Aquaporin Water Channels

Thank you very much. I am humbled, I am delighted; I am honored. This is every scientist’s dream: to give the Nobel Lecture in Stockholm. But I would not be honest if I did not tell you that I am having a little anxiety being on this platform. I have lectured a number of times in Sweden, and I thought I would share with you some events preceding a special lecture that I gave here a few years ago. Arriving at Arlanda Airport, I waited in line at the Pass Control behind a group of businessmen in suits with briefcases. I heard the first in line asked by the control officer to state the purpose of his visit to Sweden. When the man replied “business,” the officer approved and stamped his passport. One at a time, each stepped forward and was asked the same thing; each answered “business” and was approved. Eventually it was my turn, and I was dressed in rumpled clothes after spending the night in the Economy Minus section of an SAS jetliner. The officer asked me the purpose of my visit, and I said “I am here to give the von Euler Lecture at Karolinska Institute.” The officer immediately looked up, stared at me, and asked, “Are you nervous?” At that point I became intensely nervous and said “Yes, I am a little nervous.” The officer looked up again and stated “Well, you should be!“ So if the lecturers look a little nervous, the problem is at Arlanda.     

"Craziness" and "visions": experiences after a stroke.

For a stroke victim there may be at least three types of strange occurrences: incorrect saying, seeing, and thinking. To the patient only the third seems to be "crazy". After a stroke (left hemisphere), which mainly produced serious aphasia, I (the patient) felt crazy two or three times when someone said something I expected him to say. On the other hand, my initial aphasic "gibberish speech" and an occasional false vision did not seem crazy. In my case the vision is always a car or a child, seen on my extreme right, where I am otherwise blind from the stroke. I am always driving when it happens; in recent years this phenomenon occurs when I am tired or tense, or the light is poor. These rapid visions do not seem insane but merely physical problems in my eyes, much like ordinary people''s dreams.     

The paradigm of Huntington disease.

I recall it as vividly as though it had occurred but yesterday. It made a most enduring impression upon my boyish mind which was my very first impulse to choosing chorea as my virgin contribution to medical lore. Driving with my father through a wooded road leading from East Hampton to Amagansett we suddenly came upon two women, mother and daughter, both tall and thin, almost cadaverous, both bowing, twisting, grimacing. I stared in wonderment, almost in fear. What could it mean? My father paused to speak with them and we passed on. Then my Gamaliel-like instruction began; my medical education had its inception. From this point on, my interest in the disease has never wholly ceased. [George Huntington, at 59, recalling how at the age of 8 years he first saw Huntington disease while traveling with his physician father on his professional rounds in 1858].     

Experiments in a Monastery Garden

SYNOPSIS. After a brief account of my early education, studyat the University of Wien, and preliminary experiments on hybridizationconducted at the Augustinian Monastery in Brünn, Austria,I state the reasons for selecting certain features of the ediblepea, Pisum sativum, for extensive investigation of their inheritance.After eight years I reported my results to the Brünn Societyfor the Study of Natural Science, and they were published inthe following year (1866) in the Proceedings of the Society.I discovered two basic principles of inheritance: the law ofsegregation and the law of independent assortment of hypotheticalunits of heredity that I called Elemente. I conclude with someremarks on the possible relation of my work to the evolutionof organic form and on my disappointment that my studies donot seem to be known or understood, and that because of my administrativeduties at themonastery, now being the Abbot, I have no timefor further investigations.     

Caregiver perceptions of what indoor cats do "for fun"

In a survey conducted to determine enrichment activities for indoor cats in the caregivers' homes, 304 indoor-cat caregivers answered structured interviews about their cats' use of windows and other “fun activities. ”The survey asked caregivers about durations of window use, what cats watched through the windows, and in what other fun activities cats freely participated. The results indicate that, of 577 cats, 84.3% looked out windows a total of 5 hr or less a day, that cats observed 14 different categories of outdoor stimuli, and that cats participated in 17 categories of “other ”fun activities. These results suggest that cats use windows and sunlight much less often than the welfare community may expect but that caregivers (owners), when possible, should consider providing access to these.     

