intellectual vanities… about close to everything

Scientists at Carnegie Mellon University have taken an important step toward understanding how the human brain codes the meanings of words by creating the first computational model that can predict the unique brain activation patterns associated with names for things that you can see, hear, feel, taste or smell.

Researchers previously have shown that they can use functional magnetic resonance imaging (fMRI) to detect which areas of the brain are activated when a person thinks about a specific word. A Carnegie Mellon team has taken the next step by predicting these activation patterns for concrete nouns — things that are experienced through the senses — for which fMRI data does not yet exist.

The work could eventually lead to the use of brain scans to identify thoughts and could have applications in the study of autism, disorders of thought such as paranoid schizophrenia, and semantic dementias such as Pick’s disease.

The team, led by computer scientist Tom M. Mitchell and cognitive neuroscientist Marcel Just, constructed the computational model by using fMRI activation patterns for 60 concrete nouns and by statistically analyzing a set of texts totaling more than a trillion words, called a text corpus. The computer model combines this information about how words are used in text to predict the activation patterns for thousands of concrete nouns contained in the text corpus with accuracies significantly greater than chance.

The findings are being published in the May 30 issue of the journal Science.

“We believe we have identified a number of the basic building blocks that the brain uses to represent meaning,” said Mitchell, who heads the School of Computer Science’s Machine Learning Department. “Coupled with computational methods that capture the meaning of a word by how it is used in text files, these building blocks can be assembled to predict neural activation patterns for any concrete noun. And we have found that these predictions are quite accurate for words where fMRI data is available to test them.”

Just, a professor of psychology who directs the Center for Cognitive Brain Imaging, said the computational model provides insight into the nature of human thought. “We are fundamentally perceivers and actors,” he said. “So the brain represents the meaning of a concrete noun in areas of the brain associated with how people sense it or manipulate it. The meaning of an apple, for instance, is represented in brain areas responsible for tasting, for smelling, for chewing. An apple is what you do with it. Our work is a small but important step in breaking the brain’s code.”

In addition to representations in these sensory-motor areas of the brain, the Carnegie Mellon researchers found significant activation in other areas, including frontal areas associated with planning functions and long-term memory. When someone thinks of an apple, for instance, this might trigger memories of the last time the person ate an apple, or initiate thoughts about how to obtain an apple.

“This suggests a theory of meaning based on brain function,” Just added.

In the study, nine subjects underwent fMRI scans while concentrating on 60 stimulus nouns — five words in each of 12 semantic categories including animals, body parts, buildings, clothing, insects, vehicles and vegetables.

To construct their computational model, the researchers used machine learning techniques to analyze the nouns in a trillion-word text corpus that reflects typical English word usage. For each noun, they calculated how frequently it co-occurs in the text with each of 25 verbs associated with sensory-motor functions, including see, hear, listen, taste, smell, eat, push, drive and lift. Computational linguists routinely do this statistical analysis as a means of characterizing the use of words.

These 25 verbs appear to be basic building blocks the brain uses for representing meaning, Mitchell said.

By using this statistical information to analyze the fMRI activation patterns gathered for each of the 60 stimulus nouns, they were able to determine how each co-occurrence with one of the 25 verbs affected the activation of each voxel, or 3-D volume element, within the fMRI brain scans.

To predict the fMRI activation pattern for any concrete noun within the text corpus, the computational model determines the noun’s co-occurrences within the text with the 25 verbs and builds an activation map based on how those co-occurrences affect each voxel.

In tests, a separate computational model was trained for each of the nine research subjects using 58 of the 60 stimulus nouns and their associated activation patterns. The model was then used to predict the activation patterns for the remaining two nouns. For the nine participants, the model had a mean accuracy of 77 percent in matching the predicted activation patterns to the ones observed in the participants’ brains.

The model proved capable of predicting activation patterns even in semantic areas for which it was untrained. In tests, the model was retrained with words from all but two of the 12 semantic categories from which the 60 words were drawn, and then tested with stimulus nouns from the omitted categories. If the categories of vehicles and vegetables were omitted, for instance, the model would be tested with words such as airplane and celery. In these cases, the mean accuracy of the model’s prediction dropped to 70 percent, but was still well above chance (50 percent).

Plans for future work include studying the activation patterns for adjective-noun combinations, prepositional phrases and simple sentences. The team also plans to study how the brain represents abstract nouns and concepts.

Science, 2008; 320 (5880): 1191 DOI: 10.1126/science.1152876

The question of how the human brain represents conceptual knowledge has been debated in many scientific fields. Brain imaging studies have shown that different spatial patterns of neural activation are associated with thinking about different semantic categories of pictures and words (for example, tools, buildings, and animals). We present a computational model that predicts the functional magnetic resonance imaging (fMRI) neural activation associated with words for which fMRI data are not yet available. This model is trained with a combination of data from a trillion-word text corpus and observed fMRI data associated with viewing several dozen concrete nouns. Once trained, the model predicts fMRI activation for thousands of other concrete nouns in the text corpus, with highly significant accuracies over the 60 nouns for which we currently have fMRI data.

The old saying, “beauty is in the eye of the beholder,” has been scientifically show to be true. A study in a recent issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS), found that variations in eyebrow shape, eyelid position, and wrinkles significantly impact how your facial expressions, and subsequent mood, are perceived by others.

“A key complaint of those seeking facial plastic surgery is that people always tell them they look tired, even though they do not feel tired,” said John Persing, MD, ASPS member and study co-author. “We found that variations in eyebrow contour, drooping of the upper eyelid, and wrinkles may be conveying facial expressions that don’t necessarily match how patients are feeling.”

In the study, a standardized photo of a youthful face was digitally altered to change a number of variables, including eyebrow shape and position; upper and lower eyelid position; upper eyelid drooping and removal of excess skin; and facial wrinkles. Twenty health care workers were given 16 photos and asked to rate, on a scale of 0 to 5, the presence of seven expressions or emotions: tiredness, happiness, surprise, anger, sadness, disgust, and fear. The results for each altered photo were compared with scores from the original unaltered photo. Overall, eyebrow shape had a greater influence than absolute position on perceived mood.

Tiredness

Drooping of the upper eyelid was the biggest indicator of tiredness, according to the study. Simulating skin removal of the upper eyelid, as performed in some eyelid procedures, but not correcting accompanying eyelid ptosis (drooping), resulted in an increase in the perception of tiredness (and sadness). Photos that included an overall elevation of the eyebrows or an increase in the distance between the eyebrow and upper eyelid also increased the perception of tiredness.

Anger & Disgust

Lowering or slanting the inner corner of the eyebrows towards the nose, as well as adding forehead winkles significantly increased the perceived facial expressions of anger and disgust.

Fear & Surprise

Raising the upper eyelids produced an increase in the perception of surprise and fear. Also, raising the outer corner of the eyebrows produced an increase in the perception of surprise.

Sadness

Raising the inner corner of the eyebrows away from the nose was perceived as a sad facial expression.

Happiness

Happiness was perceived by raising the lower eyelid and the presence of crow’s feet, which, according to the study, seem to simulate the cheek elevation that occurs with smiling.

“The eyes and their related structures nonverbally communicate a wide range of expressions that are universal to all people,” said Dr. Persing. “Therefore facial expression should be a factor in how patients and their plastic surgeons select various rejuvenation procedures. As our findings show, even the slightest modification can elicit profound changes in how others perceive us.”

Plastic & Reconstructive Surgery. 121(5):1793-1802, May 2008.

(C)2008American Society of Plastic Surgeons

Italian investigators have published a new study on the neurobiologic correlates of the inability to express emotions (alexithymia).

A deficit in interhemispheric transfer was hypothesized in alexithymia more than 30 years ago, following the observation that split-brain patients manifest certain alexithymic characteristics. However, direct evidence of interhemispheric transfer deficit has never been provided. This study investigated the hypothesis of a transcallosal interhemispheric transfer deficit in alexithymia by means of paired-pulse transcranial magnetic stimulation.

A random sample of 300 students was screened for alexithymia using the Italian version of the 20-item Toronto Alexithymia Scale. Eight right-handed males and eight females with high alexithymic scores and an age- and gender-matched group with low alexithymic scores were selected. A first (conditioning) magnetic stimulus was delivered to one motor cortex followed by a second (test) stimulus to the opposite hemisphere at different interstimulus intervals for both motor cortices. Motor evoked responses were recorded from the abductor digit minimi muscles.

At the end of the investigation, high alexithymic subjects showed reduced transcallosal inhibition as compared to low alexithymic subjects at interstimulus intervals of 10, 12 and 14 ms in the left-to-right and right-to-left interhemispheric transfer directions.

Results point to functional differences in transcallosal interactions in high alexithymic as compared to low alexithymic subjects, supporting the hypothesis of an interhemispheric transfer deficit in alexithymia.

Psychother Psychosom. 2008;77(3):175-81. Epub 2008 Mar 10.

