations of each signal on insulin secretion. In a control medium, repetitive increases in the glucose concentration triggered oscillations in metabolism [NAD(P)H fluorescence], [Ca2+]i (fura-PE3 method), and insulin secretion. In the presence of diazoxide, metabolic oscillations persisted, but [Ca2+]i and insulin oscillations were abolished. When the islets were depolarized with high K+ with or without diazoxide, [Ca2+]i was elevated, and insulin secretion was stimulated. Forced metabolic oscillations transiently decreased or did not affect [Ca2+]i and potentiated insulin secretion with oscillations of small amplitude. These oscillations of secretion followed metabolic oscillations only when [Ca2+]i did not change. When [Ca2+]i fluctuated, these changes prevailed over those of metabolism for timing secretion. Repetitive depolarizations with high K+ in the presence of stable glucose (10 mmol/l) induced synchronous pulses of [Ca2+]i and insulin secretion with only small oscillations of metabolism. Continuous stimulation of protein kinase A (PKA) and protein kinase C (PKC) did not dissociate the [Ca2+]i and insulin pulses from the high K+ pulses. However, the amplitude of the insulin pulses was consistently increased, whereas that of the [Ca2+]i pulses was either increased (PKA) or decreased (PKC). In conclusion, metabolic oscillations can induce oscillations of insulin secretion independently of but with a lesser effectiveness than [Ca2+]i oscillations. Although oscillations in metabolism may cyclically influence secretion through an ATP-sensitive K+ channel (K+-ATP channel)-independent pathway, their regulatory effects are characterized by a hysteresis that makes them unlikely drivers of fast oscillations, unless they also involve [Ca2+]i changes through the K+-ATP channel-dependent pathway.

Animals↗

PubMed2003

Preparatory states in crossmodal spatial attention: spatial specificity and possible control mechanisms.

We used event-related functional magnetic resonance imaging to study the neural correlates of endogenous spatial attention for vision and touch. We examined activity associated with attention-directing cues (central auditory pure tones), symbolically instructing subjects to attend to one hemifield or the other prior to upcoming stimuli, for a visual or tactile task. In different sessions, subjects discriminated either visual or tactile stimuli at the covertly attended side, during bilateral visuotactile stimulation. To distinguish cue-related preparatory activity from any modulation of stimulus processing, unpredictably on some trials only the auditory cue was presented. The use of attend-vision and attend-touch blocks revealed whether preparatory attentional effects were modality-specific or multimodal. Unimodal effects of spatial attention were found in somatosensory cortex for attention to touch, and in occipital areas for attention to vision, both contralateral to the attended side. Multimodal spatial effects (i.e. effects of attended side irrespective of task-relevant modality) were detected in contralateral intraparietal sulcus, traditionally considered a multimodal brain region; and also in the middle occipital gyrus, an area traditionally considered purely visual. Critically, all these activations were observed even on cue-only trials, when no visual or tactile stimuli were subsequently presented. Endogenous shifts of spatial attention result in changes of brain activity prior to the presentation of target stimulation (baseline shifts). Here, we show for the first time the separable multimodal and unimodal components of such preparatory activations. Additionally, irrespective of the attended side and modality, attention-directing auditory cues activated a network of superior frontal and parietal association areas that may play a role in voluntary control of spatial attention for both vision and touch.

Attention↗

PubMed2003

Sources of estrogen and their importance.