Vision and Eating Behavior in Obese Subjects

Objective: Vision is one of a number of factors influencing the amount of food consumed during a meal. The purpose of this study was to investigate the impact of vision on the microstructure of the eating behavior of obese subjects. Research Methods and Procedures: Eighteen obese subjects with a body mass index (mean ± SD) of 39.1 ± 6.3 kg/m² twice consumed a standardized test meal in excess, once with and once without a blindfold. The microstructure of the eating behavior was registered by VIKTOR, a computerized eating monitor. Subjective motivation to eat (i.e., desire to eat, hunger, satiety, and prospective consumption) was rated by visual analogue scales (VASs) before, immediately after, and then hourly up to 3 hours after the test meals. Results: The obese subjects ate 24% less food when blindfolded (359 ± 194 g vs. 472 ± 179 g; p < 0.01). Despite a smaller amount of food consumed when blindfolded, there were no significant differences with or without the blindfold for any of the VASs measuring subjective motivation to eat after test meals. Discussion: The importance of vision in regulating our eating behavior was demonstrated in this study. The obese subjects ate 24% less food blindfolded without feeling less full. Eating blindfolded could be tested as a didactic tool to make obese subjects aware of what factors affect the termination of eating.     

The structure of a high fidelity DNA polymerase bound to a mismatched nucleotide reveals an "ajar" intermediate conformation in the nucleotide selection mechanism

To achieve accurate DNA synthesis, DNA polymerases must rapidly sample and discriminate against incorrect nucleotides. Here we report the crystal structure of a high fidelity DNA polymerase I bound to DNA primer-template caught in the act of binding a mismatched (dG:dTTP) nucleoside triphosphate. The polymerase adopts a conformation in between the previously established "open" and "closed" states. In this "ajar" conformation, the template base has moved into the insertion site but misaligns an incorrect nucleotide relative to the primer terminus. The displacement of a conserved active site tyrosine in the insertion site by the template base is accommodated by a distinctive kink in the polymerase O helix, resulting in a partially open ternary complex. We suggest that the ajar conformation allows the template to probe incoming nucleotides for complementarity before closure of the enzyme around the substrate. Based on solution fluorescence, kinetics, and crystallographic analyses of wild-type and mutant polymerases reported here, we present a three-state reaction pathway in which nucleotides either pass through this intermediate conformation to the closed conformation and catalysis or are misaligned within the intermediate, leading to destabilization of the closed conformation.     

Tree invasion and establishment in old fields at Hutcheson Memorial Forest

In this review I present results from pattern analysis and field experiments in New Jersey, United States concerning tree invasion and establishment in old fields. Hutcheson Memorial Forest Center (HMF) is the New Jersey study site and a logical choice to anchor a review of this topic. HMF contains the longest and largest old field permanent plot study in the USA including extensive data concerning tree invasion and establishment. HMF has also been the site of considerable old field tree experimental research. In addition, I review other investigations of old field tree invasion and establishment of the eastern deciduous biome and contrast them with HMF. I identify critical questions concerning tree invasion and establishment, indicate what progress has been made towards answering these questions and propose future experimentation. I also synthesize results into a conceptual model and investigate the relative importance of seed and seedling processes in determining tree dynamics in old fields. The idea of a possibility or “window” for tree invasion and establishment and its variation form the basis for this review. For example, the temporal variation of windows is reflected in tree establishment patterns at HMF because wind- and bird-dispersed species invaded one year after cessation of cultivation while mammal-dispersed species were not present until year 12. Although analysis of size classes of individual HMF trees imply that windows close quickly, studies are of too short duration to tell definitely. Spatial variation in invasion and establishment pattern includes exponential decline in seed and stem density with distance from forest edge which deteriorates with time as the old field becomes more structurally complex. Additional spatial heterogeneity occurs when seeds and seedlings of bird-dispersed species clump which conversely becomes more pronounced with time. Many of these HMF patterns are seen in other eastern United States old field sites. When reviewing field experiments from my site and others, I focus on the spatial and temporal variation and the difference between species in the effect of processes on tree seeds and seedlings. I do this because this variation relates directly to the dynamic nature of windows whose quantification is necessary for modeling. Combining my pattern analysis with a survey of variation in seed and seedling mortality caused by different successional processes in old fields, I conclude that seed dispersal, conditions necessary for seed germination and seed and seedling predation are the critical processes controlling and constraining tree invasion and establishment in old fields. Competition and indirect effects of litter and the environment, which modify how these processes affect tree dynamics, are also important. Therefore, processes involving the interaction of species with the environment and with other species form the principal filters on and limitations to tree invasion and establishment and not the non-interactive life-history traits of individual tree species such as growth rate or longevity. The interaction of pattern and process and the affect of many of these processes on old field community structure are also discussed.     