BACKGROUND: A deficit in interhemispheric transfer was hypothesized in alexithymia more than 30 years ago, following the observation that split-brain patients manifest certain alexithymic characteristics. However, direct evidence of interhemispheric transfer deficit has never been provided. This study investigated the hypothesis of a transcallosal interhemispheric transfer deficit in alexithymia by means of paired-pulse transcranial magnetic stimulation. METHODS: A random sample of 300 students was screened for alexithymia using the Italian version of the 20-item Toronto Alexithymia Scale. Eight right-handed males and eight females with high alexithymic scores and an age- and gender-matched group with low alexithymic scores were selected. A first (conditioning) magnetic stimulus was delivered to one motor cortex followed by a second (test) stimulus to the opposite hemisphere at different interstimulus intervals for both motor cortices. Motor evoked responses were recorded from the abductor digit minimi muscles. RESULTS: High alexithymic subjects showed reduced transcallosal inhibition as compared to low alexithymic subjects at interstimulus intervals of 10, 12 and 14 ms in the left-to-right and right-to-left interhemispheric transfer directions. CONCLUSIONS: Results point to functional differences in transcallosal interactions in high alexithymic as compared to low alexithymic subjects, supporting the hypothesis of an interhemispheric transfer deficit in alexithymia. Copyright (c) 2008 S. Karger AG, Basel.

By identifying a protein that restricts the release of HIV-1 virus from human cells, scientists believe they may be closer to identifying new approaches to treatment. The research is published in the advance online edition of Nature Medicine.

Scientists have known that most human cells contain a factor that regulates the release of virus particles, but until now they have been uncertain about the factor’s identity. Now a research team from Emory University School of Medicine, Vanderbilt University School of Medicine, and Mayo Medical School has identified CAML (calcium-modulating cyclophilin ligand) as the cellular protein that inhibits the release of HIV particles.

CAML works by inhibiting a very late step in the virus lifecycle, leading to the retention of HIV particles on the membrane of the cell. The virus has developed a means of counteracting CAML, through the action of the viral Vpu protein. When Vpu is absent, HIV particles don’t detach from the plasma membrane and instead accumulate by a protein tether at the cell surface.

When the research team depleted CAML in human cells in the laboratory, they found that Vpu was no longer required for the efficient exit of HIV-1 particles from the cell. When they expressed CAML in cell types that normally allow particles to exit freely, the particles remained attached to the cell surface.

“This research is important because it identifies CAML as an innate defense mechanism against HIV,” says senior author Paul Spearman, professor of pediatrics (infectious diseases) at Emory University School of Medicine. “We are continuing to work on the mechanism that Vpu uses to counteract CAML and on defining exactly how CAML leads to virus particle retention on the infected cell membrane. We hope this will lead us to new treatments.”

Nature Medicine

Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV-1 release overcome by Vpu

Vasundhara Varthakavi, Ellen Heimann-Nichols, Rita M Smith, Yuehui Sun, Richard J Bram, Showkat Ali, Jeremy Rose, Lingmei Ding & Paul Spearman

Published online: 25 May 2008; | doi:10.1038/nm1778

You went to a wedding yesterday. The service was beautiful, the food and drink flowed and there was dancing all night. But people tell you that you are in hospital, that you have been in hospital for weeks, and that you didn’t go to a wedding yesterday at all. The experience of false memories like this following neurological damage is known as confabulation.

The reasons why patients experience false memories such as these has largely remained a mystery. Studies in amnesic patients have associated confabulation with damage to the orbital and ventromedial prefrontal cortices. However, neuroimaging studies have associated memory-control processes which are assumed to underlie confabulation with the right lateral prefrontal cortex.

A new study by Dr Martha Turner and colleagues at University College London offers some clues as to what might be going on. They used a confabulation battery to investigate the occurrence and localisation of confabulation in an unselected series of 38 patients with focal frontal lesions.

Twelve patients with posterior lesions and 50 healthy controls were included for comparison. Significantly higher levels of confabulation were found in the frontal group, confirming previous reports. More detailed grouping according to lesion location within the frontal lobe revealed that patients with orbital, medial and left lateral damage confabulated in response to questions probing personal episodic memory (PEM).

Patients with orbital, medial and right lateral damage confabulated in response to questions probing orientation to time (OT). Performance-led analysis revealed that all patients who produced a total number of confabulations outside the normal range had a lesion affecting either the orbital region or inferior portion of the anterior cingulate.

These data provide striking evidence that the critical deficit for confabulation has its anatomical location in the inferior medial frontal lobe. Performance on tests of memory and executive functioning showed considerable variability. Although a degree of memory impairment does seem necessary, performance on traditional executive tests is less helpful in explaining confabulation.

Martha S Turner, Lisa Cipolotti, Tarek A Yousry, Tim Shallice
Institute of Cognitive Neuroscience, University College London, London, UK.

Confabulation, the pathological production of false memories, occurs following a variety of aetiologies involving the frontal lobes, and is frequently held to be underpinned by combined memory and executive deficits. However, the critical frontal regions and specific cognitive deficits involved are unclear. Studies in amnesic patients have associated confabulation with damage to the orbital and ventromedial prefrontal cortices. However, neuroimaging studies have associated memory-control processes which are assumed to underlie confabulation with the right lateral prefrontal cortex. We used a confabulation battery to investigate the occurrence and localisation of confabulation in an unselected series of 38 patients with focal frontal lesions. Twelve patients with posterior lesions and 50 healthy controls were included for comparison. Significantly higher levels of confabulation were found in the frontal group, confirming previous reports. More detailed grouping according to lesion location within the frontal lobe revealed that patients with orbital, medial and left lateral damage confabulated in response to questions probing personal episodic memory (PEM). Patients with orbital, medial and right lateral damage confabulated in response to questions probing orientation to time (OT). Performance-led analysis revealed that all patients who produced a total number of confabulations outside the normal range had a lesion affecting either the orbital region or inferior portion of the anterior cingulate. These data provide striking evidence that the critical deficit for confabulation has its anatomical location in the inferior medial frontal lobe. Performance on tests of memory and executive functioning showed considerable variability. Although a degree of memory impairment does seem necessary, performance on traditional executive tests is less helpful in explaining confabulation.

Neuroscience researchers at the Duke-NUS Graduate Medical School in Singapore have shown for the first time what happens to the visual perceptions of healthy but sleep-deprived volunteers who fight to stay awake, like people who try to drive through the night.

The scientists found that even after sleep deprivation, people had periods of near-normal brain function in which they could finish tasks quickly. However, this normalcy mixed with periods of slow response and severe drops in visual processing and attention, according to their paper, published in the Journal of Neuroscience on May 21.

“Interestingly, the team found that a sleep-deprived brain can normally process simple visuals, like flashing checkerboards. But the ‘higher visual areas’ — those that are responsible for making sense of what we see — didn’t function well,” said Dr. Michael Chee, lead author and professor at the Neurobehavioral Disorders Program at Duke-NUS. “Herein lies the peril of sleep deprivation.”

The research team, including colleagues at the University of Michigan and University of Pennsylvania, used magnetic resonance imaging to measure blood flow in the brain during speedy normal responses and slow “lapse” responses. The study was funded by grants from the DSO National Laboratories in Singapore, the National Institutes of Health, the National Institute on Drug Abuse, the NASA Commercialization Center, and the Air Force Office of Scientific Research.

Study subjects were asked to identify letters flashing briefly in front of them. They saw either a large H or S, and each was made up of smaller Hs or Ss. Sometimes the large letter matched the smaller letters; sometimes they didn’t. Scientists asked the volunteers to identify either the smaller or the larger letters by pushing one of two buttons.

During slow responses, sleep-deprived volunteers had dramatic decreases in their higher visual cortex activity. At the same time, as expected, their frontal and parietal ‘control regions’ were less able to make their usual corrections.

Scientists also could see brief failures in the control regions during the rare lapses that volunteers had after a normal night’s sleep. However, the failures in visual processing were specific only to lapses that occurred during sleep deprivation.

The scientists theorize that this sputtering along of cognition during sleep deprivation shows the competing effects of trying to stay awake while the brain is shutting things down for sleep. The brain ordinarily becomes less responsive to sensory stimuli during sleep, Chee said.

This study has implications for a whole range of people who have to struggle through night work, from truckers to on-call doctors. “The periods of apparently normal functioning could give a false sense of competency and security when in fact, the brain’s inconsistency could have dire consequences,” Chee said.

“The study task appeared simple, but as we showed in previous work, you can’t effectively memorize or process what you see if your brain isn’t capturing that information,” Chee said. “The next step in our work is to see what we might do to improve things, besides just offering coffee, now that we have a better idea where the weak links in the system are.”

Michael W. L. Chee, Jiat Chow Tan, Hui Zheng, Sarayu Parimal, Daniel H. Weissman, Vitali Zagorodnov, and David F. Dinges
Lapsing during Sleep Deprivation Is Associated with Distributed Changes in Brain Activation
J. Neurosci. 2008 28: 5519-5528; doi:10.1523/JNEUROSCI.0733-08.2008

Lapses of attention manifest as delayed behavioral responses to salient stimuli. Although they can occur even after a normal night’s sleep, they are longer in duration and more frequent after sleep deprivation (SD). To identify changes in task-associated brain activation associated with lapses during SD, we performed functional magnetic resonance imaging during a visual, selective attention task and analyzed the correct responses in a trial-by-trial manner modeling the effects of response time. Separately, we compared the fastest 10% and slowest 10% of correct responses in each state. Both analyses concurred in finding that SD-related lapses differ from lapses of equivalent duration after a normal night’s sleep by (1) reduced ability of frontal and parietal control regions to raise activation in response to lapses, (2) dramatically reduced visual sensory cortex activation, and (3) reduced thalamic activation during lapses that contrasted with elevated thalamic activation during nonlapse periods. Despite these differences, the fastest responses after normal sleep and after SD elicited comparable frontoparietal activation, suggesting that performing a task while sleep deprived involves periods of apparently normal neural activation interleaved with periods of depressed cognitive control, visual perceptual functions, and arousal. These findings reveal for the first time some of the neural consequences of the interaction between efforts to maintain wakefulness and processes that initiate involuntary sleep in sleep-deprived persons.