In premenopausal women, the ovaries are the principle source of estradiol, which functions as a circulating hormone to act on distal target tissues. However, in postmenopausal women when the ovaries cease to produce estrogen, and in men, this is no longer the case, because estradiol is no longer solely an endocrine factor. Instead, it is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor. These sites include the mesenchymal cells of adipose tissue including that of the breast, osteoblasts and chondrocytes of bone, the vascular endothelium and aortic smooth muscle cells, and numerous sites in the brain. Thus, circulating levels of estrogens in postmenopausal women and in men are not the drivers of estrogen action, they are reactive rather than proactive. This is because in these cases circulating estrogen originates in the extragonadal sites where it acts locally, and if it escapes local metabolism then it enters the circulation. Therefore, circulating levels reflect rather than direct estrogen action in postmenopausal women and in men. Tissue-specific regulation of CYP19 expression is achieved through the use of distinct promoters, each of which is regulated by different hormonal factors and second messenger signaling pathways. Thus, in the ovary, CYP19 expression is regulated by FSH which acts through cyclic AMP via the proximal promoter II, whereas in placenta the distal promoter I.1 regulates CYP19 expression in response to retinoids. In adipose tissue and bone by contrast, another distal promoter--promoter I.4--drives CYP19 expression under the control of glucocorticoids, class 1 cytokines and TNFalpha. The importance of this unique aspect of the tissue-specific regulation of aromatase expression lies in the fact that the low circulating levels of estrogens which are observed in postmenopausal women have little bearing on the concentrations of estrogen in, for example, a breast tumor, which can reach levels at least one order of magnitude greater than those present in the circulation, due to local synthesis within the breast. Thus, the estrogen which is responsible for breast cancer development, for the maintenance of bone mineralization and for the maintenance of cognitive function is not circulating estrogen but rather that which is produced locally at these specific sites within the breast, bone and brain. In breast adipose of breast cancer patients, aromatase activity and CYP19 expression are elevated. This occurs in response to tumor-derived factors such as prostaglandin E2 produced by breast tumor fibroblasts and epithelium as well as infiltrating macrophages. This increased CYP19 expression is associated with a switch in promoter usage from the normal adipose-specific promoter I.4 to the cyclic AMP responsive promoter, promoter II. Since these two promoters are regulated by different cohorts of transcription factors and coactivators, it follows that the differential regulation of CYP19 expression via alternative promoters in disease-free and cancerous breast adipose tissue may permit the development of selective aromatase modulators (SAMs) that target the aberrant overexpression of aromatase in cancerous breast, whilst sparing estrogen synthesis in other sites such as normal adipose tissue, bone and brain.

Aromatase↗

PubMed2005

Selective attention modulates neural substrates of repetition priming and "implicit" visual memory: suppressions and enhancements revealed by FMRI.

Attention can enhance processing for relevant information and suppress this for ignored stimuli. However, some residual processing may still arise without attention. Here we presented overlapping outline objects at study, with subjects attending to those in one color but not the other. Attended objects were subsequently recognized on a surprise memory test, whereas there was complete amnesia for ignored items on such direct explicit testing; yet reliable behavioral priming effects were found on indirect testing. Event-related fMRI examined neural responses to previously attended or ignored objects, now shown alone in the same or mirror-reversed orientation as before, intermixed with new items. Repetition-related decreases in fMRI responses for objects previously attended and repeated in the same orientation were found in the right posterior fusiform, lateral occipital, and left inferior frontal cortex. More anterior fusiform regions also showed some repetition decreases for ignored objects, irrespective of orientation. View-specific repetition decreases were found in the striate cortex, particularly for previously attended items. In addition, previously ignored objects produced some fMRI response increases in the bilateral lingual gyri, relative to new objects. Selective attention at exposure can thus produce several distinct long-term effects on processing of stimuli repeated later, with neural response suppression stronger for previously attended objects, and some response enhancement for previously ignored objects, with these effects arising in different brain areas. Although repetition decreases may relate to positive priming phenomena, the repetition increases for ignored objects shown here for the first time might relate to processes that can produce "negative priming" in some behavioral studies. These results reveal quantitative and qualitative differences between neural substrates of long-term repetition effects for attended versus unattended objects.

Adult↗

PubMed2004

Attentional load and sensory competition in human vision: modulation of fMRI responses by load at fixation during task-irrelevant stimulation in the peripheral visual field.

Perceptual suppression of distractors may depend on both endogenous and exogenous factors, such as attentional load of the current task and sensory competition among simultaneous stimuli, respectively. We used functional magnetic resonance imaging (fMRI) to compare these two types of attentional effects and examine how they may interact in the human brain. We varied the attentional load of a visual monitoring task performed on a rapid stream at central fixation without altering the central stimuli themselves, while measuring the impact on fMRI responses to task-irrelevant peripheral checkerboards presented either unilaterally or bilaterally. Activations in visual cortex for irrelevant peripheral stimulation decreased with increasing attentional load at fixation. This relative decrease was present even in V1, but became larger for successive visual areas through to V4. Decreases in activation for contralateral peripheral checkerboards due to higher central load were more pronounced within retinotopic cortex corresponding to 'inner' peripheral locations relatively near the central targets than for more eccentric 'outer' locations, demonstrating a predominant suppression of nearby surround rather than strict 'tunnel vision' during higher task load at central fixation. Contralateral activations for peripheral stimulation in one hemifield were reduced by competition with concurrent stimulation in the other hemifield only in inferior parietal cortex, not in retinotopic areas of occipital visual cortex. In addition, central attentional load interacted with competition due to bilateral versus unilateral peripheral stimuli specifically in posterior parietal and fusiform regions. These results reveal that task-dependent attentional load, and interhemifield stimulus-competition, can produce distinct influences on the neural responses to peripheral visual stimuli within the human visual system. These distinct mechanisms in selective visual processing may be integrated within posterior parietal areas, rather than earlier occipital cortex.

Adult↗