Campus Anthropology: A Case Study from West Bengal,India1

In this ethnographic account, I attempt to write an anthropological narrative of my own university located in a district town of the West Bengal state in India about 130 kilometres from Kolkata, the capital of the state. My account does not come under the sub-discipline of ‘Educational Anthropology’ in which formal education is studied by the anthropologists as yet another process of the transmission of culture. My point of departure entails viewing the physical and the cultural space named ‘university campus’ by situating the case study of Vidyasagar University in a theoretical and global context. The anthropological subjects in the cultural space labelled as ‘campus’ range from the Vice-Chancellors to the indigenous tribal people who were viewed as ‘encroachers’ by the university community, while the latter looked at the campus as part of their traditional village common land. Ironically, the aims and objectives of my university was to build up research and teaching towards the development of the tribal and the underprivileged people of the region in which the university is located. The case of my university and comparative cases of Columbia, Pennsylvania and Marquette Universities definitely differ in scale, but they also share one common point: expansion of a campus and its effect on the local community in the context of the ideals and objectives of university as a social institution. The empirical scenario demands the emergence of the new sub-discipline named ‘campus anthropology’.     

Teaming up: from motors to people

When I reflect on how I became a cell biologist and why I love being one today, one thing that comes to mind is the many terrific collaborations I have had. The science I am most proud of from my graduate and postdoctoral training would not have been possible without working in teams with other scientists. Now, in my own group, much of our best work is being done collaboratively, both within the lab and with other labs. In this essay, I will highlight my experiences working in teams as a trainee, the role teamwork has played in my own research group, and how important I think collaborative science is for the future of biological research.     

Seeing 'where' through the ears: effects of learning-by-doing and long-term sensory deprivation on localization based on image-to-sound substitution

Background

Sensory substitution devices for the blind translate inaccessible visual information into a format that intact sensory pathways can process. We here tested image-to-sound conversion-based localization of visual stimuli (LEDs and objects) in 13 blindfolded participants.

Methods and Findings

Subjects were assigned to different roles as a function of two variables: visual deprivation (blindfolded continuously (Bc) for 24 hours per day for 21 days; blindfolded for the tests only (Bt)) and system use (system not used (Sn); system used for tests only (St); system used continuously for 21 days (Sc)). The effect of learning-by-doing was assessed by comparing the performance of eight subjects (BtSt) who only used the mobile substitution device for the tests, to that of three subjects who, in addition, practiced with it for four hours daily in their normal life (BtSc and BcSc); two subjects who did not use the device at all (BtSn and BcSn) allowed assessment of its use in the tasks we employed. The impact of long-term sensory deprivation was investigated by blindfolding three of those participants throughout the three week-long experiment (BcSn, BcSn/c, and BcSc); the other ten subjects were only blindfolded during the tests (BtSn, BtSc, and the eight BtSt subjects). Expectedly, the two subjects who never used the substitution device, while fast in finding the targets, had chance accuracy, whereas subjects who used the device were markedly slower, but showed much better accuracy which improved significantly across our four testing sessions. The three subjects who freely used the device daily as well as during tests were faster and more accurate than those who used it during tests only; however, long-term blindfolding did not notably influence performance.