Religious leaders have contended for millennia that burning incense is good for the soul. Now, biologists have learned that it is good for our brains too. An international team of scientists, including researchers from Johns Hopkins University and the Hebrew University in Jerusalem, describe how burning frankincense (resin from the Boswellia plant) activates poorly understood ion channels in the brain to alleviate anxiety or depression. This suggests that an entirely new class of depression and anxiety drugs might be right under our noses.

“In spite of information stemming from ancient texts, constituents of Bosweilla had not been investigated for psychoactivity,” said Raphael Mechoulam, one of the research study’s co-authors. “We found that incensole acetate, a Boswellia resin constituent, when tested in mice lowers anxiety and causes antidepressive-like behavior. Apparently, most present day worshipers assume that incense burning has only a symbolic meaning.”

To determine incense’s psychoactive effects, the researchers administered incensole acetate to mice. They found that the compound significantly affected areas in brain areas known to be involved in emotions as well as in nerve circuits that are affected by current anxiety and depression drugs. Specifically, incensole acetate activated a protein called TRPV3, which is present in mammalian brains and also known to play a role in the perception of warmth of the skin. When mice bred without this protein were exposed to incensole acetate, the compound had no effect on their brains.

“Perhaps Marx wasn’t too wrong when he called religion the opium of the people: morphine comes from poppies, cannabinoids from marijuana, and LSD from mushrooms; each of these has been used in one or another religious ceremony.” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Studies of how those psychoactive drugs work have helped us understand modern neurobiology. The discovery of how incensole acetate, purified from frankincense, works on specific targets in the brain should also help us understand diseases of the nervous system. This study also provides a biological explanation for millennia-old spiritual practices that have persisted across time, distance, culture, language, and religion–burning incense really does make you feel warm and tingly all over!”

Arieh Moussaieff, Neta Rimmerman, Tatiana Bregman, Alex Straiker, Christian C. Felder, Shai Shoham, Yoel Kashman, Susan M. Huang, Hyosang Lee, Esther Shohami, Ken Mackie, Michael J. Caterina, J. Michael Walker, Ester Fride, and Raphael Mechoulam

Burning of Boswellia resin as incense has been part of religious and cultural ceremonies for millennia and is believed to contribute to the spiritual exaltation associated with such events. Transient receptor potential vanilloid (TRPV) 3 is an ion channel implicated in the perception of warmth in the skin. TRPV3 mRNA has also been found in neurons throughout the brain; however, the role of TRPV3 channels there remains unknown. Here we show that incensole acetate (IA), a Boswellia resin constituent, is a potent TRPV3 agonist that causes anxiolytic-like and antidepressive-like behavioral effects in wild-type (WT) mice with concomitant changes in c-Fos activation in the brain. These behavioral effects were not noted in TRPV3-/- mice, suggesting that they are mediated via TRPV3 channels. IA activated TRPV3 channels stably expressed in HEK293 cells and in keratinocytes from TRPV3+/+ mice. It had no effect on keratinocytes from TRPV3-/- mice and showed modest or no effect on TRPV1, TRPV2, and TRPV4, as well as on 24 other receptors, ion channels, and transport proteins. Our results imply that TRPV3 channels in the brain may play a role in emotional regulation. Furthermore, the biochemical and pharmacological effects of IA may provide a biological basis for deeply rooted cultural and religious traditions.—Moussaieff, A., Rimmerman, N., Bregman, T., Straiker, A., Felder, C. C., Shoham, S., Kashman, Y., Huang, S. M., Lee, H., Shohami, E., Mackie, K., Caterina, M. J., Walker, J. M., Fride, E., Mechoulam, R. Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain.

Researchers have developed what they believe is the first new mechanism in nearly 20 years for inhibiting a common target used to treat all HIV patients, which could eventually lead to a new class of AIDS drugs.

Image of the molecule researchers discovered that keeps the flaps from closing on the HIV-1 protease. It inhibits the flaps from closing, and prevents the protease from assembling an active virus. (Credit: Kelly Damm)

Researchers at the University of Michigan used computer models to develop the inhibiting compound, and then confirmed in the lab that the compound does indeed inhibit HIV protease, which is an established target for AIDS treatment. The protease is necessary to replicate the virus, says Heather Carlson, U-M professor of medicinal chemistry and principal investigator of the study.

Carlson stresses this is a preliminary step, but still significant.

“It’s very easy to make an inhibitor, (but) it’s very hard to make a drug,” said Carlson, who also has an appointment in chemistry. “This compound is too weak to work in the human body. The key is to find more compounds that will work by the same mechanism.”

What’s so exciting is how differently that mechanism works from the current drugs used to keep the HIV from maturing and replicating, she says. Current drugs called protease inhibitors work by debilitating the HIV-1 protease. This does the same, but in a different way, Carlson says.

A protease is an enzyme that clips apart proteins, and in the case of HIV drugs, when the HIV-1 protease is inhibited it cannot process the proteins required to assemble an active virus. In existing treatments, a larger molecule binds to the center of the protease, freezing it closed.

The new mechanism targets a different area of the HIV-1 protease, called the flap recognition pocket, and actually holds the protease open. Scientists knew the flaps opened and closed, but didn’t know how to target that as a mechanism, Carlson says.

Carlson’s group discovered that this flap, when held open by a very small molecule—half the size of the ones used in current drug treatments—also inhibits the protease.

In addition to a new class of drugs, the compound is key because smaller molecules have better drug-like properties and are absorbed much more easily.

“This new class of smaller molecules could have better drug properties (and) could get around current side effects,” Carlson said. “HIV dosing regimes are really difficult. You have to take medicine several times in the day. Maybe you wouldn’t have to do that with these smaller molecules because they would be absorbed differently.”

Kelly Damm, a former student and now at Johnson & Johnson, initially had the idea to target the flaps in this new way, Carlson says.

“In a way, this works like a door jam. If you looked only at the door when it’s shut, you’d not know you could put a jam in it,” she said. “We saw a spot where we could block the closing event, but because everyone else was working with the closed form, they couldn’t see it.”

Kelly L. Damm, Peter M. U. Ung, Jerome J. Quintero, Jason E. Gestwicki, Heather A. Carlson.

A poke in the eye: Inhibiting HIV-1 protease through its flap-recognition pocket.

Biopolymers. Volume 89, Issue 8 , Pages 643 - doi: 652.10.1002/bip.20993

Abstract
A novel mechanism of inhibiting HIV-1 protease (HIVp) is presented. Using computational solvent mapping to identify complementary interactions and the Multiple Protein Structure method to incorporate protein flexibility, we generated a receptor-based pharmacophore model of the flexible flap region of the semiopen, apo state of HIVp. Complementary interactions were consistently observed at the base of the flap, only within a cleft with a specific structural role. In the closed, bound state of HIVp, each flap tip docks against the opposite monomer, occupying this cleft. This flap-recognition site is filled by the protein and cannot be identified using traditional approaches based on bound, closed structures. Virtual screening and dynamics simulations show how small molecules can be identified to complement this cleft. Subsequent experimental testing confirms inhibitory activity of this new class of inhibitor. This may be the first new inhibitor class for HIVp since dimerization inhibitors were introduced 17 years ago. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 643-652, 2008.

New research appearing in the May issue of Psychological Science, a journal of the Association for Psychological Science, suggests that being put in a low-power role may impair a person’s basic cognitive functioning and thus, their ability to get ahead.

In their article, Pamela Smith of Radboud University Nijmegen, and colleagues Nils B. Jostmann of VU University Amsterdam, Adam Galinsky of the Kellogg School of Management at Northwestern University, and Wilco W. van Dijk of VU University Amsterdam, focus on a set of cognitive processes called executive functions. Executive functions help people maintain and pursue their goals in difficult, distracting situations. The researchers found that lacking power impaired people’s ability to keep track of ever-changing information, to parse out irrelevant information, and to successfully plan ahead to achieve their goals.

In one experiment, the participants completed a Stroop task, a common psychological test designed to exercise executive functions. Participants who had earlier been randomly assigned to a low-power group made more errors in the Stroop task than those who had been assigned to a high-power group. Smith and colleagues also found that these results were not due to low-power people being less motivated or putting in less effort. Instead, those lacking in power had difficulty maintaining a focus on their current goal.

In another experiment, participants were asked to move an arrangement of disks from a start position to a final position in as few moves as possible, known to researchers as the Tower-of-Hanoi task. This task tests the more complex ability of planning. In some trials there was a catch: participants had to move the first disk in a direction that was opposite to its final position. Low power participants made more errors and required more moves on these trials, demonstrating poor planning.

Smith and colleagues believe their results have “direct implications for management and organizations.” In high-risk industries such as health care, a single employee error can have fatal consequences. Empowering these employees could reduce the likelihood of such errors. Additionally, their work illustrates how hierarchies perpetuate themselves. By randomly assigning individuals to high and low-power conditions, they demonstrate that simply lacking power can automatically lead to performance that reinforces one’s low standing, sending the powerless towards a destiny of dispossession.

Galinsky, A. D., Magee, J. C., Gruenfeld, D. H, Whitson, J., & Liljenquist, K. A.

Social power reduces the strength of the situation: Implications for creativity, conformity, and dissonance.
Journal of Personality and Social Psychology. (in press).

Abstract
Although power is often conceptualized as the capacity to influence others, the current research explores whether power psychologically protects people from influence. In contrast to classic social psychological research demonstrating the strength of the situation in directing attitudes, expressions, and intentions, five experiments (using experiential primes, semantic primes, and role manipulations of power) demonstrate that the powerful (a) generate creative ideas that are less influenced by salient examples, (b) express attitudes that conform less to the expressed opinions of others, (c) are more influenced by their own social value orientation relative to the reputation of a negotiating partner, and (d) perceive greater choice in making counterattitudinal statements. This last experiment illustrates that power is not always psychologically liberating; it can create internal conflict, arousing dissonance, and thereby lead to attitude change. Across the experiments, high-power participants were immune to the typical press of situations, with intrapsychic processes having greater sway than situational or interpersonal ones on their creative and attitudinal expressions.

The traveller had a short night after getting everything sorted in order to travel with light heart, and light luggage as well. So when the alarm rings, he seriously asks himself, if he indeed should venture for a week in Lisbon, or rather die on the spot. Alas, before finding any decisive answer to this essential question, hi finds himself riding a half empty train through night and snow, mixed with rain, to the airport and lounges himself into the hubbub of easyjet check-in and security of Schoenefeld Airport. He crams his not so short self into a narrow seat and glides into a sleep, that is not less twisted than his body position. Before he drifts away, he notices that his neighbour does get out a Lisbon guide book and starts thouroughly studying descriptions of recommended shops, restaurants and historical sites , as a good traveller possibly should. Or, should one say, a good tourist rather, as J. Saramago points out, that travelling is discovery, tourism is finding things in the right place… The traveller decides on sleep and discovery anyhow.

After his more or less rocky rest, the traveller wakes up just in time to discover the coastline of Porto deep down outside the window, while the plane is swerving in an elegant curve towards Lisbon. Three hours are not enough sleep to enjoy a flight with easyjet. But approaching Lisbon with an airplane is one of the countless things the traveller would recommend everybody to do at least once in his life, even with easyjet. Next he has to grab his luggage and get out of the airport, suddenly hit by sunlight and dusty warm air, quite a contrast to 3° Celsius he left behind in Berlin. And once again the traveller congratulates himself for the decision to travel instead of dying on the spot. After some waiting the airport shuttle takes him to a square called Cais do Sodre. He crosses the cobble stones and asphalt between several bus and taxi stops until he finds the right bus stop for buses number 58 and number 790. As someone who is just arriving, he throws a quick glance at the river Tejo, resembling mor a bay in brilliant light than a river, and after this, encouraged by the world’s beauty, he tries his guide book Portuguese asking the driver to let him off in front of the church of São Roque. He gets a friendly nod, hoping that it conveys the friendly driver’s consent to his intentions rather than his contempt about the traveller’s pitiful level of language control. But lo, at an intimate space between high facades, intimate like an open air boudoir, he gets another intense nod and takes it as a signal to hop off the bus. São Roque is a Jesuit church, which was not damaged during the 1755’s earthquake. Its unspectacular appearance deceives, because its interior is breathtaking, though not much to the traveller’s taste. The chapels and altars glister in a sea of pure gold, lavish mosaics and rather ugly sculptures. Remarkable is the wooden roof and the wonderful roof paintings. There are also some beautiful azulejos inside. All very rich and very jesuit, the traveller finds.

Only a few meters away is the Miradouro São Pedro de Alcântara, which offers comfort tot he heart after this guilded terror, and an astonishing view of the city and Castelo São Jorge too. But all these the traveller finds out at another day…

Not far from there, as it said in the internet, across the square, the traveller finds a stairway going down. That is the Calçada do Duque, where he duly finds his appointed guesthouse, Pensão Duque.

This simple, clean place is one of the most popular places in town with backpackers. Its quaint location near the top of a long flight of pedestrian stairs lends it a particular charm. The owner, a Breton who is very proud of his heritage, speaks both French and English and sees to it that the place remains spic and span. The stairs climbing up to the reception are so narrow, as all the stairs in the house, that the traveller brushes the walls with his shoulders, wondering if there are people getting stuck attempting to ascend with bigger luggage. Alas, the patron is greeting enormously friendly, handing the traveller in a surprise together with his room keys.

The traveller climbs more narrow stairs, unlocks a door and finds himself entering a sunny, cheerful front room with white curtains bulging in the draft created by the opening door. The room is very small, but the traveller is happy: the place is clean, friendly and steps from Bairro Alto. As such, the first thing the traveller does, is to give in to the simple but cosy room’s temptation and take a nap for one hour and a shower later. After this he feels refreshed and, leaving his guesthouse, he directs himself to the Bairro Alto nearby. Bairro Alto is a picturesque working class quarter dating from the 16th century that has traditionally been the city’s bohemian haunt of artists and writers.

Its grid of streets is quiet during Good Friday. Behind colorful and graffiti-ridden façades the traveller finds a variety of traditional and international restaurants, Fado Houses, and a multitude of sleek bars and stylish alternative fashion shops, almost all closed. The main commercial streets are Rua do Norte, Rua da Atalaia, and Rua do Diário de Noticias, from where it is easy to reach the romantic Gothic ruins of Largo do Carmo. The ruins of this Gothic church are evocative reminders of the devastation left by the 1755 earthquake. At the time of the earthquake it was the largest church in Lisbon, but today the roofless nave open to the sky is all that remains of the arches and rubble that caved in on the congregation as they were attending mass. As it is Good Friday, the traveller does not have much hope to find anything open.

Hence he rather proceeds on the guesthouse’s patron’s instructions on another narrow stairway, this time outside the house and leading down, to the Praça dos Restauradores, where indeed the tourist information office is open and equipped with charming young ladies full of usefull advise about what to see and when over Easter. This large square commemorates the country’s liberation from 60 years of Spanish rule in 1640. In the center is a patterned pavement surrounding a 30-meter high obelisk with two bronze figures on the pedestal depicting Victory and Freedom. Would the traveller not know better, he would declare the winged male genius among them the sexiest man of Lisbon. On the west side is Foz Palace, the former residence of the Marquis of Foz, now housing the mentioned national tourism office. Built from the mid-18th to the mid-19th centuries, the palace may only be visited with special permission. It is said, that the interior and its furniture were inspired by Paris’ Versailles Palace and the most interesting rooms were the Renaissance-style Stove Room, the Mirror Room, and the atrium of the chapel of Our Lady of Purity, or so his travel guide tells the traveller, who sure, has no special permission to anything. Next to the palace is a building known as Eden Cinema, now serving as an aparthotel. Built in 1929 it is sure an art deco marvel, with its lavish interior having masqueraded as a Russian hotel in the Wim Wenders film “Until the End of the World.” A few steps away is the much photographed Elevador da Gloria, a funicular that links downtown to the Bairro Alto district.

The traveller leaves the tourism office with a bundle of maps, brochures, an invaluable lisboa card and a hole in his stomach that guides him right across the square to the Hard Rock Café. Hard Rock Café Lisbon claims to complete the ultimate “Discovery of our Modern Times” and launching one into an atmosphere of electrifying and priceless rock n’ roll memorabilia. Weather dusty guitars, blaring music or kinky stage outfits are something good or bad, the traveller cannot decide, because he is snatched by an overwhelmingly friendly waiter, guided to his seat and starts reading the menu, offering trendy merchandise, thirst quenching drinks and great food.

Lisbon, is said to be a dazzling city that stretches along the banks of the river Tejo before it meets the Atlantic Ocean, and has been the capital of Portugal since the thirteenth centruy. Hence this is certainly not the right place to start discovering the charming links to the past - restored palaces, majestic churches and an imposing hilltop castle, reflecting the city’s rich cultural heritage. Alas, rock music history is history too, and hunger is hunger, so the traveller enjoys his discovery without remorse…

Next the traveller finds himself sitting next to the Teatro da Trindade in the street enoying the sun and wondering whether to believe or not what could have happened to him during the last 48 hours. He is not even sure, whether it is 48 hours that passed in the whirlwind of events, as a consequence of which he left his hotel and moved in with the most amazing guy he could possibly meet. He works in Lisbon’s most amazing flower shop: Christophe Giudici - Rua da Trindade N. 28 (Chiado) - 120-468 Lisboa. The traveller invites every visitor in Lisbon to take a look at this amazing store, but it is just the merchandise that is available for purchase. Now, the traveller has this magic store in his back and his magic guy approaching from the front. But that is another story…

Taking notes standing crammed under the low railing of a tram is not helping sightseeing nor his bad handwriting, the traveller notes on his way to Jardim da Estrela. Across from Estrela Basilica stretches this delightful neighborhood park, one of the loveliest in the city and a favorite with families.