Conclusions

Together, the results demonstrate that the device allowed blindfolded subjects to increasingly know where something was by listening, and indicate that practice in naturalistic conditions effectively improved “visual” localization performance.     

Adventures in vascular biology: a tale of two mediators

I would like to thank the Royal Society for inviting me to deliver the Croonian Lecture. In so doing, the Society is adding my name to a list of very distinguished scientists who, since 1738, have preceded me in this task. This is, indeed, a great honour.For most of my research career my main interest has been the understanding of the normal functioning of the blood vessel wall and the way this is affected in pathology. During this time, our knowledge of these subjects has grown to such an extent that many people now believe that the conquering of vascular disease is a real possibility in the foreseeable future.My lecture concerns the discovery of two substances, prostacyclin and nitric oxide. I would like to describe the moments of insight and some of the critical experiments that contributed significantly to the uncovering of their roles in vascular biology. The process was often adventurous, hence the title of this lecture. It is the excitement of the adventure that I would like to convey in the text that follows.     

Complex podokinetic (PK) response to post-rotational vestibular stimulation

Recent studies identified an adaptive "Podokinetic" (PK) sensory motor system involved in sensing and controlling spatial orientation during locomotion, by referencing body orientation to the space-stable stance foot. This paper investigates the interaction of vestibular and PK systems by asking blindfolded subjects to 'step-in-place' (i.e. without turning) after exposing them to a unidirectional post-rotational vestibular stimulus. Six of the nine subjects consistently began by vigorously propelling themselves round in the direction of preceding turntable rotation, but notably without any sensation of turning. In all these subjects the speed of this PK-induced rotation progressively declined to zero over about the next 30 sec and then reversed direction with increasing speed for about 50 sec. Thereafter the speed of rotation declined slowly to zero over the next 4 to 5 minutes. Since the PK-generated body rotation presumably feeds back into the vestibular-PK drive, we formulated a closed loop model of the combined system to investigate the complex nature of the behavioral response. The simulated response of this model closely resembled the experimental data, suggesting that there is indeed a functionally closed loop operating between the vestibular and podokinetic systems in natural life.     

A Reminiscence

Leslie Orgel and Francis Crick with Gobind Khorana in Madison, Wisconsin (December 1965). I first met Leslie at the Endicott House (MIT) in February 1964. Leslie was then spending a period of time at MIT and the occasion was a party for him. During our conversation, Leslie talked about starting some experimental work. He seemed to be particularly interested in polyphosphates and the chemical activation of small molecules (building blocks).Shortly after his move to the Salk Institute in the Fall of 1964 I visited him in January 1965. He already had a lab going. I remember meeting Jim Ferris, in particular, and John Sulston sometime later. That particular time was exciting for my research as well. We had the first results on the Genetic Code using the chemical-biochemical approach that my lab had developed. Francis Crick was also at the Salk Institute during the time of my visit. Both Leslie and Francis were very excited by my results and they began to ask a lot of questions and gave me a whole lot of suggestions about further experiments. In fact, my thinking and planning of things that we were doing were so scrutinized and clarified during these discussions that, it seemed to me, my own group had only to turn out all the experiments that were needed. These interactions with Francis and Leslie continued intensively throughout that year and later. In fact, both Leslie and Francis accepted my invitation to Madison in December 1965 for more discussions.Since those early days of the Salk Institute, I have made numerous visits over the years to Leslie and his research group. It has always been very exciting to learn about the many discoveries bearing on chemical evolution that have unfolded from Leslie's research group. In addition, I have always benefitted from the insightful comments that Leslie invariably provided on my own research. I look forward to our continued interactions and friendship in the future.Leslie, A Happy Birthday!     