There are exotic plants and trees, a small duck-dotted lake, various sculptures, a children’s playground, and an attractive wrought-iron gazebo that serves as an old-fashioned bandstand. The pond-side café is in summer time probably a good place for a break, but closed on Easter Monday. Beyond the park is the English Cemetery, founded in 1717 and originally shared with the Dutch community. Novelist Henry Fielding, author of Tom Jones, died during a visit to Lisbon and is buried here. On his way up here the traveller felt tempted to take picture of any sidewalk opening from the main road. But, after doing this for a while, he decides to rather walk them, under sun umbrellas, drying laundry and a pale spring time sun. The traveller bought himself some chease, water and fruit and is enjoying the café’s terrace despite its lacking hospitality.

Travelling sets off physical time, as long as it is not about opening hours. All those people rushing through streets and having their schedules do not but highlight the completely different pace, time has for a traveller. It is travelling time, not sight seeing time.

The traveller takes the same tram #28 from Estrela to Alfama’s Largo do Graca. Most of the time the tram is not ascending quicker than the traveller would if he walked. Whereas he could walk at least upright. From the traveller’s crouched point of view, what is said to be one of those occasions where the public transit system and route also happen to be an attraction in and of itself, is nothing more than a vintage tram car that rattles and clacks its way winding up and down the hills and around the curves through much of the old city. He is old enough to have seen such vintage trams in regular function and is hence not impressed by the age of these, else, charming carriages. Instead of great views of the city, churches or other points of interest, it offers to the traveller mainly an uniterrupted view of skirts, trousers and shoes worn by Lisbon’s inhabitants, plus the pavement, where it is not crowded by pedestrians. The traveller hence offers an ingenious suggestion about Lisbon’s public transportation system: don’t use it for sightseeing, once you are over 1,75 m tall, or pay for one of the open-bus tours in their many hop-on-hop-off-varieties. From the Largo do Graca the traveller has some trouble to find the right way up to the Miradouro do Senhora do Monte (Our Lady of the Hill Viewpoint). This is the highest point in the city, and its serene atmosphere attracts young couples, next to tourists, and it is several times difficult to tell one from the other. A small image of the Virgin standing in front of a chapel dedicated to Saint Gens overlooks the city with Rio Tejo and Castelo do São Jorge.

By Graça Church (one of the city’s oldest), built in 1271 with a Baroque interior and 17th century tiles lies the Miradouro da Graça, a splendid viewpoint offering a panoramic view of the castle and central Lisbon. While the traveller tries to find an open door at Easter Monday, he is obviously entering some uniformed forces teaching facility. (His Portuguese does not allow him, to tell which, as it did not prevent him from stepping into the courtyard. But some surprisingly friendly police officers did, motioning him back into to the street.) The open-air cafe and its relaxing atmosphere has to undamage the traveller for this lost beauty. During this whole Easter he has to be content with what Lisbon has to offer from outside, with rare exceptions. And it is not much of a pain to him, given what beauty there is to be discovered from outside in this city.

With these humble thoughts the traveller makes his way down to another barred jewel: São Vicente de Fora. In the 12th century King Afonso Henriques made a vow to build churches on sites where Portuguese soldiers and northern European crusaders who fought the Moors lay buried.

While admiring the proportions of the Arco Grande do Cima, the traveller reaches the Campo da Santa Clara, famous for its Feira de Ladra, which means ‘market of thieves’. One should take this quite literally and keep an eye on one’s belongings, the traveller is told. But he is not at all afraid, as he is the only person on the square anyway. Every Tuesday and Saturday, from sunrise till sunset, second-hand goods are sold from tents, stands or just towels spread out on the ground. Furniture, old vinyl records, books and magazines, paintings and clothes.

As nothing but neat 18th century houses and trees yet to blossom are catching the traveller’s eye, he turns to the Santa Engracia Church, or the National Pantheon, that stands on the site of an earlier church that was torn down after being desecrated by a robbery in 1630. The plan to reconstruct (by master stonemason João Antunes) bears many similarities to Peruzzi’s plans for St. Peter’s in Rome.

Alfama is Lisbon’s most emblematic quarter and one of the most rewarding for the traveller during that Easter Monday thanks to its medieval alleys and outstanding views. So much nonsense and sense has been written about this neighbourhood, that the traveller does not whish to add anything to it. Particularly not, as he is not able to get under the surface of it. Because its foundation is dense bedrock, it survived the 1755 earthquake, and a walk through this old-fashioned residential neighborhood is told to be a step back in time. It is a village within a city still made up of narrow streets, tiny squares, churches, and whitewashed houses with wrought-iron balconies adorned with pots of flowers, drying laundry, and caged birds. But small shops and every day life unfolding in this atmosphere strike the traveller as nothing but modern.

Nonetheless, it was settled by the Romans and Visigoths (it was also an important Jewish quarter in the 15th century), but it was the Moors who gave the district its atmosphere and name (alhama means springs or bath, a reference to the hot springs found in the area). They were also responsible for its web of streets created as a defense system, while at the same time enabling their homes to remain cool in the summer.

Unnoticably, but told in every source of information, most of the older residents have lived here all their lives and retain a strong sense of community, although their rent-controlled homes are now dilapidated. While much of the quarter is in a state of melancholic disrepair, many buildings are stained by graffiti and mildew, on the other hand side an ambitious restoration project is under way, with several streets entirely covered in scaffolding. All of which makes the discovery of a grand coat of arms carved over a doorway, or a façade with an intact flourish of gay tilework, or a perfect little square shaded by an orange tree, the more rewarding. Here, obviously, wealthier people are moving in and invest in renovation. Other renovated buildings directly below the castle have been converted into some of the city’s most posh hotels. If that is a favour for Alfama, the traveller dares not to decide.

All in all, certainly the district has an intangible quality that needs to be experienced to be truly appreciated, and the best way to get to know it, is to get a little lost (something almost impossible to avoid), and wander around admiring the postcard-perfect views.

Lost as he is, the traveller descends to the river bank and starts ascending again, following the Rua Augusto Rosa uphill, to reach first the Miradouro de Santa Luzia. This romantic terrace by the church of Santa Luzia offers a sweeping view over Alfama’s houses, churches, and the Tagus River. On an outside wall of the church are two tile panels, one of Comercio Square before the earthquake, and another showing Christians attacking St. George’s Castle in 1147. Just a few steps away from Miradouro de Santa Luzia, a balcony opens onto the river offering another spectacular views over Alfama.

Faced by soft-toned buildings and the Decorative Arts Museum, it strikes the traveller as much as an open air room, as the Largo Trindade Coelho, with its Igreja do São Roque. There is also a statue of St. Vincent (the city’s patron saint) holding a boat with two ravens, the symbols of Lisbon. The Travessa de Santa Luzia, finally, takes him still higher, to the fiercely steep Travesso do Funil, from which the Rua do Chão da Feira leads to the castle.

At Castelo do São Jorge a female tourist cries out: “What a shame, that there are clouds!” A world readymade for a digital camera shot and only for that. Beauty defined as suitable for a holiday picture. Saint George’s Castle can be seen from almost everywhere in the city. Its oldest parts date from the 6th century, when it was fortified by the Romans, Visigoths, and eventually the Moors. It served as a Moorish royal residence until Portugal’s first king Afonso Henriques captured it in 1147 with the help of northern European crusaders on their way to the Holy Land. It was then dedicated to St. George, the patron saint of England, commemorating the Anglo-Portuguese pact dating from 1371, and became the royal palace until another one (that was destroyed in the Great Earthquake) was built in today’s Comercio Square.

It is now an oasis of peace, but just past the main gate is a statue of King Afonso Henriques and a series of cannons, reminders of the castle’s original purpose. What remains of the Alcaçovas Palace where medieval kings lived, is a stone building now housing a restaurant, and round the back, a useless multimedia exhibit on Lisbon’s history called Olissiponia. This show in three underground chambers (including the one where Vasco da Gama was once received by King Manuel) is named after Roman Lisbon, and uses images projected on a 3m(10ft) wall with narration offering an overview of the city’s history. It includes a simulation of the 1755 earthquake that depicts, among other things, the collapse of Carmo Church and the tidal wave in Lisbon harbor, and goes through all the historical periods, from the Inquisition to Salazar’s regime.

Most of the castle was destroyed over the years, especially in the Great Earthquake, but still includes a long extension of walls and 18 towers. The traveller climbs the towers and walks along the ramparts for the most breathtaking views of the city, watches peacocks, geese and ducks strutting around around just like the hosts of tourists. One of the castle’s inner towers, the Tower of Ulysses, holds the Câmara Escura, a periscope that projects sights from around the city. Now, as shadows of the sinking sun fill the more and more deserted courts, the guitarist who kept playing Bach, wraps up his belongings. Lights start flickering on the other side of the Tejo which again appears rather a bay than a river. It is time to call it a day and return to Bairro Alto where other delights are waiting for the traveller.

The other day starts with Basilica da Estrela. On his way uphill the traveller crossed Lapa and Estrela. Built in 17th century, Lapa and Estrela, west of Bairro Alto, are home to diplomatic community and the wealthy neighborhoods. A walk on Rua Sacramento, Rua do Caetano or Rua do São Domingos demonstrates what Lisbon has to offer in the way of offensive wealth and luxury.

The Largo do São Bento is dominated by the Palácio da Assembleia da Republica, Portugal’s parliament. The Palace has its origin in the first Benedictine monastery of Lisbon, established in 1598. In 1615, the monks settled in the area of the Casa da Saúde (Health House), that housed people sick with the plague. The new monastery was built during the 17th century following a Mannerist project by Jesuit architect Baltazar Álvares, later followed by João Turriano. The large building, of rectangular shape, had a church flanked by two towers, four cloisters, dormitories, kitchen, etc. When the construction works of the new building were almost finished, the destructive 1755 Lisbon earthquake damaged it.

After the Liberal Revolution (1820) and the suppression of religious orders in Portugal (1834), the monks were expelled from the monastery and the Portuguese Parliament was installed in the building, then called Palácio das Cortes or Parlamento. From then on, the old monastery was systematically adapted to its new functions. The first architect in charge was Possidónio da Silva, who designed the first session rooms.

The Chapter house (meeting place of the monks) of the monastery was totally remodelled by French architect Jean François Colson into a session room in 1867. The Portuguese Senate (upper house) used to meet in this room until the 1976 Constitution established unicameralism.

In 1895, a fire destroyed the session room of the lower house, and it was necessary to repair and expand the Parliament building. Portuguese architect Miguel Ventura Terra was put in charge of the remodelling project, which lasted until the 1940s. Ventura Terra built a new session room for the lower house (inaugurated in 1903) and altered the façade of the building, adding a neoclassical portico with columns and a triangular pediment. He also remodelled the atrium, the monumental inner stairway and many other rooms. The works were continued in the 1920s by architect Adolfo Marques da Silva.

In the 1940s, during Salazar’s Estado Novo regime, the monumental stairway in front of the portico of the Parliament was completed. The stairway was designed by Cristino da Silva, who was also responsible for the project of the gardens in the back of the Palace.

Since Portugal became a democracy after the 1974 Carnation Revolution the area in front of the palace has been the most popular location for demonstrations held in Lisbon.

In 1999 an annex building was inaugurated near the old Palace. This modern structure was designed by Fernando Távora and allowed for an expansion of the space of the Portuguese Assembly without altering its historical outlook.

Further up Rua de São Bento is the former house of the greatest 20th-century fado singer, Amália. It is now the Casa-Museu Amália Rodrigues. At the top of the Calçada rises the Basílica da Estrela. The traveller actually had his first opportunity to see the sombre neoclassical Basilica da Estrela during a stormy and rainy Easter Sunday evening for a concert where two baroque looking soloists where fighting the cave-like accoustics with all the might of there junonic busts, while the orchestra tried to sneak counterpoint structures between the amorphous sound clusters, that kept building up relentlessly. Built in the second half of the 18th century to fulfill a vow by Queen Maria I after she gave birth to a son and heir, it has a huge rococo dome and a façade with twin bell towers decorated with an array of statues of saints and allegorical figures. The spacious pink and black marble interior contains an elaborate Empire-style tomb of Queen Maria I, and an impressive Christmas manger composed of more than 500 figures. Ugly, but majestic cave, the traveller cannot help thinking.

The district above Estrela is Campo de Ourique where Fernando Pessoa spent the last 15 years of his life. His house Casa Fernando Pessoa, one of Lisbon’s small cultural activities, can be visited on Rua Coelho da Rocha. Another attraction in this district with its lonely cypresses is Prazeres, the enormous municipality cemetery.

The north end of Campo de Ourique is Amoreiras/Campolide, the business district. The biggest attraction is the Amoreiras towers. Designed by architect Tomas Taveira in 1980s, it was to provide a skyline counterbalance with Castelo de Sao Jorge. Although the traveller feels the architect missed it, the towers are nonetheless there and Amoreiras is one of the most popular shopping malls in Lisbon.

Down the Rua das Amoreiras and above Largo do Rato, the traveller descends to relax in the lovely Jardim das Amoreiras, situated under the arches at the end of Aqueduto das Águas Livres.

On his way back, in tram #15, an elderly swiss lady sitting opposite the traveller makes him discover, that some ageing faces freeze into a smile, others into bitterness. This ladies’s face is definitely one of the bitter side.

Redesigned by French architect Jean-Michel Wilmotte, the Chiado Museum specializes in 19th and 20th century contemporary art. Each room has a different theme, with paintings and sculpture illustrating the development from Romanticism to Modernism. Most of the works are Portuguese, with a few international works including some by Rodin, and French sculpture from the late 19th century.

Rodin’s masterpiece The Bronze Age so realistically depicts a naked man clasping a spear, that he was accused of taking a cast from the model. Other engaging exhibits include a self-portrait by Columbano Bordalo Pinheiro and two art deco diptychs by Portuguese modernist Almada Negreiros.

There is also a gallery of temporary exhibitions and a good café looking onto a pleasant garden and terrace with a view over Lisbon.

…Schoolfriends and the first sex at 20. Life together for 6 years without actually coming out. Breaking up when one of the two wanted a “normal” life again. The other keeps going out to “normal” clubs too, but then kisses with tourists on parking lots. That is the story, the traveller is told at the end of this day…

The Mosteiro dos Jeronimos is incredible. (Did the traveller use the adjective before?) It certainly is the most impressive symbol of Portugal’s power and wealth during the Age of Discovery. King Manuel I comissioned the construction, as extravagant as he probably was himself, in 1501 on the site of a hermitage founded by Prince Henry the Navigator, where Vasco da Gama and his crew spent their last night in Portugal in prayer before leaving for India. It was built to commemorate Vasco Da Gama’s voyage and to give thanks to the Virgin Mary for its success. Vasco da Gama’s tomb was placed inside by the entrance, as was the tomb of poet Luis de Camões, author of the epic The Lusiads in which he glorifies the triumphs of Da Gama and his compatriots. Other great figures in Portuguese history are also entombed here, like King Manuel and King Sebastião, and poets Fernando Pessoa and Alexandre Herculano.

Although the construction started on the site of a riverside chapel, where da Gama actually prayed, it was finished only in 1541. The water has long since receded. The monastery was populated by monks of the Order of Saint Jerome (Hieronymites), whose spiritual job was to give guidance to sailors and pray for the king’s soul. It is one of the great triumphs of European Gothic (UNESCO has classified it a World Heritage monument), with much of the design characterized by elaborate sculptural details and maritime motifs. This style of architecture became known as Manueline, a style of art that served to glorify the great discoveries of the age.

The cloisters are magnificent, each column differently carved with coils of rope, sea monsters, coral, and other sea motifs evocative of that time of world exploration at sea. Here is also the entrance to the former refectory that has beautiful reticulated vaulting and tile decoration on the walls depicting the Biblical story of Joseph.

The church interior is spacious with octagonal piers richly decorated with reliefs, and outside is a garden laid out in 1940 consisting of hedges cut in the shape of various municipal coats of arms of Portugal. In the center is a large fountain also decorated with coats of arms, often illuminated on special occasions.

In the 19th century a neo-manueline wing and a bell tower were added to the house of the Order of St. Jerome.

The traveller dismisses the idea of eating Pastéis de Belém in the same named café. He decides that there is no custard tart in the world worth such a queue and just takes a picture of the dumb flock of aspirants.

Across from Jeronimos Monastery, reached via an underpass by its gardens, the traveller reaches the Padrão dos Descobrimentos. This Discoveries Monument, was built on the north bank of the Tagus River in 1960 to commemorate the 500th anniversary of the death of Prince Henry the Navigator. It represents a three-sailed ship ready to depart, with sculptures of important historical figures such as King Manuel I carrying an armillary sphere, poet Camões holding verses from The Lusiads, Vasco da Gama, Magellan, Cabral, and several other notable Portuguese explorers, crusaders, monks, cartographers, and cosmographers, following Prince Henry the Navigator at the prow holding a small vessel. The only female is queen Felipa of Lancaster, mother of Henry the navigator, the brain of the discoveries. Behind every great man there is a woman…

Inside is an exhibition space with temporary exhibits, a supposedly interesting film about the city of Lisbon, and an elevator that takes visitors to the top for some bird’s-eye views of Belem and its monuments.

The pavement in front of the monument is decorated with a mosaic that was offered by the South African government in 1960, representing a compass with the map of the world charting the routes taken by the Portuguese explorers. All these do not help though. After just leaving the Mosteiro dos Jeronimos, the traveller cannot find the whole thing aesthetic in any way. It is just a monumental splotch of concrete.

Originally controversial for its striking modern architecture next to the historical Jeronimos Monastery, the Belem Cultural Center (simply referred to as CCB) was built to host Portugal’s presidency of the European Union in 1992. That is probably the reason, while the architecture, next to being modern, appears to the traveller a bit babylonian in its expression. It has since become the host of numerous international exhibitions (from photography to mixed-media installations), cultural events and congresses, and is also an arts complex with the city’s largest auditorium.

For years it was also home to the Design Museum, but that space is now occupied by the Berardo Museum of Modern and Contemporary Art.

The terrace café on the first floor with a garden overlooking the river and the Discoveries Monument is a great place to relax.