Categorical judgments do not modify sensory representations in working memory

Categorical judgments can systematically bias the perceptual interpretation of stimulus features. However, it remained unclear whether categorical judgments directly modify working memory representations or, alternatively, generate these biases via an inference process down-stream from working memory. To address this question we ran two novel psychophysical experiments in which human subjects had to reverse their categorical judgments about a stimulus feature, if incorrect, before providing an estimate of the feature. If categorical judgments indeed directly altered sensory representations in working memory, subjects’ estimates should reflect some aspects of their initial (incorrect) categorical judgment in those trials. We found no traces of the initial categorical judgment. Rather, subjects seemed to be able to flexibly switch their categorical judgment if needed and use the correct corresponding categorical prior to properly perform feature inference. A cross-validated model comparison also revealed that feedback may lead to selective memory recall such that only memory samples that are consistent with the categorical judgment are accepted for the inference process. Our results suggest that categorical judgments do not modify sensory information in working memory but rather act as top-down expectations in the subsequent sensory recall and inference process.     

Taking the "I" out of IRB--and putting "community" in

If one looks back on the history of American research ethics, a bold pattern emerges. Since World War II, about every twenty years or so a breach of the social contract between investigators and human research subjects galvanizes public and professional interest in the ethical foundations and oversight mechanisms governing research with humans.     

Plans of mice and men: from bench science to science policy

The transition from bench science to science policy is not always a smooth one, and my journey stretched as far as the unemployment line to the hallowed halls of the U.S. Capitol. While earning my doctorate in microbiology, I found myself more interested in my political activities than my experiments. Thus, my science policy career aspirations were born from merging my love of science with my interest in policy and politics. After receiving my doctorate, I accepted the Henry Luce Scholarship, which allowed me to live in South Korea for 1 year and delve into the field of science policy research. This introduction into science policy occurred at the South Korean think tank called the Science and Technology Policy Institute (STEPI). During that year, I used textbooks, colleagues, and hands-on research projects as my educational introduction into the social science of science and technology decision-making. However, upon returning to the United States during one of the worst job markets in nearly 80 years, securing a position in science policy proved to be very difficult, and I was unemployed for five months. Ultimately, it took more than a year from the end of the Luce Scholarship to obtain my next science policy position with the American Society for Microbiology Congressional Fellowship. This fellowship gave me the opportunity to work as the science and public health advisor to U.S. Senator Harry Reid. While there were significant challenges during my transition from the laboratory to science policy, those challenges made me tougher, more appreciative, and more prepared to move from working at the bench to working in the field of science policy.     

Afterword to "Moral Economies, State Spaces, and Categorical Violence"

This Afterword is a discussion of commentary and criticism of my books, The Moral Economy of the Peasant (1976), Weapons of the Weak (1985), Domination and the Arts of Resistance (1990), and Seeing Like a State (1998). I examine the relation of moral economies to globalization, and hegemony to power and resistance, in agrarian societies and in contemporary U.S. politics. I debate contemporary neoliberal projects of governance in extractive, enclave economies and in current development practices in Indonesia. I question the use and misuse of high modernism as a term in my work. I discuss neoliberal internationalism and the immanent project of "harmonizing" institutional orders throughout poor countries.     

Experiments

In this article, I have provided a brief history of my life. After tracing my family background and my early interest in physical sciences, I discuss how I entered biology under the influence of Robert Emerson. I have always enjoyed doing experiments and this led to new measurements and analyses of chlorophyll unit, efficiency of photosynthesis, excitation energy transfer, delayed light emission, thermoluminescence and electroluminescence in photosynthetic organisms. It is my view that discoveries are made because we follow our scientific curiosities.This article was written at the invitation of Govindjee.