Built in 1515 as a fortress to guard the entrance to Lisbon’s harbor, the Torre de Belém has become an amiable kitsch. Nonetheless, it was the starting point for many of the voyages of discovery, and for the sailors it was the last sight of their homeland. It is a monument to Portugal’s Age of Discovery, often serving as a symbol of the country (that in the traveller’s uncognisant mind has much better things to offer as a national symbol), and UNESCO has listed it as a World Heritage monument.

Built in the Manueline style, Belem Tower incorporates many stonework motifs, sculptures depicting historical figures such as St. Vincent and an exotic rhinoceros that inspired Dürer’s drawing of the beast, so that it is more of an artwork than a castle.

The architect, Francisco de Arruda, had previously worked on Portuguese fortifications in Morocco, which seems hardly believable to the traveller - that is not Morocco, but that he worked on castles ever. It looks like he got his training in a bakery. Anyway, these Moroccan experiences are told to be the well, from which the Moorish-style watchtowers and other Moorish influences did originate. Facing the river are arcaded windows, delicate Venetian-style loggias, and a statue of Our Lady of Safe Homecoming, a symbol of protection for sailors on their voyages. It appears to the traveller, that the construction is so overwrought with decorations, that it is just missing a good icing, in order to be a giant tart. And sure, it is a luck that it obviously was never subject to any serious attack, and that its meanest traits are the dungeons, where there were kept prisoners, who probably were not in a position at all, to enjoy their lavishly decorated abodes.

The guy who told the traveller his sad story the day before, has offered the traveller a trip to Cascais. It seems like a mixture of Turkish Kaş and Venetian Lido with its pastel painted houses. And it seems no wonder to the traveller, that since 1870, when the royal family spent their first summer in the fishing village, the place became a sophisticated resort destination with atmospheric back streets to discover. As the traveller comes too early in the year, there is still no beach craze anywhere, and most places are rather wrapped up waiting for the season to begin. Praia do Guincho, the traveller is told, would be particularly attractive for surfing and swimming.

This is the background of the second part of the story, mentioned above. Actually, the traveller’s tour guide for the day cought HIV from a girl. That was the reason for the abrupt breakup of his awkward relationship. After a period of wild rebellion against the infection, working and clubbing madly, the crush, so hard that doctors gave nothing for his survival. Two years of hospital and home care with 27 tablets to be taken per day, often more, as, after vomiting them out, they had to be taken once more. Weeks without sleep between the age of 26 and 28. Now he is working again, since one year. While the traveller listens to this, a good friend of his guide is dying in the hospital of Lymphoma, where the guy goes daily, needing, on top of this, to take care for his diabetic father, who is growing blind gradually. And, if these were not enough to wreck a life, he falls for the traveller who is in love with someone else…

La boca do inferno, or hell’s mouth, is a curiosity on the Portuguese coast, next to the city of Cascais. The site consists of a natural grotto created by the constant crashing of the waves against the cliff side. The ocean is particularly powerful on this coast. The sight and sound of the crashing and bubbling up of water inside this natural cavern is an awesome experience. The crashing sound of the waves resonates from within. It’s the devil’s cauldron! The Portuguese have capitalized on this attraction. You’ll find a number of shops at its entrance, to remember the traveller that modern world’s hell does look more like souvenir shops. The rocks next to the cauldron are decorated with plates commemorating people dying here, one of them quoting Aleister Crowley. The traveller cannot help thinking, that if anyone deserves a quote here, it is probably him.

The traveller wakes up to his last day. Despite the beautiful weather, it does cost him some effort not fall pray to melancholy about leaving Lisbon. But, it would be a shame to poison a splendid present with bleak expectations about the future. Ergo, after finishing his morning rituals the traveller directs himself to the Gulbenkian Museum, one of the world’s great museums and one of Europe’s unsung treasures. Part of the Calouste Gulbenkian Foundation, it houses a magnificent collection of Egyptian, Greek, Roman, Islamic, Asian, and European art. It was substantially renovated and modernized in 2001 (many of its masterpieces were on display in New York’s Metropolitan Museum of Art during renovation), and can’t be missed during a visit to Lisbon. This is one of the world’s finest private art collections, amassed over a period of 40 years by oil magnate Calouste Gulbenkian, who was one of the 20th century’s wealthiest men. In his later years he adopted Portugal as his home, and donated all of his stupendous art treasures to the country when he died in 1955 at the age of 86.

Of the many highlights is a haunting gold Egyptian mummy mask, an exquisite 2700-year-old alabaster bowl, a series of bronze cats and other priceless treasures in the Egyptian section, a stunning collection of Hellenic coins and a 2400-year-old Attic vase in the Greek and Roman section, rare pieces of Chinese porcelain, Japanese prints, and rich 16th and 17th century Persian tapestries.

In the huge European art section (many of the works were bought from the Hermitage in St. Petersburg), are pieces by Rembrandt (Potrait of an Old Man, and Alexander the Great), Peter Paul Rubens (Portrait of Helene Fourment), Claude Monet, Van Dyck, Ghirlandaio (15th century Portrait of a girl), Rogier Van der Weyden (St. Catherine), and Pierre-Ausguste Renoir (Potrait of Madame Claude Monet), along with French furniture and textiles.
There’s also a white marble statue of Diana by French sculptor Jean-Antoine Houdon, silver made by François-Thomas Germain once used by Catherine the Great, and René Lalique jewelry considered to be unique in the world. Gulbenkian Museum

Sharing the lovely serene gardens of the Gulbenkian Museum is the Modern Art Center, containing modern and contemporary Portuguese and foreign art displayed on two floors. There are more than 10,000 items, including works by Paula Rego, Almada Negreiros, Souza Cardoso, and Vieira da Silva.

After these the traveller cannot palate one more piece of art. He descends towards the museum’s cafeteria and finds that customers, as much as pastry and coffee of bad quality, in the world’s big art collections do have something comfortingly unchangeable.

It is time now to come back to all the places, that the traveller found closed earlier. The traveller finds it a good way to sooth parting pain, to come back to places of good memories, even if those memories are just a few days old. Not desiring another tram ride, he climbs up the hill towards Graça.

Next he is greeted by the Catedral do Sé. Lisbon’s ancient cathedral was built by Portugal’s first king on the site of an old mosque in 1150 for the city’s first bishop, the English crusader Gilbert of Hastings. From outside (with two bell towers and a splendid rose window) it resembles a medieval fortress, while inside it appears predominantly Romanesque, with a Gothic choir and ambulatory. At the entrance, to the left, is a baptismal font used in 1195 to baptize Saint Anthony who was born nearby, and in the first chapel on the left is a beautifully detailed nativity scene. In the 14th century cloisters, in what were once the gardens, there have been excavations which have revealed Roman and Visigothic remains as well as parts of the former mosque wall.

In the sacristy is the cathedral treasury with numerous sacred objects, the most important being the casket containing the remains of St. Vincent, the official patron saint of Lisbon.

Santo Antonio (better known as Saint Anthony of Padua), revered as a matchmaker, protector of young brides, and patron of the lost and found, was actually born in Lisbon, on the site of the Igreja do Santo Antonio. In the 1755 Lisbon Earthquake the Santo António Church was destroyed, with only the main chapel left standing. It was fully rebuilt after 1767. In order to collect money, St. Antony “thrones” were built all over the city, for believers to donate. Today, during the month of June, festivities take place all over Portugal to celebrate the three saints - Santo António, São João and São Pedro; of the three, Santo António is by far the most popular, and June 13 has since long been a holiday in Lisbon where the celebrations take the form of marches and “arraial”, especially in the old part of the city; and the young children build “thrones” to Santo António, asking the tourists and other visitors for small coins that they will later spend in buying sweets and candies. Workon the actual church began in 1757, and the façade blends the Baroque style with Neoclassical Ionic columns. Inside, the altar features an image of the saint with Christ in his arms, the sacristy is faced with 18th century tiles, and there is a modern tile panel commemorating the visit of Pope John Paul II to the church in 1982. Next door is a small museum with images and manuscripts relating to the life of the saint, as well as gold and silverware used to decorate the church. Mass marriages known as “St. Anthony’s Weddings” are held here during the mid-June St. Anthony’s Day celebrations.

Today’s São Vicente de Fora Church, built in 1582, stands on the site of one of those churches, which was located outside the city walls (hence the name “De Fora” meaning “on the outside”). It was inaugurated in 1629 but was severely damaged in the 1755 earthquake, when the main dome and roof collapsed. It was then restored, and in 1855 the old monastic refectory became the pantheon of the Bragança dynasty including Catherine of Bragança, a Portuguese princess who became the Queen of England when she married Charles II, and where lay the bodies of all kings from 1640 to 1910, exposed in stone sarcophagi, of which one with a mourning woman, catches the traveller’s eye. However, passed away kings in a refectorium strikes the traveller’s unruly brain as somewhat ironical.

The entrance, open today, is through a gate to the right of the façade, and, as the traveller learns on his return on this more fortunate day that same week, the interior and cloisters are adorned with exceptional 18th century tiled panels. A highlight of those is a series of panels illustrating scenes from LaFontaine’s Fables. The traveller does pay due respect to the Azulejos’ tradition, but cannot help to find them all a bit kitchy, perhaps due to his prejudice about this kind of decorative art in general. While he dedicates himself to discover a taste in what is reverred as a cornerstone in national history of arts, he finds up on the roof a terrace with superb views of the National Pantheon, Alfama, and the Tagus River.

The National Pantheon is, what attracts the traveller next. The former Igreja do Santa Engracia was named National Pantheon only in 1916. It was comissioned by King Manuel’s daughter, princess Mary, in 1568. The original church was desecrated by a robbery ad hence brought down in 1630. As so often, a Jew was blamed for this and executed, but was later exonerated. Legend has it that before dying he cursed the rebuilding of the church because of the conviction of an innocent man. It took until 1966, when the enormous dome was completed and the church inaugurated… 400 years to learn fear of curses of the innocently executed…

Today it has been designated the National Pantheon and contains the tombs of several Portuguese presidents, writer Almeida Garrett (one of the country’s leading 19th century literary figures), and in recognition of her iconic status, Amalia Rodrigues, the most famous Fado diva.

The building is on the plan of a Greek cross, and the interior is covered in breathtaking, multicolored slabs of polished marble. It is crowned with a dome that provides another, this time a 360-degree view, of the river and the city, and, at the same time a breathtaking example of Portuguese baroque architecture.

Around seven, on the Largo do Carmo, the traveller sits on one of the stone benches and cannot help thinking how hopelessly sad and yet beautiful his last day in Lisbon was. His soul feels floating in beauty. He feels the dawning evening, sad somehow, but not miserable. He did smoke a lot, during that day, which he shouldn’t have done, and it is good, that nobody knows….

A sunset in Lisbon does not mean it’s the end of the day (especially on a trip like this). For many, the day is just beginning and many bars haven’t even opened their doors yet. As it turns out, the night after this was long. Fragil is really a bar with a small dance floor. It is a landmark in Lisbon’s nightlife, as it was one of the city’s first clubs when it opened in 1983. Its popularity has dwindled, but it still gets packed on weekends by a largely gay but essentially mixed crowd in a feel-good atmosphere. And feel good is what the traveller did, with his friends who brought him there after a lavish sushi dinner. The traveller cannot remember any club in the world where there are performing a string quartett, or a drugged actress reciting unintelligable lyrics woven with music rendered by a rock solid female bandoneonist, with resident DJs spinning electronic beats in the meantime. One of the many incredible things, the traveller encountered in Lison.

As such it happened, that at 3.00 in the morning the traveller changed his flight back, after lots of gin tonic and other tasty substances, extending his stay until sunday. As his visiting schedule was all done, the traveller decided for the Olisipo Tour of Carris. Despite the sun, the open deck turned out to be a rather freezing experience while riding up to Parque das Nações and back throuth Bairro Alto.

The futuristic architecture of Eastern Lisbon is a complete contrast to the city’s old quarters. Most of it was built by innovative architects for Expo 98, the World Fair that took place in Portugal’s capital between May and September of 1998. Futurism of 1998 does not seem much avantgardist in 2008. The trouble with all the expo or olympic areas all over the world is, that the architecture there is nothing but a decoration for a media event, lasting much longer though. Afterwards nobody really knows what to do with all the chique rubbish agglomerated for the event itself. Everything reminds faintly of a ghost city, lacking age and dignity likewise.

Lisbon’s World Fair was special because it hosted a record 130 countries and international organizations, was the 100th international exhibition since the Great Exhibition of London in 1851, the last one of the 20th century, and coincided with the 500th anniversary of Vasco da Gama’s arrival in India and the United Nations’ “Year of the Oceans.”

The theme was “The Oceans: A Heritage for the Future,” and the entire area at the eastern end of the city’s waterfront was rebuilt for the event. What has not been changed still looks like worn down outskirts of a big city with storage barracks, obscure enterprises, skeletons of concrete constructions, poor neighbourhoods and, in between, lost garden villas from the 19th century. When the Expo was over, the new urban district was dubbed Parque das Nações (Park of Nations), and is now one of the largest urban redevelopment projects in Europe.

At Vasco da Gama Bridge Most people arrive by metro, which stops at the stunning Oriente Station. Vasco da Gama Bridge is 17km (11 miles) long, 10km (6 miles) of which pass over water), making it the longest bridge in Europe when it opened in 1998 and still today one of the longest in the world. (It has the same length as the road-rail tunnel-bridge linking Denmark and Sweden). Its vastness forced engineers to factor in the curvature of the Earth during its construction. That makes it a superb feat of engineering, made up of several sections supported by pillars, built at a cost of one billion US dollars. It was inaugurated on March 31, 1998 after only 18 months of construction, and just in time to carry visitors from southern Portugal, Spain, and other parts of Europe to Expo98.

Other, rather odd attractions include a modern casino, water gardens, a viewing tower, a marina, and a number of bars and restaurants with outdoor seating overlooking this bridge. Two striking twin towers designed to look like giant sailboats are apartment and office buildings named after two of Vasco da Gama’s ships, São Gabriel and São Rafael.

Lisbon’s Oceanarium is one of the world’s largest aquariums. Designed by American architect Peter Chermeyeff, it rises from the river and is reached by a footbridge. But it’s the design rather than the size that makes it outstanding. It is the first aquarium ever to incorporate world ocean habitats within a single environment, with impressive recreations of various ocean ecosystems — the Antarctic tank containing penguins, and the Pacific tank with otters playing in rock pools. They are all separated from the main tank by invisible acrylic walls, giving the impression that all the creatures are swimming in the same space. Imagine what a waste. Design as design, but manufacturing many of the used materials contributes to the pollution and ruin of the living ocean, that cannot be replaced by a water tank, regardless of its design and size.

A real jewel amidst this ghulish amassment of buildings is the Oriente Station. It was built by master architect Santiago Calatrava with a roof of glass and steel made to look like a row of trees. It houses a railway station, a metro, and a bus terminal. The entrance to the metro platform has huge tile murals designed by some of the best contemporary artists.

From the Parque das Nações the bus tour takes the traveller to the airport, past Entrecampos and the Zoo to the Parque Eduardo VII. Named after Britain’s Edward VII who visited the city in 1903 to reaffirm the Anglo-Portuguese alliance, this is the largest park in central Lisbon. With neatly clipped box hedging flanked by mosaic patterned walkways, it stretches uphill from Marquês de Pombal Square to a belvedere at the top with fine views. The big attractions in the park are the two estufas, the hothouse (with the more exotic plants) and the greenhouse filled with tropical plants, ponds, and endless varieties of palms and cacti. Opposite the estufas on the eastern side of the park, sits an ornately tiled sports pavillion dedicated to Carlos Lopes, the Portuguese athlete who won the marathon at the Los Angeles Olympic Games, and that doubles as a venue for occasional concerts and cultural events.

The tour passes many ugly concrete neighbourhoods before the bus reaches Bairro Alto again, reminding the traveller that old town or not, any beautiful city has an everyday life with social structure and economy behind.

This really last night in Lisbon the traveller spends with his new friends cooking, baking, eating… all with a splendid view over the nocturne Tejo. And, instead of sad reflections leaving a newfound love, a last delight of Lisbon should be mentioned: La Brasserie des Entrecôtes. Both the Café de Paris and the Entrecôte groups of restaurants consider the sauce’s ingredients and method of preparation to be a trade secret. All the traveller can learn, next to the ravishing taste, is that it contains 31 ingredients, 27 different spices among them.

A little gourmand gossip? The Paris newspaper Leentrecôte Monde reports that the sauce as served by Le Relais de Venise – L’Entrecôte is made from chicken livers, fresh thyme and thyme flowers, full cream (19 percent butterfat), white Dijon mustard, butter, water, salt, and pepper.

According to Le Monde, the chicken livers are blanched in one pan with the thyme until they start to turn colour. In a second pan, the cream is reduced on low heat with the mustard and infused with the flavour of the thyme flowers. The chicken livers are then finely minced and pressed through a strainer into the reduced cream. As the sauce thickens, the butter is incorporated into it with a little water, it is beaten smooth, and fresh-ground salt and pepper are added. The London newspaper The Independent, however, reports that the proprietor of Le Relais de Venise – L’Entrecôte has dismissed the Le Monde report as inaccurate.

The Café de Paris serves its entrecôte on a bed of the sauce, on a platter kept hot atop a trivet with a warming candle in the base. Initially the sauce is a stiff whipped froth, tawny in colour, but as it melts down to a liquid it reverts to its natural creamy pea-soup-green colour. At the Entrecôte groups of restaurants, the sauce is served as a creamy pea-soup-green liquid from the outset rather than as a whipped froth, it is less prone to separate, and it is less salty, and it is better than sex… well, at least better than most sex.

… A belated comment has reached the traveller that made him think, he might have rendered the sad story that was told to him,  in an unfortunate and clumsy way, so that the impression rises, he was talking about an unhappy person. “…still don’t know what to think about what you’ve written…or better…the way you’ve written them…..about your “guide”…it might be a sad story,but i’m quite happy with the person i’ve turned out to be…in spite of all the pain i’ve been trough….my life isn’t wrecked…..it has been a long way…..but sure with more light…..” The traveller wants to make this very clear instead: neither the life, nor the person he was describing, were sad in any way, but just the story the traveller tried to render. Much to his pleasure, his mentioned guide is a strong and wonderful person and he enjoyed every minute with him.